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Purpose:Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed.Experimental Design:Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1).Results:A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds.Conclusions:We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs.

Supplementary table 4

ImportanceMost prisons and jails in the US discontinue medications for opioid use disorder (MOUD) upon incarceration and do not initiate MOUD prior to release.ObjectiveTo model the association of MOUD access during incarceration and at release with population-level overdose mortality and OUD-related treatment costs in Massachusetts.Design, Setting, and ParticipantsThis economic evaluation used simulation modeling and cost-effectiveness with costs and quality-adjusted life-years (QALYs) discounted at 3% to compare MOUD treatment strategies in a corrections cohort and an open cohort representing individuals with OUD in Massachusetts. Data were analyzed between July 1, 2021, and September 30, 2022.ExposuresThree strategies were compared: (1) no MOUD provided during incarceration or at release, (2) extended-release (XR) naltrexone offered only at release from incarceration, and (3) all 3 MOUDs (naltrexone, buprenorphine, and methadone) offered at intake.Main Outcomes and MeasuresTreatment starts and retention, fatal overdoses, life-years and QALYs, costs, and incremental cost-effectiveness ratios (ICERs).ResultsAmong 30 000 simulated incarcerated individuals with OUD, offering no MOUD was associated with 40 927 (95% uncertainty interval [UI], 39 001-42 082) MOUD treatment starts over a 5-year period and 1259 (95% UI, 1130-1323) overdose deaths after 5 years. Over 5 years, offering XR-naltrexone at release led to 10 466 (95% UI, 8515-12 201) additional treatment starts, 40 (95% UI, 16-50) fewer overdose deaths, and 0.08 (95% UI, 0.05-0.11) QALYs gained per person, at an incremental cost of $2723 (95% UI, $141-$5244) per person. In comparison, offering all 3 MOUDs at intake led to 11 923 (95% UI, 10 861-12 911) additional treatment starts, compared with offering no MOUD, 83 (95% UI, 72-91) fewer overdose deaths, and 0.12 (95% UI, 0.10-0.17) QALYs per person gained, at an incremental cost of $852 (95% UI, $14-$1703) per person. Thus, XR-naltrexone only was a dominated strategy (both less effective and more costly) and the ICER of all 3 MOUDs compared with no MOUD was $7252 (95% UI, $140-$10 018) per QALY. Among everyone with OUD in Massachusetts, XR-naltrexone only averted 95 overdose deaths over 5 years (95% UI, 85-169)—a 0.9% decrease in state-level overdose mortality—while the all-MOUD strategy averted 192 overdose deaths (95% UI, 156-200)—a 1.8% decrease.Conclusions and RelevanceThe findings of this simulation-modeling economic study suggest that offering any MOUD to incarcerated individuals with OUD would prevent overdose deaths and that offering all 3 MOUDs would prevent more deaths and save money compared with an XR-naltrexone–only strategy.

Simulation models of opioid use disorder (OUD) aim at evaluating the impact of different treatment strategies on population-level outcomes. Researching Effective Strategies to Prevent Opioid Death (RESPOND) is a dynamic population state-transition model that simulates Massachusetts (MA) OUD population synthesizing data from the MA Public Health Data Warehouse, published survey studies, and randomized trials. We implement an empirical calibration approach to fit RESPOND to multiple calibration targets, including yearly counts of fatal overdoses and detox admissions in 2013-2015, and 2015 OUD population counts in MA. We used capture-recapture analysis to estimate the OUD population and to quantify uncertainty around calibration targets.1 The empirical calibration approach involves Latin hypercube sampling for a parameter search of the multidimensional space, comprising demographics of “arrivals”, overdose rates, treatment transition rates, and substance use transition probabilities. The algorithm accepts proposed parameter values when the respective model outputs are “close” to the observed calibration targets based on uncertainty ranges of targets. Calibration provided an excellent fit to the model calibration targets. The flexibility of the algorithm also allowed us to identify certain “questionable” parts of the model structure and explore the underlying relationships between the model parameters in an efficient manner. The calibrated model also provided a good fit to validation targets: non-overdose related deaths, percentage of active OUDs, and all types of overdose counts (fatal and non-fatal). In addition, the resulting set of values for the calibrated parameters will inform the priors of a more comprehensive Bayesian calibration. The calibrated RESPOND model will be employed to improve shared decision-making for OUD.

ImportanceCDC guidance emphasizes the importance of in-person education for students in grades kindergarten to 12 (K-12) during the COVID-19 pandemic. CDC encourage weekly SARS-CoV-2 testing of asymptomatic, unvaccinated students and staff (“screening”) to reduce infection risk and provide data about in-school SARS-CoV-2 prevalence where community incidence is high. The financial costs of screening assays have been described, but the human resource requirements at the school and district level to implement a SARS-CoV-2 screening program are not well known.ObjectiveTo quantify the resources required to implement a screening program in K-12 schools.Design, Setting, and ParticipantsA consortium of Massachusetts public K-12 schools was formed to implement and evaluate a range of SARS-CoV-2 screening approaches. Participating districts were surveyed weekly about their programs, including: type of assay used, individual vs. pooled screening, approaches to return of results and deconvolution (identification of positive individual specimens) of positive pools, number and type of personnel implementing the screening program, and hours spent on program implementation.Main Outcomes and MeasuresCosts, resource utilizationResultsIn 21 participating districts, over 21 weeks from January to June 2021, the positivity rate was 0.0%-0.21% among students and 0.0%-0.13% among educators/staff, and 4 out of 21 (19%) districts had at least one classroom transition to remote learning at any point due to a positive case. The average weekly cost to implement a screening program, including assay and personnel costs, was $17.00 per person tested; this was $46.68 for individual screenings and $15.61 for pooled screenings. The total weekly costs by district ranged from $1,644-$93,486, and districts screened between 58 and 3,675 people per week. The reported number of personnel working per week ranged from 1-5 to >50, and the total number of hours worked by all personnel ranged from 5-10 to >50.Conclusion and RelevanceThe human resources required to implement SARS-CoV-2 screening in Massachusetts public K-12 schools were substantial. Where screening is recommended for the 2021-22 school year due to high COVID-19 incidence (e.g., where vaccination uptake is low and/or more infectious variants predominate), understanding the human resources required to implement screening will assist districts policymakers in planning.

Background: Cancer family history is a vital part of cancer genetic counseling (GC) and genetic testing (GT), but increasing indications for germline cancer GT necessitate less labor-intensive models of collection. We evaluated the impact of GC on patient pedigrees generated by an electronic cancer family history questionnaire (eCFHQ). Methods: An Institutional Review Board–approved review of pedigrees collected through an eCFHQ was conducted. Paired pre-GC and post-GC pedigrees (n=1,113 each group) were analyzed independently by cancer genetic counselors for changes in patient-reported clinical history and to determine whether the pedigrees met NCCN GT criteria. Discrepancy in meeting NCCN GT criteria between pre-GC and post-GC pedigrees was the outcome variable of logistic regressions, with patient and family history characteristics as covariates. Results: Overall, 780 (70%) patients had cancer (affected), 869 (78%) were female, and the median age was 57 years (interquartile range, 45–66 years; range, 21–91 years). Of the 1,113 pairs of pre-GC and post-GC pedigrees analyzed, 85 (8%) were blank, 933 (84%) were not discrepant, and 95 (9%) were discrepant in meeting any NCCN GT criteria. Of the discrepant pedigrees, n=79 (83%) became eligible for testing by at least one of the NCCN GT criteria after GC. Patients with discrepant pedigrees were more likely to report no or unknown history of GT (odds ratio [OR], 4.54; 95% CI, 1.66–18.70; P=.01, and OR, 18.47; 95% CI, 5.04–88.73; PP=.02). Conclusions: For most patients (84%), a standalone eCFHQ was sufficient to determine whether NCCN GT criteria were met. More research is needed on the performance of the eCFHQ in diverse patient populations.

Background We aimed to examine the safety and efficacy of bevacizumab and carboplatin in patients with breast cancer brain metastases. Methods We enrolled patients with breast cancer and > 1 measurable new or progressive brain metastasis. Patients received bevacizumab 15 mg/kg intravenously (IV) on cycle 1 day 1 and carboplatin IV AUC = 5 on cycle 1 day 8. Patients with HER2-positive disease also received trastuzumab. In subsequent cycles, all drugs were administered on day 1 of each cycle. Contrast-enhanced brain MRI was performed at baseline, 24–96 h after the first bevacizumab dose (day + 1), and every 2 cycles. The primary endpoint was objective response rate in the central nervous system (CNS ORR) by composite criteria. Associations between germline VEGF single nucleotide polymorphisms (rs699947, rs2019063, rs1570360, rs833061) and progression-free survival (PFS) and overall survival (OS) were explored, as were associations between early (day + 1) MRI changes and outcomes. Results Thirty-eight patients were enrolled (29 HER2-positive, 9 HER2-negative); all were evaluable for response. The CNS ORR was 63% (95% CI, 46–78). Median PFS was 5.62 months and median OS was 14.10 months. As compared with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, patients with ECOG PS 1–2 had significantly worse PFS and OS (all P Conclusions The combination of bevacizumab and carboplatin results in a high rate of durable objective response in patients with brain metastases from breast cancer. This regimen warrants further investigation. Trial registration NCT01004172. Registered 28 October 2009.

Purpose: Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed. Experimental Design: Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1). Results: A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds. Conclusions: We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs.

4064 Background: E/GEJ adenocarcinoma has a high mortality rate despite curative intent therapy. The use of immune checkpoint inhibition is beneficial for treatment of this cancer in the metastatic and adjuvant settings but the role of these agents in the perioperative setting remains unclear. Here we report the results of an initial safety run-in of nivolumab when given in combination with neoadjuvant chemoradiation. Methods: Pts with a localized T1N1-3M0 or T2-3N0-2M0 E/GEJ adenocarcinoma with an ECOG PS of 0-1 and whom were deemed surgical candidates for an esophagectomy by a qualified surgeon were eligible. In step 1, pts were randomized to neoadjuvant therapy with carboplatin AUC 2 and paclitaxel 50 mg/m2 intravenously (IV) weekly x 5 along with 41.4-50.4 Gy radiation without (Arm A) or with (Arm B) nivolumab 240 mg IV during weeks 1 and 3 of treatment, followed by esophagectomy. Pts underwent a second randomization (step 2) to adjuvant nivolumab 240 mg IV every 2 weeks x 12 cycles with or without ipilimumab 1 mg/kg IV every 6 weeks during cycles 1, 4, 7 and 10. For the safety run-in, 30 pts were planned for accrual to allow for 12 evaluable pts per arm. Pts were followed for safety during neoadjuvant therapy through surgery and toxicities monitored per CTCAEv5. Pre-specified early stopping rules were defined to allow halting of the trial if deemed unsafe. Planned study accrual is 278 pts. Neoadjuvant primary endpoint is pathologic complete response rate, adjuvant primary endpoint is disease-free survival. Results: A total of 31 pts were enrolled to the safety run-in element of the study (Arm A, n = 16; Arm B n = 15). Male, 94%; White, 100%; median age, 62; esophageal adenocarcinoma, 52%; GEJ, 48%. Grade (G) 3 events occurring in more than one pt on Arm A—decreased lymphocytes (n = 5). G4 events occurring on Arm A—decreased lymphocytes (n = 1). G3 events occurring in more than one pt on Arm B—decreased lymphocytes (n = 2); anemia (n = 2); leukopenia (n = 4); hypotension (n = 2). G4 events occurring on Arm B—decreased lymphocytes (n = 3); cardiac tamponade and pericardial effusion (n = 1). Cardiac events were thought to be secondary to tumor location, not neoadjuvant treatment. On Arm B, notable G3 events seen in one pt each included colonic obstruction, wound infection and esophageal anastomotic leak. Of pts who have reached the time for surgery, 12/14 pts on Arm A and 13/13 pts on Arm B have proceeded to surgery. Of pts who have completed step 1, 7/14 pts on Arm A and 8/11 pts on Arm B have registered to step 2. Conclusions: The addition of nivolumab to carboplatin, paclitaxel and radiation in the neoadjuvant setting appears to be safe with no disproportionate level of toxicity observed between the two treatment arms. Accrual to the remainder of the trial continues with 43/278 patients accrued. Clinical trial information: NCT03604991.

1507 Background: Approximately 10% of men with advanced prostate cancer (PC) have pathogenic/likely pathogenic variants (PV) in cancer susceptibility genes and their identification may lead to targeted therapy. Genetic testing (GT) can also guide cancer surveillance and prevention for family members. While GT is recommended for men with potentially lethal PC, traditional testing models are strained, and access limited. The ProGen study examined a novel pretest model aimed at providing access to GT while promoting informed consent. Methods: Inclusion criteria were: potentially lethal PC (metastatic, localized with Gleason score ≥8, rising/persistent PSA after local therapy), diagnosis age ≤ 55 years, prior malignancy, family history suggestive of a PV and/or at oncologist’s discretion. Consented subjects from 3 sites were randomized 3:1 to video education (VE) or in-person genetic counseling (GC). Subjects who consented to GT had 67 genes analyzed (Ambry, USA) with results disclosed by telephone by a genetic counselor. Outcomes included GT uptake, PV prevalence, and survey measures of satisfaction, distress, genetics knowledge, family communication, and impact on cancer care (obtained at the time of intervention, and at 1, 4, and 12 months after result disclosure). Two-sided Fischer exact tests were used for between-arm comparisons. Results: Over a 2-year period: 662 subjects were randomized, VE or GC were completed by 604 subjects (VE: 93.1%, GC: 88.8%) of whom 596 subjects (VE:98.9%, GC:97.9%) consented to GT. To date, 591 subjects have completed GT (VE: 99.3%, GC: 98.6%). At the time of intervention, most subjects agreed or strongly agreed that their assigned arm was useful (VE: 95%, GC: 88%). Differences were not statistically significant. Notably, 84 PV were identified in 78 subjects (13.2%), with BRCA1/2 PV accounting for 32% of subjects with a positive result ( BRCA2:21, BRCA1:4). Conclusions: In this randomized trial, both novel VE and traditional GC yielded high GT uptake without significant differences in outcome measures of acceptability and satisfaction. VE enabled access to critical GT results while maintaining the core tenants of informed consent. PV were found in 13.2% of subjects, 32% of whom had BRCA1/2 PV. Analysis of collected survey data to inform strengths and limitations of VE as compared with pretest GC will be presented. Clinical trial information: NCT03328091.

TPS4651 Background: E/GEJ adenocarcinoma has a high mortality rate despite curative intent treatment. A pathologic complete response (pCR) is associated with better overall survival (OS) but occurs in less than 30% of pts. Immunotherapy is effective in the metastatic setting. Here we aim to evaluate the contribution of immunotherapy in the neoadjuvant and adjuvant settings in pts with locoregional E/GEJ cancer. Methods: This is a multi-center, randomized phase II/III trial. Surgical candidates with locoregional E/GEJ adenocarcinoma receive carboplatin AUC 2 IV and paclitaxel 50 mg/m2 IV, both weekly x 5 during concurrent radiation (50.4 Gy) either with or without nivolumab 240 mg IV during weeks 1 and 3, followed by surgery. Pts with no post-operative disease receive nivolumab 240 mg IV every 2 weeks for 12 cycles either with or without ipilimumab 1 mg/kg IV every 6 weeks for 4 cycles. Eligibility criteria include pts with T1-N1-3M0 or T2-3N0-2M0 disease whom are candidates for surgery, no prior chemotherapy or radiation for this disease, no prior immunotherapy, no significant autoimmune disease. Pts must be disease free for adjuvant treatment. Primary neoadjuvant endpoint is pCR rate; primary adjuvant endpoint is disease free survival (DFS). Secondary endpoints include toxicity, DFS and OS. Pre- and mid-treatment diffusion weighted imaging MRI will be conducted during the neoadjuvant portion of the study. A neoadjuvant safety run in of 30 pts is underway. Overall, 278 pts will be needed to detect an absolute improvement of 15% in pCR rate in pts receiving and not receiving neoadjuvant nivolumab and 236 pts will be needed to detect a HR of 0.65 in favor of adjuvant ipilimumab/nivolumab over nivolumab (90% power, one sided alpha of 0.10). Accrual is expected over 34 months at a rate of 8 patients per month. If favorable at interim analysis. Clinical trial information: NCT03604991 .