Anti-herpesvirus prophylaxis, pre-emptive treatment or no treatment in adults undergoing allogeneic transplant for haematological disease: systematic review and meta-analysis.

BACKGROUND: Herpesviridae infections incur significant morbidity and indirect effects on mortality among allogeneic haematopoietic cell transplant (allo-HCT) recipients. OBJECTIVES: To study the effects of antiviral prevention strategies among haemato-oncological individuals undergoing allo-HCT. DATA SOURCES: Cochrane Central Register of Controlled Trials, MEDLINE, Embase and LILACS. We further searched for conference proceedings and trial registries. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials (RCTs). PARTICIPANTS: Adults with haematological malignancy undergoing allo-HCT. INTERVENTIONS: Antiviral prophylaxis versus no treatment/placebo or pre-emptive treatment and pre-emptive treatment versus prophylaxis with the same agent. METHODS: Random-effects meta-analysis was conducted computing pooled risk ratios (RR) with 95% CI and the inconsistency measure (I2). The certainty of the evidence was appraised by GRADE. RESULTS: We included 22 RCTs. Antiviral prophylaxis reduced all-cause mortality (RR 0.83, 95% CI 0.7-0.99; 15 trials, I2 = 0%), cytomegalovirus (CMV) disease (RR 0.54, 95% CI 0.34-0.85; n = 15, I2 = 20%) and herpes simplex virus (HSV) disease (RR 0.29, 95% CI 0.2-0.43; n = 13, I2 = 18%) compared with no treatment/placebo or pre-emptive treatment, all with high-certainty evidence. Furthermore, antivirals reduced HSV infection, CMV pneumonitis, CMV infection and varicella zoster virus disease. Anti-CMV prophylaxis (+/- pre-emptive treatment) compared with pre-emptive treatment alone reduced non-significantly all-cause mortality (RR 0.78, 95% CI 0.6-1.02; n = 8, I2 = 0%), CMV disease (RR 0.47, 95% CI 0.23-0.97; n = 9, I2 = 30%) and HSV disease (RR 0.41, 95% CI 0.24-0.67; n = 4, I2 = 0%) with high-certainty evidence, as well as CMV and HSV infections. Antiviral prophylaxis did not result in increased adverse event rates overall or more discontinuation due to adverse events. CONCLUSIONS: Antiviral prophylaxis directed against herpesviruses is highly effective and safe, reducing mortality, HSV and CMV disease, as well as herpesvirus reactivations among allo-HCT recipients. Anti-CMV prophylaxis is more effective than pre-emptive treatment alone with respect to HSV and CMV disease and infection.

The evolving role of chemotherapy and hematopoietic cell transplants in Ph-positive acute lymphoblastic leukemia in adults.

The introduction of the tyrosine kinase inhibitors (TKI) into the treatment of patients with Ph or BCR-ABL1-positive acute lymphoblastic leukemia has revolutionized the treatment of this poor prognosis acute leukemia. The combination of TKI with chemotherapy has improved response rates and allowed more patients to proceed to allogeneic hematopoietic cell transplant (alloHCT). Older patients have excellent responses to TKI and corticosteroids or in combination with minimal chemotherapy. This raises the question as to whether patients require full-intensity chemotherapy with TKI to achieve molecular remissions. The pediatricians have proposed that cure is achievable without alloHCT in children. These results have suggested that many patients may not require traditional chemotherapy in addition to TKI to achieve remission, and that patients who achieve a negative minimal residual disease state may not require alloHCT. The data in support of these questions is presented here and a suggested future clinical trial design based on these data is proposed.

Interpreting outcome data in hematopoietic cell transplantation for leukemia: tackling common biases.

Although patient outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) have significantly improved in recent years, complications and associated mortality remain substantial. Although many transplants are performed worldwide, the number of patients enrolled prospectively into clinical trials is small. Patient and physician preferences often override treatment assignments in randomized transplant trials, biasing the common intention-to-treat analyses. Large retrospective and observational database studies are likely to detect the real effect of allo-HCT. However, they may be subject to immortal time and other biases derived from heterogeneity of allo-HCT indications and approaches and differences in referral or institutional policies affecting patient selection. Timing of the transplant procedure may be fundamental but studies commencing at start of transplant may neglect the influence of pretransplant therapies. Conversely, a prolonged lag period between the decision and execution of transplant may artificially 'improve' the outcome by 'natural' selection weeding out patients relapsing or dying before transplant. Finally, comparative nonrandomized transplantation trials often suffer from unbalanced assignment for therapy arms. We herein present common clinical dilemmas discussing proper application of available evidence in daily clinical practice. Pitfalls and caveats frequent in clinical studies of allo-SCT are highlighted to promote a balanced interpretation of available data.

Oral integrity and salivary profile in myeloma patients undergoing high-dose therapy followed by autologous SCT.

The underlying mechanism of high-dose therapy (HDT)-related oral mucositis (OM) may be partly mediated by alterations in the normal salivary composition. This study evaluated salivary antioxidant and immunological capacities observed in myeloma patients suffering from HDT-related OM, and assessed potential contribution of these factors to OM development. Twenty-five consecutive myeloma patients treated with melphalan 200 mg/m(2) followed by autologous SCT were enrolled. Patients underwent a daily assessment for OM, and salivary samples were collected on days -3 and +7 of transplantation and analyzed for secretory IgA and antioxidant capacity. The degree of mucosal damage was assessed by measuring the salivary carbonyl and albumin (Alb) levels. OM, reported in 96% of patients, appeared to be most severe on 8 day after transplantation (range: +2 to +14). Clinical mucositis was associated with significant reduction in salivary secretory IgA (54%; P=0.05), and antioxidant activity, measured by total antioxidant status (40%; P=0.0004), antioxidant capacity (ImAnOx) (23%; P=0.002) and uric acid level (51%; P=0.006). The increase found in salivary Alb (119%; P=0.024) and carbonyl (28%; P=0.047) levels, indicates mucosal and oxidative damage, respectively. These salivary changes might enhance mucositis development and symptoms. Therapeutic interventions, enhancing antioxidative and immunological activities need to be investigated.

Granulocyte transfusions for neutropenic patients with life-threatening infections: a single centre experience in 47 patients, who received 348 granulocyte transfusions.

INTRODUCTION: The role of granulocyte transfusions (GT) in patients with neutropenia-related infections remains controversial. MATERIALS AND METHODS: A retrospective analysis of 47 neutropenic patients, treated with 348 consecutive GTs for life-threatening infections between 1999 and 2004, is presented. RESULTS: The only grade III-IV toxicity observed in GT recipients was respiratory deterioration (n = 6, 12.8%). The overall infection-related mortality (IRM) approached 38%. Achievement of a neutrophil count of > 700 cells per microl after at least 50% of days of GTs (n = 33, 70%) significantly correlated with reduced IRM (27.3% vs. 64.3%, P < 0.02). GT doses of > 2 x 10(10) neutrophils per bag appeared to increase both neutophil and platelet counts following transfusion. CONCLUSION: GTs are safe and should be considered for patients with life-threatening neutropenic infections. However, prospective randomized studies of GTs are the only way to establish the true role of GTs.

Fatal voluntary salt intake resulting in the highest ever documented sodium plasma level in adults (255 mmol L-1): a disorder linked to female gender and psychiatric disorders.

Excessive ingestion of salt is a well-recognized cause of hypernatraemia in children, is uncommonly recognized in debilitated elderly persons, but is rarely diagnosed in healthy, independent adults. We report a case of fatal salt poisoning in a 20-year-old lady who suffered of post-natal depression and ingested large quantities of salt as part of exorcism ritual. She presented with the highest ever documented serum sodium level of 255 mmol L(-1), associated with severe neurological impairment that was unresponsive to aggressive hypotonic fluid replacement. Post-mortem examination ruled out any other possible probable cause of death. The medical literature was reviewed, and 16 previous cases of severe hypernatraemia in adults secondary to excessive salt ingestion were retrieved. Common features of all reported cases included female gender (95% of cases) and evidence of underlying cognitive or psychiatric disorders (all reported cases). We conclude that women with documented cognitive or psychiatric disorders, in particular depression, are susceptible for psychogenic salt poisoning. Awareness should be raised to the potentially life-risking use of salty beverages as emetics or as part of 'exorcism' rituals.

Hyperplastic gastropathy as a presenting manifestation of systemic lupus erythematosus.

A patient is described who had severe hyperplastic gastropathy as the presenting manifestation of systemic lupus erythematosus (SLE). Aggressive immunosuppressive therapy with systemic corticosteroids and immunoglobulins resulted in complete remission of lupus, and a prompt clinical and radiological regression of hyperplastic gastropathy. Hyperplastic gastropathy is an uncommon gastric illness, which is usually idiopathic but rarely is associated with Helicobacter pylori infection, cytomegalovirus infection or lymphocytic gastritis. Three previous case reports have noted a response of idiopathic hyperplastic gastropathy to systemic corticosteroid treatment, yet none of the presented patients had a systemic inflammatory disease. The presented case is the first in the medical literature in which hyperplastic gastropathy is directly linked to the development of clinical and laboratory manifestations of SLE. We suggest that hyperplastic gastropathy be added to the list of rare gastrointestinal manifestations of SLE, and that autoimmune disease be considered a possible cause of hyperplastic gastropathy. As such, any patient with symptomatic idiopathic hyperplastic gastropathy accompanied by other evidence of systemic inflammation should be considered for SLE evaluation and immunosuppressive treatment.

Automatic prediction of protein function.

Most methods annotating protein function utilise sequence homology to proteins of experimentally known function. Such a homology-based annotation transfer is problematic and limited in scope. Therefore, computational biologists have begun to develop ab initio methods that predict aspects of function, including subcellular localization, post-translational modifications, functional type and protein-protein interactions. For the first two cases, the most accurate approaches rely on identifying short signalling motifs, while the most general methods utilise tools of artificial intelligence. An outstanding new method predicts classes of cellular function directly from sequence. Similarly, promising methods have been developed predicting protein-protein interaction partners at acceptable levels of accuracy for some pairs in entire proteomes. No matter how difficult the task, successes over the last few years have clearly paved the way for ab initio prediction of protein function.