Citations

Abstract BACKGROUND: The optimum treatment for cystic vestibular schwannoma (VS) remains controversial. Anecdotally, many treating physicians feel that cystic VSs do not respond to stereotactic radiosurgery (SRS) as well as noncystic tumors. OBJECTIVE: To present outcomes after treatment of predominantly cystic VS with SRS. METHODS: A prospectively maintained clinical database of patients undergoing Gamma Knife (Elekta Instruments, Stockholm, Sweden) radiosurgery (GKRS) for VS at a single tertiary academic referral center was retrospectively reviewed. Patients diagnosed with cystic VS who were treated with GKRS between 1997 and 2014 were analyzed. Size-matched solid tumors treated with GKRS during this period were selected as controls. RESULTS: Twenty patients (12 women; median age at treatment, 56 years; range, 36-85 years) with cystic VS met inclusion criteria. The median radiologic follow-up within the cystic group was 63 months (range, 17-201 months), and the median change in tumor size was −4.9 mm (range, −10.4 to 9.3 mm). Sixteen tumors (80%) shrank, 2 (10%) remained stable, and 2 (10%) enlarged, accounting for a tumor control rate of 90%. The median radiologic follow-up in the noncystic control group was 67 months (range, 6-141 months), and the median change in size was −2.0 mm (range, −10.4 to 2.5 mm). Tumor control in the solid group was 90%. Comparing only those tumors that decreased in size showed that there was a trend toward a greater reduction within the cystic group ( P = .05). CONCLUSION: The present study demonstrates that tumor control after SRS for cystic VS may not differ from that of noncystic VS in selected cases.

Abstract Autophagy has been linked with melanoma, but no polymorphisms in autophagy related (ATG) genes have been investigated for association with melanoma prognostic indicators and survival. We examined 5 ATG gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. DNA from 911 melanoma patients was genotyped for five SNPs with a known or suspected impact on autophagic flux. While we did not identify an association with survival, a significant association was identified between the minor allele for an ATG16L polymorphism (rs2241880) and a decrease in Breslow thickness (p = 0.03), earlier tumor stage at diagnosis (OR 0.47, 95% CI 0.27-0.81, p = 0.02) and younger age at diagnosis (p = 0.02). In addition, two SNPs in ATG5 (rs2245214 and rs510432) were found to be significantly associated with increased tumor stage of melanoma (OR 1.84 95% CI 1.12-3.02, p = 0.05; OR 1.47 95% CI 1.11-1.94, p = 0.03). Finally, we identified inverse associations between the minor allele of rs2245214 and melanomas on the scalp or neck (OR 0.20, 95% CI 0.05-0.86, p = 0.03); rs1864182 (OR 0.42, 95% CI 0.21-0.88, p = 0.02) and brisk TILs, and rs510432 (OR 0.55 95% CI 0.34-0.87, p = 0.01) with non-brisk TILs, although they were not globally significant. In summary, our data suggests that ATG SNPs, while not associated with survival, may be associated with Breslow thickness, tumor stage, age at diagnosis, and aggressive histopathological factors. These associations could contribute to our current understanding of the significant role of autophagy in melanoma progression. Citation Format: Kirsten A. m. White, Li Luo, Todd A. Thompson, Salina Torres, Chien-An A. Hu, Nancy E. Thomas, Hoda Anton-Culver, Stephen B. Gruber, Lynn From, Klaus J. Busam, Irene Orlow, Peter A. Kanetsky, Lorraine D. Marrett, Richard P. Gallagher, Roberto Zanetti, Stefano Rosso, Terry Dwyer, Anne E. Cust, Allison Venn, Colin B. Begg, Marianne Berwick, Jenna Lillyquist. Variants in autophagy related genes and clinical characteristics in melanoma: a population-based study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1016.

Objectives/HypothesisTo report the preliminary outcomes of patients with single‐sided deafness and asymmetric hearing loss undergoing cochlear implantation at two centers.Study DesignRetrospective review and prospective data collection.MethodsPatients with single‐sided deafness who underwent cochlear implantation at two centers were included. Pre‐ and postoperative measures included monosyllabic word and sentence recognition in quiet for the ear implanted, and sentence recognition in noise in the best‐aided bilateral condition.ResultsAverage monosyllabic word recognition scores in quiet improved significantly from 11.3% (standard deviation [SD] 15.6%) preoperatively to 48.7% (SD 24.2%) at the 3‐month postactivation interval, although they did not increase significantly between the 3‐month and 6‐month intervals. Sentence recognition scores in quiet increased significantly from 18.4% (SD 28.5%) preoperatively to 65.9% (SD 17.9%) at the 3‐month postactivation interval, but not between the 3‐month and 6‐month intervals. Sentence recognition in noise in the best‐aided bilateral condition increased from 59% (SD 16.3%) preoperatively to 72% (SD 16.0%) at 6‐months postactivation, though the difference was not statistically significant. Thirteen of the participants reported tinnitus prior to surgery. Of those, 12 reported that tinnitus was improved after implantation, and one reported that tinnitus was unchanged.ConclusionPreliminary results suggest that speech recognition in a singly deafened ear is significantly improved after cochlear implantation, although speech recognition in noise measured in the bilateral condition remains the same at 6‐months postactivation.Level of Evidence4. Laryngoscope, 127:223–228, 2017

Objectives/HypothesisTo highlight the phenomenon of cholesteatoma arising from the vascular strip following tympanoplasty and tympanomastoidectomy.Study DesignMulti‐institutional retrospective chart review.MethodsConsecutive adult and pediatric patients evaluated between 2000 and 2015 with acquired cholesteatoma arising from the skin of a prior vascular strip were identified. Patients with evidence of residual or recurrent cholesteatoma elsewhere in the middle ear, mastoid, or ear canal were excluded.ResultsSeventeen cases (71% female, 53% right‐sided) were identified, and the mean age at presentation was 39.2 years. Patients presented on average 12.9 years following prior otologic surgery, which was most commonly tympanoplasty without mastoidectomy (59%). However, younger patients presented with symptoms sooner following prior surgery (r = 0.61, r2 = 0.37, P = 0.0095). The most common presenting symptom was otorrhea (76%). All patients were found to have mastoid cholesteatoma with bony erosion, and three patients exhibited additional tegmen or posterior fossa bone defects. The middle ear was not involved with cholesteatoma in any case. A canal wall down procedure was performed due to extensive bony canal erosion in 29% of cases.ConclusionThe vascular strip is an uncommon source of iatrogenic cholesteatoma that can present years following an otherwise uncomplicated otologic surgery. The findings presented herein highlight the importance of careful vascular strip orientation at the conclusion of otologic surgery.Level of Evidence4. Laryngoscope, 127:698–701, 2017

Abstract Purpose: Somatic mosaic mutation in the PPM1D gene have been associated with risk of breast and ovarian cancer. Somatic mosaic mutations in blood cells may be associated with older age and chemotherapy exposure. We wanted to determine if somatic mosaic mutations in PPM1D and in other genes are associated with older age and repeated exposure to chemotherapy, rather than a contributor to risk of disease. Experimental design: We used targeted capture and massively parallel genomic sequencing to sequence DNA from PBMCs from affected patients for PPM1D as well as 60 other DNA repair genes. For a number of samples with PPM1D mutations, we re-sequenced at greater depth on patients where PBMCs that were collected at diagnosis and recurrence. Results: We identified somatic mosaic mutations in exon 6 of PPM1D in 4 out of 474 (0.8%) individuals that were newly diagnosed and had no previous chemotherapy, in 3 out of 29 (10%) individuals newly diagnosed but receiving chemotherapy and in 58 of 274 (21%) individuals with relapsed platinum resistant ovarian cancer (p<0.0001). The presence of PPM1D mutations in exon 6 was strongly associated with more advanced age (p=0.011, Wilcoxon test) and more than one chemotherapy regimen (p=0.026, Fisher's exact test). In paired blood samples from 13 patients, PPM1D mutations present at relapse were either not detected or detected at a lower percentage compared to blood obtained soon after diagnosis. Somatic mosaic mutations were also identified in TP53 in 7 of 274 (2.5%) women with relapsed platinum resistant cancer. In one of these cases, we had an earlier blood sample from diagnosis in which the mutation was not present at time near diagnosis. Conclusion: We found that somatic mosaic PPM1D mutations in PMBCs are associated with advanced age and repeated exposure to chemotherapy. Mosaic mutations in other genes were not confirmed with the exception of TP53, for which mutations are also detectable after extensive treatment. It seems likely that mosaic PPM1D mutations in blood from cancer patients may be a result of selection by chemotherapy of age-induced somatic mutations during exposure to chemotherapy. Further studies are needed to determine the clinical significance of these mutations. Citation Format: Maria I. Harrell, Barbara M. Norquist, Tom Walsh, Mark F. Brady, Ming K. Lee, Robert Hershberg, Kimberly R. Kalli, Heather Lankes, Eric Q. Konnick, Colin C. Pritchard, Bradley J. Monk, John K. Chan, Robert Burger, Scott H. Kaufmann, Michael J. Birrer, Elizabeth M. Swisher. Old age and chemotherapy contribute to the selection of PPM1D somatic mosaic mutations in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B71.

Objectives/HypothesisTo evaluate outcomes of salvage surgery for vestibular schwannoma (VS) that failed primary stereotactic radiosurgery (SRS).MethodsCase‐control study of 37 patients who underwent surgical resection of sporadic VS following prior SRS at two tertiary academic referral centers between 2003 and 2015. A cohort of nonirradiated control subjects, matched according to tumor size, age, and treatment center, were used as comparison.ResultsThirty‐seven patients were included. The median time from radiation to surgical salvage was 36 months (range 9.6–153 months). Following tumor progression after SRS, 18 (49%) patients underwent gross total resection, 10 (27%) underwent near‐total resection, and nine (24%) underwent subtotal resection. Postoperative complications following salvage surgery included one (3%) case of stroke, four (11%) cases of cerebrospinal fluid leak, and two (5%) cases of meningitis. Twenty‐seven (73%) patients had good postoperative facial nerve outcome (House‐Brackmann Score I–II) at long‐term follow‐up. There were no cases of tumor recurrence or regrowth after a median length of 26 months following microsurgical salvage (range 3–114 months). The rate of satisfactory postoperative facial nerve function was not different between study and control subjects (73% vs. 76%; P = 0.8); however, less‐than‐complete resection was utilized more frequently among previously radiated patients (P = 0.01).ConclusionMicrosurgical salvage of VS following primary radiation therapy is challenging. Less‐than‐complete resection is required in a greater percentage of patients to preserve facial nerve integrity and prevent neurological complications. Long‐term follow‐up is needed to determine the risk of delayed progression following incomplete tumor removal.Level of Evidence3b. Laryngoscope, 126:2580–2586, 2016

ObjectiveWhite matter hyperintensities (WMHs) are areas of increased signal on T2‐weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD.MethodsThe study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first‐degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed‐effects piece‐wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO.ResultsMutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset.InterpretationAutosomal‐dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929–939

ObjectivesBipolar disorder (BD) is a complex disease associated with various hereditary traits, including a higher body mass index (BMI). In a prior genome‐wide association study, we found that BMI modified the association of rs12772424 – a common variant in the gene encoding transcription factor 7‐like 2 (TCF7L2) – with risk for BD. TCF7L2 is a transcription factor in the canonical Wnt pathway, involved in multiple disorders, including diabetes, cancer and psychiatric conditions. Here, using an independent sample, we evaluated 26 TCF7L2 single nucleotide polymorphisms (SNPs) to explore further the association of BD with the TCF7L2–BMI interaction.MethodsUsing a sample of 662 BD cases and 616 controls, we conducted SNP‐level and gene‐level tests to assess the evidence for an association between BD and the interaction of BMI and genetic variation in TCF7L2. We also explored the potential mechanism behind the detected associations using human brain expression quantitative trait loci (eQTL) analysis.ResultsThe analysis provided independent evidence of an rs12772424–BMI interaction (p = 0.011). Furthermore, while overall there was no evidence for SNP marginal effects on BD, the TCF7L2–BMI interaction was significant at the gene level (p = 0.042), with seven of the 26 SNPs showing SNP–BMI interaction effects with p < 0.05. The strongest evidence of interaction was observed for rs7895307 (p = 0.006). TCF7L2 expression showed a significant enrichment of association with the expression of other genes in the Wnt canonical pathway.ConclusionsThe current study provides further evidence suggesting that TCF7L2 involvement in BD risk may be regulated by BMI. Detailed, prospective assessment of BMI, comorbidity, and other possible contributing factors is necessary to explain fully the mechanisms underlying this association.