Successful Treatment of Refractory Post-Transplant Lymphoproliferative Disorder With Chimeric Antigen Receptor T-Cell Therapy in a Heart Transplant Recipient.

Post-transplant lymphoproliferative disorders (PTLDs) are opportunistic malignancies that complicate the success of hematopoietic stem cell or solid organ transplantation. These disorders often arise post-transplant due to the immunosuppression required for minimizing the risk of rejection of donor tissue. First-line treatment of these disorders includes limiting immunosuppression when permissible. Subsequent treatment includes the use of monoclonal anti-CD20 antibody (rituximab), and/or combination chemotherapy. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm in many lymphoid malignancies. It is not approved for PTLD due to exclusion of PTLD patients from pivotal clinical trials. Also, its utilization post-transplant can be complex and multidisciplinary care is of utmost importance for successful administration of a potentially curative treatment. We present a 68-year-old patient with history of heart transplant for non-ischemic cardiomyopathy, diagnosed with PTLD that was refractory to treatment using current guidelines until successfully receiving CAR T-cell therapy.

Sitravatinib combined with PD-1 blockade enhances cytotoxic T-cell infiltration by M2 to M1 tumor macrophage repolarization in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a leading cause of cancer-related mortality. Sitravatinib is a novel multi-gene tyrosine kinase inhibitor (TKI) that targets tumor-associated macrophage (TAM) receptors, VEGF, PDGF and c-Kit. Currently, sitravatinib is actively being studied in clinical trials across solid tumors and other TKIs have shown efficacy in combination with immune checkpoint inhibitors (ICI) in cancer models. In this study, we investigated the anti-tumor activity of sitravatinib alone and in combination with PD-1 blockade in an EAC rat model. Treatment response was evaluated by mortality, pre- and post-treatment MRI, gene expression, immunofluorescence and immunohistochemistry. Our results demonstrated adequate safety and significant tumor shrinkage in animals treated with sitravatinib, and more profoundly, sitravatinib and PD-1 inhibitor, AUNP-12 (P < 0.01). Suppression of TAM receptors resulted in increased gene expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines, enhanced infiltration of CD8+ T cells, and M2 to M1 macrophage phenotype repolarization in the tumor microenvironment of treated animals (P < 0.01). Moreover, endpoint immunohistochemistry staining corroborated the anti-tumor activity by downregulation of Ki67 and upregulation of Caspase-3 in the treated animals. Additionally, pretreatment gene expression of TAM receptors and PD-L1 were significantly higher in major responders compared with the non-responders, in animals that received sitravatinib and AUNP-12 (P < 0.02), confirming that TAM suppression enhances the efficacy of PD-1 blockade. In conclusion, this study proposes a promising immunomodulatory strategy using a multi-gene TKI to overcome developed resistance to an ICI in EAC, establishing rationale for future clinical development.

Survival Benefit with Re-resection and Optimal Time to Re-resection in Gallbladder Cancer: a National Cancer Database Study.

PURPOSE: Gallbladder cancer is often diagnosed incidentally after cholecystectomy. Most patients will then undergo re-resection for potential residual disease; however, overall survival (OS) benefit data in this scenario is variable. This National Cancer Database analysis (NCDB) compared OS in patients with T1b-T3 gallbladder cancer who underwent re-resection and evaluated if time to resection impacts OS. METHODS: We reviewed the NCDB for patients who received initial cholecystectomy for gallbladder cancer and were subsequently eligible for re-resection based on tumor stage (T1b-T3 disease). Patients with re-resection were subdivided into four cohorts based on time to re-resection: 0-4 weeks, 5-8 weeks, 9-12 weeks, and > 12 weeks. We used a Cox proportional hazards ratio to identify factors associated with worse survival and logistic regression to evaluate characteristics associated with re-resection. OS was calculated using Kaplan Meier curves. RESULTS: A total of 791 (5.82%) patients received re-resection. Cox proportional hazards analysis showed a comorbidity score of 1 was associated with worse survival. Patients with higher comorbidity scores and treatment at comprehensive community, integrated, or academic cancer programs were less likely to undergo re-resection. Re-resection showed significantly improved OS [HR 0.87; 95 CI 0.77-0.98; p = 0.0203]. Improved survival was appreciated when re-resection was completed at 5-8 weeks [HR 0.67; CI 0.57-0.81], 9-12 weeks [HR 0.64; CI 0.52-0.79], or > 12 weeks [HR 0.61; CI 0.47-0.78] compared to 0-4 weeks. CONCLUSION: Optimal timing to re-resection in gallbladder cancer supports previous data showing benefit at > 4 weeks. However, there was no significant survival difference as to whether re-resection was completed at 5-8 weeks, 9-12 weeks, or > 12 weeks post initial cholecystectomy.

Diffuse Large B Cell Lymphoma Raising Suspicion for an Infection: A Case Report.

Newly discovered liver lesions have a broad differential ranging from malignancy to infection. While tissue biopsy is the gold standard diagnostic modality, imaging can also aid in diagnosis. Hepatocellular carcinoma (HCC) can be diagnosed via imaging alone; however, masses suspicious for infection ultimately require biopsy and culture. We report a case of a 72-year-old male who presented with subjective fever, nausea, decreased appetite, dark urine, elevated liver function tests, and CT evidence of an exophytic liver mass. Differentials included infections such as hepatobiliary actinomycosis, abscess, solid malignancy, or lymphoma. Obtaining a definitive diagnosis with tissue biopsy endoscopically and percutaneously was quite difficult due to the location of the lesion around the porta hepatis. Subsequent laparoscopic biopsy revealed diffuse large B cell lymphoma (DLBCL).

A Route to Polyprenol Pyrophosphate-Based Probes of O-Polysaccharide Biosynthesis in Klebsiella pneumoniae O2a.

An approach for the assembly of polyprenol pyrophosphate-based probes of O-polysaccharide biosynthesis in Klebsiella pneumoniae serotype O2a is described. This convergent route features high-yielding, diastereoselective glycosylations and the late-stage installation of the polyprenol pyrophosphate moiety. Although applied to the synthesis of a nonasaccharide bearing a farnesyl group (1), the modular nature of the route makes it amenable to the synthesis of additional derivatives containing either larger glycans or different lipid domains.