Emily Van Meter Dressler

Epidemiology of meningiomas post‐Public Law 107‐206: The Benign Brain Tumor Cancer Registries Amendment Act

The current analysis follows the implementation of Public Law 107‐260, the Benign Brain Tumor Cancer Registries Amendment Act, which mandated the collection of nonmalignant brain tumors.

Plasma TNF-α and Soluble TNF Receptor Levels after Doxorubicin with or without Co- Administration of Mesna—A Randomized, Cross-Over Clinical Study

Purpose Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines. Methods Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy. Results Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration. Conclusions The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI. Trial Registration clinicaltrials.gov NCT01205503.

Demographics, patterns of care, and survival in pediatric medulloblastoma

We evaluated the American College of Surgeon’s National Cancer Data Base (NCDB) to describe current hospital-based epidemiologic frequency, survival, and patterns of care of pediatric medulloblastoma. We analyzed NCDB 1998–2011 data on medulloblastoma for children ages 0–19 years using logistic and poisson regression, Kaplan–Meier survival estimates, and Cox proportional hazards models. 3647 cases of medulloblastoma in those aged 0–19 years were identified. Chemotherapy was received by 79 and 74% received radiation, with 65% receiving both therapies. Those who received radiation were more likely to be older than four, while those who received chemotherapy were more likely to be age four and younger. Variables associated with receipt of neither radiation nor chemotherapy included age at diagnosis of <1 year, female gender, being of race other than black or white, having no insurance, and living in a residential area with a low level of high school graduates. Better overall survival was observed as age at diagnosis increased, in females, and having received radiation. Compared to medulloblastoma, NOS, better survival was observed for those with demoplastic medulloblastoma, with worse survival in those with large cell medulloblastoma. Majority received multi- disciplinary therapy and radiation had the greatest effect on survival. Ages four and under were most likely to receive chemotherapy and least likely to receive radiation. Suboptimal treatment included 17.8% that did not receive chemotherapy, of which 11.8% received neither chemotherapy nor radiation. Disparities associated with medical access were characteristics for not receiving standard treatment, which resulted in poor outcome.

Prospective validation of an intraoperative algorithm to guide surgical staging in early endometrial cancer

OBJECTIVES Prospectively validate an intraoperative surgical staging algorithm to stratify patients with early endometrial cancer by risk of lymph node metastasis. METHODS Subjects with endometrial cancer clinically confined to the uterus were prospectively enrolled at an academic cancer center between Jan 2012 and Jun 2015. Study participants were stratified intraoperatively into two groups based on risk of nodal involvement using cell type, tumor grade, myometrial invasion, and tumor size in accordance with an established protocol from the Mayo Clinic. Low risk (LR) subjects received extrafascial hysterectomy with bilateral salpingo-oophorectomy; high risk (HR) patients received complete surgical staging including bilateral pelvic and para-aortic lymphadenectomy. RESULTS Of the 200 subjects enrolled, 194 were eligible for analysis. The algorithm identified 132 (68%) HR and 62 (32%) LR cancers. Of the HR subjects, 126 had lymphadenectomy performed with 14 (11%) positive for nodal metastases. Five HR subjects experienced disease recurrence. Of the 62 LR cancers, two patients developed disease recurrence. Ten LR cancers were upgraded to HR on final pathology due to lesion size (6) and grade (4). None of these patients experienced disease recurrence. The algorithm demonstrated 90% sensitivity (18/20) and 36% specificity (62/174) as determined by positive lymph nodes and/or disease recurrence. CONCLUSIONS Intraoperative assessment of early endometrial cancer can be used to determine the extent of surgical staging. The studied algorithm has low specificity and modifications are necessary to better match the surgical procedure to the risk of metastatic cancer.

Vocal Function Exercises for Normal Voice: The Effects of Varying Dosage

Abstract Purpose: This study examined the effect of varying dosage of vocal function exercise (VFE) home practice on attainment of pre-established maximum phonation time (MPT) goals in individuals with normal voice. High dosage VFE practice was expected to result in greatest MPT. The overarching goal of this study was to contribute to a VFE dosage-response curve, potentially including a point of observable toxicity. Method: Twenty-eight females ages 18–25 with normal voice participated in this pre-post longitudinal group study. Participants were randomly assigned to one of three experimental groups and completed a six-week VFE protocol with practice twice daily. The low dosage group performed each exercise once, the traditional group twice, and the high dosage group four times. The primary outcome measure was MPT as performed on the fourth VFE using the prescribed semi-occluded vocal tract posture. Result: No toxic effects were observed. MPT increased for all participants, with significant improvement for traditional and high dosage groups. Conclusion: High dosage VFEs may yield more rapid improvement in MPT, however benefits must be weighed against the risk of increased attrition. Low dosage VFEs insufficiently improved MPT. Further research on dosage is warranted, and should include individuals with disordered voice.

A Multidimensional Study of Vocal Function Following Radiation Therapy for Laryngeal Cancers

Background: Radiation therapy (XRT) has proven to be an effective curative modality in the treatment of laryngeal cancers. However, XRT also has deleterious effects on vocal function. Aim: To demonstrate the multidimensional nature of deficits in vocal function as a result of radiation therapy for laryngeal cancer. Study Design: Cohort study. Methodology: Vocal function parameters were chosen from the 5 domains of voice assessment to complete a multidimensional assessment battery. Adults irradiated (XRT group) for laryngeal cancers were compared to a control group of individuals with no history of head and neck cancers or radiation therapy. The control group was matched in age, sex, and pack years of smoking. Results: Eighteen participants were recruited for the study. The XRT group demonstrated significantly worse clinical values as compared to the control group across select parameters in the each of the 5 domains of voice assessment. Discussion: Radiation therapy for laryngeal cancers results in multidimensional deficits in vocal function. Notably, these deficits persist long term. In the present study sample, multidimensional deficits were persistent 2 to 7 years following completion of XRT. The observed multidimensional persistent vocal difficulties highlight the importance of vocal rehabilitation in the irradiated larynx cancer population.

Effects of ageing on orofacial fine force control and its relationship with parallel change in sensory perception

Abstract Purpose: Current theoretical models suggest the importance of a bidirectional relationship between sensation and production in the vocal tract to maintain lifelong speech skills. The purpose of this study was to assess age-related changes in orofacial skilled force production and to begin defining the orofacial perception-action relationship in healthy adults. Method: Low-level orofacial force control measures (reaction time, rise time, peak force, mean hold force (N) and force hold SD) were collected from 60 adults (19–84 years). Non-parametric Kruskal Wallis tests were performed to identify statistical differences between force and group demographics. Non-parametric Spearman’s rank correlations were completed to compare force measures against previously published sensory data from the same cohort of participants. Result: Significant group differences in force control were found for age, sex, speech usage and smoking status. Significant correlational relationships were identified between labial vibrotactile thresholds and several low-level force control measures collected during step and ramp-and-hold conditions. Conclusion: These findings demonstrate age-related alterations in orofacial force production. Furthermore, correlational analysis suggests as vibrotactile detection thresholds increase, the ability to maintain low-level force control accuracy decreases. Possible clinical applications and treatment consequences of these findings for speech disorders in the ageing population are provided.

Using low-dose radiation to potentiate the effect of induction chemotherapy in head and neck cancer: Results of a prospective phase 2 trial

Purpose Low-dose fractionated radiation therapy (LDFRT) induces effective cell killing through hyperradiation sensitivity and potentiates effects of chemotherapy. We report our second investigation of LDFRT as a potentiator of the chemotherapeutic effect of induction carboplatin and paclitaxel in locally advanced squamous cell cancer of the head and neck (SCCHN). Experimental design Two cycles of induction therapy were given every 21 days: paclitaxel (75 mg/m2) on days 1, 8, and 15; carboplatin (area under the curve 6) day 1; and LDFRT 50 cGy fractions (2 each on days 1, 2, 8, and 15). Objectives included primary site complete response rate; secondary included overall survival, progression-free survival (PFS), disease-specific survival, and toxicity. Results A total of 24 evaluable patients were enrolled. Primary sites included oropharynx (62.5%), larynx (20.8%), oral cavity (8.3%), and hypopharynx (8.3%). Grade 3/4 toxicities included neutropenia (20%), leukopenia (32%), dehydration/hypotension (8%), anemia (4%), infection (4%), pulmonary/allergic rhinitis (4%), and diarrhea (4%). Primary site response rate was 23/24 (95.8%): 15/24 (62.5%) complete response, 8/24 (33.3%) partial response, and 1/24 (4.2%) stable disease. With median follow-up of 7.75 years, 9-year rates for overall survival were 49.4% (95% confidence interval [CI], 30.5-79.9), PFS was 72.2% (CI, 55.3-94.3), and disease-specific survival was 65.4% (44.3-96.4). Conclusion Chemopotentiating LDFRT combined with paclitaxel and carboplatin is effective in SCCHN and provided an excellent median overall survival of 107.2 months, with median PFS not yet reached in this locally advanced SCCHN cohort. This compares favorably to prior investigations and caused fewer grade 3 and 4 toxicities than more intensive, 3-drug induction regimens. This trial demonstrates the innovative use of LDFRT as a potentiator of chemotherapy.

p16INK4a Status and Response to Induction Low-Dose Fractionated Radiation in Advanced Head and Neck Cancer.

Objective: To evaluate the impact of p16INK4a (p16) expression on clinical efficacy of induction low-dose fractionated radiation therapy (LDFRT) with concurrent chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Study Design: Historical cohort study. Setting: Tertiary medical center. Methods: A total of 66 Patients with locally advanced SCCHN were enrolled in 2 clinical trials using paclitaxel, carboplatin, and concurrent LDFRT induction therapy. Patients were evaluated for response to induction by a multidisciplinary team and then were given definitive treatment. Adequate tissue samples from the pretreatment biopsies of 42 individuals were identified and analyzed for p16 expression. Expression was correlated with clinical outcomes. Results: Of 42 tumors, 15 (35.7%) were positive for p16. Patients with p16-positive tumors had improved response to induction, but this was not statistically significant (P = .06). Five-year overall survival was 80% in p16-positive patients and 58% in p16-negative patients (P = .025). Conclusions: p16 Expression affects treatment response in patients treated with induction LDFRT with concurrent chemotherapy. This is similar to results reported for standard induction chemotherapy.

Association of hypertension and treatment outcomes in advanced stage non-small cell lung cancer patients treated with bevacizumab or non-bevacizumab containing regimens

Background Studies suggest that bevacizumab-induced hypertension is prognostic of better outcomes in bevacizumab-treated patients with metastatic colorectal, HER2-negative breast, kidney, and pancreatic cancer. Few have examined this correlation in metastatic non-small cell lung cancer and evaluated whether hypertension independent of bevacizumab can improve the treatment outcomes. Objectives The primary objective was to determine the effect of hypertension on the overall response of advanced non-small cell lung cancer patients from start of the first-line chemotherapy to maintenance therapy. Secondary objectives include the effect of hypertension on the overall survival in all patients and on the overall response in bevacizumab-treated patients. Methods A retrospective chart review for a single institution was conducted from 2008 to 2013 on all patients with advanced non-squamous non-small cell lung cancer who received ≥ 1 cycle of combination chemotherapy. Patients were divided into hypertension versus no hypertension and into bevacizumab versus non-bevacizumab groups. Results Of the 188 advanced non-small cell lung cancer patients evaluated, 62 were treated with bevacizumab-containing regimens. The mean age at diagnosis was 58 years in both the groups. Hypertension independent of bevacizumab did not lead to improved treatment outcomes. However, in the bevacizumab subgroup, hypertensive patients had significantly higher response rates versus non-hypertensive patients (36.7% vs. 12.5%; p = 0.02). There was no significant difference in the overall survival between hypertensive versus non-hypertensive patients. Conclusion While hypertension alone did not significantly improve the treatment outcomes, hypertension in bevacizumab-treated patients with metastatic non-small cell lung cancer led to significantly improved responses. Further prospective studies are needed to confirm the association of hypertension with improved treatment outcomes in metastatic NSCLC.