Mediastinal signet-ring cell carcinoma of unknown primary: long-term survival by treatment with S-1, a novel derivative of 5-fluorouracil.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
Yoichi Nakamura
Publications and source records attributed to Yoichi Nakamura.
Serum progastrin-releasing peptide levels followed by whole-body positron emission tomography detects early recurrence of small-cell lung cancer.
A 65-year-old male smoker with severe COPD was diagnosed with limited-stage small-cell lung cancer. After receiving cisplatin/irinotecan, serum progastrin-releasing peptide (ProGRP) levels decreased to within the reference values and the lesions were markedly reduced in size. A whole-body 18F-fluorodeoxyglucose PET (FDG-PET) scan confirmed complete remission. During follow up, serum ProGRP levels increased, and a whole-body FDG-PET scan detected recurrence at the hilar lymph node that had been negative on CT. Complete remission was again achieved with second-line chemotherapy (cisplatin/etoposide) and local irradiation to the hilar lymph node. Monitoring serum ProGRP levels, followed by whole-body FDG-PET when indicated, may improve the clinical management of patients with small-cell lung cancer after initial complete remission.
Aged↗
Effects of exercise frequency on functional fitness in older adult women.
This study evaluated the effects of exercise frequency on functional fitness in older women participating in a 12-week exercise program. Participants (67.8+/-4.6 years) were divided into three different exercise groups (I, II, and III; n=34) and a control group (Group C; n=11). Group I participated in a 90-min exercise program once a week, for 12 weeks, while Group II attended it twice a week, and Group III attended three times a week. The exercise program consisted of a 10-min warm-up, 20 min of walking, 30 min of recreational activities, 20 min of resistance training, and a 10-min cool-down. The following items were measured before and after the program: muscular strength, muscular endurance, dynamic balance, coordination, and cardiorespiratory fitness (6-min walking distance). Comparisons of baseline and post-intervention measures showed significantly greater improvements in body weight, coordination, and cardiorespiratory fitness for Group III compared to the other groups (p<0.05). In addition, the greatest improvements in body fat, muscular endurance, and dynamic balance were also observed in Group III (p<0.05). However, no significant differences were found in muscular strength. Older women who participate in an exercise program three times a week gain greater functional fitness benefits than those who exercise less frequently. In order to improve functional fitness in older women, an exercise frequency of at least three times each week should be recommended.
Activities of Daily Living↗
A case of spontaneous splenorenal shunt associated with splenic artery aneurysm.
A case of large spontaneous splenorenal (S-R) shunt accompanied with splenic artery aneurysm is reported in this paper. The large blood vessel, a shunt, anatomizing the splenic vein and left renal vein is macroscopically found during the autopsy of a 71-year-old male, accompanied with liver cirrhosis and splenomegaly. Though there are many reports demonstrating medical imaging, anatomical findings are relatively poor besides describing and illustrating the appearances of the S-R shunt, the splenic artery aneurysm and related branches of the splenic vein and left renal vein, the embryologic and pathogenetic origins of these anomalies are also discussed with the description of the relationship between the S-R shunt and the splenic artery aneurysm.
Aged↗
Long-term survival in three patients with metastatic non-small cell lung cancer treated with gefitinib.
Gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), produces radiographic regression and symptom relief in patients with refractory advanced non-small cell lung cancer. However, it remains controversial whether gefitinib improves patient survival. We report three cases of refractory metastatic non-small cell lung cancer who have survived approximately 3 years since they first started gefitinib. These long-term survivors were Japanese female non-smokers with adenocarcinoma, who often had multiple lung metastases and were effectively re-treated with gefitinib. One patient had a surgical specimen available for DNA extraction and showed deletions in exon 19 of EGFR. Our experience suggests that gefitinib may improve long-term survival in selected patients. Further studies are required to identify biomarkers downstream of the EGFR mutations that are involved in multiple lung metastases and which could identify those patients who may benefit from gefitinib re-treatment.
Aged↗
BCRP/ABCG2 levels account for the resistance to topoisomerase I inhibitors and reversal effects by gefitinib in non-small cell lung cancer.
PURPOSE: Breast cancer resistance protein (BCRP) confers resistance against topoisomerase I inhibitors in cancer cells. Very recently, we reported that gefitinib reverses BCRP-mediated drug resistance by direct inhibition. However, it remains undetermined how much BCRP contributes to the resistance to topoisomerase I inhibitors in non-small cell lung cancer (NSCLC). The present study was designed to examine whether BCRP levels in NSCLC cells are correlated with the resistance to topoisomerase I inhibitors and the reversal effect by gefitinib. METHODS: BCRP levels and its function were evaluated by Western blotting and flowcytometry, respectively. Gefitinib-insensitive NSCLC cells expressed various levels of BCRP, which were closely correlated not only with the IC50 values of SN-38 (r=0.874, P<0.05) and those of topotecan (r=0.968, P<0.001), but also with the reversal effects of 1 microM gefitinib on SN-38 resistance (r=0.956, P<0.001) and topotecan resistance (r=0.977, P=0.0001). RESULTS: BCRP levels accounted for between 80 and 90% of the variation in the resistance to topoisomerase I inhibitors and the reversal effects by gefitinib. Also, gefitinib increased intracellular topotecan accumulation in proportion to the BCRP levels. CONCLUSIONS: These findings suggest that BCRP is the most important molecule responsible for topoisomerase I inhibitor resistance, and that the development of BCRP inhibitors is an effective approach for overcoming this resistance. In addition, the examination of BCRP levels in NSCLC tissues may identify an optimal patient population for treatment with topoisomerase I inhibitors alone or in combination with BCRP inhibitors.
ATP Binding Cassette Transporter, Subfamily G, Mem↗
Questionnaire on perioperative antibiotic therapy in 2003: postoperative prophylaxis.
We distributed a questionnaire to institutions accredited by the Japan Surgical Society asking about the use of antibiotics in digestive tract surgery in Japan in 2003, and compared the results with those of a similar questionnaire distributed in 1993. The period of antibiotic administration for esophageal resection was at least 6 days in 64.9% of the 1993 questionnaire responses, but less than 4 days in 60.4% of the present questionnaire responses. For distal gastrectomy, antibiotics were given for 5 days postoperatively at 53.0% of the responding institutions in the 1993 survey, but for only 3 days, at 72.4%, in the present survey. An oral antibiotic was given as part of antibacterial colon preparation before colon resection at 70% or more of the institutions in the 1993 survey, while no antibiotic colon preparation was given at 80% of the institutions in the present survey. The period of antibiotic administration for laparoscopic cholecystectomy was at least 4 days in 72% of the institutions in the 1993 survey, but this decreased remarkably to fewer than 2 days at 80.8% of the institutions in the current survey. There were no differences in the selection of antibiotics between the two surveys. The period of antibiotic administration has decreased remarkably in the last decade.
Anti-Bacterial Agents↗
Left testicular artery arching over the ipsilateral renal vein.
AIM: To report two cases of the left testicular artery arching over the left renal vein (LRV) before running downward to the testis. METHODS: The subjects were obtained from two Japanese cadavers. During the student course of gross-anatomical dissection, the anatomical relationship between the testicular vessels and the renal vein was specifically observed. RESULTS: The arching left testicular artery arose from the aorta below the LRV and made a loop around the LRV, which appeared to be mildly compressed between the arching artery and the psoas major muscle. CONCLUSION: Clinically, compression of the LRV between the abdominal aorta and the superior mesenteric artery occasionally induces LRV hypertension, resulting in varicocele, orthostatic proteinuria and hematuria. Considering that the incidence of a left arching testicular artery is higher than that of a right one, an arching left artery could be an additional cause of LRV hypertension.
Aged, 80 and over↗
[A case of "late-onset" anaphylaxis caused by fermented soybeans; Natto].
Natto is a Japanese traditional food made from fermented soybeans. We report a case of anaphylaxis caused by natto and review the literature. The patient was a 22-year-old man who showed systemic eruption with itching and pectoralgia about 10 hours after eating a meal containing natto. Results of skin tests for soybean allergen were negative, and the allergen remained unidentified. We then used a food elimination trial to confirm the allergy. However the patient did not refrain from eating natto, and he had three anaphylactic reactions might have been caused by natto. Each event occurred 10 to 14 hours after he ate a meal containing natto. We performed detailed examinations to determine the allergen. First, the prick-by-prick tests with natto and its characteristic viscous yarn-like surface were done and yielded positive results. Next, a provocation test with commercial natto (50 g) was performed and caused systemic eruption and pectoralgia about 9 hours after ingestion of the natto. The patients'plasma histamine level was elevated during the anaphylactic event. Anaphylaxis caused by natto was diagnosed. Recent studies have shown that the anaphylaxis caused by natto is of late-onset. Late-onset anaphylaxis can be considered one of IgE-mediated allergic reactions. The viscous surface of natto contains poly-gamma-glutamic acid (PGA). The hypothesized mechanism of late-onset anaphylaxis is delayed absorption or release of PGA into the bowel. In our case, the patient ate heated natto, we therefore speculate that suspect allergens were heat resistant. Patients with natto allergy must not eat natto, whether or not it is cooked or heated. Natto may induce allergic reactions up to a half-day after ingestion; thus, the clinical course and patient's diet must be considered during medical examination. Natto has recently gained popularity as a health food in foreign countries. The existence or natto allergy should be more widely recognized.
Adult↗
[A case of advanced gastric cancer--efficacy of combination therapy of doxifluridine and weekly paclitaxel].
A 65-year-old man underwent distal gastrectomy for advanced gastric cancer. Histological examination revealed that a lymph node metastasis extended to the para-aortic nodes. After operation, he was treated with TS-1 as first-line chemotherapy. After 10 months of the first-line chemotherapy, the lymph node swelling increased in size, and new lesions were detected. Then, the patient was treated by combination therapy of doxifluridine and weekly paclitaxel. Weekly paclitaxel administration (PTX 80 mg/m(2), 2 consecutive weeks, 1 week break) and oral administration of doxifluridine (600 mg/m(2), 14 consecutive days) were performed as the second-line chemotherapy. After 2 courses, abdominal CT scan showed a remarkable reduction of the para-aortic lymph nodes. The second-line chemotherapy was continued until the 7th course, then stopped without progression of the disease, and the patient maintained good quality of life. PTX/5'-DFUR combination therapy was thought to be an effective chemotherapy for advanced gastric cancer.
Adenocarcinoma↗
Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice.
BACKGROUND/AIMS: Mutations in SLC25A13, encoding the mitochondrial aspartate-glutamate carrier citrin, cause adult-onset type II citrullinemia (CTLN2) in humans. We have previously reported that although citrin-knockout (Ctrn-/-) mice fail to display symptoms of CTLN2, liver perfusion revealed a deficit in ureogenesis from ammonia accompanied by an increase in the perfusate lactate-to-pyruvate (L/P) ratio. The present study explores the effects of pyruvate, aspartate and citrate on improving the abnormalities observed in the Ctrn-/- liver. METHODS: We measured the rate of ureogenesis from ammonium chloride using the liver-perfusion system. RESULTS: Pyruvate infusion lowered the L/P ratio and corrected the deficit in ureogenesis in the Ctrn-/- liver. This effect was found to be dose-dependent in both instances. Phenazine methosulfate, a cytosolic oxidant, also improved the rate of ureogenesis in the Ctrn-/- liver and led to a fall in the L/P ratio. The addition of aspartate or citrate did not change either the rate of ureogenesis or the L/P ratio in the Ctrn-/- liver. CONCLUSIONS: Citrin deficiency disturbs urea synthesis primarily as a result of an elevated cytosolic NADH/NAD+ ratio owing to limited reoxidation of reducing equivalents. Clinically, pyruvate may have a therapeutic benefit for CTLN2 patients.
Amino Acids↗
Apparent presence of Ser133-phosphorylated cyclic AMP response element binding protein (pCREB) in brain mitochondria is due to cross-reactivity of pCREB antibodies with pyruvate dehydrogenase.
Cyclic AMP response element binding protein (CREB) is a constitutive transcription factor that activates transcription following stimulus-dependent phosphorylation at Ser133, implicated in synaptic plasticity and neuronal survival pathways. The prevailing view that CREB is exclusively nuclear has been questioned by several studies, and, for example, mitochondrial localization has been reported. Using subcellular fractionation of rat brain cortex coupled with western immunoblotting with Ser133-phospho-CREB (pCREB) antibodies, we found a robust pCREB immunoreactivity (IR) in mitochondria-enriched fractions. The pCREB antibodies also stained the mitochondria, in addition to nuclei, of glial cells in primary cortical cultures. However, two CREB antibodies against different epitopes and gel shift assay detected the CREB protein mainly in the nuclear fraction. The two-dimensional electrophoretic mobility of mitochondrial pCREB IR differed markedly from the nuclear CREB/pCREB IR, indicating that the pCREB antibody cross-reacts with another mitochondrial protein. Immunoprecipitation of the mitochondrial pCREB IR produced three bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, which were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry as E2, E1 alpha-subunit, and E1 beta-subunit of pyruvate dehydrogenase complex. The cross-reacting epitope was identified as phospho-Ser300 of the alpha-subunit. In conclusion, this study confirms the presence of pCREB-like IR in brain mitochondria that, after careful scrutiny, turned out to be pyruvate dehydrogenase rather than authentic CREB.
Adenosine Triphosphate↗
Human airway trypsin-like protease stimulates human bronchial fibroblast proliferation in a protease-activated receptor-2-dependent pathway.
Human airway trypsin-like protease (HAT) was isolated from airway secretions and localized to bronchial epithelial cells by immunohistochemistry. In the present study, we examined whether HAT could stimulate DNA synthesis and proliferation of primary human bronchial fibroblasts (HBF). HAT significantly stimulated the proliferation of HBF by 20-55%, a level similar to that of the mitogenic activity of lung mast cell tryptase (MCT). HAT also stimulated the incorporation of [3H]thymidine in HBF, and this HAT-induced DNA synthesis was abolished by leupeptin. Protease-activated receptor-2 (PAR-2) mRNA was expressed and localized to the cell surface in HBF. PAR-2 activating peptide (AP) also enhanced DNA synthesis, and both HAT and PAR-2 AP induced receptor internalization, similar to the response to trypsin. Pretreatment of HBF with anti-PAR-2 antibody significantly suppressed both HAT and PAR-2 AP-induced DNA synthesis. In addition, HAT and PAR-2 AP induced intracellular Ca2+ mobilization in HBF. The HAT-induced increase in Ca2+ was desensitized by pretreatment with trypsin or PAR-2 AP. U0126, a specific MAPK inhibitor, completely inhibited HAT-induced DNA synthesis as well as HAT-induced phosphorylation of MAPK. The effect of HAT and MCT together was additive, whereas the effect of HAT and insulin together on HBF DNA synthesis was synergistic. These results indicate that HAT stimulates fibroblast proliferation in bronchial airways through a PAR-2-dependent MEK-MAPK mediated pathway and that HAT is linked to airway processes involving fibroblasts.
Aged↗
Potentiation by high potassium of lipopolysaccharide-induced nitric oxide production from cultured astrocytes.
Uptake of K+ is an important role of astrocytes to maintain physiological lower extracellular K+ concentration in the CNS. In this study, the effect of high K+ concentration was examined on the cellular function of astrocytes from embryonic rat brain in primary culture. Nitric oxide (NO) production induced by lipopolysaccharide (LPS) was measured as an index of cellular function of astrocytes. Increasing KCl concentration to about 40 mM did not directly evoke NO production, but doubled the level of LPS (1 ng/ml)-induced NO production. K-gluconate showed a similar enhancing effect although the degree of enhancement was about half of that of KCl. Neither NaCl nor Na-gluconate showed any effect. The K(+)-channel blocker, 4-aminopyridine, but not tetraethylammonium or apamin, inhibited the enhancing effect of KCl. The LPS-induced iNOS protein expression determined by immunoblotting analysis was enhanced by high K+ treatment. The level of iNOS mRNA determined by real-time RT-PCR technique was also augmented by the presence of 40 mM KCl. These results indicate that the elevation of extracellular K+ concentration regulates astrocytic cell functions through a mechanism involving K(A)-type K(+)-channels and that potentiation of NO production by high K+ is due to the augmentation of iNOS mRNA and iNOS protein levels.
4-Aminopyridine↗
Oxygen atom transfer reactions from dioxygen to phosphines via a bridging sulfur dioxide in a trinuclear cluster complex of rhenium, [(Ph(3)P)(2)N][Re(3)(mu(3)-S)(mu-S)(2)(mu-SO(2))Cl(6)(PMe(2)Ph)(3)].
A trinuclear rhenium sulfide cluster complex, [(Ph(3)P)(2)N][Re(3)(mu(3)-S)(mu-S)(3)Cl(6)(PMe(2)Ph)(3)], synthesized from Re(3)S(7)Cl(7), dimethylphenylphosphine, and [(Ph(3)P)(2)N]Cl is readily converted to a bridging SO(2) complex, [(Ph(3)P)(2)N][Re(3)(mu(3)-S)(mu-S)(2)(mu-SO(2))Cl(6)(PMe(2)Ph)(3)], by reaction with O(2). The oxygen atoms on the SO(2) ligand react with phosphines or phosphites to form phosphine oxides or phosphates, and the original cluster complex is recovered. The reaction course has been monitored by (31)P NMR as well as by UV-vis spectroscopy. The catalytic oxygenation of PMePh(2) in the presence of the SO(2) complex shows that turnovers are 8 per hour at 23 degrees C in CDCl(3). The X-ray structures of the cluster complexes are described.
Journal Article↗
Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance.
Gefitinib ("Iressa", ZD1839) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, and the single agent is clinically effective in non-small cell lung cancer. Although gefitinib combined with various cytotoxic agents has been reported to enhance cytotoxicity in vitro and in mouse models, the mechanism remains undetermined. Here, to explore the mechanism with topoisomerase I inhibitors, we focused on the efflux pump of the breast cancer resistance protein (BCRP/ABCG2), and then examined whether gefitinib restored drug sensitivity in multidrug-resistant cancer cells overexpressing BCRP. We used PC-6 human small cell lung cancer cells and multidrug-resistant PC-6/SN2-5H cells selected with SN-38 of the active metabolite of irinotecan, and BCRP-overexpressing MCF-7/MX cells selected with mitoxantrone and BCRP cDNA transfectant MCF-7/clone 8 cells. Drug sensitivity against anticancer drugs was determined by tetrazolium dye assay, and intracellular topotecan accumulation by FACScan. The topotecan transport study was done using the plasma membrane vesicles of PC-6/SN2-5H cells. The resistant PC-6/SN2-5H cells overexpressed BCRP but not epidermal growth factor receptor mRNA. Ten micromoles of gefitinib reversed topotecan, SN-38, and mitoxantrone resistance, and increased the intracellular topotecan accumulation in the resistant cells but not in the parental cells. Furthermore, gefitinib inhibited the topotecan transport into the vesicles, and the K(i) value was 1.01 +/- 0.09 micromol/L in the Dixon plot analysis, indicating direct inhibition of BCRP by gefitinib. However, gefitinib was not transported into the vesicles with the high-performance liquid chromatography method. These results indicate that gefitinib reverses BCRP-mediated drug resistance by direct inhibition other than competitive inhibition as a BCRP substrate. Combination of gefitinib and topoisomerase I inhibitors could be clinically effective in cancers expressing BCRP.
ATP Binding Cassette Transporter, Subfamily G, Mem↗
Self-expandable metallic stent placement for palliation in gastric outlet obstructions caused by gastric cancer: a comparison with surgical gastrojejunostomy.
BACKGROUND: In patients with gastric outlet obstruction (GOO), palliative enteral stenting is a less invasive procedure compared with gastroenterostomy. Most diseases analyzed in previous studies of such stenting were pancreaticobiliary malignancies. METHODS: We reviewed the medical records of patients with GOO secondary to gastric cancer who were admitted to our institution between September 1994 and September 2004. The outcome of stent placement for GOO was compared with the outcome in patients who underwent palliative open gastrojejunostomy during the same period. Enrolled patients from both groups displayed symptomatic GOO. Patients with recurrent gastric cancer were excluded from this study. RESULTS: Twenty-two patients underwent palliative enteral stenting, and 22 patients were subjected to surgical gastrojejunostomy (bypass). There were no significant differences between the two groups regarding patient baseline characteristics. Technical success and clinical success were obtained in 100% and 77.3%, respectively, of both groups. The operating time was shorter in the stent group (30 vs 118 min; P<0.0001). The time from the procedure to the resumption of food intake was shorter in the stent group than in the bypass group (2 days vs 8 days; P<0.0001). An improvement in performance score after the procedure was observed in both groups (stent group; P=0.0264; bypass group; P=0.0235). No significant differences were observed regarding the possibility of discharge. In patients discharged, the median postoperative hospital stays were 19 days and 28 days (P=0.0558). The median survival periods were 65 days and 90 days. Minor complications were observed in 1 patient in the stent group and in 4 in the bypass group. No mortality or severe complications were observed for either group. CONCLUSIONS: Self-expandable metallic stent placement is a safe and efficacious procedure for palliation, with shorter operating time and more prompt restoration of oral intake, compared to surgical alternatives in patients with GOO caused by gastric cancer.
Aged↗
Drug susceptibility of isolates from severe postoperative intraperitoneal infections causing multiple organ failure.
PURPOSE: To select the most appropriate antibiotic regimens for life-threatening postoperative infections, we obtained isolates from patients with severe postoperative infections over a 12-year-period, and examined their drug susceptibility. METHODS: The subjects of this study were 55 patients with multiple organ failure (MOF) caused by postoperative infection. RESULTS: All strains of Methicillin-resistant Staphylococcus aureus (MRSA) were susceptible to Vancomycin (VCM) and Teicoplanin (TEIC). Only 0.3% of all the Pseudomonas aeruginosa strains were resistant to Imipenem (IPM), but 53.6% of the strains from the severe infections were resistant to IPM. On the other hand, there were few P. aeruginosa strains resistant to Meropenem (MEPM), Ceftazidime (CAZ), Ciprofloxacin (CPFX), and Pazufloxacin (PZFX), even among strains isolated from severe infections. The resistant rate of Bacteroides fragilis to Clindamycin (CLDM) was 35.9%, but there were strains resistant to IPM and Panipenem. CONCLUSION: These findings suggest that VCM or TEIC are most appropriate for severe abdominal abscess caused by MRSA, whereas MEPM, CAZ, CPFX, and PZFX are more effective against P. aeruginosa infections. The only antibiotic effective against B. fragilis infections in this study was IPM.
Abdominal Abscess↗