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Background: The search for factors beyond the radiotherapy dose that could identify patients more at risk of developing radio-induced toxicity is essential to establish personalised treatment protocols for improving the quality-of-life of survivors. To investigate the role of the intestinal microbiota in the development of radiotherapy-induced gastrointestinal toxicity, the MicroLearner observational cohort study characterised the intestinal microbiota of 136 (discovery) and 79 (validation) consecutive prostate cancer patients at baseline radiotherapy., Methods: Gastrointestinal toxicity was assessed weekly during RT using CTCAE. An average grade >1.3 over time points was used to identify patients suffering from persistent acute toxicity (endpoint). The microbiota of patients was quantified from the baseline faecal samples using 16S rRNA gene sequencing technology and the Ion Reporter metagenomic pipeline. Statistical techniques and computational and machine learning tools were used to extract, functionally characterise, and predict core features of the bacterial communities of patients who developed acute gastrointestinal toxicity., Findings: Analysis of the core bacterial composition in the discovery cohort revealed a cluster of patients significantly enriched for toxicity, displaying a toxicity rate of 60%. Based on selected high-risk microbiota compositional features, we developed a clinical decision tree that could effectively predict the risk of toxicity based on the relative abundance of genera Faecalibacterium, Bacteroides, Parabacteroides, Alistipes, Prevotella and Phascolarctobacterium both in internal and external validation cohorts., Interpretation: We provide evidence showing that intestinal bacteria profiling from baseline faecal samples can be effectively used in the clinic to improve the pre-radiotherapy assessment of gastrointestinal toxicity risk in prostate cancer patients., Funding: Italian Ministry of Health (Promotion of Institutional Research INT-year 2016, 5 × 1000, Ricerca Corrente funds). Fondazione Regionale per la Ricerca Biomedica (ID 2721017). AIRC (IG 21479)., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To report clinical outcomes of relapsed oropharyngeal squamous cell carcinoma (OPSCC) after definitive intensity-modulated (chemo)radiotherapy [(C)RT]., Materials and Methods: Data for all relapsed patients treated for OPSCC with definitive (C)RT between 2010 and 2016 were collected. Primary end-point was post-failure survival (PFS)., Results: Overall, 273 OPSCC patients completed definitive (C)RT. Of these, 42 cases (n = 26 human papilloma virus (HPV)-negative; n = 16 HPV-positive) had relapsed (n = 23 persistent disease; n = 19 recurrent disease) and were included in the final analysis. Two-year PFS for the entire population was 30.6%; 20.5% for HPV-negative and 43.8% for HPV-positive patients. Salvage curative surgery was associated with a significantly higher 2 years PFS rate (56.2%) compared with palliative treatment (22.9%) and best supportive care (0%) (p < 0.001). A positive trend in 2 years PFS was recorded in the early complete response cases (49.5%) versus patients who did not achieve a complete response within 3 months of the end of (C)RT (23.0%) (p = 0.11)., Conclusion: A higher PFS rate is achieved when relapsed OPSCC cases are treated with salvage curative intent. HPV-positive disease and early complete response within 3 months from the end of (C)RT may be related to better PFS., (© 2021 Wiley Periodicals LLC.)

Background and Purpose: Peer review of head and neck cancer radiation therapy target volumes by radiologists was introduced in our center to optimize target volume delineation. Our aim was to assess the impact of MR imaging-based radiologist peer review of head and neck radiation therapy gross tumor and nodal volumes, through qualitative and quantitative analysis., Materials and Methods: Cases undergoing radical radiation therapy with a coregistered MR imaging, between April 2019 and March 2020, were reviewed. The frequency and nature of volume changes were documented, with major changes classified as per the guidance of The Royal College of Radiologists. Volumetric alignment was assessed using the Dice similarity coefficient, Jaccard index, and Hausdorff distance., Results: Fifty cases were reviewed between April 2019 and March 2020. The median age was 59 years (range, 29-83 years), and 72% were men. Seventy-six percent of gross tumor volumes and 41.5% of gross nodal volumes were altered, with 54.8% of gross tumor volume and 66.6% of gross nodal volume alterations classified as "major." Undercontouring of soft-tissue involvement and unidentified lymph nodes were predominant reasons for change. Radiologist review significantly altered the size of both the gross tumor volume ( P  = .034) and clinical target tumor volume ( P  = .003), but not gross nodal volume or clinical target nodal volume. The median conformity and surface distance metrics were the following: gross tumor volume Dice similarity coefficient = 0.93 (range, 0.82-0.96), Jaccard index = 0.87 (range, 0.7-0.94), Hausdorff distance = 7.45 mm (range, 5.6-11.7 mm); and gross nodular tumor volume Dice similarity coefficient = 0.95 (0.91-0.97), Jaccard index = 0.91 (0.83-0.95), and Hausdorff distance = 20.7 mm (range, 12.6-41.6). Conformity improved on gross tumor volume-to-clinical target tumor volume expansion (Dice similarity coefficient = 0.93 versus 0.95, P  = .003)., Conclusions: MR imaging-based radiologist review resulted in major changes to most radiotherapy target volumes and significant changes in volume size of both gross tumor volume and clinical target tumor volume, suggesting that this is a fundamental step in the radiotherapy workflow of patients with head and neck cancer., (© 2023 by American Journal of Neuroradiology.)

Radiotherapy is a linchpin in head and neck squamous cell carcinoma (HN-SCC) treatment. Modulating tumour and/or normal tissue biology offers opportunities to further develop HN-SCC radiotherapy. The microbiota, which can exhibit homeostatic properties and be a modulator of immunity, has recently received considerable interest from the Oncology community. Microbiota research in head and neck oncology has also flourished. However, available data are difficult to interpret for clinical and radiation oncologists. In this review, we focus on how microbiota research can contribute to the improvement of radiotherapy for HN-SCC, focusing on how current and future research can be translated back to the clinic. We include in-depth discussions about the microbiota, its multiple habitats and relevance to human physiology, mechanistic interactions with HN-SCC, available evidence on microbiota and HNC oncogenesis, efficacy and toxicity of treatment. We discuss clinically-relevant areas such as the role of the microbiota as a predictive and prognostic biomarker, as well as the potential of leveraging the microbiota and its interactions with immunity to improve treatment results. Importantly, we draw parallels with other cancers where research is more mature. We map out future directions of research and explain clinical implications in detail., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To assess TNM 8 staging in discriminating overall survival (OS) amongst patients with locally advanced oral cavity squamous cell carcinoma (OCSCC) treated with surgery and post-operative radiotherapy (PORT), compared to TNM 7., Material and Methods: Data from OCSCC patients treated with surgery and PORT between January 2010 and December 2018 were reviewed. Demographics, tumour characteristics and treatment response data were collected, and patients staged according to both TNM 7 and TNM 8. OS and disease free survival (DFS) were estimated using the Kaplan Meier method. Univariate and multivariable analyses were conducted for factors affecting OS, DFS and early disease recurrence within 12 months., Results: Overall 172 patients were analyzed. Median follow up was 32 months for all patients and 48 months for surviving patients. TNM 8 staging demonstrated significant stratification of OS and DFS amongst the entire cohort, whereas TNM 7 staging did not. On multivariable analysis, TNM 8 stage, performance status (PS) and a positive surgical margin were prognostic for OS. Looking at disease recurrence within 12 months, TNM 8 stage IVB, presence of lymphovascular invasion (LVSI), younger age and lesser smoking history were predictive factors on multivariable analysis., Conclusion: TNM 8 is a good development of its predecessor in terms of predicting survival for patients with locally advanced OCSCC. We have also identified younger age (<60 years) and a smoking history of <10 pack years as risk factors for early disease recurrence, potentially representing a separate biological cohort within OCSCC patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 = 134) were recruited. The early cohort ( n = 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 = 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 = 9) with healthy controls (controls, n = 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 = 0.09). Dynamically, diversity decreased less over time in patients with rising radiation enteropathy ( P = 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 = 0.05), IL12/IL23p40 ( P = 0.03), IL15 ( P = 0.05), and IL16 ( P = 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. See related commentary by Lam et al., p. 6280 ., (©2019 American Association for Cancer Research.)

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 (TIL Hi ; diffuse, lymphocytes in >80% of tumour and stroma), moderate (TIL Mod ; patchy, present in 20-80% of tumour and stroma) or low (TIL Lo ; 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 TIL Hi and TIL Mod patients were compared with TIL Lo patients (P < 0.0001 for TIL Hi versus TIL Lo ; P < 0.0001 for TIL Mod versus TIL Lo ). Statistical significance was retained when TIL Hi and TIL Mod patients were grouped into a single category (TIL Hi ) and compared with TIL Lo 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 TIL Hi and TIL Lo on the basis of routine H&E staining stratifies patients into those with potentially favourable and unfavourable survival outcomes, respectively., (© 2019 John Wiley & Sons Ltd.)

Purpose: To investigate the feasibility of dose escalation and hypofractionation of pelvic lymph node intensity modulated radiation therapy (PLN-IMRT) in prostate cancer (PCa)., Methods and Materials: In 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., Results: Between 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., Conclusions: This 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., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The seroprevalence of Toxoplasma gondii infection among pregnant women in the Democratic Republic of Sao Tome and Principe (DRSTP) from November 2003 to March 2004 was determined by detection of serum anti-T. gondii antibodies. A short questionnaire interview for pregnant women was performed to investigate risk factors associated with T. gondii infection, including consumption of raw meat or unwashed vegetables, drinking unboiled water and keeping pets (cats and dogs). The overall seroprevalence of T. gondii infection was high (75.2%; 375/499). The older age group of > or =35 years had a significantly higher seroprevalence (85.7%; 54/63) than that of the younger age group of 15-25 years (70.4%; 178/253) (odds ratio 2.5, 95% CI 1.2-5.4; P=0.01). No significant difference in the seroprevalence of T. gondii infection was found between the pregnant women with and without exposure to the risk factors studied. However, among pregnant women with high antibody titers of > or =1:1024, it seemed likely that continual contact with pets and consumption of oocyst-contaminated water or raw unwashed vegetables rather than tissue cysts in meat was the primary route of infection. The incidence of congenital toxoplasmosis in unborn babies should be intensively monitored in the DRSTP.

The prevalence status of Toxoplasma gondii infection in children of the Democratic Republic of Sao Tome and Principe (DRSTP), Western Africa, is unknown to date. A serologic survey of T. gondii infection among pre-schoolchildren aged <5 years in the DRSTP was assessed by the latex agglutination (LA) test from November 2003 to March 2004. The overall seroprevalence of T. gondii infection was not low, reaching 21.49% (26/121). No significant gender difference in seroprevalence was found between boys (19.30%; 11/57) and girls (23.44%; 15/64) (chi2 = 0.31, P = 0.58). The older age group of 4-5 years had significantly higher seroprevalence (36.67%; 11/30) than the younger age group of <2 years (10.34%; 3/29) (chi2 = 5.64, P = 0.02). It was noteworthy that the majority of seropositive boys (90.91%; 10/11) or older children aged > or = 2 years (82.61%; 19/23) had high LA titres of > or = 1:1024, indirectly indicating acute Toxoplasma infection. This study is the first report indicating that T. gondii infection is not low in pre-schoolchildren aged <5 years in the DRSTP. Whether the DRSTP pre-schoolchildren acquire T. gondii infection through constant exposure to the parasite from their daily activities owing to poor environmental hygiene should be further evaluated.