Cumulative Risk For Development Research Articles

Cumulative risk of developing a new symptom in patients with primary biliary cholangitis and its impact on prognosis.

Background and AimSymptoms of primary biliary cholangitis (PBC) frequently impair one's quality of life (QOL). Nonetheless, with improved treatment, the prognosis of PBC also improves. QOL plays an important role in patients with PBC. In this study, we aimed to reevaluate the transition of new symptom development in PBC and its predictive factors.MethodsThis retrospective multicenter study enrolled 382 patients with PBC for symptom analysis. The impact of a newly developed symptom on PBC prognosis was investigated by Kaplan–Meier analysis with propensity score matching and logistic progression analysis.ResultsThe cumulative risk of developing a new symptom after 10 and 20 years of follow‐up was 7.6 and 28.2%, and specifically that of pruritus, which was the most common symptom, was 6.7 and 23.3%, respectively. In Cox hazard risk analysis, serum Alb level (hazard ratio [HR], 1.097; 95% confidence interval [CI], 1.033–1.165; P = 0.002), the serum D‐Bil level (HR, 6.262; 95% CI, 2.522–15.553, P < 0.001), and Paris II criteria (HR, 0.435; 95% CI, 0.183–1.036; P = 0.037) were significant independent predictors of a new symptom. Kaplan–Meier analysis showed that the overall survival and liver‐related death were not significant between patients with and without a new symptom.ConclusionThe cumulative risk of new symptom development is roughly 30% 20 years after diagnosis and could be predicted by factors including serum albumin levels, serum D‐Bil level, and Paris II criteria.

Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial

The standard of care for smouldering multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma. Here we report the long-term follow-up results of the trial. We did this open-label, randomised, controlled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1:1), via a computerised random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Randomisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrolment (≤6 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1-21, plus dexamethasone 20 mg per day on days-1-4 and days 12-15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1-21 of each 28-day cycle) up to 2 years. Group allocation was not masked from study investigators or patients. The primary endpoint was time from randomisation to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00480363. Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent randomisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n=57) or observation (n=62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67-85). Lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached [95% CI 47 months-not reached] vs 23 months [16-31]; hazard ratio [HR] 0·24 [95% CI 0·14-0·41]; p<0·0001). Progression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months-not reached vs 53 months-not reached; HR 0·43 [95% CI 0·21-0·92], p=0·024). Survival in patients who had received subsequent treatments at the time of progression to active disease did not differ between groups (HR 1·34 [95% CI 0·54-3·30]; p=0·50). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four [6%]), asthenia (four [6%]), neutropenia (three [5%]), and skin rash (two [3%]); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during induction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six [10%] of 62 patients vs one [2%] of 63 patients), but the cumulative risk of development did not differ significantly between the groups (p=0·070). This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future. Pethema (Spanish Program for the Treatment of Hematologic Diseases).

Malignancy After Liver Transplantation: Cumulative Risk for Development

Solid organ recipients are at high risk to develop malignancies due to the complex interactions of several factors, constituting a major cause of late death after transplantation. We retrospectively reviewed an historic cohort of adult liver recipients from cadaveric donors (multiorgan recipients excluded) performed from 1986-2002 with a minimum follow-up of 36 months. The Kaplan-Meier method was used to assess cumulative risk to develop malignancy and survival analyses. Among the 528 patients undergoing orthotopic liver transplantation (OLT) with a mean follow-up of 2400 days, 98 developed cancer among which 25% were skin malignancies. Sixty-seven patients developed at least 1 noncutaneous malignancy, an overall incidence of 12.7%. Eighteen percent suffered from posttransplant lymphoproliferative disease; 14%, lung cancer; 4%, Kaposi's sarcoma; 7%, genitourinary malignancies; and 17%, oropharyngeal or laryngeal cancer. The cumulative patient risks to develop noncutaneous malignancies at 5, 10, and 15 years posttransplantation were 9% (confidence interval [CI]: 0.06-0.11), 18% (CI: 0.14-0.23), and 25% (CI: 0.18-0.31), respectively. OLT recipients are at higher risk to develop malignancies after transplantation, reaching a cumulative risk of 25% at 15 years. Long-term surveillance measures and screening programs must be seriously conducted for selected groups.

Efficacy and tolerability of reboxetine compared with imipramine in a double-blind study in patients suffering from major depressive episodes

A 6-week, randomised, double-blind, multicentre study in 256 patients with a DSM-III-R diagnosis of major depression was carried out to compare the selective noradrenaline reuptake inhibitor (NARI), reboxetine, with the reference standard tricyclic antidepressant, imipramine. The efficacy of reboxetine, as measured by the extent of improvement of Hamilton Depression Rating Scale, Montgomery and Asberg Depression Rating Scale and the Clinical Global Impression Scale, was similar to that of imipramine. The improvement was observed in the overall population and in severely depressed and melancholic patients. Reboxetine tolerability compared favourably with that of imipramine. Frequency of discontinuation due to adverse events was lower in the reboxetine-treated group (10.0%) than in the imipramine-treated group (14.3%), and the cumulative risk of development (Kaplan-Meier analysis) of dry mouth, hypotension and/or related symptoms and tremor was significantly higher on imipramine than on reboxetine.