19F-magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate

Haloperidol decanoate is widely used in the maintenance treatment of schizophrenia and other psychotic disorders, but knowledge concerning its pharmacokinetics at the injected region is very limited. Because the chemical structure of haloperidol contains fluorine, in vivo 19F-magnetic resonance (MR) spectroscopy (repetition time (TR) = 1 s) and chemical shift imaging (CSI; TR = 1 s, pixel size = 15 x 15 mm) were performed in schizophrenic patients who were treated with haloperidol decanoate (three men and one woman) to measure its diachronic change at the injection point and visualize its local distribution after intramuscular injection. 19F signals (T1 time = 365 ms) were obtained at the haloperidol decanoate-injected region. The decrease rate of the signal-to-noise ratio (SNR) by 19F-MR spectroscopy seemed large in comparison with that of the plasma haloperidol concentration. The distribution was clearly visualized by 19F-CSI for a few days after the injection, but after 1 week could no longer be seen. Although the slow-release characteristics of depot neuroleptics have been explained by the slow diffusion of esterified neuroleptics from the oil vehicle, this result may suggest that there are other mechanisms involved in maintaining the plasma haloperidol concentration. In vivo 19F-MR spectroscopy and CSI are potentially applicable for the pharmacokinetic analysis of haloperidol and other drugs containing fluorine in their structure.     

A mixture of ethylene vinyl alcohol copolymer and ethanol yielding a nonadhesive liquid embolic agent to treat cerebral arteriovenous malformations: initial clinical experience

OBJECT: The authors report their clinical experience with their new nonadhesive liquid embolic agent, an ethylene vinyl alcohol copolymer (EVAL)/ethanol mixture, to treat arteriovenous malformations (AVMs). METHODS: Between June 1995 and April 2001, 57 patients with confirmed AVMs underwent embolization of their lesions with the EVAL/ethanol mixture. In 87 procedures consisting of one to three stages, the authors embolized 185 feeding arteries to occlude as much of the AVM as possible. Repeated injections under fluoroscopic control could be performed smoothly without encountering cementing of the catheter to the vessel wall. Among the 87 embolizations undertaken in 57 patients, seven procedures (8%) in six patients produced new postembolization symptoms. Resolution of these symptoms occurred within hours or days after four of the seven procedures; permanent neurological deficits remained after the other three procedures (3.4%). Of the 57 patients, three underwent postembolization radiosurgery, and 54 underwent radical treatment with microsurgical extirpation. Histopathological examination of the 54 specimens disclosed mild inflammation within the embolized lumen without inflammatory reactions in the media or adventitia. Follow-up angiograms obtained 3 years after radiosurgery was administered showed that in all three patients treated in this fashion the nidus had completely disappeared. CONCLUSIONS: The EVAL/ethanol mixture is handled easily and appears to be an effective and safe agent for preoperative embolization of AVMs.     

A nonadhesive liquid embolic agent composed of ethylene vinyl alcohol copolymer and ethanol mixture for the treatment of cerebral arteriovenous malformations: experimental study

OBJECT: The authors have developed a mixture of ethylene vinyl alcohol copolymer (EVAL) and iopamidol, which is dissolved in ethanol, as an alternative solvent to provide a safe means of embolizing arteriovenous malformations (AVMs). METHODS: A two-stage delivery technique is required to prevent premature precipitation in the catheter when using this material: the catheter is first infused with 30% ethanol and this is followed by the delivery of the EVAL-ethanol mixture. Acute angiographic changes were analyzed after superselective delivery of dimethyl sulfoxide (DMSO) and 30% ethanol into the renal artery of rabbits. Histological changes following the embolization of the renal artery achieved using the EVAL-ethanol mixture were recorded at 1 hour and at 2 and 16 weeks after the procedure. Although DMSO always produced severe, rapidly progressive vasospasm in the renal artery during a 1- to 60-minute postinfusion, 30% ethanol did not. Microscopically, the lumens of embolized vessels examined 1 hour after embolization with EVAL-ethanol appeared to be filled with EVAL sponges, leaving almost no open spaces. The space between the EVAL sponges and the inner surface of the vessels was filled with fresh thrombus. In the vessel walls of specimens examined 2 weeks after embolization there was no or a slight inflammatory reaction. Scattered in the EVAL sponges were almost equal numbers of neutrophilic granulocytes and mononuclear cells, indicative of a mild inflammatory response. In specimens examined 16 weeks postembolization, the changes noted at 2 weeks were intensified. There was no definite histopathological evidence of mural hemorrhage, perivascular extravasation of the mixture, or perivascular hemorrhage in any specimen that was examined. CONCLUSIONS: Although the degree of permanence of this embolization material is yet unknown, the mixture was easy to handle, and appeared safe and effective for AVM embolization. Its nonadhesive characteristic and its ability to be infused by repeated injections make it an attractive alternative to currently available materials. The good results obtained in this study led us to undertake a clinical trial, the results of which are contained in a companion article in this issue of the Journal of Neurosurgery.     

Brain metastases from esophageal carcinoma: natural history, prognostic factors, and outcome

BACKGROUND: Brain metastases from esophageal carcinoma are extremely rare, and information regarding the natural history, results of treatment, and possible prognostic factors in these patients is limited. METHODS: The records of 36 patients with brain metastases from esophageal carcinoma who were treated between 1986 and 2000 were reviewed. For brain metastases, 12 patients (33%) were treated with surgical resection followed by radiation therapy (S+RT), and the remaining 24 patients were treated with radiation therapy alone. RESULTS: At the initial diagnosis of esophageal carcinoma, the median primary tumor length was 8 cm (range, 2-19 cm), and 26 of 32 available patients (81%) had clinical Stage III-IV tumors according to the International Union Against Cancer 1997 criteria. At time brain metastases appeared, lung metastases were not demonstrated in 25 of 36 patients (69%) who were assessed by chest computed tomography (CT) scans. The overall median survival for all patients was 3.9 months (range, 0.6-36.8 months), and the actuarial survival rates at 12 months and 24 months were 14% and 3%, respectively. In univariate analysis, treatment modality, Karnofsky performance status (KPS), and extracranial disease status each had a statistically significant impact on survival, and, in multivariate analysis, treatment modality and KPS were statistically significant prognostic factors for survival. Five patients (14%) survived more than 1 year, all of whom were treated with S+RT. These five patients had inactive extracranial disease and, four of five patients (80%) had a 90-100% KPS. CONCLUSIONS: Brain metastases from esophageal carcinoma tended to occur in patients with a large primary tumors and/or disease in advanced clinical stages. With the appearance of brain metastases, an absence of lung metastasis frequently was observed on chest CT scans. The prognoses for these patients were generally poor, although selected patients may survive longer with intensive brain tumor treatment.     

Effect of activated human mast cells and mast cell-derived mediators on proliferation,type I collagen production and glycosaminoglycans synthesis by human dermal fibroblasts

Although an increased number of mast cells in fibrotic tissues such as scleroderma, keloid or healing wound has been highlighted, it is still unclear whether or not mast cells are fibrogenic. The aim of the present study is to determine whether functionally active human mast cells can provide human dermal fibroblasts directly with fibrogenic properties. In order to examine the effects of IgE-mediated mast cell activation on fibroblast proliferation and synthesis of type I collagen, we utilized an in vitro defined system in which cultured human mast cells were co-cultured with human dermal fibroblasts. We also employed a three-dimensional fibroblast culture system using supplementation of L-ascorbic acid as an assay system to investigate the effects of mast cell-derived mediators on synthesis of glycosaminoglycans by human fibroblast. Fibroblast proliferation was actively stimulated with IgE-activated mast cells. However, this stimulatory effect was canceled in co-cultures with a higher number of IgE-activated mast cells. In the presence of a higher number of activated mast cells, the fibroblast cell layer was destroyed, in contrast to an intact cell layer in the presence of same number of the mast cells without activation. Type I collagen synthesis was unchanged in fibroblasts co-cultured with mast cells. The total amount of main disaccharide units, particularly DELTADi-HA, was increased when fibroblasts were exposed to histamine. Thus, we conclude that other factors, in addition to mast cells, are important in the development of human tissue fibrosis or sclerosis.     

Cell-free Human T-cell Leukemia Virus Type 1 Binds to, and Efficiently Enters Mouse Cells

Human T-cell leukemia virus type 1 (HTLV–1) is an etiologic agent of adult T-cell leukemia/lymphoma and other HTLV-1–associated diseases. However, the interaction between HTLV–1 and T cells in the pathogenesis of these diseases is poorly understood. Mouse cells have been reported to be resistant to cell-free HTLV–1 infection. However, we recently reported that HTLV–1 DNA could be observed 24 h after cell-free HTLV–1 infection of mouse cell lines. To understand HTLV–1 replication in these cells in detail, we concentrated the virus produced from c77 feline kidney cell line and established an efficient infection system. The amounts of adsorption of HTLV–1 are larger in mouse T cell lines, EL4 and RLml, than those in human T cell lines, Molt4 and HUT78, and are similar to that in human kidney cell line, 293T. Unexpectedly, however, the amounts of entry of HTLV–1 are about 10–fold larger in the two mouse cell lines than those in the three human cell lines employed. Moreover, viral DNA was detectable from 1 h in EL4 and RLml cells, but only from 2–3 h in 293T, Molt4 and HUT78 cells. However, the amount of viral DNA in EL4 cells became smaller than that in Molt4 cells. HTLV–1 expression could be detected until day 1–2 in RLml and EL4 cells, and until day 4 in Molt4 cells. Our results suggest that mouse cell experiments would give useful information to dissect the early steps of cell-free HTLV–1 infection.     

Left diaphragmatic hernia associated with lower esophageal atresia

A case of combined left diaphragmatic hernia and lower esophageal atresia, which is an unusual occurrence, is described. The preoperative diagnosis was difficult because of the presence of an abnormal air bubble, thought to be the stomach, in the chest. The surgical management is discussed. Correspondence to: N. Komi     

A case of non-metastatic giant mucinous carcinoma of the breast

A surgically resected case of giant mucinous carcinoma of the breast that had remained untreated for 2 years is reported. A 64-year-old postmenopausal woman presented with a large right breast mass (17.4 x 16.5 x 14.5 cm). Although she had noticed a mass in the right breast 2 years previously, she had not sought treatment. Mucinous carcinoma was diagnosed by core needle biopsy and she underwent right modified radical mastectomy with a free skin graft. There were no lymph node metastases or distant metastases. Fourteen months postoperatively, she remains well without evidence of tumor recurrence. Although several reports have suggested that pure mucinous carcinoma of the breast has a favorable prognosis, we need to follow this case until the clinical behavior and the outcome become clear.     

Circadian variability of pharmacokinetics of 5-fluorouracil and CLOCK T3111C genetic polymorphism in patients with esophageal carcinoma

The variations of plasma concentrations of 5-fluorouracil (5-FU) were investigated in 30 esophageal cancer patients treated with repetitive protracted venous infusion (PVI) of 5-FU-based chemoradiotherapy, and in an attempt to find a new possible candidate that explains their variations, CLOCK T3111C genetic polymorphism was examined. The patients have received 2 courses of chemoradiotherapy consisting of 2 cycles of 5-day PVI of 5-FU (400 mg/m/d) with cisplatin and concurrent radiation. The plasma concentrations of 5-FU were determined at 5 PM on day 3 and 5 AM on day 4 after the beginning of each 5-FU infusion. The CLOCK T3111C genotype was determined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) and by direct sequencing. Plasma concentrations were measured in 239 samples. In the first course, the plasma concentrations of 5-FU at 5 AM were significantly lower than those at 5 PM in the first cycle, whereas a similar tendency was observed in the second cycle, although not significantly (Wilcoxon signed-rank test). The plasma concentrations of 5-FU at 5 PM and 5 AM in the second cycle were both significantly higher than those in the first cycle, and their coefficient of variation in the former was also significantly smaller than that in the latter. These phenomena in the first course were also observed in the second one. These results revealed the elevation of plasma drug concentration and its reduced circadian variation during repetitive PVI of 5-FU. In 5-FU-based chemotherapy, its administration schedule should be made in consideration of these phenomena. The CLOCK T3111C genotype did not have a significant impact on the variation of the plasma concentrations of 5-FU in this study population. Further studies are needed to clarify the mechanism of these phenomena and to identify an easy-to-assess marker of circadian rhythms for use in individualizing delivery of 5-FU.