Crit Care Clin
Critically ill patients with cancer are vulnerable to infections because of the underlying malignancy, tumor-directed therapy, immunosuppression, breaches in mucosa or skin, malnutrition, and other factors. Neutropenia remains the most important risk factor for infection. Infectious complications occurring in critically ill patients with cancer can affect the bloodstream, lungs, gastrointestinal tract, central nervous system, urinary tract, and the skin. Pneumonias are the leading cause of infection in patients with cancer admitted to the intensive care unit. Consideration of opportunistic pathogens in the differential diagnosis is important in patients with impaired cellular and/or humoral immunity or compromised splenic function.
Clin Microbiol Rev
SUMMARYHosts with compromised or naive immune systems, such as individuals living with HIV/AIDS, transplant recipients, and fetuses, are at the highest risk for complications from cytomegalovirus (CMV) infection. Despite substantial progress in prevention, diagnostics, and treatment, CMV continues to negatively impact both solid-organ transplant (SOT) and hematologic cell transplant (HCT) recipients. In this article, we summarize important developments in the field over the past 10 years and highlight new approaches and remaining challenges to the optimal control of CMV infection and disease in transplant settings.
J Exp Med
Adoptive T cell therapy (ACT) with genetically modified T cells has shown impressive results against some hematologic cancers, but efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs). For example, Fas ligand is commonly overexpressed in TMEs and induces apoptosis in tumor-infiltrating, Fas receptor-positive lymphocytes. We engineered immunomodulatory fusion proteins (IFPs) to enhance ACT efficacy, combining an inhibitory receptor ectodomain with a costimulatory endodomain to convert negative into positive signals. We developed a Fas-4-1BB IFP that replaces the Fas intracellular tail with costimulatory 4-1BB. Fas-4-1BB IFP-engineered murine T cells exhibited increased pro-survival signaling, proliferation, antitumor function, and altered metabolism in vitro. In vivo, Fas-4-1BB ACT eradicated leukemia and significantly improved survival in the aggressive KPC pancreatic cancer model. Fas-4-1BB IFP expression also enhanced primary human T cell function in vitro. Thus, Fas-4-1BB IFP expression is a novel strategy to improve multiple T cell functions and enhance ACT against solid tumors and hematologic malignancies.
J Acquir Immune Defic Syndr
BACKGROUND: Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine has proven highly effective in preventing HIV acquisition and is therefore offered to all participants in the control group as part of the standard of care package in many new HIV prevention studies. We propose a methodology for predicting HIV incidence in a hypothetical "placebo arm" for open-label studies or clinical trials with active control among African women. We apply the method to an open-label PrEP study, HIV Prevention Trials Network 082, which tested strategies to improve PrEP adherence in young African women all of whom were offered PrEP. METHODS: Our model predicted HIV infection risk for female study cohorts in sub-Saharan Africa using baseline behavioral risk factors and contemporary HIV prevalence and viral suppression in the local male population. The model was calibrated to HIV incidence in the Vaginal and Oral Interventions to Control the Epidemic study. RESULTS: Our model reproduced the annual HIV incidence of 3.2%-4.8% observed over 1 year of follow-up in the placebo groups of 4 completed clinical studies. We predicted an annual HIV incidence of 3.7% (95% confidence interval: 3.2 to 4.2) among HIV Prevention Trials Network 082 participants in the absence of PrEP and other risk reduction interventions. CONCLUSIONS: We demonstrated the potential of the proposed methodology to provide HIV incidence predictions based on assessment of individual risk behaviors and community and time-specific HIV exposure risk using HIV treatment and viral suppression data. These estimates may serve as comparators in HIV prevention trials without a placebo group.
J Acquir Immune Defic Syndr
BACKGROUND: In the 2019 State of the Union Address, President Trump announced a plan for "Ending the HIV Epidemic" in the United States, with a goal to reduce new HIV infections by 90% by 2030. Phase I of the plan set an intermediate goal of a 75% reduction within 5 years, focusing on select states and counties. METHODS: We assessed the feasibility of the first phase of the plan by estimating the fraction of HIV diagnoses that occur within the targeted region, using a statistical model to predict new HIV cases in each county. We suggested new areas that should be added to the current plan, prioritizing by both a "Density Metric" of new HIV cases and a "Gap Metric" quantifying shortcomings in antiretroviral therapy and pre-exposure prophylaxis uptake. RESULTS: We found the current plan targets less than 60% of new diagnoses. The plan should be expanded to Puerto Rico, Florida, Georgia, Louisiana, and Maryland as well as parts of New York, North Carolina, Texas, and Virginia, areas which were prioritized by both metrics. CONCLUSION: Many of the highest priority areas, both by density of HIV cases and by lack of viral suppression and pre-exposure prophylaxis use, were not covered by the original plan, particularly in the South. The current plan to end the HIV epidemic must be expanded to these areas to feasibly allow for a 75% reduction in new HIV cases within 5 years.
Pediatr Clin North Am
As treatment evolves and the population who survive childhood cancer ages and increases in number, researchers must use novel approaches to prevent, identify and mitigate adverse effects of treatment. Future priorities include collaborative efforts to pool large cohort data to improve detection of late effects, identify late effects of novel therapies, and determine the contribution of genetic factors along with physiologic and accelerated aging among survivors. This knowledge should translate to individual risk prediction and prevention strategies. Finally, we must utilize health services research and implementation science to improve adoption of survivorship care recommendations outside of specialized pediatric oncology centers.
Importance: Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients. Objective: To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML. Design, Setting, and Participants: The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020. Intervention: Discontinuation of TKIs. Main Outcomes and Measures: Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR). Results: Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P<.001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P<.001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P.001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs. Conclusions and Relevance: In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies. Trial Registration: ClinicalTrials.gov Identifier: NCT02269267.
Eur J Immunol
In inflammatory bowel disease [IBD], inflammation can occur beyond the intestine and spread systemically causing complications such as arthritis, cachexia and anemia. Here, we determine the impact of CD45, a pan-leukocyte marker and tyrosine phosphatase, on IBD. Using a mouse model of T cell transfer colitis, normal T cells CD25- CD45RBhigh CD4+ T cells were transferred into Rag1-deficient mice (RAGKO), and CD45 deficient RAGKO mice (CD45RAGKO). Delayed weight loss and systemic wasting syndrome was present in CD45RAGKO mice compared to RAGKO mice, despite equivalent inflammation in the colon. CD45RAGKO mice had reduced serum levels of TNFα, and reduced TNFα production by splenic myeloid cells. CD45RAGKO mice also had increased numbers of erythroid progenitors in the spleen, which had previously been shown to be immunosuppressive. Adoptive transfer of these erythroid progenitors into RAGKO mice reduced their weight loss and TNFα expression by splenic red pulp macrophages. In vitro, erythroid cells suppressed TNFα expression in red pulp macrophages in a phagocytosis-dependent manner. These findings show a novel role for erythroid progenitors in suppressing the pro-inflammatory function of splenic macrophages and cachexia associated with IBD. This article is protected by copyright. All rights reserved.