In the setting of hepatitis C virus (HCV) active infection, liver stiffness (LS)-based strategies identify patients with low risk of developing esophageal variceal bleeding (VB) episodes, in whom ...unnecessary upper esophagogastroduodenoscopy (UGE) screening can be safely avoided. However, after sustained virological response (SVR), data on the accuracy of the criteria predicting this outcome in HCV-infected patients with cirrhosis, with or without human immunodeficiency virus (HIV) coinfection, are very limited.
This was a multicenter prospective cohort study, where HCV-monoinfected patients and HIV/HCV-coinfected individuals were included if they had (1) SVR with direct-acting antiviral-based therapy; (2) LS ≥9.5 kPa previous to treatment; and (3) LS measurement at the SVR time-point ≥14 kPa. Diagnostic accuracy of HEPAVIR, expanded Baveno VI, and HIV cirrhosis criteria, at the time of SVR, was evaluated. Missed VB episodes, negative predictive values (NPVs), and number of spared UGEs were specifically assessed.
Four hundred thirty-five patients were included, 284 (65%) coinfected with HIV. Seven (1.6%) patients developed a first episode of VB after SVR. In patients without a previous VB episode, HEPAVIR, expanded Baveno VI and HIV cirrhosis criteria achieved NPV for first VB episode after SVR of 99.5% (95% confidence interval CI, 97.1%-100%), 100% (95% CI 97.8%-100%), and 100% (95% CI 98%-100%) while sparing 45%, 39%, and 44% of UGEs, respectively. When considering HIV coinfection, the performance of the 3 criteria was similar, both in HCV-monoinfected and HIV/HCV-coinfected individuals.
After SVR, predictive LS-based strategies accurately identify HCV-infected patients, HIV coinfected or not, with low risk of developing VB during follow-up. In these specific patients, using HIV cirrhosis criteria maximize the number of spared UGEs while missing no VB episode.
Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of ...IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.
Highlights • ALA-mediated PDT is growing in popularity in cosmetic dermatology. • PDT can cause collagen remodeling and can resolve acute inflammation. • PDT has been used to treat acne and daylight ...PDT is becoming used. • Skin rejuvenation, viral warts, psoriasis, localized scleroderma, keloids. • Pain is the main side-effect of ALA-PDT
Abstract Purpose We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein ...kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. Experimental design Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. Results Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. Conclusions WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.
Clinical applications of ginger with an expectation of clinical benefits are receiving significant attention. This systematic review aims to provide a comprehensive discussion in terms of the ...clinical effects of ginger in all reported areas. Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline, randomized controlled trials on the effects of ginger were investigated. Accordingly, 109 eligible papers were fully extracted in terms of study design, population characteristics, evaluation systems, adverse effects, and main outcomes. The reporting quality of the included studies was assessed based on the Cochrane Collaboration's tool for assessing the risk of bias in randomized trials and integrated together with studies that investigated the same subjects. The included studies that examined the improvement of nausea and vomiting in pregnancy, inflammation, metabolic syndromes, digestive function, and colorectal cancer's markers were consistently supported, whereas other expected functions were relatively controversial. Nevertheless, only 43 clinical trials (39.4%) met the criterion of having a 'high quality of evidence.' In addition to the quality assessment result, small populations and unstandardized evaluation systems were the observed shortcomings in ginger clinical trials. Further studies with adequate designs are warranted to validate the reported clinical functions of ginger.
Corticosteroids are commonly used as adjuvant therapy for acute respiratory distress syndrome by many clinicians because of their perceived anti-inflammatory effects. However, for patients with ...severe viral pneumonia, the corticosteroid treatment is highly controversial.
The purpose of this review is to systematically evaluate the effect and potential mechanism of corticosteroid administration in pandemic viral pneumonia.
We comprehensively searched all manuscripts on corticosteroid therapy for influenza, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and SARS coronavirus 2 (SARS-CoV-2) viral pneumonia from the PubMed, EMBASE, Web of Science and Cochrane Library databases.
We systematically summarized the effects of corticosteroid therapy for pandemic viral pneumonia and the potential mechanism of action for corticosteroids in coronavirus disease 2019 (COVID-19).
Observational studies showed that corticosteroid treatment was associated with increased mortality and nosocomial infections for influenza and delayed virus clearance for SARS-CoV and MERS-CoV. Limited data on corticosteroid therapy for COVID-19 were reported. Corticosteroids were used in about a fifth of patients (670/2995, 22.4%). Although clinical observational studies reported the improvement in symptoms and oxygenation for individuals with severe COVID-19 who received corticosteroid therapy, case fatality rate in the corticosteroid group was significantly higher than that in the non-corticosteroid group (69/443, 15.6% versus 56/1310, 4.3%). Compared individuals with non-severe disease, those with severe disease were more likely to receive corticosteroid therapy (201/382, 52.6% versus 201/1310, 15.3%). Although there is no evidence that corticosteroid therapy reduces mortality in people with COVID-19, some improvements in clinical symptoms and oxygenation were reported in some clinical observational studies. Excessive inflammatory response and lymphopenia might be critical factors associated with severity of and mortality from COVID-19. Sufficiently powered randomized controlled trials with rigorous inclusion/exclusion criteria and standardized dose and duration of corticosteroids are needed to verify the effectiveness and safety of corticosteroid therapy.
ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers and to penetrate ...malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown.
A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis was conducted (
= 72 BCBM;
= 28 leptomeningeal carcinomatosis subset). ANG1005 was administered intravenously at 600 mg/m
every 3 weeks. Tumor assessment was based on central nervous system (CNS) RECIST 1.1 for intracranial, and RECIST 1.1 for extracranial response. The primary endpoint was determination of intracranial objective response rate (iORR).
Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS-directed therapies was 2.8 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology facility IRF review). In the leptomeningeal carcinomatosis subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI, 5.4-9.4).
Even though the study preset rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in all patients including symptom improvement and prolonged overall survival compared to historical control for the subset of patients with leptomeningeal carcinomatosis (
= 28).
Abstract Background Giant-cell tumours of bone (GCTB) are RANK/RANK-ligand (RANKL) positive, aggressive and progressive osteolytic tumours. Denosumab, a RANKL inhibitor, was FDA-approved for adults ...and skeletally mature adolescents with unresectable GCTB or when surgical resection is likely to result in severe morbidity. Data on long-term toxicity and activity of denosumab monthly ‘GCTB-schedule’ (120 mg per 12/year, 1440 mg total dose/year) are lacking. Methods Patients with GCTB receiving denosumab, 120 mg on days 1, 8, 15, 29 and every 4 weeks thereafter, from 2006 to 2015 treated in two centres were included. Long-term toxicity was evaluated. Results Ninety-seven were identified. 43 patients underwent resection of the tumour with a median time on denosumab treatment of 12 months (range 6–45 months). Fifty-four patients had unresectable GCTB's (male/female 23/31, median age 35 years range: 13–76 years, 26% presented with lung metastases, 31% had primary tumor located to the spine, 63% were relapsed after previous surgery) with a median time on denosumab of 54 months (9–115 months). In the unresectable GCTB group, tumour control and clinical benefits were observed in all patients undergoing denosumab, whereas 40% of patients discontinuing denosumab had tumour progression after a median of 8 months (range 7–15 months). Adverse events Overall, six (6%) patients developed osteonecrosis of jaw (ONJ): 1/43 (2%) in the resectable group, 5/54 (9%) in the unresectable group, with a 5-year ONJ-free survival of 92% (95% CI 84–100). Only patients with prolonged treatment experienced mild peripheral neuropathy (6/54, 11%), skin rash (5/54, 9%), hypophosphataemia (2/54, 4%) and atypical femoral fracture (2/54, 4%). Conclusions Prolonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile. The dose-dependent toxicity observed recommends a careful and strict monitoring of patients who need prolonged treatment. Decreased dose-intensity schedules should be further explored in unresectable GCTB.
Designing translational antioxidative agents that could scavenge free radicals produced during reperfusion in brain ischemia stroke and alleviate neurologic damage is the main objective for ischemic ...stroke treatment. Herein, we explored and simply synthesized a biomimic and translational Mn
O
nanoenzyme (HSA-Mn
O
) to constrain ischemic stroke reperfusion-induced nervous system injury. This nanosystem exhibits reduced levels of inflammation and prolonged circulation time and potent ROS scavenging activities. As expected, HSA-Mn
O
effectively inhibits oxygen and glucose deprivation-mediated cell apoptosis and endoplasmic reticulum stress and demonstrates neuroprotective capacity against ischemic stroke and reperfusion injury of brain tissue. Furthermore, HSA-Mn
O
effectively releases Mn ions and promotes the increase of superoxide dismutase 2 activity. Therefore, HSA-Mn
O
inhibits brain tissue damage by restraining cell apoptosis and endoplasmic reticulum stress
. Taken together, this study not only sheds light on design of biomimic and translational nanomedicine but also reveals the neuroprotective action mechanisms against ischemic stroke and reperfusion injury.
To update the 2004 American Academy of Neurology guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs).
2004 criteria were used to ...systemically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength.
Forty-two articles were included.
The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment); rufinamide for Lennox-Gastaut syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic-clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month-16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6-17 years); oxcarbazepine for TRCFE (1 month-4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidence-based assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years of age and perampanel as monotherapy received FDA approval.
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