Yokoda, Raquel T.

Abstract Concurrent thyrotropin (TSH) secreting and growth hormone (GH) secreting pituitary adenomas are rare entities. Although tumors of the PIT-1 lineage may coexpress TSH and GH, concurrent biologically active secretion resulting in central hyperthyroidism and acromegaly is uncommon. We report the case of a 42-year-old woman presenting with weight loss, palpitations, amenorrhea, and progressive acromegalic features. Biochemical evaluation revealed central hyperthyroidism with elevated free T4 and inappropriately normal TSH, markedly elevated insulin-like growth factor 1 (IGF-1) and GH, hyperprolactinemia, and elevated α-subunit. Pituitary magnetic resonance imaging demonstrated a 2.7-cm macroadenoma with cavernous sinus extension. She underwent transsphenoidal resection without complications. Pathology confirmed a mature plurihormonal PIT-1 lineage adenoma immunopositive for TSH, GH, and prolactin with a Ki-67 of 3%. Immediately postoperatively, thyrotoxicosis and hyperprolactinemia resolved, IGF-1 levels declined, acromegalic features improved, and menses resumed. Over the ensuing months, thyroid and prolactin tests remained within normal range, but the IGF-1 level remained elevated. This case illustrates the rare presentation of a PIT-1 lineage adenoma secreting biologically active TSH, GH, and prolactin. Comprehensive hormonal evaluation and long-term biochemical and radiologic surveillance are essential, given the risk of incomplete remission despite apparent surgical cure.

Abstract Background IDH-mutant astrocytomas are classified as WHO grade 4 in the presence of conventional high-grade histologic features and/or homozygous CDKN2A/B deletion in the 5th edition of the WHO Classification of Central Nervous System Tumour guidelines. However, work over the past decade has indicated a number of other molecular alterations that warrant consideration as potential prognostic markers. Methods We used univariate Kaplan-Meier and multivariate Cox proportional hazards regression analysis to evaluate the prognostic effects of homozygous CDKN2A/B deletion, CDK4 amplification, CCND2 amplification, PDGFRA amplification/mutation, PIK3R1 mutation, PIK3CA mutation, MYCN amplification, EGFR amplification/mutation, TERT promoter mutation, and grade 4 histologic features in two independent cohorts of WHO grade 2-4 IDH-mutant astrocytoma (n = 840 and n = 367). Results The presence of CDK4 amplification, CCND2 amplification, PDGFRA alteration, PIK3R1 mutation, MYCN amplification, and EGFR alteration were each associated with reduced overall survival compared to WHO grade 2/3 astrocytomas without these molecular features. 17.7% (148/837) of otherwise grade 2/3 astrocytomas had one or more of these molecular criteria, with resulting intermediate clinical outcome in terms of overall survival (median survival of 67.3-82.0 months) compared to grade 2/3 astrocytomas without these molecular features (median survival of 135.0-140.7 months) and grade 4 astrocytomas (median survival of 35.3-45.0 months). Conclusions The presence of CDK4, CCND2, PDGFRA, PIK3R1, MYCN, and EGFR alterations result in an intermediate patient survival in IDH-mutant astrocytoma. Adding these molecular alterations should be considered in future diagnostic classification systems to improve stratification of high-risk patients.

Drug induced liver injury is a very frequent cause of hepatotoxicity and within that group, herbal and dietary supplements are a well described subcategory. The following clinical vignette describes the case of a young man with acute hepatitis secondary to the use of Ilex paraguariensis, also known as yerba mate, which is a herbal product commonly drunk in South America. This is the first written case of mate tea induced hepatotoxicity.

Abstract Purpose: Cholangiocarcinoma (CCA) is a highly lethal malignancy that often presents at advanced stages. Gemcitabine/cisplatin (GP) represents the standard-of-care but provides only a modest response rate and survival benefit. Loss of the CDK4/6 inhibitor CDKN2A is a prevalent genetic event in CCA, thus CDK4/6 inhibitors, FDA-approved in some breast cancer regimens, are hypothesized to have a role in treating CCA. Clinical challenges to target cell cycle dysregulation and exploit cytotoxic chemotherapy include predictive biomarkers for selecting patients most likely to respond. We hypothesized autophagy is involved in therapeutic resistance to CDK4/6 inhibitors, and plays a role in the activity of GP in CCA. Thus, we investigated CDK4/6 inhibitors as monotherapy, and combined with GP in CCA, measuring multiple readouts pertaining to drug synergy, putative pathway biomarkers and autophagy. Methods: The activity of 3 FDA approved CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib, as monotherapy (N=24), and combined with GP (N=10), was assessed in CCA cell lines by measuring relative cell number with Cell TiterGlo, and apoptosis with Annexin/PI and cleaved caspase3 quantification via flow cytometry. To characterize RB status for biomarker potential, protein levels of CCND1, CDK4, CDK6, RB, and CDKN2A were measured by western blot. Autophagy was measured using an autophagy flux assay, LysoTracker confocal staining, and by quantifying protein levels of LC3B, p62 and Beclin1A. Results: 22/24 (92%) of CCA cell lines were found to have at least one defect likely relevant to CDK4/6 inhibition: CDKN2A (92%), Rb1 (63%), CDK4 (23%) and cyclin D1 (32%). Protein levels of CDKN2A and RB1 showed moderate correlation with CDK4/6 inhibitor activity. Abemaciclib was the most potent CDK inhibitor in vitro (IC50≤0.5uM; palbociclib IC50>1uM; ribociclib IC50>5uM). Combined abemaciclib and GP showed higher cytotoxicity and synergy at lower doses compared to chemotherapy alone or single-agent abemaciclib. Compared to CDK4/6 inhibitors or chemotherapy alone, combination therapy enhanced growth inhibition, cell cycle arrest and caspase-dependent apoptotic cell death. Abemaciclib triggered autophagy mediated by significant increases in reactive oxygen species (ROS). Combination therapy reduced ROS production and thus autophagy, as seen by reduced autophagic flux, reduced LysoTracker mean fluorescence intensity, a decrease in the expression of LC3B-II, Beclin1A and an increase in p62. Conclusion: These results suggest CDK4/6 inhibitors interact synergistically with GP in CCA and mechanistically disrupt autophagy. This suggests potential to further explore CDKN2A and RB as biomarkers for preclinical sensitivity in CCA. Pre-clinical data supports ongoing clinical studies of this concept, as well as planned clinical studies of GP and alternative CDK4/6 inhibitors. Citation Format: Mansi Arora, James Bogenberger, Nagalo Bolni, Yumei Zhou, Latha Kannan, Jan Egan, Raquel Yokoda, Daniel H. Ahn, Mitesh J. Borad. Synergy of cyclin dependentkinase 4/6 inhibitors with cytotoxic chemotherapy in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4417.

Cholestatic liver diseases encompass a broad spectrum of pathologies, with the core injury occurring at the level of cholangiocytes and progressing to hepatic fibrosis and liver dysfunction. Primary biliary cholangitis and primary sclerosing cholangitis are the most significant progressive cholangiopathies in adults. Although rare, they commonly evolve to liver failure and need for liver transplantation. Despite recent advances in the basic knowledge of these cholangiopathies, the pathogenesis is still elusive. Targeted treatments to prevent disease progression and to preclude malignancy are not yet available. This review will address the general clinical features of both diseases, analyze their commonalities and differences, and provide a state-of-the art overview of the currently available therapeutics.

Gastrointestinal malignancies are challenging cancers with considerable economic and societal impacts on health care systems worldwide. While advances in surgical approaches have provided benefits to a proportion of patients, only modest improvements have been attained in the treatment of patients with advanced disease, resulting in limited improvement in survival rates in these patients. Oncolytic adenoviruses are being developed to address gastrointestinal malignancies. Each platform has evolved to maximize tumor-cell killing potency while minimizing toxicities. Tumor-specific bioengineered adenoviruses using chimeric promoters, prodrug convertase enzymes, lethal genes, tumor suppressor genes, and pseudo-typed capsids can provide the innovations for eventual success of oncolytic virotherapy. This article will review the developments in adenoviral platforms in the context of specific gastrointestinal cancers. From the bench to the implementation of clinical trials, this review aims to highlight advances in the field from its early days to the current state of affairs as it pertains to the application of adenoviral oncolytic therapy to gastrointestinal cancers.