Long-term outcomes of preoperative docetaxel with cisplatin plus S-1 therapy for gastric cancer with extensive nodal metastasis (JCOG1002).

BACKGROUND: Preoperative chemotherapy with cisplatin plus S-1 (CS) followed by gastrectomy with D2 plus para-aortic lymph node (PAN) dissection is regarded as a standard treatment in Japan for advanced gastric cancer with bulky lymph node (BN) and/or PAN metastasis. In the JCOG1002, we added docetaxel to CS (DCS) to further improve long-term outcomes. However, the primary endpoint, clinical response rate (RR), did not reach the expected level (Ito et al. in Gastric Cancer 20:322-31, 2017). Herein, we report our long-term survival results. METHODS: Patients with BN and/or PAN metastasis received 2 or 3 cycles of DCS therapy (docetaxel at 40 mg/m2 and cisplatin at 60 mg/m2 on day 1 and S-1 at 80 mg/m2 per day for 2 weeks, followed by a 2-week rest) followed by gastrectomy with D2 plus PAN dissection and postoperative S-1 for 1 year. RESULTS: Between July 2011 and May 2013, 53 patients were enrolled. Clinically, 17.0% had both PAN and BN metastasis, and the rest had either PAN (26.4%) or BN (56.6%) metastasis. Among all eligible patients, the 5-year overall survival was 54.9% (95% confidence interval 40.3-67.3%) at the last follow-up in May 2018. Among 44 eligible patients with R0 resection, the 5-year relapse-free survival was 47.7% (95% confidence interval 32.5-61.5%). CONCLUSIONS: Adding docetaxel to CS in preoperative chemotherapy for extensive nodal metastasis improved neither short-term outcomes nor long-term survival. Preoperative chemotherapy with CS followed by D2 + PAN dissection and postoperative S-1 remains the standard of care for patients with extensive nodal metastasis.

Endoscopic Submucosal Dissection (ESD) with Additional Therapy for Superficial Esophageal Cancer with Submucosal Invasion.

OBJECTIVE: The standard treatment for submucosal esophageal cancer is esophagectomy or chemoradiotherapy (CRT). However, these treatment modalities could deteriorate the general condition and quality of life of the patients who are intolerant to invasive therapy. It is therefore important and beneficial to develop less invasive treatment protocols for these patients. METHODS: The study included 43 patients who were clinically suspected of mucosa or submucosal esophageal cancer but underwent endoscopic submucosal dissection (ESD) as a primary treatment, due to the patients' poor performance statuses and/or preferences for less invasive therapy. According to the pathological findings and patient's general condition, whether the patient underwent additional treatments or remained hospitalized without additional treatments was thereafter decided for each patient. We retrospectively analyzed the outcomes of these patients. RESULTS: Fifteen patients underwent additional surgery, 11 patients underwent CRT/radiation therapy (RT) and 17 patients were followed without additional treatments. During the 3-year follow-up period, the relapse-free survival rates in the patients who received or did not receive additional treatments were 88% and 64%, respectively (95% confidence interval, 0.45-0.76, p=0.04). The relapse-free and overall survival rates in the patients with additional treatments were equivalent or superior to those described in previous reports of the standard treatments. Preceding ESD contributed to reduce the local relapse significantly to approximately 3.5% and additional CRT-related toxicities. CONCLUSION: Preceding ESD is very effective for the local control of cancer, and useful for histologically confirming the high-risk factors of relapse, such as ≥submucosal layer 2 (SM2) invasion and lymphovascular involvements. ESD with additional therapy may be a promising strategy for optimizing the selection of therapy depending on the patient's general condition.

A case report: pancreatic squamous cell carcinoma with effective response by S-1 therapy.

Squamous cell carcinoma (Sqc) of the pancreas is considered to be extremely rare. We report the case of a 79-year-old male with Sqc of the pancreas complicated by massive gastric ulcer fistula and multiple lymph node metastases. After completing two courses of S-1 chemotherapy, the gastric ulcer fistula and lymph node metastases improved. Sqc of the pancreas is usually associated with a poor prognosis. Various therapeutic regimens have been used for this type of cancer, but none has been proven effective. To the best of our knowledge, this report is the first on the effective response of pancreatic Sqc treated by S-1 chemotherapy.

A novel serum metabolomics-based diagnostic approach to pancreatic cancer.

BACKGROUND: To improve the prognosis of patients with pancreatic cancer, more accurate serum diagnostic methods are required. We used serum metabolomics as a diagnostic method for pancreatic cancer. METHODS: Sera from patients with pancreatic cancer, healthy volunteers, and chronic pancreatitis were collected at multiple institutions. The pancreatic cancer and healthy volunteers were randomly allocated to the training or the validation set. All of the chronic pancreatitis cases were included in the validation set. In each study, the subjects' serum metabolites were analyzed by gas chromatography mass spectrometry (GC/MS) and a data processing system using an in-house library. The diagnostic model constructed via multiple logistic regression analysis in the training set study was evaluated on the basis of its sensitivity and specificity, and the results were confirmed by the validation set study. RESULTS: In the training set study, which included 43 patients with pancreatic cancer and 42 healthy volunteers, the model possessed high sensitivity (86.0%) and specificity (88.1%) for pancreatic cancer. The use of the model was confirmed in the validation set study, which included 42 pancreatic cancer, 41 healthy volunteers, and 23 chronic pancreatitis; that is, it displayed high sensitivity (71.4%) and specificity (78.1%); and furthermore, it displayed higher sensitivity (77.8%) in resectable pancreatic cancer and lower false-positive rate (17.4%) in chronic pancreatitis than conventional markers. CONCLUSIONS: Our model possessed higher accuracy than conventional tumor markers at detecting the resectable patients with pancreatic cancer in cohort including patients with chronic pancreatitis. IMPACT: It is a promising method for improving the prognosis of pancreatic cancer via its early detection and accurate discrimination from chronic pancreatitis.

A novel serum metabolomics-based diagnostic approach for colorectal cancer.

BACKGROUND: To improve the quality of life of colorectal cancer patients, it is important to establish new screening methods for early diagnosis of colorectal cancer. METHODOLOGY/PRINCIPAL FINDINGS: We performed serum metabolome analysis using gas-chromatography/mass-spectrometry (GC/MS). First, the accuracy of our GC/MS-based serum metabolomic analytical method was evaluated by calculating the RSD% values of serum levels of various metabolites. Second, the intra-day (morning, daytime, and night) and inter-day (among 3 days) variances of serum metabolite levels were examined. Then, serum metabolite levels were compared between colorectal cancer patients (N = 60; N = 12 for each stage from 0 to 4) and age- and sex-matched healthy volunteers (N = 60) as a training set. The metabolites whose levels displayed significant changes were subjected to multiple logistic regression analysis using the stepwise variable selection method, and a colorectal cancer prediction model was established. The prediction model was composed of 2-hydroxybutyrate, aspartic acid, kynurenine, and cystamine, and its AUC, sensitivity, specificity, and accuracy were 0.9097, 85.0%, 85.0%, and 85.0%, respectively, according to the training set data. In contrast, the sensitivity, specificity, and accuracy of CEA were 35.0%, 96.7%, and 65.8%, respectively, and those of CA19-9 were 16.7%, 100%, and 58.3%, respectively. The validity of the prediction model was confirmed using colorectal cancer patients (N = 59) and healthy volunteers (N = 63) as a validation set. At the validation set, the sensitivity, specificity, and accuracy of the prediction model were 83.1%, 81.0%, and 82.0%, respectively, and these values were almost the same as those obtained with the training set. In addition, the model displayed high sensitivity for detecting stage 0-2 colorectal cancer (82.8%). CONCLUSIONS/SIGNIFICANCE: Our prediction model established via GC/MS-based serum metabolomic analysis is valuable for early detection of colorectal cancer and has the potential to become a novel screening test for colorectal cancer.

Ex vivo pig training model for esophageal endoscopic submucosal dissection (ESD) for endoscopists with experience in gastric ESD.

BACKGROUND: Esophageal endoscopic submucosal dissection (ESD) has developed in recent years because of its high rate of en bloc resection. However, for many endoscopists, technical difficulty and risks of complications are great barriers to performing esophageal ESD. In this study, we developed an original training model for esophageal ESD using isolated pig esophagus and assessed this ex vivo model in endoscopists with experience in gastric ESD. METHODS: Three endoscopists without experience in esophageal ESD but with some experience in gastric ESD performed esophageal ESD of artificial lesions in 10 consecutive sessions using this ex vivo model. The en bloc resection rate, operation time, number of muscularis propria layer injuries, and presence of perforation were recorded. We evaluated the effectiveness of this training in the three endoscopists by comparing results from the first five sessions (former period) with those from the last five sessions (latter period). RESULTS: All three endoscopists achieved en bloc resections in all trials. In the former period, injury to the muscularis propria layer for each of the three endoscopists occurred a mean of 2.2 (1-3), 0.6 (0-1), and 3.2 (1-6) times, respectively. Perforation occurred in one session performed by one endoscopist. In the latter period, the mean number of muscularis propria layer injuries for each of the three endoscopists decreased to 0.2 (0-1), 0.2 (0-1), and 0.8 (0-2), respectively. The time of operation shortened from 35.0 (25-40), 36.4 (30-50), and 29.8 (23-43) min to 23.0 (16-31), 25.6 (23-28), and 29.2 (21-37) min, respectively. CONCLUSIONS: This original ex vivo training model was helpful to endoscopists with experience in gastric ESD in acquiring the basic skills for performing esophageal ESD.

Serum metabolomics as a novel diagnostic approach for gastrointestinal cancer.

Conventional tumor markers are unsuitable for detecting carcinoma at an early stage and lack clinical efficacy and utility. In this study, we attempted to investigate the differences in serum metabolite profiles of gastrointestinal cancers and healthy volunteers using a metabolomic approach and searched for sensitive and specific metabolomic biomarker candidates. Human serum samples were obtained esophageal (n = 15), gastric (n = 11), and colorectal (n = 12) cancer patients and healthy volunteers (n = 12). A model for evaluating metabolomic biomarker candidates was constructed using multiple classification analysis, and the results were assessed with receiver operating characteristic curves. Among the 58 metabolites, the levels of nine, five and 12 metabolites were significantly changed in the esophageal, gastric and colorectal cancer patients, respectively, compared with the healthy volunteers. Multiple classification analysis revealed that the variations in the levels of malonic acid and L-serine largely contributed to the separation of esophageal cancer; gastric cancer was characterized by changes in the levels of 3-hydroxypropionic acid and pyruvic acid; and L-alanine, glucuronoic lactone and L-glutamine contributed to the separation of colorectal cancer. Our approach revealed that some metabolites are more sensitive for detecting gastrointestinal cancer than conventional biomarkers. Our study supports the potential of metabolomics as an early diagnostic tool for cancer.

Serum fatty acid profiling of colorectal cancer by gas chromatography/mass spectrometry.

AIMS: Several screening methods have been applied for the early diagnosis of colorectal cancer, but most colorectal cancer patients are not diagnosed at a localized stage. In order to find novel biomarkers for the diagnosis of colorectal cancer, profiling of the serum levels of fatty acids, which are the main components of fats and are important factors for human metabolism, was performed using the sera of colorectal cancer patients. MATERIALS & METHODS: A total of 42 colorectal cancer patients and eight healthy volunteers participated in this study. The serum levels of fatty acids, including free fatty acids and esterified fatty acids, were evaluated by gas chromatography/mass spectrometry. Then, partial least squares discriminant analysis was performed on the basis of the serum fatty acids detected by gas chromatography/mass spectrometry. RESULTS: The serum levels of the nine fatty acids exhibited distinct differences between the colorectal cancer patients and healthy volunteers: the levels of four fatty acids were higher in the colorectal cancer patients than the healthy volunteers, and those of the other five fatty acids were lower. These changes were also observed at a very early clinical stage. Furthermore, the levels of very-long-chain fatty acids had a tendency to be increased in the sera of the colorectal cancer patients. CONCLUSIONS: The pathogenesis of colorectal cancer leads to changes in the composition of serum fatty acids including free fatty acids and esterified fatty acids. These results suggest that serum fatty acid profiling may be used as a novel diagnostic tool for early-stage colorectal cancer.