A novel antipsychotic, perospirone, has antiserotonergic and antidopaminergic effects in human brain: findings from neuroendocrine challenge tests.

RATIONALE: Perospirone is a new antipsychotic drug in which dopamine D(2) antagonist and serotonin 5-HT(2) antagonist effects have been found in animal studies. It was developed by a Japanese pharmaceutical company and launched in 2001. Perospirone's receptor binding profile may resemble that of atypical antipsychotic drugs, but to date there has been no evidence relating to its receptor binding affinity in the human brain. OBJECTIVE: The purpose of this study was to investigate the receptor binding profile of perospirone via neuroendocrine challenge tests. METHODS: Twenty subjects (ten females and ten males) were tested on four occasions in a double-blind, cross-over design receiving: (a) placebo, (b) perospirone 4 mg, (c) paroxetine 20 mg, and (d) paroxetine 20 mg plus perospirone 4 mg, administered orally at 8.00 a.m. Plasma cortisol and prolactin levels were measured prior to administration and every hour for 6 h thereafter. In addition, psychological responses rated by visual analog scales and vital signs such as body temperature, pulse, and blood pressure were assessed in combination with blood sampling. RESULTS: Perospirone 4 mg increased prolactin levels significantly higher than placebo, whereas paroxetine 20 mg plus perospirone 4 mg significantly attenuated cortisol responses induced by paroxetine 20 mg. CONCLUSIONS: The present findings suggest that perospirone has the characteristics of both D(2) and 5-HT(2) antagonist in the human brain. Further PET studies in the human brain are required in order to directly investigate these effects.

Paroxetine as a 5-HT neuroendocrine probe.

RATIONALE: Acute administration of 40 mg paroxetine (a selective serotonin reuptake inhibitor) reportedly increases plasma cortisol in human subjects. This suggests that paroxetine may be a useful tool to probe brain serotonin function. OBJECTIVE: To investigate a dose-response relationship for paroxetine administration, and to determine whether a lower dose of paroxetine is sufficient to increase plasma ACTH and cortisol. METHODS: Twenty subjects were tested on three occasions in a double-blind, cross-over design receiving: (a) placebo, (b) paroxetine 20 mg and (c) paroxetine 40 mg administered orally at 8.00 a.m. In addition, five of the 20 subjects received paroxetine 20 mg plus cyproheptadine (a 5-HT(2) receptor antagonist) 4 mg and four subjects were given paroxetine 40 mg plus cyproheptadine 4 mg in an open manner. Plasma ACTH and cortisol levels were measured prior to administration and every hour for 6 h thereafter. RESULTS: Paroxetine, particularly 20 mg rather than 40 mg, significantly increased plasma ACTH and cortisol. Paroxetine 40 mg but not 20 mg caused significantly more nausea than the placebo. Cyproheptadine attenuated ACTH and cortisol responses to 20 mg but not to 40 mg paroxetine. CONCLUSIONS: Low-dose (20 mg) paroxetine has greater potential utility than larger doses as a neuroendocrine challenge test. The endocrine responses to paroxetine are probably mediated at least partially by 5-HT(2A/2C) receptors.

The clinical importance of the trimethadione tolerance test as a method for quantitative assessment of hepatic functional reserve in patients with biliary atresia.

BACKGROUND: The trimethadione (TMO) tolerance test was performed to evaluate its usefulness in the assessment of hepatic functional reserve in patients with biliary atresia. METHOD: Nineteen patients with biliary atresia after hepatic portoenterostomy (age range: 2 months to 25 years; sex: 6 males and 13 females) were studied. The study was performed in the morning after a 12-h fast. TMO was given orally, at a dose of 4 mg/kg, with 5 mL of 5% glucose 2 h before breakfast. Blood samples (0.5 mL) were collected to determine serum TMO and dimethadione (DMO), a metabolite of TMO, levels 4 h after the administration of TMO. TMO and DMO were measured by a gas-liquid chromatographic method. RESULTS: A higher total bilirubin level (over 1 mg/dL) in patients with jaundice was reflected in the smaller serum DMO/TMO ratio 4 h after the oral administration of TMO. In addition, these patients with total bilirubin levels of 1 mg/dL or less had a significantly lower DMO/TMO ratio than the control group (healthy subjects). The serum DMO/TMO ratio showed a close correlation with the Child-Pugh score, which is used for overall evaluation of severity of cirrhosis and Mayo risk scores for primary biliary cirrhosis in adults (0.856, P < 0.01 and 0.788, P < 0.01, respectively). The TMO tolerance test shows the benefit of performing a relatively early test of dynamic liver function to evaluate hepatic functional reserve in pre- and post-operative biliary atresia patients.

Intraspinal implants of fibrin glue containing glial cell line-derived neurotrophic factor promote dorsal root regeneration into spinal cord.

OBJECTIVE: The purpose of this study was to determine whether glial cell line-derived neurotrophic factor (GDNF) delivered intraspinally via a fibrin glue (FG) enhanced regeneration of cut dorsal root (DR). METHODS: FG containing GDNF was inserted into aspiration cavities in the lumbar enlargement of adult rats. The transected L5 DR stump was placed at the bottom of the cavity and sandwiched between the FG and the spinal cord. Regenerated DR axons were labeled with horseradish peroxidase (HRP) or with immunohistochemical methods for calcitonin gene-related peptide (CGRP). RESULTS: Primary afferent axons labeled with HRP regenerated into the spinal cord, received GDNF, and made frequent arborization there. Some of these were myelinated axons that established synapses on intraspinal neuronal profiles. CGRP-immunoreactive DR axons extended into the motor neurons and formed prominent varicosities around their cell bodies. Only a few axons regenerated into the spinal cords given FG without GDNF. CONCLUSIONS: Our results indicate that GDNF enhances regeneration of DR into the adult rat spinal cord and that GDNF may be effectively supplied to the intraspinal injury site via FG. Because the regenerated axons establish synapses on intraspinal neurons, this therapeutic strategy has the potential to help to rebuild spinal reflex circuits interrupted by spinal cord injury.

Carcinosarcoma with rhabdoid features of the urinary bladder in a 2-year-old girl: possible histogenesis of stem cell origin.

A case of carcinosarcoma of the urinary bladder in a 2-year-old girl is reported. The tumor, measuring 34 x 20 x 18 mm, was located in the peri-trigone area of the urinary bladder with polypoid features. Histologic examination revealed transitional cell carcinoma at the tumor surface with downward invasion. Concurrently, a sarcomatous area was found beneath the carcinoma, with these two different malignant components sharing on apparent transition without distinct boundaries. Sarcomatous components included immature round cells focally showing rhabdoid features. No rhabdomyomatous component was observed. Immunohistochemistry disclosed vimentin and cytokeratin-double positive cells at the transposition between carcinoma and sarcomatous components. In addition, ultrastructural analysis revealed that the epithelial cells had a distinct junctional complex, and the sarcomatous cells occasionally had a meshwork of cytoplasmic intermediate filaments, indicating bidirectional cytodifferentiation to epithelial and mesenchymal elements. The extremely young age at which this case of carcinosarcoma occurred suggests that the tumor may be of mesodermal stem cell origin.

Enhanced metastasis after local therapy in a murine model using C-1300 neuroblastoma.

BACKGROUND/PURPOSE: In the treatment of advanced neuroblastoma, the role of surgery has been controversial. This study was carried out to determine the effect of surgery, irradiation, and chemotherapy in inhibiting or promoting distant metastases. METHODS: Transplanted C-1300 neuroblastomas in hind legs of syngeneic mice were treated by surgery, radiation, and chemotherapy. The liver was evaluated 18 days after each treatment modality for metastases. RESULTS: Mice developed no liver metastasis when leg tumors received no treatment or chemotherapy. In the mice who had the tumor resected, liver metastases were found in 8 of 16 mice that had 7-mm tumors. One hundred percent of the mice that had 9- or 12-mm tumors presented with metastases to the liver. In mice who received radiation therapy, 100% had liver metastases. CONCLUSIONS: Local control by surgery and single-dose radiation induced liver metastasis in a murine model. Surgery to remove tumors should be used in conjunction with chemotherapy to prevent secondary liver metastases.

Extensive epidural teratoma in early infancy treated by multi-stage surgery.

We report a rare case of extensive extradural teratoma successfully treated by multi-stage laminotomy and thoracotomy. A 34-day-old, dyspneic infant had a large posterior mediastinal mass identified on a chest X-ray radiograph. Imaging studies disclosed that the mass originated from the extradural space at the level of the lower thoracic spine, extending cephalad to C4 and caudad to L4 and severely compressing the spinal cord anteriorly, causing paraplegia. The tumor expanded bilaterally through the intraspinal foramina, coalescing to form a huge mediastinal mass. The upper half of the teratoma was removed utilizing a laminotomy from T3 through T9; 2 months later the lower half was excised via a laminotomy from T11 to L3. An additional procedure was required to resect recurrent tumor through a laminotomy from T8 to T12. The reconstructed vertebral arches were well-preserved in shape, with an almost normal spinal canal.

Complete resection is not required in patients with neuroblastoma under 1 year of age.

BACKGROUND/PURPOSE: The prognosis of neuroblastoma (NB) patients when detected before 1 year of age is excellent, particularly in patients whose disease is detected by screening. In some institutions patients with stage I or II NB detected by screening have been observed closely without any treatment. Most showed tumor regression or maturation and are surviving without tumor resection. Resection of infantile NB sometimes is complicated by vascular accidents resulting in vanishing kidney or intestinal infarction. The role of surgery in the treatment of infantile NB therefore is becoming controversial. The authors have treated infants who have easily resectable primary tumors with resection and sampling for lymph node metastases. If the resection of the primary tumor seemed difficult, only biopsy was performed initially followed by chemotherapy with or without resection. The authors analyzed the clinical outcome of the infantile NB in their institution to elucidate the role of surgery in this particular group of patients. METHODS: Thirty-six patients less than 12 months of age were treated between 1982 and 1997. Twenty-five patients who showed no symptoms had NB detected by screening at 6 months. Five patients had stage IVS disease in early infancy. No patients had bone or remote lymph node metastases. N-mycamplification was not detected in any of the 28 tumors examined. There were four diploid and 12 near-triploid tumors. RESULTS: Complete resection was possible in 13 stage I and II patients without any complications. Obvious lymph node metastases were not resected in 13 patients with stage II or III NB. Partial resection leaving gross residual disease was accomplished in three patients with stage III NB. Surgical resection was not attempted in four patients because of unresectability in three patients with stage III or IVS disease and because of marked tumor shrinkage after a short course of chemotherapy in one patient with stage III NB involving the celiac axis. A neonatal cervicomediastinal stage III NB recurred very rapidly after partial resection but started to regress spontaneously 2 months postoperatively. Another neonatal stage II cervical NB progressed to stage IVS with hepatomegaly causing respiratory distress but regressed spontaneously. All the patients are alive and disease free without surgical morbidity. CONCLUSION: All of the 21 patients who underwent partial tumor resection with or without chemotherapy are alive and doing well without tumor, indicating that complete resection is not required in this particular group of patients.

Is extensive surgery required for treatment of advanced neuroblastoma?

BACKGROUND: Prognosis of advanced neuroblastoma is still disappointing although recently slightly improving because of more intensive chemotherapy supported with stem cell transfusion. Before 1985, all patients at University of Tsukuba over the age of 1 year who had stage III and IV neuroblastoma died regardless of extensive resection of the primary tumor. METHODS: Since the treatment protocol of the Study Group of Japan for Advanced Neuroblastoma was introduced in 1985, the authors treated 14 consecutive patients over the age of 1 year who had advanced neuroblastoma with six to eight cycles of the intensive induction chemotherapy regimens followed by resection of the primary and local lymph node metastasis combined with intraoperative irradiation. The resection of the primary tumor and the lymph node metastasis was much less extensive preserving adventitia with perivascular nerves to avoid postoperative vascular occlusion, intestinal dysmotility, and massive lymphorrhea, which interfere with postoperative intensive chemotherapy. If the dissection of lymph nodes from major vessels was difficult, the authors intentionally left the tumor-containing lymph nodes. RESULTS: There were macroscopic residual tumors in 8 of 14 patients. Electron beam irradiation, 10 to 15 Gy, was given to the tumor bed intraoperatively. Overall survival of these 14 patients was 63% (eight patients) at 5 years with six patients surviving without recurrence for more than 5 years. Five patients died of tumors, two of whom died before surgery. Local tumor control failed in only two patients. In one patient, the tumor recurred twice 47 months and 61 months after therapy. After undergoing a second resection at 69 months, this child has survived tumor free for 12 months after the second recurrence. The other patient who had tumor recurrence had an N-myc-amplified tumor that recurred 4 months postoperatively in the hepatoduodenal ligament locally with massive bone metastasis. The 5-year local relapse-free probability for patients with stage III and IV tumors who had an operation was 79% by the Kaplan-Meier method. CONCLUSION: Systematic extensive surgery for advanced or metastatic neuroblastoma is no longer required if supplemented with intensive pre- and postoperative chemotherapy with intraoperative radiotherapy.

[The clinical efficacy of imipenem/cilastatin sodium in orthopedic infections and drug levels in the bone tissue].

We evaluated the clinical efficacy of imipenem/cilastatin sodium (IPM/CS--a carbapenem antibiotic) against orthopedic infections, and the drug levels of the bone tissues were determined. The clinical efficacies for 6 patients in the infection group were good in 3 cases, and fair in the other 3; giving an efficacy rate of 50%. Bacteriologically, 8 strains were isolated from patients with the infection and an eradication rate of 87.5% was obtained upon the treatment. In 39 patients that were given the drug prophylactically, no postoperative infections occurred. Mean IPM levels in the bone and the bone marrow at 1 hour after administration in 5 patients of the prophylactic group were 17.3 micrograms/ml and 5.9 micrograms/g, respectively. The ratio of concentrations the bone to those in the bone marrow was 34.6%. The results of this study suggest that IMP/CS reaches to the bone tissue providing sufficient concentrations and that the drug is efficacious for the prophylaxis and the treatment of orthopedic infections.

A murine model for bone marrow metastasis established by an i.v. injection of C-1300 neuroblastoma in A/J mice.

A reproducible tumor model for bone marrow metastasis has been developed by an injection of murine C-1300 neuroblastoma (C-1300 NB) cells into the tail vein of syngeneic A/J mice. The animals died with liver metastases at 18-21 days after an injection of 10(5) tumor cells and often had bone marrow metastasis in the femur. N-methylformamide (NMF), a maturational agent, was administered to inhibit liver metastases and to extend survival in mice with advancing bone metastasis. Histological examination of bone marrow metastasis, demonstrated lesions varying from a few small colonies of C-1300 NB cells either in metaphysis or diaphysis to large foci replacing normal hematopoietic bone marrow, simultaneously invading epiphysis or cortex of bone as bone metastasis. This assay demonstrated the ability to detect neuroblastoma cells in the bone marrow histologically and could determine bone marrow TD50 by extraction of bone marrow cells after treatment with various doses of drug. Fifty per cent of mice injected with cyclophosphamide (CY) developed bone marrow metastasis without liver metastasis. Treatment with tamoxifen, an anti-calmodulin drug, suppressed tumor takes in the recipient mice with tamoxifen-dose-dependent fashion. This experimental system allows for investigations into the therapeutic response and biology of neuroblastoma metastases in the bone marrow.

[Targeting anticancer chemotherapy dispersed in lipid contrast medium in hepatoblastoma in childhood].

Fourteen cases of malignant liver tumor in childhood were experienced in our department during past 14 years. Since 1984 we have performed preoperative targeting anticancer chemotherapy using oily anticancer agents such as THP-adriamycin 30 mg/m2. These oil emulsion was making with 20 mg amounts of THP-adriamycin dissolved in 5 ml urographin and 15 ml volume of lipiodol. These mixture were administered by catheterizing the hepatic artery under X-ray monitoring in 6 cases with hepatoblastoma. Remarkable anticancer effects of this targeting chemotherapy were achieved, the serum AFP level and tumor size both showing a decrease in all cases, and the resectability of tumor showing a increase in 5 among 6 cases in comparison with 50% resectability before 1983.

Combination of N-methylformamide with cis-diamminedichloroplatinum (II) in murine mammary carcinoma: importance of timing.

The maturational agent N-methylformamide (NMF) is an antitumor agent that also enhances the response of tumor cells in vitro to chemotherapeutic agents. Here, we tested whether NMF can improve therapy of the murine MCA-K mammary carcinoma with cis-diamminedichloroplatinum(II) (cis-DDP). Although the in vitro cell cultures of MCA-K tumor cells exhibited increased sensitivity to cis-DDP cytotoxicity when they were first treated with NMF, administration of NMF to mice bearing MCA-K tumors did not enhance cis-DDP-induced tumor growth delay. However, when NMF treatment was begun after cis-DDP administration, the growth delays were significantly greater than those induced by the individual treatment, with an increase in temporary tumor regression and a small proportion of cures. These results indicate that therapeutic benefit can be achieved in this experimental tumor system when NMF is administered after cis-DDP. In addition, they demonstrate the significance of the timing of administration in combined protocols involving NMF.

The effect of N-methylformamide on radiocurability of murine tumors.

N-Methylformamide (NMF) is a polar solvent with maturational activity, i.e., it induces malignant cells to form more differentiated phenotypes. In addition, it renders tumor cells more sensitive to chemotherapeutic drugs and ionizing radiation. In the present study, NMF failed to augment radiocurability, as measured by the single-dose TCD50 assay, of two murine tumors: an 8-mm fibrosarcoma (FSA) and a 6-mm mammary carcinoma (MCA-K). NMF, at a dose of 300 mg/kg, was given ip daily for several days before and/or after local tumor irradiation.

Antitumor and antimetastatic activity of the differentiating agent N-methylformamide in murine tumor systems.

N-Methylformamide (NMF), a cell-differentiating agent, was assessed for its antitumor activity against a fibrosarcoma (FSA), a hepatocarcinoma (HCA-I) and a mammary carcinoma (MCA-K), syngeneic to C3Hf/Kam mice. Tumors were grown as solitary tumors in the leg or as artificial or spontaneous micrometastases in the lung. NMF, at a dose of 300 mg/kg, was administered i.p. daily for 6 to 18 days. NMF slowed the growth of FSA and HCA-I tumors and totally inhibited the growth of the MCA-K tumor. However, the effect was transient; tumors resumed their pretreatment growth rate upon cessation of the treatment. Histologically, MCA-K tumors treated with NMF (300 mg/kg daily for six days) underwent considerable cell depopulation and reduction in mitotic activity. The number of artificial metastases, as well as the incidence and the number of spontaneous metastases, were markedly reduced by NMF. This resulted in a prolongation of the survival of mice that had artificial metastases of MCA-K tumor. The in vitro clonogenicity of MCA-K, but not of FSA or HCA-I cells, was reduced. However, in vivo reduction of MCA-K cell clonogenicity was minimal, if any. Thus, NMF is effective in restricting the growth of both solitary tumors and metastases, but the degree of response is highly dependent on tumor type.

Enhancement of lung colony formation by admixing irradiated with viable tumor cells: dependence on host status.

The study was designed to determine whether whole-body irradiation or stimulation of the reticuloendothelial system of mice influences the ability of heavily irradiated tumor cells to enhance formation of artificial metastases when given simultaneously with viable tumor cells. Experiments were performed with a nonimmunogenic sarcoma syngeneic to C3Hf/Kam mice. Whole-body irradiation augmented and stimulation of the reticuloendothelial system abolished the metastasis-enhancing effect of tumor cells. Another observation was that heavily irradiated tumor cells can enhance formation of metastases if given i.v. within several hours before or after i.v. injection of tumor cells.

Modification of tumor and normal tissue radioresponse in mice by N-methylformamide.

The effects of the differentiation-inducing agent N-methylformamide (NMF) on the in vivo response of the murine tumor FSA and its pulmonary metastases to ionizing radiation were investigated. In addition, the radioresponse of acutely responding normal tissues was determined in mice receiving systemic NMF. A dosage of 300 mg/kg administered for 8 days had little effect on the FSA tumor growth, yet enhanced the growth inhibitory actions of ionizing radiation with dose enhancement factors ranging from 1.5 to 1.7. Administration of NMF also enhanced the radiation response of FSA micrometastases. The response to irradiation of hematopoietic tissue, jejunum, and testes in mice receiving NMF was also investigated. NMF administered before or before and after radiation enhanced the formation of endogenous spleen colonies, yet did not influence the LD50/30 for radiation. Jejunal crypt cell survival after radiation was slightly increased in mice receiving NMF, but the survival of spermatogonia after radiation was not affected. These data indicate that NMF administration results in an increase in the radiosensitivity of the FSA tumor and its metastases with no concomitant increase in the radiation response of the normal tissue tested. Thus, at least in this model system, a therapeutic gain is achieved through the combination of NMF and ionizing radiation.