Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors

Glycans, chains of sugar molecules found conjugated to cell proteins and lipids, contribute to their growth, movement and differentiation. Aberrant glycosylation is a hallmark of several medical co... Tweetable abstract There is an opportunity to utilize anti-Globo H and anti-SSEA-4 agents both as monotherapy and in combination with immune checkpoint inhibitors. It is hoped that these agents wil...

Checkpoint inhibitor therapy has introduced a revolution in contemporary anticancer therapy. It has led to dramatic improvements in patient outcomes and has spawned tremendous research into novel immunomodulatory agents and combination therapy that has changed the trajectory of cancer care. However, clinical benefit in patients with colorectal cancer has been generally limited to tumors with loss of mismatch repair function and those with specific germline mutations in the DNA polymerase gene. Unfortunately, tumors with these specific mutator phenotypes are in the minority. Recent pre-clinical and clinical studies have begun to reveal encouraging results suggesting that checkpoint inhibitor therapy can be expanded to an increasing number of colorectal tumors with microsatellite stability and the absence of traditional predictive biomarkers of checkpoint inhibitor response. These studies generally rely on combinations of checkpoint inhibitors with chemotherapy, molecular targeted therapy, radiation therapy, or other novel immunomodulatory agents. This article will review the most current data in microsatellite stable colorectal cancer.

Before the advent of rationally designed targeted antineoplastic therapies, cladribine was identified as a lymphocyte-specific cytotoxic agent. Cladribine is a purine nucleoside analogue that is resistant to cellular catabolism. Through diverse mechanisms, cladribine is equally toxic to dividing and nondividing cells, making it highly active in indolent lymphoproliferative diseases. In clinical practice, cladribine is mostly used in the treatment of hairy cell leukemia and Waldenström's macroglobulinemia. However, its remarkable activity in follicular lymphoma and other indolent non-Hodgkin's lymphoma subtypes has not been more widely appreciated. Cladribine compares favorably to other standard treatments for these conditions. Future Phase III clinical studies should incorporate cladribine into multiagent chemotherapy programs to more fully evaluate its potential in indolent non-Hodgkin's lymphoma.

Background: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) mediate cancer immune suppression by promoting an immunosuppressive microenvironment that inhibits effective anti-tumor immunity. However, they are still a poorly understood, heterogeneous mix of neutrophil subsets. This study aims to determine the Siglec expression profile on several neutrophil subsets and assess their immunosuppressive ability.Methods: We identified CD16^high and CD16^low neutrophil subsets from the low-density fractions of human peripheral blood and compared them to high-density neutrophils. We profiled the expression of the entire family of Siglecs on these three key neutrophil populations under steady-state conditions in healthy subjects as well as cancer patients. Moreover, the ability of these populations, isolated from healthy subjects, to suppress T cell proliferation was assessed.Results: Two distinct subpopulations were investigated within the low-density fraction of human peripheral blood (CD15⁺CD66b⁺CD16^low and CD15⁺CD66b⁺CD16^high) and compared to high-density neutrophils (CD15⁺CD66b⁺CD16^high). We found that in addition to CD33 (Siglec-3), Siglec-5/-14, -7, and -9, are differentially expressed on the CD16^low and CD16^high low-density subsets in both healthy, steady-state subjects, and cancer patients. Upregulated expression of CD33 on the CD16^low cells led to the initial speculation that they are MDSCs. As the differential expression of Siglec-9 between these two populations was striking, we used CD16 and Siglec-9 double staining to quantify these populations, which demonstrated that the CD16^lowSiglec-9^low population is greatly upregulated in cancer patients. The CD16^high low-density and high-density neutrophils, but not the CD16^low low-density neutrophils from healthy subjects, inhibited T cell proliferation, indicating that the CD16^lowSiglec-9^low population are not MDSCs.Conclusions: These results demonstrate that Siglecs are differentially expressed on neutrophil subsets, and along with CD16, may be used to help further define what is a PMN-MDSC. Consistent with current observations by others, PMN-MDSCs may encompass an array of neutrophil subtypes, including low-density neutrophils, and point to the need for more work to precisely define the genetic signatures of PMN-MDSCs.