Summary Background VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 ...antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. Methods In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01140347. Findings Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0–10·6) versus 7·6 months (6·0–9·3) for the placebo group (HR 0·87 95% CI 0·72–1·05; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 5% of 277 patients treated with ramucirumab vs 11 4% of 276 patients treated with placebo), hypertension (34 12% vs ten 4%), asthenia (14 5% vs five 2%), malignant neoplasm progression (18 6% vs 11 4%), increased aspartate aminotransferase concentration (15 5% vs 23 8%), thrombocytopenia (13 5% vs one <1%), hyperbilirubinaemia (three 1% vs 13 5%), and increased blood bilirubin (five 2% vs 14 5%). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. Interpretation Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. Funding Eli Lilly and Co.
Background and Aims Balloon enteroscopy–assisted ERCP has provided a marked improvement in the success rate of reaching the papilla and consecutive ERCP procedures in patients with surgically altered ...anatomy in the Roux-en-Y reconstruction setting. However, limited data are available on the outcome of balloon enteroscopy–assisted ERCP in patients with Roux-en-Y anatomy who have naïve papillae. We retrospectively evaluated the feasibility of balloon enteroscopy–assisted ERCP in Roux-en-Y reconstruction after total or subtotal gastrectomy (RYG) with native papillae. Methods We performed 123 ERCP procedures in 109 patients with RYG. Among these patients, 90 consecutive ERCPs in 90 patients with native papillae were included. When selective biliary cannulation failed, the double-guidewire technique, the precut technique, or the rendezvous technique were performed as advanced cannulation methods. Results The overall success rate of reaching the papilla was 93.5% (115/123). The total procedure success rate was 88.1% (96/109). The adverse event rate was 7.3% (8/109). The success rate of the standard cannulation of the intact papilla was 67.8% (61/90). The final cannulation success rate was 95.6% (86/90) by using advanced cannulation methods. Conclusions Standard cannulation of the intact papilla in RYG cases remains challenging and uncertain. The use of various advanced cannulation methods improves the deep cannulation rate. Once selective cannulation succeeds, the treatment success rate is very high.
Summary Background Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We ...assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen. Methods In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov , number NCT02387996 , and is completed. Follow-up is still ongoing. Findings Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96–8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0–24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9–39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5–32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5–23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3–4 treatment-related adverse events occurred in 48 (18%) of 270 patients—most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure). Interpretation Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma. Funding Bristol-Myers Squibb.
Background and Aims Extension of ampullary adenomas into the common bile duct (CBD) or pancreatic duct (PD) may be difficult to treat endoscopically. We evaluated the feasibility, safety, and ...efficacy of endoscopic radiofrequency ablation (RFA) in the management of ampullary neoplasms with intraductal extension. Methods This was a multicenter, retrospective analysis of all patients with intraductal extension of ampullary neoplasms treated with endoscopic RFA between February 2012 and June 2015. Treatment success was defined as the absence of detectable intraductal polyps by ductography, visual inspection, and biopsy sampling. Results Fourteen patients with adenoma extension into the CBD (13 ± 7 mm, n = 14) and PD (7 ± 2 mm, n = 3) underwent a median of 1 RFA sessions (range, 1-5). Additional modalities (thermal probes, argon plasma coagulation, and/or photodynamic therapy) were also used in 7 patients, and prophylactic stents were routinely placed. Thirteen assessable patients underwent a median of 2 surveillance ERCPs after completion of treatment over a median follow-up of 16 months (range, 5-46), with intraductal biopsy specimens showing no neoplasm in 12 patients at the conclusion of endoscopic treatment. Treatment success was achieved in 92%, including 100% of those treated with RFA alone. Adverse events occurred in 43% and included ductal strictures (5 patients) and retroduodenal abscess (1 patient), all of which were successfully treated endoscopically. Conclusions Endoscopic RFA, alone or in combination with other modalities, may effectively treat intraductal extension of ampullary neoplasms. Ductal strictures were common after RFA but responded to endoscopic stent therapy. RFA may be appropriate in selected patients, particularly when the main treatment alternative is pancreaticoduodenectomy.
Antinuclear antibody-negative systemic sclerosis Salazar, Gloria A., MD; Assassi, Shervin, MD, MS; Wigley, Fredrick, MD ...
Seminars in arthritis and rheumatism,
06/2015, Letnik:
44, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Abstract Objective To examine the demographic and clinical characteristics of systemic sclerosis (SSc) patients without antinuclear antibodies (ANA) compared to ANA-positive patients. Methods SSc ...patients enrolled in the Scleroderma Family Registry and DNA Repository were included. Relevant demographic and clinical data were entered by participating sites or obtained by chart review. ANA and SSc-related antibodies were determined in all investigated patients using commercially available kits at our laboratories. Results This study included 3249 patients, of whom 208 (6.4%) were ANA negative. The proportion of male patients was higher in the ANA-negative group (OR = 1.65; p = 0.008). ANA-negative patients experienced less vasculopathic manifestations of SSc. The percent predicted diffusing capacity of carbon monoxide (DLCO) was higher in ANA-negative patients ( p = 0.03). Pulmonary arterial hypertension (PAH) per right heart catheterization was less common in the ANA-negative group (OR = 0.28; p = 0.03). Furthermore, patients with negative ANA had a lower prevalence of telangiectasias and digital ulcers/pits (OR = 0.59, p = 0.03 and OR = 0.38, p = 0.01, respectively). Although diffuse cutaneous involvement was more common, the modified Rodnan Skin Score (mRSS) was lower in the ANA-negative group (2.4 points lower, p = 0.05). Furthermore, they experienced more malabsorption ( p = 0.05). There was no difference in the frequency of pulmonary fibrosis or scleroderma renal crisis. All-cause mortality was not different between the 2 groups ( p = 0.28). Conclusions In conclusion, the results of this study suggest that SSc patients who are ANA negative constitute a distinct subset of SSc with less vasculopathy (less PAH, digital ulcers, and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.
SummaryBackgroundThe PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We ...updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis. MethodsIn the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I–III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0–2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m 2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m 2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. FindingsBetween Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9–85·6), 5-year overall survival was 81·4% (95% CI 77·2–85·8) with chemoradiotherapy versus 76·1% (71·6–80·9) with radiotherapy alone (adjusted hazard ratio HR 0·70 95% CI 0·51–0·97, p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5–80·7) versus 69·1% (63·8–73·8; HR 0·70 0·52–0·94, p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3–26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4–34·3) in the radiotherapy-alone group (HR 0·74 95% CI 0·55–0·99; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0–2·1) in both groups (HR 0·99 95% CI 0·06–15·90; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% 95% CI 0·3–2·8) in the chemoradiotherapy group versus four (0·9% 95% CI 0·3–2·8) in the radiotherapy-alone group (HR 0·75 95% CI 0·17–3·33; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four 2% women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported. InterpretationThis updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival. FundingDutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.
Background and Aims Symptomatic pancreatic walled-off necrosis (WON) may be managed by endoscopic transmural drainage and endoscopic transmural necrosectomy, with stent placement at endoscopic ...drainage sites. The optimal stent choice is yet to be determined. We compared outcomes after endoscopic management of WON using either large-caliber fully covered self-expandable metal stents (LC-SEMSs) or double-pigtail plastic stents (DPPSs). Methods We performed a retrospective comparison of outcomes among patients who received LC-SEMSs or DPPSs before endoscopic transmural necrosectomy for WON. Results Among 94 patients included, WON resolution rates did not differ between the DPPS (36 patients) and LC-SEMS (58 patients) groups, whether concomitant percutaneous drainage was considered a failure (75% vs 82.8%; P = .36) or not (91.7% vs 94.8%; P = .55). Of 75 patients (80%) successfully treated without percutaneous drainage, 37 (49%) underwent endoscopic transmural drainage without subsequent endoscopic transmural necrosectomy. WON was more likely to resolve without subsequent endoscopic transmural necrosectomy in the LC-SEMS group than the DPPS group (60.4% vs 30.8%; P = .01). WON resolution without subsequent endoscopic transmural necrosectomy remained more likely with LC-SEMSs (odds ratio, 4.5 95% confidence interval, 1.5-15.5) after adjusting for patient age and size and location of WON. Rates of adverse events were similar except for clinically significant bleeding requiring endoscopic intervention, which was higher with DPPSs than LC-SEMSs (14% vs 2%; P = .02). Conclusion Management of pancreatic WON with LC-SEMSs appears to decrease both the need for repeated necrosectomy procedures and the risk of intervention-related hemorrhage.
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