Mathew Geltzeiler

An integrated approach to anti-cancer drug sensitivity prediction

A framework for design of personalized cancer therapy requires the ability to predict the sensitivity of a tumor to anticancer drugs. The predictive modeling of tumor sensitivity to anti-cancer drugs has primarily focused on generating functions that map gene expressions and genetic mutation profiles to drug sensitivity. In this paper, we present a new approach for drug sensitivity prediction and combination therapy design based on integrated functional and genomic characterizations. The modeling approach when applied to data from the Cancer Cell Line Encyclopedia shows a significant gain in prediction accuracy as compared to elastic net and random forest techniques based on genomic characterizations. Utilizing a Mouse Embryonal Rhabdomyosarcoma cell culture and a drug screen of 60 targeted drugs, we show that predictive modeling based on functional data alone can also produce high accuracy predictions. The framework also allows us to generate personalized tumor proliferation circuits to gain further insights on the individualized biological pathway.

Regional Control of Head and Neck Melanoma With Selective Neck Dissection

IMPORTANCE Historically, patients with cervical metastases from melanoma of the head and neck were treated with a radical neck dissection. This study evaluates the efficacy of limiting the extent of lymphadenectomy in this high-risk population. OBJECTIVES To determine whether limiting the extent of lymphadenectomy for patients with biopsy-proven melanoma has a negative effect on regional control. Our hypothesis was that performing a more limited lymphadenectomy does not have a negative impact on regional control. DESIGN, SETTING, AND PARTICIPANTS A retrospective, single-cohort study was performed using a prospectively collected database of patients with head and neck melanoma with histopathologically positive lymph nodes after modified radical (MRND) or selective neck dissection (SNDs) performed at a high-volume, academic, tertiary care center. INTERVENTIONS Lymphadenectomy was performed as clinically indicated. MAIN OUTCOMES AND MEASURES Primary end points were regional recurrence and regional recurrence free survival. Univariable and multivariable analyses were conducted using multiple patient characteristics. RESULTS Forty-one patients underwent SND or MRND from 2001 through 2010. The median number of positive nodes was 1 (range, 1-16). Twenty-six patients (63%) received adjuvant radiation and 23 patients (56%) received adjuvant immunotherapy or chemotherapy. The median follow-up time was 17 months (range, 1-116 months). Regional control was achieved in 29 patients (71%). Median regional recurrence-free survival was 21 months (range, 1-116 months). Age (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26), total number of nodes examined (HR, 1.05; 95% CI, 1.01-1.10), and number of sentinel lymph nodes examined (HR, 1.45; 95% CI, 1.01-2.09) were all significantly associated with increased recurrence-free survival. Tumor depth, extracapsular spread, number of nodes positive, prior SLNB, extent of lymphadenectomy, and adjuvant therapy were not significant. CONCLUSIONS AND RELEVANCE Limiting the extent of lymphadenectomy with frequent use of adjuvant radiation therapy is effective in achieving regional control of head and neck melanoma with cervical metastases.

Transoral robotic surgery for management of cervical unknown primary squamous cell carcinoma: Updates on efficacy, surgical technique and margin status ☆

IMPORTANCE Management of cervical unknown primary squamous cell carcinoma (CUP) has evolved with the introduction of transoral robotic surgery (TORS). OBJECTIVES 1. To describe the efficacy of TORS lingual and palatine tonsillectomy in identifying the primary site of malignancy. 2. To explore how the extent of surgery affects diagnostic yield. 3. To report margin status of TORS resections. DESIGN, SETTING AND PARTICIPANTS A retrospective, single-center cohort study utilizing a prospectively collected database of CUP patients in a high-volume tertiary referral center. Patient underwent operative laryngoscopy plus TORS as clinically indicated. MAIN OUTCOMES AND MEASURES Primary end point was successful identification of the primary. The extent of surgery and margin status were also examined. RESULTS From 2010-2016, 64 patients with CUP were treated. The primary tumor was found in 51 patients (80%). Fourteen patients (22%) were identified with operative laryngoscopy alone. Fifty patients underwent TORS lingual tonsillectomy ± palatine tonsillectomy with 37 primary tumors identified (74%). The primary was located in the lingual tonsil in 32 patients (86%) and palatine tonsil in 5 patients (10%, p<0.001). Negative margins were achieved in 19 patients (51%). The deep margin was the most commonly positive margin (47%, p=0.049). CONCLUSION AND RELEVANCE Operative laryngoscopy with TORS is efficacious, localizing the primary in 80% of patients. If a margin was positive, it was most commonly the deep margin. This study provides valuable information that can help standardize surgical technique, further increasing the diagnostic yield and decreasing the negative margin rate of TORS for CUP.

Predictors of extracapsular extension in HPV-associated oropharyngeal cancer treated surgically

OBJECTIVES Extracapsular extension (ECE) in cervical metastatic lymph nodes remains an indication for adding chemotherapy for patients with oropharyngeal squamous cell carcinoma (OPSCC). The aim of this study is to identify specific imaging characteristics on computed tomography (CT) scan that are predictive of ECE in order to better risk stratify patients preoperatively. MATERIALS AND METHODS A single cohort study was performed using a prospectively collected database of patients with HPV-related OPSCC who underwent transoral robotic surgery with cervical lymphadenectomy. CT scans were assessed for the presence of multiple imaging characteristics, including lymph node size, number of nodes positive, cystic appearance, and border irregularity. Univariable and multivariable analyses were performed to analyze each variables predictability of pathologic ECE. RESULTS 100 patients underwent TORS with cervical lymphadenectomy for OPSCC from 2010 to 2015. Ninety-one percent (21/23) of patients with 3 or more radiologically suspicious nodes were found to have pathologic ECE, which was a significantly greater proportion than patients with fewer suspicious nodes (p<0.001). CT scans with 3 or more radiologically suspicious nodes displayed a sensitivity and specificity of 55% and 94%, respectively with a positive predictive value (PPV) of 91% for ECE. Irregular borders and age were also correlated with ECE on multivariable analysis. CONCLUSION AND RELEVANCE The presence of 3 or more radiologically suspicious lymph nodes on CT scan has a 91% PPV for any histologic evidence of ECE. The absolute number of radiographically suspicious lymph node metastases may be a useful method for risk-stratifying patients for the presence of ECE.

Assessment of Surgical Learning Curves in Transoral Robotic Surgery for Squamous Cell Carcinoma of the Oropharynx

Importance Transoral robotic surgery (TORS) is increasingly employed as a treatment option for squamous cell carcinoma of the oropharynx (OPSCC). Measures of surgical learning curves are needed particularly as clinical trials using this technology continue to evolve. Objective To assess learning curves for the oncologic TORS surgeon and to identify the number of cases needed to identify the learning phase. Design, Setting, and Participants A retrospective review of all patients who underwent TORS for OPSCC at the University of Pittsburgh Medical Center between March 2010 and March 2016. Cases were excluded for involvement of a subsite outside of the oropharynx, for nonmalignant abnormality or nonsquamous histology, unknown primary, no tumor in the main specimen, free flap reconstruction, and for an inability to define margin status. Exposures Transoral robotic surgery for OPSCC. Main Outcomes and Measures Primary learning measures defined by the authors include the initial and final margin status and time to resection of main surgical specimen. A cumulative sum learning curve was developed for each surgeon for each of the study variables. The inflection point of each surgeon’s curve was considered to be the point signaling the completion of the learning phase. Results There were 382 transoral robotic procedures identified. Of 382 cases, 160 met our inclusion criteria: 68 for surgeon A, 37 for surgeon B, and 55 for surgeon C. Of the 160 included patients, 125 were men and 35 were women. The mean (SD) age of participants was 59.4 (9.5) years. Mean (SD) time to resection including robot set-up was 79 (36) minutes. The inflection points for the final margin status learning curves were 27 cases (surgeon A) and 25 cases (surgeon C). There was no inflection point for surgeon B for final margin status. Inflection points for mean time to resection were: 39 cases (surgeon A), 30 cases (surgeon B), and 27 cases (surgeon C). Conclusions and Relevance Using metrics of positive margin rate and time to resection of the main surgical specimen, the learning curve for TORS for OPSCC is surgeon-specific. Inflection points for most learning curves peak between 20 and 30 cases.

Nasal septal perforation secondary to systemic bevacizumab

IMPORTANCE A case of nasal septal perforation secondary to systemic bevacizumab therapy for ovarian cancer is reported. Bevacizumab is a vascular endothelial growth factor A (VEGF-A) inhibitor that is becoming more widely utilized in the oncologic community. There is only one prior report of septal perforation secondary to bevacizumab in the Otolaryngology specific literature. The purpose of this report is: 1) to raise awareness and discuss the literature surrounding the sinonasal complications of bevacizumab and 2) provide workup and treatment recommendations based on the sum of the available literature. OBSERVATIONS We review the clinical record of a 59year old patient who presented with an anterior septal perforation while taking bevacizumab therapy for ovarian cancer. She had mild symptoms. Her oncologist held bevacizumab and topical moisture therapy was started. After several weeks, the perforation remained stable and bevacizumab was restarted for her ovarian cancer. CONCLUSION AND RELEVANCE Bevacizumab is associated with both septal perforation and more widespread sinonasal toxicity. These lesions tend to produce only mild symptoms and can usually be managed conservatively. The decision to hold bevacizumab therapy should be made in conjunction with the patient and medical oncologist. Otolaryngologists should be aware of the toxicity from this increasingly common oncologic therapy.

The case for primary salivary rhabdomyosarcoma

Rhabdomyosarcomas of the parotid and submandibular glands have the histological appearance of a skeletal muscle tumor yet can be found in tissue with no striated muscular elements. We examine the potential cell-of-origin for rhabdomyosarcoma and whether salivary tumors represent primary malignancy or metastasis. We have previously established genetically engineered mouse models of rhabdomyosarcoma. In these mice, rhabdomyosarcoma is only induced when a Pax3:Foxo1 fusion oncogene is activated with concurrent loss of p53 function (for alveolar rhabdomyosarcoma) or loss of p53 function alone (for embryonal rhabdomyosarcoma) using Cre-lox technology. These mutations are only activated under the control of promoters specific for selected cell lineages, previously thought to be myogenesis-restricted. RT-PCR and immunohistochemistry for lineage-specific promoter gene products reveal these promoters are active in wild-type mouse salivary gland. Given that mouse rhabdomyosarcoma frequently originates in the salivary glands and these myogenic-related promoters are normally expressed in salivary tissue, a high likelihood exists that the salivary gland contains a cell-of-origin of this muscle-related cancer.

Mentorship in Otolaryngology: 10 Years of Experience

Objective: The Accreditation Council for Graduate Medical Education’s (ACGME) structuring of resident education attempts to utilize mentoring relationships to augment trainee development. The purpose of the current study is to better understand the nature of the mentor-mentee relationship and find areas that should be strengthened or de-emphasized.Method: The Mentorship Program in the Department of Otolaryngology–Head and Neck Surgery at Oregon Health and Science University has existed for 10 years. Mentor-mentee pairs are assigned upon matriculation. Pairs are required to meet biannually at minimum. Guidelines for discussion topics are provided. All residents and faculty participants were surveyed online.Results: Nineteen mentors and 24 mentees completed the survey, a 100% response rate. Mentor personality traits most important to residents were honesty/integrity (93%) and supportiveness (88%), while the least important characteristics were race (100%) and gender (83%). Mentor-mentee pairs discussed a wi...

Positive Margins by Oropharyngeal Subsite in Transoral Robotic Surgery for T1/T2 Squamous Cell Carcinoma

Objective To compare positive margin rates between the 2 most common subsites of oropharyngeal transoral robotic surgery (TORS), the base of tongue (BOT) and the tonsil, as well as identify preoperative imaging characteristics that predispose toward positive margins. Study Design Case series with chart review. Setting Tertiary care referral center. Subjects and Methods We compared the final and intraoperative positive margin rate between TORS resections for tonsil and BOT oropharyngeal squamous cell carcinoma (OPSCC), as well as the effect of margins on treatment. A blinded neuroradiologist examined the preoperative imaging of BOT tumors to measure their dimensions and patterns of spread and provided a prediction of final margin results. Results Between January 2010 and May 2016, a total of 254 patients underwent TORS for OPSCC. A total of 140 patients who underwent TORS for T1/T2 OPSCC met inclusion criteria. A final positive margin is significantly more likely for BOT tumors than tonsil tumors (19.6% vs 4.5%, respectively, P = .004) and likewise for intraoperative margins of BOT and tonsil tumors (35.3% vs 12.4%, respectively; P = .002). A positive final margin is 10 times more likely to receive chemoradiation compared to a negative margin, controlling for extracapsular spread and nodal status (odds ratio, 9.6; 95% confidence interval, 1.6-59.6; P = .02). Preoperative imaging characteristics and subjective radiologic examination of BOT tumors did not correlate with final margin status. Conclusion Positive margins are significantly more likely during TORS BOT resections compared to tonsil resections. More research is needed to help surgeons predict which T1/T2 tumors will be difficult to completely extirpate.

Probabilistic modeling of personalized drug combinations from integrated chemical screen and molecular data in sarcoma

Cancer patients with advanced disease exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates sequencing data with functional assay data to develop patient-specific combination cancer treatments. This computational modeling approach addresses three major challenges in personalized cancer therapy, which we validate across multiple species via computationally-designed personalized synergistic drug combination predictions, identification of unifying therapeutic targets to overcome intra-tumor heterogeneity, and mitigation of cancer cell resistance and rewiring mechanisms. These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.