American Society for Gastrointestinal Endoscopy guideline on endoscopic submucosal dissection for the management of early esophageal and gastric cancers: methodology and review of evidence.

This document from the American Society for Gastrointestinal Endoscopy (ASGE) provides a full description of the methodology used in the review of the evidence used to inform the final guidance outlined in the accompanying Summary and Recommendations document regarding the role of endoscopic submucosal dissection (ESD) in the management of early esophageal and gastric cancers. This guideline used the Grading of Recommendations, Assessment, Development and Evaluation framework and specifically addresses the role of ESD versus EMR and/or surgery, where applicable, for the management of early esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric adenocarcinoma (GAC) and their corresponding precursor lesions. For ESCC, the ASGE suggests ESD over EMR for patients with early-stage, well-differentiated, nonulcerated cancer >15 mm, whereas in patients with similar lesions ≤15 mm, the ASGE suggests either ESD or EMR. The ASGE suggests against surgery for such patients with ESCC, whenever possible. For EAC, the ASGE suggests ESD over EMR for patients with early-stage, well-differentiated, nonulcerated cancer >20 mm, whereas in patients with similar lesions measuring ≤20 mm, the ASGE suggests either ESD or EMR. For GAC, the ASGE suggests ESD over EMR for patients with early-stage, well or moderately differentiated, nonulcerated intestinal type cancer measuring 20 to 30 mm, whereas for patients with similar lesions <20 mm, the ASGE suggests either ESD or EMR. The ASGE suggests against surgery for patients with such lesions measuring ≤30 mm, whereas for lesions that are poorly differentiated, regardless of size, the ASGE suggests surgical evaluation over endosic approaches.

American Society for Gastrointestinal Endoscopy guideline on endoscopic submucosal dissection for the management of early esophageal and gastric cancers: summary and recommendations.

This clinical practice guideline from the American Society for Gastrointestinal Endoscopy (ASGE) provides an evidence-based summary and recommendations regarding the role of endoscopic submucosal dissection (ESD) in the management of early esophageal and gastric cancers. It is accompanied by the document subtitled "Methodology and Review of Evidence," which provides a detailed account of the methodology used for the evidence review. This guideline was developed using the Grading of Recommendations, Assessment, Development and Evaluation framework and specifically addresses the role of ESD versus EMR and/or surgery, where applicable, for the management of early esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric adenocarcinoma (GAC) and their corresponding precursor lesions. For ESCC, the ASGE suggests ESD over EMR for patients with early-stage, well-differentiated, nonulcerated cancer >15 mm, whereas in patients with similar lesions ≤15 mm, the ASGE suggests either ESD or EMR. The ASGE suggests against surgery for such patients with ESCC, whenever possible. For EAC, the ASGE suggests ESD over EMR for patients with early-stage, well-differentiated, nonulcerated cancer >20 mm, whereas in patients with similar lesions measuring ≤20 mm, the ASGE suggests either ESD or EMR. For GAC, the ASGE suggests ESD over EMR for patients with early-stage, well- or moderately differentiated, nonulcerated intestinal type cancer measuring 20 to 30 mm, whereas for patients with similar lesions <20 mm, the ASGE suggests either ESD or EMR. The ASGE suggests against surgery for patients with such lesions measuring ≤30 mm, whereas for lesions that are poorly differentiated, regardless of size, we suggest surgical evaluation over endoscopic approaches.

Features of endoscopic procedure site reaction associated with a recently approved submucosal lifting agent.

Endoscopic resection techniques, such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), are frequently aided by injection of submucosal lifting solutions that create a plane for dissection and protect deeper mural layers. ORISE™ gel is a recently approved synthetic lifting solution that produces a localized inflammatory reaction associated with retained gel at the injection site. We describe a series of six cases of ORISE™-associated inflammatory lesions in patients who underwent endoscopic resections. Deposits comprised pale fibrillary or hyalinized eosinophilic material, depending on their age. All cases were associated with an inflammatory reaction composed of foreign-body giant cells and scattered eosinophils. ORISE™ gel extended laterally and deeply beyond residual tumors in all cases. Histochemically, the material proved to be negative for Congo Red, and mucicarmine, faint blue with Alcian blue, but positive for PAS and PAS-D. It stained blue with trichrome. Such deposits were absent in cases, wherein other widely-available lifting solutions were used. We compared ORISE™ deposits to histologically similar extracellular deposits, namely amyloid and pulse granulomata. Unlike ORISE™ material, amyloid deposits appear as waxy, more densely eosinophilic material, and stain positive with Congo Red. Amyloid demonstrated prominent intramucosal and perivascular distributions, features not seen in this series of ORISE™ deposits. Hyalinized pulse granulomata showed strong overlap with ORISE™ deposits, since they also comprise eosinophilic material associated with giant cell reaction. On the other hand, they form ribbons of glassy material in circumscribed lobules, unlike the ill-defined ORISE™ deposits. In summary, we describe the pathologic findings at injection sites in patients who underwent endoscopic procedures aided by the recently approved lifting agent, ORISE™. Pathologists should be aware of its appearance and associated reaction to avoid confusion with other common extracellular deposits seen in the gastrointestinal tract.

Smooth muscle tumors of the gastrointestinal tract: an analysis of prognostic features in 407 cases.

Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm2 for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P < 0.0001 for all features). Age, sex, and margin status were not significantly associated with progression (P = 0.23, 0.82, and 0.07, respectively). A risk assessment table was created based on tumor site, size, and mitotic count, and Kaplan-Meier plots of progression-free survival for each subgroup revealed progression-based tiers. Based on our findings, it appears that nonesophageal gastrointestinal smooth muscle tumors measuring >10 cm and/or showing ≥3 mitoses/5 mm2 may behave aggressively, and therefore close clinical follow-up is recommended in these cases.

Smooth Muscle Tumors of the Visceral Adnexal and Uterine Ligaments and Adnexal Connective Tissue: A Clinicopathologic Study of 67 Cases.

The endopelvic fascia is a biomechanical network of supportive tissue that suspends and secures the female reproductive organs to the pelvic sidewall. Several visceral adnexal and uterine ligaments are part of this framework, and we have observed that smooth muscle tumors (SMTs) arising from these structures morphologically resemble gynecologic smooth muscle neoplasms. To determine whether gynecologic smooth muscle tumor criteria for malignancy are valid in these tumors, we evaluated the morphologic features of 67 tumors from 67 patients and correlated our findings with patient outcome. Using current uterine SMT WHO definitions, 57 tumors (85%) were classified as leiomyoma, 2 (3%) as smooth muscle tumor of uncertain malignant potential (STUMP), and 8 (12%) as leiomyosarcoma. Clinical follow-up was available for 88% of patients (range: 1-296 mo, mean: 174 mo, median: 79 mo). Only 1 case of leiomyosarcoma had metastasis at time of presentation, but 6 of 8 (75%) patients eventually died of disease. The other 2 cases of leiomyosarcoma that have not recurred are 11 and 16 mo from initial diagnosis. No cases of STUMP or leiomyoma recurred. On the basis of morphologic features and patient outcome, we believe these tumors distribute into similar categories of leiomyoma, STUMP and leiomyosarcoma, paralleling the biologic potential of uterine SMTs as well as SMTs of other gynecologic sites. We propose use of uterine WHO SMT criteria to classify spindled SMTs that arise in the visceral adnexal and uterine ligaments and adnexal connective tissue.

Tissue-based multigene expression tests for pretreatment prostate cancer risk assessment: current status and future perspectives.

Prostate cancer is a highly prevalent disease with ample spectrum of aggressiveness and treatment options. Low-risk disease can be safely managed by nonintervention strategies, such as active surveillance; however, accurate risk assessment is warranted. Molecular tests have been developed and validated to complement standard clinicopathological parameters and help to improve risk stratification in prostate cancer. Herein, we review selected tissue-based assays, including genomic prostate score, cell cycle progression score and genomic classifier, with particular emphasis on their role in patient risk assessment in a pretreatment setting, in view of their current or potential utilization in active surveillance.

PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'.

AIMS: PD-1 inhibitors facilitate immune response against certain tumour types, including melanoma. These drugs have led to prolonged survival but can also result in autoimmune-type side effects, including gastrointestinal inflammation. The histopathological effects of this medication class have not been well studied. METHODS AND RESULTS: We identified 37 gastrointestinal tract biopsies from 20 patients taking a PD-1 or PD-L1 inhibitor and evaluated clinicopathological findings. Diarrhoea was the most common symptom, and endoscopic findings ranged from mild erythema to erosion/ulceration. Common histological findings included lamina propria expansion, villous blunting (if applicable), intra-epithelial neutrophils and increased crypt/gland apoptosis, although intra-epithelial lymphocytes were rarely prominent. A few cases showed crypt rupture with resultant histiocytic/granulomatous response. Most patients responded to drug cessation and/or steroids, but follow-up endoscopies were not performed. CONCLUSIONS: PD-1/PD-L1 inhibitors can cause gastritis, enteritis and colitis, similar to other immunomodulatory antibodies (such as CTLA-4 inhibitors and PI3Kδ inhibitors), but the histological findings vary somewhat among drug classes. Clinical history, lack of prominent intra-epithelial lymphocytes and crypt rupture may help to distinguish PD-1 inhibitor gastroenterocolitis from mimics, which include other medication effect, inflammatory bowel disease, graft-versus-host disease, cytomegalovirus infection and autoimmune enteropathy.

Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases.

AIMS: Massive gastric polyposis is a rare entity that is often associated with juvenile polyposis syndrome (JPS). The aim of this study was to evaluate the clinicopathological features of 22 patients with abundant gastric juvenile-type or hyperplastic-like polyps. METHODS AND RESULTS: The study included 12 males and 10 females with a median age of 48 years (range: 13-79 years). Fourteen (64%) patients carried a diagnosis of JPS, and three had prior gastrointestinal adenocarcinomas. Patients without known JPS presented at an older median age (60 years versus 40 years; P = 0.0068). Clinical symptoms included nausea, vomiting, and abdominal pain; 23% of patients were asymptomatic. Eighteen cases showed complete or near-complete carpeting of the gastric mucosa by innumerable polyps, ranging from a few millimetres to ~100 mm. Most polyps formed long, bulbous projections and had characteristic histological features, including a smooth outer contour, prominent stromal oedema, and widely spaced, often cystically dilated glands lined by foveolar epithelium; some polyps had less stroma and more hyperplastic foveolar epithelium. All had normal underlying or adjacent mucosa. Four (18%) cases harboured adenocarcinoma, and seven (32%) others showed dysplasia. SMAD4 immunohistochemical staining showed patchy loss in polyps from 19 of 20 cases tested. Five of six (84%) patients tested had a germline SMAD4 mutation. CONCLUSIONS: Massive gastric juvenile-type polyposis can occur in patients with and without known JPS, and may mimic different conditions, such as other polyposis syndromes and Ménétrier disease. Pathologists play an important role in disease classification, as some patients lack a family or personal history of JPS, have few if any colonic polyps, and may not harbour diagnostic germline mutations.

TYMS promotes genomic instability and tumor progression in Ink4a/Arf null background.

We previously showed that elevated TYMS exhibits oncogenic properties and promotes tumorigenesis after a long latency, suggesting cooperation with sequential somatic mutations. Here we report the cooperation of ectopic expression of human TYMS with loss of Ink4a/Arf, one of the most commonly mutated somatic events in human cancer. Using an hTS/Ink4a/Arf -/- genetically engineered mouse model we showed that deregulated TYMS expression in Ink4a/Arf null background accelerates tumorigenesis and metastasis. In addition, tumors from TYMS-expressing mice were associated with a phenotype of genomic instability including enhanced double strand DNA damage, aneuploidy and loss of G1/S checkpoint. Downregulation of TYMS in vitro decreased cell proliferation and sensitized tumor cells to antimetabolite chemotherapy. In addition, depletion of TYMS in vivo by TYMS shRNA reduced tumor incidence, delayed tumor progression and prolonged survival in hTS/Ink4a/Arf -/- mice. Our data shows that activation of TYMS in Ink4a/Arf null background enhances uncontrolled cell proliferation and tumor growth, supporting the development of new agents and strategies targeting TYMS to delay tumorigenesis and prolong survival.

Lobular capillary hemangioma (pyogenic granuloma) of the gastrointestinal tract: Clinicopathologic analysis of 34 cases.

OBJECTIVES: Lobular capillary hemangioma (LCH) rarely involves the gastrointestinal (GI) tract. This study describes clinicopathologic features of LCH in a cohort of GI cases. METHODS: We defined lobular capillary hemangioma as "a proliferation of capillary-sized blood vessels arranged at least focally in a lobular configuration," searched departmental archives for cases, and recorded clinicopathologic findings. RESULTS: We identified 34 GI tract LCHs from 16 men and 10 women; 4 patients had multiple lesions. Mean age was 64 years. Cases arose in the esophagus (n = 7), stomach (n = 3), small bowel (n = 7), and colorectum (n = 17). Twelve patients had anemia or rectal bleeding. No patients had a known genetic syndrome. The lesions manifested as mucosal polyps, with median size of 1.3 cm. Microscopically, 20 lesions were ulcerated, and most involved the mucosa, with 9 extending into the submucosa. Vessel dilation was present in 27 patients, endothelial hobnailing in 13, hemorrhage in 13, and focal reactive stromal atypia in 2. Follow-up information was available for 10 patients, none of whom developed same-site recurrence. Six of the 26 cases (23%) were extradepartmental consultations, including 2 of the multifocal cases. CONCLUSIONS: Gastrointestinal tract LCHs often arise as colorectal polyps. They are typically small but can reach a few centimeters in size and can be multifocal.

Effects of Clinical and Tumor Characteristics on Survival in Patients with Hepatocellular Carcinoma with Bone Metastasis.

Background: Advanced hepatocellular carcinoma (HCC) generally has a dismal prognosis. Bone metastases from HCC are infrequent, with a poorer prognosis. However, the survival influencing factors are not yet well understood. Aim: The aim of the present study was to assess the clinical features and tumor characteristics of HCC patients with bone metastasis. Methods: A cohort of 170,576 adult patients with HCC was studied using the National Cancer Database (NCDB) spanning from 2010 to 2019, and within this group, 5285 patients (3.1%) were diagnosed with bone metastasis. We performed the Kaplan-Meier method to calculate the median overall survival (OS). We included demographics (age at diagnosis, gender, race, insurance status), comorbidity score, and treatment characteristics. Results: Of a total of 5285 HCC patients with bone metastasis, 86.2% were male and 61.2% were non-Hispanic white. Most patients (55.1%) were below 65, and 89% had a total Charlson-Deyo comorbidity score of under 3. Among patients with known tumor grade, 24.8% had well-differentiated tumors, and 36.1% had poorly differentiated tumors. Chemotherapy was administrated to 39.5% of patients. In univariate analysis, patients with well-differentiated tumors had better OS compared to poorly differentiated tumors (5.4 months vs 3.0 months, p = 0.001). Patients who received single or multiagent chemotherapy were significantly associated with improved OS compared to patients who did not receive chemotherapy (7.0 and 8.5 months vs 1.94 months, respectively). We also found mortality difference between age, comorbidity scores, facility types and race groups. Conclusion: In this cohort analysis of NCDB data, we found better OS in treatment receipt, lower tumor grade, younger age, non-Hispanic Black and Hispanic race, treatment at academic facility and lower comorbidity score in HCC patients with bone metastasis. The study results may have a consequential impact on the treatment decisions for HCC patients with bone metastasis.

Vehicle Control as a Measure of Real-World Driving Performance in Patients With Rheumatoid Arthritis.

OBJECTIVE: To quantify vehicle control as a metric of automobile driving performance in patients with rheumatoid arthritis (RA). METHODS: Naturalistic driving assessments were completed in patients with active RA and controls without disease. Data were collected using in-car, sensor-based instrumentation installed in the participants' own vehicles to observe typical driving habits. RA disease status, disease activity, and functional status were associated with vehicle control (lateral [steering] and longitudinal [braking/accelerating] acceleration variability) using mixed-effect linear regression models stratified by road type (defined by roadway speed limit). RESULTS: Across 1,292 driving hours, RA drivers (n = 33) demonstrated differences in vehicle control compared to controls (n = 23), with evidence of significant statistical interaction between disease status and road type (P < 0.001). On residential roads, participants with RA demonstrated overall lower braking/accelerating variability than controls (P ≤ 0.004) and, when disease activity was low, lower steering variability (P = 0.03). On interstates/highways, RA was associated with increased steering variability among those with moderate/high Clinical Disease Activity Index scores (P = 0.04). In models limited to RA, increases in disease activity and physical disability over 12 weeks of observation were associated with a significant increase in braking/accelerating variability on interstate/highways (both P < 0.05). CONCLUSION: Using novel naturalistic assessments, we linked RA and worsening RA disease severity with aberrant vehicle control. These findings support the need for further research to map these observed patterns in vehicle control to metrics of driver risk and, in turn, to link patterns of real-world driving behavior to diagnosis and disease activity.

Impact of Institutional Universal Microsatellite-Instability (MSI) Reflex Testing on Molecular Profiling Differences Between Younger and Older Patients with Colorectal Cancer.

INTRODUCTION: DNA mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC) is found in about 15% of early-stage diseases and 5% of metastatic diseases. We reviewed a large, single-institutional database after implementation of universal reflex dMMR/MSI-H testing in CRC to compare profiles of younger (≤50) and older (>50) patients. PATIENTS AND METHODS: Between 2009 and 2017, all patients diagnosed with CRC at the University of Florida underwent reflex somatic tumor testing for dMMR by immunohistochemistry (MLH1, PMS2, MSH2, MSH6), MSI by PCR, and Next-Generation Sequencing. Statistical analysis was conducted with 2-sample comparison tests and logistic regression models. RESULTS: There were 375 patients included in the final analysis. Patients were grouped as younger (ages ≤50 years-old; n = 80) or older (>50 years-old; n = 295). Compared to tumors from older patients, tumors from younger patients were less likely to be dMMR/MSI-H (12.5% vs. 21.4%, P = .013) and less likely to have a BRAF mutation (1.5% vs. 16.1%, P = .002). BRAF mutation status was highly associated with MMR status; BRAF-mutated tumors were 29.7 times more likely than BRAF-WT tumors to be dMMR/MSI-H (P = < .001, 95% CI 11.3-78.3). CONCLUSIONS: Tumors of younger patients were less likely than tumors of older patients to have a dMMR/MSI-H or BRAF mutation. Universal MMR/MSI testing in our dataset identified a relatively large population of older patients with sporadic CRC who were eligible for immunotherapy.

First-in-class multifunctional TYMS nonclassical antifolate inhibitor with potent in vivo activity that prolongs survival.

Although thymidylate synthase (TYMS) inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance, limiting overall benefit. Here we report a small molecule TYMS inhibitor that i) exhibited enhanced antitumor activity as compared with current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) is structurally distinct from classical antifolates, iii) extended survival in both pancreatic xenograft tumor models and an hTS/Ink4a/Arf null genetically engineered mouse tumor model, and iv) is well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we verify the compound is a multifunctional nonclassical antifolate, and using a series of analogs, we identify structural features allowing direct TYMS inhibition while maintaining the ability to inhibit dihydrofolate reductase. Collectively, this work identifies nonclassical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile, highlighting the potential for enhanced cancer therapy.

Coadministration of Immunosuppressant Treatments With Pegloticase in the Context of Solid-Organ Transplantation and Gout: A Case Report.

Refractory gout can be treated with infusions of pegloticase, which metabolizes uric acid into a product readily excreted in urine. Antidrug antibodies often develop, leading to reduced efficacy and potential infusion reactions. The concomitant administration of immunosuppressive agents has been suggested as a means of mitigating the effects of drug-related immunogenicity, rendering treatment more tolerable, and resulting in better outcomes. This report presents cases of 2 patients with tophaceous gout, each having previously undergone a solid-organ transplant, each taking immunosuppressants to prevent organ rejection, and each successfully treated with pegloticase. Although data from randomized controlled studies are needed, these cases suggest that it may be beneficial to coadminister an immunosuppressive medication to extend drug persistence with pegloticase in the management of refractory gout. This approach could allow patients to receive long-term treatment, resulting in improved patient outcomes.

Gastrointestinal Tract Injury by Yttrium-90 Appears Largely Restricted to Resin Microspheres But Can Occur Years After Embolization.

Radioembolization therapy utilizes yttrium-90 (Y90) impregnated resin (SIR-Spheres) or glass (TheraSpheres) microspheres to selectively target hepatic lesions via transarterial radioembolization. Occasional cases of gastrointestinal tract injury, secondary to nontargeted delivery of microspheres, have been reported, but large descriptive pathology series are lacking. We identified 20 cases of histologically confirmed mucosal injury associated with Y90 from 17 patients and assessed the corresponding clinical and pathologic sequelae. The mucosal biopsies were obtained from 1 to 88 months following Y90 therapy (median: 5 mo). Most cases were gastric (17, 85%), while the remaining were duodenal. Endoscopic ulceration was seen in the majority of cases (16, 80%), and mucosal erythema in the remaining 4. Histologically, a majority (19, 95%) of cases showed rounded, dark blue to purple microspheres measuring 4 to 30 µm, consistent with resin microspheres. A single case with glass microspheres demonstrated 26 µm translucent beads. Histologic evidence of ulceration was appreciated in 14 (70%) cases, and the microspheres were clearly intravascular in 6 (30%). A foreign body giant cell reaction to the microspheres was uncommon (3 cases, 15%). We additionally performed a retrospective review of all gastrointestinal tissue obtained postprocedure from 784 sequential patients treated with Y90 microspheres. Three patients (0.4%) demonstrated the presence of resin microspheres upon histologic examination. No cases involving glass-based Y90 were identified ( P =0.0078), despite the majority of patients having received glass radioembolization (630, 80%). This increased risk of secondary sphere dissemination is likely related to the increased number of particles required per activity for resin versus glass microspheres. We conclude that Y90 microspheres may be encountered in the gastrointestinal tract years after initial liver-targeted therapy and, when present, are often associated with mucosal ulceration. This finding is less likely to be encountered in patients who received Y90 radioembolization utilizing glass microspheres.

Thymidylate synthase accelerates Men1-mediated pancreatic tumor progression and reduces survival.

Clinical studies of cancer patients have shown that overexpression or amplification of thymidylate synthase (TS) correlates with a worse clinical outcome. We previously showed that elevated TS exhibits properties of an oncogene and promotes pancreatic neuroendocrine tumors (PanNETs) with a long latency. To study the causal impact of elevated TS levels in PanNETs, we generated a mouse model with elevated human TS (hTS) and conditional inactivation of the Men1 gene in pancreatic islet cells (hTS/Men1-/-). We demonstrated that increased hTS expression was associated with earlier tumor onset and accelerated PanNET development in comparison with control Men1-/- and Men1+/ΔN3-8 mice. We also observed a decrease in overall survival of hTS/Men1+/- and hTS/Men1-/- mice as compared with control mice. We showed that elevated hTS in Men1-deleted tumor cells enhanced cell proliferation, deregulated cell cycle kinetics, and was associated with a higher frequency of somatic mutations, DNA damage, and genomic instability. In addition, we analyzed the survival of 88 patients with PanNETs and observed that high TS protein expression independently predicted worse clinical outcomes. In summary, elevated hTS directly participates in promoting PanNET tumorigenesis with reduced survival in Men1-mutant background. This work will refocus attention on new strategies to inhibit TS activity for PanNET treatment.

Disseminated genitourinary histoplasmosis in a patient with AIDS with negative urine antigen testing.

Disseminated histoplasmosis is a life-threatening condition in immunocompromised patients. The majority of healthy persons have benign disease not requiring treatment. However, in persons living with HIV, mortality is high and accurate diagnosis is paramount. We present a case of a 48-year-old HIV-positive woman who presented with haematuria and flank pain. She had a history of recurrent urinary tract infection and nephrolithiasis with obstructive hydronephrosis. During cystoscopy, a bladder lesion was found. Pathological evaluation demonstrated abundant intracellular organisms with apparent budding. Subsequent urine histoplasma antigen was negative. Given the high index of suspicion for histoplasmosis based on the surgical pathology findings and epidemiological history, the patient was started immediately on antifungal therapy. One week later, PCR results of the bladder lesion confirmed the presence of Histoplasma capsulatum This case highlights a rare presentation of genitourinary histoplasmosis and the utility of surgical pathology evaluation and PCR for diagnosis.