Background
Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment ...of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM.
Methods
Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS).
Results
The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (
n
= 91), the ORR was 36.3 % (95 % confidence interval CI, 26.44–47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed.
Conclusion
Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).
Live attenuated herpes zoster vaccine administered to HIV-infected adults suppressed on antiretroviral therapy with CD4+ counts ≥200 cells/µL was generally safe and immunogenic. Antibody responses ...were similar to those observed in older adults without HIV infection who received the same vaccine.
Abstract
Background
Herpes zoster (HZ) risk is increased in human immunodeficiency virus (HIV)-infected persons. Live attenuated zoster vaccine (ZV) reduces HZ incidence and severity in adults; safety and immunogenicity data in HIV-infected adults are limited.
Methods
We conducted a randomized, double-blind, placebo-controlled trial in HIV-infected adults virally suppressed on antiretroviral therapy (ART). Participants, stratified by CD4+ count (200-349 or ≥350 cells/µL), were randomized 3:1 to receive ZV or placebo on day 0 and week 6. The primary endpoint was serious adverse event or grade 3/4 signs/symptoms within 6 weeks after each dose. Immunogenicity (varicella zoster virus VZV-specific glycoprotein enzyme-linked immunosorbent assay and interferon-γ enzyme-linked immunospot assay responses) was assessed at 6 and 12 weeks postvaccination.
Results
Of 395 participants (296 ZV vs 99 placebo), 84% were male, 47% white, 29% black, and 22% Hispanic; median age was 49 years. Safety endpoints occurred in 15 ZV and 2 placebo recipients (5.1% 95% confidence interval {CI}, 2.9%-8.2% vs 2.1% 95% CI, .3%-7.3%; P = .26). Injection site reactions occurred in 42% of ZV (95% CI, 36.3%-47.9%) vs 12.4% of placebo recipients (95% CI, 6.6%-20.6%) (P < .001). Week 12 median natural log VZV antibody titer was higher for ZV (6.30 Q1, Q3, 5.64, 6.96) vs placebo (5.48 Q1, Q3, 4.63, 6.44; P < .001) overall and in the high CD4+ stratum (P = .003). VZV antibody titers were similar after 1 or 2 ZV doses. Polymerase chain reaction-confirmed HZ occurred in 2 participants (1 ZV; 1 placebo); none was vaccine strain related.
Conclusions
Two doses of ZV in HIV-infected adults suppressed on ART with CD4+ counts ≥200 cells/µL were safe and immunogenic.
Clinical Trials Registration
NCT00851786.
Pancreatic cancer is usually advanced and drug resistant at diagnosis. A potential therapeutic approach outlined here uses nanoparticle (NP)-based drug carriers, which have unique properties that ...enhance intra-tumor drug exposure and reduce systemic toxicity of encapsulated drugs. Here we report that patients whose pancreatic cancers express elevated levels of Death Receptor 5 (DR5) and its downstream regulators/effectors FLIP, Caspase-8, and FADD had particularly poor prognoses. To take advantage of elevated expression of this pathway, we designed drug-loaded NPs with a surface-conjugated αDR5 antibody (AMG 655). Binding and clustering of the DR5 is a prerequisite for efficient apoptosis initiation, and the αDR5-NPs were indeed found to activate apoptosis in multiple pancreatic cancer models, whereas the free antibody did not. The extent of apoptosis induced by αDR5-NPs was enhanced by down-regulating FLIP, a key modulator of death receptor-mediated activation of caspase-8. Moreover, the DNA topoisomerase-1 inhibitor camptothecin (CPT) down-regulated FLIP in pancreatic cancer models and enhanced apoptosis induced by αDR5-NPs. CPT-loaded αDR5-NPs significantly increased apoptosis and decreased cell viability in vitro in a caspase-8- and FADD-dependent manner consistent with their expected mechanism-of-action. Importantly, CPT-loaded αDR5-NPs markedly reduced tumor growth rates in vivo in established pancreatic tumor models, inducing regressions in one model. These proof-of-concept studies indicate that αDR5-NPs loaded with agents that downregulate or inhibit FLIP are promising candidate agents for the treatment of pancreatic cancer.
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•The death receptor 5 pathway is upregulated in pancreatic cancer and correlates with poorer prognosis.•AMG 655 conjugated to nanoparticle surface facilitates death receptor 5 apoptosis induction in pancreatic cancer cell lines•FLIP downregulation increases response to TRAIL and nanoparticle conjugated AMG 655•Camptothecin causes downregulation of FLIP•CRISPR targeting shows conjugated AMG 655 efficacy is FADD and caspase 8 dependent
Controlled prospective study.
To determine whether driving reaction time (DRT) is influenced by primary lumbar fusion.
The effects of radiculopathy and nerve root blocks on DRT have been reported ...recently. To our knowledge, the relationship between lumbar fusion and DRT has not been previously studied although it is important for driving safety. The aim of the present study was to test the hypotheses that DRT after lumbar fusion is (1) altered after the operation, (2) influenced by pain, (3) influenced by the patient's driving skill, and (4) differs from the DRT of healthy controls.
Twenty-one consecutive patients (mean age, 53.5 years; SD 10.8) receiving primary lumbar fusion were tested for their DRT 1 day before surgery (preoperative), the day before discharge (postoperative) and 3 months after surgery (follow-up; FU). DRT was assessed using a custom-made driving simulator. The severity of back pain was determined on visual analogue scales separately for usual pain (VAS-U) and pain during testing (VAS-T). We also determined the patients' subjective driving frequency. Normative DRT data from 31 age-matched healthy controls were used for comparison.
The preoperative DRT was 685 milliseconds (Md; IQR 246) and the postoperative DRT 728 milliseconds (Md; IQR 264), which was further reduced to 671 milliseconds (Md; IQR 202) after the FU period. Statistical significance was registered between postoperative and FU DRT (P = 0.007). Moderate to high correlations (0.537 < r < 0.680) were found between the VAS rating of back pain and DRT. Control subjects had a DRT of 487 milliseconds (Md; IQR 116), which differed significantly from the DRT of patients at all 3 time points of testing (P < 0.001).
It appears safe to continue driving after discharge from the hospital following lumbar fusion. DRT improved significantly during FU, indicating a positive effect of the intervention on driving skills. DRT correlates with the severity of back pain.
Searches for Interstellar HCCSH and H2CCS McGuire, Brett A.; Shingledecker, Christopher N.; Willis, Eric R. ...
The Astrophysical journal,
10/2019, Letnik:
883, Številka:
2
Journal Article
Recenzirano
Odprti dostop
A longstanding problem in astrochemistry is the inability of many current models to account for missing sulfur content. Many relatively simple species that may be good candidates to sequester sulfur ...have not been measured experimentally at the high spectral resolution necessary to enable radioastronomical identification. On the basis of new laboratory data, we report searches for the rotational lines in the microwave, millimeter, and submillimeter regions of the sulfur-containing hydrocarbon HCCSH. This simple species would appear to be a promising candidate for detection in space owing to the large dipole moment along its b-inertial axis, and because the bimolecular reaction between two highly abundant astronomical fragments (CCH and SH radicals) may be rapid. An inspection of multiple line surveys from the centimeter to the far-infrared toward a range of sources from dark clouds to high-mass star-forming regions, however, resulted in nondetections. An analogous search for the lowest-energy isomer, , is presented for comparison, and also resulted in nondetections. Typical upper limits on the abundance of both species relative to hydrogen are 10−9-10−10. We thus conclude that neither isomer is a major reservoir of interstellar sulfur in the range of environments studied. Both species may still be viable candidates for detection in other environments or at higher frequencies, providing laboratory frequencies are available.
Summary Background About 500 000 sepsis-related deaths per year arise in the first 3 days of life. On the basis of results from non-randomised studies, use of vaginal chlorhexidine wipes during ...labour has been proposed as an intervention for the prevention of early-onset neonatal sepsis in developing countries. We therefore assessed the efficacy of chlorhexidine in early-onset neonatal sepsis and vertical transmission of group B streptococcus. Methods In a trial in Soweto, South Africa, 8011 women (aged 12–51 years) were randomly assigned in a 1:1 ratio to chlorhexidine vaginal wipes or external genitalia water wipes during active labour, and their 8129 newborn babies were assigned to full-body (intervention group) or foot (control group) washes with chlorhexidine at birth, respectively. In a subset of mothers (n=5144), we gathered maternal lower vaginal swabs and neonatal skin swabs after delivery to assess colonisation with potentially pathogenic bacteria. Primary outcomes were neonatal sepsis in the first 3 days of life and vertical transmission of group B streptococcus. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov , number NCT00136370. Findings Rates of neonatal sepsis did not differ between the groups (chlorhexidine 141 3% of 4072 vs control 148 4% of 4057; p=0·6518). Rates of colonisation with group B streptococcus in newborn babies born to mothers in the chlorhexidine (217 54% of 401) and control groups (234 55% of 429 did not differ (efficacy −0·05%, 95% CI −9·5 to 7·9). Interpretation Because chlorhexidine intravaginal and neonatal wipes did not prevent neonatal sepsis or the vertical acquisition of potentially pathogenic bacteria among neonates, we need other interventions to reduce childhood mortality. Funding US Agency for International Development, National Vaccine Program Office and Centers for Disease Control's Antimicrobial Resistance Working Group, and Bill & Melinda Gates Foundation.
Physical exercise is an important component in the management of type 1 diabetes across the lifespan. Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions ...depends, to some extent, on the intensity and duration of the type of exercise. Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life. Risk of hypoglycaemia during and after exercise can be lowered when insulin‐dose adjustments are made and/or additional carbohydrates are consumed. Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (ie, before, during and after). This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes.
Documenting isolation is notoriously difficult for species with vast polymorphic populations. High proportions of shared variation impede estimation of connectivity, even despite leveraging ...information from many genetic markers. We overcome these impediments by combining classical analysis of neutral variation with assays of the structure of selected variation, demonstrated using populations of the principal African malaria vector Anopheles gambiae. Accurate estimation of mosquito migration is crucial for efforts to combat malaria. Modeling and cage experiments suggest that mosquito gene drive systems will enable malaria eradication, but establishing safety and efficacy requires identification of isolated populations in which to conduct field testing. We assess Lake Victoria islands as candidate sites, finding one island 30 km offshore is as differentiated from mainland samples as populations from across the continent. Collectively, our results suggest sufficient contemporary isolation of these islands to warrant consideration as field‐testing locations and illustrate shared adaptive variation as a useful proxy for connectivity in highly polymorphic species.
Context:
In advanced adrenocortical carcinoma (ACC), many patients have progressive disease despite standard treatment, indicating a need for new treatment options. We have shown high and specific ...retention of 123Imetomidate (123IIMTO) in ACC lesions, suggesting that labeling of metomidate with 131I offers targeted radionuclide therapy for advanced ACC.
Objective:
Safety and efficacy of radionuclide therapy with 131IIMTO in advanced ACC.
Design/Setting:
This monocentric case series comprised 19 treatments in 11 patients with nonresectable ACC.
Patients and Intervention:
Between 2007 and 2010, patients with advanced ACC not amenable to radical surgery and exhibiting high uptake of 123IIMTO in their tumor lesions were offered treatment with 131IIMTO (1.6–20 GBq in one to three cycles of 131IIMTO).
Main Outcome Measure:
Tumor response was assessed according to response evaluation criteria in solid tumors (RECIST version 1.1) criteria, and side effects were assessed by Common Toxicity Criteria (version 4.0).
Results:
Best response was classified as partial response in one case with a change in target lesions of −51% from baseline, as stable disease in five patients, and as progressive disease in four patients. One patient died 11 d after treatment with 131IIMTO unrelated to radionuclide therapy. In patients responding to treatment, median progression-free survival was 14 months (range, 5–33) with ongoing disease stabilization in three patients at last follow-up. Treatment was well tolerated, but transient bone marrow depression was observed. Adrenal insufficiency developed in two patients.
Conclusions:
Radionuclide therapy with 131IIMTO is a promising treatment option for selected patients with ACC, deserving evaluation in prospective clinical trials.
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