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PubMed1997

Allogeneic stem cell transplantation for the treatment of hematologic malignancies: current indications and challenges.

Allogeneic stem cell transplantation is a potentially curative treatment for hematologic malignancies. Research efforts are expanding the acceptable donor pool to increase patient access to this form of therapy. Potential sources besides HLA matched siblings include partially mismatched family members, unrelated volunteers, and cord blood stem cells. Although allogeneic hematopoietic stem cell (ASC) transplantation may cure hematologic malignancies, relapse remains a problem. To prevent relapse after transplant, research efforts are focused on optimizing the delivery of systemic chemoradiotherapy, including strategies for targeting therapy to sites of disease, and augmenting the antileukemic effect of the allogeneic graft. It is a challenge to maintain clinical research in the current environment of limited resources, so new paradigms for support of this work may need consideration.

Clinical Trials as Topic↗
PubMed2006

Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies.

PTPN11 has been identified as a causative gene in Noonan syndrome (NS), responsible for about 50% of cases of NS. Given the association between NS and an increased risk of some malignancies, notably leukemia and probably some solid tumors including neuroblastoma (NB) and rhabdomyosarcoma (RMS), recent studies have reported that gain-of-function somatic mutations in PTPN11 occur in some hematological malignancies, especially de novo juvenile myelomonocytic leukemia (JMML) and in some solid tumors such as NB, although at a low frequency. In a screen for mutations of PTPN11 in 7 cell lines and 30 fresh tumors of RMS and in 25 cell lines and 40 fresh tumors of NB, we identified a missense mutation (A72T) in an embryonal RMS patient. In the RMS samples, we also detected mutations of NRAS in 1 cell line and 1 patient; both mutations were in embryonal RMSs and had no PTPN11 mutations. No mutations of PTPN11 were detected in NB. In 95 leukemia cell lines and 261 fresh leukemia samples including 22 JMMLs, 9 kinds of missense mutations were detected in 17 leukemia samples, which included 11 (50.0%) mutations in JMML samples and lower frequencies in other hematological malignancies. Furthermore, we identified 4 (18.2%) NRAS mutations and 1 (4.5%) KRAS mutation in 5 JMML samples, 1 of which had a concomitant PTPN11 mutation. Our data suggest that mutations of PTPN11 as well as RAS play a role in the pathogenesis of not only myeloid hematological malignancies but also a subset of RMS malignancies.

Cell Line, Tumor↗
PubMed1998

Mediastinal mature teratoma with coexistence of angiosarcoma, granulocytic sarcoma and a hematopoietic region in the tumor: a rare case of association between hematological malignancy and mediastinal germ cell tumor.

An association between mediastinal germ cell tumors (MGCT) and hematological malignancies (e.g. acute leukemia, malignant histiocytosis) has been recognized since 1984. A rare case of mediastinal mature teratoma with angiosarcoma, a hematopoietic region and granulocytic sarcoma is reported in a 29-year-old male. The resected tumor was 9.0 x 6.5 cm, weighed 65 g and showed extensive necrosis, forming a cyst. The histological features of the tumor showed a mature teratoma, which contained a large gland lined by ciliated epithelium, hyalinous cartilage, a paraganglion-like structure, well-differentiated angiosarcoma with atypical hematopoiesis composed of CD34-positive cells, and malignant round cells. The malignant round cells did not stain for CD34 but were positive for leukocyte common antigen (LCA) and c-kit product. From these findings, the round cells were diagnosed as granulocytic sarcoma. The patient died of metastasis of the granulocytic sarcoma in the tonsils and cervical lymph nodes 8 months after surgery. A leukemic condition was not present throughout the clinical course. The association between MGCT and hematological malignancy is a distinctive syndrome. However, its pathogenesis is still obscure and the origin of the hematopoietic malignancy has not been fully elucidated. In this particular case, it is suggested that the granulocytic sarcoma might have arisen from the abnormal hematopoietic area in the mediastinal teratoma.

Adult↗
PubMed2006

Invasive aspergillosis in children with hematologic malignancies.

The respiratory tract is the most common system affected by aspergillosis in children with hematologic malignancies. However, Aspergillus spp. tend to invade blood vessels, resulting in systemic dissemination to multiple organs including, but not limited to, the brain, bones, liver, kidneys, and skin. Because early diagnosis and treatment are critical to the patient's outcome, a high index of suspicion should be maintained in children with hematologic malignancies who are neutropenic and have prolonged fever that is unresponsive to systemic antibacterials. Several diagnostic modalities should be used simultaneously in order to establish the diagnosis in an expeditious manner. Detailed radiographic evaluations with plain radiographs, and CT scans of the chest, sinuses, brain, and other organs should be performed as soon as clinical suspicion is raised. Detection of circulating antigens, such as galactomannan and 1,3-beta-glucan, and polymerase chain reaction appear promising in aiding in the diagnosis. A definitive diagnosis requires both a positive culture from a sterile site and evidence of tissue damage demonstrated by imaging studies or microscopic evaluations of sites of infection. Because the mortality rate is very high, empiric systemic antifungal therapy with amphotericin B, or one of its lipid formulations, should be initiated while laboratory investigations to substantiate or refute the diagnosis are continued. Surgical intervention is associated with a high mortality rate but may be of benefit in children with localized disease.

Adolescent↗
PubMed2004

Treatment of invasive Aspergillosis in children with hematologic malignancies.

The respiratory tract is the most common organ involved with Aspergillosis in children with hematologic malignancies. Also Aspergillus species tend to invade blood vessels resulting in systemic dissemination to multiple organs. Early diagnosis and treatment are pivotal to the patient's outcome. A high index of suspicion should be maintained in children who have profound neutropenia and present with prolonged fever that is unresponsive to systemic antibiotics. Several diagnostic modalities should be used simultaneously in order to confirm the diagnosis in an expedited manner. Combination and sequential antifungal therapy have been shown to be of added benefit. Surgical intervention is associated with a high mortality rate, but may be indicated in children with a localized disease. In this article the authors review the epidemiology, microbiology, pathology, and clinical manifestations of invasive aspergillosis in children with hematologic malignancies. Current diagnostic approach, medical, and surgical treatment options are discussed.

Antifungal Agents↗
PubMed1994

Bone marrow transplantation in Taiwan: low incidence of acute GVHD in patients with hematologic malignancies and severe aplastic anemia.

A total of 116 consecutive patients, including 82 cases of hematologic malignancies and 34 cases of severe aplastic anemia (SAA), were treated by allogeneic bone marrow transplantation (BMT). The conditioning regimens and post-graft immunosuppressive agents were as described by Thomas in Seattle and Santos in Baltimore. The incidence of grades II-IV acute GVHD in patients with hematologic malignancies with a full HLA match, with one locus and with two loci mismatches was 6.3% (4 of 63), 0% (0 of 11) and 37.5% (3 of 8), respectively. None of SAA patients developed grade II-IV acute GVHD. The low incidence of acute GVHD after BMT among Chinese patients may be associated with the use of isolation in laminar airflow rooms and a relatively low level of genetic diversity in histocompatibility antigens. This is an interesting issue for further study.

Acute Disease↗
PubMed2003

Immunotoxin therapy of hematologic malignancies.

Patients with chemotherapy relapsed or refractory hematologic malignancies may be effectively treated with allogeneic or autologous stem cell transplants. However, many patients cannot be transplanted due to age, comorbidities, or lack of suitable donors. Further, a fraction of patients relapse post-transplant. Novel therapeutic agents that can kill multidrug-resistant malignant stem cells and are not myelosuppressive are needed. One class of such agents is immunotoxins. Immunotoxins consist of cell-selective ligands covalently linked to peptide toxins. The ligand delivers the molecule to specific cell surface receptors on malignant cells. The toxin triggers cell death either by reaching the cytosol and catalytically inactivating vital cell processes or by modifying the tumor cell surface membrane. We have synthesized immunotoxins for therapy of chemoresistant hematologic diseases. In this review, we will detail the synthesis of a number of these drugs and describe their preclinical and clinical activity. Several of these agents have shown dramatic antitumor effects in patients with hematologic neoplasms, and one immunotoxin has been approved for use by the US Food and Drug Administration (FDA). Over the next several decades, a growing number of these agents should reach the clinic.

Antineoplastic Agents↗
PubMed1991

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.

Antibodies, Monoclonal↗
PubMed1989

Serum cholesterol and triglycerides in hematological malignancies.

Serum levels of total cholesterol and triglycerides were studied in 202 patients affected by various hematological malignancies at the time of diagnosis. A hypocholesterolemia was found in 44% of patients affected by lymphoproliferative diseases and acute lymphoblastic leukemia, with an evident correlation with the clinical stage (5.7% of patients in nonadvanced stages, 67.8% in advanced stages). In acute and chronic myeloproliferative diseases, the overall incidence of hypocholesterolemia was 71%. In particular, a greater incidence of low cholesterol values was found in chronic myeloid leukemia and in idiopathic myelofibrosis than in polycythemia vera. No significant correlation was found in this group of diseases between the values of cholesterol and the main hematological parameters studied (WBC, number of circulating blasts, degree of splenomegaly, levels of hemoglobin, hematocrit). The incidence of significant alterations of triglycerides appeared negligible. It is thus possible to affirm that hypocholesterolemia constitutes an interesting biological aspect in hematological malignancies, and that total cholesterol could represent a parameter, even though secondary, in the follow-up of hematological neoplastic pathologies.

Adolescent↗
PubMed1992

Value of measurement of C-reactive protein in febrile patients with hematological malignancies.

The maximum serum levels of C-reactive protein (CRP) in 126 patients with hematological malignancies who had 554 febrile episodes were analyzed retrospectively with regard to documented infections and fever of unknown origin. The CRP levels were significantly higher when the blood culture was positive than when it was negative (p = 0.002). The CRP levels were significantly higher when the infection focus was identified than when it was not (p = 0.010). In patients with fever of unknown origin the CRP was significantly lower than in patients with microbiologically documented infections (p < 0.001). Cytotoxic treatment neither reduced nor enhanced the CRP reaction. The serial measurement of CRP is a reliable and readily available means for differentiating between bacterial infections and other causes of fever in patients with hematological malignancies, also during neutropenia and after cytotoxic treatment.

Adult↗
PubMed1999

[An analysis of autologous peripheral stem cell transplantation for hematological malignancies].

OBJECTIVE: To summarize the data of autologous peripheral stem cell transplantation (APBSCT) for 49 hematological malignancies patients. METHODS: Forty-nine patients, 18 with acute myeloid leukemia, (AML) 10 acute lymphoblastic leukemia(ALL), 14 multiple myeloma(MM), 6 non-Hodgkin's lymphoma(NHL) and 1 myelodysplastic syndrome(MDS RAEB-t) received APBSCT were retrospectively analyzed. RESULTS: Comparing to conventional chemotherapy, APBSCT can prolong the patients' disease-free survival(DFS) and overall survival (OS). The 3 and 5-year OS rates were 74.78% and 83.33% for AML/NHL; 38% and 19% for MM; 40% and 0 for ALL, respectively. The time of hematopoietic reconstitution was influenced by G-CSF administration significantly. The mean time of neutrophil recovering to 0.5 x 10(9)/L after APBSCT was +17.7 days in no G-CSF group, and +11.14 days in G-CSF group. Up to now, of the 49 patients, no APBSCT related death occur, 23 have died and 22 of them died of relapse. The most common transplantation related complications were fever, liver dysfunction and hypopotassemia, all of which can be cured by proper treatment. CONCLUSION: APBSCT can be safely performed in hematological malignancies.

Acute Disease↗
PubMed1998

[Clinical evaluation of cefozopran for infections associated with hematological malignancies].

Cefozopran (CZOP) was used as an initial antibacterial therapy for infections in patients with hematological malignancies. CZOP was given at a daily dose of 4 g by drip intravenously to patients who were febrile over 38 degrees C and were suspected as having bacterial infections. As underlying diseases, 8 patients had acute lymphoblastic leukemia (ALL), 9 acute myeloblastic leukemia (AML), 2 aplastic anemia (AA), 2 adult T cell leukemia/lymphoma (ATLL), 28 non Hodgkin lymphoma (NHL), and 2 multiple myeloma (MM). Bacterial infections diagnosed were sepsis in 7 patients, suspected sepsis in 32, bronchitis in 6, pneumonia in 5 and acute peritonitis in 1. Clinical responses among 51 evaluable cases were excellent in 14, good in 15, fair in 3, poor in 19 and the overall response rate was 57%. The overall response rates for AML, ALL, AA, ATLL, NHL and MM were 56%, 63%, 100%, 50%, 50%, and 100%, respectively. Those for sepsis, suspected sepsis, bronchitis, pneumonia and acute peritonitis were 14%, 63%, 100%, 40%, and 0%, respectively. This therapy was effective in 53% (9/17) of patients whose granulocyte count remained below 500/microliter throughout the course of CZOP therapy. Six bacterial and one fungal strains were isolated from blood and sputum of six patients including five sepsis cases; two bacteria were eradicated and bacterial change was observed in one case. As side adverse effects, 10 patients had liver dysfunction, 1 anemia, 2 proteinemia, 1 indirect bilirubinemia, 2 thrombocytopenia, and 1 eosinophilia. We tried to establish a scoring system for the severities of patients with their infections, underlying diseases, treatments for the underlying disease, and granulocyte counts in order to evaluate the efficacy of CZOP more precisely. This scoring system was consisted of three grades; severe, moderate, and mild. CZOP was effective on mild and moderate grades. These results indicate that the initial antibacterial therapy by CZOP is useful for the treatment of mild and moderate grade infections complicated with hematological malignancies.

Acute Disease↗
PubMed2003

Hematopoietic stem cell transplantation for hematological malignancies in Europe.

Hematopoietic stem cell transplants (HSCTs) are considered the best treatment option for many hematological malignancies, and transplant numbers have increased five-fold during the last decade. Only a few controlled prospective studies are available, and different opinions prevail. Data from 118 167 HSCT (36% allogeneic, 64% autologous) collected within the EBMT activity survey from 1990 to 2001 were used to assess trends over time, transplant rates and coefficient of variation (CV) of transplant rates among European countries for acute myeloid leukemia (AML; 18.5%), acute lymphocytic leukemia (ALL; 12%), chronic myeloid leukemia (CML; 11.5%), myelodysplastic syndromes (MDS; 3%), lymphoproliferative disorders (LPS; 36.3%) and multiple myeloma (MM; 18.7%). Transplant rates increased in all countries and for all indications from 1990 to 2001 from 1.7-fold (CML) to 24.8-fold (MM). Transplant rates have declined for CML since 1999. Autologous HSCT are the preferred choice for LPS and MM, allogeneic HSCT for ALL and myeloid malignancies. CVs of less than 50% suggest consensus for allogeneic HSCT in AML, ALL, CML, MDS and NHL, for autologous HSCT in LPS and MM. These data give an overview of the current status of HSCT for hematological malignancies in Europe and provide objective information for health-care providers and patient counselling.

Demography↗
PubMed2005

The role of the tumor microenvironment in hematological malignancies and implication for therapy.

The tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion, and metastasis by providing survival signals and a sanctuary site for tumor cells, by secretion of growth factors, pro-angiogenesis factors and direct adhesion molecule interactions. Our knowledge of microenvironment is only now beginning to unfold. In this review, the morphological and molecular characteristics of microenvironment in various hematological malignancies including acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, lymphoma, chronic lymphocytic leukemia, and multiple myeloma are summarized and the molecular mechanisms of microenvironment contributing to leukemogenesis are elucidated. We also aim to discuss the encouraging preclinical and clinical trials for treatment of hematological malignancies by targeting the tumor microenvironment. Further understanding of the signal transduction pathways between tumor cells and microenvironment will lead to the development of novel targeted therapeutic agents and more effective combination of current drugs for fighting hematological malignancies.

Angiogenesis Inhibitors↗
PubMed2001

Erythropoietin for the treatment of anemia associated with hematological malignancy.

Anemia is common in patients with hematological malignancy. Most patients will have their anemia attributed to the anemia of chronic disease. The anemia of chronic disease is caused by cytokine mediated suppression of erythropoiesis and low serum erythropoietin levels are found in the majority of patients with cancer. Many of these anemic patients will be symptomatic with fatigue. Data from many studies indicates that treatment of anemic patients with erythropoietin will increase their hemoglobin concentration, decrease transfusion need and also improve their quality of life. A recent study also suggests that improving the hemoglobin level may improve the patients' prognosis but this finding needs to be confirmed.

Anemia↗
PubMed2004

Footwear exchange has no influence on the incidence of febrile neutropenia in patients undergoing chemotherapy for hematologic malignancies.

OBJECTIVE: To determine whether footwear exchange affects the incidence of febrile neutropenia among patients undergoing chemotherapy for hematologic malignancies. DESIGN: Open trial with historical comparison. SETTING: The 12-bed high-efficiency particulate air-filtered hematology unit at Osaka University Hospital, Suita, Japan. PATIENTS: Those with hematologic malignancies who underwent chemotherapy from January 1997 through January 2003. Footwear exchange was discontinued in January 2000. METHODS: The surveillance system was based on the National Nosocomial Infections Surveillance System of the Centers for Disease Control and Prevention. Rates of febrile neutropenia were calculated for neutropenic patient-days (ie, days with neutropenia < 500/microL). RESULTS: From January 1997 through December 1999 and from February 2000 through January 2003, 58 and 54 patients endured 237 and 184 neutropenic periods following chemotherapy, and their total neutropenic days were 3,123 and 2,503, respectively. They showed episodes of febrile neutropenia 89 and 68 times, respectively. Infection rates were 28.5 and 27.2 per 1,000 neutropenic patient-days (P = .83), respectively. CONCLUSION: The incidence of febrile neutropenia was not affected by footwear exchange. In hematology units, changing shoes does not appear to affect the rate of infections during neutropenic periods.

Adolescent↗
PubMed2003

101 laparoscopic splenectomies for the treatment of benign and malignant hematologic disorders.

BACKGROUND: Laparoscopic splenectomy (LS) is the surgical approach of choice for patients with hematologic disorders requiring splenectomy. Patients with idiopathic thrombocytopenic purpura (ITP) have normal to slightly enlarged spleens and benefit the most from LS. METHODS: We reviewed the perioperative outcomes in 101 patients who underwent LS between May 1996 and December 2002. Patients were divided into three groups--ITP, other benign, and malignant hematologic disorders--and compared. RESULTS: The ITP patients (n = 48) had significantly smaller spleens and operative times compared with the other groups. Splenomegaly in the other benign (n = 23) and malignant hematologic disorders (n = 30) groups was responsible for higher open conversion rates and greater need for hand-assisted laparoscopic splenectomy (HALS). CONCLUSIONS: Laparoscopic splenectomy and HALS can be performed with good results for benign and malignant hematologic disorders. The benefits of HALS are similar to LS, so there should be a low threshold for HALS in patients with large spleens.

Case-Control Studies↗