Marianne Schmiegelow

Cryopreservation of semen from pubertal boys with cancer

BACKGROUND The possibility of cryopreservation of semen from adolescents has until now received only little attention. Therefore, we have investigated the possibility of cryopreservation of semen in adolescent boys with cancer. PROCEDURE Forty-five boys, aged 13-18 years, admitted because of cancer during the period January 1, 1995 to July 31, 1998 were eligible. Semen was obtained after masturbation in the majority of the cases. In three boys, semen was preserved after penile vibration or electroejaculation in general anaesthesia. The semen samples were analysed for concentration, motility, and morphology according to the WHO guidelines. The sample was transferred into straws prior to cryopreservation at 196 degrees C in liquid nitrogen. RESULTS Twenty-one boys delivered a semen sample for cryopreservation. Four boys were offered and accepted sperm banking but were not able to produce a sample. In 20 cases time did not allow an attempt of sperm banking, the boy was not assessed to be mature enough to deliver a semen sample, or the procedure was not accepted. The boys delivered 1-3 samples, and the total number of spermatozoa ranged from 0-210 millions. Median percentage of motile sperm was 50% (range 9-86%). Semen quality improved with age; however, a 13- year- old boy produced 75 million spermatozoa with 38% motile cells. CONCLUSIONS Pubertal maturation should be assessed in all boys admitted for cancer, and the possibility of sperm banking should be discussed with the patient and his parents.

Long-term neurological outcome of childhood brain tumors treated by surgery only

PURPOSE To evaluate the pattern of neurological late effects in patients who have received surgery only for a brain tumor in childhood and to identify possible risk factors for neurological sequelae. PATIENTS AND METHODS The medical, histologic, and operative records were reviewed for 65 consecutive patients operated for a benign brain tumor from 1970 to 1997, and all patients were re-examined after a median length of follow-up of 10.7 years. Thirty-four patients had posterior fossa tumors, 22 patients had cerebral hemisphere tumors, and nine patients had midline tumors. RESULTS At the time of follow-up, 20 patients (31%) had no neurological deficits, 22 patients (34%) had minor deficits that did not interfere with their daily life activities, and 23 patients (35%) had moderate or severe deficits such as severe ataxia, spastic paresis, seriously reduced vision, or epilepsy with more than two seizures per year. Fourteen of the 31 patients (45%) registered with ataxia preoperatively had recovered fully. Six of seven patients had persistence of a pre- or postoperatively developed hemiparesis. Thirteen of 23 patients had persistence of cranial nerve deficits that developed second to surgery. Fifty-five percent of the 18 patients with seizures at diagnosis were seizure-free at follow-up. At follow-up both ataxia and hemiparesis were significantly more frequent among females (P =.02 and P =.03, respectively). CONCLUSION In patients who received operation as the only treatment for their brain tumor, there was a good chance of total or partial recovery of preoperative and postoperative neurological deficits, although only one third of the patients will have no long-term neurological deficits.

Genetic disease in the children of Danish survivors of childhood and adolescent cancer.

PURPOSE Preconception radiation and chemotherapy have the potential to produce germ cell mutations leading to genetic disease in the next generation. Dose-response relationships were evaluated between cancer treatments and untoward pregnancy outcomes. PATIENTS AND METHODS A case-cohort study was conducted involving 472 Danish survivors of childhood and adolescent cancer and their 1,037 pregnancies. Adverse outcomes included 159 congenital malformations, six chromosomal abnormalities, seven stillbirths, and nine neonatal deaths. Preconception radiation doses to the gonads, uterus, and pituitary gland and administered chemotherapy were quantified based on medical records and related to adverse outcomes using a generalized estimating equation model. RESULTS No statistically significant associations were found between genetic disease in children and parental treatment with alkylating drugs or preconception radiation doses to the testes in male and ovaries in female cancer survivors. Specifically, the risk of genetic disease was similar among the children of irradiated survivors when compared with nonirradiated survivors (relative risk [RR], 1.02; 95% CI, 0.59 to 1.44; P = .94). A statistically significant association between abdomino-pelvic irradiation and malformations, stillbirths, and neonatal deaths was not seen in the children of female survivors overall (P = .07) or in the children of mothers receiving high uterine doses (mean, 13.5 Gy; max, 100 Gy; RR, 2.3; 95% CI, 0.95 to 5.56). CONCLUSION Mutagenic chemotherapy and radiotherapy doses to the gonads were not associated with genetic defects in children of cancer survivors. However, larger studies need to be conducted to further explore potential associations between high-dose pelvic irradiation and specific adverse pregnancy outcomes.

Dosimetry and growth hormone deficiency following cranial irradiation of childhood brain tumors

BACKGROUND Dosimetry of the hypothalamus-pituitary (HP) region could allow prediction of the risk of growth hormone deficiency (GHD) following cranial irradiation. PROCEDURE Nineteen children (15 boys) with a median age of 6.3 years (range 1.7-16.5) at the time of irradiation of a brain tumor not involving the HP axis were followed for 1.2-6.3 years (median 3.4) from radiotherapy (RT). The dose to a standardized anatomical model including the HP region was calculated from dose-volume histograms of 10% to 100% in steps of 10% of the HP model based on data from a computer-based treatment planning system. If GHD was suspected from insulin-like growth factor-I, serum insulin-like growth factor binding protein-3, and/or height velocity measurements, an arginine stimulation test was performed. GHD was defined by a peak GH <15mU/liter. RESULTS Ten patients developed GHD 10-26 months from irradiation. Cox regression analysis identified the 90% dose-volume of the HP box as the strongest predictor of development of GHD (P = 0.03). The median dose to the 90% dose-volume of the HP region was 37.5 Gy (range 2. 3-55.3). The cumulated risk of GHD 2.5 years after radiotherapy for children receiving more than and less than 37.5 Gy to the HP region was 87% and 33%, respectively (P = 0.036). CONCLUSIONS Dosimetry of a defined HP volume provides the opportunity to 1) calculate the exact dose delivered to this region, 2) predict the risk of GHD and, 3) in the future revise the treatment planning and thus reduce the risk of endocrine adverse effects.

Methotrexate and 6-mercaptopurine maintenance therapy for childhood acute lymphoblastic leukemia : dose adjustments by white cell counts or by pharmacokinetic parameters ?

In a consecutive study of 14 boys and 17 girls with non-B-cell ALL who were ≥1 year of age at diagnosis, the degree of myelosuppression during the last year of MTX/6MP maintenance therapy was analyzed in relation to the erythrocyte concentration of MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN, the respective major cytotoxic metabolites of MTX and 6MP). For each patient, E-MTX and E-6TGN levels were measured 2–15 (median, 6) and 2–17 (median, 7) times, respectively. From these measurements, arithmetic means of E-MTX and E-6TGN were calculated (mE-MTX and mE-6TGN, respectively). Since MTX and 6MP probably work synergistically, the product of mE-MTX and mE-6TGN was calculated for each patient (mE-MTX×6TGN). The degree of myelosuppression was registered as the mean WBC determined following cessation of the therapy minus the mean WBC measured during the therapy (mWBCshift). The mean WBCs measured on therapy (mWBCon) and off therapy were highly correlated (r=0.48,P=0.009). The median mWBCshift was 2.7×109/l (range, 1.4–4.8×109/l). In a multivariate regression analysis, the best-fit model to predict the mWBCshift included mE-MTX×6TGN, age at drug withdrawal, and mWBC in the order given [mWBCshift=4.3+0.00089×(mE-MTX×6TGN)−0.097×age−0.41×mWBCon; globalrs=0.66,P=0.0002]. Thus, the patients with higher mE-MTX×6TGN values, the younger patients, and the patients with the lowest WBC during therapy had the most pronouced degree of myelosuppression as measured by mWBCshift. These results indicate that E-MTX and E-6TGN may give a better reflection of the treatment intensity than do the WBCs alone.

Cerebral glucose metabolism in long-term survivors of childhood primary brain tumors treated with surgery and radiotherapy.

Delayed structural cerebral sequelae has been reported following cranial radiation therapy (CRT) to children with primary brain tumors, but little is known about potential functional changes. Twenty-four patients were included, diagnosed and treated at a median age of 11 years, and examined after a median recurrence free survival of 16 years by MRI and Positron Emission Tomography using the glucose analog 2-18F-fluoro-2-deoxy-D-glucose (18FDG). Three patients were not analyzed further due to diffuse cerebral atrophy, which might be related to previous hydrocephalus. Twenty-one patients were evaluable and regional cerebral metabolic rate for glucose (rCMRglc) was estimated in nontumoral brain regions in 12 patients treated with surgery alone and 9 patients treated with both surgery and CRT. Furthermore 10 normal controls matched for age at examination were included. Patients treated with both surgery and CRT had a general decreased rCMRglc compared to normal controls and patients treated with surgery alone, significantly (p < 0.05) in 5 of 11 regions of interest. No difference was found in rCMRglc between normal controls and patients treated with surgery alone. We conclude that there is a general reduction in rCMRglc in long-term recurrence free survivors of childhood primary brain tumors treated with CRT in high doses (44–56 Gy).