Posttransplant Lymphoproliferative Disorder After Solid Organ Transplant: A Heterogeneous, Aggressive Disorder.

Posttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplant. We identified 40 patients diagnosed with PTLD between 2009 and 2020 and analyzed their presentation, treatment strategies, and outcomes. Median age at diagnosis was 52.5 years (range 21.3 to 79). Median duration of immunosuppression was 95 months (range 4 to 292). Diffuse large B cell lymphoma (n = 16, 40%) and Burkitt lymphoma (n = 6, 15%) were the most common histological subtypes. First-line therapy varied. The median number of treatment lines was 1 (range 0 to 4). Sixteen patients (40%) achieved complete response after first-line therapy. Nineteen patients (47.5%) relapsed or progressed and received salvage therapy; 45% were alive at the end of the study period (median survival 52 months; range 1 to 266; 95% confidence interval 0 to 104). Causes of death included lymphoma-related (45.5%), therapy-related (27.3%), and other (27.3%). Five (22.7%) died within 3 months of diagnosis. Pearson's r test identified disease stage (P = .045) and proliferation index (P = .005) as negative predictors of response to frontline therapy. Bone marrow involvement (P = .033) and increased age (P = .018) were significant predictors of survival. Early mortality and poor response to frontline therapy are common, outlining the need for improved treatment strategies.

Shorter Diagnosis-to-Treatment Interval in Diffuse Large B-Cell Lymphoma is Associated With Inferior Overall Survival in a Large, Population-Based Registry.

BACKGROUND: Because of prolonged screening requirements, patient and time-dependent selection have been proposed as potential biases in clinical trials. The screening process may exclude patients with a need for emergent treatment (and a short period from diagnosis to treatment initiation [DTI]). We explored the impact of DTI on overall survival (OS) in a population-based cohort of patients with diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Using population-based administrative databases in Ontario, Canada, we identified adults aged ≥18 years with DLBCL treated with rituximab-based chemotherapy for curative intent between January 2005 and December 2015. Cox regression and multivariable analyses were presented to evaluate the impact of time from DTI on OS, controlling for relevant covariates. RESULTS: We identified 9,441 patients with DLBCL in Ontario; median age was 66 years, 53.6% were male, median number of comorbidities (Johns Hopkins aggregated diagnosis groups) was 10 (interquartile range [IQR], 8-13), and median DTI was 37 days (IQR, 22-61). Between treatment initiation and study end, 43% of patients died (median OS, 1 year; IQR, 0.4-2.8 years). Shorter DTI was a significant predictor of mortality (P<.001). Compared with the shortest DTI period of 0-18 days, those who commenced therapy at 19-29 days (hazard ratio [HR], 0.75; 95% CI, 0.68-0.84), 30-41 days (HR, 0.70; 95% CI, 0.63-0.78), 42-57 days (HR, 0.52; 95% CI, 0.46-0.58), and 58-180 days (HR, 0.52; 95% CI, 0.47-0.58) had improved survival. Increasing age (HR, 1.03; 95% CI, 1.03-1.04), male sex (HR, 1.23; 95% CI, 1.14-1.32), and increasing number of comorbidities (HR, 1.12; 95% CI, 1.11-1.13) were associated with inferior survival. CONCLUSIONS: Among patients with DLBCL, shorter DTI was associated with inferior OS. Therefore, DTI may represent a surrogate marker for aggressive biology. Clinical trials with lengthy screening periods are likely creating a time-dependent patient selection bias.

Statin and cyclooxygenase-2 inhibitors improve survival in newly diagnosed diffuse large B-cell lymphoma: a large population-based study of 4913 subjects.

Preclinical data suggests anti-lymphoma potential for statins, metformin and cyclooxygenase-2 (COX-2) inhibitors. We performed a retrospective population-based study of all adults aged ≥66 years diagnosed with diffuse large B-cell lymphoma (DLBCL) or transformed lymphoma treated with a rituximab containing regimen, between 2005 and 2015 in Ontario, Canada. Using administrative databases, we assessed the impact of medication exposures, prior to chemo-immunotherapy, on lymphoma survival. Cox regression analyses, controlling for sociodemographic factors and comorbidities, examined the relationship between medication exposure and survival. In total, 4913 patients were treated with curative intent (median age 75 years, 51% male) and 52·2% died at a median of 1 year from treatment initiation (67% due to DLBCL). In the year prior to commencing treatment, 45·7% received statins, 16·3% metformin, and 25·0% a COX-2 inhibitor. Adjusting for confounders, exposure to statin and COX-2 inhibitors prior to chemo-immunotherapy independently conferred a survival advantage: statin exposure for 30 days (hazard ratio [HR] 0·97, 95% confidence interval [CI] 0·96-0·98), 180 days (HR 0·84, 95% CI 0·80-0·89) and 365 days (HR 0·71, 95% CI 0·63-0·79) and COX-2 inhibitor exposure for 30 days (HR 0·95, 95% CI 0·95-0·98), 180 days (HR 0·76, 95% CI 0·66-0·86) and 365 days (HR 0·57, 95% CI 0·43-0·74). Metformin had no significant impact. This population-based study found a dose-related survival benefit of exposure to statins and COX-2 inhibitors prior to chemo-immunotherapy for newly diagnosed DLBCL.

Risk adjusted therapy in chronic lymphocytic leukemia: a phase II cancer trials Ireland (CTRIAL-IE [ICORG 07-01]) study of fludarabine, cyclophosphamide, and rituximab therapy evaluating response adapted, abbreviated frontline therapy with FCR in non-del(17p) CLL.

Minimal residual disease negative complete response (MRD-negative CR) provides an early marker for time to treatment failure (TTF) in CLL treated with fludarabine, cyclophosphamide, and rituximab (FCR). MRD was assessed after four FCR cycles (FCR4); MRD-negative CR patients discontinued treatment. Fifty-two patients (35M; 17F) were enrolled. Eighteen (18/52; 34.6%) patients reached MRD-negative CR after FCR4 and 29/52 (55.8%) were MRD-negative CR at end of treatment (EOT). Median TTF was 71.1 months (95% CI 61.3-84.1 months), with median overall survival not reached. Mutated immunoglobulin heavy chain gene rearrangements (IGHV) were associated with early MRD-negative remissions, translating into prolonged TTF. Unmutated-IGHV, mutated-SF3B1 and mutated-NOTCH1 were associated with shortened TTF. No TTF difference was observed between patients in MRD-negative CR after four versus six cycles (82.2 versus 85.3 months, p = .6306). Abbreviated FCR therapy is effective for patients achieving early MRD-negative remissions. Interim MRD assessment assists in personalizing therapy and reducing chemotherapy-associated toxicity.

Nonfamilial, MPL S505N-Mutated Essential Thrombocythaemia.

Mutations of MPL are present in a significant proportion of patients with the myeloproliferative neoplasms (MPN), primary myelofibrosis (PMF), and essential thrombocythaemia (ET). The most frequent of these mutations, W515L and W515K, occur in exon 10 of MPL, which encodes the receptor for thrombopoietin. Another exon 10 mutation, MPL S505N, has been shown to be a founder mutation in several pedigrees with familial thrombocythaemia where it is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Rare cases of sporadic, nonfamilial, MPL S505N MPN have been documented, but the presenting laboratory and clinical features have not been described in detail. The diagnosis and clinical course of a case of MPL S505N-positive MPN are presented with diagnostic features and treatment response resembling typical ET but with evidence of increasing bone marrow fibrosis. Further MPN cases possessing this genotype require reporting in order to ascertain whether any particular morphological or clinical features, if present, determine clinical course and aid the refinement of therapeutic options.

A seizure care pathway in the emergency department: preliminary quality and safety improvements.

Aim. To evaluate the utility of a seizure care pathway for seizure presentations to the emergency department (ED) in order to safely avoid unnecessary admission and to provide early diagnostic and therapeutic guidance and minimize length of stay in those admitted. Methods. 3 studies were conducted, 2 baseline audits and a 12-month intervention study and prospective data was collected over a 12-month period (Nov 2008-09). Results. Use of the Pathway resulted in a reduction in the number of epilepsy related admissions from 341 in 2004 to 276 in 2009 (P = 0.0006); a reduction in the median length of stay of those admittedfrom 4-5 days in the baseline audits to 2 days in the intervention study (P ≤ 0.001); an improvement in time to diagnostic investigations such as CT brain, MRI brain and Electroencephalography (P ≤ 0.001, P ≤ 0.048, P ≤ 0.001); a reduction in readmission rates from 45.1% to 8.9% (P ≤ 0.001); and an improvement in follow-up times from a median of 16 weeks to 5 weeks (P < 0.001). From a safety perspective there were no deaths in the early discharged group after 12 months follow-up. Conclusion. The burden of seizure related admissions through the ED can be improved in a safe and effective manner by the provision of a seizure care pathway.

Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.

Amyloid-beta (Abeta) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. Abeta aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of Abeta. Using in vivo microdialysis in mice, we found that the amount of ISF Abeta correlated with wakefulness. The amount of ISF Abeta also significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, Abeta plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease.