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Summary Background The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. Methods For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. Findings 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7–10·6). Biochemical failure (R2 0·38 [95% CI 0·11–0·64]), biochemical failure-free survival (R2 0·12 [0·0030–0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045–0·65]), and local failure (R2 0·085 [0·00–0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22–0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59–0·89]) correlated strongly. Interpretation Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. Funding Prostate Cancer Foundation and National Institutes of Health.

Purpose/Objectives To determine the utilization of and barriers to implementation of radiopharmaceutical therapy (RPT) amongst U.S. radiation oncologists. Materials/Methods An anonymous, voluntary 21-item survey directed towards attending radiation oncologists was distributed via social media platforms (Twitter, LinkedIn, Facebook, Student Doctor Network). Questions assessed practice characteristics, specific RPT prescribing patterns, RPT prescribing interest, and perceived barriers to RPT implementation. Non-parametric χ2 test was used for correlation statistics. Results Of the 142 respondents, 131 (92.3%) practiced in the U.S. and were included for this analysis. Respondents were well balanced in terms of practicing region, population size served, practice setting and years in practice. Forty-eight percent (n=63) reported prescribing at least one RPT. An additional 7% (n=8) participate in RPT administration without billing themselves. Among those that actively prescribed RPT, the mean cumulative cases per month was 4.2 (range: 1-5). The most commonly prescribed radionuclides were Radium-223 (40%; mean 2.8 cases/month), Iodine-131 (18%; mean 2.3 cases/month), Yttrium-90 (13%; mean 3.4 cases/month), “other” (8%), Samarium-153 (6%; mean 1.0 cases/month), Strontrium-89 and Phosphorous-32 (2% each; mean 1.8 and 0.4 cases/month respectively). Of those who answered “other”, Lutetium-177 dotatate was most commonly prescribed (8%). No significant (p Most radiation oncologists (56%, n=74) responded they would like to actively prescribe more RPT, while 27% (n=35) were indifferent and 17% (n=22) answered “no.” Perceived barriers to implementation were varied but broadly categorized into treatment infrastructure (44%, n=57), inter-specialty relations (41%, n=53), lack of training (23%, n=30), and financial considerations (16%, n=21). Conclusion Among surveyed U.S. radiation oncologists, a significant number reported prescribing at least one RPT. The majority expressed interest in prescribing additional RPT. Wide-ranging barriers to implementation exist, most commonly inter-specialty relations, treatment infrastructure, lack of training, and financial considerations.

INTRODUCTION AND OBJECTIVE:Tumors with mutations associated with homologous recombination deficiency (HRD) are uncommon in prostate cancer (PCa) and variably responsive to PARP inhibition. To bette...

PURPOSE/OBJECTIVE(S) To survey the utilization, interest in, and barriers to implementation of radiopharmaceuticals/unsealed sources amongst U.S. radiation oncologists. MATERIALS/METHODS An anonymous, voluntary survey directed towards attending radiation oncologists was distributed via social media platforms (Twitter, LinkedIn, SDN, Facebook). Questions assessed practice characteristics, radiopharmaceutical prescribing patterns (Iodine-131, Radium-223, Yttrium-90, Sumarium-153, Strontium-89, Phosphorous-32, "other"), prescribing interest level, and perceived barriers to implementation. Non-parametric χ2 test was used for correlation statistics. RESULTS Of the 120 respondents, 112 practiced in the U.S and were included for this analysis. Years of practice was broadly distributed with 30% (n = 34) of attendings in practice > 10 years, 21% (n = 23) 6-10 years, 25% (n = 28) 3-5 years, and 24% (n = 27) 0-2 years. Practice type included academic-main site amongst 39% (n = 44), academic-satellite in 18% (n = 20), and private practice/other in 43% (n = 48) of attendings. Forty-four percent (n = 49) of attendings served populations of > 500K, 22% (n = 25) 200-500K, 25% (n = 28) 100-200K, and 9% (n = 10) 0.05) association was noted between practice type, practice location, years of practice, or practice volume with utilization of any radiopharmaceuticals/unsealed sources. The majority (55%, n = 61) of attending radiation oncologists responded they would like to actively prescribe more radiopharmaceuticals/unsealed sources, while 30% (n = 31) were indifferent and 18% (n = 20) answered "no." Perceived barriers to implementation were varied but broadly categorized into treatment infrastructure (43%, n = 48), interspecialty relations (42%, n = 47), lack of training (21%, n = 24), and financial considerations (17%, n = 19). CONCLUSION Almost half of surveyed U.S. radiation oncologists reported prescribing at least one radiopharmaceuticals/unsealed source, of which Ra-223 was the most common. The majority expressed interest in prescribing additional radiopharmaceuticals/unsealed sources. Wide-ranging barriers to implementation exist, most commonly interspecialty relations, treatment infrastructure, lack of training, and financial considerations.

PURPOSE/OBJECTIVE(S) Cannabis use rates are increasing throughout the United States along with shifts in state-level policy. Patients with cancer use cannabis for a broad range of indications, but there is limited quality data to support many of these uses. To date, few studies have sought to understand cannabis use in populations of patients served by radiation oncology departments. MATERIALS/METHODS Standardized electronic medical record prompts were used by clinicians for cannabis history documentation for 1050 adult patients seen for initial consultation or follow-up between 10/2020 and 2/2021 at an academic radiation oncology department. Cannabis use data, including recency/frequency of use, indication, and mode of administration, were later gathered using the Michigan Radiation Oncology Analytics Resource (M-ROAR) under an IRB-approved protocol. Cannabis use characteristics were summarized, and logistic regression was used to explore associations between age and gender and recent cannabis use. RESULTS In total, 54 (5.1%) of 1050 unique patients declined to answer questions about cannabis use. Of the remaining 996 patients, 106 (10.6%) endorsed recent cannabis use (≤1 month ago), 71 (7.1%) noted remote use (> 1 month ago), and 819 (82.2%) denied history of cannabis use. The median age of those with recent cannabis use was 59.5 (IQR: 49.7-66.4) vs. 65.4 (IQR: 57.1-73.5) in all others. A multivariable logistic regression analysis revealed an association between age (OR 0.96; 95% CI: 0.95-0.97; P < 0.001) but not gender (male OR 1.24; 95% CI: 0.82-1.88; P = 0.310) and recent cannabis use. Patients noted pain (46.2%), anxiety (23.6%), insomnia (17.9%), "for the high" (17.0%), nausea (15.1%), poor appetite (14.2%), "to fight cancer" (4.7%), and depression (1.9%) as indications for use. The most common mode of administration was inhalation via smoking (47.2%), followed by oral (edibles, 36.8%), topical (15.1%), oral (drinks, 4.7%), vaping (3.8%), sublingual (1.0%), and rectal (1.0%). Most patients used cannabis daily (58.5%). Only 4 individuals (3.8%) noted use multiple times daily, while the remainder endorsed weekly (20.8%) or less than weekly (17.0%) use. CONCLUSION Approximately 10% of patients seen in a radiation oncology department reported recent cannabis use for a variety of reasons. These findings suggest a need for: 1) collection of cannabis use history in radiation oncology departments, 2) efforts to destigmatize cannabis use to facilitate frank discussions between patients and providers, 3) patient education about the fact that cannabis is not an evidence-based cancer treatment, 4) recommendation against inhaled forms of cannabis, which may carry risk of pulmonary toxicity, and 5) careful application of proven therapies to address symptoms when appropriate to provide alternatives to cannabis. Further research is needed to assess changes in cannabis use patterns over the course of cancer treatment and to evaluate risks and benefits of cannabis use in patients with cancer.

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness., A recent report suggested Black men with prostate cancer were more responsive to immunotherapy. Here, the authors analysed prostate cancer gene expression profiles and show tumours from Black men and men with African ancestry have an increased proportion of plasma cells compared to those of White men and this correlates with improved outcome following treatment.

Multiple factors influence the risk of developing pneumonitis after radiation therapy (RT) for lung cancer, but few resources exist to guide clinicians in predicting risk in an individual patient treated with modern techniques. We analyzed toxicity data from a state-wide consortium to develop an integrated pneumonitis risk model.All patients (N = 1302) received conventionally fractionated RT for stage II-III non-small cell lung cancer between April 2012 and July 2019. Pneumonitis occurring within 6 months of treatment was graded by local practitioners and collected prospectively from 27 academic and community clinics participating in a state-wide quality consortium. Pneumonitis was modeled as either grade ≥2 (G2+) or grade ≥3 (G3+). Logistic regression models were fit to quantify univariable associations with dose and clinical factors, and stepwise Akaike information criterion-based modeling was used to build multivariable prediction models.The overall rate of pneumonitis of any grade in the 6 months following RT was 16% (208 cases). Seven percent of cases (n = 94) were G2+ and1% (n = 11) were G3+. Adjusting for incomplete follow-up, estimated rates for G2+ and G3+ were 14% and 2%, respectively. In univariate analyses, gEUD, V5, V10, V20, V30, and mean lung dose (MLD) were positively associated with G2+ pneumonitis risk, whereas current smoking status was associated with lower odds of pneumonitis. G2+ pneumonitis risk of ≥22% was independently predicted by MLD of ≥20 Gy, V20 of ≥35%, and V5 of ≥75%. In multivariate analyses, the lung V5 metric remained a significant predictor of G2+ pneumonitis, even when controlling for MLD, despite their close correlation. For G3+ pneumonitis, MLD and V20 were statistically significant predictors. Number of patient comorbidities was an independent predictor of G3+, but not G2+ pneumonitis.We present an analysis of pneumonitis risk after definitive RT for lung cancer using a large, prospective dataset. We incorporate comorbidity burden, smoking status, and dosimetric parameters in an integrated risk model. These data may guide clinicians in assessing pneumonitis risk in individual patients.

Purpose/objective(s) Guideline and clinical adoption of new radiotherapeutic approaches commonly requires 5-10 years of follow-up in randomized trials to ensure long-term safety. This is resource intensive and slows the pace of advancement. We hypothesized that the relative risk (RR) of radiation-induced gastrointestinal (GI) or genitourinary (GU) toxicity would remain similar or decrease overtime with long-term follow-up. Materials/methods PubMed and Embase were systematically searched for randomized trials evaluating changes in radiotherapy (RT; hypofractionation, dose escalation, change in field size) for localized prostate cancer published between 1970 and 2020. Yearly toxicity estimates were digitally extracted for GI and GU toxicity. Short- and long-term toxicity were defined as toxicity arising in years 1-3 and 5-10 post-RT, respectively. RR differences of toxicity between trial arms were calculated, and differences between short- and long-term relative risk measures of toxicity were compared using paired sample Wilcoxon signed-rank tests weighted by trial size. Results Median follow-up was 6 years (range 3-16) of the included 29 trials (n = 18,069 men). Of trials that reported risk group (67%), 90% of patients had intermediate and high-risk disease, and 57% of patients received ADT. There was no evidence of an increase in the RR of any grade of GI or GU toxicity with follow-up beyond 3 years. The mean RR point estimate of short- vs long-term GI and GU toxicity consistently decreased over time, which was represented by negative values for all grades. Mean differences (late RR - early RR) for grade 1, 2+ and 3+ GI toxicity were (-0.12, P Conclusion While toxicity events may continue to occur over time, the relative difference at later time points is similar or lower compared to early time points. Thus, our data does not support concerns for very late relative increases in radiation-induced toxicity. Physician reported toxicity assessed up to 3 years post-treatment is likely sufficient to establish safety following alternative radiotherapy dose/fractionation schedules and target volumes in prostate cancer.

Purpose Dose to normal lung has commonly been linked with radiation-induced lung toxicity (RILT) risk, but incorporating functional lung metrics in treatment planning may help further optimize dose delivery and reduce RILT incidence. The purpose of this study was to investigate the impact of the dose delivered to functional lung regions by analyzing perfusion (Q), ventilation (V), and combined V/Q single-photon-emission computed tomography (SPECT) dose-function metrics with regard to RILT risk in patients with non-small cell lung cancer (NSCLC) patients who received radiation therapy (RT). Methods and Materials SPECT images acquired from 88 patients with locally advanced NSCLC before undergoing conventionally fractionated RT were retrospectively analyzed. Dose was converted to the nominal dose equivalent per 2 Gy fraction, and SPECT intensities were normalized. Regional lung segments were defined, and the average dose delivered to each lung region was quantified. Three functional categorizations were defined to represent low-, normal-, and high-functioning lungs. The percent of functional lung category receiving ≥20 Gy and mean functional intensity receiving ≥20 Gy (iV20) were calculated. RILT was defined as grade 2+ radiation pneumonitis and/or clinical radiation fibrosis. A logistic regression was used to evaluate the association between dose-function metrics and risk of RILT. Results By analyzing V/Q normalized intensities and functional distributions across the population, a wide range in functional capability (especially in the ipsilateral lung) was observed in patients with NSCLC before RT. Through multivariable regression models, global lung average dose to the lower lung was found to be significantly associated with RILT, and Q and V iV20 were correlated with RILT when using ipsilateral lung metrics. Through a receiver operating characteristic analysis, combined V/Q low-function receiving ≥20 Gy (low-functioning V/Q20) in the ipsilateral lung was found to be the best predictor (area under the curce: 0.79) of RILT risk. Conclusions Irradiation of the inferior lung appears to be a locational sensitivity for RILT risk. The multivariable correlation between ipsilateral lung iV20 and RILT, as well as the association of low-functioning V/Q20 and RILT, suggest that irradiating low-functioning regions in the lung may lead to higher toxicity rates.

SREBP cleavage-activating protein (Scap) is an endoplasmic reticulum membrane protein required for cleavage and activation of sterol regulatory element-binding proteins (SREBPs), which activate the transcription of genes in sterol and fatty acid biosynthesis. Liver-specific loss of Scap is well tolerated; hepatic synthesis of sterols and fatty acids is reduced, but mice are otherwise healthy. To determine whether Scap loss is tolerated in the intestine, we generated a mouse model (Vil-Scap−) in which tamoxifen-inducible Cre-ERT2, a fusion protein of Cre recombinase with a mutated ligand binding domain of the human estrogen receptor, ablates Scap in intestinal mucosa. After 4 days of tamoxifen, Vil-Scap− mice succumb with a severe enteropathy and near-complete collapse of intestinal mucosa. Organoids grown ex vivo from intestinal crypts of Vil-Scap− mice are readily killed when Scap is deleted by 4-hydroxytamoxifen. Death is prevented when culture medium is supplemented with cholesterol and oleate. These data show that, unlike the liver, the intestine requires Scap to sustain tissue integrity by maintaining the high levels of lipid synthesis necessary for proliferation of intestinal crypts.

Enterocytes are the only cell type that must balance the de novo synthesis and absorption of cholesterol, although the coordinate regulation of these processes is not well understood. Our previous studies demonstrated that enterocytes respond to the pharmacological blockade of cholesterol absorption by ramping up de novo sterol synthesis through activation of sterol regulatory element-binding protein-2 (SREBP-2). Here, we genetically disrupt both Insig1 and Insig2 in the intestine, two closely related proteins that are required for the feedback inhibition of SREBP and HMG-CoA reductase (HMGR). This double knock-out was achieved by generating mice with an intestine-specific deletion of Insig1 using Villin-Cre in combination with a germ line deletion of Insig2. Deficiency of both Insigs in enterocytes resulted in constitutive activation of SREBP and HMGR, leading to an 11-fold increase in sterol synthesis in the small intestine and producing lipidosis of the intestinal crypts. The intestine-derived cholesterol accumulated in plasma and liver, leading to secondary feedback inhibition of hepatic SREBP2 activity. Pharmacological blockade of cholesterol absorption was unable to further induce the already elevated activities of SREBP-2 or HMGR in Insig-deficient enterocytes. These studies confirm the essential role of Insig proteins in the sterol homeostasis of enterocytes.

In the vertebrate neural tube, regional Sonic hedgehog (Shh) signaling invokes a time- and concentration-dependent induction of six different cell populations mediated through Gli transcriptional regulators. Elsewhere in the embryo, Shh/Gli responses invoke different tissue-appropriate regulatory programs. A genome-scale analysis of DNA binding by Gli1 and Sox2, a pan-neural determinant, identified a set of shared regulatory regions associated with key factors central to cell fate determination and neural tube patterning. Functional analysis in transgenic mice validates core enhancers for each of these factors and demonstrates the dual requirement for Gli1 and Sox2 inputs for neural enhancer activity. Furthermore, through an unbiased determination of Gli-binding site preferences and analysis of binding site variants in the developing mammalian CNS, we demonstrate that differential Gli-binding affinity underlies threshold-level activator responses to Shh input. In summary, our results highlight Sox2 input as a context-specific determinant of the neural-specific Shh response and differential Gli-binding site affinity as an important cis-regulatory property critical for interpreting Shh morphogen action in the mammalian neural tube.

The Hedgehog signaling pathway is part of the ancient developmental-evolutionary animal toolkit. Frequently co-opted to pattern new structures, the pathway is conserved among eumetazoans yet flexible and pleiotropic in its effects. The Hedgehog receptor, Patched, is transcriptionally activated by Hedgehog, providing essential negative feedback in all tissues. Our locus-wide dissections of the cis-regulatory landscapes of fly patched and mouse Ptch1 reveal abundant, diverse enhancers with stage- and tissue-specific expression patterns. The seemingly simple, constitutive Hedgehog response of patched/Ptch1 is driven by a complex regulatory architecture, with batteries of context-specific enhancers engaged in promoter-specific interactions to tune signaling individually in each tissue, without disturbing patterning elsewhere. This structure—one of the oldest cis-regulatory features discovered in animal genomes—explains how patched/Ptch1 can drive dramatic adaptations in animal morphology while maintaining its essential core function. It may also suggest a general model for the evolutionary flexibility of conserved regulators and pathways. DOI: http://dx.doi.org/10.7554/eLife.13550.001

Glucose absorption in the small intestine is mediated by sodium dependent glucose cotransporter 1 (SGLT-1) and glucose transporter-2 (GLUT2), and is potentially linked to sweet taste receptor (STR) signaling and incretin hormone secretion. Both glucose absorption and expression of SGLT-1 are increased in obese rats, but human data is lacking. This study aimed to examine intestinal glucose absorption inmorbidly obese humans, and its relationship to glycemia, incretin responses, SGLT-1, GLUT2, and STR expression. Methods: 17 nondiabetic, morbidly obese subjects (5M:12F; 45 ± 3yrs, BMI: 48 ± 4kg/m2) and 11 lean controls (10M:1F; 44 ± 6yrs, BMI: 25 ± 1kg/m2) underwent endoscopic duodenal biopsies prior to intraduodenal glucose infusion (30g glucose over 30 min, with 3g 3-O-methylglucose (3-OMG) to estimate glucose absorption). Blood glucose and plasma concentrations of 3OMG, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP1), insulin, and glucagon were measured over 240 min. Absolute expression of SGLT-1, GLUT2 and STR (T1R2) transcripts was quantified by PCR. Results: Both the rate of glucose absorption, as assessed by the rise in plasma 3-OMG concentrations (P

BACKGROUND: Ezetimibe is a widely-used drug that lowers plasma cholesterol by blocking NPC1L1-mediated sterol absorption in small intestine. Enterocyte cholesterol homeostasis is controlled by the aggregated rates of sterol synthesis, efflux, and uptake from plasma and gut lumen. Endogenous cholesterol synthesis and low density lipoprotein (LDL) uptake are coordinately regulated by transcription factors termed Sterol Regulatory Element-Binding Proteins (SREBPs). Liver-X-receptors (LXRs), another family of transcription factors, are activated by sterols and control other aspects of sterol metabolism, especially cholesterol efflux. How blockade of cholesterol absorption by ezetimibe (EZE) affects intestinal SREBPs, LXRs, and key effector molecules, such as LDL Receptor (LDLR) and HMG-CoA Reductase (HMGR) is unknown. AIM: To study the effect of EZE on regulatory molecules that control sterol synthesis and LDL uptake in small intestine. METHODS: C57BL/6 mice were fed a chow diet with indicated drugs. Liver and small intestine were harvested. Jejunal enterocytes were isolated, and tissues fractionated for immunoblotting, which were quantified by densitometry. mRNAs were quantified by qPCR and microarray analysis. RESULTS: Feeding EZE increased active nuclear SREBP-2 by 8-fold in intestine, leading to increases in mRNAs for HMGR and LDLR by 1.3-fold +/0.03 (P

SummaryInjection of the peptide hormone ghrelin stimulates food intake in mice and humans. However, mice born without ghrelin demonstrate no significant loss of appetite. This paradox suggests either that compensation develops in mice born without ghrelin or that ghrelin is not essential for appetite control. To distinguish these possibilities, we generated transgenic mice (Ghrl-DTR) that express the diphtheria toxin receptor in ghrelin-secreting cells. Injection of diphtheria toxin in adulthood ablated ghrelin cells and reduced plasma ghrelin by 80%–95%. Ghrelin cell-ablated mice exhibited no loss of appetite or body weight and no resistance to a high-fat diet. To stimulate food intake in mice by ghrelin injection, we had to raise plasma levels many-fold above normal. Like germline ghrelin-deficient mice, the ghrelin cell-ablated mice developed profound hypoglycemia when subjected to prolonged calorie restriction, confirming that ghrelin acts to maintain blood glucose under famine conditions.