Summary
Follicular lymphoma (FL) is an indolent disease characterized by long survival but frequent relapses. Before the introduction of rituximab, the clinical course of these patients showed a ...shorter response duration (RD) after each relapse. In this study, we analysed if this pattern of shortened responses remains in patients treated in the rituximab era. We selected 348 patients newly diagnosed with FL in two institutions between 2001 and 2014 that received chemoimmunotherapy. After a median follow‐up of 6·3 years, 10‐year progression‐free and overall survivals were 53% and 72%, respectively. All patients received first‐line, 111 second‐line and 41 third‐line treatments, with a 5‐year RD of 62%, 39% and 24%, respectively (P < 0·0001). Variables predicting longer RD after first‐line treatment were normal β2microglobulin, complete remission achievement and maintenance with rituximab. Patients with longer RD after first‐line showed significantly longer RD after second‐line therapy. Autologous stem‐cell transplantation after second‐line therapy did not significantly impact RD. Median survival after first, second and third therapies was not reached, 7·6 and 4·8 years, respectively, whereas relative survival with respect to a sex‐ and age‐matched Spanish population, the decrease in the life expectancy at 10 years was 17%, 45% and 79%, respectively. Thus, RD still shortens after each relapse in patients with FL treated in first line with rituximab combinations.
MYC alterations influence the survival of patients with diffuse large B-cell lymphoma. Most studies have focused on MYC translocations but there is little information regarding the impact of ...numerical alterations and protein expression. We analyzed the genetic alterations and protein expression of MYC, BCL2, BCL6, and MALT1 in 219 cases of diffuse large B-cell lymphoma. MYC rearrangement occurred as the sole abnormality (MYC single-hit) in 3% of cases, MYC and concurrent BCL2 and/or BCL6 rearrangements (MYC double/triple-hit) in 4%, MYC amplifications in 2% and MYC gains in 19%. MYC single-hit, MYC double/triple-hit and MYC amplifications, but not MYC gains or other gene rearrangements, were associated with unfavorable progression-free survival and overall survival. MYC protein expression, evaluated using computerized image analysis, captured the unfavorable prognosis of MYC translocations/amplifications and identified an additional subset of patients without gene alterations but with similar poor prognosis. Patients with tumors expressing both MYC/BCL2 had the worst prognosis, whereas those with double-negative tumors had the best outcome. High MYC expression was associated with shorter overall survival irrespectively of the International Prognostic Index and BCL2 expression. In conclusion, MYC protein expression identifies a subset of diffuse large B-cell lymphoma with very poor prognosis independently of gene alterations and other prognostic parameters.
Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF) and one of the leading indications for liver transplantation in Western societies. Given the wide use of both prescribed ...and over the counter drugs, DILI has become a major health issue for which there is a pressing need to find novel and effective therapies. Although significant progress has been made in understanding the molecular mechanisms underlying DILI, our incomplete knowledge of its pathogenesis and inability to predict DILI is largely due to both discordance between human and animal DILI in preclinical drug development and a lack of models that faithfully recapitulate complex pathophysiological features of human DILI. This is exemplified by the hepatotoxicity of acetaminophen (APAP) overdose, a major cause of ALF because of its extensive worldwide use as an analgesic. Despite intensive efforts utilising current animal and in vitro models, the mechanisms involved in the hepatotoxicity of APAP are still not fully understood. In this expert Consensus Statement, which is endorsed by the European Drug-Induced Liver Injury Network, we aim to facilitate and outline clinically impactful discoveries by detailing the requirements for more realistic human-based systems to assess hepatotoxicity and guide future drug safety testing. We present novel insights and discuss major players in APAP pathophysiology, and describe emerging in vitro and in vivo pre-clinical models, as well as advanced imaging and in silico technologies, which may improve prediction of clinical outcomes of DILI.
Chronic right ventricular apical pacing (RVAP) has been associated with negative hemodynamic and clinical effects. The aim of the present study was to compare RVAP with right ventricular septal ...pacing (RVSP) in terms of echocardiographic features and clinical outcomes. A total of 93 patients without structural heart disease and with an indication for a permanent pacemaker were randomly assigned to receive a screw-in lead either in the RV apex (n = 46) or in the RV mid-septum (n = 47). The patients were divided into 3 subgroups according to the percentage of ventricular pacing: control group (n = 21, percentage of ventricular pacing ≤10%), RVAP group (n = 28), or RVSP group (n = 32; both latter groups had a percentage of ventricular pacing >10%). The RVAP group had more intraventricular dyssynchrony and a trend toward a worse left ventricular ejection fraction compared to the RVSP and control groups at 12 months of follow-up (maximal delay to peak systolic velocity between any of the 6 left ventricular basal segments was 57.8 ± 38.2, 35.5 ± 20.6, and 36.5 ± 17.8 ms for RVAP, RVSP, and control group, respectively; p = 0.006; mean left ventricular ejection fraction 62.9 ± 7.9%, 66.5 ± 7.2%, and 66.6 ± 7.2%, respectively, p = 0.14). Up to 48.1% of the RVAP patients showed significant intraventricular dyssynchrony compared to 19.4% of the RVSP patients and 23.8% of the controls (p = 0.04). However, no overt clinical benefits from RVSP were found. In conclusion, RVAP was associated with increased dyssynchrony compared to the RVSP and control patients. RVSP could represent an alternative pacing site in selected patients to reduce the harmful effects of traditional RVAP.
The objective of this study was to test a regenerative medicine strategy for the regeneration of articular cartilage. This approach combines microfracture of the subchondral bone with the implant at ...the site of the cartilage defect of a supporting biomaterial in the form of microspheres aimed at creating an adequate biomechanical environment for the differentiation of the mesenchymal stem cells that migrate from the bone marrow. The possible inflammatory response to these biomaterials was previously studied by means of the culture of RAW264.7 macrophages. The microspheres were implanted in a 3 mm‐diameter defect in the trochlea of the femoral condyle of New Zealand rabbits, covering them with a poly(l‐lactic acid) (PLLA) membrane manufactured by electrospinning. Experimental groups included a group where exclusively PLLA microspheres were implanted, another group where a mixture of 50/50 microspheres of PLLA (hydrophobic and rigid) and others of chitosan (a hydrogel) were used, and a third group used as a control where no material was used and only the membrane was covering the defect. The histological characteristics of the regenerated tissue have been evaluated 3 months after the operation. We found that during the regeneration process the microspheres, and the membrane covering them, are displaced by the neoformed tissue in the regeneration space toward the subchondral bone region, leaving room for the formation of a tissue with the characteristics of hyaline cartilage.
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous ...stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival (PFS) and overall survival (OS) of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. 103 patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, PFS was significantly better in the transplanted patients than in the non-transplanted group: 63% vs. 48% at 5 years (p=0.042). OS was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year OS: 70% vs. 50%, p=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged PFS (HR 0.57, 95% CI 0.35-0.93) and OS (HR 0.57, 95% CI 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study.
The poor prognosis of chronic liver disease (CLD) generates the need to investigate the evolving mechanisms of disease progression, thus disclosing therapeutic targets before development of clinical ...complications. Considering the central role of liver sinusoidal endothelial cells (LSECs) in pre-neoplastic advanced CLD, the present study aimed at investigating the progression of CLD from an endothelial holistic perspective. RNAseq defined the transcriptome of primary LSECs isolated from three pre-clinical models of advanced CLD, during the progression of the disease, and from fresh human cirrhotic tissue. At each stage of the disease, the effects of LSECs secretome on neighboring cells and proteomic analysis of LSECs-derived extracellular vesicles (EVs) were also determined. CLD was associated with deep common modifications in the transcriptome of LSECs in the pre-clinical models. Pathway enrichment analysis showed predominance of genes related with pro-oncogenic, cellular communication processes, and EVs biogenesis during CLD progression. Crosstalk experiments revealed endothelial EVs as potent angiocrine effectors. The proteome of LSECs EVs showed stage-specific signatures, including over-expression of tropomyosin-1. Proof-of-principle experiments treating cirrhotic HSCs with recombinant tropomyosin-1 suggested de-activating effects. Our data provide the basis for discovering novel biomarkers and therapeutic targets for new disease-modifying treatments for patients with advanced CLD.
Summary
The International Prognostic Index (IPI) is the most widely used score for non‐Hodgkin lymphoma but lacks the ability to identify a high‐risk population in diffuse large B‐cell lymphoma ...(DLBCL). Low absolute lymphocyte count and high monocytes have proved to be unfavourable factors. Red‐cell distribution width (RDW) has been associated with inflammation and beta‐2 microglobulin (B2M) with tumour load. The retrospective study included 992 patients with DLBCL treated with R‐CHOP. In the multivariate analysis, age, Eastern Cooperative Oncology Group performance status (ECOG‐PS), stage, bulky mass, B2M, RDW, and lymphocyte/monocyte ratio (LMR) were independently related to progression‐free survival (PFS). A new prognosis score was generated with these variables including age categorized into three groups (0, 1, 2 points); ECOG ≥ 3–4 with two; stage III/IV, bulky mass, high B2M, LMR < 2·25 and RDW > 0·96 with one each; for a maximum of 9. This score could improve the discrimination of a very high‐risk subgroup with five‐year PFS and overall survival (OS) of 19% and 24% versus 45% and 59% of R (revised)‐IPI respectively. This score also showed greater predictive ability than IPI. A new score is presented including complete blood cell count variables and B2M, which are readily available in real‐life practice without additional tests. Compared to R‐IPI, it shows a more precise high‐risk assessment and risk discrimination for both PFS and OS.
Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was ...to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or our own prototype for laboratory animals. The neuroethological assessment of seizures and general behavior were performed before surgery, and after 7, 10, and 14 days of VNS. Moreover, potential side effects were examined. Finally, the expression of 23 inflammatory markers in plasma and the left-brain hemisphere was evaluated. VNS significantly reduced seizure severity in GASH/Sal without side effects. No differences were observed between the neurostimulation devices. GASH/Sal treated with VNS showed statistically significant reduced levels of interleukin IL-1β, monocyte chemoattractant protein MCP-1, matrix metalloproteinases (MMP-2, MMP-3), and tumor necrosis factor TNF-α in the brain. The described experimental design allows for the study of VNS effects and mechanisms of action using an implantable device. This was achieved in a model of convulsive seizures in which VNS is effective and shows an anti-inflammatory effect.
Purpose
The alterations of the Subjective visual vertical test are related to vestibular pathology. Our previously validated method to distinguish between healthy and pathological individuals ...measures the deviation from the Subjective visual vertical using a mobile application installed on a smartphone fixed to a turntable anchored to the wall. The aim of this study was evaluating the intra-observer reliability of our method in individuals with or without vestibular pathology.
Methods
Participants were recruited consecutively. In each individual two measurements with an interval of 2 h were made. Both tests were performed by the same examiner. A total of 91 patients were included in this study, of which 25 were healthy and 66 diseased. Intra-observer reliability was evaluated using the intraclass correlation coefficient (ICC). To assess the clinical accuracy of the measurement, we calculated the standard error of the measurement (SEM) and the minimum detectable change (MDC) with a 95% confidence interval.
Results
Intra-observer reliability was excellent with an ICC 0.95 (0.92–0.97) in the whole sample, in healthy patients 0.91 (0.80–0.96) and in pathological patients 0.92 (0.87–0.95). The SEM was calculated to be 0.59 for the whole sample (0.26 in the “healthy” group, and 0.67 in the pathological group). Likewise, the sample’s MDC was 1.16, being 0.52 and 1.36 for the healthy and the pathological group, respectively.
Conclusions
Considering the results, our method presents an excellent intraobserver reliability. Furthermore, changes in deviation greater than 0.52 in healthy individuals and 1.36 in pathological individuals can be considered a real change in deviation.
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