A Rare Case of Subcutaneous Amyloidoma Associated with Localized Lymphoplasmacytic Lymphoma: Diagnostic Challenges and Treatment Considerations.

BACKGROUND AL amyloidomas are solitary, localized, tumor-like deposits of immunoglobulin light-chain-derived amyloid fibrils in the absence of systemic amyloidosis. A rare entity, they have been described in various anatomical sites, typically in spatial association with a sparse lymphoplasmacytic infiltrate, ultimately corresponding to a clonal, malignant, lymphomatous disorder accounting for the amyloidogenic activity. Most frequently, the amyloidoma-associated hematological disorder corresponds to either a solitary plasmacytoma or an extranodal marginal zone lymphoma of MALT. Much rarer is the association with lymphoplasmacytic lymphoma, which by itself is usually a bone marrow-bound disorder with systemic burden. The almost anecdotic combination of an amyloidoma and a localized lymphoplasmacytic lymphoma deserves attention, as it entails a thorough diagnostic workup to exclude systemic involvement and a proportionate therapeutic approach to avoid overtreatment. A review of the literature provides an insight on pathogenesis and prognosis, and can assist both pathologists and clinicians in establishing optimal patient management strategies. CASE REPORT We herein report the incidental finding of a subcutaneous amyloidoma caused by a spatially related, similarly localized lymphoplasmacytic lymphoma diagnosed in a 54-year-old female patient with no other disease localizations and a complete remission following 2 subsequent surgical excisions. CONCLUSIONS Whatever the specific combination of an amyloidoma and the related hematological neoplasm, a multidisciplinary collaboration and a comprehensive clinical-pathological staging are warranted to exclude systemic involvement and identify patients with localized diseases who would benefit from local active treatment and close follow-up.

Novel Therapies for Follicular Lymphoma and Other Indolent Non-Hodgkin Lymphomas.

OPINION STATEMENT: When selecting therapy for patients with indolent non-Hodgkin lymphoma (iNHL) including follicular (FL), marginal zone (MZL), small lymphocytic (SLL), and lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM), there are several factors to consider. With a median age around 70 at diagnosis, many patients have accumulated comorbid conditions that may limit treatment options. Although incurable for most, iNHL is a chronic disease with a median overall survival measured in years to decades. This long natural history changes the risk-to-benefit balance with a lower acceptance of toxicity early in the treatment course compared to that of aggressive lymphomas. Despite a recent rapid increase in available therapies, overall progress in iNHL has been slow for several reasons. Initial trials grouped iNHLs together making it challenging to appreciate the differential activity among subtypes. We have not been able to develop prognostic models that maintain validity in the era of chemotherapy-free options. Predictive markers have been elusive and without identified molecular signatures, it is challenging to select and sequence therapy. With these clinical factors in mind, in addition to the heterogeneity among and within iNHLs, I do not have a standard treatment algorithm and feel each patient should have an individualized treatment approach. This review focuses on recent updates and controversies in the management of iNHL with a focus on FL and MZL.

Pleural fluid MYD88 L265P mutation supporting diagnosis and decision to treat extramedullary Waldenstrom's macroglobulinemia: a case report.

BACKGROUND: Our case of a patient with untreated lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia with extramedullary pleural effusion is the first documented case of pleural fluid MYD88 L265P mutation status in a community hospital setting. Our patient was intolerant to 420 mg ibrutinib, but still achieved a lasting complete remission, as defined by National Comprehensive Cancer Network guidelines, with a dose reduction to 240 mg of ibrutinib. CASE PRESENTATION: A 72-year-old Caucasian (white) man diagnosed with monoclonal immunoglobin M kappa lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia monitored without treatment for 2 years, presented with dyspnea and a left pleural effusion. At presentation, computed tomography scans of his chest, abdomen, and pelvis showed layering left pleural effusion and para-aortic lymphadenopathy. Pleural fluid cytology demonstrated B-cell lymphoma of the lymphoplasmacytic subtype, with monoclonal kappa B-cell population on flow and a positive MYD88 L265P mutation. The pleural effusion recurred post-thoracentesis and he achieved a lasting complete remission as defined by National Comprehensive Cancer Network guideline with 240 mg ibrutinib. CONCLUSIONS: Our discussion details a comprehensive literature review of extramedullary pulmonary involvement in Waldenstrom's macroglobulinemia. Establishing a malignant etiology for pleural effusion in Waldenstrom's macroglobulinemia can be challenging, as standard techniques may be insensitive. Allele-specific polymerase chain reaction for detecting MYD88 L265P mutations is more sensitive for confirming lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia in pleural fluid. Extramedullary pulmonary involvement usually presents post-diagnosis of Waldenstrom's macroglobulinemia and responds well to Waldenstrom's macroglobulinemia-directed treatment regimens. Allele-specific polymerase chain reaction is a sensitive assay for detecting MYD88 L265P mutations in pleural fluid to support the diagnosis of malignant pleural effusion in the setting of Waldenstrom's macroglobulinemia and helps guide the treatment decision to use ibrutinib. Although intolerant of ibrutinib 420 mg, our patient achieved complete and sustained remission of pleural effusion with a dose of 240 mg with progression free survival of over 30 months.

Ibrutinib for the treatment of Bing-Neel syndrome, a complication of Waldenström macroglobulinemia: Patient case report.

Bing-Neel syndrome is a rare complication of Waldenström macroglobulinemia, characterized by infiltration of lymphoplasmacytic cells to the central nervous system. Multiple treatment modalities exist including purine analogs, bendamustine, high-dose methotrexate, or high-dose cytarabine. Of interest, ibrutinib, a Bruton tyrosine kinase inhibitor has also displayed efficacy in Bing-Neel syndrome. Current literature is limited for the treatment of Bing-Neel syndrome considering its rarity, and while ibrutinib is indicated for the treatment of Waldenström macroglobulinemia, it is utilized off-label for treatment of Bing-Neel syndrome. Additionally, debate exists regarding the recommended dosing strategy for ibrutinib for this indication with disease remission demonstrated at 560 mg and 420 mg. We present a case report that provides additional evidence for this debate with a patient who received 560 mg of ibrutinib initially and maintained disease control despite a dose reduction to 420 mg for tolerability. Ultimately, more data are needed to develop standardized Bing-Neel syndrome treatment strategies with specific consideration to the use of ibrutinib in this condition.

Eficacia y seguridad del uso de ibrutinib en el tratamiento de pacientes con macroglobulinemia de waldenström que han recibido por lo menos tres líneas de tratamiento previo / Efficacy and safety of the use of ibrutinib in the treatment of patients with waldenström macroglobulinemia who have received at least three lines of previous treatment

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de ibrutinib en el tratamiento de macroglobulinemia de Waldenström/linfoma linfoplasmocitoide. La macroglobulinemia de Waldenström (MW) es un desorden de los linfocitos B maduros asociada al linfoma linfoplasmocitico (LLP), y caracterizada por presencia de gamopatía monoclonal de inmunoglobulina M (IgM) de cualquier grado de infiltración de la médula ósea. La MW es una enfermedad rara, definida como aquella que se presenta en no más de 5 en 10,000 personas. En EsSalud, los expertos hematólogos del Hospital Nacional Edgardo Rebagliati Martins manifiestan que, en dicho hospital, se observan aproximadamente dos casos nuevos al año. En la actualidad, EsSalud cuenta con rituximab, dexametasona, ciclofosfamida, talidomida, vincristina, doxorubicina, fludarabina y prednisona para el tratamiento de MW, los cuales son utilizados mayormente en las siguientes combinaciones: rituximab, dexametasona y ciclofosfamida (DRC); talidomida, dexametasona y ciclofosfamida (CTD); y rituximab, ciclofosfamida, vincristina, doxorubicina y prednisona (R-CHOP). A pesar de las altas tasas de respuesta con dichas terapias, existe una proporción de pacientes cuya enfermedad progresa a pesar del tratamiento mencionado. En ellos se requieren otras alternativas. TECNOLOGIA SANITARIA DE INTERÉS: Las características y mecanismo de acción de ibrutinib se detallan en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N°001-SDEPFYOTS-ETS-IETSI-2017 ("IETSI" 2017) . Brevemente, ibrutinib es un inhibidor covalente de tirosina quinasa de Bruton (BTK, por sus siglas en ingles), la cual forma parte de la cascada de señalización que surge de los receptores en las células B. La activación de dicha cascada de señalización juega un rol crítico en la supervivencia y proliferación de las células B. Dado que la MW es un tipo de neoplasia de células B, la inhibición de BTK, y por lo tanto de la cascada de señalización que lleva a la proliferación de dichas células, es un blanco terapéutico para esta condición. RESULTADOS: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de ibrutinib en el tratamiento de macroglobulinemia de Waldenström/linfoma linfoplasmocitico en las bases de datos de PubMed, TRIPDATABASE y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como The National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Instituto de Evaluación de Efectividad Clínica y Sanitaria (IECS), Instituto de Evaluación de Tecnología en Salud (IETS); y especializados en hematología como American Society of Hematology (ASH), International Society of Hematology (ISH), Europan Hematology Association (EHA),European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO). RESULTADOS: se llevó a cabo una búsqueda de evidencia científica relacionada al uso de ibrutinib en el tratamiento de macroglobulinemia de Waldenström. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). A la fecha (setiembre 2017) no se han publicado resultados de ensayos clínicos aleatorizados y controlados de fase III que evalúen la eficacia y seguridad de ibrutinib en el tratamiento de pacientes con MW que han fallado a tres líneas de tratamiento, por lo que se toma la evidencia indirecta disponible a la fecha, proveniente de dos sub-estudios de ensayos clínicos en pacientes con MW previamente tratados, así como las recomendaciones de dos guías de práctica clínica (GPC) internacionales y una evaluación de tecnología sanitaria (ETS) canadiense. Las GPC identificadas se encuentran actualizadas y presentan recomendaciones homogéneas con respecto al uso de ibrutinib. Así, se tiene que tanto la GPC de National Comprehensive Cancer Network (NCCN) como la del Eighth International Workshop on Waldenström's macroglobulinemia (IWWM8) recomiendan a ibrutinib como una de las alternativas en pacientes con MW que han recibido tratamiento previo. Sin embargo, en ambos casos, la evidencia que respalda las recomendaciones es de bajo nivel. En cuanto a la ETS identificada, el comité evaluador de Canadian Agency for Drugs and Technologies in Health (CADTH) consideró que ibrutinib no es costo-efectivo dentro del sistema de salud canadiense en pacientes con MW previamente tratados, por lo que su uso podría tener un impacto presupuestario substancial en su servicio de salud. La decisión se basa en que existe aún incertidumbre respecto al beneficio clínico del fármaco sobre variables de relevancia en la toma de decisiones como la sobrevida global, la sobrevida libre de progresión y la calidad de vida, en comparación con otras alternativas. Se identificaron dos ensayos clínicos que responden indirectamente a la pregunta PICO del presente dictamen. Uno de ellos un ensayo de fase II no controlado, el otro un ensayo clínico aleatorizado (ECA) de fase III sobre el cual se reporta únicamente un sub-estudio del análisis de un solo brazo. Así, se tiene que los estudios reportan alta sobrevida global (SG) y sobrevida libre de progresión en la población de pacientes con MW previamente tratados, aunque una alta SG es esperable en esta condición ya que es indolente, lo cual por lo general implica que esta enfermedad es lentamente progresiva. Adicionalmente, estos resultados no permiten concluir con respecto a un beneficio neto de ibrutinib ya que la ausencia de grupo control no permite atribuir la sobrevida observada al uso del producto farmacéutico. En relación al control de la anemia, se observa un aumento en la hemoglobina, en comparación con los valores basales, lo cual tampoco puede ser atribuido al uso de ibrutinib. En cuanto a las variables de seguridad, se observa una alta frecuencia de neutropenia, trombocitopenia e infecciones. CONCLUSIÓN: El balance riesgo beneficio del uso de ibrutinib en MW es aún incierto ya que la evidencia disponible a la fecha no permite concluir con respecto a un beneficio neto de ibrutinib, y se observan altas frecuencias de eventos adversos. El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) no aprueba el uso ibrutinib en el tratamiento de pacientes con macroglobulinemia de Waldenström que han recibido tres líneas de tratamiento previo.

Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells.

The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics. Here we provide a comprehensive preclinical report on the anti-WM activity of VLX1570, a novel small-molecule inhibitor of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5). Both DUBs reside in the 19 S proteasome cap and their inhibition by VLX1570 results in rapid and tumor-specific apoptosis in bortezomib- or ibrutinib-resistant WM cells. Notably, treatment of WM cells with VLX1570 downregulated BCR-associated elements BTK, MYD88, NFATC, NF-κB and CXCR4, the latter whose dysregulated function is linked to ibrutinib resistance. VLX1570 administered to WM-xenografted mice resulted in decreased tumor burden and prolonged survival (P=0.0008) compared with vehicle-treated mice. Overall, our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant WM and carries a high potential for clinical translation.

[Changes in the prognosis and treatment of Waldenström macroglobulinemia. Literature overview and own experience]. / Zmeny v prognóze a v lécbe Waldenströmovy makroglobulinemie: prehled literatury a vlastní zkusenosti.

Waldenström macroglobulinemia is defined by the presence of monoclonal immunoglobulin IgM type (M-IgM) and evidence of lymphoplasmacytic bone marrow infiltration. The disease has an indolent course, the treatment is only initiated when the disease has begun to damage its carrier. The following symptoms are regarded as proven indications for initiating therapy: B symptoms, symptomatic lymphadenopathy, splenomegaly, anemia with hemoglobin below 100 g / l or thrombocytopenia < 100 × 10(9)/l, caused by lymphoplasmacytic bone marrow infiltration. Frequent indications for initiating treatment include clinical evidence of hyperviscosity or cryoglobulinemia. M-IgM tends to have a character of autoantibody reaching up to 50 %, which may harm the organism, and therefore any proven damage to the organism by an autoimmune activity of M-IgM is also an indication for treatment. The text includes an overview of rare and very rare types of damage to the organism by M-IgM autoimmune activity. A combination of rituximab, cyclophosphamide and dexamethasone (RCD) is recommended for the initial treatment, possibly extended to R-CHOP regimen (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In our cohort of 43 patients the therapy involving a combination of R-CHOP achieved 3 (8.1 %) complete remissions and 31 (83.8 %) partial remissions. The remission in 75 % of the patients lasted more than 3 years. In case of recurrence after > 2 years, the same therapy can be used, in case of a relapse within a shorter period of time different treatment schedules are recommended. High-dose chemotherapy with an autologous transplant of stem cells obtained from peripheral blood is only recommended after the first recurrence for people under 65 years of age without contraindications. The text analyses the benefits of the new drugs for the treatment of Waldenström macroglobulinemia (bendamustine, thalidomide, lenalidomide, ibrutinib and high-dose chemotherapy).

Ibrutinib for the treatment of Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a B-cell non-Hodgkin lymphoma (NHL) characterized by IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Until recently, there was no drug specifically approved for WM by the US FDA, leading to wide variations in therapeutic strategies across the globe. Ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, is the first drug approved specifically for WM by the FDA after a clinical trial showed impressive response in previously treated WM. Ibrutinib is a non-stem cell toxic and non-neurotoxic option and suitable for long-term oral maintenance therapy, with the potential of improving survival in WM. With identification of novel genetic mutations impacting response to ibrutinib, it would be possible to individualize therapy based on MYD88 and CXCR4 genotypes. However, long-term safety and efficacy data are required, and cost-effectiveness needs to be addressed before ibrutinib can gain widespread acceptance for front-line therapy of WM.

Ibrutinib in previously treated Waldenström's macroglobulinemia.

BACKGROUND: MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib. METHODS: We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects. RESULTS: After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%). CONCLUSIONS: Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.).

Bendamustine and rituximab combination is safe and effective as salvage regimen in Waldenström macroglobulinemia.

According to the European Society for Medical Oncology and National Comprehensive Cancer Network guidelines on Waldenström macroglobulinemia, bendamustine (B) may be considered a suitable therapeutic option. To address the role of B in combination with rituximab (BR), we analyzed the outcome of 71 patients with relapsed/refractory disease, median age 72 years, treated with R 375 mg/m(2) day 1 and B days 1 and 2 (dosage ranging from 50 to 90 mg/m(2)). Patients had previously received a median number of 2 lines of treatment (range 1-5). Overall and major response rates were 80.2% and 74.6%. Major toxicity was grade 3/4 neutropenia occurring in 13% of courses. There was no significant association between baseline features or patients' characteristics and response achievement. Median progression-free survival was not reached after a median follow-up of 19 months (range 3-54). None of the patients developed aggressive lymphoma or secondary myelodysplastic syndrome/acute myeloid leukemia. BR was found to be an active and well-tolerated salvage regimen leading to rapid disease control.

Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia.

We have previously shown clinical activity of a mammalian target of rapamycin (mTOR) complex 1 inhibitor in Waldenstrom macroglobulinemia (WM). However, 50% of patients did not respond to therapy. We therefore examined mechanisms of activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR in WM, and mechanisms of overcoming resistance to therapy. We first demonstrated that primary WM cells show constitutive activation of the PI3K/Akt pathway, supported by decreased expression of phosphate and tensin homolog tumor suppressor gene (PTEN) at the gene and protein levels, together with constitutive activation of Akt and mTOR. We illustrated that dual targeting of the PI3K/mTOR pathway by the novel inhibitor NVP-BEZ235 showed higher cytotoxicity on WM cells compared with inhibition of the PI3K or mTOR pathways alone. In addition, NVP-BEZ235 inhibited both rictor and raptor, thus abrogating the rictor-induced Akt phosphorylation. NVP-BEZ235 also induced significant cytotoxicity in WM cells in a caspase-dependent and -independent manner, through targeting the Forkhead box transcription factors. In addition, NVP-BEZ235 targeted WM cells in the context of bone marrow microenvironment, leading to significant inhibition of migration, adhesion in vitro, and homing in vivo. These studies therefore show that dual targeting of the PI3K/mTOR pathway is a better modality of targeted therapy for tumors that harbor activation of the PI3K/mTOR signaling cascade, such as WM.

Src tyrosine kinase regulates adhesion and chemotaxis in Waldenstrom macroglobulinemia.

PURPOSE: Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma characterized by widespread involvement of the bone marrow. Despite different options of therapy, Waldenstrom macroglobulinemia is still incurable. Src tyrosine kinase has been shown to play a central role in the regulation of a variety of biological processes, such as cell proliferation, migration, adhesion, and survival in solid tumors. We sought to determine whether the protein tyrosine kinase Src regulates adhesion, migration, and survival in Waldenstrom macroglobulinemia. EXPERIMENTAL DESIGN: We tested the expression of Src tyrosine kinase in Waldenstrom macroglobulinemia and normal cells, and the effect of the specific Src inhibitor AZD0530 on the adhesion, migration, cell cycle, and survival of a Waldenstrom macroglobulinemia cell line and patient samples. Moreover, we tested the effect of AZD0530 on cytoskeletal and cell cycle signaling in Waldenstrom macroglobulinemia. RESULTS: We show that Src is overexpressed in Waldenstrom macroglobulinemia cells compared with control B cells, and that the use of the Src inhibitor AZD0530 led to significant inhibition of adhesion, migration, and cytoskeletal signaling induced by SDF1. Moreover, inhibition of Src activity induced G(1) cell cycle arrest; however, it had minimal effect on survival of Waldenstrom macroglobulinemia cells, and no significant effect on survival of normal cells. CONCLUSIONS: Taken together, these results delineate the role of Src kinase activity in Waldenstrom macroglobulinemia and provide the framework for future clinical trials using Src inhibitors in combination with other drugs to improve the outcome of patients with Waldenstrom macroglobulinemia.

Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenström's macroglobulinemia.

PURPOSE: Resveratrol (3,4',5-tri-hydroxy-trans-stilbene) is an antioxidant constituent of a wide variety of plant species including grapes. It has gained considerable attention because of its anticancer properties, as shown in solid and hematologic malignancies. Whether resveratrol could inhibit proliferation or induce cytotoxicity in Waldenström's macroglobulinemia (WM) was investigated. EXPERIMENTAL DESIGN: We studied resveratrol-induced inhibition of proliferation and induction of cytotoxicity in WM cell lines, WM primary tumor cells, IgM-secreting cells, and peripheral blood mononuclear cells. The mechanisms of action and different signaling pathways involved were studied using Western blot and gene expression profile analysis. Resveratrol activity was also evaluated in the bone marrow microenvironment. We finally investigated whether or not resveratrol could have any synergistic effect if used in combination with other drugs widely used in the treatment of WM. RESULTS: A schematic image illustrating the location and expression of the aurora kinases A, B, and C during mitosis. Resveratrol inhibited proliferation and induced cytotoxicity against WM cells, IgM-secreting cells, as well as primary WM cells, without affecting peripheral blood mononuclear cells; down-regulated Akt, extracellular signal-regulated kinase mitogen-activated protein kinases, and Wnt signaling pathways, as well as Akt activity; induced cell cycle arrest and apoptosis; and triggered c-Jun-NH(2)-terminal-kinase activation, followed by the activation of intrinsic and extrinsic caspase pathways. Lastly, adherence to bone marrow stromal cells did not confer protection to WM cells against resveratrol-induced cytotoxicity. Furthermore, resveratrol showed synergistic cytotoxicity when combined with dexamethasone, fludarabine, and bortezomib. CONCLUSION: Our data show that resveratrol has significant antitumor activity in WM, providing the framework for clinical trials in this disease.

Perniosis en pacientes pediátricos / Perniosis(chilblains) in pediatric patients

La perniosis es una respuesta anormal al frío, que se manifiesta como lesiones violáceas, edematosas y dolorosas que generalmente afectan a zonas acrales del cuerpo. Es más frecuente en otoño e invierno, y en regiones con clima frío y húmedo. Con frecuencia. los pacientes son mujeres jóvenes, aunque este cuadro también se ha descrito en niños. El curso generalmente es autolimitado, y es suficiente empezar un tratamiento sintomático

Chilblains is an abnormal response to cold, that manifests as painful, purplish, edematous lesions, usually affecting acral sites of the body. It is more frequent in fall and winter, and in regions with cold and damp weather. The patients are usually young women, but this condition has algo been described in children. The course is nearly always self-limited, and only symptomatic treatment is necessary

Treatment for Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia is a rare form of indolent lymphoma characterized by the production of a monoclonal immunoglobulin M protein, and complications such as hyperviscosity, cytopenias and peripheral neuropathy. Conventional treatment approaches are based on alkylators or nucleoside analogs, but in the absence of a clearly superior regimen, a broad array of alternative therapies exists. Choices range from biological agents to combination chemotherapy to stem-cell transplantation. A rational approach therefore must be based on careful patient assessment and individualization of therapy.

Activity of a nitroxylated analog of daunorubicin, ruboxyl, in B-lymphoproliferative disorders.

A nitroxylated analog of daunorubicin, ruboxyl (RBX), showed low toxicity but significant lympholytic effect in preclinical evaluations. A series of studies in vitro and in animals demonstrate that RBX is a putative agent in the treatment of many neoplasms. We report the results of a study in mice in which RBX showed selective B-lymphocyte immunosuppression. On the basis of this experience, RBX was administered to 3 patients with multiple myeloma and two patients with Waldenström's disease. The results of this pilot clinical study show that this compound has good activity and low myelotoxicity and cardiotoxicity, but seems to be characterized by a threatening immunosuppressive effect.