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Platelet kinetics and decreased transfusion requirements after splenectomy for hematologic malignancy.

OBJECTIVE: Thrombocytopenia is a significant and morbid problem in patients with hematologic malignancy, resulting in frequent platelet transfusions and significant resource consumption. We undertook this study to determine the impact of splenectomy on transfusion requirements in patients with chronic leukemia, acute leukemia, myelodysplastic syndrome, and lymphoma. METHODS: Records of 134 patients with hematologic malignancies who underwent splenectomy were reviewed. Results are reported as mean +/- standard error of the mean. RESULTS: Mean preoperative (preop) platelet count was 97 +/- 8 K/microL. A significant rise in platelets, compared with preop, was observed starting on postsplenectomy day 1 (141 +/- 8 K/microL, P < 0.001 versus preop) and persisted through day 7. Counts remained significantly elevated at 3 and 6 months and years 1-5. In profoundly thrombocytopenic patients (preop levels < 20 K/microL), preop count was 11 +/- 1 K/microL. A significant postsplenectomy platelet rise persisted for at least 1 year (137 +/- 52 K/microL, P < 0.05 versus preop). An increased platelet level was observed in all hematologic subgroups; in the chronic leukemias (n = 58, P < 0.01) and in lymphoma (n = 59, P < 0.001), this reached significance. Mean platelet transfusions were significantly decreased from preop (3 months preop: 8.6 +/- 2 units) compared with postsplenectomy (3 months postsplenectomy: 5.0 +/- 1 unit, P = 0.03). This decrease was even more pronounced in profoundly thrombocytopenic patients (31.6 +/- 10.6 units preop versus 8.9 +/- 4.8 units postoperative, P = 0.01). CONCLUSIONS: In the hematologic malignancies, splenectomy produces a significant and longlasting restoration of platelet levels and a resultant decrease in platelet transfusion requirements. These beneficial effects of splenectomy hold true even for the most profoundly thrombocytopenic patients.

Adolescent↗

Circulating levels and clinical significance of soluble CD40 in patients with hematologic malignancies.

BACKGROUND: CD40 plays a critical role in immunoregulation, and CD40 ligation is being investigated as a therapy for hematologic malignancies. Although soluble CD40 (sCD40) is a potential modulator of both antitumor responses and CD40-based therapies, the levels and significance of sCD40 in patients with hematologic malignancies are unknown. METHODS: The authors evaluated serum/plasma sCD40 levels using an enzyme-linked immunoassay in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and multiple myeloma (MM). RESULTS: Levels of sCD40 were elevated in serum (>1.697 ng/mL) or plasma (>0.649 ng/mL) from 73% of patients with CLL, 80% of patients with MCL, 40% of patients with AML, 43% of patients with MDS, and 33% of patients with MM. Multivariate analysis of patients with MM demonstrated that elevated sCD40 was a significant, independent predictor of poor survival. In multivariate analysis of patients with AML, sCD40 was a significant prognostic factor when the interaction of age and sCD40 was included as a variable. Further analysis demonstrated that elevated sCD86 levels were associated with significantly shorter survival only in AML patients younger than age 64 years. Release of sCD40 by CLL cells was induced by cross-linking with CD40 monoclonal antibody. CONCLUSIONS: Many patients with hematologic malignancies have elevated circulating levels of sCD40, and these elevated levels are associated with a poor prognosis at least in patients with MM and AML, suggesting that sCD40 may have a role in modulating antitumor responses and also may be a useful prognostic marker. In addition, the findings suggested that further studies will be required to determine the effect of circulating sCD40 on the clinical effectiveness of CD40-ligating reagents used in the treatment of hematologic malignancies.

Biomarkers, Tumor↗

Proteomics in hematologic malignancies.

Basic science research in hematology has been determining the functions of gene products using classical approaches that typically involve studying one or a few genes at a time. Proteomics, defined as the study of protein properties on a large scale, provides tools to globally analyze malignant hematologic cells. A major challenge in cancer therapy is the identification of drugs that kill tumor cells while preserving normal cells. Differential display via proteomics enables analysis of direct as well as side-effects of drugs at a molecular level. Proteomics also allows a better understanding of cell signaling pathways involved during apoptosis in hematologic cells. Storing the information in a 2D electrophoresis database enhances the efficiency of proteome research on malignant cells. Finally, the work needed to be carried out on proteomic analysis prior to routine clinical adoption is discussed, and the necessity for multi-institutional collaborations is emphasized.

Animals↗

Role of fine-needle aspirates of focal lung lesions in patients with hematologic malignancies.

OBJECTIVES: To evaluate the yield and safety of transthoracic fine-needle aspiration (FNA) in the diagnosis of pulmonary disease in patients with hematologic malignancy. DESIGN: Retrospective chart review. SETTING: Tertiary-care medical center. PATIENTS: Sixty-seven patients with a hematologic malignancy or after bone marrow transplantation (BMT) for a hematologic malignancy who underwent a total of 71 FNAs for diagnosis of an unexplained parenchymal lung lesion from January 1, 1991, to June 30, 1999. RESULTS: The underlying malignancy was lymphoma in 42 patients (63%), leukemia in 8 patients (12%), after allogeneic BMT in 12 patients (18%), after autologous BMT in 3 patients (4%), and other diseases in 2 patients. Radiographs showed focal abnormalities in all cases, and were nodules in 37%, masses in 37%, focal infiltrates in 21%, and cavitary lesions in 5%. The yield of FNA for a finding specific infection or cancer was 56% (40 of 71 FNAs). The FNA with inflammatory changes was clinically sufficient in another 11 patients for a total yield of 72% (51 of 71 FNAs). The yield for lung cancer was 90% (9 of 10 FNAs), for pulmonary lymphoma was 68% (21 of 31 FNAs), and for infection was 67% (10 of 15 FNAs). Complications occurred in 18 of 71 FNAs (25%), with pneumothorax in 14 patients (20%) and chest tube placement required in 4 patients (6%). Bleeding occurred in six patients (8%), including one death in a patient with abnormal hematologic parameters. CONCLUSION: Transthoracic FNA in patients with hematologic malignancy and focal lung lesions has an excellent yield for detecting cancer and a yield comparable to bronchoscopy for the diagnosis of infections. It should be considered a useful diagnostic tool in this setting.

Biopsy, Needle↗

An expanded phase I/II trial of cyclophosphamide, etoposide, and carboplatin plus total body irradiation with autologous marrow or stem cell support for patients with hematologic malignancies.

The major cause for failure of autologous stem cell transplantation for hematologic malignancies is the risk of recurrent disease. As a result, new treatment regimens that include novel agents or combinations of agents and approaches are needed. The current report describes a large Phase I/II, single-center trial that includes 60 patients with a variety of hematologic malignancies. These patients received a fixed dose of carboplatin (1 g/m(2)/d x 72 hours by CI) etoposide (600 mg/m(2)/d x 3 days) and cyclophosphamide (2 g/m(2)/d x 3 days), plus escalating doses of total body irradiation (TBI) (at 1000, 1200, and 1295 cGy) over 3 days. Eleven patients received infusion of autologous marrow, 32 received peripheral blood stem cells, and 17 patients received both. The maximum tolerated dose of this regimen was a radiation dose of 1200 cGy given in 200-cGy fractions BID x 3 days. The dose-limiting toxicity was mucositis, with 97% of patients requiring narcotic analgesia for mouth pain. Overall treatment-related mortality was 6.7%, with 2 of the 4 deaths occurring in a group of 9 patients aged 60 and older. Responses were seen in all patient groups, but the most encouraging outcomes were seen in 12 patients with high-risk or advanced acute myelocytic lymphoma (AML), 7 of whom remain alive and free of disease beyond 5 years. This regimen is intensive and causes considerable mucositis but is otherwise well tolerated and has demonstrated activity in a number of hematologic malignancies, especially AML.

Adult↗

Fractionated total-body irradiation, etoposide, and cyclophosphamide followed by allogeneic bone marrow transplantation for patients with high-risk or advanced-stage hematological malignancies.

Myeloablative therapy followed by allogeneic bone marrow transplantation (BMT) has proven to be curative therapy in patients with hematologic malignancies. Relapse, however, remains a major cause of treatment failure for patients with advanced disease. During the past 15 years, we have gained considerable experience with the combination of fractionated total-body irradiation (FTBI) and etoposide followed by allogeneic BMT for hematologic malignancies. In an attempt to decrease post-transplant relapse rates, 67 patients under the age of 50 years with high-risk or advanced-stage hematological malignancies received an intensified regimen of FTBI and etoposide plus cyclophosphamide followed by BMT from a genotypically-matched related donor. The regimen consisted of 1320 cGy of FTBI in 11 fractions, 60 mg/kg of etoposide (VP-16), and 60 mg/kg of cyclophosphamide (CY). Fifty-three patients received cyclosporine and prednisone for graft-vs.-host disease (GVHD) prophylaxis and 14 patients received cyclosporine, methotrexate, and prednisone. Diagnosis at BMT included 45 patients with acute leukemia, 7 patients with chronic leukemia, and 15 patients with high-grade non-Hodgkin's lymphoma (NHL). Actuarial disease-free survival (DFS) at 3 years was 42% +/- 12% for the entire group with a median follow-up of 50 months (range 20-74) for 28 patients who remain alive in continued complete remission (CR). Actuarial 3-year-DFS was 38% +/- 14% in 52 patients with acute or chronic leukemia and 60% +/- 25% in 15 patients with NHL with relapse rates of 45% +/- 16% and 21% +/- 11%, respectively. DFS at 3 years was 40% +/- 18% in 32 patients with acute leukemia in 1st relapse or 2nd CR or chronic myelogenous leukemia in accelerated phase, and was 32% +/- 22% in 20 patients with more advanced disease. Regimen related mortality occurred in 9 patients (4, veno-occlusive disease of the liver; 2, multi-organ failure; 1, diffuse alveolar hemorrhage; 1, central nervous system (CNS) hemorrhage; 1, adult respiratory distress syndrome (ARDS). The combination of FTBI, etoposide, and cyclophosphamide followed by allogeneic BMT is an effective and relatively well-tolerated regimen for patients with advanced hematologic malignancies. The role for this regimen should be further defined by prospective clinical trials.

Adolescent↗

Routine use of immunophenotype by flow cytometry in tissues with suspected hematological malignancies.

BACKGROUND: Immunophenotype is an essential parameter in the diagnosis of hematological malignancies. Flow cytometry (FCM) is used in the analysis of bone marrow or peripheral blood samples but is less frequently used in the evaluation of tissue biopsies with suspected hematological malignancies. The aim of this study was to analyze the role of FCM in the diagnosis of biopsies from patients with a suspected hematological disorder. METHODS: A total of 422 consecutive biopsies were studied using standard morphology, immunohistochemistry (IHC), and FCM. Results of FCM were obtained in less than 3 h and were interpreted independently from morphology and IHC. RESULTS: A strong correlation between malignant disease and abnormal pattern of FCM was observed (218 of 250) with the exception of Hodgkin disease (P < 0.001). Overall, negative predictive value was 0.52 and positive predictive value was 1. Light chain restriction was observed in 182 of 201 B-cell lymphoma and in 0 of 142 non-B-cell disorders by FCM. In contrast, light chain pattern could only be evaluated in 38 of 91 cases by IHC. FCM allowed a rapid diagnosis of infrequent or high-grade malignancies such as histiocytic sarcoma or T-lymphoblastic lymphoma. The addition of FCM in the routine study of tissue biopsies facilitates the diagnosis of double pathology in five (1%) patients. CONCLUSIONS: FCM is a fast and reliable methodology for phenotyping tissue samples, which easily detects infrequent hematological malignancies, disease-specific phenotypes and clonality in B-cell lymphomas. Moreover, the simultaneous recognition of different cell populations allows the diagnosis of composite cell lymphomas, or double pathologies.

Biopsy↗

Prophylactic growth factor-primed donor lymphocyte infusion using cells reserved at the time of transplantation after allogeneic peripheral blood stem cell transplantation in patients with high-risk hematologic malignancies.

BACKGROUND: Standard allogeneic bone marrow transplantation (BMT) offers only a small chance of cure for most adult patients with advanced hematologic malignancies. The authors postulated that allogeneic peripheral blood stem cell transplantation (PBSCT) followed by prophylactic growth factor-primed donor lymphocyte infusion (DLI) with cells reserved at harvest would maximize the graft-versus-tumor effects in patients with hematologic malignancies who had a high risk of recurrence. METHODS: Seventeen patients with hematologic malignancies who had a high risk of recurrence were allocated on an intent-to-treat basis to allogeneic PBSCT from human leukocyte antigen-matched sibling donors followed by prophylactic growth factor-primed DLI of cells reserved at harvest for transplantation. RESULTS: The median age was 37 years (range, 19-56 years). All donors underwent two or more apheresis procedures. The median numbers of mononuclear cells (MNCs), CD34 positive (CD34+) cells, and CD3+ cells, respectively, that were collected for 17 donors were 9.0 x 10(8) MNCs/kg (range, 4.9-14.4 x 10(8) MNCs/kg), 13.0 x 10(6) CD34+ cells/kg (range, 2.4-75.2 x 10(6) CD34+ cells/kg), and 5.8 x 10(8) CD3+ cells/kg (range, 3.3-9.9 x 10(8) CD3+ cells/kg) for a mean number of 2.35 apheresis procedures (range, 2.0-4.0 procedures). The median numbers of MNCs and CD3+ cells that were cryopreserved were 2.1 x 10(8) MNCs/kg (range, 0.0-4.4 x 10(8) MNCs/kg) and 1.4 x 10(8) CD3+ cells/kg (range, 0.0-3.5 x 10(8) CD3+ cells/kg). Seven of 17 patients received additional PBSCs, with a median of 5.0 x 10(7) CD3+ cells/kg (range, 3.0-9.9 CD3+ cells/kg) between Day 41 and Day 120. The reasons for inability to administer additional PBSCs in 10 patients included early death (n = 4 patients), severe graft-versus-host disease (GVHD) (n = 3 patients), disease recurrence (n = 2 patients), and harvest failure (n = 1 patient). Of seven patients, two patients died of recurrence, and one died of cytomegalovirus pneumonitis. The surviving four patients were free of disease when last assessed (median follow-up, 597 days) but were suffering from chronic GVHD (one patient had limited GVHD, and three patients had extensive GVHD). CONCLUSIONS: The authors suggest that allogeneic PBSCT with prophylactic growth factor-primed DLI may be a potentially curative strategy for the treatment of hematologic malignancies in patients with a high risk of recurrence. Their approach may offer the additional advantage of collecting enough cells at harvest for the potential use of DLI, which is easy, convenient for donors, and cost effective.

Adult↗

Epoetin alfa as a supportive measure in hematologic malignancies.

Anemia is prevalent among cancer patients with hematologic malignancies, with fatigue and weakness, major symptoms of anemia, contributing to diminished quality of life (QOL). Data from several randomized, placebo-controlled clinical trials and three large community-based studies in patients with hematologic malignancies indicate that recombinant human erythropoietin (r-HuEPO, epoetin alfa) can correct anemia, reduce transfusion requirements, and improve QOL. Moreover, a positive relationship has been found between increased hemoglobin (Hb) levels and improvements in QOL assessments, regardless of disease state, with the greatest incremental improvement occurring when Hb increases from 11 g/dL to 12 g/dL (range, 11 to 13 g/dL). This suggests that patients with mild-to-moderate anemia may achieve the greatest QOL benefit from epoetin alfa therapy. Evidence from community-based studies suggests that epoetin alfa administered once weekly has a similar safety and efficacy profile as three-times-weekly administration. Further research is ongoing with less frequent dosing regimens. The beneficial effects of epoetin alfa therapy have been reported in studies involving patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. Evidence also exists that epoetin alfa can benefit patients with myelodysplastic syndromes (MDS), although these results have not been as impressive. Combining epoetin alfa with other cytokine growth factors may confer some additional benefit in these patients, but more rigorous investigation is required.

Anemia↗

Use of recombinant human interleukin-2 in conjunction with syngeneic bone marrow transplantation in mice as a model for control of minimal residual disease in malignant hematologic disorders.

Unlike allogeneic bone marrow transplantation (BMT), autologous BMT is not accompanied by immune-mediated graft-versus-leukemia (GVL) effects; hence, the relapse rate observed after autologous BMT in malignant hematologic disorders is higher than that observed after allogeneic BMT. Autologous BMT represents a much safer medical procedure available for many patients in need in situations where allogeneic BMT is not feasible or risky. The present experiments were designed to investigate whether it might be possible to combine the therapeutic benefits of autologous BMT with additional immunotherapy after BMT. The tumor model used for investigating GVL effects was the murine B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of BALB/c origin. BALB/c mice inoculated with 10(3) BCL1 leukemia cells were treated on day-1 with cyclophosphamide 100 mg/kg and transplanted with normal syngeneic BM cells on day 0. High-dose recombinant interleukin-2 (rIL-2) (100,000 Cetus units x 3/day intraperitoneally x 5 consecutive days) was initiated on day +1, +7, or +21 after BMT. Kinetics of lymphocyte reconstitution after syngeneic BMT indicated a steep increase in the absolute number of peripheral blood lymphocytes on days 17 through 24. All experimental groups were observed for relapse. Mice receiving no rIL-2 therapy relapsed and died within 50 days after BMT, whereas mice receiving rIL-2 showed long-term disease-free survival. Optimal time for administration of rIL-2 was noted at 3 weeks post-BMT, with 90% of the mice surviving with no evidence of disease for more than 1 year. Similarly, when 10(4) BCL1 cells were given 1 day after syngeneic BMT to simulate minimal residual disease after syngeneic BMT, rIL-2 therapy administered at 14 days post-BMT seemed effective in prolonging disease-free survival in contrast to the same regimen given at 1 day after BMT. Our data suggest that immunotherapy with rIL-2 should be further investigated as a new immunotherapeutic tool for decreasing the relapse rate after BMT for hematologic malignancies.

Animals↗

Restriction fragment length polymorphism of bcr in Japanese patients with hematological malignancies.

We surveyed DNAs from patients with various hematological malignancies by Southern blot hybridization to analyze bcr rearrangements, and detected a new restriction fragment length polymorphism (RFLP) of the breakpoint cluster region at a BamHI site in three patients. By using a 1.2-kb HindIII-BglII 3' bcr probe, unusual BamHI restriction enzyme fragments (1.9 kb and 1.4 kb) were detected from the DNAs of three patients with hematological malignancies. DNAs from cultured fibroblasts derived from the skin of a patient, as well as from peripheral leukocytes of the father of a patient and the mother of another patient, showed identical 1.9- and 1.4-kb additional bands, besides a 3.3-kb germline band, establishing that polymorphism, rather than gene arrangement, was responsible for these additional restriction enzyme fragments. However, RFLP was not detected in the DNAs of 40 normal unrelated individuals.

Blotting, Southern↗

A phase II study of neuroimmunotherapy with subcutaneous low-dose IL-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies.

Interleukin-2 (IL-2) has proven to be able to generate an effective anticancer immunity against both solid and hematologic malignancies. Moreover, recent advances in the knowledge of psychoneuroimmunology have demonstrated that anticancer immunity is under neuroendocrine control and that the pineal hormone melatonin (MLT) may stimulate the IL-2-dependent anticancer reaction. Finally, preliminary clinical studies have already shown that the concommitant administration of MLT may amplify the efficacy of IL-2 in the treatment of advanced solid neoplasms, whereas there are no data about MLT influence on IL-2 activity in hematologic malignancies. The aim of the present study was to evaluate the efficacy and tolerability of a neuroimmunotherapeutic combination of low-dose IL-2 plus MLT in advanced hematologic malignancies which did not respond to previous standard therapies. The study included 12 evaluable patients. Tumor histotypes were as follows: non-Hodgkin's lymphoma (NHL) 6; Hodgkin's disease (HD), 2; multiple myeloma, 2; acute myelogenous leukemia (ALM), 1 and chronic myelomonocytic leukemia (CMML), 1. IL-2 was injected subcutaneously at a dose of 3 million IU/day for 6 days per week for 4 weeks, corresponding to one cycle. MLT was given orally at 20 mg/day in the evening, without interruption. In non-progressing patients, a second IL-2 cycle was planned after a 3 week-rest period. A partial response was achieved in one patient with multiple myeloma. Stable disease occurred in 7 other patients (NHL, 3; HD, 1; AML, 1; CLLM, 1; multiple myeloma, 1), whereas the other 4 patients progressed. Therefore, lack of progression was obtained in 8 out of 12 (67%) patients, with a median duration of 21+ months (14-30+ months). The treatment was well tolerated in all patients. These preliminary results would suggest that the concomitant administration of low-dose IL-2 plus the pineal hormone MLT may prolong the survival time in untreatable advanced hematologic malignancies, with results comparable to those previously reported using a more toxic immunotherapy, consisting of high-dose IL-2 alone.

Adolescent↗

Activation of hepatitis B virus infection by chemotherapy containing glucocorticoid in hepatitis B virus carriers with hematologic malignancies.

Among 262 inpatients with hematologic diseases who were referred for chemotherapy or immunosuppressive therapy between January, 1985, and December, 1989, nine (3.4%) patients, including two with Hodgkin's disease (HD), three with acute myeloblastic leukemia, one with chronic myelogenous leukemia, two with multiple myeloma and one with aplastic anemia, were found to be hepatitis B virus (HBV) carriers before their chemotherapy began. All six HBV carriers who received chemotherapy containing glucocorticoid showed mild-to-moderate elevations in serum transaminase levels after the chemotherapy. Five showed a rise in titer of the hepatitis B surface antigen, HBsAg. In contrast, three HBV carriers not receiving glucocorticoid showed no change in serum transaminase after chemotherapy. One HBV carrier with HD suffered from severe icteric hepatitis after the withdrawal of multiagent chemotherapy containing glucocorticoid. The HBV-DNA polymerase rose markedly and was accompanied by a marked rise in titer of HBsAg. The results warn us to keep in mind the possibility of glucocorticoid inducing an activation of HBV infection, which may result in severe hepatitis in some HBV carriers. Although further investigation is required, it is recommended that HBsAg-positive patients with hematologic malignancies should, if possible, be treated without glucocorticoid.

Adult↗

Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies.

PURPOSE: To document the toxicity and activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with pretreated hematologic malignancies. PATIENTS AND METHODS: Two formulations of SAHA (intravenous [IV] and oral) have been assessed in two consecutive phase I trials. In both trials, dose escalation was performed in parallel and independently in patients with solid tumors and hematologic malignancies. Eligible patients were required to have adequate hepatic and renal function, an absolute neutrophil count > or = 500/microL and a platelet count more than 25,000/mL. All patients provided informed consent for study inclusion. RESULTS: A total of 39 patients with hematologic malignancy were enrolled (14 on IV SAHA and 25 on oral SAHA), of whom 35 were treated. The spectrum of diseases included patients with diffuse large B-cell lymphoma (n = 12), Hodgkin's disease (HD; n = 12), multiple myeloma (n = 2), T-cell lymphoma (n = 3), mantle cell lymphoma (n = 2), small lymphocytic lymphoma (n = 2), and myeloid leukemia (n = 2). Major adverse events with the oral formulation included fatigue, diarrhea, anorexia, and dehydration, whereas myelosuppression and thrombocytopenia were more prominent with the IV formulation. Typically, the hematologic toxicities resolved shortly after SAHA was stopped. There was no neutropenic fever or neutropenic sepsis. Reduction in measurable tumor was observed in five patients. One patient with transformed small lymphocytic lymphoma met criteria for complete response, whereas another met the criteria for partial response (PR). One patient with refractory HD had a PR, whereas three patients had stable disease for up to 9 months. CONCLUSION: These results suggest that SAHA has activity in hematologic malignancies including HD and select subtypes of non-Hodgkin's lymphoma.

Administration, Oral↗

Neoplasms associated with paraneoplastic pemphigus: a review with emphasis on non-hematologic malignancy and oral mucosal manifestations.

The review included 163 cases of paraneoplastic pemphigus (PNP) reported between 1990 and 2003, including a new unique case of PNP associated with occult breast cancer and an ovarian cyst of borderline malignancy. Hematologic-related neoplasms or disorders were associated with 84% of the cases, with non-Hodgkin lymphoma (38.6%) as the most frequent, followed by chronic lymphocytic leukemia (18.4%) and Castleman's disease (18.4%). The non-hematologic neoplasms comprised 16% of all cases: epithelial origin-carcinoma (8.6%), mesenchymal origin-sarcoma (6.2%), and malignant melanoma (0.6%). Carcinoma cases comprised 58% of the non-hematologic neoplasms. Carcinoma cases (n = 14) consisted of adenocarcinoma (n = 7), squamous cell carcinoma (n = 2), multiple skin tumors probably basal cell carcinoma (n = 1), and bronchogenic carcinoma (n = 1). Of the 10 (6.2%) sarcoma cases, there was one case each of leiomyosarcoma, liposarcoma, malignant nerve sheath tumor, poorly differentiated sarcoma, reticulum cell sarcoma, dendritic cell sarcoma and inflammatory myofibroblastic tumor. The oral mucosa was involved in all of cases. Isolated oral ulcerations were the first sign in 45% of the cases. Diffuse and persistent oral ulcerations with a progressive course could be a sign of malignancy, either recognized or occult. In the absence of a clear diagnosis, malignancy should be suspected and extensive work-up performed. The full spectrum of signs of PNP may not be present initially. Repeated biopsies, direct and indirect immunofluorescence as well as screening indirect immunofluorescence on murine bladder are required for diagnosis. Clinicians should be highly suspicious when signs and symptoms suggestive of PNP are present in cancer patients, of hematologic and non-hematologic origin.

Adenocarcinoma↗

[Allogeneic peripheral stem cell transplantation (PBSCT) for hematological malignancies].

OBJECTIVE: To evaluate the efficacy of allo-PBSCT in hematological malignancies. METHODS: Sixteen patients with hematological malignancies were treated by allo-PBSCT, started from march 1997. Five of them were ALL (CR1 4, CR2 1), 2 ANLL (CR1), 8 CML(CP 5, AP 3), and one NHL(PR). The median age was 33(18-49) years. Conditioning regimen was TBI 9-10 Gy + CTX 120 mg/kg, or TBI 10 Gy + CTX 120 mg/kg + Vp16 500 mg. A combination of cyclosporine and methotrexate was administered to prevent acute GVHD. All donors received G-CSF 5 micrograms.kg-1.d-1 for 5 to 6 days. One or three leukapheresis procedures were performed by CS 3000 plus blood cell separator to collect a median mononuclear cells of 9 x 10(8)/kg recipient weight [range(5.79-13.7) x 10(8)/kg], including a median CD34+ cells 13.9 x 10(6)/kg [range(5.69-49.00) x 10(6)/kg]. RESULTS: All patients were engrafted and hematopoietic reconstitution was rapid: neutrophils achieving 0.5 x 10(9)/L on day 12 (range, 10-15), platelets > 30 x 10(9)/L on day 13 (range, 8-24). More than grade II aGVHD occurred in 3(18.7%), and localized cGVHD in 3 patients. Leukemia relapse occurred in one patients. The median follow-up duration was 13 months. Eleven patients were alive in disease-free situation. CONCLUSION: Allo-PBSCT can rapidly reconstitute hematopoiesis with incidences of aGVHD and cGVHD not more than that in BMT.

Adolescent↗

Splenectomy in hematologic malignancy.

Fifty patients undergoing splenectomy for complications of hematologic malignancy were reviewed to define indications and results. Primary diseases included lymphoma (n = 14), chronic lymphatic leukemia (n = 13), hairy-cell leukemia (n = 12), myeloid metaplasia (n = 6), and other similar disorders (n = 5). Indications for splenectomy in these patients included cytopenia (n = 37), diagnostic laparotomy (n = 8), "small stomach" syndrome (n = 3), and abdominal pain (n = 2). Splenectomy was performed by the midline approach in 32 patients. In 40 patients, the splenic artery was ligated prior to mobilization of the spleen. The spleens averaged 1650 g; in eight patients accessory spleens were removed. Additional surgical procedures included liver biopsy (n = 30), lymph node biopsy (n = 15), and cholecystectomy (n = 3). Intraoperative blood loss averaged 750 ml. In 14 patients, drainage of the left subphrenic space was used. Splenectomy was effective in 36 of 50 patients. In seven patients, splenectomy was ineffective in correction of cytopenia. Seven mortalities were from bleeding (n = 2), pulmonary embolus (n = 2), postoperative sepsis (n = 2), and progression of primary disease (n = 1). Additional complications included reoperation for bleeding (n = 3), septic complications including pneumonia (n = 14), wound infection (n = 4), and intra-abdominal abscess (n = 2). Splenectomy for the patients with hematologic malignancy is generally effective. Meticulous hemostasis, timely administration of intraoperative platelets, surgical asepsis, and aggressive pulmonary care are essential to reduce morbidity and mortality.

Adult↗

Toxicity and immunomodulatory effects of interleukin-2 after autologous bone marrow transplantation for hematologic malignancies.

Autologous bone marrow transplantation (ABMT) for advanced hematologic malignancies is associated with high relapse rates. Interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells represent a potentially non-cross-resistant therapeutic modality that might prevent or delay relapses if used early after ABMT at a time when the tumor burden is minimal. However, high-dose chemoradiotherapy and ABMT might increase patients' susceptibility to IL-2 toxicity, and might interfere with immunologic responses to IL-2 in vivo. Therefore, to determine safety, tolerance, and immunomodulatory effects of IL-2 therapy early after ABMT, IL-2 was administered by continuous intravenous infusion to 16 patients 14 to 91 days (median, 33) after ABMT for acute leukemia, lymphoma, or multiple myeloma. Patients were sequentially assigned to escalating IL-2 "induction" doses (0.3 to 4.5 x 10(6) U/m2/d, days 1 to 5), and all patients received a nonescalating IL-2 "maintenance" dose (0.3 x 10(6) U/m2/d, days 12 to 21). Most patients exhibited mild to moderate fever, nausea, diarrhea, and/or skin rash with IL-2 infusions. The maximum tolerated "induction" dose was 3.0 x 10(6) U/m2/d; dose-limiting toxicities were hypotension and thrombocytopenia. All toxicities reversed on stopping the IL-2 infusions, and all patients completed "maintenance." Postinfusion lymphocytosis was exhibited by patients at all IL-2 dose levels. With the higher IL-2 doses, increased percentages of patients' PBMC expressed CD16 and CD56, with augmented lysis of K562 and Daudi, reflecting the induction of natural killer and circulating LAK effector activities. Increased LAK precursor activity was exhibited by patients at all IL-2 dose levels. Thus, the IL-2 therapy regimen was safely tolerated after ABMT, and pronounced immunomodulatory effects were observed with the higher IL-2 doses. These studies support the planned use of IL-2 and LAK cells after ABMT in an attempt to reduce relapses of advanced hematologic malignancies.

Adolescent↗