[Risk factor for pancreatic cancer--alcoholic abuse].
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Alcohol Drinking↗
Biomedical subjects
Bunzo Nakata
Publications and source records attributed to Bunzo Nakata.
[S-1+Low-Dose CDDP].
A review of the published literature was undertaken to ascertain the trends in treatment schedules of combination of an oral fluorouracil derivative S-1 with low-dose CDDP (25 mg/m2 or less) for un-resectable and recurrent gastric cancer. The case reports demonstrated as follows: S-1 was given as standard doses of 80-120 mg/body. With regard to CDDP administration, 4 mg/m2 or less was given for 4-consecutive weeks following 2-weeks rest and 6-10 mg/m2 was given for 3-consecutive weeks following 2-weeks rest in the case of 5-day/week CDDP administration. There have been reports of 6-8 mg/m2 CDDP given once or twice a week and weekly CDDP of 10-25 mg/m2 without grade 3 or more adverse events. A phase I study demonstrated the recommend dose of CDDP in the case of 5-day/week was 4 mg/m2 in the regimen of 4-consecutive weeks and 2-weeks rest with a standard dose of S-1. Three phase I studies on weekly low-dose CDDP with S-1 showed the recommend doses were 20-25 mg/m2. S-1+low-dose and a high-dose (30-90 mg/m2) CDDP have come into wide use in Japan. There have been no differences between the case reports and the clinical studies in quantity and quality for both regimens. The unified regimen of S-1+low-dose CDDP as an outpatient based chemotherapy should be developed.
Ambulatory Care↗
Prognostic predictive value of endoscopic ultrasound findings for invasive ductal carcinomas of pancreatic head.
OBJECTIVES: Accurate preoperative prediction of the prognosis of patients with invasive ductal carcinoma of pancreatic head (pancreatic head cancer) is important for selecting treatment methods. We retrospectively examined the prognostic predictive values of endoscopic ultrasound (EUS) findings for patients with this disease. METHODS: The subjects were 66 patients with pancreatic head cancer who had undergone EUS. We examined each EUS finding as a possible prognostic predictor, including heterogeneity of internal echo, irregularity of peripheral echo, clarity of boundary echo, dilatation of the main pancreatic duct (MPD), dilatation of the common bile duct, lymph node swelling, vessel invasion, and the presence of ascites, by univariate and multivariate analysis for survival. RESULTS: Irregular peripheral echo, portal vein invasion, superior mesenteric artery/celiac artery invasion, and the presence of ascites were significant predictors of a poorer prognosis by univariate analysis for survival. In resectable cases, EUS findings of MPD dilatation and portal invasion were significant prognostic predictors by univariate analysis, and MPD dilatation was an independent prognostic predictor by multivariate analysis. CONCLUSION: EUS may be useful for predicting the prognosis of patients with pancreatic head cancer, based on the accuracy it provides in evaluating locoregional spreading.
Adenocarcinoma↗
Caspase-8 is scarcely silenced and its activity is well correlated with the anticancer effect of tumor necrosis factor-related apoptosis-inducing ligand in gastric cancer cells.
The main apoptotic signal stimulated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) streams through caspase-8 activation and evokes caspase-3, a central apoptosis activator. In this study, the status of caspase-8 and -3 in gastric cancer cells related to the anticancer effects of TRAIL was investigated. In the caspase-8 gene promoter, 9 of 10 gastric cancer cell lines harbor no hypermethylation. The pretreatment amounts of caspase-8 and -3 in these cells were not predictors for the anticancer effect of TRAIL. Caspase-8 activity 24 h after treatment with TRAIL was well correlated with the anticancer effect of TRAIL (r=0.777, p=0.0060). Caspase-3 activity 24 h after treatment with TRAIL showed a trend towards an association with the anticancer effect of TRAIL (r=0.544, p=0.1067). These results suggested that gastric cancer might be a good target of TRAIL therapy because the majority of tumor cells have intact caspase-8 expression. The anticancer efficacy may be predicted by the degree of caspase-8 activation after TRAIL treatment.
Apoptosis Regulatory Proteins↗
[A case of anthracycline and taxane-resistant breast cancer with life-thereatening multiple liver metastases responding to oral combination chemotherapy by UFT, cyclophosphamide and medroxyprogesterone acetate].
A 53-year-old woman presented with an advanced right breast cancer together with skin manifestations and massive axillary lymph node metastases, as well as distant metastases in the lung and the liver. The patient received surgery after 6 courses of chemotherapy with epirubicine and intravenous cyclophosphamide (80/600 mg/m2). A weekly paclitaxel regimen (80 mg/m2) was started because the tumor markers increased soon after surgery. Despite chemotherapy, no response was confirmed, then weekly docetaxel (35 mg/m2) was started. Although the tumor markers decreased after administration of docetaxel, severe liver disfunction appeared and did not improve after cessation of docetaxel. Computed tomography (CT) revealed numerous metastatic nodules in the bilateral lobes of the liver. UFT (400 mg/day) and cyclophosphamide (100 mg/day) were administered for 4 weeks followed by 2 weeks cessation and then combined with continuous medroxyprogesterone acetate (800 mg/day). Liver function tests were normalized 3 months after, and the massive metastatic liver tumors disappeared completely. Lung metastasis also subsided. In spite of these good responses, tumor markers did not normalize and skin nodules appeared around the surgical site. Administration was stopped 36 weeks after initiation of the treatment.
Adenocarcinoma, Scirrhous↗
[Changes in tumor marker levels as a predictor of gemcitabine effect on patients with unresectable or recurrent pancreatic cancer].
We studied on possible association between the tumor marker (CEA, CA 19-9, and SPan-1) change and the clinical outcome after treatment with gemcitabine (GEM) in 23 patients with unresectable or recurrent pancreatic cancer. GEM was administered intravenously at a standard dose of 1000 mg/m2 weekly. One course consisted of weekly administration for 3 weeks followed by 1 week's rest. When the adverse effect did not allow the weekly administration, GEM was given bi-weekly without dose modification. Objective responses were evaluated by computed tomography and tumor marker change. Two or more courses were given for only 6 (26.1%) patients. The number of patients, administered GEM 6 or more times including by the weekly and bi-weekly method, was 12 (52.2%). Antitumor effects were evaluable in 16 patients. The clinical efficacies were 1 partial response (PR), 6 stable disease (SD), and 9 progressive disease (PD). Decreases in tumor marker levels were recognized in 9 of the 16 patients. The median survival time (MST) of the PR+NC group was significantly longer than that of the PD group (9 vs 3.5 months; p=0.0151). MST of those in the decreasing tumor marker group was significantly longer than the group with no decreases in the tumor markers (7.0 vs 5.5 months; p = 0.0478). The adverse effects at grade 3 or more were 4 (17.3%) leukopenia, 2 (8.7%) thrombocytopenia, and 1 (4.3%) skin toxicity. In conclusion, the tumor marker change after GEM treatment may be a predictor of preferable prognosis in patients with pancreatic cancer.
Adult↗
[A case of gastric cancer with peritoneal recurrence which developed during adjuvant administration of TS-1 showing complete response by weekly docetaxel regimen].
A 62-year old man had undergone total gastrectomy for Borrmann type 4 gastric cancer. No peritoneal dissemination was observed at the laparotomy. Pathological examination revealed that the tumor involved the subserosal layer, and that the lymph node metastasis extended to the left gastric nodes. Vascular and lymphatic involvement was also observed. One hundred mg/body of TS-1, an oral 5-fluorouracil (5-FU) anticancer agent, which consisted of tegafur (a prodrug of 5-FU), and two modulators (gimeracil and oteracil potassium) was given from the 16th post-operative day. A course of TS-1 consisted of consecutive administration for 4 weeks followed by 2 weeks rest. The patient complained of abdominal fullness after administration of the second course of TS-1. Computed tomography (CT) revealed massive ascites. The serum carcinoembryonic antigen (CEA) titer was elevated to 13.5 ng/ml. From these findings, the occurrence of peritoneal dissemination was suspected. Weekly docetaxel of 30 mg/m2 (40 mg/body) was given for 3 weeks followed by a week cessation. At the start of the 6th course, the serum CEA was normalized, and CT scan detected the disappearance of ascites without any new lesion. Administration of docetaxel was continued until the 10th course then stopped without relapse of the disease. No dose reduction or postponement of administration were required. The patient has survived without disease one year after cessation of the treatment. Weekly docetaxel is a safe and effective regimen for gastric cancer worth using for a second-line therapy after failure of the 5-FU-based regimen.
Adenocarcinoma↗
Combination phase I trial of a novel oral fluorouracil derivative S-1 with low-dose cisplatin for unresectable and recurrent gastric cancer (JFMC27-9902).
PURPOSE: The Japanese Foundation for Multidisciplinary Treatment of Cancer conducted a Phase I study of a novel oral fluorouracil derivative, S-1, combined with a low dose of cisplatin in unresectable and recurrent gastric cancer. EXPERIMENTAL DESIGN: S-1 was administered orally at 80-120 mg/body/day, depending on body surface area. One course consisted of consecutive administration for 28 days followed by a rest of 14 days. Low-dose cisplatin was given i.v. on days 1-5, 8-12, 15-19, and 22-26 of each course. The dose escalation of cisplatin began with an initial dose of 1 mg/m(2)/day as level 1 and was stepped up to 2, 3, 4, and 6 mg/m(2)/day as level 2, 3, 4, and 5, respectively. The regimen was repeated for at least two courses. RESULTS: A total of 24 patients was entered in the study. There was no treatment-related death. At level 5, consisting of 5 evaluable patients, dose-limiting toxicity was experienced as grade 3 appetite loss in 2 patients and grade 4 neutropenia in 1 patient. The maximum-tolerated dose of cisplatin was estimated to be 6 mg/m(2)/day. We decided on a recommended dose of cisplatin of 4 mg/m(2)/day because the dosage was one level under the maximum-tolerated dose. All 3 patients at level 4 showed partial response, suggesting promising clinical efficacy with this dosage. The serum concentration of cisplatin at level 4 was 918 +/- 92 ng/ml on day 26 of the first course. CONCLUSIONS: S-1 with low-dose cisplatin may become an effective regimen with acceptable toxicity for gastric cancer.
Administration, Oral↗
Immunohistochemical assessment for estrogen receptor and progesterone receptor status in breast cancer: analysis for a cut-off point as the predictor for endocrine therapy.
BACKGROUND: An immunohistochemical (IHC) method is commonly used for determining estrogen receptor (ER) and progesterone receptor (PR) status in breast cancer. However, the proper cut-off points of IHC have not been established. Cut-off points for ER and PR status as predictive factors for endocrine therapy are needed. METHODS: A total of 249 cases of female breast cancer were enrolled. ER and PR status by IHC were analyzed using the proportion of stained cells and staining intensity by Allred's score. RESULTS: Proportion score (PS) and intensity score (IS) were related to enzyme immunoassay (EIA) titers, for both in ER and PR (p < 0.0001, all). PS correlated with IS in both ER and PR (R = 0.47 and 0.41, respectively). ER status by IHC was related to tumor size and lymph node status, while PR was related to tumor size and menopausal status. In 152 patients who received endocrine therapy with a median follow-up term of 38 months, differences in disease-free survival were most significant using a cut-off point of PS 3 which indicated more than 10 % of cells stained positively for both ER and PR (p = 0.0007 and 0.0087, respectively). In addition, combination analysis of ER and PR using this cut-off point revealed a notable prognostic difference. CONCLUSION: A 10 % staining proportion may be an acceptable cut-off point for both ER and PR status by IHC, in terms of predicting response to endocrine therapy in breast cancer.
Adult↗
Intraductal papillary-mucinous adenoma developed in the ventral pancreas in a patient with pancreas divisum.
A 34-year-old man was admitted to our hospital with the chief complaints of back pain and epigastralgia. The physical examinations on admission disclosed no abdominal tumor. The serum concentration of total bilirubin was 1.4 mg/dl. The serum elastase-1 level was elevated to 526 ng/dl. Computed tomography showed a cystic lesion, 1 cm in diameter, in the head of the pancreas, without dilatation of the main pancreatic duct. Endoscopic retrograde cholangiopancreatography via the papilla of Vater and the accessory papilla revealed an enlarged ventral pancreatic duct and pancreas divisum. The preoperative diagnosis was mucin-producing pancreatic tumor in the ventral pancreas of a patient with pancreas divisum. A pylorus-preserving pancreatoduodenectomy was performed. The gross findings of the cut surface of the resected specimen disclosed mural nodules in the dilated duct of the ventral pancreas. A histological examination of the mural nodules in the ventral pancreas revealed mucin and intraductal papillary adenoma. Benign tumors associated with pancreas divisum are rare; to the best of our knowledge, only three cases have been reported. Although in these three patients the tumor developed in the dorsal pancreas, the tumor developed in the ventral pancreas in our patient.
Adenoma↗
Differences in dihydropyrimidine dehydrogenase activities between gastric and colorectal cancer.
We studied the relation between clinicopathological factors and dihydropyrimidine dehydrogenase (DPD) activity in gastric and colorectal carcinomas. Specimens obtained by surgery from 27 gastric and 17 colorectal carcinomas and their normal mucosa were examined. The levels of DPD activity in the gastric carcinomas and their normal mucosa were significantly higher than those in colorectal carcinomas and their normal counterparts, respectively (both P's < 0.0001). The gastric carcinomas had significantly higher DPD activities than their normal mucosa (P = 0.028), but the colorectal carcinomas did not. Among the clinicopathological factors, which included invasion/metastatic status and staging, the only effect was that of the histological differences of gastric cancer on DPD activity. That is, the level of DPD activity of the histologically undifferentiated gastric carcinoma was significantly higher than that of the differentiated type. No prognostic predictive values of DPD were recognized in either gastric and colorectal cancer. In conclusion, the higher DPD activity in gastric cancer than colorectal cancer may be due to the higher DPD activity in the background mucosa of origin, and the higher population of undifferentiated type of histological classification, compared to the colorectal counterparts.
Biomarkers, Tumor↗
Phase I/II study of combination therapy of oral fluorinated pyrimidine compound S-1 with low-dose cisplatin in patients with unresectable and/or recurrent advanced gastric cancer: a novel study design to evaluate safety and efficacy.
A phase I/II clinical trial has been planned to evaluate the safety and efficacy of combination therapy of S-1 with low-dose cisplatin in patients with unresectable or recurrent gastric cancer. A new statistically as well as clinically deliberated study design is applied to determine the maximal benefits of combination chemotherapy. This trial uses a 'continual reassessment method' for evaluating toxicity and a "two-stage method" for assessing the response rate to determine the combination that achieves adequate tumor response without toxicity in a high proportion of patients. Three specialized institutions will recruit 10-16 patients for the phase I part of the trial, and 14 institutions, in conjunction with the three specialized ones, will enroll 42 patients for the phase II part. The goal of this trial is to establish a useful chemotherapeutic treatment in an outpatient setting.
Administration, Oral↗
A case of osteoclast-type giant cell tumor of the pancreas with high-frequency microsatellite instability.
It has been reported that osteoclast-type giant cell tumor of the pancreas (OGTP) is rare, with a frequency of only 0.2% of the total reported pancreatic carcinomas. We report herein a rare case of OGTP in a 57-year-old Japanese man. Preoperative examinations showed a solid and cystic tumor, measuring 20 x 15 cm at the pancreas body. The resected specimen was a solid tumor with a giant cyst containing bloody contents. The tumor was composed of a proliferation of mononuclear cells admixed with osteoclast-type giant cells. The tumor cells were immunoreactive for vimentin, alpha1-antitrypsin, and EMA but not for CEA and cytokeratin. These findings indicated that this case was a malignant OGTP. The tumor cells showed microsatellite instability with high frequency (MSI-H). The present patient is alive 3 years after the operation, while OGTP has been reported to have a poor outcome. It has been reported that pancreatic carcinomas with MSI-H status have a favorable outcome. MSI-H might be one of the predictive markers for the long survival in OGTP.
Adult↗
[A case of gastric cancer with umbilical metastasis that responded to TS-1 with low-dose cis-platinum].
An umbilical metastasis of gastric cancer is known as Sister Mary Joseph's nodule. It ordinarily indicates a poor prognosis because umbilical metastasis often develops with peritoneal dissemination. Herein, we report a case of umbilical metastasis of gastric cancer that showed good response to chemotherapy, including the oral anticancer agent TS-1. The patient was a 55-year-old man in which gastric cancer was found by upper gastrointestinal series. Physical examination revealed an umbilical nodule that had an irregular surface and a hard consistency. Ultrasonography showed a 15 x 10 mm hypoechoic mass under the umbilicus. Core needle biopsy of the umbilical mass revealed adenocarcinoma. Peritoneal dissemination was proved by diagnostic laparoscopy. Oral anticancer agent TS-1 was administered with low-dose cis-platinum. The gastric lesion and umbilical nodule showed marked response to the chemotherapy and the response continued for 20 months. The patient died of disease progression 31 months after the initiation of the treatment.
Adenocarcinoma↗
Dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine S-1 may be effective against peritoneal dissemination in gastric cancer.
The effects of a novel oral fluoropyrimidine derivative S-1 on peritoneal metastasis from gastric cancer were investigated. OCUM-2MD3 cells, a highly peritoneal-metastatic cell line, were injected intraperitoneally in nude mice. These mice were allocated to the following three groups (each group, n=10): the S-1 group, to which 10 mg/kg body weight of S-1 was administered per os daily; the FT group, to which 100 mg/kg body weight of tegafur (FT) was administered per os daily; the control group, to which no anticancer drug was administered. Drug administration was starting the day after inoculation. The median survival time of the S-1 group was found to be significantly longer than that of the FT group (30 days vs. 23 days; P<0.005) and the control group (vs. 24 days; P<0.005). The mean values of 5-fluorouracil (5-FU) concentrations in ascites of the S-1 group at 1-4 h were 414-580 ng/ml (n=5), and those of FT group were 70-87 ng/ml (n=5), with significant differences between the two groups at each observation time. The high CDHP concentrations in ascites of the S-1 group were observed at 1-6 h after drug administration. DPD was expressed strongly in fibrous tissue around peritoneal metastasis and weakly in tumor cells of peritoneal metastasis themselves. The high concentrations and long duration of 5-FU in the peritoneal cavity after S-1 administration suggest that S-1 may be effective against peritoneal dissemination. High concentrations of CDHP may prevent 5-FU degradation in peritoneal dissemination and its surrounding fibrous tissue.
Administration, Oral↗
[Combination therapy of a novel oral fluorouracil derivative TS-1 with low-dose cisplatin for recurrent and very advanced gastric cancer].
The case reports and clinical trials on combination therapy of a novel oral 5-fluorouracil derivative TS-1 with low-dose cisplatin for gastric cancer were reviewed. In the majority of the case reports, TS-1 was administered at 80-120 mg/body per day for 4 weeks followed by a rest of 2 weeks. However, in several case reports, TS-1 administration was slightly shortened such as 3 weeks administration followed by a rest of 2 weeks. The administration of cisplatin (CDDP) varied: every day, weekly, bi-weekly, and so on; the doses were from 1 to 25 mg/m2. CDDP was mostly given at 5-10 mg/body 5 days per week, mimicking the low-dose FP (5-fluorouracil+ CDDP). In most case reports, combination therapies were undertaken on an inpatient basis due to frequent administration of CDDP, while the weekly or bi-weekly CDDP administration regimens were done on an outpatient basis. The case reports demonstrated high efficacies and few adverse effects of the combination therapy. Several case reports showed unresectable cases could be operated curatively after the combination therapy. There have been three phase I clinical trials, two of which were regimens on an outpatient basis. JFMC 27-9902, an inpatient-basis phase I clinical trial, consisted of TS-1 at 80 mg/m2 every day and CDDP at low-dose for 5 days per a week: the regimen consisted of 4 weeks administration and 2 weeks' rest. The recommended dose of CDDP was determined to be 4 mg/m2 in the JFMC27-9902 regimen. In the modified JFMC27-9902 regimen, CDDP was given twice a week on an outpatient basis. This new phase I/II clinical trial has been under way since 2003 December. In conclusion, TS-1 + low-dose CDDP combination therapy will be done on an outpatient basis in future, and may be examined as a neoadjuvant therapy as well as a conventional form of chemotherapy.
Administration, Oral↗
Very low incidence of microsatellite instability in intraductal papillary-mucinous neoplasm of the pancreas.
Intraductal papillary-mucinous carcinoma (IPMC) of the pancreas, a new entity of pancreatic cancer with a favorable prognosis, has shown a gradual increase in the number of reported cases. Patients with high-frequency microsatellite instability (MSI-H) tumors have been shown to survive longer than those with low-frequency MSI (MSI-L) or microsatellite stable (MSS) tumors in colorectal and gastric cancer. We investigated whether MSI-H in patients with IPMC can contribute to a good prognosis. The formalin-fixed paraffin-embedded tumors and surrounding normal pancreatic tissues from 10 patients with IPMCs and 16 with intraductal papillary-mucinous adenomas (IPMAs) were provided for DNA extraction after microdissection. Polymerase chain reaction (PCR) was carried out using 8 microsatellite primer marker sets. The mixed PCR samples were analyzed using a genetic analyzer. MSI-H was determined by assessment of microsatellite variations in 3 or more of the 8 tested markers. Immunohistochemical staining of the MSI-responsible proteins hMLH1 and hMSH2 was conducted for both the IPMC and IPMA samples. Ten percent of IPMC harbored MSI-H tumors, whereas no MSI-H tumors were detected in the IPMAs. Thirty percent of IPMC tumors and 25% of IPMA tumors showed MSI-L. All IPMCs and IPMAs showed normal expression of both hMLH1 and hMSH2. MSI-H and loss of hMLH1 and hMSH2 are very rare events in both IPMCs and IPMAs. We conclude that a good prognosis for patients with IPMC is not associated with MSI-H.
Adaptor Proteins, Signal Transducing↗
Prognostic value of microsatellite instability in resectable pancreatic cancer.
The significance of microsatellite instability (MSI) as a prognostic predictor for resectable pancreatic cancer patients was examined. Forty-six histologically confirmed pancreatic cancer patients who had undergone resection were studied. DNA was extracted from the paraffin block sections by means of the microdissection method. PCR was performed using eight microsatellite primer marker sets. The mixed PCR sample was analyzed by a genetic analyzer. The number of MSI-positive patients was eight (17.4%) as determined by assessment of microsatellite variations in three or more of the eight tested markers. Univariate analysis revealed that patients with MSI-positive tumors had significantly longer survival times than patients with MSI-negative tumors, although there were no significant differences in clinicopathological factors between the two groups (median survival term, 62 months versus 10 months, respectively; P = 0.011). According to univariate survival analysis, patients with T3/T4, N1, or M1 tumors, as classified by Union Internationale Contre le Cancer staging, had significantly shorter survival times than patients with less progressive tumors. Multivariate survival analysis indicated that MSI status had an independent predictive value (hazard ratio = 5.577; P = 0.007). The tumor-infiltrating leukocyte intensity in MSI-positive tumors was significantly larger than that in MSI-negative tumors, suggesting that MSI-positive tumors may induce stronger antitumor immunity. In conclusion, a patient with MSI-positive pancreatic cancer may have a comparatively better prognosis after resection, possibly due to intensive immunoreaction to the tumor.
Aged↗