Comparison of osseous healing after sagittal split ramus osteotomy and intraoral vertical ramus osteotomy.

The sagittal split ramus osteotomy (SSRO) is generally associated with greater postoperative stability than the intraoral vertical ramus osteotomy (IVRO); however, it entails a risk of inferior alveolar nerve damage. In contrast, IVRO has the disadvantages of slow postoperative osseous healing and projection of the antegonial notch, but inferior alveolar nerve damage is believed to be less likely. The purposes of this study were to compare the osseous healing processes associated with SSRO and IVRO and to investigate changes in mandibular width after IVRO in 29 patients undergoing mandibular setback. On computed tomography images, osseous healing was similar in patients undergoing SSRO and IVRO at 1year after surgery. Projection of the antegonial notch occurred after IVRO, but returned to the preoperative state within 1year. The results of the study indicate that IVRO is equivalent to SSRO with regard to both bone healing and morphological recovery of the mandible.

Therapeutic vaccination based on side population cells transduced by the granulocyte-macrophage colony-stimulating factor gene elicits potent antitumor immunity.

Among cancer immunotherapies, granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor cell vaccine (GVAX) therapies appear promising and have been shown to be safe and effective in multiple clinical trials. However, the antitumor efficacies of GVAX therapy alone are in some cases limited. Here we showed that GVAX therapy targeting cancer stem cells (CSCs) substantially suppressed tumor development in syngeneic immunocompetent mice recapitulating normal immune systems. CSCs were isolated as side population (SP) cells from 4T1 murine breast carcinoma cell line and transduced with GM-CSF gene delivered by non-transmissible Sendai virus (4T1-SP/GM). Impaired tumorigenicity of subcutaneously injected 4T1-SP/GM depended on CD8+ T cells in concert with CD4+ T cells and natural killer cells. Mice therapeutically vaccinated with irradiated 4T1-SP/GM cells had markedly suppressed tumor development of subcutaneously transplanted 4T1-SP cells compared with those treated with irradiated cells of non-transduced 4T1-SP cells or non-SP (4T1-NSP/GM) cells. Tumor suppression was accompanied by the robust accumulation of mature dendritic cells at vaccination sites and T-helper type 1-skewed systemic cellular immunity. Our results suggested that CSC cell-based GVAX immunotherapy might be clinically useful for inducing potent tumor-specific antitumor immunity.

An anti-c-Fms antibody inhibits orthodontic tooth movement.

Orthodontic force induces osteoclastogenesis in vivo. It has recently been reported that administration of an antibody against the macrophage-colony-stimulating factor (M-CSF) receptor c-Fms blocks osteoclastogenesis and bone erosion induced by tumor necrosis factor-alpha (TNF-alpha) administration. This study aimed to examine the effect of an anti-c-Fms antibody on mechanical loading-induced osteoclastogenesis and osteolysis in an orthodontic tooth movement model in mice. Using TNF receptor 1- and 2-deficient mice, we showed that orthodontic tooth movement was mediated by TNF-alpha. We injected anti-c-Fms antibody daily into a local site, for 12 days, during mechanical loading. The anti-c-Fms antibody significantly inhibited orthodontic tooth movement, markedly reduced the number of osteoclasts in vivo, and inhibited TNF-alpha-induced osteoclastogenesis in vitro. These findings suggest that M-CSF plays an important role in mechanical loading-induced osteoclastogenesis and bone resorption during orthodontic tooth movement mediated by TNF-alpha.

Communication about the ending of anticancer treatment and transition to palliative care.

BACKGROUND: Communication about the ending of anticancer treatment and transition to palliative care is a difficult task for oncologists. The primary aims of this study were to clarify family-reported degree of emotional distress and the necessity for improvement in communication methods when communicating about the ending of anticancer treatment, and to identify factors contributing to the levels of emotional distress and the necessity for improvement. METHODS: A multi-center questionnaire survey was conducted on 630 bereaved family members of cancer patents who received specialized palliative care in Japan. A total of 318 responses were analyzed (effective response rate, 62%). RESULTS: Thirty-nine percent of the bereaved family members reported that they were 'very distressed' in receiving information about the ending of anticancer treatment, and 19% reported 'considerable' or 'much' improvement was necessary in the communication methods. High-level emotional distress was significantly associated with younger patient age, female family gender, the experience of the physician stating she/he could do nothing for the patient, the physician's unwillingness to explore their feelings, and prognostic disclosure of definite survival periods without probabilities or ranges. High levels of perceived necessity for improvement in the communication methods were significantly associated with the experience of the physician stating she/he could do nothing for the patient, physicians not explaining treatment goals in specific terms, physicians not pacing the explanation with the state of family preparation, physicians not being knowledgeable about the most advanced treatments, and the atmosphere not being relaxing enough to ask questions. CONCLUSIONS: In receiving the information about ending anticancer treatment, a considerable number of families experienced high levels of emotional distress and felt a need for improvement of the communication methods. The strategies to alleviate family distress could include: (i) assuring that physicians will do their best to achieve specific goals, without saying that they can do nothing for the patient; (ii) providing information, including estimated prognosis, in careful consideration of families' preparation and the uncertainty for each patient; (iii) exploring families' emotions and providing emotional support; (iv) acquiring knowledge about advanced treatments; and (v) making the atmosphere relaxing enough to allow families to ask questions.

Establishment of a drug sensitivity panel using human lung cancer cell lines.

We established a drug sensitivity panel consisting of 24 human lung cancer cell lines. Using this panel, we evaluated 26 anti-cancer agents: three alkylators, three platinum compounds, four antimetabolites, one topoisomerase I inhibitor, five topoisomerase II inhibitors, seven antimitotic agents and three tyrosine kinase inhibitors. This panel showed the following: a) Drug sensitivity patterns reflected their clinically-established patterns of action. For example, doxorubicin and etoposide were shown to be active against small cell lung cancer cell lines and mitomycin-C and 5-fluorouracil were active against non-small cell lung cancer cell lines, in agreement with clinical data. b) Correlation analysis of the mean graphs derived from the logarithm of IC50 values of the drugs gave insight into the mechanism of each drug's action. Thus, two drug combinations with reverse or no correlation, such as the combination of cisplatin and vinorelbine, might be good candidates for the ideal two drug combination in the treatment of lung cancer, as is being confirmed in clinical trials. c) Using cluster analysis of the cell lines in the panel with their drug sensitivity patterns, we could classify the cell lines into four groups depending on the drug sensitivity similarity. This classification will be useful to elucidate the cellular mechanism of action and drug resistance. Thus, our drug sensitivity panel will be helpful to explore new drugs or to develop a new combination of anti-cancer agents for the treatment of lung cancer.

[A resected case under thoracoscopic surgery of bilateral pulmonary metastases of renal cell carcinoma ten years after radical nephrectomy].

A 68-year-old male had received a left nephrectomy for renal cell carcinoma of the clear cell type in October, 1987. He had been given Interferon alpha (IFN alpha) for one year since then. He was referred to our hospital for bilateral abnormal shadows on the chest roentgenogram in December, 1997. He underwent a video-assisted thoracoscopic biopsy of bilateral lung in January, 1998, 11 years after his nephrectomy. The resected specimens contained a coin lesions measuring approximately 2 cm in diameter, and the lesions were microscopically diagnosed as a renal cell carcinoma of the clear cell type metastatic to the lung. The patient is doing well with no signs of re-recurrence five months after the resection of the metastatic lesion.

Effect of docetaxel with cisplatin or vinorelbine on lung cancer cell lines.

Docetaxel shows substantial activity against lung cancer. To find the optimal drug combination for docetaxel, we evaluated the effects of cisplatin, etoposide, mitomycin C, irinotecan, vindesine, and vinorelbine using three human lung cancer cell lines, ABC-1, EBC-1, and SBC-3. Drug cytotoxicity was determined by MTT assay. Tumor cells were incubated for 96 hours in the presence of docetaxel and each of the test drugs stated above. The combined drug interaction was evaluated by median-effect plot analysis and improved IC50-isobologram analysis. Both methods showed strong antagonism (subadditive or protective effect) between docetaxel and etoposide when tested on ABC-1 and EBC-1 cells. Docetaxel and cisplatin displayed additive effects on all cell lines tested, when evaluated by improved IC50-isobologram analysis. The combination of docetaxel and vinorelbine exerted synergistic effect on the growth inhibition of SBC-3 cells, which showed a wide range of fractional cytotoxicity when analyzed by median-effect plot and supraadditive when analyzed by improved IC50-isobologram. These observations suggest a possibility that docetaxel can be used in combination with vinorelbine or cisplatin in the treatment of lung cancer.

Bronchial atresia with transient spontaneous disappearance of a mucocele.

We report the transient spontaneous disappearance of a mucocele due to bronchial atresia. Two years before presentation, a chest radiograph showed a hyperlucent right upper lung and a mucocele near the right hilum. A chest radiograph taken 1 year later showed that the mucocele had disappeared leaving an ovoid outline of a dilated bronchus. A chest radiograph obtained 3 months before presentation showed that the mucocele was present again. Atresia of the B3b bronchus of the right upper lobe was noted on thoracotomy. The "disappearance" of the mucocele probably was due to the clearance of mucoid material through collateral airways.

Changes of arterial oxygen saturation (SpO2) following push-back operation.

This study showed the influence of the push-back operation on the occurrence of sleep-related apnea in cleft-palate patients with an analysis of arterial oxygen saturation (SpO2) during sleep, polygraphic analysis of nasal air flow, and chest wall movements. The postoperative SpO2 was lower than that of the presurgical period in all cases, requiring from five to nine days to recover to presurgical levels. According to polygraphic analysis this depression of SpO2 was caused by peripheral obstructive apnea, while, in spite of the cessation of nasal airflow, chest wall movement continued.

High-dose etoposide treatment for CNS involvement in a patient with primary non-Hodgkin's lymphoma of the breast.

A 46-year-old man was referred to us for treatment of non-Hodgkin's lymphoma (NHL; diffuse large immunoblastic B cell type), which had initially developed in the breast. He was treated with five courses of chemotherapy with CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) and achieved a complete response. One year later, he noticed a gait disturbance. Magnetic resonance imaging (MRI) of the brain showed multiple nodules. A few abnormal cells were found in the cerebrospinal fluid (CSF). He was treated with high-dose etoposide (1,350 mg/ m2/course). After two courses, both the multiple nodular lesions in the brain and the abnormal cells in the CSF were resolved. High-dose etoposide is effective for CNS involvement by NHL.

[A case of advanced hepatocellular carcinoma, in which the tumor almost disappeared by orally administered UFT].

A 59-year-old male with liver cirrhosis was admitted to our hospital for further examination of general fatigue. A huge tumor was found in the right lobe of his liver with abdominal ultrasonography and computed tomography (CT). The titers of serum AFP (14,055 ng/ml) and PIVKA-II (more than 50.0 AU/ml) were extremely high. A tumor embolus was observed in the portal vein with abdominal angiography. According to these findings, he was diagnosed as having advanced hepatocellular carcinoma (HCC). He was treated by oral administration of UFT (600 mg/day) as an unresectable case of HCC. Three months later, the clinical symptoms were greatly improved and HCC was almost diminished with abdominal ultrasonography and CT, although a small tumor embolus was found by angiography. The titers of AFP and PIVKA-II were reduced to the normal range. This case suggests the clinical effectiveness of UFT for the treatment of HCC.

Negative regulation of catalase gene expression in hepatoma cells.

For an understanding of the molecular basis of the marked decrease in catalase activity of various tumor cells, expression of the catalase gene was studied in rat and human hepatoma cell lines and in rat liver, which was used as a control with high activity. RNA blot hybridization profiles and run-on assays indicated that the decrease in catalase activity was due to depression of catalase gene transcription. Chloramphenicol acetyltransferase (CAT) assays for the fragments with various lengths of the 5'-flanking region (up to -4.5 kb from the ATG codon) of the catalase gene revealed the presence of several cis-acting elements involved in the negative regulation of transcription. The most-upstream element with the strongest activity (-3504 to -3364 bp), when linked to the catalase promoter region (-126 bp) of the CAT construct and subjected to an in vitro transcription assay, did not yield transcripts in experiments with the hepatoma nuclear extract, whereas the unlinked template did yield transcripts. A gel shift competition assay using hepatoma nuclear extract showed the core sequence of the silencer element to be 5'-TGGGGGGAG-3'. A homology search found that the same core sequence was also present in 5'-flanking regions of the albumin gene and of some other liver enzyme genes, the expression of which has been reported to be down regulated in some hepatoma cells. Southwestern (DNA-protein) analysis demonstrated that an approximately 35-kDa nuclear protein bound to the silencer element was present in hepatoma cells but not in rat liver cells.

Conversion of 5 alpha-pregnane-3,20-dione, 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 beta-hydroxy-5 alpha-pregnan-20-one to delta 16-C19 steroids by the reconstituted delta 16-C19-steroid synthetase system.

The substrate specificity of the reconstituted delta 16-C19-steroid synthetase system, which catalyzes the formation of 5,16-androstadien-3 beta-ol or 4,16-androstadien-3-one from pregnenolone or progesterone, respectively, was studied. The reconstituted system consisted of a partially purified cytochrome P-450, NADPH-cytochrome P-450 reductase, cytochrome b5 and NADH-cytochrome b5 reductase all from pig testicular microsomes. It was found that 5 alpha-reduced C21 steroids such as 5 alpha-pregnane-3,20-dione, 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 beta-hydroxy-5 alpha-pregnan-20-one can be substrates for the enzyme system, resulting in the formation of 5 alpha-androst-16-en-3-one, 5 alpha-androst-16-en-3 alpha-ol and 5 alpha-androst-16-en-3 beta-ol, respectively. The results suggest that 5 alpha-reduced delta 16-C19 steroids might be synthesized from pregnenolone and progesterone via 5 alpha-reduced C21 steroids as intermediates. The pathways would bypass 5,16-androstadien-3 beta-ol and 4,16-androstadien-3-one which have been assumed as obligatory intermediates in the formation of 5 alpha-reduced delta 16-C19 steroids from pregnenolone and progesterone.

Determination of 17-hydroxyprogesterone in plasma by gas chromatography-mass spectrometry with high-resolution selected-ion monitoring.

A method for determining 17-hydroxyprogesterone in plasma by isotope dilution-mass spectrometry is described. For the internal standard 17-hydroxy [2H4]progesterone is used. Extraction of plasma is followed by conversion into the 3,20-dienol,17-tristrimethylsilyl ether derivative and analysis by capillary gas chromatography-mass spectrometry with selected-ion monitoring, at a resolution of 6000. The lower limit of quantitation was 1 pg, judged from a criterion of a signal-to-noise ratio of 10. The precision and accuracy of the method were satisfactory.

Formation of 5,16-androstadien-3 beta-ol from pregnenolone in human testicular microsomes.

A microsomal fraction of testicular tissue from a patient with prostatic carcinoma was incubated with [4-14C]pregnenolone in the presence of an NADPH-generating system for different periods of time. The metabolites were separated by Sephadex LH-20 column chromatography and then identified by thin-layer chromatography, radio-gas chromatography, and crystallization studies. Pregnenolone was converted to a major metabolite, 5-androstene-3 beta,17 beta-diol via 17-hydroxypregnenolone and then dehydroepiandrosterone. Another major metabolite was 5,16-androstadien-3 beta-ol, which increased with the time of incubation and accumulated in the incubation medium. After 120 min of incubation, 34.6% of the precursor was converted to 5-androstene-3 beta,17 beta-diol and 15.1% to 5,16-androstadien-3 beta-ol. In addition to the above-mentioned steroids, 16 alpha-hydroxypregnenolone, 5-pregnene-3 beta,20 alpha-diol, and 5-androstene-3 beta,17 alpha-diol were identified as minor metabolites of pregnenolone. From these results it was concluded that human testicular microsomes possess enzymic activities for the synthesis of 5,16-androstadien-3 beta-ol, as well as androgens from pregnenolone.

Internal standards for quantitative gas chromatography of individual bile acids after group separation of bile acids in urine.

Sodium glyco-7 alpha,12 alpha-dihydroxy-5 beta-cholan-24-oate, sodium tauro-7 beta,12 beta-dihydroxy-5 beta-cholan-24-oate and disodium glyco-7 alpha,12 alpha-dihydroxy-5 beta-cholan-24-oate 7 alpha-sulphate have been synthesized for the first time. These compounds, together with 7 beta,12 beta-dihydroxy-5 beta-cholan-24-oic acid, which were added to a sample prior to extraction, were found to be useful as internal standards for determination by gas chromatography of individual bile acids in each fraction after group separation of urinary bile acids.