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Breast cancer (BC) is the most common malignant tumor in females. Development of novel biomarkers or therapeutic targets may contribute toward the improvement of a patient's prognosis. Marginal zone B and B1 cell-specific protein (MZB1) is an unfolded protein response-related chaperone and mainly exists in the endoplasmic reticulum of B lymphocytes, although little is known regarding its role in BC cells. The present study aimed to investigate the significance of MZB1 expression in BC. To begin with, MZB1 mRNA expression levels in 13 BC cell lines and two non-cancerous mammary cell lines were evaluated. Next, mRNA and protein expression of MZB1 in BC patient tumor specimens was evaluated to assess the association between expression and clinicopathological factors or prognosis. MZB1 mRNA expression levels were detectable in four estrogen receptor (ER)-positive BC cell lines. When ratios of MZB1 mRNA expression levels between BC and non-cancerous specimens were evaluated, patients with stage III disease exhibited a higher ratio than patients with stage 0/I/II disease (P=0.009). Using immunohistochemistry, patients with ER-positive BC more frequently expressed MZB1, compared with patients with ER-negative BC (P=0.003). In patients with ER-positive BC, patients with MZB1-positive BC experienced shorter disease-free survival (DFS) times than patients with negative BC (P=0.026). Multivariate analysis of DFS demonstrated that MZB1 positivity was an independent prognostic factor (P=0.022). The results of the present study suggested that MZB1 expression may be associated with a more advanced stage of BC. Furthermore, in patients with ER-positive BC, MZB1 may be a potential prognostic marker.

β-1,4-N-Acetyl-galactosaminyltransferase 4 (B4GALNT4), an enzyme involved in ganglioside synthesis, is upregulated in many cancers. We examine B4GALNT4 expression and its relationship to prognosis in esophageal squamous cell carcinoma (ESCC).Expression of B4GALNT4 mRNA and B4GALNT4 protein was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively, in 17 human ESCC cell lines and/or clinical specimens from two independent cohorts of 147 and 159 ESCC patients. The contributions of B4GALNT4 to proliferation, invasion, migration, and adhesion was evaluated in ESCC cells subjected to siRNA-mediated gene knockdown. Correlations between clinicopathological parameters and B4GALNT4 expression in clinical specimens were analyzed in both patient cohorts.B4GALNT4 mRNA expression levels varied widely in ESCC cell lines, regardless of differentiation status or the originating tissue. Knockdown of B4GALNT4 significantly suppressed the proliferation, invasion, migration, and adhesion of ESCC cell lines compared with control cells. B4GALNT4 mRNA was overexpressed in ESCC tissues compared with adjacent normal esophageal tissues. High mRNA expression was significantly associated with poor disease-free survival and hematogenous recurrence, and high B4GALNT4 protein expression was also significantly related to poor disease-specific survival. On multivariable analysis, high B4GALNT4 expression was an independent predictor of poor prognosis. In both patient cohorts, high B4GALNT4 expression did not correlate with known prognostic factors, such as disease stage, lymphovascular invasion, or squamous cell-carcinoma-related antigen level.B4GALNT4 influences the malignant behavior of ESCC cells. B4GALNT4 expression may serve as a novel prognostic marker, independent of established risk factors, for ESCC patients.

Recurrence after radical resection of esophageal squamous cell carcinoma (ESCC) is common. Limited evidence is available about the differences in clinical characteristics, risk factors, and prognostic significance between nodal and distant recurrence of thoracic ESCC. We retrospectively analyzed 341 patients who underwent radical resection of thoracic ESCC and experienced (1) initial recurrence only in lymph nodes (n = 39), (2) recurrence only at distant organs (n = 57), or (3) no recurrences (n = 245) after follow-up ≥ 24 months. Clinicopathological characteristics, survival times, and risk factors were compared between the nodal and distant recurrence groups. The median follow-up time was 57.8 months. Metastasectomy as initial treatment for the recurrence was performed for six (15.4%) patients in the nodal recurrence group and one patient in the distant recurrence group. Compared with the nodal recurrence group, patients with distant recurrence had significantly shorter disease-free survival [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.10–2.57, P = 0.0169], postrecurrence survival (HR 1.77, 95% CI 1.01–3.10, P = 0.0476), and overall survival (HR 1.98, 95% CI 1.12–3.51, P = 0.0193). The distant recurrence group had significantly larger macroscopic tumor size and more advanced pathological T stage than the nodal recurrence group, whereas preoperative treatment, tumor location, number of fields dissected, tumor differentiation, lymphatic involvement, and vessel invasion were not significantly different between the two groups. Survival times and recurrence risk factors differed between patients with nodal and distant recurrence after radical resection of thoracic ESCC.

Background The three dominant recurrence patterns of gastric cancer are peritoneal, hematogenous, and nodal recurrence. Correlation between initial recurrence site and prognosis is poorly understood, particularly after standardization of postoperative S‐1 adjuvant chemotherapy. Methods We analyzed a multi‐institutional database of 3484 patients who underwent gastrectomy for gastric cancer between 2010 and 2014. Patients who experienced recurrences after curative gastrectomy classified into peritoneal, hematogenous, or nodal recurrence groups, according to their initial recurrence sites, and their prognoses were compared. Results We included 313 patients in the analysis, of whom 190 patients (63%) were treated with postoperative adjuvant chemotherapy. Pathological disease states were stage I: n = 20 (6%), stage II: n = 62 (20%), and stage III: n = 231 (74%). Patients were categorized into groups by peritoneal (n = 127), hematogenous (n = 123), and nodal (n = 63) recurrence. The peritoneal recurrence group tended to have longer recurrence‐free survival, but shorter post‐recurrence survival, than the other two groups. Median disease‐specific survival after curative resection by group were peritoneal: 25.8 months, hematogenous: 29.0 months, and nodal: 27.8 months (peritoneal vs hematogenous, P = .152; hematogenous vs nodal, P = .955; peritoneal vs nodal, P = .213). Conclusions Prognoses after curative resection for gastric cancer were similar among patients with peritoneal, hematogenous, or nodal recurrences., We used a multi‐institutional dataset to see whether prognosis and site of initial recurrence after curative resection for gastric cancer were correlated. We found that prognoses were similar among patients with peritoneal, hematogenous, or nodal recurrences.

Hematogenous recurrence is a challenging clinical finding that often leads to fatalities of patients with gastric cancer. Therefore, the identification of specific biomarkers and potential therapeutic target molecules for hematogenous recurrence is required to improve the outcomes of these patients. Here, transcriptome and bioinformatics analyses were conducted to uncover candidate molecules differentially expressed in patients with hematogenous recurrence of gastric cancer. One potential candidate identified was asialoglycoprotein receptor 2 (ASGR2), and siRNA experiments were conducted to determine the effect of manipulating ASGR2 expression has on cell phenotypes. ASGR2 mRNA expression analysis using quantitative real-time reverse-transcription PCR was conducted with stage II/III gastric cancer clinical specimens (n = 95). Transcript levels were increased in gastric cancer cells as compared with a control nontumorigenic epithelial cell line. Knockdown of ASGR2 decreased the adhesion and migration potential. Thus, although gastric cancer cell–invasive activity was significantly decreased by knockdown, forced expression of ASGR2 promoted invasive activity. Using a mouse hepatic metastasis model, knockdown of ASGR2 resulted in the absence of hepatic metastasis formation. High ASGR2 expression in primary gastric cancer tissues was an independent predictor of shorter disease-free and overall survival. Finally, patients with high ASGR2 expression were more likely to have a high cumulative rate of hematogenous recurrence but not peritoneal or nodal recurrence. Implications: ASGR2 expression is associated with the malignant phenotypes in gastric cancer and represents a specific biomarker of hematogenous recurrences after curative resection for gastric cancer. Mol Cancer Res; 16(9); 1420–9. ©2018 AACR.

Background/aim This retrospective study focused on the correlation between molecular markers and prognostic outcomes of colon cancer patients depending on sidedness. Materials and methods A total of 117 stage I-III colon cancer patients who underwent colectomy were enrolled. Novel methylation markers (KIF1A, PAX5 and VGF) were selected for epigenetic evaluation and p53 and ERCC1 protein expression was examined for the investigation of genetic alterations. Results High frequency of methylation was observed in 68.2% of right-sided and 39.7% of left-sided colon cancer cases (p=0.004). Abnormal p53 was identified in 52.3% of right-sided and 75.3% of left-sided cases (p=0.015). In right-sided cases, highly methylated genes demonstrated significantly favorable disease-free survival (p=0.049). Regarding left-sided cases, advanced T stage (p=0.028) and abnormal p53 (p=0.028) were revealed to be significant predictive factors of the disease-free survival outcome. Conclusion Molecular alterations, as significant prognostic factors, might differ depending on the sidedness of colon cancers.

Background: Curative treatment for gastric cancer (GC) comprising gastrectomy with systematic lymph node dissection can result in postoperative complications. Postoperative pneumonia is sometimes fatal, like surgery-related complications such as anastomotic leakage. In this retrospective study, we analyzed a multi-institutional collaborative dataset with the aim of identifying predictors of postgastrectomy pneumonia. Methods: From a retrospective database of 3,484 patients who had undergone gastrectomy for GC at nine Japanese institutions between 2010 and 2014, 1,415 patients who met all eligibility criteria were identified as eligible for analysis. Predictive values of 31 candidate variables for postoperative pneumonia were assessed. Results: Forty-two patients (3.0%) had grade II or higher postoperative pneumonia. Preoperative systemic inflammation score (SIS) had the greatest area under the curve (0.655) for predicting postoperative pneumonia (optimal cutoff value = 2). The odds ratio (OR) of high SISs associated with postoperative pneumonia was 3.10 (95% confidence interval [CI], 1.54–6.07; p < 0.001). Multivariate binomial logistic analysis identified high SIS as an independent risk factor for postoperative pneumonia (OR, 2.31; 95% CI, 1.19–4.48; p = 0.013). A forest plot revealed that ORs of high SISs were highest in female patients. Conclusions: Our findings indicate that the preoperative SIS may serve as a simple predictor of postgastrectomy pneumonia, assisting physicians’ efforts to take preventive measures against this complication.

Background/aim Establishment of mouse xenograft models is necessary for oncological research and depends on the characteristics of the cell lines and the immune system of the host. In this study, we describe the development of mouse xenograft models using human gastric cancer (GC) cell lines. Materials and methods MKN1 stably-expressing luciferase (MKN1-Luc), N87, KATO III, MKN45 stably-expressing luciferase (MKN45-Luc), NUGC4, and OCUM-1 human GC cell lines were injected intraperitoneally into mice to establish peritoneal metastasis models. MKN45-Luc were injected into subcutaneously implanted spleen, and MKN1-Luc and MKN45-Luc were injected directly into the portal veins of mice for the establishment of hepatic metastasis models. Results Peritoneal metastasis was formed after implantation of MKN1-Luc, N87, KATO III, MKN45-Luc, and NUGC4 in nude mice, but not formed in OCUM-1 even in NOD/SCID mice. After intrasplenic injection of MKN45-Luc, we found no hepatic metastasis formation. We identified hepatic metastasis formation after direct injection of MKN45-Luc and MKN1-Luc into the portal veins of NOD/SCID mice. Conclusion Peritoneal and hepatic metastasis mouse xenograft models were successfully established using several human GC cell lines.

Purpose The aim of this randomized, multicenter, noncomparative, phase II trial was to investigate the efficacy and safety of two potential first-line treatments, capecitabine and oxaliplatin (CapOX) plus bevacizumab (BEV) and capecitabine and irinotecan (CapIRI) plus bevacizumab, in Japanese patients with metastatic colorectal cancer (mCRC). Patients and Methods Patients with untreated mCRC were randomly assigned to receive either CapOX plus bevacizumab (CapOX/BEV arm: bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 2,000 mg/m2 on days 1–14, every 3 weeks) or CapIRI plus bevacizumab (CapIRI/BEV arm: bevacizumab 7.5 mg/kg and irinotecan 200 mg/m2 on day 1 and capecitabine 1,600 mg/m2 on days 1–14, every 3 weeks). The primary endpoint was overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results A total of 107 patients were enrolled. The intent-to-treat population comprised 54 patients in the CapOX/BEV arm and 53 patients in the CapIRI/BEV arm. The median follow-up period was 35.5 months. ORR was 56% in the CapOX/BEV arm and 55% in the CapIRI/BEV arm. Median PFS and OS were 12.4 and 26.7 months in the CapOX/BEV arm and 11.5 and 28.7 months in the CapIRI/BEV arm, respectively. The frequencies of hematological and nonhematological adverse events above grade 3 were 13% and 30% in the CapOX/BEV arm and 25% and 23% in the CapIRI/BEV arm, respectively. Conclusion CapOX plus bevacizumab and CapIRI plus bevacizumab are equally effective and feasible as the first-line treatments in Japanese patients with mCRC. Implications for Practice The CCOG-1201 study was designed to evaluate the efficacy and safety of capecitabine and oxaliplatin plus bevacizumab and capecitabine and irinotecan plus bevacizumab as a first-line treatment in Japanese patients with metastatic colorectal cancer. This article reports on the trial and efforts to define the role of these regimens, including the effect of KRAS status and UGT1A1 polymorphisms in metastatic colorectal cancer.

Few well-controlled studies have compared postoperative complications between Billroth I (B-I) and Roux-en-Y (R-Y). The aim of the present study was to compare the incidence of overall and severe postoperative complications by reconstruction method after distal gastrectomy. We performed a multi-institutional dataset study of patients who underwent distal gastrectomy with B-I or R-Y reconstruction from 2010 to 2014. Using propensity scores to strictly balance the significant variables, we compared postoperative complications between the techniques. After matching, we enrolled 1014 patients (n = 507 in each group). The incidence of postoperative complications in the R-Y group was significantly higher vs the B-I group (29% vs 17%, P

Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Most GC patients are diagnosed when the cancer is in an advanced stage, and consequently, some develop metastatic lesions that generally cause cancer-related death. Metastasis establishment is affected by various conditions, such as tumor location, hemodynamics and organotropism. While digestive cancers may share a primary site, certain cases develop hematogenous metastasis with the absence of peritoneal metastasis, and vice versa. Numerous studies have revealed the clinicopathological risk factors for hematogenous metastasis from GC, such as vascular invasion, advanced age, differentiation, Borrmann type 1 or 2 and expansive growth. Recently, molecular mechanisms that contribute to metastatic site determination have been elucidated by advanced molecular biological techniques. Investigating the molecules that specifically participate in metastasis establishment in distinct secondary organs will lead to the development of novel biomarkers for patient stratification according to their metastatic risk and strategies for preventing and treating distinct metastases. We reviewed articles related to the molecular landscape of hematogenous metastasis from GC.

Lysyl oxidase (LOX) family genes, particularly lysyl oxidase-like protein 2 (LOXL2), have been implicated in carcinogenesis, metastasis, and the epithelial-to-mesenchymal transition (EMT) in various cancers. This study aimed to explore the clinical implications of LOXL2 expression in pancreatic cancer (PC) in the context of EMT status. LOX family mRNA expression was measured in PC cell lines, and LOXL2 protein levels were examined in surgical specimens resected from 170 patients with PC. Higher LOXL2 expression was observed in cell lines from mesenchymal type PC than in those from epithelial type PC. A significant correlation between LOXL2 expression and the EMT status defined based on the expression of E-cadherin and vimentin was observed in surgical specimens (P P P = 0.03) was a significant independent prognostic factor for patients with PC. Additionally, LOX inhibition significantly decreased PC cell proliferation, migration, and invasion in vitro. In conclusion, LOXL2 expression is potentially associated with PC progression, and LOXL2 expression represents a biomarker for predicting the prognosis of patients with PC who have undergone complete resection.

Liver metastasis remains a serious problem in the management of gastric cancer (GC). Our aims were to identify through transcriptome analysis a molecule that mediates hepatic metastasis in GC, and to evaluate its potential as a diagnostic marker and a therapeutic target. The effects of knocking out a relevant molecule using genome editing were evaluated in vitro experiments and in mouse xenograft models. Expression levels of candidate molecule in 300 pairs of gastric tissues were determined to assess whether differentially expressed genes predicted hepatic recurrence, metastasis, or both. Transcriptome data identified the overexpression of synaptotagmin VII (SYT7) in GC tissues with hepatic metastasis. Its expression in the GC cell lines was high, particularly in those that exhibited a differentiated phenotype, and positively correlated with the expression of SNAI1 and TGFB3, and inversely with RGS2. SYT7 knockout inhibited the proliferation of GC cells, indicated by increased apoptosis with activated caspase and loss of mitochondria membrane potential, G2/M cell-cycle arrest and attenuated cell migration, invasion, and adhesion. The tumorigenicity of SYT7-knockout cells was moderately reduced in a mouse model of subcutaneous metastasis in which the levels of BCL2 and HIF1A were decreased and was more strikingly attenuated in a model of hepatic metastasis. The SYT7 levels in the primary GC tissues were significantly associated with hepatic recurrence, metastasis, and adverse prognosis. SYT7 represents a tool for prediction and monitoring of hepatic metastasis from GC as well as being a promising therapeutic target.

Background Peritoneal metastasis is a frequent cause of death in patients with gastric cancer. The aim of this study was to identify molecules responsible for mediating peritoneal metastasis of gastric cancer. Methods Transcriptome and bioinformatics analyses were conducted to identify molecules associated with peritoneal metastasis. The therapeutic effects of intraperitoneally administered small interfering (si) RNA were evaluated using mouse xenograft models. Expression of mRNA and protein was determined in gastric tissues from patients with gastric cancer. Results Synaptotagmin XIII (SYT13) was expressed at significantly higher levels in patients with peritoneal recurrence, but not in those with hepatic or distant lymph node recurrence. Inhibition of SYT13 expression in a gastric cancer cell line transfected with SYT13-specific siRNA (siSYT13) was associated with decreased invasion and migration ability of the cells, but not with proliferation and apoptosis. Intraperitoneal administration of siSYT13 significantly inhibited the growth of peritoneal nodules and prolonged survival in mice. In an analysis of 200 patients with gastric cancer, SYT13 expression in primary gastric cancer tissues was significantly greater in patients with peritoneal recurrence or metastasis. A high level of SYT13 expression in primary gastric cancer tissues was an independent risk factor for peritoneal recurrence. Conclusion SYT13 expression in gastric cancer is associated with perioneal metatases and is a potential target for treatment.

INTRODUCTION Optical trocar access is a technique to place the initial trocar in laparoscopic surgery. With optical trocar access, each tissue layer can be visualized before insertion, which can help prevent organ injury, and air leaks at the trocar site can be minimized even in obese patients. The aim of this study was to compare the time needed for trocar insertion using optical trocar access and an open method in patients who underwent laparoscopic gastrointestinal surgery. METHODS We reviewed our prospectively collected database and identified 384 patients who underwent laparoscopic gastrointestinal surgery involving initial trocar insertion near the umbilicus by either the optical trocar access or the open method. Before the two methods were compared, propensity score matching was used to adjust for essential variables between the optical trocar access and open groups. RESULTS Patients categorized in the optical trocar access and open groups were matched one-to-one by propensity score matching, and 137 pairs of patients were generated. The time needed for trocar insertion was significantly shorter in the optical trocar access group than in the open group (36.6 vs 209.8 s, P

Although peritoneal metastasis is a serious concern in patients with gastric cancer, no acceptable and specific biomarker is available. We aimed to identify a candidate biomarker to predict peritoneal metastasis of gastric cancer. Metastatic pathway-specific transcriptome analysis was conducted by comparison of patient groups with no recurrence and with peritoneal, hepatic, and nodal recurrence. Fifteen cell lines and 262 pairs of surgically resected gastric tissues were subjected to messenger RNA (mRNA) expression analysis. Polymerase chain reaction array analysis was performed to explore coordinately expressed cancer-related genes. To evaluate the in situ protein localization and expression patterns, immunohistochemical staining was performed. From transcriptome data, troponin I2 (TNNI2) was identified as a candidate molecule specifically overexpressed in gastric cancer prone to peritoneal metastasis. TNNI2 mRNA was expressed at differential levels, independent of differentiated phenotype of cell lines. Epithelial to mesenchymal transition-related genes, tumor inhibitor of metalloproteinase 1 (TIMP1), and vacuolar protein sorting 13 homolog A (VPS13A) were expressed with TNNI2 at correlation coefficient > 0.7. The optimal cutoff of TNNI2 expression was determined as 0.00017. High TNNI2 expression was significantly and specifically associated with peritoneal metastasis and served as an independent risk marker for peritoneal recurrence after curative gastrectomy. Prevalence of peritoneal recurrence increased in parallel with staining intensity of TNNI2. TNNI2 expression in gastric tissues may serve as a specific biomarker for prediction of peritoneal metastasis of gastric cancer and contribute to improvement of patient management.

Intraperitoneal administration of paclitaxel had been considered a promising option to treat peritoneal metastasis, the most frequent pattern of recurrence in gastric cancer after D2 gastrectomy, but its safety and efficacy after gastrectomy had not been fully explored. A phase II randomized comparison of postoperative intraperitoneal (IP) vs. intravenous (IV) paclitaxel was conducted. Patients with resectable gastric linitis plastica, cancer with minimal amount of peritoneal deposits (P1), or cancer positive for the peritoneal washing cytology (CY1) were eligible. After intraoperative confirmation of the above disease status and of resectability, patients were randomized to be treated either by the IP therapy (paclitaxel 60 mg/m2 delivered intraperitoneally on days 0, 14, 21, 28, 42, 49, and 56) or the IV therapy (80 mg/m2 administered intravenously using the identical schedule) before receiving further treatments with evidence-based systemic chemotherapy. The primary endpoint was 2-year survival rate. Of the 86 patients who were randomized intraoperatively, 83 who actually started the protocol treatment were eligible for analysis (n = 39, IP group; n = 44, IV group). The 2-year survival rate of the IP and IV groups was 64.1% (95% CI 47.9–76.9) and 72.3% (95% CI 56.3–83.2%), respectively (p = 0.5731). The IP treatment did not confer significant overall or progression-free survival benefits, and was associated with particularly poor performance in patients with residual disease, including the CY1 P0 population. We were unable to prove superiority of the IP paclitaxel over IV paclitaxel delivered after surgery to control advanced gastric cancer with high risk of peritoneal recurrence.

Fluorouracil monotherapy, instead of the FOLFOX or FOLFIRI regimen, is administered to patients intolerant to oxaliplatin or irinotecan because of their adverse effects. A prospective clinical trial was designed to evaluate the efficacy and safety of fluorouracil monotherapy combined with panitumumab administered to patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) intolerant to oxaliplatin and irinotecan. Screening for potential serum biomarkers to predict early therapeutic responses was conducted. This single-arm, open-label multicenter phase II trial recruited patients with KRAS WT mCRC from 16 institutes between January 2012 and October 2014. Panitumumab (6 mg/kg) was intravenously administered every 2 weeks, combined with fluorouracil monotherapy, in 2-week cycles. The primary objective was overall response rate, and secondary endpoints included disease-control rate, progression-free survival, overall survival, toxicity, and blood-test data. Forty patients (male, 65.0%; median age, 74 years; colon cancer, 72.5%) met eligibility criteria and received 7 cycles (median) of fluorouracil chemotherapy combined with panitumumab. There were no treatment-related deaths. Median time to treatment failure was 3.2 months. 23 (57.5%) patients experienced at least one adverse effect ≥ grade 3. The response rate was 10.0% (95% confidence interval 2.8–23.7%). Median progression-free survival and overall survival were 4.3 and 11.3 months, respectively. Total lactase dehydrogenase (LDH) levels and those of LDH-4 and LDH-5, quickly changed with disease reduction or progression. Fluorouracil monotherapy combined with panitumumab was safely administered to patients with KRAS WT mCRC intolerant to oxaliplatin and irinotecan. Serum LDH levels may predict early responses.

BACKGROUND: Most previous reports to analyze risk factors for peritoneal recurrence in patients with colon cancer have been observational studies of a population-based cohort. OBJECTIVE: This study aimed to determine the risk factors for peritoneal recurrence in patients with stage II to III colon cancer who underwent curative resection. DESIGN: This was a pooled analysis using a combined database obtained from 3 large phase III randomized trials (N = 3714). SETTINGS: Individual patient data were collected from the Japanese Foundation for Multidisciplinary Treatment of Cancer clinical trials 7, 15, and 33, which evaluated the benefits of postoperative 5-fluorouracil–based adjuvant therapies in patients with locally advanced colorectal cancer. PATIENTS: We included patients who had stage II to III colon cancer and underwent curative resection with over D2 lymph node dissection. MAIN OUTCOME MEASURES: Main outcomes measured were risk factors for peritoneal recurrence without other organ metastasis after curative surgery. RESULTS: Peritoneal recurrence occurred in 2.3% (86/3714) of all patients undergoing curative resection. Mean duration from operation to peritoneal recurrence was 17.0 ± 10.3 months. Of these patients with peritoneal recurrence, 29 patients (34%) had recurrence in ≥1 other organ. Multivariate analysis showed that age (≥60 y: HR = 0.531; p = 0.0182), pathological T4 (HR = 3.802; p < 0.0001), lymph node involvement (HR = 3.491; p = 0.0002), and lymphadenectomy (D2: HR = 1.801; p = 0.0356) were independent predictors of peritoneal recurrence. The overall survival was lower in patients who developed peritoneal recurrence than in those with other recurrence (HR = 1.594; p = 0.002). LIMITATIONS: The regimens of adjuvant chemotherapy were limited to oral 5-fluorouracil. CONCLUSIONS: Our findings clarified the risk factors for peritoneal recurrence in patients who underwent curative resection for colon cancer. See Video Abstract at http://links.lww.com/DCR/A609.

Objective: To develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of gastric cancer (GC). Background: Advanced GC frequently recurs because of undetected micrometastases even after curative resection. Peritoneal metastasis has been the most frequent recurrent pattern after gastrectomy and is incurable. Methods: We conducted a recurrence pattern-specific transcriptome analysis in an independent cohort of 16 patients with stage III GC who underwent curative gastrectomy and adjuvant S-1 for screening candidate molecules specific for peritoneal metastasis of GC. Next, another 340 patients were allocated to discovery and validation sets (1:2) to evaluate the diagnostic and predictive value of the candidate molecule. The results of quantitative reverse-transcription PCR and immunohistochemical analysis were correlated with clinical characteristics and survival. The effects of siRNA-mediated knockdown on phenotype and fluorouracil sensitivity of GC cells were evaluated in vitro, and the therapeutic effects of siRNAs were evaluated using a mouse xenograft model. Results: Synaptotagmin VIII (SYT8) was identified as a candidate biomarker specific to peritoneal metastasis. In the discovery set, the optimal cut-off of SYT8 expression was established as 0.005. Expression levels of SYT8 mRNA in GC tissues were elevated in the validation set comprising patients with peritoneal recurrence or metastasis. SYT8 levels above the cut-off value were significantly and specifically associated with peritoneal metastasis, and served as an independent prognostic marker for peritoneal recurrence-free survival of patients with stage II/III GC. The survival difference between patients with SYT8 levels above and below the cut-off was associated with patients who received adjuvant chemotherapy. Inhibition of SYT8 expression by GC cells correlated with decreased invasion, migration, and fluorouracil resistance. Intraperitoneal administration of SYT8-siRNA inhibited the growth of peritoneal nodules and prolonged survival of mice engrafted with GC cells. Conclusions: SYT8 represents a promising target for the detection, prediction, and treatment of peritoneal metastasis of GC., ファイル公開：2019-03-01

To investigate the efficacy and safety of planned postoperative adalimumab (ADA) therapy for Japanese patients with Crohn’s disease (CD). The subjects of this study were 26 patients who underwent bowel resection for CD. All patients received subcutaneous injections of ADA 160/80 mg at the time of surgery and 2 weeks later, followed by 40 mg every 2 weeks thereafter. The primary endpoint of this study was the incidence of endoscopic recurrence, defined by Rutgeerts endoscopic recurrence scale ≥ i2, 1 year after surgery. After the median follow-up period of 41.3 months, the median number of treatments with ADA was 56 and the median time-to-treatment failure was 25.6 months. Endoscopic recurrence was observed in 34.6% of the patients 1 year after surgery. Univariate analyses showed that preoperative ADA therapy was significantly associated with endoscopic recurrence. Clinical recurrence developed in 16.7% of the patients within 1 year after surgery. Secondary surgery for recurrence was not required. Although adverse events (≥ grade 3) were experienced by 15.4% of patients, none was withdrawn from this study. Planned postoperative ADA therapy reduced the incidence of endoscopic and clinical recurrence after bowel resection in Japanese patients with CD. This trial is registered with the University Hospital Medical Information Network (UMIN000007514).

Background/Aims: Do serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 levels serve as prognostic indicators in patients with gastric cancer (GC)? This is a question that has long been disputed. The aim of this study was to evaluate the significance of perioperative serum levels of CEA and CA19-9 for predicting the recurrence and long-term survival after patients with pT2-4 GC undergo curative gastrectomy. Methods: This study included 251 patients with radically resected pT2-4 GC without preoperative treatment. Associations between the preoperative and postoperative serum levels of CEA or CA19-9 and postoperative long-term outcomes and recurrence patterns were evaluated. Results: Preoperative CEA >5.0 ng/mL was an independent prognostic factor of overall survival. Elevation of both preoperative CEA and CA19-9 levels showed no synergistic adverse effects on prognosis. Preoperative levels of these markers achieved superior predictive performance compared with the postoperative values. Adverse prognosis is significantly associated with persistent elevation of CEA levels before and after gastrectomy. Elevation of CEA levels, particularly at postoperative measurement, was significantly associated with hematogenous recurrence. Conclusion: Determination of perioperative CEA levels facilitated predictions of recurrence patterns and prognosis among patients with pT2-4 GC who underwent curative gastrectomy., ファイル公開日: 2018/12/01

Background: Gastric cancer (GC) relapse can occur even if curative resection is achieved. Biomarkers predicting recurrence are needed to provide appropriate postoperative surveillance and perioperative therapeutic strategy. Methods: A global expression profiling was performed using tissues from GC patients with synchronous liver-confined metastasis. Family with sequence similarity 46, member C (FAM46C), was identified as a candidate biomarker. mRNA expression analysis, direct nucleotide sequencing, bisulfite sequencing and copy number assays for FAM46C were performed with eleven GC cell lines. Expression levels of FAM46C in primary GC tissues from 129 patients who underwent curative GC resection were determined and correlated with clinicopathological factors, including postoperative outcome. Results: Levels of FAM46C mRNA differed among GC cell lines. Point mutations in FAM46C were detected in five GC cell lines accompanied with reduced FAM46C transcription. No hypermethylation was found in the promoter region of FAM46C. Copy number alterations were found in six GC cell lines with differing FAM46C transcription levels. Reduced FAM46C mRNA expression levels were detected in 117 (91 %) GC specimens compared with adjacent noncancerous tissues. Low FAM46C expression levels were significantly associated with larger macroscopic GC tumor sizes. The low FAM46C expression group was likely to have shorter disease-free survival than the high group and low FAM46C level was identified as an independent risk factor for recurrence after curative resection. FAM46C expression levels were low in all cases that were later found to have hepatic recurrence. Conclusions: Reduced GC expression of FAM46C is a potential biomarker to predict hepatic recurrence after curative gastrectomy.

Introductions: The prognosis after resection of pancreatic ductal adenocarcinoma (PDAC) is still limited though the survival benefit is recently reported by neo-adjuvant chemotherapy (NAC). The existence of cancer stem cells (CSCs) is known as one of the important mechanisms for cancer cells to survive against chemotherapy. We hypothesized that the population of CSCs among cancer cells after chemotherapy could contribute recurrence after surgical resections, and could be detected by some CSC markers. Methods: We checked elevation of CSC markers in resected cases after pre-operative therapy (NAC with gemcitabine plus nab-paclitaxel, n=3; NAC with FOLFIRINOX, n=3; and neo-adjuvant chemo-radiotherapy (NACRT) with S1+Radiation, n=3) compared to surgery alone (n=3) with RT2 Profiler PCR Array. As CSC models, we performed sphere formation assay with PDAC cell lines (Panc1 and BXPC3) and evaluated the expression of CSC markers with qRT-PCR. Then, we performed qRT-PCR with 48 PDAC resected cases including 26 cases with pre-operative therapy (54%). Results: RT2 Profiler PCR Array showed higher expression of some CSC markers with pre-operative treatment (n=9) than without them (n=3). Spheroid assay showed elevation of CSC markers in spheroid compared to parental cells (Panc1: 10 among 16 markers, BXPC3 14 among 16 markers). In the cohort of 48 resected PDAC patients, ALDH1, Nanog, SOX2, MYC CXCR4 and DCLK1 showed significantly higher expression in pre-operative therapy than in surgery alone (P Conclusions: Our findings indicated that CSCs are more in resected tissues after NAC and NACRT than in without pre-operative therapy. YAP1 expression in tumors or CXCR4 in adjacent parenchyma of pancreas can be prognosis markers after surgical resection for PDAC. Citation Format: Yoshikuni Inokawa, Suguru Yamada, Masamichi Hayashi, Yuki Sunagawa, Fuminori Sonohara, Hideki Takami, Norifumi Hattori, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera. The impact of cancer stem cell markers in the tissues of pancreatic ductal adenocarcinoma for prognosis after surgical resections [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6016.

The albumin–bilirubin (ALBI) score was initially developed for assessing liver dysfunction severity and was suggested to have prognostic value in patients with hepatocellular carcinoma. We aimed to evaluate the prognostic impact of ALBI grade in patients with advanced gastric cancer (GC) after radical gastrectomy. This study included 283 patients who underwent radical gastrectomy for pT2-4 GC without preoperative treatment. ALBI was calculated as follows: (log10 bilirubin (μmol/L) × 0.66) + (albumin (g/L) × −0.0852) and categorized into grades 1 (≤−2.60), 2 (−2.60

Background Molecular biomarkers capable of predicting recurrence patterns and prognosis are helpful for risk stratification and providing appropriate treatment to patients with hepatocellular carcinoma (HCC). In this study, we focused on G protein-coupled receptor 155 (GPR155), a cell surface signaling protein, as a candidate biomarker. Methods We analyzed GPR155 expression, DNA methylation, and copy number in HCC cell lines. The clinical significance of GPR155 expression was evaluated using 144 pairs of surgically resected liver and normal tissues with subgroup analysis based on hepatitis virus infection. Results GPR155 mRNA expression levels were differential and were decreased in 89% of HCC cell lines. No DNA methylation was detected, whereas copy number alterations were present in five (56%) HCC cell lines. GPR155 mRNA expression level was independent of background liver status and significantly lower in HCC tissues than corresponding normal liver tissues. The expression patterns of GPR155 protein by immunohistochemical staining were significantly associated with those of GPR155 mRNA. Downregulation of GPR155 was significantly associated with more aggressive HCC phenotypes including high preoperative α-fetoprotein, poor differentiation, serosal infiltration, vascular invasion, and advanced disease stage. Patients with downregulation of GPR155 were more likely to have worse prognosis after curative resection irrespective of hepatitis virus infection. Patients who experienced extrahepatic (distant) recurrences had significantly lower GPR155 expression than those with intrahepatic (liver confined) recurrences. Conclusions Downregulation of GPR155 may serve as a prognosticator that also predicts initial recurrence sites independent of hepatitis virus infection. Electronic supplementary material The online version of this article (10.1186/s12885-017-3629-2) contains supplementary material, which is available to authorized users.

The poor prognosis and increasing incidence of esophageal squamous cell carcinoma (ESCC) highlight the need for identification of novel ESCC‑associated molecular events to improve the diagnosis, and treatment of this disease. Non‑specific cytotoxic cell receptor protein 1 (NCCRP1) was reported to be abundantly expressed in human squamous epithelium and to be involved in cell proliferation; however, the role of NCCRP1 in ESCC remains unclear. To elucidate the oncological roles of NCCRP1 in ESCC, NCCRP1 expression, DNA methylation, and copy numbers were analyzed in ESCC cell lines. Nine ESCC cell lines demonstrated different NCCRP1 mRNA expression levels and all exhibited hypermethylation of the NCCRP1 promoter, but no copy number loss. Additionally, NCCRP1 expression was determined in 213 surgically resected esophageal tissue samples. NCCRP1 mRNA expression levels were reduced in ESCC tissues compared with corresponding non‑cancerous adjacent tissues in 204 (95.8%) patients. Patients in the low NCCRP1 expression group tended to have a higher recurrence rate and a shorter overall survival time compared with those in the high NCCRP1 expression group. Additionally, multivariate analysis revealed that low NCCRP1 expression was an independent prognostic factor (hazard ratio, 1.75; 95% confidence interval, 1.08‑2.87; P=0.022). The findings of the current study indicate that NCCRP1 acts as a putative tumor suppressor that is inactivated through promoter hypermethylation, and serves as a promising biomarker to predict postoperative prognosis in ESCC.

Purpose Although S-1 based chemotherapy for patients with advanced gastric cancer has generally been accepted in Japan, discontinuations of treatment have been reported due to grade 3 or more adverse events. The present randomized phase II study was conducted to test whether alternate-day administration of S-1 would be comparably efficient and reduce adverse events compared with conventional daily administration in the first-line chemotherapy for advanced gastric cancer. Methods 132 patients with advanced gastric cancer were randomly assigned to 1:2 ratios to receive treatment with daily at a standard dose of 80 mg/m2/day or alternate-day administration group received S-1 on 4 days a week. The primary end point was progression-free survival (PFS), and the secondary end points were safety, overall survival, time to treatment failure (TTF), disease control rate, and response rate. Results The 6-month PFS rate of the alternate-day administration group was 20.9% and failed to show significant difference from the pre-specified threshold at 15% (p = 0.117), whereas that of the daily administration group was 39.1% and significantly higher than the threshold (p = 0.001). The hazard ratio of the alternate-day administration group compared with the daily administration group was 1.753 (95% confidence interval (CI) 1.15–2.68, p = 0.010). With regard to OS, the hazard ratio of the alternate-day administration group compared with the daily administration group was 1.487 (95% CI 0.97–2.29, p = 0.072). The median TTF were 4.2 and 2.8 months in the daily and alternate-day administration group, respectively (p = 0.007). Conclusion The alternate-day administration of S-1 was not recommended as the first-line therapy for patients with advanced gastric cancer.

This study assessed the impact of postoperative complications on the colorectal cancer survival and recurrence after curative surgery using pooled individual patients’ data from three large phase III randomized trials. In total, 5530 patients were included in this study. The patients were classified as those with postoperative complications (C group) and those without postoperative complications (NC group). The risk factors for the overall survival (OS) and the disease‐free survival (DFS) were analyzed. Postoperative complications were found in 861 (15.6%) of the 5530 patients. The OS and DFS rates at 5 years after surgery were 68.9% and 74.8%, respectively, in the C group and 75.8% and 82.2%, respectively, in the NC group, values that were significantly different between the two groups (P

Breast cancer (BC) is the most common malignancy among women. Identifying novel biomarkers to predict prognosis accurately is important in managing this disease. The regulatory factor X1 (RFX1) gene is a member of the regulatory factor X gene family. Its protein reportedly downregulates the proto-oncogene c-myc, but its role in BC has been unclear. In this study, expression and methylation status of RFX1 were determined in BC cell lines. We then evaluated RFX1 mRNA expression levels with regard to clinicopathological factors including postoperative prognosis in 167 patients with BC. Expression of RFX1 was heterogeneous among cell lines, and we found no DNA methylation at the RFX1 promoter region. Patients were categorized into groups with high or low RFX1 expression, based on ratio of RFX1 mRNA expression in BC and adjacent non-cancerous tissues. The high RFX1 group was significantly associated with low T factor (P=0.028), earlier disease stage (P=0.015), positive expression of estrogen receptor (P=0.005) and progesterone receptor (P=0.011), negative expression of human epidermal growth factor receptor 2 (P=0.001). The high RFX1 group experienced more favorable disease-free survival (P=0.007) and overall survival (P=0.013). In multivariate analysis, RFX1 expression was an independent prognostic factor for disease-free survival. Our findings indicate that RFX1 may serve as a prognostic marker for BC.

AIM To identify simple and sensitive markers for postoperative complications after gastrectomy, the predictive values were compared among candidate preoperative factors. METHODS Three-hundred and twelve patients with previously untreated clinical T2-4 gastric cancer who underwent a D2 standard gastrectomy (distal gastrectomy or total gastrectomy) were included in the analysis. Correlations between 21 parameters that can be determined by preoperative routine blood tests and clinically relevant postoperative complications (grade II or higher according to the Clavien-Dindo classification) were evaluated. The optimal cutoff values and clinical significance of the selected markers were further evaluated by subgroup analyses according to age, body mass index, operative procedure and clinical disease stage. RESULTS Sixty-six patients (21.1%) experienced grade II or higher postoperative complications. The platelet-lymphocyte ratio (PLR, total lymphocyte count/platelet count × 100) exhibited the highest area under the curve value (0.639) for predicting postoperative complications among the 21 parameters, and the optimal cutoff value was determined to be 0.71 (sensitivity = 70%, specificity = 56%). In the univariate analysis, the odds ratio of a low PLR for the occurrence of postoperative complications was 2.94 (95%CI: 1.66-5.35, P < 0.001), and a multivariate binomial logistic analysis involving other potential risk factors identified a low PLR as an independent risk factor for postoperative complications (OR = 3.32, 95%CI: 1.82-6.25, P < 0.001). In subgroups classified according to age, body mass index, operative procedure and clinical disease stage, the low PLR group exhibited an increased incidence of postoperative complications. CONCLUSION The preoperative PLR is a simple and useful predictor of complications after curative gastrectomy in patients with clinical T2-4 gastric cancer.

Background: Little information from prospective clinical trials is available on the influences of surgical approaches on postoperative body compositions and nutritional status. We designed a prospective non-randomized trial to compare postoperative chronological changes in body composition and nutritional status between laparoscopic and open distal gastrectomy for stage I gastric cancer (GC). Methods: Body compositions and nutritional indicators in blood tests were measured at the baseline and at the 1st, 3rd, 6th, and 12th postoperative months (POM). The primary end point was the decrease relative to the baseline in the body muscle mass at POM 6. Results: Ninety-six patients for the laparoscopic group and 52 for the open group were eligible for data analysis. No significant differences were found in any baseline demographics, body compositions, and nutritional indicators between the groups. The changes of body muscle mass at POM 6 were similar in both groups. Overall, no significant differences between the groups were observed in any of the body composition and nutritional indicators during the first year after surgery. Conclusions: Postoperative body compositions and nutritional status were not affected by surgical approaches during the first 12 months after surgery in patients who underwent distal gastrectomy for stage I GC.

Background: Advantages of neoadjuvant chemotherapy combined with monoclonal antibodies for treating patients with resectable colorectal cancer liver metastasis (CLM) have not been established. The purpose of this study was to evaluate the efficacy and safety of oxaliplatin-based regimen (FOLFOX or XELOX) plus monoclonal antibodies (cetuximab or bevacizumab) treatment in patients with resectable CLM. Methods: A single-arm, open-label, multicenter, phase II trial was conducted for patients aged ≥ 20 years with resectable and untreated CLM. Patients received preoperative FOLFOX (6 cycles) or XELOX (4 cycles). Cetuximab or bevacizumab was administered to patients with wild-type or mutated KRAS codons 12 and 13, respectively. The primary endpoint was progression-free survival (PFS). Results: Between January 2010 and June 2012, 47 patients were enrolled from 12 institutions. Wild-type or mutant KRAS sequences were examined in 32 and 15 patients, respectively. Twenty-one (45 %) patients experienced Grades 3/4 adverse events, and 55 % of all patients responded to therapy. The sizes of tumors of patients in the wild-type KRAS group were significantly reduced compared with those of the mutant KRAS group. The overall rates of liver resection and postoperative morbidity were 83 and 14 %, respectively, and the median PFS was 15.6 months. The median PFS times of the KRAS wild-type and mutant groups were 22.5 months and 10.5 months, respectively. Conclusions: Neoadjuvant therapy using FOLFOX/XELOX combined with monoclonal antibodies did not improve PFS, although it was administered safely and had less adverse effects after liver resection.

Background: Systemic hemostasis and thrombosis activation has been implicated in tumor progression and metastasis. This study aimed to investigate the use of coagulation factors as a novel prediction method for postoperative outcomes after curative gastrectomy in patients with stage II/III gastric cancer (GC). Methods: Overall, 126 patients with stage II/III GC who underwent gastrectomy between May 2003 and February 2016 were eligible for inclusion in the study. We retrospectively evaluated the predictive value of preoperative platelet count and plasma fibrinogen and d-dimer levels, and coagulation score (0: fibrinogen and d-dimer both below upper limits; 1: either fibrinogen or d-dimer over upper limits; 2: both fibrinogen and d-dimer over upper limits) for short- and long-term outcomes. Results: Postoperative complications were significantly more frequent in patients with elevated preoperative d-dimer levels compared with those with normal d-dimer levels (26 vs. 10 %; p = 0.032). The prevalence of postoperative complications showed a stepwise increase in proportion to the coagulation score. Patients with a coagulation score of 2 had significantly larger tumors (p = 0.013) and significantly greater intraoperative blood loss (p = 0.004) than those who scored 0 or 1. Coagulation score showed the highest values distinguished high-risk patients in overall and disease-free survival, and a coagulation score of 2 was an independent prognostic factor for recurrence. Patients with a coagulation score of 2 experienced a significantly higher prevalence of liver metastasis as an initial recurrence than those who scored 0 or 1 (p = 0.019). Conclusions: The coagulation score is a simple and promising predictor for postoperative complications and recurrence after gastrectomy in stage II/III GC patients.

Introduction Laparoscopy-assisted distal gastrectomy is one of the major treatments for early stage gastric cancer, particularly in the East Asia. In this method, extracorporeal anastomosis is performed via a small laparotomy wound, but excessive tissue traction may be encountered during the anastomotic procedure. Therefore, we developed an original procedure for extracorporeal Billroth-I reconstruction: end-to-end stapling gastroduodenostomy with complete double stapling technique. This procedure aims to reduce the problems related to maneuvers through a small laparotomy. Methods An end-to-end anastomosis is constructed on the transection line using a circular stapler inserted from the distal end of the greater curvature of the remnant stomach. Short-term outcomes were reviewed in 218 consecutive patients who underwent complete double stapling technique reconstruction after laparoscopy-assisted distal gastrectomy between 2002 and 2012. Findings from GI endoscopy were reviewed in 110 patients. Results The mean operative time was 216 min, and mean blood loss was 163 mL. There was no conversion to the open surgery and no operative death. Eight patients (3.6%) had anastomosis-related postoperative complications. In follow-up endoscopic examinations 1 year after surgery, grade 3 or higher residual food was seen in 17.2% of patients. Gastritis extending to the entire remnant stomach was observed in 8.2% of patients, and grade 3 gastritis was seen in 2.7%. Los Angeles classification grade A or higher reflux esophagitis was found in 10.9%. Conclusions Billroth-I reconstruction by the complete double stapling technique is a safe and feasible procedure. This method provides satisfactory short-term outcomes, including the incidence of reflex remnant gastritis and esophagitis.

The prognosis of advanced hepatocellular carcinoma (HCC) is dismal. Novel molecular targets for diagnosis and therapy is urgently required. This study evaluated expression and functions of the protein arginine methyltransferase 5 (PRMT5) in HCC. Using HCC cell lines, the expression levels of PRMT5 mRNA were determined using the quantitative real-time reverse-transcription polymerase chain reaction, and the effect of a small interfering PRMT5-siRNA on cell phenotype was evaluated. Further, PRMT5 expression was determined in 144 pairs of resected liver tissues to evaluate its clinical significance. Regardless of their differentiated phenotypes, nine HCC cell lines expressed different levels of PRMT5 mRNA. Inhibition of PRMT5 expression significantly decreased the proliferation, invasion, and migration of HCC cell lines. Although the level of PRMT5 mRNA was not influenced by patient's background liver status, it was significantly higher in HCC tissues than in the corresponding noncancerous tissues. High levels of PRMT5 mRNA in HCC tissues were significantly associated with advanced disease stage and adverse prognosis. In conclusion, our results indicate that PRMT5 may act as a putative oncogene in HCC and that the levels of PRMT5 mRNA represent a promising prognostic marker and a potential target of molecular therapy for HCC.

Purpose: Reliable risk estimates of recurrence are necessary to establish optimal postoperative surveillance strategies. The purpose of the present study was to clarify changes in the hazard rate (HR) for tumor recurrence over time in Japanese patients with colon cancer. Methods: Data for 3984 patients from three clinical trials evaluating the benefit of adjuvant chemotherapy for colon cancer were analyzed. Estimated HRs were plotted over time for the entire cohort, as well as for node-positive and node-negative patients separately. The changes in risk were further analyzed according to eight clinical variables, and factors predictive of early (3 years) recurrence were explored using Cox's regression analysis. Results: In node-positive patients, there was a prominent HR peak 0.6 years after surgery, whereas HR remained at consistently low levels in node-negative patients. In node-positive patients, HR decreased steadily until 3 years, after which the decline in HR plateaued. Those with T4 tumors had a prominent HR peak around 1 year, including node-negative patients. The HR for T1/T2 Stage III colon cancers showed a similar pattern as that for T1-T3 node-negative colon cancers. Cox regression analysis revealed that a lack of adjuvant chemotherapy, positive node status, T3/T4 factors, and male gender predict early recurrence, whereas patients with lymph node metastasis, T4 tumors, and a lesser extent of lymph node removal have a higher risk of recurrence 3-4 years after surgery (P

Purpose: Dose adjustment of 5-fluorouracil (FU) based on pharmacokinetic monitoring has been shown to reduce toxicities and increase efficacy compared with dosing based on body surface area in patients with metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of pharmacokinetic dose adjustment of FU in a modified FOLFOX7 (mFOLFOX7) plus bevacizumab regimen in Japanese patients with previously untreated mCRC. Methods: This single-arm, multicenter phase II trial enrolled 48 patients with mCRC. Treatment consisted of 5 mg/kg intravenous bevacizumab followed by mFOLFOX7 (oxaliplatin 85 mg/m2 on day 1, infused leucovorin 200 mg/m2, followed by a 2400 mg/m2 infusion of FU for 46 h starting on day 1), repeated every 2 weeks. FU concentrations were measured by immunoassay between 18 and 36 h after the start of continuous FU infusion, and the FU dose was then adjusted if required in subsequent cycles. The primary endpoint was response rate. Results: The median initial area under the concentration–time curve for FU was 23 mg h/L. Twenty-nine patients (60%) achieved the target concentration at the first cycle, and all 48 achieved it within the fourth cycle. The overall frequency of grade 3/4 adverse effects was 38%, with no significant difference between patients who did and not require dose adjustments. The overall response rate was 48% (95% confidence intervals = 34–62%). The median progression-free and overall survival rates were 11.3 and 24.1 months, respectively. Conclusions: Pharmacokinetic dose adjustment of FU in mFOLFOX7 plus bevacizumab can optimize FU concentrations promptly and is safe in Japanese patients with mCRC.

When assessing outcome in hepatocellular carcinoma (HCC), it is important to consider prognostic factors in background non-tumorous liver tissue as well as in the tumor, since multiple occurrence is associated with background liver status such as hepatitis. The current study aimed to elucidate molecular prognostic predictors that have an association with HCC background non-tumorous tissue. Microarray expression profiling identified aldo-keto reductase family 1, member B10 (AKR1B10) as a putative non-tumorous prognostic factor, and AKR1B10 gene expression was investigated in 158 curatively resected HCC cases by reverse transcription-quantitative polymerase chain reaction. AKR1B10 expression (AKR1B10 value/GAPDH value × 1,000) was significantly higher in tumor tissue (median, 9.2200; range, 0.0003–611.0200; n=158) than in the corresponding non-tumorous tissue (median, 0.5461; range, 0.0018–69.0300; n=158) (P

The prognosis for patients with advanced gastric cancer (GC) remains poor. The identification of biomarkers relevant to the recurrence and metastasis of GC is advantageous for stratifying patients and proposing novel molecular targets. In the present study the oncological roles of SAM domain, SH3 domain and nuclear localization signals 1 (SAMSN1), a mediator of B‑cell function, were elucidated in GC. The expression and methylation status of SAMSN1 were investigated in a panel of 11 GC cell lines. Immunohistochemical staining was performed to determine the pattern of SAMSN1 protein expression in gastric tissues. The prognostic impact of SAMSN1 expression was determined by analyzing 175 pairs of surgically resected gastric tissues. A marked decrease in the level of SAMSN1 mRNA was detected in 8/11 GC cell lines as compared with that in a non‑transformed intestinal epithelium cell line (FHs 74) without promoter methylation. The mean expression level of SAMSN1 mRNA was reduced in GC tissues compared with normal adjacent tissues, an observation that was independent of tumor differentiation. The pattern of SAMSN1 protein expression was significantly correlated with that of SAMSN1 mRNA. Low SAMSN1 mRNA expression was significantly associated with tumor size (>60 mm; P=0.026) and shorter overall survival times (P=0.004). Multivariate analysis identified low SAMSN1 mRNA expression as an independent prognostic factor for poor overall survival (hazard ratio, 1.80; 95% confidence interval, 1.07–3.05; P=0.025). The difference in survival between the low and high SAMSN1 expression groups was more marked in patients with stage II/III GC compared to those with stage IV GC. In patients with stage II/III GC who underwent curative surgery, low SAMSN1 expression was associated with reduced disease free survival times. The results of the present study indicate that downregulation of SAMSN1 transcription may affect the progression and recurrence of GC, and therefore may represent a novel biomarker of GC.