Summary Background Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In ...a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. Methods In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov , number NCT01495585. Findings Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were −0·73 log IU/mL in group 1 (95% CI 0·17–1·31; p=0·03) and −1·54 log IU/mL in group 2 (1·21–1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change ( r2 =0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days SE 0·24), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 SE 0·06 vs 0·739 0·05, p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Interpretation Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. Funding National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health , and Eiger Biopharmaceuticals Inc.
This phase 1 trial aimed to identify the maximally tolerated hypofractionated dose schedule for postoperative radiation therapy (PORT) after radical prostatectomy. Secondary objectives included ...biochemical control and quality of life (QoL) measures.
Patients were treated on 1 of 3 dose levels (DLs): 56.4 Gy in 20 fractions (DL1), 51.2 Gy in 15 fractions (DL2), and 44.2 Gy in 10 fractions (DL3). Treatment was delivered to the prostate bed without pelvic nodal irradiation. Dose escalation followed a standard 3 + 3 design with an expansion for 6 additional patients at the maximally tolerated hypofractionated dose schedule. Acute dose-limiting toxicity (DLT) was defined as grade 3 toxicity lasting >4 days within 21 days of PORT completion; late DLT was defined as grade 4 gastrointestinal (GI) or genitourinary (GU) toxicity.
Between January 2018 and August 2019, 15 patients underwent radiation treatment: 3 on DL1, 3 on DL2, and 9 on DL3. The median follow-up was 24 months. There were no DLTs, and the maximally tolerated hypofractionated dose schedule was identified as DL3. Two of the 15 patients (13.3%) experienced biochemical failure (prostate-specific antigen >0.1). Ten of 15 patients (67%) had grade 2+ acute toxicities, consisting of transient GI toxicities. Three patients experienced late grade 2+ GI toxicity, and 5 patients experienced late grade 2+ GU toxicity. Late grade 3 GU toxicity occurred in 2 patients. There were no grade 4+ acute or late toxicities. There were no significant differences in GI measures of QoL, however, there was an increase in GU symptoms and corresponding decrease in GU QoL between 12 and 24 months.
The maximum tolerated hypofractionated dose schedule for hypofractionated PORT to the prostate bed was determined to be 44.2 Gy in 10 daily fractions. The most frequent clinically significant toxicities were late grade 2+ GU toxicities, which corresponded to a worsening of late GU QoL.
Prostate biopsies are usually performed by urologists in the office setting using transrectal ultrasound (US) guidance. The current standard of care involves obtaining 10-14 cores from different ...anatomic sections. Biopsies are usually not directed into a specific lesion because most prostate cancers are not visible on transrectal US. Color Doppler, US contrast agents, elastography, magnetic resonance (MR) imaging, and MR imaging/US fusion are proposed as imaging methods to guide prostate biopsies. Prostate MR imaging and fusion biopsy create opportunities for diagnostic and interventional radiologists to play an increasingly important role in the screening, evaluation, diagnosis, targeted biopsy, surveillance, and focal therapy of patients with prostate cancer.
Background Necator americanus Ancylostoma-secreted protein 2 ( Na -ASP-2) is secreted by infective hookworm larvae on entry into human hosts. Vaccination of laboratory animals with recombinant Na ...-ASP-2 provides significant protection against challenge infections. In endemic areas antibodies to Na -ASP-2 are associated with reduced risk of heavy N americanus infections. Objective To assess the safety and immunogenicity of recombinant Na -ASP-2 adjuvanted with Alhydrogel in healthy Brazilian adults previously infected with N americanus. Methods Participants were randomized to receive Na -ASP-2 or hepatitis B vaccine. Major IgG and IgE epitopes of the Na -ASP-2 molecule were mapped by using sera from these same subjects. Seroepidemiologic studies in adults and children residing in hookworm-endemic areas were conducted to assess the prevalence of IgE responses to Na -ASP-2. Results Vaccination with a single dose of Na -ASP-2 resulted in generalized urticarial reactions in several volunteers. These reactions were associated with pre-existing Na -ASP-2–specific IgE likely induced by previous hookworm infection. Surveys revealed that a significant proportion of the population in hookworm-endemic areas had increased levels of IgE to Na -ASP-2. Epitope mapping demonstrated sites on the Na -ASP-2 molecule that are uniquely or jointly recognized by IgG and IgE antibodies. Conclusion Infection with N americanus induces increased levels of total and specific IgE to Na -ASP-2 that result in generalized urticaria on vaccination with recombinant Na -ASP-2. These data advance knowledge of vaccine development for helminths given their propensity to induce strong TH 2 responses. Study data highlight the important differences between the immune responses to natural helminth infection and to vaccination with a recombinant helminth antigen.
Abstract Purpose Multiparametric MRI (mpMRI) and fusion biopsy (FBx) detect more high-risk prostate cancer (PCa) and less low-risk PCa than systematic biopsy (SBx). However, there remains a small ...subset of patients where SBx captures higher grade disease than FBx. We aim to identify potential mechanisms for failure of FBx biopsy in detection of clinically significant (CS) PCa. Methods We reviewed a prospectively maintained database of patients undergoing mpMRI followed by FBx and SBx from 2007-2014. In patients disease upgraded to CS disease (Gleason ≥ 7) by SBx over FBx, independent re-review of MR imaging, archived biopsy imaging, and whole mount pathology, as well as needle coordinate mapping were conducted. Multivariate logistic regression analysis was performed to determine predictors for upgrading by SBx. Results Disease upgrading based on SBx over FBx occurred in 135/1003 (13.5%) patients, of which only 62 (6.2%) were to intermediate (Gleason=7) N=51, 5.1% or high risk PCa (Gleason≥8) N=11, 1.1%. On multivariate analysis, lower PSA (p <0.001), higher MRI prostate volume (p <0.001), and lower number of target cores (p=0.001) were predictors of upgrading by SBx. Main mechanisms for under-grading by FBx included mpMRI reader oversight, presence of MR invisible cancer, FBx technique error, and intra-lesion Gleason heterogeneity. Conclusions MRI and FBx rarely misses CS PCa, as only 62/1003 (6.2%) cases were upgraded to CS disease by SBx. Imaging and biopsy techniques are continually refined and further studies will help to clarify mechanisms of FBx failure and patient populations which benefit from SBx in addition to FBx.
Abstract Purpose The purpose of this review is to summarize the available data about the clinical and economic effectiveness of MRI in the diagnosis and management of prostate cancer and to provide ...practical recommendations for the use of MRI in the screening, diagnosis, staging and surveillance of prostate cancer. Materials and Methods A panel of clinicians with expertise in the diagnosis and management of prostate cancer evaluated the current published data regarding the use and effectiveness of MRI in the management of prostate cancer. For those clinical scenarios where adequate studies are available for analysis, recommendations are made on the basis of data; where such studies are not available; recommendations are made on the basis of expert consensus. Results At this time the data support the use of MRI for patients with a previous negative biopsy and ongoing concerns about increased risk of prostate cancer. The data regarding the utility of MRI for initial biopsy suggest a possible role for MRI in an initial biopsy in some circumstances. There is currently insufficient evidence to recommend MRI for screening, staging or surveillance of prostate cancer. Conclusion MRI offers superior anatomic detail, the ability to evaluate cellular density based on water diffusion and blood flow based on contrast enhancement. MRI-targeted biopsy may increase the diagnosis of clinical significant cancers by identifying specific lesions not visible on conventional ultrasound. MRI adds cost to the management of prostate cancer. The clinical indications for the use of MRI in the management of prostate cancer are rapidly evolving.
Abstract Objectives To determine whether supplemental biopsy of hypoechoic ultrasound lesions (HUL) incidentally found during MRI-transrectal ultrasound (TRUS) fusion-targeted prostate biopsy results ...in improved prostate cancer (PCa) detection. Methods Patients underwent MRI-TRUS targeted biopsy as part of an ongoing prospective trial from August 2007 to February 2015. For men with HUL, the biopsy pathology of HUL and MRI lesions was classified according to the updated 2014 International Society of Urological Pathology (ISUP) grading system. The detection of PCa by MRI-targeted biopsy with and without HUL biopsy was compared. Results Of 1260 men in the trial, 106 underwent biopsy of 119 HUL. PCa was diagnosed in 52/106 men (49%) by biopsy of either MRI lesions or HUL. Biopsy of HUL in addition to MRI lesions resulted in 4 additional diagnoses of high-grade (ISUP Grade 3-5) PCa vs biopsy of MRI lesions alone (20 vs 16 men, p=0.046). Three of these cases were upgraded from lower grade (ISUP Grade 1-2) PCa on MRI-guided biopsy alone, and only 1 case (1% of cohort) was diagnosed that would have been missed by MRI-guided biopsy alone. Supplemental biopsy of HUL did not change the PCa risk category in 96% (102/106) of men with HUL. Conclusions Supplemental biopsy of HUL yields a small increase in the detection of higher grade PCa as compared to biopsy of MRI lesions alone. As upgrading is rare, routinely screening for HUL during MRI-targeted biopsy remains controversial.
Objective To assess the evidence regarding the effect of time of gluten introduction and breastfeeding on the risk of developing celiac disease (CD). Study design We included randomized controlled ...trials and observational studies evaluating the proper timing for introducing gluten to the infant diet, the appropriate quantity of gluten consumption at weaning, and the effect of breastfeeding on CD risk. Studies were located through the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), EMBASE (Ovid), and System for Information on Grey Literature in Europe (SIGLE). Two independent authors collected the data. Results A total of 1982 studies were identified, 15 of which were eligible for data extraction. A meta-analysis was performed on 2 randomized controlled trials, 10 cohort studies, and 1 case-control study. There was a 25% increase in CD risk with late (>6 months) vs recommended (4-6 months) gluten introduction (risk ratio RR, 1.25; 95% CI, 1.08-1.45). There was no significant effect of breastfeeding vs no breastfeeding on CD risk (OR, 0.55; 95% CI, 0.28-1.10), with substantial heterogeneity ( I2 = 92%) among studies. Conclusion There is currently no evidence to support that early introduction of gluten to the infant diet increases the risk of CD; however, late introduction of gluten may be associated with increased risk of CD. More studies are needed that control for potential confounders and that evaluate environmental factors in low-risk families.
Exercise tolerance is an important clinical aspect of chronic obstructive pulmonary disease that can be easily and reliably measured with the 6-minute walking test (6MWT). To improve the utility of ...the 6MWT for patient and health care system management, the interpretation of the functional status measure in relation to death and hospitalization should be elucidated.
Three-year, prospective, multicenter observational study to evaluate the predictive power of 6MWD for death or exacerbation-related hospitalization and to evaluate the factors that help determine 6MWD.
We measured 6MWD at baseline and annually in 2110 patients with clinically stable Global Initiative for Obstructive Lung Disease (GOLD) stage II-IV COPD and recorded exacerbation-related hospitalizations and all-cause mortality. During the study, 200 patients died and 650 were hospitalized. Using receiver operating characteristics, the best predictive thresholds of the 6MWD were 334 m for increased risk of death and 357 m for exacerbation-related hospitalization (area under the curve 0.67 and 0.60 respectively); however, the discriminatory thresholds, especially for mortality, were influenced by age. The mean (SE) 6MWD declined by 1.6 (1.2) m per year in GOLD II, 9.8 (1.3) m per year in GOLD III, and 8.5 (2.4) m per year in GOLD IV.
The 6MWD provides prognostic information that may be useful for identifying high-risk patients with COPD.
Abstract Objective The aim of this work was to assess the prognostic value of absolute N-terminal-pro–B-type natriuretic peptide (NT-proBNP) concentration in combination with changes during admission ...because of acute heart failure (AHF) and early after hospital discharge. Background In AHF, readmission and mortality rates are high. Identifying those at highest risk for events early after hospital discharge might help to select patients in need of intensive outpatient monitoring. Methods and results We evaluated the prognostic value of NT-proBNP concentration on admission, at discharge, 1 month after hospital discharge and change over time in 309 patients included in the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study. Primary outcome measures were mortality and the combined end point of heart failure (HF) readmission or mortality. In a multivariate Cox regression analysis, change in NT-proBNP concentration during admission, change from discharge to 1 month after discharge, and the absolute NT-proBNP concentration at 1 month after discharge were of independent prognostic value for both end points (hazard ratios for HF readmission or mortality: 1.71, 95% confidence interval CI 1.13–2.60, Wald 6.4 P = .011 versus 2.71, 95% CI 1.76–4.17, Wald 20.5 P < .001 versus 1.81, 95% CI 1.13–2.89, Wald 6.1 P = .014, respectively. Conclusions Knowledge of change in NT-proBNP concentration during admission because of AHF in combination with change early after discharge and the absolute NT-proBNP concentration at 1 month after discharge allows accurate risk stratification.
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