Quality of Life With Pembrolizumab for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: KEYNOTE-040.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) affects health-related quality of life (HRQoL); few treatments have demonstrated clinically meaningful HRQoL benefit. KEYNOTE-040 evaluated pembrolizumab vs standard of care (SOC) in patients with recurrent and/or metastatic HNSCC whose disease recurred or progressed after platinum-containing regimen. METHODS: Patients received pembrolizumab 200 mg or SOC (methotrexate, docetaxel, or cetuximab). Exploratory HRQoL analyses used European Organisation for Research and Treatment of Cancer (EORTC) 30 quality-of-life, EORTC 35-question quality-of-life head and neck cancer-specific module, and EuroQoL 5-dimensions questionnaires. RESULTS: The HRQoL population comprised 469 patients (pembrolizumab = 241, SOC = 228). HRQoL compliance for patients in the study at week 15 was 75.3% (116 of 154) for pembrolizumab and 74.6% (85 of 114) for SOC. The median time to deterioration in global health status (GHS) and QoL scores were 4.8 months with pembrolizumab and 2.8 months with SOC (hazard ratio = 0.79, 95% confidence interval [CI] = 0.59 to 1.05). At week 15, GHS / QoL scores were stable for pembrolizumab (least squares mean [LSM] = 0.39, 95% CI = -3.00 to 3.78) but worsened for SOC (LSM = -5.86, 95% CI = -9.68 to -2.04); the LSM between-group difference was 6.25 points (95% CI = 1.32 to 11.18; nominal 2-sided P = .01). A greater difference in the LSM for GHS / QoL score occurred with pembrolizumab vs docetaxel (10.23, 95% CI = 3.15 to 17.30) compared with pembrolizumab vs methotrexate (6.21, 95% CI = -4.57 to 16.99) or pembrolizumab vs cetuximab (-1.44, 95% CI = -11.43 to 8.56). Pembrolizumab-treated patients had stable functioning and symptoms at week 15, with no notable differences from SOC. CONCLUSIONS: GHS / QoL scores were stable with pembrolizumab but declined with SOC in patients at week 15, supporting the clinically meaningful benefit of pembrolizumab in recurrent and/or metastatic HNSCC.

Pembrolizumab as First-line Therapy in Cisplatin-ineligible Advanced Urothelial Cancer (KEYNOTE-052): Outcomes in Older Patients by Age and Performance Status.

BACKGROUND: Patients with treatment-naive advanced urothelial cancer (UC) ineligible for cisplatin-based chemotherapy are typically older and have comorbidities, representing a difficult-to-treat population. OBJECTIVE: To evaluate the safety and antitumor activity of first-line pembrolizumab in subgroups of cisplatin-ineligible older patients (aged ≥65 and ≥75 yr) with advanced UC in KEYNOTE-052 (NCT02335424), including those with poor performance status (Eastern Cooperative Oncology Group performance status score 2 [ECOG PS2]). DESIGN, SETTING, AND PARTICIPANTS: Patients were cisplatin ineligible, had treatment-naive, histologically/cytologically confirmed, locally advanced/metastatic UC with measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1]), and had ECOG PS0-2. Patient subgroups analyzed were aged ≥65yr (n = 302), ≥75 yr (n = 179), ≥65yr with ECOG PS2 (≥65yr+ECOG PS2; n = 119), and ≥75 yr+ECOG PS2 (n = 78). INTERVENTION: All patients received pembrolizumab 200mg intravenously every 3 wk until confirmed progression, intolerable toxicity, patient withdrawal, or 24 mo of therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was objective response rate (ORR) as per RECIST v1.1. The key secondary endpoints were overall survival (OS), duration of response (DOR), and safety. RESULTS AND LIMITATIONS: ORRs for the ≥65yr, ≥75 yr, ≥65yr+ECOG PS2, and ≥75 yr+ECOG PS2 subgroups were 29%, 27%, 29%, and 31%, respectively; rates of complete and partial responses were similar across subgroups (9%, 5%, 6%, and 6%, and 20%, 22%, 23%, and 24%, respectively). Median DOR and OS were also consistent across the ≥65yr and ≥65yr+ECOG PS2 subgroups and the ≥75 yr and ≥75 yr+ECOG PS2 subgroups. Study limitations included open-label design, lack of a comparator group, and nature of post hoc exploratory analysis. CONCLUSIONS: The clinical benefit of pembrolizumab in advanced UC appeared to be consistent regardless of age and/or poor performance status. PATIENT SUMMARY: This study looked at whether older age and poorer performance status affect how well patients with previously untreated advanced urothelial cancer ineligible for standard-of-care treatment respond to pembrolizumab. Outcomes with pembrolizumab were not affected by older age or poorer performance status, making it an effective option.

Efficacy, immunogenicity, and safety of a 9-valent human papillomavirus vaccine in Latin American girls, boys, and young women.

BACKGROUND: A 9-valent human papillomavirus (HPV6/11/16/18/31/33/45/52/58; 9vHPV) vaccine was developed to expand coverage of the previously developed quadrivalent (HPV6/11/16/18; qHPV) vaccine. METHODS: Efficacy, immunogenicity, and safety outcomes were assessed in Latin American participants enrolled in 2 international studies of the 9vHPV vaccine, including a randomized, double-blinded, controlled with qHPV vaccine, efficacy, immunogenicity, and safety study in young women aged 16-26 years, and an immunogenicity and safety study in girls and boys aged 9-15 years. Participants (N=5312) received vaccination at Day 1, Month 2, and Month 6. Gynecological swabs were collected regularly in young women for cytological and HPV DNA testing. Serum was analyzed for HPV antibodies in all participants. Adverse events (AEs) were also monitored in all participants. RESULTS: The 9vHPV vaccine prevented HPV 31-, 33-, 45-, 52-, and 58-related high-grade cervical, vulvar, and vaginal dysplasia with 92.3% efficacy (95% confidence interval 54.4, 99.6). Anti-HPV6, 11, 16, and 18 geometric mean titers at Month 7 were similar in the 9vHPV and qHPV vaccination groups. Anti-HPV antibody responses following vaccination were higher among girls and boys than in young women. Most (>99%) 9vHPV vaccine recipients seroconverted for all 9 HPV types at Month 7. Antibody responses to the 9 HPV types persisted over 5 years. The most common AEs were injection-site related, mostly of mild to moderate intensity. CONCLUSIONS: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Latin American young women, girls, and boys. These data support 9vHPV vaccination programs in Latin America, a region with substantial cervical cancer burden.

Antibody persistence and evidence of immune memory at 5years following administration of the 9-valent HPV vaccine.

BACKGROUND: The 9-valent HPV (9vHPV) vaccine was developed to prevent infection and disease related to 9 HPV types (HPV6/11/16/18/31/33/45/52/58) which cause approximately 90% of cervical cancers, HPV-related vulvar, vaginal and anal cancers, and genital warts worldwide. In a pivotal efficacy study, the 9vHPV vaccine prevented infection and disease due to the 9 vaccine types. Duration of protection remains to be determined. Vaccines that induce long-term protection are generally characterized by the generation of immune memory. The purpose of this report is to assess the persistence of HPV antibody response and existence of immune memory at 5years post-vaccination. METHODS: A subset of subjects (N=150) who received 3 doses of 9vHPV vaccine at day 1, month 2 and month 6 in the pivotal efficacy study continued in a study extension and received a fourth dose of 9vHPV vaccine at month 60. Serum HPV antibody levels were measured pre-dose 4 and at 7 and 28days post-dose 4 by competitive Luminex immunoassay. Adverse events were assessed using a vaccination report card. RESULTS: HPV antibodies induced following the 3-dose series of 9vHPV vaccine in the base study persisted through month 60 with seropositivity rates ranging from 77.5% to 100%. Geometric mean titers at 1week and 1month post-dose 4 were 1.25-4.10 and 1.65-4.88-fold higher, respectively, than levels observed 1month following the completion of the three-dose primary series. Seropositivity rates were >99% and 100% at 1week and 1month post-dose 4, respectively. The fourth dose of 9vHPV vaccine was generally well tolerated. CONCLUSIONS: A three-dose regimen of the 9vHPV vaccine induced persistent HPV antibody response through 5years post-vaccination. Administration of a fourth dose resulted in a strong anamnestic response to all 9 vaccine types. These findings suggest that the efficacy of the 9vHPV vaccine will be long lasting. Clinical Trials.gov Identifier:NCT00543543.

Design of a long-term follow-up effectiveness, immunogenicity and safety study of women who received the 9-valent human papillomavirus vaccine.

The 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets four HPV types (6/11/16/18) also covered by the quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). Vaccine efficacy to prevent HPV infection and disease was established in a Phase III clinical study in women 16-26years of age. A long-term follow-up (LTFU) study has been initiated as an extension of the Phase III clinical study to assess effectiveness of the 9vHPV vaccine up to at least 14years after the start of vaccination. It includes participants from Denmark, Norway and Sweden and uses national health registries from these countries to assess incidence of cervical pre-cancers and cancers due to the 7 oncogenic types in the vaccine (HPV 16/18/31/33/45/52/58). Incidences will be compared to the estimated incidence rate in an unvaccinated cohort of similar age and risk level. This LTFU study uses a unique design: it is an extension of a Phase III clinical study and also has elements of an epidemiological study (i.e., endpoints based on standard clinical practice; surveillance using searches from health registries); it uses a control chart method to determine whether vaccine effectiveness may be waning. Control chart methods which were developed in industrial and manufacturing settings for process and production monitoring, can be used to monitor disease incidence in real-time and promptly detect a decrease in vaccine effectiveness. Experience from this innovative study design may be applicable to other medicinal products when long-term outcomes need to be assessed, there is no control group, or outcomes are rare.

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.

Importance: Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. Objective: To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Design, Setting, and Participants: Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Interventions: Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. Main Outcomes and Measures: The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Results: Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Conclusions and Relevance: Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01984697.

Effects of an internet support system to assist cancer patients in reducing symptom distress: a randomized controlled trial.

BACKGROUND: Cancer patients experience many physical and psychosocial problems for which they need support. WebChoice is an Internet-based, interactive health communication application that allows cancer patients to monitor their symptoms and problems, provides individually tailored information and self-management support, e-communication with expert cancer nurses, and an e-forum for group discussion with other patients. OBJECTIVE: The objective of this study was to examine the effects of WebChoice on symptom distress (primary outcome), depression, self-efficacy, health-related quality of life, and social support (secondary outcomes). METHODS: In this 1-year repeated-measures randomized controlled trial, 325 breast and prostate cancer patients were randomized into 1 experimental group with access to WebChoice and 1 control group who received URLs of publicly available cancer Web sites. RESULTS: Group differences on symptom distress were significant only for the global symptom distress index on the Memorial Symptom Assessment Scale (slope estimate, -0.052 [95% confidence interval, -0.101 to -0.004]; t = 4.42; P = .037). There were no significant group differences on secondary outcomes. Additional analyses showed significant within-group improvements in depression in the experimental group only. In the control group, self-efficacy and health-related quality of life deteriorated significantly over time. CONCLUSION: This randomized controlled trial is one of the first to evaluate effects of an interactive health communication application to support cancer patients in illness management on symptoms. Although only 1 hypothesis was partially supported, the combined results show a clear trend toward better scores in the intervention group on most outcome measures. IMPLICATIONS FOR PRACTICE: If findings can be supported with additional research, WebChoice may become an important tool to support nursing care that can equip cancer patients to better manage their illness.

Effects of a computer-supported interactive tailored patient assessment tool on patient care, symptom distress, and patients' need for symptom management support: a randomized clinical trial.

OBJECTIVE: To examine the effects of a computer-assisted, interactive tailored patient assessment (ITPA) tool in oncology practice on: documented patient care, symptom distress, and patients' need for symptom management support during treatment and rehabilitation. DESIGN AND METHODS: For this repeated measures clinical trial at a university hospital in Norway, 145 patients starting treatment for leukemia or lymphoma were randomly assigned to either an intervention (n=75) or control group (n=70). Both groups used the ITPA for symptom assessments prior to inpatient and outpatient visits for up to one year. The assessment summary, which displayed patients' self-reported symptoms, problems, and distress in rank-order of the patient's need for support, was provided to physicians and nurses in the intervention group only but not in the control group. RESULTS: Significantly more symptoms were addressed in the intervention group patient charts versus those of the control group. Symptom distress in the intervention group decreased significantly over time in 11 (58%) of 19 symptom/problem categories versus 2 (10%) for the control group. Need for symptom management support over time also decreased significantly more for the intervention group than the control group in 13 (68%) symptom categories. CONCLUSION: This is the first study to show that an ITPA used in an interdisciplinary oncology practice can significantly improve patient-centered care and patient outcomes, including reduced symptom distress and reduced need for symptom management support.

Improvements in distal lung function correlate with asthma symptoms after treatment with oral montelukast.

STUDY OBJECTIVES: The distal airways are likely to contribute to asthma pathobiology and symptoms but have rarely been specifically evaluated in relation to systemic oral therapy. We hypothesized that treatment with montelukast, an oral cysteinyl-leukotriene receptor antagonist, would improve both proximal and distal lung physiology in patients with mild asthma. DESIGN: Randomized, double-blind, crossover design. SETTING: Academic referral center. PATIENTS: Subjects with mild asthma limited to using short-acting inhaled beta(2)-agonists. INTERVENTIONS: Nineteen subjects with mild asthma underwent a baseline assessment of lung function, lung mechanics, and symptoms, followed by randomization to therapy with montelukast, 10 mg taken in the evening, or placebo in a crossover, double-blind fashion. Each treatment phase lasted 4 weeks, with a 2-week washout period. A repeat evaluation was performed during the last week of each treatment phase. MEASUREMENTS AND RESULTS: Montelukast resulted in improvement in (mean +/- SD) proximal and distal lung function parameters (change in FEV(1): montelukast, 0.16 +/- 0.06 L; placebo, -0.05 +/- 0.05 L; p = 0.008); change in specific conductance: montelukast, 7.2 +/- 2.9% predicted; placebo, -17 +/- 8% predicted; p = 0.007; change in % predicted residual volume [RV]: montelukast, 18.4 +/- 8.3% predicted; placebo, 3.0 +/- 2.9% predicted; p = 0.05). Improvement in symptoms (ie, wheeze and chest tightness) correlated with improvements in RV while receiving montelukast, but not while receiving placebo (Pearson coefficients: 0.55 and 0.66, respectively; p < 0.008 and 0.04, respectively). CONCLUSIONS: The systemically acting oral agent montelukast improves proximal and distal lung physiology. Improvements in distal lung function correlate with improvements in asthma symptoms.

Surface enhanced laser desorption/ionization (SELDI) time-of-flight mass spectrometry to identify patients with chronic obstructive pulmonary disease.

There are currently no blood tests to identify the majority of smokers at risk for chronic obstructive pulmonary disease (COPD). We used plasma protein profiles from surface enhanced laser desorption/ionization (SELDI) time-of-flight mass spectrometry to identify a panel of protein biomarkers that can distinguish patients with COPD from closely matched controls. Plasma was obtained from 30 COPD subjects and 30 controls matched for age, sex, and smoking history. Plasma protein profiles were generated using Cu2+-immobilized metal affinity capture (IMAC) and strong anion exchanger (Q10) protein chips. Classification and regression tree (CART) analysis identified a panel of 5 biomarkers using the IMAC protein chip that could distinguish COPD patients from controls with sensitivity and specificity of 91.67% and 88.33%, respectively. The 10-fold cross-validation yielded 81.67% sensitivity and 81.67% specificity. This demonstrates the feasibility of using SELDI as a diagnostic test for COPD; however, larger cohorts will be needed to validate these biomarkers and determine their predictive value longitudinally.

Improved neurobehavioral functioning in emphysema patients following lung volume reduction surgery compared with medical therapy.

STUDY OBJECTIVES: The goal of this study was to evaluate the neuropsychological and psychological functioning of emphysema patients following lung volume reduction surgery (LVRS) compared with patients receiving only medical therapy (MT). DESIGN: Patients with moderate-to-severe emphysema who were enrolled in the National Emphysema Treatment Trial at two sites (National Jewish Medical and Research Center and Ohio State University) were given a neuropsychological battery at baseline, 6 to 10 weeks later (following participation in pulmonary rehabilitation), and at 6 months following randomization to either LVRS or MT treatment. SUBJECTS AND MEASUREMENTS: Twenty patients randomized to MT, 19 patients randomized to LVRS, and 39 matched, healthy control subjects completed a battery of tests that measured cognitive functioning, depression, anxiety, and quality of life (QoL). RESULTS: Controlling for practice, patients in the LVRS treatment arm at the 6-month follow-up demonstrated significant improvement compared with MT patients in cognitive tasks involving sequential skills and verbal memory. The LVRS patients also showed significant reductions in depression compared with the MT patients, as well as improved physical and psychosocial QoL. Correlational analysis indicated that improved immediate verbal memory in the LVRS group was related to improved QoL. No associations were found between changes in cognitive function and changes in depression, exercise performance, or pulmonary functioning. CONCLUSION: Patients who received LVRS demonstrated improvement in specific neuropsychological functions, depression, anxiety, and QoL scores compared with patients with continued MT treatment 6 months following randomization. However, mechanisms for these neurobehavioral changes are unclear. Improved verbal memory and sequential skills following LVRS were not directly associated with depression or exercise capacity. Nonetheless, LVRS led to a strong and likely clinically significant improvement in neuropsychological functioning over and above that explained by practice effects or MT. This finding adds to the growing list of clinical benefits of LVRS over MT, and supports additional research into the underlying mechanisms of this therapeutic effect.

Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency.

Patients who have common variable immunodeficiency (CVID) and granulomatous/lymphocytic interstitial lung disease (GLILD) are at high risk for early mortality and B cell lymphomas. Infection with human herpes virus type 8 (HHV8), a B cell lymphotrophic virus, is linked to lymphoproliferative disorders in people who have secondary immunodeficiencies. Therefore, we determined the prevalence of HHV8 infection in CVID patients with GLILD. Genomic DNA isolated from peripheral blood mononuclear cells was screened by nested- and real time-quantitative PCR (QRT-PCR) for the presence of HHV8 genome. It was positive in 6/9 CVID patients with GLILD (CVID-GLILD), 1/21 CVID patients without GLILD (CVID-control), and no patients receiving intravenous gamma globulin (n = 13) or normal blood donors (n = 20). Immunohistochemistry (IHC) demonstrated expression of the latency-associated nuclear antigen-1 (LANA-1) in the biopsies of the lung, liver, and bone marrow of four patients with CVID-GLILD. One CVID-GLILD patient developed a B cell lymphoma during the course of the study. QRT-PCR demonstrated high copy number of HHV8 genome and IHC showed diffuse staining for LANA-1 in the malignant lymph node. HHV8 infection may be an important factor in the pathogenesis of the interstitial lung disease and lymphoproliferative disorders in patients with CVID.

Short-term impact of a randomized multifaceted intervention for wheezing infants in low-income families.

OBJECTIVE: To present an interim analysis of the effect of a home-based intervention with low-income caregivers of wheezing infants at risk for childhood asthma on mediating variables. METHOD: Infants aged 9 to 24 months with 3 or more physician-documented wheezing episodes were randomly assigned to environmental support intervention (ES) (n = 90) or control (n = 91) groups. Nurse home visitors intervened for 1 year to decrease allergen and environmental tobacco smoke exposure and improve symptom perception and management. Assessments at baseline and 12 months included allergens in house dust, infant urinary cotinine levels, caregivers' symptom reports, quality of life, illness management, and quality of caregiving. Medical records were coded for hospitalizations, emergency department visits, and corticosteroid bursts. RESULTS: Within the ES group, cockroach allergen levels were significantly reduced and there was a trend toward reduction in dog dander levels. Among infants with detectable urinary cotinine, levels were significantly reduced in the ES group. Caregiver psychological resources modified the impact, and low-resource ES caregivers were the most strongly affected. Asthma knowledge and provider collaboration improved significantly in the ES group. Neither reports of infant symptoms nor emergency department visits or hospitalizations showed positive intervention effects. Number of corticosteroid bursts for infants was significantly higher for the ES group. CONCLUSIONS: The Childhood Asthma Prevention Study intervention was effective in reducing several environmental exposures and improving illness management. However, even with an intensive home-based intervention, we failed to reduce respiratory symptoms or medical use in the ES group relative to the control group, illustrating the difficulty of changing the course of early asthma development among low-income infants.

Macrophages kill human papillomavirus type 16 E6-expressing tumor cells by tumor necrosis factor alpha- and nitric oxide-dependent mechanisms.

The expression of adenovirus serotype 2 or 5 (Ad2/5) E1A sensitizes cells to killing by NK cells and activated macrophages, a property that correlates with the ability of E1A to bind the transcriptional coadaptor proteins p300-CBP. The E6 oncoproteins derived from the high-risk human papillomaviruses (HPV) interact with p300 and can complement mutant forms of E1A that cannot interact with p300 to induce cellular immortalization. Therefore, we determined if HPV type 16 (HPV16) E6 could sensitize cells to killing by macrophages and NK cells. HPV16 E6 expression sensitized human (H4 and C33A) and murine (MCA-102) cell lines to lysis by macrophages but not by NK cells. The lysis of cells that expressed E6 by macrophages was p53 independent but dependent on the production of tumor necrosis factor alpha (TNF-alpha) or nitric oxide (NO) by macrophages. Unlike cytolysis assays with macrophages, E6 expression did not significantly sensitize cells to lysis by the direct addition of NO or TNF-alpha. Like E1A, E6 has been reported to sensitize cells to lysis by TNF-alpha by inhibiting the TNF-alpha-induced activation of NF-kappaB. We found that E1A, but not E6, blocked the TNF-alpha-induced activation of NF-kappaB, an activity that correlated with E1A-p300 binding. In summary, Ad5 E1A and HPV16 E6 sensitized cells to lysis by macrophages. Unlike E1A, E6 did not block the ability of TNF-alpha to activate NF-kappaB or sensitize cells to lysis by NK cells, TNF-alpha, or NO. Thus, there appears to be a spectrum of common and unique biological activities that result as a consequence of the interaction of E6 or E1A with p300-CBP.

Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels of serum immunoglobulins and an inability to make specific antibodies. OBJECTIVE: We sought to determine the prevalence, clinical characteristics, and effect on survival of noninfectious pulmonary disease in patients with CVID. METHODS: A retrospective analysis of 69 patients with CVID was performed. Patients were divided into 3 groups on the basis of the type of pulmonary disease present: group 1 (n=29), no pulmonary disease; group 2 (n=23), chronic respiratory symptoms without diffuse radiographic abnormalities; and group 3 (n=18), chronic respiratory symptoms and diffuse radiographic abnormalities. Group 3 patients were divided into 2 subgroups on the basis of the histopathologic pattern seen on biopsy. Group 3A (n=13) included patients with granulomatous lung disease, lymphocytic interstitial pneumonia, follicular bronchiolitis, and lymphoid hyperplasia, a group of syndromes referred to as granulomatous-lymphocytic interstitial lung disease (GLILD). Group 3B (n=5) consisted of patients with all other types of interstitial lung disease (ILD). RESULTS: Fifty-eight percent of patients with CVID had noninfectious pulmonary complications. Group 3A (GLILD) patients had worse prognosis than the other groups, with a median survival of 13.7 versus 28.8 years (P<.001). Lymphoproliferative disease occurred in 31% of patients with GLILD. GLILD was associated with the presence of dyspnea (P<.05); splenomegaly (P<.05); restrictive pulmonary physiology; consolidation, ground-glass, and reticular radiographic abnormalities; and low CD3+ (P<.05) and CD8+ cell populations (P<.01). CONCLUSION: ILD is common in patients with CVID. The presence of GLILD was associated with a worse prognosis and increased prevalence of lymphoproliferative disorders.

A catalytic antioxidant attenuates alveolar structural remodeling in bronchopulmonary dysplasia.

Superoxide anion and other oxygen-free radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia. We tested the hypothesis that a catalytic antioxidant metalloporphyrin AEOL 10113 can protect against hyperoxia-induced lung injury using a fetal baboon model of bronchopulmonary dysplasia. Fetal baboons were delivered by hysterotomy at 140 days of gestation (term = 185 days) and given 100% oxygen for 10 days. Morphometric analysis of alveolar structure showed that fetal baboons on 100% oxygen alone had increased parenchymal mast cells and eosinophils, increased alveolar tissue volume and septal thickness, and decreased alveolar surface area compared with animals given oxygen as needed. Treatment with AEOL 10113 (continuous intravenous infusion) during 100% oxygen exposure partially reversed these oxygen-induced changes. Hyperoxia increased the number of neuroendocrine cells in the peripheral lung, which was preceded by increased levels of urine bombesin-like peptide at 48 hours of age. AEOL 10113 inhibited the hyperoxia-induced increases in urine bombesin-like peptide and numbers of neuroendocrine cells. An increasing trend in oxygenation index over time was observed in the 100% oxygen group but not the mimetic-treated group. These results suggest that AEOL 10113 might reduce the risk of pulmonary oxygen toxicity in prematurely born infants.

Immunomodulatory effects of melatonin in asthma.

Patients with nocturnal asthma demonstrate circadian variations in airway inflammation. We hypothesized that melatonin, a circadian rhythm regulator, modulates circadian inflammatory variations in asthma. The effect of melatonin stimulation on peripheral blood mononuclear cell cytokine production was evaluated at 4:00 P.M. and 4:00 A.M. in normal control subjects, patients with nocturnal asthma, and patients with non-nocturnal asthma. Melatonin was proinflammatory, causing significantly increased production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha at 4:00 P.M. and 4:00 A.M. in all subject groups (range, 12.8 +/- 3.3 to 131.72 +/- 16.4%, p < or = 0.0003). The observed increases in cytokine production did not change between 4:00 P.M. and 4:00 A.M. in control subjects or in patients with nocturnal asthma (p > 0.05, both cases). At 4:00 P.M., the cytokine response to melatonin of patients with nocturnal asthma was greater than that of control subjects or patients with non-nocturnal asthma and did not change significantly at 4:00 A.M. At 4:00 P.M., the cytokine response of patients with non-nocturnal asthma was less than that of patients with nocturnal asthma and rose significantly at 4:00 A.M. (p = 0.0001, all comparisons). Melatonin is proinflammatory in both patients with asthma and healthy subjects. Patients with nocturnal asthma demonstrate the largest daytime cytokine response and cannot be further stimulated at 4:00 A.M., suggesting chronic overstimulation in vivo. These results suggest differential immunomodulatory effects of melatonin based on asthma clinical phenotype and may indicate an adverse effect of exogenous melatonin in asthma.