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Background: Hypoxic ischemic brain injury (HIBI) induced by cardiac arrest (CA) seems to predominate in cortical areas and to a lesser extent in the brainstem. These regions play key roles in modulating the activity of the autonomic nervous system (ANS), that can be assessed through analyses of heart rate variability (HRV). The objective was to evaluate the prognostic value of various HRV parameters to predict neurological outcome after CA., Methods: Retrospective monocentric study assessing the prognostic value of HRV markers and their association with HIBI severity. Patients admitted for CA who underwent EEG for persistent coma after CA were included. HRV markers were computed from 5 min signal of the ECG lead of the EEG recording. HRV indices were calculated in the time-, frequency-, and non-linear domains. Frequency-domain analyses differentiated very low frequency (VLF 0.003-0.04 Hz), low frequency (LF 0.04-0.15 Hz), high frequency (HF 0.15-0.4 Hz), and LF/HF ratio. HRV indices were compared to other prognostic markers: pupillary light reflex, EEG, N20 on somatosensory evoked potentials (SSEP) and biomarkers (neuron specific enolase-NSE). Neurological outcome at 3 months was defined as unfavorable in case of best CPC 3-4-5., Results: Between 2007 and 2021, 199 patients were included. Patients were predominantly male (64%), with a median age of 60 [48.9-71.7] years. 76% were out-of-hospital CA, and 30% had an initial shockable rhythm. Neurological outcome was unfavorable in 73%. Compared to poor outcome, patients with a good outcome had higher VLF (0.21 vs 0.09 ms 2 /Hz, p < 0.01), LF (0.07 vs 0.04 ms 2 /Hz, p = 0.003), and higher LF/HF ratio (2.01 vs 1.01, p = 0.008). Several non-linear domain indices were also higher in the good outcome group, such as SD2 (15.1 vs 10.2, p = 0.016) and DFA α1 (1.03 vs 0.78, p = 0.002). These indices also differed depending on the severity of EEG pattern and abolition of pupillary light reflex. These time-frequency and non-linear domains HRV parameters were predictive of poor neurological outcome, with high specificity despite a low sensitivity., Conclusion: In comatose patients after CA, some HRV markers appear to be associated with unfavorable outcome, EEG severity and PLR abolition, although the sensitivity of these HRV markers remains limited., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Severe Pneumocystis jirovecii pneumonia (PJP) requiring intensive care has been the subject of few prospective studies. It is unclear whether delayed curative antibiotic therapy may impact survival in these severe forms of PJP. The impact of corticosteroid therapy combined with antibiotics is also unclear., Methods: This multicentre, prospective observational study involving 49 adult intensive care units (ICUs) in France was designed to evaluate the severity, the clinical spectrum, and outcomes of patients with severe PJP, and to assess the association between delayed curative antibiotic treatment and adjunctive corticosteroid therapy with mortality., Results: We included 158 patients with PJP from September 2020 to August 2022. Their main reason for admission was acute respiratory failure (n = 150, 94.9%). 12% of them received antibiotic prophylaxis for PJP before ICU admission. The ICU, hospital, and 6-month mortality were 31.6%, 35.4%, and 40.5%, respectively. Using time-to-event analysis with a propensity score-based inverse probability of treatment weighting, the initiation of curative antibiotic treatment after 96 h of ICU admission was associated with faster occurrence of death [time ratio: 6.75; 95% confidence interval (95% CI): 1.48-30.82; P = 0.014]. The use of corticosteroids for PJP was associated with faster occurrence of death (time ratio: 2.48; 95% CI 1.01-6.08; P = 0.048)., Conclusion: This study showed that few patients with PJP admitted to intensive care received prophylactic antibiotic therapy, that delay in curative antibiotic treatment was common and that both delay in curative antibiotic treatment and adjunctive corticosteroids for PJP were associated with accelerated mortality., (© 2024. The Author(s).)

The burden of CMV infection and disease is important in pediatric hematopoietic stem cell transplantation (HSCT), notably in the subgroup of patients with inborn errors of immunity (IEIs). Letermovir (LMV) is now a standard of care for CMV prophylaxis in adult sero-positive (R+) recipients, but is not yet labeled for children. Published pediatric studies are still scarce. We report a monocentric real-life use of LMV in 36 HSCT pediatric recipients with IEIs considered at high-risk of CMV infection including 14 patients between 2 and 12 months of age. A homogenous dosage proportional to the body surface area was used. Pharmacokinetic (PK) was performed in 8 patients with a median of 6 years of age (range 0,6;15). The cumulative incidence of clinically significant CMV infections (CS-CMVi) and the overall survival of patients under LMV were compared to a very similar historical cohort under (val)aciclovir prophylaxis. LMV tolerance was good. As compared to the historical cohort, the incidence of CS-CMVi was significantly lower in LMV group (5 out of 36 transplants (13.9%) versus 28 of the 62 HSCT (45.2%)) (p = 0.002). Plasma LMV exposures did not significantly differ with those reported in adult patients. In this high-risk pediatric HSCT cohort transplanted for IEIs, CMV prophylaxis with LMV at a homogenous dosage was well tolerated and effective in preventing CS-CMVi compared with a historical cohort., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The cerebellum's role in posttreatment neurocognitive decline is unexplored. This study investigated associations between cerebellar microstructural integrity using quantitative neuroimaging biomarkers and neurocognition among patients with primary brain tumors receiving partial-brain radiation therapy (RT)., Methods and Materials: In a prospective trial, 65 patients underwent volumetric brain magnetic resonance imaging, diffusion tensor imaging, and memory, executive function, language, attention, and processing speed (PS) assessment before RT and at 3, 6, and 12 months after RT. Delis-Kaplan Executive Function System-Trail Making (D-KEFS-TM) visual scanning and number and letter sequencing and Wechsler Adult Intelligence Scale, Fourth Edition, coding were used to evaluate PS. The cerebellar cortex and white matter (WM) and supratentorial structures subserving the previously mentioned cognitive domains were autosegmented. Volume was measured within each structure at each time point along with diffusion biomarkers (fractional anisotropy and mean diffusivity) in WM structures. Linear mixed-effects models assessed cerebellar biomarkers as predictors of neurocognitive scores. If associated, cerebellar biomarkers were evaluated as independent predictors of cognitive scores controlling for domain-specific supratentorial biomarkers., Results: Left (P = .04) and right (P < .001) cerebellar WM volume declined significantly over time. Cerebellar biomarkers were not associated with memory, executive function, or language. Smaller left cerebellar cortex volume was associated with worse D-KEFS-TM number (P = .01) and letter (P = .01) sequencing scores. A smaller right cerebellar cortex volume correlated with worse D-KEFS-TM visual scanning (P = .02) and number (P = .03) and letter (P = .02) sequencing scores. Greater right cerebellar WM mean diffusivity, indicating WM injury, was associated with worse D-KEFS-TM visual scanning performance (P = .03). Associations remained significant after controlling for corpus callosum and intrahemispheric WM injury biomarkers., Conclusions: Injury to the cerebellum as measured with quantitative biomarkers correlates with worse post-RT PS, independent of corpus callosum and intrahemispheric WM damage. Efforts to preserve cerebellar integrity may preserve PS., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Amygdalae are bilateral, almond-shaped structures located anterior to the hippocampi, critical to limbic system functions of emotional processing and memory consolidation. The amygdalae are heterogeneous, composed of multiple nuclei with distinct structural and functional properties. We prospectively assessed associations between longitudinal changes in amygdala morphometry, including component nuclei, and functional outcomes in patients with primary brain tumors receiving radiation therapy (RT)., Methods and Materials: On a prospective longitudinal trial, 63 patients underwent high-resolution volumetric brain magnetic resonance imaging and testing for mood (Beck Depression Inventory and Beck Anxiety Inventory), memory (Brief Visuospatial Memory Test-Revised [BVMT] Total Recall and Delayed Recall; Hopkins Verbal Learning Test-Revised [HVLT] Total Recall and Delayed Recall), and health-related quality-of-life outcomes (Functional Assessment of Cancer Therapy-Brain Social/Family Well-Being and Emotional Well-Being) at baseline and 3, 6, and 12 months after RT. Amygdalae, including 8 nuclei, were autosegmented bilaterally using validated techniques. Linear mixed-effects models assessed longitudinal change in amygdalae and nuclei volumes and associations with dose and outcomes. Wilcoxon rank sum tests compared amygdala volume change between patient groups with worse and more stable outcomes at each time point., Results: Atrophy was found in the right amygdala at 6 months (P = .001) and the left amygdala at 12 months (P = .046). A higher dose was associated with atrophy of the left amygdala (P = .013) at 12 months. The right amygdala showed dose-dependent atrophy at 6 months (P = .016) and 12 months (P = .001). Worse BVMT-Total, HVLT-Total, and HVLT-Delayed performance was associated with smaller left lateral (P = .014, P = .004, and P = .007, respectively) and left basal (P = .034, P = .016, and P = .026, respectively) nuclei volumes. Increased anxiety at 6 months was associated with greater combined (P = .031) and right (P = .007) amygdala atrophy. Greater left amygdala atrophy (P = .038) was noted in patients with decreased emotional well-being at 12 months., Conclusions: Bilateral amygdalae and nuclei undergo time- and dose-dependent atrophy after brain RT. Atrophy in amygdalae and specific nuclei was associated with poorer memory, mood, and emotional well-being. Amygdalae-sparing treatment planning may preserve neurocognitive and neuropsychiatric outcomes in this population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Brain radiation therapy can impair fine motor skills (FMS). Fine motor skills are essential for activities of daily living, enabling hand-eye coordination for manipulative movements. We developed normal tissue complication probability (NTCP) models for the decline in FMS after fractionated brain radiation therapy (RT)., Methods and Materials: On a prospective trial, 44 patients with primary brain tumors received fractioned RT; underwent high-resolution volumetric magnetic resonance imaging, diffusion tensor imaging, and comprehensive FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS]; and Grooved Pegboard dominant/nondominant hands) at baseline and 6 months postRT. Regions of interest subserving motor function (including cortex, superficial white matter, thalamus, basal ganglia, cerebellum, and white matter tracts) were autosegmented using validated methods and manually verified. Dosimetric and clinical variables were included in multivariate NTCP models using automated bootstrapped logistic regression, least absolute shrinkage and selection operator logistic regression, and random forests with nested cross-validation., Results: Half of the patients showed a decline on grooved pegboard test of nondominant hands, 17 of 42 (40.4%) on grooved pegboard test of -dominant hands, and 11 of 44 (25%) on DKEFS-MS. Automated bootstrapped logistic regression selected a 1-term model including maximum dose to dominant postcentral white matter. The least absolute shrinkage and selection operator logistic regression selected this term and steroid use. The top 5 variables in the random forest were all dosimetric: maximum dose to dominant thalamus, mean dose to dominant caudate, mean and maximum dose to the dominant corticospinal tract, and maximum dose to dominant postcentral white matter. This technique performed best with an area under the curve of 0.69 (95% CI, 0.68-0.70) on nested cross-validation., Conclusions: We present the first NTCP models for FMS impairment after brain RT. Dose to several supratentorial motor-associated regions of interest correlated with a decline in dominant-hand fine motor dexterity in patients with primary brain tumors in multivariate models, outperforming clinical variables. These data can guide prospective fine motor-sparing strategies for brain RT., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Despite their promise, circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection face challenges in test performance, due mostly to the limited abundance of ctDNA and its inherent variability. To address these challenges, published assays to date demanded a very high-depth sequencing, resulting in an elevated price of test. Herein, we developed a multimodal assay called SPOT-MAS (screening for the presence of tumor by methylation and size) to simultaneously profile methylomics, fragmentomics, copy number, and end motifs in a single workflow using targeted and shallow genome-wide sequencing (~0.55×) of cell-free DNA. We applied SPOT-MAS to 738 non-metastatic patients with breast, colorectal, gastric, lung, and liver cancer, and 1550 healthy controls. We then employed machine learning to extract multiple cancer and tissue-specific signatures for detecting and locating cancer. SPOT-MAS successfully detected the five cancer types with a sensitivity of 72.4% at 97.0% specificity. The sensitivities for detecting early-stage cancers were 73.9% and 62.3% for stages I and II, respectively, increasing to 88.3% for non-metastatic stage IIIA. For tumor-of-origin, our assay achieved an accuracy of 0.7. Our study demonstrates comparable performance to other ctDNA-based assays while requiring significantly lower sequencing depth, making it economically feasible for population-wide screening., Competing Interests: VN VTCN is affiliated with Gene Solutions. The author has no other competing interests to declare, TN HTN is affiliated with Gene Solutions. The author has no other competing interests to declare, ND NNTD is affiliated with Gene Solutions. The author has no other competing interests to declare, TP TMQP is affiliated with Gene Solutions. The author has no other competing interests to declare, GN GTHN is affiliated with Gene Solutions. The author has no other competing interests to declare, TN TDN is affiliated with Gene Solutions. The author has no other competing interests to declare, TT TTTT is affiliated with Gene Solutions. The author has no other competing interests to declare, DV, TP, TJ, VN, HN, TN, QD, TD, AT, VN, VN, LH, QT, TP, TH, BN, TN, TN, DP, BP, TV, TN, TT, MT, NT, TL, TT, MD, HB, VK, TP, DT, TL, TP, ML, VC, TD No competing interests declared, TN THHN is affiliated with Gene Solutions. The author has no other competing interests to declare, LH LAKH is affiliated with Gene Solutions. The author has no other competing interests to declare, TT THT is affiliated with Gene Solutions. The author has no other competing interests to declare, DV DHV is affiliated with Gene Solutions. The author has no other competing interests to declare, TT TMTT is affiliated with Gene Solutions. The author has no other competing interests to declare, MN MNN is affiliated with Gene Solutions. The author has no other competing interests to declare, TV TTVV is affiliated with Gene Solutions. The author has no other competing interests to declare, AN ANN is affiliated with Gene Solutions. The author has no other competing interests to declare, TT TTT is affiliated with Gene Solutions. The author has no other competing interests to declare, VT VUT is affiliated with Gene Solutions. The author has no other competing interests to declare, ML MPL is affiliated with Gene Solutions. The author has no other competing interests to declare, TD TTD is affiliated with Gene Solutions. The author has no other competing interests to declare, TP TVP is affiliated with Gene Solutions. The author has no other competing interests to declare, HN HDN is affiliated with Gene Solutions. The author has no other competing interests to declare, DN DSN holds equity in Gene Solutions.DSN is affiliated with Gene Solutions. The author has no other competing interests to declare, DT DKT is affiliated with Gene Solutions. The author has no other competing interests to declare, HT HST is affiliated with Gene Solutions. The author has no other competing interests to declare, HG HG holds equity in Gene Solutions. The funder Gene Solutions provided support in the form of salaries for HG who is inventor on the patent application (USPTO 17930705).HG is affiliated with Gene Solutions. The author has no other competing interests to declare, HN HNN holds equity in Gene Solutions. The funder Gene Solutions provided support in the form of salaries for HNN who is inventor on the patent application (USPTO 17930705).HNN is affiliated with Gene Solutions. The author has no other competing interests to declare, MP MDP holds equity in Gene Solutions. The funder Gene Solutions provided support in the form of salaries for MDP who is inventor on the patent application (USPTO 17930705).MDP is affiliated with Gene Solutions. The author has no other competing interests to declare, LT LST holds equity in Gene Solutions. The funder Gene Solutions provided support in the form of salaries for LST who is inventor on the patent application (USPTO 17930705).LST is affiliated with Gene Solutions. The author has no other competing interests to declare, (© 2023, Nguyen, Nguyen et al.)

Background: We analyzed post-radiation (RT) neurocognitive outcomes in an ethnically diverse pediatric brain tumor population undergoing photon radiotherapy (XRT) and proton radiotherapy (PRT)., Procedure: Post-RT neurocognitive outcomes from 49 pediatric patients (37% Hispanic/Latino) with primary brain tumors were analyzed. Tests included cognitive outcomes, behavioral outcomes, and overall intelligence. For each outcome, proportion of patients with cognitive impairment (scores <1.5 SD) was calculated. The Fisher exact tests compared proportion of patients with impairment and t tests compared T-scores between XRT (n=32) and PRT (n=17) groups. Linear regression assessed associations between radiation modality and outcomes., Results: Median follow-up was 3.2 and 1.8 years in the XRT and PRT groups, respectively. The median RT dose was 54.0 Gy. We found impairment in 16% to 42% of patients across most neurocognitive domains except executive function. There was no difference in scores between XRT and PRT groups. Regression analyses revealed no association of neurocognitive outcomes with radiation modality. Non-Hispanic patients had better Verbal Comprehension Index and General Ability Index scores than Hispanic patients ( P <0.05)., Conclusions: Among pediatric patients with brain tumors receiving RT, all cognitive domains were affected except executive function. Radiation modality was not associated with neurocognitive outcomes. Hispanic patients may be more vulnerable to posttreatment cognitive effects that warrant further study., Competing Interests: Supported by the National Institutes of Health [F31 NS111883-01 (A.R.); F32NS119285-01A1 (A.S.); 1TL1TR001443 (M.S., A.Y.); 1KL2TR001444, R01 CA238783-01 to J.A.H.-G.); and American Cancer Society (RSG-15-229-01-CCE to C.R.M.)]. The remaining authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Panzi General Reference Hospital (HGR Panzi) in the Democratic Republic of Congo follows a large number of patients living with HIV-1 (PLWHIV). Although antiretrovirals (ARVs) are available, HIV-1 viral load (HIV-VL) measurement has only been implemented in the hospital since 2018. No data on ARV resistance levels and ARV dosage in plasma have yet been published for this region. We determined the prevalence of virological failure due to ARV resistance amongst patients and assessed the degree of genotypic resistance of the viral strains., Methods: We performed an HIV-VL test and determined dosage of ARVs on samples collected from 205 PLWHIV at HGR Panzi between 2017 and 2018, including 13 ARV-naive patients. Genotypic resistance testing was performed on all samples with detectable HIV-VLs, and interpreted with the Agence Nationale de Recherches sur le Sida (ANRS) 2018 algorithm., Results: Baseline resistance to NNRTIs was found in 2 of the 13 treatment-naive individuals (15%). ARV dosage was non-optimal for 44/192 of treated patients (22.9%), with an HIV-VL ≥1000 IU/mL for 40/192 (20.8%) of them. In particular, treatment-experienced viruses presented resistance to at least one NRTI (52.5%), to at least one NNRTIs (70%) or to at least one PIs (15%). Finally, two samples contained viruses with resistance polymorphism in the integrase gene., Conclusions: The high level of resistance to ARVs observed during this study, mainly due to treatment compliance default, fully justifies the implementation of means for closer patient monitoring. The provision of VL tests and therapeutic education management tools in a PLWHIV follow-up remains an absolute necessity to best adapt the current treatment lines in this region., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The SPOT-MAS assay "Screening for the Presence Of Tumor by Methylation And Size" detects the five most common cancers in Vietnam by evaluating circulating tumor DNA in the blood. Here, we validated its performance in a prospective multi-center clinical trial, K-DETEK. Our analysis of 2795 participants from 14 sites across Vietnam demonstrates its ability to detect cancers in asymptomatic individuals with a positive predictive value of 60%, with 83.3% accuracy in detecting tumor location. We present a case report to support further using SPOT-MAS as a complementary method to achieve early cancer detection and provide the opportunity for early treatment.

Methods: This retrospective study evaluated patients who received three-fraction accelerated partial breast irradiation (APBI) via brachytherapy for breast cancer between January 2016 and April 2020. Inclusion criteria included age ≥18 years and early-stage unilateral breast cancer with negative lymph nodes. We evaluated acute toxicity (<6 weeks), late toxicity (≥6 weeks), and cosmetic outcomes. Frequencies of each variable were calculated. Cancer-specific outcomes were determined via the Kaplan-Meier method., Results: Thirty consecutive patients received three-fraction APBI of 2,250 cGy over 2 d. All cancers were stage T2 or less. Median time to last follow-up was 22 months. Local recurrence-free survival was 95.8% at 22 months. Seventeen (56.7%) patients reported an acute toxicity event. All were grade 1 except one patient with grade 2 (fatigue). No patient experienced ≥ grade 3 acute toxicity. One (3.3%) patient reported grade 3 late toxicity (tissue fibrosis). No patients had breast edema, fat necrosis, or non-healing wounds. There were no ≥ grade 3 cosmetic events., Discussion: Three-fraction APBI via brachytherapy was successful in preventing disease recurrence and death in this study, with still limited follow-up. Although acute and late toxicities or adverse cosmetic outcomes were seen, very few were grade 2 or higher and compare favorably to those reported in prior 10-fraction APBI studies., Conclusions: This study provides early single institutional evidence that three-fraction APBI may become a feasible treatment alternative., (Copyright © 2022 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets., Methods: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured., Results: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively., Conclusions: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations., (© 2022. The Author(s).)

Purpose: Pediatric brain tumor patients are vulnerable to radiotherapy (RT) sequelae including endocrinopathies. We compared post-RT neuroendocrine outcomes between pediatric brain tumor patients receiving photons (XRT) versus protons (PRT)., Methods: Using a prospectively maintained single-institution database, we analyzed 112 pediatric primary brain tumor patients (80 XRT, 32 PRT) from 1996 to 2019. Patient/treatment characteristics and endocrinopathy diagnoses (growth hormone deficiency [GHD], sex hormone deficiency [SHD], hypothyroidism, and requirement of hormone replacement [HRT]) were obtained via chart review. Univariable/multivariable logistic regression identified neuroendocrine outcome predictors. Time-adjusted propensity score models accounted for treatment type. Craniospinal irradiation (CSI) patients were evaluated as a sub-cohort., Results: Median follow-up was 6.3 and 4.4 years for XRT and PRT patients respectively. Medulloblastoma was the most common histology (38%). Half of patients (44% in XRT, 60% in PRT) received CSI. Common endocrinopathies were GHD (26% XRT, 38% PRT) and hypothyroidism (29% XRT, 19% PRT). CSI cohort PRT patients had lower odds of hypothyroidism (OR 0.16, 95% CI[0.02-0.87], p = 0.045) on multivariable regression and propensity score analyses. There were no significant differences in endocrinopathies in the overall cohort and in the odds of GHD or HRT within the CSI cohort. SHD developed in 17.1% of the XRT CSI group but did not occur in the PRT CSI group., Conclusion: Endocrinopathies were common among pediatric brain tumor survivors. Among CSI patients, PRT was associated with lower risk of hypothyroidism, and potentially associated with lower incidence of SHD. Future studies should involve collaborative registries to explore the survivorship benefits of PRT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ., Materials and Methods: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC., Results: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings., Conclusion: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Hereditary cancer syndromes (HCS) are responsible for 5-10% of cancer cases. Genetic testing to identify pathogenic variants associated with cancer predisposition has not been routinely available in Vietnam. Consequently, the prevalence and genetic landscape of HCS remain unknown., Methods: 1165 Vietnamese individuals enrolled in genetic testing at our laboratory in 2020. We performed analysis of germline mutations in 17 high- and moderate- penetrance genes associated with HCS by next generation sequencing., Results: A total of 41 pathogenic variants in 11 genes were detected in 3.2% individuals. The carrier frequency was 4.2% in people with family or personal history of cancer and 2.6% in those without history. The percentage of mutation carriers for hereditary colorectal cancer syndromes was 1.3% and for hereditary breast and ovarian cancer syndrome was 1.6%. BRCA1 and BRCA2 mutations were the most prevalent with the positive rate of 1.3% in the general cohort and 5.1% in breast or ovarian cancer patients. Most of BRCA1 mutations located at the BRCA C-terminus domains and the top recurrent mutation was NM&#95;007294.3:c.5251C>T (p.Arg1751Ter). One novel variant NM&#95;000038.6(APC):c.6665C>A (p.Pro2222His) was found in a breast cancer patient with a strong family history of cancer. A case study of hereditary cancer syndrome was illustrated to highlight the importance of genetic testing., Conclusion: This is the first largest analysis of carrier frequency and mutation spectrum of HCS in Vietnam. The findings demonstrate the clinical significance of multigene panel testing to identify carriers and their at-risk relatives for better cancer surveillance and management strategies., Competing Interests: H-DN, NN, DD, VUT, HHN, ML, YN, HT, M-DP, HG, and LT are current employees of Gene Solutions, Vietnam. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tran, Nguyen, Pham, Phan, Nguyen, Nguyen, Nguyen, Doan, Le, Nguyen, Jasmine, Nguyen, Nguyen, Nguyen, Do, Tran, Nguyen, Le, Nguyen, Do, Truong, Tang, Phan, Nguyen, Giang and Tu.)

We compared the proportion of participants achieving first undetectable HIV-1 RNA (VL) in seminal plasma (SP) and blood plasma (BP) in 19 men starting dolutegravir-based regimen at primary HIV infection. At baseline, median VL was 6.5 (interquartile range [IQR], 5.6-7.9) and 4.5 (IQR, 3.5-5.0) log10 copies/mL in BP and SP, respectively. Between baseline and week 48, significantly higher proportion of participants achieved first VL below limit of quantification in SP (93.0%) than in BP (84.2%; P = .008). Time to first undetectable VL was 8 weeks in SP (95% confidence interval [CI], 5.6-10.4) and 24 weeks in BP (95% CI, 14.1-33.9)., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: Primary brain malignancies (PBMs) pose significant morbidity and poor prognosis. Despite NCCN recommendations that palliative care should be integrated into general oncologic care plans, it has been historically underused in patients with PBM. We sought to examine trends and factors associated with inpatient palliative care use in patients with PBM., Methods: Data from the 2007-2016 National (Nationwide) Inpatient Sample was analyzed for descriptive statistics and trends. Multivariable logistic regression was used to identify factors associated with inpatient palliative care in patients with PBMs., Results: Of the 510,238 observed hospitalizations of adults with PBM in a 10-year period, 37,365 (7.3%) had an associated inpatient palliative care consult. Rates of inpatient palliative care have increased significantly over the 10-year period, from 2.3 in 2007 to 11.9% in 2011. Patients receiving inpatient palliative care were less likely to receive inpatient oncologic treatment such as brain surgery, chemotherapy, or radiation compared to those without palliative care (14.6% with palliative care vs. 42.4% without, p < 0.001). They were more likely to receive life-sustaining treatments such as intubation, mechanical ventilation, tracheostomy, nutritional support, hemodialysis, or CPR (21.0% with palliative care vs. 10.4% without, p < 0.001). Palliative care was associated with decreased cost of admission ($18,602 with palliative care vs. $20,077 without). In a multiple variable logistic regression, age, non-elective admission, comorbidities, history of chemotherapy and radiation, and mechanical ventilation were associated with significantly increased odds of receiving palliative care., Conclusions: Inpatient palliative care utilization for patients hospitalized with PBM significantly increased between 2007 and 2016, though the service is still underutilized in the context of the severe symptoms and poor prognosis associated with PBM., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: We conducted the first prospective longitudinal study examining the independent association between patient-reported health-related quality of life (hrQoL) (physical, social/family, emotional, functional, and brain cancer-specific) and neurocognitive function (NCF), while controlling for mood symptoms in patients with primary brain tumors., Methods and Materials: Patients with primary brain tumors (n = 59) receiving brain radiation therapy underwent hrQOL (Functional Assessment of Cancer Therapy-Brain), mood (Beck Depression and Anxiety Inventories), and neurocognitive evaluation at baseline and 3, 6, and 12 months postradiation therapy in a prospective clinical trial. Neurocognitive assessments measured attention/processing speed, memory, and executive function, including the Delis-Kaplan Executive Function System Verbal Fluency, Hopkins Verbal Learning Test Revised (HVLT-R), and Brief Visuospatial Memory Test. Subjects underwent neurocognitive, mood, and hrQoL assessments in the same testing session. Multivariable linear mixed-effects models assessed associations between hrQOL and NCF over time, controlling for patient, tumor, and treatment characteristics as well as timepoint-specific patient-reported mood (ie, anxiety and depression symptoms). P values were adjusted for multiple comparisons., Results: Higher physical hrQoL was associated with better verbal memory (HVLT-R Total Recall, P = .047), and higher functional hrQoL was associated with better executive function (Delis-Kaplan Executive Function System Verbal Fluency Switching Total, P = .009) and verbal memory (HVLT-R Delayed Recall, P = .006). Higher brain tumor-specific hrQoL was associated with better verbal and nonverbal memory (HVLT-R Total, P = .004 and Delayed Recall, P = .030; Brief Visuospatial Memory Test Total, P = .049 and Delayed Recall, P = .049). There was no association between social/family or emotional hrQoL and NCF after controlling for mood., Conclusions: Higher physical, functional, and brain tumor-specific hrQoL were associated with better executive function and memory among patients with primary brain tumors. Physical and functional impairments are correlated with cognitive performance. Interventions to maximize quality of life after treatment may influence neurocognition and vice versa., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Clinical variables-age, family history, genetics-are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death., Methods: Genotype/phenotype data were obtained from a nested case-control Cohort of Swedish Men (n = 3279; 2163 with prostate cancer, 278 prostate cancer deaths). PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes, body mass index) were tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models with/without PHS were compared with log-likelihood tests., Results: Median age at last follow-up/prostate cancer death was 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol (HR 1.74 [1.40-2.15]), diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol (HR 1.45 [1.19-1.76]), diabetes (HR 0.62 [0.42-0.90]) all remained associated with fatal disease. Including PHS46 or PHS166 improved multivariable models for fatal prostate cancer (p < 10 -15 )., Conclusions: PHS had the most robust association with fatal prostate cancer in a multivariable model with common risk factors, including family history. Adding PHS to clinical variables may improve prostate cancer risk stratification strategies., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: We explored fine motor skills (FMS) before and after brain radiotherapy (RT), analyzing associations between longitudinal FMS and imaging biomarkers of cortical and white matter (WM) integrity in motor regions of interest (ROIs)., Methods: On a prospective trial, 52 primary brain tumor patients receiving fractionated brain RT underwent volumetric brain MRI, diffusion tensor imaging, and FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS], Grooved Pegboard Dominant Hands [PDH], and Grooved Pegboard Nondominant Hands [PNDH]) at baseline and 3-, 6-, and 12-month post-RT. Motor ROIs autosegmented included: sensorimotor cortices and superficial WM, corticospinal tracts, cerebellar cortices and WM, and basal ganglia. Volume (cc) was measured in all ROIs at each timepoint. Diffusion biomarkers (FA [fractional anisotropy] and MD [mean diffusivity]) were additionally measured in WM ROIs. Linear mixed-effects models assessed biomarkers as predictors of FMS scores. P values were corrected for multiple comparisons., Results: Higher RT dose was associated with right paracentral cortical thinning (β = -2.42 Gy/(month × mm), P = .03) and higher right precentral WM MD (β = 0.69 Gy/(month × µm2/ms), P = .04). Higher left (β = 38.7 points/(month × µm2/ms), P = .004) and right (β = 42.4 points/(month × µm2/ms), P = .01) cerebellar WM MD, left precentral cortical atrophy (β = -8.67 points/(month × mm), P = .02), and reduced right cerebral peduncle FA (β = -0.50 points/month, P = .01) were associated with worse DKEFS-MS performance. Left precentral cortex thinning was associated with worse PDH scores (β = -17.3 points/(month × mm), P = .02). Left (β = -0.87 points/(month × cm3), P = .001) and right (β = -0.64 points/(month × cm3), P = .02) cerebellar cortex, left pons (β = -19.8 points/(month × cm3), P = .02), and right pallidum (β = -10.8 points/(month × cm3), P = .02) atrophy and reduced right internal capsule FA (β = -1.02 points/month, P = .03) were associated with worse PNDH performance., Conclusions: Biomarkers of microstructural injury in motor-associated brain regions were associated with worse FMS. Dose avoidance in these areas may preserve FMS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To assess in real life whether two-drug regimens (2-DRs) given 4-5 days a week in virally suppressed patients can maintain viral suppression over 48 and 96 weeks., Methods: This observational single-centre study enrolled all patients who initiated an intermittent 2-DR between 01/01/2016 and 30/06/2019. The primary outcome was the rate of virological failure (VF), defined as confirmed plasma viral load (pVL) ≥50 copies/mL or single pVL ≥50 copies/mL followed by ART change at week 48 (W48) and W96. Secondary outcomes were the 2-DR intermittent strategy success rate (pVL <50 copies/mL with no ART change), change in CD4 count, CD4/CD8 ratio and rate of residual viraemia., Results: Eighty-five patients were included; 67/85 (79%) were men, median age = 57 years (IQR = 50-63), CD4 nadir = 233 cells/mm3 (110-327), ART duration = 21 years (13-24), duration of virological suppression = 6.5 years (3.7-10.8) and CD4 count = 658 cells/mm3 (519-867). Intermittent 2-DRs consisted of integrase strand transfer inhibitor (INSTI)/NNRTI (58%), INSTI/NRTI (13%), two NRTIs (11%), PI/NRTI (7%) and other combinations (11%). The median follow-up was 90 weeks (IQR = 64-111). Overall, four VFs occurred, leading to a virological success rate of 98.8% (95% CI = 93.6-100) at W48 and 95.3% (95% CI = 88.4-98.7) at W96. Resuming the same 2-DR 7 days a week led to viral resuppression in three patients, whereas the M184V mutation emerged in one patient, leading to ART modification. There was no significant change in the CD4 count or residual viraemia rate, but a small increase in the CD4/CD8 ratio (P = 0.009) occurred over the study period., Conclusions: This observational study shows the potential for intermittent 2-DRs to maintain a high virological success rate, which should be assessed in larger prospective randomized studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The corpus callosum (CC) and intrahemispheric white matter tracts (IHWM) subserve critical aspects of attention and processing speed. We analyzed imaging biomarkers of microstructural injury within these regions and association with attention and processing speed performance before and after radiation therapy in primary brain tumor patients., Methods and Materials: In a prospective clinical trial, 44 primary brain tumor patients underwent cognitive testing and magnetic resonance imaging/diffusion-weighted imaging at baseline (pre-radiation therapy) and 3-, 6-, and 12-months post-radiation therapy. CC (subregions, total) and IHWM tracts (left/right without CC, total) were autosegmented; tumor, tumor bed, and edema were censored. Biomarkers included volume changes (cm 3 ), mean diffusivity ([MD]; higher values indicate white matter injury), fractional anisotropy ([FA]; lower values indicate white matter injury). Reliable-change indices measured changes in attention (Weschler Adult Intelligence Scale [WAIS-IV] digits-forward; Delis-Kaplan Executive Function System Trail Making [D-KEFS-TM] visual-scanning), and processing speed (WAIS-IV coding; D-KEFS-TM number-sequencing, letter-sequencing), accounting for practice effects. Linear mixed-effects models evaluated associations between mean radiation dose and biomarkers (volume, MD, FA) and imaging biomarkers and neurocognitive performance. Statistics were corrected for multiple comparisons., Results: Processing speed declined at 6 months following radiation therapy (number sequencing, letter sequencing; P < .04). Seizures and antiepileptic drug therapy were associated with lower visual-scanning attention reliable-change indices at 6 months (P = .039). Higher radiation dose correlated with smaller midanterior CC volume (P = .023); lower FA in posterior CC, anterior CC, and total CC (all P < .03); and higher MD in anterior CC (P = .012). Smaller midanterior CC and left IHWM volume correlated with worse processing speed (coding, letter-sequencing, number-sequencing; all P < .03). Higher FA in right, left, and total IHWM correlated with better coding scores (all P < .01). Lower FA in total IHWM (P = .009) was associated with worse visual-scanning attention scores. Higher FA in midposterior CC (P = .029) correlated with better digits-forward attention scores., Conclusions: The CC demonstrated radiation dose-dependent atrophy and WM injury. Microstructural injury within the CC and IHWM was associated with attention and processing speed decline after radiation therapy. These areas represent possible avoidance regions for preservation of attention and processing speed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46)., Materials and Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy., Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer., Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

An overview of common approaches used to assess a dose response for radiation therapy-associated endpoints is presented, using lung toxicity data sets analyzed as a part of the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic effort as an example. Each component presented (eg, data-driven analysis, dose-response analysis, and calculating uncertainties on model prediction) is addressed using established approaches. Specifically, the maximum likelihood method was used to calculate best parameter values of the commonly used logistic model, the profile-likelihood to calculate confidence intervals on model parameters, and the likelihood ratio to determine whether the observed data fit is statistically significant. The bootstrap method was used to calculate confidence intervals for model predictions. Correlated behavior of model parameters and implication for interpreting dose response are discussed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS 1 ) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS 2 (PHS 1 , adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS 2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10 -180 ). Comparing the 80 th /20 th PHS 2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS 2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans., (© 2020 Union for International Cancer Control.)

Purpose: Primary brain tumor patients are vulnerable to depression and anxiety symptoms, which may affect their neurocognitive functioning. We performed a prospective longitudinal analysis to examine the association between depression and anxiety symptoms and domain-specific neurocognitive functioning in primary brain tumor patients receiving radiation therapy (RT)., Methods and Materials: On a prospective trial, 54 primary brain tumor patients receiving RT underwent comprehensive neurocognitive evaluation at baseline (pre-RT), and 3, 6, and 12 months post-RT. Neurocognitive assessments measured attention/processing speed, verbal and visuospatial memory, and executive functioning, including Delis-Kaplan Executive Function System Trail-Making Test (DKEFS-TMT), DKEFS Verbal Fluency, and Brief Visuospatial Memory Test-Revised. Depression and anxiety symptoms were also assessed at each time point with Beck Depression and Anxiety Inventories (BDI-II and BAI), respectively. Higher scores reflect more numerous or severe depression or anxiety symptoms. Univariable and multivariable linear mixed-effects models assessed associations between BDI-II and BAI scores and domain-specific neurocognitive scores over time, controlling for pre-existing depression or anxiety disorders and other patient, tumor, and treatment characteristics., Results: Higher BAI scores were associated with worse attention and processing speed in univariable analyses: DKEFS-TMT visual scanning (P = .003), number sequencing (P = .011), and letter sequencing (P <.001). On multivariable analyses, these associations remained significant (all P ≤ .01). Higher BDI-II scores were also associated with poorer attention/processing speed (DKEFS-TMT Letter Sequencing) in univariable (P = .002) and multivariable (P = .013) models. Higher BAI scores were associated with worse visuospatial memory (Brief Visuospatial Memory Test-Revised Delayed Recall) on univariable (P = .012) but not multivariable analyses (P = .383). Similarly, higher BDI-II scores were associated with poorer executive functioning (DKEFS Verbal Fluency Category Switching) on univariable (P = .031) but not multivariable analyses (P = .198)., Conclusions: Among primary brain tumor patients receiving RT, increased depression and anxiety were independently associated with worsened neurocognition, particularly in attention/processing speed. Depression and anxiety symptoms should be controlled for in prospective clinical trials and managed in the clinical setting to optimize neurocognitive functioning., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Our purpose was to investigate the association between imaging biomarkers of radiation-induced white matter (WM) injury within perisylvian regions and longitudinal language decline in patients with brain tumors., Methods and Materials: Patients with primary brain tumors (n = 44) on a prospective trial underwent brain magnetic resonance imaging, diffusion-weighted imaging, and language assessments of naming (Boston Naming Test [BNT]) and fluency (Delis-Kaplan Executive Function System Category Fluency [DKEFS-CF]) at baseline and 3, 6, and 12 months after fractionated radiation therapy (RT). Reliable change indices of language function (0-6 months), accounting for practice effects (RCI-PE), evaluated decline. Bilateral perisylvian WM regions (superficial WM subadjacent to Broca's area and the superior temporal gyrus [STG], inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus [IFOF], and arcuate fasciculus) were autosegmented. We quantified volume and diffusion measures of WM microstructure: fractional anisotropy (FA; lower values indicate disruption) and mean diffusivity (MD; higher values indicate injury). Linear mixed-effects models assessed mean dose as predictor of imaging biomarker change and imaging biomarkers as longitudinal predictors of language scores., Results: DKEFS-CF scores declined at 6 months post-RT (RCI-PE, -0.483; P = .01), whereas BNT scores improved (RCI-PE, 0.262; P = .04). Higher mean dose to left and right regions was predictive of decreased volume (left-STG, P = .02; right-ILF and IFOF, P = .03), decreased FA (left-WM tracts, all P < .01; right-STG and IFOF, P < .02), and increased MD of left-WM tracts (all P < .03). Volume loss within left-Broca's area (P = .01), left-ILF (P = .01), left-IFOF (P = .01), and left-arcuate fasciculus (P = .04) was associated with lower BNT scores. Lower FA correlated with poorer DKEFS-CF and BNT scores within left-ILF (P = .02, not significant), left-IFOF (P = .02, .04), and left-arcuate fasciculus (P = .01, .01), respectively. Poorer DKEFS-CF scores correlated with increased MD values within the left-arcuate fasciculus (P = .03). Right-sided biomarkers did not correlate with language scores., Conclusions: Patients with primary brain tumors experience language fluency decline post-RT. Poorer fluency and naming function may be explained by microstructural injury to left-sided perisylvian WM, representing potential dose-avoidance targets for language preservation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: While peer review is critical for quality and safety in radiotherapy, there are neither formal guidelines nor format examples for brachytherapy (BT) peer review. We report on a gynecologic BT peer-review method implemented at a high-volume academic center., Methods and Materials: We analyzed discussions at bimonthly gynecologic BT peer-review rounds between July and December 2018. Rounds consisted of 2-5 attending physicians with gynecologic BT expertise, 1-2 BT physicists, and trainees. Peer-review targets included clinical case review, contours, implant technique, dose/fractionation, and target/organ-at-risk (OAR) dosimetry. The projected/final target and OAR dosimetry were analyzed., Results: 55 separate implants from 44 patients were reviewed. Implants were mostly reviewed after the first BT fraction (n = 16, 29%) or at another time point during BT (n = 20, 36%). One (2%) implant was presented prospectively. The applicator type and BT technique were reviewed for all implants. Dose/fractionation was evaluated for 46 implants (84%); contours were discussed for 21 (38%). Target and OAR dosimetry were reviewed for 54 (98%) and 28 implants (51%), respectively. Six cases (11%) underwent minor changes to the applicator type to improve target and/or OAR dosimetry. One case (2%) had a major change recommended to the dose/fractionation., Conclusions: Gynecologic BT peer review may enhance BT quality by allowing for implant optimization and formal review of challenging cases, ultimately improving medical decision-making and team communication. Peer review should be implemented in centers offering gynecologic BT., (Published by Elsevier Inc.)

Background and purpose Recently published HyTEC report summarized lung toxicity data and proposed guidelines of mean lung dose (MLD) <8 Gy and normal lung receiving at least 20 Gy, V 20Gy <10-15% to avoid lung toxicity. Support for preferred use of a particular dosimetric parameter has been limited. We performed a detailed dose-volume analysis of data on radiation pneumonitis (RP) following lung stereotactic body radiation therapy (SBRT) to search for parameters showing the strongest correlation with RP. Materials and methods Two patient cohorts (primary and metastatic lung tumor patients) from previously reported studies were analyzed. Total number of patients was 96, and incidence of grade ≥2 RP was 13.5% (13/96). Fitting to the logistic function was performed to investigate correlation between incidence of RP and reported dosimetric and volumetric parameters. Another independent cohort was used to explore correlation between dosimetric parameters. Results Among normal lung parameters (MLD and reported V x ), only MLD consistently showed significant correlation with incidence of RP. Gross tumor volume (GTV), internal target volume, planning target volume (PTV), and minimum dose covering 95% of GTV or PTV did not show statistical significance. A significant correlation between reported V x and MLD was observed in all cohorts. Conclusions In considering tumor- and target-specific (e.g., GTV, PTV) and normal lung-specific (e.g., MLD, V x ) metrics, MLD was the only parameter that consistently correlated with incidence of RP across both cohorts. Because SBRT planning constraints allow small normal lung volumes to receive high doses, utility of MLD is not obvious. The parallel structure of lung is one possible explanation, but correlation between dosimetric parameters obscures elucidation of the preferred or mechanistically based parameter to guide radiotherapy planning., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Moiseenko et al.)

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR 98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR 98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR 98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening., Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups., Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age., Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS., Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions., (©2020 American Association for Cancer Research.)

Background: Hematologic toxicity is a critical problem limiting treatment delivery in cancer patients undergoing concurrent chemoradiotherapy. However, the extent to which anatomic variations in radiation dose limit chemotherapy delivery is poorly understood. A unique natural experiment arises in patients with head and neck and cervical cancer, who frequently undergo identical chemotherapy but receive radiation to different regions of the body. Comparing these cohorts can help elucidate to what extent hematologic toxicity is attributable to marrow radiation as opposed to chemotherapy. Methods: In this longitudinal cohort study, we compared hematologic toxicity and bone marrow compensatory response in 148 patients (90 cervix, 58 head/neck) undergoing chemoradiotherapy with concurrent weekly cisplatin 40 mg/m 2 . We used linear mixed effect models to compare baseline and time-varying peripheral cell counts and hemoglobin levels between cohorts. To assess bone marrow compensatory response, we measured the change in metabolically active bone marrow (ABM) volume on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Results: We observed greater reductions in log-transformed lymphocyte, platelet, and absolute neutrophil counts (ANC) for cervix compared to head/neck cancer patients (fixed effects for time-cohort interaction [95% CI]: lymphocytes, -0.06 [-0.09, -0.031]; platelets,-0.028 [-0.051, -0.0047]; ANC, -0.043 [-0.075, -0.011]). Mean ANC nadirs were also lower for cervical vs. head/neck cancer cohorts (2.20 vs. 2.85 × 10 3 per μL, p < 0.01). Both cohorts exhibited reductions in ABM volume within the radiation field, and increases in ABM volume in out-of-field areas, indicating varying compensatory response to radiation injury. Conclusions: Cervical cancer patients had faster decreases in ANC, lymphocyte, and platelet counts, and lower ANC nadirs, indicating a significant effect of pelvic irradiation on acute peripheral blood cell counts. Both cohorts exhibited a compensatory response with increased out-of-field bone marrow activity., (Copyright © 2020 Vitzthum, Heide, Park, Williamson, Sheridan, Huynh-Le, Sirak, Wei, Tarnawski, Mahantshetty, Nguyen, Mayadev, Yashar, Sacco and Mell.)

Background: Radionuclide radium-223 improves survival in men with metastatic castrate-resistant prostate cancer. The United States (US) Food and Drug Administration Adverse Events Reporting System (FAERS) is a post-market pharmacovigilance database valuable for adverse event (AE) assessments. We analyzed FAERS to identify disproportionate AE signals related to radium-223, and to explore radium-223's international utilization., Materials and Methods: We identified 2182 radium-223 cases associated with AE(s) from 2013 to 2018. The duration of radium-223 therapy was calculated. Reporting odds ratio (ROR) and proportional reporting ratio (PRR), with 95% confidence intervals (CIs), were calculated for AEs of interest. ROR shows disproportionate signals if the lower limit of the 95% CI > 1. PRR shows disproportionate signals if PRR ≥ 2, χ 2 statistic ≥ 4, and ≥ 3 AEs were reported. We identified any US Food and Drug Administration enforcement actions for radium-223., Results: A majority (60.8%) of events occurred outside the US. Among patients with radium-223-associated AEs, the median therapy duration was only 56 days (corresponding to 2-3 treatment cycles). Disproportionate signals were detected for general health deterioration (ROR, 5.03; 95% CI, 4.23-5.98 and PRR, 4.94; 95% CI, 4.16-5.87), bone pain (ROR, 4.53; 95% CI, 3.67-5.59 and PRR, 4.48; 95% CI, 3.63-5.53), and hematologic AEs including anemia (ROR, 2.89; 95% CI, 2.55-3.27 and PRR, 2.80; 95% CI, 2.48-3.17), thrombocytopenia (ROR, 3.22; 95% CI, 2.77-3.74 and PRR, 3.16; 95% CI, 2.72-3.67), and pancytopenia/bone marrow failure (ROR, 4.83; 95% CI, 4.11-5.67 and PRR, 4.73; 95% CI, 4.03-5.55). There were no enforcement actions for radium-223., Conclusions: Patients with metastatic castrate-resistant prostate cancer experiencing AEs are only receiving one-half the prescription dose of radium-223 required for survival benefit. Radium-223 is associated with health deterioration, bone pain, and hematologic AEs. Real-world analyses are important for ongoing radium-223 risk-benefit assessments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Optimal prostate cancer (PCa) screening strategies will focus on men likely to have potentially lethal disease. Age-specific incidence rates (ASIRs) by modern clinical risk groups could inform risk stratification efforts for screening., Methods: This cross-sectional population study identified all men diagnosed with PCa in Norway from 2014 to 2017 (n = 20,356). Age, Gleason score (primary plus secondary), and clinical stage were extracted. Patients were assigned to clinical risk groups: low, favorable intermediate, unfavorable intermediate, high, regional, and metastatic. Chi-square tests analyzed the independence of Gleason scores and modern PCa risk groups with age. ASIRs for each risk group were calculated as the product of Norwegian ASIRs for all PCa and the proportions observed for each risk category., Results: Older age was significantly associated with a higher Gleason score and more advanced disease. The percentages of men with Gleason 8 to 10 disease among men aged 55 to 59, 65 to 69, 75 to 79, and 85 to 89 years were 16.5%, 23.4%, 37.2%, and 59.9%, respectively (P < .001); the percentages of men in the same age groups with at least high-risk disease were 29.3%, 39.1%, 60.4%, and 90.6%, respectively (P < .001). The maximum ASIRs (per 100,000 men) for low-risk, favorable intermediate-risk, unfavorable intermediate-risk, high-risk, regional, and metastatic disease were 157.1 for those aged 65 to 69 years, 183.8 for those aged 65 to 69 years, 194.8 for those aged 70 to 74 years, 408.3 for those aged 75 to 79 years, 159.7 for those aged ≥85 years, and 314.0 for those aged ≥85 years, respectively. At the ages of 75 to 79 years, the ASIR of high-risk disease was approximately 6 times greater than the ASIR at 55 to 59 years., Conclusions: The risk of clinically significant localized PCa increases with age. Healthy older men may benefit from screening., (© 2020 American Cancer Society.)

Introduction: We investigated multi-domain baseline neurocognition of primary brain tumor patients prior to radiotherapy (RT), including clinical predictors of function and association between pre-RT and post-RT impairment on a prospective trial., Methods: A multi-domain neuropsychological battery (memory, executive functioning, language, attention, processing) was performed on 37 patients, pre-RT and 3-(n = 21), 6-(n = 22) and 12-(n = 14) months post-RT. Impairment rate was the proportion of patients with standardized T-scores ≤ 1.5 standard deviations below normative means. Per-patient impairment across all domains was calculated using a global deficit score (GDS; higher value indicates more impairment). Associations between baseline GDS and clinical variables were tested. Global GDS impairment rate at each time point was the fraction of patients with GDS scores > 0.5., Results: Statistically significant baseline neurocognitive impairments were identified on 4 memory (all p ≤ 0.03) and 2 out of 3 (p = 0.01, p = 0.027) executive functioning tests. Per-patient baseline GDS was significantly associated with tumor volume (p = 0.048), tumor type (p = 0.043), seizure history (p = 0.007), and use of anti-epileptics (p = 0.009). The percentage of patients with the same impairment status at 3-, 6-, and 12-months as at baseline were 88%, 85%, and 85% respectively., Conclusions: Memory and executive functioning impairment were the most common cognitive deficits prior to RT. Patients with larger tumors, more aggressive histology, and use of anti-epileptics had higher baseline GDS values. GDS is a promising tool to encompass multi-domain neurocognitive function, and baseline GDS can identify those at risk of cognitive impairment.

Purpose: We used quantitative magnetic resonance imaging to prospectively analyze the association between microstructural damage to memory-associated structures within the medial temporal lobe and longitudinal memory performance after brain radiation therapy (RT)., Methods and Materials: Patients with a primary brain tumor receiving fractionated brain RT were enrolled on a prospective trial (n = 27). Patients underwent high-resolution volumetric brain magnetic resonance imaging, diffusion-weighted imaging, and neurocognitive testing before and 3, 6, and 12 months post-RT. Medial temporal lobe regions (hippocampus; entorhinal, parahippocampal, and temporal pole white matter [WM]) were autosegmented, quantifying volume and diffusion biomarkers of WM integrity (mean diffusivity [MD]; fractional anisotropy [FA]). Reliable change indices measured changes in verbal (Hopkins Verbal Learning Test-Revised) and visuospatial (Brief Visuospatial Memory Test-Revised [BVMT-R]) memory. Linear mixed-effects models assessed longitudinal associations between imaging parameters and memory., Results: Visuospatial memory significantly declined at 6 months post-RT (mean reliable change indices, -1.3; P = .012). Concurrent chemotherapy and seizures trended toward a significant association with greater decline in visuospatial memory (P = .053 and P = .054, respectively). Higher mean dose to the left temporal pole WM was significantly associated with decreased FA (r = -0.667; P = .002). Over all time points, smaller right hippocampal volume (P = .021), lower right entorhinal FA (P = .023), greater right entorhinal MD (P = .047), and greater temporal pole MD (BVMT-R total recall, P = .003; BVMT-R delayed recall, P = .042) were associated with worse visuospatial memory. The interaction between right entorhinal MD (BVMT-R total recall, P = .021; BVMT-R delayed recall, P = .004) and temporal pole FA (BVMT-R delayed recall, P = .024) significantly predicted visuospatial memory performance., Conclusions: Brain tumor patients exhibited visuospatial memory decline post-RT. Microstructural damage to critical memory regions, including the hippocampus and medial temporal lobe WM, were associated with post-RT memory decline. The integrity of medial temporal lobe structures is critical to memory performance post-RT, representing possible avoidance targets for memory preservation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Marriage has been associated with enhanced survival among cancer patients, but conflicting correlations have been suggested in cervical cancer. We assessed the impact of marital status on receipt of brachytherapy and survival in women with locally advanced cervical cancer., Methods and Materials: Three thousand, eight hundred and twelve patients with Stage IB2-IVA cervical cancer diagnosed from 2006 to 2015 treated with external beam radiotherapy were identified from the California Cancer Registry. Chi-square tests were used to compare patient characteristics by marital status and boost type. The association of marital status with brachytherapy (BT) receipt was assessed using multiple logistic regression. Fine and Gray competing risks and Cox proportional hazards regressions were used to estimate cervical cancer-specific survival (CCSS) and overall survival (OS), respectively., Results: Most women were unmarried (58.8%). Half (50.4%) received BT, while 33.1% received no boost; most (86.3%) received chemotherapy. Unmarried women had similar odds of receiving BT as married women (OR = 1.07, 95% CI: 0.90-1.28, p = 0.4370) but were less likely to receive chemotherapy (84.3% vs. 89.1%, p < 0.0001). Singlehood was significantly associated with worse CCSS (subdistribution hazard ratio = 1.21, 95% CI: 1.03-1.42, p < 0.0174) and OS (hazard ratio = 1.18, 95% CI: 1.03-1.36, p < 0.0153). Not receiving a radiation boost was also significantly associated with worse CCSS (subdistribution hazard ratio = 1.21, 95% CI: 1.02-1.43, p = 0.0317) and OS (hazard ratio = 1.21, 95% CI: 1.05-1.40, p = 0.0100)., Conclusions: There were no differences in BT receipt in married vs. unmarried patients. However, unmarried patients had worse CCSS and OS and were less likely to receive chemotherapy. Interventions targeting social factors are needed to improve outcomes in this vulnerable population., (Published by Elsevier Inc.)

Background and Purpose: The amygdalae are deep brain nuclei critical to emotional processing and the creation and storage of memory. It is not known whether the amygdalae are affected by brain radiotherapy (RT). We sought to quantify dose-dependent amygdala change one year after brain RT., Materials and Methods: 52 patients with primary brain tumors were retrospectively identified. Study patients underwent high-resolution, volumetric magnetic resonance imaging before RT and 1 year afterward. Images were processed using FDA-cleared software for automated segmentation of amygdala volume. Tumor, surgical changes, and segmentation errors were manually censored. Mean amygdala RT dose was tested for correlation with amygdala volume change 1 year after RT via the Pearson correlation coefficient. A linear mixed-effects model was constructed to evaluate potential predictors of amygdala volume change, including age, tumor hemisphere, sex, seizure history, and bevacizumab treatment during the study period. As 51 of 52 patients received chemotherapy, possible chemotherapy effects could not be studied. A two-tailed p-value <0.05 was considered statistically significant., Results: Mean amygdala RT dose (r = -0.28, p = 0.01) was significantly correlated with volume loss. On multivariable analysis, the only significant predictor of amygdala atrophy was radiation dose. The final linear mixed-effects model estimated amygdala volume loss of 0.17% for every 1 Gy increase in mean amygdala RT dose (p = 0.008)., Conclusions: The amygdala demonstrates dose-dependent atrophy one year after radiotherapy for brain tumors. Amygdala atrophy may mediate neuropsychological effects seen after brain RT., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: For patients with cancer, marijuana may be an alternative to prescription opioid analgesics. This study analyzed self-reported marijuana and prescription opioid use among people with cancer over a 10-year time period., Methods: Population-based data sets from the US National Health and Nutrition Examination Survey between 2005 and 2014 were compiled for respondents aged 20 to 60 years. Respondents with cancer and respondents without cancer were propensity score-matched (1:2) by demographics to compare substance use. Outcomes included current marijuana and prescription opioid use (ie, within the past 30 days). Pearson chi-square tests and logistic regressions were performed; a 2-tailed P value < .05 was significant., Results: There were 19,604 respondents, and 826 people with cancer were matched to 1652 controls. Among the respondents with cancer, 40.3% used marijuana within the past year, and 8.7% used it currently. Respondents with cancer were significantly more likely to use prescription opioids (odds ratio [OR], 2.43; 95% CI, 1.68-3.57; P < .001). Cancer was not associated with current marijuana use in a multivariable conditional logistic regression but was associated with current opioid use (OR, 1.82; 95% CI, 1.17-2.82; P = .008). Among all survey respondents, the odds of marijuana use significantly increased over time (OR, 1.05; 95% CI, 1.01-1.10; P = .012), whereas the odds of opioid use did not significantly change. There were no significant differences in the longitudinal odds of marijuana or opioid use over time between respondents with a cancer diagnosis and those without one., Conclusions: This population-based analysis revealed a considerable proportion of respondents with cancer self-reporting marijuana use (40.3%) and a significantly higher prevalence of opioid use among respondents with cancer. In the midst of an opioid epidemic, an evolving political landscape, and new developments in oncology, quantifying the prevalence of opioid and marijuana use in the US population, especially among patients with cancer, is particularly relevant. Although opioid use did not significantly change from 2005 to 2014 among all respondents, marijuana use did increase, likely reflecting increased availability and legislative changes. A cancer diagnosis did not significantly affect longitudinal opioid or marijuana use., (© 2019 American Cancer Society.)

Purpose: Compared with conventional radiation therapy, intensity modulated radiation therapy (IMRT) may reduce acute toxicity from anal cancer treatment, potentially leading to improved long-term outcomes. We analyze the effect of IMRT on short- and long-term outcomes among a large sample of US veterans., Methods and Materials: From a national Veterans Affairs database, we identified 779 patients (n = 403 conventional radiation therapy, n = 376 IMRT) with locally advanced anal squamous cell carcinoma diagnosed between 2000 and 2015 and treated with concurrent chemoradiation therapy. Radiation treatment planning and dosimetric constraints were not standardized across patients. We analyzed the effect of IMRT on short-term outcomes (acute toxicity, treatment breaks, and incomplete chemotherapy) and long-term outcomes (survival and ostomy placement) in multivariable logistic regression, Fine-Gray, and frailty models, adjusting for potential confounders., Results: IMRT was associated with decreased radiation treatment breaks ≥5 days (odds ratio [OR] 0.58; 95% confidence interval [CI] 0.37-0.91; P = .02), increased rates of receiving 2 cycles of mitomycin C chemotherapy (OR 2.04; 95% CI 1.22-3.45; P = .007), increased rates of receiving 2 cycles of any chemotherapy (OR 3.45; 95% CI 1.82-6.25; P < .001), and decreased risk of ostomy related to tumor recurrence or progression (subdistribution hazard ratio 0.60; 95% CI 0.37-0.99; P = .045). IMRT was not associated with a decrease in grade 3 to 4 hematologic toxicity (P = .79), hospitalization for gastrointestinal toxicity (P = .59), or cancer-specific survival (P = 0.18)., Conclusions: Among a large sample of US veterans with anal cancer, IMRT was associated with higher rates of receiving 2 chemotherapy cycles, decreased radiation treatment breaks, and decreased rates of ostomy placement. IMRT appears to offer substantial benefits over conventional radiation therapy for patients undergoing concurrent chemoradiation therapy for anal cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To study the effects of immunosuppression on treatment toxicity, long-term cancer recurrence risk, and survival among human immunodeficiency virus (HIV)-positive anal cancer patients., Methods and Materials: From a nationwide retrospective cohort of veterans with anal cancer we identified 142 HIV-positive patients with stage I-III disease, diagnosed between 2000 and 2015 and treated with definitive-intent chemotherapy and radiation. We used regression models to study the impact of pretreatment CD4 counts and longitudinal posttreatment CD4 counts on outcomes including acute toxicity, long-term ostomy rates, cancer recurrence, cancer-specific survival, and overall survival. All models were adjusted for potential confounders., Results: The median pretreatment CD4 count was 375 cells/mm 3 , which dropped to 157 cells/mm 3 after treatment. Each 100-cell/mm 3 decrease in pretreatment CD4 count was associated with an increased risk of acute hematologic toxicity (odds ratio 1.19, 95% confidence interval [CI] 1.01-1.42, P=.04) and hospitalization for hematologic toxicity (odds ratio 1.24, 95% CI 1.00-1.54, P=.049) but not gastrointestinal toxicity, tumor recurrence, or cancer-specific mortality (P>.05). Each 100-cells/mm 3 decrease in posttreatment CD4 count increased the risk of recurrence by 54% (hazard ratio 1.54, 95% CI 1.09-2.17, P=.01) and cancer mortality by 46% at a trend level (hazard ratio 1.46, 95% CI 0.99-2.14, P=.06). Neither pre- nor posttreatment CD4 count influenced long-term ostomy rates or overall survival (all P>.05)., Conclusions: Lower pretreatment CD4 counts were associated with acute hematologic toxicity, and lower posttreatment CD4 count levels were associated with an increased risk of tumor recurrence. These results suggest that immune surveillance may play an important role in long-term disease control in anal cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: An outbreak of Pneumocystis jirovecii pneumonia (PCP) occurred among heart transplant recipients (HTR) at the outpatient clinic of a university hospital, from March to September 2015. Clinical, therapeutic, biological, and molecular data were analyzed to determine its origin and control the outbreak., Methods: Clinical and biological data regarding all HTR followed in the outpatient clinic were collected. PCP diagnosis was based on microscopy and real-time polymerase chain reaction (PCR). Investigations were performed by building a transmission map, completed by genotyping Pneumocystis isolates and by a control of chemoprophylaxis observance. Asymptomatic exposed patients were screened for colonization using real-time PCR., Results: Among 124 HTR, 7 PCP cases were confirmed. Screening identified 3 additional patients colonized by P. jirovecii. All patients were cured, and no further cases were identified after trimethoprim-sulfamethoxazole prophylaxis was introduced in the entire cohort. Genotyping demonstrated the same strain in all PCP cases and colonized patients. All cases were linked with possible transmission chains from 2 possible index patients. Interhuman transmission was significantly associated with more frequent visits in the outpatient clinic. Six cases were receiving atovaquone as a prophylaxis. The occurrence of PCP was significantly associated with atovaquone prophylaxis., Conclusions: This is the first outbreak with detailed molecular analysis in HTR so far. Genotyping and transmission chain confirmed interhuman transmission in all colonized/infected PCP cases. Outpatient clinic layout and high encounters probably caused this PCP cluster, which was controlled after systematic trimethoprim-sulfamethoxazole prophylaxis in exposed patients.

Background: Obesity has high prevalence among HIV-infected patients. Increased adipose tissue mass affects the pharmacokinetics of numerous drugs, but few data are available for antiretroviral drugs., Objectives: In this study we aimed to explore the pharmacokinetics of antiretroviral drugs and the immuno-virological response in obese patients with HIV infection., Patients and Methods: We examined data from 2009 to 2012 in our hospital's database for HIV-1-infected patients who received an antiretroviral drug (abacavir, emtricitabine, lamivudine, tenofovir, efavirenz, etravirine, nevirapine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir or raltegravir). Obese patients were defined as those with BMI ≥30 kg/m 2 and normal-weight patients as those with BMI 19-25 kg/m 2 . Plasma concentrations ( C 12/24 ) were compared for each antiretroviral drug using a Mann-Whitney test. Suboptimal dosing and virological outcome were assessed by logistic regression, adjusting on covariates., Results: We enrolled 291 obese and 196 normal-weight patients. Among the 12 analysed antiretroviral drugs, tenofovir, efavirenz and lopinavir C 12 values were significantly lower in obese than normal-weight patients: 66 versus 86 ng/mL, 1498 versus 2034 ng/mL and 4595 versus 6420 ng/mL, respectively ( P  <   0.001). Antiretroviral drug C 12/24 values were more frequently below efficacy thresholds for obese than for normal-weight patients after adjustment for other covariates ( P  <   0.001). Although obese patients showed a higher CD4 count than normal-weight patients (510 versus 444 cells/mm 3 , P  <   0.001), the groups did not differ in virological failure rate., Conclusions: This study highlights the impact of obesity on antiretroviral drug plasma exposure, but identifies no consequence of this suboptimal exposure on the immuno-virological control in this population., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)