Gonadal function in pediatric patients following treatment for hodgkin disease

Gonadal function was assessed by determination of the serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in 24 children and adolescents 6—98 months after completion of treatment for Hodgkin disease that included pelvic irradiation and/or combination chemotherapy. Four of the five women and six of the nine men who received pelvic irradiation had elevations of serum FSH. Nine of these patients with an elevated FSH received combination chemotherapy in addition to pelvic irradiation. Five of seven males who received combination chemotherapy but no pelvic irradiation and were postpubertal at the time of evaluation had an elevated FSH level. Three of these five were prepubertal at the time of treatment. These results suggest that gonadal dysfunction occurred frequently among children and adolescents following treatment that included combination chemotherapy for Hodgkin disease.     

Thyroid function in pediatric patients after neck irradiation for Hodgkin disease

Thyroid function was evaluated in a consecutively treated group of children and adolescents with Hodgkin disease who received incidental radiation to the thyroid gland. Ten of 27 (36.7%) were found to have elevated concentrations of thyroid-stimulating hormone (TSH). Two groups of patients had an increased incidence of thyroid dysfunction — those who had not had a pretreatment lymphangiogram and those who were less than 13 years of age at the time of neck irradiation. The estimated percentage of patients who did not have a pretreatment lymphangiogram who will develop TSH elevation was 67.7% and of patients who were 13 years of age or less when irradiated, 64.8%. Thyroid dysfunction developed in 6/7 patients who had both of these risk factors present.     

Gonadal function of young patients with beta-thalassemia following bone marrow transplantation

Bone marrow transplantation (BMT) can induce short- and long-term impairment of gonadal function. Patients with beta-thalassemia represent a special group, as their primary diagnosis and its treatment modalities are responsible for gonadal dysfunction. To address the effect of BMT on puberty and gonadal function, we investigated 25 patients (12 males) with thalassemia who received allogenic BMT during childhood or adolescence and at the post-transplant evaluation were at an age that the pubertal process should have started. Pubertal stage by Tanner of breast and pubic hair, as well as testicular volume were assessed pre-BMT once and post-BMT at least twice. Menstrual history was recorded. FSH, LH, testosterone and estradiol levels were also determined. The impact of BMT appears to be different in the two sexes. Males seem to have higher tolerance, as all males who were pubertal at the time of BMT had normal testosterone, and all but one normal gonadotropin levels. From those who were prepubertal at BMT, 62% proceeded to normal pubertal development. Post-menarcheal females seem to be an extremely sensitive group to the deleterious effect of the transplantation process, as 100% of the post-menarcheal females exhibited amenorrhea and elevated gonadotropin levels. These findings are important for pre- and post-BMT counseling.     

Gonadal and sexual function in men treated for childhood cancer

BACKGROUND: Insofar as a majority of children with malignant diseases are cured, the late effects of treatment are of major importance. PROCEDURE: A retrospective study was conducted of gonadal and sexual function of 77 adult male survivors of childhood malignancies treated and cured at a single center from 1970 to 1989 and followed for a median of 13 years. The study included an interview, physical examination, sperm test, and hormonal analyses. RESULTS: One-third of the patients were treated for hematological malignancies, one-third for CNS tumors, and one-third for other malignancies. Eleven patients required androgen substitution after treatment for tumors of the pituitary-hypothalamic region or acute lymphoblastic leukemia including testicular irradiation and/or orchiectomy. In three patients the testicles were removed. The other eight had small testicles, and those providing sperm samples had azoospermia, and sexual function was disturbed in most of them. Most of the remaining 66 patients had small testicles. Normozoospermia was found in 63%, oligozoospermia in 20%, and azoospermia in 17%. Although there was a highly significant correlation between testicular volume and sperm test, 25% of patients with testicles of <10 ml had normozoospermia. Sexual function was normal in 46 patients, and they were married at a frequency comparable to the normal population. Twenty-one patients had no signs of gonadal dysfunction. CONCLUSIONS: Patients treated for tumors in the hypothalamic-pituitary region or treated with testicular irradiation or with high doses of alkylating agents had severe gonadal and sexual dysfunction. Most of the other patients had good prospects for preserved gonadal and sexual function.     

Gonadal function following chemotherapy for childhood Hodgkin's disease

Gonadal function was assessed in 101 postpubertal subjects after chemotherapy for childhood Hodgkin's disease. All had received ChIVPP (chlorambucil, vinblastine, procarbazine, and prednisolone) chemotherapy alone, with no radiotherapy below the diaphragm. Gonadotropin levels were available in 46 (79.3%) male and 32 (74.4%) female subjects. The mean age at diagnosis in the male cohort was 12.2 years (range 8.2–15.3) and in the females 13.0 years (9.0–15.2). The males and the females were studied at a median of 6 years (range 2.5–11.1) and 4.3 years (range 1.9–11.5) from diagnosis, respectively. Forty-one (89.1%) male subjects had elevated follicle-stimulating hormone (FSH) levels, confirming severe germinal epithelial damage. Germinal epithelial damage was seen in subjects up to 10 years out of therapy. Subtle Leydig cell dysfunction was identified in 24.4% with raised luteinizing hormone (LH) levels. All subjects, however, progressed spontaneously through puberty. Seventeen (53%) women had raised gonadotropin levels, with variable estradiol levels. Of these, 10 subjects presented with symptomatic ovarian failure and 6 received hormone replacement therapy (HRT). Nine women had 11 successful pregnancies, two of whom had previously had symptoms of ovarian failure with one requiring HRT. A much higher prevalence of ovarian failure has been observed, than has previously been considered in the prepubertal and pubertal female following combination chemotherapy. These conclusions have important implications for future counseling, management, and research in this population. © 1996 Wiley-Liss, Inc.     

The management of Hodgkin disease in the young child

Although childhood Hodgkin disease is sensitive to the treatment regimens devised for Hodgkin disease in adults, long-term toxicity is enhanced in the developing individual. As a result, there have been dual goals in the design of clinical trials for pediatric Hodgkin disease: 1) to reduce long-term organ injury; and 2) to increase efficacy. Radiation dose and field has been reduced by enhanced reliance on chemotherapy, thus limiting the risks of hypoplasia, hypothyroidism, secondary cancers, and valvular and atherosclerotic heart disease. Multiagent, chemotherapeutic regimens for children have been developed to avoid the risks of sterility, leukemia, and cardiopulmonary toxicity. Newer approaches advocate for early dose intensity to limit cumulative therapy using response-based paradigms. Targeting molecular mechanisms specific for the Reed-Sternberg cell may allow for less toxic and more efficacious treatments in the future.     

Gonadal function after combination chemotherapy for Hodgkin's disease in childhood.

The effect of quadruple chemotherapy (mustine, vincristine, procarbazine, and prednisolone) on gonadal function was investigated in 15 males and 2 females treated for Hodgkin''s disease during childhood. The 2 females have regular menstrual cycles with evidence of ovulation in one. Twelve of the males have shown normal progression of pubertal development since completing their treatment. Nine out of 10 late pubertal or adult subjects had small testes but only one developed gynaecomastia. All 4 prepubertal subjects had normal basal and peak gonadotrophin responses to luteinising hormone-releasing hormone. Nine of the 12 subjects studied during puberty or adulthood had either an increased basal serum follicle-stimulating hormone (FSH) level or an exaggerated FSH response to luteinising hormone-releasing hormone. Each of the 6 males who provided semen for analysis was azoospermic after an interval of between 2.4 and 8 (mean 5.3) years after completion of treatment. We conclude that severe testicular damage is common after treatment with mustine, vincristine, procarbazine, and prednisolone in childhood. The germinal epithelium is particularly vulnerable and the resultant azoospermia is likely to be irreversible. The Leydig cells are less susceptible to cytotoxic-induced damage. Pubertal development is normal and there is no indication for androgen replacement therapy.     

Hodgkin disease in ataxia-telangiectasia patients with poor outcomes

BACKGROUND: To determine the presenting clinicopathologic features and treatment outcomes of 11 ataxia-telangiectasia (A-T) patients with Hodgkin disease. PROCEDURE: We reviewed the charts of 412 A-T patients to ascertain cases of Hodgkin disease. The data analyzed included date of diagnosis, duration of symptoms, chest radiographic findings, stage and histology, therapy, and outcome. RESULTS: The six male and five female patients had a median age at diagnosis of 12.2 years. Eight patients presented with fever, cough, and/or cervical lymphadenopathy with a median duration of symptoms of 3 months. Five patients had abnormal chest radiographic findings a median of 3 months prior to diagnosis and were treated with antibiotics for presumed pneumonia. Mediastinal and hilar adenopathy in addition to bilateral infiltrates were present. Histopathology reports were available for nine patients. Three had nodular sclerosing and two each had lymphocyte depleted, mixed cellularity, and not otherwise specified histology. Eight patients had stage IV disease, one had stage III, and in two the staging was not documented. Six patients received reduced-dose chemotherapy, two received radiation therapy, two did not receive therapy, and in one the treatment was not documented. In no patient did the Hodgkin disease remit and all died with a median survival of 3 months. Eight died of pneumonia and three of multiple system organ failure. CONCLUSIONS: A-T patients with Hodgkin disease have markedly reduced survival compared to Hodgkin disease in the general population. Their poor outcomes may be due to advanced Hodgkin disease, failure to recognize coincident chronic lung disease, and the use of non-standard treatment regimens.     

Gonadal function of young adults after therapy of malignancies during childhood or adolescence

Abstract As the survival rate of children with malignancies has increased over past decades, the follow up of adult long-term survivors (LTS) of childhood cancer should focus on late effects of disease and treatment. Gonadal function was therefore studied in 54 LTS (aged 17–29 years; 33 male, 21 female) 2–18 years after treatment for malignancies during childhood or adolescence. To analyse the sensitivity of different diagnostic methods, tests of endocrine function (n=52), spermiograms (n=14), gynaecological status (n=20) and ultrasonography of the gonads (n=53) were compared with the results of equivalent tests in 23 age-matched normal controls (12 male, 11 female). There were no differences between male and female LTS concerning age at diagnosis, gonadal dose of irradiation (XRT) and doses of applied chemotherapeutic agents. Whereas male LTS had elevated levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) before (P<0.05;P<0.001) and after (P<0.01;P<0.001) stimulation with gonadotropin releasing hormone, female LTS exhibited normal endocrine function. Accordingly, male patients exhibited lower testicular volumes than normal controls, as measured with a Prader orchidometer (P<0.01) or by ultrasonography (P<0.001). Gynaecological status and ultrasonography of the gonads were normal in female LTS and controls. Whereas all spermiograms of normal controls (n=8) showed a normal sperm cell density (SCD), only 2 of 14 male LTS exhibited a normal SCD (P<0.001). Azoospermic LTS (n=9) had been treated more often with alkylating agents and had received higher (P<0.05) gonadal doses of XRT. All male LTS with testicular volumes below the normal range (<13 ml) and basal FSH levels above the normal range (>10 IU/I) exhibited azoospermia, whereas LTS with normal values for testicular volume and basal FSH had a normal SCD.Conclusion A sex-specific susceptibility for gonadal damage after treatment for malignancies might be responsible, in part, for the impaired gonadal function of male LTS. Therapy with alkylating agents and/or high gonadal doses of XRT were important risk factors for azoospermia. A simple method to estimate potential fertility in individual LTS is to measure testicular volume, using a Prader orchidometer, and basal FSH serum levels.Part of this work was presented at the XXVIth Meeting of the International Society of Paediatric Oncology (SIOP), September 20–24, 1994, Paris, France     

Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease

Hepatosplenic T cell lymphoma (HSTCL) are rare cancers ( approximately 100 published cases worldwide) and comprise 5% of peripheral T cell lymphomas. As of October 5, 2006, the FDA's Adverse Event Reporting System has received 8 cases of HSTCL in young patients using infliximab, a tumor necrosis factor-alpha blocking agent, to treat inflammatory bowel disease (6 of the 8 cases had a fatal outcome). All 8 patients were receiving concomitant immunosuppressant therapy (eg, azathioprine, prednisone). It has not been established that infliximab had an exclusive or primary role in the pathogenesis of these HSTCL cases; however, it appears that patients using this product may be at greater risk for developing this rare lymphoma.     

Three unusual arteriovenous fistulas presenting in young children successfully treated with transarterial endovascular embolization

Endovascular approaches can be utilized to manage arteriovenous fistulas (AVFs) either as a stand alone therapy or in conjunction with surgical excision. The goal of treatment is to completely obliterate the AVF. These vascular malformations are rare in childhood and pose a treatment challenge. We describe 3 children who were diagnosed with vascular malformations on magnetic resonance imaging and were subsequently found to have unusual AVFs on angiography. These single-feeder fistulas were successfully occluded with transarterial embolization using platinum coils.     

Osteonecrosis in patients with Hodgkin disease following combination chemotherapy

Three cases of osteonecrosis in patients receiving prednisone as part of multidrug chemotherapy for lymphoma are presented. These patients are discussed in the context of previously reported series. The etiology of steroid-induced osteonecrosis and its radiologic manifestations are reviewed with regard to the need for biopsy to confirm the diagnosis. In light of this complication, the need for prednisone in lymphoma chemotherapy is considered.     

Long-term pulmonary function in survivors of childhood Hodgkin disease and non-Hodgkin lymphoma

BACKGROUND: The aim of our study was to evaluate the long-term effects of chemotherapy and/or radiotherapy on lung function in 75 childhood Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) survivors several years after treatment. PATIENTS AND METHODS: We studied 37 HD and 38 NHL survivors. These patients were divided into two groups according to the treatment protocols applied. Group I consisted of 23 patients who were treated with both chemotherapy and thoracic irradiation and Group II consisted of 52 patients who were treated with chemotherapy and no thoracic irradiation. A detailed history of smoking habits, respiratory symptoms, and diseases was recorded. Complete physical examinations and pulmonary function tests [PFT, including spirometry, lung volume, and diffusion capacity for carbon monoxide (DLCO)] were performed on all subjects. RESULTS: No patients reported acute or chronic respiratory symptoms or diseases. Pulmonary function abnormality (reduced lung volume and diffusion capacity) was found in 13% of patients at a median 5 years after diagnosis. The percentage of predicted normal value of forced expiratory volume in the 1st sec (FEV(1)), residual volume (RV), and DLCO were significantly lower in Group I than these values for Group II. There were no significant differences in PFT parameters between patients with HD and NHL (P > 0.05). It appears that the risk of reduced lung function was greater the younger the patient in therapy. CONCLUSION: Chemotherapy or chemo-radiotherapy-induced pulmonary sequalae in childhood may remain asymptomatic for many years.     

Evaluation of left ventricular function in long-term survivors of childhood Hodgkin disease

BACKGROUND: Data on the presence of myocardial abnormalities in long-term Hodgkin disease survivors are contradictory. The purpose of this study was to determine if myocardial performance index (MPI) was capable of discovering cardiac abnormalities. PROCEDURE: Echocardiographic evaluation was performed in 31 survivors of Hodgkin disease (mean age 17.0 years), who received doxorubicin as part of chemotherapeutic treatment (median dose 164.8 +/- 42.5 mg/m(2)). Control group comprised 22 healthy subjects (mean age 16.7 years). RESULTS: Peak A velocity was increased (P = 0.004) and peak E/A velocity ratio was lower (P = 0.002) in patients compared to controls. Mean isovolumetric contraction time was longer in patients than in controls (P = 0.0001). Ejection time was significantly shorter in patients than in the controls (P = 0.001). Consequently, the MPI was significantly greater in the patients than in the controls (P = 0.0001). Abnormal MPI was found in 25/31 patients (83%). CONCLUSIONS: The Doppler-derived index of combined systolic and diastolic myocardial performance demonstrates the presence of subtle cardiac abnormalities in the majority of Hodgkin disease survivors.     

Clinical response and adverse events in young patients with sickle cell disease treated with hydroxyurea

The authors studied the long-term clinical and hematological response to hydroxyurea (HU) therapy in young patients, with either S/β-thalassemia (β^thal) (8 patients) or SS (6 patients). All patients with S/β^thal responded well to treatment. Longitudinal evaluation of Hb, HbF, and MCV showed a significant increase compared to baseline levels, but the pattern of HbF changes varied among patients. Changes in HbF and Hb correlated well with baseline HbF. Favorable clinical responses, as documented by decline in hospitalization days for vasoocclusive crisis and transfused units of packed red blood cells, were also noted. During treatment, 1 patient was diagnosed with Hodgkin's lymphoma and 2 patients developed bilateral avascular necrosis of the femoral head. HU seems to be effective in a high proportion of young patients with sickle cell disease and in particular with S/β^thal, but cannot eliminate occurrence of serious adverse events.