Intracoronary pharmacotherapy in the management of coronary microvascular dysfunction

Although percutaneous coronary intervention restores optimal epicardial blood flow in most cases, abnormal myocardial perfusion may still persist. This might be as a result of macro and microembolization, neutrophil plugging, vasoconstriction, myocyte contracture, local intracellular and interstitial edema, intramural haemorrhage, and endothelial blistering. Local delivery of intracoronary pharmacotherapy via the coronary arteries may increase local drug concentration several fold, and may improve drug efficacy. Several pharmacological agents such as adenosine, calcium channel blockers, alpha blockers, beta(2) receptor activators, vasodilators, antithrombotics, and antiplatelet agents have been used to treat coronary microvascular dysfunction. This article reviews the results of trials of intracoronary pharmacotherapy to date

Transfusion associated microchimerism: a heretofore little recognized complication following transfusion

Potent antiplatelet and antithrombotic agents have significantly reduced mortality in the setting of acute coronary syndromes and percutaneous coronary intervention. However these agents are associated with increased bleeding which is in turn associated with adverse clinical outcomes. In many centers, transfusion is often used to correct for blood loss. Blood transfusion in the setting of acute coronary syndrome has been associated with adverse clinical outcomes including increased mortality. Transfusion associated microchimerism (TA-MC) is a newly recognized complication of blood transfusion. There is engraftment of the donor's hematopoietic stem cells in patients who then develop microchimerism. This article discusses the association of bleeding/blood transfusion with adverse outcomes and the potential role of TA-MC in clinical outcomes

Use of the TIMI frame count in the assessment of coronary artery blood flow and microvascular function over the past 15 years

Since its introduction, the TIMI frame count method has contributed to the understanding of the pathophysiology of coronary artery disease. In this article, the evolution of the TFC method and its applicability in the assessment of various therapeutic modalities are described

Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer

Abstract Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls. Adipose tissue loss is identified up to 6 months, and skeletal muscle wasting is identified up to 18 months before the clinical diagnosis of pancreatic cancer and is not present in the matched control population. Tissue losses are of similar magnitude in cases diagnosed with localized compared with metastatic disease and are not correlated with at-diagnosis circulating levels of CA19-9. Skeletal muscle wasting occurs in the 1–2 years before pancreatic cancer diagnosis and may signal an upcoming diagnosis of pancreatic cancer

G-CSF rescue of FOLFIRINOX-induced neutropenia leads to systemic immune suppression in mice and humans

Background Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes and neutrophils that contribute to both systemic and local immunosuppression in the tumor microenvironment. The effect of recombinant G-CSF (pegfilgrastim or filgrastim) on the production of myeloid-derived suppressive cells is unknown. Here we examined patients with pancreatic cancer, a disease known to induce myeloid-derived suppressor cells (MDSCs), and for which pegfilgrastim is routinely administered concurrently with FOLFIRINOX but not with gemcitabine-based chemotherapy regimens.Methods Serial blood was collected from patients with pancreatic ductal adenocarcinoma newly starting on FOLFIRINOX or gemcitabine/n(ab)paclitaxel combination chemotherapy regimens. Neutrophil and monocyte frequencies were determined by flow cytometry from whole blood and peripheral blood mononuclear cell fractions. Serum cytokines were evaluated pretreatment and on-treatment. Patient serum was used in vitro to differentiate healthy donor monocytes to MDSCs as measured by downregulation of major histocompatibility complex II (HLA-DR) and the ability to suppress T-cell proliferation in vitro. C57BL/6 female mice with pancreatic tumors were treated with FOLFIRINOX with or without recombinant G-CSF to directly assess the role of G-CSF on induction of immunosuppressive neutrophils.Results Patients receiving FOLFIRINOX with pegfilgrastim had increased serum G-CSF that correlated with an induction of granulocytic MDSCs. This increase was not observed in patients receiving gemcitabine/n(ab)paclitaxel without pegfilgrastim. Interleukin-18 also significantly increased in serum on FOLFIRINOX treatment. Patient serum could induce MDSCs as determined by in vitro functional assays, and this suppressive effect increased with on-treatment serum. Induction of MDSCs in vitro could be recapitulated by addition of recombinant G-CSF to healthy serum, indicating that G-CSF is sufficient for MDSC differentiation. In mice, neutrophils isolated from spleen of G-CSF-treated mice were significantly more capable of suppressing T-cell proliferation.Conclusions Pegfilgrastim use contributes to immune suppression in both humans and mice with pancreatic cancer. These results suggest that use of recombinant G-CSF as supportive care, while critically important for mitigating neutropenia, may complicate efforts to induce antitumor immunity

Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders

Background Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed.Methods This multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18).Results In the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder’s TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response.Conclusions Pembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab