Cloudy fluid, cloudy diagnosis.

Here, we report a case of a patient with cloudy effluent that was initially diagnosed as bacterial peritonitis. The persistence of a cloudy effluent despite antibiotic therapy led to an extensive peritoneal dialysis (PD) effluent analysis, with the final diagnosis being high-grade B-cell lymphoma. This case will increase the awareness of this rare presentation of a lymphoproliferative disorder reminding clinicians to consider this diagnosis as a part of the differential diagnosis PD effluent.

Persistent replication of SARS-CoV-2 in a severely immunocompromised patient treated with several courses of remdesivir.

Microbiological response of SARS-CoV-2 to remdesivir in immunocompromised patients has not been evaluated. We present the case of a severely immunocompromised patient with persistent replication of SARS-CoV-2, who required different courses of remdesivir. Short courses of remdesivir might be insufficient in immunocompromised patients due to prolonged viral clearance.

Comparison of one-catheter strategy versus conventional two-catheter strategy on the volume of radiological contrast and diagnostic coronary catheterization performance by transradial access: A systematic review and meta-analysis of randomized clinical trials / Comparación de la estrategia de catéter único versus la estrategia convencional de dos catéteres sobre el volumen de contraste radiológico y el rendimiento del cateterismo coronario diagnóstico por acceso transradial: una revisión sistemática y meta-análisis de ensayos clínicos aleatorizados

Abstract Background: One-catheter strategy, based in multipurpose catheters, allows exploring both coronary arteries with a single catheter. This strategy could simplify coronary catheterization and reduce the volume of contrast administration, by reducing radial spasm. To date, observational studies showed greater benefits regarding contrast consumption and catheterization performance than controlled trials. The aim of this work is to perform the first systematic review and meta-analysis of randomized clinical trials (RCT) to adequately quantify the benefits of one-catheter strategy, with multipurpose catheters, over conventional two-catheter strategy on contrast consumption, and catheterization performance. Methods: A search in PubMed, CINALH, and CENTRAL databases was conducted to identify randomized trials comparing one-catheter and two-catheter strategies. The primary outcome was volume of iodinated contrast administrated. Secondary endpoints, evaluating coronary catheterization performance included: arterial spasm, fluoroscopy time, and procedural time. Results: Five RCT were included for the final analysis, with a total of 1599 patients (802 patients with one-catheter strategy and 797 patients with two-catheter strategy). One-catheter strategy required less administration of radiological contrast (difference in means [DiM] [95% confidence interval (CI)]; −3.831 mL [−6.165 mL to −1.496 mL], p = 0.001) as compared to two-catheter strategy. Furthermore, less radial spasm (odds ratio [95% CI], 0.484 [0.363 to 0.644], p < 0.001) and less procedural time (DiM [95% CI], −72.471 s [−99.694 s to −45.249 s], p < 0.001) were observed in one-catheter strategy. No differences on fluoroscopy time were observed. Conclusions: One-catheter strategy induces a minimal reduction on radiological contrast administration but improves coronary catheterization performance by reducing arterial spasm and procedural time as compared to conventional two-catheter strategy.

Resumen Antecedentes: La estrategia de catéter único permite explorar ambas coronarias con un solo catéter. Nuestro objetivo es realizar la primera revisión sistemática y meta-análisis de ensayos clínicos aleatorizados para cuantificar adecuadamente los beneficios de la estrategia de catéter único, con catéteres multipropósito, sobre la estrategia convencional de dos catéteres. Métodos: Se realizó una búsqueda en PubMed, CINALH y CENTRAL, identificando ensayos aleatorizados que compararan estrategias de un catéter y dos catéteres. El resultado primario fue volumen de contraste administrado. Los secundarios, que evaluaron el rendimiento del cateterismo, incluyeron: espasmo radial, tiempo de fluoroscopia y de procedimiento. Resultados: Se incluyeron cinco ensayos, totalizando 1,599 pacientes (802 con estrategia de un catéter y 797 con estrategia de dos catéteres). La estrategia de catéter único requirió menos contraste (diferencia-de-medias; −3.831 mL [−6.165 mL a −1.496 mL], p = 0.001), presentando menos espasmo radial (odds ratio, 0.484 [0.363 a 0.644], p < 0.001) y menos tiempo de procedimiento (diferencia-de-medias; −72.471 s [−99.694 s a −45.249 s], p < 0.001). No hubo diferencias en el tiempo de fluoroscopia. Conclusiones: La estrategia de catéter único induce una reducción mínima en la administración de contraste, pero mejora el rendimiento del cateterismo al reducir el espasmo radial y el tiempo de procedimiento en comparación con la estrategia convencional.

Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study.

Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (P inf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.

PiwiRNA-651 as marker of treatment response and survival in classical Hodgkin lymphoma.

PiwiRNAs, small non-coding RNAs processed by Piwi proteins, are involved in maintaining genome stability in germline cells. Recently, piwiRNA expression has been identified in some tumors. We have examined the potential reactivation of the Piwi/piwiRNA pathway in classical Hodgkin lymphoma (cHL). We found that Piwi proteins and three selected piwiRNAs, including piR-651, were expressed in cHL patients and cell lines, indicating that the Piwi/piwiRNA pathway is active in cHL. Interestingly, low levels of piR-651 were associated with lack of complete response to first-line treatment, as well as shorter disease-free and overall survival in a cohort of 94 cHL patients. At diagnosis, piR-651 was underexpressed in cHL serum samples compared to healthy controls, while after complete remission, piR-651 levels increased to levels similar to healthy controls. This is the first evidence that piwiRNAs are active in tumor and serum samples and impact prognosis in cHL.

[Spanish consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria]. / Consenso español para el diagnóstico y tratamiento de la hemoglobinuria paroxística nocturna.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of the haematopoietic progenitor cells due to a somatic mutation in theX-linked phosphatidylinositol glycan class A gene. The disease is characterized by intravascular haemolytic anaemia, propensity to thromboembolic events and bone marrow failure. Other direct complications of haemolysis include dysphagia, erectile dysfunction, abdominal pain, asthenia and chronic renal failure (65% of patients). The disease appears more often in the third decade of life and there is no sex or age preference. Detection of markers associated with glucosyl phosphatidyl inositol deficit by flow cytometry is currently used in the diagnosis of PNH. For years, transfusions have been the mainstay of therapy for PNH. A breakthrough in treatment has been the approval of the humanized monoclonal antibody eculizumab, which works by blocking the C5 complement protein, preventing its activation and therefore haemolysis. Several studies have confirmed that treatment with eculizumab avoids or decreases the need for transfusions, decreases the probability of thrombosis, improves the associated symptomatology and the quality of life in patients with PNH, showing an increase in survival. Because of rapid advances in the knowledge of the disease and its treatment, it may become necessary to adapt and standardize clinical guidelines for the management of patients with PNH.

Prognosis of patients with diffuse large B cell lymphoma not reaching complete response or relapsing after frontline chemotherapy or immunochemotherapy.

A retrospective study was performed to assess the outcome of patients with diffuse large B cell lymphoma (DLBCL) who did not achieve complete response or who relapsed before and after the use of rituximab. Clinical features and outcome of 816 (425 M/391 F; median age 63 years) patients diagnosed from 1991 to 2001 (pre-rituximab era, N = 348) and from 2002 to 2012 (rituximab era, N = 468) in a single institution were evaluated. Five hundred fifty-three patients achieved complete remission (CR), 57 partial response (PR), and 206 were refractory with a median overall survival of 15, 1.5, and 0.4 years, respectively. Patients receiving rituximab had lower risk of refractoriness or relapse. In primarily refractory and PR patients, there was not a difference in survival depending on whether patients received or not rituximab-containing frontline treatment. Early death rate was 11%, including 3.6% due to infectious complications. Rituximab did not modify these figures. In the relapse setting, 5-year survival from relapse was 25% for patients who never received rituximab, 54% for those who received rituximab only at relapse, and 48% for those treated with immunochemotherapy both as frontline and at relapse. In conclusion, relapsed/refractory patients with DLBCL show poor prognosis despite the use of frontline immunochemotherapy. New therapeutic approaches are needed in this group of patients.

MiR-SNPs as markers of toxicity and clinical outcome in Hodgkin lymphoma patients.

BACKGROUND: In recent years, microRNA (miRNA) pathways have emerged as a crucial system for the regulation of tumorogenesis. miR-SNPs are a novel class of single nucleotide polymorphisms that can affect miRNA pathways. DESIGN AND METHODS: We analyzed eight miR-SNPs by allelic discrimination in 141 patients with Hodgkin lymphoma and correlated the results with treatment-related toxicity, response, disease-free survival (DFS) and overall survival (OS). RESULTS: The KRT81 (rs3660) GG genotype was associated with an increased risk of neurological toxicity (P = 0.016), while patients with XPO5 (rs11077) AA or CC genotypes had a higher rate of bleomycin-associated pulmonary toxicity (P = 0.048). Both miR-SNPs emerged as independent factors in the multivariate analysis. The XPO5 AA and CC genotypes were also associated with a lower response rate (P = 0.036). XPO5 (P = 0.039) and TRBP (rs784567) (P = 0.022) genotypes emerged as prognostic markers for DFS, and XPO5 was also associated with OS (P = 0.033). In the multivariate analysis, only XPO5 emerged as an independent prognostic factor for DFS (HR: 2.622; 95%CI 1.039-6.620; P = 0.041). Given the influence of XPO5 and TRBP as individual markers, we then investigated the combined effect of these miR-SNPs. Patients with both the XPO5 AA/CC and TRBP TT/TC genotypes had the shortest DFS (P = 0.008) and OS (P = 0.008). CONCLUSION: miR-SNPs can add useful prognostic information on treatment-related toxicity and clinical outcome in Hodgkin lymphoma and can be used to identify patients likely to be chemoresistant or to relapse.

Lestaurtinib inhibition of the Jak/STAT signaling pathway in hodgkin lymphoma inhibits proliferation and induces apoptosis.

Standard cytotoxic chemotherapy for Hodgkin Lymphoma (HL) has changed little in 30 years; the treatment for patients with relapsed or refractory disease remains challenging and novel agents are under development. JAK/STAT constitutive activation plays an important role in the pathogenesis of HL. Lestaurtinib is an orally bioavailable multikinase inhibitor that has recently been shown to inhibit JAK2 in myeloproliferative disorders. The potential role of Lestaurtinib in HL therapy is unknown. We have analyzed the effect of Lestaurtinib treatment in five HL cell lines from refractory patients, L-428, L-1236, L-540, HDML-2 and HD-MY-Z. At 48 h, a dose-dependent cell growth inhibition (23%-66% at 300 nM) and apoptotic increment (10%-64% at 300 nM) were observed. Moreover, Lestaurtinib inhibited JAK2, STAT5 and STAT3 phosphorylation and reduced the mRNA expression of its downstream antiapoptotic target Bcl-xL. In addition, we have analyzed the effect of Lestaurtinib treatment in lymph nodes from four classic HL patients. We observed a decrease in cell viability at 24 hours of treatment in three patients (mean decrease of 27% at 300 nM). Our findings provide, for the first time, a molecular rationale for testing JAK2 inhibitors, specifically Lestaurtinib, in HL patients.

Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia.

The association between seven polymorphisms in the genes hOCT1 and MDR1, encoding for imatinib transporter proteins, and the response to imatinib 400mg/daily was investigated in 65 patients newly diagnosed with chronic-phase chronic myeloid leukemia. The AA genotype at the rs6935207 hOCT1 polymorphic locus was not detected in patients with inadequate response to imatinib. The CC genotype at the rs1045642 (C3435T) MDR1 locus was associated with primary failure, whereas a T allele at the rs2032582 (G2677T/A) MDR1 locus seemed to protect from primary failure. Beside, the MDR1 haplotype 1236T-2677G-3435C was more frequently found in patients primarily resistant to imatinib.

Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients.

Hydroxyurea (HU) is frequently given as treatment for myelofibrosis (MF), but data on its efficacy and tolerability are scarce. The results of HU therapy were evaluated in 40 patients with hyperproliferative manifestations of primary (n = 32), post-polycythemia vera (n = 6), or post-essential thrombocythemia (n = 2) myelofibrosis. Median interval between diagnosis and HU start was 6.2 months (range 0-141.7). Reasons for treatment were constitutional symptoms (55%), symptomatic splenomegaly (45%), thrombocytosis (40%), leukocytosis (28%), pruritus (10%), and bone pain (8%). The starting dose was 500 mg/day, subsequently adjusted to the individual efficacy and tolerability. Response was bone pain 100%, constitutional symptoms 82%, pruritus 50%, splenomegaly 40%, and anemia 12.5%. According to the International Working Group for Myelofibrosis Research and Treatment criteria, clinical improvement was achieved in 16 patients (40%). Median duration of response was 13.2 months (range 3-126.2). Worsening of the anemia or appearance of pancytopenia were observed in 18 patients, requiring administration of erythropoietin-stimulating agents (n = 17) and/or danazol (n = 9). Oral or leg ulcers appeared in five patients and one had gastrointestinal symptoms. HU is an effective and generally well-tolerated therapy for the hyperproliferative manifestations of MF. The accentuation of the anemia often induced by HU is usually manageable with concomitant treatment.

Hematopoiesis-related microRNA expression in myelodysplastic syndromes.

MicroRNAs (miRNAs) are negative regulators of expression of genes involved in hematopoiesis. The present study sought to link hematopoiesis-relevant miRNAs with myelodysplastic syndromes (MDS) and MDS progression to acute myeloid leukemia (AML). We assessed 25 mature miRNAs in total RNA from bone marrow (BM) and peripheral blood (PB) of 25 newly diagnosed patients with MDS and 12 controls. Twelve miRNAs in BM and six in PB were differentially expressed between patients with MDS and controls. Three of these miRNAs, belonging to the cluster 17-92, were overexpressed in both BM and PB. miR-15a in BM ( p = 0.034) and miR-16 in PB ( p = 0.005) were differentially expressed between low-risk and high-risk groups. miR-222 ( p = 0.0023) and miR-181a ( p = 0.014) expression was higher in AML than in MDS in both BM and PB. This study adds further evidence to the role of miRNAs in the pathogenesis of MDS and their transformation into AML.

Regulation of JAK2 by miR-135a: prognostic impact in classic Hodgkin lymphoma.

The behavior of classic Hodgkin lymphoma (cHL) is determined by both the intrinsic features of the tumor cells and the characteristics of the microenvironment, making the analysis of entire lymph nodes an effective approach to understanding the disease. We examined the influence of our previously reported 25-microRNA signature for cHL on clinical outcome in 89 homogeneously treated cHL patients with a median follow-up of 80 months. Patients with low miR-135a expression had a higher probability of relapse (P = .04) and a shorter disease-free survival (P = .02). Functional analysis of cHL cell lines showed that mature miR-135a levels increased after pre-miR-135a transfection, causing apoptosis and decreased cell growth. Target analysis showed a direct regulation by miR-135a of JAK2, a cytoplasmic tyrosine kinase involved in a specific subset of cytokine receptor signaling pathways. miR-135a-mediated JAK2 down-regulation led to decreased mRNA and protein levels of the antiapoptotic gene Bcl-xL, suggesting a role for Bcl-xL in miR-135a/JAK2-mediated apoptosis. Our findings confirm the critical role of miR-135a in the survival of cHL cells and in the prognosis of cHL patients, indicating that novel treatment approaches targeting miR-135a may potentially benefit these patients.

Common variants in NLRP2 and NLRP3 genes are strong prognostic factors for the outcome of HLA-identical sibling allogeneic stem cell transplantation.

The inflammasomes are macromolecular cytosolic complexes involved in the production of interleukin-1beta (IL-1beta) and IL-18 in response to several pathogen-derived stimuli. Such interleukins have been implicated in the origin of severe allogeneic stem cell transplant (allo-SCT) complications. We analyzed the relationship between the interindividual variability in inflammasome protein-encoding genes in donors and patients and clinical outcome after allo-SCT. Fourteen common genetic variants in 5 genes of the inflammasome, namely, NLRP1, NLRP2, NLRP3, CARD8, and CASP5, were genotyped in 133 human leukocyte antigen-identical sibling pairs undergoing allo-SCT. In the multivariate analysis, donor variants in NLRP2 and NLRP3 were the most important prognostic factors for the clinical outcome after allo-SCT. Thus, donor TT genotype at rs10925027 in NLRP3 was associated with disease relapse (odds ratio (OR) = 6.3, P = 1 x 10(-7)), and donor GG genotype at rs1043684 in NLRP2 was associated with nonrelapse mortality (OR = 4.4, P = 6 x 10(-4)) and overall survival (OR = 3.1, P = .001). In addition, patient AA genotype at rs5862 in NLRP1 was associated with nonrelapse mortality (OR = 2.8, P = .005) and overall survival (OR = 2.0, P = .009). These results suggest that inflammasome genetic variants are important prognostic factors for the outcome of allo-SCT. If validated in larger studies, including unrelated allo-SCT, NLRPs genotype would become an important factor in donor selection.

Anemia associated with impaired erythropoietin secretion after allogeneic stem cell transplantation: incidence, risk factors, and response to treatment.

After allogeneic stem cell transplantation (allo-SCT) some patients develop persistent anemia in association with an inadequate erythropoietin (Epo) secretion. We determined the frequency and risk factors for this complication and the response to treatment with erythropoiesis stimulating proteins (ESP). Of 83 evaluable allo-SCT patients, 63 (76%) developed persistent anemia at a median of 34 (range: 30-244) days after allo-SCT. Forty-one (49%) patients had anemia considered as primary, and in all of them inadequate serum Epo levels (median 43.3, range: 2.5-134, mU/mL) were found. A high creatinine level during the first month after allo-SCT was associated with primary anemia (relative risk [RR] 2.5, P = .01). Of the 41 patients, 35 received ESP. Transfusion independence and an Hb level higher than 10 g/dL was achieved in 29 of 30 (97%) evaluable patients. Median ferritin levels at the beginning and at the end of the ESP treatment was 1628 (range: 168-5208) and 805 (range: 14-7443) ng/mL, respectively (P = .04). In conclusion, anemia associated with impaired Epo secretion after allo-SCT is more frequent than usually recognized and it is associated to early postransplantation renal damage. This complication easily reverts with ESP, which seems to contribute to reduce iron overload.

MicroRNA expression profiling in classic Hodgkin lymphoma.

MicroRNAs (miRNAs) are negative regulators of gene expression that play an important role in hematopoiesis and tumorigenesis. We analyzed miRNA expression in classic Hodgkin lymphoma (cHL) and the influence of Epstein-Barr virus (EBV) infection on the miRNA expression profiles. The expression of 157 miRNAs in lymph nodes from 49 cHL patients and 10 reactive lymph nodes (RLNs) was analyzed by real-time polymerase chain reaction (PCR). Hierarchic clustering revealed 3 well-defined groups: nodular sclerosis cHL, mixed cellularity cHL, and RLNs. A distinctive signature of 25 miRNAs differentiated cHL from RLNs, and 36 miRNAs were differentially expressed in the nodular sclerosis and mixed cellularity subtypes. These results were validated in a set of 30 cHLs and 5 RLNs, and in 3 cHL cell lines. miR-96, miR-128a, and miR-128b were selectively down-regulated in cHL with EBV. Our findings suggest that miRNAs play an important role in the biology of cHL and may be useful in developing therapies targeting miRNAs.

Kinetics of recovery of dendritic cell subsets after reduced-intensity conditioning allogeneic stem cell transplantation and clinical outcome.

BACKGROUND AND OBJECTIVES: Dendritic cells (DC) play a critical role in the regulation of alloimmune responses and might influence the outcome of allogeneic stem cell transplantation (allo-SCT). We studied the clinical relevance of early reconstitution of DC after reduced-intensity conditioning allo-SCT (allo-RIC). DESIGN AND METHODS: This study included 79 adult patients undergoing allo-RIC from HLA-identical siblings. Peripheral blood samples were drawn from patients at 1 month (+1m) and 3 months (+3m) after the transplant. DC were identified as positive for HLA-DR and negative for CD3, CD19, CD14 and CD56. The expression of CD33, CD123 and CD16 was used to identify myeloid DC, plasmacytoid DC and CD16(+) DC subpopulations, respectively. RESULTS: Patients whose DC count at +1m was lower than the median had a higher probability of treatment-related mortality (TRM) (60% vs 12%; p=0.02), poorer overall survival (OS) (15% vs 45%; p=0.002) and worse event-free survival (EFS) (20% vs 38%; p=0.03). A multivariate analysis confirmed that low DC counts had a detrimental effect on OS (RR 3.2; p=0.007), relapse (RR 4.1; p=0.01), and EFS (RR 6; p=0.001). Low CD16(+) DC counts were observed to have a detrimental effect on EFS, which was due to both a higher incidence of deaths caused by infections (50% vs 0%, p=0.05) and a higher incidence of relapse (57% vs 50%; p=0.03). Indeed, the number of CD16(+) DC at +3 m was the most important prognostic factor for EFS (RR 6; p=0.001). Interpretations and Conclusions This study shows the clinical importance of DC recovery, especially of the CD16(+) DC subset, in the outcome of patients treated with allo-RIC.

Herpes simplex and Epstein-Barr virus lymphadenitis in a patient with chronic lymphocytic leukemia treated with fludarabine.

Multiple herpes virus co-infection is a very rare complication in patients with chronic lymphocytic leukemia (CLL). We describe a patient with a CLL who developed an herpes virus lymphadenitis. Inmunohistochemical study was positive for HSV-1, HSV-2, and Epstein-Barr Virus (EBV). The coinfection of EBV with a profile of expresion of viral latent genes type III, is usually seen in inmunodepressed patients. To the best of our knowledge, this is the first reported case of a multiple human herpes virus infection mimicking Richter syndrome.