Transforming growth factor-beta1 induced hepatocyte apoptosis--a possible mechanism for growth of colorectal liver metastasis

The mechanisms of colonization and growth of metastatic liver tumors from colorectal cancers remain obscure. Forty-three resected colorectal metastatic liver tumors with surrounding livers were evaluated for apoptotic index (AI), proliferation index (PI), and immunohistochemical expressions of TGF-beta1. TGF-beta receptor II, Fas, and Fas-ligand. All the parameters were significantly higher in the peri-tumoral livers than in the tumors with the exception of PI, which was significantly high in tumors. Enhanced TGF-beta1 expression was noticed at the interface between the metastatic tumor and the adjacent liver parenchyma. The AIs of hepatocytes in the TGF-beta1-positive areas (8.7 +/- 7.5%, n = 43) were significantly higher when compared with those in the TGF-beta1-negative areas (2.4 +/- 4.5%, n = 42) (p < 0.001). However, the same kind of correlation could not be found in metastatic tumors. The enhanced expression of TGF-beta1 and hepatocyte apoptosis in the peri-tumoral liver parenchyma may suggest that TGF-beta1 plays a substantial role in the development of colorectal liver metastasis.     

Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation

We investigated the biological effects of the active oxygen produced by P450s. First, we identified which isoforms of P450 efficiently produced active oxygen using electron spin resonance. Eight forms of P450 purified from rat liver were used. Of these, CYP1A2, 2B1, 2C11 and 3A2 produced hydroxyl radicals efficiently. Phenobarbital (PB) which is a typical inducer of CYP2B1 and 3A2 induced production of hydroxyl radicals by rat liver and ketoconazole, an inhibitor of P450, inhibited production of hydroxyl radicals in vitro. PB is a tumor promoter as well as the P450-inducer. We investigated oxidation of the genomic DNA by the hydroxyl radicals produced by PB-inducible P450 in vitro and in vivo. 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation in vivo was assayed by HPLC. PB strongly induced the production of 8-OHdG in the rat liver. While ketoconazole inhibited the production of 8-OHdG in vivo. These results suggest that active oxygen produced by P450 oxidized genomic DNA and induction of P450 increased oxidative stress that may contribute to tumor initiation and promotion.     

S-1-induced, prolonged complete regression of lung metastasis from gastric cancer refractory to 5'-DFUR: a case report with pharmacokinetic study

S-1 is an oral fluoropyrimidine reported to be most active for gastric cancer. However, few studies have documented a complete response (CR) of lung metastasis to S-1 treatment. We describe a 66-year-old woman in whom S-1 induced complete regression of lung metastasis from gastric cancer, that had been refractory to another oral fluoropyrimidine, 5'-deoxy-5-fluorouridine (5'-DFUR). After preoperative chemotherapy with a combination of etoposide, adriamycin and cisplatin and with methotrexate plus 5-fluorouracil, the patient underwent a total gastrectomy with lower esophagectomy for advanced diffuse-type gastric cancer with invasion of the esophagus in May 1993. She received postoperative adjuvant chemotherapy with 5'-DFUR (600 mg/day) for 3 years. However, a solitary metastasis to the left lung was detected in November 1996 and she underwent partial resection of the left lung. Chemotherapy with 5'-DFUR was reinitiated after operation, but re-metastasis to the left lung with elevation of the serum carcinoembryonic antigen (CEA) level was diagnosed in June 1999. Treatment with S-1 was started in August. S-1 was given orally in a dose of 100 mg/day for 28 consecutive days, followed by a 14-day recovery; treatment was repeated every 6 weeks. The metastatic lesion in the left lung completely regressed after two courses of S-1 and the serum CEA level returned to the normal range. The patient received a total of 10 courses of S-1. The dose of S-1 was reduced to 80 mg/day from the sixth course because of grade 2 skin rash. Pharmacokinetic studies after administration of S-1 revealed high and prolonged plasma 5-FU levels. Nearly 4 years have passed since complete regression of the lung metastasis. This may be the first report to document a prolonged complete response of lung metastasis from gastric cancer induced by single-agent chemotherapy with S-1.     

The use of artificial neural network analysis to improve the predictive accuracy of prostate biopsy in the Japanese population

OBJECTIVE: We examined the efficacy of an artificial neural network analysis (ANNA) based on parameters available from previously existing examinations for improving the predictive accuracy of prostate cancer screening in the Japanese population. METHODS: Two hundred and twenty-eight patients with prostate-specific antigen (PSA) of 2-10 ng/ml were enrolled in this study. Two artificial neural network analysis (ANNA) models were constructed: ANNA1 with patient age, total PSA, free to total PSA ratio, prostate volume, transition zone volume (TZ), PSA density (PSAD) and PSA-TZ density (PSATZ) as input variables, and ANNA2 with presumed circle area ratio (PCAR), digital rectal examination (DRE) findings and chief complaint added as variables. The predictive accuracies of the ANNA models were compared with conventional PSA and volume-related parameters and a logistic regression (LR) model by receiver operating characteristic (ROC) curve analysis. RESULTS: Of 228 patients, 58 (25.5%) were diagnosed with prostate cancer. While ANNA2 had a slightly larger area under the curve (AUC) than ANNA1 (0.782 versus 0.793, P = 0.8477), the AUC of ANNA2 was significantly greater than those of ln(PSA), PSAD, PSATZ and free to total PSA ratio (P = 0.0004, 0.0230, 0.0304, and 0.0037, respectively). The accuracy of ANNA2 was significantly better than that of LR analysis at 90 and 95% sensitivity levels (P = 0.0051 and P < 0.0001, respectively). At 95% sensitivity level, ANNA2 reduced unnecessary biopsies by 40.0% with a negative predictive value of 95.7%. CONCLUSIONS: To determine the indication of prostate biopsy for PSA value in the range of 2-10 ng/ml, the ANNA model has the possibility to reduce unnecessary biopsies without missing many cases of cancers.     

Recurrent ovarian cancer with cancer peritonitis treated with weekly paclitaxel infusion--a clinicopharmacological study

We treated a patient with recurrent ovarian cancer with cancerous peritonitis by weekly paclitaxel (w-TXL) therapy (65 mg/m2). Abdominocentesis was not performed to eliminate ascites, in order to maintain higher quality of life (QOL), and critical adverse reaction was not seen for 12 months. We measured the TXL concentration in blood plasma and ascites after TXL infusion by HPLC method. The TXL titer in plasma was 427 ng/ml after infusion, 23 ng/ml after 24 hours and under 10 ng/ml after 48 hours. The TXL titer in ascites was 41 ng/ml after infusion, 37 ng/ml after 6 hours, 18 ng/ml after 12 hours, 10 ng/ml after 24 hours and under 10 ng/ml after 48 hours. TXL transportation from blood to ascites was good. This result suggested that intravenous infusion of TXL was effective for cancerous peritonitis treatment.     

Intrahepatic arterial chemotherapy with 5-fluorouracil and intramuscular interferon-alpha for a patient with diffuse type of hepatocellular carcinoma

We report a case of diffuse type advanced hepatocellular carcinoma (HCC), which was successfully treated by a combination therapy of interferon-alpha (IFN) and 5-fluorouracil (5-FU). A 74-year-old man underwent distal gastrectomy 6 years ago for gastric cancer. In April 2002, an increased serum alpha-feto-protein (AFP) level was noted and a computed tomography (CT) of the abdomen revealed a diffuse type of HCC. He was treated with a combination therapy of IFN (5x10(6) units/body i.m., days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26) and 5-FU (500 mg/body/day i.a., days 1-5, 8-12 continuously). The treatment was repeated every 4 weeks with a maximum of five cycles. After 5 cycles, serum AFP levels fell from 665 ng/ml to a normal level. CT showed a reduced size of the tumor. He has been well and continue to receive IFN (3x10(6) units/body i.m., two times a week) and 5-FU (500 mg/body/day i.a., once a week) at the outpatient clinic for the last 16 months.     

A case of postoperative pelvic metastasis and multiple liver metastases of the rectal cancer successfully treated by arterial infusion therapy with 5-FU/leucovorin

A 55-year-old man underwent a rectal amputation for rectal cancer in 1994. As the tumor marker was elevated in 2002, we performed an abdominal CT scan and detected local and multiple liver recurrences. We treated the patient with intra-arterial infusion of 5-FU/LV via the internal iliac artery and the hepatic artery. The chemotherapy was performed on a weekly basis; it consisted of 5-FU (500 mg/body), administered for 5 hours to bilateral reservoirs through an infusion pump and l-leucovorin (400 mg/body), administered intravenously for 2 hours. After 18 administrations of this regimen during a hospital stay and after a discharge from the hospital as an outpatient, the multiple liver metastases that were observed have disappeared. Further, the local recurrences showed a partial reduction in tumor size with a decrease in perineal pain. Subsequently, the patient did not require further doses of morphine. He exhibited no severe side effects except for grade 1 nausea, and his QOL was also good. Therefore, local intra-arterial infusion chemotherapy with 5-FU/LV appears to have been effective for rectal cancer recurrences.     

Utility of dopa decarboxylase as a novel marker for the detection of peritoneal micro-metastases of gastric cancer with realtime RT-PCR

We have examined the utility of DDC as a novel marker for the detection of peritoneal micrometastases of gastric cancer. DDC mRNA in the peritoneal wash from 114 gastric cancer patients was quantified for a comparison of carcinoembryonic antigen (CEA) mRNA by means of real-time RT-PCR with a fluorescently labeled probe to predict peritoneal recurrence. The cut-off value was set at the upper limit of the quantitative value for non-cancer patients, and those above this cut-off value constituted the micrometastasis (MM+) group. Thirteen of 15 cases with peritoneal dissemination were MM+DDC (87% sensitivity), and one of 48 t1 cases was MM+ (98% specificity). DDC levels in peritoneal washes from patients with synchronous peritoneal metastases were more than 50 times higher than in those from patients without metastasis (p<0.01). For 15 cases of peritoneal dissemination (seven cases were cytologically positive), DDC was positive in 13 cases (87% sensitivity), but CEA failed to detect micrometastases in four cases (73% sensitivity), indicating that DDC is in some cases superior to CEA for the detection of peritoneal micrometastases of gastric cancer in terms of sensitivity as well as specificity, especially for poorly differentiated adenocarcinomas. Combination of CEA and DDC improved the accuracy of diagnosis up to 93%. These results suggest that DDC is potentially a novel marker for peritoneal dissemination of gastric cancer and that quantitative RT-PCR of DDC is reliable and efficient for the selection of patients for adjuvant intraperitoneal chemotherapy to prevent peritoneal recurrence.     

Complete response in an elderly patient with advanced gastric cancer treated with TS-1

The patient was an 89-year-old woman whose complaints were anorexia and weight loss. As a result of various examinations, she was diagnosed with advanced gastric cancer, Borrmann 3. TS-1 was administered at 75 mg/day for two weeks followed by one-week discontinvation during hospitalization; This course was then repeated after discharge. Anorexia and weight loss improved after two weeks, and complete response (CR) was obtained after 10 months of treatment. No cancer cells were confirmed by endoscopic biopsy. During this period no severe toxicities occurred. This TS-1 administration schedule appears to be a feasible and effective therapy for elderly patients with advanced gastric cancer.