Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs. PATIENTS AND METHODS: Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over. RESULTS: From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months [95% confidence interval (CI) 1.6-2.9 months] with pimitespib versus 1.4 months (0.9-1.8 months) with placebo [hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006]. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo [HR 0.42 (0.21-0.85), one-sided P = 0.007]. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients. CONCLUSIONS: Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.

Multicenter prospective trial of total gastrectomy versus proximal gastrectomy for upper third cT1 gastric cancer.

BACKGROUND: The appropriate surgical procedure for patients with upper third early gastric cancer is controversial. We compared total gastrectomy (TG) with proximal gastrectomy (PG) in this patient population. METHODS: A multicenter, non-randomized trial was conducted, with patients treated with PG or TG. We compared short- and long-term outcomes between these procedures. RESULTS: Between 2009 and 2014, we enrolled 254 patients from 22 institutions; data from 252 were included in the analysis. These 252 patients were assigned to either the PG (n = 159) or TG (n = 93) group. Percentage of body weight loss (%BWL) at 1 year after surgery, i.e., the primary endpoint, in the PG group was significantly less than that of the TG group (- 12.8% versus - 16.9%; p = 0.0001). For short-term outcomes, operation time was significantly shorter for PG than TG (252 min versus 303 min; p < 0.0001), but there were no group-dependent differences in blood loss and postoperative complications. For long-term outcomes, incidence of reflux esophagitis in the PG group was significantly higher than that of the TG group (14.5% versus 5.4%; p = 0.02), while there were no differences in the incidence of anastomotic stenosis between the two (5.7% versus 5.4%; p = 0.92). Overall patient survival rates were similar between the two groups (3-year survival rates: 96% versus 92% in the PG and TG groups, respectively; p = 0.49). CONCLUSIONS: Patients who underwent PG were better able to control weight loss without worsening the prognosis, relative to those in the TG group. Optimization of a reconstruction method to reduce reflux in PG patients will be important.

Reflux after esophagectomy with gastric conduit reconstruction in the posterior mediastinum for esophageal cancer: original questionnaire and EORTC QLQ-C30 survey.

Reflux following an esophagectomy with gastric conduit reconstruction in the posterior mediastinum is a clinically significant problem. In this study, we investigated the frequency and impact of reflux on the quality of life (QOL) among 158 patients who underwent an esophagectomy for esophageal cancer using an original questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30). Reflux frequency was assessed using the original questionnaire. The number of patients who complained of reflux every day, two or three times a week, once a week, or less than once a week was 16 (10.1%), 21 (13.3%), 26 (16.5%), and 60 (38.0%), respectively. Out of 35 patients (22.2%) reported no reflux symptoms. Patients were divided into two groups: those with reflux ≥ once/week (63 patients) and those with low frequency of symptoms (95 patients). Time elapsed following surgery was the only factor to influence reflux frequency. Reflux frequency decreased within two years of surgery; however, the frequency plateaued after more than two years. QOL was assessed using the EORTC QLQ-C30. The ≥ once/week reflux group had a significantly lower global health status score than the low-frequency reflux group (59.6 ± 24.2 vs. 70.8 ± 20.7; P = 0.007). In addition, the ≥ once/week reflux group had a significantly lower social functioning score than the low-frequency reflux group (81.6 ± 24.1 vs. 88.4 ± 19.8; P = 0.035). Regarding symptoms, the ≥ once/week reflux group had significantly higher scores for fatigue, nausea, and vomiting, dyspnea and insomnia compared to the low-frequency reflux group (fatigue: 42.4 ± 21.9 vs. 28.9 ± 18.4, P < 0.001; nausea and vomiting: 17.3 ± 17.1 vs. 4.9 ± 10.6, P < 0. 001; dyspnea: 29.2 ± 26.0 vs. 21.7 ± 26.8, P = 0.043; insomnia: 22.2 ± 31.1 vs. 10.5 ± 21.7, P = 0.015). Thus, reflux after an esophagectomy was associated with a lower QOL.

Utility of initial induction chemotherapy with 5-fluorouracil, cisplatin, and docetaxel (DCF) for T4 esophageal cancer: a propensity score-matched analysis.

Although no consensus is available on the treatment of esophageal squamous cell carcinoma (ESCC) invading adjacent organs (T4), establishing effective induction treatments is crucial to altering an unresectable status and achieving curative resection. Here, we evaluated the efficacy of chemotherapy using 5-fluorouracil, cisplatin, and docetaxel (DCF) as the initial induction treatment for T4 ESCC. Fifty patients without distant metastasis who underwent initial induction chemotherapy using DCF for T4 ESCC were propensity score-matched with 50 patients who underwent radiotherapy concurrent with cisplatin and 5-fluorouracil (CRT). In the DCF group, 24 (48.0%) patients underwent surgery, achieving a 64% clinical response rate compared to 72.0% for induction CRT. CRT was also performed in another 24 (48.0%) patients in the DCF group in whom surgical resection was not indicated. The DCF group had significantly higher overall resectability than the CRT group (78.0% vs. 48.0%, P = 0.0017). The esophageal perforation rate during induction treatments was significantly lower in the DCF group than the CRT group (4.0% vs. 18.0%, P = 0.0205). Prognosis was significantly better in the DCF group than the CRT group (5-year cancer-specific survival 42.1% vs. 22.2%, P = 0.0146). Thus, induction DCF chemotherapy in patients with T4 ESCC reduced esophageal perforation and increased overall resectability, leading to better survival than CRT alone. Therefore, DCF chemotherapy may be an effective and safe option for initial induction treatment of T4 ESCC.

Comparison of short-term outcomes between 2- and 3-field lymph node dissection for esophageal cancer.

Although 3-field lymph node dissection (3-FLD) is often performed for thoracic esophageal squamous cell carcinoma (ESCC), the clinical effects of cervical lymph node dissection in addition to mediastinal and abdominal dissections on postoperative complications remain unclear. A total of 367 ESCC patients who underwent curative esophagectomy for thoracic esophageal cancer in our hospital from 2010 to 2015 were included in the study: 157 patients who underwent 2-field lymph node dissection (2-FLD) and 210 patients who underwent 3-FLD. Clinicopathological parameters and postoperative complications based on the Clavien-Dindo classification were compared between the two groups. We performed propensity score matching (PSM) analyses to compare the groups with well-balanced backgrounds. In terms of patient background, clinical T (p < 0.001), N (p < 0.001), and M (p = 0.002) stage of tumor was significantly more advanced; therefore, preoperative treatment was more frequently performed in the 3-FLD group than in the 2-FLD group (91.0% vs. 79.0%, P< 0.001). However, perioperative parameters including operation time, blood loss, and the number of dissected mediastinal and abdominal lymph nodes did not differ between the groups. In terms of postoperative complications, the occurrence rate of pneumonia increased significantly in patients with 3-FLD compared to 2-FLD (grade III or higher: 10.5% vs. 3.2%, P= 0.025). Although the duration of systemic inflammatory response syndrome (SIRS) was longer in the 3-FLD group than in the 2-FLD group (median 3 days vs. 2 days, P= 0.025), other postoperative parameters (including the highest level of postoperative serum C-reactive protein, intensive care unit stay, re-operation rate, and postoperative hospital stay) were similar between the groups. After PSM, the differences in the background between the groups disappeared. PSM analysis showed that there was no significant difference in each complication between the groups. The duration of SIRS tended to be longer in the 3-FLD group than in the 2-FLD group, but the difference was not significant. The field of lymphadenectomy negatively impacted the short-term outcome in ESCC patients in terms of pneumonia and inflammatory response. However, because the results of the PSM analyses indicate that the short-term outcome was similar between the two groups, 3-FLD could be as feasible as 2-FLD in ESCC patients.

Inter-institutional heterogeneity in outcomes of chemotherapy for metastatic gastric cancer: correlative study in the JCOG9912 phase III trial.

BACKGROUND: The standard chemotherapy regimen for gastric cancer has been established by several phase III trials. However, few studies have evaluated inter-institutional heterogeneity in randomised trials; such research may assure the generalisability of the results and also the reliability of the study group itself. PATIENTS AND METHODS: The Japan Clinical Oncology Group (JCOG)9912 phase III trial compared irinotecan plus cisplatin and S-1 alone with fluorouracil alone for metastatic gastric cancer, and finally demonstrated the non-inferiority of S-1 alone with respect to overall survival (OS). Mixed effects models were used to evaluate outcomes of 658 patients from 22 hospitals. After adjustment for nine background factors, the heterogeneity in OS, progression-free survival (PFS), and incidences of grade 3-4 adverse events among hospitals was estimated. We also estimated the correlation between outcomes and either hospital volume or medical oncology clinical experience. RESULTS: A large degree of heterogeneity in median OS was observed for fluorouracil alone (range, 8.3-13.3 months), while the difference in median PFS between hospitals was small (range, 2.4-3.4 months). Although some heterogeneity in the treatment effect of irinotecan plus cisplatin or S-1 alone was observed in OS and PFS, the HRs did not exceed 1.00 in any hospital for either regimen. There was minimal heterogeneity in the incidences of grade 3-4 adverse events. There was a trend towards correlation between greater medical oncology clinical experience and both better OS after fluorouracil alone and a lower HR for OS after irinotecan plus cisplatin, but it was not statistically significant. CONCLUSIONS: Large inter-institutional heterogeneity was observed in OS, but not in PFS, after the standard regimen, but there was little heterogeneity in the treatment effects of irinotecan plus cisplatin or S-1 alone, indicating that the final results of the JCOG9912 trial can be generalised to the target population. TRIAL REGISTRATION NUMBER: NCT00142350.

Impact of number of [(18)F]fluorodeoxyglucose-PET-positive lymph nodes on survival of patients receiving neoadjuvant chemotherapy and surgery for oesophageal cancer.

BACKGROUND: [(18) F]fluorodeoxyglucose (FDG)-PET has been used to evaluate the response of primary tumours to neoadjuvant therapy for oesophageal cancer. The clinical significance of the number of PET-positive nodes before and after therapy has not been investigated previously. METHODS: [(18) F]FDG-PET was performed before and 2-3 weeks after completion of neoadjuvant chemotherapy to identify the number of PET-positive nodes, and these numbers were assessed in relation to metabolic changes in the primary tumour. RESULTS: Of 302 patients in total, 90 had no PET-positive nodes, 83 had one, 59 had two and 70 patients had three or more positive nodes before therapy. After treatment, the numbers were: none in 207 patients, one in 59, two in 20 and three or more in 16 patients. The number of PET-positive nodes after treatment was influenced by both the number of PET-positive nodes before therapy and the response to preoperative therapy, and correlated with the number of metastatic lymph nodes. Overall survival was longer in patients who had no PET-positive nodes after treatment than in those who had one or more. Multivariable analysis identified the numbers of PET-positive nodes before and after chemotherapy as independent prognostic factors, together with clinical response, tumour depth and lymph node involvement. CONCLUSION: The number of PET-positive nodes after treatment correlated with survival in patients with oesophageal cancer who underwent neoadjuvant chemotherapy.

Distribution of involved abdominal lymph nodes is correlated with the distance from the esophagogastric junction to the distal end of the tumor in Siewert type II tumors.

BACKGROUND: The optimal surgical approach for Siewert type II adenocarcinoma of the esophagogastric junction (AEG) has not yet been agreed. Here we investigated whether the distance from the esophagogastric junction (EGJ) to the distal end of the tumor was related to the distribution of involved abdominal lymph nodes in Siewert type II tumors. METHODS: A total of 288 patients with pT2-4 AEG Siewert II, treated by R0 surgical resection at 7 institutions in Japan, were retrospectively investigated. The distribution of involved abdominal nodes was correlated with the distance from the EGJ to the distal end of the tumor. RESULTS: In patients where the distance from the EGJ to the distal end of the tumor was ≤30 mm, the frequency of nodal involvement along the greater curvature or antrum was low (2.2%). In contrast, in patients where the distance was >50 mm, the incidence of this nodal involvement was 20.0%. In patients where the distance was 30-50 mm incidence was intermediate (8.0%). Multivariate analyses showed that the distance from the EGJ to the distal end of the tumor was significantly related to lymph node involvement along the greater curvature or antrum (odds ratio 3.7, 95% confidence interval 1.3-11, p = 0.006). CONCLUSIONS: When the distance from the EGJ to the distal end of the tumor is ≤ 30 mm for Siewert II AEG, esophagectomy or proximal gastrectomy is sufficient from the point of view of abdominal lymphadenectomy. However, a total gastrectomy should be considered for abdominal lymphadenectomy when this distance is > 50 mm.

Ten-year follow-up results of a randomized clinical trial comparing left thoracoabdominal and abdominal transhiatal approaches to total gastrectomy for adenocarcinoma of the oesophagogastric junction or gastric cardia.

BACKGROUND: The optimal surgical approach for treatment of oesophagogastric junction (OGJ) cancer is controversial. A randomized clinical trial (JCOG9502) comparing transhiatal (TH) and left thoracoabdominal (LTA) approaches was stopped after the first interim analysis owing to limited efficacy for LTA resections. Complete 10-year follow-up data are now available. METHODS: Patients with histologically proven adenocarcinoma of the OGJ or gastric cardia with oesophageal invasion of 3 cm or less were randomized to a TH or LTA approach. Both groups underwent total gastrectomy and splenectomy with D2 nodal dissection plus para-aortic lymphadenectomy above the left renal vein. For LTA, a thorough mediastinal lymphadenectomy below the left inferior pulmonary vein was also mandatory. The primary endpoint was overall survival. RESULTS: A total of 167 patients (82 TH, 85 LTA) were enrolled. The 10-year overall survival rate was 37 (95 per cent c.i. 26 to 47) per cent for the TH approach and 24 (15 to 34) per cent for the LTA technique (P = 0·060). The hazard ratio for death was 1·42 (0·98 to 2·05) for the LTA technique. Subgroup analysis based on the Siewert classification indicated non-significant survival advantages in favour of the TH approach. CONCLUSION: LTA resections should be avoided in the treatment of adenocarcinoma of the OGJ or gastric cardia. REGISTRATION NUMBER: NCT00149266 (https://www.clinicaltrials.gov).

Monitoring gastric cancer progression with circulating tumour DNA.

BACKGROUND: Circulating tumour DNA (ctDNA) is an emerging candidate biomarker for malignancies and may be useful for monitoring the disease status of gastric cancer. METHODS: We performed targeted deep sequencing of plasma cell-free DNA (cfDNA) by massively parallel sequencing in patients with tumours harbouring TP53 mutations. The quantitative values of TP53-ctDNA during the clinical course were compared with the tumour status. RESULTS: Three out of ten patients with TP53 mutations in primary tumours showed detectable TP53 mutation levels in preoperative cfDNA. Although the cfDNA concentrations were not always reflective of the disease course, the ctDNA fraction correlated with the disease status. CONCLUSIONS: ctDNA may serve as a useful biomarker to monitor gastric cancer progression and residual disease.

Phase II study of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1).

BACKGROUND: S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. To date, no studies have evaluated the efficacy and safety of trastuzumab combined with SP in patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC. METHODS: Patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1-14, cisplatin (60 mg m(-2)) intravenously on day 1, and trastuzumab (course 1, 8 mg kg(-1); course 2 onward, 6 mg kg(-1)) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and adverse events. RESULTS: A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence interval (CI)=54-80%), and the disease control rate was 94% (95% CI=84-99%). Median OS, PFS, and TTF were estimated as 16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), and anaemia (15%). CONCLUSIONS: Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patients with HER2-positive AGC.

Relevance of [18F]fluorodeoxyglucose positron emission tomography-positive lymph nodes after neoadjuvant chemotherapy for squamous cell oesophageal cancer.

BACKGROUND: Several studies have examined the clinical significance of metabolic response in primary tumours by [(18) F]fluorodeoxyglucose positron emission tomography ((18) F-FDG-PET) in patients with oesophageal cancer who undergo neoadjuvant therapy. The relevance of the metabolic response in lymph nodes is unclear. METHODS: Consecutive patients with oesophageal cancer who underwent neoadjuvant chemotherapy followed by surgery were studied. (18) F-FDG-PET was performed before and 2-3 weeks after completion of neoadjuvant chemotherapy, assessing FDG uptake in primary tumours and lymph nodes considered to be metastatic. RESULTS: Before therapy, 156 (73·9 per cent) of 211 patients had PET-positive nodes, of whom 89 (57.1 per cent) had no evidence of metabolic activity in these lymph nodes following chemotherapy. There was a significant relationship between post-treatment lymph node status assessed by FDG-PET and numbers of pathologically confirmed metastatic lymph nodes. Patients with post-treatment PET-positive nodes had shorter survival than those without (5-year survival rate 25 versus 62·6 per cent; P < 0·001). There was no difference in survival between patients with PET-positive nodes before but not after therapy and patients who had PET-negative nodes throughout (5-year survival rate 59 versus 71 per cent respectively; P = 0·207). Multivariable analysis identified post-treatment nodal status assessed by FDG-PET and tumour depth as independent prognostic factors. CONCLUSION: Identification of PET-positive lymph nodes after completion of chemotherapy is a predictor of poor prognosis of patients with oesophageal cancer scheduled for surgery. FDG-PET lymph node status after neoadjuvant chemotherapy is more important than that before chemotherapy.

NY-ESO-1 antibody as a novel tumour marker of gastric cancer.

BACKGROUND: NY-ESO-1 antibodies are specifically observed in patients with NY-ESO-1-expressing tumours. We analysed whether the NY-ESO-1 humoral immune response is a useful tumour marker of gastric cancer. METHODS: Sera from 363 gastric cancer patients were screened by enzyme-linked immunosorbent assay (ELISA) to detect NY-ESO-1 antibodies. Serial serum samples were obtained from 25 NY-ESO-1 antibody-positive patients, including 16 patients with curative resection and 9 patients who received chemotherapy alone. RESULTS: NY-ESO-1 antibodies were detected in 3.4% of stage I, 4.4% of stage II, 25.3% of stage III, and 20.0% of stage IV patients. The frequency of antibody positivity increased with disease progression. When the NY-ESO-1 antibody was used in combination with carcinoembryonic antigen and CA19-9 to detect gastric cancer, information gains of 11.2% in stages III and IV, and 5.8% in all patients were observed. The NY-ESO-1 immune response levels of the patients without recurrence fell below the cutoff level after surgery. Two of the patients with recurrence displayed incomplete decreases. The nine patients who received chemotherapy alone continued to display NY-ESO-1 immune responses. CONCLUSION: When combined with conventional tumour markers, the NY-ESO-1 humoral immune response could be a useful tumour marker for detecting advanced gastric cancer and inferring the post-treatment tumour load in seropositive patients.

High expression of Lin28 is associated with tumour aggressiveness and poor prognosis of patients in oesophagus cancer.

BACKGROUND: Lin28 is a negative regulator of the tumour suppressor microRNA, let-7, suggesting its role in tumourigenesis. However, the clinical significance of Lin28 expression in oesophageal cancer has not been elucidated. METHODS: Lin28 and Lin28B expression was examined by immunohistochemistry in 161 tissues from patients with oesophageal cancer who had undergone curative surgery. The relationship between the expressions of Lin28 and Lin28B and various clinicopathological factors was examined. In vitro assays were conducted to determine the role of Lin28 in aggressiveness of oesophageal cancers using oesophageal cancer cell line. RESULTS: Lin28 and Lin28B were overexpressed in oesophageal cancer cells compared with non-cancerous epithelial cells, especially in the invasive front. High expression of Lin28 and Lin28B correlated significantly with lymph node metastasis and poor prognosis. High expression of Lin28B expression correlated significantly with low expression of let-7. Multivariate analysis also identified Lin28B expression as an independent prognostic factor. In vitro assays showed that the proliferative and invasive activities were significantly reduced in Lin28B-knockdown cells, compared with control cells. CONCLUSION: High expression of Lin28 is associated with poor prognosis and high tumour aggressiveness in oesophageal cancer and these effects are mediated through increased proliferation and invasiveness of oesophageal cancer cells.

Prospective randomized trial of preoperative enteral immunonutrition followed by elective total gastrectomy for gastric cancer.

BACKGROUND: Perioperative enteral immunonutrition is thought to reduce postoperative morbidity in patients undergoing major gastrointestinal surgery. This study assessed the clinical effects of preoperative enteral immunonutrition in well nourished patients with gastric cancer undergoing total gastrectomy. METHODS: Well nourished patients with primary gastric cancer, fit for total gastrectomy, were randomized to either a control group with regular diet, or an immunonutrition group that received regular diet supplemented with 1000 ml/day of immunonutrients for 5 consecutive days before surgery. The primary endpoint was the incidence of surgical-site infection (SSI). Secondary endpoints were rates of infectious complications, overall postoperative morbidity and C-reactive protein (CRP) levels on 3-4 days after surgery. RESULTS: Of 244 randomized patients, 117 were allocated to the control group and 127 received immunonutrition. SSIs occurred in 27 patients in the immunonutrition group and 23 patients in the control group (risk ratio (RR) 1.09, 95 per cent confidence interval 0.66 to 1.78). Infectious complications were observed in 30 patients in the immunonutrition group and 27 in the control group (RR 1.11, 0.59 to 2.08). The overall postoperative morbidity rate was 30.8 and 26.1 per cent respectively (RR 1.18, 0.78 to 1.78). The median CRP value was 11.8 mg/dl in the immunonutrition group and 9.2 mg/dl in the control group (P = 0.113). CONCLUSION: Five-day preoperative enteral immunonutrition failed to demonstrate any clear advantage in terms of early clinical outcomes or modification of the systemic acute-phase response in well nourished patients with gastric cancer undergoing elective total gastrectomy. REGISTRATION NUMBER: ID 000000648 (University Hospital Medical Information Network (UMIN) database).

Overexpression of PFTK1 predicts resistance to chemotherapy in patients with oesophageal squamous cell carcinoma.

BACKGROUND: Recently, PFTK1 was identified as a member of the cyclin-dependent kinase family; however, its expression and clinical significance in oesophageal squamous cell carcinoma (ESCC) have not been evaluated. METHODS: PFTK1 expression was initially examined by expression microarray in 77 ESCC patients. Using independent samples of 223 patients, PFTK1 expression was evaluated immunohistochemically to assess the relationship between expression and various clinicopathological parameters. The association between PFTK1 and the response to chemotherapy was also investigated in pretreatment samples of 85 patients who received chemotherapy as first treatment. RESULTS: Significant upregulation of PFTK1 expression was noted in ESCC compared with normal epithelium. PFTK1 expression was positive in 51.6% (115 out of 223) of the tumours, but did not correlate with any clinicopathological parameter. The 5-year overall survival rate was poorer in patients positive for PFTK1 (43.6%) than those with negative expression (66.2%, P<0.001). Uni- and multivariate analyses identified PFTK1 as an independent marker of prognosis (RR=2.428, 95% CI=1.615-3.711, P<0.001). Out of 85 biopsy samples, 40 (47.1%) tumours showed PFTK1-positive expression, and the response rate to chemotherapy was significantly lower than PFTK1-negative tumours (27.9% vs 72.1%, P<0.001). CONCLUSION: PFTK1 is not only useful as a prognostic marker, but also as a predictor of the response to chemotherapy.

Phase II trial of preoperative S-1 plus cisplatin followed by surgery for initially unresectable locally advanced gastric cancer.

BACKGROUND: The aim of this study was to evaluate the efficacy and feasibility of preoperative chemotherapy with S-1 plus cisplatin in patients with initially unresectable locally advanced gastric cancer. METHODS: We enrolled patients with initially unresectable locally advanced gastric cancer because of severe lymph node metastases or invasion of adjacent structures. Preoperative chemotherapy consisted of S-1 at 80 mg/m(2) divided in two daily doses for 21 days and cisplatin at 60 mg/m(2) intravenously on day 8, repeated every 35 days. If a tumor decreased in size, patients received 1 or 2 more courses. Surgery involved radical resection with D2 lymphadenectomy. RESULTS: Between December 2000 and December 2007, 27 patients were enrolled on the study. No CR was obtained, but PR was seen in 17 cases, and the response rate was 63.0%. Thirteen patients (48.1%) had R0 resections. There were no treatment related deaths. The median overall survival time (MST) and the 3-year overall survival (OS) of all patients were 31.4 months and 31.0%, respectively. Among the 13 patients who underwent curative resection, the median disease-free survival (DFS) and the 3-year DFS were 17.4 months and 23.1%, respectively. The MST and the 3-year OS were 50.1 months and 53.8%, respectively. The most common site of initial recurrence after the R0 resection was the para-aortic lymph nodes. CONCLUSIONS: Preoperative S-1 plus cisplatin can be safely delivered to patients undergoing radical gastrectomy. This regimen is promising as neoadjuvant chemotherapy for resectable gastric cancer. For initially unresectable locally advanced gastric cancer, new trials using more effective regimens along with extended lymph node dissection are necessary.

Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma.

BACKGROUND: Although multidrug resistance protein 2 (MRP2) confers chemoresistance in some cancer types, its implication on oesophageal squamous cell carcinoma (ESCC) remains unclear. METHODS: We evaluated MRP2 expression by immunohistochemistry and RT-PCR using 81 resected specimens from ESCC patients who did or did not receive neo-adjuvant chemotherapy (NACT), including 5-fluorouracil, doxorubicin, and cisplatin (CDDP). Correlation between MRP2 expression and response to chemotherapy was also examined in 42 pre-therapeutic biopsy samples and eight ESCC cell lines. RESULTS: MRP2-positive immunostaining was more frequently observed in ESCCs with NACT than in those without NACT (27.3 vs 5.4%). The MRP2-positive patients showed poorer prognosis than MRP2-negative patients (5-year survival rate, 25.6 vs 55.7%). Concordantly, ESCC with NACT showed 2.1-fold higher mRNA expression of MRP2 than those without NACT (P=0.0350). In pre-therapeutic biopsy samples of patients with NACT, non-responders showed 2.9-fold higher mRNA expression of MRP2 than responders (P=0.0035). Among the panel of ESCC cell lines, TE14 showed the highest MRP2 mRNA expression along with the strongest resistance to CDDP. Inhibition of MRP2 expression by small-interfering RNA reduced chemoresistance to CDDP. CONCLUSION: Our data suggested that MRP2 is one of molecules, which regulate the sensitivity to chemotherapy including CDDP in advanced ESCC patients.

Functional outcomes after extended surgery for gastric cancer.

BACKGROUND: Extended gastrectomy with para-aortic nodal dissection (PAND) or thorough dissection of mediastinal nodes using a left thoracoabdominal (LTA) approach is an alternative to D2 lymphadenectomy, with variable postoperative results. METHODS: Two randomized controlled trials have been conducted to compare D2 lymphadenectomy alone (263 patients) versus D2 lymphadenectomy plus PAND (260), and the abdominal-transhiatal (TH) approach (82) versus the LTA approach (85), in patients with gastric cancer. Prospectively registered secondary endpoints bodyweight, symptom scores and respiratory function were evaluated in the present study. RESULTS: Bodyweight was comparable after D2 and D2 plus PAND, but higher after TH than after LTA procedures at 1 and 3 years. At 1- and 3-year follow-up symptom scores were comparable between D2 and D2 plus PAND. A LTA approach resulted in significantly worse scores than a TH approach in terms of meal volume, return to work, incisional pain and dyspnoea up to 1 year. The decrease in vital capacity was significantly greater after LTA than TH procedures up to 6 months. CONCLUSION: Bodyweight and postoperative symptoms were not affected by adding PAND to a D2 procedure. A LTA approach aggravated weight loss, symptoms and respiratory functions compared with a TH approach.