A well-functioning vascular access (VA) is a mainstay to perform an efficient hemodialysis (HD) procedure. There are three main types of access: native arteriovenous fistula (AVF), arteriovenous graft, and central venous catheter (CVC). AVF, described by Brescia and Cimino, remains the first choice for chronic HD. It is the best access for longevity and has the lowest association with morbidity and mortality, and for this reason AVF use is strongly recommended by guidelines from different countries. Once autogenous options have been exhausted, prosthetic fistulae become the second option of maintenance HD access alternatives. CVCs have become an important adjunct in maintaining patients on HD. The preferable locations for insertion are the internal jugular and femoral veins. The subclavian vein is considered the third choice because of the high risk of thrombosis. Complications associated with CVC insertion range from 5% to 19%. Since an increasing number of patients have implanted pacemakers and defibrillators, usually inserted via the subclavian vein and superior vena cava into the right heart, a careful assessment of risk and benefits should be taken. Infection is responsible for the removal of about 30%–60% of HD CVCs, and hospitalization rates are higher among patients with CVCs than among AVF ones. Proper VA maintenance requires integration of different professionals to create a VA team. This team should include a nephrologist, radiologist, vascular surgeon, infectious disease consultant, and members of the dialysis staff. They should provide their experience in order to give the best options to uremic patients and the best care for their VA.

The major histocompatibility complex I (MHC-I) presents antigenic peptides to tumor-specific CD8+ T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell surface HLA amounts were discovered using a pooled human kinome shRNA interference–based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output–dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases.

CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6-HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infi ltrating lymphocytes to kill DLBCL cells in an MHC class I and II-dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas. SIGNIFICANCE: We have leveraged the molecular characterization of different types of CREBBP mutations to defi ne a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBPmutant cells in tandem with promoting antitumor immunity.

The proviral insertion in murine (PIM) lymphoma proteins are a serine/threonine kinase family composed of three isoformes: Pim-1, Pim-2 and Pim-3. They play a critical role in the control of cell proliferation, survival, homing and migration. Recently, overexpression of Pim kinases has been reported in human tumors, mainly in hematologic malignancies. In vitro and in vivo studies have confirmed their oncogenic potential. Indeed, PIM kinases have shown to be involved in tumorgenesis, to enhance tumor growth and to induce chemo-resistance, which is why they have become an attractive therapeutic target for cancer therapy. Novel molecules inhibiting Pim kinases have been evaluated in preclinical studies, demonstrating to be effective and with a favorable toxicity profile. Given the promising results, some of these compounds are currently under investigation in clinical trials. Herein, we provide an overview of the biological activity of PIM-kinases, their role in hematologic malignancies and future therapeutic opportunities.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0095-z) contains supplementary material, which is available to authorized users.

Bendamustine demonstrated synergistic efficacy with bortezomib against multiple myeloma (MM) cells in vitro and seems an effective treatment for relapsed-refractory MM (rrMM). This phase II study evaluated bendamustine plus bortezomib and dexamethasone (BVD) administered over six 28-day cycles and then every 56 days for six further cycles in patients with rrMM treated with ⩽4 prior therapies and not refractory to bortezomib. The primary study end point was the overall response rate after four cycles. In total, 75 patients were enrolled, of median age 68 years. All patients had received targeted agents, 83% had 1–2 prior therapies and 33% were refractory to the last treatment. The response rate⩾partial response (PR) was 71.5% (16% complete response, 18.5% very good PR, 37% partial remission). At 12 months of follow-up, median time-to-progression (TTP) was 16.5 months and 1-year overall survival was 78%. According to Cox regression analysis, only prior therapy with bortezomib plus lenalidomide significantly reduced TTP (9 vs 17 months; hazard ratio=4.5; P=0.005). The main severe side effects were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), neuropathy (8%) and gastrointestinal and cardiovascular events (both 6.5%). The BVD regimen is feasible, effective and well-tolerated in difficult-to-treat patients with rrMM.

BackgroundCachexia may occur in 40% of cancer patients, representing the major cause of death in more than 20% of them. The aim of this study was to investigate the role of leptin, ghrelin and obestatin as diagnostic and predictive markers of cachexia in oncologic patients. Their impact on patient survival was also evaluated.Methods140 adults with different cancer diagnoses were recruited. Thirty healthy volunteers served as control. Serum ghrelin, obestatin and leptin were tested at baseline and after a follow-up period of 18 months.ResultsGhrelin levels were significantly higher in cancer patients than in healthy subjects (573.31 ± 130 vs 320.20 ± 66.48 ng/ml, p < 0.0001), while obestatin (17.42 ± 7.12 vs 24.89 ± 5.54 ng/ml, p < 0.0001) and leptin (38.4 ± 21.2 vs 76.28 ± 17.48 ng/ml, p < 0.0001) values were lower. At ROC analyses the diagnostic profile of ghrelin (AUC 0.962; sensitivity 83%; specificity 98%), obestatin (AUC 0.798; sensitivity 74.5%; specificity 81.5%) and leptin (AUC 0.828; sensitivity 79%; specificity 73%) was superior to that of albumin (AUC 0.547; sensitivity 63%, specificity 69.4%) for detecting cachexia among cancer patients. On Cox multivariate analyses ghrelin (HR 1.02; 95% CI 1.01 – 1.03; p < 0.0001) and leptin (HR 0.94; 95% CI 0.92 – 0.96; p < 0.0001) were significant predictors of death even after correction for other known risk factors such as presence of metastasis and chronic kidney disease.ConclusionGhrelin and leptin are promising biomarkers to diagnose cachexia and to predict survival in cancer patients.

Background. The aims of this study were to evaluate the complications that occur after trauma and the characteristics of individuals who develop complications, to identify potential risk factors that increase their incidence, and finally to investigate the relationship between complications and mortality. Methods. We did a population-based retrospective study of trauma patients admitted to ICUs of a level I trauma center. Logistic regression analyses were performed to determine independent predictors for complications. Results. Of the 11,064 patients studied, 3,451 trauma patients developed complications (31.2%). Complications occurred significantly more in younger male patients. Length of stay was correlated with the number of complications (R = 0.435, P < 0.0001). The overall death rate did not differ between patients with or without complications. The adjusted odds ratio (OR) of developing complication for patients over age 75 versus young adults was 0.7 (P < 0.0001). Among males, traumatic central nervous system (CNS) injury was an important predictor for complications (adjusted OR 1.24). Conclusions. Complications after trauma were found to be associated with age, gender, and traumatic CNS injury. Although these are not modifiable factors, they may identify subjects at high risk for the development of complications, allowing for preemptive strategies for prevention.

No abstract