Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group.

Main objective of this study was to confirm that surgery alone is an effective and safe treatment for localised resectable neuroblastoma except stage 2 with amplified MYCN gene (MYCNA). Of 427 eligible stages 1-2 patients, 411 had normal MYCN and 16 had MYCNA. Of the 288 stage 1 patients with normal MYCN, 1 died of complications and 16 relapsed, 2 of whom died; 5-year relapse-free survival (RFS) and overall survival (OS) rates were 94.3% (95% confidence interval (CI): 91.6-97) and 98.9% (95% CI: 97.7-100), respectively. Of the 123 stage 2 patients with normal MYCN, 1 died of sepsis and 22 relapsed, 8 of whom died (RFS 82.8%, 95% CI: 76.2-89.5; OS 93.2%, 95% CI: 88.7-97.8). In stage 2, OS and RFS were worse for patients with elevated LDH and unfavourable histopathology. Of 16 children with MYCNA, 7 were stage 1 (5 relapses and 4 deaths) and 9 were stage 2 (3 relapses and 2 deaths) patients. In conclusion, surgery alone yielded excellent OS for both stage 1 and 2 neuroblastoma without MYCNA, although stage 2 patients with unfavourable histopathology and elevated LDH suffered a high number of relapses. Both stage 1 and 2 patients with MYCNA were at greater risk of relapse.

Efficacy of carboplatin given in a phase II window study to children and adolescents with newly diagnosed metastatic soft tissue sarcoma.

AIM: The activity of carboplatin was evaluated in a phase II window study in previously untreated children with metastatic soft tissue sarcoma. METHODS: Children with poor-risk metastatic disease (over 10 years and/or with bone/bone marrow involvement) treated in the SIOP MMT 98 study were scheduled to receive two courses of intravenous carboplatin (area under curve [AUC] of 10), 21 days apart. RESULTS: Sixteen eligible patients were entered into the rhabdomyosarcoma (RMS) group. Response (complete remission or partial remission) was seen in five children (31%, 95% confidence interval (CI) 14-56%). Ten eligible patients with other soft tissue sarcomas were recruited into the non-RMS group. Two responses (20%, 95% CI 6-51%) were seen. Toxicity in both groups was predictable nausea, vomiting and marrow suppression and there were no toxic deaths. CONCLUSION: Single-agent carboplatin at AUC of 10 has an acceptable toxicity profile but only moderate efficacy in poor-risk metastatic soft tissue sarcoma.

Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group 'Survey' 1982-1992.

In 1982 the European Neuroblastoma Study Group (ENSG) established a prospective registry for patients with newly diagnosed neuroblastoma ('The ENSG Survey'). Clinical information was collected primarily to: (a) establish an ENSG database; and (b) investigate prognostic factors in neuroblastoma. This paper summarises the results of the survey. By 1992, 1277 patients with a median age of 26 months (range: 0-289 months), gender ratio of 1.19 M:F had been registered from 30 centres. The median follow-up of survivors is 9.7 years (range: 1-14 years). Overall 5-year survival (S) is 45% (95% CI 42-48%), and event-free survival (EFS) is 43% (95% CI 40-45%). For both survival and EFS the key established prognostic factors, stage and age, are highly significant (P<0.001). In particular, patients under 1 year of age at diagnosis, whatever the disease stage, had a more favourable prognosis than older patients; stage 2 (EFS 93% (95% (CI 85-97) versus 76% (95% CI 67-86), P=0.02), stage 3 (EFS 91% (95% CI 82-96) versus 52% (95% CI 44-60), P<0.001) and stage 4 (EFS 59% (95% CI 48-69) versus 16% (95% CI 13-19), P<0.001). Multivariate analysis established that the anatomical location of the primary tumour (i.e. abdominal versus other sites) and primary tumour volume also conferred a statistically significant difference. In stage 4 disease the 20% of patients without demonstrable bone marrow involvement had a more favourable prognosis than those with infiltrated marrow (EFS 36% (95% CI 13-19) versus 16% (95% CI 29-45), P<0.001). Urine catecholamine metabolite levels (raised versus normal), histology (ganglioneuroblastoma versus neuroblastoma) and gender had no significant effect on outcome after stage and age were accounted for. 5-year survival following first relapse is only 5.6% (95% CI 2.8-8.4). This ENSG Survey provides secure data for future comparisons with new prognostic factors and treatment programmes.

Itraconazole oral solution as antifungal prophylaxis in children undergoing stem cell transplantation or intensive chemotherapy for haematological disorders.

This was an open study of oral antifungal prophylaxis in 103 neutropenic children aged 0-14 (median 5) years. Most (90%) were undergoing transplantation for haematological conditions (77% allogeneic BMT, 7% autologous BMT, 6% PBSC transplants and 10% chemotherapy alone). They received 5.0 mg/kg itraconazole/day (in 10 mg/ml cyclodextrin solution). Where possible, prophylaxis was started at least 7 days before the onset of neutropenia and continued until neutrophil recovery. Of the 103 who entered the study, 47 completed the course of prophylaxis, 27 withdrew because of poor compliance, 19 because of adverse events and 10 for other reasons. Two patients died during the study and another five died within the subsequent 30 days. No proven systemic fungal infections occurred, but 26 patients received i.v. amphotericin for antibiotic-unresponsive pyrexia. One patient received amphotericin for mycologically confirmed oesophageal candidosis. Three patients developed suspected oral candidosis but none was mycologically proven and no treatment was given. Serious adverse events (other than death) occurred in 21 patients, including convulsions (7), suspected drug interactions (6), abdominal pain (4) and constipation (4). The most common adverse events considered definitely or possibly related to itraconazole were vomiting (12), abnormal liver function (5) and abdominal pain (3). Tolerability of study medication at end-point was rated as good (55%), moderate (11%), poor (17%) or unacceptable (17%). Some patients had poor oral intakes due to mucositis. No unexpected problems of safety or tolerability were encountered. We conclude that itraconazole oral solution may be used as antifungal prophylaxis for neutropenic children.

Sputum induction as an aid to diagnosis of active cytomegalovirus infection following bone marrow transplantation.

An 8-year-old boy received an allogeneic bone marrow transplant (BMT) for relapsed T cell acute lymphoblastic leukaemia. Because he was seropositive for cytomegalovirus (CMV), serial virological specimens were taken throughout the transplant period, and included those obtained by sputum induction. Sixty-one days following BMT he became unwell, and was found to have mild tachypnoea and reduced oxygen saturations. All investigations were negative, apart from that obtained by sputum induction, which was positive for CMV. He received appropriate therapy with good response. We conclude that the technique of sputum induction can be applied to aid diagnosis of active CMV infection following BMT.

Acyclovir-resistant herpes simplex virus infections in a bone marrow transplant population.

Over a 3-month period, four patients who had received unrelated donor (UD) bone marrow transplants (BMT) presented with severe mucocutaneous herpes simplex virus (HSV) infection while receiving acyclovir (ACV) prophylaxis. Sensitivity testing of the isolates revealed three to be acyclovir-resistant and in one patient the infection was also characterised by a marked failure to respond to foscarnet (phosphonoformic acid). The emergence of ACV-resistant HSV infections in themselves is a new and challenging problem, and yet a far greater problem will become evident if these infections develop resistance to non thymidine kinase dependent therapy.

Prophylaxis of toxoplasmosis infection with pyrimethamine/sulfadoxine (Fansidar) in bone marrow transplant recipients.

Prophylaxis against toxoplasmosis with weekly administration of pyrimethamine/sulfadoxine (Fansidar) was assessed for efficacy and toxicity in bone marrow transplant (BMT) recipients over a 21 month period. Sixty-nine of 90 consecutive seropositive patients were evaluable. Fansidar was administered from the time of established engraftment (median day 40, range days 13-100). Medication was scheduled to be continued until 6 months or longer in cases of continued immunosuppression (median 10 months, range day 72 to 22 months). No proven case of toxoplasmosis occurred in patients receiving prophylaxis. In addition, there were no cases of Pneumocystis carinii. Side-effects included BM suppression requiring cessation (n = 4) or interruption (n = 8) of therapy and rash (n = 1). To evaluate toxicity associated with prolonged therapy, 42 evaluable patients were assessed at 6 months following transplant (or at least 4 months of continuous treatment). Haematological toxicity was minimal and compounded in three patients showing moderate derangement by cytomegalovirus infection and graft-versus-host disease. Fansidar is an effective prophylactic agent against toxoplasmosis in BMT patients.

Immune reconstitution after BMT in children.

Serial assessment of peripheral blood T and B cell recovery and serum immunoglobulins was performed in 19 children for the first year following BMT and compared with normal values established from healthy children. Immunophenotypic analysis on bone marrow was performed in selected cases by Southern blotting of the immunoglobulin heavy chain (IgH) gene. We found no significant differences between T cell-replete or depleted allogeneic bone marrow transplants. Lymphocyte numbers were low until 9 months post-BMT. T cell numbers (CD2, CD3, CD5) were also low until 12 months but B cell numbers (CD19) became normal at 3 months. Both CD4+ and CD8+ T cell subsets were low post-BMT with depression of CD4+ greater and more prolonged than that of CD8+. No overshoot of CD8+ was seen. The principal effect of GVHD or its treatment was further depression of CD4+ cells but with no increase in CD8+; recovery of B cells was also delayed. Recovery of IgG was slow with only six of 11 children reaching an age-adjusted normal level by 1 year, whereas there was more rapid recovery of IgM and IgA. Several children had an increase in lymphocytes of immature appearance in their bone marrow at varying times post-BMT with increased cells of phenotype CD19+, CD10+, HLA-DR+ and TdT+. In each case Southern blotting showed a germline pattern of the IgH indicating a polyclonal early B cell regenerative population.

Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation.

We conducted a retrospective review of the clinical features and outcome of adenovirus infection in 572 consecutive patients transplanted in a single centre over a 10 year period. One hundred patients (17%) had a total of 105 episodes of adenovirus infection diagnosed at a median of 18 days post transplant (range 2-150 days). The incidence was higher in children than adults (21% vs 9%, P < 0.001) and in unrelated donor vs matched sibling donor transplants (26% vs 9%, P < 0.001). Diarrhoea and fever were the most common presenting features. Reflecting these symptoms, the most common site of isolation was the stool. Serotypes 1, 2 and 7 were the most frequently seen (total of 41/68 or 60% of evaluable cases). In six patients (6%) adenovirus infection was the direct cause of death occurring at a median of 72 days post transplant (range 18-365 days). Five of these six patients had pulmonary involvement and four had associated graft-versus-host disease (GVHD). Three further patients were considered to have severe adenoviral disease (total incidence 9%). Isolation of virus from multiple sites correlated with a poor outcome (P < 0.001). Comorbid viral infection was common in this group with 50% of all patients having other viruses isolated (predominantly polyoma virus and cytomegalovirus). We conclude that adenovirus is commonly isolated after bone marrow transplant and is a cause of significant morbidity but was a rare cause of mortality (6/572 = 1%) in our patient group as a whole. The relative infrequency of severe infection will make it difficult for the transplant physician to decide which patients should receive experimental antiviral drugs such as ribavirin and cidofovir or immunomodulatory therapy with donor white cell infusions.

The outcome of 26 patients with respiratory syncytial virus infection following allogeneic stem cell transplantation.

Respiratory syncytial virus (RSV) is known to cause acute lung injury in the immunocompromised host, especially recipients of bone marrow allografts. Specific prognostic factors for the development of severe life-threatening disease remain to be identified as does the optimum treatment of established disease. Over a 5-year period the incidence and outcome of RSV in BMT recipients was analysed retrospectively. Prognostic factors assessed included type of transplant, engraftment status at the time of infection, the presence of lower respiratory tract disease, viral genotype and treatment received. During the study period, 26 of 336 (6.3%) allogeneic stem-cell recipients were identified as having RSV. Five patients (19.2%) died as a direct result of RSV. One patient died secondary to an intracranial bleed with concomitant RSV. There were four patients with graft failure (two primary and two secondary) attributable to the presence of RSV, two of whom subsequently died of infections related to prolonged myelosuppression. The presence of lower respiratory tract infection and a poor overall outcome was the only statistically significant association. Unrelated donor transplants and AML as the underlying disease appeared to be associated with a poorer outcome. Engraftment status, viral genotype and RSV treatment received did not correlate with outcome. We conclude that future studies are required to identify early sensitive and reproducible prognostic factors of RSV in the immunocompromised host. The roles of intravenous and nebulised ribavirin need to be clarified by prospective controlled trials.

Influenza A and the virus associated haemophagocytic syndrome: cluster of three cases in children with acute leukaemia.

At the height of the United Kingdom influenza A epidemic in December 1989, three children receiving treatment for non-T cell acute leukaemia developed pancytopenia with concomitant influenza A infection. Bone marrow histology showed prominent marrow erythrophagocytosis by morphologically mature histiocytes, consistent with the picture of virus associated haemophagocytic syndrome (VAHS). In two cases there was an initial spontaneous recovery, though recurrence of VAHS developed in one case in association with a different viral infection (cytomegalovirus) following autologous bone marrow transplantation. The third child died from cardiorespiratory failure secondary to infection with influenza A and Klebsiella pneumoniae sepsis. It is suggested that influenza A should be added to the list of infective causative agents.

Transient erythroblastopenia of childhood with CD10, TdT, and cytoplasmic mu lymphocyte positivity in bone marrow.

Over three years, three children presented with anaemia, reticulocytopenia, and marrow erythroblastopenia. A pronounced lymphocytosis was also evident in two of the marrow aspirates, with increased numbers of cells bearing the immunophenotype TdT+, CD10+ HLA DR+, and cytoplasmic mu +, and reported to be compatible with acute lymphoblastic leukaemia (ALL). The clinical course of the illness was fully compatible with transient erythroblastopenia of childhood (TEC), and all three children remained well one to four years after initial presentation. It is concluded that increased numbers of lymphoid cells with a common or pre-B ALL phenotype may be found in bone marrow aspirates of children with TEC, and should not be misdiagnosed as acute leukaemia.

Pneumocystis carinii, cytomegalovirus, and severe transient immunodeficiency.

Pneumocystis carinii infection is rare in infants, and raises strong concerns of immune deficiency. This report describes the unusual case of a male infant with concurrent chest infections caused by P carinii and cytomegalovirus. Investigation was complicated by the strong suspicion of non-accidental injury, including subdural haematomas. The case illustrates how to investigate for possible immunodeficiency. Low immune function tests at presentation slowly improved and have remained normal on longterm follow up. Possible explanations for the transient severe clinical immunodeficiency in this case are discussed.

Cytomegalovirus pneumonitis and bone marrow transplantation: identification of a specific high risk group.

AIMS: To study the association between cytomegalovirus (CMV) excretion and interstitial pneumonitis in allogeneic bone marrow transplant (BMT) recipients, with reference to donor and recipient CMV antibody response. METHODS: The incidence of CMV excretion was prospectively studied in 62 allogeneic bone marrow transplantations performed on adults and children. All recipients received CMV seronegative blood products. Prophylaxis with high dose acyclovir and CMV immune globulin was given to high risk patients (donor or recipient, or both, CMV seropositive). RESULTS: CMV excretion was detected in eight of 26 (31%) high risk patients but in only one of 36 low risk patients (donor and recipient both CMV seronegative). Five of the eight (63%) excretors in the high risk category developed CMV, of whom four (80%) belonged to the seropositive recipient/seronegative donor group, and included the three CMV seropositive recipients whose CMV complement fixation antibody titres were 64 or greater before transplantation. CONCLUSIONS: These findings suggest that there is a subgroup of patients at especially high risk of developing CMV.

Aspergillus antigen testing in bone marrow transplant recipients.

AIMS: To assess the clinical usefulness of a commercial aspergillus antigen enzyme linked immunosorbent assay (ELISA) in the diagnosis of invasive aspergillosis (IA) in bone marrow transplant recipients, and to compare it with a commercial latex agglutination (LA) test. METHODS: In total, 2026 serum samples from 104 bone marrow transplant recipients were tested. These comprised 67 sera from seven patients who had died with confirmed IA, 268 sera from nine patients who had died with suspected IA, and 1691 sera from 88 patients with no clinical, radiological, or microbiological signs of IA. RESULTS: The ELISA was more sensitive than the LA test. All patients who were ELISA positive were also LA positive, and a positive LA result never preceded a positive ELISA. Twelve of 16 patients with confirmed or suspected IA were ELISA positive on two or more occasions, compared with 10 of 15 who were LA positive. ELISA was positive before LA in five patients (range, 2-14 days), and became positive on the same day in the remainder. Aspergillus antigen was detected by ELISA a median of 15 days before death (range, 4-233). Clinical and/or radiological evidence of IA was noted in all patients, and a positive ELISA was never the sole criterion for introduction of antifungal treatment. Two samples (one from each of two patients without IA) gave false positive results. CONCLUSIONS: The aspergillus ELISA is a specific indicator of invasive aspergillosis if the criterion of two positive samples is required to confirm the diagnosis. However, the test is insufficiently sensitive to diagnose aspergillosis before other symptoms or signs are apparent, and hence is unlikely to lead to earlier initiation of antifungal treatment. It is therefore unsuitable for screening of asymptomatic patients at risk of invasive aspergillosis, but does have a useful role in confirming the diagnosis in symptomatic patients.

Use of the Pastorex aspergillus antigen latex agglutination test for the diagnosis of invasive aspergillosis.

AIMS: To evaluate the Pastorex aspergillus antigen latex agglutination test for the diagnosis of invasive aspergillosis in patients undergoing liver or bone marrow transplantation. METHODS: Serum samples were taken at least twice weekly post-transplant and tested for Aspergillus antigen. Latex agglutination test results were compared with microbiological examination of respiratory, urine and bile specimens. Serum samples from liver transplant patients were also tested for antibodies to Aspergillus fumigatus by counter immunoelectrophoresis. RESULTS: Eight of the 91 patients studied developed invasive aspergillosis. Positive latex agglutination tests were obtained in eight of 187 (4.3%) serum samples from four of these eight patients. The other four patients with invasive aspergillosis gave consistently negative latex agglutination tests. A positive latex agglutination test was the first indication of invasive aspergillosis in two patients; these patients were already on amphotericin B. Positive latex agglutination tests were the only evidence of invasive aspergillosis in one patient who subsequently died of the infection. False positive latex agglutination tests were obtained in five of 83 (6%) patients with no evidence of invasive aspergillosis and misleading positive cultures seen in nine of 83 (10.8%). No antibodies were detected in three of four liver transplant patients with invasive aspergillosis. Conversely, antibodies were detected in 63 of 262 (24%) serum samples from 43 liver transplant patients with no evidence of invasive aspergillosis; one of these patients had an antibody titre of 1:2 on four separate occasions. CONCLUSIONS: The Pastorex aspergillus antigen latex agglutination test, when used alone, lacks sensitivity and specificity for the early diagnosis of invasive aspergillosis. A diagnosis was made in all patients with invasive aspergillosis when both culture and antigen tests were performed although using these criteria a false positive diagnosis would have been made in 13 of 83 (15.6%) patients. Microbiological and serial serological investigations for antigen should both be performed and the results considered in conjunction with radiological and clinical evidence.

Acute monoblastic leukemia of infancy in Klinefelter's syndrome.

A 7-month-old infant with Klinefelter's syndrome was diagnosed as having acute monoblastic leukemia (AMoL). Chromosome studies of bone marrow at diagnosis showed the karyotype 46,XXY,-Y,t(10;11)(p13;q14). This is the first report of M5A leukemia associated with Klinefelter's syndrome.

Fanconi syndrome after ifosfamide.

A 2-year-old boy developed the Fanconi syndrome 1 year after being treated successfully for a neuroblastoma. This is probably an unusual complication of ifosfamide.

An assessment of sputum induction as an aid to diagnosis of respiratory infections in the immunocompromised child.

Sputum induction using nebulised hypertonic saline was performed in two groups of immunocompromised children, one group with symptoms of respiratory infection and one group without. The asymptomatic group were bone marrow transplant (BMT) recipients, all seropositive for cytomegalovirus infection (CMV). Organisms were identified in three of 14 induced sputum specimens obtained from the symptomatic group (CMV N = 1, Haemophilus influenzae N = 2), but in none of 12 specimens from the asymptomatic group. Adverse effects encountered were minor. Four symptomatic patients with negative induced sputum samples underwent bronchoalveolar lavage, and no further organisms were identified. Sputum induction can be a useful adjunct to the diagnosis of respiratory pathogens in this group of patients.

Neonatal neuroblastoma.

Over nine years, 33 children with neonatal neuroblastoma were registered with the UKCCSG (United Kingdom Children's Cancer Study Group). Tumours of all stages were found, but stage 4S disease predominated. Five tumours were detected prenatally by ultrasonography. Treatment varied according to tumour stage. The overall survival of the group was 91%. Ten children have had long term complications as a result of their disease, usually as a result of spinal tumour involvement. The good overall prognosis in this age group is encouraging, but the poor neurological outcome of patients with intraspinal extension is of concern.