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.

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.

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.

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.

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.

Prevalencia de maloclusiones asociadas a trastornos temporomandibulares (TTM): análisis fotográfico / Prevalence of temporomandibular disorders (TMD) associated malocclusions: a photographic analysis

Los trastornos temporomandibulares (TTM) son alteraciones del funcionamiento del sistema estomatognático. Tienen etiologíamultifactorial y sintomatología variada. El objetivo del trabajo fue determinar la prevalencia de maloclusiones que se consideran asociadasal desarrollo de TTM en pacientes pre-ortodóncicos. Se analizaron 261 estudios fotográficos iníciales de pacientes entre 11 y 45 años, deambos sexos, que ingresaron a la Cátedra de Ortodoncia de la Facultad de Odontología de la Universidad de Buenos Aires (FOUBA). Se determinó la presencia o ausencia de las siguientes maloclusiones asociadas a TTM (MATTM): mordida invertida posteriorunilateral (MIPU), mordida invertida posterior bilateral (MIPB), mordida en tijera (MT), mordida invertida anterior (MIA), mordida abierta anterior (MAA) y mordida profunda (MP). De los 261 pacientes, se registraron 51(19,54 por ciento) sin MATTM, 154 pacientes(59 por ciento) presentaron al menos una MATTM, 52 pacientes (19,92 por ciento) presentaron dos MATTM, 3 pacientes (1,15 por ciento) presentaron tres MATTM y 1 paciente (0.39 por ciento) cuatro MATTM, 72 pacientes(27.58 por ciento) presentaron mordida invertida uni lateral (MIUL), 70 pacientes (26.82 por ciento) presentaron M.P, 46 pacientes (17.62 por ciento) presentaron MIA, 38 pacientes(14.55 por ciento) presentaron MAA, 33 pacientes (12.64 por ciento) presentaron MIBL y 12 pacientes (4.59 por ciento) presentaron MT. Se concluye que es importante realizar un minucioso examen clínico para evaluar la presencia de TTM previamente al tratamiento ortodóncico, ya que sólo el 19,54 por ciento de lospacientes evaluados no registró mal oclusiones asociadas a TTM, mientras que el 59 por ciento presentó al menos una. La maloclusión a pesar de que solo es uno de los factores etiológicos dentro de la etiología multifactorial del desarrollo de TTM, es importante tenerla en cuenta y darle una solución, idealmente de manera interdisciplinaria.

Temporomandibular disorders (TMD) are pathologies of the function of the stomatognathic system. They have a multifactorial etiologyand diverse symptomatology. The aim of the study was to determine the prevalence of malocclusions that are considered associated withTMD development in pre-orthodontic patients. A total of 261 initial photographic diagnostic studies were analyzed; these comprisedpatients between the ages of 11 and 45 from the Department of Orthodontics, FOUBA. The presence and absence of the followingTTM (MATTM) associated malocclusions was analyzed detected: unilateral posterior Crossbite (UPC), bilateral posterior Crossbite(BPC), scissor bite (SB), anterior Crossbite (AC), anterior open bite (AOB) and deep bite (DB). The findings in the 261 patientstreated were: 51 patients (19, 54%) presented MATMD, 154 patients (59%) presented at least one MATTM, 52 patients (19,92%)presented two MATTMs, 3 patients (1,15%) presented three MATTMs and 1 patient (0,39%) presented four MATTMs, 72patients (27,58%) presented IUPO, 70 patients (26,82%) presented DB, 46 patients (17,62%) presented (AC), 38 patients(14,55%) presented AOB, 33 patients (12,64%) presented BPC and 12 patients (4.59%) presented SB. It is concluded that it isimportant to carry out a thorough clinical examination to evaluate the presence of TMD prior to orthodontic treatment, as only 19,54%of the patients treated showed no malocclusions associated with TMD, while 59% presented at least one. Although malocclusions are onlysome of the etiological factors in the multifactorial etiology of TMD development, it is important to take them into account and provide asolution for them, ideally an interdisciplinary solution.

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.

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.

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.

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.

Percutaneous coronary interventions and bypass surgery in patients with cardiac allograft vasculopathy: a single-center experience.

INTRODUCTION: Cardiac allograft vasculopathy (CAV) remains a major impediment to long-term survival after heart transplantation (HT). Limited data exist regarding the impact of coronary revascularization in these patients. OBJECTIVE: To evaluate the outcomes of revascularization procedures in patients with CAV compared with patients who did not undergo revascularization. METHODS: Retrospective analysis of 249 patients who underwent HT at our center between June 1998 and December 2009 and who were examined by coronary angiography after HT. We included patients with moderate or severe CAV according to the International Society for Heart and Lung Transplantation (ISHLT) nomenclature to evaluated outcomes after revascularization or diagnostic angiography. Major adverse cardiovascular events (MACE) comprised death, acute coronary syndrome, coronary revascularization, admission because of heart failure not due to an acute rejection episode, and cardiac retransplantation. RESULTS: Moderate or severe CAV was detected in 43 patients. Twelve (27.9%) underwent coronary revascularization: eight percutaneous interventions and four bypass surgeries. Indications for revascularization were symptomatic ischemia or noninvasive evidence of ischemia (n = 6, 14.0%) or high-risk asymptomatic CAV (n = 6; 14.0%), namely, lesions located in the left main or proximal anterior descending arteries or multivessel disease with left ventricular dysfunction. The remaining 31 (72.1%), who did not undergo revascularization showed an absence of ischemia during exercise echocardiography (n = 11; 25.6%) or diffuse disease not amenable to revascularization (n = 20; 46.5%). During a mean follow-up of 3.0 ± 2.4 years, MACE occurred in three revascularized patients (25.0%), in one with absence of stress-induced ischemia (9.1%) and in 13 with nonrevascularizable disease (65%; P = .012). CONCLUSIONS: Revascularization procedures were effective in HT patients with evidence of ischemia or high-risk CAV. Patients with absence of stress-induced ischemia have a good prognosis without revascularization. On the other hand, diffuse nonrevascularizable CAV is associated with a poor prognosis.

Prevalence of donor-transmitted coronary artery disease and its influence on heart transplant outcomes.

BACKGROUND: It is uncertain whether donor-transmitted coronary artery disease (DTCAD) affects heart transplant (HT) recipients. METHODS: This retrospective analysis includes records of all patients who underwent a HT at our center over an 8-year period, who survived for at least 1 month, and who were examined by coronary angiography within 2 months post-HT. We distinguished angiographically from keep ultrasonography (IVUS) detected DTCAD. Major adverse cardiovascular events (MACE) comprised death, myocardial infarction, unstable angina, coronary revascularization, and admission because of heart failure not due to an acute rejection episode. RESULTS: Among the 171 patients of mean age 53±13 years and including 83% men, 65 (38%) were evaluated by IVUS. Donors were aged 40±14 years (range=14-73). Angiographic DTCAD affected seven patients (4.1%), and IVUS-detected DTCAD, 35 (53.8% of those examined by IVUS). DTCAD donors were older than non-DTCAD donors, by an average of 13 years (P=.001) for angiographic DTCAD and 18 years (P<.0001) for IVUS-detected DTCAD. Two patients underwent percutaneous revascularization upon detection of angiographic DTCAD. The angiographic- and IVUS-detected DTCAD groups did not differ significantly from the corresponding non-DTCAD groups as regards MACE incidence during 54±41 and 38±20 months follow-up, respectively. Cox regression analysis with adjustment for relevant confounders confirmed that IVUS-detected DTCAD was not a predictor of MACE (hazard ratio 1.2, 95% confidence interval 0.2-8.1). CONCLUSIONS: Among HT patients surviving≥1 month, angiographic- and IVUS-detected DTCAD showed prevalences of <10% and >50%, respectively. Neither detection method was associated with a greater long-term incidence of MACE.

[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.