Morphologic Spectrum of HPV-associated Sinonasal Carcinomas.

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection has been increasingly recognized as a risk factor for sinonasal tract carcinomas. However the prevalence and prognostic significance of HPV-associated sinonasal carcinomas is not well known due to limited studies and inconsistency in HPV testing modalities in literatures. Morphologically, HPV-associated sinonasal carcinomas encompass a diverse group of tumors. HPV-associated sinonasal adenocarcinoma has not been reported. The purpose of this study was to determine the prevalence, morphologic spectrum and prognostic implication of HPV-associated sinonasal carcinomas. METHODS: This cohort included 153 sinonasal carcinomas. Tissue microarrays were constructed. P16 immunohistochemistry and HR-HPV E6/7 in-situ Hybridization (ISH) were performed. Carcinomas were deemed HPV-associated based on a positive ISH testing. Clinicopathologic data was collected. RESULTS: 28/153 (18%) sinonasal carcinomas were HPV-associated. HPV-associated carcinomas consisted of 26 (93%) squamous cell carcinomas and variants, 1 (3.5%) HPV-related multiphenotypic sinonasal carcinoma and 1 (3.5%) adenocarcinoma. The HPV-associated adenocarcinoma closely resembled HPV-associated endocervical adenocarcinoma morphologically. HPV-associated carcinomas occurred in 8 (29%) women and 20 (71%) men with a median age of 66 years old. HPV-associated carcinomas were predominantly located at nasal cavity. A trend toward improved overall survival and progression free survival in HPV-associated carcinomas patients was observed, yet without statistical significance. CONCLUSION: Our study identifies a novel HPV-associated sinonasal adenocarcinoma subtype, highlights the broad morphologic spectrum of HPV-associated sinonasal carcinomas, and supports routine p16 testing during pathology practice regardless of tumor subtype followed by a confirmatory HR-HPV testing. This practice is critical for studying the clinical behavior of HPV-associated sinonasal carcinomas.

A platform-independent AI tumor lineage and site (ATLAS) classifier.

Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples. We assessed performance independently in 10,376 total tumor samples, including 1490 metastatic samples, achieving an accuracy of 91.4% for cancer site-of-origin and 97.1% for cancer lineage. High confidence predictions (encompassing the majority of cases) were accurate 98-99% of the time in both localized and remarkably even in metastatic samples. We also identified emergent properties of our lineage scores for tumor types on which the model was never trained (zero-shot learning). Adenocarcinoma/sarcoma lineage scores differentiated epithelioid from biphasic/sarcomatoid mesothelioma. Also, predicted lineage de-differentiation identified neuroendocrine/small cell tumors and was associated with poor outcomes across tumor types. Our platform-independent single-sample approach can be easily translated to existing RNA-seq platforms. ATLAS can complement and guide traditional histopathologic assessment in challenging situations and tumors of unknown primary.

Risk Factors Associated With Distress Among Postoperative Patients in an Academic Gynecologic Oncology Practice.

BACKGROUND: Distress among gynecologic oncology patients correlates with poor clinical outcomes and decreased quality of life. The purpose of this study was to determine risk factors for elevated NCCN Distress Thermometer (DT) results among postoperative gynecologic oncology patients. PATIENTS AND METHODS: We performed a retrospective chart review of all postoperative visits over a 5-year period. NCCN DT results were analyzed as both discretized values (DT ≤3 = low distress; DT 4-8 = moderate distress; DT ≥9 = high distress) and continuous variables. Patients with a DT score ≥4 were referred to social work. Univariate and multivariate regression analyses were performed to compare NCCN DT results with clinical and sociodemographic variables. Statistical significance was P<.05. RESULTS: In total, 1,795 NCCN DT results were included, with uterine (37.72%) being the most common disease site. Benign pathology was known prior to completion of the NCCN DT in 13.15% of patients. Most patients (71.75%) endorsed low levels of distress. Moderate/High levels of distress were reported by 28.25% of patients. Increasing levels of distress were significantly associated with younger age (P=.006), history of depression (P≤.001), status as a current smoker (P=.028), and history of asthma (P=.041). Knowledge of benign pathology was associated with low levels of distress (P=.002). Procedure type and disease site were not associated with distress. CONCLUSIONS: More than one-fourth of postoperative patients in a gynecologic oncology practice reported moderate or high distress. Distress was highest among those with malignancy regardless of disease site or surgical intervention. Benign pathology correlated with decreased distress. Identified associations with distress provide opportunities for prevention, early intervention, and tailored counseling.

A Pilot Study of Pembrolizumab in Combination With Y90 Radioembolization in Subjects With Poor Prognosis Hepatocellular Carcinoma.

BACKGROUND: Combination checkpoint inhibition therapy with yttrium-90 (Y90) radioembolization represents an emerging area of interest in the treatment of advanced hepatocellular carcinoma (HCC). HCRN GI15-225 is an open-label, single-arm multicenter, pilot study (NCT03099564). METHODS: Eligible patients had poor prognosis, localized HCC defined as having portal vein thrombus, multifocal disease, and/or diffuse disease that were not eligible for liver transplant or surgical resection. Patients received pembrolizumab 200 mg intravenously every 3 weeks in conjunction with glass yttrium-90 (Y90) radioembolization TheraSphere. Primary endpoint was 6-month progression-free survival (PFS6) per RECIST 1.1. Secondary endpoints included time to progression (TTP), objective response rate (ORR), overall survival (OS), and safety/tolerability. RESULTS: Between October 23, 2017 and November 24, 2020, 29 patients were enrolled: 2 were excluded per protocol. Fifteen of the remaining 27 patients were free of progression at 6 months (55.6%; 95% CI, 35.3-74.5) with median PFS 9.95 months (95% CI, 4.14-15.24) and OS 27.30 months (95% CI, 10.15-39.52). One patient was not evaluable for response due to death; among the remaining 26 patients, ORR was 30.8% (95% CI, 14.3-51.8) and DCR was 84.6% (95% CI, 65.1-95.6). CONCLUSION: In patients with localized, poor prognosis HCC, pembrolizumab in addition to glass Y90 radioembolization demonstrated promising efficacy and safety consistent with prior observations (ClinicalTrials.gov Identifier: NCT03099564; IRB Approved: 16-3255 approved July 12, 2016).

Randomized phase II selection design with order constrained strata.

The exploratory nature of phase II trials makes it quite common to include heterogeneous patient subgroups with different prognoses in the same trial. Incorporating such patient heterogeneity or stratification into statistical calculation for sample size can improve efficiency and reduce sample sizes in single-arm phase II trials with binary outcomes. However, such consideration is lacking in randomized phase II trials. In this paper, we propose methods that can utilize some natural order constraints that may exist in stratified population to gain statistical efficiency for randomized phase II designs. For thoroughness and simplicity, we focus on the randomized phase II selection designs in this paper, although our method can be easily generalized to the randomized phase II screening designs. We consider both binary and time-to-event outcomes in our development. Compared with methods that do not use order constraints, our method is shown to improve the probabilities of correct selection or reduce sample size in our simulation and real examples.

Phase 2 trial of tremelimumab in patients with metastatic urothelial cancer previously treated with programmed death 1/programmed death ligand 1 blockade.

INTRODUCTION: Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade has changed the landscape of treatment for metastatic urothelial cancer, but single-agent cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade in metastatic urothelial cancer has been underexplored. A prior phase 2 trial of tremelimumab in PD-1/PD-L1-blockade naive patients with metastatic urothelial cancer revealed activity comparable to that observed with PD-1/PD-L1 blockade raising the hypothesis that these classes of immune checkpoint inhibitors might be non-cross-resistant. METHODS: The current phase 2 trial treated patients with PD-1/PD-L1 blockade-resistant metastatic urothelial cancer with single-agent tremelimumab (750 mg intravenously every 28 days for up to 7 cycles). The primary end point was objective response rate. RESULTS: Twenty-six patients were enrolled and 24 patients were evaluable for response. The objective response rate was 8.3%, composed of a total of two partial responses that lasted 10.9 and 24.0 months. Stable disease was observed in another 20.8% of patients, with a median duration of stable disease of 5.4 months. Diarrhea occurred in 15 patients (58%), elevated hepatic transaminases occurred in seven patients (27%), and adrenal insufficiency occurred in two patients (8%); one patient died after experiencing immune-related hepatitis. CONCLUSIONS: High dose CTLA-4 blockade in patients with PD-1/PD-L1-resistant metastatic urothelial cancer has modest activity and is associated with treatment-related toxicity similar to prior reports.

Associations between specialty care and improved outcomes among patients with diabetic foot ulcers.

OBJECTIVE: Specialty care may improve diabetic foot ulcer outcomes. Medically underserved populations receive less specialty care. We aimed to determine the association between specialty care and ulcer progression, major amputation, or death. If a beneficial association is found, increasing access to specialty care might help advance health equity. RESEARCH DESIGN AND METHODS: We retrospectively analyzed a cohort of Wisconsin and Illinois Medicare patients with diabetic foot ulcers (n = 55,409), stratified by ulcer severity (i.e., early stage, osteomyelitis, or gangrene). Within each stratum, we constructed Kaplan-Meier curves for event-free survival, defining events as: ulcer progression, major amputation, or death. Patients were grouped based on whether they received specialty care from at least one of six disciplines: endocrinology, infectious disease, orthopedic surgery, plastic surgery, podiatry, and vascular surgery. Multivariate Cox proportional hazard models estimated the association between specialty care and event-free survival, adjusting for sociodemographic factors and comorbidities, and stratifying on ulcer severity. RESULTS: Patients who received specialty care had longer event-free survival compared to those who did not (log-rank p<0.001 for all ulcer severity strata). After adjusting, receipt of specialty care, compared to never, remained associated with improved outcomes for all ulcer severities (early stage adjusted hazard ratio 0.34, 95% CI 0.33-0.35, p<0.001; osteomyelitis aHR 0.22, 95% CI 0.20-0.23, p<0.001; gangrene aHR 0.22, 95% CI 0.20-0.24, p<0.001). CONCLUSIONS: Specialty care was associated with longer event-free survivals for patients with diabetic foot ulcers. Increased, equitable access to specialty care might improve diabetic foot ulcer outcomes and disparities.