Moderate dose cranial radiotherapy causes central adrenal insufficiency in long-term survivors of childhood leukaemia.

Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy. The survival rate in the Scandinavian countries is now around 85 %. ALL patients treated with cranial radiotherapy (CRT) are at risk for growth hormone deficiency (GHD), but little is known about other pituitary insufficiencies, e.g. ACTH. Adult ALL patients (median age at study 25 years), treated with 24 Gy (18-30) of CRT during childhood were investigated. We performed an insulin tolerance test (ITT) to evaluate cortisol secretion. We measured basal serum ACTH and cortisol levels before and after 5 years of GH therapy. 14 out of 37 (38 %) ALL patients had a subnormal cortisol response to an ITT (257-478 nmol/L) while there was no significant difference in basal cortisol levels between 44 patients and controls (P > 0.3). Female, but not male ALL patients had significantly lower ACTH levels compared to controls (P = 0.03). After 5 years of GH therapy only male ALL patients had significantly lowered basal plasma cortisol (P = 0.02). ALL survivors, treated with a moderate dose CRT, have a central adrenal insufficiency 20 years after diagnosis. An increased awareness of the risk for an adrenal insufficiency is of importance and life-long surveillance of the entire hypothalamic-pituitary axis is recommended in these patients.

Nonmetastatic Ewing family tumors: high-dose chemotherapy with stem cell rescue in poor responder patients. Results of the Italian Sarcoma Group/Scandinavian Sarcoma Group III protocol.

BACKGROUND: High-dose chemotherapy (HDT) was added to conventional chemotherapy in Ewing sarcoma family tumor (EFT) patients, poor responders (PRs) to induction chemotherapy in order to improve their survival. PATIENTS AND METHODS: Patients aged ≤40 years with nonmetastatic Ewing sarcoma (ES) received vincristine (V), doxorubicin (A), cyclofosfamide (C), actinomycin (Ac), ifosfamide (I) and etoposide (E) (VACAc-IE regimen) as induction chemotherapy. As maintenance treatment, good responders (GR) received nine cycles of VACAc-IE regimen. PRs received three cycles of VAC-IE, mobilizing cycle with CE and HDT with Busulfan and Melphalan with stem cell support. RESULTS: Three hundred patients [median age 15 years (3-40 years)] entered the study. One patient refused local treatment, 242 (81%) underwent surgery [with radiotherapy (RT) in 80] and 57 (19%) RT alone. No toxic deaths were recorded. Overall GR were 146 (49%). Twenty-eight PR did not receive HDT. At a median follow-up of 64 months (21-116 months), 5-year overall and event-free survival (EFS) were 75% and 69%, respectively. Five-year EFS was 75% for GR, 72% for PR treated with HDT and 33% for PR who did not receive HDT. CONCLUSIONS: High-dose therapy added to the VACA-IE regimen in PR patients is feasible and effective. Selected groups of patients with ES can benefit from HDT.

High risk of azoospermia in men treated for childhood cancer.

Childhood cancer survivors (CCS) have an increased risk of impaired spermatogenesis, but data regarding the disease- and treatment-related risk factors of azoospermia are scarce. Such information is crucial both for counselling CCS and for selecting patients for testicular tissue cryopreservation. The proportion of azoospermic men in CCS was 18% [95% confidence interval (CI): 12-26], specifically for leukaemias (19%; 95% CI: 5.5-42), Hodgkin's disease (53%; 95% CI: 29-76), non-Hodgkin's lymphoma (11%; 95% CI: 0.28-48) and testicular cancer (11%; 95% CI: 0.28-48). In CCS treated with high doses of alkylating agents, the proportion of azoospermic men was 80% (95% CI: 28-99) and if radiotherapy was used additionally, the proportion was 64% (95% CI: 35-87). In CCS with subnormal Inhibin B levels, the proportion of azoospermic men was 66% (95% CI: 47-81) and for those with elevated follicle-stimulating hormone (FSH) levels, the proportion was 50% (95% CI: 35-67). Among CCS with subnormal testicular volume (≤ 24 mL), azoospermia was found in 61% (95% CI: 39-80) of the cases. Most childhood cancer diagnoses are associated with an increased risk of azoospermia, especially in CCS receiving testicular irradiation, high doses of alkylating drugs and other types of cytotoxic treatment, if combined with irradiation. Inhibin B, FSH and testicular volume can be used as predictors for the risk of azoospermia.

Returning to a changed ordinary life--families' lived experience after completing a child's cancer treatment.

The aim of the study was to illuminate the families' lived experience after completing a child's cancer treatment. The study took place at a University Hospital in southern Sweden. Interviews were carried out with 10 mothers, eight fathers, four patients and two siblings from a total of 10 families. The interviews were analysed with a hermeneutical phenomenological approach. One essential theme emerged from their stories, 'returning to a changed ordinary life--incorporating a trying and contradictory experience'. The families felt relieved that the treatment was over yet they experienced strains in their daily life. Family members felt changed and especially the parents needed to focus on themselves in order to recover. Closeness with other people, especially their own family, was important. The previously sick children felt a loss of concern from their parents when treatment had ended, in contrast to siblings who experienced increased attention from their parents. Parents experienced being in uncharted territory and sometimes missed the security of hospital. For professionals it is important to offer the family a structured follow-up to help them in their daily life after the child's treatment is completed.

New structural chromosomal rearrangements in congenital leukemia.

The karyotypic abnormalities and clinical data on three patients in whom acute leukemia was diagnosed within the first 6 months of life are presented. The four structural chromosomal rearrangements detected in the bone marrow from these patients, i.e., t(7;12)(q36;p13) and t(1;19)(q11;q11) in case 1, t(2;10;11;12)(q21q31;p13;q13;q24) in case 2, and t(11;19)(q23;p13) in case 3, have not previously been associated with congenital leukemia. Acquired chromosomal changes have until now been reported in only 31 leukemic infants in this age group. Of the total material, 18 patients had acute lymphoblastic leukemia and 16 had acute nonlymphocytic leukemia. The by far most frequently recorded cytogenetic aberration has been t(4q;11q), seen in 14 cases of lymphoblastic leukemia. Although t(4q;11q) has not been found in a single patient with acute nonlymphocytic leukemia, these leukemias have often had other rearrangements involving the same region of 11q. Hence, genetic material around 4q21 may be active in lymphocytic differentiation, whereas gene(s) in 11q23 may be important in the neoplastic process in a less cell-type specific manner and perhaps particularly vulnerable to neoplastic rearrangement in fetal life. The finding of four cases out of 34 with translocations between 11q23 and chromosome 19 indicates that this rearrangement might characterize a specific cytogenetic subgroup of leukemia in the very young.

Five-year results in Ewing's sarcoma. The Scandinavian Sarcoma Group experience with the SSG IX protocol.

The first Scandinavian protocol for Ewing's sarcoma, SSG IV, resulted in a local control rate of 74% and 5-year metastasis-free survival (MFS) of 43%. The second protocol, SSG IX, was started in order to improve upon these results. It featured four chemotherapy cycles, each consisting of two courses of VAI (vincristine, doxorubicin, ifosfamide) alternating with one course of PAI (cisplatin, doxorubicin, ifosfamide) at 3-weekly intervals. Total treatment time was 35 weeks. Local therapy was given at week 9. Inoperable or non-radically operated patients received hyperfractionated accelerated radiotherapy 1.5 Gy twice daily between chemotherapy courses to a total dose of 42-60 Gy, depending on surgical radicality and tumour localisation. 88 patients were included (58 male, 30 female, mean age 20 years; range 5-65 years). The tumour (73 M0 and 15 M1) was located centrally in 31 patients (35%), in the extremities in 34 (39%) and other sites in 23 (26%) of cases. The median size of tumour was 10 cm (range 2-23), soft tissue was invaded in 87%. Surgery was the local therapy for 60 (68%) patients: amputation in 8 and local excision in 52. The surgical margins were wide in 35 patients, marginal in 14 and intralesional in 3. Radiotherapy was given to 17 non-radically operated patients postoperatively and to 28 patients with inoperable tumours primarily. Histological responses were evaluated in 52 patients. 9 local recurrences were observed (10%). Distant metastases developed in 24 M0 patients (33%). The estimated 5-year MFS was 58% and overall survival (OS) 70% for M0 and 27% and 28% for M1 patients, respectively. Survival was favourable in patients with non-metastatic extremity tumours (90%) and tumours operated with wide margins (90%). Patients with a total necrosis after chemotherapy had a better OS than those with a partial or poor response (P=0.003). The toxicity (World Health Organisation) was acceptable (gastrointestinal G1-2; haematological G3-4). The SSG IX protocol gave better local control and survival rates than the SSG IV. Whether this is due to a higher therapeutic efficacy of the present protocol cannot be ascertained in this comparison with a historical control.

Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders.

From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume < 190 ml, 24-h serum methotrexate > 4.5 microM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in > 70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome.

Flare phenomenon in osteosarcoma after complete remission.

A patient undergoing cytostatic therapy for osteosarcoma of the right humerus had bone scans at 2-mo intervals. A skeletal focus of increased radiotracer accumulation occurred and subsequently was confirmed by CT and MRI. A necrotic metastasis was found during biopsy. There were no remaining viable tumor cells. This finding confirms the presence of the flare phenomenon in skeletal metastases in primary malignant bone tumors and that radionuclide imaging may fail to detect intramedullary foci of viable metastases in these tumors.

High resolution banding analysis of the reciprocal translocation t(6;9) in acute nonlymphocytic leukemia.

The cytogenetic, hematologic, and clinical characteristics of a 13-year-old girl with acquired t(6;9)(p23;q34) and dysmyelopoietic syndrome developing into acute myelomonocytic leukemia are described, bringing the total number of patients with t(6;9) and hematologic disease described in the literature up to 19. The diagnosis has been acute myeloid leukemia in the great majority of these patients; only four have had acute myelomonocytic leukemia. High resolution analysis at the 550 band stage localized the breakpoints in chromosomes #6 and #9 to p23 and 9q34.3, respectively. Previous investigations employing high resolution cytogenetics have mapped the typical 9q breakage site in chronic myeloid leukemia to 9q34.1. In situ hybridization studies have demonstrated that the cellular oncogene c-abl remains on the derivative 9q+ chromosome in t(6;9), whereas it is moved to the Ph marker in t(9;22). Thus, the combined data indicate that c-abl is located between 9q34.1 and 9q34.3, i.e., in subband 9q34.2 or its immediate vicinity.

Reciprocal translocation (11;19)(q23;p13) in congenital acute lymphoblastic leukemia.

The cytogenetic, clinical, and immunologic findings ina 4-month-old girl with acute lymphoblastic leukemia (ALL) are reported. The malignant lymphoblasts were characterized cytogenetically by the reciprocal translocation t(11;19)(q23;p13); immunologically by an immature pre-B-ALL phenotype. In spite of the high-risk nature of the leukemia, the patient attained complete remission relatively quickly and is still free of disease 3 years after diagnosis. Because the only two previously reported ALL patients with t(11;19) also seem to have responded well to therapy, this cytogenetic abnormality might turn out to be an indicator of favorable prognosis in ALL.

Hepatitis B immunization in a low-incidence province of Canada: comparing alternative strategies.

This study provides a comparative cost-effectiveness analysis of three universal immunization programs for hepatitis B virus (HBV). Using three theoretical cohorts of infants, 10-year-olds, and 12-year-olds, a universal immunization program was compared with a prenatal screening/newborn immunization program involving testing of prepartum women and immunization of newborns of HBsAg-positive mothers. A Markov long-term outcome model used Manitoba data to estimate costs and health outcomes across the lifespan. The model was based on an HBV incidence rate of 19/100,000 and a discount rate of 5% and incorporated the most recent treatment advances (interferon therapy). Cost-effectiveness was calculated as the ratio of dollars spent per year of life saved, with costs determined from the perspective of a third-party payer. The universal infant-immunization program, although not cost-saving, was associated with a low, economically attractive cost-effectiveness ratio of $15,900 (Canadian) per year of life saved, a figure substantially lower than the ratios of $97,600 and $184,800 (Canadian) associated with the universal programs for 10- and 12-year-olds, respectively. Cost-effectiveness ratios were found to be sensitive to changes in immunization costs, HBV incidence rates, and the rate at which protective antibody levels are lost over time: If these variables move in the directions suggested by current trends, the authors anticipate an increasing economic appeal of universal programs well into the future. A universal program of HBV immunization for infants appears to be economically practical in regions where HBV infection rates are low and stable.

Effects of ethanol on fatty acid esterification and oxidation in isolated rat hepatocytes.

In hepatocytes from fed rats, ethanol significantly increased fatty acid esterification but had little effect on fatty acid oxidation.

The effect of preparation for lumbar puncture on children undergoing chemotherapy.

At the University Hospital in Lund, Sweden, a preparation program was developed for children undergoing lumbar punctures (LPs) during chemotherapy for leukemia or lymphoma. Subsequently, a study was initiated to determine whether a preparation program for children prior to treatment would reduce their anxiety and improve their cooperation. This study also was undertaken to examine whether reinforcing the preparation information prior to each LP would be beneficial. The 30 children who participated in the study were divided into three groups: a control group whose members did not receive preparation and two other groups whose members were exposed to different numbers of preparation programs. The parents and the nurse in charge evaluated the children's reactions during treatment using two 6-point rating scales: an anxiety scale and a noncooperation behavior scale. Two unbiased, trained observers later viewed video recordings of the children's reactions and evaluated them using the same tools. In addition, each child rated his or her experience of pain on a 10 cm visual analogue scale. Based on these ratings, the groups were analyzed to determine if within-group differences existed from one treatment to the next and to determine if between-group differences existed at the various times of treatment. Few statistically significant differences were found, but the results indicate that the children in the most informed group exhibited sustained reductions in their perceptions of pain. This may signify that reinforcing the preparation information before each of the LPs enabled these children to cope with the pain more effectively.

Chemotherapy in Ewing's sarcoma. The Scandinavian Sarcoma Group experience.

During the past 15 years the Scandinavian Sarcoma Group has treated 140 patients with Ewing's sarcoma. Two protocols have been used. SSG IV included 52 patients between 1984 and 1990 and SSG IX, 88 patients since 1990. After 5 years of treatment, local recurrences occurred in 19% of the patients (M0 + M1) in the SSG IV group and 10% in the SSG IX group. Distant metastases developed in 57% of the M0-patients in the SSG IV group and in 33% in the SSG IX group. Tumor-related survival (overall) of M0-patients was 49% in SSG IV and 70% in SSG IX, and the metastasis-free survival rate 45% and 58%, respectively. Patients having a localized extremity tumor had a survival rate of 90% (SSG IX). In both treatment groups, good responders to chemotherapy had a better survival rate than poor ones (SSG IV, p < 0.02, GI-II vs. G II-IV and SSG IX, p < 0.003, GI-III vs. G IV). In conclusions local control and survival rates were better with SSG IX than SSG IV.

Prognostic factors in bone sarcomas.

Based on a literature review and the SSG experience, the most important prognostic factors in high-grade osteosarcoma appear to be the presence of detectable metastases at diagnosis, tumour volume, old age, sex, histologic response, and possibly tumoral P-glycoprotein expression. However, for an adolescent patient with non-metastatic extremity disease, there is no consensus regarding prognostic factors at initial presentation, and currently there is thus no established method for dividing them into high- and low risk groups for the purpose of treatment differentiation. It should also be remembered that available prognostic factors have been identified only in a retrospective manner, following aggressive treatment of all patients. Thus patients in "favourable" prognostic groups may simply be patients who have had a good effect from aggressive treatment, and how they would have done with reduced treatment remains to be shown. Obviously the best method for prognostication would be the direct demonstration of micrometastatic disease in the lungs or in peripheral blood. In the relatively near future, this may become possible with immunoscintigrapy or immunohistochemistry utilizing monoclonal antibodies [29-31]. In Ewing's sarcoma, the most powerful factors indicating poor prognosis are metastases at diagnosis, poor histologic response, large tumour size and possibly pelvic localisation. There appears to be a somewhat better international consensus regarding prognostic factors in Ewing's sarcoma than in osteosarcoma. Although several studies have implemented intensified treatment for poor prognostic groups [8, 32], the role (if any) of high-dose treatment with stem cell rescue remains to be proven. The same factors are prognostic both for the development of metastases and local recurrence, but in addition, surgical treatment as opposed to radiotherapy appears to reduce local failure rate [12, 17, 33, 34]. As in osteosarcoma, the near future offers promise regarding the detection and quantification of micrometastatses and minimal residual disease, by means of PCR techniques recognizing specific genetic changes in the Ewing family of tumors [35].

Chromosomal aberrations in Wilms' tumour.

In 26 consecutive patients operated for Wilms' tumour samples from the tumour were genetically analyzed. Clonal acquired chromosome aberrations were found in 13 patients and a constitutional trisomy 18 as the sole change in 1. The chromosome number was altered in 13 patients. Numerical changes occurred in 16 patients and breakpoint of chromosome 1 in 6 patients. There was no structural alteration of chromosome 11. The observed cytogenetic heterogeneity illustrates the complexity of genetic changes involved in the genesis and progression of Wilms' tumour. To further elucidate the phenotypic impact of chromosomal aberrations the correlation to histology and the clinical course will be important.

Abdominal manifestations of non-Hodgkin's lymphomas.

25 children (18 boys and 7 girls) were treated for non-Hodgkin's lymphomas (NHL) during 1982-1990. The age at diagnosis was 2-15 years. Five of the 25 children died. Of the 25 children 6 patients had the diagnosis of intraabdominal NHL. The presenting abdominal symptoms for these 6 patients were abdominal pain in 4 cases, nausea 3, abdominal distention 2, icterus 1 and diarrhoea 1. Four of the 6 patients with abdominal NHL underwent laparotomy but the diagnosis was unknown before surgery. The indication for explorative laparotomy was in all cases a tumor of unknown etiology combined with ascites in 2 cases and icterus in 1 case. At surgery there was a tumor localized around the porta hepatitis in 1 case and in the right ovarium in 1 case. Furthermore, spread infiltrative growth of tumor was found in 3 cases, with infiltration of the peritoneum in 2 of these cases. A specimen for peroperative histological examination was taken and gave the conclusive diagnosis of NHL in 4 of 6 cases. Staging laparotomy, palliative tumor resection and radical surgery are preferably avoided. For proper treatment an adequate biopsy is important. The management of children with NHL is a multidisciplinary approach.

National reevaluation of staging in Wilms tumor.

In order to evaluate if incorrect staging of Wilms tumor resulted in inadequate treatment a retrospective reevaluation was performed. During 1982-1990 153 patients were treated in Sweden. The review revealed that 6 cases were not Wilms tumor and 25 cases had incomplete information. The remaining material consisted of 122 cases. The survey of the charges revealed that the initial distribution was stage I 58, stage II 17, stage III 21, stage IV 15 and stage V 11. The stage was changed in 12 cases, mainly in the initial stage I. The causes for changing of the stage were thick needle puncture preoperatively in 4, capsule histologically not intact 4, tumor not radically excised 2, tumor rupture peroperatively 1 and lymph node malignancy 1. The staging procedure cannot be safely performed by a single doctor. It is dependent on cooperation in a pediatric oncologic team including the pediatric surgeon.