Monocytic Myeloid-Derived Suppressor Cells Underpin Resistance to Adoptive T Cell Therapy in Nasopharyngeal Carcinoma.

Advanced, late-stage Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) is incurable, and its treatment remains a clinical and therapeutic challenge. Results from a phase II clinical trial in advanced NPC patients employing a combined chemotherapy and EBV-specific T cell (EBVST) immunotherapy regimen showed a response rate of 71.4%. Longitudinal analysis of patient samples showed that an increase in EBV DNA plasma concentrations and the peripheral monocyte-to-lymphocyte ratio negatively correlated with overall survival. These parameters were combined into a multivariate analysis to stratify patients according to risk of death. Immunophenotyping at serial time points showed that low-risk individuals displayed significantly decreased amounts of monocytic myeloid-derived suppressor cells postchemotherapy, which subsequently influenced successful cytotoxic T-lymphocyte (CTL) immunotherapy. Examination of the low-risk group, 2 weeks post-EBVST infusion, showed that individuals with a greater overall survival possessed an increased frequency of CD8 central and effector memory T cells, together with higher levels of plasma interferon (IFN)-γ, and cytotoxic lymphocyte-associated transcripts. These results highlight the importance of the rational selection of chemotherapeutic agents and consideration of their impact on both systemic immune responses and downstream cellular immunotherapy outcomes.

Dominant-negative NFKBIA mutation promotes IL-1ß production causing hepatic disease with severe immunodeficiency.

Although IKK-ß has previously been shown as a negative regulator of IL-1ß secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1ß expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1ß secretion was elevated in the patient's stimulated leukocytes, in her induced pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient's hypersecretion of IL-1ß correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1ß release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1ß secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.

Frailty in Hospitalized Older Adults: Comparing Different Frailty Measures in Predicting Short- and Long-term Patient Outcomes.

OBJECTIVES: Data for the assessment of frailty in acutely ill hospitalized older adults remains limited. Using the Frailty Index (FI) as "gold standard," we compared (1) the diagnostic performance of 3 frailty measures (FRAIL, Clinical Frailty Scale [CFS], and Tilburg Frailty Indicator [TFI]) in identifying frailty, and (2) their ability to predict negative outcomes at 12 months after enrollment. DESIGN: Prospective cohort study. PARTICIPANTS: We recruited 210 patients (mean age 89.4 ± 4.6 years, 69.5% female), admitted to the Department of Geriatric Medicine in a 1300-bed tertiary hospital. MEASUREMENTS: Premorbid frailty status was determined. Data on comorbidities, severity of illness, functional status, and cognitive status were gathered. We compared area under receiver operator characteristic curves (AUC) for each frailty measure against the reference FI. Multiple logistic regression was used to examine the independent association between frailty and the outcomes of interest. RESULTS: Frailty prevalence estimates were 87.1% (FI), 81.0% (CFS), 80.0% (TFI), and 50.0% (FRAIL). AUC against FI ranged from 0.81 (95% confidence interval [CI] 0.72-0.90: FRAIL) to 0.91 (95% CI 0.87-0.95: CFS). Only FRAIL was associated with higher in-hospital mortality (6.7% vs 1.0%, P = .031). FRAIL and CFS were significantly associated with increased length of hospitalization (10 [6.0-17.5] vs 8 [5.0-14.0] days, P = .043 and 9 [5.0-17.0] vs 7 [4.25-11.75] days, P = .036, respectively). CFS and FI were highly associated with mortality at 12-month (CFS, frail vs nonfrail: 32.9% vs 2.5%, P < .001, and FI, frail vs nonfrail: 30.6% vs 3.7%, P < .001). CFS also conferred the greatest risk of 12-month mortality (odds ratio [OR] 5.78, 95% CI 3.19-10.48, P < .001) and composite outcomes of institutionalization and/or mortality (OR 3.69, 95% CI 2.31-5.88, P < .001), adjusted for age, sex, and severity of illness. CONCLUSION: Our study affirms the utility of frailty assessment tools among older persons in acute care. FRAIL conferred highest risk of in-hospital mortality. However, CFS had greatest risk of mortality and institutionalization within 12 months.

Frailty and Risk of Adverse Outcomes in Hospitalized Older Adults: A Comparison of Different Frailty Measures.

OBJECTIVES: There is a paucity of data for the assessment of frailty in acutely ill hospitalized older adults. We aim to (1) compare the performance of frailty measures [5-item scale of fatigue, resistance, ambulation, illnesses, and loss of weight) (FRAIL), Tilburg Frailty Indicator (TFI), and Clinical Frailty Scale (CFS)] in identifying frailty, using the widely adopted Frailty Index (FI) as "gold standard," and (2) compare their ability to predict negative outcomes among hospitalized older adults. DESIGN: Prospective cohort study. SETTING: Acute inpatient care. PARTICIPANTS: A total of 210 patients (mean age 89.4 ± 4.6 years, 69.5% female) admitted to the Department of Geriatric Medicine. MEASUREMENTS: Premorbid frailty status was assessed by FI, FRAIL, TFI, and CFS. We collected data on comorbidities, severity of illness, functional status, and cognitive status. We compared area under receiver operator characteristic curves for FRAIL, TFI, and CFS against the reference FI. Multiple logistic regression was performed to examine the association between frailty and the primary outcome of in-hospital mortality. RESULTS: Frailty prevalence estimates were 87.1% (FI), 50% (FRAIL), 80% (TFI), and 81% (CFS). Area under receiver operator characteristics against FI ranged from 0.81 [95% confidence interval (CI) 0.72-0.90: FRAIL] to 0.91 (95% CI 0.87-0.95: CFS), with no significant difference on receiver operating characteristic curve contrast. Frailty, as defined by FRAIL score ≥3, was associated with higher in-hospital mortality (6.7% vs 1.0%, P = .031) and length of hospitalization [10 days (6.0-17.5) vs 8 days (5.0-14.0), P = .043]. FI [odds ratio (OR) = 1.15, 95% CI 1.00-1.33, P = .05], FRAIL (OR = 3.31, 95% CI 1.43-7.67, P = .005), and CFS (OR = 2.57, 95% CI 1.14-5.83, P = .023) independently predicted in-hospital mortality adjusted for age, sex, and severity of illness. CONCLUSIONS: FRAIL and CFS are simple frailty measures that may identify older adults at highest risk of adverse outcomes of hospitalization. FRAIL performed better in predicting in-hospital mortality.

Twice-weekly pegylated interferon-α-2a and ribavirin results in superior viral kinetics in HIV/hepatitis C virus co-infected patients compared to standard therapy.

BACKGROUND: Hepatitis C virus (HCV)/HIV co-infected patients have more rapid progression of liver fibrosis and only modest cure rates (sustained virologic responses, SVRs) when compared to HCV monoinfected patients. METHOD: We compared the virologic responses of either twice-weekly peginterferon-α-2a 180 µg/week (for 4 weeks, followed by weekly dosing) or weekly peginterferon-α-2a 180 µg/week, and weight-based ribavirin (1-1.2 g/day), among HIV/HCV co-infected genotype-1 individuals. RESULTS: Patients receiving the investigational dosing had lower levels of HCV RNA at all time points after initiation of therapy. More patients on this arm achieved clinically relevant early virological responses at weeks 1, 2, 4, 12, and 24. The enhanced early virologic response observed with the investigational arm was associated with a higher induction of interferon-stimulated genes. This early double dose regimen also resulted in a rapid normalization of liver enzymes. Twice-weekly peginterferon-α-2a was associated with more frequent early virological responses with similar safety profiles when compared with standard therapy. CONCLUSION: Our results, when confirmed in larger randomized clinical trials, may provide a novel therapeutic approach to improve SVR among HIV/HCV co-infected patients, especially African-American patients.