ERK1/2 pro-survival signalling is suppressed by pirtobrutinib in ibrutinib-resistant MYD88-mutated lymphoma cells.

Covalent Bruton's tyrosine kinase-inhibitors (cBTK-i) are highly active in MYD88-mutated (MYD88Mut) Waldenstrom's macroglobulinaemia and suppress nuclear factor kappa-light-chain-enhancer of activated B cells and extracellular signal-regulated kinases-1/2 (ERK1/2)-related signalling. BTKCys481 mutations are associated with cBTK-i acquired resistance and are accompanied by reactivation of ERK1/2 that promotes inflammatory cytokine secretion and paracrine-mediated resistance of BTK wild-type (BTKWT) tumour cells. Pirtobrutinib is a non-covalent BTK-inhibitor that binds at non-BTKCys481 sites. We show that pirtobrutinib blocked p-ERK1/2, ERK1/2-driven inflammatory cytokines, and overcame paracrine-mediated resistance in MYD88Mut lymphoma cells expressing mutated BTKCys481. Our results provide important mechanistic insights for the activity of pirtobrutinib in MYD88Mut lymphomas carrying BTKCys481 mutations.

Adherence to Mediterranean diet in Spanish patients with psoriasis: Cardiovascular benefits?

Several studies have evaluated the role of individual nutrients on psoriasis. Only a few of them have evaluated the benefits of healthy dietary patterns and the effect of the Mediterranean diet on psoriasis with promising results. Moderate-severe psoriasis is associated with chronic systemic inflammation and increased cardiovascular risk. In this study the present authors measure the adherence to the Mediterranean diet to determine the grade of association with severity of psoriasis, a cardiovascular profile, and systemic inflammation. Our aim was to determine a cut-off point that approximates the real clinical practice by differentiating patients with systemic or biological treatment.

Ixazomib-induced cutaneous necrotizing vasculitis.

Ixazomib is a second-generation proteasome inhibitor that has been approved in the combination treatment of multiple myeloma and is currently under clinical investigation for the management of Waldenstrom's macroglobulinemia. While cutaneous adverse events secondary to proteasome inhibitors have been reported, the side effect profile of ixazomib remains to be documented. We report two patients, one with multiple myeloma and one with Waldenstrom's macroglobulinemia, who developed cutaneous necrotizing vasculitis after the initiation of ixazomib. Both patients exhibited no signs of systemic vasculitis and completed their anti-cancer regimens with resolution of their respective eruptions following dose reductions in ixazomib and initiation of low-dose prednisone. A collaborative effort towards the characterization of such cutaneous toxicities facilitates early intervention, maintenance of life-preserving anti-cancer therapy, and allows clinicians opportunity to better understand the pathophysiology of vasculitis. Moreover, appropriate identification and characterization of cutaneous toxicities from novel therapies allows providers to accurately identify safety concerns, treat toxicity, and improve patient quality of life.

High-Definition Video Recording: Taking Sport Technology to the Operating Room.

Filming surgeries for teaching purposes, publications, and patient records has become increasingly popular as the systems for digital recording have evolved, becoming high-quality systems, both smaller and lighter. Digital recording allows long-term storage, retrieval, and database organization. In addition, sharing digital contents has also become easier since video sharing sites and social networks make it possible to upload these contents onto the Internet. We describe a simple and economical system for surgeons to record surgeries in high definition under sterile conditions without any interference with the surgeon's line of vision.

Halogenated Natural Products in Dolphins: Brain-Blubber Distribution and Comparison with Halogenated Flame Retardants.

Halogenated natural products (MHC-1, TriBHD, TetraBHD, MeO-PBDEs, Q1, and related PMBPs) and halogenated flame retardants (PBDEs, HBB, Dec 602, Dec 603, and DP) in blubber and brain are reported from five Alboran Sea delphinids (Spain). Both HNPs and HFRs were detected in brain, implying that they are able to surpass the blood-brain barrier and reach the brain, which represents a new finding for some compounds, such as Q1 and PMBPs, MHC-1, TriBHD, TetraBHD, or Dec 603. Moreover, some compounds (TetraBHD, BDE-153, or HBB) presented higher levels in brain than in blubber. This study evidence the high concentrations of HNPs in the marine environment, especially in top predators. It shows the importance of further monitoring these natural compounds and evaluating their potential toxicity, when most studies focus on anthropogenic compounds only. While no bioaccumulation was found for ∑HNPs, ∑HFRs increased significantly with body size for both common and striped dolphins. Studies evaluating BBB permeation mechanisms of these compounds together with their potential neurotoxic effects in dolphins are recommended.

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy.

BACKGROUND: Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear. PATIENTS AND METHODS: We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses. RESULTS: PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission. CONCLUSIONS: This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.

Comparative outcomes of oncologic therapy in gastric extranodal marginal zone (MALT) lymphoma: analysis of the SEER-Medicare database.

BACKGROUND: Therapy for gastric marginal zone (MALT) lymphoma is largely based on single-arm trials. This observational study compared survival with radiotherapy, rituximab and combination chemoimmunotherapy in this disease. PATIENTS AND METHODS: Gastric MALT lymphoma cases diagnosed between 1997 and 2007 were selected from the Surveillance, Epidemiology and End Results-Medicare database. Propensity score analysis and competing risk models were used to compare survival in patients with stage IE treated with radiation or chemotherapy, and in patients of all stages treated with rituximab alone or with chemoimmunotherapy. RESULTS: Among 1134 patients, 21% underwent radiation and 24% chemotherapy as initial treatment. In the balanced cohort of 347 patients with stage IE, radiotherapy alone was associated with a better cause-specific survival [hazard ratio (HR) 0.27, P < 0.001]. Patients receiving systemic therapy had better survival if it incorporated rituximab (HR 0.53, P = 0.017). After adjustment for confounding, the outcomes of those who received rituximab alone or combination chemoimmunotherapy were not statistically different (P = 0.14). CONCLUSIONS: In elderly patients with stage IE gastric MALT lymphoma, radiotherapy was associated with lower risk of lymphoma-related death than chemotherapy. In those requiring systemic treatment, addition of cytotoxic chemotherapy to rituximab in the first-line regimen was not associated with improved survival.

Report of consensus panel 7 from the 11th international workshop on Waldenström macroglobulinemia on priorities for novel clinical trials.

Recent advances in the understanding of Waldenström macroglobulinemia (WM) biology have impacted the development of effective novel agents and improved our knowledge of how the genomic background of WM may influence selection of therapy. Consensus Panel 7 (CP7) of the 11th International Workshop on WM was convened to examine the current generation of completed and ongoing clinical trials involving novel agents, consider updated data on WM genomics, and make recommendations on the design and prioritization of future clinical trials. CP7 considers limited duration and novel-novel agent combinations to be the priority for the next generation of clinical trials. Evaluation of MYD88, CXCR4 and TP53 at baseline in the context of clinical trials is crucial. The common chemoimmunotherapy backbones, bendamustine-rituximab (BR) and dexamethasone, rituximab and cyclophosphamide (DRC), may be considered standard-of-care for the frontline comparative studies. Key unanswered questions include the definition of frailty in WM; the importance of attaining a very good partial response or better (≥VGPR), within stipulated time frame, in determining survival outcomes; and the optimal treatment of WM populations with special needs.

Report of consensus panel 2 from the 11th international workshop on Waldenström's macroglobulinemia on the management of relapsed or refractory WM patients.

The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients' prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.

[The effectiveness of rituximab in refractory autoimmune thrombocytopenic purpura and haemolytic anaemia]. / Efectividad de rituximab en púrpura tombocitopénica y anemia hemolítica autoinmune refractarias.

OBJECTIVE: To evaluate the efficacy and safety of treatment with rituximab in patients presenting autoimmune thrombocytopenic purpura and haemolytic anaemia. METHOD: A check was carried out of the medical records of the patients starting treatment with rituximab for compassionate use in 2004 at doses of 375 mg/m2 per week for 4 weeks. The rate of patients achieving full response in accordance with the best criteria found in the bibliography was assessed. All adverse reactions described in the medical records were gathered. RESULTS: Six patients with thrombocytopenic purpura were candidates for treatment. Five began treatment, four of them completed treatment, and three of these patients achieved full response. This response was achieved at different times and was sustained for at least six months. Two patients with autoimmune haemolytic anaemia were treated and both achieved full response again at different times and in this case, it was sustained for at least 8 months. One patient suffered mild adverse reactions to treatment. CONCLUSIONS: Rituximab is a new perspective for the treatment of refractory autoimmune cytopenias, and has a good safety profile.

Utilidad de los radioligandos PSMA en el diagnóstico y tratamiento del carcinoma de próstata / The role of PSMA radioligands in the diagnosis and treatment of prostate carcinoma

El cáncer de próstata (CP) es el tumor más frecuente en varones en Occidente y la quinta causa de muerte relacionada con el cáncer. El uso de radioligandos antígeno prostático específico de membrana (PSMA) ha supuesto un importante avance tanto en su diagnóstico, a través de la imagen molecular de tomografía por emisión de positrones (PET), como en su tratamiento en fases avanzadas de la enfermedad. En este artículo, se hace una revisión de la aportación de los estudios PET con radioligandos PSMA en la estadificación inicial, en la detección tumoral en la recidiva bioquímica (elevación del antígeno prostático específico [PSA]) tras un tratamiento con intención curativa, y en los estadios más avanzados de la enfermedad (CP resistente a la castración o CPRC). Se analiza, además, la aportación de la terapia con radioligandos PSMA (PSMA-TRL) en pacientes con CPRC que progresan a la terapia estándar (AU)

Prostate cancer (PC) is the most common tumor in men in the West and the fifth leading cause of cancer-related death. The use of prostate-specific membrane antigen (PSMA) radioligands has represented an important advance in both in the diagnosis by positron emission tomography (PET) molecular imaging and the treatment of advanced stages of the disease. This article reviews the contribution of PET studies with PSMA radioligands in the initial staging, tumor detection in biochemical recurrence (elevation of PSA) after treatment with curative intent, and in the more advanced stages of the disease (castration-resistant PC [CRPC]). The contribution of PSMA radioligand therapy in CRPC patients who progress to standard therapy is also analyzed (AU)

The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom's Macroglobulinemia.

CXCR4(WHIM) somatic mutations are common Waldenstrom's Macroglobulinemia (WM), and are associated with clinical resistance to ibrutinib. We engineered WM cells to express the most common WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis), CXCR(S338X) mutation in WM. Following SDF-1a stimulation, CXCR4(S338X) WM cells exhibited decreased receptor internalization, enhanced and sustained AKT kinase (AKT) and extracellular regulated kinase (ERK) signaling, decreased poly (ADP-ribose) polymerase and caspase 3 cleavage, and decreased Annexin V staining versus CXCR4 wild-type (WT) cells. CXCR4(S338X)-related signaling and survival effects were blocked by the CXCR4 inhibitor AMD3100. SDF-1a-treated CXCR4(S338X) WM cells showed sustained AKT and ERK activation and decreased apoptotic changes versus CXCR4(WT) cells following ibrutinib treatment, findings which were also reversed by AMD3100. AKT or ERK antagonists restored ibrutinib-triggered apoptotic changes in SDF-1a-treated CXCR4(S338X) WM cells demonstrating their role in SDF-1a-mediated ibrutinib resistance. Enhanced bone marrow pAKT staining was also evident in CXCR4(WHIM) versus CXCR4(WT) WM patients, and remained active despite ibrutinib therapy in CXCR4(WHIM) patients. Last, CXCR4(S338X) WM cells showed varying levels of resistance to other WM relevant therapeutics, including bendamustine, fludarabine, bortezomib and idelalisib in the presence of SDF-1a. These studies demonstrate a functional role for CXCR4(WHIM) mutations, and provide a framework for investigation of CXCR4 inhibitors in WM.

Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia.

We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1-16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76-96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38-67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12-not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.

Renal dysfunction after orthotopic heart transplantation: incidence, natural history, and risk factors.

BACKGROUND: Renal dysfunction is a common complication after orthotopic heart transplantation (HT). The importance of factors other than exposure to immunosuppressive drugs is unclear. The purpose of this study was to determine the incidence and natural history of renal dysfunction following heart transplantation, and to evaluate a number of variables as risk factors for this condition. METHODS: We examined the creatinine levels at 1, 6, 12, 24, and 60 months in 262 consecutive heart transplant patients who survived at least 1 year. The potential risk factors included pre- and posttransplantation diabetes mellitus, arterial hypertension, and drugs used to control arterial hypertension. RESULTS: 17.2% of patients showed mild renal dysfunction (creatinine 1.5-2.5 mg/dL) and 1.9% moderate dysfunction (creatinine >2.5 mg/dL) at 1 month; 29.8% showed mild and 1.1% moderate dysfunction at 6 months; 33.2% showed mild and 1.9% moderate dysfunction at 1 year; 40% showed mild, 0.9% moderate and 0.4% severe dysfunction (requiring dialysis or renal transplantation) at 2 years; and 43.6% showed mild, 1.7% moderate and 0.9% severe dysfunction at 5 years. None of the conditions analyzed as possible risk factors showed a significant association with renal dysfunction except the use of diuretics. CONCLUSION: The incidence of renal dysfunction after orthotopic heart transplantation was 33.6% within the first year after transplant and 44% within the first five years, although more than 95% of cases were mild. The incidence increased with time after transplantation. Renal dysfunction seems likely to be multifactorial in origin, but no individual risk factors were identified.

Psychiatric consultation and post-traumatic stress disorder in burned patients.

We report a prospective study of 65 burned inpatients referred for psychiatric consultation. All of the subjects in the sample were evaluated by a structured questionnaire and clinical interview. Reasons for referral were: suicide attempt by burning (n = 7), substance dependence (n = 8) and behaviour disturbed by coping difficulties (n = 50). The diagnoses were adjustment disorder (n = 40), alcohol dependence (n = 7), opiate dependence (n = 2), dementia (n = 3), depressive disorder (n = 5), schizophrenia (n = 1), delirium (n = 1) and post-traumatic stress disorder (n = 5). Patients with post-traumatic stress disorder (PTSD) were specifically and carefully evaluated. There were no significant differences between patients with PTSD and adjustment disorder for severity and type of burn injuries. We conclude that PTSD is apt to be missed by the medical staff of burn units.

[Combined valvular and coronary surgery]. / Cirugía valvular y coronaria asociadas.

Combined valvular and coronary surgery is more common every day. Coexistence of valvular and coronary disease makes a complex setting of physiopathological interactions, specially in the ischemic mitral regurgitation. So an ideal surgical strategy, including a thorough knowledge of valvular shape, ventricular function and myocardial reserve, as well as new mitral repair techniques and cardioplegic myocardial protection is essential. Despite these conditions, combined surgical mortality is higher than in isolated valve or coronary surgery. Severe complications in the early postoperative period and long term follow up are also more frequent. In any case, combined valvular and coronary surgery remains a challenge for surgical groups all over the world.

[Pulmonary hypertension and early mortality after orthotopic heart transplantation]. / Hipertensión pulmonar y mortalidad precoz después del trasplante cardíaco ortotópico.

INTRODUCTION AND OBJECTIVES: To study the relationship between hemodynamic parameters before heart transplantation and the mortality rate at the first week posttransplant. METHODS: 85 patients had an orthotopic heart transplant. Before the operation we measured: vascular pulmonary resistance, index of vascular pulmonary resistance, pulmonary arterial pressure systolic and median and transpulmonary gradient. Ten patients with values of vascular pulmonary resistance higher than four Wood units and/or pulmonary artery systolic pressure higher than 60 mmHg, had a test of pulmonary vascular reactivity, the result of that test did not contraindicate the transplant. We used the Student's t test and chi 2 with continuity correction and the Fisher's exact test for the analysis of the data. RESULTS: During the study period eight patients were dead (9.4%). The causes of death were: acute disfunction of the graft, 5 patients; multiorgan failure, 2 patients and septic shock, 1 patient. We compared the parameters of both groups of patients live and dead and could find a significant difference between the data with higher values in the death group: pulmonary arterial systolic pressure (p < 0.01); pulmonary arterial median pressure (p < 0.03) and transpulmonary gradient (p < 0.02). We also saw that the relative risk of mortality was 10.4 when the pulmonary artery systolic pressure was > or = 50 mmHg and 5.7 when the pulmonary vascular resistance was > or = 5 Wood units. CONCLUSIONS: It is important a good evaluation of the pulmonary hemodynamic before the heart transplantation for a better selection of the receptor. The severe pulmonary hypertension (pulmonary vascular resistance > or = 5 Wood units or pulmonary artery systolic pressure > or = 50 mmHg) was associated with a higher rate of early death.