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Purpose: To evaluate the long-term sequelae of treatment for malignant germ cell tumors (GCT) during childhood and adolescence., Patients and Methods: Of 128 patients treated for GCT at St. Jude Children's Research Hospital between 1962 and 1988, 73 are long-term survivors (continuously disease-free for > or =5 years after diagnosis), with a median follow-up of 11.3 years). Survivors' ages at diagnosis ranged from birth to 18.3 years (median, 9.2 years); 64% (47 patients) were female. Initial surgical resection was followed by observation for stage I germinomas (n = 2), testicular tumors (n = 13), and selected cases of ovarian or sacrococcygeal tumors (n = 2), and by radiation therapy (RT) for patients with stage II to III germinoma (n = 8). The remaining 48 patients received postoperative chemotherapy (vincristine, dactinomycin, and cyclophosphamide [VAC] +/- doxorubicin, 1962 to 1978; VAC and/or cisplatin, vinblastine, and bleomycin [PVB], 1979 to 1988). RT was added to the chemotherapy for 21 patients. Late complications involving various organ systems and their relationship to treatment were evaluated., Results: More than two-thirds of long-term survivors (n = 50) had at least 1 complication, and half (n = 38) had > 1 organ system affected. The systems most often involved included the musculoskeletal (41% of survivors), endocrine (42%), cardiovascular (16% excluding those who had only abnormal chest radiograph), gastrointestinal (25%), genitourinary tract (23%), pulmonary (19%), and neurologic (16%) systems. High-frequency hearing loss occurred in 58% (11 of 19) of patients treated with cisplatin. Musculoskeletal, gastrointestinal, and urinary tract abnormalities were most frequent in patients whose treatment included RT., Conclusions: A high frequency of late effects after treatment for pediatric GCT, particularly in patients who received RT, was demonstrated. Treatment sequelae could be anticipated from the intensity and type of therapeutic modalities. Treatment-directed screening evaluations may improve quality of life in long-term survivors of pediatric GCT through timely identification of sequelae that can be prevented or ameliorated.

Purpose: To determine the impact of treatment toxicity on long-term survival in pediatric Hodgkin's disease., Patients and Methods: We studied late events in 387 patients treated for pediatric Hodgkin's disease on four consecutive clinical trials at St Jude Children's Research Hospital from 1968 to 1990. Relative risks, actuarial risks, and absolute excess risks for cause-specific deaths were calculated., Results: As of April 1997, 316 (82%) of patients were alive, with a median follow-up of 15.1 (range, 2.9 to 28.6) years. In this cohort, which represented 5,623 person-years of follow-up, 71 fatal events resulted from Hodgkin's disease (n=36), second malignancies (n=14), infections (n=7), accidents (n=7), cardiac disease (n=6), and asphyxiation (n=1). The 5-year estimated event-free survival (EFS) for the entire cohort was 79.6%+/-2.1 %, which declined to 63.1%+/-4.4% by 20 years. Cumulative incidences of cause-specific deaths at 25 years were 9.8%+/-1.6% for Hodgkin's disease, 8.1%+/-2.6% for second malignancy, 4.0%+/-1.8% for cardiac disease, 3.9%+/-1.5% for infection, and 2.1%+/-0.8% for accidents. Standardized incidence ratios showed excess risk for all second malignancies (12; 95% confidence interval [CI], 8 to 17), acute myeloid leukemia (81; 95% CI, 16 to 237), solid tumors (11; 95% CI, 7 to 16), and breast cancer (33; 95% CI, 12 to 72). Standardized mortality ratios also showed excess mortality from cardiac disease (22; 95% CI, 8 to 48) and infection (18; 95% CI, 7 to 38)., Conclusion: Compared with age- and sex-matched control populations, survivors of pediatric Hodgkin's disease who were treated before 1990 face an increased risk of early mortality related to second cancers, cardiac disease, and infection.

Background: Standard therapy for pediatric nonrhabdomyosarcoma soft tissue sarcomas (PNRSTS) consists of surgical resection with or without radiotherapy. The role of chemotherapy in the treatment of these tumors has not yet been defined. We investigated the efficacy and toxicity of an ifosfamide-based regimen in controlling disease in children with high-risk PNRSTS., Patients and Methods: Between January 1992 and June 1994 at St. Jude Children's Research Hospital, we treated 11 children and young adults with PNRSTS who were at high risk for treatment failure by using a combined modality regimen that comprised aggressive surgery, radiotherapy, and chemotherapy including vincristine, ifosfamide, and doxorubicin (VID). Nine of these patients had grade 3 disease and one had grade 2 tumor; due to insufficient tissue, the disease grade of the remaining patient could not be established. Metastases were present at diagnosis in 2 children., Results: Therapy was generally well tolerated, with minimal morbidity and no mortality. The most common toxicity was grade 4 neutropenia, which occurred in 51% of evaluable courses. Among 4 patients evaluable for response to chemotherapy alone, 1 child attained a partial response and 3 had stable disease. One child had a response to chemotherapy and concurrent irradiation. At a median follow-up of 30 months, 10 of 11 patients are alive; 8 of 11 patients are alive without evidence of disease., Conclusion: Aggressive multimodality therapy for PNRSTS is well tolerated, despite frequent and profound neutropenia. Although adjuvant chemotherapy for this group of cancers remains unproved, the rate of tumor control achieved in this pilot study encourages further investigation in a multi-institutional setting.

Background: The authors' aims were to define the frequency, characteristics, and methods of detection of breast masses in young women treated for childhood cancer and to develop screening guidelines for the growing population of long term survivors., Methods: The authors reviewed medical records of all female patients treated for malignancy at a childhood cancer center over a 34-year period to identify those who developed a breast mass and to determine the cumulative incidence of breast cancer as a second primary cancer., Results: A breast mass was identified in 66 patients who had been diagnosed with a malignancy at a median age of 13.8 years (range, 0.4-24.4 years). Masses were initially detected by breast self-detection in 32 and clinical examination in 28; the method of detection was unknown in 6 cases. Breast lesions were benign in 41 patients and malignant in 26; 1 patient had both a benign and a malignant lesion. Of the 26 malignant masses, 14 represented metastases of the primary malignancy and 12 were primary breast cancers as second primary cancers. The median interval to a primary breast cancer as a second primary cancer was 13.6 years (range, 9.2-24.4 years), and the median age at detection was 27.7 years (range, 12.5-43.1 years). The 25-year cumulative incidence of primary breast cancer as a second primary cancer in this cohort was 1.7% (95% CI, 0.4%-2.9%). This represented a 20-fold increase (95% CI, 10-36) over the expected incidence in age-matched and race-matched controls., Conclusions: Young women treated for childhood cancer have a significantly increased risk of breast cancer compared with age-matched controls. For this group of patients, the authors recommend patient education regarding this risk and the importance of properly conducted self-examination as the foundation of breast cancer screening. In addition, clinical and mammographic screening should be instituted at a younger age and performed more frequently than recommended for the general population of women.

Purpose: We report the treatment and outcome of patients with peripheral primitive neuroectodermal tumor (PNET) and extraosseous Ewing's tumor (EOE) using Ewing's-directed therapy, including an ifosfamide and etoposide window., Methods: Seventeen pediatric patients with peripheral PNET (n = 14) or EOE (n = 3) were enrolled between 1988 and 1992 on our institutional Ewing's protocol. Induction therapy comprised a 9-week "window" of ifosfamide and etoposide, followed by 9 weeks of therapy with cyclophosphamide and Adriamycin (Adria Laboratories, Columbus, OH). Response assessment after 17 weeks was followed by surgery and/or radiotherapy (doses based on tumor size and response to induction), repeat evaluation, and maintenance chemotherapy with alternating courses of vincristine/dactinomycin, ifosfamide/etoposide, and cyclophosphamide/Adriamycin for a total of 45 weeks., Results: At diagnosis, 8 patients had large lesions (>8 cm) and 3 had pulmonary metastases (1 with large tumor). Surgical resection was performed at diagnosis for 9 patients and after induction therapy for 5. During window therapy, all of the 9 evaluable patients responded (8 partial, I objective), and no patient without measurable disease developed disease progression. Responses were maintained or improved during subsequent induction in six of the patients with residual disease. Fourteen patients received local radiotherapy. At 49 to 94 months after diagnosis, 12 patients are disease-free (1 in second remission), 4 have died, and 1 is alive with disease. The five-year overall and progression-free survival rates are 77 +/- 13% and 62 +/- 16%, respectively., Conclusion: The use of consistent Ewing's-directed combined-modality therapy for patients with soft tissue peripheral PNET/EOE results in survival similar to that of patients with osseous Ewing's tumor. The combination of ifosfamide and etoposide appears active and should be incorporated in future treatment protocols.

Background: Rhabdomyosarcoma is the most frequently encountered soft tissue sarcoma in children younger than 15 years of age., Methods: The authors reviewed the early and long-term morbidity rate and clinical outcome of pelvic exenteration for genitourinary rhabdomyosarcoma (GU-RMS) in children. Of 43 patients with this diagnosis who were seen at St Jude Children's Research Hospital between 1963 and 1994, 17 underwent pelvic exenteration. These 13 boys and four girls ranged in age from 6 months to 15 years (median, 3.5 years). Their primary sites included prostate (n = 12), bladder (n = 4), and uterus (n = 1). All patients received multiagent chemotherapy and either preoperative or postoperative radiation therapy. Anterior exenteration was performed in 15 patients and total exenteration in two. The complications were classified as early or late (occurring within or after 30 days from the date of surgery) and as major or minor (depending on the risk of death or physical or functional disability)., Results: Thirteen of the 17 patients (76%) had 49 surgery-related complications. Wound infection (24%), fistula, abscess, and malnourishment (12% each) were the most common early major complications, with hydronephrosis (35%), bowel obstruction (24%), acute pyelonephritis, fistula, lymphedema, and ureter stenosis (12% each) making up the majority of late complications in this category. Relatively frequent minor complications included protracted paralytic ileus and hematuria (18%), cholelithiasis, chronic diarrhea and, peristoma skin irritation (12%). Disease-free survival was associated with the timing of surgery (P = .002). All but one of the 12 patients who underwent surgery within 6 months of diagnosis are alive, compared with only one of five whose surgery was performed after a longer interval. Pelvic exenteration for GU-RMS was associated with a high rate of serious complications in this series of patients treated over 31 years., Conclusion: With recent advances in surgical techniques, as well as improvements in preoperative and postoperative care, this procedure should continue to be applied in cases resistant to conventional therapy.

Soft tissue sarcomas (STS) of the hand are rare in children and adolescents. From 1965 through 1995, 18 children with STS of the hand were treated at our institution. Rhabdomyosarcoma (RMS) was diagnosed in 11 patients; alveolar histological results predominated (7 of 11 cases). Seven patients presented with metastatic disease and died 4 to 23 months (median, 9 months) from diagnosis; their surgical treatment comprised above-elbow amputation (n = 1), local excision (n = 1), and biopsy (n = 5). For the four patients who presented with localized RMS, surgery consisted of wide local excision (n = 1), local excision (n = 2), or ray amputation (n = 1). With an average follow-up of 5.5 years (range, 4 months to 18 years), 3 of the 11 patients diagnosed with RMS still survive (27%). The remaining seven patients presented with nonrhabdomyosarcomatous soft tissue sarcoma (NRSTS); the most common histological variants were epithelioid and malignant fibrous histiocytoma (two cases each). Surgical treatment for these patients comprised ray amputation (n = 3), wide local excision (n = 3), excisional biopsy (n = 1), and regional lymph node dissection (n = 3). One patient received adjuvant multiagent chemotherapy; three patients received supplemental radiotherapy. Six of the seven (85%) patients are alive with no evidence of disease at an average follow-up of 4.7 years (range, 6 months to 12 years).

We prospectively used ultrasonography to detect thyroid abnormalities in 96 long-term survivors of childhood cancer, who received head and neck radiation therapy at a median age of 8.9 years. The median time interval since irradiation was 10.8 years (range 5.6-22.8 years). Most survivors of leukemia received 24 Gy cranial irradiation for central nervous system prophylaxis; patients with solid tumors received between 20 and 66 Gy (median 37.5 Gy). The total evaluation included clinical history, physical examination, thyroid function tests, and thyroid ultrasonography; radionuclide scans were performed in patients whose abnormalities persisted on subsequent ultrasound exams. Clinical history and physical examination revealed thyroid abnormalities in 14 patients (15%), but ultrasound detected abnormalities in 42 patients (44%). These findings included inhomogeneity (n = 29), cysts (n = 15), and nodules (n = 22) and occurred in nearly half of patients treated with 15 Gy or more directly to the thyroid gland. Radionuclide scans confirmed the presence of thyroid nodules in 13 of 15 patients with ultrasonographic evidence of nodules. Six patients had thyroid neoplasia, including one case of papillary carcinoma. All patients with neoplasia had nodules demonstrated on ultrasonography. Our experience suggests that in childhood cancer survivors, ultrasonography is a sensitive, affordable, and noninvasive means of detecting subtle parenchymal abnormalities. We recommend thyroid ultrasonography for childhood cancer survivors who received head and neck irradiation. A baseline study should be obtained within 1 year of completion of therapy. The frequency of subsequent examinations should be based on the radiation dose and the patient's age at the time of irradiation.

There is a clear association between multimodal therapy for bone tumors and the development of skeletal complications; however, this has not been addressed in children with soft tissue sarcomas. We reviewed records of the 70 children treated for soft tissue sarcoma of the lower extremity at St. Jude Children's Research Hospital between 1962 and 1991. Of the 12 patients who received radiation after surgical excision of their tumors, three subsequently developed fractures. Two of the three had also received chemotherapy. Our findings indicate that, although the risk of fracture after therapy for soft tissue sarcoma may be multifactorial, radiation may play a significant role. Minimizing the size of surgical incisions, improving radiotherapy techniques, maximizing chemotherapy, and emphasizing physical therapy and appropriate follow up can all serve to decrease long-term toxicities. Such optimal use of therapy could subsequently reduce side effects, such as osteoporosis and muscle and bone atrophy, that predispose patients to fractures.

Background: The pulmonary toxicity of bleomycin-containing chemotherapy combined with mantle radiotherapy in children treated for Hodgkin's disease was longitudinally assessed., Methods: The results of serial pulmonary function studies in 37 children, newly diagnosed and treated at St. Jude Children's Research Hospital between September 23, 1983, and June 30, 1988, with cyclophosphamide, vincristine, and procarbazine (COP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus low dose mantle radiotherapy are analyzed. All patients had pulmonary function studies at least before the first bleomycin dose, after completion of radiotherapy, and serially upon discontinuation of therapy. Bleomycin therapy was withheld whenever measured carbon monoxide diffusing capacity was less than 50% of the predicted value., Results: Vital capacity, diffusing capacity, and diffusing capacity per unit of alveolar volume declined during the first 6 months of therapy but improved there after. At 2 years postdiagnosis, diffusing capacity per unit of alveolar volume remained significantly reduced. Only one patient was symptomatic at the 2-year point. The survival rate of these patients was 95% at a median follow up of 93 months., Conclusion: If bleomycin is with held when diffusing capacity is diminished to 50% predicted, clinical compromise of pulmonary function appears to be minimal in pediatric patients receiving alternating cycles of COP/ ABVD in combination with low-dose mantle radiotherapy. Survival was excellent, even with reduction of the total bleomycin dose.

Less is known about the clinical features and treatment outcome in pediatric large cell non-Hodgkin lymphoma (NHL) than the lymphoblastic and small noncleaved cell subtypes of NHL. To characterize presenting features and assess possible risk factors associated with this diagnosis, we analyzed data for 91 patients treated on a succession of multiagent regimens from 1975 to 1990. Five-year event-free survival (EFS) (+/- SE) was related to disease extent (St Jude system): stage I (n = 24), 95% +/- 5%; stage II (n = 20), 84% +/- 9%; stage III (n = 38), 50% +/- 10%; and stage IV (n = 9), 22% +/- 11%. Advanced stage disease, age < or = 5 years and serum LDH > 500 U/l were associated with poorer EFS in the univariate model (p < 0.001, 0.005, and 0.002, respectively). In the multivariate model, advanced stage and age retained prognostic significance (p = 0.001 and 0.02, respectively), but LDH did not. Among limited stage cases, age < or = 5 years was the only adverse risk feature (p = 0.016); treatment era (pre- vs. post-1979) was the only significant feature in patients with advanced disease (p = 0.004). Intrathoracic primaries were associated with a better outcome than other sites among the 38 stage III patients (p = 0.005). Only one of eight patients with bone marrow disease remains failure-free. The excellent results for limited stage pediatric large cell NHL permit consideration of treatment modifications to decrease toxicity; for cases with advanced disease, especially those with bone marrow involvement, novel therapeutic approaches are clearly needed.

The ability of short-inversion-time inversion recovery (STIR) magnetic resonance imaging to depict infradiaphragmatic lymphadenopathy was evaluated in 25 consecutive patients with newly diagnosed Hodgkin disease. All patients underwent computed tomography (CT) and multiplanar STIR imaging prior to lymphography (LAG). The STIR and CT images were evaluated for paraaortic and parailiac node enlargement. Findings were compared with LAG findings, which showed the architectural pattern of the opacified lymph nodes. In the upper paraaortic region, STIR imaging showed more abnormal nodes than did CT or LAG. In the lower paraaortic and parailiac regions, lymph node enlargement was shown equally well with STIR and LAG, whereas CT showed fewer enlarged lymph nodes. LAG showed paraaortic or parailiac focal tumor infiltration in three patients with normal-size nodes, and hyperplasia in two patients with enlarged nodes. STIR imaging showed more abnormal infradiaphragmatic nodes than did CT because of improved lymph node conspicuity. STIR imaging may be a useful addition to CT for staging pediatric Hodgkin disease.

Ninety-three patients with a diagnosis of acute pharyngitis/tonsillitis due to Streptococcus pyogenes were randomly assigned to receive 100 mg of cefpodoxime proxetil orally with food every 12 hours or 250 mg of penicillin V potassium orally on an empty stomach every six hours. Treatment efficacy was evaluated in 30 cefpodoxime-treated and 33 penicillin-treated patients. After 10 days of treatment, S pyogenes was eradicated from the throat culture in 29 of the 30 cefpodoxime-treated patients and in 30 of the 33 penicillin-treated patients. Twenty days after treatment termination, infection recurred in one patient of each treatment group. Clinical cure or improvement was found in 97% of the patients in each group. Adverse medical events occurred in nine of the 48 cefpodoxime-treated patients and in four of the 45 penicillin-treated patients; these were probably related to the study drug in seven and two patients, respectively. The most common adverse events were nausea (in three cefpodoxime and one penicillin patient) and diarrhea (in three and two). No patient showed colitis related to Clostridium difficile. No clinically significant abnormal laboratory test results were found in either treatment group. It is concluded that cefpodoxime proxetil is as effective and safe as penicillin V potassium in the treatment of pharyngitis due to S pyogenes.

Safety, tolerance, and pharmacology of 9-beta-methylcarbacyclin calcium (ciprostene calcium) was investigated in healthy male volunteers. This stable prostacyclin analogue was infused intravenously into groups of 12, 11, and three volunteers for three, six, and eight hours, respectively, in doses up to 480 ng/kg/min. Based on the tolerance data obtained, a single-blind, placebo-controlled study was conducted. Seven subjects were infused for 8 hr/d for three days with ciprostene at a maximum dose of 160 ng/kg/min and seven subjects received placebo. One subject from each group did not complete the infusion schedule, and they were not included in the final analysis. During infusion of ciprostene, consistent changes in blood pressure and heart rate did not occur. Most frequent adverse drug reactions consisted of headache, restlessness, nausea, perspiration, flushing, and jaw pain. As compared with placebo, ADP-induced platelet aggregation was inhibited during the infusion period (P = .048). Significant (P = .04) elevations of platelet cyclic AMP were observed in subjects during infusion of ciprostene. Pre- versus postinfusion routine laboratory evaluations, fibrinogen concentration, antiplasmin activity, and plasminogen and template bleeding times remained unchanged. Placebo- and drug-treated subjects had a daily postinfusion shortening of euglobulin clot lysis time (ECLT). The preinfusion minus postinfusion ECLT for ciprostene subjects on days 2 and 3 (133 and 118 min, respectively) compared with placebo (239 and 217 min) suggest a trend to increased fibrinolytic activity. Based on the outcome of this trial, it is estimated that ciprostene is about 15 times less potent than prostacyclin.(ABSTRACT TRUNCATED AT 250 WORDS)

Imperative and declarative performative behavior was examined in nonretarded and Down's syndrome children operating at two stages of sensorimotor intelligence. In both groups, more advanced types of performative behavior generally associated with a higher sensorimotor stage. Relative to the nonretarded children of the same sensorimotor stages, the Down's syndrome children relied more heavily on gestures in their imperative and declarative usage. Evidence was also obtained suggesting that the correspondence between sensorimotor stage and performative behavior is closer at younger ages than at older ages.

The clinical development programme for cefmetazole sodium included over 4000 patients treated by 78 investigators. Cefmetazole therapy was compared with that of cefoxitin sodium (cefoxitin) for the treatment of urinary tract, skin and soft tissue, lower respiratory, abdominal, and gynaecological infections (with cefoxitin-sensitive pathogens) and for the prevention of postoperative wound infection in patients undergoing surgical procedures. Both cefmetazole and cefoxitin were administered intravenously in all studies. Cefmetazole was as effective as cefoxitin in the treatment of the infections studied. In the surgical wound infection prophylaxis studies, multiple-dose cefmetazole therapy was more effective than multiple-dose cefoxitin therapy in patients undergoing lower gastrointestinal surgery; this difference approached statistical significance. Both multiple-dose and single-dose cefmetazole therapy were as effective as multiple-dose cefoxitin treatment in the other types of surgery studied. Clinical laboratory findings and adverse medical events reported among cefmetazole patients were similar to those observed in patients treated with cefoxitin.