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Background Given concerns about risks associated with the growing use of mobile phones over recent decades, the authors analyzed temporal trends in incidence rates of nonmalignant meningioma and vestibular schwannoma in the United States. Methods The incidence of nonmalignant meningioma and vestibular schwannoma among adults in the Surveillance, Epidemiology, and End Results 18 registries during 2004 through 2017 was evaluated according to the method of diagnosis: microscopically (MC) or radiographically confirmed (RGC). Annual percent changes (APCs) and 95% CIs were estimated using log-linear models. Results Overall meningioma rates (n = 108,043) increased significantly from 2004 to 2009 (APC, 5.4%; 95% CI, 4.4%-6.4%) but subsequently rose at a slower pace through 2017 (APC, 1.0%; 95% CI, 0.6%-1.5%). Rates for MC meningiomas changed little from 2004 to 2017 (APC, -0.3%; 95% CI, -0.7%, 0.1%) but rose rapidly for RGC meningiomas until 2009 (APC, 9.5%; 95% CI, 7.8%-11.1%) and rose more modestly thereafter (APC, 2.3%; 95% CI, 1.5%-3.0%). Overall vestibular schwannoma rates (n = 17,475) were stable (APC, 0.4%; 95% CI, -0.2%, 1.0%), but MC vestibular schwannoma rates decreased (APC, -1.9%; 95% CI, -2.7%, -1.1%), whereas RGC vestibular schwannoma rates rose (2006-2017: APC, 1.7%; 95% CI, 0.5%-3.0%). For each tumor, the trends by diagnostic method were similar for each sex and each racial/ethnic group, but RGC diagnosis was more likely in older patients and for smaller tumors. Meningioma trends and the proportion of RGC diagnoses varied notably by registry. Conclusions Overall trends obscured differences by diagnostic method in this first large, detailed assessment, but the recent stable rates argue against an association with mobile phone use. Variation among registries requires evaluation to improve the registration of these nonmalignant tumors. Lay summary The etiology of most benign meningiomas and vestibular schwannomas is poorly understood, but concerns have been raised about whether mobile phone use contributes to risk of developing these tumors. Descriptive studies examining temporal trends could provide insight; however, globally, few registries collect these nonmalignant cases. In the United States, reporting benign meningiomas and vestibular schwannomas became required by law in 2004. This was the first large, systematic study to quantify and characterize incidence trends for meningioma and vestibular schwannoma according to whether the tumors were diagnosed microscopically or only radiographically. Differential trends across registries and by diagnostic method suggest that caution should be used when interpreting the patterns.

BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assgined to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design. RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantie 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%. CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.

Oncocytomas represent a subset of benign pituitary adenomas that are characterized by significant mitochondrial hyperplasia. Mitochondria are key organelles for energy generation and metabolic intermediate production for biosynthesis in tumour cells, so understanding the mechanism underlying mitochondrial biogenesis and its impact on cellular metabolism in oncocytoma is vital. Here, we studied surgically resected pituitary oncocytomas by using multi-omic analyses. Whole-exome sequencing did not reveal any nuclear mutations, but identified several somatic mutations of mitochondrial DNA, and dysfunctional respiratory complex I. Metabolomic analysis suggested that oxidative phosphorylation was reduced within individual mitochondria, and that there was no reciprocal increase in glycolytic activity. Interestingly, we found a reduction in the cellular lactate level and reduced expression of lactate dehydrogenase A (LDHA), which contributed to mitochondrial biogenesis in an in vitro cell model. It is of note that the hypoxia-response signalling pathway was not upregulated in pituitary oncocytomas, thereby failing to enhance glycolysis. Proteomic analysis showed that 14-3-3η was exclusively overexpressed in oncocytomas, and that 14-3-3η was capable of inhibiting glycolysis, leading to mitochondrial biogenesis in the presence of rotenone. In particular, 14-3-3η inhibited LDHA by direct interaction in the setting of complex I dysfunction, highlighting the role of 14-3-3η overexpression and inefficient oxidative phosphorylation in oncocytoma mitochondrial biogenesis. These findings deepen our understanding of the metabolic changes that occur within oncocytomas, and shine a light on the mechanism of mitochondrial biogenesis, providing a novel perspective on metabolic adaptation in tumour cells. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

BACKGROUND Outcomes projects can be a catalyst for determining disease- and treatment-related consequences for patients with rare tumors. The Adult Ependymoma Outcomes (AEO) survey uses self-reported experience to evaluate how this tumor affects patient groups throughout the illness trajectory. METHODS Patients completed the AEO survey via a Web-based portal. The survey included questions on treatment, tumor recurrence, and current health status; the MD Anderson Symptom Inventory Brain Tumor and Spine Tumor modules; and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). RESULTS The sample included 264 participants (57% female) with a median age of 46 years (range, 18-77 years). Radiation treatment was commonly used for patients who had brain involvement (χ2(1) = 20.7; P

Emerging evidence is demonstrating the extent of T-cell infiltration within the tumor microenvironment has favorable prognostic and therapeutic implications. Hence, immunotherapeutic strategies that augment the T-cell signature of tumors hold promising therapeutic potential. Recently, immunotherapy based on intratumoral injection of mannan-BAM, toll-like receptor ligands and anti-CD40 antibody (MBTA) demonstrated promising potential to modulate the immune phenotype of injected tumors. The strategy promotes the phagocytosis of tumor cells to facilitate the recognition of tumor antigens and induce a tumor-specific adaptive immune response. Using a syngeneic colon carcinoma model, we demonstrate MBTA’s potential to augment CD8(+) T-cell tumor infiltrate when administered intratumorally or subcutaneously as part of a whole tumor cell vaccine. Both immunotherapeutic strategies proved effective at controlling tumor growth, prolonged survival and induced immunological memory against the parental cell line. Collectively, our investigation demonstrates MBTA’s potential to trigger a potent anti-tumor immune response.

Objectives/Hypothesis To review the fistula rate in irradiated patients undergoing salvage laryngectomy, compare the effect of closure type on fistula rate, and examine possible perioperative risk factors that might contribute to an increased fistula rate. Study Design Case series with chart review. Methods We conducted a retrospective review of the University of Pittsburgh head and neck tumor registry and identified 73 patients from 1998 to 2011 who had received prior radiation before total laryngectomy or salvage laryngectomy and who had either primary closure, pectoralis major myofascial (PMMF) flap onlay, or pectoralis major myocutaneous (PMMC) flap. Results Fistula was more common in patients who underwent initial primary closure (45%) than in patients who had immediate PMMF onlay (10.5%). The fistula rate for patients who underwent immediate PMMC flap was 28.6%, intermediate to primary closure and PMMF flap. Several factors were evaluated for relationship to fistula, but no significant associations were identified. However, patients with fistula tended to have longer inpatient stays and may have been more likely to have a history of cardiovascular or hypoxic disease. Conclusion Pharyngocutaneous fistula is a well-established complication of total laryngectomy and is especially a concern in patients with a previous history of radiation. Our retrospective review demonstrates that PMMF onlay flap appears to be more effective in reducing the rate of fistula compared to primary closure in these patients. Myocutaneous augmentation flaps, in contrast, have a fairly high fistula rate and may be better replaced with alternative closures such as free flaps. Level of Evidence 4. Laryngoscope, 124:2680–2686, 2014

Objectives/Hypothesis This study aims to evaluate the pattern of nodal metastasis to level V in parotid cancer and to examine the clinical value of level V neck dissection (LVND). Study Design Retrospective cohort study. Methods Retrospective chart review of 86 patients (47 N0 nodal metastasis [N0] neck and 39 positive nodal metastasis [N+] neck) who received parotidectomy and neck dissection was performed. The prevalence of pathological nodal metastasis in level V neck was evaluated and correlated with locoregional recurrence. Results LVND was performed in 10.6% and 28.2% of patients with clinical NO (cN0) and cN+ neck disease, respectively. The prevalence of pathological positive nodal metastasis was 0% (cN0) and 81.8% (cN+). In patients with cN0 neck, the rate of recurrence in level V was 6%. Conclusion In our patient cohort with predominantly high-grade parotid cancer, LVND was necessary in patients with cN+ neck because there was a high likelihood for pathologically positive nodal metastasis. In patients with cN0 neck, the rate of recurrence in level V was low enough not to warrant a routine inclusion of LVND. Level of Evidence 4. Laryngoscope, 125:118–121, 2015

Background The clinical utility of intraparotid lymph node metastasis in primary parotid cancer is unknown, and this study was undertaken to address this gap in knowledge. Methods A medical chart review was performed on 86 patients who underwent parotidectomy with neck dissection (39 cN+ and 47 cN0). The disease-specific mortality and locoregional recurrence (LRR) were correlated with intraparotid lymph node metastasis status. Results Using intraparotid lymph node metastasis status to predict cervical nodal metastasis resulted in a sensitivity and specificity of 70% and 90.6%, respectively (positive predictive value [PPV] of 87.3%). Patients with positive intraparotid lymph node metastasis had a worse 3-year disease-specific mortality compared with patients with negative intraparotid lymph node metastasis (p = .0037). Patients with cN0 neck but positive intraparotid lymph node metastasis were more likely to develop locoregional recurrence than patients without intraparotid lymph node metastasis (p = .08). Conclusion In patients with cN0 neck but positive intraparotid lymph node metastasis, intraparotid lymph node metastasis presence was strongly associated with a worse disease-specific survival and placed them at a higher risk of locoregional recurrence. © 2013 Wiley Periodicals, Inc. Head Neck 36: 1634–1637, 2014

BACKGROUND: Evaluating the severity of symptoms in patients with primary brain tumors (PBTs) is important in clinical care and research but may be difficult due to patient neurocognitive (NC) impairment. This study was conducted to evaluate the congruence of symptom reporting in patient and caregiver dyads, examining potential impact of NC impairment and Karnofsky performance status (KPS). METHODS: PBT patients undergoing NC testing and their caregivers were included in this study. These dyads (paired patient and caregiver group) completed the MD Anderson Symptom Inventory-Brain Tumor Module prior to testing, and impairment was categorized based on NC test scores. Concordance and equivalency was then assessed using Bland-Altman analysis and 2 one-sided techniques. RESULTS: A total of 115 dyads participated. Median patient and caregiver age was 49 and 51 years, respectively, and 63% of patients were male (73% female caregivers). Most patients had a good KPS (≥90, 66%) but were classified as NC impaired (58%). Caregiver's report of patient symptoms are congruent to the self-report of the patient. Equivalency between patient and caregiver report were found using prespecified confidence intervals. KPS group (good, ≥90; poor, ≤80) comparisons of equivalency indicated no significant differences in symptoms and interference reporting between dyads (good = 0.49, P > .05; and poor = 0.3, P > .05) overall, but there was a tendency for higher report by caregivers if the patients had a poor KPS. CONCLUSIONS: Caregivers of PBT patients have similar assessments of symptom severity (highly congruent) with patient self-report regardless of NC function or KPS. These findings suggest that caregivers may serve as proxy report of symptoms for primary brain tumor patients. Cancer 2012. © 2012 American Cancer Society.

BACKGROUND: Therapeutic options for patients with anaplastic gliomas (AGs) are limited despite better insights into glioma biology. The authors previously reported improved outcome in patients with recurrent glioblastoma treated with thalidomide and irinotecan compared with historical controls. Here, results of the AG arm of the study are reported, using this drug combination. METHODS: Adults with recurrent AG previously treated with radiation therapy, with Karnofsky performance score ≥70, adequate organ function and not on enzyme-inducing anticonvulsants were enrolled. Treatment was in 6-week cycles with irinotecan at 125 mg/m2 weekly for 4 weeks followed by 2 weeks off, and thalidomide at 100 mg daily increased to 400 mg/day as tolerated. The primary endpoint was progression-free survival rate at 6 months (PFS-6), and the secondary endpoints were overall survival (OS) and response rate (RR). RESULTS: In 39 eligible patients, PFS-6 for the intent-to-treat population was 36% (95% confidence interval [CI] = 21%, 53%), median PFS was 13 weeks (95% CI = 6%, 28%) and RR was 10%(95% CI = 3%, 24%). Radiological findings included 2 complete and 2 partial responses and 17 stable disease. Median OS from study registration was 62 weeks, (95% CI = 51, 144). Treatment-related toxicities (grade 3 or higher) included neutropenia, diarrhea, nausea, and fatigue; 6 patients experienced venous thromboembolism. Four deaths were attributable to treatment-related toxicities: 1 from pulmonary embolism, 2 from colitis, and 1 from urosepsis. CONCLUSIONS: The combination of thalidomide and irinotecan did not achieve sufficient efficacy to warrant further investigation against AG, although a subset of patients experienced prolonged PFS/OS. A trial of the more potent thalidomide analogue, lenalidomide, in combination with irinotecan against AG is currently ongoing. Cancer 2012;3599–3606. © 2011 American Cancer Society.

Objectives/Hypothesis: The objective of the study was to evaluate a naturally derived liver extracellular matrix (L-ECM) scaffold for repair of an acute injury to the vocal fold lamina propria in a canine model. Methods: The vocal fold lamina propria was removed bilaterally in four dogs. One vocal fold in each dog was repaired with a porcine L-ECM scaffold, which was chosen because it contains hepatocyte growth factor, an antifibrotic growth factor that aids the healing of vocal folds. The other vocal fold was left untreated. At 3 months after surgery, morphologic and histologic analysis was performed to assess the vocal fold shape, collagen density, collagen composition, elastic fiber content, and glycosaminoglycan content. Results: The L-ECM–treated vocal fold showed increased collagen density in the superficial aspect of the vocal fold (P < .05). The L-ECM–treated vocal fold also showed an increased collagen III/I ratio as compared to the nontreated group (P < .05). However, the elastic fiber content was found to be increased in both groups, and the glycosaminoglycan content was decreased in both groups as compared to the normal vocal fold (P < .05) with no differences detected between groups. Conclusions: The L-ECM scaffold did not restore the biochemical composition or histologic appearance of the injured vocal fold as compared to normal. However, the increased ratio of collagen III/I and elastic fiber content suggests that L-ECM leads to formation of connective tissue that may be more pliable as compared to no treatment. Additional investigation, including functional assessment, is warranted. Laryngoscope, 2009

BACKGROUND: In addition to neurologic symptoms, fatigue is commonly reported in patients with primary brain tumors during radiation therapy and in long–term survivors of low–grade brain tumors. Other factors have not been explored. The aim of this study was to identify demographic and clinical factors that predict fatigue severity and to evaluate the association of fatigue with other symptoms throughout the disease trajectory. METHODS: Two hundred one patients with primary brain tumors completed the M. D. Anderson Symptom Inventory–Brain Tumor Module and a demographic checklist. Clinical data, including treatment, tumor grade, and performance status, were also collected. Correlations among fatigue and other recorded symptoms were evaluated. Logistic regression modeling was performed to evaluate factors associated with fatigue severity. RESULTS: Fatigue severity was associated with symptoms including pain, drowsiness, distress, difficulty sleeping, and weakness as well as overall symptom severity and interference. Poor performance status (Karnofsky scale) (odds ratio [OR], 5.73; P = .001), female sex (OR, 2.48; P = .005), and disease status (OR, 2.20; P = .013) were the strongest predictors of fatigue. Severity of fatigue for women was primarily predicted by disease status (OR, 3.33; P = .01) For men, antidepressant use (OR, 4.43; P = .013) in addition to opioids (OR, 3.46; P = .017) and performance status (OR, 12.47; P = .0001) predicted fatigue severity. CONCLUSIONS: Fatigue should not be considered a solitary symptom with 1 root cause, but a complex symptom related to the severity of other symptoms and potentially having various etiologies. Future studies should consider these factors in planning interventions and assessing response. Cancer 2010. © 2010 American Cancer Society.