Interleukin-6 and tumour necrosis factor-α cooperatively promote cell cycle regulators and proliferate rheumatoid arthritis fibroblast-like synovial cells.

Objective: To elucidate the roles of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) in cell cycle regulation and proliferation of rheumatoid arthritis fibroblast-like synovial cells (RA-FLSs). Methods: Under stimulation with IL-6/soluble interleukin-6 receptor (sIL-6R) and TNF-α, we examined the expression of cell cycle regulators [p16INK4a, p21Cip1, p27Kip1, cyclin-dependent kinase-4 (CDK4), CDK6, Cyclin D, Cyclin E, and retinoblastoma protein (pRB)] by quantitative polymerase chain reaction, Western blotting, and immunofluorescence staining. The expression of pRB, with or without 10% foetal bovine serum, was examined by Western blotting. DNA synthesis and cell viability were examined by the BrdU assay and WST-8 assay, respectively. After transfection with siRNA/p16INK4a, siRNA/p21Cip1, siRNA/p27Kip1, siRNA/CDK4, or siRNA/CDK6, RA-FLSs were successively stimulated with or without IL-6/sIL-6R or TNF-α to determine cell viability. Results: IL-6/sIL-6R significantly decreased the expression of p16INK4a, and increased p21Cip1, Cyclin E1, CYCLIN D, and pRB. TNF-α decreased the expression of CDK4, and significantly increased p27Kip1, CDK6, Cyclin E1/E2, CYCLIN D, CYCLIN E, pRB, and phosphorylated pRB (phospho-pRB). By immunofluorescence staining, CYCLIN D and phospho-pRB were simultaneously stained in the single cell. In serum-free culture, the expression of pRB was apparently decreased. DNA synthesis and cell viability were significantly increased by IL-6/sIL-6R and TNF-α. Silencing of CDK6 attenuated the cell viability induced by IL-6 and TNF-α. Conclusion: The results indicate that IL-6 and TNF-α interact with each other in regulating the cell cycle and accelerate the proliferation of RA-FLSs.

Selective interference of mTORC1/RAPTOR protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism with Akt and autophagy induction.

OBJECTIVE: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates nutrients to execute cell growth and protein synthesis. We hypothesized that mTOR is essential for the intervertebral disc, the largest avascular, low-nutrient organ. Our objective was to elucidate roles of mTOR signaling in human disc cells. DESIGN: The mTOR exists in two complexes: mTORC1 containing the regulatory-associated protein of mTOR (RAPTOR) and mTORC2 containing the rapamycin-insensitive companion of mTOR (RICTOR). To analyze their functions in human disc nucleus pulposus cells, RNA interference (RNAi) of mTOR targeting mTORC1 and mTORC2, RAPTOR targeting mTORC1, or RICTOR targeting mTORC2 or rapamycin, a pharmacological mTORC1 inhibitor, was applied. First, mTOR signaling including Akt, p70/ribosomal S6 kinase (p70/S6K), and autophagy were assessed. Then, apoptosis, senescence, and matrix metabolism were evaluated under pro-inflammatory interleukin-1 beta (IL-1ß) stimulation. RESULTS: Western blotting showed significant decreases in specific proteins by each RNAi (all P < 0.0001). In mTOR signaling, RNAi of mTOR and RICTOR decreased p70/S6K and Akt phosphorylation, whereas RAPTOR RNAi decreased p70/S6K but increased Akt phosphorylation. All RNAi treatments increased light chain 3 (LC3)-II and decreased p62/sequestosome 1 (p62/SQSTM1), indicating enhanced autophagy. In apoptosis, IL-1ß-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and poly (ADP-ribose) polymerase (PARP) and caspase-9 cleavage decreased by RAPTOR RNAi. In senescence, IL-1ß-induced senescence-associated beta-galactosidase (SA-ß-gal)-positive cells and p16/INK4A expression also decreased by RAPTOR RNAi. In matrix metabolism, RAPTOR RNAi reduced IL-1ß-induced catabolic matrix metalloproteinase (MMP) release and activation and up-regulated anabolic gene expression. These findings were all consistent with rapamycin administration. Additional disc-tissue analysis detected expression and phosphorylation of mTOR-signaling molecules in varying ages. CONCLUSION: Selective interference of mTORC1/RAPTOR protects against inflammation-induced apoptosis, senescence, and matrix catabolism possibly through Akt and autophagy induction in human disc cells.

Attenuation of pain behaviour by local administration of alpha-2 adrenoceptor antagonists to dorsal root ganglia in a rat radiculopathy model.

BACKGROUND: There were several reports suggesting α-adrenoceptor antagonists are effective to treat neuropathic pain. The aims of this study were as follows: (1) to introduce drug delivery system for dorsal root ganglion (DRG) neurons; (2) to elucidate the effects of α-adrenoceptor antagonists in acute, subacute or chronic phase and (3) to determine which subtype of adrenoceptor was mainly involved. METHOD: We used 130 male Sprague-Dawley rats. After root constriction, rats received three local injections of α-adrenoceptor antagonists around DRG. We administered the non-selective α-adrenoceptor antagonist phentolamine for 3 consecutive days from day 0, 4 or 11 after the surgery, and the α1-adrenoceptor antagonist prazosin, the α1-adrenoceptor antagonist silodosin, the more preferred α1-adrenoceptor than prazosin and the α2-adrenoceptor antagonist yohimbine for 3 consecutive days from day 0 after the surgery. RESULTS: Phentolamine and yohimbine continually attenuated pain behaviour. Prazosin at high dose attenuated pain behaviour, however, prazosin at low dose did not attenuate pain behaviour every experimental day. Silodosin had no analgesic effect. Phentolamine injections from day 4 after surgery attenuated pain behaviour that had been established on the 3rd experimental day until the 28th post-operative day, although effect of phentolamine wore off. Phentolamine injections from day 11 after surgery temporarily attenuated pain behaviour that had been established on the 3rd, 7th and 10th experimental days. CONCLUSIONS: This study showed α-adrenoceptor antagonists could suppress pain behaviour via α2-adrenoceptor in acute phase and temporary attenuate pain behaviour in chronic phase. These findings presented potentials sympathetic nerve blockade contributed to treat neuropathic pain.

High CC chemokine receptor 7 expression improves postoperative prognosis of lung adenocarcinoma patients.

BACKGROUND: Chemokines and chemokine receptors not only have significant roles in cancer metastasis and tumorigenesis but also act as antitumour agents. The interaction between the Crk-like adaptor protein (CrkL), which is encoded by the CRKL gene, and non-receptor tyrosine kinase c-ABL is reported to transform many cells into malignant cells. We examined the effects of CC chemokine receptor 7 (CCR7), CCR7 ligands and CrkL and c-ABL in lung adenocarcinoma. METHODS: One hundred and twenty patients with lung adenocarcinoma were included in this historical cohort analysis. We examined CCR7 and CCR7 ligands and CrkL and c-ABL mRNA expressions in surgically resected lung adenocarcinoma specimens and evaluated their contribution to prognosis, and the relationship with epidermal growth factor receptor (EGFR) and TP53 mutations. RESULTS: High CCR7 mRNA expressions indicated better prognoses than those of the groups with low CCR7 mRNA expressions (P=0.007, HR=2.00, 95% CI of ratio: 1.22 -3.31). In lung adenocarcinoma, CrkL and c-ABL mRNAs were related to CCR7 mRNA expression (P<0.0001). CrkL and c-ABL mRNA expressions were influenced by EGFR mutations. A high expression of CCL19 was a good prognostic factor of lung adenocarcinoma. CONCLUSION: We propose that CCR7 and CCL19 are clinically good prognostic factors and that CCR7 is strongly related to CrkL and c-ABL kinase mRNA expression in lung adenocarcinoma.

The relationship between n-3 long-chain polyunsaturated fatty acids and pulse wave velocity in diabetic and non-diabetic patients under long-term hemodialysis. A horizontal study.

BACKGROUND: Diabetes mellitus (DM) and deficiency in n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) are known to increase the incidence of cardiovascular disease (CVD). However, it has not yet been reported whether n-3 LCPUFAs are related to arteriosclerosis in patients under long-term hemodialysis (HD). METHODS: Pulse wave velocity from the brachium to the ankle (baPWV) was measured as a marker of arteriosclerosis with a volume-plethysmographic apparatus in 147 long-term HD patients (non-diabetic (non-DM): 51 males/42 females, 62 +/- 14 y; and DM: 33 males/21 females, 67 +/- 9 y). The fatty acid composition of the total phospholipid fraction from washed RBCs was analyzed by gas chromatography. Analyses were adjusted for age, sex, diastolic blood pressure, pulse, body mass index, duration of HD treatment, smoking status, LDL/HDL-cholesterol ratios and diabetes mellitus (DM). RESULTS: The mean baPWV was 18.9 +/- 5.2 and 23.7 +/- 6.3 m/s in non-DM and DM patients, respectively. The mean baPWV in DM patients was significantly higher than that of non-DM patients after adjustment (p = 0.0002). Multiple regression analysis showed that there was a significant inverse association between baPWV and docosahexaenoic acid (DHA) levels (p = 0.017) and DHA/arachidonic acid (AA) ratios (p = 0.012) in RBC in non-DM patients after adjustment but not in DM patients. CONCLUSIONS: We suggest that n-3 LCPUFAs may be a negative risk factor of CVD also in non-DM HD patients. In DM patients the effects of n-3 PUFAs on the vascular system became undetectable probably because DM overwhelmingly affected PWV. Further studies in a prospective manner are necessary.

A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+ patients.

Chemokines and their receptors are key factors in the onset and progression of AIDS. Among them, accumulating evidence strongly indicates the involvement of IL-8 and its receptors, CXCR1 and CXCR2, in AIDS-related conditions. Through extensive investigation of genetic variations of the human CXCR1-CXCR2 locus, we identified a haplotype of the CXCR1 gene (CXCR1-Ha) carrying two nonsynonymous single nucleotide polymorphisms, CXCR1_300 (Met to Arg) in the N terminus extracellular domain and CXCR1_142 (Arg to Cys) in the C terminus intracellular domain. Transfection experiments with CXCR1 cDNAs corresponding to the CXCR1-Ha and the alternative CXCR1-HA haplotype showed reduced expression of CD4 and CXCR4 in CXCR1-Ha cells in human osteosarcoma cells as well as in Jurkat and CEM human T lymphocytes. Furthermore, the efficiency of X4-tropic HIV-1(NL4-3) infection was significantly lower in CXCR1-Ha cells than in CXCR1-HA cells. The results were further confirmed by a series of experiments using six HIV-1 clinical isolates from AIDS patients. A genetic association study was performed by using an HIV-1(+) patient cohort consisting of two subpopulations of AIDS with extreme phenotypes of rapid and slow progression of the disease. The frequency of the CXCR1-Ha allele is markedly less frequent in patients with rapid disease onset than those with slow progression (P = 0.0003). These results provide strong evidence of a protective role of the CXCR1-Ha allele on disease progression in AIDS, probably acting through modulation of CD4 and CXCR4 expression.

Ghrelin enhances glucose-induced insulin secretion in scheduled meal-fed sheep.

The purpose of this study was to investigate the effects of physiologic levels of ghrelin on insulin secretion and insulin sensitivity (glucose disposal) in scheduled fed-sheep, using the hyperglycemic clamp and hyperinsulinemic euglycemic clamp respectively. Twelve castrated Suffolk rams (69.8 +/- 0.6 kg) were conditioned to be fed alfalfa hay cubes (2% of body weight) once a day. Three hours after the feeding, synthetic ovine ghrelin was intravenously administered to the animals at a rate of 0.025 and 0.05 mug/kg body weight (BW) per min for 3 h. Concomitantly, the hyperglycemic clamp or the hyperinsulinemic euglycemic clamp was carried out. In the hyperglycemic clamp, a target glucose concentration was clamped at 100 mg/100 ml above the initial level. In the hyperinsulinemic euglycemic clamp, insulin was intravenously administered to the animals for 3 h at a rate of 2 mU/kg BW per min. Basal glucose concentrations (44+/- 1 mg/dl) were maintained by variably infusing 100 mg/dl glucose solution. In both clamps, plasma ghrelin concentrations were dose-dependently elevated and maintained at a constant level within the physiologic range. Ghrelin infusions induced a significant (ANOVA; P < 0.01) increase in plasma GH concentrations. In the hyperglycemic clamp, plasma insulin levels were increased by glucose infusion and were significantly (P < 0.05) greater in ghrelin-infused animals. In the hyperinsulinemic euglycemic clamp, glucose infusion rate, an index of insulin sensitivity, was not affected by ghrelin infusion. In conclusion, the present study has demonstrated for the first time that ghrelin enhances glucose-induced insulin secretion in the ruminant animal.

Changes in expression of the genes for the leptin receptor and the growth hormone-releasing peptide/ghrelin receptor in the hypothalamic arcuate nucleus with long-term manipulation of adiposity by dietary means.

Changes in leptin and ghrelin levels occur with alterations in adiposity, but signalling may be affected by levels of the relevant receptors. We measured expression of the leptin receptor (Ob-Rb) and the ghrelin/growth hormone releasing peptide receptor (GHS-R) in the arcuate nucleus of sheep held at either high or low levels of adiposity. Plasma growth hormone (GH) levels were lower in Fat animals and higher in Lean animals. Plasma insulin and leptin levels were higher in Fat animals and lower in Lean animals. Frozen hypothalamic sections of arcuate nucleus were extracted and mRNA levels measured for mRNA for Ob-Rb and GHS-R. Gene expression for both Ob-Rb and GHS-R was higher in Lean animals than in Fat animals, with no difference in expression between Fat and Normal animals. A second group of animals (n = 4 per group) was used for double-labelling immunohistochemistry to determine whether the increase in Ob-Rb gene expression was translated into Ob-Rb protein and to ascertain whether this effect is localised to the cells of the arcuate nucleus that produce either neuropeptide Y (NPY) and/or pro-opiomelanocortin-derived peptides. Lean animals displayed a 255% increase in immunoreactive NPY cells (P < 0.005), a 167% increase in cells with Ob-Rb (P < 0.037) protein and a 344% increase in cells that were staining for both NPY and Ob-Rb (P < 0.02). There was no difference between the Normal and Lean animals in the number of cells that were detected with an adrenocorticotrophic hormone (ACTH) antibody or the number of ACTH-immunoreactive cells that also stained for Ob-Rb. Finally, we measured plasma ghrelin levels in Normal, Fat and Lean ewes (n = 4/group); levels were higher (P < 0.05) in Fat animals than in Lean animals. We conclude that lowering body weight leads to increased expression of Ob-Rb, ghrelin/GHS-R expression and proportion of NPY cells that express Ob-Rb in the arcuate nucleus. This may be an adaptive mechanism to increase responsivity to both leptin and ghrelin.

GH secretory responses to ghrelin and GHRH in growing and lactating dairy cattle.

Release of growth hormone (GH) is known to be regulated mainly by GH-releasing hormone (GHRH) and somatostatin (SRIF) secreted from the hypothalamus. A novel peripheral release-regulating hormone, ghrelin, was recently identified. In this study, differences of the GH secretory response to ghrelin and GHRH in growing and lactating dairy cattle were investigated and an alteration of plasma ghrelin levels was observed. The same amounts of ghrelin and GHRH (0.3 nmol/kg) were intravenously injected to suckling and weanling calves, early and mid-lactating cows and non-lactating cows. Plasma ghrelin levels were also determined in dairy cattle in various physiological conditions. The peak values of ghrelin-induced GH secretion were increased in early lactating cows compared to those in non-lactating cows. The relative responsiveness of GH secretion to ghrelin was also increased compared with that to GHRH in early lactating cows. GH secretory responses to GHRH were blunted in mature cows with and without lactation. Conversely, GHRH-induced GH secretory response was greater than that to ghrelin in calves, and also greater in calves than in mature cows. Plasma ghrelin concentrations were elevated in early lactating cows compared to those in non-lactating cows. Plasma GH concentrations were higher in suckling calves and early lactating cows compared with those in non-lactating cows. These results suggest that GHRH is an effective inducer of GH release in growing calves, and that the relative importance of ghrelin in contributing to the rise in plasma GH increases in early lactating cows.

Effects of ghrelin on food intake and neuroendocrine function in sheep.

Ghrelin, a novel acylated peptide, is the endogenous ligand for growth hormone secretagogue (GHS) receptor. Ghrelin is produced mainly in the oxyntic glands of the stomach, but also produced in the intestines, kidneys, hypothalamus and pituitary gland. Circulating ghrelin levels have been shown to rise before a meal and fall afterwards, suggesting that anticipation of a meal may stimulate secretion. In some species, ghrelin administration has been shown to stimulate growth hormone (GH) secretion, and to cause weight gain by increasing food intake and reducing metabolic utilization of fat. Furthermore, intracerebroventricular and intravascular administration of ghrelin increases gastric acid output in a dose-dependent manner. Thus, ghrelin may play an important role in controlling feeding behavior and energy homeostasis. We have investigated the role of ghrelin in the control of feeding and neuroendocrine function in ruminants using sheep as an experimental model. This mini review describes mechanisms regulating ghrelin secretion at feeding time, and also focuses on the neuroendocrine functions of ghrelin.

A transient ghrelin surge occurs just before feeding in a scheduled meal-fed sheep.

Ghrelin, a gastric-derived peptide, has recently been identified as an endogenous natural ligand for the growth hormone (GH) secretagogue receptor. However, secretory characteristics of ghrelin are still obscure in ruminants. To investigate the diurnal rhythm in ghrelin secretion and its relationship to GH secretion, plasma ghrelin and GH concentrations were determined in Suffolk rams fed with a roughage diet once daily (Experiment 1). Abrupt increases (P<0.05) in plasma ghrelin occurred just before a meal-feeding compared with that at 1h before feeding, then rapidly fell with a minimum during the feeding. A pulsatile surge (P<0.01) in plasma GH concentrations, which seemed to follow a single surge in plasma ghrelin, was observed during the feeding. In Experiment 2, plasma ghrelin and GH were determined in sheep subjected to a pseudo-feeding of 2h to determine whether feed ingestion itself influences ghrelin and GH secretions. Compared with those at 1h before feeding, a tendency of increases (P<0.1) in plasma ghrelin and significant increases (P<0.05) in GH occurred just before and during a pseudo-feeding, respectively. Plasma ghrelin temporally declined within 1h after the start of the pseudo-feeding, and increased again and maintained higher levels during the last period of the pseudo-feeding. These results suggest that the transient surge of ghrelin secretion just before a scheduled meal feeding would not be due to the ingestion of feed, and that a pulsatile increase in plasma GH during the actual- or pseudo-feeding could be induced by the transient ghrelin surge.

Simultaneous resection of pancreas and liver metastases from different metachronous primary cancers.

Resection of a pancreatic head tumor and partial resection of the liver for metastatic lesions were carried out simultaneously in a 72-year-old woman. The patient had a history of two previous operations, right nephrectomy for renal cell carcinoma (clear cell type), done 14 years previously, and an Autincloss procedure for cancer of the left breast (solid tubular carcinoma); (T1N0M0; stage I) done 7 years previously. At the current presentation, preoperative radiographic examination showed a hypervascular tumor in each of the pancreatic and hepatic lesions, but with different patterns. On the basis of histological findings in the two resected specimens, it was difficult to establish whether the hepatic tumor originated from the renal cell carcinoma or the breast cancer, but postoperative immunohistochemical studies for carcinoembryonic antigen (CEA), estrogen receptors, and gross cystic disease fluid protein (GCDFP)-15 showed that the pancreatic tumor had metastasized from the renal cell carcinoma, and the liver tumor from the breast cancer. The immunohistochemical investigation of different markers thus proved to be useful in making the final diagnosis of metastatic lesions from different and metachronous cancers.

Effects of concomitant use of doxifluridine, radiotherapy and immunotherapy in patients with advanced cervical cancer.

Clinical effects of doxifluridine (group A, 600 mg/body/day; group B, 800 mg/body/day) combined with radiotherapy and immunotherapy were evaluated in patients with advanced cancer of the uterine cervix. Response rates were 84.2% (16/19 patients) in group A and 100% (18/18 patients) in group B, respectively (p=0.230). There was no significant difference in adverse reaction incidence between the methods but significantly higher grade adverse reaction were observed in group B than in group A (p=0.048). Time to progression (TTP) was longer in group B than in group A (p=0.081). The optimal 5'-DFUR dose was 800 mg/body (group B), by which higher grade adverse reactions were fully controlled and TTP was prolonged.

Effects of alendronate on bone metastases and hypercalcemia after surgery for hepatocellular carcinoma.

Alendronate, a bisphosphonate compound, lowers serum calcium in patients with cancer-associated hypercalcemia through its inhibitory effect on bone resorption and as a result symptoms associated with hypercalcemia improve. This study was carried out to investigate the effects of alendronate in patients with hypercalcemia due to bone metastasis of hepatocellular carcinoma (HCC). Two patients were evaluated. Their corrected serum calcium and alpha-fetoprotein (AFP) levels and their computed tomography (CT), bone scintigraphy and magnetic resonance imaging (MRI) findings were evaluated before and during alendronate treatment. After treatment, not only the corrected serum calcium levels but also AFP levels and bone pain decreased; in addition, the regression of the metastatic focus was noted in the MRI analysis. These tumor inhibitory effects of alendronate have not been reported in HCC before; and alendronate might serve to prevent bone metastases in patients with HCC. In conclusion, two patients who developed hypercalcemia associated with bone metastasis after surgery for HCC were treated with alendronate and they experienced alleviation of the pain due to bone metastasis, improvement of their quality of life and a marked decrease in AFP levels with tumor regression.

Iron K Line Variability in the Low-Luminosity Active Galactic Nucleus NGC 4579.

We present results of new ASCA observations of the low-luminosity active galactic nucleus (LLAGN) NGC 4579 obtained on 1998 December 18 and 28, and we report on the detection of variability of an iron K emission line. The X-ray luminosities in the 2-10 keV band for the two observations are nearly identical (LX approximately 2x1041 ergs s(-1)), but they are approximately 35% larger than that measured in 1995 July by Terashima et al. An Fe K emission line is detected at 6.39+/-0.09 keV (source rest frame), which is lower than the line energy 6.73+0.13-0.12 keV in the 1995 observation. If we fit the Fe lines with a blend of two Gaussians centered at 6.39 and 6.73 keV, the intensity of the 6.7 keV line decreases, while the intensity of the 6.4 keV line increases, within an interval of 3.5 yr. This variability rules out thermal plasmas in the host galaxy as the origin of the ionized Fe line in this LLAGN. The detection and variability of the 6.4 keV line indicates that cold matter subtends a large solid angle viewed from the nucleus and that it is located within approximately 1 pc from the nucleus. It could be identified with an optically thick standard accretion disk. If this is the case, a standard accretion disk is present at the Eddington ratio of Lbol/LEdd approximately 2x10-3. A broad disk-line profile is not clearly seen, and the structure of the innermost part of accretion disk remains unclear.

Phase II study of irinotecan and cisplatin as first-line chemotherapy in advanced or recurrent cervical cancer.

Irinotecan (CPT-11) and cisplatin are singly active against cervical cancer. We evaluated the efficacy and toxicity of CPT-11 plus cisplatin as first-line chemotherapy in patients with advanced or recurrent cervical cancer. Twenty-nine chemotherapy-naive patients with advanced or recurrent cervical cancer were treated with CPT-11 (60 mg/m(2)) on days 1, 8, and 15 by intravenous infusion over 90 min, followed by cisplatin (60 mg/m(2) i.v.) on day 1 over 90 min. The patients' median age was 57 years (range 35-75). Nineteen patients (66%) had advanced primary disease. Six patients with recurrent disease (21%) had been treated with prior radiotherapy. The remaining 4 patients (14%) had residual or recurrent disease after radical surgery. The histologic diagnoses were squamous cell carcinoma in 25 patients (87%), adenocarcinoma in 3, and adenosquamous cell carcinoma in 1. All eligible patients were included in the toxicity and response analysis based on the intent to treat. Two patients (7%) achieved a complete response and 15 (52%) a partial response (overall response rate: 59%, 95% confidence interval; 41-74%). Stable disease was recorded in 6 patients (21%) and progressive disease in 3 patients (10%). In 3 patients, image-guided evaluation of response was judged to be unfeasible at the time of independent extramural review (10%). The median time to response was 32 days (range 16-62 days). The median survival was 27. 7+ months (range, 6.4-52.8+ months). Two dose-limiting side effects were observed: grade 3 (28%) or 4 (45%) neutropenia and grade 3 (7%) or 4 (7%) diarrhea. Other severe toxicities included anemia (45%), thrombocytopenia (3%), nausea/vomiting (31%), and alopecia (7%). The combination of CPT-11 with cisplatin is an active regimen for treatment of advanced or recurrent cervical cancer albeit with a significant degree of myelosuppression.

Intraoperative microwave coagulation therapy for large hepatic tumors.

We report new surgical techniques for intraoperative microwave coagulation therapy (IMCT), conducted in three patients with large liver neoplasms with poor liver function or difficult tumor location. Anterolateral thoracotomy was performed for tumors in the right lobe to obtain a good operative field. Four electrode needles were inserted for microwave irradiation, with settings of 60 W, 45 s for coagulation and 1 s for dissociation. Clamping of the hepatoduodenal ligament was performed during IMCT. We began the coagulation at the bottom of the tumor, irradiating the tumor and the surrounding parenchyma to create regional necrosis with a safe margin. With these methods, we treated two women diagnosed with large hepatocellular carcinoma with liver cirrhosis and a man with liver metastasis from rectal cancer. The postoperative course of these patients was uneventful. A marked low-density area was seen in the region of therapy and no enhanced findings were observed on enhanced computed tomography postoperatively. However, in one patient, transcatheter embolization (TAE) was performed 1 month postoperatively because recurrence was noted on the bottom of the tumor. Thus, IMCT destroys the peripheral part of the tumor that may remain viable after TAE, but combination therapy with TAE is preferable, especially when a viable part exists within tumors. IMCT is an active, safe, and nontoxic therapeutic modality for large hepatic tumors, and is particularly applicable in patients with large hepatocellular carcinomas and poor liver function.

A phase II trial of docetaxel in platinum pre-treated patients with advanced epithelial ovarian cancer: a Japanese cooperative study.

BACKGROUND: This phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in Japanese patients with advanced ovarian cancer. PATIENTS AND METHODS: Docetaxel was administered at a dose of 70 mg/m2 intravenously to patients with platinum pretreated advanced ovarian cancer. Treatment was repeated every three weeks. No routine corticosteroid premedication was given. RESULTS: Ninety patients with advanced ovarian cancer were entered and sixty were assessable for response. The overall response rate was 28% in the assessable patients (95% confidence interval (95% CI): 17.54%-41.4%). CA125 responses were seen in 8 (24%) of 34 assessable patients for CA125 criteria. The 36 platinum-refractory patients had a response rate of 25% compared with 33% in the platinum-sensitive patients. The predominant toxicity was neutropenia, with 86% of the patients experiencing grade 3 or 4. Hypersensitivity reactions occurred in 37% of the patients and were not life threatening. Edema was mild and infrequent. CONCLUSION: Docetaxel at 70 mg/m2 demonstrated effectiveness as a treatment of both platinum-sensitive and platinum-refractory ovarian cancer patients, with a low incidence of severe hypersensitivity reactions and edema.

Phase II clinical study on the effects of recombinant human interleukin-3 on thrombocytopenia after chemotherapy for advanced ovarian cancer. SDZ ILE 964 [IL-3] Study Group.

The efficacy, safety, and optimum clinical dose of recombinant human interleukin-3 (rhIL-3) was examined in ovarian cancer patients with thrombocytopenia after cancer chemotherapy. In cases with a platelet count < 75,000/mm3 during the control observation period, rhIL-3 was administered subcutaneously at a dose of 5 or 10 micrograms/kg, once a day for 10 days starting from day 4 of the subsequent chemotherapy course. Comparison between the control observation period and the rhIL-3 administration period showed a significant improvement or a tendency toward improvement in increasing the nadir platelet count and the recovery of the platelet count. The major adverse reactions were pyrexia, fatigue, and headache, which were well controlled by the use of antipyretics, analgesics, and antiinflammatory agents. Adverse reactions were for the most part transient and disappeared quickly during or after rhIL-3 administration. Although severe adverse reactions were not observed, the incidence of grade 2 and 3 adverse reactions according to a World Health Organization (WHO) Toxicity Scale were slightly higher in the 10 micrograms/kg/d group. As a consequence, the 5 micrograms/kg/d dose was considered to have a slightly better safety profile than the 10 micrograms/kg/d dose. Although there was no significant difference in the efficacy (the platelet count) between the two doses, the safety profile of the 5 micrograms/kg/d dose was slightly better than the 10 micrograms/kg/d group. Therefore, the 5 micrograms/kg/d was considered to be the optimum clinical dose.

Follow up of women with simple ovarian cysts detected by transvaginal sonography in the Tokyo metropolitan area.

OBJECTIVE: To investigate the management of women with asymptomatic ovarian masses, to determine the appropriate duration of follow up, and to identify diagnostic indicators of growing cysts. DESIGN: Review of women's hospital records. SETTING: Tokyo Metropolitan Cancer Detection Center, Japan. POPULATION: Two hundred and twenty-five pre- and postmenopausal women with a diagnosis of ovarian cyst < 6 cm in diameter and normal serum level of CA125, diagnosed between 1 October 1990 and 25 December 1991. MAIN OUTCOME MEASURE: Change in size of cyst as shown by ultrasound. RESULTS: Seventy-five months after initial diagnosis, 29 (13%) of the masses had progressed, 31 (14%) had persisted, and 165 (73%) had regressed. One hundred and nine masses (48%) had regressed within six months of the initial diagnosis. In univariate analysis transvaginal ultrasonographic assessment of morphology findings, cyst diameter, carcinoembyronic antigen (CEA) and CA19-9 were associated with the prognosis of the cyst. Multivariate regression analysis demonstrated that only the initial serum CA19-9 level and serum CEA level were significant predictors of ovarian masses that regressed (P for trend = 0.004 and 0.02, respectively). CONCLUSION: Simple ovarian cysts in patients with a normal level of CA125 have a low risk for ovarian cancer. Vaginal ultrasound at six months will identify regression of most simple cysts. CA19-9 and CEA at the initial diagnosis are useful parameters to predict future regression of ovarian cysts.