Purpose: Radiotherapy is important in managing pelvic cancers. However, radiation enteropathy may occur and can be dose limiting. The gut microbiota may contribute to the pathogenesis of radiation enteropathy. We hypothesized that the microbiome differs between patients with and without radiation enteropathy.Experimental Design: Three cohorts of patients (n ¼ 134) were recruited. The early cohort (n ¼ 32) was followed sequentially up to 12 months post-radiotherapy to assess early radiation enteropathy. Linear mixed models were used to assess microbiota dynamics. The late cohort (n ¼ 87) was assessed cross-sectionally to assess late radiation enteropathy. The colonoscopy cohort compared the intestinal mucosa microenvironment in patients with radiation enteropathy (cases, n ¼ 9) with healthy controls (controls, n ¼ 6). Fecal samples were obtained from all cohorts. In the colonoscopy cohort, intestinal mucosa samples were taken. Metataxonomics (16S rRNA gene) and imputed metataxonomics (Piphillin) were used to characterize the microbiome. Clinician-and patient-reported outcomes were used for clinical characterization.Results: In the acute cohort, we observed a trend for higher preradiotherapy diversity in patients with no self-reported symptoms (P ¼ 0.09). Dynamically, diversity decreased less over time in patients with rising radiation enteropathy (P ¼ 0.05). A consistent association between low bacterial diversity and late radiation enteropathy was also observed, albeit nonsignificantly. Higher counts of Clostridium IV, Roseburia, and Phascolarctobacterium significantly associated with radiation enteropathy. Homeostatic intestinal mucosa cytokines related to microbiota regulation and intestinal wall maintenance were significantly reduced in radiation enteropathy [IL7 (P ¼ 0.05), IL12/IL23p40 (P ¼ 0.03), IL15 (P ¼ 0.05), and IL16 (P ¼ 0.009)]. IL15 inversely correlated with counts of Roseburia and Propionibacterium.Conclusions: The microbiota presents opportunities to predict, prevent, or treat radiation enteropathy. We report the largest clinical study to date into associations of the microbiota with acute and late radiation enteropathy. An altered microbiota associates with early and late radiation enteropathy, with clinical implications for risk assessment, prevention, and treatment of radiation-induced side-effects. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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PurposeTo investigate the feasibility of dose escalation and hypofractionation of pelvic lymph node intensity modulated radiation therapy (PLN-IMRT) in prostate cancer (PCa).Methods and MaterialsIn a phase 1/2 study, patients with advanced localized PCa were sequentially treated with 70 to 74 Gy to the prostate and dose-escalating PLN-IMRT at doses of 50 Gy (cohort 1), 55 Gy (cohort 2), and 60 Gy (cohort 3) in 35 to 37 fractions. Two hypofractionated cohorts received 60 Gy to the prostate and 47 Gy to PLN in 20 fractions over 4 weeks (cohort 4) and 5 weeks (cohort 5). All patients received long-course androgen deprivation therapy. Primary outcome was late Radiation Therapy Oncology Group toxicity at 2 years after radiation therapy for all cohorts. Secondary outcomes were acute and late toxicity using other clinician/patient-reported instruments and treatment efficacy.ResultsBetween August 9, 2000, and June 9, 2010, 447 patients were enrolled. Median follow-up was 90 months. The 2-year rates of grade 2+ bowel/bladder toxicity were as follows: cohort 1, 8.3%/4.2% (95% confidence interval 2.2%-29.4%/0.6%-26.1%); cohort 2, 8.9%/5.9% (4.1%-18.7%/2.3%-15.0%); cohort 3, 13.2%/2.9% (8.6%-20.2%/1.1%-7.7%); cohort 4, 16.4%/4.8% (9.2%-28.4%/1.6%-14.3%); cohort 5, 12.2%/7.3% (7.6%-19.5%/3.9%-13.6%). Prevalence of bowel and bladder toxicity seemed to be stable over time. Other scales mirrored these results. The biochemical/clinical failure–free rate was 71% (66%-75%) at 5 years for the whole group, with pelvic lymph node control in 94% of patients.ConclusionsThis study shows the safety and tolerability of PLN-IMRT. Ongoing and planned phase 3 studies will need to demonstrate an increase in efficacy using PLN-IMRT to offset the small increase in bowel side effects compared with prostate-only IMRT.

PRLR is significantly more expressed in MBC than in gynaecomastia, and with different patterns of reactivity, suggesting a role for PRL in male breast carcinogenesis.

Clinical evaluation of tumour‐infiltrating lymphocytes as a prognostic factor in patients with human papillomavirus‐associated oropharyngeal squamous cell carcinoma Aims The majority of patients with human papillomavirus (HPV)‐associated oropharyngeal squamous cell carcinoma (OpSCC) have favourable survival outcomes, but a significant minority of individuals will die of their disease. There are currently no definitive criteria with which to identify HPV‐associated OpSCC patients with poor outcomes. Recent reports suggest that quantitative evaluation of T‐cell subpopulations in OpSCC may be of prognostic value, but the methods used have limited utility in a clinical diagnostic setting. We therefore sought to determine the clinical prognostic utility of tumour‐infiltrating lymphocyte (TIL) evaluation in patients with HPV‐associated OpSCC within the context of a diagnostic histopathology setting. Methods and results Representative diagnostic haematoxylin and eosin (H&E)‐stained slides from 232 consecutive HPV‐associated OpSCC patients were classified as containing a high (TILHi; diffuse, lymphocytes in >80% of tumour and stroma), moderate (TILMod; patchy, present in 20–80% of tumour and stroma) or low (TILLo; sparse or absent, present in <20% of tumour and stroma) TILs. Interobserver reliability was assessed, and TIL category was then correlated with overall survival (OS) and disease‐free survival (DFS). Univariate and multivariate analyses showed statistically significant differences in OS and DFS estimates when TILHi and TILMod patients were compared with TILLo patients (P < 0.0001 for TILHi versus TILLo; P < 0.0001 for TILMod versus TILLo). Statistical significance was retained when TILHi and TILMod patients were grouped into a single category (TILHi) and compared with TILLo patients (P < 0.0001). Conclusion We demonstrate the prognostic utility of TILs in patients with HPV‐associated OpSCC in clinical practice. A binary system classifying HPV‐associated OpSCC into TILHi and TILLo on the basis of routine H&E staining stratifies patients into those with potentially favourable and unfavourable survival outcomes, respectively.

Impact of pelvic radiotherapy for prostate cancer on global metabolic profiles and microbiota-driven gastrointestinal late side-effects: a longitudi-

Nivolumab is an anti-PD-1 monoclonal antibody currently used as immunotherapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of disease progression after platinum-based chemotherapy. This study evaluates real-world safety and treatment outcomes of non-trial nivolumab use. A retrospective multicenter cohort study of patients with recurrent/metastatic HNSCC treated with nivolumab between January 2017 and March 2020 was performed. Overall, 123 patients were included. The median age was 64 years, the majority of patients were male (80.5%) and had a smoking history (69.9%). Primary outcomes included overall response rate (ORR) of 19.3%, median progression-free survival (PFS) of 3.9 months, 1-year PFS rate of 16.8%, a median overall survival (OS) of 6.5 months and 1-year OS rate of 28.6%. These results are comparable to the CHECKMATE-141 study. Of 27 patients who had PD-L1 status tested, positive PD-L1 status did not significantly affect PFS (p = 0.86) or OS (p = 0.84). Nivolumab was well tolerated with only 15.1% experiencing immune-related toxicities (IRT) and only 6.7% of patients stopping due to toxicity. The occurrence of IRT appeared to significantly affect PFS (p = 0.01) but not OS (p = 0.07). Nivolumab in recurrent/metastatic HNSCC is well tolerated and may be more efficacious in patients who develop IRT.