Cardiovascular events among recipients of hematopoietic stem cell transplantation-A systematic review and meta-analysis.

Cardiovascular diseases are an emerging cause of mortality and morbidity in survivors of hematopoietic stem cell transplantation (HSCT); however, the incidence of cardiovascular events (CVEs) in this population is not well described. This systematic review summarizes the evidence on the incidence of CVEs in HSCT recipients. Medline and Embase were searched from inception to December 2020. Inclusion criteria were cohort studies and phase 3 randomized controlled trials that reported CVEs among adults who underwent HSCT for hematological malignancies. After reviewing 8386 citations, 57 studies were included. The incidence of CVEs at 100 days was 0.19 (95% CI: 0.17-0.21) per 100 person-days after autologous HSCT and 0.06 (95% CI: 0.05-0.07) per 100 person-days after allogeneic HSCT. This higher incidence after autologous HSCT was driven by reports of arrhythmia from one population-based study in patients with multiple myeloma. The incidence of long-term CVEs was 3.98 (95% CI; 3.44-4.63) per 1000 person-years in survivors of autologous HSCT and 3.06 (95% CI; 2.69-3.48) per 1000 person-years in survivors of allogeneic HSCT. CVEs remain an important but under-reported cause of morbidity and mortality in recipients of HSCT. Future studies are required to better understand the incidence and risk factors for CVEs in HSCT recipients.

An MDS-specific frailty index based on cumulative deficits adds independent prognostic information to clinical prognostic scoring.

The frailty index (FI) is based on the principle that the more deficits an individual has, the greater their risk of adverse outcomes. It is expressed as a ratio of the number of deficits present to the total number of deficits considered. We developed an MDS-specific FI using a prospective MDS registry and assessed its ability to add prognostic power to conventional prognostic scores in MDS. The 42 deficits included in this FI included measurements of physical performance, comorbidities, laboratory values, instrumental activities of daily living, quality of life and performance status. Of 644 patients, 440 were eligible for FI calculation. The median FI score was 0.25 (range 0.05-0.67), correlated with age and IPSS/IPSS-R risk scores and discriminated overall survival. With a follow-up of 20 months, survival was 27 months (95% CI 24-30.4). By multivariate analysis, age >70, FI, transfusion dependence, and IPSS were significant covariates associated with OS. The incremental discrimination improvement of the frailty index was 37%. We derived a prognostic score with five risk groups and distinct survivals ranging from 7.4 months to not yet reached. If externally validated, the MDS-FI could be used as a tool to refine the risk stratification of current clinical prognostication models.

Dysbiosis in early sepsis can be modulated by a multispecies probiotic: a randomised controlled pilot trial.

The gut is hypothesised to play an important role in the development and progression of sepsis. It is however unknown whether the gut microbiome and the gut barrier function is already altered early in sepsis development and whether it is possible to modulate the microbiome in early sepsis. Therefore, a randomised, double blind, placebo-controlled pilot study to examine the alterations of the microbiome and the gut barrier in early sepsis and the influence of a concomitant probiotic intervention on dysbiosis at this early stage of the disease was conducted. Patients with early sepsis, defined as fulfilling the sepsis definition from the 2012 Surviving Sepsis Campaign guidelines but without signs of organ failure, received multispecies probiotic (Winclove 607 based on Omnibiotic® 10 AAD) for 28 days. Gut microbiome composition, function, gut barrier and bacterial translocation were studied. Patients with early sepsis had a significantly lower structural and functional alpha diversity, clustered differently and showed structural alterations on all taxonomic levels. Gut permeability was unaltered but endotoxin, endotoxin binding proteins and peptidoglycans were elevated in early sepsis patients compared to controls. Probiotic intervention successfully increased probiotic strains in stool and led to an improvement of functional diversity. Microbiome composition and function are altered in early sepsis. Probiotic intervention successfully modulates the microbiome and is therefore a promising tool for early intervention in sepsis.

Soluble CD163 and soluble mannose receptor predict survival and decompensation in patients with liver cirrhosis, and correlate with gut permeability and bacterial translocation.

BACKGROUND: Activated hepatic macrophages play a key role in inflammation and fibrosis progression in chronic liver disease. AIM: To assess the prognostic value of soluble (s)CD163 and mannose receptor (sMR) in cirrhotic patients and explore associations with markers of intestinal permeability (lactulose-mannitol ratio, diamine oxidase), bacterial translocation (endotoxin, lipopolysaccharide-binding protein) and markers of systemic immune activation (interleukin-6, interleukin-8, sCD14). METHODS: We prospectively investigated 101 cirrhotic patients (Child-Pugh class A: n = 72, Child-Pugh classes B and C: n = 29) and 31 healthy controls. Patients were observed for a median follow-up of 37 months. RESULTS: Median plasma levels of sCD163 and soluble mannose receptor were significantly elevated in cirrhotic patients (P < .001) and increased with disease severity (sCD163 in healthy controls = 1.3, Child-Pugh class A = 4.2, Child-Pugh classes B and C = 8.4 mg/L; sMR in healthy controls = 15.8, Child-Pugh class A = 36.5, Child-Pugh classes B and C = 66.3 µg/dL). A total of 21 patients died during the observation period. Patients with sCD163 levels above 5.9 mg/L showed significantly reduced survival (survival rate after 36 months: 71% versus 98%, P < .001). Patients with soluble mannose receptor levels above 45.5 µg/dL developed significantly more complications of cirrhosis within 12 months (73% versus 9%, P < .001). Furthermore, both variables correlated with the lactulose-mannitol ratio, diamine oxidase, lipopolysaccharide and interleukin-8. CONCLUSION: Our data demonstrate the prognostic value of sCD163 in predicting long-term survival in patients with liver cirrhosis and identify soluble mannose receptor as a prognostic marker for occurrence of cirrhosis-associated complications. The correlation between gut barrier dysfunction and activation of macrophages points towards a link between them.

MicroRNAs 223-3p and 93-5p in patients with chronic kidney disease before and after renal transplantation.

Chronic kidney disease (CKD) is associated with a multifactorial dysregulation of bone and vascular calcification and closely linked to increased cardiovascular mortality and concomitant bone disease. We aimed to investigate specific microRNA (miRNA) signatures in CKD patients to find indicators for vascular calcification and/or bone mineralization changes during CKD and after kidney transplantation (KT). A miRNA array was used to investigate serum miRNA profiles in CKD patients, then selected miRNAs were quantified in a validation cohort comprising 73 patients in CKD stages 3 to 5, 67 CKD patients after KT, and 36 healthy controls. A spectrum of biochemical parameters including markers for kidney function, inflammation, glucose, and mineral metabolism was determined. The relative expression of miR-223-3p and miR-93-5p was down-regulated in patients with CKD stage 4 and 5 compared to healthy controls. This down-regulation disappeared after kidney transplantation even when lower glomerular filtration rates (eGFR) persisted. MiR-223-3p and miR-93-5p were associated with interleukin-6 (IL-6) and eGFR levels, and by trend with interleukin-8 (IL-8), C-peptide, hematocrit, and parathyroid hormone (PTH). This study contributes new knowledge of serum miRNA expression profiles in CKD, potentially reflecting pathophysiological changes of bone and calcification pathways associated with inflammation, vascular calcification, mineral and glucose metabolism. Identified miRNA signatures can contribute to future risk markers or future therapeutic targets in bone and kidney disease.

Randomised clinical trial: the effects of a multispecies probiotic vs. placebo on innate immune function, bacterial translocation and gut permeability in patients with cirrhosis.

BACKGROUND: Probiotics may correct intestinal dysbiosis and proinflammatory conditions in patients with liver cirrhosis. AIM: To test the effects of a multispecies probiotic on innate immune function, bacterial translocation and gut permeability. METHODS: In a randomised, double blind, placebo-controlled study, stable cirrhotic out-patients either received a daily dose of a probiotic powder containing eight different bacterial strains (Ecologic Barrier, Winclove, Amsterdam, The Netherlands) (n = 44) or a placebo (n = 36) for 6 months and were followed up for another 6 months. RESULTS: We found a significant but subclinical increase in neutrophil resting burst (2.6-3.2%, P = 0.0134) and neopterin levels (7.7-8.4 nmol/L, P = 0.001) with probiotics but not with placebo. Probiotic supplementation did not have a significant influence on neutrophil phagocytosis, endotoxin load, gut permeability or inflammatory markers. Ten severe infections occurred in total; one during intervention in the placebo group, and five and four after the intervention has ended in the probiotic and placebo group, respectively. Liver function showed some improvement with probiotics but not with placebo. CONCLUSIONS: Probiotic supplementation significantly increased serum neopterin levels and the production of reactive oxygen species by neutrophils. These findings might explain the beneficial effects of probiotics on immune function. Furthermore, probiotic supplementation may be a well-tolerated method to maintain or even improve liver function in stable cirrhosis. However, its influence on gut barrier function and bacterial translocation in cirrhotic patients is minimal.

Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia.

On the basis of the data suggesting that adolescents and young adult patients with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric protocols, we assessed the feasibility of treating adult patients aged 18-50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18-50 years were enrolled at 13 participating centers. Seventy-eight patients (85%) achieved a complete remission (CR) after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival (DFS) for the patients achieving a CR was 69% (95% confidence interval (CI) 56-78%) and the 4-year overall survival (OS) for all eligible patients was 67% (95% CI 56-76%). The 4-year DFS for the 64 patients who achieved a CR and were Philadelphia chromosome negative (Ph-) was 71% (95% CI 58-81%), and for all 74 Ph- patients the 4-year OS was 70% (95% CI 58-79%). We conclude that a pediatric-like treatment strategy for young adults with de novo ALL is feasible, associated with tolerable toxicity, and results in improved outcomes compared with historical regimens in young adult patients with ALL.

A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults.

The use of all-trans-retinoic acid (atra) and anthracyclines (with or without cytarabine) in the treatment of acute promyelocytic leukemia (apl) has dramatically changed the management and outcome of the disease over the past few decades. The addition of arsenic trioxide (ato) in the relapsed setting-and, more recently, in reduced-chemotherapy or chemotherapy-free approaches in the first-line setting-continues to improve treatment outcomes by reducing some of the toxicities associated with anthracycline-based approaches. Despite those successes, a high rate of early death from complications of coagulopathy remains the primary cause of treatment failure before treatment begins. In addition to that pressing issue, clarity is needed about the use of ato in the first-line setting and the role of hematopoietic stem-cell transplantation (hsct) in the relapsed setting. The aim for the present consensus was to provide guidance to health care professionals about strategies to reduce the early death rate, information on the indications for hsct and on the use of ato in induction and consolidation in low-to-intermediate-risk and high-risk apl patients.

Multiple partners can kiss-and-run: Bax transfers between multiple membranes and permeabilizes those primed by tBid.

During apoptosis Bid and Bax are sufficient for mitochondrial outer membrane permeabilization, releasing pro-apoptotic proteins such as cytochrome c and Smac/Diablo into the cytoplasm. In most cells, both Bid and Bax are cytoplasmic but bind to mitochondrial outer membranes to exert pro-apoptotic functions. Binding to membranes is regulated by cleavage of Bid to truncated Bid (tBid), by conformation changes in tBid and Bax, and by interactions with other proteins. At least at the peripherally bound stage, binding is reversible. Therefore, regulation of apoptosis is closely linked with the interactions of tBid and Bax with mitochondria. Here we use fluorescence techniques and cell-free systems containing mitochondria or liposomes that faithfully mimic tBid/Bax-dependent membrane permeabilization to study the dynamic interactions of the proteins with membranes. We confirm that the binding of both proteins to the membrane is reversible by quantifying the binding affinity of proteins for the membrane. For Bax, both peripherally bound (inactive) and oligomerized (active) proteins migrate between membranes but much slower than and independent of tBid. When re-localized to a new membrane, Bax inserts into and permeabilizes it only if primed by an activator. In the case of tBid, the process of transfer is synergetic with Bax in the sense that tBid 'runs' faster if it has been 'kissed' by Bax. Furthermore, Mtch2 accelerates the re-localization of tBid at the mitochondria. In contrast, binding to Bcl-XL dramatically impedes tBid re-localization by lowering the off-rate threefold. Our results suggest that the transfer of activated tBid and Bax to different mitochondria is governed by dynamic equilibria and potentially contributes more than previously anticipated to the dissemination of the permeabilization signal within the cell.

Evidence-based guidelines for the use of tyrosine kinase inhibitors in adults with Philadelphia chromosome-positive or BCR-ABL-positive acute lymphoblastic leukemia: a Canadian consensus.

Adult Philadelphia chromosome-positive (Ph+) or BCR-ABL-positive (BCR-ABL+) acute lymphoblastic leukemia (all) is an acute leukemia previously associated with a high relapse rate, short disease-free survival, and poor overall survival. In adults, allogeneic hematopoietic cell transplant in first remission remains the only proven curative strategy for transplant-eligible patients. The introduction of tyrosine kinase inhibitors (tkis) in the treatment of patients with Ph+ or BCR-ABL+ all has significantly improved the depth and duration of complete remission, allowing more patients to proceed to transplantation. Although tkis are now considered a standard of care in this setting, few randomized trials have examined the optimal use of tkis in patients with Ph+ all. Questions of major importance remain, including the best way to administer these medications, the choice of tki to administer, and the schedule and the duration to use. We present the results of a systematic review of the literature with consensus recommendations based on the available evidence.

Optimizing outcomes with azacitidine: recommendations from Canadian centres of excellence.

Myelodysplastic syndromes (mdss) constitute a heterogeneous group of malignant hematologic disorders characterized by marrow dysplasia, ineffective hematopoiesis, peripheral blood cytopenias, and pronounced risk of progression to acute myeloid leukemia. Azacitidine has emerged as an important treatment option and is recommended by the Canadian Consortium on Evidence-Based Care in mds as a first-line therapy for intermediate-2 and high-risk patients not eligible for allogeneic stem cell transplant; however, practical guidance on how to manage patients through treatment is limited. This best practice guideline provides recommendations by a panel of experts from Canadian centres of excellence on the selection and clinical management of mds patients with azacitidine. Familiarity with the referral process, treatment protocols, dose scheduling, treatment expectations, response monitoring, management of treatment breaks and adverse events, and multidisciplinary strategies for patient support will improve the opportunity for optimizing treatment outcomes with azacitidine.

Short communication: Effect of supplementation with Lactobacillus casei Shirota on insulin sensitivity, ß-cell function, and markers of endothelial function and inflammation in subjects with metabolic syndrome--a pilot study.

Based on animal studies, intake of probiotic bacteria was suggested to improve insulin sensitivity by reducing endotoxinemia and inflammation. The objective of this study was to determine the effects of supplementation with the probiotic strain Lactobacillus casei Shirota (LcS) over 12 wk on insulin sensitivity, ß-cell function, inflammation, and endothelial dysfunction parameters in subjects with metabolic syndrome. In a randomized-controlled study, 30 subjects with metabolic syndrome either received Lactobacillus casei Shirota 3 times daily for 12 wk or served as controls with standard medical therapy. Fasting blood samples were taken and a 75-g oral glucose tolerance test was performed to derive indices for insulin sensitivity and ß-cell function. In addition, parameters to assess endothelial function and inflammation markers were determined. Even though the insulin sensitivity index significantly improved after 3 mo of probiotic supplementation (0.058±0.021 vs. 0.038±0.025), the change was not significantly different compared with the control group. No improvements were seen in additional indices of insulin sensitivity (quantitative insulin sensitivity check index, insulin sensitivity by oral glucose tolerance test, and homeostasis model assessment for insulin resistance) and ß-cell function (first and second phase insulin secretion, and homeostasis model assessment for ß-cell function). Probiotic supplementation resulted in a significant reduction in soluble vascular cell adhesion molecule-1 (sVCAM-1) level (1,614±343 vs. 1,418±265 ng/mL). No significant changes in parameters used to assess low-grade inflammation or endothelial dysfunction were observed. Intake of LcS for 12 wk in subjects with metabolic syndrome did not improve insulin sensitivity, ß-cell function, endothelial function, or inflammation markers in this trial.

The influence of probiotic supplementation on gut permeability in patients with metabolic syndrome: an open label, randomized pilot study.

BACKGROUND/OBJECTIVES: Obesity and metabolic disorders are linked to inflammation via gut microbiota and/or gut permeability. Gut-derived endotoxin triggers inflammation leading to metabolic syndrome (MetS) and contributing to oxidative stress. We intended to investigate the effect of Lactobacillus casei Shirota on gut permeability, presence of endotoxin and neutrophil function in MetS. SUBJECTS/METHODS: Patients with MetS were randomized to receive 3 × 6.5 × 109 CFU L. casei Shirota (probiotic group) or not for 3 months. Gut permeability was assessed by a differential sugar absorption method and by determination of diaminooxidase serum levels, endotoxin by an adapted limulus amoebocyte lysate assay, neutrophil function and toll-like receptor (TLR) expression by flow cytometry and ELISA was used to detect lipopolysaccharide-binding protein (LBP) and soluble CD14 (sCD14) levels. RESULTS: Twenty-eight patients and 10 healthy controls were included. Gut permeability was significantly increased in MetS compared with controls but did not differ between patient groups. None of the patients were positive for endotoxin. LBP and sCD14 levels were not significantly different from healthy controls. High-sensitive C-reactive protein and LBP levels slightly but significantly increased after 3 months within the probiotics group. Neutrophil function and TLR expression did not differ from healthy controls or within the patient groups. CONCLUSIONS: Gut permeability of MetS patients was increased significantly compared with healthy controls. L. casei Shirota administration in the MetS patients did not have any influence on any parameter tested possibly due to too-short study duration or underdosing of L. casei Shirota.

cml biology for the clinician in 2011: six impossible things to believe before breakfast on the way to cure.

Chronic myeloid leukemia (cml) is a model disease in oncology: it is the first human cancer linked to a distinct chromosomal abnormality, ultimately causing constitutive overactivity of a known oncogenic tyrosine kinase that represents a drug target. The introduction of the tyrosine kinase inhibitor imatinib into clinical practice has far exceeded expectations and resurrected hope that the fundamental insights from the "war on cancer" can lead to significant therapeutic advances. Nevertheless, the current perception among clinicians is that imatinib and its newer more potent cousins offer superb long-term disease control for most patients, but that cure without transplantation has remained elusive. However, several important laboratory-based observations over the last few years have changed those perceptions. Several of those developments are discussed here, including direct manipulation of the apoptosis pathway in cancer cells and prevention of disease progression with the use of antioxidants. Intriguing results from a French study indicate that, if disease progression is halted, a small but significant group of patients may be able to stop imatinib therapy without disease recurrence. And for patients whose disease, because of resistant stem cells, needs a more direct attack than tyrosine kinase inhibitors alone, several approaches investigated in laboratory and animal models seem promising, and some are ripe for clinical testing, including inhibitors of Smoothened and 5-lipoxygenase, and suppression of autophagy. Thus, there is realistic hope that true cure of cml, without transplantation, may be a feasible goal in the near future.

Still embedded together binding to membranes regulates Bcl-2 protein interactions.

The dysregulation of apoptosis is a key step in developing tumours, and mediates resistance to cancer therapy. Many different signals for cell death converge on permeabilization of the outer mitochondrial membrane, which is controlled by the Bcl-2 family of proteins. The importance of this step is becoming increasingly relevant as the first generation of small molecules that inhibit the interaction of Bcl-2 family proteins enters clinical trials as anticancer agents. The Bcl-2 family can be divided into three classes: BH3-only proteins that are activated by various forms of cellular stress, Bax and Bak proteins that mediate mitochondrial membrane permeabilization, and inhibitory proteins such as Bcl-2 and Bcl-XL. The recently proposed embedded together model emphasizes the fact that many of the regulatory interactions between different classes of Bcl-2 family members occur at intracellular membranes, and binding to membranes causes conformational changes in the proteins that dictate functions in a dynamic manner. Within this context, recent results indicate that Bcl-XL functions as a dominant-negative Bax, a concept that resolves the paradox of similar structures but opposite functions of Bcl-XL and Bax. We have also shown that the conformational change that allows Bax to insert into the outer mitochondrial membrane is the rate-limiting step in the multistep process of Bax activation. Nevertheless, investigating the structure of activated Bax or Bak as monomers and as components of the oligomeric structures that mediate membrane permeabilization is the focus of ongoing research (and controversy) at many laboratories worldwide.

A phase I study of tipifarnib combined with conventional induction and consolidation therapy for previously untreated patients with acute myeloid leukemia aged 60 years and over.

Patients aged 60 years and over with previously untreated acute myeloid leukemia were enrolled in a Phase I study combining tipifarnib with standard induction therapy. The regimen consisted of cytarabine 100 mg/m(2)/day continuous intravenous (i.v.) infusion on days 1-7, daunorubicin 60 mg/m(2)/day i.v. push x 3 on days 6-8 and tipifarnib twice daily on days 6-15. Tipifarnib was escalated over four dose levels (200, 300, 400 and 600 mg). Patients achieving complete response (CR) were eligible to receive one consolidation using the same regimen. The following dose-limiting toxicities (DLTs) were identified during induction: dose level I: 2/6 (hyperbilirubinemia, respiratory arrest), level II: 0/3, level III: 0/3 and level IV: 4/10 (one each of diarrhea, neutropenic enterocolitis, arrhythmia and delayed hematologic recovery post-consolidation). There were no DLTs due to delayed hematologic recovery post-induction. Of 22 evaluable patients, there were 10 CR, 2 morphologic leukemia-free state (MLFS), 2 partial remission (PR) and 8 non-responders. Of seven patients with adverse risk cytogenetics, there were four CR/MLFS and one PR. In summary, this regimen was well tolerated and the maximum tolerated dose was not reached, although somewhat more severe gastrointestinal toxicity was seen at dose level IV. Tipifarnib 600 mg b.i.d. is considered the recommended dose for further study using this regimen.

Intravenous immunoglobulin as an adjunct to plasma exchange for the treatment of chronic thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease. Therapeutic plasma exchange (TPE) is the most effective therapy; however, despite TPE, about one-third of TTP patients will relapse. A subset of patients with TTP has antibodies to ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) and may become resistant to conventional treatments. We describe a patient with TTP and high-titre anti-ADAMTS13 antibodies who developed a chronic, relapsing course of TTP despite frequent TPE. Once adjuvant treatment with intravenous immunoglobulin (IVIG) was added, remission was achieved. Even during remission, anti-ADAMTS13 antibodies remained elevated. We conclude that IVIG may sustain remission in some patients with chronic, relapsing TTP.