Busulphan is active against neuroblastoma and medulloblastoma xenografts in athymic mice at clinically achievable plasma drug concentrations

High-dose busulphan-containing chemotherapy regimens have shown high response rates in children with relapsed or refractory neuroblastoma, Ewing's sarcoma and medulloblastoma. However, the anti-tumour activity of busulfan as a single agent remains to be defined, and this was evaluated in athymic mice bearing advanced stage subcutaneous paediatric solid tumour xenografts. Because busulphan is highly insoluble in water, the use of several vehicles for enteral and parenteral administration was first investigated in terms of pharmacokinetics and toxicity. The highest bioavailability was obtained with busulphan in DMSO administered i.p. When busulphan was suspended in carboxymethylcellulose and given orally or i.p., the bioavailability was poor. Then, in the therapeutic experiments, busulphan in DMSO was administered i.p. on days 0 and 4. At the maximum tolerated total dose (50 mg kg(-1)), busulphan induced a significant tumour growth delay, ranging from 12 to 34 days in the three neuroblastomas evaluated and in one out of three medulloblastomas. At a dose level above the maximum tolerated dose, busulphan induced complete and partial tumour regressions. Busulphan was inactive in a peripheral primitive neuroectodermal tumour (PNET) xenograft. When busulphan pharmacokinetics in mice and humans were considered, the estimated systemic exposure at the therapeutically active dose in mice (113 microg h ml(-1)) was close to the mean total systemic exposure in children receiving high-dose busulphan (102.4 microg h ml(-1)). In conclusion, busulphan displayed a significant anti-tumour activity in neuroblastoma and medulloblastoma xenografts at plasma drug concentrations which can be achieved clinically in children receiving high-dose busulphan-containing regimens.     

Chemotherapy for unresectable and recurrent intramedullary glial tumours in children. Brain Tumours Subcommittee of the French Society of Paediatric Oncology (SFOP).

Adjuvant treatment for intramedullary tumours is based on radiotherapy. The place of chemotherapy in this setting has yet to be determined. Between May 1992 and January 1998, eight children with unresectable or recurrent intramedullary glioma were treated with the BB SFOP protocol (a 16-month chemotherapy regimen with carboplatin, procarbazine, vincristine, cyclophosphamide, etoposide and cisplatin). Six children had progressive disease following incomplete surgery and two had a post-operative relapse. Three patients had leptomeningeal dissemination at the outset of chemotherapy. Seven of the eight children responded clinically and radiologically, while one remained stable. At the end of the BB SFOP protocol four children were in radiological complete remission. After a median follow-up of 3 years from the beginning of chemotherapy, all the children but one (who died from another cause) are alive. Five patients remain progression-free, without radiotherapy, 59, 55, 40, 35 and 16 months after the beginning of chemotherapy. The efficacy of this chemotherapy in patients with intramedullary glial tumours calls for further trials in this setting, especially in young children and patients with metastases.     

Paraneoplastic encephalomyelitis in a child with neuroblastoma

We present the case of a 12-year-old boy who developed progressive limbic dysfunction associated with a posterior cord syndrome in conjunction with complex partial seizures and intrathecal synthesis of IgG. Although the cerebral CT scan appeared normal, MR imaging showed signal abnormalities in both temporal lobes. As these clinical features reminded us of the well-known paraneoplastic encephalomyelitis (PNEM) in adults, we looked for a tumour and found a pelvic neuroblastoma. The diagnosis of PNEM was supported by the discovery of the antibody anti-HU in the serum of our patient.

     

Rheumatological presentation of developmental bone diseases

Developmental bone disease may be present, with rheumatological disorders as the major symptoms, even in children. The major lesions encountered are early osteo arthritis, osteo chondromatosis and vertebral involvement with two leading types, pseudo Scheuermann's disease or pseudo ankylosing spondylitis. This paper presents the different features and lists the rheumatological problems in bone dysplasia.     

Factor analysis as a means of determining response to chemotherapy in patients with osteogenic sarcoma

The prognosis of localized osteogenic sarcoma (OS) has improved considerably since the introduction of neoadjuvant chemotherapy. However, there is a subset of patients who do not show full benefit from neoadjuvant chemotherapy because of chemoresistance. The early identification of poor responders to chemotherapy during neoadjuvant therapy remains difficult. In order to evaluate the role of bone scintigraphy we report our experience of dynamic technetium-99m hydroxymethylene diphosphonate bone scintigraphy in 19 cases of paediatric osteogenic sarcomas. Before the beginning of chemotherapy, a dynamic scan was recorded during 30 min followed by static images at 3 h. The procedure was repeated halfway through the course of chemotherapy (6th week). Histological grading of the response to chemotherapy was carried out in the 12th week, showing nine good responses and ten poor responses. Factor analysis of dynamic structures (FADS) applied to dynamic scans allowed us to identify three factors termed vascular, soft tissue and osseous factors. The effect of chemotherapy on each factor was evaluated. Using FADS we were able to detect all the poor histological responders with the combination of vascular and osseous factors. Six out of nine good histological responders were also classified as scintigraphic responders. FADS applied to dynamic bone scans allowed us to identify at an early stage all the poor histological responders to neoadjuvant chemotherapy. This method may have clinical relevance for the therapeutic strategy in patients with OS.     

Liver morphology and function in visceral leishmaniasis (Kala-azar).

AIM--To study the morphology and function of the liver in visceral leishmaniasis (Kala-azar). METHODS--Percutaneous liver biopsy specimens from 18 patients with confirmed visceral leishmaniasis were examined under light and electron microscopy before and after treatment with pentovalent antimony. The tissue was also examined for hepatitis B surface and core antigens using immunoperoxidase staining. Liver function was investigated in nine patients before and after treatment. RESULTS--Specimens before treatment showed Kupffer cells and macrophages colonised by leishmania parasites in 40% of cases. A chronic mononuclear cell infiltrate had affected the portal tracts and lobules. Ballooning degeneration of the hepatocytes, fibrosis of the terminal hepatic venules, and pericellular fibrosis were common findings. The fibrosis was related to Ito cells transforming to fibroblast-like cells. None of the patients had hepatitis B infection. All patients had biochemical evidence of liver dysfunction before treatment. Liver function improved after treatment. CONCLUSION--Visceral leishmaniasis causes morphological and functional disturbance in the liver. Focal fibrosis rather than cirrhosis occurs. The exact aetiology of hepatic damage is unclear but may have an immunological basis.     

Comparative genomic hybridization detects specific cytogenetic abnormalities in pediatric ependymomas and choroid plexus papillomas

Pathogenesis and genetic abnormalities of ependymomas are not well known and differential diagnosis with choroid plexus tumors may be difficult when these tumors are located in the ventricles. We analyzed 16 samples of primary pediatric ependymomas and seven choroid plexus tumors for significant gains or losses of genomic DNA, using comparative genomic hybridization (CGH). Four ependymoma samples were obtained after surgery for relapse, including one patient whose tumor was analyzed at diagnosis and at first and second relapses. Three out of 16 ependymomas and none of the choroid plexus tumors appeared normal by CGH. In the remaining ependymomas, the number of regions with genomic imbalance was limited. The most frequent copy number abnormality in ependymomas was 22q loss. In one patient from whom multiple samples could be analyzed during tumor progression, no abnormality was present at diagnosis; gain of chromosome 9 and loss of 6q were observed at first relapse and, at second relapse, additional genomic imbalances were loss of 3p, 10q, and chromosome 15. In choroid plexus tumors, recurrent abnormalities were gains of chromosome 7 and region 12q. The recurrent chromosomal abnormalities were clearly different between ependymomas and choroid plexus papillomas (CPP). Recurrent loss of 22q suggests that this region harbors tumor suppressor genes important in the pathogenesis of ependymomas; however, other pathogenic pathways may exist involving 6q and chromosome 10 losses or gain of 1q and chromosome 9. CPP can be distinguished from ependymoma on the basis of CGH abnormalities.     

The importance of gynecological examination in adolescent girls and adult women with Prader–Willi syndrome

Current published guidelines for routine care of women with Prader–Willi syndrome (PWS) do not include recommendations for gynecologic examinations. We describe our experience with gynecological examinations in women with PWS and offer recommendations for routine health care for these patients. Data were collected on all 41 PWS females ages ≥12 year, followed in our national Israeli multidisciplinary clinic between the years 2011 and 2022. Menstrual data and findings on external gynecological examination, including evaluation of the vulva and hymen were recorded at yearly visits. During the gynecological evaluation the topic of sexual education was discussed. Pelvic ultrasound, specifically for antral follicular count, was performed for those visiting the clinic during 2020–2022. Blood samples for luteinizing hormone (LH), follicular stimulating hormone (FSH), and estradiol were obtained routinely and DEXA scans for bone density were done when indicated. Of the 41 women, (median age at start of follow-up 17 years, range [12.3–39], BMI 30.4 kg/m² [IQR 23.5–37.1]), 39 women agreed to external gynecological examination. Eleven women (27%) had spontaneous menses, with menarche at the age of 14 to as late as 31 years. The hymen was intact in all except one. Poor hygiene was observed in eight women, three women with vulvovaginitis, and five with irritated vulva related to poor hygiene. Gynecological ultrasound was performed in 27 women. In 22, endometrial thickness was less than 5 mm. The median antral follicular count (AFC) was 6 (<10th percentile for age). No correlation between AFC and menstruation or BMI was found. Mean FSH level was 5.7 ± 3.6 IU, LH was 2.29 ± 2.23, and estradiol was 128 ± 76 pmol/L. Data on DEXA measurements were available in 25 women aged 16–39. Median spine T score was −1.3 (range between 0.5 and −3.7), and hip T score was −1.2 (range between 0.8 and −3.3). A negative correlation was found between endometrial thickness and the presence of osteopenia or osteoporosis (r = −0.5, p = 0.013). Despite our recommendations, only eight of 14 women agreed to hormonal treatment or contraception. One woman who received treatment had a thromboembolic event. Routine health care for women with PWS should include gynecological examinations. The gynecological evaluation should include external genital examination, assessment of hygiene, obtaining a blood sample for hormone levels, and documenting a history of sexual experience or sexual abuse. Hormonal treatment or contraception should be offered when appropriate.     

Potent therapeutic activity of irinotecan (CPT-11) and its schedule dependency in medulloblastoma xenografts in nude mice

The anti-tumor activity of irinotecan (CPT-11), a DNA-topoisomerase I inhibitor, was evaluated in 5 advanced stage subcutaneous medulloblastoma xenografts in nude mice, using different schedules of administration. With a 5-day schedule, the highest i.v. dose tested (40 mg kg⁻¹ day⁻¹) induced complete regressions in all xenografts but 1, and delays in tumor growth always exceeded 30 days. Two xenografts, IGRM11 and IGRM33, were highly sensitive, and animals survived tumor-free beyond 120 days after treatment. CPT-11 clearly retained its anti-tumor activity at a lower dosage (27 mg kg⁻¹ day⁻¹). CPT-11 was significantly more active than cyclophosphamide, thiotepa and etoposide against the 3 xenografts evaluated. To study the schedule dependency of its anti-tumor activity, CPT-11 was given i.v. at the same total doses over the same period (33 days) using either a protracted or a sequential schedule in IGRM34-bearing mice. With a dose of 10 mg kg⁻¹ day⁻¹ given on days 0–4, days 7–11, days 21–25 and days 28–32 (total dose, 200 mg kg⁻¹), 3 of 6 animals were tumor free on day 378. The same total dose given with a sequential schedule, i.e., 20 mg kg⁻¹ day⁻¹ on days 0–4 and days 28–32, failed to induce complete regression. The plasma pharmacokinetics of CPT-11 and SN-38 were studied in IGRM34-bearing animals after a single i.v. dose of 10 and 40 mg kg⁻¹. The plasma clearance rate of CPT-11 was dose dependent. The ratio between the SN-38 and CPT-11 area under the curve in plasma was 0.4–0.65, i.e., significantly higher than that observed in humans at the maximum tolerated dose (0.01–0.05). Conversely, this ratio was 10-fold lower in tumor than in plasma. Clinical development of irinotecan is warranted in pediatric malignancies. Int. J. Cancer 73:156–163, 1997. © 1997 Wiley-Liss, Inc.     

Antiinfective Prophylaxis with Ceftazidime and Teicoplanin in Children Undergoing High-Dose Chemotherapy and Bone Marrow Transplantation

Sixty children treated for solid tumors with high-dose chemotherapy followed by bone marrow transplantation were randomly assigned to one of two antibiotic protocols. Group A received prophylaxis consisting of ceftazidime plus teicoplanin beginning before the onset of aplasia and fiver; group B received exactly the same antibiotic regimen but beginning at the onset of fever. The two groups were compared in terns of the rate of septicemia, fever of unknown origin, the time-lapse before the appearance of septicemia, the sensitivity of the causative organisms to the antibiotics, the effect of the latter on the intestinal flora, and the rate of fungal infections. The incidence of septicemia was significantly lower in group A (6.6%) than in group B (24.0%), mainly due to the prevention of episodes of early onset. Similarly, the appearance of the first episode of fever was delayed in group A, and the overall duration was reduced. Amphotericin B was prescribed empirically with the same rule in both groups, but three children in group A did not require amphotericin B. The effect on the intestinal flora was similar in the two groups; it must, however, be closely monitored so that the presence of potential pathogens can be dealt with appropriately.