Sarbajit Mukherjee

Clinicopathological characteristics and outcomes of rare histologic subtypes of gallbladder cancer over two decades: A population-based study

Background There is limited literature about the clinicopathological characteristics and outcomes of rare histologic variants of gallbladder cancer (GBC). Methods Using SEER database, surgically managed GBC patients with microscopically confirmed adenocarcinoma, adenosquamous/squamous cell carcinoma and papillary carcinoma were identified from 1988 to 2009. Patients with second primary cancer and distant metastasis at presentation were excluded. The effect of clinicopathological variables on overall survival (OS) and disease specific survival (DSS) were analyzed using univariate and multivariate proportional hazards modeling. All associations were considered statistically significant at an alpha error of 0.01. Results Out of 4738 cases, 217 adenosquamous/squamous (4.6%), 367 papillary (7.7%), and 4154 adenocarcinomas (87.7%) were identified. Median age was 72 years. Higher tumor grade (grade 2, 3, 4 versus grade 1), higher T stage (T2, T3, T4 versus T1), lymph node positivity (N1 versus N0) and adenosquamous/squamous histology (versus adenocarcinoma) had worse OS and DSS (p < .001). Papillary GBC had better OS and DSS than adenocarcinoma (HR = 0.7; p < .001). Radical surgery (versus simple cholecystectomy) had better OS (HR = 0.83, p = 0.002) in multivariate analysis. OS rates at 3 and 5 years were 0.56 and 0.44 for papillary, 0.3 and 0.22 for adenocarcinoma, and 0.14 and 0.12 for adenosquamous/squamous histology, while DSS rates at 3 and 5 years were 0.67 and 0.61 for papillary, 0.38 and 0.31 for adenocarcinoma, and 0.17 and 0.16 for adenosquamous/squamous subtypes respectively. Conclusion Papillary GBC had better survival outcomes while adenosquamous/squamous GBC had worse survival outcomes compared to gallbladder adenocarcinoma.

Do proton pump inhibitors modulate the efficacy of anti-PD-1/PD-L1 therapy? A retrospective study

Cancer immunotherapy is one of the most rapidly evolving fields in medicine. Immune checkpoint inhibitors act by releasing a molecular brake-like programmed death-1 (PD-1) or its ligand PD-L1, thus enabling the immune system to attack and destroy cancer cells. These drugs are used to treat a number of patients with a wide variety of solid tumors including metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial cancer, head and neck cancer, gastroesophageal cancer, hepatocellular carcinoma, and hematologic malignancies like Hodgkin’s lymphoma. Currently, there are several Food and Drug Administration-approved immune checkpoint inhibitors that target the PD-1/PD-L1 pathway: nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. A healthy immune system is capable of destroying tumor cells. However, tumor cells and antigen-presenting cells often express immune checkpoints like PD-L1 on their surface. When PD-L1 molecules bind to PD-1 molecules on T cells, they inhibit T-cell function and the tumor cells evade immune surveillance. Immune checkpoint inhibitors directed against PD-1/PD-L1 restore immune function by inhibiting those inhibitory molecules. Unbalancing of immune system leads to immunerelated adverse events (IRAEs) in some patients treated with anti-PD-1/PD-L1 therapy. Diarrhea/colitis and pneumonitis are frequent causes of hospitalization among patients receiving immunotherapy. Grade 3/4 immune-mediated diarrhea/colitis are seen in approximately 1 to 2% of cases, while the incidence of grade 3/4 pneumonitis have been reported in up to 1% patients. Other IRAEs include endocrinopathies, hepatotoxicity, renal toxicity, and dermatologic toxicity. Recently, the composition of gut microbiome has been an active area of interest in cancer immunotherapy. Gopalakrishnan et al. analyzed the oral and fecal microbiome in melanoma patients treated with anti-PD-1/PD-L1 therapy and showed that there is a significant difference in the diversity and composition of gut microbiome among responders vs. nonresponders. In their study, they showed that the within sample diversity of gut microbiome, which takes into account both the number of different species as well as their relative distribution, was significantly higher among responders compared to non-responders. Proton pump inhibitors (PPIs) are commonly used around the world for different indications including gastro-esophageal reflux disease and prevention and treatment of peptic ulcer disease. In 2013, esomeprazole (PPI), was the second largest drug in the US in terms of revenue. A recent study by Imhann et al. found that PPI use was associated with a decreased diversity of the gut microbiome as compared to the non-users. Based on the information presented above, it was hypothesized that cancer patients receiving anti-PD-1/ PD-L1 therapy, while taking PPIs concurrently, will have a different outcome compared to those who are not using PPIs. A retrospective review was performed on 158 patients aged 18 years or older, treated at the University of Oklahoma Health Sciences Center with anti-PD-1/PD-L1 therapy between 2014 and 2016. PPI use was assessed based on medical record review of prescribed and self-reported medications. This study was approved by the institutional review board. Our primary objective was to investigate whether the

Degloving the Feet: A Severe Case of Hand-Foot Syndrome After Induction Chemotherapy

A 21-year-old man with relapsed refractory FLT3-mutated acute myeloid leukemia (AML) received third-line induction chemotherapy with clofarabine, cytarabine, and sorafenib. Within 7 days, he started having hand and foot pain with erythema. Over the next few days, his symptoms progressed, and he developed large flat bullae and severe desquamation of his feet (Figures 1 and 2). He was diagnosed with grade 3 hand-foot syndrome. He was unable to walk for 1 week due to severe pain and swelling, but his symptoms gradually resolved within 3 weeks. Treatment consisted of oral pyridoxine, topical steroids, and other supportive measures, including ice packs, leg elevation, avoidance of friction, and topical creams. Palmar-plantar erythodysesthesia, also known as handfoot syndrome (HFS), is a known chemotherapy complication. The condition is usually self-limited, resolving within a few weeks of stopping the culprit medication. HFS has been commonly reported with cytarabine and sorafenib but is less common with clofarabine. Grade 3 or higher HFS occurred in 3% of patients receiving a combination of clofarabine and cytarabine as induction therapy for AML. The severe HFS in this patient could be attributed to any of the 3 medications he received or the cumulative effect of the combination.

Ibritumomab tiuxetan (Zevalin) and elevated serum human anti-murine antibody (HAMA)

Ibritumomab Tiuxetan (Zevalin) is an anti CD-20 murine monoclonal antibody linked to the radio-isotope 90-yttrium (90Y) by the chelator Tiuxetan. It is FDA approved for treatment of relapsed low grade or follicular B-cell Non-Hodgkins Lymphoma (NHL) or newly diagnosed follicular NHL following an initial response to first-line chemotherapy. Patients may develop Human Anti-Murine Antibodies (HAMA), following exposure to murine antibodies. There is a concern for development of hypersensitivity reactions with Ibritumomab, especially in patients with an elevated HAMA titer. Here we describe a case of a 66 year old male with elevated HAMA titer successfully treated with Zevalin without any hypersensitivity reactions. Existing literature supports our observation that Zevalin can be safely used in most patients with elevated HAMA titers.