Michela Ribersani

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.

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.

Bone marrow transplantation for thalassemia from alternative related donors: improved outcomes with a new approach

Bone marrow transplantation (BMT) performance can be limited by a lack of ideal donors, and the role of alternative donor hematopoietic cell transplantation in thalassemia is not well established. Here we used a new treatment protocol (Pc 26.1) in 16 thalassemia patients to perform BMT using phenotypically HLA-identical or 1-antigen-mismatched relatives (related donors [RDs]). We compared these results with HLA-matched sibling (matched sibling donors [MSDs]) BMT in 66 patients. The entire RD group and 88% of MSD group had sustained engraftment. Rejection incidence was 0% in the RD and 12% (95% confidence interval [95% CI], 6%-21%) in MSD groups (P = .15), with respective thalassemia-free survival probabilities of 94% (95% CI, 63%-99%) and 82% (95% CI, 70%-89%) (P = .24). Transplant-related mortality was 6% (95% CI, 1%-26%) in the RD group and 8% (95% CI, 3%-16%) in the MSD group (P = .83). The intensified new protocol was not associated with increased nonhematologic toxicity. The present data show that the Pc 26.1 preparative regimen allows thalassemia patients to safely undergo BMT from RDs who are not HLA-matched siblings, with transplant outcomes similar to patients with MSD grafts.

Intermediate-dose cyclophosphamide and granulocyte colony-stimulating factor is a valid alternative to high-dose cyclophosphamide for mobilizing peripheral blood CD34+ cells in patients with multiple myeloma

Peripheral blood stem cells (PBSC) are widely used in the setting of dose-intensive chemotherapies in patients with multiple myeloma (MM). Although the granulocyte colony-stimulating factor (G-CSF), following chemotherapy or not, is considered the standard growth factor for mobilizing PBSC, the optimal chemotherapeutic regimen still remains to be defined. Cyclophosphamide (CTX) is an effective drug in the treatment of MM which is capable of mobilizing PBSC if followed by growth factors, even though administration of high-dose CTX (7 g/m2) results in severe toxicity requiring hospitalization and increasing costs. We have retrospectively analyzed the results obtained in 38 newly diagnosed MM patients treated with 1.2 g/m2 CTX on days 1 and 3 combined with 40 mg dexamethasone daily for 4 days. The results were compared with those obtained in 25 newly diagnosed MM patients treated with 7 g/m2 CTX. A higher number of CD34+ cells/kg was collected during the first leukapheresis and a statistically significant lower consumption of G-CSF was observed following two doses of 1.2 g/m2 CTX compared to the 7 g/m2 CTX dose. The possibility of treating patients with day-hospital regimens, with a satisfactory yield of hematopoietic cells harvested, may have relevant economic implications for treatment strategies in MM patients.

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

Abstract: 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 patients 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.

High-Dose Idarubicin, Busulphan and Melphalan for Autologous Stem Cell Transplantation in Multiple Myeloma Responsive to DAV Chemotherapy: Comparison with a Historical Control

Since 1997, 32 newly diagnosed multiple myeloma patients responsive to DAV chemotherapy were autografted with idarubicin-intensified busulphan-melphalan (ida-bu-mel). Main endpoints of the study were transplant-related toxicity, overall survival (OS) and progression-free survival (PFS). The results were compared with a historical control group of 38 patients treated with the ‘standard’ bu-mel regimen. Concerning time to engraftment, no significant difference was observed between the two groups, while toxicity was significantly higher in the intensive conditioning group, regarding grade IV mucositis, duration of profound neutropenia, incidence of infections and platelet requirement. Five-year OS and PFS are 73 versus 78% and 37 versus 48% for the intensive and standard regimen, respectively (p value not significant). The ida-bu-mel schedule appears to be a feasible and effective regimen for newly diagnosed multiple myeloma patients; nevertheless, no apparent benefit in OS and PFS arises from the comparison with a historical control treated with standard bu-mel, which is better tolerated and at least equally effective.

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.

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.

Haematopoietic stem cell transplantation in Nigerian sickle cell anaemia children patients

Background: Sickle cell anaemia (SCA) remains associated with high risks of morbidity and early death. Children with SCA are at high risk for ischaemic stroke and transient ischaemic attacks, secondary to intracranial arteriopathy involving carotid and cerebral arteries. Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCA. We report our experience with transplantation in a group of patients with the Black African variant of SCA. Patients and Methods: This study included 31 consecutive SCA patients who underwent bone marrow transplantation from human leukocyte antigen (HLA)-identical sibling donors between 2010 and 2014 following a myeloablative-conditioning regimen. Results: The median patient age was 10 years (range 2–17 years). Before transplantation, 14 patients had recurrent, painful, vaso-occlusive crisis; ten patients had recurrent painful crisis in association with acute chest syndrome; three patients experienced ischaemic stroke and recurrent vaso-occlusive crisis; two patients experienced ischaemic stroke; one patient exhibited leukocytosis; and one patient exhibited priapism. Of the 31 patients, 28 survived without sickle cell disease, with Lansky/Karnofsky scores of 100. All surviving patients remained free of any SCA-related events after transplantation. Conclusion: The protocols used for the preparation to the transplant in thalassaemia are very effective also in the other severe haemoglobinopathy as in the sickle cell anaemia with 90% disease free survival. Today, if a SCA patient has a HLA identical family member, the cellular gene therapy through the transplantation of the allogeneic haemopoietic cell should be performed. Tomorrow, hopefully, the autologous genetically corrected stem cell will break down the wall of the immunological incompatibility.