Does telaprevir possess a direct antidiabetic effect?

Hepatitis C virus (HCV) induces insulin resistance, which improves upon viral clearance. Telaprevir is a protease inhibitor effective against HCV genotype 1. We reported a case, whose history suggests that telaprevir may induce some antidiabetic effect independently of its suppression of HCV. A 56-year-old woman with obesity, type 2 diabetes treated with sitagliptin and metformin, and HCV-related cirrhosis was given triple therapy with pegylated interferon-alpha, ribavirin and telaprevir. After 2 weeks of treatment, HCV RNA was no longer detectable but the patient described a pronounced drop in the capillary glucose levels and episodes of hypoglycaemia that compelled her to stop all antidiabetic treatment. One month after stopping telaprevir, she had to resume her antidiabetic treatment, despite a persisting virological response. Despite reaching a sustained virological response, her diabetes progressed. Although the suppression of HCV replication may have played a role in reducing glucose intolerance, the fact that this patient resumed her prior antidiabetic treatment upon completing the telaprevir treatment, while still aviremic, suggests that telaprevir may have an additional antidiabetic effect. Further evidence about the possible role and mechanisms of telaprevir as antidiabetic agent is warranted.

Comparing Anticoagulation Strategies for Venous Thromboembolism Associated With Active Cancer: A Systematic Review and Meta-Analysis.

Background: Current guidelines recommend several direct oral anticoagulant agents (DOACs) equally for managing cancer-associated venous thromboembolism (VTE). Objectives: The aim of this study was to assess the efficacy and safety of DOACs in patients with active cancer. Methods: Literature searches were conducted in PubMed, Embase, and Cochrane Central in November 2022. Randomized controlled trials investigating anticoagulation strategies (vitamin K antagonists, parenteral anticoagulation [eg, low-molecular weight heparin], and DOACs) for VTE in patients with active cancer were identified for network meta-analysis. The outcomes included recurrent VTE, recurrent pulmonary embolism, recurrent deep venous thrombosis, major bleeding, clinically relevant nonmajor bleeding (CRNMB), and a composite outcome of major bleeding or CRNMB. Pooled HRs and 95% CIs were estimated using either the HR or relative risk provided from each study. Random-effects models were used for all the analyses. Results: Seventeen randomized controlled trials involving 6,623 patients with active cancer were included. No significant differences were found among the DOACs for efficacy outcomes (recurrent VTE, pulmonary embolism, and deep venous thrombosis). In terms of major bleeding, apixaban was similarly safe compared with dabigatran and rivaroxaban but was associated with a decreased risk compared with edoxaban (HR: 0.38; 95% CI: 0.15-0.93). Regarding CRNMB, edoxaban was similarly safe compared with apixaban but was associated with a decreased risk compared with rivaroxaban (HR: 0.31; 95% CI: 0.10-0.91). Compared with parenteral anticoagulation, apixaban was associated with a reduced risk for recurrent VTE (HR: 0.60; 95% CI: 0.38-0.93) without increasing bleeding, edoxaban was associated with an increased risk for major bleeding or CRNMB (HR: 1.35; 95% CI: 1.02-1.79), and rivaroxaban was associated with an increased risk for CRNMB (HR: 3.76; 95% CI: 1.43-9.88). Conclusions: DOACs demonstrate comparable efficacy but exhibit different safety profiles. Apixaban may confer an antithrombotic benefit without an increased risk for bleeding, distinguishing it from other contemporary anticoagulation strategies in patients with active cancer and VTE.

Durable Response after Olaparib Treatment for Perihilar Cholangiocarcinoma with Germline BRCA2 Mutation.

INTRODUCTION: Despite major advances in surveillance and management, advanced cholangiocarcinoma (CCA) still carries a dismal prognosis. In recent years, several actionable genomic alterations in pancreatobiliary malignancies have been identified. For instance, homologous recombination deficiency (HRD) has been considered a predictive biomarker of clinical response to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. CASE REPORT: A 53-year-old man with a stage 3 (T4N0M0) BRCA2-mutant CCA developed intolerable toxicity after 44 cycles of gemcitabine/cisplatin. In light of his HRD positivity, treatment was switched to single-agent olaparib. The patient showed a partial radiological response, which was maintained after 8 months of olaparib discontinuation (progression-free survival >36 months). CONCLUSION: Given the durable response observed, olaparib can be a valuable therapeutic tool in BRCA-mutant CCAs. Ongoing and future clinical trials are needed to confirm the role of PARP inhibition in similar patients and to define the clinicopathological and molecular profile of the individuals most likely to benefit.

Antimetastatic defense by CD8+ T cells.

Metastasis is an intricate process whereby tumor cells migrate from the primary tumor, survive in the circulation, seed distal organs, and proliferate to create metastatic foci. CD8+ T cells can detect and eliminate tumor cells. Research on CD8+ T cell-dependent antitumor immunity has classically focused on its role in the primary tumor. There is increasing evidence, however, that CD8+ T cells have unique antimetastatic functions in various steps of the metastatic cascade. Here, we review the mechanisms whereby CD8+ T cells control metastatic lesions. We discuss their role in each step of metastasis, metastatic dormancy, and metastatic clonal evolution as well as the consequent clinical repercussions.

A novel evidence-based predictor tool for hospitalization and length of stay: insights from COVID-19 patients in New York city.

Predictive models for key outcomes of coronavirus disease 2019 (COVID-19) can optimize resource utilization and patient outcome. We aimed to design and internally validate a web-based calculator predictive of hospitalization and length of stay (LOS) in a large cohort of COVID-19-positive patients presenting to the Emergency Department (ED) in a New York City health system. The study cohort consisted of consecutive adult (> 18 years) patients presenting to the ED of Mount Sinai Health System hospitals between March 2020 and April 2020, diagnosed with COVID-19. Logistic regression was utilized to construct predictive models for hospitalization and prolonged (> 3 days) LOS. Discrimination was evaluated using area under the receiver operating curve (AUC). Internal validation with bootstrapping was performed, and a web-based calculator was implemented. From 5859 patients, 65% were hospitalized. Independent predictors of hospitalization and extended LOS included older age, chronic kidney disease, elevated maximum temperature, and low minimum oxygen saturation (p < 0.001). Additional predictors of hospitalization included male sex, chronic obstructive pulmonary disease, hypertension, and diabetes. AUCs of 0.881 and 0.770 were achieved for hospitalization and LOS, respectively. Elevated levels of CRP, creatinine, and ferritin were key determinants of hospitalization and LOS (p < 0.05). A calculator was made available under the following URL: https://covid19-outcome-prediction.shinyapps.io/COVID19_Hospitalization_Calculator/ . This study yielded internally validated models that predict hospitalization risk in COVID-19-positive patients, which can be used to optimize resource allocation. Predictors of hospitalization and extended LOS included older age, CKD, fever, oxygen desaturation, elevated C-reactive protein, creatinine, and ferritin.

CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer.

Some breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39+PD-1+CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNFα and IFNγ. Immunotherapy reduces the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevents metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not total CD8+ T cells correlates with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Thus, we suggest that a primary breast tumor could prime a systemic, CD39+PD-1+CD8+ T cell response that favors metastatic dormancy in the lungs.

Eosinophils suppress Th1 responses and restrict bacterially induced gastrointestinal inflammation.

Eosinophils are predominantly known for their contribution to allergy. Here, we have examined the function and regulation of gastrointestinal eosinophils in the steady-state and during infection with Helicobacter pylori or Citrobacter rodentium We find that eosinophils are recruited to sites of infection, directly encounter live bacteria, and activate a signature transcriptional program; this applies also to human gastrointestinal eosinophils in humanized mice. The genetic or anti-IL-5-mediated depletion of eosinophils results in improved control of the infection, increased inflammation, and more pronounced Th1 responses. Eosinophils control Th1 responses via the IFN-γ-dependent up-regulation of PD-L1. Furthermore, we find that the conditional loss of IFN-γR in eosinophils phenocopies the effects of eosinophil depletion. Eosinophils further possess bactericidal properties that require their degranulation and the deployment of extracellular traps. Our results highlight two novel functions of this elusive cell type and link it to gastrointestinal homeostasis and anti-bacterial defense.

CSF1R-dependent myeloid cells are required for NK­mediated control of metastasis.

Myeloid leukocytes are essentially involved in both tumor progression and control. We show that neo-adjuvant treatment of mice with an inhibitor of CSF1 receptor (CSF1R), a drug that is used to deplete tumor-associated macrophages, unexpectedly promoted metastasis. CSF1R blockade indirectly diminished the number of NK cells due to a paucity of myeloid cells that provide the survival factor IL-15 to NK cells. Reduction of the number of NK cells resulted in increased seeding of metastatic tumor cells to the lungs but did not impact on progression of established metastases. Supplementation of mice treated with CSF1R-inhibitor with IL-15 restored numbers of NK cells and diminished metastasis. Our data suggest that CSF1R blockade should be combined with administration of IL-15 to reduce the risk of metastasis.

Gemcitabine Synergizes with Immune Checkpoint Inhibitors and Overcomes Resistance in a Preclinical Model and Mesothelioma Patients.

PURPOSE: Combination of immune checkpoint inhibitors with chemotherapy is under investigation for cancer treatment. EXPERIMENTAL DESIGN: We studied the rationale of such a combination for treating mesothelioma, a disease with limited treatment options. RESULTS: The combination of gemcitabine and immune checkpoint inhibitors outperformed immunotherapy alone with regard to tumor control and survival in a preclinical mesothelioma model; however, the addition of dexamethasone to gemcitabine and immune checkpoint inhibitors nullified the synergistic clinical response. Furthermore, treatment with gemcitabine plus anti-PD-1 resulted in an objective clinical response in two patients with mesothelioma, who were resistant to gemcitabine or anti-PD-1 as monotherapy. CONCLUSIONS: Thus, treatment of mesothelioma with a combination of gemcitabine with immune checkpoint inhibitors is feasible and results in synergistic clinical response compared with single treatment in the absence of steroids.