A pilot study of tandem high-dose chemotherapy with stem cell rescue as consolidation for high-risk neuroblastoma: Children's Oncology Group study ANBL00P1.

Increasing treatment intensity has improved outcomes for children with neuroblastoma. We performed a pilot study in the Children's Oncology Group to assess the feasibility and toxicity of a tandem myeloablative regimen without TBI supported by autologous CD34-selected peripheral blood stem cells. Forty-one patients with high-risk neuroblastoma were enrolled; eight patients did not receive any myeloablative consolidation procedure and seven received only one. Two patients out of 41 (4.9%) experienced transplant-related mortality. CD34 selection was discontinued after subjects were enrolled due to serious viral illness. From the time of study enrollment, the overall 3-year EFS and OS were 44.8 ± 9.6% and 59.2 ± 9.2% (N=41). These results demonstrate that tandem transplantation in the cooperative group setting is feasible and support a randomized comparison of single vs tandem myeloablative consolidation with PBSC support for high-risk neuroblastoma.

Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: a report from the Children's Oncology Group.

BACKGROUND: This Phase II study was designed to determine response to chemotherapy and survival after response-based radiation (RT) in children with CNS germ cell tumors. PROCEDURE: Children with germinomas and normal markers received cisplatin 100 mg/m(2) + etoposide, alternating with vincristine + cyclophosphamide (CPM) 2 g/m(2)/d, for four cycles. Children with nongerminomatous tumors or with abnormal markers received doubled doses of cisplatin and CPM. For germinoma patients in complete response (CR), RT was decreased from 50.4 to 30.6 Gy. High-risk patients received neuraxis RT: 50.4 Gy local + 30.6 Gy neuraxis in CR; 54 Gy local + 36 Gy if less than CR. RESULTS: Of 12 germinoma patients, 4 had cerebrospinal fluid (CSF) human chorionic gonadotropin (HCG) 6.9-21 mIU/ml. Of 14 nongerminomatous patients, HCG in serum or CSF was >50 mIU/ml in 9, alpha-fetoprotein (AFP) abnormal in 9. Four germinoma patients attained CR, six PR, one SD, one not evaluable after resection. Two nongerminomatous patients had CR, three PR, three SD, one PD, four not evaluable after resection; one inadequately treated patient had progressive disease (PD). Both PD patients died; one SD patient died during a seizure. Eleven germinoma patients are PF at median 66 months; one patient in CR refused RT, had PD at 10 months, received RT, and was PF at 56 months. Eleven of 14 nongerminomatous patients were PF at median 58 months. CONCLUSION: Response (germinoma, 91%; nongerminomatous, 55%) and survival are encouraging after this regimen plus response-based RT.

Paclitaxel for the treatment of progressive or recurrent childhood brain tumors: a pediatric oncology phase II study.

PURPOSE: To assess the efficacy and define the toxicity of paclitaxel given at a dosage of 350 mg/m2 every 3 weeks as a 24-hour continuous infusion to children with recurrent or progressive primary brain tumors. PATIENTS AND METHODS: Seventy-three eligible patients, ages 4 months to 19 years, with progressive or recurrent primary brain tumors were treated according to a Pediatric Oncology Group (POG) phase II protocol with paclitaxel (POG 9330). Tumor histologic strata included: astrocytoma (n = 4), malignant glioma (n = 13), medulloblastoma (n = 16), brain stem glioma (n = 15), ependymoma (n = 13), and miscellaneous histologies (n = 12). All patients had previous histologic confirmation of a primary intracranial or spinal cord tumor with magnetic resonance imaging or computed tomography documentation of unequivocally measurable progressive or recurrent disease. All patients had received previous therapy including surgery, radiation therapy, and/or chemotherapy, but no patient had been previously treated on more than one phase II trial. Paclitaxel was administered as a 24-hour intravenous infusion at a dosage of 350 mg/m2 every 3 weeks. Neurologic and neuroradiologic reevaluations were performed after every second course. Patients were allowed to continue therapy for a total of 18 cycles in the absence of progressive disease or unacceptable toxicity. RESULTS: Seventy-five patients were enrolled onto the POG 9330 protocol; two ineligible patients were removed from the study before receiving any therapy. Of the 73 eligible patients, 72 were evaluable for toxicity and 70 were either fully or partially evaluable for disease response. There was one complete response and three partial responses (5.7%). Twenty patients had stable disease for more than 2 months. Toxicities included mild nausea, central nervous system toxicity, myelosuppression, and febrile neutropenia, including one septic death. One grade 2 and two grade 3 allergic reactions occurred. No cardiac toxicities or arthralgias were reported. CONCLUSION: Paclitaxel is well tolerated in children with recurrent or progressive brain tumors at this dosage and schedule and may result in short-term disease stabilization in this patient population. The lack of a significant number of patients with measurable disease regression, however, precludes it from being identified as an active agent when administered as a single agent by 24-hour continuous infusion.

Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma.

Children with neuroblastoma receiving high-dose carboplatin as part of their conditioning regimen for autologous marrow transplantation have a high incidence of speech frequency hearing loss. We evaluated hearing loss in 11 children with advanced stage neuroblastoma who underwent autologous marrow transplantation, following a conditioning regimen containing high-dose carboplatin (2g/m2, total dose). Audiometric evaluations were obtained at diagnosis, prior to and following transplant. Exposure to other known ototoxins also was assessed. All patients sustained worsening of hearing following high-dose carboplatin. Nine of the 11 children (82%) had evidence of speech frequency hearing loss post transplant for which hearing aids were recommended (grades 3-4). Three of the nine children had speech frequency loss prior to transplant which progressed following transplant. The entire group was heavily pre-treated with platinum-containing chemotherapy pre-BMT and had extensive exposure to other ototoxins, including aminoglycoside antibiotics, diuretics, and noise exposure - all of which could have exacerbated the effects of carboplatin. High-dose carboplatin is ototoxic, particularly in patients who have been primed with previous platinum therapy or other ototoxic agents. We conclude that further efforts are needed to monitor and minimize this complication. In cases where hearing loss is inevitable due to cumulative ototoxic exposures, families need to be adequately prepared for the tradeoffs of potentially curable therapy.

[The clinical picture and stability of non-cognitive symptoms in patients with Alzheimer's disease]. / Das Erscheinungsbild und die Verlaufsstabilität von nicht-kognitiven Symptommustern bei Patienten mit Alzheimerscher Krankheit.

The purpose of this study was to investigate noncognitive symptoms in Alzheimer's disease in order to identify symptom patterns and to study stability of such patterns prospectively. Furthermore, variables were examined which could be associated with certain types of symptom patterns or could be predictors of change of these patterns. Forty-eight patients with the clinical diagnosis of probable Alzheimer's disease were included in this study and were assessed weekly over a three-week period. Noncognitive symptoms were rated according to the Behavioral Abnormalities in Alzheimer's Disease Rating Scale (BEHAVE-AD) and the Dementia Mood Assessment Scale (DMAS) and to a set of items specifically assessing misidentifications. By means of principal component factor analysis different noncognitive symptom patterns were obtained yielding a four-factor solution. They were mapped as rational domains with respect to clinical experience: 'depression', 'apathy', 'psychotic symptoms/aggression', 'misidentifications/agitation'. Demographic and clinical variables were not associated with the factor solutions and did not predict change of the factor values. The results demonstrate that in Alzheimer's disease there are distinct noncognitive symptom patterns with at least short-term prospective stability. None of the examined clinical variables, such as age at entry, the status of the patients (outpatient or inpatient) or dementia severity, exerted substantial influence on the noncognitive symptom patterns. Further investigations should concentrate on the pathological and prognostical correlates of noncognitive symptom patterns in Alzheimer's disease.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

PURPOSE: A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS: A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS: Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION: The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Presentation and stability of noncognitive symptom patterns in patients with Alzheimer disease.

The purpose of this study was to investigate noncognitive symptoms in Alzheimer disease to identify symptom patterns and to study stability of such patterns prospectively. Furthermore, variables were examined that could be associated with certain types of symptom patterns or could be predictors of change of these patterns. Forty-eight patients with the clinical diagnosis of probable Alzheimer disease were included in this study and were assessed weekly over a 3-week period. Noncognitive symptoms were rated according to the Behavioral Abnormalities in Alzheimer's Disease Rating Scale and the Dementia Mood Assessment Scale and to a set of items that specifically assess misidentifications. By means of principal component factor analysis different noncognitive symptom patterns were obtained, yielding a four-factor solution. They mapped onto rational domains with respect to clinical experience: depression, apathy, psychotic symptoms/aggression, and misidentifications/agitation. Demographic and clinical variables were not associated with the factor solutions and did not predict change of the factor values. The results demonstrate that in Alzheimer disease there are distinct noncognitive symptom patterns that hold at least short-term prospective stability. None of the examined clinical variables, such as age at entry, the status of the patients (outpatient or inpatient), or dementia severity, exerted substantial influence on the noncognitive symptom patterns. Further investigations should concentrate on the pathological and prognostic correlates of noncognitive symptom patterns in Alzheimer disease.

Chemotherapy for patients with recurrent or refractory neuroblastoma: a POG Phase II study.

PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of three different salvage regimens (Rx) in children with recurrent or refractory neuroblastoma. PATIENTS AND METHODS: Forty-six children with recurrent or refractory neuroblastoma received treatment according to one of three regimens: Rx 1 (five patients), high-dose cisplatin (HDP) (200 mg/m2) with concurrent sodium thiosulfate (STS) (9.9 g/m2) as a nephroprotectant and etoposide (VP-16) (200 mg/m2/day for 3 days); Rx 2 (22 patients), high-dose carboplatin (HD-CBDCA) (500 mg/m2/day for 2 days) and VP-16 (100 mg/m2/day for 3 days); Rx 3 (19 patients), ifosfamide (1.5 g/m2/day for 3 days) followed by CBDCA (400 mg/m2) on day 4. Chemotherapy was administered every 3-4 weeks. Responses were assessed following four courses with or without surgery. Patients achieving less than a partial response (PR) on their primary treatment were crossed over to the next regimen (i.e., Rx 1 --> Rx 2 <--> Rx 3). RESULTS: Rx 1 was ended early owing to grade 4 nephrotoxicity in two patients following their first course. Ten of 22 evaluated patients (45%) primarily (n = 19) or secondarily (n = 3) treated by Rx 2 responded [five complete response (CR) and five PRs]. Nine of the 23 evaluated patients (39%) on Rx 3 as primary (n = 18) or secondary (n = 5) treatment responded (one CR and eight PRs). Grades 3-4 neutropenia and thrombocytopenia occurred after 80% and 50% of courses administered on Rx 2 and Rx 3, respectively. Central venous line infections were the most commonly documented infections on these regimens. CONCLUSIONS: Rx 2 and Rx 3 are active combinations in patients with recurrent or refractory neuroblastoma and are associated with manageable toxicity. HDP administered as a short i.v. infusion with concurrent STS infusion cannot be safely given to children with neuroblastoma pretreated with cisplatin.

[Nootropic drug evaluation for general practice]. / Zur Nootropikabewertung für die Praxis.

Treatment with "nootropic drugs" of patients suffering from dementia is often described as arbitrary. To define the potential usefulness of nootropic drugs, effects and side effects, economic aspects in comparison to other treatment approaches were studied. A summary of literature published concerning these criteria underlines the efficacy of nootropics in improving the symptoms at the beginning and in postponing the progress of the disease. The majority of substances does not lead to severe side effects. There are not enough studies comparing the effects of the substances or on prophylactic effects. Delayed admission to care units leads to a positive cost effect of nootropics. Thus, also for economic reasons it seems advisable to treat patients with nootropics. Better effects are gained when nootropic treatment is combined with training and changing of the structure of the environment. A proposal for a rational treatment with nootropics is derived from the data.

[Medicamentous therapy of alcoholic polyneuropathy. Randomized double-blind study comparing 2 vitamin B preparations and a nucleotide preparation]. / Die medikamentöse Therapie der alkoholischen Polyneuropathie. Randomisierte Doppelblindstudie zum Vergleich zweier Vitamin-B-Präparate und eines Nukleotid-Präparates.

In a randomized double-blind study involving 303 patients with alcoholic polyneuropathy the efficacy and tolerability of the combinations thiamine/pyridoxine, benfotiamine/pyridoxine, and the nucleotides of cytidine and uridine administered orally for 21 days were compared. Pain and paraesthesia, measured on a visual 10-cm-long analogue scale, as also pallaesthesia and the strength of the dorsiflexion and plantar flexors of the foot, clearly improved in all treatment groups. Clinically relevant differences in efficacy were not observed. All the drugs tested were well tolerated.

Desmoplastic small cell tumor: a report of three cases and a review of the literature.

PURPOSE: Desmoplastic round cell tumor (DSCT) is a highly malignant abdominal tumor first described in 1991, with subsequent cases predominantly noted in pathologic case reports. The authors evaluated response to alternating, intensive chemotherapy in three patients with DSCT, and reviewed the clinical experience with this newly described tumor as reported in the literature. PATIENTS AND METHODS: Three adolescent boys with DSCT were treated intravenously with vincristine 2 mg/m2, doxorubicin 75 mg/m2, cyclophosphamide 1.8 g/m2, alternating with 5-day cycles of etoposide 100 mg/m2/day, ifosfamide 1.8 g/m2/day for a total of 11-15 courses. RESULTS: Each patient showed initial tumor regression during chemotherapy, but developed progressive disease within 8-18 months. One patient subsequently showed a transient response to doxorubicin 45 mg/m2 plus 5-fluorouracil 500-600 mg/m2. All three patients died of disease within 20 months of diagnosis. A comprehensive literature review of clinical data on 101 reported cases of DSCT is presented. The median age was 21 years (range 6-38 years) with 78 male patients and 23 female patients. Ninety-nine cases involved tumor mass in the abdominal-pelvic cavity in proximity to the mesentery. Metastatic seeding to the omentum was most common, followed by spread of disease to liver, distant lymph nodes, lung, and occasionally to scrotum or to ovary. Tumor response to chemotherapy was noted in approximately 50% of 40 patients who received combinations of doxorubicin, cisplatin, cyclophosphamide, etoposide, and/or 5-fluorouracil. Four of 13 patients who received additional radiotherapy were alive at 24-48 months. Median survival was 17 months (range: 3-72 months), with only two patients reported disease free beyond 2 years at 40 and 48 months. CONCLUSION: DSCT should be included in the differential diagnosis of small round cell tumors in children and young adults. Tumor regression has been noted during multiagent chemotherapy, but prolonged survival is rare with current therapies.

A phase I study of acivicin in refractory pediatric solid tumors. A Pediatric Oncology Group study.

Forty-two patients with progressive solid tumors and brain tumors were entered in this Phase I study of the glutamine antagonist acivicin given intravenously over thirty minutes daily for five days. The major toxicities encountered were myelosuppression and central nervous system toxicity (nightmares and somnolence). The maximum tolerated dosage on this schedule was 26 mg/M2 daily for five days. Six patients including three patients with brain tumor had stable disease.

[Dementia and disorders of the thyroid gland]. / Demenz und Schilddrüsenstörungen.

Cognitive deficits pretending dementia can be caused by thyroid dysfunction. The literature addressing pathophysiology and therapy of thyroid dysfunction is reviewed. A shorter duration and less severe course of thyroid dysfunction seem to indicate a better response to therapy. There are not studies on the latency between therapy and response. It is recommended to measure at least TSH in the differential diagnosis of dementive syndromes. Degenerative dementia can occur in coincidence with thyroid dysfunction. Therapy would improve at least symptoms caused by the thyroid dysfunction.

Urological aspects of intra-abdominal desmoplastic small round cell tumor of childhood: a preliminary report.

To our knowledge intra-abdominal desmoplastic round cell tumor has not previously been described in the pediatric urological literature. This lesion has only recently been recognized as a clinicopathological entity with predilection for adolescent boys. We report on 2 patients who presented with urological symptoms and a large abdominal or pelvic tumor that was biopsied at exploratory laparotomy. Complete surgical excision was impossible in both patients, who subsequently underwent multiagent chemotherapy. Histological and immunohistochemical staining are distinctive in this condition. The tumor is associated with a poor prognosis, despite multidisciplinary, multimodal therapy.

The desmoplastic round cell tumor: a new solid tumor of childhood.

Three patients with a new, pathologically distinct solid tumor of childhood have been treated recently. The disease is characterized by male predominance, adolescent onset, an extensive abdominal primary tumor, and aggressive metastases to regional lymph nodes, liver, and lung. Two patients presented with vague abdominal pain and the third with testicular pain. All three noted fatigue and malaise of less than two months' duration with minimal associated weight loss. Computed tomography (CT) scans of the abdomen and chest were obtained for initial preoperative staging, and then all three underwent surgical exploration. Widespread disease was found in each case. In no instance was complete tumor extirpation possible because of extensive peritoneal spread and lymphatic and hepatic metastases. Histologically, all three tumors consisted of round blue cells with a dense desmoplastic reaction and focal rhabdoid features. Immunohistochemical markers for epithelial, neural, and muscle elements were positive. Aggressive multidrug chemotherapeutic regimens were used in each case, and all three patients are alive and well but with known residual disease. We conclude that in cases of the desmoplastic round cell tumor of childhood, CT scans underestimate the extent of disease, and exploratory laparotomy is necessary for diagnosis and appropriate staging. Surgery is usually palliative because of extensive spread. Awareness of this newly recognized aggressive solid tumor of childhood is essential to define its natural history and guide the development of effective multidisciplinary therapeutic regimens.

Pre-irradiation chemotherapy and hyperfractionated radiation therapy 66 Gy for children with brain stem tumors. A phase II study of the Pediatric Oncology Group, Protocol 8833.

BACKGROUND: Fewer than 20% of children with intrinsic brain stem tumors survive longer than 2 years. Although some improvement has been noted in recent trials using higher doses of hyperfractionated radiation therapy (HRT), the feasibility of pre-irradiation chemotherapy has not been explored in these patients with poor prognosis. METHODS: Between February 1988 and March 1989, 37 patients were entered onto a Phase II Pediatric Oncology Group study for evaluating the feasibility, response, and toxicity of treating children with high-risk brain stem tumors with chemotherapy followed by HRT (66 Gy). Chemotherapy consisted of four cycles of cisplatin (100 mg/m2) plus cyclophosphamide (3 g/m2). RESULTS: Of 32 eligible patients, 65% improved clinically during the first 2-3 cycles of chemotherapy; 75% of those improving were weaned from steroids. On neuroradiology review of scans before and after chemotherapy, 3 patients had partial responses (PR, > 50% shrinkage), 23 had stable disease (SD), and 6 had progressive disease (PD). The median survival was 9 months. The three patients who attained a PR on chemotherapy were among the longest survivors at 38 plus, 44 plus, and 40 months. Toxicities included profound but brief marrow suppression, transient electrolyte-renal dysfunction, and ototoxicity. Brain stem swelling from intravenous fluids caused transient deterioration in two patients. Six patients developed an unusual syndrome of transient marrow suppression after HRT. CONCLUSIONS: This study suggests that pre-irradiation chemotherapy can be successfully added to the treatment of patients with brain stem tumors with both clinical and objective responses noted, but that other agents must be identified to overcome the apparent development of drug resistance and to improve survival.