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ImportanceIntraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can give rise to pancreatic cancer (PC). Limited population data exist on their prevalence, natural history, or risk of malignant transformation (IPMN-PC).ObjectiveTo fill knowledge gaps in epidemiology of IPMNs and associated PC risk by estimating population prevalence of IPMNs, associated PC risk, and proportion of IPMN-PC.Design, Setting, and Participants: This retrospective cohort study was conducted in Olmsted County, Minnesota. Using the Rochester Epidemiology Project (REP), patients aged 50 years and older with abdominal computed tomography (CT) scans between 2000 and 2015 were randomly selected (CT cohort). All patients from the REP with PC between 2000 and 2019 were also selected (PC cohort). Data were analyzed from November 2021 through August 2023.Main outcomes and MeasuresCIs for PC incidence estimates were calculated using exact methods with the Poisson distribution. Cox models were used to estimate age, sex, and stage–adjusted hazard ratios for time-to-event end points.ResultsThe CT cohort included 2114 patients (1140 females [53.9%]; mean [SD] age, 68.6 [12.1] years). IPMNs were identified in 231 patients (10.9%; 95% CI, 9.7%-12.3%), most of which were branch duct (210 branch-duct [90.9%], 16 main-duct [6.9%], and 5 mixed [2.2%] IPMNs). There were 5 Fukuoka high-risk (F-HR) IPMNs (2.2%), 39 worrisome (F-W) IPMNs (16.9%), and 187 negative (F-N) IPMNs (81.0%). After a median (IQR) follow-up of 12.0 (8.1-15.3) years, 4 patients developed PC (2 patients in F-HR and 2 patients in F-N groups). The PC incidence rate per 100 person years for F-HR IPMNs was 34.06 incidents (95% CI, 4.12-123.02 incidents) and not significantly different for patients with F-N IPMNs compared with patients without IPMNs (0.16 patients; 95% CI, 0.02-0.57 patients vs 0.11 patients; 95% CI, 0.06-0.17 patients; P = .62). The PC cohort included 320 patients (155 females [48.4%]; mean [SD] age, 72.0 [12.3] years), and 9.8% (95% CI, 7.0%-13.7%) had IPMN-PC. Compared with 284 patients with non-IPMN PC, 31 patients with IPMN-PC were older (mean [SD] age, 76.9 [9.2] vs 71.3 [12.5] years; P = .02) and more likely to undergo surgical resection (14 patients [45.2%] vs 60 patients [21.1%]; P = .003) and more-frequently had nonmetastatic PC at diagnosis (20 patients [64.5%] vs 130 patients [46.8%]; P = .047). Patients with IPMN-PC had better survival (adjusted hazard ratio, 0.62; 95% CI, 0.40-0.94; P = .03) than patients with non-IPMN PC.Conclusions and RelevanceIn this study, CTs identified IPMNs in approximately 10% of patients aged 50 years or older. PC risk in patients with F-N IPMNs was low and not different compared with patients without IPMNs; approximately 10% of patients with PC had IPMN-PC, and they had better survival compared with patients with non-IPMN PC.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

Background Studies during the COVID-19 pandemic have demonstrated an association between COVID-19 virus infection and the development of acute ischemic stroke, particularly large vessel occlusion (LVO). Studying the characteristics and immunohistochemistry of retrieved stroke emboli during mechanical thrombectomy for LVO may offer insights into the pathogenesis of LVO in COVID-19 patients. We examined retrieved COVID-19 emboli from the STRIP, EXCELLENT, and RESTORE registries and compared their characteristics to a control group. Methods We identified COVID-positive LVO patients from the STRIP, RESTORE, and EXCELLENT studies who underwent mechanical thrombectomy. These patients were matched to a control group controlling for stroke etiology based on Trial of Org 10172 in Acute Stroke Treatment criteria. All clots were stained with Martius Scarlet Blue (MSB) along with immunohistochemistry for interleukin-6 (IL-6), C-reactive protein (CRP), von Willebrand factor (vWF), CD66b, fibrinogen, and citrullinated Histone H3. Clot composition was compared between groups. Results Nineteen COVID-19-positive patients and 38 controls were included. COVID-19-positive patients had a significantly higher percentage of CRP and vWF. There was no difference in IL-6, fibrin, CD66b, or citrullinated Histone H3 between groups. Based on MSB staining, there was no statistically significant difference regarding the percentage of red blood cells, white blood cells, fibrin, and platelets. Conclusions Our study found higher concentrations of CRP and vWF in retrieved clots of COVID-19-positive stroke patients compared to COVID-19-negative controls. These findings support the potential role of systemic inflammation as indicated by elevated CRP and endothelial injury as indicated by elevated vWF as precipitating factors in thrombus development in these patients.

ABSTRACT The ninth American Society for Microbiology Conference on Biofilms was convened in-person on 13–17 November 2022 in Charlotte, NC. As the first of these conferences since prior to the start of the COVID-19 pandemic, the energy among the participants of the conference was clear, and the meeting was a tremendous success. The mixture of >330 oral and poster presentations resoundingly embodied the vitality of biofilm research across a wide range of topics and multiple scientific disciplines. Special activities, including a pre-conference symposium for early career researchers, further enhanced the attendee experience. As a general theme, the conference was deliberately structured to provide high levels of participation and engagement among early career scientists.

Abstract Autoimmune gastritis is a relatively common but likely underdiagnosed form of chronic gastritis that is associated with iron-deficiency anemia as well as vitamin B12/cobalamin deficiency. This disease confers a 13-fold increased risk of gastric well-differentiated neuroendocrine tumors, due to persistently elevated gastrin levels, and a 3- to 7-fold increased risk of gastric adenocarcinoma. The case described here has a typical presentation of the disease, and the following review highlights key histologic features that aid in the identification of this inflammatory process. Additionally, background information on ancillary testing and mechanisms of disease are discussed with a focus on details most useful for the pathologist who is presented with the opportunity to make this often unexpected but medically significant diagnosis.

Abstract Background Carbapenem-resistant Acinetobacter baumannii (CRAb) is 1 of the most problematic antimicrobial-resistant bacteria. We sought to elucidate the international epidemiology and clinical impact of CRAb. Methods In a prospective observational cohort study, 842 hospitalized patients with a clinical CRAb culture were enrolled at 46 hospitals in five global regions between 2017 and 2019. The primary outcome was all-cause mortality at 30 days from the index culture. The strains underwent whole-genome analysis. Results Of 842 cases, 536 (64%) represented infection. By 30 days, 128 (24%) of the infected patients died, ranging from 1 (6%) of 18 in Australia-Singapore to 54 (25%) of 216 in the United States and 24 (49%) of 49 in South-Central America, whereas 42 (14%) of non-infected patients died. Bacteremia was associated with a higher risk of death compared with other types of infection (40 [42%] of 96 vs 88 [20%] of 440). In a multivariable logistic regression analysis, bloodstream infection and higher age-adjusted Charlson comorbidity index were independently associated with 30-day mortality. Clonal group 2 (CG2) strains predominated except in South-Central America, ranging from 216 (59%) of 369 in the United States to 282 (97%) of 291 in China. Acquired carbapenemase genes were carried by 769 (91%) of the 842 isolates. CG2 strains were significantly associated with higher levels of meropenem resistance, yet non-CG2 cases were over-represented among the deaths compared with CG2 cases. Conclusions CRAb infection types and clinical outcomes differed significantly across regions. Although CG2 strains remained predominant, non-CG2 strains were associated with higher mortality. Clinical Trials Registration. NCT03646227.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)—histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63 -rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.