JNJ-64041757 (JNJ-757) is a live, attenuated, double-deleted Listeria monocytogenes–based immunotherapy expressing human mesothelin. JNJ-757 was evaluated in patients with advanced NSCLC as ...monotherapy (phase 1) and in combination with nivolumab (phase 1b/2).
Patients with stage IIIB/IV NSCLC who had received previous therapy were treated with JNJ-757 (1 × 108 or 1 × 109 colony-forming units CFUs) alone (NCT02592967) or JNJ-757 (1 × 109 CFU) plus intravenous nivolumab 240 mg (NCT03371381). Study objectives included the assessment of immunogenicity, safety, and efficacy.
In the monotherapy study, 18 patients (median age 63.5 y; women 61%) were treated with JNJ-757 (1 × 108 or 1 × 109 CFU) with a median duration of 1.4 months (range: 0–29). The most common adverse events (AEs) were pyrexia (72%) and chills (61%), which were usually mild and resolved within 48 hours. Peripheral proinflammatory cytokines and lymphocyte activation were induced posttreatment with transient mesothelin-specific T-cell responses in 10 of 13 biomarker-evaluable patients. With monotherapy, four of 18 response-evaluable patients had stable disease of 16 or more weeks, including one patient with a reduction in target lesions. In the combination study, 12 patients were enrolled (median age 63.5 y; women 33%). The most common AEs with combination therapy were pyrexia (67%) and chills (58%); six patients had grade 3 AEs or greater, including two cases of treatment-related fatal pneumonitis. The best overall response for the combination was stable disease in four of nine response-evaluable patients.
As monotherapy, JNJ-757 was immunogenic and tolerable, with mild infusion-related fever and chills. The limited efficacy of JNJ-757, alone or with nivolumab, did not warrant further investigation of the combination.
Study objective Randomized trials suggest that nonoperative treatment of uncomplicated appendicitis with antibiotics-first is safe. No trial has evaluated outpatient treatment and no US randomized ...trial has been conducted, to our knowledge. This pilot study assessed feasibility of a multicenter US study comparing antibiotics-first, including outpatient management, with appendectomy. Methods Patients aged 5 years or older with uncomplicated appendicitis at 1 US hospital were randomized to appendectomy or intravenous ertapenem greater than or equal to 48 hours and oral cefdinir and metronidazole. Stable antibiotics-first-treated participants older than 13 years could be discharged after greater than or equal to 6-hour emergency department (ED) observation with next-day follow-up. Outcomes included 1-month major complication rate (primary) and hospital duration, pain, disability, quality of life, and hospital charges, and antibiotics-first appendectomy rate. Results Of 48 eligible patients, 30 (62.5%) consented, of whom 16 (53.3%) were randomized to antibiotics-first and 14 (46.7%) to appendectomy. Median age was 33 years (range 9 to 73 years), median WBC count was 15,000/μL (range 6,200 to 23,100/μL), and median computed tomography appendiceal diameter was 10 mm (range 7 to 18 mm). Of 15 antibiotic-treated adults, 14 (93.3%) were discharged from the ED and all had symptom resolution. At 1 month, major complications occurred in 2 appendectomy participants (14.3%; 95% confidence interval CI 1.8% to 42.8%) and 1 antibiotics-first participant (6.3%; 95% CI 0.2% to 30.2%). Antibiotics-first participants had less total hospital time than appendectomy participants, 16.2 versus 42.1 hours, respectively. Antibiotics-first-treated participants had less pain and disability. During median 12-month follow-up, 2 of 15 antibiotics-first-treated participants (13.3%; 95% CI 3.7% to 37.9%) developed appendicitis and 1 was treated successfully with antibiotics; 1 had appendectomy. No more major complications occurred in either group. Conclusion A multicenter US trial comparing antibiotics-first to appendectomy, including outpatient management, is feasible to evaluate efficacy and safety.
Summary Background Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to ...investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis. Methods For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel). Findings We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 93% of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68–0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5–14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58–0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12–19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 53% of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 95% CI 0·69–1·09; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 59% of 3978 men) showed that docetaxel improved failure-free survival (0·70 0·61–0·81; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5–10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 88% of 3109 men) showed that addition of bisphosphonates improved survival (0·88 0·79–0·98; p=0·025), which translates to 5% (1–8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 0·83–1·07; p=0·323), which translates to an absolute improvement in survival of 2% (−3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 66% of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 0·89–1·18; p=0·724) or zoledronic acid (0·98 0·82–1·16; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials. Interpretation The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small. Funding Medical Research Council UK.
Abstract Background Ultrasound (US) measurement of the optic nerve sheath diameter (ONSD) has been utilized as an indirect assessment of intracranial pressure. It is usually performed by trained ...ultrasonographers. Objectives To evaluate whether or not emergency physicians (EP) are capable of measuring the ONSD accurately by US. Materials and Methods A retrospective measurement of ONSD was conducted on computed tomography (CT) scans of the head or facial bones. These patients had undergone ocular US performed by EPs prior to CT scanning. The CT scan measurements of ONSD read by a board-certified radiologist were compared with that of the US read by a registered diagnostic medical sonographer. A difference in measurements of the ONSD ≥ 0.5 mm between the two modalities was considered as significant for this study. Results The ONSD measurements were performed with CT scan and compared to that of the US. Of the 61 patients studied, 36 (59%) were male and 25 (41%) were female. The average age was 56 ± 17 years. All but 3 patients had ONSD measurements that were between 5 and 6 mm. Discrepancy in measurements of the ONSD between US and CT for both groups fell within our predetermined value (0.5 mm) for the majority of cases. None of the measurements were above 6 mm. The intraclass correlation coefficient was 0.9 (95% confidence interval 0.8846–0.9303). Conclusion Emergency physicians were capable of accurately measuring the ONSD using bedside US. Prospective studies with a larger sample size are recommended to validate these findings.
Abstract This study sought to prospectively examine the clinical and radiographic differences between direct anterior (DA-THA) and mini-posterior approach total hip arthroplasty (MPA-THA). Fifty-four ...patients were prospectively randomized to either MPA or DA-THA. Patient recorded diaries were collected. Radiographs were reviewed. SF-36, WOMAC and HHS scores were tabulated. Time to ambulation without any assistive device favored DA-THA (22 vs. 28 days, P = 0.04). Three week SF mental scores favored MPA-THA (60.66 vs. 58.43, P = 0.01). In a randomized prospective trial, patients undergoing DA-THA voluntarily quit use of all walking aids on average 6 days earlier than patients with a MPA-THA. Little additional clinical or radiographic benefit was seen between the cohorts.
Several fast solar wind streams and stream interaction regions (SIRs) were observed by the Parker Solar Probe (PSP) during its first orbit (2018 September-2019 January). During this time, several ...recurring SIRs were also seen at 1 au at both L1 (Advanced Composition Explorer (ACE) and Wind) and the location of the Solar Terrestrial Relations Observatory-Ahead (STEREO-A). In this paper, we compare four fast streams observed by PSP at different radial distances during its first orbit. For three of these fast stream events, measurements from L1 (ACE and Wind) and STEREO-A indicated that the fast streams were observed by both PSP and at least one of the 1 au monitors. Our associations are supported by simulations made by the ENLIL model driven by GONG-(ADAPT-)WSA, which allows us to contextualize the inner heliospheric conditions during the first orbit of PSP. Additionally, we determine which of these fast streams are associated with an SIR and characterize the SIR properties for these events. From these comparisons, we find that the compression region associated with the fast-speed streams overtaking the preceding solar wind can form at various radial distances from the Sun in the inner heliosphere inside 0.5 au, with the suprathermal ion population (energies between 30 and 586 keV) observed as isolated enhancements suggesting localized acceleration near the SIR stream interface at ∼0.3 au, which is unlike those seen at 1 au, where the suprathermal enhancements extend throughout and behind the SIR. This suprathermal enhancement extends further into the fast stream with increasing distance from the Sun.
Abstract Hookah (water pipe) smoking is a major new understudied epidemic affecting youth. Because burning charcoal is used to heat the tobacco product, hookah smoke delivers not only nicotine but ...also large amounts of charcoal combustion products, including carbon-rich nanoparticles that constitute putative coronary vasoconstrictor stimuli and carbon monoxide, a known coronary vasodilator. We used myocardial contrast echocardiography (MCE) perfusion imaging with intravenous lipid shelled microbubbles in young adult hookah smokers to determine the net effect of smoking hookah on myocardial blood flow. In nine hookah smokers (age 27±5 years, mean±SD), we measured myocardial blood flow velocity (β), myocardial blood volume (A), myocardial blood flow (A x β) as well as myocardial oxygen consumption (MVO2 ) before and immediately after 30 minutes of ad lib hookah smoking. Myocardial blood flow did not decrease with hookah smoking but rather increased acutely (88±10 to 120±19 a.u.·s-1 , mean±SE, p=0.02), matching a mild increase in MVO2 (6.5±0.3 to 7.6±0.4 ml·min-1 , p<0.001). This was manifested primarily by increased myocardial blood flow velocity (0.7±0.1 to 0.9±0.1 s-1 , p=0.01) with unchanged myocardial blood volume (133±7 to 137±7 a.u., p=ns), the same pattern of coronary microvascular response seen with a low-dose β-adrenergic agonist. Indeed, with hookah, the increased MVO2 was accompanied by decreased heart rate variability, an indirect index of adrenergic over-activity, and eliminated by β-adrenergic blockade (i.v. propranolol). In conclusion, nanoparticle-enriched hookah smoke either is not an acute coronary vasoconstrictor stimulus or its vasoconstrictor effect is too weak to overcome the physiologic dilation of coronary microvessels matching mild cardiac β-adrenergic stimulation.
Objective The study objectives were to (1) compare survival after lung transplantation in patients requiring pretransplant mechanical ventilation or extracorporeal membrane oxygenation with that of ...patients not requiring mechanical support and (2) identify risk factors for mortality. Methods Data were obtained from the United Network for Organ Sharing for lung transplantation from October 1987 to January 2008. A total of 15,934 primary transplants were performed: 586 in patients on mechanical ventilation and 51 in patients on extracorporeal membrane oxygenation. Differences between nonsupport patients and those on mechanical ventilation or extracorporeal membrane oxygenation support were expressed as 2 propensity scores for use in comparing risk-adjusted survival. Results Unadjusted survival at 1, 6, 12, and 24 months was 83%, 67%, 62%, and 57% for mechanical ventilation, respectively; 72%, 53%, 50%, and 45% for extracorporeal membrane oxygenation, respectively; and 93%, 85%, 79%, and 70% for unsupported patients, respectively ( P < . 0001). Recipients on mechanical ventilation were younger, had lower forced vital capacity, and had diagnoses other than emphysema. Recipients on extracorporeal membrane oxygenation were also younger, had higher body mass index, and had diagnoses other than cystic fibrosis/bronchiectasis. Once these variables, transplant year, and propensity for mechanical support were accounted for, survival remained worse after lung transplantation for patients on mechanical ventilation and extracorporeal membrane oxygenation. Conclusion Although survival after lung transplantation is markedly worse when preoperative mechanical support is necessary, it is not dismal. Thus, additional risk factors for mortality should be considered when selecting patients for lung transplantation to maximize survival. Reduced survival for this high-risk population raises the important issue of balancing maximal individual patient survival against benefit to the maximum number of patients.
Objectives The objectives of this study were to determine adverse outcomes during pregnancy in women with dilated cardiomyopathy (DCM) and to compare their cardiac outcomes with those of nonpregnant ...women with DCM. Background Women with DCM are at risk for complications during pregnancy, but few studies have examined outcomes in this specific population. Methods This was a substudy of a larger prospective cohort study of outcomes in women with heart disease. Maternal cardiac, obstetric, and fetal outcomes in pregnancy in women with DCM were examined. For comparison, cardiac outcomes in nonpregnant women with DCM (n = 18) matched by age and left ventricular (LV) systolic function were examined. A matched-pair survival analysis was used to compare groups. Results Thirty-six pregnancies in 32 women with DCM were included. Thirty-nine percent (14 of 36) of the pregnancies were complicated by at least 1 maternal cardiac event. In the multivariate analysis, moderate or severe LV dysfunction and/or New York Heart Association functional class III or IV (p = 0.003) were the main determinants of adverse maternal cardiac outcomes during pregnancy. In the subset of women with moderate/severe LV dysfunction, 16-month event-free survival was worse in pregnant women compared with nonpregnant women (28 ± 11% vs. 83 ± 10%, p = 0.02). The adverse neonatal event rate was highest among women with obstetric and cardiac risk factors (43%). Conclusions In pregnant women with DCM the risk of adverse cardiac events is considerable, and pre-pregnancy characteristics can identify women at the highest risk. Pregnancy seems to have a short-term negative impact on the clinical course in women with DCM.
Summary Background Every year, 1·1 million babies die from prematurity, and many survivors are disabled. Worldwide, 15 million babies are born preterm (<37 weeks' gestation), with two decades of ...increasing rates in almost all countries with reliable data. The understanding of drivers and potential benefit of preventive interventions for preterm births is poor. We examined trends and estimate the potential reduction in preterm births for countries with very high human development index (VHHDI) if present evidence-based interventions were widely implemented. This analysis is to inform a rate reduction target for Born Too Soon. Methods Countries were assessed for inclusion based on availability and quality of preterm prevalence data (2000–10), and trend analyses with projections undertaken. We analysed drivers of rate increases in the USA, 1989–2004. For 39 countries with VHHDI with more than 10 000 births, we did country-by-country analyses based on target population, incremental coverage increase, and intervention efficacy. We estimated cost savings on the basis of reported costs for preterm care in the USA adjusted using World Bank purchasing power parity. Findings From 2010, even if all countries with VHHDI achieved annual preterm birth rate reductions of the best performers for 1990–2010 (Estonia and Croatia), 2000–10 (Sweden and Netherlands), or 2005–10 (Lithuania, Estonia), rates would experience a relative reduction of less than 5% by 2015 on average across the 39 countries. Our analysis of preterm birth rise 1989–2004 in USA suggests half the change is unexplained, but important drivers include non-medically indicated labour induction and caesarean delivery and assisted reproductive technologies. For all 39 countries with VHHDI, five interventions modelling at high coverage predicted a 5% relative reduction of preterm birth rate from 9·59% to 9·07% of livebirths: smoking cessation (0·01 rate reduction), decreasing multiple embryo transfers during assisted reproductive technologies (0·06), cervical cerclage (0·15), progesterone supplementation (0·01), and reduction of non-medically indicated labour induction or caesarean delivery (0·29). These findings translate to roughly 58 000 preterm births averted and total annual economic cost savings of about US$3 billion. Interpretation We recommend a conservative target of a relative reduction in preterm birth rates of 5% by 2015. Our findings highlight the urgent need for research into underlying mechanisms of preterm births, and development of innovative interventions. Furthermore, the highest preterm birth rates occur in low-income settings where the causes of prematurity might differ and have simpler solutions such as birth spacing and treatment of infections in pregnancy than in high-income countries. Urgent focus on these settings is also crucial to reduce preterm births worldwide. Funding March of Dimes, USA, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institutes of Health, USA.
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