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Between May 1984 and May 1992, 75 children 3-19 (median 9) years of age underwent autologous marrow transplant. Clinical data were obtained from the BMT Registry of the AIEOP (Italian Association of Pediatric Hemato/Oncology). Fifty-six children were transplanted after marrow +/- other site(s) relapse and 19 after an isolated extramedullary relapse. The transplant preparative regimens varied according to the center performing the transplant. Seven patients (9%) died of transplant-related complications. Forty-four (58.6%) of 75 patients relapsed again following autologous BMT. The 5-year DFS was 27.8%. An isolated extramedullary relapse was the only variable that statistically influenced DFS. In this retrospective study, autologous BMT for patients with ALL in second CR following marrow relapse did not offer an encouraging result (13% probability of DFS at 5 years), whereas autologous BMT following an (early) isolated extramedullary relapse resulted in nearly 70% DFS. Autologous BMT may be appropriate for this latter group of patients.

Six patients with chronic hepatitis C who were cured of malignancy were treated with recombinant interferon-alpha at the dose of 4 MU/m2 for 12 months; the post-treatment follow up period was 12 months. Therapy was stopped within 6 months in three patients because of persistently abnormal alanine aminotransferase levels. In the remaining three patients, a complete normalization of alanine aminotransferase levels was obtained during treatment but it was not maintained after the end of interferon therapy. In addition, no patient cleared hepatitis C virus ribonucleic acid in serum. These results suggest that recombinant interferon is not effective in patients with chronic hepatitis C who were cured of a previous malignancy.

Fifty-nine children, aged 1-15 years, with acute myelogenous leukemia (AML) received a bone marrow transplant (BMT) from an HLA-identical sibling (n = 57) or from an identical twin (n = 2), while in first remission (CR). These children represent, to the best of our knowledge, all children grafted in first CR in 11 Italian centers between 1980 and 1990. Patients were prepared with total body irradiation (TBI) plus cyclophosphamide (CY) (n = 50) or melphalan (n = 2) or with busulfan plus CY (n = 7). GVHD prophylaxis consisted of cyclosporin A (n = 48), methotrexate (n = 7) or cyclosporin and methotrexate (n = 2). Survivors have been followed for 21-137 months (median 59 months). Actuarial relapse-free survival was 58% at 66-137 months (95% confidence interval (CI) 44-72). Actuarial risk of relapse was 23% at 48 months (95% CI 10.9-34.8). Risk of non-relapse deaths was 33% in the period 1980-87 and 4% in the period 1988-90 (p = 0.02). In multivariate analysis patients with a blood cell count > 14 x 10(9)/l at diagnosis showed a lower relapse-free survival compared with patients with counts < 14 x 10(9)/l (p = 0.006). We could not detect an effect of FAB subtype, patient age, time to achieve remission or transplant-related variables, including year of BMT, on relapse-free survival. In conclusion, allogeneic marrow transplantation can achieve long-term relapse-free survival in over 50% of children with AML and should be considered as consolidation therapy if a matched sibling is available.(ABSTRACT TRUNCATED AT 250 WORDS)

Photopheresis (ECP) is a new therapy for oncological and autoimmune diseases consisting in the reinfusion of 3-9 x 10(9) leukocytes, taken from the patient by leukapheresis, and treated in an extracorporeal system with 8-methoxypsoralen and ultraviolet light A. Nine patients affected by T cell immunomediated diseases (2 scleroderma, 1 chronic GVHD, 1 polyarteritis, 1 rheumatoid arthritis and 4 heart transplant patients with numerous episodes of acute rejection) were treated with ECP. Photopheresis was performed on 2 consecutive days every 3-4 weeks. All patients affected by autoimmune diseases experienced an improvement during treatment with ECP. In 2 of the 4 patients with heart transplant, rejection was reversed by photopheresis. No major side effects were observed during the treatment. In conclusion ECP is a safe and well tolerated therapy. Although the number of patients is small, ECP seems to be an effective modality in many diseases.

From July 1987 to July 1991, 12 children underwent AMBT following high-dose cytarabine (HD Ara-C) plus 14.4 Gy hyperfractionated total body irradiation (hyfr-TBI) for early isolated extramedullary relapse of ALL, while in first BM remission. No patient received intrathecal prophylaxis following AMBT. One patient died on day +5 due to sepsis and three patients, two of them transplanted in second and third CNS relapse, respectively, died from BM relapse occurring 1.5, 4 and 5 months after AMBT. Eight of the 12 survive disease-free with a median follow-up of 24 months (range 14-62 months). The toxicity of HD Ara-C plus hyfr-TBI was acceptable and well controlled with supportive therapy. These results suggest that ABMT following HD Ara-C plus hyfr-TBI may eradicate leukemia from extramedullary sites of ALL relapse.

From March, 1990 to February, 1992, we administered fluconazole as antifungal prophylaxis at doses of 3-5 mg/kg/day to 40 patients with prolonged and severe neutropenia following intensive chemotherapy. Fungemia was observed in 3 out 40 patients, and all three of them were due to Candida non-albicans strains: two Candida parapsilosis and one Candida guilliermondi. In vitro sensitivity tests showed that all three isolated strains were susceptible to amphotericin. In one case, Candida guilliermondi was tested for sensitivity to fluconazole and found to be resistant. We conclude that fluconazole prophylaxis proved effective in preventing Candida albicans infections, but it could also contribute to the emergence of Candida non-albicans strains. It might be possible that fluconazole at higher doses could prevent the selection of less susceptible Candida strains.

We reviewed the records of all patients with a diagnosis of malignancy who were treated at our center and who had not had chemotherapy for at least 18 months, to assess the prevalence of chronic hepatitis B surface antigen (HBsAg)-negative hepatitis, to assess the prevalence of a marker of hepatitis C virus infection, and to determine the severity of chronic liver disease. Of 557 eligible patients, 38 (6.8%) had chronic HBsAg-negative hepatitis. Of these 38 patients, 20 (52.6%) had a marker of hepatitis C virus infection. The prevalence of chronic HBsAg-negative hepatitis was higher in patients previously treated for leukemia than in patients treated for another malignancy (11.8% vs 4.6%; p = 0.004). The liver biopsy revealed chronic active hepatitis or cirrhosis or both in 8 (28%) of 28 patients with clinical chronic HBsAg-negative hepatitis. Four patients without hepatitis C virus infection who underwent liver biopsy had hepatitis B virus antigen in the liver, confirmed by immunohistochemistry studies. One patient uninfected with hepatitis C virus had hemochromatosis. We conclude that infection with hepatitis C virus was the major cause of chronic HBsAg-negative hepatitis in pediatric patients previously treated for malignancy; the cause remained unidentified in 30% of the patients.

In order to identify subtle changes in cell morphology and nuclear pattern modification during thymus ontogenesis, cell image analysis using System for Analytical Microscopy in Biological Applications (SAMBA 200) was applied in 9 stages of rat thymus development. The morphometric and chromatin parameters made it possible not only to identify automatically between the two main cell populations in the thymus gland (lymphoid and epithelial cells), but also to classify automatically 5 lymphoid sub-populations (lymphoid stem cells, lymphoblasts, large lymphocytes, medium lymphocytes and small lymphocytes). The evaluation of the 18 parameters during the lymphoid cell differentiation was studied in detail. The nuclear texture parameters made it possible to discriminate, in each cell subpopulation, 4 phases of cell cycle (G0, G1, S-phase, and cells in G2). Evaluation of the nuclear parameters of the cell cycle in each lymphoid sub-population was studied in this investigation. The results illustrate the high majority of the lymphoid stem cells at the 14-day-old embryo stage while in the 20-day-old embryo the small lymphocytes become the main part of the whole lymphoid population. From the continuously renewed modification of lymphoid nuclear image analysis we discuss the origin of thymus lymphocytes. Lymphoid cells can be distinguished into different functional states and the striking morphological changes appearing during cell differentiation are related with drastic structural changes occurring in chromatin pattern from undifferentiated lymphoid stem cells to small lymphocytes. Terminal cell differentiation is associated with inhibited cell proliferation. The relative increase of chromatin condensation and nuclear pattern heterogeneity which reaches an extreme in small lymphocytes is accompanied by a progressive diminution of the nuclear area during the successive differentiation of the lymphoid population. Using one parameter of the nuclear texture features from the co-occurrence matrix (as LM or CON) and one parameter of the nuclear textures from the run-length section matrix (as GLD or RPC) the image analysis can discriminate between the different states of lymphoid cell differentiation.

In our Pediatric Haemato-Oncology Unit, 42 young patients cured of their malignancy were left with chronic delta hepatitis. The severity of liver disease in many of these patients prompted us to start a pilot study on the effect of recombinant alpha 2b interferon, given at a dose of 5 MU/square meter thrice weekly. All nine patients included in the study (five males, mean age: 15 years) had well-compensated liver disease, including five cases with active hepatitis and cirrhosis. At the end of the 3rd month of therapy, two patients with cirrhosis developed a biochemical exacerbation leading to hepatic decompensation, which was fatal in one case. The reasons for this unfavourable outcome remain unclear. Basic immunological tests were normal, but one of the two patients was the single case with anti-liver-kidney microsome antibodies. On the other hand, both patients seroconverted from hepatitis B e antigen to antibody at the time of exacerbation, suggesting that liver damage could have been the result of cell-mediated cytotoxicity to hepatitis B virus antigens. The results of this study, which has been interrupted at the 4th month, suggest that interferon therapy for chronic delta hepatitis has to be considered cautiously in young patients cured of pediatric malignancies. In fact, no beneficial effect was seen and the treatment appeared to be harmful in at least two out of nine patients treated.

Seventy-two consecutive patients with acute lymphocytic leukemia (ALL) who had undergone liver biopsy within 3 months of completing chemotherapy were studied to evaluate histological features after 2 to 3 years of chemotherapy and to correlate liver disease to the treatment schedule, the number of transfused blood units, and the identified etiology. Fibrosis due to antiblastic drugs was the most frequent histological finding. Histological liver disease was not related either to the chemotherapy schedule or the number of transfused blood units. HBV with or without delta virus and HCV infections were related to a more severe histological liver disease. In about 40% patients with chronic liver disease, no etiology was demonstrated. Immunohistochemistry revealed HBcAg in the liver of 3 HBsAg-negative patients. In conclusion, liver biopsy could be useful in patients with persistent abnormal liver function tests after the completion of chemotherapy and in patients with markers for hepatotropic virus infection.

Acute non lymphocytic leukemia (AnLL) is the most common second malignancy (SM) in survivors of childhood Hodgkin's Disease (HD). Chemotherapy responsiveness is usually poor and death ensues briefly after diagnosis. We report the case of a 13 year-old girl, affected by HD, stage IV, mixed cellularity, who developed AnLL one year after the HD treatment was stopped. Autologous Bone Marrow Transplantation (ABMT) was performed 9 months after complete remission (CR) was achieved by chemotherapy. Presently, the patient is alive and on continues CR, 3 years and 7 months after ABMT. ABMT may be a promising approach for secondary AnLL, the prognosis of which is almost invariably fatal with conventional chemotherapy.

A 20-year-old patient with chronic delta virus hepatitis (CDVH), cured of acute lymphoblastic leukemia (ALL), developed hepatocellular carcinoma (HCC) 14 years after hepatitis B virus (HBV) infection. The association between chronic HBV infection and HCC is well known, but CDVH patients affected by HCC are rarely reported in literature. To our knowledge, the case we describe is the first HCC case reported in literature occurring in a young boy with CDVH. We could expect further similar cases, considering 1) the high prevalence of HDV infection in children affected by ALL in our series, 2) the previous ALL treatment, and 3) a possible natural predisposition to cancer.

We studied 145 children with acute lymphocytic leukemia (ALL) in remission who had been off chemotherapy for at least 2 years, to assess the prevalence of hepatitis delta virus (HDV) infection, and to determine whether HDV infection was associated with more severe chronic liver disease. The prevalence of chronic HBV infection was 41.5% (60/145). The prevalence of HDV infection among these patients with chronic HBV infection was 50% (30/60). Eighty-five patients were HBsAg-negative. There was evidence that HDV-infected children had more severe chronic liver disease than did HBsAg-positive, anti-HDV-negative patients: (1) their serum ALT levels were significantly more likely to be elevated at long-term follow-up (27/30 vs. 10/26, p = 0.0001); (2) their mean ALT levels were significantly higher 3 years after the cessation of chemotherapy (128 vs. 84 IU/L, p = 0.001); and (3) they were more likely to have either chronic acute hepatitis or cirrhosis when liver biopsy was done (18/23 vs. 6/18, p = 0.0038). Children who were HBsAg-negative had the lowest alanine aminotransferase (ALT) levels and were least likely to have chronic active hepatitis or cirrhosis (3/31). We conclude that infection with HDV in children with ALL is associated with serious chronic liver disease. In long-term survivors, HDV infection is a major cause of morbidity and an adverse prognostic factor in terms of leukemia-free survival.

The incidence of acute and chronic liver damage and its relation to hepatitis B virus (HBV) infection was evaluated in 164 consecutive children with acute leukemia seen in ten Italian hemato-pediatric units. Thirteen out of 164 children (7.9%) had acute hepatitis (AH) during treatment, while 8/90 (8.8%) showed an acute exacerbation of liver damage within 6 months after therapy withdrawal. Seven of the 13 children with AH while on therapy were HBsAg positive. In 12/13 cases, liver disease progressed to chronicity. Five of eight children who developed AH after completion of treatment were HBsAg positive. Eighty-nine patients (54.2%) developed biochemical evidence of chronic hepatitis during therapy; 48/89 were followed after cessation of treatment and 33 of them showed persisting evidence of liver cell necrosis. Thirty-three out of 133 children (24.8%) tested for serum HBsAg were found positive: 26 (78.7%) of them developed chronic hepatitis. Sixty-four out of 133 patients were evaluated after cessation of treatment: Chronic hepatitis persisted in 16/22 HBsAg-positive (72.7%) and in 17/42 HBsAg-negative (40.4%) children during follow-up. The outcome of these liver diseases after treatment withdrawal did not differ significantly in relation to HBV serology, suggesting that viral rather than toxic agents were responsible for liver damage also in most HBsAg-negative patients. The high incidence of chronic HBV infection in children with leukemia found in this multicentric study could suggest a need for active immunization with HBV vaccine, but the efficacy of such approach in this clinical setting is still to be validated.