Benefit of pazopanib in advanced gastrointestinal stromal tumours: results from a phase II trial (SSG XXI, PAGIST).

BACKGROUND: Patients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib. PATIENTS AND METHODS: Since all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were ≥18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission + partial remission + stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks. RESULTS: Seventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome. CONCLUSION: Pazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting.

Follicular lymphoma in Sweden: nationwide improved survival in the rituximab era, particularly in elderly women: a Swedish Lymphoma Registry study.

Treatment for follicular lymphoma (FL) improved with rituximab. In Sweden, first-line rituximab was gradually introduced between 2003 and 2007, with regional differences. The first national guidelines for FL were published in November 2007, recommending rituximab in first-line therapy. Using the population-based Swedish Lymphoma Registry, 2641 patients diagnosed with FL from 2000 to 2010 were identified and characterized by year and region of diagnosis, age (median, 65 years), gender (50% men), first-line therapy and clinical risk factors. Overall and relative survivals were estimated by calendar periods (2000-2002, 2003-2007 and 2008-2010) and region of diagnosis. With each period, first-line rituximab use and survival increased. Survival was superior in regions where rituximab was quickly adopted and inferior where slowly adopted. These differences were independent in multivariable analyses. Ten-year relative survival for patients diagnosed 2003-2010 was 92%, 83%, 78% and 64% in the age groups 18-49, 50-59, 60-69 and ⩾70, respectively. With increasing rituximab use, male sex emerged as an adverse factor. Survival improved in all patient categories, particularly in elderly women. The introduction and the establishment of rituximab have led to a nationwide improvement in FL survival. However, rituximab might be inadequately dosed in younger women and men of all ages.

Impact of chemotherapy regimen and rituximab in adult Burkitt lymphoma: a retrospective population-based study from the Nordic Lymphoma Group.

BACKGROUND: Standard treatment of adult Burkitt lymphoma is not defined due to the lack of randomised trials. In this situation, population-based data may represent a useful contribution in order to identify an optimal treatment strategy. PATIENTS AND METHODS: The aims of this study were to investigate the outcome for adult HIV-negative BL with different chemotherapy regimens, and to assess possible improvement within the time frame of the study. The study population was identified through the Swedish and Danish lymphoma registries 2000-2009. RESULTS: A total of 258 patients were identified. Since 2000, overall survival (OS) improved significantly only for younger patients (<65 years). Intensive regimens such as the Berlin-Frankfurt-Münster, hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and cyclophosphamide, vincristine, doxorubicin, methotrexate, ifosfamide, etoposide, and cytarabine (CODOX-M/IVAC) were associated with a favourable 2-year OS of 82%, 83%, and 69%, respectively. The low-intensive CHOP/CHOEP regimens achieved a 2-year OS of 38.8%, confirming their inadequacy for the treatment of BL. In a multivariate analysis, rituximab was not significantly associated with improved OS. CONCLUSIONS: In this population-based retrospective series of adult BL, intensive chemotherapy regimens were associated with favourable outcome. The impact of the addition of rituximab remains uncertain and warrants further investigation.

Applicability of an exaggerated forearm wash test for efficacy testing of two corticosteroids, tacrolimus and glycerol, in topical formulations against skin irritation induced by two different irritants.

BACKGROUND/PURPOSE: Alternatives to corticosteroids in the treatment of irritant contact dermatitis (ICD) are needed and may include glycerol and topical immunomodulators like tacrolimus. Because the efficacy of different treatments in experimentally induced ICD may vary depending on the irritant applied, we tested the efficacy of four anti-irritant compounds using the two different irritants sodium lauryl sulfate (SLS) and nonanoic acid (NON). METHODS: In a randomized, double-blind, controlled trial, healthy volunteers were exposed to 5% SLS and 50% NON (the right and the left forearm, respectively) in a cumulative wash test. Induction of ICD was obtained by three daily washings for 7 days, followed by a maintenance phase with two daily washings for 12 days. Treatment (triamcinolone acetonide, clobetasol propionate, tacrolimus and glycerol ointment) was started at day 7 and applied immediately after washing. Vehicle and no treatment served as the control. Reactions were evaluated clinically and instrumentally. RESULTS: No treatments were significantly better than the other treatments and controls. There was a tendency toward a dose-dependent response to corticoid treatment, and a trend toward worsened irritancy by tacrolimus on SLS-irritated skin. Explained variance in the experiment by anova revealed a very small effect of treatments compared with an immense and significant subject effect. CONCLUSION: No claims of effective anti-irritant properties for any of the ointments can be maintained. Application of the present wash test as a tool for anti-irritant efficacy testing may be complicated by the small observed variance explained by treatment.

[Multilevel analysis of regional disparities in survival after heart failure: differences between county health services affect little patients' prognosis]. / Multinivåanalys av regionala skillnader i överlevnad efter hjärtsvikt: landstingens egenskaper har föga inflytande på patientens prognos.

The prognosis for patients suffering from heart failure in Sweden differs from county to county, indicating a need for a comparative study in order to uncover the reasons. Conventional single-level analytical methods, however, underestimate the statistical uncertainty in such studies, leading to an inappropriate ranking of regions. Consequently, public opinion and decision-making may be misled. Conventional methods are also unable to disentangle the extent to which differences in prognosis may depend on individual or regional factors. Multilevel analysis, on the other hand, provides a better estimate of statistical uncertainty, and can both identify and quantify the extent to which differences in prognosis depend on either patient-related or regional factors. Using multilevel analysis, we examined the one-year mortality of 38,343 heart failure patients for the period 1992-1995 in every county in Sweden. Regional differences in one-year mortality were found to be very small, the most relevant factors being individual ones. The limited differences distinguishable at the county level may be explained in part by physician density: the more physicians in a county, the better an individual patient's prognosis.

Diastolic blood pressure and area of residence: multilevel versus ecological analysis of social inequity.

STUDY OBJECTIVES: To study geographical differences in diastolic blood pressure and the influence of the social environment (census percentage of people with low educational achievement) on individual diastolic blood pressure level, after controlling for individual age and educational achievement. To compare the results of multilevel and ecological analyses. DESIGN: Cross sectional analysis performed by multilevel linear regression modelling, with women at the first level and urban areas at the second level, and by single level ecological regression using areas as the unit of analysis. SETTING: Malmö, Sweden (population 250 000). PARTICIPANTS: 15 569 women aged 45 to 73, residing in 17 urban areas, who took part in the Malmö Diet and Cancer Study (1991-1996). MAIN RESULTS: In the "fixed effects" multilevel analysis, low educational achievement at both individual (beta=1.093, SE=0.167) and area levels (beta=2.966, SE=1.250) were independently associated with blood pressure, although in the "random effects" multilevel analysis almost none of the total variability in blood pressure across persons was attributable to areas (intraclass correlation=0.3%). The ecological analysis also found an association between the area educational variable and mean diastolic blood pressure (beta=4.058, SE=1.345). CONCLUSIONS: The small intraclass correlation found indicated very marginal geographical differences and almost no influence of the urban area on individual blood pressure. However, these slight differences were enough to detect an effect of the social environment on blood pressure. The ecological study overestimated the associations found in the "fixed" effects multilevel analysis, and neither distinguished individual from area levels nor provided information on the intraclass correlation. Ecological analyses are inadequate to evaluate geographical differences in health.