Platelet ATP, Thyroid Hormone Receptor on Integrin αvß3 and Cancer Metastasis.

Activated platelets may contribute to the metastatic behavior of tumor cells when the cancer cells and platelets interact. The interaction requires cell and platelet surface integrin. Thyroid hormone as L-thyroxine (T4) is the principal ligand for a hormone receptor on integrin αvß3 on tumor cells and platelets. T4 activates the integrin, promoting platelet aggregation and degranulation (local ATP release) and stimulating tumor cell proliferation. By a variety of molecular mechanisms reviewed here, extracellular ATP promotes tumor cell invasiveness and metastasis and supports a role for T4 as a pro-metastatic factor.

New Interfaces of Thyroid Hormone Actions With Blood Coagulation and Thrombosis.

Substantial clinical evidence indicates hyperthyroidism enhances coagulation and increases the risk of thrombosis. In vitro and clinical evidence implicate multiple mechanisms for this risk. Genomic actions of thyroid hormone as 3,5,3'-triiodo-L-thyronine (T3) via a nuclear thyroid hormone receptor have been implicated, but recent evidence shows that nongenomic mechanisms initiated at the receptor for L-thyroxine (T4) on platelet integrin αvß3 are prothrombotic. The T4-initiated mechanisms involve platelet activation and, in addition, cellular production of cytokines and chemokines such as CX3CL1 with procoagulatory activities. These procoagulant actions of T4 are particulary of note because within cells T4 is not seen to be functional, but to be only a prohormone for T3. Finally, it is also possible that thyroid hormone stimulates platelet-endothelial cell interaction involved in local thrombus generation. In this brief review, we survey mechanisms by which thyroid hormone is involved in coagulation and platelet functions. It is suggested that the threshold should be lowered for considering the possibility that clinically significant clotting may complicate hyperthyroidism. The value of routine measurement of partial thromboplastin time or circulating D-dimer in patients with hyperthyroid or in patients treated with thyrotropin-suppressing dosage of T4 requires clinical testing.

Plasmablastic Lymphoma: Case Report of Prolonged Survival of an Advanced Human Immunodeficiency Patient and Literature Review.

Clinical Practice Points. Plasmablastic lymphoma (PBL) is a rare and highly aggressive variant of diffuse large B cell lymphoma with median survival of advanced stage patients varying between 6 and 15 months in previous reports. We report here a human immunodeficiency virus-infected patient surviving over 12 years following treatment for advanced PBL with EPOCH chemotherapy and intrathecal therapy. This case highlights the potential for improved survival in PBL with intensive chemotherapy. Further, literature review suggests promising prospects utilizing novel targeted therapies to increase the rate of prolonged responses.

Patterns of monoclonal immunoglobulins and serum free light chains are significantly different in black compared to white monoclonal gammopathy of undetermined significance (MGUS) patients.

Monoclonal gammopathy of undetermined significance (MGUS), the precursor to multiple myeloma, is more common in blacks than whites. The serum free light chain (sFLC) assay is an important prognostic test in MGUS, but no study has evaluated sFLC levels and ratios in black MGUS patients. One-hundred and twenty-five black MGUS patients at two urban centers were compared to the white population of the Mayo Clinic. The median age for blacks was 73 years [41-94] and 75% were male. The M-protein isotype in blacks was 81% IgG, 13% IgA, 2% IgM, and 4% biclonal compared to 70%, 12%, 16%, and 2%, respectively, in whites, (P < 0.0005). The median M-protein concentration for blacks was 0.44 gm/dL (trace-2.33) compared to 1.2 gm/dl in whites. An abnormal sFLC ratio was present in 45% of black compared to 33% of white (P = 0.01) patients. Using the Mayo Clinic risk model, black patients had a significantly lower proportion of higher risk MGUS compared to whites: low 43%, low-intermediate 45%, high-intermediate 10%, and high 2% (P = 0.014). Black patients with MGUS have significantly different laboratory findings compared to whites. The biologic basis for these disparities and their effect on prognostic assessment is unknown. Prognostic models based on these biomarkers should be used cautiously in nonwhite populations.

Treatment of splenic marginal zone lymphoma: splenectomy versus rituximab.

Splenic marginal zone lymphoma (SMZL) is an uncommon indolent B-cell lymphoma causing marked splenic enlargement with CD20-rich lymphoma cells infiltrating blood and bone marrow. In the pre-rituximab era, the treatment of choice for patients with symptomatic splenomegaly or threatening cytopenia was splenectomy, since chemotherapy had limited efficacy. Responses to splenectomy occurred in approximately 90% of patients. However, SMZL patients are often elderly and poor surgical risks. Since approval of rituximab, treatment of such patients with the anti-CD20 antibody both alone or in combination with chemotherapy has shown remarkable responses. In retrospective series of rituximab monotherapy totaling 52 patients, including both chemotherapy-naive and -refractory patients, overall responses of 88% to 100% were noted with marked and prompt regression of splenomegaly and improvement of cytopenias. Sustained responses occurred both with and without rituximab maintenance in 60% to 88% of patients at 3 years. Relapsed patients responded to second courses of rituximab monotherapy. Overall survival was comparable to that reported following splenectomy. Rituximab in combination with purine nucleosides may provide further improvement in progression-free survival; however, confirmatory prospective trials are necessary. These results suggest that splenectomy should no longer be considered as initial therapy for SMZL but rather as palliative therapy for patients not responsive to immunotherapy with or without chemotherapy.

Multiple bony amyloidomas as an initial presentation of myeloma.

Amyloidosis complicating multiple myeloma is an uncommon but well-recognized phenomenon. Multiple bone amyloidomas are rare as the initial presenting feature of myeloma. Solitary bone amyloidomas share common features with those of patients who have solitary plasmacytomas and progression to disseminated myeloma is common. We report a case of an elderly man who presented with extensive amyloid deposition in multiple plasmacytoma sites as well as evidence of amyloid in a fat pad aspirate but with none of the usual organ damage associated with systemic amyloidosis. This presentation is similar to a subset of patients said to have macrofocal myeloma. These patients are typically aged < 40 years, have no bone marrow involvement, and have a good prognosis. This report may represent the first description of macrofocal myeloma associated with amyloid deposition in an older individual.

Familial myeloma and monoclonal gammopathy: a report of eight African American families.

Previous descriptions of familial myeloma have been mainly of Caucasian families. We report here eight African American families with familial multiple myeloma and monoclonal gammopathy identified over a 30 year period. Six patients with multiple myeloma (MM) and two with monoclonal gammopathy of unknown significance (MGUS) reported a family history of MM or had family members with MGUS found on screening. A pedigree compiled for each family included a history of other cancers. In the eight families, 21 of 58 first degree relatives had a plasma cell dyscrasia including 12 MM, eight MGUS, and one amyloidosis patient(s). The age of the MM patients ranged from 50 to 78 years (median 61 years). Four families had two members with MM, including one mother-son and three sibling pairs. Two MM families each had two additional first degree relatives with MGUS, with three generations involved in one family. Anticipation was suggested in two families with parent-child pairs with monoclonal gammopathy. The eight pedigrees had 66 members, 21 of whom had a diagnosis of cancer, including non-Hodgkin lymphoma and Hodgkin disease, or a clonal myeloproliferative disorder other than MM. Although the mode of genetic transmission and anticipation cannot be confirmed due to the small sample size, the increased number of MM and MGUS family members suggests underlying genetic susceptibility factors for plasma cell dyscrasias and possibly for other cancers in these families.

Rituximab monotherapy for splenic marginal zone lymphoma.

In this retrospective study, rituximab was found to be effective therapy in 10 of 11 patients with splenic marginal zone lymphoma, inducing prompt reduction in splenomegaly, improvement in blood counts in 9 patients and clearance of a pleural effusion in 1 patient. Median response duration was 21 months (range 4 to 37 months). Two patients who relapsed at 21 and 23 months responded to retreatment. Rituximab should be considered in patients who are poor candidates for splenectomy.

Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP).

Plasma exchange is the standard treatment for thrombotic thrombocytopenic purpura (TTP). For patients refractory to plasma exchange, treatment options are limited and often unsuccessful. The platelet thrombi that form in acquired TTP are believed to result from the presence of procoagulant ultralarge multimers of von Willebrand factor (VWF) in the circulation due to autoantibody inhibition of VWF cleaving protease (ADAMTS-13), the enzyme that normally cleaves the ultralarge multimers. Rituximab, a chimeric monoclonal antibody against CD20, has been recognized as a useful therapy for antibody-mediated autoimmune disease. We therefore treated four patients with recurrent TTP with 2 or 4 weekly doses of rituximab in addition to corticosteroids, vincristine, plasma, or continuing plasma exchange. Three patients responded with prompt improvement in microangiopathic hemolytic anemia and thrombocytopenia, which allowed plasma exchange to be discontinued or avoided and prednisone to be rapidly discontinued. Two of the 3 responders have remained in unmaintained complete remission for 13+ months. The third patient relapsed at 13 months; a second course of rituximab and prednisone resulted in an unmaintained remission for 6+ months. All four patients were tested for ADAMTS-13 activity and its inhibitor at a point in their course when samples were available. Low ADAMTS-13 activity was noted in 3 patients tested at relapse, and the inhibitor activity was detectable in 2 patients. ADAMTS-13 activity increased during remission in one of these 2 patients although the patient had a persistence of the inhibitor. One patient tested only during remission had a normal ADAMTS-13 level. We conclude that rituximab may have a role and deserves further study in the treatment of patients with relapsing TTP.

Rituximab in the treatment of acquired factor VIII inhibitors.

Autoantibodies against factor VIII (FVIII) are rare but can cause life-threatening bleeding requiring costly factor replacement and prolonged immunosuppression. We report 4 consecutively treated patients whose acquired FVIII inhibitors responded rapidly to immunosuppressive regimens that included rituximab, a monoclonal antibody against CD20(+) B cells. Three patients had spontaneously occurring inhibitors. The fourth, a patient with mild hemophilia A, developed both an autoantibody and an alloantibody following recombinant FVIII treatment. Pretreatment FVIII activities ranged from less than 1% to 4% and inhibitor titers from 5 to 60 Bethesda units (BU). One patient with polymyalgia rheumatica who developed the inhibitor while receiving prednisone responded to single agent rituximab. The hemophilia patient had rapid resolution of the autoantibody, whereas the alloantibody persisted for months. Responses continue off treatment from more than 7 to more than 12 months. This report adds to the growing evidence that rituximab has efficacy in immune disorders resulting from autoantibody formation.