Ionizing radiation (IR) damage, whether intentional, accidental, or therapeutic, reverberates throughout the body. The FDA has approved the use of palliative care and leukocyte growth factors for hematologic depletion (H-ARS), but no treatments have been approved for gastrointestinal damage (GI-ARS). Synthetic PIF (sPIF) safely replicates endogenous PIF’s preventative, reparatory, and regenerative effects. Specifically relevant for radiation-induced damage, sPIF reduces oxidative stress. Subcutaneous (SC) sPIF prevents LD100/30 mortality at 2 w post-treatment and restores GI function post-6Gy exposure (in mice). Daily SC sPIF for 14 d, starting 24 h post-LD85/40 (7.17 Gy) total-body ɣ-irradiation (TBI), increases survival 2.76-fold (14.7% (5/34) to 40.7% (24/59); p = 0.0036) by 4 w post-therapy. All sPIF-treated mice survived for the first 10 d, while only 80% survived in the sham group (p = 0.0034). The sPIF-treated group reached 50% survival at 23 di, while this figure was reached at 19 d in the sham-treated group, with a 21% delay. Importantly, sPIF delays weight loss for up to 25 d, increasing weight by ~12% above baseline and improving colon architecture; in the sham, both weight and colon recovery failed. sPIF partially prevents declines in hemoglobin and platelets, with no bleeding/sepsis observed, while WBC counts declined. sPIF’s safety and lack of deleterious drug-to-drug interaction were documented in a First-in-Human, FDA-approved clinical trial for autoimmune disease. Chronic FDA-guided toxicology/toxicokinetic studies demonstrated NOAEL and the highest safety margin. Collectively, sPIF safely and significantly increases survival, weight gain, and colon crypt scale, directly supporting its suitability for FDA-ARS animal-rule approval.

An urn contains a known number of balls of two different colors. We describe the random variable counting the smallest number of draws needed in order to observe at least c of both colors when sampling without replacement for a prespecified, positive integer value of c . This distribution is the finite sample analogy to the maximum negative binomial distribution described by Zhang et al. [14]. We describe the modes, approximating distributions, and estimation of the contents of the urn. This distribution is used to estimate the sample size for planning a stratified clinical trial.

Enrolling patients to the standard of care (SOC) arm in randomized clinical trials, especially for rare diseases, can be very challenging due to the lack of resources, restricted patient population availability, and ethical considerations. As the therapeutic effect for the SOC is often well documented in historical trials, we propose a Bayesian platform trial design with hybrid control based on the multisource exchangeability modelling (MEM) framework to harness historical control data. The MEM approach provides a computationally efficient method to formally evaluate the exchangeability of study outcomes between different data sources and allows us to make better informed data borrowing decisions based on the exchangeability between historical and concurrent data. We conduct extensive simulation studies to evaluate the proposed hybrid design. We demonstrate the proposed design leads to significant sample size reduction for the internal control arm and borrows more information compared to competing Bayesian approaches when historical and internal data are compatible.

Abstract Introduction: Advances in adjuvant chemotherapy with 5-fluorouracil, irinotecan, and oxaliplatin (FFX) have improved survival for patients (pts) with resectable PDAC yet few are cured by the current standard of care. Neoadjuvant FFX may lead to early control of micrometastasis and enhance cure rates for this aggressive malignancy. Methods: We performed a single-arm phase-2 clinical trial for resectable PDAC evaluating 6 months of perioperative modified (m) FFX (NCT02047474). Patients underwent baseline pancreatic protocol CT and were reviewed for resectability by a multidisciplinary panel. Enrolled pts received 6 cycles of neoadjuvant mFFX followed by surgery and 6 cycles of adjuvant mFFX. The primary endpoint was a ≥ 66% 12-month progression-free survival (PFS). Additional endpoints included overall survival (OS), circulating tumor DNA (ctDNA), tumor molecular features and tumor Keratin 17 levels. Whole blood was prospectively collected and processed to stored plasma (median volume 5.4 mL, range: 2.6 – 10.2) for retrospective ctDNA analysis using a personalized, tumor-informed ctDNA assay (SignateraTM). Survival rates were estimated by Kaplan-Meier. Results: Forty-six pts enrolled with 63 months median follow up, median age of 65 [R 46–80], 36 (78%) were ECOG 0, 30 (65%) had an endobiliary stent and no pts had staging laparoscopy. All pts started mFFX, and 37 pts (80%) completed all 6 preop cycles. Thirty-three pts (72%) underwent surgery with 3 pts developing investigator-assessed progression during neoadjuvant mFFX. Six pts were unresectable intraoperatively, and 27 pts (59%) underwent resection per protocol (25 R0, 2 R1). Ten additional pts underwent surgery off protocol. The 12-month PFS was 78% (95% CI: 64.2–94.4), median PFS and OS were 36.5 months (95% CI: 16.6–74.5) and 37.2 months (95% CI 17.5–not reached), respectively. Two-year OS was 59% (95% CI: 45.8–74.7). Baseline ctDNA was detected in 16/22 (73%) pts, and after 6 cycles of mFFX ctDNA was detected in 3/17 (18%) of pts. Patients with a positive ctDNA test 4 weeks post-resection had worsened PFS (HR 34.0, 95% CI: 2.6-4758.6; P = 0.006) and OS (HR: 11.7, 95% CI: 1.5–129.9; P = 0.021) compared to ctDNA negative. Mutational signature analysis revealed predominant signatures to be COSMIC signatures SBS1 and SBS5 (age related), and SBS15 (mismatch repair deficiency associated) which was associated with improved OS. Using Keratin 17 as a biomarker of the basal molecular subtype, either in diagnostic needle aspirates or surgical specimens, we found that high K17 expression was associated with worse survival. Conclusion: The perioperative mFFX clinical trial for resectable PDAC met its primary endpoint with a promising survival rate, and R0 resection rate of 93%. These findings warrant further evaluation in a randomized clinical trial. Most pts with detectable ctDNA at baseline experience ctDNA clearance after 6 cycles of neoadjuvant mFFX. In the post-operative setting, ctDNA positivity was strongly associated with recurrence. Signature SBS15 and low K17 were associated with improved OS. Citation Format: Michael Cecchini, Ronald Salem, Marie Robert, Suzanne Czerniak, Moein Rajaei, Jeffrey Townsend, Ondrej Blaha, Daniel Zelterman, Jaykumar Thumar, Jeremy Kortmansky, Wajih Zaheer, Neal Fischbach, Justin Persico, Stacey Stein, Sajid Khan, Charles Cha, Kevin Billingsley, John Kunstman, Sumedha Chowdhury, Robert Tseng, Carlos Mauricio, Deanne Yugawa, Luisa Escobar-Hoyos, Kimberly Johung, Christina Wiess, Erik Spickard, Vasily N. Aushev, George Laliotis, Adham Jurdi, Minetta C. Liu, Jill Lacy. A phase II study of peri-operative modified FOLFIRINOX in localized pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A002.

Importance:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. Objective:To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. Design, Setting, and Participants:This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. Interventions:Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. Main Outcomes and Measures:The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. Results:Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). Conclusions and Relevance:This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. Trial Registration:ClinicalTrials.gov Identifier: NCT02047474.

Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2− metastatic breast cancer (MBC) patients. However, 30–40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels of the CDK4/6 downstream substrates Rb (S780) and FoxM1 (T600) were higher in patients with progressive disease (PD) compared to responders ( p = 0.02). Systemic PI3K/AKT/mTOR activation in tumor epithelia and stroma/immune cells was detected in patients with PD. This activation was not explained by underpinning genomic alterations alone. As the number of FDA-approved targeted compounds increases, functional protein-based signaling analyses may become a critical component of response prediction and treatment selection for MBC patients.

Supplementary Figure Legends

Supplementary Figure 1, Tables 1-4 from A SNP in a let-7 microRNA Complementary Site in the KRAS 3′ Untranslated Region Increases Non–Small Cell Lung Cancer Risk

Table of Mutant Allele Fractions

BACKGROUND:Perforated necrotizing enterocolitis is a major cause of morbidity and mortality in premature infants, and the optimal treatment is uncertain. We designed this multicenter randomized trial to compare outcomes of primary peritoneal drainage with laparotomy and bowel resection in preterm infants with perforated necrotizing enterocolitis.METHODS:We randomly assigned 117 preterm infants (delivered before 34 weeks of gestation) with birth weights less than 1500 g and perforated necrotizing enterocolitis at 15 pediatric centers to undergo primary peritoneal drainage or laparotomy with bowel resection. Postoperative care was standardized. The primary outcome was survival at 90 days postoperatively. Secondary outcomes included dependence on parenteral nutrition 90 days postoperatively and length of hospital stay.RESULTS:At 90 days postoperatively, 19 of 55 infants assigned to primary peritoneal drainage had died (34.5 percent), as compared with 22 of 62 infants assigned to laparotomy (35.5 percent, P=0.92). The percentages of infants who depended on total parenteral nutrition were 17 of 36 (47.2 percent) in the peritoneal-drainage group and 16 of 40 (40.0 percent) in the laparotomy group (P=0.53). The mean (+/-SD) length of hospitalization for the 76 infants who were alive 90 days after operation was similar in the primary peritoneal-drainage and laparotomy groups (126+/-58 days and 116+/-56 days, respectively; P=0.43). Subgroup analyses stratified according to the presence or absence of radiographic evidence of extensive necrotizing enterocolitis (pneumatosis intestinalis), gestational age of less than 25 weeks, and serum pH less than 7.30 at presentation showed no significant advantage of either treatment in any group.CONCLUSIONS:The type of operation performed for perforated necrotizing enterocolitis does not influence survival or other clinically important early outcomes in preterm infants. (ClinicalTrials.gov number, NCT00252681.).

Supplementary Methods, Figures 1-9 from Hypoxia-Regulated Delta-like 1 Homologue Enhances Cancer Cell Stemness and Tumorigenicity

Elder abuse affects one in six older persons globally. Three limitations impede progress in prevention: most research is victim- rather than perpetrator-based; the reliance on explicit, self-reported factors; and failure to account for psychological factors, such as dehumanization, that motivate abuse. The current study addressed these gaps by examining whether implicit and explicit dehumanization of t could explain elder abuse proclivity. In a web-based survey of 585 family caregivers of older persons, dehumanization was found to be prevalent with 51% of the caregivers implicitly and 31% explicitly dehumanizing older persons. As predicted, implicit and explicit dehumanization contributed to elder abuse proclivity (OR = 1.23, 95% CI = 1.02-1.50, p = .03) and (OR = 1.26, 95% CI = 1.05-1.51, p = .01), respectively, after adjusting for relevant covariates including caregiver burden, and caregivers' and care-recipients' health. Developing caregiver-based interventions to humanize older persons may complement ongoing efforts in reducing elder abuse.

Detailed Individual Characteristics of 49 Enrolled Patients

Supplementary Table 1 from A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk

Supplementary Figure 2 from A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk

Waterfall plots demonstrating the percent change in sum of RECIST v1.1 target lesions compared to baseline. Twenty-five out of 26 patients were included; 1 patient withdrew consent and no follow-up imaging was available for review. The waterfall plots are color-coded by (A) best overall response (PR, SD, PD), (B) cohort (1-6), and (C) tumor type (melanoma, RCC, NSCLC). The majority of patients who experienced disease progression on the study had progression in non-target lesions, as denoted by as asterisk (*), and therefore the percent change in tumor from baseline by RECIST is less than the 20% disease progression threshold for multiple patients who had PD.

Association between pre-treatment CD4+ T-cell density from available baseline tumor tissue (n=14) and the duration of time on treatment in days.

S1. Dose-response curve of MCF7 cells. S2. Western blotting analysis of Pol beta in cell lines. S3. Pol beta and XPA interact in vitro. S4. The effect of E295K Pol beta expression on survival following cisplatin treatment. Table S1. Difference in viability of crosslinking agents from high-throughput screen.