Novel histologic score predicts recurrent intestinal metaplasia after successful endoscopic eradication therapy.

Endoscopic eradication therapy (EET) is an effective treatment for Barrett's esophagus (BE); however, disease recurrence remains problematic requiring surveillance post-treatment. While data regarding predictors of recurrence are limited, uncontrolled reflux may play a significant role. Our aim was to develop a scoring system based on histopathologic reflux in surveillance biopsies following EET to identify patients at high risk for recurrence of BE. Patients were identified from two centers in the treatment with resection and endoscopic ablation techniques for BE consortium. Hematoxylin and eosin-stained slides of surveillance biopsies post-EET were assessed for histologic changes associated with reflux from a cohort of patients who also underwent pH-metry (derivation cohort). We developed a novel scoring system (Recurrent Epithelial Changes from Uncontrolled Reflux [RECUR]) composed of dilated intercellular spaces, epithelial ballooning, basal cell hyperplasia, and parakeratosis, to identify patients with abnormal esophageal acid exposure. This scoring system was then used to grade surveillance biopsies from patients with or without recurrence of BE following EET (validation cohort). Of 41 patients in the derivation cohort, 19.5% had abnormal acid exposure times (AET) while on proton pump inhibitor therapy. The mean (SD) RECUR score for patients with AET <4% was 4.0 (1.6), compared with 5.5 (0.9) for AET ≥4% (P = 0.015). In the validation cohort consisting of 72 patients without recurrence and 64 patients with recurrence following EET, the RECUR score was the only significant predictor of recurrence (odds ratio: 1.36, 95% confidence interval: 1.10-1.69, P = 0.005). Histologic grading of surveillance biopsies using the RECUR scoring system correlates with BE recurrence following EET.

Human Immunodeficiency Virus Infection Promotes Human Papillomavirus-Mediated Anal Squamous Carcinogenesis: An Immunologic and Pathobiologic Review.

BACKGROUND: Anal squamous cell carcinoma (SCC) is a rare gastrointestinal malignancy with rising incidence, both in the United States and internationally. The primary risk factor for anal SCC is human papillomavirus (HPV) infection. However, there is a growing burden of disease in patients with human immunodeficiency virus (HIV) and HPV coinfection, with the incidence of anal SCC significantly increasing in this population. This is particularly true in HIV-infected men. The epidemiologic correlation between HIV-HPV coinfection and anal SCC is established; however, the immunologic mechanisms underlying this relationship are not well understood. SUMMARY: HIV-related immunosuppression due to low circulating CD4+ T cells is one component of increased risk, but other mechanisms, such as the effect of HIV on CD8+ T lymphocyte tumor infiltration and the PD-1/PD-L1 axis in antitumor and antiviral response, is emerging as significant contributors. The goal of this article is to review existing research on HIV-HPV coinfected anal SCC and precancerous lesions, propose explanations for the detrimental synergy of HIV and HPV on the pathogenesis and immunologic response to HPV-associated cancers, and discuss implications for future treatments and immunotherapies in HIV-positive patients with HPV-mediated anal SCC. Key Messages: The incidence of anal squamous cell carcinoma is increased in human immunodeficiency virus (HIV)-infected patients, even in patients on highly active antiretroviral therapy. Locoregional HIV infection may enhance human papillomavirus oncogenicity. Chronic inflammation due to HIV infection may contribute to CD8+ T lymphocyte exhaustion by upregulating PD-1 expression, thereby blunting cytotoxic antitumor response.

Primary Signet Ring Cell Carcinoma of the Ileal Pouch.

A 55-year-old man with a history of ulcerative colitis status post ileal pouch-anal anastomosis underwent evaluation for pouchitis. He was found to have signet ring cell cancer within the pouch. Primary cancers of the ileal pouch are rare. Signet ring cell carcinoma is a rare form of adenocarcinoma that can involve the gastrointestinal tract and other organs. We present a case of a signet ring cell carcinoma arising from an ileal pouch.

The effect of human immunodeficiency virus and human papillomavirus strain diversity on the progression of anal squamous intraepithelial lesions.

Anal squamous cell carcinoma (SCC) is a human papillomavirus (HPV)-mediated malignancy with increasing incidence. Human immunodeficiency virus (HIV) infection is a significant risk factor for anal SCC; however, it is unknown if HIV infection alters anal lesion progression and HPV strain profile. This study aims to determine whether HIV coinfection is associated with progression of HPV-mediated anal lesions and on their HPV strain diversity. This is a retrospective cohort study of adults with anal squamous intraepithelial lesion (SIL) who presented for anorectal sampling between 2010 and 2019. Using the full cohort, we performed clinicopathologic epidemiologic analysis of HIV coinfection on lesion progression. Using a subset of patients, we conducted molecular analysis of HPV strain diversity as related to HIV status and progression. Our cohort included 2203 individuals, of which 940 (43%) were HIV+. HIV+ status was associated with faster progression at all levels of dysplasia. Our molecular cohort included 329 adults, of which 190 (57.8%) were HIV+. HIV+ status was associated with higher HPV strain diversity (median: 7 [5-9] versus median: 4 [4-6], P < .001). Latent class analysis identified specific HPV strain signatures associated with progression. We demonstrate that HIV+ individuals had faster rates of anal SIL progression and that almost all HPV strains were more prevalent in anal samples from HIV+ adults. Our results imply that HIV+ adults with anal SIL should undergo more frequent screening and obtain HPV genotyping at initial presentation, as it shows value as a biomarker of lesion progression.

Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies.

BACKGROUND: Individualized neoantigen-specific immunotherapy (iNeST) requires robustly expressed clonal neoantigens for efficacy, but tumor mutational heterogeneity, loss of neoantigen expression, and variable tissue sampling present challenges. It is assumed that clonal neoantigens are preferred targets for immunotherapy, but the distributions of clonal neoantigens are not well characterized across cancer types. METHODS: We combined multiregion sequencing (MR-seq) analysis of five untreated, synchronously sampled metastatic solid tumors with re-analysis of published MR-seq data from 103 patients in order to characterize their globally clonal neoantigen content and factors that would impact neoantigen targeting. RESULTS: Branching evolution in colorectal cancer and renal cell carcinoma led to fewer clonal neoantigens and to clade-specific neoantigens (those shared across a subset of tumor regions but not fully clonal), with the latter not being readily distinguishable in single tumor samples. In colorectal, renal, and bladder cancer, most tumors had few globally clonal neoantigens. Prioritizing mutations with higher purity-adjusted and ploidy-adjusted variant allele frequency enriched for globally clonal neoantigens (those found in all tumor regions), whereas estimated cancer cell fraction derived from clustering-based tools, surprisingly, did not. Neoantigen quality was associated with loss of neoantigen expression in the bladder cancer case, and HLA-allele loss was observed in the renal and non-small cell lung cancer cases. CONCLUSIONS: We show that tumor type, multilesion sampling, neoantigen expression, and HLA allele retention are important factors for iNeST targeting and patient selection, and may also be important factors to consider in the development of biomarker strategies.

Chronic Diarrhea Secondary to Newly Diagnosed VIPoma.

Vasoactive intestinal polypeptide-secreting tumors (VIPoma) are a rare pancreatic neuroendocrine tumor that can cause chronic diarrhea with 1 case per 10 million people per year. Diagnosis is made based on a combination of laboratory evaluation (serum VIP level), imaging findings (functional positron emission tomography-computed tomography [PET-CT]), and histological analysis (chromogranin A stain). We present a case of a male with 6 months of diarrhea and malaise who was found to have significant kidney injury and hypokalemia requiring admission to the medical intensive care unit. Subsequent laboratory evaluation while admitted eventually showed a low stool osmotic gap (-11 mOsm/kg) consistent with secretory diarrhea, in addition to significantly elevated VIP levels at 940 pg/mL (normal <75). Cross-sectional imaging with functional Gallium-68 dotatate PET-CT confirmed metastatic functional neuroendocrine tumor indicative of a VIPoma. Pathology on subsequent metastatic liver lesion aspiration was consistent with a well-differentiated VIPoma, and symptoms dramatically improved following initiation of octreotide therapy.