Secondary pulmonary alveolar proteinosis in hematologic malignancies

Pulmonary alveolar proteinosis (PAP), characterized by deposition of intra-alveolar PAS positive protein and lipid rich material, is a rare cause of progressive respiratory failure first described by Rosen et al. in 1958. The intra-alveolar lipoproteinaceous material was subsequently proven to have been derived from pulmonary surfactant in 1980 by Singh et al. Levinson et al. also reported in 1958 the case of 19-year-old female with panmyelosis afflicted with a diffuse pulmonary disease characterized by filling of the alveoli with amorphous material described as “intra-alveolar coagulum”. This is probably the first reported case of PAP in relation to hematologic malignancy. Much progress has been made on PAP first described by Rosen which is currently classified as idiopathic or primary or autoimmune PAP. Idiopathic PAP occurs as a result of auto-antibodies directed against granulocyte–macrophage colony stimulating factor (GM-CSF) impeding the surfactant clearing function of alveolar macrophages leading to progressive respiratory failure. Whole lung lavage and GM-CSF therapy has improved outcomes in patients with idiopathic PAP. Despite major advancement in the management of hematologic malignancy and its complications, little is known about the type of PAP first described by Levinson and now known as secondary PAP; a term also used when PAP occurs due to other causes such as occupational dusts. In this article we review and analyze the limited literature available in secondary PAP due to hematologic malignancies and present a case of PAP associated with chronic lymphocytic leukemia successfully treated with bendamustine and rituximab.     

The immunoproteasome as a target in hematologic malignancies

Suppression of proteasome function with the first-in-class small molecule inhibitor bortezomib is a rational therapeutic strategy against several hematologic malignancies, including multiple myeloma and mantle cell lymphoma. Second-generation inhibitors such as carfilzomib, ixazomib, and marizomib that, like bortezomib, target both the constitutive proteasome and the immunoproteasome, are also in clinical trials and showing encouraging activity. While the efficacy of these agents is well documented, toxicities associated with their use, such as peripheral neuropathy and gastrointestinal effects, can necessitate dose reductions or even discontinuations, possibly hampering their anti-neoplastic effects. These findings suggested that it could be possible to improve the therapeutic index of this class of drugs by specifically targeting only the immunoproteasome. Since the immunoproteasome is a unique target found in lymphoid-derived cells, immunoproteasome-specific inhibitors (IPSIs) could preserve efficacy while reducing treatment-emergent toxicities since they would spare other tissues with little to no immunoproteasome expression. This review discusses the current state of development of IPSIs, and the potential of using such agents for the treatment of hematologic malignancies.     

Acute leukemia as a complication of long-term treatment of advanced breast cancer.

Acute nonlymphocytic leukemia occurred in four women after long-term therapy for advanced breast cancer. The patients had inoperable/metastatic breast cancer that had been well-controlled with chemotherapy for many years (7 years and 4 months, 7 years and 1 month, 6 years and 3 months, and 4 years and 7 months, respectively). Two of the patients had also received extensive radiotherapy. The chemotherapeutic agent that all four patients had received in common was cyclophosphamide.     

Alpha interferon in the treatment of hematologic malignancies

The interferons are an important first member of a family of biologic response-modifiers used in treating human malignancies. Activities associated with the interferons include inhibition of viral replication, influence on cellular protein production, direct antiproliferative effects, and a variety of modulatory effects on the immune response. These regulatory functions of interferon underlie the interest in its use as an anticancer agent. Alpha interferon is the most extensively studied interferon species. Although antitumor activity has been seen both in vitro and in vivo in some solid malignancies, the most impressive responses have occurred in the hematologic malignancies. More than 90 percent of patients with hairy cell leukemia have a sustained recovery of their peripheral blood cell counts with alpha interferon therapy. Approximately 50 percent of patients with low-grade non-Hodgkin's lymphoma and cutaneous T cell lymphoma demonstrate a response to alpha interferon. More than 80 percent of patients with chronic myelogenous leukemia have a response to alpha interferon, and in one study, nearly half of the patients with response had complete suppression of the Philadelphia chromosome clone on at least one examination. Ongoing clinical trials are addressing such issues as optimal dosage, duration of alpha interferon therapy, and combinations of alpha interferon with other biologic agents, chemotherapy drugs, and radiation.     

Ras processing as a therapeutic target in hematologic malignancies

Knowledge of signal transduction pathways has uncovered therapeutic targets for cancer. Based on genetic and biochemical studies of leukemia cells, inhibiting hyperactive Ras represents a rational therapeutic strategy for many hematologic malignancies. Because posttranslational processing by farnesyltransferase is essential for transformation by oncogenic Ras, specific inhibitors of this enzyme are being evaluated as cancer therapeutics. The authors review recent laboratory insights on farnesyltransferase biology and on the development of inhibitors, summarize preclinical and clinical data in myeloid malignancies, and briefly discuss other strategies of interfering with hyperactive Ras.     

Deep vein thrombosis: a less noticed complication in hematologic malignancies and immunologic disorders

Journal of Thrombosis and Thrombolysis - Deep vein thrombosis (DVT) is a common complication in hematologic malignancies and immunologic disorders that coagulation and inflammatory factors play a...     

Thiabendazole for the treatment of strongyloidiasis in patients with hematologic malignancies.

A total of 21 patients with hematologic malignancies were given thiabendazole for treatment of strongyloidiasis. Fifteen patients were cured. Since there were no relapses, it is unlikely that maintenance therapy has a role in the management of strongyloidiasis in this population of patients.     

Cefpirome as empirical treatment for febrile neutropenia in patients with hematologic malignancies

Cefpirome, a fourth generation cephalosporin, was administered during 154 episodes of febrile neutropenia in 106 patients. We assessed the clinical efficacy of cefpirome and its activity against isolated pathogens in neutropenic patients with hematologic malignancies. In addition, the pharmacokinetics and optimal dosing regimen of cefpirome during neutropenia were investigated.     

Whole genome scanning as a cytogenetic tool in hematologic malignancies

Over the years, methods of cytogenetic analysis evolved and became part of routine laboratory testing, providing valuable diagnostic and prognostic information in hematologic disorders. Karyotypic aberrations contribute to the understanding of the molecular pathogenesis of disease and thereby to rational application of therapeutic modalities. Most of the progress in this field stems from the application of metaphase cytogenetics (MC), but recently, novel molecular technologies have been introduced that complement MC and overcome many of the limitations of traditional cytogenetics, including a need for cell culture. Whole genome scanning using comparative genomic hybridization and single nucleotide polymorphism arrays (CGH-A; SNP-A) can be used for analysis of somatic or clonal unbalanced chromosomal defects. In SNP-A, the combination of copy number detection and genotyping enables diagnosis of copy-neutral loss of heterozygosity, a lesion that cannot be detected using MC but may have important pathogenetic implications. Overall, whole genome scanning arrays, despite the drawback of an inability to detect balanced translocations, allow for discovery of chromosomal defects in a higher proportion of patients with hematologic malignancies. Newly detected chromosomal aberrations, including somatic uniparental disomy, may lead to more precise prognostic schemes in many diseases.     

Secondary hemochromatosis. I. Transfusion (exogenous) hemochromatosis

1. Secondary hemochromatosis has been sharply separated from simple hemosiderosis by defining the former as "a condition acquired as a consequence ofanemia, blood transfusions, or both, and characterized by increased hepatic andtotal body iron content and unequivocal portal cirrhosis of the liver."

2. Previously reported cases are critically reviewed in the light of this definition.

3. Two new cases of secondary (exogenous) hemochromatosis are reported.

4. Anemia is postulated as the basic etiologic factor in secondary hemochromatosis by causing increased iron absorption; iron introduced in the form ofblood transfusions probably only accelerates a process already in progress.

5. Prolonged futile oral iron therapy may be harmful.

6. A plea is made for a strict concept of secondary hemochromatosis as well asfor thorough documentation of future reports.

Submitted on February 28, 1953 Accepted on May 22, 1953     

支气管镜及相关检查对血液肿瘤肺部并发症的诊断价值

目的:探讨纤维支气管镜(FB)及相关检查对血液肿瘤移植及化疗后肺部并发症的病因诊断价值.方法:回顾分析经胸部CT、血、痰病原学检查不能明确诊断的38例肺部并发症患者,接受FB检查、支气管肺泡灌洗(BAL)、刷片,部分经支气管镜肺活检(TBLB)的确诊情况.结果:38例患者中26例经FB确诊,总诊断率68.42%.其中,...     

Immune markers in hematologic malignancies.

The precise delineation of biologic traits that distinguish normal hematopoietic cells from their malignant counterparts is of fundamental importance in understanding all aspects of hematologic malignancies. An increasingly sophisticated technologic battery has been utilized to dissect out these differences--primarily utilization of monoclonal antibodies, by immunoperoxidase, immunoalkaline phosphatase and flow cytometric techniques. An even more basic understanding of normal and malignant hematopoietic cells has begun to evolve as molecular biology begins to unravel gene misprogramming by Southern and Northern blot analysis and the polymerase chain reaction. These techniques not only help distinguish a normal cell from a malignant one, but characterize the malignant clone as B-lymphoid, T-lymphoid or myeloid and allow further subcategorization within these broad lineages. These distinctions are vital to the entire spectrum of basic and clinical research involving hematologic malignancies and are assuming an increasingly important role in their diagnosis, prognosis and treatment.     

Management of infections during intensive treatment of hematologic malignancies

 In febrile neutropenic patients with high-grade hematologic malignancies, empirical antimicrobial intervention is mandatory. Large randomized clinical trials have elucidated the benefit of broad-spectrum beta lactam antibiotics used as single drugs or in combination with aminoglycosides in order to provide activity against gram-negative aerobes as well as against streptococci and Staphylococcus aureus. As a result, infection-related mortality was reduced to less than 10% also in patients undergoing intensified remission induction or consolidation therapy for acute leukemias. Distinct subgroups of patients have been identified who need an empirical modification of antimicrobial treatment, i.e., patients with catheter-related infections, patients with pulmonary infiltrates, and patients with unexplained fever not responding to first-line antibiotics. In two consecutive, prospectively randomized trials conducted by the Paul Ehrlich Society it was demonstrated that empirical antifungal therapy is beneficial for second-line treatment in patients with persistent unexplained fever and should be part of the first-line approach in patients with lung infiltrates. The empirical addition of glycopeptides, however, should be restricted to patients with catheter-related infections due to coagulase-negative staphylococci. Received: 12 April 1997 / Accepted: 26 June 1997     

Epigenetics in the hematologic malignancies

A wealth of genomic and epigenomic data has identified abnormal regulation of epigenetic processes as a prominent theme in hematologic malignancies. Recurrent somatic alterations in myeloid malignancies of key proteins involved in DNA methylation, post-translational histone modification and chromatin remodeling have highlighted the importance of epigenetic regulation of gene expression in the initiation and maintenance of various malignancies. The rational use of targeted epigenetic therapies requires a thorough understanding of the underlying mechanisms of malignant transformation driven by aberrant epigenetic regulators. In this review we provide an overview of the major protagonists in epigenetic regulation, their aberrant role in myeloid malignancies, prognostic significance and potential for therapeutic targeting.     

Isophosphamide therapy for hematologic malignancies in patients refractory to prior treatment.

Isophosphamide was administered to 27 patients with acute leukemia and to 15 patients with malignant lymphoma refractory to primary therapy. The starting dose of isophosphamide was 1200 mg/m2 administered as a daily continuous infusion x 5 days; the courses of treatment were repeated every 2-3 weeks. Of the 27 patients with acute leukemia, four achieved complete remission, two achieved partial remission, and two achieved hematologic improvement. However, no responses occurred in ten patients with acute myelogenous leukemia (AML). Thus, the response rate was 47% (eight responses among among 17 patients, in patients with acute lymphoblastic leukemia and acute undifferentiated leukemia. Seven of the 15 patients with malignant lymphoma responded. Most responses (five of six patients) occurred in patients with diffuse histiocytic lymphoma. Twenty-one of the 42 patients had received prior therapy with cyclophosphamide and 12 of these patients (two with leukemia and ten with lymphoma) responded, thus suggesting that as in the treatment of L1210 leukemia, isophosphamide is effective for tumors resistant to prior cyclophosphamide therapy. No significant genitourinary toxicity occurred; however, myelosuppression became the dose-limiting toxicity. Isophosphamide is active in malignant lymphomas and acute leukemias (except AML) and may have a role in combination regimens for such diseases.     

Radioimmunotherapy for treatment of B-cell lymphomas and other hematologic malignancies

PURPOSE OF REVIEW: Radioimmunotherapy has emerged as one of the most promising treatment options for hematologic malignancies. This review will present the latest information on radioimmunotherapy for treatment of hematologic malignancies in various clinical settings and assess its long-term safety profile. RECENT FINDINGS: Recent data suggest that radioimmunotherapy with 131I-tositumomab or 90Y-ibritumomab tiuxetan not only induces high response rates but also results in durable remissions in patients with relapsed or refractory indolent non-Hodgkin's lymphomas. Even more notable response rates have been observed when radioimmunotherapy is used as front-line treatment in patients with indolent non-Hodgkin's lymphomas. The use of radioimmunotherapy has been evaluated in the treatment of aggressive lymphomas with promising results, but it remains investigational. Standard doses of radioimmunotherapy given as a conditioning regimen for hematopoietic stem-cell transplant or myeloablative doses of radioimmunotherapy given in conjunction with stem-cell support have yielded encouraging outcomes with durable remissions and a low incidence of treatment-related mortality. SUMMARY: The safety and efficacy of radioimmunotherapy has been demonstrated for patients with B-cell lymphomas and other hematologic malignancies in various clinical settings. A number of randomized phase III clinical trials are currently underway to further define radioimmunotherapy's role in the treatment of lymphomas.     

Is atherosclerosis a complication of long-term corticosteroid treatment?

In clinical practice, arteriosclerotic heart disease has not been recognized as a complication of long-term corticosteroid treatment. Yet, an increasing body of evidence suggests that prolonged corticosteroid therapy accelerates the development of atherosclerosis. An important element in this process may be the fact that corticosteroids induce or exacerbate several known coronary risk factors, including hypertension, hypercholesterolemia, hypertriglyceridemia, and impairment of glucose tolerance. One group of patients that is often exposed to long-term corticosteroid treatment is that with rheumatoid arthritis. These patients have an increased mortality, with cardiovascular disease appearing to be a major contributor to this decreased survival. The weight of evidence relates the development of atherosclerosis to corticosteroid use. However, no long-term epidemiologic or morphologic studies have been performed to elucidate this issue. Until these are accomplished, prolonged therapy with this medication, particularly in younger persons, should be avoided whenever possible.