The relevance of fatigue to relapse rate in multiple sclerosis: Applying patient preference data to the OPTIMUM trial.

BACKGROUND: In the OPTIMUM trial in patients with relapsing MS, treatment differences in annualized relapse rate (ARR, 0.088) and change in fatigue at week 108 (3.57 points, measured using the Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis, symptom domain (FSIQ-RMS-S)) favored ponesimod over teriflunomide. However, the importance of the fatigue outcome to patients was unclear. OBJECTIVE: To assess the importance of the OPTIMUM FSIQ-RMS-S results using data from an MS discrete choice experiment (DCE). METHODS: The DCE included components to correlate levels of physical and cognitive fatigue with FSIQ-RMS-S scores. Changes in relapses/year and time to MS progression equivalent to the treatment difference in fatigue in OPTIMUM were determined for similar fatigue levels as mean baseline fatigue in OPTIMUM. RESULTS: DCE participants would accept 0.06 more relapses/year or a 0.15-0.17 year decrease in time to MS progression for a 3.57-point difference in physical fatigue on the FSIQ-RMS-S. To improve cognitive fatigue by 3.57-points on the FSIQ-RMS-S, DCE participants would accept 0.09-0.10 more relapses/year or a 0.24-0.28 year decrease in time to MS progression. CONCLUSION: MS patients would accept 0.06 more relapses/year to change their fatigue by a similar magnitude as the between-treatment difference observed in the OPTIMUM trial.

Phase 2 studies of lenalidomide, subcutaneous bortezomib, and dexamethasone as induction therapy in patients with newly diagnosed multiple myeloma.

There are limited prospective data on lenalidomide, subcutaneous bortezomib, and dexamethasone (RsqVd) in transplant-eligible/transplant-ineligible patients with newly diagnosed multiple myeloma. Reliable biomarkers for efficacy and toxicity are required to better tailor therapy. Two parallel studies were conducted by Cancer Trials Ireland (CTI; NCT02219178) and the Dana-Farber Cancer Institute (DFCI; NCT02441686). Patients received four 21-day cycles of RsqVd and could then receive either another 4 cycles of RsqVd or undergo autologous stem cell transplant. Postinduction/posttransplant, patients received lenalidomide maintenance, with bortezomib included for high-risk patients. The primary endpoint was overall response rate (ORR) after 4 cycles of RsqVd. Eighty-eight patients were enrolled and 84 treated across the two studies; median age was 64.7 (CTI study) and 60.0 years (DFCI study), and 59% and 57% had stage II-III disease. Pooled ORR after 4 cycles in evaluable patients was 93.5%, including 48.1% complete or very good partial responses (CTI study: 91.9%, 59.5%; DFCI study: 95.0%, 37.5%), and in the all-treated population was 85.7% (44.0%). Patients received a median of 4 (CTI study) and 8 (DFCI study) RsqVd cycles; 60% and 31% of patients (CTI study) and 33% and 51% of patients (DFCI study) underwent transplant or received further RsqVd induction, respectively. The most common toxicity was peripheral neuropathy (pooled: 68%, 7% grade 3-4; CTI study: 57%, 7%; DFCI study: 79%, 7%). Proteomics analyses indicated elevated kallikrein-6 in good versus poor responders, decreased midkine in good responders, and elevated macrophage inflammatory protein 1-alpha in patients who stopped treatment from neurotoxicity, suggesting predictive biomarkers warranting further investigation.

Treatment patterns and outcomes of unfit and elderly patients with Mantle cell lymphoma unfit for standard immunochemotherapy: A UK and Ireland analysis.

Mantle cell lymphoma (MCL) presenting in elderly, unfit patients represents a clinical challenge. Front-line 'attenuated' or low-intensity immunochemotherapy is often employed, although outcomes are relatively unexplored. We report outcomes of attenuated immunochemotherapy in 95 patients with MCL across 19 centres in the UK and Ireland considered unfit for full-dose rituximab-bendamustine or rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP). Regimens examined were rituximab-cyclophosphamide, vincristine, prednisolone (R-CVP) (n = 19), dose-attenuated R-CHOP (n = 22), dose attenuated rituximab-bendamustine (n = 24) and rituximab-chlorambucil (n = 30). The primary outcome was progression-free survival (PFS). The secondary outcomes included overall response, overall survival (OS) and toxicity. The median (range) age was 79 (58-89) years and 50% were aged ≥80 years. The median (range) Cumulative Illness Rating Scale-Geriatric score was 6 (0-24). The median PFS for all patients was 15 months [95% confidence interval (CI) 8·7-21·2) and median OS was 31·4 months (95% CI 19·7-43·2). By multivariable analysis (MVA), the only clinical factor associated with an inferior PFS was blastoid morphology [hazard ratio (HR) 2·90, P = 0·01). Notably, higher treatment intensity (R-CHOP/R-bendamustine composite) provided an independently superior PFS compared with R-CVP/R-chlorambucil (MVA HR 0·49, P = 0·02). Factors associated with inferior OS by MVA were Eastern Cooperative Oncology Group Performance Status (HR 2·14, P = 0·04), blastoid morphology (HR 4·08, P = 0·001) and progression of disease at <24 months status (HR 5·68, P < 0·001). Overall, survival after front-line dose-attenuated immunochemotherapy is unsatisfactory. Clinical trials investigating novel agents such as Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors in this specific clinical setting are warranted.

Efficacy of subcutaneous interferon ß-1a on MRI outcomes in a randomised controlled trial of patients with clinically isolated syndromes.

AIM: The REbif FLEXible dosing in early MS (REFLEX) study compared several brain MRI outcomes in patients presenting with clinically isolated syndromes suggestive of multiple sclerosis and treated with two dose-frequencies of subcutaneous interferon (IFN) ß-1a or placebo. METHODS: Patients were randomised (1:1:1) to IFN ß-1a, 44 µg subcutaneously three times a week or once a week, or placebo three times a week for up to 24 months. MRI scans were performed every 3 months, or every 6 months if the patient developed clinically definite multiple sclerosis. End points analysed included: number of combined unique active lesions per patient per scan; numbers and volumes of new T2, T1 hypointense and gadolinium-enhancing (Gd+) lesions per patient per scan; and brain volume. RESULTS: 517 patients were randomised (intent-to-treat population: subcutaneous IFN ß-1a three times a week, n=171; subcutaneous IFN ß-1a once a week, n=175; placebo, n=171). Combined unique active lesions were lower in patients treated with subcutaneous IFN ß-1a versus placebo (mean (SD) lesions per patient per scan: three times a week 0.6 (1.15); once a week 1.23 (4.26); placebo 2.70 (5.23); reduction versus placebo: three times a week 81%; once a week 63%; p<0.001) and with three times a week versus once a week (48% reduction; p=0.002). The mean numbers of new T2, T1 hypointense and Gd+ lesions were all significantly lower in the two active treatment arms compared with placebo (p≤0.004 for three times a week or once a week) and in the three times a week group compared with once a week (p≤0.012). CONCLUSIONS: Both subcutaneous IFN ß-1a 44 µg regimens improved MRI outcomes versus placebo, with the three times a week regimen having a more pronounced effect than once a week dosing. TRIAL REGISTRATION: clinicaltrial.gov identifier, NCT00404352.

Hepatitis C community prevalence is over-estimated: a prospective, birth cohort study.

BACKGROUND: Hepatitis C virus infection is often asymptomatic, and many patients may be unaware they are infected. Community-based, birth cohort screening has been advocated to identify these patients. It has been estimated that 0.7-1% of individuals born between 1965 and 1985 in Ireland are infected. The cost-effectiveness of screening is critically dependent on the population prevalence. AIMS: The aim is to determine the community prevalence of hepatitis C virus infection in the birth cohort 1965-1985. METHODS: Residual serum samples from blood tests ordered by community general practitioners were anonymised and analysed for the presence of hepatitis C antibody ± antigen. Twelve large general hospitals throughout the country participated. RESULTS: A total of 14,320 samples were tested, 9347 of which were from the birth cohort 1965-1985. Seventy-two samples were positive for hepatitis C antibody of which 12 were positive for hepatitis C antigen (17%). The overall prevalence of hepatitis C antigen in the birth cohort was 0.09%. A higher prevalence (0.39%) was identified in males in two urban areas of Dublin. CONCLUSIONS: Hepatitis C virus seroprevalence was much lower than previously estimated. The proportion of antibody positive patients with hepatitis C antigen was also lower than expected suggesting the effects of treatment and/or high spontaneous viral clearance. Universal birth cohort screening is unlikely to be cost-effective. Targeted birth cohort screening in high prevalence areas could be considered.

A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia.

This retrospective analysis assessed the response, safety and duration of response to standard dose rituximab 375 mg/m(2) weekly for four weeks as therapy for patients with primary or secondary warm autoimmune haemolytic anaemia (WAIHA), who had failed initial treatment. Thirty-four patients received rituximab for WAIHA in seven centres in the Republic of Ireland. The overall response rate was 70·6% (24/34) with 26·5% (9/34) achieving a complete response (CR). The time to response was 1 month post-initiation of rituximab in 87·5% (21/24) and 3 months in 12·5% (3/24) of patients. The median duration of follow-up was 36 months (range 6-90 months). Of the patients who responded, 50% (12/24) relapsed during follow up with a median time to next treatment of 16·5 months (range 6-60 months). Three patients were re-treated with rituximab 375 mg/m2 weekly for four weeks at relapse and responded. There was a single episode of neutropenic sepsis. Rituximab is an effective and safe treatment for WAIHA but a significant number of patients will relapse in the first two years post treatment. Re-treatment was effective in a small number of patients, suggesting that intermittent pulse treatment or maintenance treatment may improve long-term response.

Diagnosing, imaging, and successfully treating a debilitating case of Bing-Neel syndrome: A multidisciplinary feat.

Key Clinical Message: We present a case of Bing-Neel syndrome a rare central nervous system lymphoplasmocytic lymphoma associated with Waldenstrom macroglobulinemia. Diagnosis should be considered in the context of unexplained neurological symptoms in the presence of macroglobulinemia. Abstract: Waldenstroms macroglobulinaemia (WM) is a rare B-cell lymphoma representing ~2% of all hematological malignancies. While most neurological complications of WM are secondary to the overproduction of immunoglobulin M (IgM), Bing-Neel syndrome (BNS) is an extremely rare direct central nervous system (CNS) infiltration by malignant lymphoplasmocytic lymphoma (LPL) cells. Limited information on BNS exists in the literature with sparse case reports and case series. Here, we present a diagnostically challenging BNS case successfully treated with systemic chemoimmunotherapy and ibrutinib, with remarkable clinical response.

Treatment preferences in relation to fatigue of patients with relapsing multiple sclerosis: A discrete choice experiment.

Background: Treatment decisions for multiple sclerosis (MS) are influenced by many factors such as disease symptoms, comorbidities, and tolerability. Objective: To determine how much relapsing MS patients were willing to accept the worsening of certain aspects of their MS in return for improvements in symptoms or treatment convenience. Methods: A web-based discrete choice experiment (DCE) was conducted in patients with relapsing MS. Multinomial logit models were used to estimate relative attribute importance (RAI) and to quantify attribute trade-offs. Results: The DCE was completed by 817 participants from the US, the UK, Poland, and Russia. The most valued attributes of MS therapy to participants were effects on physical fatigue (RAI = 22.3%), cognitive fatigue (RAI = 22.0%), relapses over 2 years (RAI = 20.7%), and MS progression (RAI = 18.4%). Participants would accept six additional relapses in 2 years and a decrease of 7 years in time to disease progression to improve either cognitive or physical fatigue from "quite a bit of difficulty" to "no difficulty." Conclusion: Patients strongly valued improving cognitive and physical fatigue and were willing to accept additional relapses or a shorter time to disease progression to have less fatigue. The impact of fatigue on MS patients' quality of life should be considered in treatment decisions.

Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: Model-Based Meta-Analyses for Confirmed Disability Accumulation and Annualized Relapse Rate.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory autoimmune disorder and the most common cause of non-traumatic disability in young adults. The Phase 3 OPTIMUM study evaluated the efficacy and safety of oral ponesimod, a selective sphingosine-1-phosphate (S1P) receptor 1 modulator, vs. teriflunomide in patients with relapsing multiple sclerosis (RMS). The aim of this analysis was to assess the effect of ponesimod and other disease modifying treatments (DMTs) compared to placebo, as measured by 12-week confirmed disability accumulation (CDA) and annualized relapse rate (ARR) in RMS patients. METHODS: A database was developed by Certara Inc. (USA) based on relevant clinical trials identified from searching the following sources: PubMed, clinicaltrials.gov, FDA and EMEA documents, and conference abstracts. This database consisted of 203 unique randomized controlled trials (RCTs) with 74 MS treatments and was subsequently filtered to include RCTs with more than 25 patients receiving monotherapy to treat RMS for at least 48 weeks. A model-based meta-analysis (MBMA) was performed on the filtered database to assess treatment effects measured by CDA and ARR. Analyzed data for CDA were digitized from published Kaplan-Meier plots. A Weibull distribution was assumed to adequately capture the relationship of CDA probability over time, and hazard ratios (HRs) between treatments were assumed constant over time (proportional hazards). HRs were estimated for 12-week CDA for 17 DMTs vs. placebo. Additionally, mean ARR for each treatment arm was modelled, where relative effect versus placebo was estimated as a fixed effect parameter for each unique drug. A dose-response relationship was included if data for multiple doses were available. Relative treatment effect covariates explored for CDA and ARR included: percent of patients with relapsing-remitting MS (RRMS), trial start year, mean duration of disease, percent of patients who received DMTs within the prior 2 years (pDMT), mean number of relapses in the prior year, mean age, mean baseline EDSS score, and mean treatment duration (for ARR). RESULTS: The 12-week CDA model utilized longitudinal data from 26 RCTs (18 unique treatments [including placebo]), 69 treatment arms, 31,160 patients). The ARR model utilized data from 40 RCTs (18 unique treatments [including placebo], 100 treatment arms, 33,686 patients). Compared to placebo, ponesimod significantly reduced 12-week CDA by 39% (HR: 0.61; 95% CI: 0.45-0.82) and reduced ARR by 53% (rate ratio [RR]: 0.47; 95% CI: 0.39-0.58). Except for three DMTs (interferon ß-1b, glatiramer acetate, ozanimod), HR of 12-week CDA vs. placebo was significantly lower for the DMTs included in this analysis (HR range: 0.41 to 0.79). The ARR was significantly reduced for all DMTs compared to placebo (RR range: 0.29 to 0.82). A dose-response relationship indicated a potential dose-dependent effect (12-week CDA: 6 treatments; ARR: 8 treatments). Relative treatment effect was found to be significantly smaller in trials including more patients with prior DMT usage. Cross-trial heterogeneity in relative effects was assessed and found to be negligible; however, there is a possibility that confounders remain which may impact estimated relative treatment effects. CONCLUSIONS: Compared to placebo, ponesimod 20 mg significantly reduced both the risk of 12-week CDA and mean ARR, suggesting it has robust efficacy in the treatment of RMS. The study was funded by Janssen Research & Development, LLC.

Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis: Results From Randomized Phase 2b Core and Extension Studies.

OBJECTIVE: To evaluate the dose-response relationship of 10, 20, and 40 mg ponesimod and long-term efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and Extension studies in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: In the Core study, 464 patients were randomized (1:1:1:1): placebo (n = 121), 10 mg (n = 108), 20 mg (n = 116), or 40 mg ponesimod (n = 119) once daily for 24 weeks. Patients who completed the Core study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks) and TP2 and TP3 (up to 432 weeks). The 40 mg dose was discontinued due to low tolerability at the end of TP1, and the 10 mg dose was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated. RESULTS: A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg = 139, 20 mg = 145, and 40 mg = 151) at any time during the Core and/or the Extension study. As of March 31, 2019, 214 patients were still on ponesimod treatment. The median (range) of ponesimod exposure was 7.95 (0-9.36) years. Ponesimod 20 mg, from Core up to the end of TP3, was associated with sustained low clinical activity (ARR for confirmed relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9%, and 6-month CDA was 20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common adverse events were nasopharyngitis (30%), headache (24%), and upper respiratory tract infection (21%). CONCLUSION: The effects on multiple sclerosis disease control were maintained with ponesimod 20 mg for approximately 8 years with no new safety concerns identified. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in individuals with RRMS, long-term treatment with ponesimod 20 mg was associated with a sustained low annualized confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free. TRIAL REGISTRATION INFORMATION: EudraCT Number 2008-006786-92 (Core study) and EudraCT Number 2009-011470-15 (Extension study).

Musculoskeletal manifestations of lymphoma: a case series.

Lymphomas are a heterogenous group of cancers of the lymphatic system in which disease primarily arises in lymph nodes. Extranodal disease is common; however, musculoskeletal involvement is rare. Imaging plays an important role in the diagnosis and staging of all lymphomas. In this case series, we present examples of musculoskeletal involvement of lymphoma encountered at our institution. We outline the clinical presentation and imaging findings of each and use these cases to review the features that can help to differentiate lymphoma from other musculoskeletal lesions.

The risk of malignancy is not increased in patients with multiple sclerosis treated with subcutaneous interferon beta-la: analysis of data from clinical trial and post-marketing surveillance settings.

BACKGROUND: Risks that are potentially associated with long-term therapies should be assessed. OBJECTIVE: The present analyses were performed to determine the risk of malignancy in patients with multiple sclerosis (MS) receiving subcutaneous (sc) interferon (IFN) beta-1a, using pooled safety data from key clinical trials and data from the Merck Serono Global Drug Safety database. METHODS: The standard Medical Dictionary for Regulatory Activities query "malignancies" was used to retrieve relevant cases from each data set. The incidence of malignancies per 1000 patient-years was calculated using the pooled safety data from clinical trials. The reporting rates of malignancy types were calculated for the post-marketing setting based on sales volume. Malignancies were grouped by organ localization and classified as medically confirmed or not medically confirmed according to the source of each report. The number of reported cases of each type was compared with the expected number in the general population. RESULTS: Analysis of pooled safety data from 12 key clinical trials did not show an increased incidence of malignancy per 1000 patient-years with sc IFN beta-1a (4.0; 95% confidence interval (CI): 2.9-5.5) compared with placebo (6.4; 95% CI: 3.3-11.2). Analysis of the database shows that among the medically confirmed cases, reported to expected ratios ranged from 1 : 6 to 1 : 18 for solid tumours and from 1 : 2 to 1 : 9 for lymphohaematopoietic tumours. CONCLUSION: Safety data from both clinical trial and post-marketing settings suggest that treatment with sc IFN beta-1a does not increase the risk of malignancy in patients with MS.

Biclonal lymphoproliferative disorders: another association with NOTCH1-mutated chronic lymphocytic leukaemias.

INTRODUCTION: Biclonal lymphoid disorders, when two distinct lymphoproliferative disorders (LPD) co-exist, are rare (incidence of 1.4%) and associated with a poor prognosis. NOTCH1 mutations occur in 10% of CLL at diagnosis, associated with a short disease-free interval and increased risk of Richter's transformation. We hypothesised that the incidence of NOTCH1 mutations in CLL with a second LPD may be increased, because the mutation occurs early in leukaemogenesis, permitting clonal divergence. METHODS: We identified 19 patients with biclonal LPD at diagnosis: 11 with CLL and a second LPD (group A) and 8 with a second distinct CLL (group B). NOTCH1 mutation analysis was performed and clinical outcome investigated. RESULTS: Ten of 19 (52%) were NOTCH1 mutated: 5 in group A (45%) and 5 in group B (62.5%) with a favourable clinical outcome observed among this cohort with 28.7 (range 1-99) months of follow-up. CONCLUSION: In conclusion, we identified a significant (52%) incidence of NOTCH1 mutations in CLL in the context of biclonal LPD, associated with an indolent clinical course.

Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial.

Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS). Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. Design, Setting, and Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity. Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days. Main Outcomes and Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status. Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]). Conclusions and Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators. Trial Registration: ClinicalTrials.gov Identifier: NCT02425644.

A Surviving Case of Acanthamoeba Granulomatous Amebic Encephalitis in a Hematopoietic Stem Cell Transplant Recipient.

BACKGROUND Acanthamoeba are free-living amoebae with potential to infect immunocompromised hosts. The mortality rate of granulomatous amebic encephalitis (GAE) due to Acanthamoeba exceeds 90% and there are currently no reports of survival of this infection in recipients of hematopoietic stem cell transplant. CASE REPORT We report herein the case of a 32-year-old man presenting to our service with abrupt neurological deterioration and seizures 5 months after allogeneic stem cell transplantation for Hodgkin lymphoma. Clinical and imaging findings were non-specific at presentation. Multiple circumscribed, heterogenous, mass-like lesions were identified on MRI. Brain biopsy was performed and revealed multiple cysts and trophozoites suggesting a diagnosis of granulomatous amebic encephalitis. PCR testing confirmed Acanthamoeba. Treatment with miltefosine, metronidazole, azithromycin, fluconazole, pentamidine isethionate, and co-trimoxazole was instituted and the patient survived and shows continued improvement with intensive rehabilitation. CONCLUSIONS We report the first successful outcome in this setting. The diagnosis would have been missed on cerebrospinal fluid analysis alone, but was rapidly made by histological analysis of brain biopsy. This diagnostically challenging infection is likely under-recognized. Early brain biopsy and commencement of a prolonged miltefosine-containing anti-ameba regimen can be curative.

Integrating Data From Randomized Controlled Trials and Observational Studies to Assess Survival in Rare Diseases.

Background Conducting randomized controlled trials to investigate survival in a rare disease like pulmonary arterial hypertension has considerable ethical and logistical constraints. In many studies, such as the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) randomized controlled trial, evaluating survival is further complicated by bias introduced by allowing active therapy among placebo-treated patients who clinically deteriorate. Methods and Results SERAPHIN enrolled and followed patients in the same time frame as the US Registry to Evaluate Early And Long-term PAH Disease Management, providing an opportunity to compare observed survival for SERAPHIN patients with predicted survival had they received real-world treatment as in the Registry to Evaluate Early And Long-term PAH Disease Management. From the Registry to Evaluate Early And Long-term PAH Disease Management (N=3515), 734 patients who met SERAPHIN eligibility criteria were selected and their data used to build a prediction model for time to death up to 3 years based on 10 baseline prognostic variables. The model was used to predict a survival curve for each of the 742 SERAPHIN patients via their baseline variables. The average of these predicted survival curves was compared with observed survival of the placebo (n=250) and macitentan 10 mg (n=242) groups using a log-rank test and Cox proportional hazard model. Observed mortality risk for patients randomized to placebo, 62% of whom were taking background pulmonary arterial hypertension therapy, tended to be lower than that predicted for all SERAPHIN patients (16% lower; P=0.259). The observed placebo survival curve closely approximated the predicted survival curve for the first 15 months. Beyond that time, observed risk of mortality decreased compared with predicted mortality, potentially reflecting the impact of crossover of patients in the placebo group to active therapy. Over 3 years, risk of mortality observed with macitentan 10 mg was 35% lower than predicted mortality ( P=0.010). Conclusions These analyses show that, in a rare disease, real-world observational data can complement randomized controlled trial data to overcome some challenges associated with assessing survival in the setting of a randomized controlled trial. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifiers: NCT00660179 and NCT00370214.

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.

Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion.

OBJECTIVES: The goal of this study was to identify the factors responsible for embolic complications of direct current (DC) cardioversion of atrial arrhythmias. BACKGROUND: Direct current cardioversion of atrial fibrillation (AF) carries a risk of thromboembolism, which is reduced, but not eliminated, by anticoagulation. The risk of embolism after conversion of atrial flutter is believed to be lower. No series to date has included enough patients receiving anticoagulants or enough patients with atrial flutter to estimate the risk in these groups. METHODS: We reviewed the case records of 1,950 patients who underwent 2,639 attempts at DC cardioversion. RESULTS: Cardioversion was performed within two days of the apparent onset of the arrhythmia in 443 episodes, 352 without subsequent prolonged anticoagulation with one embolic complication. Cardioversion was preceded by warfarin therapy for > or = 3 weeks in 1,932 instances. No embolic complication occurred in 779 attempts performed with an international normalized ratio (INR) of > or = 2.5 (95% confidence limits 0% to 0.48%). Of 756 cases in which the INR was <2.5 or was not measured before conversion, nine were complicated by thromboembolism. Embolism was significantly more common at an INR of 1.5 to 2.4 than at an INR > or = 2.5 (0.93% vs. 0%, p = 0.012). The incidence of embolism after conversion of atrial flutter or tachycardia was similar to that after cardioversion of AF (0.72% vs. 0.46%, p = NS). CONCLUSIONS: The INR should be > or = 2.5 at the time of cardioversion if the duration of AF is uncertain or >2 days. Cardioversion of atrial flutter presents similar risks and requires similar anticoagulation.

Molecular heterogeneity of familial myeloproliferative neoplasms revealed by analysis of the commonly acquired JAK2, CALR and MPL mutations.

The myeloproliferative neoplasms (MPN) are clonal, hematological malignancies that include polycythemia vera, essential thrombocythemia and primary myelofibrosis. While most cases of MPN are sporadic in nature, a familial pattern of inheritance is well recognised. The phenotype and status of the commonly acquired JAK2 V617F, CALR exon 9 and MPL W515L/K mutations in affected individuals from a consecutive series of ten familial MPN (FMPN) kindred are described. Affected individuals display the classical MPN phenotypes together with one kindred identified suggestive of hereditary thrombocytosis. In affected patients the JAK2 V617F mutation is the most commonly acquired followed by CALR exon nine mutations with no MPL W515L/K mutations detected. The JAK2 V617F and CALR exon 9 mutations appear to occur at approximately the same frequency in FMPN as in the sporadic forms of these diseases. The familial nature of MPN may often be overlooked and accordingly more common than previously considered. Characterisation of these FMPN kindred may allow for the investigation of molecular events that contribute to this inheritance.