Anticancer Res
. 2020 Jul;40(7):3685-3696. doi: 10.21873/anticanres.14357.
Protection of Bortezomib-induced Neurotoxicity by Antioxidants
Yosuke Iijima 1, Kenjiro Bandow 2, Shigeru Amano 3, Motohiko Sano 4, Shunsuke Hino 5, Takahiro Kaneko 5, Norio Horie 5, Hiroshi Sakagami 6
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PMID: 32620607 DOI: 10.21873/anticanres.14357
Abstract
Background/aim: Although chemotherapy agents, such as oxaliplatin, cisplatin, paclitaxel and bortezomib frequently cause severe peripheral neuropathy, very few studies have reported the effective strategy to prevent this side effect. In this study, we first investigated whether these drugs show higher neuropathy compared to a set of 15 other anticancer drugs, and then whether antioxidants, such as sodium ascorbate, N-acetyl-L-cysteine, and vitamin B12 have any protective effect against them.

Materials and methods: Rat PC12 cells were induced to differentiate into neuronal cells by repeated overlay of serum-free medium supplemented with nerve growth factor. The cytotoxic levels of anticancer drugs against four human oral squamous cell carcinoma cell lines, three normal oral cells, and undifferentiated and differentiated PC12 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Cells were sorted for apoptotic cells (distributed into subG1 phase) and cells at different stages of cell cycle (G1, S and G2/M).

Results: All 19 anticancer drugs showed higher cytotoxicity against PC12 compared to oral normal cells. Among them, bortezomib showed the highest cytotoxicity against both undifferentiated and differentiated PC12 cell and, committed them to undergo apoptosis. Sodium ascorbate and N-acetyl-L-cysteine, but not vitamin B12, completely reversed the cytotoxicity of bortezomib.

Conclusion: Bortezomib-induced neuropathy might be ameliorated by antioxidants.

Keywords: Anticancer drugs; NGF; PC12; antioxidant; bortezomib; differentiation; neurotoxicity; overlay method; protection.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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Anticancer Res
. 2020 Jul;40(7):3781-3792. doi: 10.21873/anticanres.14367.
Pan- And Isoform-specific Inhibition of the Bromodomain and Extra-terminal Proteins and Evaluation of Synergistic Potential With Entospletinib in Canine Lymphoma
Weibo Kong 1 2, Sina Sender 1, Simon Villa Perez 1, Anett Sekora 1, Barbara Ruetgen 3, Christian Junghanss 1, Ingo Nolte 2, Hugo Murua Escobar 4 2
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PMID: 32620617 DOI: 10.21873/anticanres.14367
Abstract
Background/aim: Canine B-cell lymphoma represents a useful in vivo model for human diffuse large B-cell lymphoma (DLBCL). Pan-Bromodomain and extra-terminal (BET) inhibition targeting BRD2/3/4 and selective inhibition of BRD4, as well as spleen tyrosine kinase (SYK) inhibition, are currently evaluated as haematologic cancer therapy. Herein, we characterized the differences in the biologic response of isoform-specific or pan-BET inhibition alone or in combination with SYK inhibition.

Materials and methods: I-BET151 (pan-inhibitor) and AZD5153 (BRD4 inhibitor) were combined with Entospletinib (SYK inhibitor) and comparatively analysed in the canine DLBCL cell line CLBL-1. Dose- and time-dependent cellular responses were analysed by cell number, metabolic activity, apoptosis/necrosis, and cell morphology. The synergistic potential was evaluated through the Bliss independence model.

Results: I-BET151 and AZD5153 showed significant dose- and time-dependent inhibitory effects. Adding Entospletinib to I-BET151 or AZD5153 had no additional synergistic effects.

Conclusion: Entospletinib did not enhance the inhibitory effects of the pan- or isoform-specific BET.

Keywords: BCR; BET inhibitor; Bromodomain (BRD); SYK inhibitor; canine DLBCL; lymphoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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3
Anticancer Res
. 2020 Jun;40(6):3097-3108. doi: 10.21873/anticanres.14291.
Interaction Between CCL18 and GPR30 Differs From the Interaction Between Estradiol and GPR30
Roland Schmidt-Wolf 1, Gernot Zissel 2
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PMID: 32487604 DOI: 10.21873/anticanres.14291
Abstract
Background/aim: C-C motif chemokine ligand 18 (CCL18) is overexpressed in the microenvironment of tumors, promotes invasion and metastasis and is thus important for the therapeutic outcome of many tumor entities. The Gs-coupled seven-transmembrane receptor GPR30 is known as both a CCL18 and an estrogen receptor; its activation by estradiol leads to a transactivation of membrane-tethered pro-heparin-binding EGF-like growth factor and the MAPK/ERK pathway. We examined whether this signaling pathway remains the same under CCL18 stimulation, as opposed to estradiol stimulation.

Materials and methods: We investigated the effects of CCL18 on the lung cancer cell line A549, that show low GPR30 expression and the breast cancer cell lines MCF-7, that has high GPR30 expression and MDA-MB-231. These cells were stimulated in different media with CCL18 and then analyzed by qPCR, In-Cell Western®, western blot and ELISA.

Results: Many similarities on the effect of CCL18 on the already known estradiol-activated signaling pathway via the G protein-coupled estrogen receptor GPR30 were identified. GPR30 is involved in the expression of matrix metalloproteinases (MMPs), which may play a role in the transactivation of ERK-1/-2 via the cleavage of membrane-bound HB-EGF, via Src-related tyrosine kinases and Gβγ-subunits. With increasing CCL18 concentration, the expression of MMP7 decreased in A549 cells. With decreasing estrogen content of the medium, there was an increasing effect of CCL18 on the inhibition of the relative expression of MMP7. Inhibition of GPR30 with G15 also resulted in a decrease in the relative expression of MMP7, irrespective of the subsequent stimulation with CCL18. This is a rather unexpected result, because the estrogen estradiol and CCL18 both activate GPR30. MCF-7 cells which express more GPR30 did not show any dependence of the relative MMP7 expression on CCL18 except in estrogen-free FCS medium. CCL18 induced an increased relative ERK activation in In-Cell western (ICW) at A549 cells. Stimulation with CCL18 caused decreased ERK activation with simultaneous inhibition of adenylate cyclase in MCF-7. However, stimulation with CCL18 and simultaneous inhibition of cyclooxygenase in MCF-7 resulted in increased ERK activation. In A549, stimulation with CCL18 and co-incubation with dbcAMP resulted in decreased ERK activation in both ICW and Western blot.

Conclusion: In summary, the Gs-coupled receptor GPR30 plays an important role in the signaling pathway of CCL18. CCL18 and estradiol may not lead to the same signaling pathway after activating GPR30.

Keywords: Ccl18 protein; cancer; epithelial-mesenchymal transition (EMT); gpr30; metastasis.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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4
Review Anticancer Res
. 2020 Jul;40(7):3619-3631. doi: 10.21873/anticanres.14351.
Gene Polymorphisms and Circulating Levels of MMP-2 and MMP-9: A Review of Their Role in Breast Cancer Risk
SuÉlÈne Georgina Dofara 1 2 3, Sue-Ling Chang 1 2, Caroline Diorio 4 2 3
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PMID: 32620601 DOI: 10.21873/anticanres.14351
Abstract
MMP-2 and MMP-9 genes have been suggested to play a role in breast cancer. Their functions have been associated with invasion and metastasis of breast cancer; however, their involvement in the development of the disease is not well-established. Herein, we reviewed the literature investigating the association between circulating levels and polymorphisms of MMP-2 and MMP-9 and breast cancer risk. Various studies report conflicting results regarding the relationship of polymorphisms in MMP-2 and MMP-9 and breast cancer risk. Nevertheless, it appears that the T allele in rs243865 and rs2285053 in MMP-2 are associated with reduced risk of breast cancer. In addition, high levels of latent form and low levels of active form of MMP-2 were observed in breast cancer patients compared to controls. For MMP-9, high latent levels and low total levels were found in breast cancer patients compared to controls. Additional studies are needed to comprehend the role of these genes in breast carcinogenesis.

Keywords: Matrix metalloproteinases; breast cancer risk; circulating levels; gelatinases; polymorphisms; review.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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5
Anticancer Res
. 2020 Jun;40(6):3147-3153. doi: 10.21873/anticanres.14296.
Six Candidate miRNAs Associated With Early Relapse in Pediatric B-Cell Acute Lymphoblastic Leukemia
Ernest K Amankwah 1 2, Meenakshi Devidas 3, David T Teachey 4, Karen R Rabin 5, Patrick A Brown 6 7
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PMID: 32487609 DOI: 10.21873/anticanres.14296
Abstract
Background/aim: Few studies have evaluated the role of miRNAs in pediatric acute lymphoblastic leukemia (ALL) relapse and a consensus of a clinically significant miRNA signature is yet to be identified. In this study, we evaluated miRNAs associated with pediatric B-ALL early relapse in two independent sample sets.

Materials and methods: We performed global miRNA profiling on diagnostic bone marrow specimens from six early relapse (≤3 years after diagnosis) and six age- and cytogenetics-matched prolonged remission (≥4 years) patients (first set) and an independent set of 14 early relapse and 14 matched prolonged remission specimens (second set).

Results: Twelve and 39 top differentially expressed miRNAs were observed in the first and second sets, respectively; however, there was no overlap between the top candidates. In post-hoc analyses six miRNAs (miR-101-3p, miR-4774-5p, miR-1324, miR-631, miR-4699-5p and miR-922) among the top candidates in the second, but not the first set, were consistently upregulated in early relapse compared to remission specimens in both first (fold change=1.13-2.19, q<0.38) and second (fold change=1.48-4.78, all q<0.05) sets. Four (miR-631, mir-101-3p, miR-922 and miR-1324) of these miRNAs have been previously implicated in key functional oncogenic pathways in adult cancers.

Conclusion: This study suggests that six candidate miRNAs, not previously implicated in pediatric ALL, are associated with early relapse in pediatric B-ALL. Validation and investigation of mechanistic roles of these miRNAs in a larger cohort are warranted, so that they may be used as prognostic markers for early relapse of pediatric B-ALL.

Keywords: ALL; Pediatric; epigenetic; miRNA; relapse.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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6
Review Anticancer Res
. 2020 Jul;40(7):3633-3643. doi: 10.21873/anticanres.14352.
Savi Scout® Radar Localisation of Non-palpable Breast Lesions: Systematic Review and Pooled Analysis of 842 Cases
Iham Kasem 1, Kefah Mokbel 2
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PMID: 32620602 DOI: 10.21873/anticanres.14352
Abstract
Background/aim: With the increase in detection of non-palpable breast lesions through screening, wire-guided localisation (WGL) has long been the favoured method for preoperative localisation. However, this technique comes with several limitations. New methods have been developed, including several non-radioactive, wireless options. We aimed to assess the effectiveness of Savi Scout® localisation (SSL) through this pooled analysis and systematic review.

Materials and methods: A number of databases were searched for records reporting data on localisation and retrieval of SSL reflectors, as well as re-excision rate. We included our own data from 20 patients (22 reflectors) at our institution.

Results: A total of 842 reflectors were inserted across eleven studies and our own data. Pooled analysis revealed an overall successful deployment rate of 99.64% and a successful retrieval rate of 99.64% using SSL. A statistically significant difference in re-excision rate was found in a smaller pooled analysis conducted across four studies comparing SSL and WGL (12.9% and 21.1% respectively, p<0.01).

Conclusion: The Savi Scout® localisation system is a safe and effective alternative to WGL. It facilitates flexible scheduling by decoupling radiology and surgery interventions and may reduce the need for re-excision procedures for positive surgical margins.

Keywords: Savi Scout®; breast cancer; non-palpable breast lesions; non-wire localisation; radar localisation; reflector-guided localisation; review.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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7
Anticancer Res
. 2020 Jun;40(6):3129-3138. doi: 10.21873/anticanres.14294.
Paclitaxel, Carboplatin and 1,25-D3 Inhibit Proliferation of Ovarian Cancer Cells In Vitro
Tea Kuittinen 1, Päivi Rovio 2, Tiina Luukkaala 3 4, Marita Laurila 5, Seija Grénman 6 7, Anne Kallioniemi 8 9, Johanna Mäenpää 8
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PMID: 32487607 DOI: 10.21873/anticanres.14294
Abstract
Background/aim: The combination of paclitaxel and carboplatin is the standard chemotherapy for ovarian cancer. Previous studies have implied that vitamin D (1,25-D3) may have growth inhibitory effects in ovarian cancer. This study aimed to investigate the effect of paclitaxel, carboplatin and 1,25-D3 on the growth of ovarian cancer cells in vitro, based on the hypothesis that 1,25-D3 might potentiate the effect of paclitaxel and/or carboplatin.

Materials and methods: Three non-commercial ovarian carcinoma cell lines UT-OV-1(mucinous), UT-OV-3B (serous) and UT-OV-4 (endometrioid) were exposed to different concentrations of 1,25-D3, paclitaxel and carboplatin, respectively. The cell viability was measured using a Crystal violet assay kit. The cellular vitamin D receptor (VDR) mRNA levels were measured by qRT-PCR using the LightCycler equipment.

Results: The growth-inhibitory effect of the combination of paclitaxel and carboplatin was 56% in UT-OV-1, 33% in UT-OV-3B and 47% in UT-OV-4 cells. Single 1,25-D3 (10 μM) inhibited the growth of UT-OV-3B and UT-OV-4 by 23% and 28%, respectively, whereas no effect was seen in UT-OV-1 cells. These results are in line with the finding that the expression of VDR was high in UT-OV-3B and UT-OV-4, but very low in UT-OV-1. The combination of 1,25-D3, paclitaxel and carboplatin resulted in 61%, 46% and 58% growth reduction in UT-OV-1, UT-OV-3B and UT-OV-4 cells, respectively. The additive effect of 1,25-D3 was 21% in UT-OV-4, 20% in UT-OV-3B and 12% in UT-OV-1 cell line.

Conclusion: The results imply that combining 1,25-D3 with paclitaxel and carboplatin may potentiate their growth inhibitory effect on ovarian cancer cells with high VDR expression.

Keywords: 1,25-D3; VDR; Vitamin D; carboplatin; growth inhibition; in vitro; ovarian cancer; paclitaxel.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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8
Review Anticancer Res
. 2020 Jul;40(7):3605-3618. doi: 10.21873/anticanres.14350.
Review of the Role of Radiomics in Tumour Risk Classification and Prognosis of Cancer
Yeo Li Wen 1 2, Michelle Leech 3
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PMID: 32620600 DOI: 10.21873/anticanres.14350
Abstract
Radiomics, an emerging field in radiation therapy, is hypothesized to improve classification of tumour risk and prognosis. Despite encouraging results, there are issues of practicality and interpretation of radiomic data. This study investigates the emerging role of radiomics in tumour risk classification and prognosis of breast and prostate cancer. A literature search was conducted using predefined terms to retrieve studies related to radiomics. Studies were evaluated and selected upon meeting the criteria defined. A total of 19 relevant publications were selected from 63 publications identified. Data from studies revealed significant area under the curve (AUC) values and high discriminative power. Significant AUC values for biochemical recurrence of disease and disease-free survival were reported for prognosis. Radiomics show promising potential in discriminating tumour risk and predicting prognosis of cancer using specified features. It is an alternative to conventional predictive tools and has the ability to improve with the use of existing tools.

Keywords: Radiomics; classification; prediction; prognosis; review; tumour risk.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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9
Anticancer Res
. 2020 Jul;40(7):4105-4113. doi: 10.21873/anticanres.14409.
Usefulness of Tumor Tissue Biopsy for Predicting the Biological Behavior of Hepatocellular Carcinoma
Taro Shioga 1, Reiichiro Kondo 2, Sachiko Ogasawara 2, Jun Akiba 3, Shinji Mizuochi 2, Hironori Kusano 2, Yutaro Mihara 2, Masahiko Tanigawa 2, Yoshinao Kinjyo 2, Yoshiki Naito 3, Ryoko Kuromatsu 4, Osamu Nakashima 5, Hirohisa Yano 2
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PMID: 32620659 DOI: 10.21873/anticanres.14409
Abstract
Background/aim: Assessment of the biological behavior of tumors is important for choosing an appropriate cancer therapy. In hepatocellular carcinoma (HCC), the biological behaviour can be assessed by tumor morphology and molecular biology. This study investigated the usefulness of tumor tissue biopsy for predicting the biological behavior of HCC.

Patients and methods: We studied 43 patients who underwent hepatectomy and preoperative liver tumor biopsy for HCC. We performed clinicopathological and immunohistochemical (IHC) analyses. The expression of the following molecules was examined: regulator of G-protein signaling 5 (RGS5), glypican-3 (GPC3), keratin 19 (K19), epithelial cell adhesion molecule (EpCAM), protein induced by vitamin K absence or antagonist-II (PIVKA-II), β-Catenin, and p53.

Results: There was an overall 83.7% agreement regarding tumor differentiation between the preoperative biopsy specimens and the resected specimens. The accuracy of IHC analysis was more than 70% for all molecules between the preoperative biopsy specimens and the resected specimens. The RGS5-positive biopsy cases had higher serum α-fetoprotein levels (p=0.04), a higher rate of moderately or poorly differentiated tumors (p=0.02) and portal vein invasion (p=0.0003) than the RGS5-negative biopsy cases. The GPC3-positive biopsy cases were younger (p=0.04), had higher serum PIVKA-II levels (p=0.01), and a higher rate of portal vein invasion (p=0.03) than the GPC3-negative biopsy cases. The PIVKA-II-positive biopsy cases had significantly higher serum PIVKA-II levels than the PIVKA-II-negative biopsy cases (p=0.02). The other molecular markers showed no significantly different clinical findings between the positive and negative cases.

Conclusion: In HCC, there was a high agreement rate of both the histopathological and IHC findings between preoperative biopsy specimens and resected specimens. In the biopsy specimens of HCC, RGS5 and GPC3 expression were useful molecular makers for predicting portal vein invasion. Liver tumor biopsy is useful for predicting the biological behavior of HCC through histopathological and immunohistochemical findings.

Keywords: Hepatocellular carcinoma; immunohistochemistry; tumor morphology.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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10
Anticancer Res
. 2020 Jun;40(6):3325-3331. doi: 10.21873/anticanres.14315.
Melanoma Risk Estimation Based on Objective Measures as a Complement to Self-Assessment
Adam Carlsson 1, Magnus Falk 2
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PMID: 32487628 DOI: 10.21873/anticanres.14315
Abstract
Background/aim: A variety of self-tests addressing individual skin cancer risk are available online. These are generally based on self-estimated measures, such as self-rated skin sensitivity to sun exposure, affecting its reliability. The aim of this study was to investigate whether the addition of objective variables, by means of ultraviolet (UV) sensitivity phototesting and nevi count, could be of contributory value for the composition of a comprehensive risk score for skin cancer, and whether the use of such a score could contribute to change of behavior in the sun after assessment of individual risk.

Patients and methods: A sample of 70 voluntary participants, all university students, were recruited for the study. The participants rated their sun exposure habits by filling out the Sun Exposure and Protection Index (SEPI) questionnaire, and their skin UV-sensitivity was decided both by self-estimation, using Fitzpatricks's skin type scale, and objectively, by the performance of a UV-sensitivity phototest. Finally, the number of pigmented nevi on the lower arm was counted both by the participants themselves and by a trained observer. A cumulated skin cancer risk score was calculated on the basis on these three variables (sun habits, UV-sensitivity and nevi count), and the outcome compared whether based on the participants' self-assessments or on the objective assessment. The individual risk score, based on objective measures, along with a tailored sun protection advice, was communicated to the participants, and after three weeks they once again filled-out the SEPI part addressing propensity to increase sun protection.

Results: The results showed good correlation between the self-assessed and trained observer performed nevi count, but poor agreement between self-estimated and objectively measured skin UV-sensitivity. For the cumulative risk score, the self-performed score was on average slightly lower than its reference, but no systematic difference could be observed. At follow-up, high-risk individuals showed a significant decrease in total SEPI score (p<0.05).

Conclusion: Objective assessment of nevi count and skin UV-sensitivity might be of significant value when estimating individual skin cancer risk, in order to communicate tailored sun protection advice.

Keywords: Malignant melanoma; questionnaire; sun habits; tailored advice; ultraviolet radiation.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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11
Anticancer Res
. 2020 Jul;40(7):4041-4046. doi: 10.21873/anticanres.14400.
Radiotherapy Dose and Volume De-escalation in Ocular Adnexal Lymphoma
Stephan Rehn 1, Khaled Elsayad 2, Michael Oertel 1, Andrea Baehr 1, Nicole Eter 3, Uwe Haverkamp 1, Georg Lenz 4, Hans Theodor Eich 1
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PMID: 32620650 DOI: 10.21873/anticanres.14400
Abstract
Aim: Modern radiotherapy (RT) technique and therapy de-escalation have led to encouraging results in lymphoma management. In this study, we aimed to describe the oncological and toxicity outcome in patients with ocular adnexal lymphoma.

Patients and methods: A total of 45 patients with 52 orbital lesions who were treated at our Institution between 2003 and 2019 were considered. Clinical characteristics, treatment outcomes, and toxicity were assessed. Patients receiving 4-6 Gy were categorized as receiving ultra-low-dose RT, 24-30.6 Gy as standard-dose RT, and >30.6 Gy as high-dose RT.

Results: The predominant histological subtype was marginal zone lymphoma in 39 lesions (75%). Radiation dose ranged from 4-50.4 Gy. In the whole cohort, 11% of the lesions were treated with ultra-low-dose RT, 33% with standard-dose RT, and 56% with high-dose RT; 60% of lesions were treated using intensity-modulated RT (IMRT), while 44% of lesions were treated with partial orbital RT. The median duration of follow-up was 33 months. The overall response rate was 94% (complete response rate=83%). The 5-year local control rate, progression-free survival, and overall survival were 100%, 76%, and 92%, respectively. We did not detect any significant difference in progression-free or overall survival regarding different radiation doses and volumes. Ultra-low-dose RT was associated with a significantly lower rate of grade 2 late toxicities (0% vs. 6% and 31%, p=0.05) in comparison with standard-dose and high-dose RT, respectively. Patients who received IMRT had a significant fewer acute grade 2 (16% vs. 43%, p=0.05) and a trend towards lower late grade 2 toxicities (9% vs. 33%, p=0.06).

Conclusion: Radiation dose and volume de-escalation seem to be safe and effective, with excellent local control and survival in the management of ocular adnexal lymphoma. IMRT seems to be associated with less toxicity.

Keywords: Low-dose; intensity-modulated radiotherapy; moderate-dose RT; toxicity; ultra-low.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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12
Anticancer Res
. 2020 Jun;40(6):3307-3314. doi: 10.21873/anticanres.14313.
Race Does Not Affect Survival in Patients With Prostate Cancer Treated With Radiation Therapy
Joyson Kodiyan 1, Mark Ashamalla 2, Adel Guirguis 2, Hani Ashamalla 2
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PMID: 32487626 DOI: 10.21873/anticanres.14313
Abstract
Background/aim: Recent evidence has shown that African American men with prostate cancer may have more radiosensitive disease with greater overall survival (OS) with radiotherapy compared to Caucasian men. We compared OS in African American and Caucasian men receiving radiotherapy utilizing the National Cancer Database.

Patients and methods: African American or Caucasian men with N0M0 prostate adenocarcinoma diagnosed between 2004 and 2013 were selected and grouped into favorable and unfavorable risk based on clinical T-stage, clinical Gleason score, and prostate-specific antigen. Patients with favorable risk received brachytherapy or dose-escalated external beam radiation (EBRT); those with unfavorable risk received EBRT plus anti-androgen therapy with/without brachytherapy. African American and Caucasian men in each subgroup were propensity score-matched and analyzed for survival. Sensitivity analysis used treatment-race and age-race interaction terms.

Results: 27,150 patients met the inclusion criteria, with a median age of 68 (range=38-90) years and median follow-up of 59.93 (range=48-142.62) months. OS was equivalent between African American and Caucasian race in favorable risk [log-rank p=0.82; hazard ratio (HR)=0.928; 95% confidence intervaI (CI)=0.583-1.477, p=0.753] and unfavorable-risk subgroups (log-rank p=0.87, HR=1.078, 95% CI=0.843-1.379, p=0.550). No significant interaction existed between treatment and race for either cohort but there was a significant interaction between race and age in those with unfavorable risk (HR=1.046, 95% CI=1.009-1.084, p=0.015), with greater OS in those of Caucasian race ≤60 years (HR=0.320, 95% CI=0.137-0.752, p=0.009).

Conclusion: African American and Caucasian men have similar survival when treated with risk-appropriate definitive radiotherapy. However, younger (age ≤60 years) African American men with unfavorable risk have poorer survival than their Caucasian counterparts and may harbor a significantly different biology of disease.

Keywords: Prostate; race; radiation; survival.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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13
Review Anticancer Res
. 2020 Jul;40(7):3591-3604. doi: 10.21873/anticanres.14349.
Fecal Occult Blood Tests in Colorectal Cancer Screening: Systematic Review and Meta-analysis of Traditional and New-generation Fecal Immunochemical Tests
Jannica Meklin 1, Kari SyrjÄnen 2 3, Matti Eskelinen 4
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PMID: 32620599 DOI: 10.21873/anticanres.14349
Abstract
Background/aim: Noninvasive fecal occult blood tests (FOBTs) are recommended by current guidelines for colorectal cancer (CRC) screening. Our aim was to assess the diagnostic performance of traditional guaiac-based FOBTs (gFOBT) and new-generation immunochemical FOBTs (iFOBT) in CRC screening by carrying out a systematic review and meta-analysis.

Patients and methods: PubMed, Embase, Cochrane Library, and Web of Science were searched for eligible articles published before February 17, 2020. Three independent investigators conducted study assessment and data extraction. Diagnosis-related indicators for use of FOBTs in the detection of CRC (as the endpoint) in a screening setting were summarized, and further stratified by the type of FOBT (gFOBT vs. iFOBT). STATA software was used to conduct the meta-analysis. Pooled sensitivities and specificities were calculated using a random-effects model. Hierarchical summary receiver operating characteristic curves were plotted and area under the curves (AUC) were calculated.

Results: The electronic search identified 573 records after duplicates were removed, of which 75 full-text articles were assessed for eligibility. Finally, a total of 31 studies were eligible for the meta-analysis. In the ROC comparison test, there was a statistically significant difference in the performance of gFOBT and iFOBT tests, with AUC=0.77 (95% confidence intervaI=0.75-0.79) and AUC=0.87 (95% confidence intervaI=0.85-0.88), respectively (p=0.0017). In formal meta-regression, test brand did not prove to be a significant study-level covariate that would explain the observed heterogeneity between the studies.

Conclusion: New-generation iFOBTs were found to have a significantly higher diagnostic performance as compared with gFOBTs, advocating the use of only fecal immunochemical tests in all newly implemented CRC screening programs.

Keywords: FIT; Fecal occult blood; HSROC; ROC; colorectal cancer screening; false negative; false positive; fecal immunochemical test; gFOBT; guaiac-based test; iFOBT; meta-analysis; sensitivity; specificity.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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14
Review Anticancer Res
. 2020 Jun;40(6):3543-3550. doi: 10.21873/anticanres.14343.
Tumor-to-nipple Distance Should Not Preclude Nipple-sparing Mastectomy in Breast Cancer Patients. Personal Experience and Literature Review
Piero Fregatti 1 2, Marco Gipponi 3, Gabriele Zoppoli 4, Matteo Lambertini 5, Eva Blondeaux 2, Liliana Belgioia 6, Raffaele Derosa 1, Federica Murelli 1 2, Francesca Depaoli 7, Marcello Ceppi 8, Alessandro Garlaschi 9, Daniele Friedman 1 2
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PMID: 32487656 DOI: 10.21873/anticanres.14343
Abstract
Background/aim: A retrospective study was performed in 246 breast cancer patients to define whether tumor-to-nipple distance (TND) assessment by breast MRI may select patients eligible to nipple-sparing mastectomy (NSM) as compared to permanent section assessment of retroareolar margin.

Patients and methods: Pre- and post-operative parameters including imaging data, histology of the primary tumor, biologic prognostic factors, and adjuvant regimens were retrieved; patients with close/positive retroareolar margins underwent nipple or NAC excision. The primary endpoint was loco-regional recurrence (LRR).

Results: Patients with TND ≤2 cm had a significantly higher rate of invasive ductal carcinoma (p<0.003) and excision margins less than 2 mm (p<0.000). Eleven retroareolar specimens were positive at definitive pathology; final re-excision specimen examination showed residual disease in seven patients (63.6%). At a median follow-up of 31 to 33 months, no NAC recurrence did occur; disease-free survival was more than 96%, and LRR was homogeneously distributed among TND subgroups.

Conclusion: Therapeutic NSM is a safe procedure independently of TND assessed at preoperative breast MRI. Permanent section assessment of retroareolar tissue is more accurate and cost-effective than frozen section. Furthermore, delayed nipple and/or NAC excision did not impair local disease control.

Keywords: Breast cancer; breast MRI; nipple-sparing mastectomy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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15
Review Anticancer Res
. 2020 Jun;40(6):3039-3047. doi: 10.21873/anticanres.14284.
The Role of MSCs in the Tumor Microenvironment and Tumor Progression
Sung Yong Ahn 1
Affiliations expand
PMID: 32487597 DOI: 10.21873/anticanres.14284
Abstract
Over the past few decades, longevity without disease has become an important topic worldwide. However, as life expectancy increases, the number of patients with cancer is also increasing. Tumor progression is related to interactions between tumor cells and mesenchymal stem cells (MSCs) in the tumor microenvironment. MSCs are multipotent stromal cells known to be present in a variety of locations in the body, including bones, cartilage, fat, muscles, and dental pulp. MSCs migrate toward inflamed areas during pathological immune responses. MSCs also migrate toward tumor stroma and participate in tumor progression. MSCs can contribute to tumor progression by interacting with tumor cells via paracrine signaling and differentiate into diverse cell types. This also enables MSCs to make direct contact with tumor cells in tumor stroma. Interactions between tumor cells and MSCs enhance tumorigenic and metastatic potential, in addition to stimulating epithelial to mesenchymal transition. Herein, we reviewed the research associated with the tumor-enhancing role of MSCs in tumor progression, from primary tumor growth to distant tumor metastasis.

Keywords: Mesenchymal stem cells; review; tumor microenvironment; tumor progression.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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16
Anticancer Res
. 2020 Jul;40(7):4067-4074. doi: 10.21873/anticanres.14404.
The Impact of Severe Infectious Complications on Long-term Prognosis for Gastric Cancer
Yukio Maezawa 1 2, Toru Aoyama 3, Mihwa Ju 3, Keisuke Komori 3, Kazuki Kano 3, Sho Sawazaki 3, Masakatsu Numata 3, Tsutomu Hayashi 3 4, Takanobu Yamada 3 4, Hiroshi Tamagawa 3, Tsutomu Sato 3, Takashi Ogata 4, Haruhiko Cho 3 2, Takashi Oshima 3 4, Norio Yukawa 3, Takaki Yoshikawa 3 5, Munetaka Masuda 3, Yasushi Rino 3
Affiliations expand
PMID: 32620654 DOI: 10.21873/anticanres.14404
Abstract
Background: The aim of this study was to evaluate the impact of postoperative infectious complications on long-term outcomes after curative resection of gastric cancer.

Patients and methods: Patients who underwent curative gastrectomy with lymphadenectomy for gastric cancer at Yokohama City University and Kanagawa Cancer Center from January 2000 to August 2015 were retrospectively selected from medical records. Clinicopathological factors between patients with and without infectious complications were compared. Prognostic factors of long-term survival were analyzed by univariate and multivariate Cox proportional hazards analyses.

Results: A total of 2,254 patients were eligible for inclusion in the present study. Fifty-eight patients had postoperative infectious complications (IC group); 2,196 had no postoperative infectious complications (NC group). In the IC group, the median age (p=0.031), body mass index (p=0.004), American Society of Anesthesiologists physical status (p=0.006) and percentage of male patients (p<0.001) were higher in comparison to the NC group. The operation time was longer (p<0.001) and the incidence of intestinal-type histology was higher (p=0.017) in the IC group. The 5-year overall survival rates of the IC and NC groups were 59.8% and 83.2%, respectively (p<0.001). Univariate and multivariate analyses demonstrated that postoperative infectious complications were a significant risk factor for poorer overall survival (hazard ratio=2.38; 95% confidence interval=1.47-3.85, p<0.001).

Conclusion: Perioperative management is necessary to reduce the incidence of postoperative infectious complications and improve the survival of patients after curative resection of gastric cancer.

Keywords: Gastric cancer; postoperative infectious complications; prognostic factor.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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17
Anticancer Res
. 2020 Jun;40(6):3411-3415. doi: 10.21873/anticanres.14325.
National Comprehensive Analysis of Characteristics of Acral Lentiginous Melanoma
Maria T Huayllani 1, David J Restrepo 1, Daniel Boczar 1, Francisco R Avila 1, Sanjay P Bagaria 2, Aaron C Spaulding 3, Brian D Rinker 1, Antonio J Forte 4
Affiliations expand
PMID: 32487638 DOI: 10.21873/anticanres.14325
Abstract
Background/aim: Acral lentiginous melanoma (ALM) is the least common subtype of cutaneous melanoma and typically occurs on the palms, soles, and nails. Tumor characteristics and disease severity in the US population are not well understood. Our aim was to analyze the characteristics of ALM of the extremities.

Patients and methods: We queried the National Cancer Database to identify patients with the diagnosis of ALM and common malignant melanoma located in the extremities (CMME). We compared demographic, tumor, and treatment characteristics between patients with ALM and those with CMME. Statistical analysis was performed with chi-squared test and multivariate logistic regression models.

Results: We identified 5,203 patients with ALM and 118,485 with CMME. When compared with patients with CMME, those with ALM were more likely to be older than 80. years at diagnosis [odds ratio (OR)=2.85, 95% confidence intervaI (CI)=2.12-3.82; p<0.001], have stage III disease (OR=4.22, 95% CI=1.47-12.16; p=0.01), and have ulceration (OR=1.52, 95% CI=1.33-1.74; p<0.001). Moreover, patients with ALM were less likely to have a mitotic count of 1/mm2 or greater (OR=0.57, 95% CI=0.48-0.67; p<0.001). No statistical difference was found for sex, lymph node involvement, regression, and use of surgery, radiotherapy, and immunotherapy between groups.

Conclusion: Age, disease stage, ulceration, and mitotic count are independent factors associated with ALM. Knowledge of the disease characteristics may allow for better diagnosis and understanding of disease pathophysiology.

Keywords: Acral lentiginous melanoma; National Cancer Database; malignant melanoma; tumor characteristics.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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18
Anticancer Res
. 2020 Jun;40(6):3459-3468. doi: 10.21873/anticanres.14332.
Correlation of Iodine Quantification and FDG Uptake in Early Therapy Response Assessment of Non-small Cell Lung Cancer: Possible Benefit of Dual-energy CT Scan as an Integral Part of PET/CT Examination
Jan Baxa 1, Jaroslav Ludvik 2, Martin Sedlmair 3, Thomas Flohr 3, Bernhard Schmidt 3, Petr Hošek 4, Milos Pesek 5, Martin Svatoň 5, Jiri Ferda 2
Affiliations expand
PMID: 32487645 DOI: 10.21873/anticanres.14332
Abstract
Aim: To compare iodine-related and fluorine-18 fluorodeoxyglucose (18F-FDG) parameters during staging of lung cancer as well as during early follow-up, while investigating potential use and possible substitutability in the assessment of therapeutic response or prediction.

Patients and methods: Patients (n=45) with confirmed lung cancer underwent 18F-FDG positron-emission tomography (PET) using single-source dual-energy computed tomography was performed for staging and early follow-up. Correlation of FDG uptake and iodine-related parameters was assessed and comparison with therapy response was performed.

Results: A strong correlation was found between the volumetric FDG parameters metabolic tumour volume (MTV) and total lesion glycolysis (TLG) and iodine uptake (IU) in staging (IU vs. MTV: rs=0.894; p<0.001 and IU vs. TLG: rs=0.874; p<0.001) and follow-up (IU vs. MTV: rs=0.934, p<0.001 and IU vs. TLG: rs=0.935, p<0.001). We also found significant correlation of change in these values between timepoints. We observed a significant correlation of IU, MTV and TLG with early therapy response and IU was found as a possible strong predictor.

Conclusion: Strong correlation of IU and volume-based FDG parameters was proved in staging, follow-up and change during therapy. Potential role of IU in prediction of early therapy-response was identified. Our study suggests a significant benefit of using the dual-energy computed tomography as a part of 18F-FDG PET/CT in patients with lung cancer.

Keywords: Multidetector computed tomography; dual-energy; fluorodeoxyglucose; iodine; lung cancer; positron-emission tomography.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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19
Anticancer Res
. 2020 Jul;40(7):4173-4182. doi: 10.21873/anticanres.14417.
Sorafenib Might Induce Sarcopenia in Patients With Hepatocellular Carcinoma by Inhibiting Carnitine Absorption
Makoto Amanuma 1, Hidenari Nagai 2, Yoshinori Igarashi 1
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PMID: 32620667 DOI: 10.21873/anticanres.14417
Abstract
Background/aim: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of cancers. Sorafenib, an oral multi-target TKI, improves the median overall survival time in patients with hepatocellular carcinoma (HCC). It also inhibits the absorption of carnitine by down-regulating the human organic cationic transporter OCTN2 located largely in the small intestinal mucosa and skeletal muscle. The aim of the study was to determine, by assessing carnitine metabolism, whether sarcopenia is induced in patients with HCC who are receiving sorafenib.

Patients and methods: This retrospective study included 110 adult Japanese patients with liver cirrhosis and HCC who received sorafenib. Sorafenib was administered at a dose of 200-800 mg/day for 4 weeks. Blood samples were collected before and after treatment, and serum carnitine fraction and myostatin levels were measured. Cross-sectional areas (cm2) of the skeletal muscles at the third lumbar vertebra level were determined by manually outlining computed tomography images before and after treatment. The cross-sectional areas were normalized for height [skeletal muscle index (SMI), cm2/m2].

Results: Patients were allocated to two groups according to Child-Pugh (CP) class; 81 had CP-A liver function, and 29 had CP-B. SMI after treatment was significantly lower than that before treatment in both groups. Serum levels of total carnitine and free carnitine after treatment were significantly lower than those before treatment in both groups. There were no differences in serum levels of myostatin before and after treatment in either group.

Conclusion: Sorafenib might decrease serum levels of carnitine by inhibiting carnitine absorption. Decreasing of serum levels of carnitine might lead to presarcopenia.

Keywords: HCC; carnitine; liver cirrhosis; sarcopenia; sorafenib.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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20
Anticancer Res
. 2020 Jun;40(6):3119-3128. doi: 10.21873/anticanres.14293.
Knockdown of Myoferlin Suppresses Migration and Invasion in Clear-Cell Renal-Cell Carcinoma
Alexander Cox 1, Chenming Zhao 2, Yuri Tolkach 3, Daniel Nettersheim 4, Doris Schmidt 2, Glen Kristiansen 3, Stefan C Mueller 2, Manuel Ritter 2, Stefan Hauser 2, Joerg Ellinger 2
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PMID: 32487606 DOI: 10.21873/anticanres.14293
Abstract
Background/aim: Myoferlin (MYOF) has emerged as an oncogenic protein in various human cancer types. This study was conducted to investigate comprehensively the expression and functional properties of MYOF in clear-cell renal-cell carcinoma (ccRCC) with respect to its value as diagnostic biomarker and therapeutic target.

Materials and methods: mRNA and protein expression of MYOF were assessed by quantitative polymerase chain reaction and immunohistochemistry. siRNA-mediated knockdown of MYOF was performed in the RCC cell line ACHN followed by proliferation, migration and invasion assays.

Results: MYOF mRNA and protein expression were significantly up-regulated in ccRCC. Higher mRNA levels were measured in advanced tumors. MYOF protein expression was increased in tumors with higher histological grades, and those with positive lymph node and surgical margin status. MYOF knockdown led to reduction of migration and invasion in ACHN cells, whereas expression of angiogenesis-associated genes tyrosine-protein kinase receptor-2 (TIE2), angiopoietin 2 (ANG2) and caveolin-1 (CAV1) was up-regulated following knockdown.

Conclusion: MYOF may serve as a diagnostic biomarker of tumor progression and a potential therapeutic target in ccRCC.

Keywords: Biomarker; immunohistochemistry; knockdown; myoferlin; renal cell carcinoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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21
Anticancer Res
. 2020 Jul;40(7):3961-3965. doi: 10.21873/anticanres.14388.
Seizures Prior to Radiotherapy of Gliomas: Prevalence, Risk Factors and Survival Prognosis
Jaspar Witteler 1, Troels W Kjaer 2, Soeren Tvilsted 3, Steven E Schild 4, Dirk Rades 5
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PMID: 32620638 DOI: 10.21873/anticanres.14388
Abstract
Background/aim: Seizures represent a common manifestation of gliomas. This study evaluated the prevalence of pre-radiotherapy seizures, potential risk factors and associations with survival.

Patients and methods: Eight factors were analyzed in 222 patients for associations with seizures including number, size and location of glioma, World Health Organization (WHO) grade, performance score, gender, age and upfront resection. These factors plus pre-radiotherapy symptoms and seizures were assessed for survival.

Results: Prevalence of pre-radiotherapy seizures was 29.3%. A significant correlation was found for grade II (p=0.002), trends for age ≤59 years (p=0.123) and lack of upfront resection (p=0.113). Unifocal gliomas (p<0.001), grade II (p=0.045) and upfront resection (p<0.001) showed significant associations with survival (univariate analyses). A trend was found for seizures (p=0.075) and age ≤59 years (p=0.091). In the multivariate analysis, grade II (p=0.002) and upfront resection (p=0.004) maintained significance; unifocal gliomas showed a trend (p=0.062).

Conclusion: Pre-radiotherapy seizures appeared to be correlated with WHO grade, age and lack of upfront resection, and with better survival.

Keywords: Glioma; prevalence; radiation therapy; risk factors; seizures; survival.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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22
Anticancer Res
. 2020 Jul;40(7):3713-3722. doi: 10.21873/anticanres.14360.
MicroRNAs Associated With Biological Pathways of Left- And Right-sided Colorectal Cancer
Stralina Eneh 1 2, Sami Heikkinen 3, Jaana M Hartikainen 1 2, Teijo Kuopio 4 5 6, Jukka-Pekka Mecklin 6 7 8, Veli-Matti Kosma 1 2 9, Arto Mannermaa 10 2 9
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PMID: 32620610 DOI: 10.21873/anticanres.14360
Abstract
Background/aim: MicroRNAs (miRNAs) regulate the development of colorectal cancer (CRC). We aimed to investigate miRNAs and their relation to cancer-related signaling pathways in site-specific CRC.

Materials and methods: We used a total of 24 left- and right-sided Finnish CRC samples (discovery cohort) and The Cancer Genome Atlas public mature miRSeq dataset of 201 CRC samples (validation cohort). MiRNA differential expression and biological pathway analyses were performed using DESeq2 and the DIANA/mirPath tool, respectively.

Results: We found 17 significantly differentially up-regulated [false discovery rate (FDR) <0.05] miRNAs in left-sided CRC ("left miRNAs"), and 15 in right-sided CRC ("right miRNAs"). The left miRNAs participate in the mTor, Wnt, PI3K-Akt signaling pathways (FDR<0.05). The right miRNAs participate in the TGF-β signaling pathway. We also observed that both cohorts share six miRNAs. One of these (hsa-miR-196b-5p) was significantly (FDR<0.05) up-regulated in left-sided CRC. The rest of them (hsa-miR-625-3p, hsa-miR-155-5p, hsa-miR-625-5p, hsa-miR-31-5p and hsa-miR-330-5p) showed significant (FDR<0.05) up-regulation in right-sided CRC.

Conclusion: Left and right miRNAs are associated with predominant biological pathways of left- and right-sided CRC, respectively. Our results may be beneficial for classifying CRC and for future biomarker studies of site-specific CRC.

Keywords: Left-sided colorectal cancer; biological pathways; microRNA; right-sided colorectal cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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23
Published Erratum Anticancer Res
. 2020 Jun;40(6):3589.
Erratum
No authors listed
PMID: 32487662
Erratum for
Genetic Variations of VEGFA Gene Are Associated With Infiltration of Adjacent Tissues and the Clinical Outcome of Patients With Nasopharyngeal Carcinoma.
Psoma E, Koliou GA, Dimitrakopoulos FI, Papadopoulou K, Rontogianni D, Bobos M, Visvikis A, Kosmidis PA, Fountzilas G, Constantinidis J, Kalogera-Fountzila A.
Anticancer Res. 2020 Feb;40(2):677-688. doi: 10.21873/anticanres.13997.
PMID: 32014908
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24
Published Erratum Anticancer Res
. 2020 Jul;40(7):4205.
Errata
No authors listed
PMID: 32620672
Erratum for
Expression of Kisspeptin (KISS1) and its Receptor GPR54 (KISS1R) in Prostate Cancer.
Xoxakos I, Petraki C, Msauel P, Armakolas A, Grigorakis A, Stefanakis S, Koutsilieris M.
Anticancer Res. 2020 Feb;40(2):709-718. doi: 10.21873/anticanres.14001.
PMID: 32014912
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25
Published Erratum Anticancer Res
. 2020 Jul;40(7):4205.
Errata
No authors listed
PMID: 32620671
Erratum for
Neocarzinostatin, Aptamer Conjugates for Targeting EpCAM-positive Tumor Cells.
Athyala PK, Kanwar JR, Chitipothu S, Kanwar RK, Krishnakumar S, Watson JP, Narayanan J.
Anticancer Res. 2017 Jul;37(7):3615-3629. doi: 10.21873/anticanres.11732.
PMID: 28668853
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26
Anticancer Res
. 2020 Jun;40(6):3527-3534. doi: 10.21873/anticanres.14341.
Diagnostic Reliability, Accuracy and Safety of Ultrasound-guided Biopsy and Ascites Puncture in Primarily Inoperable Ovarian Tumours
Pavel Vlasak 1, Jiri Bouda 1, Jan Kostun 1, Denis Berezovskiy 1, Michal Zikan 2, Vit Weinberger 3, Ondrej Ondic 4, Zdenek Rusavy 1, Radek Kucera 5, Ondrej Topolcan 5, Zdenek Novotny 1, Jiri Presl 6
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PMID: 32487654 DOI: 10.21873/anticanres.14341
Abstract
Background/aim: To compare the diagnostic reliability, accuracy and safety of ultrasound-guided biopsy (Tru-Cut biopsy) and ascites puncture in patients with a primarily inoperable malignant ovarian tumor.

Patients and methods: This is a retrospective analysis of the studied methods in consecutively examined patients and a prospective validation of these methods. 79 women with a suspected primarily inoperable ovarian tumor underwent Tru-Cut biopsies and were included in the ultrasound-guided biopsy group. In addition, 55 patients after ascites puncture were enrolled in the comparison group. Both procedures were performed in 48 patients for the prospective validation.

Results: Significant differences in favour of ultrasound-guided biopsy were found in all studied variables (malignancy confirmation 72.9% vs. 95.8%, tumor origin 52.1% vs. 89.6%, histologic subtype 43.8% vs. 85.4% and accuracy, i.e. agreement of preoperative and definitive diagnosis 43.7% vs. 95.4%).

Conclusion: Ultrasound-guided biopsy is an accurate, reliable, safe and minimally invasive method. Owing to the high reliability and accuracy, it has the capacity to replace ascites puncture with cytologic examination or a more invasive method (laparoscopy, laparotomy) for adequate tumor sampling.

Keywords: Tru-Cut biopsy; ascites; ovarian cancer; puncture.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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27
Meta-Analysis Anticancer Res
. 2020 Jun;40(6):3469-3476. doi: 10.21873/anticanres.14333.
Comparison Between Biweekly and Weekly Cetuximab in Patients With Metastatic Colorectal Cancer: A Meta-analysis
Akihisa Matsuda 1, Takeshi Yamada 2, Supaschin Jamjittrong 3, Seiichi Shinji 2, Ryo Ohta 2, Hiromichi Sonoda 2, Tunyaporn Kamonvarapitak 3, Kumiko Sekiguchi 4, Masao Miyashita 4, Hideyuki Suzuki 4, Hiroshi Yoshida 3
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PMID: 32487646 DOI: 10.21873/anticanres.14333
Abstract
Background/aim: Although weekly administration of cetuximab is the standard regimen in patients with metastatic colorectal cancer (mCRC), the efficacy and safety of a biweekly regimen is a pending issue. We conducted this meta-analysis to compare the efficacy and safety of a biweekly vs. a weekly regimen of cetuximab in the treatment of mCRC.

Patients and methods: We conducted a comprehensive electronic literature search up to January 2020 to identify studies directly comparing the efficacy and safety of biweekly cetuximab administration and conventional weekly administration in patients with mCRC. We then performed a meta-analysis using random-effects models to calculate risk ratios and mean differences with 95% confidence intervals.

Results: Four studies with a total of 381 patients were included in this meta-analysis. The meta-analysis showed that biweekly administration conferred equivalent efficacy, including objective response rate, disease-control rate, progression-free survival, and overall survival, as well as safety, including skin toxicity, gastrointestinal toxicity, and hematologic toxicity, compared with weekly administration in patients with mCRC.

Conclusion: Results from this meta-analysis support the administration of biweekly instead of weekly cetuximab, which is beneficial for both patients and health resources.

Keywords: Cetuximab; biweekly; metastatic colorectal cancer; weekly.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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28
Anticancer Res
. 2020 Jul;40(7):4001-4010. doi: 10.21873/anticanres.14394.
Comprehensive Analysis and Clinical Implication of PD-L1 Expression Considering HPV Status in Oropharyngeal Squamous Cell Carcinoma
Ji Yun Jeong 1 2, Tae-In Park 3, Dongbin Ahn 4
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PMID: 32620644 DOI: 10.21873/anticanres.14394
Abstract
Background/aim: This study was conducted to comprehensively evaluate programmed cell death ligand 1 (PD-L1) expression, and analyze the clinical and prognostic implications of PD-L1 expression in oropharyngeal squamous cell carcinoma (OPSCC).

Patients and methods: We evaluated the expression of PD-L1 using the antibodies SP263 and SP142 in 106 patients with OPSCC, using immunohistochemistry. PD-L1 expression was subdivided into tumor cell score (TC), immune cell score (IC), and combined score (CS). Correlations between each PD-L1 expression and HPV status, clinicopathological features, and survival were analyzed.

Results: The expression levels of PD-L1 SP263 and SP142 were significantly correlated. High PD-L1 SP263 TC and CS and SP142 IC and CS were associated with HPV positivity. PD-L1 expression showed no effect on survival in all patients' group. However, in the subgroup analysis, high TC and CS of both PD-L1 SP263 and SP142 were correlated with shorter time to recurrence in the HPV positive group.

Conclusion: High expression of PD-L1 was associated with HPV positivity in OPSCC. In addition, high expression of PD-L1 might suggest a poorer outcome, especially in the HPV positive subgroup. PD-L1 could be a useful predictive and prognostic biomarker in OPSCC.

Keywords: Programmed cell death ligand 1; human papillomavirus; oropharyngeal squamous cell carcinoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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29
Anticancer Res
. 2020 Jul;40(7):4087-4093. doi: 10.21873/anticanres.14407.
The Impact of Hypertension on the Clinicopathological Outcome and Progression of Renal Cell Carcinoma
Tomoyuki Makino 1, Kouji Izumi 2, Hiroaki Iwamoto 1, Suguru Kadomoto 1, Renato Naito 1, Hiroshi Yaegashi 1, Kazuyoshi Shigehara 1, Yoshifumi Kadono 1, Atsushi Mizokami 1
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PMID: 32620657 DOI: 10.21873/anticanres.14407
Abstract
Background/aim: Hypertension is a risk factor for occurrence of renal cell carcinoma; however, it remains unclear whether hypertension affects development and prognosis of renal cell carcinoma. This study evaluated the impact of hypertension on the progression of renal cell carcinoma.

Patients and methods: Renal cell carcinoma patients who were treated from October 2007 to December 2018 at our Institution were retrospectively analyzed.

Results: Of 462 patients, the number of patients with and without hypertension was 234 (including 227 treated with anti-hypertensive agents) and 228, respectively. The tumor size was significantly smaller in the hypertension group than in the non-hypertension group (median 32 and 45 mm, respectively, p=0.010). The 5-year cancer-specific and metastasis-free survival in the hypertension group were significantly better than those in the non-hypertension group (93.6% and 80.4%, and 84.6% and 73.0%, respectively, p=0.021 and p=0.017). Propensity score matching revealed significantly better metastatic-free survival in the hypertension group than the non-hypertension group (p=0.022).

Conclusion: Renal cell carcinoma patients with hypertension show better prognosis with low metastasis possibility.

Keywords: Anti-hypertensive agent; hypertension; renal cell carcinoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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30
Anticancer Res
. 2020 Jul;40(7):3847-3855. doi: 10.21873/anticanres.14374.
Tyrosine Kinase Inhibitors and Everolimus Reduce IGF1R Expression in HPV16-positive and -Negative Squamous Cell Carcinoma
Bendikt Kramer 1, Angela Schell 2, Christoph Aderhold 2, Lena Huber 2, C Emika Mueller 3, Nicole Rotter 2, Richard Birk 2 3
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PMID: 32620624 DOI: 10.21873/anticanres.14374
Abstract
Background/aim: The effects of tyrosine kinase inhibitors (TKI) in head and neck squamous cell cancer (HNSCC) are not fully understood. We investigated the effects of selective TKIs erlotinib, gefitinib, nilotinib, and dasatinib and the mTOR-inhibitor everolimus on the expression of insulin-like growth factor 1 receptor (IGF1R) in HPV-positive and HPV-negative squamous cancer cell lines.

Materials and methods: HPV-negative UMSCC-11A and UMSCC-14C cells and HPV-positive CERV196 cells were treated with TKIs or everolimus. Protein concentration of IGF1R was measured using ELISA.

Results: IGF1R expression was significantly reduced by all tested TKIs and everolimus in both HPV-negative cancer cell lines. In HPV-positive squamous cancer cells we observed significant protein inhibition.

Conclusion: The crosstalk between epidermal growth factor receptors and IGF1R could be of central interest for the development of novel medical approaches for individualized therapy.

Keywords: IGF1R; TKI; dasatinib; erlotinib; everolimus; gefitinib; head and neck squamous cell carcinoma (HNSCC); insulin-like growth factor 1 receptor; nilotinib.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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31
Anticancer Res
. 2020 Jul;40(7):3915-3924. doi: 10.21873/anticanres.14382.
Reflector-guided Localization of Non-palpable Breast Lesions: The First Reported European Evaluation of the SAVI SCOUT® System
Salim Tayeh 1, Samantha Muktar 1, Jennifer Heeney 1, Michael J Michell 1, Nicholas Perry 1, Tamara Suaris 1, David Evans 1, Anmol Malhotra 1, Kefah Mokbel 2
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PMID: 32620632 DOI: 10.21873/anticanres.14382
Abstract
Background: Wire-guided localization (WGL) has been the mainstay for localizing non-palpable breast lesions before excision. Due to its limitations, various wireless alternatives have been developed. In this prospective study, we evaluate the role of radiation-free wireless localization using the SAVI SCOUT® localization at a European centre.

Patients and methods: This technique was evaluated in a prospective cohort of 20 patients. The evaluation focused on clinical and pathological parameters in addition to patient and physician acceptance.

Results: SAVI SCOUT reflectors (n=23) were deployed to localize 22 occult breast lesions and one axillary lymph node in 20 patients. The mean deployment duration was 5.6 min, with a mean distance from the lesion of 0.6 mm. The migration rate was 0% and the mean identification and retrieval time was 25.1 min. In patients undergoing therapeutic excision for malignancy (n=17), only one (5.9%) required reoperation for positive surgical margins. Radiologists and surgeons rated the technique as better than WGL and patient satisfaction was high.

Conclusion: Our study demonstrates that wireless localization using SAVI SCOUT® is an effective and time-efficient alternative to WGL with excellent physician and patient acceptance.

Keywords: SAVI SCOUT; breast cancer; non-wire localization; reflector localization.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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32
Anticancer Res
. 2020 Jun;40(6):3071-3080. doi: 10.21873/anticanres.14288.
Retinoids Augment Thiazolidinedione PPARγ Activation in Oral Cancer Cells
Raul Rosas 1, Seth Buryska 2, Robert Silver 3, Beverly Wuertz 4, Frank Ondrey 2
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PMID: 32487601 DOI: 10.21873/anticanres.14288
Abstract
Background/aim: Head and neck squamous cell carcinoma affects nearly 500,000 people annually. Augmenting PPARγ functional activation is linked with multiple anti-carcinogenic processes in aerodigestive cell lines and animal models. PPARγ/RXRα heterodimers may be key partners in this activation.

Materials and methods: CA 9-22 and NA cell lines were treated with the PPARγ agonist ciglitazone and/or the RXRα agonist 9-cis-retinoic acid. PPARγ functional activation, cellular proliferation, apoptosis activity, and phenotype were subsequently analyzed.

Results: Ciglitazone and 9-cis-retinoic acid independently activated PPARγ and down-regulated the carcinogenic phenotype in vitro. Combination treatment significantly augmented these effects, further decreasing proliferation (p<0.0001), and increasing PPARγ functional activation (p<0.0001), apoptosis (p<0.05), and adipocyte differentiation markers (p<0.0001).

Conclusion: The efficacy of the combination of ciglitazone and 9-cis-retinoic acid afforded lowering treatment concentrations while maintaining desired therapeutic outcomes, optimistically supporting the feasibility and practicality of this novel treatment option.

Keywords: 9-cis-retinoic acid; PPARγ; ciglitazone; head and neck squamous carcinoma; retinoids; thiazolidinedione.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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33
Anticancer Res
. 2020 Jun;40(6):3579-3587. doi: 10.21873/anticanres.14348.
Neoadjuvant Treatment in Upper Rectal Cancer Does Not Improve Oncologic Outcomes But Increases Postoperative Morbidity
Nicolas Tabchouri 1, Yassine Eid 2, Gilles Manceau 3, Alice Frontali 4, Zaher Lakkis 5, Ephrem Salame 1, Thierry Lecomte 6, Sophie Chapet 7, Gilles Calais 7, Bruno Heyd 5, Mehdi Karoui 3, Arnaud Alves 2, Yves Panis 4, Mehdi Ouaissi 8
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PMID: 32487661 DOI: 10.21873/anticanres.14348
Abstract
Background/aim: Neoadjuvant chemoradiation/radiation therapy in locally advanced (LA) upper rectal adenocarcinoma management remains unclear. The aim of this study was to compare outcomes between neoadjuvant chemoradiation therapy (CRT) and upfront surgery (US).

Patients and methods: A total of 127 patients were retrospectively included from 5 centers (79 treated with US and 48 with CRT). CRT and US groups were compared in terms of postoperative complications and long-term oncological and functional results.

Results: Total mesorectal excision (TME) was more frequent in CRT (58% vs. 20% in US, p<0.001). CRT was associated with more overall and severe postoperative complications (60% vs. 30%, p<0.001 and 17% vs. 1%, p=0.002, respectively), and was the only risk factor [OR=18.8 (2.2-160.2), p=0.007]. Five-year overall survival and 5-year recurrence-free survival were similar between CRT and US (96% vs. 91% p=0.256 and 85.4% vs. 85%, p=0.495). The functional results were similar between the two groups.

Conclusion: CRT did not improve long-term oncological outcomes in patients with LA upper rectal adenocarcinoma, but increased postoperative complications compared with US.

Keywords: Upper rectal cancer; chemoradiation therapy; long-term functional results; neoadjuvant treatment; recurrence-free and overall survival.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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34
Anticancer Res
. 2020 Jul;40(7):4147-4156. doi: 10.21873/anticanres.14414.
C-Reactive Protein and Absolute Lymphocyte Count Can Predict Overall Survival of Patients Treated With Eribulin
Atsushi Sata 1 2, Reiko Fukui 1, Yoshimasa Miyagawa 1, Ayako Bun 1, Hiromi Ozawa 1, Yukie Fujimoto 1, Tomoko Higuchi 1, Michiko Imamura 1, Yasuo Miyoshi 3
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PMID: 32620664 DOI: 10.21873/anticanres.14414
Abstract
Background/aim: We investigated the efficacy of neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and C-reactive protein (CRP) in predicting overall survival of metastatic breast cancer patients treated with eribulin.

Patients and methods: Overall, 74 patients treated with eribulin were enrolled and their baseline levels of NLR, ALC, and CRP retrieved. Cutoff values of NLR, ALC, and CRP were set at 3.0, 1500/μl, and 0.3 mg/dl, respectively. Overall survival (OS) was compared according to marker levels.

Results: The OS of NLR-low, ALC-high, and CRP-low groups at baseline was significantly longer than that of NLR-high, ALC-low, and CRP-high groups (p=0.0027, p=0.0013, and p=0.0164, respectively). The combination of ALC and CRP was significantly associated with OS by multivariate analysis (p=0.048).

Conclusion: Baseline levels of NLR, ALC, and CRP were significantly associated with OS in patients treated with eribulin. The combination of ALC and CRP improved the predictive efficacy compared to individual markers.

Keywords: Breast cancer; absolute lymphocyte count; c-reactive protein; eribulin; overall survival.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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35
Anticancer Res
. 2020 Jun;40(6):3239-3246. doi: 10.21873/anticanres.14305.
NCAPH Is Required for Proliferation, Migration and Invasion of Non-small-cell Lung Cancer Cells
Byeol Kim 1, Seok Won Kim 2, Ji-Yeon Lim 1, Seon-Joo Park 3
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PMID: 32487618 DOI: 10.21873/anticanres.14305
Abstract
Background/aim: Non-structural maintenance of chromosomes condensin I complex subunit H (NCAPH) is implicated in correct chromosome condensation and segregation during mitosis. However, the functional role of NCAPH in the pathogenesis of non-small-cell lung cancer (NSCLC) remains unclear. The aim of this study was to elucidate the role of NCAPH in NSCLC cells.

Materials and methods: A549 and H1299 NSCLC cells were transfected with small-interfering RNA (siRNA) against NCAPH. Subsequently, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony-formation assay and flow cytometry analysis were performed to reveal the role of NCAPH in NSCLC cells. In addition, migration and invasion assay were also performed.

Results: NCAPH knockdown inhibited cell proliferation, induced cell-cycle arrest at G2/M phase, and prevented colony formation, migration and invasion by NSCLC cells.

Conclusion: NCAPH is involved in NSCLC progression and development, and may be a potential therapeutic target for NSCLC treatment.

Keywords: NCAPH; NSCLC; cell cycle; chromosome; condensin.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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36
Anticancer Res
. 2020 Jun;40(6):3435-3444. doi: 10.21873/anticanres.14329.
Clinical Utility of Combined Circulating Tumor Cell and Circulating Tumor DNA Assays for Diagnosis of Primary Lung Cancer
Seong Mi Moon 1 2, Ji-Ho Kim 3, Seong Keun Kim 4, Seonwoo Kim 5, Hyuk-Jung Kwon 3, Jin-Sik Bae 3, Sunghoon Lee 3, Hye Seon Lee 4, Mi-Young Choi 4, Byung Hee Jeon 4, Byeong-Ho Jeong 1, Kyungjong Lee 1, Hong Kwan Kim 6, Jhingook Kim 6, Sang-Won Um 7
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PMID: 32487642 DOI: 10.21873/anticanres.14329
Abstract
Background/aim: Although it has been suggested that circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) might be used in a complementary manner in lung cancer diagnosis, limited confirmatory data are available. In this prospective study, we evaluated the diagnostic performance of each assay separately and in combination.

Patients and methods: From March 2018 to January 2019, patients with suspected primary lung cancer, who underwent routine lung cancer work-up and peripheral blood sampling, were prospectively enrolled in the study. Epithelial cell adhesion molecule and cytokeratin served as markers of CTCs. In terms of ctDNA analysis, single-nucleotide variants were evaluated via next-generation sequencing.

Results: We analyzed 111 patients, including 99 with primary lung cancer and 12 with benign pulmonary disease. The median number of CTCs in 10 ml of blood was 3. The most frequently detected single nucleotide variants of ctDNA were TP53, CDKN2A, and EGFR. The diagnostic sensitivity of conventional tumor marker (combination of carcinoembryonic antigen/CYFRA 21-1/neuron-specific enolase) was 66.7%, while those of the ctDNA and CTC assays were 72.7% and 65.7%, respectively. The sensitivity of the CTC/ctDNA combination (95.0%) was significantly greater than those of the CTC (p<0.001), ctDNA (p<0.001), or conventional tumor marker (p<0.001) alone. Subgroup analysis revealed that the sensitivity of the combination assay was greater than those of the CTC or ctDNA assays alone, regardless of tumor stage or histopathology type.

Conclusion: The CTC/ctDNA combination assay enhanced the sensitivity of primary lung cancer diagnosis. The combination assay strategy may be clinically useful and could enhance the early detection of lung cancer (ClinicalTrials.gov number: NCT03479099).

Keywords: Liquid biopsy; circulating tumor DNA; circulating tumor cell; diagnosis; primary lung cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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37
Anticancer Res
. 2020 Jul;40(7):3751-3757. doi: 10.21873/anticanres.14364.
Adiponectin Is Inversely Associated With Tumour Grade in Colorectal Cancer Patients
Rita Polito 1 2, Ersilia Nigro 1 2, Landino Fei 3, Laura DE Magistris 4, Maria Ludovica Monaco 2, Rosa D'Amico 3, Silvio Naviglio 4, Giuseppe Signoriello 5, Aurora Daniele 6 2
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PMID: 32620614 DOI: 10.21873/anticanres.14364
Abstract
Background/aim: Colorectal cancer is frequently associated with metabolic diseases. Adiponectin (APN) is an insulin-sensitizing adipokine circulating as low molecular weight (LMW), medium molecular weight (MMW) and high molecular weight (HMW) oligomers; the latter are the most bio-active oligomers. APN, through AdipoR1, AdipoR2 and T-cadherin receptors, regulates inflammation, and proliferation. Considering the anti-proliferative and anti-inflammatory properties of APN, we investigated the involvement of the "APN system" in colorectal cancer.

Materials and methods: A total of 44 colorectal cancer patients and 51 healthy controls were recruited. We analysed APN and HMW oligomers in sera, AdipoR1, AdipoR2 and T-cadherin expression in non-cancerous and cancerous colon tissues.

Results: we found statistically lower levels of APN in patients compared to controls, with a specific decrease of HMW oligomers. Importantly, APN correlated to cancer grade. AdipoR1 was found overexpressed in cancerous compared to non-cancerous tissues while AdipoR2 and T-cadherin were down-regulated.

Conclusion: The deregulated expression of the "APN system" in colorectal cancer with a specific correlation to tumor grade suggests APN as a promising biomarker in colorectal cancer.

Keywords: AdipoR1; AdipoR2; Colorectal cancer; T-cadherin; adiponectin; high-molecular weight oligomers.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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38
Anticancer Res
. 2020 Jul;40(7):3925-3929. doi: 10.21873/anticanres.14383.
Primary and Interval Debulking Surgery Provide Similar Survival and Platinum Sensitivity Outcomes in Advanced Ovarian Cancer: A Retrospective Study
Oliver Glover 1, Viren Asher 1, Anish Bali 1, Summi Abdul 1, Anna Collins 2, Andrew Phillips 3
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PMID: 32620633 DOI: 10.21873/anticanres.14383
Abstract
Background/aim: CHORUS and EORTC55971 trials demonstrated that neoadjuvant chemotherapy followed by interval debulking surgery (IDS) or primary debulking surgery (PDS) offered the same survival rates. These trials have since been criticised due to poor surgical complexity. We compared overall (OS), progression free (PFS), and platinum sensitivity in advanced ovarian cancer (AOC) patients undergoing IDS or PDS, who had received either intermediate or high complexity surgery to achieve complete cytoreduction.

Patients and methods: All patients with AOC treated between February 2014 and May 2019 obtaining complete cytoreduction with intermediate/high surgical complexity were included. Recurrence was defined according to GCIG criteria on radiological findings and/or CA125 levels.

Results: Seventy-one patients (38 PDS and 33 IDS) with full recurrence data were identified. No statistical difference was seen between groups in OS, PFS or platinum sensitive interval.

Conclusion: PDS or IDS were both acceptable treatment options for AOC, showing similar survival and platinum sensitivity outcomes in patients undergoing intermediate or high complexity surgery.

Keywords: IDS; Ovarian cancer; PDS; debulking surgery; surgical complexity.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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39
Anticancer Res
. 2020 Jun;40(6):3139-3145. doi: 10.21873/anticanres.14295.
Anti-infectious and Anti-tumor Activities of β-glucans
Vaclav Vetvicka 1, Jana Vetvickova 2
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PMID: 32487608 DOI: 10.21873/anticanres.14295
Abstract
Background/aim: The aim of this study was to directly compare the anti-infectious and anti-cancer effects of five commercially available glucans.

Materials and methods: We used five different glucans isolated from algae, yeast, bacteria, oat, and mushroom. We compared their effects on the stimulation of phagocytosis of blood cells, on the secretion of IL-2, and on the inhibition of melanoma and breast and lung cancers. In addition, we evaluated the effects of glucan supplementation on two experimental models of infection.

Results: Most of the tested glucans stimulated phagocytosis and IL-2 secretion, reduced cancer growth, and ameliorated some effects of experimental infections.

Conclusion: Glucans can produce significant pleiotropic effects, but the activity varies among individual samples.

Keywords: Glucan; IL-2; cancer; infection; phagocytosis.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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40
Anticancer Res
. 2020 Jul;40(7):3669-3683. doi: 10.21873/anticanres.14356.
Modulation of Estrogen α and Progesterone Receptors in Triple Negative Breast Cancer Cell Lines: The Effects of Vorinostat and Indole-3-Carbinol In Vitro
Fatemeh Nouriemamzaden 1, Beverly Word 1, Ebony Cotton 1, Anfernee Hawkins 1, Kai Littlejohn 1, Rhonda Moore 2, Gustav Miranda-Carbon 3, Chinna Nneka Orish 4, Beverly Lyn-Cook 5
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PMID: 32620606 DOI: 10.21873/anticanres.14356
Abstract
Background/aim: Triple negative cancer (TNBC) is a subtype of breast cancer that is highly aggressive, with poor prognosis and responds differently to treatments. This study investigated the role of vorinostat and indole-3-carbinol (I3C) on regulating critical receptors that are not normally expressed in TNBC.

Materials and methods: Using real-time PCR, immunostaining, and western blots, the re-expression of estrogen receptor α (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) receptors was examined in four different TNBC cell types.

Results: ERα was re-expressed in three subtypes using vorinostat and I3C. Re-expression of the PR by vorinostat was also detected. Neither vorinostat nor I3C resulted in re-expression of the HER2 receptor. A significant decrease in growth and sensitivity to tamoxifen was also noted.

Conclusion: The results of this study show that vorinostat and I3C modulate the re-expression of critical receptors in certain subtypes of TNBC through several pathways and these effects can be influenced by the molecular profiles of TNBCs.

Keywords: HDAC activity; HDAC7; I3C; Vorinostat; estrogen receptor; progesterone receptor; triple negative breast cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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41
Anticancer Res
. 2020 Jun;40(6):3379-3386. doi: 10.21873/anticanres.14321.
The Role of Radiotherapy for Patients With Thyroid Cancer in the Modern Era
Laith Samhouri 1, Jan Kriz 1, Khaled Elsayad 1, Mohammed Channaoui 1, Andreas Pascher 2, Burkhard Riemann 3, Rainer Wiewrodt 4, Uwe Haverkamp 1, Sergiu Scobioala 1, Hans Theodor Eich 5
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PMID: 32487634 DOI: 10.21873/anticanres.14321
Abstract
Background/aim: Thyroid cancer (TC) is a relatively rare malignancy. The mainstay treatment is surgery followed by radioactive iodine (RAI) and medical systemic treatments. The role of external beam radiotherapy (EBRT) in TC is controversial regarding the survival benefits. The aim of this study was to analyse the effectiveness of EBRT for different forms of TC in different stages.

Patients and methods: Between January 1990 and 2016, 75 patients underwent 255 radiotherapy (RT) courses at our Institution. Local control (LC) and progression-free survival (PFS) were analyzed.

Results: The cohort consisted of 22 patients who received curative RT and 53 patients who received RT in a palliative setting. The estimated 5-year LC for the curative group was 92±8% and the palliative group 78±7%. The estimated 5-year PFS for the curative group was 27±9% and for palliative group 31±6%.

Conclusion: The addition of RT in TC seems to be safe and effective. Our analysis showed an excellent local control (median >15 years) regardless of the treatment setting.

Keywords: Thyroid cancer; curative; palliative setting; stereotactic radiotherapy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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42
Anticancer Res
. 2020 Jun;40(6):3091-3096. doi: 10.21873/anticanres.14290.
Oncogenic miRNAs Identified in Tear Exosomes From Metastatic Breast Cancer Patients
Sachiko Inubushi 1 2 3, Hiroki Kawaguchi 1, Sachiko Mizumoto 4, Tomonari Kunihisa 4, Motoi Baba 4, Yukiya Kitayama 5, Toshifumi Takeuchi 5, Robert M Hoffman 2 3, Ryohei Sasaki 6
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PMID: 32487603 DOI: 10.21873/anticanres.14290
Abstract
Background/aim: Exosomes are produced by normal and cancer cells. Exosomes are found in the serum of cancer patients and have been used for diagnosis and prognosis. Recently tears from non-cancer patients have been found to contain exosomes. In the present report we describe tears from advanced breast-cancer patients.

Materials and methods: We found oncogenic miRNAs in the exosomes isolated from tear fluids obtained from five patients with metastatic breast cancer and compared them with tear exosomes form eight healthy volunteers.

Results: Tear exosomes had a significantly higher quantity of exosome markers than serum exosomes (CD9, CD63). Tear exosomes were subjected to quantitative reverse-transcription polymerase reaction (qRT-PCR), and western blot analysis to elucidate the status of miRNAs, previously reported in serum from patients with metastatic breast cancer. qRT-PCR and western-blot analysis revealed that breast-cancer-specific miR-21 and miR-200c were highly expressed in tear exosomes from metastatic breast cancer patients in contrast to tear exosomes from healthy volunteers.

Conclusion: Tear exosomes can be a potential source of diagnostic and prognostic biomarkers for metastatic breast cancer, and possibly other cancers or diseases.

Keywords: Exosomes; biomarkers; breast cancer; extracellular vesicles; miRNA; tears.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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43
Anticancer Res
. 2020 Jul;40(7):3765-3779. doi: 10.21873/anticanres.14366.
Epigenetic Regulation of APAF-1 Through DNA Methylation in Pancreatic Cancer
Ausra Lukosiute-Urboniene 1 2, Augustina Mazeike 3, Mintaute Kazokaite 4 5, Giedre Silkuniene 4, Mantas Silkunas 4, Vidmantas Barauskas 2, Giedrius Barauskas 6, Antanas Gulbinas 4, Albertas Dauksa 4 6, Zilvinas Dambrauskas 4 6
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PMID: 32620616 DOI: 10.21873/anticanres.14366
Abstract
Background/aim: Apoptotic peptidase activating factor 1 (APAF-1) is essential regulator of apoptosis and inactivation by DNA methylation is common event in numerous cancer types. We investigated the regulation of APAF-1 through DNA methylation in pancreatic cancer.

Materials and methods: Datasets from 44 patients after pancreatoduodenectomy and the pancreatic adenocarcinoma (PDAC) cell lines Capan-2 and MIA PaCa-2 treated with decitabine were analyzed by RT-PCR, immunoblotting, methylation-specific PCR analysis, apoptosis and viability assays to identify effects of APAF-1 regulation.

Results: APAF-1 mRNA and protein levels were significantly down-regulated, and APAF-1 methylation status was associated with perineural invasion in PDAC. Decitabine inhibited cell viability and increased apoptosis rates, however failed to restore APAF-1 mRNA and protein levels in cells.

Conclusion: APAF-1 gene hypermethylation may contribute to the progression of PDAC through perineural invasion. Decitabine could sensitize pancreatic cancer cells to apoptosis and growth retardation, however, not directly through the APAF-1 demethylation process.

Keywords: APAF-1; DNA methylation; Pancreatic cancer; decitabine.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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44
Anticancer Res
. 2020 Jul;40(7):3983-3990. doi: 10.21873/anticanres.14391.
Features of Hepatocellular Carcinoma With Micro Hepatic Vein Invasion and Their Correlation With Hepatitis B and C Virus
Yuhki Sakuraoka 1, Keiichi Kubota 2, Genki Tanaka 2, Takayuki Shimizu 2, Kazuma Tago 2, Kyung Hwa Park 2, Takatsugu Matsumoto 2, Takayuki Shiraki 2, Shozo Mori 2, Yukihiro Iso 2, Taku Aoki 2
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PMID: 32620641 DOI: 10.21873/anticanres.14391
Abstract
Background/aim: Few studies have studied micro hepatic vein invasion in hepatocellular carcinoma (HCC). We explored the correlation between hepatic vein invasion and hepatitis B/C virus infection.

Patients and methods: Between April 2000 and February 2018, 869 patients underwent liver resection for HCC at a single center. The patients were divided into two groups: those with micro hepatic vein invasion (VV+) and those without (VV-). The clinical data, overall survival (OS) and correlations with the presence of hepatitis B and C viruses were investigated.

Results: There were 817 VV- patients and 43 VV+ patients. OS was 66.2 months for VV- patients and 9.9 months for VV+ patients (p=0.0010). VV+ patients had significantly higher levels of serum HBV DNA (p=0.016).

Conclusion: HCC patients with micro hepatic vein invasion showed significantly shorter OS. A higher level of HBV DNA appears to be a risk factor for micro hepatic vein invasion.

Keywords: Microvascular invasion; hematogenous metastasis; hepatocellular carcinoma; prognosis.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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45
Anticancer Res
. 2020 Jun;40(6):3297-3306. doi: 10.21873/anticanres.14312.
An Animal Model of Colorectal Cancer Liver Metastasis With a High Metastasis Rate and Clonal Dynamics
Ki Beom Bae 1 2, Sun-Hee Kim 3 2 4, Mi Seon Kang 5, Dong-Hyun Kim 6
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PMID: 32487625 DOI: 10.21873/anticanres.14312
Abstract
Background: Various animal models have been introduced into the study of liver metastasis of colorectal cancer, but they have not been compared under the same conditions. The aim of this study was to identify an optimized mouse model that showed a high rate of hepatic metastasis and expression of clonal dynamics.

Materials and methods: Athymic nude mice (n=30) were divided into two equal groups for the creation of a splenic injection model (SIM) and surgically orthotopic implantation model (SOIM) of liver metastasis of colorectal cancer using HCT116 cells. Hepatic metastasis was confirmed by gross and microscopic examinations. Expression of MET transcriptional regulator MACC1 (MACC1) in colon cancer cell lines and metastatic tumors in the group with a higher liver metastasis rate was confirmed by quantitative reverse-transcription-polymerase chain reaction.

Results: The observation time was significantly shorter for SIM than for SOIM (33.0±6.8 vs. 41.2±7.2 days, p<0.001). The rate of hepatic metastasis was significantly higher in SIM than in SOIM (76.9% vs. 38.4%, p=0.038). MACC1 was expressed in Colo201, HCT116, HT29, LS513, SW620, and WiDr cells but not in SW480 cells. All hepatic metastases in SIM mice expressed MACC1, and metastatic HCT116 cells had significantly greater expression than did the original HCT116 cells (p<0.001).

Conclusion: With a higher rate of hepatic metastasis with clonal dynamics in a shorter observation time than the SOIM, SIM appears to be a good animal model for identifying new targets and in drug development for colorectal cancer liver metastasis. SOIM should also be considered for the study of the full steps of metastasis.

Keywords: Colorectal cancer; animal model; clonal dynamics; liver metastasis; orthotopic implantation; splenic injection.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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46
Anticancer Res
. 2020 Jun;40(6):3287-3296. doi: 10.21873/anticanres.14311.
Tranilast Inhibits TGF-β1-induced Epithelial-mesenchymal Transition and Invasion/Metastasis via the Suppression of Smad4 in Human Lung Cancer Cell Lines
Koji Takahashi 1, Toshi Menju 2, Shigeto Nishikawa 1, Ryo Miyata 1, Satona Tanaka 1, Yojiro Yutaka 1, Yoshito Yamada 1, Daisuke Nakajima 1, Masatsugu Hamaji 1, Akihiro Ohsumi 1, Toyofumi Fengshi Chen-Yoshikawa 3, Toshihiko Sato 1, Makoto Sonobe 4, Hiroshi Date 1
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PMID: 32487624 DOI: 10.21873/anticanres.14311
Abstract
Background/aim: Transforming growth factor β1 (TGF-β1) is an important epithelial-mesenchymal transition (EMT) activator that regulates the expression of E-cadherin and vimentin through Smad signalling. Tranilast is an anti-allergic drug that inhibits TGF-β1, and is used in the treatment of keloids and hypertrophic scars. We investigated whether tranilast inhibits TGF-β1-induced EMT and invasiveness in human non-small cell lung cancer cell lines.

Materials and methods: We examined the effects of tranilast treatment on EMT markers, TGF-β1/Smad signalling, and cell invasiveness in A549 and PC14 cells. Tumours from a mouse orthotopic lung cancer model with or without tranilast treatment were also immunohistochemically evaluated.

Results: Tranilast increased E-cadherin expression via Smad4 suppression and inhibited cell invasion in TGF-β1-stimulated cells. Tranilast treatment of the in vivo mouse model reduced the pleural dissemination of cancer cells and suppressed vimentin and Smad4 expression.

Conclusion: Tranilast inhibited TGF-β1-induced EMT and cellular invasion/metastasis by suppressing Smad4 expression in cancer cells.

Keywords: EMT; Smad4; TGF-β1; tranilast.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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47
Anticancer Res
. 2020 Jun;40(6):3395-3400. doi: 10.21873/anticanres.14323.
Tumor-infiltrating Lymphocyte Score Based on FDG PET/CT for Predicting the Effect of Neoadjuvant Chemotherapy in Breast Cancer
Shinsuke Sasada 1, Yuri Kimura 2, Akiko Emi 2, Norio Masumoto 2, Takayuki Kadoya 2, Koji Arihiro 3, Morihito Okada 2
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PMID: 32487636 DOI: 10.21873/anticanres.14323
Abstract
Aim: To investigate whether tumor-infiltrating lymphocyte (TIL) scoring based on 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) can predict the pathological response to neoadjuvant chemotherapy.

Patients and methods: A total of 261 patients with breast cancer underwent complete resection after neoadjuvant chemotherapy. PET-TIL score was calculated using tumor size, Ki-67 labeling index, and maximum standardized uptake value (SUVmax) on FDG PET/CT. The efficacy of the PET-TIL score in predicting the pathological complete response (pCR) was retrospectively evaluated.

Results: pCR rates were 11.4%, 58.6%, and 38.8% in luminal, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative breast cancer, respectively. The corresponding median PET-TIL scores were 28, 37, and 45. pCR rates were 20.0% and 44.2% in the low and high PET-TIL score groups, respectively (p<0.001). HER2-positive and triple-negative subtypes and high PET-TIL score were independent predictors for pCR.

Conclusion: PET-TIL score can predict pCR after neoadjuvant chemotherapy in breast cancer.

Keywords: Breast cancer; PET; SUV; neoadjuvant chemotherapy; pathological complete response; tumor-infiltrating lymphocyte.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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48
Anticancer Res
. 2020 Jul;40(7):4023-4027. doi: 10.21873/anticanres.14397.
Prognostic Impact of a Novel Tumor Marker and Inflammation Index for Patients With Non-small-cell Lung Cancer
Masaki Tomita 1, Ryo Maeda 2, Takanori Ayabe 2, Kunihide Nakamura 3
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PMID: 32620647 DOI: 10.21873/anticanres.14397
Abstract
Background/aim: Different tumor markers and systemic inflammation have been linked with cancer development and poor outcome. We aimed to establish a novel non-invasive prognostic index for patients with resectable non-small cell lung cancer (NSCLC) based on serum carcinoembryonic antigen (CEA) and C-reactive protein (CRP).

Patients and methods: Four hundred and sixty-two patients curatively resected for NSCLC between 2008 and 2014 were included. All patients with a follow-up period of less than 5 years were omitted. The geometric mean of the normalized serum CEA and CRP levels was used as a novel tumor marker and inflammation index (TMII). The cut-off value of TMII was determined by receiver operating characteristic (ROC) curve analysis. Univariate and multivariate analyses were used to identify the relative risk factors for survival.

Results: ROC curve analysis revealed a TMII cut-off value of 0.46. The group with high TMII displayed more adverse clinical characteristics. Furthermore, compared to patients with low TMII, the group with high TMII had significantly poorer survival. On multivariate analysis, TMII was independently associated with survival.

Conclusion: We established a novel prognostic index (TMII) based on serum CEA and CRP. Preoperative TMII may predict poor outcomes in patients with NSCLC.

Keywords: C-reactive protein; Tumor marker; carcinoembryonic antigen; inflammation index; non-small cell lung cancer; novel index; prognosis; surgery.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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49
Anticancer Res
. 2020 Jul;40(7):3967-3972. doi: 10.21873/anticanres.14389.
Non-invasive Detection of Bladder Cancer by UBC Rapid Test, Ultrasonography and Cytology
Vivian Barak 1, Dror Itzkovich 2, Roland Einarsson 3, Ofer Gofrit 2, Dov Pode 2
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PMID: 32620639 DOI: 10.21873/anticanres.14389
Abstract
Background/aim: There is a need to diagnose early bladder cancer by non-invasive tests. This study aimed to explore the clinical value of three non-invasive methods, UBC Rapid, ultrasound (US), and urine cytology, separately and in combination, for the primary diagnosis and surveillance of bladder-cancer.

Patients and methods: Urine samples were obtained from 106 patients who presented with symptoms of bladder cancer and patients followed-up after transurethral resection of bladder tumors (TURB). Each patient underwent US, cystoscopy, cytology and UBC Rapid test. The sensitivity and specificity of all methods and combinations were calculated and related to cystoscopy and biopsy.

Results: Voided urine samples assayed with UBC Rapid and cytology yielded a sensitivity and specificity of 58.3% and 75.9%, and 57.1% and 98.0%, respectively and for US 76.2% and 98.1%. The combination of all three methods resulted in a sensitivity and specificity of 95.8% and 67.3%, and the combination of UBC Rapid and US, gave a sensitivity of 91.3%, and a specificity of 72.2%, The combination of UBC Rapid and cytology yielded a sensitivity and specificity of 84.6% and 71.2%.

Conclusion: Combined use of UBC Rapid, US and cytology improved the sensitivity of bladder cancer detection.

Keywords: Bladder cancer; UBC Rapid; tumor markers.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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50
Review Anticancer Res
. 2020 Jun;40(6):3453-3457. doi: 10.21873/anticanres.14331.
Occurrence of Glioma in Pregnant Patients: An Institutional Case Series and Review of the Literature
Pawan Singh 1, Emmanuel Mantilla 2, Josie Sewell 3, Kimmo J Hatanpaa 4, Edward Pan 5
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PMID: 32487644 DOI: 10.21873/anticanres.14331
Abstract
Background/aim: Gliomas present a uniquely challenging clinical situation in the context of pregnancy, with no standard recommendations. This case series aimed to describe the treatment regimen and outcomes of five pregnant patients with gliomas.

Patients and methods: This is a retrospective study. A patient database from electronic medical records was evaluated to identify pregnant patients with gliomas treated at our institution between 2008-2018.

Results: Five study patients who were pregnant with gliomas were identified. Of these, 4 were diagnosed during pregnancy, while 1 was diagnosed prior to her pregnancy. One patient had grade 2 astrocytoma, 1 had grade 3 anaplastic astrocytoma, and 3 had grade 4 glioblastomas (GBM). All patients received surgery, and one patient received radiation therapy without concurrent chemotherapy during her pregnancy. All delivered healthy babies. Three of the 5 patients remain alive, and 2 of the 5 were progression-free at the last follow-up.

Conclusion: Treatment plans must be specifically tailored to the individual patient based on the glioma grade, the mother's desire to continue the pregnancy, and the risks of delaying treatment until after pregnancy. Additional studies need to be performed to definitively establish uniform guidelines for the treatment of pregnant patients with glioma.

Keywords: IDH mutated; Pregnancy; glioma; radiation.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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51
Anticancer Res
. 2020 Jul;40(7):4075-4080. doi: 10.21873/anticanres.14405.
Retzius-sparing Robotic-assisted Radical Prostatectomy Facilitates Early Continence Regardless of Neurovascular Bundle Sparing
Po-Chi Liao 1, Sheng-Chun Hung 1 2, Ju-Chuan Hu 1, Kun-Yuan Chiu 3 4
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PMID: 32620655 DOI: 10.21873/anticanres.14405
Abstract
Background/aim: Retzius-sparing robotic-assisted radical prostatectomy (RARP) has had better results in early continence rate and comparable oncological safety compared to the retropubic approach. However, the role the neurovascular bundle (NVB) sparing plays in the rate of early continence after catheter removal remains unclear. In this study, we sought to compare the early continence rate between Retzius-sparing RARP and the retropubic approach RARP to assess whether NVB sparing affects the continence rate in patients with prostate cancer.

Patients and methods: This was a retrospective case series of 133 patients who underwent RARP from 2004 to 2017. 92 patients underwent retropubic RARP and 41 patents underwent Retzius-sparing RARP. All procedures were performed by a single surgical team in a single institution. Baseline patient characteristics were recorded and analyzed. Continence results and oncological outcomes were compared between the two groups. Continence outcome of Retzius-sparing RARP with NVB sparing was also analyzed.

Results: No differences in age, prostate size, pathology T stage, PSA, and NVB sparing were found between the two groups. The oncological results including surgical margin and biochemical recurrence rate at one year showed no difference between the two groups. With respect to immediate continence results, the Retzius-sparing group showed a better continence result compared to the retropubic approach (75.6% vs. 26.1 %, respectively, p<0.001) after catheter removal. However, there was no difference between the two groups after 6 months. Furthermore, no significant difference in immediate continence result was found in the Retzius-sparing group between patients with NVB sparing (75 %) and those without (75 % vs. 78%, respectively, p=1.00).

Conclusion: Retzius-sparing RARP may provide a better immediate continent result compared to retropubic RARP. In Retzius-sparing RARP, NVB sparing did not enhance immediate continence after the operation.

Keywords: Retzius-sparing approach; Robotic-assisted radical prostatectomy; continence; retropubic approach.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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52
Anticancer Res
. 2020 Jun;40(6):3535-3542. doi: 10.21873/anticanres.14342.
Inflammation Caused by Surgical Stress Has a Negative Impact on the Long-term Survival Outcomes in Patients With Colorectal Cancer
Masatsune Shibutani 1, Shigetomi Nakao 2, Kiyoshi Maeda 2, Hisashi Nagahara 2, Tatsunari Fukuoka 2, Yasuhito Iseki 2, Kosei Hirakawa 2, Masaichi Ohira 2
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PMID: 32487655 DOI: 10.21873/anticanres.14342
Abstract
Background/aim: Inflammation is known to promote the progression of cancer, and there is increasing evidence that inflammation caused by the antitumor response of the host and post-operative infectious complications worsens the prognosis for colorectal cancer. However, the impact of post-operative inflammation caused by surgical stress on long-term survival is unclear.

Patients and methods: A total of 274 patients who underwent curative operation for stage II/III colorectal cancer were enrolled and assessed for the serum C-reactive protein (CRP) levels on postoperative day (POD) 1 and 7 and postoperative infectious complications.

Results: The high POD-1 CRP group had a significantly lower relapse-free and overall survival rate than the low POD-1 CRP group. Similarly, the high POD-7 CRP group had a significantly lower relapse-free and overall survival rate than the low POD-7 CRP group. Sub-group analysis limited to patients without postoperative infectious complications indicated that the high POD-7 CRP group tended to have a lower relapse-free survival rate and a significantly lower overall survival rate than the low POD-7 CRP group.

Conclusion: Inflammation caused by postoperative infectious complications and by surgical stress worsens long-term survival outcomes after a curative operation for colorectal cancer.

Keywords: Inflammation; colorectal cancer; surgical stress; survival.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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53
Anticancer Res
. 2020 Jul;40(7):4183-4190. doi: 10.21873/anticanres.14418.
A Single Institution's Experience of Definitive Radiotherapy Using Volumetric-modulated Arc Therapy for Hypopharyngeal Cancers
Katsumaro Kubo 1, Yuji Murakami 2, Nobuki Imano 2, Yuki Takeuchi 2, Ikuno Nishibuchi 2, Tomoki Kimura 2, Daisuke Kawahara 2, Kentaro Miki 2, Akito Saito 2, Takeo Nakashima 2, Takao Hamamoto 3, Tsutomu Ueda 3, Sachio Takeno 3, Yasushi Nagata 2
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PMID: 32620668 DOI: 10.21873/anticanres.14418
Abstract
Background/aim: The present study aimed to analyze the treatment outcome after definitive radiotherapy (dRT) using volumetric-modulated arc therapy (VMAT) in patients with hypopharyngeal cancer (HPC), including an examination of late toxicities.

Patients and methods: A total of 62 patients with HPC, who underwent dRT using VMAT, were analyzed. Overall survival (OS), progression-free survival (PFS), laryngoesophageal dysfunction-free survival (LEDFS), and locoregional control (LRC) were calculated.

Results: The median follow-up period was 49 months. The 3- and 5-year OS, PFS, LEDFS, and LRC rates were 77% and 60%, 61% and 56%, 66% and 53%, and both 79%, respectively. Regarding late toxicities, 11 (17.7%) patients developed grade ≥2 late toxicity. Grade 3 dysphagia was observed in 4 (6.5%) patients, and grade 2 xerostomia in 6 (9.7%).

Conclusion: VMAT was an effective treatment for HPC, with a low incidence of late toxicities.

Keywords: Hypopharyngeal cancer; laryngoesophageal dysfunction-free survival; volumetric-modulated arc therapy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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54
Anticancer Res
. 2020 Jul;40(7):3707-3712. doi: 10.21873/anticanres.14359.
The Contribution of Interleukin-12A Genotypes to Oral Cancer Risk in Taiwanese
Ching-Hao Li 1, Liang-Chun Shih 1 2 3, Che-Lun Hsu 3, Hsu-Tung Lee 4 5, Yun-Chi Wang 1 2, Wen-Shin Chang 1 2, Chia-Wen Tsai 6 2, Chi-Yuan Li 6, DA-Tian Bau 6 2 7
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PMID: 32620609 DOI: 10.21873/anticanres.14359
Abstract
Background/aim: Oral cancer incidence is highest worldwide in Taiwan, and practical markers for personalized therapeutic strategies such as immunotherapies, is lacking. Interleukin-12 (IL12) is a cytokine that is reported to exhibit potent tumoricidal effects, however, its genotypic contribution to oral cancer is still largely unknown. We aimed to examine whether IL12A rs568408 and rs2243115 genotypes are associated with oral cancer risk in Taiwan.

Materials and methods: Genotypic characteristics of IL12A were determined among 958 oral cancer cases and age- and gender-matched individuals via typical polymerase chain reaction-restriction fragment length polymorphism methodology.

Results: The variant genotypes of IL12A rs568408 and rs2243115 were not found to be significantly associated with elevated oral cancer risk (all p>0.05). Moreover, there was no interaction between IL12A genotypes and personal smoking, alcohol drinking and betel quid chewing behaviors (all p>0.05).

Conclusion: IL12A rs568408 and rs2243115 genotypes may not serve as good predictors for oral cancer risk.

Keywords: Alcohol drinking; Taiwan; betel quid; genotype; interleukin-12A; oral cancer; polymorphism; smoking.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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55
Review Anticancer Res
. 2020 Jul;40(7):3651-3658. doi: 10.21873/anticanres.14354.
Minimizing Fertility-sparing Treatment for Low Volume Early Stage Cervical Cancer; Is Less the (R)Evolution?
Charalampos Theofanakis 1, Dimitrios Haidopoulos 2, Nikolaos Thomakos 2, Alexandros Rodolakis 2, Christina Fotopoulou 3
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PMID: 32620604 DOI: 10.21873/anticanres.14354
Abstract
Background/aim: The aim of this study was to conduct a review on less radical fertility-sparing surgical treatment for early-stage cervical cancer.

Materials and methods: We conducted a Medline search from 2014 to 2018 regarding less radical fertility-sparing techniques, such as simple trachelectomy or cervical conization, with pelvic lymphadenectomy. We also assessed the impact of the removal of the parametrium on the obstetric and oncologic outcome, in women who desire to preserve their fertility.

Results: We analyzed studies about cervical conization and simple trachelectomy, together with pelvic lymphadenectomy in early-stage cervical cancer. We also assessed the importance of parametrial involvement in reducing morbidity, without jeopardizing the oncologic outcome of these patients. Studies demonstrate that in tumors ≤2 cm, without lymphovascular Space Invasion and without evidence of parametrial involvement, a less radical fertility-sparing surgical approach could increase pregnancy rates and have a positive effect on the quality of life of these patients.

Conclusion: Standard fertility-sparing treatment for early-stage cervical cancer is still radical trachelectomy with pelvic lymphadenectomy. However, studies suggest that the omission of parametrectomy is a feasible and safe option. Simple trachelectomy or cervical conization, both combined with pelvic lymphadenectomy are acceptable approaches in a selected group of patients with early-stage cervical cancer.

Keywords: Cervical cancer; conization; parametrial involvement; pelvic lymphadenectomy; review; simple trachelectomy; small volume.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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56
Anticancer Res
. 2020 Jun;40(6):3155-3161. doi: 10.21873/anticanres.14297.
Sirtuin 1 Activation Suppresses the Growth of T-lymphoblastic Leukemia Cells by Inhibiting NOTCH and NF-κB Pathways
Salwa M Okasha 1, Mai Itoh 1, Shuji Tohda 2
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PMID: 32487610 DOI: 10.21873/anticanres.14297
Abstract
Background/aim: The deacetylase sirtuin1 (SIRT1) inhibits tumor suppressor p53 and may promote tumorigenesis; however, SIRT1 effects on leukemia cells are controversial. The aim of this study was to clarify the activity of SIRT1 in leukemia cells.

Materials and methods: The effects of SIRT1 inhibition or activation and SIRT1 knockdown or overexpression were examined in two T cell acute lymphoblastic leukemia (T-ALL) cell lines carrying NOTCH1 mutations and three acute myeloid leukemia (AML) cell lines.

Results: The growth of T-ALL cells was promoted by SIRT1 inhibition and SIRT1 knockdown but was reduced by SIRT1 activation and overexpression; however, no effects were observed in AML cells. SIRT1 activation decreased NOTCH, NF-κB, and mTOR signaling and inhibited p53, suggesting that the possible mechanisms of T-ALL growth suppression by SIRT1 are independent of p53.

Conclusion: SIRT1 activators acting through the down-regulation of NOTCH, NF-κB, and mTOR pathways can be novel targeted drugs for NOTCH1-mutated T-ALLs.

Keywords: NF-κB; NOTCH; Sirtuin1; leukemia; p53.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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57
Anticancer Res
. 2020 Jul;40(7):4137-4145. doi: 10.21873/anticanres.14413.
Coprevalence and Incidence of Lung Cancer in Patients Screened for Abdominal Aortic Aneurysm
Anna Hohneck 1 2, Tetyana Shchetynska-Marinova 3, Gerhard Ruemenapf 4, Margarita Pancheva 3, Ralf Hofheinz 5, Judit Boda-Heggemann 6, Elena Sperk 6, Philipp Riffel 7, Julia Michels 3, Martin Borggrefe 3 2, Ibrahim Akin 3 2, Martin Sigl 3
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PMID: 32620663 DOI: 10.21873/anticanres.14413
Abstract
Background/aim: Lung diseases are common in patients with abdominal aortic aneurysms (AAA). This study evaluates the prevalence of lung cancer (LC) in high-risk patients screened for AAA.

Patients and methods: Six hundred and one male patients (≥65 years of age, cardiovascular high-risk profile) were enrolled and followed prospectively over a median of 16.5 months.

Results: In 29 patients (4.8%) LC and in another 50 patients (8.3%) AAA were found. The prevalence of LC among patients with AAA was even higher (9 of 50, 18.0%). Twenty-one patients had an initial diagnosis of LC, with an incidence of 12.0% (6 of 50) in patients with AAA. During follow-up, 14 of 70 patients with AAA and/ or LC (20.0%) deceased. The highest mortality was found in patients with LC only (8 of 20, 40.0%), followed by patients with both AAA and LC (3 of 9, 33.3%), while patients with AAA only had the lowest mortality rate (3 of 41, 7.3%).

Conclusion: In patients with a high cardiovascular risk profile, a high prevalence of both AAA and LC were found, whereby the prognosis is largely determined by the LC. Therefore, LC is of particular importance in the setting of screening and surveillance of AAA.

Keywords: Abdominal aortic aneurysm; high cardiovascular risk profile; lung cancer; screening.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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58
Review Anticancer Res
. 2020 Jun;40(6):3013-3030. doi: 10.21873/anticanres.14282.
Second-line Treatment in Advanced Biliary Tract Cancer: Today and Tomorrow
Alessandro Rizzo 1, Angela Dalia Ricci 2, Nastassja Tober 2, Maria Concetta Nigro 2, Mirta Mosca 2, Andrea Palloni 2, Francesca Abbati 2, Giorgio Frega 2, Stefania DE Lorenzo 2, Simona Tavolari 2, Giovanni Brandi 2
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PMID: 32487595 DOI: 10.21873/anticanres.14282
Abstract
Biliary tract cancer (BTC) patients usually have poor prognosis. Whereas combination chemotherapy has been shown to improve survival in the frontline setting, second-line treatment is subject to a lot of debate in the scientific community. Recent data of the ABC-06 trial has provided slight evidence for the use of second-line chemotherapy after progression on cisplatin plus gemcitabine combination. In this study, mFOLFOX plus active symptom control (ASC) improved overall survival (OS) after progression on cisplatin-gemcitabine combination compared with ASC alone, with an increase in 6- and 12-month OS rate. Although genomic studies have paved the way for a new age in cancer management, the "Precision Medicine Era" in BTC is still limited to intrahepatic cholangiocarcinoma and primarily focused on isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) targeted therapies. We herein review recent published data regarding the use of second-line treatment after failure of standard first-line therapies in BTC patients, with a particular focus on ongoing active and recruiting clinical trials.

Keywords: Biliary tract cancer; chemotherapy; cholangiocarcinoma; review; second-line; targeted therapy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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59
Anticancer Res
. 2020 Jun;40(6):3169-3190. doi: 10.21873/anticanres.14299.
Investigation of the Involvement of Parkin in Parkinson's Disease and Cancer by Monitoring the Changes in SH-SY5Y Cells at the Nuclear Proteome Level
Abula Ayimugu 1, Mehmet Sarihan 2, Murat Kasap 3, Gurler Akpinar 2
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PMID: 32487612 DOI: 10.21873/anticanres.14299
Abstract
Background/aim: During the last two decades, Parkinson's disease (PD)-associated genes have been associated with cancer; however, a shared pathogenic mechanism has yet to be discovered. Parkin, an E3 ubiquitin ligase that is involved in early-onset Parkinson's disease, has also been reported to exert tumor suppressor activity. However, the details about the role of Parkin in cancer remain unknown. The present study aimed at identifying differentially regulated nuclear proteins and nuclear phosphoproteins whose levels were affected by Parkin expression.

Materials and methods: SHS-SY5Y cells expressing either wild-type Parkin or its mutant under tetracycline control were used in this study; cells not expressing Parkin served as control. Nuclear proteins were enriched from Parkin-expressing and control cells to perform a comparative proteomics study using two-dimensional gel electrophoresis (2D) coupled to matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF/TOF) mass spectrometry analysis. Changes in phosphoproteome and nuclear phosphoproteome were also studied by staining the 2D gels with ProQ diamond phosphoprotein stain. The identified proteins were subjected to bioinformatics analysis to elucidate the reactomes and relevant pathways.

Results: Six nuclear proteins, namely NCL, DDIT3, PARP1, HMGB1, TCTP and TPI were shown to be differentially regulated in cells expressing Parkin protein. Regulations in phosphorylation levels of ENPL, PRDX4, ECHM, ALDOA SET, DHSA, RCC1 and DULRD were also detected. Bioinformatics analysis of differentially regulated proteins highlighted the involvement of Parkin in DNA repair.

Conclusion: Several nuclear protein candidates whose expression or phosphorylation levels were altered in cells expressing Parkin. Bioinformatics analysis of these proteins indicated that the nuclear form of Parkin may play a significant role in DNA repair and contribute to prevention of tumorogenesis via maintaining DNA integrity.

Keywords: 2D gel electrophoresis; Parkin; neuroblastoma cancer; nuclear proteome; phosphoproteome.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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60
Anticancer Res
. 2020 Jun;40(6):3505-3512. doi: 10.21873/anticanres.14338.
Clinical Significance of Nucleoli Cytomorphology Assessment in Patients With Uveal Melanoma
Tomasz Berus 1, Anna Markiewicz 2, Przemysław Biecek 3, Jolanta Orłowska-Heitzman 4, Agnieszka Hałoń 5, Bożena Romanowska-Dixon 2, Piotr Donizy 5
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PMID: 32487651 DOI: 10.21873/anticanres.14338
Abstract
Aim: To assess the prognostic significance of nucleolar morphological parameters in a large cohort of patients with uveal melanoma.

Patients and methods: The presence, size and number of nucleoli of cancer cells were assessed in haematoxylin and eosin (HE)-stained slides of 164 formalin-fixed paraffin-embedded primary uveal melanoma tissue specimens. The results were correlated with clinicopathological features and patient survival.

Results: The presence of macronucleoli and multiple nucleoli significantly correlated with the epithelioid type of uveal melanoma, high mitotic rate, and marked pleomorphism. There was a positive correlation between the presence of macronucleoli as well as the number of nucleoli and the largest tumour basal diameter. The increased nucleolus count in tumour cells positively correlated with primary tumour (pT) staging. The presence of both prominent and multiple nucleoli was associated with significantly reduced overall and disease-free survival.

Conclusion: Histological assessment of nucleolar morphology in routine HE staining would be a helpful low-cost method to obtain reliable prognostic information.

Keywords: H&E staining; Nucleolus; prognosis; uveal melanoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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61
Anticancer Res
. 2020 Jul;40(7):4115-4121. doi: 10.21873/anticanres.14410.
Magnetic Resonance and Ultrasound Fusion Imaging to Characterise Ovarian Masses: A Feasibility Study
Adrien Crestani 1, Claire Theodore 2, Jean-Marc Levaillant 2, Isabelle Thomassin-Naggara 3 4, Dounia Skalli 2, GrÉgoire Miaihle 2, Yohann Dabi 2, Bassam Haddad 2, Cyril Touboul 2 5
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PMID: 32620660 DOI: 10.21873/anticanres.14410
Abstract
Background/aim: Magnetic resonance (MR) and ultrasound (US) fusion imaging (MR-US fusion) is already used to guide prostate biopsies and has been proven accurate for diagnosing cervical cancer. In this study, we aimed to evaluate the feasibility and performance of MR-US fusion for characterizing adnexal masses.

Patients and methods: A retrospective study was conducted between 2014 and 2018 including women referred to our Gynaecological Oncology Department for characterization of an adnexal mass (n=106). Performance of MR-US fusion was evaluated in a subgroup of patients who underwent surgery (n=26). Two readers, blinded to final histology, performed and rated US findings according to the International Ovarian Tumor Analysis simple rules score, MR according to Ovarian-Adnexal Reporting Data System Magnetic score, and MR-US fusion through a tailored score. The reference outcome was the final pathology.

Results: MR-US fusion had a sensitivity of 100% (95%CI=80-100), specificity of 89% (95%CI=52-99), positive likelihood ratio of 9 (95%CI=1.4-57), and accuracy of 96% (95%CI=80-99).

Conclusion: MR-US fusion is feasible for characterizing adnexal masses to predict ovarian cancer.

Keywords: IOTA simple rules; MR-US fusion; Magnetic resonance; O-RADS MRI scoring system; adnexal masses; ovarian cancer; ultrasound.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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62
Anticancer Res
. 2020 Jul;40(7):3801-3809. doi: 10.21873/anticanres.14369.
Papillary Thyroid Cancer Tumor Spheres Cultured by Passaging Without Sorting Exhibit Cancer Stemness
Jun-Min Cho 1, Hyun Jeong Lee 1, Jai Hyun Chung 1, Woo Young Kim 2, Myoung Hee Kang 3, Kee Soo Ha 4, Sang Uk Woo 1, Jae Bok Lee 1
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PMID: 32620619 DOI: 10.21873/anticanres.14369
Abstract
Aim: Cancer stem-like cell (CSC) markers and the role of CSCs derived from papillary thyroid carcinoma (PTC) in pathogenesis are unclear. This study aimed to investigate CSC properties using tumor spheres from passaged PTC cells but without sorting CSCs.

Materials and methods: To identify the properties of CSCs derived from PTC, the expression of SRY-box transcription factor 2(SOX2), octamer-binding transcription factor 4 (OCT4), Nanog homeobox (NANOG), thyroglobulin (TG), thyroid-stimulating hormone receptor (TSHR), E-cadherin, YES-associated protein 1 (YAP1), and signal transducer and activator of transcription 3 (STAT3) was investigated in tumor spheres serially passaged without sorting CSCs.

Results: The cultured tumor spheres had cancer stemness; high expression of OCT4, SOX2, NANOG, and YAP1; low expression of E-cadherin; and varied expression of TG, TSHR, and STAT3. PTC tumor spheres transfected with small interfering RNA targeting YAP1 had fewer CSC properties than the non-transfected tumor spheres did.

Conclusion: Tumor spheres derived from PTC cells by passaging without sorting CSCs have more stem-like cell properties, and less differentiation potential. Thus, this simple and cost-effective method can be used for the enrichment of PTC stemness for employment in cell-based models, reducing the need for use of animal models.

Keywords: Thyroid cancer; papillary; tumor stem cells.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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63
Anticancer Res
. 2020 Jul;40(7):4017-4022. doi: 10.21873/anticanres.14396.
Skin Architecture, Kidney Transplantation, and Their Relationship to Basal and Squamous Cell Carcinomas
Anna Capasso 1, Giancarlo Bilancio 2, Michael W Lee 1 3, Giuseppe Palladino 2, Rosa Maria Pollastro 4, Mariadelina Simeoni 4, Carmine Secondulfo 5, Andrea Ronchi 6, Alessandro Caputo 5, Renato Franco 6, Pio Zeppa 5, Giovambattista Capasso 4 7, Davide Viggiano 8 7
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PMID: 32620646 DOI: 10.21873/anticanres.14396
Abstract
Background/aim: Squamous cell carcinoma (SCC) is highly prevalent in kidney transplant patients (KT). It is characterized by the presence of an inflammatory infiltrate. In this study, we examined the presence of similar infiltrates in intact skin, which could be regarded as a precancerous step.

Patients and methods: We retrospectively analyzed skin biopsies of 19 non-transplanted patients with a diagnosis of SCC or basal cell carcinoma (BCC) and 17 KT with either SCC or BCC.

Results: KT showed increased inflammatory infiltrate in the subepithelial region, compared to non-transplanted patients. The density of basal cell nuclei was also different among the four groups with an interaction effect between tumor type and transplantation. The extent of inflammatory infiltrates did not correlate with the eGFR and proteinuria.

Conclusion: KT with a non-melanoma skin cancer show increased intact skin inflammatory infiltrate and alterations in the density of the basal cell layer compared to non-transplanted patients.

Keywords: Immunosuppression; kidney transplantation; onconephrology; skin.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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64
Anticancer Res
. 2020 Jul;40(7):3883-3888. doi: 10.21873/anticanres.14378.
Phase 1b Study of IGF-Methotrexate Conjugate in the Treatment of High-grade Myelodysplastic Syndromes
Hassan B Alkhateeb 1, Mrinal M Patnaik 1, Aref Al-Kali 1, Darci L Zblewski 1, Samantha Wallerich 1, Hugh McTavish 2, Arkadiusz Z Dudek 3 4
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PMID: 32620628 DOI: 10.21873/anticanres.14378
Abstract
Background/aim: The insulin-like growth factor type 1 receptor (IGF-1R) is overexpressed in myelodysplastic syndrome (MDS) cells, and 765IGF-Methotrexate (IGF-MTX) is a conjugate of methotrexate and a variant of insulin-like growth factor-1 (IGF-1) designed to selectively target cancer cells through binding to IGF-1R. The aim of this study was to determine whether IGF-MTX would be effective to treat MDS.

Patients and methods: In this phase I clinical trial, two patients with high grade MDS or oligoblastic acute myeloid leukemia (O-AML) that had failed standard therapy were treated with IGF-MTX.

Results: No dose-limiting toxicity was observed. Both patients had stable or improved cell counts and CD34+ myelodysplastic cell counts and exceeded their life expectancy (both alive at 1.9 years despite a life expectancy of less than 6 months). Bone marrow blast counts decreased from 22% to 5% in one patient, and from 17% to 16% in the other.

Conclusion: In conclusion, IGF-MTX at 0.20 μM equivalents per kg was well tolerated, caused no cytopenia, and produced stable disease and extension of life.

Keywords: IGF-1R; IGF-MTX; chronic myelomonocytic leukemia; myelodysplastic syndrome; oligoblastic acute myeloid leukemia; phase 1 study.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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65
Anticancer Res
. 2020 Jul;40(7):3759-3764. doi: 10.21873/anticanres.14365.
Chromosome 17 In Situ Hybridization Grid-based Analysis in Oral Squamous Cell Carcinoma
Aristeidis Chrysovergis 1, Vasileios Papanikolaou 1, Nicholas Mastronikolis 2, Evangelos Tsiambas 3, Vasileios Ragos 4, Dimitrios Peschos 5, Christos Riziotis 6 7, Chara Stavraka 8, Dimitrios Roukas 9, Efthymios Kyrodimos 1
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PMID: 32620615 DOI: 10.21873/anticanres.14365
Abstract
Background/aim: Oral squamous cell carcinoma (OSCC) is an aggressive malignancy due to its increased ability for local metastases and distant lymph node metastases. Extensive cytogenetic analyses have detected chromosome instability (CI) patterns in OSCC including gross chromosome numerical alterations, such as polysomy and sporadically monosomy that negatively affect the biological behaviour of the malignancy. Our aim was to investigate the frequency and impact of chromosome 17 (Chr 17) numerical imbalances in OSCC.

Materials and methods: Fifty (n=50) formalin-fixed, paraffin-embedded primary OSCCs tissue sections were used. Chromogenic in situ hybridization (CISH) was implemented for detecting Chr 17 centromeric numerical imbalances. Concerning the screening process in CISH slides, a novel real-time reference and calibration grid platform was implemented.

Results: Chr 17 multiple copies were observed in 12/50 (24%) of the examined cases. Polysomy was observed in 10/50 (20%) tissue sections, monosomy in 2/50 (4%), whereas the rest of them demonstrated a normal, diploid pattern (38/50-76%). Chr 17 numerical differences were associated with the grade of differentiation of the examined tumors (p=0.001).

Conclusion: Chr 17 numerical imbalances (polysomy predominantly and monosomy) are observed in sub-groups of OSCCs correlating with a progressive dedifferentiation of malignant tissues. The proposed grid-based platform on CISH slides provides a novel, fast and accurate screening-mapping mechanism for detecting chromosome numerical aberrations.

Keywords: Carcinoma; chromosome; grid; microscopy; oral; polysomy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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66
Anticancer Res
. 2020 Jul;40(7):3839-3846. doi: 10.21873/anticanres.14373.
Novel Prognostic Factor for Uveal Melanoma: Bioinformatics Analysis of Three Independent Cohorts
Suji Choi 1, Mihyang Ha 1, Jung Sub Lee 2, Hye Jin Heo 3, Ga Hyun Kim 3, Sae-Ock Oh 3, Jae Jung Lee 4, Tae Sik Goh 5, Yun Hak Kim 6 7
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PMID: 32620623 DOI: 10.21873/anticanres.14373
Abstract
Background/aim: Because 50% of uveal melanoma metastasize within 10 years of diagnosis, there is urgent need for accurate prognostic factors.

Materials and methods: To identify genes that can act as prognostic factors in uveal melanoma, we performed survival analyses using three independent cohorts. Using log-rank test and univariate cox regression, genes which could stratify the prognosis in all cohorts simultaneously depending on their expression levels were selected as novel biomarkers. Hub genes were obtained by analyzing the interaction and relationship between the selected genes using String and Cytoscape. Additionally, prognostic power was calculated by using C-indices and AUC.

Results: A total of 37 oncogene-like and 14 tumor suppressor-like genes were selected. Protein-protein analysis revealed that NDUFB9, NDUFV2, CYC1 among oncogene-like genes, CTNNB1 among tumor suppressor-like genes were found to be hub genes and core biomarkers in uveal melanoma.

Conclusion: NDUFB9, NDUFV2, CYC1 and CTNNB1 genes may act as prognostic factors in uveal melanoma.

Keywords: Gene Expression Omnibus; The Cancer Genome Atlas; Uveal melanoma; bioinformatics; prognosis.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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67
Anticancer Res
. 2020 Jun;40(6):3315-3323. doi: 10.21873/anticanres.14314.
Efficacy of Adjuvant Combination Therapy With Trastuzumab and Chemotherapy in HER2-positive Early Breast Cancer: A Single Institutional Cohort Study From Clinical Practice
Masahiro Okamoto 1, Wakako Tajiri 1, Hiroki Ueo 1, Takanobu Masuda 1, Hideki Ijichi 1, Chinami Koga 1, Yoshiaki Nakamura 1, Kenichi Taguchi 2, Shinji Ohno 3, Eriko Tokunaga 4
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PMID: 32487627 DOI: 10.21873/anticanres.14314
Abstract
Background/aim: To evaluate the improvement in the prognosis by adjuvant trastuzumab in clinical practice and the risk factors for distant recurrence, we retrospectively investigated the prognosis of HER2-positive early breast cancer in our department before and after the introduction of adjuvant trastuzumab.

Patients and methods: Cohorts A and B included 161 and 182 cases, respectively, who underwent surgery before (2000-2007) and after (2008-2015) the introduction of adjuvant trastuzumab.

Results: The rates of relapse-free and distant metastasis-free survival were significantly better in cohort B than in cohort A. The risk factors of distant recurrence found in cohort A, such as the presence of lymph node metastasis, lymphatic invasion, and a low histological grade, did not increase the risk in cohort B.

Conclusion: Many risk factors seemed to have been negated by adjuvant trastuzumab administration. Therefore, further escalation of adjuvant treatment should be carefully considered.

Keywords: Breast cancer; HER2; trastuzumab.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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68
Anticancer Res
. 2020 Jul;40(7):4131-4135. doi: 10.21873/anticanres.14412.
Pembrolizumab and Radiotherapy for Platinum-refractory Recurrent Uterine Carcinosarcoma With an Abscopal Effect: A Case Report
Mitsutake Yano 1 2 3, Saki Aso 4 2, Miho Sato 4, Yoko Aoyagi 4 2, Harunobu Matsumoto 4 2, Kaei Nasu 2 5
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PMID: 32620662 DOI: 10.21873/anticanres.14412
Abstract
Background: Immune responses due to radiotherapy and immune checkpoint inhibitors potentially have synergistic effects.

Case report: Here, we report a 65-year-old Japanese woman presenting with high-grade endometrial cancer. She was diagnosed with carcinosarcoma, stage IB. A month post-surgery, lung, and mediastinal lymph node metastasis/recurrence was detected. Progressive disease (with high microsatellite instability) with local recurrence and bone metastasis was detected after six chemotherapy cycles with paclitaxel and carboplatin. After combination therapy with pembrolizumab (2 mg/kg, tri-weekly, 10 cycles) and pelvic radiotherapy (30 Gy/10 fractions), enhanced computed tomography revealed a complete response. The patient survived for 14 months with the residual tumour post-relapse. This is the first case of a complete response of recurrent endometrial carcinosarcoma upon combinatorial pembrolizumab and radiotherapy.

Conclusion: Combinatorial immune checkpoint inhibitors and local radiotherapy cause the abscopal effect and may be a promising treatment strategy for advanced or recurrent carcinosarcomas refractory to traditional chemotherapy.

Keywords: Carcinosarcoma; abscopal effect; endometrial neoplasms; microsatellite instability; pembrolizumab; radiotherapy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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69
Anticancer Res
. 2020 Jun;40(6):3513-3517. doi: 10.21873/anticanres.14339.
Pattern of Local Failure and Its Risk Factors of Locally Advanced Non-small Cell Lung Cancer Treated With Concurrent Chemo-radiotherapy
Takanori Abe 1, Nao Kobayashi 2, Tomomi Aoshika 2, Yasuhiro Ryuno 2, Satoshi Saito 2, Mitsunobu Igari 2, Ryuta Hirai 2, Y U Kumazaki 2, Y U Miura 3, Kyoichi Kaira 3, Hiroshi Kagamu 3, Shin-Ei Noda 2, Shingo Kato 2
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PMID: 32487652 DOI: 10.21873/anticanres.14339
Abstract
Background/aim: The treatment outcome of locally advanced non-small cell lung cancer (LA-NSCLC) has been improved over the past years but local failure is still common for these patients. The purpose of this study is to analyze the pattern of local failure and its risk factor of concurrent chemo-radiotherapy (CCRT) for locally advanced LA-NSCLC.

Patients and methods: We evaluated 77 patients treated with CCRT for LA-NSCLC from July 2007 to December 2017 at our institution. Most of the patients were treated with 60 Gy in 30 fractions of radiotherapy and concurrent chemotherapy. The median follow-up time was 26 months.

Results: Among the 77 patients, 50 developed progressive disease during follow-up, including 14 with only local recurrence (LR), 10 with only distant metastasis and 26 with both. Of the 14 patients with only LR, 12 had primary tumor recurrence and 2 had recurrence in lymph nodes. A primary tumor volume of 50 cm3 was identified as the optimal cut-off value that was significantly correlated with primary tumor recurrence and overall survival.

Conclusion: Primary tumor recurrence without lymph node and distant metastasis was observed in 12 patients (16%). Primary tumor volume of 50 cm3 was the optimal cut-off value for the prediction of primary tumor recurrence.

Keywords: Local failure; concurrent chemo-radiotherapy; locally advanced non-small cell lung cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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70
Comparative Study Anticancer Res
. 2020 Jun;40(6):3401-3410. doi: 10.21873/anticanres.14324.
Hydro-MDCT for Gastric Adenocarcinoma Staging. A Comparative Study With Surgical and Histopathological Findings for Selecting Patients for Echo-endoscopy
Marco DI Girolamo 1, Francesco Carbonetti 2, Paolo Bonome 2, Andrea Grossi 2, Federica Mazzuca 3, Luigi Masoni 4
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PMID: 32487637 DOI: 10.21873/anticanres.14324
Abstract
Background/aim: In local staging of gastric adenocarcinoma CT is the modality of choice. Less frequently used in a few selected patients is echo-endoscopy. Aim of this study was to evaluate the accuracy of hydro-multidetector-computed tomography (hydro-MDCT) in the evaluation of gastric adenocarcinomas with subsequent surgical and histopathological correlation to select cases for echo-endoscopy.

Patients and methods: A total of 65 patients with gastric adenocarcinomas, diagnosed by endoscopy and biopsy, underwent contrast-enhanced hydro-MDCT with subsequent tumor, nodes, metastases (TNM) classification. The distension of the gastric lumen was obtained after the oral administration of 500 ml of water.

Results: Hydro-MDCT always detected gastric cancer and in 49/65 patients the assessment of T-parameter was identical to the histopathological results (accuracy: 75%). We found overstaging in 12 and understaging in 4 cases. N-parameter with MDCT was in agreement with histo-pathology in 69%of patients; in metastatic disease hydro-MDCT had an accuracy of 99%. Hydro-MDCT has proven to be a reliable diagnostic technique in evaluating gastric cancer T3-T4 stages in comparison to T1 and T2: in defining T2-stage we found the highest number of errors (37%).

Conclusion: Hydro-MDCT is a reliable technique in the preoperative staging of gastric adenocarcinoma. Echo-endoscopy could be particularly useful in doubtful cases to evaluate the muscularis propria infiltration (T2 vs. T3) and characterize the peri-gastric lymph nodes.

Keywords: Stomach neoplasms; contrast media; echo-endoscopy; multidetector computed tomography; neoplasm staging.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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71
Review Anticancer Res
. 2020 Jun;40(6):3031-3037. doi: 10.21873/anticanres.14283.
Is Perineural Invasion a Novel Prognostic Factor Useful to Tailor Adjuvant Treatment in Patients Treated With Primary Surgery for Cervical and Vulvar Carcinoma?
Angiolo Gadducci 1, Sabina Pistolesi 2, Stefania Cosio 3, Antonio Giuseppe Naccarato 2
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PMID: 32487596 DOI: 10.21873/anticanres.14283
Abstract
Perineural invasion (PNI) is detected in 7.0-35.1% of cervical carcinomas. This histological finding correlates with cervical invasion, lymph-vascular space invasion (LVSI), tumor size, positive resection margins, parametrial invasion, node metastases and advanced stage. Some authors have reported that PNI has no prognostic relevance, others have found that PNI is related to disease-free survival or overall survival (OS) at univariate analysis, and others have observed that it is an independent poor prognostic factor for OS. The evaluation of PNI status should be included in the decision-making process for planning adjuvant treatment. PNI has been found in 7.6-52.4% of vulvar carcinomas. This feature, which is strongly associated with depth of invasion, LVSI, tumor size, advanced stage and nodal involvement, is an independent prognostic variable for the risk of recurrence and death in most series. PNI should be evaluated routinely in histopathology reports of vulvar carcinoma and could help clinicians to tailor adjuvant treatment.

Keywords: Perineural invasion; adjuvant therapy; cervical cancer; review; surgery; vulvar cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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72
Anticancer Res
. 2020 Jul;40(7):3873-3882. doi: 10.21873/anticanres.14377.
Pathological Validity of Using Near-infrared Fluorescence Imaging for Securing Surgical Margins During Liver Resection
Yoshihiko Tashiro 1, Takeshi Aoki 2, Takahito Hirai 1, Tomotake Koizumi 1, Doaa A Mansou 1 3, Tomokazu Kusano 1, Kazuhiro Matsuda 1, Kosuke Yamada 1, Koji Nogaki 1, Tomoki Hakozaki 1, Yusuke Wada 1, Hideki Shibata 1, Kodai Tomioka 1, Tatsuya Yamazaki 1, Kazuhiko Saito 1, Akira Fujimori 1, Yuta Enami 1, Robert M Hoffman 4 5, Masahiko Murakami 1
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PMID: 32620627 DOI: 10.21873/anticanres.14377
Abstract
Background/aim: This study investigated the use of near-infrared fluorescent imaging for securing safe margins during liver resection.

Patients and methods: This study included 125 patients who underwent liver tumor resection in 2014-2018. Indocyanine green testing was performed 2-14 days before surgery. Histopathological specimens of hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) were evaluated using fluorescent microscopy.

Results: Fluorescence microscopy identified signals in 26/53 (49.0%) and 36/72 (50%) cases of HCC and CRLM, respectively. HCC demonstrated total, partial, rim, and combined fluorescence patterns; CRLM uniformly demonstrated rim fluorescence. Although rim fluorescence was seen in both HCC and CRLM, no malignancy was confirmed pathologically in the peritumoral area demonstrating fluorescence. The median widths of fluorescence from the tumor edge in HCC and CRLM were 1227.5 μm and 1608 μm, respectively, with no significant difference.

Conclusion: Near-infrared fluorescent imaging can reliably detect safe surgical margins intraoperatively during liver resection.

Keywords: ICG fluorescence-guided surgery; Surgical margin; fluorescence pattern; fluorescence width; laparoscopic liver resection.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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73
Review Anticancer Res
. 2020 Jul;40(7):3645-3649. doi: 10.21873/anticanres.14353.
FGD3 Gene as a New Prognostic Factor in Breast Cancer
Tommaso Susini 1, Irene Renda 2
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PMID: 32620603 DOI: 10.21873/anticanres.14353
Abstract
Despite the establishment of the traditional prognostic factors for breast cancer, patients belonging to the same histological and molecular subgroup often present quite different outcomes. Recently, the introduction of gene expression profiling, assessed by RT-qPCR and microarray DNA analysis, offered a view of the whole cell gene activity and the ability to identify new transcripts that are associated with outcome. This review aimed to gather all recent trials about new breast cancer prognostic factors, focusing on the most promising one, the FGD3 gene, and to discuss the real feasibility of a molecular approach in everyday clinical practice. In conclusion, all literature concerning this subject indicated that expression of the FGD3 gene is a strong marker of good prognosis in breast cancer patients and that immunohistochemistry represents an efficient, inexpensive, reproducible evaluation method, affordable also by small Institutions.

Keywords: Breast cancer; FGD3 gene; precision medicine; prognostic factor; review.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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74
Anticancer Res
. 2020 Jun;40(6):3559-3564. doi: 10.21873/anticanres.14345.
Epithelial-Mesenchymal Transition Status of Circulating Tumor Cells Is Associated With Tumor Relapse in Head and Neck Squamous Cell Carcinoma
Hiroe Tada 1, Hideyuki Takahashi 1, Shota Ida 1, Yurino Nagata 1, Kazuaki Chikamatsu 2
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PMID: 32487658 DOI: 10.21873/anticanres.14345
Abstract
Background/aim: We aimed to elucidate the clinical implication of the epithelial-mesenchymal plasticity of circulating tumor cells (CTCs) in patients with head and neck squamous cell carcinoma (HNSCC).

Patients and methods: CTCs isolated from 44 patients with non-recurrent/metastatic HNSCC and 42 with recurrent/metastatic (R/M) HNSCC were classified into four epithelial-mesenchymal transition (EMT) statuses based on the expression of epithelial (keratin 19) and mesenchymal (vimentin) markers and the relationships between EMT status in CTCs and clinical factors were investigated.

Results: E+M- CTC phenotype was more frequent in patients without recurrence/metastasis (p=0.0468) and was also more frequent in those with a complete response (p=0.0346). The E+M+ phenotype constituted the major proportion of the CTCs detected in patients with R/M HNSCC (p=0.0374).

Conclusion: CTCs may play unique roles at various stages of metastasis through transitioning from epithelial to mesenchymal phenotypes.

Keywords: Epithelial–mesenchymal transition; circulating tumor cell; head and neck squamous cell carcinoma; metastasis; recurrence.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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75
Anticancer Res
. 2020 Jul;40(7):4029-4032. doi: 10.21873/anticanres.14398.
Synchronous Primary Pancreatic Ductal Carcinoma and Colonic Adenocarcinoma Present in a Patient With History of Skin Squamous Cell Carcinoma
Can Cao 1 2, Purvi Parikh 3, Koorosh Moezardalan 4, Archana Anantharaman 5, Ali Azarm 4, Jinping Lai 6
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PMID: 32620648 DOI: 10.21873/anticanres.14398
Abstract
The synchronous diagnosis of two or more primary malignancies in a patient is overall rare. This is a case report of a 70-year-old female with a history of skin squamous cell carcinoma presenting with occult hematochezia. Colonoscopy and biopsy results confirmed a microsatellite stable (MMS) adenocarcinoma in the ascending colon, and subsequent computed tomography (CT) scans identified a 3.2 cm right colonic mass and a 5.0 cm mass in the pancreatic body. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) confirmed the presence of pancreatic ductal adenocarcinoma (PDAC). The patient underwent neo-adjuvant FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin) chemotherapy prior to the simultaneous distal pancreatectomy and right hemicolectomy for both pancreatic and colonic tumors. The pathology diagnoses included moderately differentiated pancreatic ductal carcinoma (PDAC) with histiocyte-like features (tumor stage: ypT3N1M0) and moderately differentiated colonic adenocarcinoma, intestinal type (tumor stage: ypT3N0M0). To the best of our knowledge, this is the first documented case of synchronous primary colonic adenocarcinoma and PDAC in the English literature.

Keywords: Synchronous primary malignancy; chemotherapy; colonic adenocarcinoma; immunohistochemistry; microsatellite stable; pancreatic ductal carcinoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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76
Anticancer Res
. 2020 Jul;40(7):4011-4015. doi: 10.21873/anticanres.14395.
Safety and Efficacy of Gemcitabine, Docetaxel, Capecitabine, Cisplatin as Second-line Therapy for Advanced Pancreatic Cancer After FOLFIRINOX
Jean-David Fumet 1 2 3 4 5, Julie Vincent 1, Leila Bengrine 1, Audrey Hennequin 1, Laura Granconato 1, Remi Palmier 1, FranÇois Ghiringhelli 6 2 3 4 5
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PMID: 32620645 DOI: 10.21873/anticanres.14395
Abstract
Background/aim: The aim of this monocentric study was to evaluate the efficacy and tolerability of a polychemotherapy regimen based on gemcitabine, docetaxel, capecitabine, cisplatin (PDGX) as second-line for advanced pancreatic cancer after FOLFIRINOX.

Patients and methods: Patients received FOLFIRINOX as first-line regimen were retrospectively identified between January 2016 and January 2019. After disease progression or unacceptable toxicity, patients eligible for second-line therapy were treated in our center by PDGX.

Results: During this period, 18 patients received PDGX regimen as second-line therapy. Main grade 3 toxicities were hematologic, which required dose adaptation in 14/18 patients. No toxic death was observed. Median second-line progression-free survival (PFS) and overall survival (OS) were 2,91 and 5,3 months, respectively. Total OS from the initiation of first-line was and 11,9 months.

Conclusion: Second-line PDGX regimen after FOLFIRINOX failure is feasible, with notable toxicity profile and is associated with poor clinical outcomes.

Keywords: Pancreatic cancer; capecitabine; chemotherapy; cisplatin; docetaxel; gemcitabine.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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77
Anticancer Res
. 2020 Jun;40(6):3255-3264. doi: 10.21873/anticanres.14307.
EBV Rta-induced IL-6 Promotes Migration of Bystander Tumor Cells Through IL-6R/JAK/STAT3 Pathway In Vitro
Kuo-Lung Tung 1, Yen-Ting Wu 2, Cheng Liu 1 3, Sheng-Chieh Lin 1, Chin-Han Wu 1, Shih-Yi Wu 2, Yao Chang 4, Yu-Yan Lan 5
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PMID: 32487620 DOI: 10.21873/anticanres.14307
Abstract
Background/aim: Rta, a transactivator of Epstein-Barr virus, is associated with progression of nasopharyngel carcinoma (NPC); however, its mechanism of contribution to the pathogenesis of NPC remains unclear. Interleukin-6 (IL-6), a tumor promoter, is detected in NPC. This in vitro study examined whether and how Rta promotes NPC progression by up-regulating IL-6.

Materials and methods: Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time PCR, ELISA, immunoblotting assays, reporter gene assays, and transwell migration assays were performed.

Results: In NPC cells, Rta up-regulated IL-6 expression at the mRNA and protein levels, and the Rta's C-terminus was essential for promoter activation and expression of IL-6. The induction of IL-6 by Rta also required activation of extracellular signal-regulated kinase 1/2 and activator protein-1. Furthermore, IL-6 secreted from Rta-expressing NPC cells promoted migration of Rta-negative NPC cells by activating IL-6 receptor/Janus kinase/signal transducer and activator of transcription 3 pathway.

Conclusion: Rta contributes to progression of NPC cells through induction of IL-6 in vitro.

Keywords: Epstein-Barr virus; Rta; cell migration; interleukin-6; nasopharyngeal carcinoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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78
Anticancer Res
. 2020 Jul;40(7):3743-3749. doi: 10.21873/anticanres.14363.
Determination of Immediate vs. Kinetic Growth Retardation in Physically Plasma-treated Cells by Experimental and Modelling Data
Lyubomir Haralambiev 1 2, Arnab Bandyophadyay 3, Bettina Suchy 1, Martin Weiss 4, Axel Kramer 5, Sander Bekeschus 6, Axel Ekkernkamp 1 2, Alexander Mustea 7, Lars Kaderali 3, Matthias B Stope 8
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PMID: 32620613 DOI: 10.21873/anticanres.14363
Abstract
Background/aim: The antiproliferative effects of cold atmospheric plasma (CAP) make it a promising application option in oncology. The aim of the present study was to examine whether short-term CAP treatment leads to an initial partial elimination of the treated cells or to long-term impairement and inhibition of cell growth.

Materials and methods: Cells were treated with CAP and biostatistical modelling was used to estimate growth rates over the incubation time. Four cell lines (U2-OS and MNNG osteosarcoma cells, 3T3 fibroblasts, HaCaT keratinocytes) and three CAP sources (MiniJet-R, kINPen MED, Maxium) were used.

Results: The antiproliferative efficacy of CAP was due to a significant reduction in cell count during treatment and the long-lasting inhibition of growth rate in the remaining cells, detectable in all cell lines and after treatment using all three CAP devices.

Conclusion: Induction of cell death and inhibition of cell growth are part of a general mechanism of biological CAP efficacy. However, data contradict the hypothesis that cancer cells respond more sensitively to CAP treatment compared to non-malignant cells.

Keywords: Cold atmospheric plasma; antiproliferative effect; cell growth inhibition; growth rate.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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79
Anticancer Res
. 2020 Jun;40(6):3333-3343. doi: 10.21873/anticanres.14316.
Symptomatic Intraosseous Vascular Malformation of Infraorbital Rim: A Case Report With Literature Survey
Reinhard E Friedrich 1, Ulrich Grzyska 2, Felix K Kohlrusch 3, Simon VON Kroge 4, Tobias Vollkommer 3, Andreas M Luebke 5
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PMID: 32487629 DOI: 10.21873/anticanres.14316
Abstract
Background/aim: Intraosseous orbital hemangiomas or vascular malformations (VM) are rare. This report is intended to complement the experience of diagnosing and treating a rare vascular lesion at this site. Special attention is paid to three-dimensional imaging and the morphological distinction between the two entities in this location.

Case report: A 54-year-old female was examined and surgically treated for an exophytic firm mass of the infraorbital, which had become palpable as a hard mass due to growth in size. At first, a bone tumor, for example, an osteoma, was suspected. Intraoperatively, an osseous expansion with distinct fenestrations of the newly grown bone's surface, was detected. The lesion was firmly attaching to the orbital rim. The densely vascularized tumor was well defined to the soft tissues but had grown in continuity from the orbital floor and rim. Vascularized cavities caused the tumor to have a slightly reddish color. The histological examination confirmed the suspicion of the lesion's vascular origin. The lesion's immunohistochemical expression profile approved the final diagnosis of intraosseous VM.

Conclusion: The symptoms of intraosseous vascular lesions of the orbit are determined by location and size. Modern imaging techniques facilitate the estimation of tumor-like expansion of lesions. However, the imaging characteristics of intraosseous vascular lesions are very variable. The symptoms of the patient presented herein show that growth phases of a vascular orbital malformation can occur in later stages of life and are initially indistinguishable from a neoplasm. In individual cases, patient care necessitates advanced diagnostic measures to establish the diagnosis and determine surgical therapy.

Keywords: 3D reconstruction; Vascular malformation; bone mineral density; cone beam computed tomography; differential diagnosis; haemangioma; immunohistochemistry; intraosseous; orbit.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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80
Anticancer Res
. 2020 Jul;40(7):3931-3937. doi: 10.21873/anticanres.14384.
The Association Between Extracellular Water-to-Total Body Water Ratio and Therapeutic Durability for Advanced Lung Cancer
Yoshimi Noda 1, Hidekazu Suzuki 2, Tomohiro Kanai 2, Yumiko Samejima 2, Shingo Nasu 2, Ayako Tanaka 2, Naoko Morishita 2, Norio Okamoto 2, Tomonori Hirashima 2
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PMID: 32620634 DOI: 10.21873/anticanres.14384
Abstract
Background/aim: Extracellular water-to-total body water ratio (ECW/TBW) measured by bioelectrical impedance analysis (BIA) reportedly predicts clinical outcomes of various diseases. The aim of this retrospective study was to examine the association between ECW/TBW and therapeutic durability of chemotherapy and/or immune checkpoint inhibitors in advanced lung cancer.

Patients and methods: Patients with advanced lung cancer underwent BIA before chemotherapy and/or treatment with immune checkpoint inhibitors at our hospital between June 2018 and November 2019.

Results: Of 75 patients, 18 with ECW/TBW ≥0.4 were assigned to the overhydrated group (OH-G) and 57 patients ECW/TBW <0.4 were assigned to the non-overhydrated group (NOH-G). The median time-to-treatment failure was significantly shorter in the OH-G than in the NOH-G (p=0.003). Multivariate analysis revealed that ECW/TBW ≥0.4 predicted treatment failure [hazard ratio (HR)=2.508, 95% confidence interval (CI)=1.19-5.27; p=0.01].

Conclusion: The ECW/TBW may be an objective parameter for predicting therapeutic durability in advanced lung cancer.

Keywords: ECW/TBW; Lung cancer; bioelectrical impedance analysis; prognostic factor.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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81
Anticancer Res
. 2020 Jun;40(6):3429-3434. doi: 10.21873/anticanres.14328.
Seizures Prior to Whole-brain Irradiation for Metastatic Disease: Prevalence, Risk Factors and Association With Survival
Dirk Rades 1, Jaspar Witteler 2, Liesa Dziggel 2, Troels W Kjaer 3, Soeren Tvilsted 4, Steven E Schild 5
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PMID: 32487641 DOI: 10.21873/anticanres.14328
Abstract
Background/aim: Seizures are a serious condition for patients with brain metastases. Prevalence, risk factors and a potential association of seizures with survival prior to whole-brain irradiation (WBI) for cerebral metastases were retrospectively investigated.

Patients and methods: In 1,934 patients, the prevalence of pre-treatment seizures (pre-WBI) was determined. Seven pre-treatment characteristics were evaluated for associations with seizures. Ten characteristics including pre-treatment symptoms (none vs. seizures only vs. seizures+others vs. others only) and seizures (yes vs. no) were analyzed for survival.

Results: In 251 patients (13.0%), pre-treatment seizures were documented. The occurrence of seizures was significantly associated with 1-3 brain metastases and lack of extra-cerebral spread. On multivariate analysis, age, gender, performance score, number of metastases and extra-cerebral spread were significantly associated with survival; pre-treatment symptoms and seizures showed associations on univariate but not on multivariate analyses.

Conclusion: Few brain metastases and lack of extra-cerebral spread were independent risk factors for pre-treatment seizures. Seizures appeared positively associated with survival.

Keywords: Seizures; brain metastases; prevalence; risk factors; survival; whole-brain irradiation.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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82
Review Anticancer Res
. 2020 Jun;40(6):3049-3053. doi: 10.21873/anticanres.14285.
Tumor Handling of Early-stage Cervical Cancer: A Literature Analysis of Villoglandular Adenocarcinoma of the Cervix
Anna Dietl 1, Konrad Aumann 2, Matthias W Beckmann 3
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PMID: 32487598 DOI: 10.21873/anticanres.14285
Abstract
Background/aim: Recent studies have demonstrated the inferior overall survival outcomes of patients with early-stage cervical cancer who undergo minimally invasive surgery (MIS). One possible explanation for these unexpected results is intraoperative tumor manipulation.

Materials and methods: Considering this hypothesis, we have reviewed the literature on the oncological outcomes of patients with villoglandular adenocarcinoma (VGA) of the cervix, an uncommon variant of cervical cancer that has an excellent prognosis.

Results: VGA generally presents as an exophytic mass arising from the endocervix. In a systematic review, we identified 221 patients treated surgically for VGA (FIGO stage Ia-Ib1). Of these, 11 developed recurrence, and four died. The recurrence sites in 8 cases were the pelvis (n=3), vaginal cuff (n=3), episiotomy scar (n=1), and cervix (n=1). Furthermore, 23 VGA-patients were treated by MIS, four experienced recurrence, and one died. Three intraabdominal metastases after MIS were reported.

Conclusion: Excessive tumor-handling during MIS or manipulations, e.g. cervix-dilation (during delivery), can worsen the otherwise excellent prognosis.

Keywords: Early-stage cervical cancer; minimal handling; minimal invasive surgery; review; villoglandular adenocarcinoma of the uterine cervix.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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83
Anticancer Res
. 2020 Jun;40(6):3445-3451. doi: 10.21873/anticanres.14330.
Umbilical Defunctioning Ileostomy for Rectal Cancer Results in Reduced Risk for Incisional Hernia
Ken Eto 1, Makoto Kosuge 2, Masahisa Ohkuma 2, Daisuke Ito 2, Yasuhiro Takeda 2, Saori Yatabe 2, Hiroshi Sugano 2, Naoki Takada 2, Tomotaka Kumamoto 2, Katsuhiko Yanaga 2
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PMID: 32487643 DOI: 10.21873/anticanres.14330
Abstract
Background/aim: Umbilical defunctioning ileostomy (UDI) spares one incision, which may reduce the overall incidence of incisional hernia. Our aim was to evaluate the occurrence and risk factors of incisional hernias between UDI and conventional defunctioning ileostomy (CDI) after ileostomy closure.

Patients and methods: Incidence of incisional hernia after ileostomy closure was compared between UDI (n=51) and CDI (n=86) groups. Risk factors for incisional hernia were also considered through a retrospective analysis.

Results: The overall incidence of incisional hernia was 5.9% in the UDI group, which was significantly lower than the 22.1% (7.0% at the midline incision and 15.1% at the stoma site) in the CDI group (p=0.012). Multivariate analysis showed higher BMI (p=0.035) and CDI (p=0.031) as risk factors for developing incisional hernias overall.

Conclusion: UDI results in fewer incisional hernias than CDI and seems to be superior to CDI from the standpoint of overall incidence of incisional hernias.

Keywords: Umbilical defunctioning ileostomy; incisional hernia; laparoscopic surgery; rectal cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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84
Anticancer Res
. 2020 Jul;40(7):3991-3994. doi: 10.21873/anticanres.14392.
Russell Body Gastroesophagitis Concurrent With Barrett's Esophagus
Juwairiya Arshi 1, Joshua Nguyen 1, Feng Yin 2
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PMID: 32620642 DOI: 10.21873/anticanres.14392
Abstract
Background: Russell body gastroesophagitis is a rare entity characterized by the accumulation of immunoglobulins within the cytoplasm of plasma cells.

Case report: Here, we present the case of a 41-year-old male with history of gastroesophageal reflux disease who presented with nausea, vomiting, and altered mental status. Candida esophagitis was noted on upper endoscopy. After treatment, a surveillance endoscopy revealed salmon colored mucosa in the distal esophagus and mild gastric erythema. The biopsy confirmed Barrett's esophagus that was negative for dysplasia and mild chronic inactive gastritis. Interestingly, diffusely infiltrating Russell body-containing plasma cells (Mott cells) were present in the distal esophagus and extending into the gastric cardia. The Mott cells were highlighted on CD138 immunostaining and Periodic acid-Schiff stain. Immunostaining for cytokeratin AE1/AE3 was negative. There was no evidence of Helicobacter pylori organisms on the gastric mucosa.

Conclusion: This is the first report on Russell body-containing plasma cells diffusely involving both esophagus and gastric cardia with concurrent Barrett's esophagus.

Keywords: Barrett's esophagus; Mott cells; Russell body esophagitis; Russell body gastritis.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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85
Anticancer Res
. 2020 Jul;40(7):4081-4086. doi: 10.21873/anticanres.14406.
Predicting the Risk of Subsequent Distant Brain Metastases After Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy in Elderly Patients
Dirk Rades 1, Trang Nguyen 2, Liesa Dziggel 2, Oliver Blanck 3, Steven E Schild 4
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PMID: 32620656 DOI: 10.21873/anticanres.14406
Abstract
Background/aim: Treatment for elderly patients with few brain metastases is controversial. A score was generated to predict distant brain metastases (DBMs) after stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT).

Patients and methods: Ten characteristics were retrospectively analyzed for freedom from new DBMs in 104 elderly patients receiving SRS or FSRT alone for 1-3 brain metastases. Characteristics that were significant or showed a trend on multivariate analysis were used for the score.

Results: On multivariate analysis, favorable histology (p=0.026) and single brain metastasis (p=0.006) showed significant associations with freedom from DBMs. A trend was found for supra-tentorial location only (p=0.065). Three groups were designed, 10-14, 16-20 and 21-25 points, with 6-month rates of freedom from DBMs of 10%, 54% and 95%, respectively (p<0.0001). Positive predictive values to predict DBMs and freedom from DBMs at 6 months were 91% and 94%.

Conclusion: This new score provided high accuracy in predicting DBMs and freedom from DBMs.

Keywords: Stereotactic radiosurgery; distant brain metastases; elderly patients; fractionated stereotactic radiotherapy; prognostic instrument.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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86
Anticancer Res
. 2020 Jun;40(6):3209-3220. doi: 10.21873/anticanres.14302.
Tannic Acid Inhibits Non-small Cell Lung Cancer (NSCLC) Stemness by Inducing G 0/G 1 Cell Cycle Arrest and Intrinsic Apoptosis
Nipin Sp 1, Dong Young Kang 1, Doh Hoon Kim 1, Ji-Seung Yoo 2, Eun Seong Jo 1, Alexis Rugamba 1, Kyoung-Jin Jang 3, Young Mok Yang 3
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PMID: 32487615 DOI: 10.21873/anticanres.14302
Abstract
Background/aim: Non-small cell lung cancer (NSCLC) is one among the most common cancers worldwide. Recently, dietary phytochemicals have been reported as an attractive approach to improve the symptoms of NSCLC patients. Tannic acid is a natural polyphenol, which is known to have anticancer effects on in vitro models of breast, gingival and colon cancer. However, the molecular mechanisms associated with the actions of tannic acid on A549 human lung cancer cells have not been elucidated.

Materials and methods: In this study, we analyzed the effect of tannic acid on A549 cells and their underlying mechanisms using western blotting, flow cytometry, invasion assay and tumorsphere formation assay.

Results: Tannic acid treatment suppressed the viability of A549 cells through cell cycle arrest and induction of the intrinsic pathways of apoptosis. In addition, the various malignant phenotypes of A549 cells including invasion, migration, and stemness were inhibited by tannic acid treatment.

Conclusion: Tannic acid could be used as an effective inhibitor of lung cancer progression.

Keywords: G0/G1 cell cycle arrest; Lung cancer; intrinsic apoptosis; tannic acid.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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87
Anticancer Res
. 2020 Jul;40(7):3857-3863. doi: 10.21873/anticanres.14375.
Activity of Alcohol Dehydrogenase and Aldehyde Dehydrogenase in Lung Cancer Cells
Karolina Orywal 1, Wojciech Jelski 2, MirosŁaw Dariusz KozŁowski 3, Barbara Mroczko 2 4
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PMID: 32620625 DOI: 10.21873/anticanres.14375
Abstract
Background: The aim of this study was to define the alterations in the activity of alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in normal and cancerous lung cells.

Materials and methods: Lung tissues were taken from 36 patients during surgical resection of cancer. The activities of tested enzymes were measured by spectrofluorometric method (ADH I, ADH II, total ALDH) and photometric method (ADH III, ADH IV, total ADH).

Results: The activities of class II and III ADH were significantly lower in lung cancer cells compared to histologically normal lung tissue.

Conclusion: Reduced activity of isoenzyme class II ADH may affect disorders in retinoic acid biosynthesis, leading to its deficit. Lower ADH III activity may result in depletion of glutathione, and in initiation of oxidative stress, leading to cancer progression. These data suggest that alterations in ADH isoenzyme activities can contribute to carcinogenesis in human lungs.

Keywords: Alcohol dehydrogenase isoenzymes; aldehyde dehydrogenase; carcinogenesis; lung cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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88
Anticancer Res
. 2020 Jul;40(7):4059-4066. doi: 10.21873/anticanres.14403.
Long-term Efficacy of Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of the Polish Adult Leukemia Study Group Observational Study
Bartosz Pula 1, Elzbieta Iskierka-Jazdzewska 2, Monika Dlugosz-Danecka 3, Agnieszka Szymczyk 4, Marek Hus 4, Agnieszka Szeremet 5, Joanna Drozd-Sokolowska 6, Anna Waszczuk-Gajda 6, Jan M Zaucha 7, Jadwiga Holojda 8, Weronika Piszczek 9, Pawel Steckiewicz 10, Malgorzata Wojciechowska 11, Michal Osowiecki 12, Wanda Knopinska-Posluszny 13, Marek Dudzinski 14, Daria Zawirska 15, Edyta Subocz 16, Janusz Halka 16, Andrzej Pluta 17, Ryszard Wichary 18, Beata Kumiega 19, Bozena K Budziszewska 20, Wojciech Jurczak 3, Ewa Lech-Maranda 20 21, Krzysztof Giannopoulos 22, Tadeusz Robak 2, Krzysztof Jamroziak 20
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PMID: 32620653 DOI: 10.21873/anticanres.14403
Abstract
Background/aim: To study the long-term clinical efficacy and tolerability of ibrutinib monotherapy in real-world relapsed and refractory chronic lymphocytic leukemia (RR-CLL) patients outside clinical trials.

Patients and methods: Clinical data of 171 RR-CLL patients treated with ibrutinib were collected within the observational study of the Polish Adult Leukemia Study Group.

Results: Median patient age was 64 years. Patients were pretreated with 3 (1-10) median lines of therapy, while 42 (24.6%) had 17p deletion. The median observation time was 40 months (range=1-59 months), while median ibrutinib monotherapy reached 37.5 months (range=0.4-59.2 months). Response was noted in 132 (77.2%) patients. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 61.1% (95%CI=49.3-70.9%) and 56.8% (95%CI=45.6-66.6%), respectively. At the time of analysis 97 (56.7%) remained under ibrutinib monotherapy.

Conclusion: Ibrutinib is clinically effective and tolerable as a monotherapy in real-world RR-CLL patients.

Keywords: Ibrutinib; chronic lymphocytic leukemia; therapy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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89
Anticancer Res
. 2020 Jun;40(6):3221-3229. doi: 10.21873/anticanres.14303.
Possible Diagnostic Application of CXCL12 and CXCR4 as Tumor Markers in Breast Cancer Patients
Emilia Dąbrowska 1, Andrzej Przylipiak 2, Monika Zajkowska 3, Barbara M Piskor 2, Iwona Sidorkiewicz 4, Maciej Szmitkowski 3, Slawomir Lawicki 5
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PMID: 32487616 DOI: 10.21873/anticanres.14303
Abstract
Background/aim: Chemokines are cytokines involved not only in inflammatory but also in inappropriate response of the immune system in breast cancer (BC) progression. We examined the diagnostic usefulness of CXCL12, CXCR4 and CA 15-3 in BC patients, based on ROC curve analysis.

Materials and methods: The study group consisted of 100 patients with BC; the control group consisted of 35 women with benign breast disease and 35 healthy patients. The median concentration of chemokines was measured by ELISA and that of CA 15-3 by chemiluminescent microparticle immunoassay.

Results: The concentrations of CXCL12 and CXCR4 in the BC group were significantly higher than those in the control groups. The AUC value of CXCL12 (0.7502) was the highest of all the chemokines measured in the BC patients.

Conclusion: There may be a link between CXCL12, CXCR4 and BC that can assist in the diagnosis, markedly when combined with CA 15-3.

Keywords: Breast cancer; C-X-C motif chemokine ligand 12; C-X-C motif chemokine receptor 4; tumor marker.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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90
Anticancer Res
. 2020 Jul;40(7):3947-3952. doi: 10.21873/anticanres.14386.
Evaluating the Platelet Distribution Width-to-Plateletcrit Ratio as a Prognostic Marker for Patients With Breast Cancer
Hideya Takeuchi 1, Daiki Noda 2, Miyuki Abe 2, Kentaro Anami 2, Michiyo Miyawaki 2, Atsushi Osoegawa 2, Kenji Sugio 2
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PMID: 32620636 DOI: 10.21873/anticanres.14386
Abstract
Aim: This study aimed to evaluate plateletcrit (PCT) and platelet distribution width-to-PCT ratio (PDW/PCT) as potential prognostic biomarkers in patients with breast cancer.

Patients and methods: Information of 337 patients was retrospectively reviewed. The Cox regression proportional hazards model was used to evaluate the prognostic value of PCT and PDW/PCT compared to the platelet distribution width-to-platelet count ratio (PDW/P) and red cell distribution width-to-platelet count ratio (RDW/P).

Results: Large tumor size (p<0.01), lymph node involvement, and increased PDW/P, RDW/P, and PDW/PCT (p<0.05) were significantly associated with inferior disease-free survival (DFS) according to the univariate analysis. The multivariate analysis showed that large tumor size (p<0.01) and increased PDW/PCT (p<0.05) were significant prognostic factors for poor DFS.

Conclusion: To our knowledge, this is the first report to show that PDW/PCT is a significant prognostic factor for patients with breast cancer. Therefore, it might be an attractive biomarker providing additional prognostic information for these patients.

Keywords: Breast cancer; platelet distribution width; plateletcrit; prognostic factor.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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91
Anticancer Res
. 2020 Jul;40(7):3905-3913. doi: 10.21873/anticanres.14381.
Real-world Evaluation of Oral Vinorelbine in the Treatment of Metastatic Breast Cancer: An ESME-MBC Study
Pierre Heudel 1, Suzette Delaloge 2, Damien Parent 3, Nicolas Madranges 4, Christelle Levy 5, Florence Dalenc 6, Etienne Brain 7, Lionel Uwer 8, Veronique D'Hondt 9, Paule Augereau 10, Audrey Mailliez 11, Christophe Perrin 12, Jean-Sebastien Frenel 10, Marie-Paule Sablin 7, Marie-Ange Mouret-Reynier 13, Thomas Vermeulin 14, Jean-Christophe Eymard 3, Thierry Petit 15, Jean-Marc Ferrero 16, Silvia Ilie 17, Anthony Goncalves 18, GaËlle Chenuc 19, Mathieu Robain 20, GaËtane Simon 20, David Perol 21
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PMID: 32620631 DOI: 10.21873/anticanres.14381
Abstract
Background/aim: Vinorelbine is indicated for use in the treatment of MBC as a single agent or in combination but there is little real world data on this molecule and even less on its oral form. We exploited the Unicancer Epidemiology Strategy Medical-Economics (ESME) metastatic breast cancer (MBC) database to investigate current patterns of use of oral vinorelbine (OV), as well as outcomes of patients receiving this drug.

Patients and methods: Data were collected retrospectively from women and men treated for MBC between 2008 and 2014 at one of 18 French Comprehensive Cancer Centres. The efficacy of OV was evaluated in terms of progression-free (PFS) and overall survival (OS) and treatment duration. The population and patterns of OV usage were also described.

Results: A total of 1806 patients (11% of the ESME MBC database) were included in this analysis. OV was prescribed as monotherapy (46%) or in combination (29%), especially with capecitabine. mainly in later treatment lines. Median PFS was 3.3 months: 2.9 months for single agent, 3.6 months for combination therapy. Median OS was 40.9 months.

Conclusion: Real-world data offer complementary results to the data from traditional clinical trials, but they concern a much larger population. In this ESME MBC cohort, OV was only prescribed to a small subset of MBC patients. OV was mainly given as single agent to patients with heavily pre-treated MBC; less commonly, it was co-administered with capecitabine or anti-HER2, in earlier lines of therapy. PFS was modest but in line with previous reports.

Keywords: ESME; Vinorelbine; metastatic breast cancer; real-world data; retrospective study.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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92
Anticancer Res
. 2020 Jun;40(6):3109-3118. doi: 10.21873/anticanres.14292.
New Pancreatic Cancer Biomarkers eIF1, eIF2D, eIF3C and eIF6 Play a Major Role in Translational Control in Ductal Adenocarcinoma
Nicole Golob-Schwarzl 1 2, Philip Puchas 1, Margit Gogg-Kamerer 1, Wilko Weichert 3, Benjamin Göppert 4, Johannes Haybaeck 5 6
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PMID: 32487605 DOI: 10.21873/anticanres.14292
Abstract
Background/aim: Pancreatic cancer is one of the deadliest forms of cancer and ranks among the leading causes of cancer-related death worldwide. The most common histological type is ductal adenocarcinoma (PDAC), accounting for approximately 95% of cases. Deregulation of protein synthesis has been found to be closely related to cancer. The rate-limiting step of translation is initiation, which is regulated by a broad range of eukaryotic translation initiation factors (eIFs).

Patients and methods: Human PDAC samples were biochemically analyzed for the expression of various eIF subunits on the protein level (immunohistochemistry, immunoblot analyses) in 174 cases of PDAC in comparison with non-neoplastic pancreatic tissue (n=10).

Results: Our investigation revealed a significant down-regulation of four specific eIF subunits, namely eIF1, eIF2D, eIF3C and eIF6. Concomitantly, the protein (immunoblot) levels of eIF1, eIF2D, eIF3C and eIF6 were reduced in PDAC samples as compared with non-neoplastic pancreatic tissue.

Conclusion: Members of the eIF family are of relevance in pancreatic tumor biology and may play a major role in translational control in PDAC. Consequently, they might be useful as potential new biomarkers and therapeutic targets in PDAC.

Keywords: PI3K/AKT/mTOR pathway; Pancreatic cancer; biomarker; eukaryotic translation initiation factors.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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93
Anticancer Res
. 2020 Jun;40(6):3387-3393. doi: 10.21873/anticanres.14322.
Fractionated Stereotactic Sequential Boost in a Selected Cohort of Glioblastoma Patients: A Mono-institutional Analysis
Alessandro Marchionni 1, Isabella Palumbo 2, Giampaolo Montesi 3, Vittorio Bini 4, Claudio Zucchetti 5, Nunzia Cenci 6, Pietro Chiarini 7, Stefano Saccia 8, Cynthia Aristei 9, Marco Lupattelli 8
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PMID: 32487635 DOI: 10.21873/anticanres.14322
Abstract
Aim: To retrospectively assess toxicity and survival in 15 selected Glioblastoma patients treated with a sequential fractionated stereotactic radiotherapy (FSRT) boost after chemo-radiotherapy (CHT-RT) and compare their survival outcomes with a control group.

Patients and methods: Toxicity was assessed with the CTCAE 3.0 scale. The Kaplan-Meier method was used to design survival curves, log-rank test for bivariate analysis and Cox proportional hazard regression model for multivariate analysis.

Results: The median follow-up was 16 months (range=5-60). One case of headache and one of radionecrosis (RN) occurred. Median overall survival (OS) was 25 months in the boost group vs. 14 in the no-boost group (p=0.004). Median progression-free survival (PFS) was 15 months in the boost group versus 8 in the no-boost group (p=0.046). At multivariate analysis FSRT boost resulted significantly associated with OS and PFS.

Conclusion: In our series a sequential FSRT boost resulted in safe outcomes and significantly associated with survival.

Keywords: Glioblastoma; boost; fractionated stereotactic radiotherapy; survival; toxicity.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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94
Anticancer Res
. 2020 Jul;40(7):3973-3981. doi: 10.21873/anticanres.14390.
Resumption of Trastuzumab in Patients With Disease Recurrence After (Neo-) Adjuvant Anti-HER2-therapy in Patients With HER2-positive Breast Cancer
Lars Christian Hanker 1, Frank FÖrster 2, Jan SchrÖder 3, Andrea Grafe 4, Thomas Hitschold 5, Tobias Hesse 6, Claus Richard Lattrich 7, Achim Rody 8
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PMID: 32620640 DOI: 10.21873/anticanres.14390
Abstract
Background/aim: HER2-positive breast cancers eventually relapse in about one third of patients. Is anti-HER2-directed therapy with Herceptin® (trastuzumab) effective in re-treatment? Between 2008 and 2018, 216 patients with recurrent HER2-positive breast cancer (BC) were re-treated with Herceptin (HER) during first-line therapy. This study assessed the effectiveness and tolerability of re-treatment with HER.

Patients and methods: After approval from Ethical committee, the NIS was conducted according to German Drug Act. Re-treatment with HER was documented at routine visits starting with a basic observational period of maximum 12 months and a follow-up period of maximum additional four years.

Results: HER2-positive BC relapsed after a median of 36.5 months (mos). Patients were re-treated with HER +/- chemotherapy +/- endocrine therapy. HER-containing regimens resulted in median progression-free survival (mPFS) of 12.7 (95%CI=10.5-14.8) mos and overall survival (OS-2) of 31.6 mos (95%CI=28.8-38.4) since recurrence diagnosis. Differentiation of recurrence types (local, visceral, non-visceral) unfolded worst prognosis for patients with visceral metastases. Cardiac monitoring within this non-interventional study (NIS) did not result in new safety concerns.

Conclusion: Re-therapy with HER in the first-line setting of advanced HER2-positive breast cancer is effective and without unexpected or intensified adverse events.

Keywords: HER2-positive; metastatic breast cancer; re-therapy; trastuzumab.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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95
Anticancer Res
. 2020 Jul;40(7):3831-3837. doi: 10.21873/anticanres.14372.
Cytotoxicity of Exogenous Acetoacetate in Lithium Salt Form Is Mediated by Lithium and Not Acetoacetate
Raichel Cohen-Harazi 1, Sarah Hofmann 2, Valeria Kogan 2, Hadas Fulman-Levy 2, Karin Abaev 2, Olga Shovman 2, Tamara Brider 2, Igor Koman 2
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PMID: 32620622 DOI: 10.21873/anticanres.14372
Abstract
Background/aim: The ketogenic diet has recently gained interest as potential adjuvant therapy for cancer. Many researchers have endeavored to support this claim in vitro. One common model utilizes treatment with exogenous acetoacetate in lithium salt form (LiAcAc). We aimed to determine whether the effects of treatment with LiAcAc on cell viability, as reported in the literature, accurately reflect the influence of acetoacetate.

Materials and methods: Breast cancer and normal cell lines were treated with acetoacetate, in lithium and sodium salt forms, and cell viability was assessed.

Results: The effect of LiAcAc on cells was mediated by Li ions. Our results showed that the cytotoxic effects of LiAcAc treatment were significantly similar to those caused by LiCl, and also treatment with NaAcAc did not cause any significant cytotoxic effect.

Conclusion: Treatment of cells with LiAcAc is not a convincing in vitro model for studying ketogenic diet. These findings are highly important for interpreting previously published results, and for designing new experiments to study the ketogenic diet in vitro.

Keywords: Ketogenic diet; acetoacetate; breast cancer; ketone bodies; lithium.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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96
Anticancer Res
. 2020 Jul;40(7):3897-3903. doi: 10.21873/anticanres.14380.
Geographical Differences in Likelihood of Home Death Among Palliative Cancer Patients: A National Population-based Register Study
Jonas Nilsson 1 2 3, Bertil Axelsson 2 4, Georg Holgersson 5, Tobias Carlsson 6, Michael Bergqvist 6 2 7, Stefan Bergstrom 6 2
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PMID: 32620630 DOI: 10.21873/anticanres.14380
Abstract
Background/aim: Previous studies have shown discrepancies between patient's desired and actual death place. As planning of family support and involvement of palliative home care teams seem to improve the chance to meet patients preferences, geographical availability of specialized palliative home care could influence place of death.

Patients and methods: Data of patients diagnosed and deceased between January 2011 until December 2014 with lung, brain, colorectal, breast and prostate cancer was collected from Swedish national registers and multiple regression analyses were performed.

Results: Patients with lung, brain, colorectal, and prostate cancer who resided in rural municipalities had a higher likelihood of dying at home than dying in hospital settings, compared to those who lived in urban areas.

Conclusion: Patients in Sweden, with the exception of breast cancer patients, have a higher likelihood of home death than inpatient hospital death when residing in rural areas compared to when residing in urban areas.

Keywords: Geographical; home death; palliative cancer patients; register study.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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97
Anticancer Res
. 2020 Jul;40(7):3793-3799. doi: 10.21873/anticanres.14368.
Photosensitizer With Illumination Enhances In Vivo Antitumor Effect of Anti-ROBO1 Immunotoxin on Maxillary Sinus Squamous Cell Carcinoma
Noriko Komatsu 1 2, Miku Komatsu 3, Riuko Ohashi 4 5, Akira Horii 3, Kazuto Hoshi 1, Tsuyoshi Takato 1 6, Takahiro Abe 7, Takao Hamakubo 8
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PMID: 32620618 DOI: 10.21873/anticanres.14368
Abstract
Background/aim: Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of cancer worldwide. Our study focused on the axon guidance receptor roundabout guidance receptor 1 (ROBO1) as a target for monoclonal antibody therapy of HNSCC. We previously showed that saporin-conjugated anti-ROBO1 (B5209B) immunotoxin (IT-ROBO1) enhanced cytotoxic effects on HNSCC cells in combination with the photosensitizer aluminum phthalocyanine disulphonate (AlPcS2a) and illumination. We examined the effects of this combination therapy in a mouse xenograft model.

Materials and methods: IT-ROBO1 was intraperitoneally administered to HSQ-89 (derived from Japanese maxillary sinus squamous carcinoma, RCB0789; RIKEN, Tsukuba, Japan) xenografted mice. After 3 days, AlPcS2a was injected subcutaneously around the tumor and the area was illuminated at 650 nm for 30 min. The growth of the tumor was evaluated and the effects on the tumor were examined.

Results: Pronounced anti-tumor effects were elicited by the administration of IT-ROBO1 and AlPcS2a with light illumination on tumor size and pathological characteristics.

Conclusion: The results showed that photosensitizer treatment with illumination robustly enhanced the antitumor effect of the IT-ROBO1 immunotoxin.

Keywords: HNSCC; ROBO1; drug delivery system; immunotoxin; photochemical internalization.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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98
Anticancer Res
. 2020 Jul;40(7):3953-3960. doi: 10.21873/anticanres.14387.
Intrahepatic Tumor Burden as a Novel Factor Influencing the Introduction of Second-line Chemotherapy for Hepatocellular Carcinoma
Michihisa Moriguchi 1 2, Takeshi Aramaki 2, Rui Sato 2, Kenji Iwai 2, Satoshi Tsuchiya 2, Koiku Asakura 3, Aya Takahashi 4, Yuya Seko 4, Atsushi Umemura 4, Kanji Ymaguchi 4, Masahiro Endo 3, Yoshito Itoh 4
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PMID: 32620637 DOI: 10.21873/anticanres.14387
Abstract
Background/aim: To examine the factors influencing the introduction of the second-line chemotherapy and discuss the selection of first-line agent for hepatocellular carcinoma (HCC).

Patients and methods: We retrospectively studied 154 patients with HCC who received sorafenib therapy.

Results: A total of 109 (70.8%) patients, maintained Child-Pugh grade A and Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 upon sorafenib discontinuation. Multivariate analysis revealed that the up-to-seven criteria status in the hepatic lesion [p=0.019; odds ratio=OR, 2.685], albumin-bilirubin (ALBI) grade (p=0.002; OR=3.589), and macroscopic vascular invasion (MVI) (p=0.008; OR=2.972) were significant factors at sorafenib initiation that influenced the maintenance of Child-Pugh grade A and ECOG-PS ≤1 upon therapy discontinuation.

Conclusion: Not only ALBI grade and MVI, but also up-to-seven criteria status in the hepatic lesion influence the introduction of second-line therapy, and could affect the selection of the first-line therapy.

Keywords: Hepatocellular carcinoma; second-line therapy; sequential therapy; sorafenib; tumor burden.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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99
Review Anticancer Res
. 2020 Jun;40(6):3055-3063. doi: 10.21873/anticanres.14286.
PARP Inhibitors as Therapeutic Options for Tyrosine Kinase-dependent Leukemia: A Review
Caio Bezerra Machado 1, Emerson Lucena DA Silva 1, Manoel Odorico DE Moraes Filho 1, Maria Elisabete Amaral DE Moraes 1, Caroline Aquino Moreira-Nunes 2
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PMID: 32487599 DOI: 10.21873/anticanres.14286
Abstract
The idea of utilizing poly-ADP-ribose polymerase inhibitors (PARPi) as therapeutics for cancer has grown in popularity since its original approval for clinical usage in treatment of BRCA DNA repair-associated-mutated ovarian cancer. In this study, we evaluated experimental data regarding in vitro studies utilizing PARPi as a treatment for tyrosine kinase (TK)-dependent leukemia. Studies from 2015 to 2019 were compiled and the ones with most relevant TK pathways and PARP inhibition were analyzed. PARPi showed activity against many leukemia cell lines and samples from patients with primary leukemia, especially when combined with other signaling pathway inhibitor drugs, improving upon the hypothesis that the utilization of PARPi has potential as a new therapeutic approach in treatment of primary leukemia and TK-dependent leukemia.

Keywords: Leukemia; PARP inhibitors; review; tyrosine kinase.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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100
Anticancer Res
. 2020 Jun;40(6):3355-3360. doi: 10.21873/anticanres.14318.
Classification Model to Estimate MIB-1 (Ki 67) Proliferation Index in NSCLC Patients Evaluated With 18 F-FDG-PET/CT
Barbara Palumbo 1, Rosanna Capozzi 2, Francesco Bianconi 3, Mario Luca Fravolini 4, Silvia Cascianelli 4, Salvatore Gerardo Messina 5, Guido Bellezza 6, Angelo Sidoni 6, Francesco Puma 2, Mark Ragusa 7
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PMID: 32487631 DOI: 10.21873/anticanres.14318
Abstract
Background/aim: Proliferation biomarkers such as MIB-1 are strong predictors of clinical outcome and response to therapy in patients with non-small-cell lung cancer, but they require histological examination. In this work, we present a classification model to predict MIB-1 expression based on clinical parameters from positron emission tomography.

Patients and methods: We retrospectively evaluated 78 patients with histology-proven non-small-cell lung cancer (NSCLC) who underwent 18F-FDG-PET/CT for clinical examination. We stratified the population into a low and high proliferation group using MIB-1=25% as cut-off value. We built a predictive model based on binary classification trees to estimate the group label from the maximum standardized uptake value (SUVmax) and lesion diameter.

Results: The proposed model showed ability to predict the correct proliferation group with overall accuracy >82% (78% and 86% for the low- and high-proliferation group, respectively).

Conclusion: Our results indicate that radiotracer activity evaluated via SUVmax and lesion diameter are correlated with tumour proliferation index MIB-1.

Keywords: 18F-FDG PET/CT; MIB-1; artificial intelligence; non-small-cell lung cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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