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Xuan Zheng,1,* Bo Chen,1,* Jian-Xiong Wu,2 Angela Y Jia,3 Wei-Qi Rong,2 Li-Ming Wang,2 Fan Wu,2 Yu-Ting Zhao,1 Ye-Xiong Li,4 Wei-Hu Wang5 1Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Abdominal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA; 4Department of Radiation Oncology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Radiation Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China *These authors contributed equally to this work Purpose: To evaluate the role of adjuvant radiotherapy after narrow-margin (

Yu-Ting Zhao,1,* Zhi-Kai Liu,2,* Qiu-Wen Wu,3 Jian-Rong Dai,1 Tao Zhang,1 Angela Y Jia,4 Jing Jin,1 Shu-Lian Wang,1 Ye-Xiong Li,1 Wei-Hu Wang5 1Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 2Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 3Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA; 4Department of Medicine, Weill Cornell Medicine, New York, NY, USA; 5Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital and Institute, Beijing, China *These authors contributed equally to this work Aims: To assess motion magnitude in different parts of the liver through surgical clips in postoperative patients with hepatocellular carcinoma and to examine the correlation between the clip and diaphragm motion.Methods: Four-dimensional computed tomography images from 30 liver cancer patients under thermoplastic mask immobilization were selected for this study. Three to seven surgical clips were placed in the resection cavity of each patient. The liver volume on computed tomography image was divided into the right upper (RU), right middle (RM), right lower (RL), hilar, and left lobes. Agreement between the clip and diaphragm motion was assessed by calculating intraclass correlation coefficient, and Bland–Altman analysis (Diff). Furthermore, population-based and patient-specific margins for internal motion were evaluated.Results: The clips located in the RU lobe showed the largest motion, (7.5±1.6) mm, which was significantly more than in the RM lobe (5.7±2.8 mm, p=0.019), RL lobe (4.8±3.3 mm, p=0.017), and hilar lobe (4.7±2.7 mm, p

Background: We performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC)., Patients and Methods: SPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant., Results: We did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15-0.28) versus without concomitant statins (aHR: 0.31 [0.24-0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS., Conclusions: In this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS., Competing Interests: Declaration of Competing Interest Dr. Roy reports Young Investigator Award from the Prostate Cancer Foundation which funded this research. In addition, Dr. Roy reports research grant from Swim Across America and honorarium from Varian. Dr. Spratt reports personal fees from Blue Earth, personal fees from Janssen, personal fees from AstraZeneca, Gammatile, Varian, and Boston Scientific, outside the submitted work. Dr. Kishan reported receiving personal fees from ViewRay, Inc, Varian Medical Systems, and Boston Scientific; receiving speaking honoraria, consulting fees, and research support from Varian Medical Systems, ViewRay, Inc, and Intelligent Automation; receiving grants from Janssen and Point Biopharma; and receiving research funding from ViewRay, Inc, outside the submitted work. Dr. Agarwal reports consulting or advisory roles for Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, Merck, Novartis, Eisai, Seagen, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, Gilead Sciences and research funding from Bayer, Bristol Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas. Dr. Chowdhury, receiving honoraria, fees for serving on a speaker’s bureau, consulting fees, and travel support from Johnson and Johnson, Astellas Pharma, and Sanofi and grant support, honoraria, fees for serving on a speaker’s bureau, consulting fees, and travel support from Clovis Oncology. Dr. Jia reports personal fees from Blue Earth, and Myovant. Dr. Ong reports personal fees from Janssen, Bayer, AstraZeneca, and Pfizer. Dr. Morgan reports personal fees from Astellas, Bayer, Janssen, and TerSera and a research grant (institutional) from Knight Therapeutics, outside the submitted work. Dr. Swami reports consultancy to Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, Pfizer, AstraZeneca and Gilead and research funding to institute from Janssen, Exelixis and Astellas/Seattle Genetics. Dr. Saad reports grants, personal fees, and non-financial support from Janssen, during the conduct of the study; grants, personal fees, and non-financial support from Astellas, grants, personal fees, and non-financial support from Bayer, outside the submitted work. Dr. Wallis has received honoraria from AbbVie, Astellas, Astra Zeneca, Bayer, EMD Serono, Knight Therapeutics, Merck, Haymarket Media, Science & Medicine Canada, TerSera Canada, and Tolmar Pharmaceuticals Canada; reports consulting fees from Janssen Oncology, SESEN Bio, and Precision Point Specialty LLC; and has received research funding from Knight Therapeutics and Tolmar Pharmaceuticals, outside the submitted work. Dr. Malone has received honoraria from Astellas, Bayer, Janssen, and Sanofi; and travel and accommodations support from TerSera and Sanofi. There are no other conflicts of interest among the other authors., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: Early PSA response has been found to be prognostic of outcomes in metastatic hormone sensitive prostate cancer. We performed a secondary analysis of the TITAN trial to determine if early PSA response was predictive of treatment efficacy in metastatic hormone sensitive prostate cancer patients., Materials and Methods: Early PSA response was defined as achieving a PSA level of ≤ 0.2 ng/mL by 6 months of random assignment. A Cox proportional hazard model was constructed in a landmark population with an interaction term between the treatment and early PSA response to determine differential treatment effect on overall survival (OS). We applied multivariable Cox proportional hazard regression model with time to early PSA response fitted with restricted cubic spline to determine the association of time to early PSA response with OS., Results: Approximately 24% (124/524) of patients in the androgen deprivation therapy (ADT) alone group and 61% (321/524) in the apalutamide group had PSA response ≤ 0.2 ng/mL by 6 months. Longer time to early PSA response was associated with significantly superior OS in the apalutamide group. There was a significant difference in treatment effect from apalutamide on OS ( P = .03 for interaction) among 6-month PSA responders (HR: 0.66; 95% CI: 0.44-1.00) vs nonresponders (HR: 1.14; 95% CI: 0.89-1.46). This difference in treatment effect was not statistically significant at 3 months ( P = .17 for interaction). Among 6-month PSA responders, 3-year confounder-adjusted OS was 84% (80%-88%) for the apalutamide group and 74% (66%-82%) for the ADT alone group. Among nonresponders, 3-year adjusted OS for the 2 treatment arms were 58% (52%-65%) and 56% (51%-60%), respectively., Conclusions: Early PSA response by 6 months was a predictor of treatment efficacy from ADT plus apalutamide on OS. Longer time to early PSA response was associated with superior OS in the apalutamide arm.

Importance: Preclinical studies suggest that exposure to prostate-directed local therapy (LT) may influence the efficacy of subsequent systemic therapy including androgen receptor pathway inhibitors. However, there is insufficient clinical evidence to support this premise in patients with nonmetastatic castrate-resistant prostate cancer (nmCRPC)., Objective: To determine whether exposure to prior prostate-directed LT (radical prostatectomy [RP], radiation therapy [RT], or both) played any effect-modifying role in the treatment effect of apalutamide on metastasis-free survival (MFS) and overall survival (OS) in patients with nmCRPC., Design, Setting, and Participants: This post hoc secondary analysis used individual patient data from SPARTAN (Study of Apalutamide [ARN-509] in Men With Non-Metastatic Castration-Resistant Prostate Cancer), a phase 3, double-blinded, placebo-controlled randomized clinical trial conducted at 332 sites in 26 countries. Between October 14, 2013, and December 15, 2016, patients with nmCRPC and a prostate-specific antigen doubling time of 10 months or less were randomly assigned to apalutamide vs placebo; all patients received androgen deprivation therapy. The final data analysis was performed on December 31, 2023., Exposure: Prior prostate-directed LT., Main Outcomes and Measures: Separate Cox proportional hazards regression models were constructed for OS and MFS, which included prior LT, treatment group, and an interaction term, in addition to a minimally sufficient set of confounders. Adjusted hazard ratios (HRs) with 95% CIs for MFS and OS were determined for the apalutamide groups with or without prior LT., Results: Among the 1179 evaluable patients included in this analysis, 795 received prior LT and 384 did not. The median age of patients with and without prior LT was 70 (IQR, 45-90) years and 75 (IQR, 50-95) years, respectively. The median follow-up was 52.0 (IQR, 51.5-52.8) months. A differential treatment effect of apalutamide on MFS was observed between patients with and without prior LT (P for interaction = .009), with greater benefits for those with prior LT (adjusted HR, 0.22 [95% CI, 0.17-0.27]) compared with those without prior LT (adjusted HR, 0.35 [95% CI, 0.25-0.51]). However, there was insufficient evidence of a differential treatment effect on OS among subgroups stratified by exposure to prior LT (P for interaction = .23), with improved OS in the subgroup with prior LT (adjusted HR, 0.72 [95% CI, 0.57-0.92]) but no significant difference in OS in the subgroup without prior LT (adjusted HR, 0.92 [95% CI, 0.64-1.31])., Conclusions and Relevance: This post hoc analysis of the SPARTAN trial provides evidence of an interaction between prior LT and apalutamide in patients with nmCRPC, with a clinically significant and more favorable treatment effect from apalutamide on MFS among patients with prior LT. Further studies are needed to validate these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT01946204.

Competing Interests: AYJ reports personal fees from Myovant and Blue Earth Diagnostics. DES reports personal fees from Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen, and Pfizer.

Prostate-specific membrane antigen (PSMA) positron emission tomography or computed tomography (PET/CT) has emerged as a superior imaging option to conventional imaging for prostate cancer. The majority of early evidence and prospective trials evaluated PSMA PET/CT in the biochemical recurrence or metastatic setting. However, there has been an increasing number of prospective trials in the primary setting. The purpose of this narrative review was to describe the role of PSMA PET/CT in localized primary prostate cancer. This narrative review focuses on the prospective evidence available in this setting. We detail the current practice and future potential for PSMA PET/CT to be used in multiple stages of localized primary prostate cancer. The most common practice currently for PSMA PET/CT is in the primary nodal and metastatic staging of high-risk prostate cancer. We describe other roles of PSMA PET/CT, including in intermediate-risk prostate cancer as well as local staging and the impact on radiation therapy and surgical management. We also discuss the potential future roles of PSMA PET/CT in prediagnosis such as risk stratification for biopsy, prognosis, and specific surgical roles. Potential pitfalls of PSMA PET/CT are also addressed. PSMA PET/CT has already had a significant influence on prostate cancer, and there will continue to be a greater role for this imaging modality in localized primary prostate cancer., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This study leverages CDC National Health Interview Survey data to examine Financial Distress (FD) among genitourinary (GU) cancer survivors, specifically prostate cancer (PC), kidney cancer (KC), and bladder cancer (BC). It investigates the economic impacts faced by these patients, especially in relation to disparities in insurance coverage and its effects on material, psychological, and behavioral aspects of FD., Methods: We retrospectively analyzed responses from GU cancer survivors, stratifying by cancer status and age (18-64 years, ≥65 years). Medical financial hardship was divided into three domains: material, psychological, and behavioral. Associations between cancer history, hardship, and clinical factors were assessed using generalized ordinal logistic regressions., Results: Significant health care access disparities were found, particularly for mental health services, with 25% of younger BC survivors and 4.7% of younger KC survivors reporting affordability issues, in contrast to 2.7% of noncancer individuals. Dental care was also problematic, with higher avoidance rates among younger BC (27%) and KC (15%) survivors compared with the general population. Surprisingly, noncancer individuals reported more difficulty in affording prescriptions than BC survivors across both age groups. PC survivors, however, showed lower FD across all domains versus noncancer controls, indicating fewer concerns about medical bills and a lesser tendency to forgo care., Conclusion: The study underscores significant gaps in the financial support system for GU cancer survivors, with urgent needs in mental and dental health care access. Policy interventions, including comprehensive insurance reforms, are imperative to alleviate the financial burdens on these individuals.

Background and Objective: The extent of prostate cancer found on biopsy, as well as prostate cancer grade and genomic tests, can affect clinical decision-making. The impact of these factors on the initial management approach and subsequent patient outcomes for men with favorable-grade prostate cancer has not yet been determined on a population level. Our objective was to explore the association of Decipher 22-gene genomic classifier (GC) biopsy testing on the initial use of conservative management versus radical prostatectomy (RP) and to determine the independent effect of GC scores on RP pathologic outcomes., Methods: A total of 87 140 patients diagnosed with grade group 1 and 2 prostate cancer between 2016 and 2018 from the Surveillance, Epidemiology, and End Results registry data were linked to GC testing results (2576 tested and 84 564 untested with a GC). The primary endpoints of interest were receipt of conservative management or RP, pathologic upgrading (pathologic grade group 3-5), upstaging (pathologic ≥T3b), and adverse pathologic features (pathologic upgrading, upstaging, or lymph node invasion). Multivariable logistic regressions quantified the association of variables with outcomes of interest., Key Findings and Limitations: GC tested patients were more likely to have grade group 2 on biopsy (51% vs 46%, p < 0.001) and lower prostate-specific antigen (6.1 vs 6.3, p = 0.016). Conservative management increased from 37% to 39% and from 22% to 24% during 2016-2018 for the GC tested and untested populations, respectively. GC testing was significantly associated with increased odds of conservative management (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.9-2.4, p < 0.001). The distribution of biopsy GC risk was as follows: 45% low risk, 30% intermediate risk, and 25% high risk. In adjusted analyses, higher GC (per 0.1 increment) scores (OR 1.24, 95% CI 1.17-1.31, p < 0.001) and percent positive cores (1.07, 95% CI 1.02-1.12, p = 0.009) were significantly associated with the receipt of RP. A higher GC score was significantly associated with all adverse outcomes (pathologic upgrading [OR 1.29, 95% CI 1.12-1.49, p < 0.001], upstaging [OR 1.31, 95% CI 1.05-1.62, p = 0.020], and adverse pathology [OR 1.27, 95% CI 1.12-1.45, p < 0.001]). Limitations include observational biases associated with the retrospective study design., Conclusions and Clinical Implications: Men who underwent GC testing were more likely to undergo conservative management. GC testing at biopsy is prognostic of adverse pathologic outcomes in a large population-based registry., Patient Summary: In this population analysis of men with favorable-risk prostate cancer, those who underwent genomic testing at biopsy were more likely to undergo conservative management. Of men who initially underwent radical prostatectomy, higher genomic risk but not tumor volume was associated with adverse pathologic outcomes. The use of genomic testing at prostate biopsy improves risk stratification and may better inform treatment decisions than the use of tumor volume alone., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To determine the prevalence and severity of SpaceOAR-related adverse events using the Manufacturer and User Facility Device Experience (MAUDE) database., Methods: We analyzed SpaceOAR-related adverse event reports in the Manufacturer and User Facility Device Experience (MAUDE) database from January 2015 to May 2023. For each report, the event type, associated device and patient problems, event description, event timing, and event severity stratified by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE) grading system were recorded., Results: From 2015 to 2022, 206,619 SpaceOAR devices were sold. From January 2015 to May 2023, we identified 981 reports describing 990 SpaceOAR-related adverse events. Malfunctions were the most common event type (N = 626), followed by patient injuries (N = 350) with few reported deaths (N = 5). Device positioning problems were the most frequent device issue (N = 686). Pain was the most reported patient problem (N = 216). Abscesses and fistulas related to the device were each reported in 91 events. A noteworthy portion of relevant adverse events occurred before the initiation of radiation (N = 35, 22.4%), suggesting the device, rather than the radiation, was responsible. In total, 470 (50.2%) and 344 (36.7%) of the adverse events were CTCAE grade 1 and 2, respectively. There were 123 (13.1%) events that were CTCAE grade ≥3., Conclusion: We identified multiple reports of SpaceOAR-related adverse events, many of which are more serious than have been reported in clinical trials. While SpaceOAR use is common, suggesting these events are rare, these data highlight the need for continued postmarket surveillance., Competing Interests: Declaration of Competing Interest Daniel E. Spratt receives research funding from the National Institutes of Health and the Prostate Cancer Foundation and personal fees from Astellas, AstraZeneca, Bayer, BlueEarth, Boston Scientific, Elekta, GT Medical Technologies Inc, Myovant, Pfizer, Janssen, Novartis, and Varian. Elisha T. Fredman serves as a consultant to Boston Scientific for the SpaceOAR product. The other authors have no conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objective: Polygenic risk scores (PRSs) have been developed to identify men with the highest risk of prostate cancer. Our aim was to compare the performance of 16 PRSs in identifying men at risk of developing prostate cancer and then to evaluate the performance of the top-performing PRSs in differentiating individuals at risk of aggressive prostate cancer., Methods: For this case-control study we downloaded 16 published PRSs from the Polygenic Score Catalog on May 28, 2021 and applied them to Michigan Genomics Initiative (MGI) patients. Cases were matched to the Michigan Urological Surgery Improvement Collaborative (MUSIC) registry to obtain granular clinical and pathological data. MGI prospectively enrolls patients undergoing surgery at the University of Michigan, and MUSIC is a multi-institutional registry that prospectively tracks demographic, treatment, and clinical variables. The predictive performance of each PRS was evaluated using the area under the covariate-adjusted receiver operating characteristic curve (aAUC), and the association between PRS and disease aggressiveness according to prostate biopsy data was measured using logistic regression., Key Findings and Limitations: We included 18 050 patients in the analysis, of whom 15 310 were control subjects and 2740 were prostate cancer cases. The median age was 66.1 yr (interquartile range 59.9-71.6) for cases and 56.6 yr (interquartile range 42.6-66.7) for control subjects. The PRS performance in predicting the risk of developing prostate cancer according to aAUC ranged from 0.51 (95% confidence interval 0.51-0.53) to 0.67 (95% confidence interval 0.66-0.68). By contrast, there was no association between PRS and disease aggressiveness., Conclusions and Clinical Implications: Prostate cancer PRSs have modest real-world performance in identifying patients at higher risk of developing prostate cancer; however, they are limited in distinguishing patients with indolent versus aggressive disease., Patient Summary: Risk scores using data for multiple genes (called polygenic risk scores) can identify men at higher risk of developing prostate cancer. However, these scores need to be refined to be able to identify men with the highest risk for clinically significant prostate cancer., (Copyright © 2024. Published by Elsevier B.V.)

The discovery of small molecules that target the extracellular domain of prostate-specific membrane antigen (PSMA) has led to advancements in diagnostic imaging and the development of precision radiopharmaceutical therapies. In this review, we present the available existing data and highlight the key ongoing clinical evaluations of PSMA-based imaging in the management of primary, biochemically recurrent, and metastatic prostate cancer. We also discuss clinical studies that explore the use of PSMA-based radiopharmaceutical therapy (RPT) in metastatic prostate cancer and forthcoming trials that investigate PSMA RPT in earlier disease states. Multidisciplinary collaboration in clinical trial design and therapeutic administration is critical to the continued progress of this evolving radiotheranostics field., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Artificial intelligence (AI) applications have enabled remarkable advancements in healthcare delivery. These AI tools are often aimed to improve accuracy and efficiency of histopathology assessment and diagnostic imaging interpretation, risk stratification (i.e., prognostication), and prediction of therapeutic benefit for personalized treatment recommendations. To date, multiple AI algorithms have been explored for prostate cancer to address automation of clinical workflow, integration of data from multiple domains in the decision-making process, and the generation of diagnostic, prognostic, and predictive biomarkers. While many studies remain within the pre-clinical space or lack validation, the last few years have witnessed the emergence of robust AI-based biomarkers validated on thousands of patients, and the prospective deployment of clinically-integrated workflows for automated radiation therapy design. To advance the field forward, multi-institutional and multi-disciplinary collaborations are needed in order to prospectively implement interoperable and accountable AI technology routinely in clinic., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Importance: Randomized clinical trials have demonstrated the noninferiority of shorter radiotherapy (RT) courses (termed hypofractionation) compared with longer RT courses in patients with localized prostate cancer. Although shorter courses are associated with cost-effectiveness, convenience, and expanded RT access, their adoption remains variable., Objective: To identify the current practice patterns of external beam RT for prostate cancer in the US., Design, Setting, and Participants: This cohort study obtained data from the National Cancer Database, which collects hospital registry data from more than 1500 accredited US facilities on approximately 72% of US patients with cancer. Patients were included in the sample if they had localized prostate adenocarcinoma that was diagnosed between 2004 and 2020 and underwent external beam RT with curative intent. Analyses were conducted between February and March 2023., Exposures: Radiotherapy schedules, which were categorized as ultrahypofractionation (≤7 fractions), moderate hypofractionation (20-30 fractions), and conventional fractionation (31-50 fractions)., Main Outcomes and Measures: Longitudinal pattern in RT fractionation schedule was the primary outcome. Multivariable logistic regression was performed to evaluate the variables associated with shorter RT courses. Covariables included age, National Comprehensive Cancer Network risk group, rurality, race, facility location, facility type, median income, insurance type or status, and Charlson-Deyo Comorbidity Index., Results: A total of 313 062 patients with localized prostate cancer (mean [SD] age, 68.8 [7.7] years) were included in the analysis. There was a temporal pattern of decline in the proportion of patients who received conventional fractionation, from 76.0% in 2004 to 36.6% in 2020 (P for trend <.001). From 2004 to 2020, use of moderate hypofractionation increased from 22.0% to 45.0% (P for trend <.001), and use of ultrahypofractionation increased from 2.0% to 18.3% (P for trend <.001). By 2020, the most common RT schedule was ultrahypofractionation for patients in the low-risk group and moderate hypofractionation for patients in the intermediate-risk group. On multivariable analysis, treatment at a community cancer program (compared with academic or research program; odds ratio [OR], 0.54 [95% CI, 0.52-0.56]; P < .001), Medicaid insurance (compared with Medicare; OR, 1.49 [95% CI, 1.41-1.57]; P < .001), Black race (compared with White race; OR, 0.90 [95% CI, 0.87-0.92]; P < .001), and higher median income (compared with lower median income; OR, 1.28 [95% CI, 1.25-1.31]; P < .001) were associated with receipt of shorter courses of RT., Conclusions and Relevance: Results of this cohort study showed an increase in the use of shorter courses of RT for prostate cancer from 2004 to 2020; a number of social determinants of health appeared to be associated with reduced adoption of shorter treatment courses. Realignment of reimbursement models may be necessary to enable broader adoption of ultrahypofractionation to support technology acquisition costs.

Purpose: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods., Materials and Methods: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R 2 ). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed., Results: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R 2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively., Conclusion: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

Background: Management of localized or recurrent prostate cancer since the 1990s has been based on risk stratification using clinicopathological variables, including Gleason score, T stage (based on digital rectal exam), and prostate-specific antigen (PSA). In this study a novel prognostic test, the Decipher Prostate Genomic Classifier (GC), was used to stratify risk of prostate cancer progression in a US national database of men with prostate cancer., Methods: Records of prostate cancer cases from participating SEER (Surveillance, Epidemiology, and End Results) program registries, diagnosed during the period from 2010 through 2018, were linked to records of testing with the GC prognostic test. Multivariable analysis was used to quantify the association between GC scores or risk groups and use of definitive local therapy after diagnosis in the GC biopsy-tested cohort and postoperative radiotherapy in the GC-tested cohort as well as adverse pathological findings after prostatectomy., Results: A total of 572 545 patients were included in the analysis, of whom 8927 patients underwent GC testing. GC biopsy-tested patients were more likely to undergo active active surveillance or watchful waiting than untested patients (odds ratio [OR] =2.21, 95% confidence interval [CI] = 2.04 to 2.38, P < .001). The highest use of active surveillance or watchful waiting was for patients with a low-risk GC classification (41%) compared with those with an intermediate- (27%) or high-risk (11%) GC classification (P < .001). Among National Comprehensive Cancer Network patients with low and favorable-intermediate risk, higher GC risk class was associated with greater use of local therapy (OR = 4.79, 95% CI = 3.51 to 6.55, P < .001). Within this subset of patients who were subsequently treated with prostatectomy, high GC risk was associated with harboring adverse pathological findings (OR = 2.94, 95% CI = 1.38 to 6.27, P = .005). Use of radiation after prostatectomy was statistically significantly associated with higher GC risk groups (OR = 2.69, 95% CI = 1.89 to 3.84)., Conclusions: There is a strong association between use of the biopsy GC test and likelihood of conservative management. Higher genomic classifier scores are associated with higher rates of adverse pathology at time of surgery and greater use of postoperative radiotherapy.In this study the Decipher Prostate Genomic Classifier (GC) was used to analyze a US national database of men with prostate cancer. Use of the GC was associated with conservative management (ie, active surveillance). Among men who had high-risk GC scores and then had surgery, there was a 3-fold higher chance of having worrisome findings in surgical specimens., (© The Author(s) 2023. Published by Oxford University Press.)

Introduction: Patients with metastatic prostate cancer, especially in the castrate-resistant setting, have a poor prognosis. Many agents have been approved for metastatic prostate cancer, such as androgen receptor pathway inhibitors, taxane-based chemotherapy, radiopharmaceuticals, and immunotherapy. However, prostate cancer remains the leading cause of cancer deaths in nonsmoking men. Fortunately, many more novel agents are under investigation., Areas Covered: We provide an overview of the broad group of novel therapies for metastatic prostate cancer, with an emphasis on active and recruiting clinical trials that have been recently published and/or presented at national or international meetings., Expert Opinion: The future for patients with metastatic prostate cancer is promising, with further development of novel therapies such as radiopharmaceuticals. Based on a growing understanding of prostate cancer biology, novel agents are being designed to overcome resistance to approved therapies. There are many trials using novel agents either as monotherapy or in combination with already approved agents with potential to further improve outcomes for men with advanced prostate cancer.

Introduction: Metastatic castrate resistant prostate cancer (mCPRC) remains an aggressive form of prostate cancer that no longer responds to traditional hormonal treatment alone. Despite the advent of novel anti-androgen medications, many patients continue to progress, and as a result, there is a growing need for additional treatment options., Areas Covered: Lutetium-177 ( 177 Lu) - PSMA-617 has become one of the new frontline treatment options for refractory metastatic castrate resistant prostate cancer after the failure of novel anti-androgen therapy and chemotherapy. Lu-177 has been used in real-world prospective trials and is now becoming utilized in newer phase III clinical trials. Here, we present a comprehensive overview of the current literature, covering retrospective studies, prospective studies, and clinical trials that established Lutetium-177-PSMA-617 ( 177 Lu-PSMA-617) for the treatment of mCRPC., Expert Opinion: 177 Lu - PSMA-617 has been approved for treatment of mCRPC based on positive phase III studies. While this treatment is tolerable and effective, biomarkers are necessary to determine which patients will benefit. In the future, radioligand treatments will likely be utilized in earlier lines of therapy and potentially in combination with other prostate cancer treatments.

Purpose: The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT)., Materials and Methods: Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer-specific mortality., Results: Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points ( P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer-specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT., Conclusion: ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.

To compare liver cancer resectability rates before and during the COVID-19 pandemic., Background: Liver cancers usually present with nonspecific symptoms or are diagnosed through screening programs for at-risk patients, and early detection can improve patient outcomes. In 2020, the COVID-19 pandemic upended medical care across all specialties, but whether the pandemic was associated with delays in liver cancer diagnosis is not known., Methods: We performed a retrospective review of all patients evaluated at the Johns Hopkins Multidisciplinary Liver Cancer Clinic from January 2019 to June 2021 with a new diagnosis of suspected or confirmed hepatocellular carcinoma (HCC) or biliary tract cancer (BTC)., Results: There were 456 liver cancer patients (258 HCC and 198 BTC). From January 2019 to March 2020 (pre-pandemic), the surgical resectability rate was 20%. The subsequent 6 months (early pandemic), the resectability rate decreased to 11%. Afterward from October 2020 to June 2021 (late pandemic), the resectability rate increased to 27%. The resectability rate early pandemic was significantly lower than that for pre-pandemic and later pandemic combined (11% lower; 95% confidence interval [CI], 2%-20%). There was no significant difference in resectability rates pre-pandemic and later pandemic (7% difference; 95% CI, -3% to 16%). In subgroup analyses, the early pandemic was associated with a larger impact in BTC resectability rates than HCC resectability rates. Time from BTC symptom onset until Multidisciplinary Liver Clinic evaluation increased by over 6 weeks early pandemic versus pre-pandemic (Hazard Ratio, 0.63; 95% CI, 0.44-0.91)., Conclusions: During the early COVID-19 pandemic, we observed a drop in the percentage of patients presenting with curable liver cancers. This may reflect delays in liver cancer diagnosis and contribute to excess mortality related to the COVID-19 pandemic., Competing Interests: Disclosure: D.L. was funded by a grant from the Johns Hopkins Center for Innovative Medicine. M.Y. was funded by grants from the National Institutes of Health and National Cancer Institute. The remaining authors declare that they have nothing to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The purpose of his study was to report on a cohort of patients managed with nonoperative management (NOM) with a watch-and-wait strategy after achieving complete response (CR) to sequential short-course radiation therapy (SCRT) and consolidation chemotherapy., Methods: This was a retrospective study of patients treated SCRT and chemotherapy who achieved a CR and were managed with NOM. Bowel function was assessed with European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30, EORTC Quality of Life Questionnaire-Colorectal Cancer 29, and the low anterior resection syndrome (LARS) questionnaires. Endpoints included overall survival (OS), freedom from local failure (FFLF), freedom from distant metastasis, and disease-free survival (DFS)., Results: Twenty-six patients met inclusion criteria. Seven (26.9%) patients developed local failure at a median of 6.8 months following CR, of which 5 were successfully salvaged. Median FFLF was not reached, with 6-month, 1-, and 2-year FFLF rates of 100.0%, 82.3%, and 71.3%. Median OS was not reached, with 6-month, 1-, and 2-year OS rates of 100%. Median DFS was not reached, with 6-month, 1-, and 2-year DFS rates of 100%, 95.0%, and 89.4%. Questionnaire response rate was 83.3%. Median LARS score was 27. Major, minor, and no LARS occurred in 3 (20%), 6 (40%), and 6 (40%) patients, respectively. There were no differences in questionnaire scores between patients who had the majority of their anal sphincter complex irradiated and those who did not., Conclusion: NOM with a watch-and-wait strategy is safe and feasible in patients with locally advanced rectal cancer who achieve CR after sequential SCRT and chemotherapy, with evidence for good anorectal function., Competing Interests: J.M. receives royalties from Uptodate and Springer and honorarium from Springer. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Prostate-specific membrane antigen is a transmembrane protein found predominately on prostate epithelium and is expressed at high levels in prostate cancer. In this review, we discuss the background, clinical data, patient selection, side effects, and necessary resources to deliver lutetium-177 prostate-specific membrane antigen in the research setting, or as standard of care if approved by the United States Food and Drug Administration. Targeted radionuclide therapeutics require understanding of fundamental principles of radiobiology and physics, and radiation oncologists and medical physicists are well-suited to play an integral role in their delivery and treatment response monitoring as key components of a multidisciplinary care team., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: To analyse the performance of multicentre pre-treatment MRI-based radiomics (MBR) signatures combined with clinical baseline characteristics and neoadjuvant treatment modalities to predict complete response to neoadjuvant (chemo)radiotherapy in locally advanced rectal cancer (LARC)., Methods: Baseline MRI and clinical characteristics with neoadjuvant treatment modalities at four centres were collected. Decision tree, support vector machine and five-fold cross-validation were applied for two non-imaging and three radiomics-based models' development and validation., Results: We finally included 674 patients. Pre-treatment CEA, T stage, and histologic grade were selected to generate two non-imaging models: C model (clinical baseline characteristics alone) and CT model (clinical baseline characteristics combining neoadjuvant treatment modalities). The prediction performance of both non-imaging models were poor. The MBR signatures comprising 30 selected radiomics features, the MBR signatures combining clinical baseline characteristics (CMBR), and the CMBR incorporating neoadjuvant treatment modalities (CTMBR) all showed good discrimination with mean AUCs of 0.7835, 0.7871 and 0.7916 in validation sets, respectively. The three radiomics-based models had insignificant discrimination in performance., Conclusions: The performance of the radiomics-based models were superior to the non-imaging models. MBR signatures seemed to reflect LARC's true nature more accurately than clinical parameters and helped identify patients who can undergo organ preservation strategies., (© 2022. The Author(s).)

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that originate in endocrine tissues throughout the body. Though most are indolent, clinical outcomes vary greatly based on histologic differentiation and grade. Peptide receptor radionuclide therapy has emerged as a promising treatment for patients with locally advanced and/or metastatic disease refractory to standard of care treatment. The phase III NETTER-1 trial found that [ 177 Lu] Lu-DOTA-[Tyr 3 ]-octreotate improved disease-free survival versus octreotide alone for somatostatin receptor-positive gastroenteropancreatic NETs and had a favorable toxicity profile, leading to Food and Drug Administration approval. [ 177 Lu] Lu-DOTA-[Tyr 3 ]-octreotate is an important new treatment that expands the role of radiation in the treatment of NETs. Several important trials are ongoing to better elucidate the role of this treatment., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups., Methods: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855., Findings: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group., Interpretation: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended., Funding: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology., Competing Interests: Declaration of interests AUK reports personal fees from Varian Medical Systems, ViewRay, and Intelligent Automation; and research support from ViewRay, the American Society for Radiation Oncology, the Prostate Cancer Foundation, and the Jonsson Comprehensive Cancer Center, all outside the submitted work. FYF reports a consulting or advisory role for Astellas, Bayer, BlueEarth Diagnostics, Celgene, EMD Serono, Genentech, Janssen, Myovant, Ryovant, Bristol Myers Squibb, Exact Sciences, Varian, Bluestar Genomics, and Serimmun; and research funding from Zenth Epigenetics. AN reports personal fees from AstraZeneca, outside the submitted work. LS reports personal fees from Sanofi Canada and Varian Medical Systems, outside the submitted work. JAE reports personal fees from Blue Earth, Boston Scientific, AstraZeneca, Taris Biomedical, Merck, Roviant Pharma, and Myovant Sciences. HMS is a member of a clinical trial steering committee for Janssen and reports stock from Radiogel for an inactive role on medical advisory board, all outside of the submitted work. MBR reports personal fees from Amgen, Clovis, Janssen, Bayer, and Abrx; and research support from Janssen and Merck, outside the submitted work. NGN reports research funding from Janssen, Lantheus, and Bayer; and consulting fees from Oncolinea. DES declares personal fees from Janssen, AstraZeneca, and BlueEarth, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cervical cancer is a socially and scientifically distinguishable disease. Its pathogenesis, sexual transmission of high-risk HPV to a metaplastic portion of the uterine cervix, makes cervical cancer preventable by safe and effective HPV vaccines commercially available since 2006. Despite this, cervical cancer remains the deadliest gynecologic cancer in the world. Regrettably, global incidence and mortality rates disproportionately affect populations where women are marginalized, where HIV infection is endemic, and where access to preventive vaccination and screening for preinvasive disease are limited. In the United States, cervical cancer incidence has gradually declined over the last 25 years, but mortality rates remain both constant and disparately higher among communities of color because of the adverse roles that racism and poverty play in outcome. Until these conditions improve and widespread prevention is possible, treatment innovations are warranted. The last standard-of-care treatment changes occurred in 1999 for locally advanced disease and in 2014 for metastatic and recurrent disease. The viral and immunologic nature of HPV-induced cervical cancer creates opportunities for both radiation and immunotherapy to improve outcomes. With the advent of T cell-directed therapy, immune checkpoint inhibition, and techniques to increase the therapeutic window of radiation treatment, an overdue wave of innovation is currently emerging in cervical cancer treatment. The purpose of this review is to describe the contemporary developmental therapeutic landscape for cervical cancer that applies to most tumors and to discuss notable rare histologic subtypes that will not be adequately addressed with these treatment innovations.

Vaginal necrosis is a late radiation tissue injury with serious morbidity complications. It is rare, and its incidence is not well assessed in prospective trials. Patient comorbidities and radiation dose can significantly increase the risk. As treatment of gynecologic malignancies often involve a multidisciplinary approach, timely diagnosis and appropriate management by physicians of the team are crucial. Untreated vaginal necrosis can lead to infection, hemorrhage, necrosis-related fistulation to the bladder or rectum, perforation, and death. In this review, we describe the pathophysiology of vaginal necrosis, its clinical course, and management options., Competing Interests: Declaration of Competing Interest The authors have no relevant conflicts of interest to disclose. Dr. Viswanathan is the principal investigator for NIH R01 CA237005., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Multidisciplinary care has been associated with improved survival in patients with primary liver cancers. We report the practice patterns and real world clinical outcomes for patients presenting to the Johns Hopkins Hospital (JHH) multidisciplinary liver clinic (MDLC). We analyzed hepatocellular carcinoma (HCC, n = 100) and biliary tract cancer (BTC, n = 76) patients evaluated at the JHH MDLC in 2019. We describe the conduct of the clinic, consensus decisions for patient management based on stage categories, and describe treatment approaches and outcomes based on these categories. We describe subclassification of BCLC stage C into 2 parts, and subclassification of cholangiocarcinoma into 4 stages. A treatment consensus was finalized on the day of MDLC for the majority of patients (89% in HCC, 87% in BTC), with high adherence to MDLC recommendations (91% in HCC, 100% in BTC). Among patients presenting for a second opinion regarding management, 28% of HCC and 31% of BTC patients were given new therapeutic recommendations. For HCC patients, at a median follow up of 11.7 months (0.7-19.4 months), median OS was not reached in BCLC A and B patients. In BTC patients, at a median follow up of 14.2 months (0.9-21.1 months) the median OS was not reached in patients with resectable or borderline resectable disease, and was 11.9 months in patients with unresectable or metastatic disease. Coordinated expert multidisciplinary care is feasible for primary liver cancers with high adherence to recommendations and a change in treatment for a sizeable minority of patients.

Background: Recurrence is the major cause of mortality in patients with resected HCC. However, without a standard approach to evaluate prognosis, it is difficult to select candidates for additional therapy., Methods: A total of 201 patients with HCC who were followed up for at least 5 years after curative hepatectomy were enrolled in this retrospective, multicentre study. A total of 3144 radiomics features were extracted from preoperative MRI. The random forest method was used for radiomics signature building, and five-fold cross-validation was applied. A radiomics model incorporating the radiomics signature and clinical risk factors was developed., Results: Patients were divided into survivor (n = 97) and non-survivor (n = 104) groups based on the 5-year survival after surgery. The 30 most survival-related radiomics features were selected for the radiomics signature. Preoperative AFP and AST were integrated into the model as independent clinical risk factors. The model demonstrated good calibration and satisfactory discrimination, with a mean AUC of 0.9804 and 0.7578 in the training and validation sets, respectively., Conclusions: This radiomics model is a valid method to predict 5-year survival in patients with HCC and may be used to identify patients for clinical trials of perioperative therapies and for additional surveillance.

Background: There is continued debate regarding the optimal combinations of radiation therapy and chemotherapy in the preoperative treatment of locally advanced rectal adenocarcinomas. We report our single-institution experience of feasibility and early oncologic outcomes of short-course preoperative radiation therapy (5 Gy X 5 fractions) followed by consolidation neoadjuvant chemotherapy., Methods: We reviewed the records of 26 patients with locally advanced rectal adenocarcinoma. All patients underwent short course radiotherapy (5 Gy X 5 fractions) followed by chemotherapy [either modified infusional and bolus 5-fluorouracail and oxalipatin (mFOLFOX6) or capecitabine and oxaliplatin] prior to consideration for surgery. A full course of chemotherapy was defined as at least 8 weeks of chemotherapy., Results: There were five clinical (c) T2, 16 cT3, and five cT4 rectal tumors, with 88% cN+. Twenty-five patients received a median of 4 cycles (range 3 to 8) of mFOLFOX6 (with one cycle defined as a two-week period); one patient received 3 cycles of capecitabine and oxaliplatin. All patients completed SCRT; 81% completed the full course of neoadjuvant chemotherapy with 19% requiring dose reductions in chemotherapy, most commonly due to neuropathy. Nineteen patients underwent post-treatment endoscopic evaluation, and nine patients were noted to achieve a complete clinical response (CCR). Six of the nine patients who achieved CCR opted for a non-operative approach of watch-and-wait. Twenty patients underwent surgical resection; pathologic complete response was observed in seven (35%) of these twenty. The main radiation-associated toxicity was proctitis with CTCAE Grade 2 proctitis observed in seven patients (27%). Post-operative Clavien-Dindo Grade 3 complications within 30 days of surgery were identified in six patients (30%), with no Grade 4 or 5 adverse events. Median length of hospital stay was 4.5 days (range 2-16 days); three patients were readmitted within a 30 day period., Conclusions: Short course preoperative radiotherapy followed by neoadjuvant chemotherapy was well-tolerated and achieved oncologic outcomes that compare favorably with short-course radiation therapy alone or long-course chemoradiotherapy. This regimen is associated with high rates of clinical and pathologic complete response.

OBJECTIVE Spinal stereotactic body radiation therapy (SBRT) has emerged as an attractive method to deliver high doses of radiation to oligometastatic spinal tumors with radioresistant histology. Because SBRT is a palliative therapy, attention to potential radiation toxicities is paramount when counseling patients. The objective of this study was to report radiation-induced myositis after SBRT, a previously undescribed complication. METHODS A total of 667 patients received 891 spine SBRT treatments (either 24 Gy in 1 fraction or 27 Gy in 3 fractions) from 2011 to 2016 and underwent retrospective review. Eleven patients were identified as having radiographic evidence of myositis following SBRT. Clinical and pathologic results were collected, including receipt of anti-vascular endothelial growth factor (VEGF) therapy, radiation dose, equivalent dose in 2-Gy fractions (EQD2), biologically effective dose (BED), and volume of muscle treated. Treatment toxicities were classified according to the Common Terminology Criteria for Adverse Events (CTCAE; version 4.03). Univariate statistical analyses were performed to evaluate the relationships between radiation fractionation schedule and myositis and between anti-VEGF therapy and myositis. RESULTS The cumulative incidence of myositis was 1.9% at 1 year. The median of the mean dose administered to muscle with myositis was 17.5 Gy. The median EQD2 was 55.1 Gy, and the median BED was 82.7 Gy. The median time to the development of clinical symptoms was 1.4 months, while the median time to imaging evidence was 4.7 months. Two patients (18.2%) had CTCAE grade 3 complications. Single-fraction spine SBRT (HR 4.5, 95% CI 1.2-16.9; p = 0.027) was associated with increased risk of developing myositis whereas receipt of anti-VEGF therapy was not (HR 2.2, 95% CI 0.6-7.1; p = 0.2). CONCLUSIONS Radiation myositis following spinal radiosurgery is a rare but important complication. Single-fraction treatment schedules may be associated with increased risk of myositis but should be validated in a larger series.

Aim: This project aimed to improve patients' knowledge on the importance of hand hygiene. It involved providing patients with a patient and family education on the importance of hand hygiene using a patient information leaflet that introduces the rationale of hand hygiene, possible consequences of poor hand hygiene, and the seven steps of hand hygiene., Methods: This projected used a preimplementation and postimplementation audit strategy using the Joanna Briggs Institute Practical Application of Clinical Evidence System and Getting Research Into Practice programs. The implementation occurred in three phases over a period of 6 months from January 2014 to June 2014. The audits took place in two orthopaedic wards in a large acute care setting tertiary hospital in Singapore and involved a sample size of 54 patients. It involved going through the medical records of the cases, assessment of patient knowledge based on the audit criteria, and checking if the patients received the patient information leaflet on hand hygiene., Results: The postimplementation audit found significant improvements in all three audit criteria. The percentage of patients who demonstrated knowledge in the importance of hand hygiene saw an improvement of 48.1%. There was an improvement of 44.5% in nurses' compliance to the documentation of patient education being carried out. The percentage of patients who received a patient information leaflet on hand hygiene saw an increase of 36.1%., Conclusion: This project demonstrated that a preimplementation and postimplementation audit is a viable method to implement change and translate evidence into practice. Through this project, patients gained an understanding on the importance of hand hygiene and could take better ownership of their well being. This may potentially improve hospitalization experience and benefit health outcomes. The positive results of this project are contributed by the enthusiastic involvement of all the stakeholders, from patients and their caregivers to the bedside nurses and nursing leaders. The sustenance will be an ongoing challenge to the project.

Three-dimensional conformal radiotherapy in combination with transarterial chemoembolization (TACE) has been beneficial in patients with unresectable hepatocellular carcinoma (HCC). There have been few clinical reports on the use of intensity-modulated radiotherapy (IMRT) in combination with TACE for these patients. The purpose of this study was to assess the efficacy and toxicity of IMRT following TACE in unresectable HCC.The medical records of consecutive patients with unresectable HCC, who underwent IMRT following TACE from January 2009 to June 2014, were retrospectively reviewed in order to assess the overall survival (OS), progression-free survival (PFS), tumor response, and treatment-associated toxicity.A total of 64 lesions in 54 patients were included in the analysis. IMRT was delivered at a median dose of 50 Gy (range 44-70 Gy) at 1.8 to 2.0 Gy per fraction. The overall response rate was achieved in 64.8% of patients with complete response in 20.4% of patients at 3 months after completion of IMRT. The median OS was 20.2 months (95% CI = 8.6-31.9), and the actuarial 1-, 2-, and 3-year OS rates were 84.6%, 49.7%, and 36.7%, respectively. The median PFS was 10.5 months (95% CI = 7.3-13.7) and the 1-, 2-, and 3-year PFS rates were 44.2%, 23.4%, and 14.6%, respectively. The responders had a significantly higher OS rate than the nonresponders (3-year OS 48.0% vs 14.4%, P = 0.001). During and the first month following IMRT, 10 (18.5%) patients developed grade 3 hematological toxicity, and 3 (5.6%) developed grade 3 hepatic toxicity. No patient experienced grade 4 or 5 toxicity. Radiation-induced liver disease was not observed.Our findings suggest that IMRT following TACE could be a favorable treatment option for both its safety profile and clinical benefit in patients with unresectable HCC.

Background: The current study is the first to examine the effectiveness and toxicity of postoperative intensity-modulated radiotherapy (IMRT) in the treatment of intrahepatic cholangiocarcinoma (ICC) abutting the vasculature. Specifically, we aim to assess the role of IMRT in patients with ICC undergoing null-margin (no real resection margin) resection., Methods: Thirty-eight patients with ICC adherent to major blood vessels were included in this retrospective study. Null-margin resection was performed on all patients; 14 patients were further treated with IMRT. The median radiation dose delivered was 56.8 Gy (range, 50-60 Gy). The primary endpoints were overall survival (OS) and disease-free survival (DFS)., Results: At a median follow-up of 24.6 months, the median OS and DFS of all patients (n=38) were 17.7 months (95% CI, 13.2-22.2) and 9.9 months (95% CI, 2.8-17.0), respectively. Median OS was 21.8 months (95% CI, 15.5-28.1) among the 14 patients in the postoperative IMRT group and 15.0 months (95% CI, 9.2-20.9) among the 24 patients in the surgery-only group (P=0.049). Median DFS was 12.5 months (95% CI, 6.8-18.2) in the postoperative IMRT group and 5.5 months (95% CI, 0.7-12.3) in the surgery-only group (P=0.081). IMRT was well-tolerated. Acute toxicity included one case of Grade 3 leukopenia; late toxicity included one case of asymptomatic duodenal ulcer discovered through endoscopy., Conclusions: The study results suggest that postoperative IMRT is a safe and effective treatment option following null-margin resections of ICC. Larger prospective and randomized trials are necessary to establish postoperative IMRT as a standard practice for the treatment of ICC adherent to major hepatic vessels.

Monoclonal antibodies (mAbs) are biological macromolecules with complex post-translational modifications that can be observed when assessing product variants. The N- and C-terminal heterogeneities of commercially produced antibodies have been observed and extensively studied over the past 30 years. This review summarizes the current literature on detectable antibody termini variants from cultured cells. The presence of these heterogeneities can be detected by many different analytical methods, mostly based on sequence, charge and size differences. Examples are presented that highlight terminal heterogeneities, methods of detection, and their impact on the quality of mAbs. Regulatory considerations are also discussed regarding the potential impact on product quality, safety, and efficacy., (Published by Elsevier Ltd.)

Background: The miRNA deregulation is commonly observed in human malignancies, where they act as tumour suppressors or oncogenes. Despite the association of several miRNAs with bladder cancer, little is known about the miRNAs that contribute to bladder cancer progression from non-muscle invasive (NMI) to muscle-invasive (MI) disease., Methods: We first profiled the expression of miRNAs and mRNAs in a cohort of urothelial carcinomas and further characterised the role of miR-126 in invasion, as it emerged as the most downregulated miRNA between MI and NMI tumours., Results: We found that restoration of miR-126 levels attenuated the invasive potential of bladder cancer cells. Mechanistically, we identified the role of miR-126 in invasion through its ability to target ADAM9. Notably, a significant inverse correlation between miR-126 and ADAM9 expression was observed, where ADAM9 was upregulated in MI bladder cancer cells. While knockdown of ADAM9 attenuated the invasiveness of cells with low miR-126 levels, experimental upregulation of ADAM9 recapitulated the invasive phenotype. Furthermore, ADAM9 expression assessed by immunohistochemistry significantly correlated with poor prognosis in patients with urothelial carcinoma., Conclusions: In this study we describe the role of miR-126 in bladder cancer progression, identifying miR-126 and ADAM9 as potential clinical biomarkers of disease aggressiveness.

miRNAs are small noncoding RNAs with critical roles in a large variety of biological processes such as development and tumorigenesis. miRNA expression profiling has been reported to be a powerful tool to classify tissue samples, including cancers, based on their developmental lineage. In this study, we have profiled the expression of miRNAs in bladder carcinoma in situ (CIS) and distinct cell compartments of the normal bladder, namely umbrella and basal-intermediate urothelial cells, as well as the muscularis propria. We identified several miRNAs differentially expressed between umbrella and basal-intermediate cells (miR-133a, miR-139-3p, miR-142-3p, miR-199b-5p, and miR-221). In situ hybridization confirmed the expression of miR-133a and miR-139-3p in umbrella cells, and miR-142-3p in basal-intermediate cells. Strikingly, miRNA expression levels of CIS most closely resembled the miRNA profile of umbrella cells. Finally, we examined well-established umbrella and basal-intermediate cell immunohistochemical biomarkers in an independent series of CIS samples. Again, this analysis revealed the significant expression of umbrella-specific markers in CIS when compared to non-CIS lesions. Overall, our studies represent a comprehensive and accurate description of the different miRNAs expressed in CIS tumors and three distinct histological areas of the urinary bladder. Notably, this study provides evidence of the possible origin relationship between CIS and normal umbrella cells., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Altered microRNA (miRNA) expression may occur early in bladder cancer and may play a role in carcinogenesis and tumor behavior. We evaluated whether alterations in miRNA expression could improve disease stratification and outcome prognosis in bladder tumors and noninvasive diagnosis in urinary samples. miR-143, miR-222, and miR-452 expression levels were analyzed by quantitative RT-PCR (RT-qPCR) in paired urinary and matching tumors and in two independent prospective series of tumors and urinary specimens. Differential expression of miR-143, miR-222, and miR-452 in urine were verified by in situ hybridization in matching tumors. Tumor miRNA expression by RT-qPCR correlated with tumor grade, size, and presence of carcinoma in situ for miR-222, recurrence (miR-222 and miR-143), progression (miR-222 and miR-143), disease-specific survival (miR-222), and overall survival (miR-222). Protein expression patterns of potential miRNA targets, including vascular endothelial growth factor, BCL2, v-erb-b2 erythroblastic leukemia viral oncogene (ERBB) homolog 3, and ERBB4, were evaluated by IHC in tissue arrays containing tumors for which miRNAs were assessed by RT-qPCR. Target expression correlated with expression of their predicted regulatory miRNAs, recurrence (ERBB3), progression (ERBB4), disease-specific survival (ERBB3 and ERBB4), and overall survival (ERBB3 and ERBB4). Furthermore, RT-qPCR of miR-452 (area under the curve, 0.848) and miR-222 (area under the curve, 0.718) in urine provided high accuracies for bladder cancer diagnosis. Thus, bladder tumors were characterized by changes in miRNA expression that could aid in tumor stratification and clinical outcome prognosis, and miRNAs were detected in urinary specimens for noninvasive diagnosis., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The objectives of this study were twofold: (i) to determine the mechanism(s) of Senecio-induced toxicity in human hepatoblastoma cells (HepG2) in vitro and whether such toxicity could be prevented using N-acetyl-cysteine (NAC), and (ii) to evaluate whether caspases are involved in Senecio-induced apoptosis. Cells were treated with aqueous extracts of Senecio (10 mg x mL-1) with and without NAC. Cytotoxicity was determined by using the MTT assay. Total glutathione (GSH) was measured by using the Tietze assay. Cells were also treated with aqueous extracts of Senecio in the presence or absence of 50 micromol/L caspase-3 inhibitor (IDN) for 24 h. Apoptosis was determined by transmission electron microscopy, and DNA fragmentation was determined by ELISA and terminal dUTP nick-end labelling (TUNEL). Senecio produced cytotoxicity and depleted GSH in a concentration- and time-dependent manner. A significant depletion in GSH was observed after 15 min (p < 0.001 vs. control), whereas significant cytotoxicity was only observed after 3 h (p < 0.001 vs. control). Treatment with NAC prevented Senecio-induced GSH depletion and resulted in a significant decrease in Senecio-induced cytotoxicity (p < 0.001 vs. NAC-untreated cells). Treatment with Senecio for 24 h resulted in 22% +/- 2.5% (p < 0.001) apoptosis (vs. control). Pretreatment with 50 mumol caspase inhibitor reduced Senecio-induced apoptosis significantly (vs. non-exposed to IDN) (12% +/- 1.5%; p < 0.05). Our results suggest the mechanism of Senecio-induced cytotoxicity in HepG2 cells in vitro involves depletion of cellular GSH. Cytotoxicity is reduced by supplementation with NAC, which thus prevents GSH depletion. Caspase activation is involved in Senecio-induced apoptosis.