Huaising Cindy Ko, MD

PURPOSE: To characterize image quality and feasibility of using ViewRay MRI (VR)-guided brachytherapy planning for cervical cancer.

METHODS AND MATERIALS: Cervical cancer patients receiving intracavitary brachytherapy with tandem and ovoids, planned using 0.35T VR MRI at our institution, were included in this series. The high-risk clinical target volume (HR-CTV), visible gross tumor volume, bladder, sigmoid, bowel, and rectum contours for each fraction of brachytherapy were evaluated for dosimetric parameters. Typically, five brachytherapy treatments were planned using the T2 sequence on diagnostic MRI for the first and third fractions, and a noncontrast true fast imaging with steady-state precession sequence on VR or CT scan for the remaining fractions. Most patients received 5.5 Gy × 5 fractions using high-dose-rate Ir-192 following 45 Gy of whole-pelvis radiotherapy. The plan was initiated at 5.5 Gy to point A and subsequently optimized and prescribed to the HR-CTV. The goal equivalent dose in 2 Gy fractions for the combined external beam and brachytherapy dose was 85 Gy. Soft-tissue visualization using contrast-to-noise ratios to distinguish normal tissues from tumor at their interface was compared between diagnostic MRI, CT, and VR.

RESULTS: One hundred and forty-two fractions of intracavitary brachytherapy were performed from April 2015 to January 2017 on 29 cervical cancer patients, ranging from stages IB1 to IVA. The median HR-CTV was 27.78 cc, with median D90 HR-CTV of 6.1 Gy. The median time from instrument placement to start of treatment using VR was 65 min (scan time 2 min), compared to 105 min using diagnostic MRI (scan time 11 min) (t-test, p < 0.01). The contrast-to-noise ratio of tumor to cervix in both diagnostic MRI and VR had significantly higher values compared to CT (ANOVA and t-tests, p < 0.01).

CONCLUSIONS: We report the first clinical use of VR-guided brachytherapy. Time to treatment using this approach was shorter compared to diagnostic MRI. VR also provided significant advantage in visualizing the tumor and cervix compared to CT. This presents a feasible and reliable manner to image and plan gynecologic brachytherapy.

Objective We evaluated the ability of the American Joint Committee on Cancer (AJCC) seventh edition staging system to prognosticate the overall survival of patients with human papillomavirus (HPV)-positive laryngeal squamous cell carcinoma. Study Design Retrospective analysis. Setting National Cancer Database. Subjects and Methods Patients diagnosed with laryngeal squamous cell carcinoma who were treated with curative intent were identified in the National Cancer Database. Multivariate analysis was utilized to determine factors correlated with overall survival in the HPV-negative and HPV-positive cohorts. Unadjusted and propensity score-weighted Kaplan-Meier estimation was used to determine overall survival of HPV-negative and HPV-positive patients across AJCC stage groupings. Results We identified 3238 patients with laryngeal squamous cell carcinoma, of which 2812 were HPV negative and 426 were HPV positive. Overall survival adjusted for age, sex, and comorbidity status confirmed significant differences among all consecutive stage groupings (I vs II, P < .001; II vs III, P < .05; III vs IVA, P < .001; IVA vs IVB, P < .05) in the HPV-negative cohort, whereas only stages IVAs and IVB ( P < .01) exhibited a significant difference in overall survival for HPV-positive patients. Conclusion The current AJCC staging system does not accurately distinguish risk of mortality for patients with HPV-positive disease. These data support the consideration of HPV status in estimating prognosis as well as clinical trial design and clinical decision making for patients with laryngeal squamous cell carcinoma.

Importance: Radiotherapy (RT)-based organ preservation approaches for patients with advanced laryngeal cancer have been established stepwise through prospective randomized clinical trials. However, broad adoption of these approaches has stimulated discussion about long-term results challenging their applicability in a heterogeneous patient population, most recently for patients with T3 disease.

Objective: To define outcomes in patients with clinical T3N0M0 glottic laryngeal cancer treated with definitive surgical and RT-based approaches.

Design, Setting, and Participants: This retrospective cohort study included patients treated from January 1, 2004, through December 31, 2013, with a median follow-up time of 58 months (range, 0-126.6 months) in the National Cancer Database. Of the 4003 patients with T3N0M0 disease, 2622 received definitive therapy defined by the study protocol. Data were obtained from the clinical oncology database sourced from hospital registry data that are collected from more than 1500 Commission on Cancer-accredited facilities. Data were analyzed from September 14, 2016, through April 24, 2017.

Interventions: Radiotherapy, chemoradiotherapy, surgery, surgery and RT, or surgery and chemoradiotherapy.

Main Outcomes and Measures: Five-year overall survival (OS).

Results: A total of 2622 patients (2251 men [85.9%] and 371 women [14.1%]; median age, 64 years [range, 19-90 years]) were included in the analytic cohort. In the overall patient cohort, the adjusted 5-year survival probability was 53%. No statistical differences were observed between the primary surgery (53%; 95% CI, 48%-57%) and primary RT (54%; 95% CI, 52%-57%) cohorts. In multivariate analysis, patient factors associated with decreased OS included age (hazard ratio [HR], 1.04; 95% CI, 1.03-1.04), insurance status (HR, 1.26; 95% CI, 1.06-1.50), and increasing comorbidity (HR, 1.20; 95% CI, 1.02-1.42).

Conclusions and Relevance: Current management of T3N0M0 glottic laryngeal cancer relies largely on RT-based organ preservation approaches. The present study substantiates randomized clinical trial data supporting the use of RT-based organ preservation approaches for patients with T3N0M0 glottic laryngeal cancer without compromising OS.

PURPOSE: We examined overall survival in a large cohort of patients with human papillomavirus (HPV)-positive and HPV-negative non-oropharyngeal squamous cell carcinoma of the head and neck (non-OPSCC).

METHODS: Patients diagnosed with non-OPSCC and known HPV status were identified in the National Cancer Database (NCDB). Multivariate logistic regression was applied to examine factors associated with HPV status. Multivariate analysis was utilized to determine factors correlated with overall survival. Propensity score-weighted Kaplan-Meier estimation was used to adjust for confounders in survival analyses. Multiple imputation method was used for sensitivity analysis.

RESULTS: We identified 19,993 non-OPSCC patients with 5070 being positive for HPV in the NCDB. Median follow-up was 23.5 months. HPV-positive patients were more commonly male, white, with a lower comorbidity index score, presenting with T-stage <2, and N-stage ≥1. Unadjusted 3-year overall survival was 62% and 80% for HPV-negative and HPV-positive patients, respectively (p < 0.0001). On multivariate analysis, mortality was reduced for HPV-positive patients with early stage (HR = 0.68) and locally advanced disease (HR = 0.46). Adjusted 3-year overall survival was 65% for HPV-negative and 76% for HPV-positive patients (p < 0.0001). The survival advantage of HPV was maintained in all subsites and robust on sensitivity analysis.

CONCLUSIONS: Patients with HPV-positive non-OPSCC exhibit similar characteristics as HPV-positive OPSCC. Overall survival was significantly higher for patients with HPV-positive versus HPV-negative non-OPSCC. These data reveal that HPV-positive non-OPSCC represent a favorable cohort that warrants recognition in the design of future clinical trial investigation.

BACKGROUND: There is a paucity of data regarding head and neck squamous cell carcinomas (HNSCCs) and N3 nodal disease.

METHODS: Retrospective analysis of patients with N3 HNSCC identified in the National Cancer Database (NCDB) was performed.

RESULTS: We identified 4867 patients with N3 HNSCC treated with primary surgery or chemoradiotherapy (CRT). Propensity-adjusted median survival was 54.2 and 44.8 months for surgery and CRT, respectively (P = .06). Oropharyngeal primary subsite demonstrated a survival advantage with surgery versus CRT with propensity-adjusted median survivals of 86.0 and 61.9 months, respectively (P < .05).

CONCLUSION: Management of N3 HNSCC relies largely on CRT. Patients with N3 nodal disease with nonoropharyngeal primary tumors exhibit 5-year overall survival approaching 30% independent of initial treatment modality. Patients with oropharyngeal primaries exhibit improved outcomes with surgery largely influenced by the human papillomavirus (HPV)-negative subset. These data represent the most comprehensive analysis of N3 HNSCC outcomes and serves as a foundation for future research and clinical management.

PURPOSE/OBJECTIVE(S): To evaluate treatment trends and overall survival of patients with small cell carcinoma of the head and neck region.

MATERIALS/METHODS: Patients from 2004 to 2012 were identified from the National Cancer Database. Patient demographics and overall survival were analyzed. Multivariable analysis was used to identify predictors of survival.

RESULTS: Among 347,252 head and neck patients a total of 1042 (0.3%) patients with small cell carcinoma were identified. 17% of patients were diagnosed as stage I/II, 61% as stage III/IVA/IVB and 22% as stage IVC disease. The distribution by anatomic site was 9% oral cavity, 12% oropharynx, 35% larynx, 4% hypopharynx, 10% nasopharynx and 30% nasal cavity and paranasal sinuses. The median overall survival by anatomical site was 20.8months for oral cavity, 23.7months for oropharynx, 17.9months for larynx/hypopharynx, 15.1months for nasopharynx and 36.4months for nasal cavity primary tumors. On multivariable analysis across stage, patients with nasal cavity and paranasal sinuses tumors had the best survival and patients with nasopharynx primaries had the worst survival. In stage I/II patients, type of treatment delivered resulted in no overall survival difference (p=0.78). In patients with locally advanced disease, there was no difference in survival between those treated with combined surgery, radiotherapy and chemotherapy compared to those treated only with radiotherapy and chemotherapy (p=0.46). The addition of radiotherapy to chemotherapy in the metastatic setting did not result in improved survival (p=0.14).

CONCLUSIONS: Small cell carcinoma of the head and neck is a rare malignancy with a poor prognosis. The addition of surgery to radiotherapy and chemotherapy did not improve survival in patients with locally advanced disease.

PURPOSE/OBJECTIVES: We observed a number of patients who developed Lhermitte's sign (LS) following radiation to the head and neck (H/N), since instituting volumetric modulated arc therapy (VMAT). We aimed to investigate the incidence of LS following VMAT-based RT without chemotherapy, and determine the dosimetric parameters that predict its development. We explored whether the role of inhomogeneous dose distribution across the spinal cord, causing a "bath-and-shower" effect, explains this finding.

METHODS AND MATERIALS: From 1/20/2010-12/9/2013, we identified 33 consecutive patients receiving adjuvant RT using VMAT to the H/N without chemotherapy at our institution. Patients' treatment plans were analyzed for dosimetric parameters, including dose gradients along the anterior, posterior, right, and left quadrants at each cervical spine level. Institutional Review Board approval was obtained.

RESULTS: 5 out of 33 (15.2%) patients developed LS in our patient group, all of whom had RT to the ipsilateral neck only. LS patients had a steeper dose gradient between left and right quadrants across all cervical spine levels (repeated-measures ANOVA, p = 0.030). Within the unilateral treatment group, LS patients received a higher mean dose across all seven cervical spinal levels (repeated-measures ANOVA, p = 0.046). Dose gradients in the anterior-posterior direction and mean doses to the cord were not significant between LS and non-LS patients.

CONCLUSIONS: Dose gradients along the axial plane of the spinal cord may contribute to LS development; however, a threshold dose within the high dose region of the cord may still be required. This is the first clinical study to suggest that inhomogeneous dose distributions in the cord may be relevant in humans. Further investigation is warranted to determine treatment-planning parameters associated with development of LS.

PURPOSE: Perineural invasion (PNI) is a frequent pathological finding in head and neck cancers. When adjuvant radiation to cranial nerves at risk in head and neck cancers with PNI is considered, there is a need for consensus on which nerves are at risk and how to contour these nerves. This contouring guide attempts to address this need.

METHODS AND MATERIALS: Representative patient diagnostic computed tomographic (CT) scans with contrast of the neck were used to create example contours. The cranial nerves V2, V3, VII, and XII, and sample primary tumor sites were initially delineated using the Varian Eclipse planning system by 5 radiation oncologists. All of the images were then reviewed with a diagnostic radiologist to establish consensus for delineating the cranial nerves.

RESULTS: We provided detailed contouring and planning guidelines on a CT atlas, with figures to help illustrate internerve connections, based on clinical experience, literature-based patterns of failure, and established anatomic connections between cranial nerves. Tumor bed, cranial nerve, and elective target volumes are depicted.

CONCLUSIONS: These planning guidelines and atlas provide anatomic, clinical, and technical recommendations for guiding radiation oncologists in the planning and delivery of intensity modulated radiation therapy for head and neck cancer with PNI.

IMPORTANCE: A significant proportion of patients who have had a first episode of erysipelas or uncomplicated cellulitis will subsequently develop a recurrence. There is disagreement about how effective antibiotic prophylaxis is for preventing recurrent cellulitis.

OBJECTIVE: To determine if antibiotic prophylaxis is effective in preventing recurrent cellulitis compared to no prophylaxis using a systematic review and meta-analysis.

DATA SOURCES: Studies in any language identified by searching Medline, EMBASE, Cochrane Library, CINAHL, TRIP database, clinical practice guidelines websites, and ongoing trials databases up to 31st August 2012. Search terms included cellulitis, erysipelas, controlled clinical trial, randomized, placebo, clinical trials, randomly, and trial.

STUDY SELECTION: Only controlled trials comparing antibiotic prophylaxis to no antibiotic prophylaxis in patients age 16 years and above, and after 1 or more episodes of cellulitis, were included.

DATA EXTRACTION AND SYNTHESIS: Independent extraction of articles was done by 2 investigators using predefined data extraction templates, including study quality indicators. PROSPERO registration number: CRD42012002528. Meta-analyses were done using random-effects models.

MAIN OUTCOMES AND MEASURES: The primary outcome was the number of patients with a recurrence of cellulitis. Secondary outcomes were (1) the time to next episode of recurrence, (2) quality of life measures, and (3) adverse events (e.g. allergic reactions, nausea).

RESULTS: Five randomized controlled trials (n = 535), with 260 patients in the intervention arm and 275 in the comparator group met our inclusion criteria. 44 patients (8%) in the antibiotic prophylaxis group and 97 patients (18%) in the comparator group had an episode of cellulitis. Antibiotic prophylaxis significantly reduced the number of patients having recurrent cellulitis, with a risk ratio (RR) of 0.46 (95% CI 0.26-0.79). None of the studies reported severe adverse effects to antibiotics. There was methodological heterogeneity amongst the studies in terms of types of antibiotic used, delivery modes, number of recurrences of cellulitis at study entry, and study quality.

CONCLUSION AND RELEVANCE: Antibiotic prophylaxis can prevent recurrent cellulitis. Future research should aim to identify the ideal type, dosage, and duration of antibiotics for prophylaxis, as well as to identify the group of patients who will benefit most from antibiotic prophylaxis.

For decades, the paradigm of drug discovery and development has relied on immortalized cell lines, animal models of human disease, and clinical trials. With the discovery of induced pluripotent stem cell (iPSC) technology in 2007, a new human in vitro drug testing platform has potentially augmented this set of tools by providing additional ways to screen compounds for safety and efficacy. The growing number of human disease models made with patient-specific iPSCs has made it possible to conduct research on a wide range of disorders, including rare diseases and those with multifactorial origin, as well as to simulate drug effects on difficult-to-obtain tissues such as brain and cardiac muscle. Toxicity and teratogenicity assays developed with iPSC-derived cells can also provide an additional layer of safety before advancing drugs to clinical trials. The incorporation of iPSC technology into drug therapy development holds promise as a more powerful and nuanced approach to personalized medicine.