Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients.

PURPOSE: Nongastrointestinal locations represent about 30% to 40% of all low-grade mucosa-associated lymphoid tissue (MALT) lymphomas. We report a retrospective analysis of 75 patients with nongastrointestinal low-grade MALT lymphoma, presenting their clinical, therapeutic, and follow-up data with respect to the initial location of the lymphoma. PATIENTS AND METHODS: From January 1988 to October 1997, 75 patients with untreated nongastrointestinal low-grade MALT lymphoma were subjected to treatments ranging from local radiotherapy and local interferon alfa administration to chemotherapy. The lymphomas were located in the lung (19 patients), orbital soft tissue (16 patients), skin (seven patients), thyroid (seven patients), lachrymal gland (six patients), conjunctiva (six patients), salivary gland (six patients), breast (three patients), eyelid (two patients), larynx (one patient), bone marrow (one patient), and trachea (one patient). RESULTS: Complete and partial remissions were achieved in 59 (79%) and 16 (21%) of the 75 patients, respectively, with an overall response rate of 100%. All but two of the patients are still alive, with a median follow-up of 47 months; these two patients died from other causes. The estimated time to treatment failure rate is 30% at 5 years. In the thyroid and lachrymal gland sites, no relapses were reported. CONCLUSION: Our data regarding the largest reported series of nongastrointestinal MALT lymphomas confirm the good prognosis of this particular clinicopathologic entity and the significant efficacy of different therapeutic approaches to specific sites.

Intravenous melphalan and dexamethasone followed by lymphoblastoid alpha interferon in higher risk multiple myeloma patients.

Intermittent courses of melphalan and prednisone is still the standard chemotherapy for the initial treatment of multiple myeloma (MM) in patients who cannot undergo high-dose chemotherapy/radiotherapy with either allogeneic or autologous stem cell transplantation. However, the absorption of the drug from the gastrointestinal tract is highly variable from patient to patient and therefore, different plasma levels of the drug are reached in the blood of individual MM patients. In order to overcome this limitation we decided to use intermediate dose (15-30 mg/m2, day 1) intravenous melphalan in resistant or relapsing MM patients as well as in untreated patients not eligible for a more aggressive protocol. Moreover, considering the good results obtained by other investigators using dexamethasone alone or associated with interferon in the treatment of resistant or relapsing MM patients, dexamethasone (40 mg total dose, day 1) and the lymphoblastoid alpha interferon (3 MU, 3 times a week x 3 weeks, from day 8 to day 26 of each course) were added to intravenous melphalan. Courses were repeated every 5 weeks for a total of 6 cycles. We treated 62 MM patients obtaining a response (defined as reduction > 25% of the initial monoclonal component value associated with disappearance of the clinical symptoms) in 38 out 62 evaluable patients (61%) and stable disease (defined as a decrease of < 25% in the base-line serum monoclonal component level with disappearance of all symptoms present at diagnosis) in 9 (14.5%) more patients. The overall median response duration was 14 months and the overall median survival duration (from the time of inclusion in this protocol) for the 62 patients entered into the study was 34 months. No severe (Grade 3-4 of the WHO) hematological as well as non hematological toxicities were observed. This lack of severe toxicity allowed us to administer the drugs on an outpatient basis. In conclusion, the overall response and the low grade of toxicity in this category of patients are encouraging and suggest that this protocol is both effective and safe treatment for high risk MM patients.

Hematopoietic SCT for the Black African and non-Black African variants of sickle cell anemia.

Sickle cell anemia (SCA) remains associated with high risks of morbidity and early death. Allogeneic hematopoietic SCT (HSCT) is the only curative treatment for SCA. We report our experience with transplantation in a group of patients with the non-Black African variant and the Black African variant of SCA. This study included 40 consecutive SCA patients (13 patients with the non-Black African variant and 27 with the Black African variant) who underwent BM transplantation from HLA-identical sibling donors between June 2004 and May 2013, following a myeloablative-conditioning regimen. All patients obtained sustained engraftment. One patient (non-Black African variant) became a stable mixed chimera with 25% donor cells more than 6 years after transplantation. The probabilities of survival, SCA-free survival and TRM at 5 years after transplant were 91%, 91% and 9%, respectively. All surviving patients remained free of any SCA-related events after transplantation. Our results confirm that it is possible to offer a greater than 90% chance of cure to children with SCA. HSCT should be considered the standard of care for who have an HLA-identical donor, before complications result from the sickling of RBC.

Isolated granulocytic sarcoma of the skin in an elderly patient: good response to treatment with local radiotherapy and low-dose methotrexate.

Granulocytic sarcoma of the skin is frequently associated with haematological diseases and is rarely isolated. The disease generally develops into acute systemic myeloid leukaemia and is associated with a poor prognosis. We report an elderly patient presenting isolated granulocytic sarcoma of the skin who showed a very good response to treatment with local radiotherapy and low-dose methotrexate.

Cell cycle regulation and induction of apoptosis by IL-6 variants on the multiple myeloma cell line XG-1.

Interleukin-6 (IL-6) serum levels and the proliferative activity of bone marrow plasma cells have been described as important prognostic factors for survival duration in multiple myeloma (MM) patients. Since growth of neoplastic plasma cells is frequently promoted by IL-6, inhibition of its activity has been considered for the management of MM patients. With a similar rationale, IL-6 variants characterized by wild-type or increased affinity for the ligand-specific IL-6 alpha receptor chain and reduced ability to bind and/or dimerize the gp 130 chain have recently been generated. In the present study, the antiproliferative effects of the variants Sant1, Sant5, and Sant7, characterized by increasing antagonistic activity, were investigated by means of a detailed cell kinetic and apoptotic analysis of the IL-6-dependent MM XG-1 cell line. A significant reduction in the mean percent of XG-1 cells in active S-phase (DNA/bromodeoxyuridine incorporation) from 41% to 28.1% (p=0.04), 25.8% (p=0.04), and 15.3% (p=0.02), respectively, was observed using Sant1, Sant5, and Sant7. These effects were confirmed using the acridine-orange (AO) flow-cytometric technique, which showed a similar reduction of S-phase (34.2% of baseline value) in the presence of Sant1, Sant5, and Sant7, as well as a significant G1b arrest (from 44.5% to 47.6%, 48%, and 64.9%). Furthermore, IL-6 variants were capable of down-regulating the G1 cell cycle regulatory protein cyclin D1 expression. Cell cycle effects were coupled with a significant increase of apoptosis, measured by the AO and the terminal deoxynucleotidyl transferase assays, from 12.9% (control culture with IL-6) to 21.2% (Sant1), 29.1% (Sant5), and 23.5% (Sant7). These results were comparable to those obtained by depriving XG-1 of recombinant IL-6. Our study documents the antiproliferative activity exerted by IL-6 mutants on the XG-1 cell line, thus supporting the investigation of these molecules on primary MM cells.

Hepatocellular mitochondrial alterations in patients with chronic hepatitis C: ultrastructural and biochemical findings.

OBJECTIVE: Hepatitis C virus (HCV) infection is associated with increased lipoperoxidation, which may lead to interference with mitochondrial function with possible depletion of mitochondrial DNA (mtDNA). We correlated the ultrastructural findings of liver biopsy specimens with the lipoperoxidation markers and contents of mtDNA in chronic hepatitis C (CHC) patients with a different HCV genotype. METHODS: Liver biopsy samples obtained from 75 CHC patients were processed for histological and electron microscopic examination. Twenty-two subjects without known liver disease served as controls. Hepatic glutathione in its reduced (H-GSH) and oxidized (H-GSSG) forms were determined from biopsy specimens by high-performance liquid chromatography. Plasmatic and lymphocytic GSH and erythrocytic malonyldialdehyde (MDA) were also determined, along with the ratio between mtDNA and nuclear DNA (nDNA). RESULTS: Ultrastructural alterations of the mitochondria were documented in 23 patients with genotype 1b, compared with 15 patients with genotype 2a/2c (p = 0.020) and seven patients with genotype 3a (p < 0.001). A significant depletion of H-GSH and lymphocytic GSH, an increase of H-GSSG and MDA, and a reduction of the mtDNA/nDNA ratio were documented in patients with genotype 1b, compared with patients with genotype 2a/2c and 3a and with controls. CONCLUSIONS: In patients with genotype 1b frequent ultrastructural alterations of the mitochondria may be observed, and the depletion of mtDNA in these patients may represent the expression of a greater impairment of the process of oxidative phosphorylation. An increased production of free radicals in patients with genotype 1b may influence the evolution of the liver disease by enhancement of the cytopathic effect of HCV.

Serum ferritin and hepatic glutathione concentrations in chronic hepatitis C patients related to the hepatitis C virus genotype.

BACKGROUND/AIMS: Increased serum ferritin is thought to be responsible for activation of glutathione turnover in patients with chronic hepatitis C. The aim of the study was to evaluate a possible correlation between levels of serum ferritin and concentrations of hepatic, plasmatic and lymphocytic glutathione in a selected cohort of chronic hepatitis C patients in relation to the hepatitis C virus genotype. METHODS: The study considered 130 chronic hepatitis C patients and 23 control subjects. Hepatic glutathione was determined from biopsy liver specimens by high performance liquid chromatography. Total Iron Score was assessed by scoring iron separately within hepatocytes, sinusoidal cells and portal tracts. Blood samples were tested for determination of serum ferritin, and plasmatic and lymphocytic glutathione levels. Hepatic and erythocyte malonyldialdehyde were also determined along with peripheral blood mononuclear cell cytotoxic assay. RESULTS: Patients with genotype 1b showed higher levels of serum ferritin compared to patients with genotype 2a/2c and 3a and to controls, along with a significant reduction of the concentrations of hepatic, plasmatic and lymphocytic glutathione and peripheral blood mononuclear cell cytotoxic activity. The levels of serum ferritin correlated significantly to Total Iron Score, to hepatic, plasmatic and lymphocytic glutathione, to hepatic and erythrocyte malonyldialdehyde and to peripheral blood mononuclear cell cytotoxic activity. CONCLUSIONS: The levels of serum ferritin correlate significantly to lipoperoxidation markers in chronic hepatitis C patients. The increased production of free radicals with a reduced peripheral blood mononuclear cell cytotoxic activity may represent, especially in patients with genotype 1b, a factor underlying the resistance to interferon therapy and may influence the evolution of the liver disease by enhancement of the cytopathic effect of hepatitis C virus.

Acute promyelocytic leukaemia: epidemiology and risk factors. A report of the GIMEMA Italian archive of adult acute leukaemia. GIMEMA Cooperative Group.

Acute promyelocytic leukaemia (APL) exhibits peculiar epidemiological, clinical, cytogenetic and molecular features, compared to the other acute myeloid leukaemias (AML). Data on epidemiology and occupational risk factors for APL desumed from the GIMEMA archive are reported and compared with those of the other AML. An exploratory case-case study was designed on AML patients from 56 haematology centres in Italy. Overall, 4296 patients older than 15 yr with a new diagnosis of acute leukaemia were recorded between July 1992 and July 1997. Of these, 335 were classified as APL, and 2894 as other AML. The median age of APL patients was 43 compared to 59 yr for the other AML (p < 0.00001). In order to identify peculiar risk factors for APL development, different parameters were compared in the 2 groups. After adjusting by age no significant differences were observed with regard to education, lifetime prevalence of cancer among siblings and previous diseases in the patient's history. Occupational exposure as a possible risk factor for APL showed no increased risk compared to other AML among farmers, builders and leather workers. A significant association was found in electricians (OR=4.4, 95% CI=2.0-9.7) and a weak association was found in wood workers (OR=3.2, 95% CI=0.8-10.8). The proportion of APL with respect to other AML was significantly higher in the north east of Italy compared to the rest of the country (OR=1.7, 95% CI=1.3-2.2). These data confirm the younger age of APL patients compared to the other AML. A possible role of electromagnetic fields is suggested by the higher risk of APL in electrical workers and in the more industrialized areas of the country.