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INTRODUCTION: Chronic pancreatitis (CP) remains difficult to manage with few treatment options. Prior studies have implicated prostaglandin E 2 (PGE 2 ) in mediating chronic inflammation in the pancreas. Therefore, we aimed to evaluate whether indomethacin, a cyclooxygenase-2 enzyme inhibitor, would reduce PGE 2 levels in CP. METHODS: In this pilot multicenter randomized controlled trial, participants with CP received oral indomethacin (50 mg) or placebo twice daily for 28 days. Measurement of PGE 2 levels in pancreatic fluid collected endoscopically after secretin administration at baseline and posttreatment (day 28) was performed. Quality of life and pain were also assessed at baseline and posttreatment. RESULTS: A total of 27 participants were randomized (indomethacin = 13, placebo = 14). Although PGE 2 levels decreased after treatment in pancreas fluid, plasma, and saliva in the indomethacin group, there was no significant difference in mean change in pancreas fluid PGE 2 levels between the indomethacin and placebo groups (−457.7 pg/mL vs −840.4 pg/mL, P = 0.25). There was also no significant change in pain severity composite score (−1.3 indomethacin vs −0.5 placebo, P = 0.33), but the improvement in pain interference score (−2.9 indomethacin vs −0.4, P = 0.058) trended toward significance. There was no difference in adverse events between the 2 groups. DISCUSSION: In this phase 1/2 study, oral indomethacin was safe and well tolerated by patients with CP. Although there was no significant difference in change in PGE 2 levels, further studies are needed to determine the effect of indomethacin on the inflammatory pathway of CP and patient-centered outcomes.

Stem cell-derived kidney organoids enable human genetic disease modeling to identify the parathyroid hormone 1 receptor as a potential new therapeutic target for developmental polycystic kidney disease.

Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of metastatic TNBC. Further study demonstrated that MTAP deficiency or inhibition rendered TNBC susceptibility to chemotherapeutic agents, particularly PARPi. Mechanistically, targeting MTAP that synergized with PARPi by disrupting the METTL16-MAT2A axis involved in methionine metabolism and depleting in vivo s-adenosylmethionine (SAM) levels. Exhausted SAM in turn impaired PARPi-induced DNA damage repair through attenuation of MRE11 recruitment and end resection by diminishing MRE11 methylation. Notably, brain metastatic TNBC markedly benefited from a lower dose of PARPi and MTAP deficiency/inhibition synergy due to the inherently limited methionine environment in the brain. Collectively, our findings revealed a feed-forward loop between methionine metabolism and DNA repair through SAM, highlighting a therapeutic strategy of PARPi combined with MTAP deficiency/inhibition for TNBC.

Tuberous sclerosis complex (TSC) is a highly variable autosomal dominant disease characterized by dysregulated organ development and growth. Benign tumors, termed hamartomas, may occur across organ systems but typically involve the kidney, brain, skin, heart, and lung. The diagnosis, surveillance, and clinical management of TSC requires a multidisciplinary approach, adopted by dedicated multispecialty centers worldwide. Nephrology involvement predominantly stems from the morbidity and mortality related to the prototypical kidney lesion, angiomyolipomas, whose presence and degree confers risk of CKD, hypertension, retroperitoneal bleeding, and possibly renal cell carcinoma. Surveillance of kidney structural lesions, kidney function, and BP may enable early interventions that limit kidney-related morbidity and mortality, such as mammalian target of rapamycin inhibitor therapy. We review the epidemiology, genetics, and pathogenesis of TSC and how these inform the evaluation, diagnosis, and clinical management of TSC from the vantage point of the treating nephrologist.

Kidney organoids are an increasingly established model of polycystic kidney disease (PKD). Derived from human pluripotent stem cells (hPSCs), organoids may be generated from induced pluripotent stem cells (iPSCs) of patients that bear naturally occurring mutations or from CRISPR mutant hPSCs by virtue of their genetic tractability. PKD is the leading inheritable cause of kidney failure (KF), accounting for ∼5%–10% of the kidney transplant and dialysis needs worldwide. PKD is a disorder of considerable genetic heterogeneity, composed of typical adult-onset autosomal dominant (ADPKD) and fetal-onset autosomal recessive (ARPKD) forms, which share pathomechanisms. Despite advances in our understanding of the genetic and molecular underpinnings of PKD, the limited clinical treatment options have raised concerns regarding the faithfulness of preclinical models. Kidney organoids have emerged as a promising platform to study PKD by mimicking human-specific responses, enabling personalized medicine, and supporting high-throughput screens. Yet, valid criticisms have related to the relative immaturity of kidney organoids for modeling adult-onset forms of PKD, the faithfulness of organoids in modeling the cystic distribution of afflicted patients, and their batch-to-batch variability limiting experimental reproducibility. Here, we summarize a decade of kidney organoid models of PKD, emphasizing their role in advancing translational and therapeutic applications while addressing their limitations and future potential.

LBA4005 Background: To date, no phase 3 clinical trial has demonstrated an overall survival (OS) benefit in patients with locally advanced pancreatic adenocarcinoma (LA-PAC). TTFields are electric fields that disrupt cancer cell division. TTFields therapy is approved for glioblastoma, pleural mesothelioma, and metastatic non-small cell lung cancer. A phase 2 trial in PAC demonstrated the safety and preliminary efficacy of TTFields therapy with gemcitabine with or without nab-paclitaxel. We report final data from PANOVA-3 (NCT03377491), the largest global, phase 3, randomized, open-label trial in LA-PAC to date. Methods: Adult patients with newly diagnosed unresectable LA-PAC were randomized 1:1 to receive TTFields therapy (150 kHz) with gemcitabine/nab-paclitaxel (GnP) or GnP. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), local PFS, objective response rate (ORR), and pain-free survival. Distant PFS (metastases beyond the pancreas and regional lymph nodes) was assessed post hoc. Survival data were compared using the Kaplan-Meier method and a log-rank test. Results: 571 patients were randomized. Baseline characteristics were generally well balanced between the study arms. OS was significantly longer with TTFields/GnP than with GnP (median 16.2 [95% CI: 15.0, 18.0] vs 14.2 months [95% CI: 12.8, 15.4]; HR 0.82 [95% CI: 0.68, 0.99], p=0.039). One-year survival rate was also significantly improved with TTFields/GnP vs GnP (68.1% [95% CI: 62.0-73.5] vs 60.2% [95% CI: 54.2-65.7], p=0.029). There was no significant difference in PFS or local PFS between arms. Pain-free survival was significantly longer with TTFields/GnP vs GnP (median 15.2 [95% CI: 10.3, 22.8] vs 9.1 months [95% CI: 7.4, 12.7]; HR 0.74 [95% CI: 0.56, 0.97], p=0.027). Post-hoc analysis showed significant distant PFS benefit (median 13.9 [95% CI: 12.2, 16.8] vs 11.5 months [95% CI: 10.4, 12.9], HR 0.74 [95% CI: 0.57, 0.96], p=0.022) with TTFields/GnP vs GnP. ORR was similar between arms (36.1% [95% CI: 30.0, 42.4] vs 30.0% [95% CI: 24.3, 36.2], p=0.094). 97.8% and 98.9% of patients who received TTFields/GnP and GnP, respectively, had adverse events (AEs) and 88.6% and 84.3% had grade ≥3 AEs. The most frequent grade ≥3 AEs were neutropenia (47.8% and 47.6%) and anemia (21.9% and 22.3). 81% of patients receiving TTFields/GnP had device-related AEs, mostly grade 1/2 skin AEs, e.g., dermatitis (27.7%), rash (17.5%), and pruritus (15.0%); grade 3 and grade 4 device-related AEs occurred in 9.1% and 0.4% of patients, respectively. Conclusions: PANOVA-3 is the largest phase 3 trial exclusively performed in patients with LA-PAC and the first to show a statistically significant OS benefit. With no additive systemic toxicity and a statistically significant pain-free survival benefit, TTFields therapy is a potential new standard treatment for LA-PAC. Clinical trial information: NCT03377491 .

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

Background: When missing data are present in clinical outcomes studies, complete-case analysis (CCA) is often performed, whereby patients with missing data are excluded. While simple, CCA analysis may impart selection bias and reduce statistical power, leading to erroneous statistical results in some cases. However, there exist more rigorous statistical approaches, such as single and multiple imputation, which approximate the associations that would have been present in a full dataset and preserve the study’s power. The purpose of this study is to evaluate how statistical results differ when performed after CCA analysis versus imputation methods. Methods: This simulation study analyzed a sample dataset consisting of 2204 shoulders, with complete datapoints from a larger multicenter total shoulder arthroplasty database. From the sampled dataset of demographics, surgical characteristics, and clinical outcomes, we created five test datasets, ranging from 100 to 2000 shoulders, and simulated 10–50% missingness in the postoperative American Shoulder and Elbow Surgeons (ASES) score and range of motion in four planes in missing completely at random (MCAR), missing at random (MAR), and not missing at random (NMAR) patterns. Missingness in outcomes was remedied using CCA, three single imputation techniques, and two multiple imputation techniques. The imputation performance was evaluated relative to the native complete dataset using the root mean squared error (RMSE) and the mean absolute percentage error (MAPE). We also compared the mean and standard deviation (SD) of the postoperative ASES score and the results of multivariable linear and logistic regression to understand the effects of imputation on the study results. Results: The average overall RMSE and MAPE were similar for MCAR (22.6 and 27.2%) and MAR (19.2 and 17.7%) missingness patterns, but were substantially poorer for NMAR (37.5 and 79.2%); the sample size and the percentage of data missingness minimally affected RMSE and MAPE. Aggregated mean postoperative ASES scores were within 5% of the true value when missing data were remedied with CCA, and all candidate imputation methods for nearly all ranges of sample size and data missingness when data were MCAR or MAR, but not when data were NMAR. When data were MAR, CCA resulted in overestimates of the SD. When data were MCAR or MAR, the accuracy of the regression estimate (β or OR) and its corresponding 95% CI varied substantially based on the sample size and proportion of missing data for multivariable linear regression, but not logistic regression. When data were MAR, the width of the 95% CI was up to 300% larger when CCA was used, whereas most imputation methods maintained the width of the 95% CI within 50% of the true value. Single imputation with k-nearest neighbor (kNN) method and multiple imputation with predictive mean matching (MICE-PMM) best-reproduced point estimates and intervariable relationships resembling the native dataset. Availability of correlated outcome scores improved the RMSE, MAPE, accuracy of the mean postoperative ASES score, and multivariable linear regression model estimates. Conclusions: Complete-case analysis can introduce selection bias when data are MAR, and it results in loss of statistical power, resulting in loss of precision (i.e., expansion of the 95% CI) and predisposition to false-negative findings. Our data demonstrate that imputation can reliably reproduce missing clinical data and generate accurate population estimates that closely resemble results derived from native primary shoulder arthroplasty datasets (i.e., prior to simulated data missingness). Further study of the use of imputation in clinical database research is critical, as the use of CCA may lead to different conclusions in comparison to more rigorous imputation approaches.