The correlation between dose of folinic acid and neurotoxicity in children and adolescents treated for osteosarcoma with high-dose methotrexate (HDMTX): a neuropsychological and psychosocial study.

BACKGROUND: This study has been performed to examine the currently used doses of folinic acid (FA) and to determine the importance of the dose of FA in preventing subtle neurotoxicity. Thirty osteosarcoma patients were an appropriate population studied as they have no intrinsic neurological involvement. The neuropsychological and psychosocial status was tested in 2 groups of patients treated with similar protocols containing repeated doses of high-dose methotrexate, but different doses of FA. The patients received 300 to 600 mg/m or 120 to 250 mg/m FA in their protocols. METHODS: Eighteen tests or subtests of neuropsychological assessment were tested. RESULTS: Eleven of 18 tests were significant at the P=0.025 level favoring the group treated with high dose of FA. There were no clear results in the psychosocial measures with only a single measure of self-esteem (understanding) being significantly higher (P=0.024) in the group treated with high dose of FA, other measures had no statistical significance. CONCLUSIONS: A correlation between a higher dose of FA after high-dose methotrexate and a better neuropsychological status was clearly shown. The doses of FA used in the low FA group, 120 to 250 mg/m, were similar to those used by several groups treating children with leukemia; some have used even lower doses and report gross neurotoxicity.

Osteogenic sarcoma in a child with familial expansile osteolysis syndrome: an accidental association?

We present the first reported case of a child with familial expansile osteolysis syndrome (FEO) who developed osteogenic sarcoma (OS) of the iliac bone. A 17-year-old adolescent presented with pain and a mass on the left pelvis. He was from a family with several members who had been diagnosed with FEO, from which he also suffered. The median life expectancy of affected members of the family was reported as 25 to 30 years, with death ensuing as a result of various respiratory and cardiac complications of severe skeletal deformations, characteristic of increased bone turnover as seen in FEO. Biopsy of the patient's mass revealed chondroblastic OS. He was treated according to the P9754 protocol for patients with newly diagnosed nonmetastatic OS. Chemotherapy consisted of HD-MTX, ifosfomide, doxorubicin, and cisplatin. Complete resection of the tumor was carried out, but the patient subsequently developed metastatic disease and died (histologic response to neoadjuvant chemotherapy-85%). The patient's alkaline phosphatase level that was highly elevated before the start of chemotherapy, dropped significantly during treatment, with repeated elevation soon after definitive surgery, while he was recuperating and not on treatment. We speculate that chemotherapy affected not only the malignant cells of OS but normal osteoblasts as well, with a decreasing level of alkaline phosphatase even in the absence of any clinical and radiographic signs of OS. We also think that increased bone turnover, characteristic of a condition such as FEO, may facilitate de novo development of OS.

Unusual leptomeningeal dissemination in a child with extracranial metastatic alveolar rhabdomyosarcoma.

The authors describe a 6-year-old boy diagnosed with alveolar rhabdomyosarcoma located in the thigh, with distal metastases to lungs, bones, and bone marrow. A very good partial response to first-line chemotherapy was obtained, but the child developed fatal leptomeningeal dissemination immediately after complete resection of the primary tumor. This case demonstrates the rapidity with which leptomeningeal spread of extracranial metastatic alveolar rhabdomyosarcoma can occur and underscores the importance of diagnostic lumbar puncture and brain radiological investigations at diagnosis, even when the tumors are not in the parameningeal location.

Nasopharyngeal carcinoma in the pediatric age group: the northern Israel (Rambam) medical center experience, 1989-2004.

Nasopharyngeal carcinoma (NPC) is rare in children, accounting for less than 1% of all malignancies. Radiation therapy has been the mainstay of treatment of many years, but to improve survival, the use of chemotherapy has been advocated. This is a retrospective analysis of 13 patients less than 20 years of age treated for NPC the Rambam Medical Center during 1989 to 2004. Eight boys and five girls with a median age of 14.5 years (range 10-19) were included. Median follow up (including patients who died) was 6.15 years (range 1-15 years). Duration of symptoms was 1 to 24 months (median 5 months). Of the 13 patients, one patient had stage I, 6 had stage III, 5 had stage IV-A, and 1 had stage IV-B disease. Ten patients (77%) had undifferentiated carcinoma (WHO type III) and three patients (23%) had nonkeratinizing carcinoma (WHO type II). Most of the children received two or three courses of neoadjuvant multiagent chemotherapy consisting of cisplatin and 5-FU, followed by radiotherapy with doses in excess of 60 Gy. One child received concomitant chemoradiation. Ten of the 13 patients (77%) are alive without disease 6 years after diagnosis (range 1-15 years). One patient developed local and distant metastases 1 year after diagnosis and is currently receiving combined radiochemotherapy. Two patients died. Overall survival was 84%; event-free survival was 77%. Nine patients (69%) developed moderate to severe long-term complications. Pediatric NPC is curable by combined radiation and chemotherapy, with doses of radiation in excess of 60 Gy. Long-term follow-up is important for early detection of second malignancies as well as for radiation-induced endocrinologic deficiencies and other normal tissue complications.

Atrial metastasis detected by two-dimensional echocardiography.

With recent improvements in therapeutic procedures and prolongation of survival, the incidence of cardiac metastasis is likely to increase. The aim of the current study was retrospectively to analyze cases of atrial metastases detected by echocardiography at our center. We report on a series of 10 patients with various solid malignancies and secondary atrial involvement detected by echocardiography. Transesophageal and transthoracic echocardiographic studies were performed using an Acuson 128XP, Aspen or Sequoia (Mountain View CA). Seven patients had cardiac symptoms at the time of diagnosis of atrial metastasis. After diagnosis, therapy included surgery, chemotherapy or radiotherapy. Echocardiography was also used in monitoring response to therapy. One patient with Wilms' tumor has remained free of disease for 50+ months and a patient with Kaposi's sarcoma is alive with disease 20+ months after diagnosis. The remaining eight patients died with disease 3-24 months after being diagnosed with atrial metastasis. Atrial metastases can be diagnosed in patients without cardiac symptoms, and is probably more prevalent than was previously recognized. Echocardiography is a useful diagnostic tool in detecting secondary atrial tumors.

Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia.

BACKGROUND: Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with combination chemotherapy containing methotrexate (MTX), drug resistance contributes to treatment failure for a substantial fraction of patients. The primary transporter for folates and MTX is the reduced folate carrier (RFC). Impaired drug transport is a documented mechanism of MTX resistance in patients with ALL; however, to the authors' knowledge it is not known whether inactivating RFC mutations are a contributing factor. METHODS: The authors devised a genomic polymerase chain reaction-single strand conformational polymorphism assay followed by sequencing and screened the entire RFC coding region for sequence alterations in DNA from 246 leukemia specimens from patients with diverse ethnic variation, 24 at the time of recurrence and the rest at the time of diagnosis. This cohort was comprised of 203 B-precursor ALL specimens (82.5%), 32 T-lineage ALL specimens (13%), and 11 acute myeloblastic leukemia specimens (4.5%). RESULTS: Of 246 DNA samples, only 3 diagnosis B-precursor ALL specimens (1.2%) were found to harbor alterations in the RFC gene, including heterozygous single nucleotide changes resulting in D56H and D522N substitutions in the first extracellular loop and the C-terminus of this transporter, respectively. The third sample had a sequence alteration in exon 3 that could not be identified because of the lack of availability of DNA. CONCLUSIONS: Whereas inactivating RFC mutations are a frequent mechanism of MTX resistance in human leukemia cell lines and in patients with osteosarcoma, they are not common and do not appear to play any significant role in intrinsic or acquired resistance to MTX in childhood leukemia. This is the first study of RFC mutations in multiple pediatric leukemia specimens.

The prevalence of low selenium levels in newly diagnosed pediatric cancer patients.

Low selenium (Se) levels have been found in assoiciation with high incidences of various types of adult cancer. Much less is known about this issue among pediatric cancer patients. Forty-two pediatric patients with a variety of newly diagnosed malignancies were divided into two groups, 20 with localized disease (LD) and 22 with widespread disease (WSD). Analysis of serum collected before the commencement of treatment showed that half the patients had low Se serum levels, lower and more common in WSD than in LD. There was no significant difference in the prevalence of low albumin levels among patients with low Se levels, and most of the newly diagnosed children did not suffer from malnutrition. It was concluded that Se deficiency is common among newly diagnosed pediatric cancer patients, Se levels are lower in WSD than LD, and low Se levels are more prevalent in WSD patients than in LD patients.

Sperm cryopreservation in adolescents with newly diagnosed cancer.

BACKGROUND: Referring male patients (pts) for pretreatment sperm cryopreservation (SCP) is a routine practice in adult oncology. Our aim was to evaluate the semen quality and feasibility of sperm cryopreservation in male adolescents diagnosed with cancer prior to the commencement of treatment. METHODS: All consecutive adolescents from 14 to 19 years of age with newly diagnosed cancer were referred to this study. The following parameters of semen analysis were investigated: (1) volume of collected sample (N >or= 2.0 ml); (2) total sperm concentration (N >or= 20 x 10(6)/ml); (3) percentage of motile spermatozoa (N >or= 50%). The results were compared with normal values characteristic of healthy young men. RESULTS: Sixty-two attempts to collect sperm were made by the 27 adolescents. Of the 40/62 (64.5%) attempts, which resulted in a normal sperm count in each sample, only nine (22.5%) demonstrated normal sperm motility. Only 9/62 (14.5%) attempts resulted in normal sperm motility. Nineteen of 62 (30.6%) attempts produced a normal volume of ejaculate, while three pts were unable to produce any sperm. Only 4/62 (6.5%) attempts produced semen that could be considered normal in all the parameters. CONCLUSIONS: Only a minority of adolescents newly diagnosed with cancer is able to produce sperm that can be considered normal, compared with healthy young men. Despite this, SCP should be offered and is a technically feasible procedure for these patients in light of the recent advances in assisted reproductive technologies. Further studies are required to develop treatment protocols for this group of pts to lessen damage to fertility function.

Concomitant focal fibrocartilaginous dysplasia of the tibia and eosinophilic granuloma of the jaw in a child.

This 2-year-old child presented with concomitant eosinophilic granuloma of the lower jaw and focal fibrocartilaginous dysplasia of the right tibia. Her eosinophilic granuloma was diagnosed on the basis of the clinical picture, imaging studies and the characteristic histologic appearance. Focal fibrocartilaginous dysplasia was revealed incidentally during the eosinophilic granuloma staging process. After chemotherapy, all signs of eosinophilic granuloma subsided, but focal fibrocartilaginous dysplasia remained without signs of clinical or radiographic progression. The importance of differentiating these two conditions is stressed in order to avoid ineffective and inappropriate treatment of focal fibrocartilaginous dysplasia.