Collagenous Gastritis: An Atypical Presentation of a Rare Disease.

Collagenous gastritis is a rare inflammatory condition of unknown etiology defined histologically by subepithelial deposition of collagen bands ≥ 10 µm in the lamina propria. Adults typically present with diarrhea, often attributed to concurrent collagenous sprue or collagenous colitis. Children more commonly present with abdominal pain and anemia, with inflammation typically limited to the stomach. Herein, we present a case of collagenous gastritis in a 38-year-old female with a history of iron deficiency and hypothalamic amenorrhea who presented with a one-year history of microcytic anemia. Celiac disease panel, Helicobacter pylori testing, and anti-parietal cell and intrinsic factor antibodies were negative. Esophagogastroduodenoscopy revealed diffusely erythematous and nodular gastric mucosa in the antrum and pylorus. Biopsy from the gastric body showed complete loss of oxyntic glands and deposition of a thick band of collagen under the surface epithelium infiltrated by a few eosinophils, consistent with collagenous gastritis with severe atrophy. She was treated with omeprazole 40 mg daily for six weeks and iron supplementation. Our patient's symptoms and endoscopic findings are consistent with previously described pediatric, but not adult, cases of collagenous gastritis, yielding insight into the variable clinical presentation of this rare disease.

Belzutifan (MK-6482): Biology and Clinical Development in Solid Tumors.

PURPOSE OF REVIEW: To review the biology, drug development, and clinical data regarding the efficacy and safety of belzutifan (MK-6482), a small molecule inhibitor of HIF-2α. RECENT FINDINGS: Belzutifan, a second-generation HIF-2α inhibitor, was shown to provide clinically meaningful benefit in the treatment of VHL-associated tumors (including ccRCC, pancreatic lesions as well as neuroendocrine tumor, and CNS hemangioblastomas). The recommended dose of belzutifan is 120 mg orally daily and half-life is 14 h. In pretreated ccRCC, belzutifan achieved disease control rate of 80% in phase I trial. The most common side effects include anemia and hypoxia related symptoms. Investigation into the important role HIF-2α plays in the expression of genes associated with angiogenesis, erythropoiesis, carcinogenesis, and progression of tumors and the discovery of structural vulnerability within HIF-2α have resulted in the development of a new therapy that has demonstrated efficacy and safety in recent clinical trials. Further research is ongoing to optimize therapeutic benefits from this new exciting therapeutic modality and to improve the outcome of HIF-2α-driven tumors.

A Thrombotic Thrombocytopenic Purpura-Like Syndrome in HIV and Streptococcus pneumoniae Meningitis.

Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by the formation of diffuse thromboses in small blood vessels, which can result in neurological and renal impairment, fever, and purpura, among additional sequelae. TTP-like syndromes are disease processes that have similar signs and symptoms as TTP but without a severe deficiency in ADAMTS13 levels. We present a case of a young male with advanced human immunodeficiency virus (HIV) and Streptococcus pneumoniae meningitis presenting with a thrombotic microangiopathy (TMA). Although his ADAMTS13 level was not suggestive of TTP, at 54.4% (normal low ADAMTS13: >66.8% activity; severe ADAMTS13 deficiency: ≤10% activity), he improved only after plasmapheresis was initiated, supporting a diagnosis of a TTP-like syndrome likely due to his streptococcal meningitis. We discuss the importance of treating patients with TTP-like syndromes and advanced HIV with highly active antiretroviral therapy (HAART). We also highlight the increased prevalence of TMA and TTP among HIV patients and that many of these patients do not have a severe deficiency in levels of serum ADAMTS13.

ONECUT2 as a key mediator of androgen receptor-independent cell growth and neuroendocrine differentiation in castration-resistant prostate cancer.

Despite androgen dependence in a majority of castration-resistant prostate cancers, some cancer cells are independent of androgen receptor (AR) function, a feature of heterogeneity in prostate cancer. One of the aggressive variants of prostate cancer that are AR independent is neuroendocrine prostate cancer (NEPC). This manuscript will focus on the new finding of human one cut domain family member 2 (ONECUT2) transcription factor and its role in castration resistance, especially in NEPC.

Gangrene of the Foot After Coronary Artery Bypass Graft Surgery.

Coronary artery bypass grafting (CABG) is the most common surgery performed by cardiothoracic surgeons worldwide. Risks of CABG include neurological outcomes, deep vein thrombosis, renal or gastrointestinal injury, and death. Perioperatively, some patients may need intra-aortic balloon pump (IABP) use to help assist with cardiac function. In this case, a 75-year-old man presented with multivessel myocardial infarction requiring IABP for cardiac assistance prior to undergoing CABG. Eighteen days after his CABG, his toes turned black at home. A CT angiogram showed aortic atherosclerosis, right tibioperoneal trunk stenosis, mild atherosclerotic right proximal anterior tibial artery stenosis, and multifocal occlusive lesions in the right and left infrapopliteal vessels. Vascular surgery performed balloon angioplasty of the right anterior tibial artery and podiatry performed a transmetatarsal amputation of the dry gangrene. The aim of this case report is to present a rare complication of CABG with peri-operative IABP use and to highlight the need for prompt diagnosis and treatment of dry gangrene.

Cardiovascular Toxicity of Androgen Deprivation Therapy.

PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) is the standard of care for the treatment of advanced prostate cancer (PC). ADT, particularly with GnRH agonists, leads to increased risk of cardiovascular disease, including myocardial infarction, hypertension, and stroke. This review discusses the options of ADT, the mechanism of ADT-associated cardiovascular side effects, and potential benefit by using GnRH antagonists. RECENT FINDINGS: GnRH antagonists have relatively less cardiovascular adverse effects compared to GnRH agonists. We highlight on a recently published phase III clinical trial on the oral GnRH antagonist, relugolix, and its comparative benefit to traditional GnRH agonist regarding development of cardiovascular disease. Recent data reinforces that GnRH antagonists have a more favorable cardiovascular outcomes compared to GnRH agonists yet maintain a similar efficacy profile. From the data we reviewed, GnRH antagonists may be the preferred method of ADT for PC, but further data with primary cardiovascular outcomes are warranted.

Hypoxia-Inducible Factor-2α as a Novel Target in Renal Cell Carcinoma.

Hypoxia-inducible factor (HIF), an important mediator of hypoxia response, is implicated in tumorigenesis in the setting of pseudohypoxia, such as in the inactivation of von Hippel-Lindau tumor suppressor protein (pVHL), leading to development and progression of clear cell renal cell carcinoma (ccRCC). Targeting downstream molecules in HIF pathway, such as vascular endothelial growth factor (VEGF), has led to improvement in clinical outcome for patients with advanced ccRCC, but such therapy thus far has been limited by eventual resistance and treatment failure. Following the discovery of HIF-2α playing a key role in ccRCC carcinogenesis, inhibitors targeting HIF-2α have been developed and have demonstrated encouraging efficacy and safety profile in clinical trials. This review discusses HIF-2α as a promising therapeutic target for ccRCC.

Update on the Inflammatory Hypothesis of Coronary Artery Disease.

PURPOSE OF REVIEW: The pathogenesis and progression of coronary artery disease (CAD) is now known to be largely driven by inflammation on top of the well-accepted role for the disequilibrium between cholesterol deposition and removal from the arterial wall. Recent clinical trials have supported the inflammatory hypothesis of CAD and will be discussed in this review. RECENT FINDINGS: The clinical trial Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) found that treatment with canakinumab, an anti-interleukin-1ß agent, resulted in a reduction in non-fatal myocardial infarction, non-fatal stroke, or death. This provided evidence for the inflammatory hypothesis of CAD. However, canakinumab is not cost-effective for widespread therapy and more cost-effective treatments are warranted. The Cardiovascular Inflammation Reduction Trial (CIRT), Colchicine Cardiovascular Outcomes Trial (COLCOT), and Low-Dose Colchicine 2 (LoDoCo2) are recent clinical trials that increased the understanding of the inflammatory hypothesis of CAD. Cost-effective therapies targeting inflammation are the future of preventative CAD treatment. Additional clinical trials with anti-inflammatory and anti-cytokine agents would help delineate the most beneficial target for CAD prevention.

BRCA Mutations, Homologous DNA Repair Deficiency, Tumor Mutational Burden, and Response to Immune Checkpoint Inhibition in Recurrent Ovarian Cancer.

PURPOSE: Homologous DNA repair-deficient (HRD) ovarian cancers (OCs), including those with BRCA1/2 mutations, have higher levels of genetic instability, potentially resulting in higher immunogenicity, and have been suggested to respond better to immune checkpoint inhibitors (ICIs) than homologous DNA repair-proficient OCs. However, clinical evidence is lacking. The study aimed to evaluate the associations between BRCA1/2 mutations, HRD, and other genomic parameters and response to ICIs and survival in OC. METHODS: This is a single-institution retrospective analysis of women with recurrent OC treated with ICIs. BRCA1/2 mutation status and clinicopathologic variables were abstracted from the medical records. Targeted and whole-exome sequencing data available for a subset of patients were used to assess tumor mutational burden (TMB), HRD, and fraction of genome altered (FGA). ICI response was defined as lack of disease progression for ≥ 24 weeks. Associations of BRCA1/2 status and genomic alterations with progression-free survival (PFS) and overall survival (OS) were determined using Cox proportional hazards models. RESULTS: Of the 143 women treated with ICIs, 134 had known BRCA1/2 mutation status. Deleterious germline or somatic BRCA1/2 mutations were present in 31 women (24%). There was no association between presence of BRCA1/2 mutations and response (P = .796) or survival. Genomic analysis in 73 women found no association between TMB (P = .344) or HRD (P = .222) and response, PFS, or OS. There were also no significant differences in somatic genetic alterations between responders and nonresponders. High FGA was associated with an improvement in PFS (P = .014) and OS (P = .01). CONCLUSION: TMB, BRCA1/2 mutations, and HRD are not associated with response or survival, cautioning against their use as selection criteria for ICI in recurrent OC. FGA should be investigated further as a biomarker of response to immunotherapy in OC.

Utility of serum CA-125 monitoring in patients with ovarian cancer undergoing immune checkpoint inhibitor therapy.

OBJECTIVE: This study aimed to evaluate the utility of serum cancer antigen-125 (CA-125) levels to monitor patients with epithelial ovarian cancer (EOC) undergoing immune checkpoint inhibitor (ICI) therapy. METHOD: This was a single-center retrospective review of all patients with EOC who were treated with ICI therapy from January 2013 to May 2017. This study compared the percentage change in baseline CA-125 in patients who had clinical benefit, defined as complete response, partial response, or stable disease by RECIST 1.1, with duration ≥24 weeks, versus those who did not. The groups were compared by Wilcoxon rank-sum test. RESULTS: Fifty-nine (66%) of 89 patients who underwent ICI therapy had CA-125 data at baseline and during treatment. Of those who derived clinical benefit, 11/15 (73%) experienced an increase in CA-125 from baseline to end of treatment. Of those who did not derive clinical benefit, 36/44 (82%) experienced a CA-125 increase (p = 0.48). The average % increase from baseline to within 12 weeks of treatment initiation for patients with and without clinical benefit was 34% and 195%, respectively (p = 0.008). CONCLUSION: Our analysis demonstrates a statistically significant difference in the magnitude of increase in CA-125 levels within the first 12 weeks of treatment between patients who achieved clinical benefit and those who did not. However, both groups of patients were equally likely to experience an increase in CA-125 within 12 weeks. These findings suggest that physicians should apply caution when using early CA-125 data to guide treatment decisions for patients with EOC undergoing ICI therapy.

Mixed Serous and Clear Cell Adenocarcinoma of the Ovary Presenting with Symptomatic Hypercalcemia: A Case Report and Clinical Considerations.

INTRODUCTION: Hypercalcemia is a common phenomenon in patients with cancer but is more common among certain cancer types. Hypercalcemia in ovarian cancer is the common presenting sign in small cell carcinoma of the ovary, hypercalcemic type; however, there are no known documented cases of hypercalcemia as the presenting sign for mixed serous and clear cell adenocarcinoma. This case report describes symptomatic hypercalcemia as the presenting sign of mixed serous and clear cell carcinoma of the ovary. CASE PRESENTATION: A 60-year-old woman with a medical history of hypertension and hyperlipidemia presented to the outpatient clinic with weakness, nausea, emesis, constipation, and an unintended 9-kg (20-lb) weight loss. Her calcium level was elevated at 15.7 mg/dL (reference range = 8.5-10.3 mg/dL). She was treated for hypercalcemia and subsequently admitted to the hospital 4 times because of recurrence of symptoms. On outpatient workup, she was noted to have an abnormal positron emission tomography scan showing intense activity in the uterus consistent with malignancy. An exploratory laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymph node staging was performed, and pathologic findings demonstrated high-grade ovarian carcinoma with serous and clear cell features. DISCUSSION: Hypercalcemia is a rare but possible primary presenting symptom of ovarian cancer. In these patients, serum calcium measurements could possibly serve as a tumor marker for disease.

Concurrent Birt-Hogg-Dubé Syndrome and Hereditary Paraganglioma-Pheochromocytoma Syndrome Presenting as Metastatic Renal Cell Carcinoma in a 25-Year-Old Man: A Case Report.

INTRODUCTION: Birt-Hogg-Dubé syndrome and hereditary paraganglioma-pheochromocytoma syndrome are rare genetic cancer syndromes that predispose patients to renal neoplasia. We report a case of a 25-year-old man with both Birt-Hogg-Dubé syndrome and hereditary paraganglioma-pheochromocytoma syndrome who presented with painless gross hematuria and was found to have metastatic clear cell renal carcinoma. CASE PRESENTATION: A previously healthy, 25-year-old man presented to his outpatient primary care physician with painless gross hematuria. Urinalysis results demonstrated hemoglobinuria, and serum chemistry results demonstrated a creatinine level of 1.61 mg/dL (baseline of 0.96 mg/dL). A computed tomography scan showed that the patient had a left renal mass, renal vein thrombosis with inferior vena cava extension, and nodal and hepatic metastasis. Biopsy specimens of the left renal mass and liver demonstrated clear cell carcinoma. The patient underwent cytoreductive nephrectomy, caval thrombectomy, and partial colectomy with reanastomosis. He received palliative therapy with 1 mg/kg of ipilimumab and 3 mg/kg of nivolumab for 4 cycles. CONCLUSION: To our knowledge, this is the first known case report to date documenting a patient with concurrent Birt-Hogg-Dubé syndrome and hereditary paraganglioma-pheochromocytoma syndrome. This case demonstrates the exceptionally young presentation of metastatic renal cell carcinoma with this genotype.

CRISPR/Cas9 for the Clinician: Current uses of gene editing and applications for new therapeutics in oncology.

Precise genomic editing has given rise to treatments in previously untreatable genetic diseases and has led to revolutions in treatment for cancer. In the past decade, the discovery and development of clustered regularly interspaced short palindromic repeats (CRISPR) technologies has led to advances across medicine and biotechnology. Specifically, the CRISPR/Cas9 system has improved translational discovery and therapeutics for oncology across tumor types. In this review, we briefly summarize the history and development of CRISPR, explain CRISPR-Cas systems and CRISPR gene editing tools, highlight the development and application of CRISPR technologies for translational and therapeutic purposes in different oncologic tumors, and review novel treatment paradigms using CRISPR in immuno-oncology, including checkpoint inhibitors and chimeric antigen receptor T cell therapy.

Early disease progression and treatment discontinuation in patients with advanced ovarian cancer receiving immune checkpoint blockade.

OBJECTIVE: Delayed responses observed with immune checkpoint blockade (ICB) present a challenge for patients with peritoneal malignancies, who risk early symptomatic disease progression requiring treatment discontinuation. While efforts are ongoing to define the biomarkers of response, it is equally important to identify patients at risk for early discontinuation. We sought to investigate the timing of disease progression in epithelial ovarian cancer (EOC) patients treated with ICB and to identify pre-treatment clinical parameters associated with early discontinuation. METHODS: Retrospective analysis was performed on EOC patients treated with ICB at MSKCC from January 2013 to May 2017. Cutoffs for early and very early discontinuation due to disease progression were defined at 12 and 8 weeks, respectively. Univariate and multivariate logistic regression models were built based on pre-treatment clinical variables. RESULTS: Of 108 identified patients, 89 were included in the analysis. Forty-six (51.7%) patients discontinued therapy early, 30 of which (33.7%) discontinued therapy very early. Eight patients (9.0%) died within 12 weeks of ICB initiation from disease progression. In multivariate analyses, bulky peritoneal disease (p = 0.009, OR: 4.94) and liver parenchymal metastases (p = 0.001, OR: 8.08) were associated with early discontinuation. Liver parenchymal metastases (p = 0.001, OR 6.64), and high neutrophil-to-lymphocyte ratio (p = 0.021, OR: 3.54), were associated with very early discontinuation. CONCLUSIONS: Over 50% of EOC patients suffer disease progression requiring early discontinuation of ICB. Pre-treatment prognostic clinical characteristics may identify patients at highest risk for early discontinuation due to disease progression and warrant caution in using these agents in late line patients with advanced disease.