Abstract Objectives To assess anti-TNF-α therapy response in uveitis associated with sarcoidosis refractory to conventional immunosuppressive therapy. Methods Open-label, multicenter, retrospective ...study on patients with sarcoid uveitis who underwent anti-TNF-α therapy because of inadequate response to conventional therapy including corticosteroids and at least 1 systemic synthetic immunosuppressive drug. The main outcome measurements were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness, and immunosuppression load. Results A total of 17 patients (8 men; 29 affected eyes; mean ± standard deviation age 38.4 ± 16.8; range: 13−76 years) were studied. The patients had bilateral hilar lymphadenopathy (58.8%), lung parenchyma involvement (47.1%), peripheral lymph nodes (41.2%), and involvement of other organs (52.9%). Angiotensin-converting enzyme was elevated in 58.8%. The most frequent ocular pattern was bilateral chronic relapsing panuveitis. The first biologic agent used was adalimumab in 10 (58.8%) and infliximab in 7 (41.2%) cases. Infliximab 5 mg/kg intravenously every 4−8 weeks and adalimumab 40 mg subcutaneously every 2 weeks were the most common administration patterns. In most cases anti-TNF-α therapy was given in combination with immunosuppressive drugs. The mean duration of follow-up was 33.9 ± 17.1 months. Significant improvement was observed following anti-TNF-α therapy. Baseline results versus results at 2 years from the onset of biologic therapy were the following: the median of cells in the ocular anterior chamber (interquartile range — IQR) 0.5 (0−2) versus 0 (0−0) ( p = 0.003), vitritis 0 (0−1.25) versus 0 (0−0) ( p = 0.008), macular thickness (391.1 ± 58.8 versus 247 ± 40.5 µm) ( p = 0.028), and visual acuity 0.60 ± 0.33 versus 0.74 ± 0.27; p = 0.009. The median daily (interquartile range) dose of prednisone was also reduced from 10 (0−30) mg at the onset of the anti-TNF-α therapy to 0 (0−0) mg at 2 years ( p = 0.02). Significant reduction was also achieved in the immunosuppressive load. Conclusion Anti-TNF-α therapy is effective in sarcoid uveitis patients refractory to conventional immunosuppressive therapy. Infliximab and adalimumab allowed a substantial reduction in prednisone dose despite having failed standard therapy.
Background EUS-guided cholangiopancreatography (ESCP) allows transmural access to biliopancreatic ducts when ERCP fails. Data regarding technical details, safety, and outcomes of ESCP are still ...unknown. Objective To evaluate outcomes of ESCP in community and referral centers at the initial development phase of this procedure, to identify the ESCP stages with higher risk of failure, and to evaluate the influence on outcomes of factors related to the endoscopist. Design Multicenter retrospective study. Setting Public health system hospitals with experience in ESCP in Spain. Patients A total of 125 patients underwent ESCP in 19 hospitals, with an experience of <20 procedures. Intervention ESCP. Main Outcome Measurements Technical success and complication rates in the initial phase of implantation of ESCP are described. The influence of technical characteristics and endoscopist features on outcomes was analyzed. Results A total of 125 patients from 19 hospitals were included. Biliary ESCP was performed in 106 patients and pancreatic ESCP was performed in 19. Technical success was achieved in 84 patients (67.2%) followed by clinical success in 79 (63.2%). Complications occurred in 29 patients (23.2%). Unsuccessful manipulation of the guidewire was responsible for 68.2% of technical failures, and 58.6% of complications were related to problems with the transmural fistula. Limitations Retrospective study. Conclusion Outcomes of ESCP during its implantation stage reached a technical success rate of 67.2%, with a complication rate of 23.2%. Intraductal manipulation of the guidewire seems to be the most difficult stage of the procedure.
Summary Background Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients with untreated multiple myeloma; however, toxic ...effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain efficacy and to reduce toxic effects. Methods Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32), plus either melphalan (9 mg/m2 on days 1–4) or daily thalidomide (100 mg), and prednisone (60 mg/m2 on days 1–4). The first cycle was followed by five cycles of bortezomib once per week for 5 weeks (1·3 mg/m2 on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91), consisting of one conventional cycle of bortezomib for 3 weeks (1·3 mg/m2 on days 1, 4, 8, and 11) every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with a computerised random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00443235. Findings In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p=0·9), including 36 (28%) and 26 (20%) complete remissions, respectively (p=0·2). Treatment with VTP resulted in more serious adverse events (40 31% vs 20 15%, p=0·01) and discontinuations (22 17% vs 15 12%, p=0·03) than did treatment with VMP. The most common toxicities (grade 3 or worse) were infections (one 1% in the VTP group vs nine 7% in the VMP group), cardiac events (11 8% vs 0), and peripheral neuropathy (nine 7% vs 12 9%). After maintenance therapy, the complete remission rate was 42% (40 44% patients in complete remission in the bortezomib plus thalidomide group, 34 39% in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neuropathy. Interpretation Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly patients with multiple myeloma. Funding Pethema (Spanish Program for the Treatment of Hematologic Diseases).
Background Adenoma detection rate (ADR) has become the most important quality indicator for colonoscopy. Objective The aim of this study was to investigate which modifiable factors, directly related ...to the endoscopic procedure, influenced the ADR in screening colonoscopies. Design Observational, nested study. Setting Multicenter, randomized, controlled trials. Patients Asymptomatic people aged 50 to 69 years were eligible for a multicenter, randomized, controlled trial designed to compare colonoscopy and fecal immunochemical testing in colorectal cancer screening. A total of 4539 individuals undergoing a direct screening colonoscopy were included in this study. Intervention Colonoscopy. Main Outcome Measurements Bowel cleansing, sedation, withdrawal time in normal colonoscopies, and cecal intubation were analyzed as possible predictors of adenoma detection by using logistic regression analysis, adjusted for age and sex. Results In multivariate analysis, after adjustment for age and sex, factors independently related to the ADR were a mean withdrawal time longer than 8 minutes (odds ratio OR 1.51; 95% CI, 1.17-1.96) in normal colonoscopies and split preparation (OR 1.26; 95% CI, 1.01-1.57). For advanced adenomas, only withdrawal time maintained statistical significance in the multivariate analysis. For proximal adenomas, withdrawal time and cecal intubation maintained independent statistical significance, whereas only withdrawal time longer than 8 minutes and a <10-hour period between the end of preparation and colonoscopy showed independent associations for distal adenomas. Limitations Only endoscopic variables have been analyzed. Conclusion Withdrawal time was the only modifiable factor related to the ADR in colorectal cancer screening colonoscopies associated with an increased detection rate of overall, advanced, proximal, and distal adenomas.
Summary Background Maintenance therapy improves outcomes in various tumour types, but cumulative toxic effects limit the choice of drugs. We investigated whether maintenance therapy with vinflunine ...would delay disease progression in patients with advanced urothelial carcinoma who had achieved disease control with first-line chemotherapy. Methods We did a randomised, controlled, open-label, phase 2 trial in 21 Spanish hospitals. Eligible patients had locally advanced, surgically unresectable, or metastatic transitional-cell carcinoma of the urothelial tract, adequate organ function, and disease control after four to six cycles of cisplatin and gemcitabine (carboplatin allowed after cycle four). Patients were randomly assigned (1:1) to receive vinflunine or best supportive care until disease progression. We initially used block randomisation with a block size of six. Four lists were created for the two stratification factors of starting dose of vinflunine and presence of liver metastases. After a protocol amendment, number of cisplatin and gemcitabine cycles was added as a stratification factor, and eight lists were created, still with a block size of six. Finally, we changed to a minimisation procedure to reduce the risk of imbalance between groups. Vinflunine was given every 21 days as a 20 min intravenous infusion at 320 mg/m2 or at 280 mg/m2 in patients with an Eastern Cooperative Oncology Group performance status score of 1, age 75 years or older, previous pelvic radiotherapy, or creatinine clearance lower than 60 mL/min. The primary endpoint was median progression-free survival longer than 5·3 months in the vinflunine group, assessed by modified intention to treat. Comparison of progression-free survival between treatment groups was a secondary endpoint. This trial is registered with ClinicalTrials.gov , number NCT01529411. Findings Between April 12, 2012, and Jan 29, 2015, we enrolled 88 patients, of whom 45 were assigned to receive vinflunine and 43 to receive best supportive care. One patient from the vinflunine group was lost to follow-up immediately after randomisation and was excluded from the analyses. One patient in the best supportive care group became ineligible for the study and did not receive treatment due to a delay in enrolment, but was included in the intention-to-treat efficacy analysis. After a median follow-up of 15·6 months (IQR 8·5–26·0), 29 (66%) of 44 patients in the vinflunine group had disease progression and 24 (55%) had died, compared with 36 (84%) of 43 patients with disease progression and 32 (74%) deaths in the best supportive care group. Median progression-free survival was 6·5 months (95% CI 2·0–11·1) in the vinflunine group and 4·2 months (2·1–6·3) in the best supportive care group (hazard ratio 0·59, 95% CI 0·37–0·96, p=0·031). The most common grade 3 or 4 adverse events were neutropenia (eight 18% of 44 in the vinflunine group vs none of 42 in the best supportive care group), asthenia or fatigue (seven 16% vs one 2%), and constipation (six 14% vs none). 18 serious adverse events were reported in the vinflunine group and 14 in the best supportive care group. One patient in the vinflunine group died from pneumonia that was deemed to be treatment related. Interpretation In patients with disease control after first-line chemotherapy, progression-free survival exceeded the acceptable threshold with vinflunine maintenance therapy. Moreover, progression-free survival was longer with vinflunine maintenance therapy than with best supportive care. Vinflunine maintenance had an acceptable safety profile. Further studies of the role of vinflunine are warranted. Funding Pierre-Fabre Médicament.
BACKGROUND COPD ranks within the top three causes of mortality in the global burden of disease, yet it remains largely underdiagnosed. We assessed the underdiagnosis of COPD and its determinants in ...national and international surveys of general populations. METHODS We analyzed representative samples of adults aged ≥ 40 years randomly selected from well-defined administrative areas worldwide (44 sites from 27 countries). Postbronchodilator FEV1 /FVC < lower limit of normal (LLN) was used to define chronic airflow limitation consistent with COPD. Undiagnosed COPD was considered when participants had postbronchodilator FEV1 /FVC < LLN but were not given a diagnosis of COPD. RESULTS Among 30,874 participants with a mean age of 56 years, 55.8% were women, and 22.9% were current smokers. Population prevalence of (spirometrically defined) COPD ranged from 3.6% in Barranquilla, Colombia, to 19.0% in Cape Town, South Africa. Only 26.4% reported a previous lung function test, and only 5.0% reported a previous diagnosis of COPD, whereas 9.7% had a postbronchodilator FEV1 /FVC < LLN. Overall, 81.4% of (spirometrically defined) COPD cases were undiagnosed, with the highest rate in Ile-Ife, Nigeria (98.3%) and the lowest rate in Lexington, Kentucky (50.0%). In multivariate analysis, a greater probability of underdiagnosis of COPD was associated with male sex, younger age, never and current smoking, lower education, no previous spirometry, and less severe airflow limitation. CONCLUSIONS Even with substantial heterogeneity in COPD prevalence, COPD underdiagnosis is universally high. Because effective management strategies are available for COPD, spirometry can help in the diagnosis of COPD at a stage when treatment will lead to better outcomes and improved quality of life. CHEST 2015; 148(4):971-985
Background Although empiric exclusion from the diet of the 6 food groups most likely to trigger allergies achieves eosinophilic esophagitis (EoE) remission in children, data on its prolonged efficacy ...and effects on adults are lacking. Objective We sought to evaluate the efficacy of a 6-food elimination diet in inducing and maintaining prolonged remission in patients with adult EoE. Methods Sixty-seven consecutive patients with adult EoE were prospectively recruited and treated exclusively with a diet avoiding cereals, milk, eggs, fish/seafood, legumes/peanuts, and soy for 6 weeks. Subsequent challenge was undertaken by sequentially reintroducing all excluded single foods, followed by endoscopy and biopsies, which were developed every 6 weeks in case of response (eosinophil peak count reduction to <15/high-power field hpf). A food was considered a trigger for EoE and removed from the diet if pathologic eosinophilic infiltration (≥15 eosinophils/hpf) reappeared. Food-specific serum IgE measurements and skin prick tests were performed before initiating the diet. Results Forty-nine (73.1%) patients exhibited significantly reduced eosinophil peak counts (<15 eosinophils/hpf) before sequential single-food reintroduction. A single offending food antigen was identified in 35.71% of patients, 2 food triggers were identified in 30.95%, and 3 or more food triggers were identified in 33.3%. Cow's milk was the most common food antigen (61.9%), followed by wheat (28.6%), eggs (26.2%), and legumes (23.8%). Prior allergy tests showed no concordance with food-reintroduction challenge results. All patients who continued to avoid the offending foods maintained histopathologic and clinical EoE remission for up to 3 years. Conclusions An empiric 6-food elimination diet effectively induced remission of active adult EoE, which was maintained for up to 3 years with individually tailored, limited exclusion diets.
Venous thromboembolism (VTE) is a serious, frequent, and preventable medical complication in hospitalized patients. Although the efficacy of prophylaxis (pharmacological and/or mechanical) has been ...demonstrated, compliance with prophylaxis is poor at international and national levels.
To determine the indication and use of pharmacological thromboprophylaxis in hospitalized patients in Uruguay.
An observational, descriptive, cross-sectional, multicentre study involving 31 nationwide healthcare facilities was conducted. Baseline characteristics associated with hospital admission, the percentage of the population with an indication for thromboprophylaxis, and the percentage of patients receiving pharmacological thromboprophylaxis were assessed. The VTE risk was determined using the Padua score for medical patients; the Caprini score for surgical patients; the Royal College of Obstetricians and Gynaecologists (RCOG) guidelines for pregnant-postpartum patients.
1925 patients were included, representing 26% of hospitalized patients in Uruguay. 71.9% of all patients were at risk of VTE. Of all patients at risk of VTE, 58.6% received pharmacological thromboprophylaxis. The reasons for not receiving thromboprophylaxis were prescribing omissions in 16.1% of cases, contraindication in 15.9% and 9.4% of patients were already anticoagulated for other reasons. Overall, just 68% of patients were "protected" against VTE. Recommendations of major thromboprophylaxis guidelines were followed in 70.1% of patients at risk.
Despite the progress made in adherence to thromboprophylaxis indications, nonadherence remains a problem, affecting one in six patients at risk of VTE in Uruguay.
Summary Background Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are ...no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects. Methods In our observational, prospective study we enrolled previously untreated adults (≥18 years) with clear-cell renal-cell carcinoma at 15 institutions in the Spanish Oncology Genitourinary Group in Spain. Patients received sunitinib according to local practice guidelines. We assessed RECIST response, progression-free survival (PFS), overall survival, and toxicity of sunitinib with 16 key polymorphisms in nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012, and rs307821), PDGFR -α (rs35597368), VEGF-A (rs2010963, rs699947, and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503, and rs2032582), and ABCB2 (rs2231142). We assessed associations with efficacy and toxicity by use of univariable and multivariable analyses (with clinical factors associated with outcomes as covariates). We adjusted for multiplicity using the Bonferroni method; p values of less than 0·0031 before adjustment were deemed to still be significant after adjustment. Findings We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio HR per allele 3·57, 1·75–7·30; punadjusted =0·00049, padjusted =0·0079) and rs307821 (3·31, 1·64–6·68; punadjusted =0·00085, padjusted =0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67–8·41; punadjusted =0·0014, padjusted =0·022). No other SNPs were associated with sunitinib response or toxicity. Interpretation Polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal-cell carcinoma with decreased sunitinib response and tolerability. If confirmed, these results should promote interventional studies testing alternative therapeutic approaches for patients with such variants. Funding Pfizer.
Background Chronic inflammatory diseases have been associated with increased prevalence of subclinical atherosclerosis. Hidradenitis suppurativa (HS) is a chronic inflammatory disease involving ...intertriginous skin. Objective We sought to investigate the potential association between HS and subclinical atherosclerosis. Methods This study included 68 patients with HS and 136 age- and sex-matched healthy control subjects. Patients with history of cardiovascular events, diabetes mellitus, chronic kidney disease, or another concomitant inflammatory condition were excluded. Carotid intima-media thickness and carotid plaques were measured by carotid ultrasonography. Adjustments were made for age, sex, and traditional cardiovascular risk factors. Results Patients had greater carotid intima-media thickness values than control subjects (0.615 ± 0.097 vs 0.578 ± 0.098 mm; P = .012). Carotid plaques were also more frequent in patients than in control subjects (30.9% vs 22.1%). In the multivariable regression model adjusted for age, sex, and traditional cardiovascular risk factors, HS was significantly related to the presence of carotid plaques (odds ratio 2.99, 95% confidence interval 1.26-7.13; P = .013). Limitations Causality could not be assessed. Conclusions These results indicate an increased frequency of subclinical atherosclerosis in patients with HS. Accordingly, HS should be considered a disease associated with potentially increased cardiovascular risk.
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