Estimates of Environmental Exposure to Radiofrequency Electromagnetic Fields and Risk of Lymphoma Subtypes.

We investigated the association between environmental exposure to radiofrequency electromagnetic fields (RF-EMF) and risk of lymphoma subtypes in a case-control study comprised of 322 patients and 444 individuals serving as controls in Sardinia, Italy in 1998-2004. Questionnaire information included the self-reported distance of the three longest held residential addresses from fixed radio-television transmitters and mobile phone base stations. We georeferenced the residential addresses of all study subjects and obtained the spatial coordinates of mobile phone base stations. For each address within a 500-meter radius from a mobile phone base station, we estimated the RF-EMF intensity using predictions from spatial models, and we performed RF-EMF measurements at the door in the subset of the longest held addresses within a 250-meter radius. We calculated risk of lymphoma and its major subtypes associated with the RF-EMF exposure metrics with unconditional logistic regression, adjusting by age, gender and years of education. In the analysis of self-reported data, risk associated with residence in proximity (within 50 meters) to fixed radio-television transmitters was likewise elevated for lymphoma overall [odds ratio = 2.7, 95% confidence interval = 1.5-4.6], and for the major lymphoma subtypes. With reference to mobile phone base stations, we did not observe an association with either the self-reported, or the geocoded distance from mobile phone base stations. RF-EMF measurements did not vary by case-control status. By comparing the self-reports to the geocoded data, we discovered that the cases tended to underestimate the distance from mobile phone base stations differentially from the controls ( P = 0.073). The interpretation of our findings is compromised by the limited study size, particularly in the analysis of the individual lymphoma subtypes, and the unavailability of the spatial coordinates of radio-television transmitters. Nonetheless, our results do not support the hypothesis of a link between environmental exposure to RF-EMF from mobile phone base stations and risk of lymphoma subtypes.

A 30-year epidemiologic survey (1974-2003) of haematological malignancies on the island of Sardinia: temporal changes in incidence and a geographic comparison of incidence rates.

In a previous survey of newly diagnosed haematological malignancies (HMs) in Sardinia from 1974 to 1993, we observed a marked increase in the incidence of many HMs that we chiefly attributed to improvements in case ascertainment. To better define the nature of this increase, we extended the survey by an additional decade (1994-2003), applying the same previously used methods. The incidence of HMs further increased from 1994 to 2003. The incidence rate of total HMs (THMs), standardised to the world population, was 30.15 × 10(5) person-years vs. 21.58 from 1984 to 1993 and 15.26 from 1974 to 1983. The temporal variations in the incidence differed in different HMs and were correlated with the diseases clinical characteristics and the increased availability of diagnostic tools and skills in Sardinia. These observations support the hypothesis that the temporal differences in the incidence rates observed for many HMs in Sardinia over the 30-year survey period were caused by temporal differences in diagnostic efficiency rather than by disease occurrence. An important exception was the increase in non-Hodgkin's lymphoma, which represents a true increase in occurrence, similarly to most Western countries. The incidence rates of HMs already having or reaching stable values in the decade 1994-2003 were similar to those of most Western countries. No significant evidence emerged to suggest that Sardinian particularities influenced the occurrence of HMs. This study demonstrates the extent to which diagnostic efficiency can influence incidence evaluations and emphasises the importance of prolonged observation to determine the validity of incidence rates for both temporal and geographic comparisons.

Genetic analysis of the 2q33 region containing CD28-CTLA4-ICOS genes: association with non-Hodgkin's lymphoma.

There is strong evidence that altered immunological function entails an increased risk of lymphoma, although the current knowledge of aetiological factors for lymphomas is limited. The CTLA4 gene encodes a receptor that provides a negative signal to the T-cell once an immune response is initiated and completed. We analysed the 2q33 chromosomal region harbouring CD28, CTLA4 and ICOS genes, which are closely linked and have related functions in immune regulation, for association in 100 non-Hodgkin's lymphoma (NHL) patients and in 128 healthy controls; both groups originated from Sardinia. There was a strong association of the CTLA4 49A and the 3'-untranslated region (AT)(82) alleles with NHL [odds ratio (OR) = 2, 95% confidence interval (CI) = 1.2-3.2, and OR = 1.6, 95% CI = 1.1-2.4 respectively]. CTLA4-318C:49A:(AT)(82) was the most represented haplotype in the studied population and was associated with NHL (P = 0.0029, OR = 1.76, 95% CI = 1.2-2.5). Strong linkage disequilibrium was detected between CD28, CTLA4 and ICOS and a 'common' haplotype was found very frequently among NHLs. However, no independent association between CD28, ICOS, D2S72 markers and NHL was observed. Our findings enable CTLA4 from adjacent functionally related genes as the true causative risk gene for NHL susceptibility at least in Sardinian patients.

Secondary acute myeloid leukaemia: results of conventional treatments. Experience of GIMEMA trials.

BACKGROUND: The aim of the study was to evaluate the outcome of acute myeloid leukaemia (AML) in patients with a previous malignancy (sAML) treated with chemo- and/or radiotherapy, enrolled in conventional trials. PATIENTS AND METHODS: In a multicentre setting, a prospective non-concurrent analysis was performed on 2513 new AML patients, aged 12-78 years, consecutively enrolled in EORTC-GIMEMA trials between 1987 and 2001. Thirty-eight patients with sAML were identified and compared with a group of 114 de novo AML patients matched according to age, French-American-British criteria, white blood cell count at diagnosis, trial and time of diagnosis of AML. Induction treatment response, disease-free survival (DFS), duration and overall survival (OS) were evaluated in the two groups. RESULTS: Comparing the complete remission (CR) rate between 38 sAML patients and 114 de novo AML patients, selected according to the previously reported criteria, we observed no difference in the CR rates [25/38 (66%) versus 66/114 (58%); Pearson chi(2) 0.7393, P=0.390] as well as no differences while comparing the DFS and the OS between the two groups. CONCLUSION: The results of this study suggest that sAML patients are characterised by a good performance status permitting their recruitment in conventional trials without a previous myelodysplastic phase. Similar to de novo AML patients, sAML patients show good response to treatment and the possibility of cure.

Primary mediastinal large B-cell lymphoma (PMLBCL): long-term results from a retrospective multicentre Italian experience in 138 patients treated with CHOP or MACOP-B/VACOP-B.

The optimal treatment of primary mediastinal large B-cell lymphoma (PMLBCL) is still undefined. In the absence of randomised studies, we retrospectively analysed: (a) the effectiveness of two chemotherapy regimens (CHOP vs MACOP-B/VACOP-B) in complete remission (CR) achievement and event-free survival (EFS) and (b) the role of mediastinal involved-field radiotherapy (IF-RT) as consolidation. From 1982 to 1999, 138 consecutive patients affected by PMLBCL were treated in 13 Italian institutions with CHOP (43) or MACOP-B/VACOP-B (95). The two groups of patients were similar as regard to age, gender, presence of bulky mediastinal mass, pleural effusion, stage and international prognostic indexes category of risk. Overall, 75.5% of patients in CR received IF-RT as consolidation. Complete remission was 51.1% in the CHOP group and 80% in MACOP-B/VACOP-B (P<0.001). Relapse occurred in 22.7% of CHOP- and in 9.2% of MACOP-B/VACOP-B-treated patients (n.s.). Event-free patients were 39.5% in CHOP and 75.7% in the MACOP-B/VACOP-B group (P<0.001). The addition of IF-RT as consolidation improved the outcome, irrespectively of the type of chemotherapy (P=0.04). At a multivariate analysis, achievement of CR (P<0.0001) and type of CT (MACOP-B/VACOP-B) retained the significance for OS (P=0.008) and EFS (P=0.03). In our experience, MACOP-B/VACOP-B appears to positively influence OS and EFS in patients affected by PMLBCL, as compared to CHOP. Consolidation IF-RT on mediastinum further improves the outcome of CR patients.

Partial deletions of long arm of chromosome 6: biologic and clinical implications in adult acute lymphoblastic leukemia.

Within 285 adult acute lymphoblastic leukemias (ALL) included in the multicenter GIMEMA 0496 trial and prospectively studied by conventional cytogenetics, 18 cases (6%) with long arm deletion of chromosome 6 (6q) were identified. These cases were divided into: (i) del(6q) only (n = 6); (ii) del(6q) plus other numerical and/or structural abnormalities (n = 8); (iii) del(6q) and other 'specific' translocations (n = 4). The biologic and clinical features of the patients carrying this anomaly, as well as their outcome, were compared with those of 267 patients without del(6q). A T cell phenotype was more frequently associated with del(6q) cases in general (P = 0.001) and particularly with cases presenting del(6q) as the isolated abnormality (P = 0.0027). No significant difference with respect to multidrug resistance (MDR)/P glycoprotein expression was observed between the two groups of patients (21% vs 28% of MDR-positive cases, respectively). A BCR-ABL fusion transcript was less frequently detected in cases with del(6q) (11%) compared with those without the anomaly (29%). p15 and p16 deletions were identified by Southern blot analysis in 21% of cases with del(6q) and in 26% of cases without del(6q). In this latter group, a T cell phenotype was less frequently associated with p15 and/or p16 deletion than in the group carrying del(6q) (36% vs 100% of cases, P = 0.011). Overall, patients with ALL and del(6q) had a high complete remission (CR) rate (83%); however, they had a lower 18 month event-free survival (31% vs 41%) and a higher relapse rate (70% vs 37%, P = 0.02) compared with patients without del(6q). To date, this is the largest series of adult ALL cases reported with del(6q) homogeneously treated, which have also been prospectively studied for MDR expression and for the detection of known fusion genes. This anomaly, as an isolated change, identifies a subset of cases with hyperleukocytosis (median WBC count 52 x 10(9)/l) and a strict correlation with a T cell phenotype. Overall, del(6q) seems to be associated with an unfavorable clinical outcome, although this finding will need to be confirmed by extended FISH analysis.

Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO).

One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), 6-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 x 10(9)/L (range, 0-0.5 x 10(9)/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27). Of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%. The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% versus 98% for patients with neutrophil counts less than versus greater than 0.2 x 10(9)/L (P =.001) and 88% versus 87% for patients aged less than versus more than 16 years (P =.8). The actuarial probability of discontinuing CyA was 38%. Patients who did not achieve a white blood cell (WBC) count of 5 x 10(9)/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%). This update confirms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome. Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF. (Blood. 2000;95:1931-1934)

Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO)

About 30% of patients with severe aplastic anaemia (SAA) unresponsive to one course of immunosuppressive (IS) therapy with antithymocyte or antilymphocyte globulin can achieve complete or partial remission after a second IS treatment. Among various second-line treatments, rabbit ATG (r-ATG) could represent a safe and effective alternative to horse ALG (h-ALG). In a multicentre study, 30 patients with SAA (17 males and 13 females, median age 21 years, range 2-67) not responding to a first course with h-ALG plus cyclosporin (CyA) and granulocyte colony stimulating factor (G-CSF), were given a second course using r-ATG (3.5 mg/kg/d for 5 d), CyA (5 mg/kg orally from day 1 to 180) and G-CSF (5 microg/kg subcutaneously from day 1 to 90). The median interval between first and second treatment was 151 d (range 58-361 d). No relevant side-effects were observed, but one patient died early during treatment because of sepsis. Overall response, defined as transfusion independence, was achieved in 23/30 (77%) patients after a median time of 95 d (range 14-377). Nine patients (30%) achieved complete remission (neutrophils >/=2.0 x 109/l, haemoglobin >/=11 g/dl and platelets >/=100 x 109/l). The overall survival rate was 93% with a median follow-up of 914 d (range 121-2278). So far, no patient has relapsed. Female gender was significantly associated with a poorer likelihood to respond (P = 0.0006). These data suggest that r-ATG is a safe and effective alternative to h-ALG for SAA patients unresponsive to first-line IS treatment.

Graft-versus-leukemia effects after allogeneic bone marrow transplantation are active also in the presence of clones with chromosomal anomalies in addition to the Ph chromosome.

Two male patients with Philadelphia-chromosome (Ph+) chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation (ABMT) in the first chronic phase after busulfan treatment. In both cases, the donor was a sister, and engrafting was demonstrated by chromosome analyses which showed only donor cells in the BM. Cytogenetic relapse occurred 29 and 30 months after ABMT, respectively, when host cells reappeared: in both cases, the Ph and additional anomalies typical of the blastic phase of CML were evident. We then monitored the chromosome picture for 52 and 39 months, respectively: no striking evolution occurred, and cells with the Ph and additional anomalies persisted together with donor cells, which were a minority in the first patient and a great majority in the second throughout the observation period. A clinical relapse was observed in the first patient, but the disease never progressed to a blastic phase, whereas the second patient has not relapsed 7 years after ABMT. We reviewed data from the literature on cytogenetic relapse after ABMT in CML without clinical relapse, especially the 12 patients in whom cytogenetic relapse included chromosome anomalies in addition to the Ph, as in our patients. We suggest that graft-versus-leukemia (GVL) reactions in such patients are able to arrest progression of the leukemic blastic clone and prevent a possible relapse in blastic phase.

Acute intestinal pseudo-obstruction: report of two cases.

Two cases of acute intestinal pseudo-obstruction diagnosed over a 6-year period are reported. One patient had acute colonic pseudo-obstruction (Ogilvie's syndrome) associated with severe cardiopulmonary disease and the other a rare idiopathic small bowel pseudo-obstruction: both were treated successfully. The various treatments and a short review of the literature are presented.

Acute nonlymphocytic leukemia with eosinophilic differentiation.

Four cases of de novo acute nonlymphocytic leukemia (ANLL) with early eosinophilic differentiation are described. The clinical course did not differ from that of the usual forms of ANLL. Morphologic and cytochemical features that can support this diagnosis are discussed. Particularly, the cyanide-resistant peroxidase stain appeared to be a specific marker of eosinophilic differentiation. Acute eosinophilic leukemia is a distinct entity, and this unusual subtype of ANLL can be set apart from other forms of ANLL characterized by hypereosinophilia.

HLA antigens in Sardinian patients with diabetes mellitus.

HLA-B8 and HLA-Bw15, two antigens associated with juvenile diabetes mellitus in Caucasians of North Europe, have a very low frequency in Sardinian population, who nevertheless have a high frequency of diabetes. The association between diabetes and HLA in Sardinian population has therefore been investigated in 60 patients with diabetes, mellitus (32 with juvenile diabetes and 28 with maturity onset diabetes) and 96 normal, unrelated random controls. No disturbance of HLA distributions was found in maturity onset diabetes, but the frequencies of B8 and Bw35 were increased among juvenile diabetics (18.7 percent and 28.1 percent respectively, compared with 2.0 and 11.4 percent in healthy controls). B18 antigen frequency was also increased, although not significantly, in juvenile diabetes mellitus (65.6 percent compared with 50 percent in controls). In contrast the frequency of HLA-Bw15 in two groups of diabetics differed little from that of controls.