Summary Background We compared standard adjuvant anthracycline chemotherapy with anthracycline–taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the ...final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. Methods BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18–70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov , number NCT00688740. Findings Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90–126), disease-free survival was 62% (95% CI 58–65) for patients in the TAC group and 55% (51–59) for patients in the FAC group (hazard ratio HR 0·80, 95% CI 0·68–0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72–79) for patients in the TAC group and 69% (65–72) for patients in the FAC group (HR 0·74, 0·61–0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3–4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. Interpretation Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation. Funding Sanofi.
Summary Background Direct-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and ...adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration. Methods In this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with ClinicalTrials.gov , number NCT01805882. Findings Between Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83–100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75–100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75–100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs. Interpretation In this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis. Funding National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences.
Background Confocal laser endomicroscopy (CLE) enables in vivo microscopic imaging of the GI tract mucosa. However, there are limited data on endoscope-based CLE (eCLE) for imaging Barrett's ...esophagus (BE). Objective To compare high-definition white-light endoscopy (HDWLE) alone with random biopsy (RB) and HDWLE + eCLE and targeted biopsy (TB) for diagnosis of BE neoplasia. Design Multicenter, randomized, controlled trial. Setting Academic medical centers. Patients Adult patients with BE undergoing routine surveillance or referred for early neoplasia. Intervention Patients were randomized to HDWLE + RB (group 1) or HDWLE + eCLE + TB (group 2). Real-time diagnoses and management plans were recorded after HDWLE in both groups and after eCLE in group 2. Blinded expert pathology diagnosis was the reference standard. Main Outcome Measurements Diagnostic yield, performance characteristics, clinical impact. Results A total of 192 patients with BE were studied. HDWLE + eCLE + TB led to a lower number of mucosal biopsies and higher diagnostic yield for neoplasia (34% vs 7%; P < .0001), compared with HDWLE + RB but with comparable accuracy. HDWLE + eCLE + TB tripled the diagnostic yield for neoplasia (22% vs 6%; P = .002) and would have obviated the need for any biopsy in 65% of patients. The addition of eCLE to HDWLE increased the sensitivity for neoplasia detection to 96% from 40% ( P < . 0001) without significant reduction in specificity. In vivo CLE changed the treatment plan in 36% of patients. Limitations Tertiary-care referral centers and expert endoscopists limit generalizability. Conclusion Real-time eCLE and TB after HDWLE can improve the diagnostic yield and accuracy for neoplasia and significantly impact in vivo decision making by altering the diagnosis and guiding therapy. (Clinical trial registration number: NCT01124214 .)
The Alliance for Academic Internal Medicine (AAIM) supports the need for a uniform subspecialty fellowship training and advanced residency training start date. At present, training programs and their ...sponsoring institutions vary widely in the timing of institutional orientation and fellowship/advanced residency training start dates. Some institutions conduct orientation programs before the scheduled completion of the initial training program, which leads to conflicts for the resident between current and future obligations. AAIM believes that requiring residents to report for fellowship before completion of residency training is disruptive to medical education, creates unnecessary stress for the residents, and risks, violating federal labor laws and Center for Medicare and Medicaid Services graduate medical education funding rules. Adoption of Jul 1, 2015 as the earliest start date for all training and orientation activities can be endorsed internally by AAIM institutions and would resolve these conflicts. Here, Barrett et al examine AAIM adoption of a uniform subspecialty fellowship and other advanced training.
Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. ...Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci ( NOD2, MHC , and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78 ), even after exclusion of NOD2, MHC , and 3p21 (p=9·23 × 10−18 ). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4 ). Interpretation Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. Funding International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
Abstract Whyte J, Barrett AM. Advancing the evidence base of rehabilitation treatments: a developmental approach. Translational research refers to the development of new scientific discoveries into ...evidence-based treatments for human diseases and conditions. This developmental process requires that a number of scientific, as well as social and psychological obstacles, be overcome during a sequence of research stages that address different goals. Rehabilitation, like other biomedical disciplines, requires this kind of developmental process. For a variety of reasons, however, development of rehabilitation treatments is less linear than the familiar phases of pharmaceutical research. In addition, research on treatments intended to address impairments (body structure/function, in terms of the International Classification of Functioning, Disability and Health ), faces the challenge of determining the likely impact of an impairment-level treatment on the multifaceted activities and aspects of participation that are the typical goals of rehabilitation treatments. This article describes the application of treatment theory and enablement theory to the development of new impairment-based treatments, and examines similarities and differences between the developmental sequence needed for rehabilitation treatment research versus pharmaceutical research in other areas of medicine.
Current management of Coats disease Sigler, Eric J., MD; Randolph, John C., MD; Calzada, Jorge I., MD ...
Survey of ophthalmology,
2014, January-February 2014, 2014 Jan-Feb, 2014-1-00, 20140101, Letnik:
59, Številka:
1
Journal Article
Recenzirano
Abstract Since its original description in 1908, Coats disease has been recognized as an idiopathic cause of severe vision loss with a remarkable diversity in clinical presentation and morphology. ...Key clinical and imaging variables are helpful in differentiating Coats disease from life-threatening malignancies, and proper management revolves around a thorough knowledge of the differential diagnosis. Despite significant advancement in scientific understanding of the disease process and clinical spectrum, the underlying etiology remains obscure, and both primary and secondary forms are recognized. With the development of anti-VEGF therapy, vitreoretinal specialists have a new, effective adjunct to the clinical management of exudates, macular edema, and serous retinal detachment. We highlight the history, diagnostic challenges, evolving clinical spectrum, and current management of Coats disease.
Summary Background New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged ...tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. Methods In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m2 every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov , number NCT00802945. Findings 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4–40·6) achieved an objective response (two 3% had a complete response and 18 26% had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6–46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6–46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven 20% of 35 patients on the 14-day schedule vs eight 23% of 35 patients on the 21-day schedule), fatigue (five 14% vs three 9%), neutropenia (four 11% vs four 11%), and dehydration (three 9% vs four 11%); 14 20% patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten 14% patients with diarrhoea (six 17% patients on the 14-day schedule vs four 11% on the 21-day schedule), six 9% with dehydration (two 6% vs four 11%), two 3% with nausea (two 6% vs none), and two 3% with vomiting (two 6% vs none). Interpretation On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m2 every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer. Funding Nektar Therapeutics.
Summary The purpose of this study was to identify potential predictors of function and tendon healing after arthroscopic rotator cuff repair that will enable the orthopaedic surgeon to determine ...which patients can expect a successful outcome. Between 2003 and 2005, the Arthroscopic Rotator Cuff Registry was established to collect demographic, intraoperative, functional outcome, and ultrasound data prospectively on all patients who underwent primary arthroscopic rotator cuff repair. At total of 193 patients met the study criteria, and 127 (65.8%) completed the 2-year follow-up. The most significant independent factors affecting ultrasound outcome were age (odds ratio OR, 1.08; 95% confidence interval CI, 1.02-1.14; P = .006) and tear size (OR, 2.29; 95% CI, 1.55-3.38; P < .001). After adjustment for age and tear size, the intraoperative factors found to be significantly associated with a tendon defect were concomitant biceps procedures (OR, 11.39; 95% CI, 2.90-44.69; P < .001) and acromioclavicular joint procedures (OR, 3.85; 95% CI, 1.46-10.12; P = .006). In contrast to the ultrasound data, the functional outcome variables, such as satisfaction (OR, 3.92; 95% CI, 2.00-7.68; P < .001) and strength (OR, 10.05; 95% CI, 1.61-62.77; P = .01), had a greater role in predicting an American Shoulder and Elbow Surgeons score greater than 90. The progression from a single-tendon rotator cuff tear to a multiple-tendon tear with associated pathology increased the likelihood of tendon defect by at least 9 times, and therefore, earlier surgical intervention for isolated, single-tendon rotator cuff tears could optimize the likelihood of ultrasound healing and an excellent functional outcome.
Abstract Background Bilateral pelvic discontinuity is characterized by complete dissociation of the superior and inferior pelvis secondary to bone loss or fracture. The end result is a freely mobile ...inferior pelvis at the level of each discontinuity which presents a significant reconstruction challenge. This clinical entity has not been described previously, and the results of surgical treatment are not known. Methods We retrospectively reviewed all identified cases of pelvic discontinuity (PD) treated with revision THA at one institution. We identified 133 pelvic discontinuities. Within this group, 6 patients had bilateral simultaneous PDs. Preoperative, intraoperative, and postoperative data and radiographic imaging were reviewed preoperatively and postoperatively for the characteristics of the dissociation and assessing PD healing and fixation of components after surgery. Results There were no preoperative factors that could distinguish these patients from the rest of the group of discontinuities (3 rheumatoid arthritis, 2 osteonecrosis of the femoral head, 1 developmental dysplasia). The reconstructions performed included 2 cup/cage, 5 posterior plating and uncemented cup, 3 cage alone, and 2 cups only. Ten of 12 hips had at least 1 complication postoperatively. At final follow-up, only 1 patient (17%) had radiographic evidence that both discontinuities had healed (posterior plate with uncemented cup). Conclusions Bilateral pelvic discontinuity is rare but presents the surgeon with a major reconstructive challenge. Only 1 patient went on to radiographic healing with current treatment strategies. Continued motion of the contralateral pelvic dissociation may account for the high failure rates. Surgeons should be aware of the challenges presented by this diagnosis and develop strategies to improve outcomes.
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