Salomao, Marcela

Abstract High-grade gliomas (HGGs) are aggressive tumors with poor outcomes and limited treatment options. Here, we combined genomic and transcriptomic tumor profiling with drug testing in a patient-derived 3-dimensional culture model to identify individualized treatments and predictive biomarkers. Activity of single agents targeting frequently dysregulated glioma pathways was relatively poor ex vivo and generally reflected historical patient data. However, compounds targeting PI3K, epigenetic, and survival/senescence signaling were effective in some cases. Drug sensitivity correlated with transcriptional rather than genomic features and suggested heterogeneity as a resistance mechanism. Bromodomain and extraterminal domain inhibition was particularly effective in tumors enriched in the mesenchymal transcriptional subtype, promoted proneural transition, and was overcome by upregulated PI3K signaling. Notably, combinations were largely effective, with 6 strategies exhibiting stronger efficacy than corresponding single agents in most cases (58-77%). This study identifies HGG vulnerabilities and associated biomarkers, resistance mechanisms, and effective combination strategies that warrant further clinical validation. Graphical Abstract

Introduction. Increased steatosis on preimplant liver frozen section is associated with delayed graft function and primary nonfunction. Efforts to standardize histologic assessment have proven difficult. Frozen section artifact and lipopeliosis complicate the detection of steatosis. We aimed to develop and validate an AI model to recognize large droplet fat and fat induced artifact (FIA)/lipopeliosis on preimplantation frozen section and to correlate the AI results with post-transplant clinical parameters. Methods. The model was applied to 161 consecutive liver transplant specimens with preimplant slides. Results were correlated with traditional and Banff histologic assessment and clinical parameters. Results. By traditional assessment, steatosis ranged from 0%–40%. The AI model identified a range of 0 to 15.9% steatosis. There was no difference in patient survival by any measures of steatosis. AI steatosis correlated with increased risk of early allograft dysfunction (OR = 1.63, P < .001), respiratory failure (OR = 1.21, P = .003), and more advanced fibrosis (OR = 1.18, P = .030), but was not correlated with graft or patient survival. FIA/lipopeliosis were identified in a range of 0 to 6.42%. In univariate analysis the percentage of FIA/lipopeliosis correlated with both graft and patient survival ( P = .044 and P = .009, respectively), but was not associated with increased risk of early allograft dysfunction, respiratory failure, or advanced fibrosis. Conclusions. We developed an AI model that quantitates large droplet fat and FIA/lipopeliosis on frozen section slides and found a correlation with post-transplant outcomes. Further studies on larger, multi-institutional cohorts with higher fat containing donors are necessary to determine the role this model may have in organ acceptance decisions.

ABSTRACT Capillary malformation-arteriovenous type 2 syndrome (CM-AVM2) is a rare, genetic vascular disorder associated with abnormal capillary malformations and arteriovenous malformations. We present a case of CM-AVM2 with refractory diarrhea and failure to thrive due to aberrant, telangiectatic capillaries, and subepithelial collagen deposition found throughout the GI tract on bidirectional endoscopy. The patient was recalcitrant to standard therapies, so bevacizumab was trialed, but the patient expired. This is the first case of CM-AVM2 with diffuse GI mucosal involvement resulting in malabsorption. There is no treatment for this pathology, but treatment with bevacizumab or a mammalian target of rapamycin inhibitor may be efficacious.

AimsInflammatory bowel disease (IBD)‐associated serrated lesions are categorized into three distinct subtypes: traditional serrated adenoma (TSA)‐like lesion, sessile serrated lesion (SSL)‐like lesion, and serrated lesion, not otherwise specified (NOS). Although the risk of neoplastic progression of serrated lesions without dysplasia has not been shown to exceed that of sporadic cases, the clinicopathologic features of the three serrated subtypes with dysplasia remain poorly understood in the context of IBD.Methods and ResultsWe analysed 87 serrated lesions with dysplasia (collectively referred to as serrated dysplasia) identified endoscopically in 58 IBD patients, including 51 (59%) TSA‐like dysplasia, 24 (28%) SSL‐like dysplasia, and 12 (14%) serrated dysplasia NOS. Inclusion criteria required all three serrated subtypes to show morphologic evidence of dysplasia and to be located within areas of colitis. We also compared the clinicopathologic features of serrated dysplasia with those of 239 conventional (adenomatous) dysplastic lesions from 149 IBD patients. The cohort included 39 (67%) men and 19 (33%) women, with a mean age of 54 years and a mean IBD duration of 20 years. Most patients had ulcerative colitis (n = 41; 71%) and pancolitis (n = 48; 83%). The majority of serrated lesions with dysplasia had a polypoid or visible endoscopic appearance (n = 73; 84%), with a mean size of 1.4 cm, and were found in the left colon (n = 66; 76%). Most lesions (n = 73; 84%) demonstrated low‐grade dysplasia at the time of biopsy diagnosis, whereas high‐grade dysplasia (HGD) was identified in the remaining 14 (16%) lesions. SSL‐like dysplasia was more frequently associated with ulcerative colitis (94%) compared to TSA‐like dysplasia (67%) and serrated dysplasia NOS (56%) (P = 0.042). Although only seven (12%) patients had a concurrent history of primary sclerosing cholangitis, it was exclusively identified in the TSA‐like dysplasia group (19% versus 0% in both the SSL‐like dysplasia group and the serrated dysplasia NOS group; P = 0.017). Serrated dysplasia NOS more commonly demonstrated HGD at the time of biopsy diagnosis (42%) compared to TSA‐like dysplasia (12%) and SSL‐like dysplasia (13%) (P = 0.022). Serrated dysplasia NOS was also more frequently associated with synchronous and/or metachronous nonconventional dysplasia (60%) compared to TSA‐like dysplasia (16%) and SSL‐like dysplasia (9%) (P = 0.037). Serrated dysplasia, regardless of subtype, was associated with high rates of advanced neoplasia (HGD or colorectal cancer) at the previous biopsy site or in the same colonic segment during follow‐up. Within a mean follow‐up time of 13 months, advanced neoplasia was detected in 50% of the TSA‐like dysplasia group, 67% of the SSL‐like dysplasia group, and 100% of the serrated dysplasia NOS group (P = 0.622). Moreover, at least one‐third of patients in each group (58% in the TSA‐like dysplasia group, 44% in the SSL‐like dysplasia group, and 33% in the serrated dysplasia NOS group; P = 0.332) developed synchronous/metachronous dysplasia, with at least 50% of these lesions progressing to advanced neoplasia within a mean follow‐up time of 11 months (P = 1.000). The serrated dysplasia group showed nearly six times the incidence of advanced neoplasia upon follow‐up (59%) compared to the conventional dysplasia group (10%) (P < 0.001).ConclusionTSA‐like dysplasia, SSL‐like dysplasia, and serrated dysplasia NOS show distinct clinicopathologic features. However, all three serrated subtypes were associated with high rates of advanced neoplasia (50%–100%) during follow‐up, suggesting that these lesions could potentially be combined into one diagnostic category, such as serrated dysplasia.

Context.— Gastrointestinal manifestations of Kaposi sarcoma are rare but may cause morbidity. Lower gastrointestinal involvement is particularly rare, and lesions may resemble conventional bowel polyps. Objective.— To study 15 patients who presented with lower gastrointestinal tract Kaposi sarcoma with polypoid architecture. Design.— The surgical pathology files of the departments of pathology at multiple institutions were searched for cases of Kaposi sarcoma forming polyps in the lower gastrointestinal tract (jejunum, colon, rectum); 15 cases with such features were identified. Clinicopathologic information was extracted from the medical record and documented by reviewing individual hematoxylin-eosin–stained slides. Results.— The patients were 13 men and 2 women aged 26–80 years (median = 44 years). Gastrointestinal tract involvement was multifocal in 11 cases and unifocal in 4. The tumors involved the rectum, rectosigmoid junction, cecum, ascending colon, transverse colon, and descending colon and presented as polypoid lesions measuring 0.2–2.1 cm. Six patients had upper gastrointestinal tract involvement in addition to lower gastrointestinal lesions. Histologically, the tumors were characterized in 6 cases by a dense spindle cell proliferation in the lamina propria; however, the remaining cases showed only a subtle fascicular spindle cell proliferation in the lamina propria that did not form an expansile mass. Conclusions.— Biopsies of gastrointestinal polyps showing absence of the common features of hyperplastic or adenomatous polyps, particularly in immunocompromised patients, should be carefully examined for the presence of a stromal spindle cell proliferation. Use of immunohistochemical stains, particularly human herpesvirus-8, can help in establishing the correct diagnosis.

The nonalcoholic steatohepatitis clinical research network (NASH-CRN) system is commonly used for histologic assessment of disease activity and fibrosis in NASH. Despite this, the system does not fully capture the range of disease activity and fibrosis. As such, an expanded NAS (E-NAS) grading and staging system with a calculated E-NAS index was developed by our group. In this follow up study, we aim to revalidate the E-NAS system and compare its reliability to existing systems. Hematoxylin and eosin and trichrome stained sections from 40 liver biopsies were reviewed digitally by four hepatopathologists and assessed using the NASH-CRN and E-NAS systems as well as a modified Ishak fibrosis stage. The pathologist's gestalt impression of disease activity and fibrosis was scored on a Visual Analogue Scale (VAS), which ranged from 0 (no activity/fibrosis) to 100 (the worst activity/fibrosis ever seen). Inter-rater reliability was assessed, and Spearman correlation coefficients were calculated. The E-NAS index had higher inter-rater agreement versus the NAS score (ICC 0.70 vs 0.61). The inter-rater agreement for ballooning in the E-NAS system was also higher at 0.67 compared to the NAS (ICC 0.60). ICCs for fibrosis were comparable between all the systems assessed (0.78 to 0.88). Finally, the calculated E-NAS index was higher with increasing stage of fibrosis compared to the NAS suggesting that it associates better with fibrosis. In summary, the E-NAS system demonstrates substantial inter-rater reliability as well as improved correlation with disease activity VAS and fibrosis compared to the NAS score.

Various subtypes of nonconventional dysplasia have been recently described in inflammatory bowel disease (IBD). We hypothesized that goblet cell deficient dysplasia and serrated dysplasia may be the primary precursor lesions for goblet cell deficient (GCDAC) and serrated (SAC) variants of colonic adenocarcinoma, respectively. Clinicopathologic features of 23 GCDAC and 10 SAC colectomy cases were analyzed. All dysplastic lesions found adjacent to the colorectal cancers (n = 22 for GCDACs and n = 10 for SACs) were subtyped as conventional, nonconventional, or mixed-type dysplasia. As controls, 12 IBD colectomy cases with well to moderately differentiated adenocarcinoma that lacked any mucinous, signet ring cell, low-grade tubuloglandular, or serrated features while retaining goblet cells throughout the tumor (at least 50% of the tumor) were evaluated. The cohort consisted of 19 (58%) men and 14 (42%) women, with a mean age of 53 years and a long history of IBD (mean duration: 18 y). Twenty-seven (82%) patients had ulcerative colitis. GCDACs (57%) were more often flat or invisible than SACs (10%) and controls (25%; P = 0.023). The GCDAC and SAC groups were more likely to show lymphovascular invasion (GCDAC group: 52%, SAC group: 50%, control group: 0%, P = 0.001) and lymph node metastasis (GCDAC group: 39%, SAC group: 50%, control group: 0%, P = 0.009) than the control group. Notably, GCDACs and SACs were more frequently associated with nonconventional dysplasia than controls (GCDAC group: 77%, SAC group: 40%, control group: 0%, P < 0.001). Goblet cell deficient dysplasia (73%) was the most prevalent dysplastic subtype associated with GCDACs (P = 0.049), whereas dysplasias featuring a serrated component (60%) were most often associated with SACs (P = 0.001). The GCDAC group (75%) had a higher rate of macroscopically flat or invisible synchronous dysplasia compared with the SAC (20%) and control (33%) groups (P = 0.045). Synchronous dysplasia demonstrated nonconventional dysplastic features more frequently in the GCDAC (69%) and SAC (40%) groups compared with the control group (0%; P = 0.016). In conclusion, goblet cell deficient dysplasia and dysplasias featuring a serrated component could potentially serve as high-risk markers for GCDACs and SACs, respectively.

Validated nonbiopsy methods to assure duodenal mucosal healing in celiac disease are lacking, yet ongoing mucosal injury is associated with anemia, osteoporosis, and lymphoma. Most providers utilize clinical data as surrogates of mucosal status to avoid additional esophagogastroduodenoscopy. The reliability of such surrogates to predict mucosal recovery has been incompletely evaluated. The aim of this study was to rigorously assess patterns of histologic mucosal recovery at follow-up in celiac disease and to correlate findings with clinical data. Gastrointestinal pathologists from 13 centers evaluated initial and follow-up duodenal biopsies from 181 celiac disease patients. Marsh scores and intraepithelial lymphocytes (IELs)/100 enterocytes were assessed blindly. Histology at follow-up was correlated with symptoms, immunoglobulin A anti–tissue transglutaminase titers and gluten-free diet adherence. Fifty-six/181 (31%) patients had persistent villous blunting and 46/181 (25%) patients had just persistently elevated IELs at follow-up, with only 79/181 (44%) patients having complete histologic remission. IEL normalization (82/181; 45%) lagged villous recovery (125/181;69%). In a minority of patients, villous blunting was limited to proximal duodenal biopsies. No correlation was found between Marsh scores and symptoms, normalization of immunoglobulin A anti–tissue transglutaminase serology, or diet adherence. Children showed greater recovery of Marsh score (P<0.001) and IELs (P<0.01) than adults. Persistent mucosal injury is common in celiac disease, with discordant villous/IEL normalization. Pathologist awareness of expected findings in celiac disease follow-up biopsies, including their frequent lack of correlation with clinical data, is important for patient management, and has implications for eligibility criteria for therapeutics currently in development.