Chronic fatigue in childhood cancer survivors is associated with lifestyle and psychosocial factors; a DCCSS LATER study.

BACKGROUND: The purpose of this study was to determine factors associated with chronic fatigue (CF) in childhood cancer survivors (CCS). PATIENTS AND METHODS: Participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort, a nationwide cohort of CCS (≥5 years after diagnosis) and siblings as controls. Fatigue severity was assessed with the 'fatigue severity subscale' of the Checklist Individual Strength ('CIS-fatigue'). CF was defined as scoring ≥35 on the 'CIS-fatigue' and having fatigue symptoms for ≥6 months. Twenty-four parameters were assessed, categorized into assumed fatigue triggering, maintaining and moderating factors. Multivariable logistic regression analyses were carried out to investigate the association of these factors with CF. RESULTS: A total of 1927 CCS participated in the study (40.7% of invited cohort), of whom 23.6% reported CF (compared with 15.6% in sibling controls, P < 0.001). The following factors were associated with CF: obesity [versus healthy weight, odds ratio (OR) 1.93; 95% confidence interval (CI) 1.30-2.87], moderate physical inactivity (versus physical active, OR 2.36; 95% CI 1.67-3.34), poor sleep (yes versus no, OR 2.03; 95% CI 1.54-2.68), (sub)clinical anxiety (yes versus no, OR 1.55; 95% CI 1.10-2.19), (sub)clinical depression (yes versus no, OR 2.07; 95% CI 1.20-3.59), pain (continuous, OR 1.49; 95% CI 1.33-1.66), self-esteem (continuous, OR 0.95; 95% CI 0.92-0.98), helplessness (continuous, OR 1.13; 95% CI 1.08-1.19), social functioning (continuous, OR 0.98; 95% CI 0.97-0.99) and female sex (versus male sex, OR 1.79; 95% CI 1.36-2.37). CONCLUSION: CF is a prevalent symptom in CCS that is associated with several assumed maintaining factors, with lifestyle and psychosocial factors being the most prominent. These are modifiable factors and may therefore be beneficial to prevent or reduce CF in CCS.

Clinical and self-reported markers of reproductive function in female survivors of childhood Hodgkin lymphoma.

PURPOSE: To evaluate the impact of treatment for Hodgkin lymphoma (HL) on clinical reproductive markers and pregnancy outcomes. METHODS: This study was embedded within the DCOG LATER-VEVO study; a Dutch, multicenter, retrospective cohort study between 2004 and 2014. Serum anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B, antral follicle count (AFC), and self-reported (first) pregnancy outcomes were evaluated in female childhood HL survivors and controls. RESULTS: 84 HL survivors and 798 controls were included, aged 29.6 and 32.7 years old at time of assessment. Median age at HL diagnosis was 13.4 years. Cyclophosphamide equivalent dose (CED-score) exceeded 6000 mg/m2 in 56 women and 14 survivors received pelvic irradiation. All clinical markers were significantly deteriorated in survivors (odds-ratio for low AMH (< p10) 10.1 [95% CI 4.9; 20.6]; low AFC (< p10) 4.6 [95% CI 2.1; 9.9]; elevated FSH (> 10 IU/l) 15.3 [95% CI 5.7; 41.1], low Inhibin B (< 20 ng/l) 3.6 [ 95% CI 1.7; 7.7], p < 0.001). Pregnancy outcomes were comparable between survivors and controls (± 80% live birth, ± 20% miscarriage). However, survivors were significantly younger at first pregnancy (27.0 years vs 29.0 years, P = 0.04). Adjusted odds-ratio for time to pregnancy > 12 months was 2.5 [95% CI 1.1; 5.6] in survivors, p = 0.031. Adverse outcomes were specifically present after treatment with procarbazine and higher CED-score. CONCLUSION: HL survivors appear to have an impaired ovarian reserve. However, chance to achieve pregnancy seems reassuring at a young age. Additional follow-up studies are needed to assess fertile life span and reproductive potential of HL survivors, in particular for current HL treatments that are hypothesized to be less gonadotoxic.

Health-related quality of life in Dutch adult survivors of childhood cancer: A nation-wide cohort study.

AIM: To investigate the health-related quality of life (HRQOL) of Dutch adult childhood cancer survivors (CCS) and to identify risk factors of impaired HRQOL. METHODS: Adult CCS (age >18, diagnosed <18, ≥5 years since diagnosis) from the Dutch LATER registry completed the Medical Outcome Study Short Form 36 (SF-36) to measure HRQOL and provided sociodemographic characteristics. Age-adjusted mean SF-36 scale scores of CCS were compared to the Dutch general population for men and women separately using t-tests, with effect size d. Multivariate logistic regression models were built to identify sociodemographic and cancer-related risk factors for impaired physical and mental HRQOL. RESULTS: Both male and female CCS (N = 2301, mean age = 35.4 years, 49.6% female) reported significantly (p ≤ .005) worse HRQOL than the general population on almost all scales of the SF-36 (-.11 ≤ d ≤ -.56). Largest differences were found on vitality and general health perceptions. Significant risk factors (p ≤ .05) for impaired physical HRQOL were female sex, older age at diagnosis, not having a partner, low educational attainment, disease recurrence and exposure to radiotherapy, specifically to lower extremity radiation. Odds ratios (ORs) ranged from 1.6 to 3.7. Significant risk factors for impaired mental HRQOL were age 26-35 years, male sex, not having a partner and low educational attainment. ORs ranged from 1.3 to 2.0. CONCLUSION: Adult CCS had worse HRQOL than the general population. CCS most at risk were those with low educational attainment and without a partner. Adult CCS could benefit from routine surveillance of their HRQOL. Special attention for CCS' vitality and health perceptions and beliefs is warranted.

Pregnancy, time to pregnancy and obstetric outcomes among female childhood cancer survivors: results of the DCOG LATER-VEVO study.

PURPOSE: To evaluate pregnancy rates, time to pregnancy (TTP) and obstetric outcomes in female childhood cancer survivors (CCSs) and to identify specific diagnosis- and treatment-related factors associated with these outcomes. METHODS: The study is part of the DCOG LATER-VEVO study, a nationwide multicenter cohort study evaluating fertility among long-term Dutch female CCSs. Data were collected by questionnaire. The current study included 1095 CCSs and 812 controls, consisting of sisters of CCSs and a random sample of women from the general population. RESULTS: Among the subgroup of women who ever had the desire to become pregnant, the chance of becoming pregnant was significantly lower for CCSs than controls (OR 0.5, 95%CI 0.4-0.8). Moreover, TTP was 1.1 times longer for CCSs compared to controls (p = 0.09) and was significantly longer in survivors of CNS and renal tumours. Overall, no differences were found between CCSs and controls regarding the probability of ever having had a miscarriage, still birth, or induced abortion. However, CCSs had a significantly increased risk of delivering preterm (OR 2.2, 95%CI 1.3-3.7) and delivering via caesarean section (OR 1.8, 95%CI 1.2-2.6). Treatment with lower abdominal/pelvic radiotherapy was strongly associated with several adverse obstetric outcomes. CONCLUSION: CCSs are less likely to have ever been pregnant. Among those who do become pregnant, certain subgroups of CCSs are at increased risk of longer TTP. Moreover, as pregnant CCSs, especially those treated with lower abdominal/pelvic radiotherapy, are more likely to develop various adverse obstetric outcomes, appropriate obstetric care is highly advocated.

Long-term effects of childhood cancer treatment on hormonal and ultrasound markers of ovarian reserve.

STUDY QUESTION: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)? SUMMARY ANSWER: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT. WHAT IS KNOWN ALREADY: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited. STUDY DESIGN, SIZE, DURATION: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT. LIMITATIONS, REASONS FOR CAUTION: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests. TRIAL REGISTRATION NUMBER: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922.

The influence of genetic variation on late toxicities in childhood cancer survivors: A review.

INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.

Reproductive intentions and use of reproductive health care among female survivors of childhood cancer.

STUDY QUESTION: Do female childhood cancer survivors (CCSs) express a decreased desire to have children and do they use reproductive health care more often compared to women without a history of cancer? SUMMARY ANSWER: Overall, no difference was found in the desire to have children between CCSs and controls, whereas CCSs consult a fertility specialist more often, at a younger age, and sooner after their first attempt at conceiving. WHAT IS KNOWN ALREADY: Female CCSs may face a shorter than anticipated reproductive window as a result of their cancer treatment. Little is known about their desire to have children and use of reproductive health care, especially in relation to their former cancer treatment. STUDY DESIGN, SIZE, DURATION: This study is part of the DCOG LATER-VEVO study, a nationwide retrospective cohort study on female fertility in Dutch CCSs. In total, 1749 CCSs and 1673 controls were invited for the study. Data collection took place between January 2008 and May 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on the desire to have children and use of reproductive health care were collected by questionnaire. The control group consisted of sisters from CCSs and females from the general population. In total, 1106 (63%) CCSs and 818 (49%) controls completed the questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no difference was found in the desire to have children between CCSs and controls (86% and 89%, respectively). However, survivors of a CNS tumour were less likely to desire children and CCSs without biological children at time of study were more likely to report that their desire to have children was unfulfilled because of medical reasons (9%), compared to controls (1%). In total, 12% of CCSs ever consulted a fertility specialist compared to 10% of controls (OR = 1.7, 95% CI: 1.3-2.4). Mean (SD) age at time of their first visit was 27.7 (4.4) years for CCSs and 29.9 (3.9) years for controls (P < 0.01). In total, 43% of CCSs consulted a fertility specialist within 12 months after they had started trying to achieve a pregnancy, compared to 27% of controls. Risk factors for consulting a fertility specialist included a previous diagnosis of renal tumour, leukaemia, lymphoma or a CNS tumour, and treatment with alkylating chemotherapy, gonadotoxic radiotherapy or both. In total, 70% of CCSs reported a female factor as cause of subfertility compared to 34% of controls (OR = 4.5, 95% CI: 2.3-8.7) and in this specific group, CCSs seemed more likely to use fertility treatment (OR = 2.9, 95% CI: 1.0-8.2). LIMITATIONS, REASONS FOR CAUTION: Because of the low number of CCSs who used fertility treatment, we were not able to look at specific diagnoses and treatment types associated with using fertility treatment. Nevertheless, we were able to identify diagnostic- and treatment-related risk factors for consulting a fertility specialist. Details regarding consultations with a fertility specialist and fertility treatment were based on self-report and may therefore be subject to recall bias. WIDER IMPLICATIONS OF THE FINDINGS: Decisions about parenthood affect all CCSs. It's important to evaluate reproductive intentions and function timely after cancer treatment, so CCSs can be adequately counselled regarding family planning and fertility treatment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Dutch Cancer Society (Grant no. VU 2006-3622) and the Children Cancer Free Foundation (Project no. 20). TRIAL REGISTRATION NUMBER: NTR2922.

Validity of self-reported data on pregnancies for childhood cancer survivors: a comparison with data from a nationwide population-based registry.

STUDY QUESTION: To what degree do records registered in the Netherlands Perinatal Registry (PRN) agree with self-report in a study questionnaire on pregnancy outcomes in childhood cancer survivors (CCSs)? SUMMARY ANSWER: This study suggests that self-reported pregnancy outcomes of CCSs agree well with registry data and that outcomes reported by CCSs agree better with registry data than do those of controls. WHAT IS KNOWN ALREADY: Many studies have shown that childhood cancer treatment may affect fertility outcomes in female CCSs; however, these conclusions were often based on questionnaire data, and it remains unclear whether self-report agrees well with more objective sources of information. STUDY DESIGN, SIZE, DURATION: In an nationwide cohort study on fertility (inclusion period January 2008 and April 2011, trial number: NTR2922), 1420 CCSs and 354 sibling controls were invited to complete a questionnaire regarding socio-demographic characteristics and reproductive history. In total, 879 CCSs (62%) and 287 controls (81%) returned the questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS: The current validation study compared the agreement between pregnancy outcomes as registered in the PRN and self-reported outcomes in the study questionnaire. A total of 589 pregnancies were reported in CCSs, and 300 pregnancies in sibling controls, of which 524 could be linked to the PRN. MAIN RESULTS AND THE ROLE OF CHANCE: A high intra-class correlation coefficient (ICC) was found for birthweight (BW) (0.94 and 0.87 for CCSs and controls, respectively). The self-reported BWs tended to be higher than reported in the PRN. For gestational age (GA), the ICC was high for CCSs (0.88), but moderate for controls (0.49). CCSs overestimated GA more often than controls. The Kappa values for method of conception and for method of delivery were moderate to good. Multilevel analyses on the mean difference with regard to BW and GA showed no differences associated with time since pregnancy or educational level. LIMITATIONS, REASONS FOR CAUTION: Not all pregnancies reported could be linked to the registry data. In addition, the completeness of the PRN could not be assessed precisely, because there is no information on the number of missing records. Finally, for some outcomes there were high proportions of missing values in the PRN registry. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that questionnaires are a reliable method of data collection, and that for most variables, self-report agrees well with registry data. STUDY FUNDING/COMPETING INTEREST: This work was supported by the Dutch Cancer Society (grant no. VU 2006-3622) and by Foundation Children Cancer Free. None of the authors report a conflict of interest. TRIAL REGISTRATION NUMBER: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922.

Discriminative ability of conventional echocardiography and tissue Doppler imaging techniques for the detection of subclinical cardiotoxic effects of treatment with anthracyclines.

This study investigated improvement of diagnosing myocardial damage caused by anthracyclines using tissue Doppler imaging (TDI). The optimal set of conventional echocardiographic and/or TDI parameters, needed for the discrimination of survivors from healthy controls, was retrospectively assessed. A total of 60 patients and 99 controls, age range 8.5 to 17.6 years, were studied. The survivors received 50 to 400 mg/m(2) cumulative dose of anthracyclines, with a mean follow-up of 7.3 (+/-2.3) years. The parameters used in the discriminant score (S-score) were selected from a large set of 51 echocardiographic parameters, using logistic regression analysis (stepwise selection). The correct classification probability (C-index) and the generalized distance (d) between the distributions of S-scores were used to measure the overall discriminative performance of each echocardiographic technique separately and in combination. The overall discriminative performance of the conventional echo-Doppler parameters (C = 77.3%, d = 1.04) was lower than that of the TDI (C = 84.2%, d = 1.37); the highest C-index was obtained using both techniques (C = 89.2%, d = 1.66). The set of parameters includes: LV fractional shortening and MV early diastolic flow velocity, two long-axis and five apical 4-CV TDI wall velocities (systolic and diastolic). In the patient group, the S-score was positively associated with cumulative dose of anthracyclines (p = 0.05) and duration of treatment (p = 0.01). The diagnostic index S-score, based on a limited number of variables from both techniques simultaneously, could retrospectively discriminate asymptomatic children with anthracycline-induced cardiomyopathy from healthy controls. The potentials of the S-score for serial and prospective studies are further investigated.

Tissue Doppler imaging in detection of myocardial dysfunction in survivors of childhood cancer treated with anthracyclines.

The applicability of tissue Doppler imaging (TDI) was investigated for estimating cardiac function in long-term survivors of childhood cancer treated with anthracyclines. A total of 63 children (age range 7.8-17.3 y) underwent standard echo Doppler cardiographic studies of blood flow velocities, left ventricular dimensions and fractional shortening, followed by measurements of peak myocardial velocities and direction using the noninvasive tissue Doppler imaging (TDI) technique. All 63 were late survivors (median 7.1 y, range 3.5-13.5 y after end of therapy) who had received mean (+/- SD) cumulative dose of 242 (+/- 141) mg/m(2) of anthracyclines. The control group consisted of 160 healthy subjects (age range 4 to 17.9 y). Standard echo-Doppler anatomical parameters that were found significantly (p < 0.01) different for the study group are: RV wall thickness (decreased); LV diameter (increased); and LV fractional shortening (decreased). Studied hemodynamic parameters were not found to be different between the two groups. Quantitative TDI parameters: peak late diastolic myocardial velocities, as well as transmyocardial systolic and diastolic velocity differences, were significantly lower in late survivors than in the healthy pediatric population (p < 0.01). Qualitative local functional impairment of the movement of the left ventricular walls was detected in 20% of the patients. TDI might become a useful noninvasive method for detecting subclinical myocardial damage in apparently healthy children who received moderate doses of anthracyclines for treatment of childhood malignancy. Prospective studies with TDI for the detection of regional myocardial abnormalities are recommended.

Shortened and diminished pubertal growth in boys and girls treated for acute lymphoblastic leukaemia.

Statural growth during puberty was studied longitudinally in 28 patients treated for acute lymphoblastic leukaemia. All patients received prophylactic cranial irradiation. The age at diagnosis was below 7 years, the age at final investigation was above 16 years for girls and above 18 years for boys. Growth was analysed using the Kernel estimation. In girls the onset of puberty and menarche was at a younger age, as compared to reference values, and the duration of the pubertal growth spurt was shorter. Compared to early maturing girls, the growth velocity at peak height velocity was lower. This resulted in a final height which was shorter than expected on the basis of the height standard deviation score before the start of puberty. In boys the duration of the pubertal growth spurt was shorter and the height gain during the growth spurt less than in the reference population. In both sexes the bone age development was accelerated.

Influence of treatment modalities on body weight in acute lymphoblastic leukemia.

Weight for height of 92 patients (51 girls and 41 boys) treated for acute lymphoblastic leukemia (ALL) was evaluated in a longitudinal study. Fifty-four patients received cranial irradiation (CI) with a dose of 18 or 24 Gy and 38 patients did not receive CI. Seventy-seven patients were treated according to a normal-risk protocol and 15 patients received more intensive chemotherapy according to a high-risk protocol. In most of the patients the duration of follow-up was 12 years for irradiated patients and 4.5 years for the nonirradiated patients. Thirty of 92 patients were treated according to a protocol without CI, but with a difference in the use of corticosteroids: 19 patients received dexamethasone during the remission-induction and maintenance treatment and 11 patients received prednisone. The influence of dexamethasone vs. prednisone, sex, CI and high-dose vs. low-dose chemotherapy on weight for height was evaluated. Patients who received dexamethasone showed a significant increase in weight for height immediately after the start of therapy. In patients who received CI, weight for height significantly increased after the first year of treatment. The overweight in these patients persisted during the whole follow-up period. The weight for height of patients treated with prednisone and of patients who did not receive CI was below the mean of the normal population during treatment but was not different from normal after cessation of therapy. No difference in weight gain was seen between boys and girls and between patients who were treated with high vs. normal-risk protocols.

Chemotherapy plays a major role in the inhibition of catch-up growth during maintenance therapy for childhood acute lymphoblastic leukemia.

OBJECTIVE: In children treated for acute lymphoblastic leukemia (ALL), catch-up growth occurs after cessation of therapy and not during maintenance therapy. In this study we investigated whether this inhibition of catch-up growth during maintenance treatment is attributable to the influence of chemotherapy or to the influence of corticosteroids. PATIENTS: Forty-six children treated for ALL were included in the study. In 27 patients maintenance therapy comprised vincristine (VCR), prednisone (Pred), or dexamethasone (Dexa) alternated with 6-mercaptopurine (6-MP) and methotrexate (MTX) and 19 patients received maintenance therapy with 6-MP and MTX only. Treatment did not include cranial irradiation. RESULTS: Statural growth during maintenance treatment was comparable in both groups over the study period of 1.5 years. CONCLUSION: Chemotherapy with 6-MP and MTX, and not corticosteroids, is the main factor that prevents catch-up growth from occurring during maintenance therapy for ALL.

Influence of treatment modalities on prepubertal growth in children with acute lymphoblastic leukemia.

The statural growth of 85 prepubertal children treated for acute lymphoblastic leukemia was evaluated in a longitudinal study over 4.5 years. Patients were divided into three groups according to central nervous system prophylaxis: 37 patients received cranial irradiation with a dose of 24 Gy, 15 received a dose of 18 Gy, and 33 were not irradiated. According to the risk of leukemia, patients were divided into normal-risk (n = 74) and high-risk (n = 11) groups. The duration of treatment was 2 years, during which all patients showed growth retardation. The relative standard deviation score for height declined from 0 to -0.7 for the irradiated patients and from 0 to -0.2 for the non-irradiated group (P = 0.0001). There was no difference in growth pattern between cranial irradiation with 18 versus 24 Gy and chemotherapeutic treatment according to high-risk versus normal-risk protocols. However, a negative synergistic effect of more intensive chemotherapy and cranial irradiation on growth was demonstrated.

Determination of propionate in bread using capillary zone electrophoresis.

A method for the determination of propionate in bread is described. The propionate was extracted from the bread with a repeated extraction procedure and measured using capillary zone electrophoresis in the indirect UV mode applying a background electrolyte of 0.005 M Tris adjusted at pH 4.6 by adding benzoic acid. Using laboratory-baked bread containing known amounts of sodium propionate, recoveries of ca. 95% could be established, validating the method.

Rapid VAC high dose melphalan regimen, a novel chemotherapy approach in childhood soft tissue sarcomas.

Forty-three children with malignant soft tissue sarcomas (IRS Groups II-IV) were treated with rapid dose delivery chemotherapy protocol comprising six courses of vincristine, adriamycin and cyclophosphamide, given in most cases within 8 weeks (Rapid VAC). This was followed in 36 patients by high dose melphalan with autologous bone marrow rescue. Twenty-six patients also received irradiation to the site of primary tumour. The Rapid VAC regimen was well tolerated and largely administered as an out-patient. There was one toxic death which occurred 2 months after high dose melphalan due to a combination of infection and possible anthracycline cardiomyopathy. Stages were, (Intergroup Rhabdomyosarcoma Study (IRS) system) Group, Group II--four patients. Group III--27 patients and Group IV--12 patients; International Society of Paediatric Oncology (SIOP) staging, Stage I--11, Stage II--13, Stage III--7, Stage IV--12. Actuarial survival at 5 years for all stages is 57% and event free survival 44%. For patients with non-metastatic diseases, 62% and 53% respectively. This treatment strategy utilises the philosophy of rapid drug delivery with high dose consolidation and enables all chemotherapy to be finished within a 4 month period. In general, a conservative approach was applied to both radiation and surgery to minimise late sequelae related to these treatment modalities. Although the small number of high risk patients in this study limits conclusions regarding efficacy in these subgroups the overall results with this regimen appear to be comparable to that with other approaches.

Response rates in relapsed Wilms' tumor. A need for new effective agents.

Three hundred eighty-one children with Wilms' tumor were treated in the United Kingdom Children's Cancer Study Group WT1 Study (1982 to 1986). Seventy-one patients had relapses during or after treatment with surgery and chemotherapy, and radiation therapy, depending on stage and histologic characteristics. Forty-nine patients were evaluable for disease response to second-line chemotherapy alone. Evaluation of response to chemotherapy was impossible in the remaining patients because either surgery or radiation therapy was used at the time of relapse. With second-line combination chemotherapy (which included ifosfamide, etoposide/VM26, cisplatin/carboplatin, bleomycin, melphalan, and Thiotepa [Lederle Laboratories, Pearl River, NY]), there were five complete responses and 12 partial responses. In patients with favorable histologic findings, six of nine with Stage I, five of ten with Stage II, none of 11 with Stage III, three of 16 with Stage IV, and one of five with Stage V disease survived. Two survivors were treated with chemotherapy alone; the others received combined treatment with chemotherapy, radiation therapy, and/or surgery. For those with unfavorable histologic findings of any stage, only two of 20 survived. The authors conclude that, even for patients with localized disease with favorable histologic findings, the "salvage" rate is little more than 50%, and for all other stages and histologic findings the likelihood of cure after relapse is remote. There is clearly a need for additional effective chemotherapeutic agents for these patients.