Medicine by Alexandros G. Sfakianakis: 07/18/19

Thursday, July 18, 2019

Otology & Neurotology

Speech Perception Growth Patterns in Prelingual Deaf Children With Bilateral Sequential Cochlear Implantation
Objective: To evaluate speech perception following the first (CI-1) and second (CI-2) cochlear implantation (CI) in children with sequential bilateral CI. Study Design: Retrospective. Patients: Seventy children with follow-up for 60 months post CI-1 and 36 months post CI-2. Main Outcome Measures: Word recognition score (WRS) was the main outcome. WRSs were compared by age at CI operation (group A ≤ 3.5 yr, B 3.6–8.6, for CI-1; group I ≤ 3.5 yr, II 3.6–7.0, III 7.1–13, IV > 13, for CI-2). Results: For CI-1, the WRS of group A exceeded 80% at 24 months post procedure, earlier than group B (54 mo). Group A also had a shorter period of CI-1 use up to the WRS plateau than group B. CI-2 showed an initial burst of WRS growth much earlier than CI-1. This initial burst was most robust within 3 months in group II, but modest in group IV. The periods of CI-2 use (11–17 mo) up to the WRS plateau were much shorter than CI-1 (40–64 mo). Group I did not show the best WRS at 1 month post CI but later exceeded the other groups. Conclusion: Children received an immediate benefit by a burst of WRS growth from CI-2 earlier than CI-1, even within 3 months, suggesting that CI-1 gets the auditory cortex ready to foster speech processing from CI-2. The CI-2 performance depends on age at CI-2 implantation and on CI-1 performance. Our current findings will be relevant for clinicians who are counselling parents on CI-2 surgery. Address correspondence and reprint requests to Hong Ju Park, M.D., Ph.D., Department of Otorhinolaryngology-Head and Neck Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; E-mail: dzness@hotmail.com The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Long-term outcomes of bone conduction hearing implants in patients with bilateral microtia-atresia
Objectives: To evaluate the long-term outcomes of three different types of bone conduction hearing implants (BCHI)—BAHA, Ponto, and Bonebridge—in Mandarin-speaking patients with bilateral microtia-atresia. Methods: This cohort study enrolled 59 patients affected by bilateral microtia-atresia, with an upper bone conduction threshold limit of 30 dB HL at frequencies of 0.5 to 4 kHz. All subjects underwent unilateral BCHI surgery, including 26 (18 males, 8 females, of mean age 8.7 ± 1.9 yr) implanted with BAHA devices; 10 (7 males, 3 females, of mean age 11.7 ± 2.8 yr) implanted with Ponto devices; and 23 (14 males, 9 females, of mean age 9.0 ± 1.8 yr) implanted with Bonebridge devices. The main outcome measures included long-term audiological benefits, patient satisfaction, and complications. Each subject acted as his or her own control. Results: Two years after BCHI surgery, the mean hearing thresholds in the BAHA, Ponto, and Bonebridge groups had improved to 22.6 ± 1.6 dB HL, 21.6 ± 1.2 dB HL, and 22.5 ± 1.5 dB HL, respectively. The mean percentages of subjects in these three groups recognizing speech at 65 dB SPL under quiet conditions were 97.7 ± 4.2%, 96.3 ± 1.1%, and 94.4 ± 9.4%, respectively, whereas the mean percentages recognizing speech under noise conditions (signal:noise ratio +5) were 87.0 ± 1.8%, 89.3 ± 9.3%, and 85.3 ± 4.7%, respectively. Questionnaires revealed patients' benefits and satisfaction with this surgery. Three (11.5%) of 26 patients in the BAHA group and 1 (10%) of 10 in the Ponto group experienced skin irritation, but all recovered after local treatment. Five (19.2%) patients in the BAHA group and two (20%) in the Ponto experienced abutment extrusion about 6 months postoperatively, with all achieving good results after revision surgery to replace the abutment. One (3.8%) patient in the BAHA group experienced local chronic inflammation and underwent surgery to replace the BAHA with a Bonebridge implant. One (4.3%) patient in the Bonebridge group developed a local infection 3 months postoperatively and underwent implant removal. Conclusions: All three BCHIs were well tolerated after long-term follow-up, and all improved audiometric thresholds and the intelligibility of speech in the presence of both quiet and noise. These implants should be considered valid and safe options for the functional rehabilitation of patients with bilateral microtia-atresia. Address correspondence and reprint requests to Xiaowei Chen, M.D., Department of Otolaryngology, Peking Union Medical College Hospital, #1 shuaifuyuan, Beijing 100730, China; E-mail: chenxw_pumch@163.com This work was supported by grant to X.C. from the General Programs of National Natural Science Foundation of China (81271053) and The National Key Research and Development Program of China (2016YFC0901501). The authors have received no payment in the preparation of this manuscript. The authors alone are responsible for the content and writing of this article. X.C. acted as head surgeon for the BCHIs performed in this study and collected data. X.F. analyzed data, composed the manuscript, and participated in some of the operations as an assistant. T.Y., X.N., Y.W., and Y.F. participated in some of the operations as assistants, and collected and analyzed data. All authors read and approved the final manuscript. The authors disclose no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://journals.lww.com/otology-neurotology). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Anatomical Correlates and Surgical Considerations for Localized Therapeutic Hypothermia Application in Cochlear Implantation Surgery
Hypothesis: Application of localized, mild therapeutic hypothermia during cochlear implantation (CI) surgery is feasible for residual hearing preservation. Background: CI surgery often results in a loss of residual hearing. In preclinical studies, local application of controlled, mild therapeutic hypothermia has shown promising results as a hearing preservation strategy. This study investigated a suitable surgical approach to deliver local hypothermia in patients utilizing anatomical and radiologic measurements and experimental measurements from cadaveric human temporal bones. Methods: Ten human cadaveric temporal bones were scanned with micro-computed tomography and anatomical features and measurements predicting round window (RW) visibility were characterized. For each bone, the standard facial recess and myringotomy approaches for delivery of hypothermia were developed. The St. Thomas Hospital (STH) classification was used to record degree of RW visibility with and without placement of custom hypothermia probe. Therapeutic hypothermia was delivered through both approaches and temperatures recorded at the RW, RW niche, over the lateral semicircular canal and the supero-lateral mastoid edge. Results: The average facial recess area was 13.87 ± 5.52 mm2. The introduction of the cooling probe through either approach did not impede visualization of the RW or cochleostomy as determined by STH grading. The average temperatures at RW using the FR approach reduced by 4.57 ± 1.68 °C for RW, while using the myringotomy approach reduced by 4.11 ± 0.98 °C for RW. Conclusion: Local application of therapeutic hypothermia is clinically feasible both through the facial recess and myringotomy approaches without limiting optimal surgical visualization. Address correspondence and reprint requests to Suhrud M. Rajguru, Ph.D., University of Miami Ear Institute, 1095 NW 14 Terrance, Lois Pope Life Center, Room 4-25, Miami, Florida 33134; E-mail: s.rajguru@miami.edu E.P. and A.V.E. have equal contribution. This work was supported by a Research Grant from Cochlear, R01 DC01379801A1 and a pilot award from National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002736, Miami Clinical and Translational Science Institute. S.M.R. and C.K. are named inventors on intellectual property related to the design of hypothermia system and probe discussed here. The authors declare no competing financial interests related to the findings presented. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Evaluation of the Effect of Diclofenac Sodium and 5-Fluourasil in a 3D Cholesteatoma Cell Culture Model
Introduction: Middle ear cholesteatoma is a benign disease with invasive and destructive clinical behaviors. It increases the rate of both chronic otitis media complications and revision surgeries. The most effective treatment of middle ear cholesteatoma is surgical excision, and there is no medical treatment for this disease. Exploring new medical treatment options may help to create treatment alternatives instead of surgery. Materials and Methods: Required cholesteatoma tissues for cell culture were excised from 4 different participants who underwent surgery in our clinic and agreed to give tissue for the study. Cholesteatoma-derived keratinocytes and fibroblasts were cocultured in temperature-sensitive culture dishes to make a three-dimensional (3D) cholesteatoma model. Then, the effects of 1% and 2% diclofenac sodium on viability and cell proliferation rates were examined using WST-1 and annexin-V tests. Results: Cell viability and proliferation rates were found to be lower and apoptosis rates were higher in the diclofenac sodium group versus the negative and positive control groups. Conclusion: In this present study, we described a new 3D cholesteatoma cell culture model developed using cell sheet technology and demonstrated the efficacy of diclofenac sodium on cholesteatoma for the first time in the literature. It may be used in patients with chronic otitis media with cholesteatoma, but further studies investigating ototoxic and neurotoxic effects of this molecule are needed. Address correspondence and reprint requests to Ahmet Kara, Sakarya University Training and Research Hospital, 54000 Korucuk, Sakarya, Turkey. E-mail: doktor.kbb@hotmail.com Funding: This study has been funded by Turkey Scientific and Technological Research Center (project number: 216S961) (TUBITAK). Date of presentation at scientific meeting: AAO-HNSF Annual Meeting & OTO Experience, 7–10.10.2018. The research protocol was approved by the Kocaeli University Animal Ethics Committee (KU GOKAEK 2013). The authors report no conflicts of interest Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Hearing Preservation With the Use of Flex20 and Flex24 Electrodes in Patients With Partial Deafness
Objective: To evaluate the impact of electrode length on hearing preservation (HP) in Partial Deafness Treatment–Electrical Complement (PDT-EC) subjects. Study Design: Retrospective case review. Setting: Tertiary referral center. Patients: Twenty-three PDT-EC patients (with preoperative air-conduction thresholds ≤30 dB up to 500 Hz) were divided into two groups: Flex20 electrode (Med-EL GmbH, Innsbruck, Austria) (12 patients) and Flex24 electrode (Med-EL GmbH, Innsbruck, Austria) (11 patients). Interventions: All participants were subjected to minimally invasive cochlear implantation using the round window approach. Main Outcome Measure(s): Pure tone audiometry (125–8000 Hz) was performed preoperatively and at 1, 6, 12, and 24 months postoperatively. HP was established using the HEARRING group formula. Speech understanding was assessed preoperatively and at 12 and 24 months postoperatively. Results: Analysis of HP for every individual indicates that more than half the patients with Flex20 and Flex24 had complete HP at 6 months follow-up. None of the patients from either group had complete loss of hearing. At activation, average air-conduction thresholds for low frequencies (125–500 Hz) were slightly better for the short electrode (M = 29.03) than for the long (M = 39.10) but the difference was not statistically significant (p = 0.067). The effect of electrode (Flex20 versus Flex24) was not significant in terms of pure tone audiometry and speech recognition at long-term follow-up. Conclusions: In the early postoperative period, complete HP was possible in a majority of patients from both groups, but slightly better HP outcomes were achieved by Flex20. In the long term, the length of the electrodes does not affect the degree of HP or speech understanding. Address correspondence and reprint requests to Piotr H. Skarzynski, Ph.D., M.D., M.S., Mokra 17 Street, 05-830 Kajetany, Poland; E-mail: p.skarzynski@ifps.org.pl No other benefits were received. The authors disclose no conflicts of interest. Supplemental digital content is available in the text. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://journals.lww.com/otology-neurotology). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Validating a New Tablet-Based Tool in the Determination of Cochlear Implant Angular Insertion Depth
Objective: The objective of this study is to determine the reliability of a new tablet-based software that utilizes postoperative computed tomography to determine angular insertion depth (AID), cochlear duct length (CDL), and the cochlear place frequency of individual electrodes in cochlear implant recipients. Patients: Twenty adult cochlear implant recipients with lateral-wall electrode arrays of varying lengths were included in the study. Intervention: Cochlear and electrode array measurements were made by 2 otolaryngologists using a tablet-based software. The user manually identifies the modiolus, round window, and each electrode contact to calculate AID. The user also manually identifies cochlear landmarks to calculate the CDL. The AID and CDL are applied to the Greenwood function to obtain an estimate of the cochlear place frequency for each electrode. Main Outcome Measure(s): The primary outcome measure was the reliability of the instrument, as assessed with intra and interrater reliability of measured AID and CDL. The resultant differences in the estimated cochlear place frequency of the most apical electrode were also evaluated. Results: A broad range of AIDs were observed (390°–659°). Intraclass correlation coefficients for intra (0.991) and interrater reliability (0.980) of AID of the most apical electrode contact were excellent. Intra (0.820) and interrater reliability (0.784) of CDL were also excellent. The estimated cochlear place frequency for the most apical electrode differed by an average of 6.7% (0–18.7%) across the 2 raters. Conclusion: There is excellent agreement amongst clinicians in the determination of AID and CDL, resulting in small changes in estimated cochlear place frequency of the most apical electrode using this new software. Address correspondence and reprint requests to Michael W. Canfarotta, M.D., Department of Otolaryngology/Head and Neck Surgery, 170 Manning Drive, CB 7070, Physicians Office Building, Room G-190, Chapel Hill, NC 27599-7070, USA. E-mail: michael.canfarotta@unchealth.unc.edu Financial Disclosures/Conflicts of Interest: This project was funded in part by the NIH through NIDCD (T32 DC005360). The senior authors, H.C.P., K.D.B., and B.P.O., serve on the surgical advisory board for MED-EL Corporation. M.T.D. is supported by a research grant from MED-EL Corporation. M.W.C. and E.B. declare that involvement in research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author Contributions: M.W.C., M.T.D., and B.P.O. designed experiments. Implanting surgeons were H.C.P., K.D.B., and B.P.O. M.W.C., M.T.D., E.B., and B.P.O. wrote the article, and all authors contributed significantly to analysis and revisions leading to its final form. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Differentiation Between Eosinophilic Otitis Media and Otitis Media Associated With Eosinophilic Granulomatosis With Polyangiitis
Objective: To perform comparisons and clarify differences in clinical manifestations between eosinophilic otitis media (EOM) and otitis media associated with eosinophilic granulomatosis with polyangiitis (EGPA). Study Design: Retrospective case review. Setting: Tertiary referral center. Patients: Twenty-two ears of 11 patients exhibiting EOM (EOM group) and 20 ears of 12 patients exhibiting otitis media associated with EGPA (EGPA group). Main Outcome Measures: Otological manifestations, nasal and paranasal manifestations, incidence of asthma, positivity for serum antineutrophil cytoplasmic antibodies (ANCA), total serum immunoglobulin (Ig) E level, peripheral blood eosinophil fraction, and hearing outcomes. Results: The incidence and age of onset of asthma and chronic rhinosinusitis were comparable between the EOM and EGPA groups. Moreover, otological findings and hearing outcomes at the initial visit were similar in both groups. Computed tomography images of the paranasal sinus showed predominant opacification of the ethmoid sinus in both groups. Although the total serum IgE level was not significantly different, the peripheral blood eosinophil fraction was significantly larger in the EGPA group than in the EOM group (p = 0.0035). Furthermore, the rate of myeloperoxidase–antineutrophil cytoplasmic antibodies (ANCA) positivity was significantly higher in the EGPA group than in the EOM group (p = 0.019). Conclusions: The findings of the present study suggest that the phenotypic characteristics of EOM closely resemble those of otitis media associated with EGPA in early stages before the appearance of vasculitis. Therefore, it is challenging to differentiate the two conditions purely on the basis of otorhinological examinations. Address correspondence and reprint requests to Atsushi Fukuda, M.D., Department of Otolaryngology–Head & Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan; E-mail: atsushi.fukuda@huhp.hokudai.ac.jp The authors do not have any conflicts of interest to declare. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Characteristics and Outcomes of Pediatric Vestibular Schwannomas
Objective: To review the demographics, treatment modalities, and survival of children with vestibular schwannomas. Study Design: Analysis using the Surveillance, Epidemiology, and End Results (SEER) database. Subjects and Methods: Pediatric patients from birth to 18 years in the SEER database were included from 2004 to 2014 based on a diagnosis of vestibular schwannoma using the primary site International Classification of Diseases (ICD) O-3 code of C72.4: acoustic nerve and the ICD O-3 histology codes of 9540/1: neurofibromatosis, Not Otherwise Specified (NOS); 9560/0: neurilemoma, NOS; or 9570/0: neuroma, NOS. Results: One hundred forty-eight pediatric vestibular schwannomas (VSs) cases were identified. The mean age at diagnosis was 13.9 years (range, 4.0–18.0). Eighty-five (57.4%) patients were women. Seventy-seven (52.0%) patients had isolated unilateral VSs while 71 (48.0%) patients had either bilateral VSs or unilateral VSs with other brain, spinal cord, or cranial nerve tumors. Eighty two (55.4%) patients received surgical resection only, 45 (30.4%) received no treatment, 6 (4.1%) received radiation only, and 12 (8.1%) received surgery and radiation. The median tumor size for patients who received no treatment was 9.5 mm (interquartile range [IQR]: 8.0) compared with 33.5 mm (IQR: 23.0) for patients who received surgical care and 41.0 mm (IQR: 1.5) for patients who received both surgery and radiation (p < 0.001). The 5-year overall survival rate was 97%. Conclusion: Pediatric VSs tend to be diagnosed in adolescence. No men or women predominance was appreciated. Treatment varied according to tumor size. Survival rates for children with vestibular schwannomas are excellent. These data may assist healthcare providers when counseling children with vestibular schwannomas and their families. Address correspondence and reprint requests to Tyler A. Janz, M.D., University of Central Florida College of Medicine, Orlando, FL; E-mail: tjanz@knights.ucf.edu This is the first submission on this topic. The authors have no funding, financial relationships, or conflicts of interest to disclose. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

High-dose Corticosteroids for Adult Bell's Palsy: Systematic Review and Meta-analysis
Objectives: To compare the efficacy and safety of high-dose corticosteroids (initial prednisolone [PSL] of 100 mg or more daily) and standard-dose corticosteroids (initial PSL of 50–60 mg) in patients with Bell's palsy. Study Design: A systematic review and meta-analysis. Data Sources: Medline, Embase, Cochrane Central Register of Controlled Trials, Ichushi-Web, Web of Science, and CINAHL, combined with data from ClinicalTrials.gov. Study Selection: Published and unpublished cohort studies comparing high- and standard-dose corticosteroids in adult patients with Bell's palsy were included. Data Extraction: Study characteristics (study design, patient's number), patient characteristics (sex, age, disease severity, prescription of antivirals), and outcomes (nonrecovery, any adverse effects). Data Synthesis: From the 1,974 identified articles, 8 studies were met eligible criteria. Of the included studies, the initial dose in high-dose corticosteroids regimens varied from 120 mg to 200 mg PSL daily. Compared with standard-dose corticosteroids, high-dose corticosteroids were associated with a significantly decreased nonrecovery at 6 months after disease onset (odds ratio 0.42, 95% confidence interval 0.22–0.80; very low quality) in patients with Bell's palsy. No severe adverse effects were observed in patients receiving high- or standard-dose corticosteroids. Conclusion: High-dose corticosteroids reduce nonrecovery in patients with Bell's palsy. The dose of high-dose corticosteroids was varied and further prospective study is needed to identify an adequate dose of corticosteroids in these patients. Address correspondence and reprint requests to Takashi Fujiwara, M.D., Ph.D., Department of Otolaryngology Head and Neck Surgery, Kurashiki Central Hospital, 1-1-1 Miwa, Kurahiki, Okayama 710-8602, Japan; E-mail: t.fujiwarabi@gmail.com All authors declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. The authors disclose no conflicts of interest. Supplemental digital content is available in the text. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jcraniofacialsurgery.com). Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Endre Hőgyes (1847–1906), Forgotten Father of the Vestibulo-Ocular Reflex
Objective: Throughout the history of vestibular research, the discovery of the vestibulo-ocular reflex in 1881 by Endre Hőgyes (1847–1906) is rarely mentioned. The aim of this study is to review Hőgyes' vestibular research articles, all originally written in Hungarian and emphasize their epoch-making content. Main Data Sources: Hőgyes' vestibular publications, originally written in Hungarian, which describe various eye movements of the rabbit in response to vestibular stimulation by rotation about three axes. Results: Hőgyes was the first to use a three-axis turntable on an experimental animal, in this case a rabbit. He found that depending on the plane of rotation, different types of binocular eye movements were produced. He then demonstrated by destructive and excitatory experiments, the anatomical pathways and the physiological function producing this phenomenon. Ultimately, he explained the exact connections between the inner ear labyrinth and certain muscle contractions during eye movements. He identified this pathway as the "associating center of the ocular movements," later defined as the vestibulo-ocular reflex. Hőgyes' discovery was only superficially noted during his lifetime and ignored after his death. Conclusion: Hőgyes was the first to demonstrate the vestibulo-ocular reflex. He was forgotten during the ensuing 140 years probably because his articles were appeared only in Hungarian and because a short time later, Róbert Bárány's award of the Nobel Prize overshadowed many of Bárány's predecessors and contemporaries, including Hőgyes and relegated them to the background. Address correspondence and reprint requests to László T. Tamás, M.D., 9028, Győr, Vak Bottyán u.14/A, Hungary; E-mail: ltamas@gyor.net Dr. L.T.T. and Dr. A.M. helped in data collection, analysis, and interpretation, critically reviewing and editing the manuscript. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Anti-Cancer Drugs

Melanoma: the new perspectives from clinical and translational research

The prognosis of metastatic melanoma has not changed throughout the 20th century. However, in the last decade, we have witnessed a continuous improvement in survival, with many long-term survivors. These results are largely because of the simultaneous development of the knowledge in the biology of metastatic malignant melanoma and of the relationship between the disease and the host's immune system that allowed the development of effective new treatments. In this overview, we summarize the therapies available today, their biological rationale, and the research field currently under investigation divided into three main chapters: target therapies, immunotherapies, and their combination.

Poly (ADP-ribose) polymerase inhibitors combined with other small-molecular compounds for the treatment of ovarian cancer

Ovarian cancer is a heterogeneous disease with complex molecular and genetic hallmarks. Benefitting from profound understanding of molecular mechanisms in ovarian cancer pathogenesis, novel targeted drugs have been actively explored in preclinical studies and clinical trials. Considered as one of the most potent and effective targeted therapies for the treatment of ovarian cancer, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) take advantages of synthetic lethality mechanisms to prevent DNA damage repair in cancer cells and cause their death, especially in cancers with BRCA mutations. Mounting evidence has indicated that the combination of PARPis with cytotoxic drugs or other targeted drugs has shown favorable synergistic effects. Excitingly, the antitumor activity of combination therapy of PARPis has been actively tested in multiple clinical trials and in-vitro or in-vivo experiments. In this review, we will briefly discuss the molecular mechanisms of PARPis combined with other therapeutic small-molecular compounds for the treatment of ovarian cancer.

Knockdown of long noncoding RNA-taurine-upregulated gene 1 inhibits tumor angiogenesis in ovarian cancer by regulating leucine-rich α-2-glycoprotein-1

To investigate the role of long noncoding RNA taurine-upregulated gene 1 (TUG1) on ovarian cancer-induced angiogenesis and to explore possible signaling pathways. Ovarian cancer cell line SKOV3 or CAOV3 was transfected with short hairpin-TUG1 to suppress TUG1 expression. Supernatant from cultured cancer cells was used as a condition medium to incubate endothelial cell line human umbilical vein endothelial cells, whose proliferation rate was quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Migration and invasion of endothelial cells were examined by wound healing and Transwell assays, followed by in-vitro angiogenesis assay. One of the secretory factors mediating angiogenesis, leucine-rich α-2-glycoprotein-1 (LRG1), was measured in ovarian cancer cells. Signaling pathway mediating angiogenesis was further detected by western blotting. TUG1 was down-regulated in ovarian cancer cells by short hairpin RNA. Conditional medium originating from TUG1-knockdown cancer cells led to suppressed proliferation, migration, or invasion of endothelial cell line human umbilical vein endothelial cells. LRG1 expression and secretion was suppressed in ovarian cancer cells after TUG1 knockdown. Moreover, recombinant LRG1 rescued TUG1 knockdown-induced angiogenesis inhibition, and LRG1 probably mediated angiogenesis by tumor growth factor-β signaling pathway in endothelial cells. Long noncoding RNA-TUG1 mediates angiogenesis of endothelial cells by regulating LRG1 secretion from ovarian cancer cells partially through tumor growth factor-β pathway. Our results indicate the potency of TUG1 as a biomarker and therapeutic target for tumor-induced angiogenesis.

Pyrimethamine exerts significant antitumor effects on human ovarian cancer cells both in vitro and in vivo

Pyrimethamine has been used principally to treat infections from protozoan parasites. Although previous studies have shown that pyrimethamine exhibited anticancer activity by inducing cellular apoptosis, there are none that show that pyrimethamine possesses anticancer activity with respect to ovarian cancer. We examined the roles of pyrimethamine on apoptosis and proliferation, DNA damage, and cell cycle distribution of human ovarian cancer cell lines in vitro. To investigate the antitumor efficacy of pyrimethamine in vivo, we established two intraperitoneal ovarian carcinoma models in nude mice. Pyrimethamine significantly induced apoptosis of ovarian cancer cells via growth inhibition, cell cycle arrest, and nuclear DNA damage in vitro and manifested antitumor activity by inhibiting tumor growth, thereby prolonging the survival time of tumor-bearing mice. We also demonstrated that pyrimethamine increased the expression of caspase-9 and decreased the expression of X-linked inhibitor of apoptosis protein. In conclusion, the antitumor effects of pyrimethamine were associated with enhanced apoptosis of tumor cells and inhibition of the growth of intratumoral microvessels. Our results indicate that pyrimethamine may provide an effective approach toward inhibiting the growth of ovarian cancer with minimal adverse effects.

MiR-29a inhibits cell proliferation and migration by targeting the CDC42/PAK1 signaling pathway in cervical cancer

Cervical cancer is the second most common gynecological malignancy worldwide and the tumorigenesis mechanisms of cervical cancer are still unclear. This study aimed to reveal the role of miR-29a in cervical cancer. The expression level of miR-29a and CDC42 was measured using qRT-PCR. Cell proliferation, apoptosis, migration, and invasion were detected using colony formation, flow cytometry analysis, wound-healing assay, and Transwell assay, respectively. Luciferase reporter assay was used to determine the binding of miR-29a with CDC42. CDC42/p21-activated kinase 1 (PAK1) pathway-related proteins were measured by western blotting. MiR-29a was downregulated and CDC42 was upregulated in cervical cancer cells. Luciferase reporter assay showed that miR-29a negatively regulated the expression of CDC42 by directly targeting 3′-UTR of CDC42. Cell proliferation, migration, and invasion were markedly inhibited, whereas cell apoptosis was significantly increased in Hela and CaSki cells transfected with miR-29a mimics. These effects were partly recovered by CDC42 overexpression. Protein levels of PAK1, p-PAK1, p-LIMK, and p-cofilin were significantly downregulated by miR-29a mimics, which was reversed by CDC42 overexpression and was increased by the miR-29a inhibitor. MiR-29a inhibited cell proliferation, migration, and invasion, as well as promoted cell apoptosis through repressing the PAK1/LIMK signaling pathway by targeting CDC42 in cervical cancer.

Construction of an miRNA–mRNA regulatory network in colorectal cancer with bioinformatics methods

Colorectal cancer (CRC) is the third most common cancer worldwide. This study aimed to explore the regulatory mechanisms of miRNAs in CRC. Differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) in CRC tissue samples compared with control samples in mRNA and miRNA datasets were screened. Functional and pathway enrichment analysis of the DEGs was carried out. Targets of the DEMs were identified. Overlaps between the DEGs and targets of DEMs were selected. The miRNA–mRNA regulatory network of these overlaps was constructed and visualized. The candidate genes selected were validated by quantitative real-time PCR. DEGs were identified and considered DEGs-1 and DEGs-2. A total of 584 genes in DEGs-1 and 527 genes in DEGs-2 were obtained, including 465 overlaps, and 44 DEMs were identified. The overlaps were enriched in 46 Gene Ontology terms and 19 Kyoto Encyclopedia of Genes and Genomes pathways. Moreover, 137 overlapped genes between targets of the DEMs and the 465 overlaps were obtained. The miRNA–mRNA regulating network of the 137 overlapped genes was constructed. Extracellular matrix-related proteins and pathways might play critical roles in the development of CRC. The quantitative real-time PCR results of the candidates were in agreement with the bioinformatics analysis. miR-128, miR-182, and miR-143 might be key miRNAs regulating cell proliferation and metastasis of CRC.

Upregulation of sine oculis homeobox homolog 3 is associated with proliferation, invasion, migration, as well as poor prognosis of esophageal cancer

Esophageal cancer (EC) is a common cancer worldwide. Sine oculis homeobox homolog (SIX3) is a human transcription factor that regulates the progression of vertebrate eye and fetal forebrain. However, studies on the function of SIX3 in human tumorigenesis remain rare. In this study, we aim to evaluate the role and the significance of SIX3 in EC. The TCGA database and clinical samples were used to assess the expression of SIX3 in EC patients. The Kaplan–Meier method and Cox's proportional hazards model were performed to analyze the correlations between SIX3 expression and EC clinical outcomes. The expressions of SIX3 in EC cells were measured by quantitative reverse transcription PCR analysis. The cell proliferation was detected using cell counting kit-8 and colony formation assay. The migration and invasion capacity of EC cells were evaluated using wound healing and Transwell methods. Western blot assay was used to measure the alterations in some important protein expression levels in the PI3K/Akt signaling pathway. We found that SIX3 was highly expressed in the EC tissues and cells. In addition, high expression of SIX3 was related to poor survival. The knockdown of SIX3 significantly inhibited the proliferation, migration, and invasion of ECA109 cells. A similar pattern was also found in the proliferation and migration of SKGT-4 cell line. The expression levels of some key proteins in the PI3K/Akt signaling pathway were obviously decreased after cells were transfected with si-SIX3, possibly resulting in PI3K/AKT signaling inactivation. In addition, E-cadherin and N-cadherin showed some change. Collectively, the results shed light on a potentially promoting role of SIX3 in human EC. Thus, SIX3 might be considered a novel prognostic biomarker and therapeutic target for EC patients.

Development of transferrin-modified poly(lactic-co-glycolic acid) nanoparticles for glioma therapy

Glioma is a primary intracranial malignant tumor with poor prognosis. In this study, we aimed to develop transferrin (Tf)-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles to deliver temozolomide (TMZ) to glioma and evaluate their efficacy to kill glioma. TMZ-loaded nanoparticles were prepared by nanoprecipitation technique and targeted by Tf. Tf-PLGA-TMZ and PLGA-TMZ were characterized for average particle sizes and zeta potentials, cellular uptake and cytotoxicity as well as in-vitro drug release of these nanoparticles were evaluated in human glioma U87MG cells. In-vivo antiglioma efficacy of Tf-PLGA-TMZ was evaluated in nude mice. Polydispersity ratio increased from 0.132 to 0.150, while encapsulation efficiency decreased from 69.4 to 55.8% after Tf modification of PLGA-TMZ. High performance liquid chromatography test showed that Tf-targeted nanoparticles were better internalized into U87MG cells than nontargeted nanoparticles. Moreover, Tf-PLGA-TMZ significantly decreased the viability of U87MG cells compared with nontargeted nanoparticles (P<0.05). In addition, Tf-PLGA-TMZ significantly decreased tumor volume and improved the survival of nude mice injected with U87MG cells. Tf-modified PLGA nanoparticles could be used for effective delivery of TMZ and have promise for the treatment of glioma.

Evodiamine inhibits migration and invasion by Sirt1-mediated post-translational modulations in colorectal cancer

Colorectal cancer (CRC) is one of the most difficult cancers to cure. An important prognostic factor is metastasis, which precludes curative surgical resection. Recent evidences show that Evodiamine (EVO) exerts an inhibitory effect on cancer cell apoptosis, migration, and invasion. In this study, we investigated the effects of EVO on the metastasis of CRC cells in vitro and in vivo. In vitro, wound-healing and transwell assay showed that migration and invasion of HT-29 and HCT-116 CRC cells were inhibited significantly by EVO. Western blot and RT-PCR showed that EVO reduced the expression of matrix metalloproteinase-9 in a dose-dependent manner. In EVO-induced cells, the intracellular NAD+/NADH ratio was increased, the level of Sirt1 was increased, and acetyl-NF-κB P65 was decreased. This process was inhibited by nicotinamide, an inhibitor of Sirt1. In vivo, EVO reduced tumor metastasis markedly. These findings provide evidences that EVO suppresses the migration and invasion of CRC cells by inhibiting the acetyl-NF-κB p65 by Sirt1, resulting in suppression of metalloproteinase-9 expression in vitro and in vivo.

Novel small molecule decreases cell proliferation, migration, clone formation, and gene expression through ERK inhibition in MCF-7 and MDA-MB-231 breast cancer cell lines

The Ras–Raf–MEK1/2–ERK1/2 pathway is an attractive target for the development of anticancer agents because of the high prevalence of ERK activation in human cancers. However, resistance is often developed despite initial clinical response, most likely because of activation of cross-talk pathways. In Research Genetic Cancer Center (RGCC), we are in the process of synthesizing a novel ERK inhibitor, targeting the final stage of the pathway, thus minimizing cross-talk. We have synthesized an intermediate molecule –RGCC416 – and tested its biological activity. MCF-7 and MDA-MB-231 cells were used. Cell viability was measured by crystal violet and cell proliferation by the methyl tetrazolium assay using various compound concentrations. Cell migration and colony formation were determined to assess the ability of invasion and single cancer cell growth, respectively. Expression of genes linked to MAPK/PI3K pathways was determined by PCR. ERK and phospho-ERK levels were determined in both the cytoplasm and the nucleus by western blot. It was found that although the compound did not affect viability, it significantly decreased cell proliferation, migration, and colony formation in both cell lines. In MDA-MB-231, this is possibly through retaining phospho-ERK to the cytoplasm, where it cannot activate cancer-associated genes. There was no difference in ERK levels in MCF-7 cells. This could be because of the different pathways that these cells utilize for survival. We have synthesized a molecule, which could be a promising ERK inhibitor, leading to possible novel treatment options for breast cancer patients.

Clinical Reports

Treatment of ALK-rearranged non-small-cell lung cancer with brigatinib as second or later lines: real-world observations from a single institution
Maximilian Hochmair, Christoph Weinlinger, Sophia Schwab, Jakob Naber, Ulrike Setinek, Dagmar Krenbek, Matthias H. Urban, Hannah Fabikan, Stefan Watzka, Renate Koger, Andreas Fazekas, Erwin Bitterlich, Arschang Valipour, Otto C. Burghuber

Poor outcome for patients with gastric cancer and lung metastases treated with ramucirumab and paclitaxel
Giandomenico Roviello, Silvia P. Corona, Andrea G. Multari, Roberto Petrioli, Pietro Rosellini, Michele Aieta

Efficacy and safety of apatinib in advanced sarcoma: an open-label, nonrandomized, single-center study of 45 patients
Yao Weitao, Wu Fangxing, Cai Qiqing, Wang Jiaqiang

Case Reports

Misleading impaired liver function in a non-small-cell lung cancer patient treated with pembrolizumab: a case report
Giorgia A. Osman, Arnaldo Marra, Daniela Iacono, Valerio Giannelli, Serena Ricciardi, Daniele Remotti, Andrea Vecchione, Alberto Ricci, Paolo Palange, Maria R. Migliorino

Apatinib, combined with chemotherapy or alone is effective in treating angiosarcoma: a case report
Mingyang Liu, Yongmin Liu, Huannan Guo, Dongwei Fu, Lili Lv, Chunhong Chen, Yanlin Li, Wenqian Zhang, Ming Yao, Limin Zhao

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Solid Pseudopapillary Neoplasms of the Pancreas: Clinicopathologic and Radiologic Features According...

Solid Pseudopapillary Neoplasms of the Pancreas: Clinicopathologic and Radiologic Features According to SizeRiccardo De Robertis1, Giovanni Marchegiani2, Matteo Catania3, Maria Chiara Ambrosetti3, Paola Capelli4, Roberto Salvia2 and Mirko D'Onofrio3 Show lessShare Share+ Affiliations:Citation: American Journal of Roentgenology: 1-8. 10.2214/AJR.18.20715AbstractFull TextReferencesPDFPDF PlusAdd to FavoritesPermissionsDownload CitationABSTRACT :OBJECTIVE. The purpose of this study was to retrospectively...

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