Summary Background Chronic injury in kidney transplants remains a major cause of allograft loss. The aim of this study was to identify a gene set capable of predicting renal allografts at risk of ...progressive injury due to fibrosis. Methods This Genomics of Chronic Allograft Rejection (GoCAR) study is a prospective, multicentre study. We prospectively collected biopsies from renal allograft recipients (n=204) with stable renal function 3 months after transplantation. We used microarray analysis to investigate gene expression in 159 of these tissue samples. We aimed to identify genes that correlated with the Chronic Allograft Damage Index (CADI) score at 12 months, but not fibrosis at the time of the biopsy. We applied a penalised regression model in combination with permutation-based approach to derive an optimal gene set to predict allograft fibrosis. The GoCAR study is registered with ClinicalTrials.gov , number NCT00611702. Findings We identified a set of 13 genes that was independently predictive for the development of fibrosis at 1 year (ie, CADI-12 ≥2). The gene set had high predictive capacity (area under the curve AUC 0·967), which was superior to that of baseline clinical variables (AUC 0·706) and clinical and pathological variables (AUC 0·806). Furthermore routine pathological variables were unable to identify which histologically normal allografts would progress to fibrosis (AUC 0·754), whereas the predictive gene set accurately discriminated between transplants at high and low risk of progression (AUC 0·916). The 13 genes also accurately predicted early allograft loss (AUC 0·842 at 2 years and 0·844 at 3 years). We validated the predictive value of this gene set in an independent cohort from the GoCAR study (n=45, AUC 0·866) and two independent, publically available expression datasets (n=282, AUC 0·831 and n=24, AUC 0·972). Interpretation Our results suggest that this set of 13 genes could be used to identify kidney transplant recipients at risk of allograft loss before the development of irreversible damage, thus allowing therapy to be modified to prevent progression to fibrosis. Funding National Institutes of Health.
Summary Background Infectious complications and associated mortality are a major concern in acute pancreatitis. Enteral administration of probiotics could prevent infectious complications, but ...convincing evidence is scarce. Our aim was to assess the effects of probiotic prophylaxis in patients with predicted severe acute pancreatitis. Methods In this multicentre randomised, double-blind, placebo-controlled trial, 298 patients with predicted severe acute pancreatitis (Acute Physiology and Chronic Health Evaluation APACHE II score ≥8, Imrie score ≥3, or C-reactive protein >150 mg/L) were randomly assigned within 72 h of onset of symptoms to receive a multispecies probiotic preparation (n=153) or placebo (n=145), administered enterally twice daily for 28 days. The primary endpoint was the composite of infectious complications—ie, infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis, or infected ascites—during admission and 90-day follow-up. Analyses were by intention to treat. This study is registered, number ISRCTN38327949. Findings One person in each group was excluded from analyses because of incorrect diagnoses of pancreatitis; thus, 152 individuals in the probiotics group and 144 in the placebo group were analysed. Groups were much the same at baseline in terms of patients' characteristics and disease severity. Infectious complications occurred in 46 (30%) patients in the probiotics group and 41 (28%) of those in the placebo group (relative risk 1·06, 95% CI 0·75–1·51). 24 (16%) patients in the probiotics group died, compared with nine (6%) in the placebo group (relative risk 2·53, 95% CI 1·22–5·25). Nine patients in the probiotics group developed bowel ischaemia (eight with fatal outcome), compared with none in the placebo group (p=0·004). Interpretation In patients with predicted severe acute pancreatitis, probiotic prophylaxis with this combination of probiotic strains did not reduce the risk of infectious complications and was associated with an increased risk of mortality. Probiotic prophylaxis should therefore not be administered in this category of patients.
Background The prognosis of patients with liver metastasis is generally considered dismal, and combined resections of the primary tumor and metastasectomies are not recommended. In highly selected ...patients, however, resections are performed. The evidence for this indication is limited. The aim of the current study was to assess the operative and oncologic outcomes of patients with combined pancreatic and liver resections of synchronous liver metastases. Methods In a retrospective analysis of 6 European pancreas centers, we identified 69 patients with pancreatic ductal adenocarcinoma and synchronous liver metastasis who underwent simultaneous pancreas and liver metastasis resections. Patients receiving exploration without tumor resection served as the control group. Results Overall survival (OS) appeared to be prolonged in the group of resected patients (median 14 vs 8 months, P < .001). Subgroup analysis revealed that the survival benefit of the resected patients was driven by pancreatic ductal adenocarcinomas localized in the pancreatic head (median OS 13.6 vs 7 months, P < .001). Body/tail pancreatic ductal adenocarcinomas showed no benefit of resection (median OS 14 vs 15 months, P = .312). In the multivariate analysis, tumor resection was the only independent prognosticator for OS (hazard ratio 2.044, 95% confidence interval 1.342–3.114). Conclusion The data of this retrospective and selective patient cohort suggested a clear survival benefit for patients undergoing synchronous pancreas and liver resections for pancreatic ductal adenocarcinoma, but due to the limitations of this retrospective study and very strong potential for selection bias, a strong conclusion for resection cannot be drawn. Prospective trials must validate these data and investigate the use of combined operative and systemic treatments in case of resectable metastatic pancreatic cancer. Is it time for a multicenter, prospective trial?
Summary Background Bendamustine plus rituximab is a standard of care for the management of patients with relapsed or refractory chronic lymphocytic leukaemia. New therapies are needed to improve ...clinically relevant outcomes in these patients. We assessed the efficacy and safety of adding idelalisib, a first-in-class targeted phosphoinositide-3-kinase δ inhibitor, to bendamustine plus rituximab in this population. Methods For this international, multicentre, double-blind, placebo-controlled trial, adult patients (≥18 years) with relapsed or refractory chronic lymphocytic leukaemia requiring treatment who had measurable lymphadenopathy by CT or MRI and disease progression within 36 months since their last previous therapy were enrolled. Patients were randomly assigned (1:1) by a central interactive web response system to receive bendamustine plus rituximab for a maximum of six cycles (bendamustine: 70 mg/m2 intravenously on days 1 and 2 for six 28-day cycles; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2–6) in addition to either twice-daily oral idelalisib (150 mg) or placebo until disease progression or intolerable study drug-related toxicity. Randomisation was stratified by high-risk features ( IGHV , del17p, or TP53 mutation) and refractory versus relapsed disease. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. This trial is ongoing and is registered with ClinicalTrials.gov , number NCT01569295. Findings Between June 26, 2012, and Aug 21, 2014, 416 patients were enrolled and randomly assigned to the idelalisib (n=207) and placebo (n=209) groups. At a median follow-up of 14 months (IQR 7–18), median progression-free survival was 20·8 months (95% CI 16·6–26·4) in the idelalisib group and 11·1 months (8·9–11·1) in the placebo group (hazard ratio HR 0·33, 95% CI 0·25–0·44; p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib group were neutropenia (124 60% of 207 patients) and febrile neutropenia (48 23%), whereas in the placebo group they were neutropenia (99 47% of 209) and thrombocytopenia (27 13%). An increased risk of infection was reported in the idelalisib group compared with the placebo group (grade ≥3 infections and infestations: 80 39% of 207 vs 52 25% of 209). Serious adverse events, including febrile neutropenia, pneumonia, and pyrexia, were more common in the idelalisib group (140 68% of 207 patients) than in the placebo group (92 44% of 209). Treatment-emergent adverse events leading to death occurred in 23 (11%) patients in the idelalisib group and 15 (7%) in the placebo group, including six deaths from infections in the idelalisib group and three from infections in the placebo group. Interpretation Idelalisib in combination with bendamustine plus rituximab improved progression-free survival compared with bendamustine plus rituximab alone in patients with relapsed or refractory chronic lymphocytic leukaemia. However, careful attention needs to be paid to management of serious adverse events and infections associated with this regimen during treatment selection. Funding Gilead Sciences Inc.
Summary Background Breast-conserving surgery for palpable breast cancer is associated with tumour-involved margins in up to 41% of cases and excessively large excision volumes. Ultrasound-guided ...surgery has the potential to resolve both of these problems, thereby improving surgical accuracy for palpable breast cancer. We aimed to compare ultrasound-guided surgery with the standard for palpable breast cancer—palpation-guided surgery—with respect to margin status and extent of healthy breast tissue resection. Methods In this randomised controlled trial, patients with palpable T1–T2 invasive breast cancer were recruited from six medical centres in the Netherlands between October, 2010, and March, 2012. Eligible participants were randomly assigned to either ultrasound-guided surgery or palpation-guided surgery in a 1:1 ratio via a computer-generated random sequence and were stratified by study centre. Patients and investigators were aware of treatment assignments. Primary outcomes were surgical margin involvement, need for additional treatment, and excess healthy tissue resection (defined with a calculated resection ratio derived from excision volume and tumour diameter). Data were analysed by intention to treat. This trial is registered at http://www.TrialRegister.nl , number NTR2579. Findings 134 patients were eligible for random allocation. Two (3%) of 65 patients allocated ultrasound-guided surgery had tumour-involved margins compared with 12 (17%) of 69 who were assigned palpation-guided surgery (difference 14%, 95% CI 4–25; p=0·0093). Seven (11%) patients who received ultrasound-guided surgery and 19 (28%) of those who received palpation-guided surgery required additional treatment (17%, 3–30; p=0·015). Ultrasound-guided surgery also resulted in smaller excision volumes (38 SD 26 vs 57 41 cm3 ; difference 19 cm3 , 95% CI 7–31; p=0·002) and a reduced calculated resection ratio (1·0 SD 0·5 vs 1·7 1·2; difference 0·7, 95% CI 0·4–1·0; p=0·0001) compared with palpation-guided surgery. Interpretation Compared with palpation-guided surgery, ultrasound-guided surgery can significantly lower the proportion of tumour-involved resection margins, thus reducing the need for re-excision, mastectomy, and radiotherapy boost. By achieving optimum resection volumes, ultrasound-guided surgery reduces unnecessary resection of healthy breast tissue and could contribute to improved cosmetic results and quality of life. Funding Dutch Pink Ribbon Foundation, Osinga-Kluis Foundation, Toshiba Medical Systems.
Abstract Background & Aims Probiotics can reduce symptoms of irritable bowel syndrome (IBS), but little is known about their effects on psychiatric comorbidities. We performed a prospective study to ...evaluate the effects of Bifidobacterium longum NCC3001 ( BL ) on anxiety and depression in patients with IBS. Methods We performed a randomized, double-blind, placebo-controlled study of 44 adults with IBS and diarrhea or a mixed-stool pattern (based on Rome III criteria) and mild to moderate anxiety and/or depression (based on the Hospital Anxiety and Depression scale) at McMaster University in Canada, from March 2011 to May 2014. At the screening visit, clinical history and symptoms were assessed and blood samples were collected. Patients were then randomly assigned to groups and given daily BL (n=22) or placebo (n=22) for 6 weeks. At week 0, 6 and 10, we determined patients’ levels of anxiety and depression, IBS symptoms, quality of life, and somatization using validated questionnaires. At week 0 and 6, stool, urine and blood samples were collected, and functional magnetic resonance imaging (fMRI) test was performed. We assessed brain activation patterns, fecal microbiota, urine metabolome profiles, serum markers of inflammation, neurotransmitters and neurotrophin levels. Results At week 6, 14/22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7/22 patients in the placebo group (P=.04). BL had no significant effect on anxiety or IBS symptoms. Patients in the BL group had a mean increase in quality of life score compared with the placebo group. The fMRI analysis showed that BL reduced responses to negative emotional stimuli in multiple brain areas, including amygdala and fronto–limbic regions, compared with placebo. The groups had similar fecal microbiota profiles, serum markers of inflammation, and levels of neurotrophins and neurotransmitters, but the BL group had reduced urine levels of methylamines and aromatic amino acids metabolites. At week 10, depression scores were reduced in patients given BL vs placebo. Conclusion In a placebo-controlled trial, we found that the probiotic BL reduces depression but not anxiety scores and increases quality of life in patients with IBS. These improvements were associated with changes in brain activation patterns that indicate that this probiotic reduces limbic reactivity. ClinicalTrials.gov no. NCT01276626.
Summary Background Carriers of APOE ε2 and ε4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral ...amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome. Methods We investigated the association of APOE ε2 and ε4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE ε4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3–6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH. Findings For patients with lobar ICH, carriers of the APOE ε2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2·5×10−5 ), in both replication phases (p=0·008 in Europeans and p=0·016 in African-Americans), and in the meta-analysis (p=3·2×10−8 ). In the meta-analysis, each copy of APOE ε2 increased haematoma size by a mean of 5·3 mL (95% CI 4·7–5·9; p=0·004). Carriers of APOE ε2 had increased mortality (odds ratio OR 1·50, 95% CI 1·23–1·82; p=2·45×10−5 ) and poorer functional outcomes (modified Rankin scale score 3–6; 1·52, 1·25–1·85; p=1·74×10−5 ) compared with non-carriers after lobar ICH. APOE ε4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1·08, 0·86–1·36; p=0·52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality. Interpretation Vasculopathic changes associated with the APOE ε2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the ε2 variant might allow identification of those at increased risk of mortality and poor functional outcomes. Funding US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.
Study objective Cervical spine injuries in children are rare. However, immobilization and imaging for potential cervical spine injury after trauma are common and are associated with adverse effects. ...Risk factors for cervical spine injury have been developed to safely limit immobilization and radiography in adults, but not in children. The purpose of our study is to identify risk factors associated with cervical spine injury in children after blunt trauma. Methods We conducted a case-control study of children younger than 16 years, presenting after blunt trauma, and who received cervical spine radiographs at 17 hospitals in the Pediatric Emergency Care Applied Research Network (PECARN) between January 2000 and December 2004. Cases were children with cervical spine injury. We created 3 control groups of children free of cervical spine injury: (1) random controls, (2) age and mechanism of injury-matched controls, and (3) for cases receiving out-of-hospital emergency medical services (EMS), age-matched controls who also received EMS care. We abstracted data from 3 sources: PECARN hospital, referring hospital, and out-of-hospital patient records. We performed multiple logistic regression analyses to identify predictors of cervical spine injury and calculated the model's sensitivity and specificity. Results We reviewed 540 records of children with cervical spine injury and 1,060, 1,012, and 702 random, mechanism of injury, and EMS controls, respectively. In the analysis using random controls, we identified 8 factors associated with cervical spine injury: altered mental status, focal neurologic findings, neck pain, torticollis, substantial torso injury, conditions predisposing to cervical spine injury, diving, and high-risk motor vehicle crash. Having 1 or more factors was 98% (95% confidence interval 96% to 99%) sensitive and 26% (95% confidence interval 23% to 29%) specific for cervical spine injury. We identified similar risk factors in the other analyses. Conclusion We identified an 8-variable model for cervical spine injury in children after blunt trauma that warrants prospective refinement and validation.
Background Acutely ill hospitalized medical patients are at risk for VTE. We assessed the incidence of VTE in the observational International Medical Prevention Registry on Venous Thromboembolism ...(IMPROVE) study and derived VTE risk assessment scores at admission and associative VTE scores during hospitalization. Methods Data from 15,156 medical patients were analyzed to determine the cumulative incidence of clinically observed VTE over 3 months after admission. Multiple regression analysis identified factors associated with VTE risk. Results Of the 184 patients who developed symptomatic VTE, 76 had pulmonary embolism, and 67 had lower-extremity DVT. Cumulative VTE incidence was 1.0%; 45% of events occurred after discharge. Factors independently associated with VTE were previous VTE, known thrombophilia, cancer, age > 60 years, lower-limb paralysis, immobilization ≥ 7 days, and admission to an ICU or coronary care unit (first four were available at admission). Points were assigned to each factor identified to give a total risk score for each patient. At admission, 67% of patients had a score ≥ 1. During hospitalization, 31% had a score ≥ 2; for a score of 2 or 3, observed VTE risk was 1.5% vs 5.7% for a score ≥ 4. Observed and predicted rates were similar for both models (C statistic, 0.65 and 0.69, respectively). During hospitalization, a score ≥ 2 was associated with higher overall and VTE-related mortality. Conclusions Weighted VTE risk scores derived from four clinical risk factors at hospital admission can predict VTE risk in acutely ill hospitalized medical patients. Scores derived from seven clinical factors during hospitalization may help us to further understand symptomatic VTE risk. These scores require external validation.
Background The perceived risk of serious bleeding is an obstacle to the use of oral anticoagulation in East Asia. The efficacy and safety of apixaban in East Asian patients with atrial fibrillation ...are unknown. Methods ARISTOTLE included 18,201 patients with nonvalvular atrial fibrillation randomized to apixaban 5 mg twice daily or warfarin. The efficacy and safety of apixaban and warfarin among patients recruited from East Asia (n = 1,993) were compared with those recruited from outside East Asia (n = 16,208). Results Compared with warfarin, apixaban resulted in a consistent reduction in stroke or systemic embolism in East Asian (hazard ratio HR 0.74, 95% CI 0.50-1.10) and non–East Asian (HR 0.81, 95% CI 0.66-0.99) patients (interaction P = .70). Consistent benefits of apixaban over warfarin were also seen for major bleeding in East Asian (HR 0.53, 95% CI 0.35-0.80) and non–East Asian (HR 0.72, 95% CI 0.62-0.83) patients (interaction P = .17). There was a greater reduction in major or clinically relevant nonmajor bleeding with apixaban compared with warfarin in East Asian (HR 0.49, 95% CI 0.35-0.67) than in non–East Asian (HR 0.71, 95% CI 0.63-0.79) patients (interaction P = .03). Numerically higher rates of intracranial bleeding were seen in East Asian patients with warfarin but not with apixaban. Conclusions Apixaban resulted in similar reductions in stroke or systemic embolism and major bleeding and greater reductions in major or clinically relevant nonmajor bleeding in patients from East Asia. Warfarin is associated with more intracranial bleeding, particularly in patients from East Asia.
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