Summary Background Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to ...long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. Methods Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524 ) and EudraCT (number 2012-001334-33). Findings Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49·5%) of 107 VGX-3100 recipients and 11 (30·6%) of 36 placebo recipients had histopathological regression (percentage point difference 19·0 95% CI 1·4–36·6; p=0·034). In the modified intention-to-treat analysis 55 (48·2%) of 114 VGX-3100 recipients and 12 (30·0%) of 40 placebo recipients had histopathological regression (percentage point difference 18·2 95% CI 1·3–34·4; p=0·034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78·4%) than in the placebo group (24/42, 57·1%; percentage point difference 21·3 95% CI 5·3–37·8; p=0·007). Interpretation VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Funding Inovio Pharmaceuticals.
The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK-positive or ALK-negative advanced ...NSCLC, respectively.
Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1.
In the avelumab plus lorlatinib group (ALK-positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group (ALK-negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%–70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%–57%) with avelumab plus crizotinib (all partial responses).
Avelumab plus lorlatinib treatment in ALK-positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK-negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group.
NCT02584634
Background Patients with coronary artery disease (CAD) are characterized by an impaired cardiometabolic risk profile including high levels of atherogenic apolipoprotein (apo) B-containing lipoprotein ...levels. Genetic studies have highlighted a critical role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism and CAD risk. Objective To determine whether improving dietary quality and increasing physical activity levels improve parameters of the cardiometabolic risk profile such as plasma apoB and PCSK9 levels in patients with CAD. Methods We recruited 86 men aged between 39 and 80 years (82 of them on statins) undergoing coronary artery bypass graft (CABG) surgery. These patients participated in a 1-year lifestyle modification program aiming at achieving a minimum of 150 minutes/week of physical activity and improving diet quality by following dietary guidelines. We used magnetic resonance imaging to measure visceral adipose tissue and a modified Bruce protocol to measure fitness levels before and after the intervention. Results Plasma apoB and low-density lipoprotein cholesterol levels were not modified by the intervention (−3.0%, P = .08 and 1.3%, P = .56, respectively), whereas non-HDL cholesterol decreased by 4.5% ( P = .04) and triglycerides by 13% ( P = .002). In contrast, PCSK9 levels increased by 5.2% after the intervention ( P = .05). HDL cholesterol and apolipoprotein A-I levels also increased (+12%, P < .0001 and + 6%, P < .0001, respectively). PCSK9 levels increased with improvements in fitness ( r = 0.23, P = .04) and visceral fat mobilization ( r = −0.23, P = .04). Conclusion In post-CABG patients, a lifestyle modification program lead to significant improvements in some parameters of the lipoprotein profile but unexpectedly increased plasma PCSK9 levels.
About 5% of patients with coronavirus disease-2019 are admitted to the ICU for acute hypoxemic respiratory failure. Opinions differ on whether invasive mechanical ventilation should be used as ...first-line therapy over noninvasive oxygen support. The aim of the study was to assess the effect of early invasive mechanical ventilation in coronavirus disease-2019 with acute hypoxemic respiratory failure on day-60 mortality.
Multicenter prospective French observational study.
Eleven ICUs of the French OutcomeRea network.
Coronavirus disease-2019 patients with acute hypoxemic respiratory failure (Pao
/Fio
≤ 300 mm Hg), without shock or neurologic failure on ICU admission, and not referred from another ICU or intermediate care unit were included.
We compared day-60 mortality in patients who were on invasive mechanical ventilation within the first 2 calendar days of the ICU stay (early invasive mechanical ventilation group) and those who were not (nonearly invasive mechanical ventilation group). We used a Cox proportional-hazard model weighted by inverse probability of early invasive mechanical ventilation to determine the risk of death at day 60.
The 245 patients included had a median (interquartile range) age of 61 years (52-69 yr), a Simplified Acute Physiology Score II score of 34 mm Hg (26-44 mm Hg), and a Pao
/Fio
of 121 mm Hg (90-174 mm Hg). The rates of ICU-acquired pneumonia, bacteremia, and the ICU length of stay were significantly higher in the early (
= 117 48%) than in the nonearly invasive mechanical ventilation group (
= 128 52%),
< 0.01. Day-60 mortality was 42.7% and 21.9% in the early and nonearly invasive mechanical ventilation groups, respectively. The weighted model showed that early invasive mechanical ventilation increased the risk for day-60 mortality (weighted hazard ratio =1.74; 95% CI, 1.07-2.83, p=0.03).
In ICU patients admitted with coronavirus disease-2019-induced acute hypoxemic respiratory failure, early invasive mechanical ventilation was associated with an increased risk of day-60 mortality. This result needs to be confirmed.
To assess the potential therapeutic effect of intratendinous injection of platelet-rich plasma (PRP) under ultrasound (US) guidance to treat tendon tears and tendinosis in a pilot study with ...long-term follow-up.
The study included 408 consecutive patients referred for treatment by PRP injection of tendinopathy in the upper (medial and lateral epicondylar tendons) and the lower (patellar, Achilles, hamstring and adductor longus, and peroneal tendons) limb who received a single intratendinous injection of PRP under US guidance. Clinical and US data were retrospectively collected for each anatomic compartment for upper and lower limbs before treatment (baseline) and 6 weeks after treatment. Late clinical data without US were collected until 32 months after the procedure (mean, 20.2 months). The McNemar test and regression model were used to compare clinical and US data.
QuickDASH score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and residual US size of lesions were significantly lower after intratendinous injection of PRP under US guidance at 6 weeks and during long-term follow-up compared with baseline (P < .001 in upper and lower limb) independent of age, gender, and type of tendinopathy (P > .29). No clinical complication was reported during follow-up.
Intratendinous injection of PRP under US guidance appears to allow rapid tendon healing and is well tolerated.
Background Vital dyes are widely used for lymphatic mapping and sentinel lymph node biopsy in patients with malignant tumors, and reports of anaphylactic reactions are becoming more frequent. ...Objective Our aims were to describe specific clinical features of hypersensitivity reactions to Patent Blue (Guerbet, Roissy, France), results of the allergy workup, and their consequences for patient management. Methods We report a series of 14 clinical cases of dye-induced anaphylaxis recorded between 2004 and 2006 in 4 member centers of a network of French allergoanesthesia outpatient clinics. Results Reactions appeared to be relatively severe (6/14 grade III reactions). An average 30 ± 6–minute delay was observed between dye injection and symptom onset. In 9 (65%) patients reactions were sustained for several hours, requiring prolonged continuous epinephrine infusion and transfer to an intensive care unit. Prick test results were positive in 8 patients. In 5 patients prick test results were negative, whereas intradermal test results were positive. Conclusion Anesthesiologists and allergologists must be aware of this specific risk and of the clinical characteristics of these reactions, which are usually delayed and long lasting.
Abstract Objective Early unplanned readmission to the intensive care unit (ICU) carries a poor prognosis, and post-ICU mortality may be related, in part, to premature ICU discharge. Our objectives ...were to identify independent risk factors for early post-ICU readmission or death and to construct a prediction model. Design Retrospective analysis of a prospective database was done. Setting Four ICUs of the French Outcomerea network participated. Patients Patients were consecutive adults with ICU stay longer than 24 hours who were discharged alive to same-hospital wards without treatment-limitation decisions. Main results Of 5014 admitted patients, 3462 met our inclusion criteria. Age was 60.6 ± 17.6 years, and admission Simplified Acute Physiology Score II (SAPS II) was 35.1 ± 15.1. The rate of death or ICU readmission within 7 days after ICU discharge was 3.0%. Independent risk factors for this outcome were age, SAPS II at ICU admission, use of a central venous catheter in the ICU, Sepsis-related Organ Failure Assessment and Systemic Inflammatory Response Syndrome scores before ICU discharge, and discharge at night. The predictive model based on these variables showed good calibration. Compared with SAPS II at admission or Stability and Workload Index for Transfer at discharge, discrimination was better with our model (area under receiver operating characteristics curve, 0.74; 95% confidence interval, 0.68-0.79). Conclusion Among patients without treatment-limitation decisions and discharged alive from the ICU, 3.0% died or were readmitted within 7 days. Independent risk factors were indicators of patients' severity and discharge at night. Our prediction model should be evaluated in other ICU populations.
Optimization of Total Hip Arthroplasty Implantation Rousseau, Marc-Antoine, MD, PhD; Lazennec, Jean Y., MD, PhD; Boyer, Patrick, MD, MS ...
The Journal of arthroplasty,
2009, 2009-1-00, Letnik:
24, Številka:
1
Journal Article
Recenzirano
Abstract The anterior pelvic plane (APP) is currently used as superficial anatomical landmark for three-dimensional orientation during total hip arthroplasty (THA), specifically when using computer ...aided surgery. However, the actual parameter for characterizing the pelvic orientation is the sacral slope, which correlates with other functional spinal parameters. The goal of the paper was to investigate relationships between APP and sacral slope. Both were measured on 328 lateral radiographs of the pelvis in standing position by two observers. The poor correlation between APP and sacral slope suggest keeping using the reference to the APP for the per-operative orientation in the 3D space, while individually adjusting the preoperative planning to the sacral slope.
A head-to-head comparison was performed between vascular endothelial growth factor blockade and laser for treatment of diabetic macular edema (DME).
Two similarly designed, double-masked, randomized, ...phase 3 trials, VISTA(DME) and VIVID(DME).
We included 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME with central involvement.
Eyes received either intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation.
The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy endpoints at week 52 included the proportion of eyes that gained ≥ 15 letters from baseline and the mean change from baseline in central retinal thickness as determined by optical coherence tomography.
Mean BCVA gains from baseline to week 52 in the IAI 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (P < 0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (P < 0.0001) in VIVID. The corresponding proportions of eyes gaining ≥ 15 letters were 41.6% and 31.1% versus 7.8% (P < 0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% (P < 0.0001) in VIVID. Similarly, mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 μm (P < 0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 μm (P < 0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse events, including the Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events and vascular deaths, were similar across treatment groups.
At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general, IAI was well-tolerated.
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