Citations

INTRODUCTION: Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis. Barrett's esophagus (BE) is a critical precursor of EAC. Patients with BE undergo endoscopic surveillance to monitor disease progression although only a small fraction develop EAC. These procedures are invasive and have limited accuracy in predicting BE progression. We evaluated the utility of an 8-protein mass spectrometry panel in predicting progression in patients with BE. METHODS: Eighty untreated controls and 20 cases were selected from our institutional tissue registry. Quantitative mass-spectrometry was performed on microdissected tissue sections. Data were split into 80% training and 20% test sets. We used Least Absolute Shrinkage and Selection Operator-regularized regression to train a logistic classifier on training data. Classifier performance was evaluated in test data. RESULTS: Ninety-two samples had sufficient tissue for mass spectrometry analysis (18 progressors, 74 nonprogressors). The multivariable regression model produced a sensitivity of 100% and a specificity of 39% in the overall cohort, with AUCs of 0.75 and 0.89 in the overall and test cohorts, respectively. Cox proportional hazards time-to-progression (TTP) showed a hazard ratio of 66.1 (95% CI 7.79–561, P = 0.00012) for the model prediction. DISCUSSION: The promising performance of the model generated here suggests that the test may aid in selecting patients most likely to benefit from active BE surveillance. Moreover, the association of this model's prediction with time-to-progression may offer decision support for management of patients likely to progress quickly. These results support continued development of this proteomic panel as a risk stratification tool for patients with BE.

Abstract Isatuximab is an immunoglobulin G1κ monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells. Anti-CD38 antibodies have shown efficacy as monotherapy and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. This multicenter, cooperative group phase 2 trial was designed to evaluate hematologic response, organ response, and safety of isatuximab monotherapy for the treatment of relapsed AL amyloidosis. Isatuximab at 20 mg/kg was administered IV weekly during the first 28-day cycle, and then every other week during cycles 2 to 24. Forty-three patients were registered, with 35 patients being evaluable for response. The overall hematologic response rate was 77.1%, with 57% of patients achieving a very good partial response (VGPR) or better. The median time to partial response (PR) or better was 1.1 months. Renal response occurred in 50% (7/14) of patients with renal involvement, and cardiac response occurred in 57% (8/14) of patients who were evaluable utilizing N-terminal pro b-type natriuretic peptide (NT-proBNP) with cardiac involvement. The most common treatment-related grade ≥3 adverse events included lymphopenia (n = 3, 8.5%) and infection (n = 2, 6%). Isatuximab demonstrated substantial efficacy in previously treated patients with AL amyloidosis, and was associated with a good safety profile. This trial was registered at www.clinicaltrials.gov as #NCT03499808.

Abstract Objective The aim of this study was to evaluate a large cohort of gallbladder amyloid cases to determine clinical and morphologic features. Methods Cholecystectomy specimens (N = 118) typed using proteomics-based techniques between 2008 and 2023 were identified. Clinical and morphologic features were reviewed. Results Six amyloid types were identified: ATTR (n = 63, 53.4%), AL (n = 46, 39.0%), AA (n = 4, 3.4%), AApoA1 (n = 2, 1.7%), ALECT2 (n = 2, 1.7%), and AEFEMP1 (n = 1, 0.8%). Amyloidogenic mutations were detected in 3 ATTR cases and 2 AApoA1 cases. Morphologic review (n = 26) revealed perimuscular vessel involvement in all cases. Amyloidosis was an unexpected diagnosis first made on the cholecystectomy specimen in half of the patients with clinical information (n = 10). All 9 patients with follow-up had evidence of systemic disease. In 2 patients, cholecystic involvement was initially missed and only retrospectively identified after the diagnosis of cardiac amyloidosis. Conclusions In patients with clinical data, amyloidosis was often unexpected, the gallbladder was commonly the first tissue sampled with amyloidosis, and all patients had systemic disease. Thorough review of cholecystectomy specimens with careful inspection of perimuscular vessels, coupled with a low threshold for ordering Congo red stain in elderly individuals and amyloid typing using a robust method such as proteomics, can prevent a delay in amyloid diagnosis and management.

Abstract Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive forms of pancreatic cancer, is associated with poor survival outcomes and currently ranks as the third leading cause of cancer-related death in the United States. Despite its clinical significance, the mechanisms of PDAC development and progression remain, in part, poorly understood. In this study, we provide evidence of a novel role of sorting nexin 10 (SNX10), a member of the sorting nexin family, in the regulation of KRAS-induced pancreatic carcinogenesis. We demonstrate that SNX10 is downregulated in PDAC, especially in advanced cases. Furthermore, mutational analysis revealed SNX10 genetic alterations in PDAC cases. Functional studies demonstrated that SNX10 overexpression in human PDAC cells inhibited cell proliferation and colony formation. Moreover, SNX10 overexpression induced G1-phase cell-cycle arrest and decreased KRAS signaling activity. Using a novel Snx10 knockout mouse crossed with a Kras-driven PDAC model, we observed reduced survival, increased tumor cell proliferation, enhanced aggression, and heightened inflammation. Collectively, these findings highlight SNX10 as a tumor suppressor candidate in PDAC and underscore its promise as a foundation for new therapeutic approaches. Significance: SNX10 plays a crucial role in reducing pancreatic tumorigenesis. This discovery offers valuable insights into PDAC’s biology and the development of new effective treatments.

AimThe aim of this study was to compare the histopathologic features of MMF‐induced colitis and colonic GVHD and develop a digital tool using deep learning convolutional neural networks (CNNs) to semi‐automate the quantification of eosinophils.MethodsMMF and GVHD colitis cases were retrieved. A cohort of transplant patients who were at risk for developing GVHD and were on MMF at the time of biopsy was also identified. Cases were reviewed for histologic features and a deep learning CNN was trained to quantify lamina propria eosinophils. Clinical history was collected.ResultsNinety‐five patients were included in the study group: GVHD (n = 37), MMF (n = 25) and GVHD vs. MMF (n = 33). Within the GVHD vs. MMF group, one patient was thought to have definitive MMF colitis and one possible MMF colitis. The GVHD group had a significantly higher apoptotic count compared to the MMF group (median: 7 vs. 2, P = 0.03). Neuroendocrine aggregates were present in the GVHD (N = 12) and GVHD vs. MMF (N = 4) groups while absent in the MMF group. The MMF group had a higher semi‐quantitative eosinophil score and a higher automated eosinophil count as detected by the deep learning CNN (median eos/HPF: MMF 19.2, GVHD vs. MMF 3.6, GVHD 3.4, P < 0.001).ConclusionsLower eosinophil counts, higher apoptotic counts and neuroendocrine cell aggregates favour the diagnosis of GVHD. AI models for eosinophil quantification may serve as an ancillary tool for assessing this differential diagnosis. Given the rarity of MMF‐induced colitis in SCT patients, pathologists should have a high threshold for making this diagnosis in this population.

Background: Studies have suggested a synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a key target and master transcriptional factor regulating myeloma cell survival. Method: A 3 + 3 phase I trial was conducted to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least one prior line of therapy. Three dose levels (DLs) were planned. The cycle length was 28 days. IBR was administered orally daily in doses of 560 mg on DL1-2 and 840 mg on DL3, LEN was administered orally on days 1–21 in doses of 15 mg on DL1 and 25 mg on DL2-3, and DEX was administered orally on days 1, 8, 15, and 22 in a dose of 40 mg if age < 75 years or in a dose of 20 mg if it was ≥75 years for DL1-3. Patients with a glomerular filtration rate (GFR) <60 but ≥30 mL/min were treated in accordance with the manufacturer’s instructions with LEN 10 mg. Dose-limiting toxicities (DLTs) included the following: grade 4 neutropenia lasting more than 5 days, thrombocytopenia, febrile neutropenia, nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; and grade 3–4 hyperglycemia or a thrombotic/embolic event, and other nonhematologic toxicities. The overall response rate (ORR) was defined as the percentage of patients with a partial response (PR), very good partial response (VGPR), or complete response (CR) according to IMWG criteria on two consecutive evaluations at least 4 weeks apart. The clinical benefit rate (CBR) was defined as the percentage of patients with stable disease (SD) or a better outcome on two consecutive evaluations at weeks apart. Results: Fourteen patients (DL1: six patients; DL2: three patients; DL3: five patients) were registered for the study from March 2019 to May 2023, prior to its closure due to limited accrual. Thirteen patients are included in the summary of toxicities and response as one patient on DL3 halted participation prior to the start of the treatment. Two patients on DL3 were excluded from the determination of MTD: one having discontinued cycle 1 treatment due to COVID-19 infection and the another having mistakenly taken 280 mg/day of IBR instead of the assigned 840 mg/day dose during cycle 1. Only one patient developed a DLT, on DL1 with grade 3 non-viral hepatitis. The median number of cycles administered was 4 (range: 1–56). Severe toxicities reported included grade 4 lymphocytopenia (1), grade 4 thrombocytopenia (1), and grade 5 sepsis in the setting of PD (1). Disease responses included a VGPR on DL1 and CR on DL3. Thus, the ORR was 15.4% (90% CI: 2.8–41.0%). One patient on DL1 maintained SD for 4.6 years before discontinuing the treatment to undergo an alternative therapy. Another five patients maintained SD for ≥ 2 consecutive cycles. Thus, the CBR was 61.5% (90% CI: 35.5–83.4%). Conclusions: The combination of LEN with IBR in RR MM proved feasible, with manageable toxicities and the majority of discontinuations being due to disease progression.

For over a century, scientists reported the disruption of normal nuclear shape and size in cancer. These changes have long been used as tools for diagnosis and staging of malignancies. However, to date, the mechanisms underlying these aberrant nuclear phenotypes and their biological significance remain poorly understood. Using a model of pancreatic ductal adenocarcinoma (PDAC), the major histological subtypes of pancreatic cancer, we found that oncogenic mutant KRAS reduces nuclear size. Transcriptomic and protein expression analysis of mutant KRAS–expressing PDAC cells revealed differential levels of several nuclear envelope–associated genes. Further analysis demonstrated the nuclear lamina protein, Emerin (EMD), acted downstream of KRAS to mediate nuclear size reduction in PDAC. Analysis of human PDAC samples showed that increased EMD expression associates with reduced nuclear size. Finally, in vivo genetic depletion of EMD in a mutant KRAS–driven PDAC model resulted in increased nuclear size and a reduced incidence of poorly differentiated PDAC. Thus, our data provide evidence of a potentially novel mechanism underlying nuclear size regulation and its effect in PDAC carcinogenesis.

INTRODUCTION: The risk of progression to esophageal adenocarcinoma in Barrett's esophagus (BE) increases with advancing degrees of dysplasia. There is a critical need to improve the diagnosis of BE dysplasia, given substantial interobserver variability and overcalls of dysplasia during manual community pathologist reads. We aimed to externally validate a previously cross-validated BE dysplasia diagnosis deep learning model (BEDDLM) that predicts dysplasia grade on whole slide images (WSIs). METHODS: We digitized nondysplastic BE (NDBE), low-grade (LGD), and high-grade dysplasia (HGD) histology slides from 3 external academic centers. A consensus read by 2 expert study pathologists was used as the criterion standard. Slide stain characteristics were normalized using cycle-generative adversarial networks. WSIs were assessed by BEDDLM using an ensemble approach, combining a “You Only Look Once” model followed by a ResNet101 classifier model. RESULTS: We included 489 WSIs. Consensus histopathology revealed 232 NDBE, 117 LGD, and 140 HGD WSIs. The mean age (SD) was 66.9 (11.4) years; 413 (84.7%) were men. Using the BEDDLM ensemble model, sensitivity and specificity for NDBE were 73.3% (95% confidence interval [CI]: 67.09%–78.85%) and 93.4% (95% CI: 89.62%–96.10%); for LGD, 84.6% (95% CI: 76.78%–90.62%) and 80.6% (95% CI: 76.26%–84.54%); and for HGD, 80.7% (95% CI: 73.19%–86.89%) and 94.8% (95% CI: 91.97%–96.91%), respectively. The F1 score was 0.81, 0 0.69, and 0.83 for NDBE, LGD, and HGD, respectively. DISCUSSION: Our externally validated deep learning model demonstrates substantial accuracy for the diagnosis of BE dysplasia grade on WSIs.

Pediatric regional anesthesia offers significant benefits, yet its adoption faces barriers, including perceived overcomplexity. This study aimed to identify and establish a set of core, high-value, low-complexity nerve blocks to improve perioperative pain management in pediatric patients. A four-round modified Delphi consensus study was conducted with an international panel of pediatric and regional anesthesia experts. An initial long list of regional techniques was compiled by the Steering Committee and refined through iterative input. Panelists rated each technique on a 10-point Likert scale for importance. Consensus was defined as ≥75% of panelists assigning a mean importance score of ≥8. Techniques receiving 50%–74% agreement were categorized as having strong agreement and considered for inclusion. The final selection was confirmed through a virtual roundtable discussion. Thirty-three experts representing 12 pediatric and regional societies participated. Consensus was reached on six regional techniques, with strong agreement (*) on two additional techniques, identifying eight core pediatric regional anesthesia blocks: supraclavicular brachial plexus block, rectus sheath block, transverse abdominis plane block*, suprainguinal fascia iliaca block*, femoral nerve block, adductor canal block, popliteal sciatic nerve block, and landmark-based caudal block. This consensus-driven framework defines a core set of pediatric regional anesthesia techniques that balance clinical effectiveness, feasibility, and accessibility. These findings provide a practical entry point for practitioners looking to incorporate pediatric regional anesthesia into their practice, regardless of prior experience. Future efforts should focus on standardized training, implementation research, and policy initiatives to support widespread adoption and improve perioperative pain management in children globally.