Michael Feely

PD-1 Inhibitor Gastroenterocolitis Case Series and Appraisal of “Immunomodulatory Gastroenterocolitis”

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.

IgG4-related cholecystitis presenting as biliary malignancy: report of three cases.

An increased awareness of IgG4-related diseases has led to an escalation in the number of sites known to be involved by this fibroinflammatory disease. We report three cases of IgG4-related cholecystitis which were thought to represent biliary malignancies both clinically and radiographically. All three cases underwent surgery tailored towards presumed malignant neoplasms. Only following pathologic examination was the true nature of the disease identified. Recognition of the clinical, radiographic, and pathologic presentation of IgG4-related cholecystitis is essential for the consideration of this disease process prior to surgical management for suspected gallbladder malignancies. However, the pre-operative diagnosis remains challenging and extensive surgical intervention is often necessary given the distressing presentation of IgG4-related cholecystitis.

The pancreatic tumor microenvironment drives changes in miRNA expression that promote cytokine production and inhibit migration by the tumor associated stroma

The pancreatic adenocarcinoma (PDAC) microenvironment is largely comprised of fibrotic tumor associated stroma (TAS) that contributes to the lethal biology of PDAC. microRNA (miRNA) are small non-coding RNAs that regulate gene expression. We hypothesized that interactions between PDAC cells and TAS cells within the microenvironment modulate miRNA expression and thus, tumor biology. We observed that miR-205 and members of the miR-200 family (miR-200a, -200b, -200c, -141 and miR-429) were exclusively expressed in PDAC cells, consistent with an epithelial miRNA signature, while miR-145 and miR-199 family members (miR-199a and -199b) were solely expressed in TAS cells, consistent with a stromal miRNA signature. This finding was confirmed by qRT-PCR of RNA obtained by laser-capture microdissection of surgical specimens. Using an in vitro co-culture model, we further demonstrated regulation of miRNA expression by cell-cell contact. Forced expression in TAS cells of miR-200b/-200c and miR-205 to mimic these observed changes in miRNA concentrations induced secretion of GM-CSF and IP10, and notably inhibited migration. These data suggest interactions within the tumor microenvironment alter miRNA expression, which in turn have a functional impact on TAS.

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

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.

Molecular Classification of Hepatocellular Carcinoma and Precision Medicine

The incidence of hepatocellular carcinoma in increasing globally and malignant liver tumors now represents the second leading cause of cancer-related mortality worldwide [1–3]. In the United States, the incidence of hepatocellular carcinoma has tripled over the past 30 years where it has become the fastest rising cause of cancer-related deaths [4]. With this emergence has come an increased effort, largely within the preceding decade, to better appreciate the molecular pathogenesis of this disease. As with other malignancies that have been examined in this way, the eventual goal of these investigations is to identify potential targets for therapy and to correlate these molecular mechanisms with patient prognosis. Here a summary of many of the molecular mechanisms identified in hepatocellular carcinoma is provided as well as outline of the current attempts at a molecular classification system of these tumors.

Anti-Inflammatory Biologics and Anti-Tumoral Immune Therapies-Associated Colitis: A Focused Review of Literature

An increasing number of drugs including monoclonal antibodies and small molecules, either anti-inflammatory or immunity-enhancing, have been developed to treat human diseases and the number of medications in these classes is likely to expand in the future. The two most commonly used categories of such therapies are the anti-inflammatory group (anti- tumor necrosis factor (TNF) α, anti-interleukins/interleukin receptors, and anti-integrin bodies) and the anti-tumoral agents (immune checkpoint inhibitors, anti-CD20, and anti-endothelial growth factor). Although the anti-inflammatory biologics have brought about a revolutionary effect in the management of a variety of autoimmune disorders including rheumatologic diseases, inflammatory bowel disease, and inflammatory dermatological diseases, their ability to induce colitis in patients without a prior history of colitis or exacerbate quiescent colitis has been increasingly and unexpectedly recognized. While the use of immune-augmenting monoclonal antibody therapies results in a significant survival benefit in a subset of patients with malignancies, these monoclonal antibodies also have the ability to cause colitis through an apparent autoimmune mechanism. Colitis associated with these medications may demonstrate multiple histologic patterns including increased apoptosis (graft versus host disease (GVHD)-like), autoimmune enteropathy pattern, acute colitis pattern, ischemic colitis, inflammatory bowel disease pattern, either ulcerative colitis-like, Crohn’s disease-like, or fulminant colitis-like. In addition, anti-inflammatory biologics are known to cause or reactivate latent infections such as tuberculosis and increase the risk for malignancies including high-grade lymphomas as well as indolent lymphoproliferative disorders. Thus, the differential diagnosis for colitis in patients receiving therapeutic anti-inflammatory biologics or anti-tumoral agents can be broad. Optimal diagnosis and treatment requires a multidisciplinary approach. This review aims to provide an overview of the literature on the clinical features, histology, and treatment of these newly recognized anti-inflammatory biologic and anti-tumoral immune therapy-induced colitises and hopes this outlines will raise the vigilance of all clinicians of these entities.

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.

Stroma-derived extracellular vesicles deliver tumor-suppressive miRNAs to pancreatic cancer cells

The biology of tumor-associated stroma (TAS) in pancreatic ductal adenocarcinoma (PDAC) is not well understood. The paradoxical observation that stroma-depletion strategies lead to progression of PDAC reinforced the need to critically evaluate the functional contribution of TAS in the initiation and progression of PDAC. PDAC and TAS cells are unique in their expression of specific miRNAs, and this specific miRNA expression pattern alters host to tumor microenvironment interactions. Using primary human pancreatic TAS cells and primary xenograft PDAC cells co-culture, we provide evidence of miRNA trafficking and exchanging between TAS and PDAC cells, in a two-way, cell-contact independent fashion, via extracellular vesicles (EVs) transportation. Selective packaging of miRNAs into EVs led to enrichment of stromal specific miR-145 in EVs secreted by TAS cells. Exosomes, but not microvesicles, derived from human TAS cells demonstrated a tumor suppressive role by inducing PDAC cell apoptosis. This effect was mitigated by anti-miR-145 sequences. Our data suggest that TAS-derived miRNAs are delivered to adjacent PDAC cells via exosomes and suppress tumor cell growth. These data highlight that TAS cells secrete exosomes carrying tumor suppressive genetic materials, a possible anti-tumor capacity. Future work of the development of patient-derived exosomes could have therapeutic implications for unresectable PDAC.