Jürgen Brämswig

The effects of different cumulative doses of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin's disease during childhood or adolescence.

Testicular function was evaluated in 75 boys after treatment for Hodgkins disease with involved‐field or extended‐field irradiation and stage‐dependent chemotherapy (vincristine, prednisone, procarbazine, Adriamycin [doxorubicin], and cyclophosphamide [OPPA/COPP]). Although pubertal development and testosterone levels were normal in all patients, 18 of 75 (24.0%) had elevated basal and 65/74 (87.8%) elevated stimulated luteinizing hormone (LH) levels, demonstrating chemotherapy‐induced Leydig cell damage. In addition, there was a 40.5% and 53.4% incidence of elevated basal and stimulated FSH values, respectively, indicating severe impairment of spermatogenesis as confirmed by azoospermia in four patients. Testicular dysfunction was observed in patients treated before as well as during puberty. The incidence of elevated basal follicle stimulating hormone (FSH) and LH values was significantly higher in patients who had received higher cumulative doses of chemotherapy, i.e., 28.9% and 13.2% with two OPPA, 45.5% and 36.4% with two OPPA/two COPP, and 62.5% and 43.8% with two OPPA/four to six COPP, respectively. Chemotherapy for Hodgkins disease causes a high and apparently dose‐related incidence of testicular dysfunction in prepubertal as well as in pubertal boys affecting Leydig cell function as well as spermatogenesis. Circumstantial evidence indicates that procarbazine is the major gonadotoxic agent involved.

Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for hodgkin disease in children and adolescents: Report from the longitudinal GPOH follow‐up project of the German–Austrian DAL‐HD studies

To analyze the impact of mediastinal irradiation on the incidence of cardiac late effects in long‐term survivors of pediatric Hodgkin disease (HD).

Breast Cancer in Young Women After Treatment for Hodgkin’s Disease During Childhood or Adolescence: An Observational Study With up to 33-Year Follow-up

BACKGROUND The treatment of Hodgkins disease (HD; also called Hodgkins lymphoma) in children and adolescents with radiotherapy and chemotherapy leads to high survival rates but has a number of late effects. The most serious one is the development of a secondary malignant tumor, usually in the field that was irradiated. In women, breast cancer can arise in this way. METHOD Data on the occurrence of secondary breast cancer (sBC) were collected from 590 women who were treated in five consecutive pediatric HD treatment studies in the years 1978-1995 and then re-evaluated in a late follow-up study after a median interval of 17.8 years (maximum, 33.7 years). Information was obtained from 1999 onward by written inquiry to the participants and their treating physicians. The cumulative incidence of sBC was calculated by the Gooley method. RESULTS By July 2012, sBC had been diagnosed in 26 of 590 female HD patients; the breast cancer was in the irradiated field in 25 of these 26 patients. Their age at the time of treatment for HD was 9.9 to 16.2 years (the pubertal phase), and sBC was discovered with a median latency of 20.7 years after HD treatment (shortest latency, 14.3 years) and at a median age of 35.3 years (youngest age, 26.8 years). The radiation dose to the supradiaphragmatic fields ranged from 20 to 45 Gy. The cumulative incidence for sBC 30 years after treatment for HD was 19% (95% confidence interval, 12% to 29%). For women aged 25 to 45 in this series, the frequency of breast cancer was 24 times as high as in the corresponding normal population. CONCLUSION Women who were treated for HD in childhood or adolescence have an increased risk of developing breast cancer as young adults. The risk is associated with prior radiotherapy and with the age at which it was administered (the pubertal phase). Because of these findings, a structured breast cancer screening project for this high-risk group has been initiated in collaboration with the German Consortium for Hereditary Breast and Ovarian Cancer (Deutsches Konsortium für familiären Brust- und Eierstockkrebs).

Prediction of splenic involvement in children with Hodgkin's disease. Significance of clinical and intraoperative findings. A retrospective statistical analysis of 154 patients in the German therapy study DAL-HD-78.

In 154 splenectomized children and adolescents with histologically proven Hodgkins disease in the therapy study DAL‐HD‐78, the incidence of splenic involvement was 39%. In single‐parameter analyses 6 of 16 examined pre‐ and intraoperative findings showed significant correlation to splenic involvement: B‐symptoms, palpable splenic enlargement, mediastinal/lung hilus involvement, nodular changes of splenic surface, enlarged lymph nodes at splenic hilus/pancreatic tail, or enlargement of other upper‐abdominal lymph nodes. The results of multivariant analyses (Cox regression model) of these six parameters showed that the two most significant intraoperative parameters—changes of splenic surface and enlargement of lymph nodes at splenic hilus/pancreatic tail‐gave almost all of the information which can be obtained about splenic involvement. With these two parameters, an intraoperative decisional strategy for selective splenectomy has been developed which allows the omission of splenectomy in about two thirds of children with Hodgkins disease while still obtaining detailed information about infradiaphragmatic spread of disease. Since minor splenic involvement remains undetected in about 10% of the nonsplenectomized patients (i.e., 6% of all patients), this method should be used only in combination with chemotherapy.

Secondary Malignancies Following Treatment for Hodgkin's Lymphoma in Childhood and Adolescence

BACKGROUND About 155 persons under age 18 develop Hodgkins lymphoma (HL) in Germany every year. More than 90% survive at least 20 years. They may, however, suffer from late sequelae of treatment, including secondary malignant neoplasia (SMN). METHODS 2548 patients from the German, Austrian, and Swiss pediatric Hodgkins lymphoma studies that were conducted over the period 1978-2002 were asked every 2-3 years about possible late sequelae of treatment, either directly or through their physicians. The documented cases of SMN were analyzed for cumulative incidence, standardized incidence rates (SIR), and absolute excess risk (AER). RESULTS 147 cases of SMN were diagnosed in 138 of the 2548 patients, including 47 cases of thyroid cancer, 37 of breast cancer, and 15 of hematopoietic neoplasia. The cumulative incidence of SMN at 20, 25, and 30 years was 7% , 11.2% , and 18.7% , respectively. These percentages are rather low compared to other international studies. For all types of SMN, the SIR was 9.1 and the AER was 16.8. Among the 123 patients with secondary solid tumors, 105 (85% ) had a tumor in the irradiated region. CONCLUSION Survivors of pediatric HL must be informed about the risk of late sequelae of treatment for HL, including SMN in the irradiated region, and that they will need regular follow-up examinations. In the future, radiotherapy for children and adolescents should be further reduced or entirely avoided.

Growth Hormone Treatment Adherence in Prepubertal and Pubertal Children with Different Growth Disorders

Background/Aims: Treatment of children with growth disorders with recombinant human growth hormone is necessary for improved outcomes, including final height. Methods: Adherence data from the Observational Study Saizen®-online, recorded with the easypod™ device collected between October 2009 and May 2011, were analyzed in pediatric patients receiving recombinant human growth hormone treatment for a variety of growth disorders. Results: Data from 75 children (46 boys, 29 girls) with different growth disorders were analyzed over a period of 343 ± 201 (SD) days. Boys and girls showed similar mean ± SD adherence rates of 90.5 ± 3.1% and 92.2 ± 10.7%, respectively. Pubertal children (n = 41) had a significantly lower adherence rate (89.1 ± 13.7%) than prepubertal children (n = 29) (96.5 ± 3.9%; p < 0.005). There were nonsignificant differences in adherence rates according to diagnosis: growth hormone deficiency (n = 48) 91.4 ± 11.0%, small for gestational age (n = 18) 91.1 ± 15.3%, Turner syndrome (n = 6) 86.0 ± 14.5%, and chronic renal failure (n = 3) 99.3 ± 1.0%, although the latter two groups were small. Conclusion: Our data indicate that only a small number of pediatric patients using the easypod device had poor adherence to treatment. Further reliable adherence data are required to identify factors affecting long-term adherence in this population.

Assessment of Primary Cancer Incidence in Growth Hormone-Treated Children: Comparison of a Multinational Prospective Observational Study with Population Databases

Background/Aims: Although results of the majority of clinical studies have shown no association between growth hormone (GH) treatment in childhood and risk of primary cancer, concerns remain regarding the potential influence of GH therapy on neoplastic cell growth. This study evaluated the incidence of primary malignancies in a large observational study of paediatric GH treatment. Methods: Primary cancer incidence was assessed in a cohort of 19,054 GH-treated children without a reported prestudy history of malignancy in the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). The standardised incidence ratio (SIR) for primary cancer in GH-treated children was determined by comparing cancer incidence in the GeNeSIS study population with incidence rates for country-, age-, and sex-matched cohorts of the general population. Results: During a mean follow-up of 3.4 years in GeNeSIS (64,705 person-years), 13 incident potential primary cancers were identified in GH-treated patients. The SIR (95% confidence interval) for all observed cancers was 1.02 (0.54-1.75), and the crude incidence was 20.1 (10.7-34.4) cases per 100,000 person-years. Conclusion: Acknowledging the relatively short follow-up in our study, GH-treated children without a history of previous malignancy did not have a higher risk of all-site primary cancer during the study when compared to general-population cancer registries.

Sodium Chloride Supplementation Is Not Routinely Performed in the Majority of German and Austrian Infants with Classic Salt-Wasting Congenital Adrenal Hyperplasia and Has No Effect on Linear Growth and Hydrocortisone or Fludrocortisone Dose

Introduction: Sodium chloride supplementation in salt-wasting congenital adrenal hyperplasia (CAH) is generally recommended in infants, but its implementation in routine care is very heterogeneous. Objective: To evaluate oral sodium chloride supplementation, growth, and hydrocortisone and fludrocortisone dose in infants with salt-wasting CAH due to 21-hydroxylase in 311 infants from the AQUAPE CAH database. Results: Of 358 patients with classic CAH born between 1999 and 2015, 311 patients had salt-wasting CAH (133 females, 178 males). Of these, 86 patients (27.7%) received oral sodium chloride supplementation in a mean dose of 0.9 ± 1.4 mmol/kg/day (excluding nutritional sodium content) during the first year of life. 225 patients (72.3%) were not treated with sodium chloride. The percentage of sodium chloride-supplemented patients rose from 15.2% in children born 1999–2004 to 37.5% in children born 2011–2015. Sodium chloride-supplemented and -unsupplemented infants did not significantly differ in hydrocortisone and fludrocortisone dose, target height-corrected height-SDS, and BMI-SDS during the first 2 years of life. Conclusion: In the AQUAPE CAH database, approximately one-third of infants with salt-wasting CAH receive sodium chloride supplementation. Sodium chloride supplementation is performed more frequently in recent years. However, salt supplementation had no influence on growth, daily fludrocortisone and hydrocortisone dose, and frequency of adrenal crisis.

Correspondence (letter to the editor): In Reply

The authors of the article agree that a thorough family history is needed in female patients included in the screening program who are at high risk for developing breast cancer following treatment for Hodgkins disease. The guidelines provide for an initial examination of young adult women at risk for breast cancer. However, there should be no delay in admitting patients as early as possible to the centers of the consortium for familial breast cancer even though the results of genetic counseling and investigations are not yet available. The necessary consultations can be performed in parallel to the breast cancer screening. We also support Dr Tsamaloukas in advocating an effective follow-up for long-term survivors of malignancies. We published prospective findings of the incidence of breast cancer as one of the late effects of Hodgkin lymphoma treatment. (1). Additional publications have shown that long-term follow-up has been organized not only in the US but also in Germany, for pedriatric patients (2– 4). The guidelines of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) by S. Schuster et al. give additional information for identification, prevention and treatment of children, adolescents, and young adults with cancer. This guideline introduces concepts for the immediate and long-term follow-up for these patients.