Biomedical subjects

Yuichiro Doki

Publications and source records attributed to Yuichiro Doki.

At least 19 recordsLinked to original sources

PubMed2026

Prevalence and chronology of colibactin-associated mutational processes and their microbiome spectra in Japanese colorectal cancer.

The incidence of colorectal cancer (CRC) has risen in recent decades, with a disproportionate increase observed among younger individuals in Japan and other countries. The etiological contribution of the gut microbiota to CRC pathogenesis is recognized, yet the mechanisms involved remain to be fully clarified. Here we integrated whole-genome sequencing (WGS) and transcriptome profiling of CRC with whole-genome metagenomic sequencing of fecal samples to interrogate host-microbiome interactions at high resolution. Application of interpretable artificial intelligence enabled the stratification of CRC into four distinct microbiome-informed subtypes. WGS analysis identified mutational signatures SBS88 and ID18, linked to colibactin exposure, as early clonal events detected in 44.8% of non-hypermutated patients. Notably, these signatures were significantly more frequent among patients born after the 1960s. Microbiome-based subclassification revealed subtype-specific clinical and molecular features. Collectively, our findings indicate that colibactin exposure constitutes a prevalent and potentially modifiable risk factor for CRC in the Japanese population.

Humans↗

PubMed2026

Real-world outcomes of ipilimumab plus nivolumab in esophageal squamous cell carcinoma: a multi-institutional large cohort study.

BACKGROUND: Combination immune checkpoint inhibition with ipilimumab plus nivolumab (NIVO + IPI) has shown promising efficacy in advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate648 trial. However, real-world evidence regarding its safety, efficacy as first-line therapy, and host-related biomarkers relevant to immunotherapy remains limited. METHODS: This multicenter retrospective study evaluated a large cohort of 111 patients with unresectable advanced or recurrent ESCC who received first-line NIVO + IPI therapy. Treatment response, treatment-related adverse events, and prognostic factors were analyzed. RESULTS: The objective response and disease control rates in cases with target lesions were 44.0% and 70.7%, respectively. Treatment-related adverse events ≥ Grade 2 occurred in 58 (52.3%) patients, including one Grade 4 event (type 1 diabetes) and two Grade 5 events (biliary infection and myocarditis). The median overall survival (OS) and progression-free survival were 22 months (95% confidence interval [CI]: 13-not reached) and 5 months (95% CI 3-8), respectively. OS was significantly affected by lymph node metastasis in unresectable advanced disease and by liver metastasis in recurrent disease. Multivariate analysis of OS identified the C-reactive protein-to-albumin ratio (CAR), a marker of host immune-inflammatory status, as the only independent prognostic parameter (hazard ratio = 2.99, 95% CI 1.35-6.63, P = 0.0071). CONCLUSIONS: In this large real-world cohort, first-line NIVO + IPI therapy demonstrated meaningful clinical activity and an acceptable safety profile in advanced ESCC. Treatment outcomes varied according to metastatic patterns, suggesting an influence of organ-specific immune microenvironments, and CAR emerged as a simple and robust prognostic biomarker. These findings support the real-world applicability of dual immune checkpoint blockade and highlight the importance of host immune context in patient selection.

Humans↗

PubMed2007

The gene expression profile represents the molecular nature of liver metastasis in colorectal cancer.

The major cause of death in colorectal cancer is related to liver metastasis. Although the metastatic process has been well studied, many aspects of the molecular genetic basis of metastasis remain unclear. Elucidation of the molecular nature of liver metastasis is urgent to improve the outcome of colorectal cancer. We analyzed the chronological gene expression profiles of 104 colorectal samples corresponding to oncogenic development including normal mucosa, localized and metastasized primary tumors, and liver metastatic lesions as fundamental samples using a custom cDNA microarray. The gene expression patterns in 104 samples were classified into four groups closely associated with their metastatic status, and the genes of each group appropriately reflected the metastatic process. To investigate the existence of metastatic potential in primary tumors using metastasis-related genes detected by chronological analysis, we performed a hierarchical cluster and supervised classification analysis of 28 independent primary tumors. Hierarchical cluster analysis segregated the tumors according to their final metastatic status, rather than their clinical stages, and the profile of metastasized primary tumors resembled one of a metastatic lesion apart from a primary lesion rather than one of a non-metastasized primary tumor. Using the supervised classification approach, the expression profile of these genes allowed the classification of tumors diagnosed as localized cancer into two classes, the localized and the metastasized class, according to their final metastatic status. The disease-free survival and overall survival were significantly longer in the localized class than the metastasized class. Chronological analysis of the gene expression profile provides a better understanding of the metastatic process. Our results suggest that the metastatic potential is already encoded in the primary tumor and is detectable by a gene expression profile, which allows the prediction of liver metastasis in patients diagnosed with localized tumors and also the design of new strategies for the treatment and diagnosis of colorectal cancer.

Aged↗

PubMed2007

Stronger growth-inhibitory effect of interferon (IFN)-beta compared to IFN-alpha is mediated by IFN signaling pathway in hepatocellular carcinoma cells.

Interferon (IFN) is a promising drug for prevention and treatment of hepatocellular carcinoma (HCC) in combination with chemotherapeutic agents. We previously reported that the spectra of antiproliferative activity and synergistic effect of IFN-beta when combined with anticancer drugs are more potent than those of IFN-alpha in HCC cells. However, the mechanism of the diverse antitumor effects of the IFNs is not understood yet. We studied the expression of IFN alpha receptor 2 (IFNAR2), STATs, and IFN-alpha, IFN-beta's growth-inhibitory effect, signal transduction and binding to IFNAR2 on three HCC cell lines and a tumor xenografted mouse model (12 animals/group). From the results, IFN-beta showed a significantly stronger growth-inhibitory effect than IFN-alpha on the HuH7 cell line (expressing low IFNAR2), however it was similarly high on PLC/PRF/5 and weak on HLE. In the nude mouse tumor xenograft model, IFN-beta injection significantly suppressed tumor volume relative to vehicle injection, while IFN-alpha showed weaker growth-inhibition. IFN signal transduction (phosphorylated-STAT1, 3) induced by IFN-beta was higher than that by IFN-alpha in HuH7 and tumor xenografts. Pretreatment of hepatoma cells with anti-IFNAR2 antibody blocked the IFN signaling, more for IFN-alpha. IFN-alpha's antiproliferative effect was reduced by the antibody in lower concentrations compared to that of IFN-beta. Taken together, the HCC cells that express low IFNAR2 and are resistant to IFN-alpha were sensitive to the growth-inhibitory effect of IFN-beta, which might be mediated by stronger IFN signal transduction and distinct binding to IFNAR compared to IFN-alpha.

Antineoplastic Agents↗

PubMed2006

Prediction of peritoneal metastasis in advanced gastric cancer by gene expression profiling of the primary site.

Peritoneal metastasis is the most common cause of tumour progression in advanced gastric cancer. Clinicopathological findings including cytologic examination of peritoneal lavage have been applied to assess the risk of peritoneal metastasis, but are sometimes inadequate for predicting peritoneal metastasis in individuals. Hence, we tried to construct a new prediction system for peritoneal metastasis by using a PCR-based high throughput array with 2304 genes. The prediction system, constructed from the learning set comprised of 30 patients with the most informative 18 genes, classified each case into a 'good signature group' or 'poor signature group'. Then, we confirmed the predictive performance in an additional validation set comprised of 24 patients, and the prediction accuracy for peritoneal metastasis was 75%. Kaplan-Meier analysis with peritoneal metastasis revealed significant difference between these two groups (P=0.0225). By combining our system with conventional clinicopathological factors, we can identify high risk cases for peritoneal metastasis more accurately.

Aged↗

PubMed2006

Vitamin K2 has growth inhibition effect against hepatocellular carcinoma cell lines but does not enhance anti-tumor effect of combination treatment of interferon-alpha and fluorouracil in vitro.

Several studies have recently reported the efficacy of combination therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). However, the clinical effect of this treatment was not complete. The new therapeutic modality should be necessary to rise up this clinical response rate. Recently, the anti-tumor effect of Vitamin K2 has been reported in terms of decreased recurrence rate of HCC patients. The aim of this study was to explore the additive or synergistic effect of Vitamin K2 to combined therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) against hepatocellular carcinoma (HCCs). The study was conducted using three hepatoma cell lines (PLC/PRF/5, Hep3B and HepG2). The 3-(4-5-dimethylthiazol-2-yl)-2, 5-dyphenyl tetrazolium bromide (MTT) assay (48h) revealed anti-tumor effect of IFNalpha and 5-FU. Cell growth assay (3-7 days) showed growth inhibitory effect of Vitamin K2 on three cell lines after day 5. But additional effect of combination treatment of Vitamin K2 and IFNalpha/5-FU was not observed in any time course from 48h to 7 days. Cell cycles were assessed with flowcytometry. Although either Vitamin K2 or IFNalpha/5-FU alone has the influence to the cell cycles, no significant change was shown in the combination of Vitamin K2 and IFNalpha/5-FU. In conclusion, Vitamin K2 itself has potentially growth inhibitory effect for HCC cell lines, but does not enhance the anti-tumor effect of IFNalpha and 5-FU.

Journal Article↗

PubMed2006

A prospective trial for avoiding cervical lymph node dissection for thoracic esophageal cancers, based on intra-operative genetic diagnosis of micrometastasis in recurrent laryngeal nerve chain nodes.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the usefulness of intra-operative genetic diagnosis of RN node micrometastasis in the decision-making of 3FL for thoracic esophageal cancers. METHODS: Eighty-nine patients with middle and lower thoracic esophageal cancer were enrolled in a prospective study, in which 3FL was performed when RN node metastasis was revealed by intra-operative histological examination and/or genetic analysis using real-time RT-PCR assay. For other cases, 2FL was performed. RESULTS: Of the 89 patients, 3FL was performed for 33 patients and 2FL for 56 patients. In the 3FL group, RN node metastasis was both histologically and genetically positive in 19 patients, histologically negative and genetically positive in 11, and histologically positive and genetically negative in 3, with cervical node metastasis being detected in 7, 3, and 0 patients, respectively. In the 2FL group, only one patient had cervical node recurrence during the follow-up period. The post-operative survival in this study was equivalent to that of the historical controls (3-year survival rates 63.9% vs. 52.3%, P = 0.1513) of 66 3FL patients when 3FL was the first choice for thoracic esophageal cancers. CONCLUSIONS: Intra-operative histological and genetic diagnosis of RN node metastasis may help avoid unnecessary cervical node resection. A Phase III trial should be done.

Aged↗

PubMed2006

Factors affecting the prognosis of patients with esophageal cancer undergoing salvage surgery after definitive chemoradiotherapy.

BACKGROUND AND OBJECTIVES: Although salvage surgery after definitive chemoradiotherapy (CRT) is common, the safety and indication has not yet been established. METHODS: We retrospectively compared the mortality and morbidity of 24 patients who underwent salvage surgery with those of historical controls treated with neoadjuvant CRT followed by planned esophagectomy during the same period, and analyzed the prognostic factor of salvage surgery. RESULTS: Preoperative serum albumin (3.7 vs. 4.1 g/dl, P = 0.0157) and lymphocyte count (763 vs. 964/mm(3), P = 0.0111) in the salvage group were significantly lower than those in the neoadjuvant group. A significant difference was also observed in operation time (567 vs. 474 min, P = 0.0381), C-reactive protein (CRP) on postoperative day 1 (11.2 vs. 8.7 mg/dl, P = 0.0021), and postoperative systemic inflammatory response syndrome (SIRS) duration (3.5 vs. 2.9 days, P = 0.0486). There were three hospital deaths in the salvage group, whereas no patient died in the neoadjuvant group. Multivariate analysis showed curability (R0 vs. R1 + R2) to be the strongest prognostic factor of salvage surgery (P = 0.0064). R1 + R2 operation was more frequently performed in the salvage group (33% vs. 13%), and the reason for all cases was unresectable T4, which had been underestimated preoperatively. CONCLUSIONS: Salvage surgery is a highly invasive and morbid operation, which is performed on immunocompromised hosts. The indication must be carefully considered, with care taken to avoid non-curative surgery.

Aged↗

PubMed2006

Clinical significance of the second cycle response to cisplatin-based chemotherapy as preoperative treatment for esophageal squamous cell carcinoma.

BACKGROUND: Repeating two cycles of cisplatin-based chemotherapy is standard protocol for preoperative treatment for advanced esophageal squamous cell carcinoma (ESCC). However, the second cycle of chemotherapy is often less effective than the first. METHODS: Forty-six patients with advanced ESCC underwent two (41) or one (5) cycle of chemotherapy, consisting of cisplatin, adriamycin, and 5-fluorouracil (5-FU), followed by surgery. RESULTS: The tumor reduction rates (RR) for the first and second cycles of chemotherapy were 33.3 +/- 22.5% versus 11.5 +/- 42.6%, with the second showing less effectiveness and larger deviation. The second cycle RR was closely correlated with the pathological findings of the surgical specimens, including the effect of chemotherapy, tumor depth, and lymph node metastases, and with postoperative survival rates, which were 75.2% and 26.8% (P = 0.0028) at 3 years for good and poor responders. The first cycle RR showed correlation with neither. The second cycle RR was the only independent prognostic factor among the preoperative parameters in multivariate analysis. CONCLUSIONS: The second cycle of cisplatin-based chemotherapy in ESCC is less effective, but more closely related with postoperative survival than the first. Treatment other than surgery should be considered for ESCC resistant to second cycle chemotherapy.

Adult↗

PubMed2006

Expression of hepatoma-derived growth factor is correlated with lymph node metastasis and prognosis of gastric carcinoma.

PURPOSE: Hepatoma-derived growth factor (HDGF) is a unique nuclear/growth factor and might play an important role in the development and progression of carcinomas. In the present study, association of HDGF expression with recurrence and prognosis of gastric carcinoma was examined. PATIENTS AND METHODS: HDGF expression in 317 patients with gastric carcinoma (233 males and 84 females) with ages ranging from 26 to 81 years (median, 60 years) was analyzed by immunohistochemistry. Samples with >90% of tumor cells to express positive immunoreactivity similar to or stronger than that in endothelial cells both for nucleus and cytoplasm were regarded as HDGF index level 2, and others as HDGF index level 1. RESULTS: One hundred and eighty-two cases showed level 1 HDGF expression, whereas 135 cases showed level 2 HDGF expression. Patients with level 2 expression showed higher rates of proximal tumor location (P < 0.0001), large tumor size (P < 0.0001), infiltrative tumor growth (P < 0.0001), presence of vascular and lymphatic invasion (P < 0.0001 for both), presence of lymph node metastasis (P < 0.0001), deep tumor invasion (P < 0.0001), and poorer disease-free and overall survival (P < 0.0001 for both) compared to those with level 1 expression. Multivariate analysis revealed HDGF expression level as an independent prognosticator for disease-free and overall survival. CONCLUSION: HDGF expression level was shown to be a prognostic factor for gastric carcinoma.

Adult↗

PubMed2006

Ghrelin reduction after esophageal substitution and its correlation to postoperative body weight loss in esophageal cancer patients.

BACKGROUND: Body weight loss is observed commonly after esophagectomy with gastric tube reconstruction in thoracic esophageal cancer patients. The functional and anatomical alteration of the stomach by this surgery should affect ghrelin secretion, a novel gastric hormone that upregulates body weight through appetite control and metabolic reaction. METHODS: Early-phase postoperative alteration of serum ghrelin was measured before and at day 3 and day 7 after surgery in 9 patients. With 26 other patients, who had previously undergone surgery from 3 months to 67 months (mean, 25 months) before the present study period, the late-phase postoperative alteration of serum ghrelin was investigated along with postoperative body weight loss and serum leptin. RESULTS: Serum ghrelin concentration, which was equivalent to the control group before surgery (88.6 fmol/mL vs 97.5 fmol/mL) significantly decreased by half at 3 and 7 days after surgery. Thereafter, the serum ghrelin decline continued in the outpatients within 1 year after surgery (58.8 fmol/mL), while it was marginal in those from 1 to 3 years after surgery (77.2 fmol/mL). Serum ghrelin was significantly higher than the control after 3 years (185.1 fmol/mL). Thus, a significant positive correlation was observed between ghrelin and time after surgery (P < .0001). Postoperative body weight loss was significant, averaged as DeltaBMI - 2.7 in the outpatients (P < .0001). Until 3 years after surgery, a significant correlation between ghrelin and postoperative body weight loss was observed (P = .0152), with those having higher serum ghrelin showing less body weight loss. Serum leptin correlated well with body weight (P = .0144), but not with postoperative time, the degree of body weight loss, or serum ghrelin concentration. CONCLUSION: Gastric tube replacement for esophagectomy resulted in temporary reduction of ghrelin production, which is associated with body weight loss after surgery. The decline of ghrelin may play some role in the serious body weight loss after esophagectomy, thus encouraging clinical application of exogenous recombinant ghrelin for these patients.

Aged↗

PubMed2006

Clinical significance of class III beta-tubulin expression and its predictive value for resistance to docetaxel-based chemotherapy in gastric cancer.

Docetaxel, one of the most effective anticancer drugs for gastric cancer, targets beta-tubulin, the major protein in mitotic spindles. Eight isotypes of beta-tubulin, with tissue and organ-specific expression, have been identified in mammalian cells. We examined class III beta-tubulin expression in gastric cancer and assessed its relationship with sensitivity to docetaxel-based chemotherapy. A total of 115 paraffin-embedded gastric tumors were analyzed by immunohistochemistry for class III beta-tubulin expression. Twenty patients with advanced gastric cancer received preoperative docetaxel-based chemotherapy. Their biopsied specimens, obtained by endoscopy before chemotherapy were examined for class III beta-tubulin expression. The relationship between expression and chemosensitivity was assessed. Forty-two (36.4%) of 115 cases were confirmed to be positive for class III beta-tubulin expression. There was no association between clinicopathological status and prognosis. Among the patients positive for class III beta-tubulin expression, only 16.7% showed no response to chemotherapy, while 64.3% responded to the chemotherapy in the negative group. Our results suggest that class III beta-tubulin is a simple and useful predictive marker for the clinical response to docetaxel-based chemotherapy in gastric cancer.

Adult↗

PubMed2006

Expression of type I interferon receptor as a predictor of clinical response to interferon-alpha therapy of gastrointestinal cancers.

Interferon (IFN) is used in the treatment of many malignancies and viral disorders. We recently reported a significant correlation between the efficacy of IFN-alpha combined with chemotherapy in the treatment of advanced hepatocellular carcinoma (HCC) and IFN-alpha/type I IFN receptor (IFNAR2) expression. It is possible that the expression of IFNAR2 in gastrointestinal cancerous tissue, apart from HCC, may predict the efficacy of IFN-alpha combination therapy. We investigated the expression of IFNAR2 in 100 gastrointestinal cancerous tissues. IFNAR2 expression was examined using immunohistochemistry, in surgically resected tissue samples (20 esophageal, 20 gastric, 20 colorectal, 20 cholangiocarcinoma, and 20 pancreatic samples). The expression rate of IFNAR2 was 35.0% (7/20), 25.0% (5/20), 20.0% (4/20), 45.0% (9/20), and 25.0% (5/20) in esophageal, gastric cancer, colorectal, cholangiocarcinoma and pancreatic cancer samples, respectively. In our previous report, the expression rate of IFNAR2 in HCC samples was 64.8% (59/91). Thus, the expression rates of IFNAR2 in the five types of gastrointestinal cancers tested here were low, compared with HCC. The clinical efficacy of IFN-alpha mono- or combination therapies in patients with gastrointestinal neoplasms is expected to be lower than in patients with HCC based on the expression level of IFNAR2.

Gastrointestinal Neoplasms↗

PubMed2005

Bile acid promotes the proliferation of squamous cell carcinoma of the esophagus, independent of its inducing COX-2 expression.

BACKGROUND: We have reported G1 progression and cyclooxygenase-2 (COX-2) induction during carcinogenesis of the squamous epithelium of the esophagus. As bile acid induces COX-2 expression and promotes carcinogenesis in the digestive tract, we investigated the effect of bile acid on the proliferation of squamous cell carcinoma of the esophagus (ESCC). MATERIALS AND METHODS: MTT assay, Western blot analysis of COX-2 and cell cycle-related molecules in the G1 phase (Rb, CDC25A, cyclin D1), and CDK2 kinase assay were performed on chenodeoxycholic acid (CDCA) exposure to ESCC cell lines (TE2R, TE3, TE13, TE15). RESULTS: In the presence of gradient bile acid concentration (up to 100 microm), growth of ESCC cell lines was stimulated at a low concentration (maximally at 20-30 microm), but suppressed at a higher concentration. Only a low dose of bile acid induced the expression of cyclin D1 and CDC25A and showed high Rb phosphorylation and high CDK2 kinase activity. In contrast, bile acid progressively induced COX-2 expression in a dose-dependent manner, regardless of its biphasic effects on cell proliferation, and a COX-2 specific inhibitor (JTE-522) did not suppress growth stimulation by a low dose of bile acid. CONCLUSIONS: Bile acid at a low dose stimulates the proliferation of ESCC by inducing G1-regulating molecules. However, COX-2 expression, which is also induced by bile acid, does not affect cell proliferation. Further work is needed to elucidate its role in carcinogenesis.

Bile Acids and Salts↗

PubMed2005

Overexpression of ADAM9 enhances growth factor-mediated recycling of E-cadherin in human colon cancer cell line HT29 cells.

Growth factor-mediated stimulation of epithelial cells induces the disassembly of E-cadherin-mediated cell-cell adhesion. We found that overexpression of a disintegrin and metalloprotease 9 (ADAM9) enhanced growth factor-mediated induction of endocytosis and dynamic recycling of E-cadherin in HT29 human colon cancer cells. In addition, ubiquitination and degradation of E-cadherin were reduced in these cells. ADAM9 constitutively interacted with E-cadherin, and the two proteins co-localized at the plasma membrane of HT29 cells. Administration of a metalloprotease inhibitor or overexpression of an ADAM9 mutant lacking metalloprotease activity attenuated growth factor-dependent endocytosis and recycling of E-cadherin as well as scattering of HT29 cells. These results suggest that the metalloprotease activity of ADAM9 mediates growth factor-induced endocytosis and dynamic recycling of E-cadherin and prevents E-cadherin degradation.

ADAM Proteins↗

PubMed2005

Postoperative ghrelin levels and delayed recovery from body weight loss after distal or total gastrectomy.

BACKGROUND: Body weight loss is a common but one of the most serious sequelae after gastrectomy. Ghrelin, a novel gastric hormone that up-regulates body weight through appetite control and metabolic reaction, seems to be affected by gastric surgery. PATIENTS AND METHODS: Early postoperative alteration of serum ghrelin was evaluated at days 3 and 7 after gastrectomy for 13 hospital patients. In 64 outpatients who had previously undergone total gastrectomy (TG: 26 patients) or distal gastrectomy (DG: 38 patients) 4.6 months to 136 months (average, 41 months) earlier, the association between their serum ghrelin and leptin levels and postoperative body weight was investigated. RESULTS: Serum ghrelin declined immediately and greatly after TG to 12% of the preoperative level (day 3 and day 7), whereas the decline was less significant after DG at 39% (day 3) and 56% (day 7). In outpatients, serum ghrelin after TG was very low compared with the control (18.6 fmol/mL versus 92.1 fmol/mL, P<0.0001), irrespective of the period after surgery, whereas the level after DG recovered and was equivalent to the control (73.4 fmol/mL, P=0.355). Body weight loss was more apparent in TG patients than in DG patients, showing postoperative reduction of body mass index (DeltaBMI) -3.940 versus -1.949 (P<0.0001). Serum leptin concentration, reflecting the systemic fat volume, significantly correlated with BMI in both TG and DG patients, and tended to be lower in TG patients than in DG patients (800 pg/mL versus 1158 pg/mL, P=0.236). CONCLUSION: Persistent decline of serum ghrelin and body weight was observed commonly after total gastrectomy. Further study is needed as to whether or not ghrelin administration can improve the body weight level for these patients.

Aged↗

PubMed2005

Feasibility and efficacy of combination therapy with preoperative and postoperative chemoradiation, extended pancreatectomy, and postoperative liver perfusion chemotherapy for locally advanced cancers of the pancreatic head.

BACKGROUND: The outcome after resection of advanced pancreatic cancers is extremely poor because of the high incidence of the postoperative development of liver metastasis and local recurrence. We performed a combination of chemoradiation and liver perfusion chemotherapy and extended pancreatectomy. METHODS: Nineteen patients with T3 pancreatic head cancers were enrolled. A total of 24 Gy in 12 fractions of 10-MV x-rays with a concurrent intravenous infusion of 5-fluorouracil (5-FU; 3 g/12 days) was administered to the pancreatic head area. An extended pancreaticoduodenectomy was performed, and catheters were placed into the gastroduodenal artery and the superior mesenteric vein. During the first 28 postoperative days, 5-FU was continuously infused via the hepatic artery and portal vein (3.5 g/28 days x 2). Finally, 36 Gy in 18 fractions with 5-FU (3 g/6 days) was applied to the pancreatic bed. RESULTS: After preoperative chemoradiation, four patients did not undergo surgical resection because of distant metastases. Fifteen patients underwent pancreaticoduodenectomy, liver perfusion chemotherapy, and postoperative chemoradiation. No patient developed grade 3 toxicity as a result of preoperative chemoradiation, but one patient (7%) developed grade 3 leukopenia during the postoperative treatments. The morbidity rate was 20% (3 of 15 patients), and the mortality rate was 0%. The overall 3-year survival rate was 53%. The 3-year disease-free survival rate was 66% in patients who pathologically responded well (>50%), versus 0% in patients with poor responses (P = .04). CONCLUSIONS: A combination of preoperative and postoperative chemoradiation plus postoperative liver perfusion chemotherapy with an extended pancreatectomy is feasible, and the long-term outcomes are also promising.

Adult↗

PubMed2005

Prediction of recurrence in advanced gastric cancer patients after curative resection by gene expression profiling.

The prognosis of patients with advanced gastric cancer remains unfavorable. Even after curative resection, 40% of patients with advanced gastric cancer die of recurrence. Conventional clinicopathlogic findings are sometimes inadequate for predicting recurrence in individuals. Hence, we tried to construct a new diagnostic system, which predicts recurrence in patients with advanced gastric cancer after curative resection based on molecular analysis. Gastric cancer progression is a function of multiple genetic events that may affect the expression of large number of genes. We performed gene expression profiling with 2,304 genes in 60 advanced gastric cancer patients who underwent curative resection using a PCR array technique, a high-throughput quantitative RT-PCR technique. The diagnostic system, which was constructed from the learning set comprised of 40 patients with the most informative 29 genes, classified each case into a good-signature or poor-signature group. Then, we confirmed the predictive performance in an additional test set comprised of 20 patients, and the prediction accuracy for recurrence was 75%. Kaplan-Meier analysis revealed significant difference between the good-signature and the poor-signature group (p = 0.0125). Especially in patients with smaller tumor (< or = 5 cm), less developed LN metastasis (N(0,1)), or earlier stage (stages I and II), the prediction accuracy was high (88.9%, 84.6%, or 81.8%, respectively). Our diagnostic system based on systematic analysis of gene expression profiling can predict the recurrence at clinically meaningful level. By combining our system with conventional clinicopathologic factors, we can improve the prediction of recurrence in patients with advanced gastric cancer who underwent curative surgery.

Aged↗