Flavio Rossetti

Autologous bone marrow transplantation for treatment of isolated central nervous system relapse of childhood acute lymphoblastic leukemia

The purpose of this study was to assess the role of ABMT in children with ALL who are in 2nd CR after an early isolated CNS relapse. All children experiencing an isolated CNS relapse at 10 AIEOP centers (Associazione Italiana Emato-Oncologia Pediatrica) from 1986 to 1992 were eligible for this study. The series included 69 patients who relapsed within 3 years from diagnosis: 19 underwent ABMT, nine patients underwent ALLO-BMT from an HLA-identical sibling, and 41 received conventional chemotherapy (CHEMO). Statistical analysis was performed using a Cox’s regression model, adjusting for the waiting time before transplantation and prognostic factors. The 5 years DFS was 56.3% (s.e. 12.3) for patients in the ABMT group. This compared favorably with the poor result (12.6% (s.e. 5.9)) seen in the CHEMO group. The risk of failures was reduced by one-third in the ABMT group as compared to the CHEMO group in the multivariate analysis (P < 0.01). in the allo group four out of nine patients were in ccr 4–5 years post-transplant. this study suggests that abmt may also represent a valuable therapeutic choice for patients lacking a matched familiar donor in 2nd cr after an early isolated cns relapse.

Chronic hepatitis B surface antigen-negative hepatitis after treatment of malignancy

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.

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in Italy

From January 1984 to December 1994, ABMT was performed on 154 children (101 males, 53 females; median age 10, range 3–21 years) with ALL and registered for BMT by the AIEOP (Italian Association of Paediatric Haemato-Oncology). All patients were in CR: 98 were in 2nd CR and 56 were in >2nd CR. Fifteen children (9.7%) died of transplant-related mortality. Ninety-five patients (61.6%) relapsed at a median of 5 (range 1–42) months after ABMT. The 8-year EFS according to pre-BMT status was 34.6% (s.e. 4.9) for 2nd CR patients and 10.6% (s.e. 5.6) for patients in >2nd CR. By univariate analysis, site of relapse (isolated extramedullary (IE) vs BM: EFS = 68.5% vs 18.2%; P < 0.0001) and tbi containing regimen (tbi vs no TBI: EFS = 48.1 vs 15.4%; P = 0.0023) were significant factors for 2nd CR patients. When the 2nd CR subset with BM involvement was analysed, TBI became insignificant (EFS = 25.4 vs 11.8%). No factors influenced EFS in patients in >2nd CR. By multivariate analysis, site of relapse was the only significant factor in 2nd CR patients (P < 0.0001). in conclusion, abmt is an effective treatment after one early ie relapse. few patients can be rescued after bm relapse.

High-Dose Cytosine Arabinoside and Viridans Streptococcus Sepsis in Children with Leukemia

We report three cases of fulminant sepsis due to viridans streptococci in leukemic children treated with high-dose cytosine arabinoside (Ara-C). The major predisposing factors to this occurrence are the presence of oropharingeal mucositis, which is the entry of streptococci into the bloodstream, and the use of antibiotic prophylactic regimens against gram-negative bacteria. In order to avoid fatal events during viridans streptococci sepsis, specific measures such as penicillin prophylaxis or early antibiotic treatment are needed. We suggest that the prompt empiric use of a glycopeptide antibiotic in addition to the conventional association of a beta-lactam plus an aminoglycoside may significantly decrease the mortality rate due to fulminant streptococci sepsis while the patient is severely neutropenic. In this regard, our current policy considers the addition of an anti-gram-positive antibiotic to the first-choice fever treatment in neutropenic patients who have received high-dose Ara-C.

Interferon for chronic hepatitis C in patients cured of malignancy.

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 amnotransferase 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.

LEUKEMIA AND LIVER-DISEASE IN CHILDHOOD - CLINICAL AND HISTOLOGICAL-EVALUATION

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.

Delta virus and childhood leukemia

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.

Applications of Extracorporeal Photochemotherapy in “Non-oncological” Diseases

Photopheresis (ECP) is a new therapy for oncological and autoimmune diseases consisting in the reinfusion of 3-9x 109 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.

CHRONIC TYPE B HEPATITIS AND PRIMARY HEPATOCELLULAR CARCINOMA IN CHILDREN

Sir: Recent studies have shown that primary hepatocellular carcinoma (PHC) in childhood is aetiologically related to hepatitis B virus (HBV) infection [1]. So far, there are no prospective studies, however, of the development of PHC in children with chronic type B hepatitis, and little is known about risk factors and early diagnosis of the turnout in this population. In 1976 in Padua we started a longitudinal study of biopsy-proven chronic type B hepatitis, and since 1985 we have introduced alpha-fetoprotein determination among routine tests to be performed every 6 months during follow up. Overall 103 children, including 5 with histological features of cirrhosis, have been followed up for a mean period of 6.1 _+ 2.9 years (mean + SD). During the observation period none of the patients had signs of liver failure or portal hypertension, but one out of five children with cirrhosis developed high alpha-fetoprotein levels and was found to have PHC, before the appearance of any clinical symptoms. We report here the clinical history of this patient. The first child of apparently healthy, non-consanguineous parents, was born in 1978 after an uncomplicated gestation and full-term delivery. He was found to be HBsAg positive at the age of 15 months when his younger brother died of fulminant hepatitis B. At this time his mother was also found to be HBsAg positive. The boy came to our attention at the age of 24 months: he was a well grown asymptomatic child with moderate hepatomegaly and a threefold increase of alanine aminotransferase (ALT) levels. Liver function tests were normal, hepatitis Be antigen (HBeAg) was negative while antiHBe was positive. Six months later liver biopsy showed features of chronic active hepatitis with associated cirrhosis, while HBV DNA was undetectable in serum. By the age of 36 months ALT had become normal and 15 months later liver biopsy was consistent with inactive cirrhosis. Since then the patient has remained asymptomatic, with normal ALT levels. He was followed at regular intervals up to October 1985 when alpha4etoprotein levels were normal. During subsequent years we received information about the childs health but could not see the patient until February 1989.

Is Gamma Glutamil Transferase a Sensitive Marker for Detection of the Non‐A/Non‐B Carrier State?

We read the interesting study reported by B. Brotman and A.M. Prince about gamma glutamyl transferase (GGTP) as a potential surrogate marker for the detection of the non-Ahon-B carrier state [I]. 37 children cured from leukemia or another oncological disease and off therapy for at least as long as 2 years were checked. All of them were treated and followed up at the Hemato-Oncologic-Division Department of Pediatrics in Padua (Italy). They had chronic hepatitis with clinical evidence of non-A/non-B infection: in fact they received blood transfusion at the onset of their oncological disease and later developed a chronic liver disease; abnormal levels of sGPT and histological findings of infectious liver damage were found but no serological evidence for HBV, CMV or EBV infection. Only 3 of the 37 had increased GGTP levels at the last