Summary Background Previous phase 2 studies have shown antitumour activity with gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary-tract cancers (BTCs). In this phase 2 study, we ...assessed the efficacy and safety of combined bevacizumab with GEMOX (GEMOX-B) in patients with advanced BTCs, and investigated how changes in 18-fluorodeoxyglucose (18 FFDG)-PET correlate with clinical outcome. Methods Patients with advanced measurable BTCs were given the following treatment on days 1 and 15 of a 28-day cycle: bevacizumab 10 mg/kg, followed by gemcitabine 1000 mg/m2 (10 mg/m2 per min) and oxaliplatin 85 mg/m2 (2-h infusion). 18 FFDG-PET scans were obtained at baseline and after completion of the second cycle. The primary endpoint was progression-free survival (PFS). Efficacy and safety analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00361231. Findings 35 patients were enrolled and evaluable for efficacy and toxicity. Median PFS was 7·0 months (95% CI 5·3–10·3), and PFS at 6 months was 63% (47–79), which was below the targeted rate of 70%. Grade 3–4 toxic effects included neutropenia (n=7), raised alanine aminotransferase concentrations (n=5), peripheral neuropathy (n=5), and hypertension (n=5). 18 FFDG-PET scans showed a significant decrease in maximum standardised uptake value (SUVmax ) after two cycles of treatment (5·72 SD 2·01 at baseline; 3·73 SD 1·88 after two cycles; p<0·0001). These changes were more pronounced in patients with partial response or stable disease than those with progressive disease (24 patients, −2·80 SD 1·95 vs five patients, 1·41 SD 3·13; p=0·009). Change in SUVmax was a significant predictor of PFS (HR 1·35, 1·14–1·60, p=0·0006) and overall survival (1·25, 1·05–1·50, p=0·01). Interpretation GEMOX-B showed antitumour activity with tolerable safety in patients with advanced BTCs. Decreases in SUVmax on 18 FFDG-PET scans after treatment were associated with disease control and increases in PFS and overall survival. Funding Genentech Oncology and Sanofi-Aventis.
Intensive (longer and more frequent) hemodialysis has emerged as an alternative to conventional hemodialysis for the treatment of patients with end-stage renal disease. However, given the differences ...in dialysis delivery and models of care associated with intensive dialysis, alternative approaches to patient management may be required. The purpose of this work was to develop a clinical practice guideline for the Canadian Society of Nephrology. We applied the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach for guideline development and performed targeted systematic reviews and meta-analysis (when appropriate) to address prioritized clinical management questions. We included studies addressing the treatment of patients with end-stage renal disease with short daily (≥5 days per week, <3 hours per session), long (3-4 days per week, ≥5.5 hours per session), or long-frequent (≥5 days per week, ≥5.5 hours per session) hemodialysis. We included clinical trials and observational studies with or without a control arm (1990 and later). Based on a prioritization exercise, 6 interventions of interest included optimal vascular access type, buttonhole cannulation, antimicrobial prophylaxis for buttonhole cannulation, closed connector devices, and dialysate calcium and dialysate phosphate additives for patients receiving intensive hemodialysis. We developed 6 recommendations addressing the interventions of interest. Overall quality of the evidence was very low and all recommendations were conditional. We provide detailed commentaries to guide in shared decision making. The main limitation was the very low overall quality of evidence that precluded strong recommendations. Most included studies were small single-arm observational studies. Three randomized controlled trials were applicable, but provided only indirect evidence. Published information for patient values and preference was lacking. In conclusion, we provide 6 recommendations for the practice of intensive hemodialysis. However, due to very low-quality evidence, all recommendations were conditional. We therefore also highlight priorities for future research.
Background Practices in vascular access management with intensive hemodialysis may differ from those used in conventional hemodialysis. Study Design We conducted a systematic review to inform ...clinical practice guidelines for the provision of intensive hemodialysis. Setting & Population Adult patients receiving maintenance (>3 months) intensive hemodialysis (frequent ≥5 hemodialysis treatments per week and/or long >5.5 hours per hemodialysis treatment). Selection Criteria for Studies We searched EMBASE and MEDLINE (1990-2011) for randomized and observational studies. We also searched conference proceedings (2007-2011). Interventions (1) Central venous catheter (CVC) versus arteriovenous (AV) access, (2) buttonhole versus rope-ladder cannulation, (3) topical antimicrobial cream versus none in buttonhole cannulation, and (4) closed connector devices among CVC users. Outcomes Access-related infection, survival, hospitalization, patency, access survival, intervention rates, and quality of life. Results We included 23, 7, and 5 reports describing effectiveness by access type, buttonhole cannulation, and closed connector device, respectively. No study directly compared CVC with AV access. On average, bacteremia and local infection rates were higher with CVC compared with AV access. Access intervention rates were higher with more frequent hemodialysis, but access survival did not differ. Buttonhole cannulation was associated with bacteremia rates similar to those seen with CVCs in some series. Topical mupirocin seemed to attenuate this effect. No direct comparisons of closed connector devices versus standard luer-locking devices were found. Low rates of actual or averted (near misses) air embolism and bleeding were reported with closed connector devices. Limitations Overall, evidence quality was very low. Limited direct comparisons addressing main review questions, small sample sizes, selective outcome reporting, publication bias, and residual confounding were major factors. Conclusions This review highlights several differences in the management of vascular access in conventional and intensive hemodialysis populations. We identify a need for standardization of vascular access outcome reporting and a number of priorities for future research.
Background Patients treated with conventional hemodialysis (HD) develop disorders of mineral metabolism that are associated with increased morbidity and mortality. More frequent and longer HD has ...been associated with improvement in hyperphosphatemia that may improve outcomes. Study Design Systematic review and meta-analysis to inform the clinical practice guideline on intensive dialysis for the Canadian Society of Nephrology. Setting & Population Adult patients receiving outpatient long (≥5.5 hours/session; 3-4 times per week) or long-frequent (≥5.5 hours/session, ≥5 sessions per week) HD. Selection Criteria for Studies We included clinical trials, cohort studies, case series, case reports, and systematic reviews. Interventions Dialysate calcium concentration ≥1.5 mmol/L and/or phosphate additive. Outcomes Fragility fracture, peripheral arterial and coronary artery disease, calcific uremic arteriolopathy, mortality, intradialytic hypotension, parathyroidectomy, extraosseous calcification, markers of mineral metabolism, diet liberalization, phosphate-binder use, and muscle mass. Results 21 studies were identified: 2 randomized controlled trials, 2 reanalyses of data from the randomized controlled trials, and 17 observational studies. Dialysate calcium concentration ≥1.5 mmol/L for patients treated with long and long-frequent HD prevents an increase in parathyroid hormone levels and a decline in bone mineral density without causing harm. Both long and long-frequent HD were associated with a reduction in serum phosphate level of 0.42-0.45 mmol/L and a reduction in phosphate-binder use. There was no direct evidence to support the use of a dialysate phosphate additive. Limitations Almost all the available information is related to changes in laboratory values and surrogate outcomes. Conclusions Dialysate calcium concentration ≥1.5 mmol/L for most patients treated with long and long-frequent dialysis prevents an increase in parathyroid hormone levels and decline in bone mineral density without increased risk of calcification. It seems prudent to add phosphate to the dialysate for patients with a low predialysis phosphate level or very low postdialysis phosphate level until more evidence becomes available.
Background Acral lentiginous melanoma has increased mortality compared with other melanoma subtypes and disproportionately affects ethnic minorities. Acral melanocytic lesions have not been well ...studied in diverse populations of the United States. Objective We sought to assess the prevalence, awareness, and dermoscopic patterns of acral melanocytic lesions in skin-of-color and non-Hispanic white patients. Methods We prospectively examined the palms and soles of 1052 patients presenting to dermatology clinics in New York, NY, and Miami, FL, from October 2013 to April 2015. Results Acral melanocytic lesions were observed in 36% of our cohort. Skin-of-color patients were more likely to have acral melanocytic lesions than non-Hispanic white patients ( P < .01). Acral melanocytic lesions correlated with increased mole counts, particularly on non-Hispanic white patients. The majority of lesions demonstrated benign dermoscopic patterns. We observed 2 lesions with the parallel ridge pattern in our cohort, both found to be atypical nevi on biopsy specimen. Patients often lacked awareness of the presence of their lesions. Limitations Interobserver variability in assessing dermoscopic patterns is a limitation. Conclusions Melanocytic lesions of the palms and soles are common, particularly in a cohort of multiple ethnicities from the United States. Dermoscopy of acral lesions is an important clinical tool for diagnosis and management of these lesions.
ABSTRACT PURPOSE Lower continuity of care has been associated with higher rates of adverse outcomes for persons with multiple chronic medical conditions. It is unclear, however, whether this ...relationship also exists within integrated systems that offer high levels of informational continuity through shared electronic health records. METHODS We conducted a retrospective cohort study of 12,200 seniors with 3 or more chronic conditions within an integrated delivery system. Continuity of care was calculated using the Continuity of Care Index, which reflects visit concentration with individual clinicians. Using Cox proportional hazards regression permitting continuity to vary monthly until the outcome or censoring event, we separately assessed inpatient admissions and emergency department visits as a function of primary care continuity and specialty care continuity. RESULTS After adjusting for covariates (demographics; baseline, primary, and specialty care visits; baseline outcomes; and morbidity burden), greater primary care continuity and greater specialty care continuity were each associated with a lower risk of inpatient admission (respective hazard ratios (95% CIs) = 0.97 (0.96, 0.99) and 0.95 (0.93, 0.98)) and a lower risk of emergency department visits (respective hazard ratios = 0.97 (0.96, 0.98) and 0.98 (0.96, 1.00)). For the subgroup with 3 or more primary care and 3 or more specialty care visits, specialty care continuity (but not primary care continuity) was independently associated with a decreased risk of inpatient admissions (hazard ratio = 0.94 (0.92, 0.97)), and primary care continuity (but not specialty care continuity) was associated with a decreased risk of emergency department visits (hazard ratio = 0.98 (0.96, 1.00)). CONCLUSIONS In an integrated delivery system with high informational continuity, greater continuity of care is independently associated with lower hospital utilization for seniors with multiple chronic medical conditions. Different subgroups of patients will benefit from continuity with primary and specialty care clinicians depending on their care needs.
Summary Background The licensed live, attenuated varicella-zoster virus vaccine prevents herpes zoster in adults older than 50 years. We aimed to determine whether intradermal administration of ...zoster vaccine could enhance vaccine immunogenicity compared with conventional needle subcutaneous administration. Methods In this randomised, dose-ranging study, adults aged 50 years or older who had a history of varicella or who had resided in a country with endemic varicella-zoster virus infection for 30 years or more were eligible. Participants received the approved full or a 1/3 dose of zoster vaccine given subcutaneously or one of four intradermal doses (full, 1/3, 1/10, or 1/27 dose) using the MicronJet600 device. The two subcutaneous doses and the four intradermal doses were randomised (1·5:1:1:1:1:1) by computer generated sequence with randomisation stratified by age (50–59 years or 60 years or older). The primary immunogenicity endpoint was the change from baseline in IgG antibody to varicella-zoster virus-specific glycoproteins (gpELISA) measured at 6 weeks. All patients were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov , number NCT01385566. Findings Between Sept 2, 2011, and Jan 13, 2012, 224 participants were enrolled from three clinics in the USA and 223 were randomly assigned: 52 to receive the full dose subcutaneous zoster vaccine, 34 to receive the 1/3 dose subcutaneous zoster vaccine, 34 to receive the full dose intradermal zoster vaccine, 35 to receive the 1/3 dose intradermal zoster vaccine, 34 to receive the 1/10 dose intradermal zoster vaccine, and 34 to receive the 1/27 dose intradermal zoster vaccine. Full dose zoster vaccine given subcutaneously resulted in a gpELISA geometric mean fold-rise (GMFR) of 1·74 (90% CI 1·48–2·04) at 6 weeks post-vaccination compared with intradermal administration which resulted in a significantly higher gpELISA GMFR of 3·25 (2·68–3·94; p<0·0001), which also remained high at 18 months. An apparent dose–response relation was observed with intradermal administration (1/3 dose subcutaneous GMFR 1·64 90% CI 1·36–1·99, 1/3 dose intradermal 2·58 (2·13–3·13), 1/10 dose intradermal 2·22 1·83–2·69, and 1/27 dose intradermal 1·64 1·35–2·00). Each partial dose of zoster vaccine given intradermaly had a gpELISA GMFR comparable to that of full dose zoster vaccine given subcutaneously. Transient erythema and induration were more common after intradermal administration (31% erythema for full subcutaneous dose and 77% for intradermal dose). Interpretation Intradermal zoster vaccine showed a greater increase in varicella-zoster virus gpELISA antibody compared with subcutaneous zoster vaccine at comparable doses. Larger and longer studies of intradermal administration of live, attenuated zoster vaccine are needed to provide convincing evidence of improved cell mediated immunity. Funding Merck & Co Inc.
Abstract Purpose Evaluating patient-centered care for complex patients requires morbidity measurement appropriate for use with a variety of clinical outcomes. We compared the contributions of ...self-reported morbidity and morbidity measured using administrative diagnosis data for both patient-reported outcomes and utilization outcomes. Methods Using a cohort of 961 persons aged 65 years or older with 3 or more medical conditions, we explored 9 health outcomes as a function of 4 independent variables representing different types of morbidity measures: International Classification of Diseases, Ninth Revision (ICD-9) , a self-reported weighted count of conditions, and self-reported symptoms of depression and of anxiety. Outcomes varied from self-reported health status to utilization. Depending on the outcome measure, we used multivariate linear, negative binomial, or logistic regression, adjusting for demographic characteristics and length of enrollment to assess associations between dependent and all 4 independent variables. Results Higher morbidity measured by ICD-9 diagnoses was independently associated with less favorable levels of 7 of the 9 clinical outcomes. Higher self-reported disease burden was significantly associated with less favorable levels of 8 of the outcomes, controlling for the 3 other morbidity measures. Morbidity measured by diagnosis code was more strongly associated with higher utilization, whereas self-reported disease burden and emotional symptoms were more strongly associated with patient-reported outcomes. Conclusions A comprehensive assessment of morbidity requires both subjective and objective measurement of disease burden as well as an assessment of emotional symptoms. Such multidimensional morbidity measurement is particularly relevant for research or quality assessments involving the delivery of patient-centered care to complex patient populations.
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