Showing papers in "Hematology-oncology Clinics of North America in 2007"

Coagulation 2006: a modern view of hemostasis.

Abstract: The authors propose that hemostasis occurs in a stepwise process, regulated by cellular components in vivo. The effectiveness of hemostasis in vivo depends not only on the procoagulant reactions but also on the fibrinolytic process. Causes of coagulopathic bleeding include consumption of coagulation factors and platelets, excessive fibrinolysis, hypothermia, and acidosis. Generation of the right amount of thrombin during the coagulation process not only may be essential for effective hemostasis but also may set the stage for effective wound healing.

Drug-induced thrombocytopenia.

Abstract: Drug-induced thrombocytopenia (DIT) is a relatively common clinical disorder. It is imperative to provide rapid identification and removal of the offending agent before clinically significant bleeding or, in the case of heparin, thrombosis occurs. DIT can be distinguished from idiopathic thrombocytopenic purpura, a bleeding disorder caused by thrombocytopenia not associated with a systemic disease, based on the history of drug ingestion or injection and laboratory findings. DIT disorders can be a consequence of decreased platelet production (bone marrow suppression) or accelerated platelet destruction (especially immune-mediated destruction).

Emerging Targeted Therapies for Breast Cancer

Abstract: Breast cancer is the most common neoplasia among women in the world. For the last few years there has been an increasing interest in the development of agents against molecular targets considered to be involved in the process of malignant transformation or tumor progression. Experimental data indicate that various intracellular signaling pathways may be activated or overexpressed in patients who have breast cancer. Targeted therapies against these pathways have recently become one of the most active and promising areas of development in oncology.

The Role of the Bone Marrow Microenvironment in the Pathophysiology of Myeloma and Its Significance in the Development of More Effective Therapies

Abstract: Multiple myeloma (MM) is viewed as a prototypic disease state for the study of how neoplastic cells interact with their local bone marrow (BM) microenvironment. This interaction reflects not only the osteotropic clinical behavior of MM and the clinical impact of the lytic bone lesions caused by its tumor cells but also underlines the broadly accepted notion that nonneoplastic cells of the BM can attenuate the activity of cytotoxic chemotherapy and glucocorticoids. This article summarizes the recent progress in characterization, at the molecular and cellular levels, of how the BM milieu interacts with MM cells and modifies their biologic behavior.

Heparin-induced thrombocytopenia.

Abstract: Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug effect that is characterized by platelet activation, hypercoagulability, and a resulting increased risk for thrombosis, both venous and arterial. This disorder is autoimmune-like, because the target antigen is a multimolecular complex of the "self" protein, platelet factor 4, and heparin. HIT usually begins 5 to 10 days after starting heparin, especially when administered intra- or perioperatively, although a rapid onset of thrombocytopenia can occur if heparin is given to a patient with circulating HIT antibodies that resulted from a recent heparin exposure. The clinical diagnosis is supported if heparin-dependent, platelet-activating antibodies are detectable. Treatment includes cessation of heparin and use of an alternative non-heparin anticoagulant, such as danaparoid, lepirudin, or argatroban. Warfarin must be avoided or postponed, as the acute phase of HIT poses a high risk for coumarin necrosis, particularly limb loss due to venous limb gangrene.

The International Harmonization Project for Response Criteria in Lymphoma Clinical Trials

Abstract: Clinical trials are critical to the development of newer and more effective treatments. Standardized response criteria are essential to assess and compare the activity of various therapies within and among studies and to facilitate the evaluation of new treatments by regulatory agencies. The International Harmonization Project developed revised guidelines with the goal of improved comparability among studies, leading to accelerated new agent development resulting in the rapid availability of improved therapies for patients who have lymphoma. Modifications of these recommendations are expected as new information and improved technologies become available.

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

Abstract: A serious disorder with characteristic microvascular thrombosis involving the brain and other organs, thrombotic thrombocytopenic purpura (TTP) typically presents with thrombocytopenia, hemolysis with schistocytes on blood smears, and mental changes or seizures. It may progress rapidly to a fatal end if the patient is not treated immediately with plasma. Recent advances have shown that TTP is caused by deficiency of a circulating, von Willebrand factor cleaving metalloprotease, ADAMTS13. This new knowledge will provide clues to improve the diagnosis and management of this intriguing disease.

Complications of multiple myeloma

Abstract: Multiple myeloma, also known as myeloma or plasma cell myeloma, is a progressive hematologic disease. Complications of multiple myeloma include renal insufficiency, hematologic complications (anemia, bone marrow failure, bleeding disorders), infections, bone complications (pathologic fractures, spinal cord compression, hyercalcemia), and neurologic complications (spinal cord and nerve root compression, intracranial plasmacytomas, leptomeningeal involvement, among others). This article reviews these various complications connected to multiple myeloma, examining their various causes and possible treatment.

Inflammation, proinflammatory mediators and myocardial ischemia-reperfusion Injury.

Abstract: Ischemic myocardium must be reperfused to terminate the ischemic event; otherwise the entire myocardium involved in the area at risk will not survive. However, there is a cost to reperfusion that may offset the intended clinical benefits of minimizing infarct size, postischemic endothelial and microvascular damage, blood flow defects, and contractile dysfunction. There are many contributors to this reperfusion injury. Targeting only one factor in the complex web of reperfusion injury is not effective because the untargeted mechanisms induce injury. An integrated strategy of reducing reperfusion injury in the catheterization laboratory involves controlling both the conditions and the composition of the reperfusate. Mechanical interventions such as gradually restoring blood flow or applying postconditioning may be used independently in or conjunction with various cardioprotective pharmaceuticals in an integrated strategy of reperfusion therapeutics to reduce postischemic injury.

Chemotherapy for metastatic breast cancer.

Abstract: Cytotoxic chemotherapy is a mainstay of treatment for advanced breast cancer. Treatment of metastatic (also called stage IV, advanced, or recurrent) breast cancer is not considered curative. Rather, the goals of treatment with chemotherapy are to prolong survival, alleviate or prevent tumor-related symptoms or complications, and improve quality of life. While the purpose of chemotherapy is to prevent or alleviate symptoms, chemotherapy paradoxically carries considerable toxicities that cause substantial symptoms in patients, notoriously including fatigue, nausea, vomiting, diarrhea, hair loss, mucositis, neutropenia, and neuropathy. Balancing the benefits and the side effects of chemotherapy is further complicated by the natural history of advanced breast cancer, which can be quite prolonged and typically involves multiple lines of chemotherapy, especially in patients whose tumors respond to treatment.

Imaging of neuroendocrine tumors.

Abstract: Neuroendocrine tumors may arise from a wide range of organs and may occur in various locations in the body. They include carcinoid tumors, paragangliomas (pheochromocytomas), medullary thyroid carcinomas, and islet cell tumors of the pancreas. In this article the authors focus on the more common tumors with origins primarily in the abdomen, namely carcinoid, paraganglioma, and pancreatic islet cell tumors. Imaging assists in delineating the sites and extent of disease, in preoperative planning for resection of the primary tumor and metastatic disease, and in follow-up. Discussion is restricted to the main imaging modalities used in these tumors: cross-sectional imaging, namely CT and MRI, and nuclear medicine studies.

Immune Thrombocytopenic Purpura

Abstract: Immune thrombocytopenic purpura (ITP) is an autoantibody-mediated thrombocytopenic disorder in which accelerated destruction of platelets occurs; platelet production may also be impaired by these antibodies. ITP is characterized by mucocutaneous bleeding. Rarely, more severe hemorrhages, such as intracranial hemorrhage, may occur. Traditional therapies, such as steroids, immunoglobulin therapy, and splenectomy, generally reduce peripheral destruction of platelets. More recently, with a better understanding of the immunopathologic mechanisms underlying thrombocytopenia, several new treatments have been developed, including thrombopoietic agents, specific inhibitors of Fcγ receptor (FcγR) signaling, and B-cell depletion therapies. This article outlines current understanding of the epidemiology, etiology, diagnosis, and treatment of ITP. The focus is on recent pathophysiologic insights and areas of potential controversy in which studies are ongoing.

Pheochromocytoma: Advances in Genetics, Diagnosis, Localization, and Treatment

Abstract: Pheochromocytomas are rare, catecholamine-secreting tumors arising most frequently in the chromaffin cells of the adrenal glands. Recent studies have suggested that genetic mutations are more frequent than previously appreciated in patients with these lesions. Advances continue to be made not only in the genetic evaluation of these patients but also in the biochemical confirmation and tumor localization. Surgery remains the definitive treatment, and advances in laparoscopic techniques as well as cortical-sparing procedures have reduced the morbidity associated with tumor resection.

Clinical Presentation and Management of Carcinoid Tumors

Abstract: The generally indolent nature of neuroendocrine tumors is an advantage in the management of patients who have localized disease, and surgery alone is often curative. This same property presents a challenge in the treatment of patients who have metastatic disease, in whom standard cytotoxic chemotherapy has a limited benefit. In such patients, the use of somatostatin analogs, interferon, and the treatment of hepatic metastases may provide effective palliation. The highly vascular nature of carcinoid tumors has led to the investigation of antiangiogenic agents in this setting. Preliminary reports of activity associated with agents targeting the vascular endothelial growth factor pathway suggest that such strategies may play a role in the future treatment of patients who have this disease.

Medullary Thyroid Carcinoma

Abstract: Medullary thyroid carcinoma is a neuroendocrine tumor derived from the C cells of the thyroid gland and accounts for approximately 5% of all thyroid carcinomas. Approximately 30% of the cases are associated with an autosomal dominant syndrome called multiple endocrine neoplasia type 2, and the identification of these individuals is important because affected family members may benefit from an early diagnosis. The treatment of this disease is predominantly surgical, and the impact of radiotherapy and chemotherapy is limited. The identification of the associated molecular events has lead to the development of specific molecular targeted agents that may change the way this disease is treated in the near future.

Platelet hyperreactivity: predictive and intrinsic properties.

Abstract: Platelet thrombi are central to the development of most vascular ischemic events. There is marked interindividual variation in platelet responsiveness, with some subjects displaying platelet hyperreactivity. An increasing number of reports indicate that there are laboratory measures of platelet function that predict clinical thrombotic events. Some, but not all, measures of platelet function are reproducible. Platelet hyperreactivity can be assessed with multiple stimuli in multiple assays and is more likely to be present in women and in subjects who have elevated fibrinogen levels.

Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

Abstract: In 1978, the term "monoclonal gammopathy of undetermined significance" (MGUS) was introduced. MGUS is defined as a serum monoclonal (M) protein less than 3.0 g/dL; less than 10% plasma cells in the bone marrow, if done; little or no M protein in the urine; and absence of lytic bone lesions, anemia, hypercalcemia or renal insufficiency. This article discusses the recognition, prevalence, natural history, and progression of MGUS. Management of the disease is discussed along with its association with other disorders. Information on smoldering multiple myeloma is included.

Transfusion algorithms and how they apply to blood conservation: the high-risk cardiac surgical patient.

Abstract: Considerable blood product support is administered to the cardiac surgery population. Due to the multifactorial etiology of bleeding in the cardiac bypass patient, blood products frequently and empirically are infused to correct bleeding, with varying success. Several studies have demonstrated the benefit of algorithm-guided transfusion in reducing blood loss, transfusion exposure, or rate of surgical re-exploration for bleeding. Some transfusion algorithms also incorporate laboratory-based decision points in their guidelines. Despite published success with standardized transfusion practices, generalized change in blood use has not been realized, and it is evident that current laboratory-guided hemostasis measures are inadequate to define and address the bleeding etiology in these patients.

Prognostic factors and staging in multiple myeloma.

Abstract: The field of multiple myeloma prognostication is replete with studies that have shown the value of independent predictors in determining clinical outcome. It is clear that host factors and factors intrinsic to the cells are the ultimate determinants of prognosis. In the immediate period after diagnosis, those factors related to the host are likely to be more relevant, whereas with passing time factors intrinsic to the cells predominate. At a minimum, we recommend that a comprehensive molecular cytogenetic assessment be performed at diagnosis, together with conventional evaluation, including β 2 -microglobulin and albumin. In addition, information on proliferative activity of plasma cells may be of value. The introduction of novel methods of prognostication should be strongly considered in all clinical trials.

Pathophysiology of Multiple Myeloma Bone Disease

Abstract: Multiple myeloma is a plasma cell malignancy characterized by the frequent development of osteolytic bone lesions. The multiple myeloma–induced bone destruction is a result of the increased activity of osteoclasts that occurs adjacent to multiple myeloma cells. This activity is accompanied by suppressed osteoblast differentiation and activity, resulting in severely impaired bone formation and development of devastating osteolytic lesions. Recently the biologic mechanism involved in the imbalance between osteoclast activation and osteoblast inhibition induced by multiple myeloma cells has begun to be clarified. In this article, the pathophysiology underlying the imbalanced bone remodeling and potential new strategies for the treatment of bone disease in multiple myeloma are reviewed.

Adrenal cortical carcinoma--review of current knowledge and treatment practices.

Abstract: Adrenal cortical carcinoma is a rare endocrine malignancy with a poor long-term prognosis. Accurate diagnosis and preoperative evaluation of the patient presenting with an adrenal mass maximize the opportunity for optimal treatment planning. Surgery still offers the best chance for cure. Despite curability with complete surgical resection, the rate of recurrence is unacceptably high. In metastatic or recurrent disease, systemic treatment options are limited to chemotherapy with or without mitotane. Therapeutic options are often outdated and associated with significant toxicities. A multidisciplinary approach has the best chance for offering optimized management of this lethal disease. Improved understanding of the molecular pathogenesis of this rare malignancy will lead to advancement in the available therapies that may improve this outcome.

New aspects in descriptive, etiologic, and molecular epidemiology of Hodgkin's lymphoma.

Abstract: Epstein-Barr virus (EBV) has remained the main candidate suggested as the infection causing Hodgkin's lymphoma for several years. However, EBV genome has been found only within the tumor in about 20%-40% of Hodgkin's lymphoma cases with a prior diagnosis of infectious mononucleosis. Recently, autoimmune and related conditions have drawn attention to a potential role for immune-related and inflammatory conditions in the etiology and pathogenesis of the malignancy. Evidence from multiple affected families from case series, a twin study, a case-control study, and population-based registry studies implicate a role for genetic factors. Simultaneously, data from Eastern Asia and among Chinese immigrants in North America indicate increasing incidence trends for Hodgkin's lymphoma being associated with westernization. These results emphasize an interaction between environmental and genetic risk factors in Hodgkin's lymphoma.

Heparin-induced Thrombocytopenia, a Prothrombotic Disease

Abstract: Heparin-induced thrombocytopenia (HIT) is a serious, yet treatable prothrombotic disease that develops in approximately 0.5% to 5% of heparin-treated patients and dramatically increases their risk of thrombosis (odds ratio, 37). The antibodies that mediate HIT (ie, heparin-platelet factor 4 antibodies) occur more frequently than the overt disease itself, and, even in the absence of thrombocytopenia, are associated with increased thrombotic morbidity and mortality. HIT should be suspected whenever the platelet count drops more than 50% from baseline (or to 9 /L) beginning 5 to 14 days after starting heparin (or sooner if there was prior heparin exposure) or new thrombosis occurs during, or soon after heparin treatment, with other causes excluded. When HIT is strongly suspected, with or without complicating thrombosis, heparins should be discontinued, and a fast-acting, nonheparin alternative anticoagulant such as argatroban should be initiated immediately. With prompt recognition, diagnosis, and treatment of HIT, the clinical outcomes and health economic burdens of this prothrombotic disease are improved significantly.

Molecular Pathogenesis of Multiple Myeloma

Abstract: Several genetic mechanisms underlying the pathogenesis of multiple myeloma have been elucidated in the past decade. In particular, the presence of two distinct karyotypic patterns, that identify two patient groups and drive different pathogenetic and prognostic paths in the development of myeloma, have been identified, and the role of reciprocal chromosomal translocations and cyclin dysregulation have been identified. Despite this progress, several questions of critical importance remain to be addressed for the understanding of the pathogenesis of multiple myeloma. For example, little is known about the role of the primary events, including cyclin D overexpression and multiple myeloma set domain activity in the early pathogenesis of the disease. The additional lesions that promote the evolution of monoclonal gammopathy of undetermined significance to multiple myeloma (MM) and, within MM, the progression toward a more aggressive and proliferative disease is only starting to emerge. The heterotypic relationship between the stroma and the MM plasma cells also has not been fully explored. The understanding of the biology of MM cancer stem cells and of the pathways driving their maintenance, proliferation, and differentiation is still in its infancy. Recent and ongoing high-resolution genomic studies are leading the way toward a more refined and conclusive understanding of this disease.

Transfusion risks and transfusion-related pro-inflammatory responses.

Abstract: Despite improvements in blood screening and administration techniques, serious adverse events related to transfusion continue to occur, albeit at a much lower incidence. In addition to the development and implementation of new screening and blood purification/modification techniques and implementation of an optimal blood management program, the incidence and consequences of transfusion reactions can be reduced by a basic understanding of transfusion-related complications. Although acute hemolytic transfusion reactions, transfusion-associated anaphylaxis and sepsis, and transfusion-associated acute lung injury occur infrequently, diligence in administration of blood and monitoring for development of respective signs/symptoms can minimize the severity of these potentially life-threatening complications. In addition, emerging blood-banking techniques such as psoralen-UV inactivation of pathogens and use of patient identification systems may attenuate the incidence of adverse events related to transfusion. With respect to optimizing blood management by means of an effective blood management program involving pharmacologic and nonpharmacologic strategies, the ability to reduce use of blood products and to decrease operative time or re-exploration rates has important implications for disease prevention, blood inventory and costs, and overall health care costs.

The balance of thrombosis and hemorrhage in surgery.

Abstract: Postoperative hemorrhage and thrombosis is a significant problem during the perioperative period. Understanding the complex and dynamic interplay of factors, proteins, and enzymes during coagulation is imperative to maintain balance between hemostasis and thrombosis. To improve patient outcome, each patient should be risk stratified for bleeding or thrombosis during the preoperative examination. Additional research focused on improvement in screening tools, monitoring, and therapeutic regimens for surgical patients with a coagulopathy are warranted.

Acquired Platelet Dysfunction

Abstract: Acquired platelet dysfunction is encountered frequently in clinical practice. The usual clinical presentation is that of mucosal bleeding, epistaxis, or superficial epidermal bleeds. Often, the dysfunctional platelets are related to a medication or a systemic disorder. Normally, when platelets are exposed to damaged endothelium, they adhere to the exposed basement membrane collagen and change their shape from smooth disks to spheres with pseudopodia. Then, they secrete the contents of their granules, a process referred to as the release reaction. Additional platelets form aggregates on those platelets that have adhered to the vessel wall. As a result, the primary hemostatic plug is formed, and bleeding is arrested. This article reviews the various forms of acquired platelet dysfunction that result in decreased platelet aggregation, adhesion, or secretion.

Protease activated receptors: clinical relevance to hemostasis and inflammation.

Abstract: The protease-activated receptors (PARs) are a unique family of vascular receptors that confer on cells an ability to sense, and respond to, local changes in the proteolytic environment. They are activated by serine proteases of the blood coagulation cascade, notably thrombin, and are linked to thrombotic and inflammatory effector pathways. In surgery with cardiopulmonary bypass (CPB), thrombin is generated in large quantities in the extracorporeal circuit and can exert systemic effects by way of platelet and endothelial PAR1. Aprotinin (Trasylol), a serine protease inhibitor used in cardiac surgery, preserves platelet function, and attenuates the inflammatory response by protecting the PAR 1 receptor on platelets and endothelium.

Platelets as Mediators of Inflammation

Abstract: An expanding body of evidence continues to build on the central role of inflammation in the progression and clinical manifestations of atherosclerosis. Platelets, long thought to play only a reactionary role at the time of endothelial disruption, are now recognized as important mediators of the inflammatory process. Platelet activation, which is modulated by both inflammatory and hemostatic factors, can lead to the release of hundreds of proteins—many with known proinflammatory functions. Although compelling evidence is lacking that antiplatelet therapies directly lower markers of inflammation, there are intriguing, although preliminary, data suggesting that markers of inflammation predict the clinical benefit of antiplatelet therapies.

Molecular targeted therapy for neuroendocrine tumors.

Abstract: Although endocrine tumors are often slow growing, most can be life threatening and are considered resistant to conventional cytotoxic chemotherapy. The recent emergence of molecularly targeted therapy in oncology has brought renewed interest in the development of novel agents for this rare group of diseases. Preliminary results from phase II studies have shown promising results for VEGF and mTOR inhibitors in carcinoid and islet cell carcinoma and RET inhibitors in medullary thyroid carcinoma. Large confirmatory studies are planned.