The indications for splenectomy in hematological diseases are well known. In particular, they include idiopathic thrombocytopenic purpura (ITP), hereditary spherocytosis (HS) and Hodgkin's disease (HD) (as a part of subdiaphragmatic staging). We present here our initial experience of 10 cases (6 ITP, 2 HS and 2 HD) managed with a laparoscopic approach as opposed to the traditional laparotomy. Advantages over the open operation include decrease of post-operative pain, pulmonary sequelae and infections, cosmetic advantages, faster recovery and reduced hospitalization.

Adult↗

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Development of autoimmune thyroid diseases during long-term treatment of hematological malignancies with alpha-interferons.

In recent years recombinant alpha-interferons (alpha-IFNs) have been widely used in the treatment of several hematological malignancies. Prolonged courses of IFN have been shown to induce autoantibodies and to support the exacerbation or even the development of autoimmune diseases. In this report we describe the development of symptomatic autoimmune thyroid diseases in 4 (7.4%) out of 54 patients in chronic treatment with recombinant alpha-IFNs in our department. Two patients developed a disease resembling Hashimoto's thyroiditis after 17 and 49 months of continuous IFN treatment, while the other two developed a typical Graves' disease after 41 and 52 months of therapy. The mechanism by which IFN induces autoimmune thyroid diseases, the choice of searching for anti-thyroid autoantibodies before starting long-term IFN treatment, the option of discontinuing IFN therapy in the presence of overt thyroid diseases, and the management of these diseases are discussed.

Autoimmune Diseases↗

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The expression of the multidrug resistance related glycoprotein in adult acute lymphoblastic leukemia.

BACKGROUND: More than 50% of adults with acute lymphoblastic leukemia (ALL) actually die with resistant leukemia. The multidrug resistance (MDR) related P170 glycoprotein may be involved in treatment failure. METHODS: P170 content of leukemic cells was assayed by immunocytochemistry with the MRK-16 monoclonal antibody in 41 consecutive cases of adult ALL (27 at onset and 14 at relapse). RESULTS: Positive cells were found in 11/14 cases at relapse and in 18/27 cases at onset. All cases with a high WBC, FAB L3, B-mature phenotype, and t(9; 22) were positive. In the 27 patients who were studied at onset and were treated with the same protocol, the overall failure rate was 44% in negative cases and 83% in positive cases. CONCLUSION: P170 overexpression may contribute to drug resistance and to chemotherapy failure in adult ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

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p170-dependent multidrug resistance. Restoring full sensitivity to idarubicin with verapamil and cyclosporin A derivatives.

BACKGROUND: Cell sensitivity to anthracyclines and other drugs depends on several factors, including overexpression of a 170Kd transmembrane glycoprotein (P170) that enhances drug efflux from the cells. Since the result of treatment is negatively related to the expression of P170 in leukemia, malignant lymphoma and other tumors, it is important to investigate drugs and methods that can modify multidrug resistance (MDR). MATERIALS AND METHODS: Using an MTT-microcultured tetrazolium colorimetric method, we assayed sensitivity to daunorubicin (DNR) and to its 4-demethoxy derivative idarubicin (IDA) in two MDR cell lines (CEM VLB and LOVO DX) and in their respective non-MDR parental lines (CEM and LOVO 109), with and without three MDR modifiers, namely the D-isomer of verapamil (DVRP), cyclosporin A (CyA) and the new CyA derivative SDZ PSC 833. RESULTS: We showed that down-modulation of resistance with MDR modifiers was greater for DNR than for IDA in MDR cells. However, we also demonstrated that restoration of full sensitivity could only be achieved for IDA, not for DNR. DVRP and CyA in combination were more effective than either compound alone and could abolish P170-related resistance to IDA at concentrations of 1-2 microM and 1.6 microM, respectively. SDZ PSC 833 alone was even more effective and set MDR to zero at a concentration ranging between 0.8 and 1.6 microM. CONCLUSIONS: These data suggest that combinations of IDA and MDR modifiers may improve the results of cancer and leukemia treatment and that they are worth investigating in vivo, with attention to possible effects on drug pharmacokinetics and on normal tissue damage.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Overexpression of MDR-related p170 glycoprotein in chronic myeloid leukemia.

BACKGROUND AND METHODS: Philadelphia (Ph) positive chronic myeloid leukemia (CML) cannot be induced into a true remission with conventional chemotherapy. Blast cells and precursors obtained from 51 Ph+ CML cases were assayed for expression of the multidrug resistance (MDR)-associated glycoprotein (p170) by immunocytochemistry (APAAP) with the MRK-16 monoclonal antibody. RESULTS AND CONCLUSIONS: Positive cells were found in 11/17 cases in chronic phase (65%), in 4/8 cases in accelerated phase, and in 23/26 cases in blastic phase (89%). The proportion of positive cells, which ranged between less than 1% and 95%, was higher in blastic phase (mean 32 +/- 29.9) than in chronic phase (mean 3 +/- 5.3) (p = 0.006). These findings show that p170 overexpression is common in Ph+ CML, especially after progression to blastic phase, and suggest that p170-related MDR may contribute significantly to treatment failure.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Expression of multidrug resistance gene (MDR-1) in human normal leukocytes.

BACKGROUND: The mdr-1 gene, which codes for a 170-kd transmembrane glycoprotein (P170), is frequently overexpressed in multidrug resistant (MDR) tumor cell lines and in spontaneous tumors, including leukemia and lymphoma. However, it is also constitutively expressed as a normal gene in normal tissues. METHODS: We used human mdr-1 cDNA and three anti-P170 monoclonal antibodies (MoAbs: MRK-16, C-219 and JSB-1) to investigate the normal peripheral blood leukocyte content of mdr-1 specific mRNA and of P170 through immunocytochemistry and flow cytometry. RESULTS: We did not find any increase in mdr-1-specific mRNA, while small amounts of P170 were easily detectable in about two thirds of the lymphocytes and monocytes and in about one third of the granulocytes. The level of P170 expression in leukocytes was similar to that found in non-MDR tumor cell lines. CONCLUSIONS: mdr-1 is constitutively expressed in human normal leukocytes at levels that cannot significantly affect drug resistance. Accordingly, low-level mdr-1 expression in leukemic cells should not be considered a label of pleiotropic drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Autologous bone marrow transplantation in non-Hodgkin's lymphomas: prediction of mononuclear cell yield in bone marrow harvests.

We retrospectively analyzed the factors influencing the mononuclear cell (MNC) yield on bone marrow (BM) harvests in a cohort of 15 non-Hodgkin's lymphoma patients undergoing autologous bone marrow transplantation. All the patients were treated with the F-MACHOP regimen and four of them also received radiotherapy on bulky disease. Before harvesting, the patients underwent complete peripheral blood (PB) count, BM biopsy and aspirate. WBC and MNC/microL were determined on the pre-harvest PB and BM aspirate samples using an automated counter. The following variables were examined in univariate and multivariate regression analysis for possible influence on the MNC yield in the harvests: age, sex, number of cycles of CT, previous radiotherapy, state of the disease at the time of harvest, interval between the end of therapy and BM harvest, cellularity of the BM biopsy, absolute WBC and MNC counts in the PB before harvesting, absolute WBC and MNC counts in the BM aspirate performed before harvesting. The amount of marrow harvested was constant for all patients: 21.2 +/- 0.24 microL/kg B.W. Among the factors analyzed, two correlated strongly with the MNC yield/kg B.W. in the harvests: the MNC count in pre-harvest PB (r = 0.823; p = 0.0001) and the MNC count in pre-harvest BM aspirate (r = 0.802; p = 0.0003). A regression equation was generated that allows calculation of the MNC/kg yield prior to harvesting.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Computed tomography, magnetic resonance and gallium 67 scintigraphy for the imaging of residual lymphoma.

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Adolescent↗

PubMedDate not supplied

Overcoming PGP-related multidrug resistance. The cyclosporine derivative SDZ PSC 833 can abolish the resistance to methoxy-morpholynil-doxorubicin.

BACKGROUND: The results obtained so far in studies designed to neutralize P glycoprotein (PGP)-related multidrug resistance (MDR) by using MDR reversal agents, have not yet fulfilled the promise of the experiments which were performed in vitro. In order to improve PGP-related MDR neutralization, we tested in vitro the activity of the cyclosporine derivative SDZ PSC 833 (PSC) together with doxorubicin (DOX) and with two new DOX derivatives named 4' iodo 4' deoxy-doxorubicin (IODODOX) and methoxy-morpholynil-doxorubicin (MMDOX, FCE 23762) using four different human cell lines and their multi-drug resistant variants. METHODS: Anthracycline toxicity was evaluated by using the MTT method after a 7-day culture with continuous exposure to the antitumor drugs with or without the addition of PSC. RESULTS: PSC significantly downmodulated the toxicity of all three anthracyclines in all the four cell systems. However, despite the great increase caused by PSC in the toxicity of DOX and a more modest effect on the toxicity of the two DOX derivatives, this MDR reversal agent could only completely block the PGP mediated MMDOX resistance whereas DOX refractoriness was only decreased. CONCLUSIONS: The combination of MMDOX or IODODOX with PSC 1.6 microM is more efficient than the combination of DOX plus PSC for the full reversion of PGP-mediated drug resistance. Careful clinical studies are required to evaluate if these associations can also effectively and safely neutralize MDR in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

The F-MACHOP regimen in the treatment of aggressive non-Hodgkin's lymphomas: a single center experience in 72 patients.

BACKGROUND: Since July 1991 we have employed the F-MACHOP regimen for the treatment of aggressive non-Hodgkin's lymphomas (NHL). The aim of the present study was to evaluate the response rate and the toxicity of this chemotherapy program. PATIENTS AND METHODS: Seventy-two consecutive patients entered the study and were treated with the F-MACHOP regimen for 6 planned courses, given every 21 days. G- or GM-CSF were administered whenever required. RESULTS: Sixty-six patients (92%) obtained a response: 38 (53%) a complete remission (CR) and 28 (39%) a partial remission (PR); 4 (6%) proved to be resistant and 2 (3%) died of chemotherapy-related toxicity. Fifty-seven patients with a good performance status were subsequently selected to undergo autologous stem cell transplantation (ASCT). During chemotherapy, grade III-IV neutropenia was observed in 59% of the patients; a significant drop in hemoglobin levels was detected, with blood transfusions being required in 21% of the cases; platelet counts were unaffected. The main extrahematological toxic events were: alopecia (100% of the patients), osteoarthromyalgias (58%), grade I-II neuropathy (53%) and grade I-II hepatic toxicity (43%). CONCLUSIONS: Our study confirms the efficacy of the F-MACHOP regimen in obtaining a high rate of response (CR + PR) in most aggressive NHL cases, with an acceptable toxicity and a low rate of toxic deaths. This regimen enables the majority of patients to be selected for ASCT as consolidation therapy without significant toxicity.

Adolescent↗

PubMedDate not supplied

Effect of fludarabine and arabinosylcytosine on multidrug resistant cells.

BACKGROUND AND OBJECTIVE: Anthracyclines are first-line drugs in the treatment of acute leukemia, but the sensitivity of leukemic cells to anthracyclines can be downmodulated by multidrug resistance (MDR) transport proteins like Pgp. Pgp overexpression is negatively related to treatment response. Alternative drugs may be required to overcome the MDR problem. METHODS: Arabinosylcytosine (ara-C) and 9-beta-D-arabinofuranosyl-2-fluoro-adenine monophosphate (fludarabine, F-ara) were tested alone and in combination in four pairs of leukemia and tumor non-MDR and MDR cell lines. Toxicity was assayed by growth inhibition with the microcultured MTT assay. RESULTS: MDR cells were more sensitive than or as sensitive as non-MDR cells to ara-C and to F-ara alone. The resistance index to ara-C was decreased upon pre-exposure of the MDR cells to low-dose F-ara (10 ng/mL), showing that the combination of ara-C and F-ara was more active on MDR cells than on non-MDR parental ones. INTERPRETATION AND CONCLUSIONS: Neither sensitivity to ara-C nor sensitivity to F-ara was influenced by Pgp overexpression. These data provide a rationale for more extensive and more intensive testing of combinations of ara-C and F-ara in Pgp-mediated MDR acute leukemia. In relapsed/resistant and in secondary acute leukemias, increasing the dose of ara-C and combining ara-C with F-ara might be more rewarding than administering anthracyclines or other Pgp-processable compounds.

Antineoplastic Agents↗

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Retrospective analysis of 23 cases with peripheral T-cell lymphoma, unspecified: clinical characteristics and outcome.

BACKGROUND AND OBJECTIVE: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of post-thymic malignancies relatively uncommon in the Western world and their prognosis and therapeutic approach are still not well defined. The aim of this study was to retrospectively analyze the clinical, hematological and histological features at diagnosis, the relevance of the International Prognostic Index and the outcome of a group of 23 patients affected by peripheral T-cell lymphoma, unspecified (PTCL-U), according to the Revised European-American Classification of Lymphoid Neoplasms (REAL), observed between September 1985 and April 1995 at our Institution. METHODS: Patients were separated into different prognostic groups according to Ann Arbor stage, cell size and International Prognostic Index. All patients had been treated with multiagent combination chemotherapy, mainly CHOP (9 cases) and F-MACHOP (9 cases), and were evaluable for response. The treatment was intensified with allogeneic bone marrow transplantation (BMT) in 1 patient and with autologous BMT in 4 patients. RESULTS: Median age was 55 (range 18-77) years and 70% of the patients were males. Four patients were in stage II (17%), 5 in stage III (22%) and 14 in stage IV (61%). Patient risk was classified according to the International Prognostic Index as follows: 8 cases (35%) low risk, 2 cases (9%) low-intermediate, 8 cases (35%) high-intermediate, 5 cases (21%) high. Median follow-up time was 20 months (range 2-132). Median progression-free survival (PFS) and overall survival (OS) for all the patients studied were 10 and 34 months, respectively. Stage IV was associated with a poorer response rate and a shorter PFS (median 6 months) and OS (median 32 months). No statistical correlation was found between cell size and overall response (complete + partial remission), PFS (p = 0.38) or OS (p = 0.59), although a better trend was observed for the large cell group. A less favorable outcome was observed in patients in the high-intermediate + high risk groups, where median PFS and OS were 7 and 24 months, respectively, than in patients in the low + low-intermediate risk groups. No difference in response or outcome was detected between patients treated with the CHOP and the F-MACHOP regimens, while all 5 patients given high-dose chemotherapy and BMT are alive and in CR. INTERPRETATION AND CONCLUSIONS: Our experience shows that PTCL-U are rare lymphomas frequently having an aggressive presentation. The response to conventional polychemotherapeutic regimens like CHOP or F-MACHOP is generally poor, especially in those cases with advanced stage and a high-intermediate or high International Prognostic Index. The observation that all five patients who were treated with bone marrow transplantation are alive and in complete remission suggests using this strategy, particularly in young patients with a poor International Prognostic Index.

Adolescent↗