Preoperative Myosteatosis and Prognostic Nutritional Index Predict Survival in Older Patients With Resected Biliary Tract Cancer.

Background/Aim: Sarcopenia accompanied by systemic inflammation is associated with poor prognosis in patients with cancer. This study evaluated the prognostic significance of sarcopenia (myopenia and myosteatosis) and systemic inflammatory markers in older patients (aged ≥80 years) with resected biliary tract cancer. Patients and Methods: Patients who underwent resection for biliary tract cancer between July 2010 and January 2023 at the NHO Fukuyama Medical Center were retrospectively reviewed. Preoperative computed tomography measured myopenia and myosteatosis, using the psoas muscle index and modified intramuscular adipose tissue content. Associations between clinicopathological characteristics, inflammation-based prognostic scores, and overall survival were analyzed using Cox proportional hazards models. Results: Univariate analysis revealed low C-reactive protein-to-albumin ratio (<0.125), low prognostic nutritional index (<42), low modified intramuscular adipose tissue content, higher T-stage (T3-4), lymph node metastasis, and postoperative complications associated with worse overall survival in older patients (aged ≥ 80 years) with resected biliary tract cancer (n=48). Multivariate analysis identified low prognostic nutritional index (<42) (p=0.007), low modified intramuscular adipose tissue content (p=0.015), higher T-stage (T3-4) (p<0.001), lymph node metastasis (p=0.001), and postoperative complications (p=0.017) as independent predictors of overall survival. Conclusion: Preoperative myosteatosis and low prognostic nutritional index are independent prognostic factors for overall survival in older patients (aged ≥80 years) with resected biliary tract cancer. These factors may be useful for risk stratification and clinical decision-making. Early interventions, such as nutritional support and physical exercise, may improve outcomes after resection of biliary tract cancer.

Prognostic Significance of Sarcopenia and Systemic Inflammatory Markers in Biliary Tract Cancer: A Retrospective Cohort Study.

PURPOSE: To evaluate the prognostic significance of sarcopenia and systemic inflammatory markers in patients with surgically resected biliary tract cancer (BTC). METHODS: Between July 2010 and December 2022, 146 patients were recruited. Sarcopenia was assessed using the psoas muscle index. Preoperative inflammatory markers were used to calculate the prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio. Cox regression analysis was performed to determine prognostic factors for overall survival (OS) and recurrence-free survival (RFS). P < 0.05 was considered statistically significant. RESULTS: Sixty-four patients had sarcopenia. Sarcopenia was associated with body mass index (< 22 kg/m2), lymph node metastasis, and low PNI (< 42). R1/R2 resection (P = 0.02), sarcopenia (P < 0.001), lymph node metastasis (P = 0.007), intrahepatic cholangiocarcinoma (P < 0.001), and low PNI (P = 0.01) were independent predictors of OS, while male sex (P = 0.04), R1/R2 resection (P < 0.001), lymph node metastasis (P = 0.005), intrahepatic cholangiocarcinoma (P < 0.001), tumor differentiation (other than well; P = 0.003), and low PNI (P = 0.03) were independent predictors of RFS. Patients were stratified into no sarcopenia and high PNI (≥ 42; A), sarcopenia or low PNI (B), and sarcopenia and low PNI (C) groups. Group C had worse OS than the other two groups (P < 0.001 and P = 0.02, respectively). CONCLUSION: Sarcopenia is associated with the PNI. Sarcopenia and the PNI are independent prognostic factors among patients with resected BTC. Sarcopenia may have better prognostic value when combined with the PNI.

Predictive values of sarcopenia and systemic inflammation-based markers in advanced hepatocellular carcinoma after hepatectomy.

BACKGROUND: Sarcopenia accompanied by systemic inflammation is associated with poor prognosis in patients with advanced hepatocellular carcinoma (HCC). However, the effect of sarcopenia combined with systemic inflammation on the prognosis of patients with advanced HCC who underwent hepatectomy is unclear. This study aimed to evaluate the effect of sarcopenia and inflammation on the prognosis of patients with advanced HCC. METHODS: This retrospective study included 151 patients recruited between July 2010 and December 2022. We defined advanced HCC as that presenting with vascular invasion or tumor size ≥2 cm or multiple tumors. Sarcopenia was assessed using the psoas muscle index. Preoperative inflammatory markers were used by calculating the prognostic nutritional index, albumin-globulin ratio (AGR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio. Cox regression analysis was performed to determine the prognostic factors for overall survival. RESULTS: Of 151 patients, sarcopenia occurred in 84 (55.6 %). Sarcopenia was significantly associated with male sex, older age, body mass index (<25 kg/m2), and a higher NLR. In the multivariate analysis, AGR <1.25 (hazard ratio [HR], 2.504; 95% confidence interval [CI]: 1.325-4.820; p < 0.05); alpha-fetoprotein levels ≥25 ng/mL (HR, 1.891; 95% CI: 1.016-3.480; p = 0.04); and sarcopenia (HR, 1.908; 95% CI: 1.009-3.776; p < 0.05) were independent predictors of overall survival. The sarcopenia and low AGR groups had significantly worse overall survival than either the non-sarcopenia and high AGR or sarcopenia and low AGR groups. CONCLUSION: Sarcopenia and AGR are independent prognostic factors in patients with advanced HCC. Thus, sarcopenia may achieve a better prognostic value when combined with AGR.

Synchronous Double Primary Combined Hepatocellular-cholangiocarcinoma and Cholangiolocarcinoma in a Cirrhotic Liver.

Both combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and cholangiolocarcinoma are rare primary liver cancers. cHCC-CCA is believed to originate from transformed hepatocellular carcinoma or liver stem/progenitor cells. Cholangiolocarcinoma is characterized by ductular reaction-like anastomosing cords and glands resembling cholangioles or canals containing hepatocellular carcinoma components and adenocarcinoma cells. According to the 2019 revision of the World Health Organization criteria, a subtype with stem cell features as a subclassification of cHCC-CCA was abolished for lack of conclusive evidence of the stem cell origin theory. That led to the classification of cholangiolocarcinoma with hepatocytic differentiation as cHCC-CCA. Consequently, cholangiolocarcinoma without hepatocytic differentiation is classified as a subtype of small-duct cholangiocarcinoma and is assumed to originate from the bile duct. Herein, we report the first case of double primary cHCC-CCA and cholangiolocarcinoma without hepatocytic differentiation in different hepatic segments of a cirrhotic liver. We believe this case supports the validity of the new World Health Organization criteria because the pathological finding of cHCC-CCA in this case shows the transformation of hepatocellular carcinoma to cholangiocarcinoma. Furthermore, this case may demonstrate that immature ductular cell stemness and mature hepatocyte cell stemness in hepatocarcinogenesis can coexist in the same environment. The results provide valuable insights into the mechanisms of growth, differentiation, and regulation of liver cancers.

Preoperative C-reactive protein-to-albumin ratio as a prognostic factor in biliary tract cancer: A systematic review and meta-analysis.

BACKGROUND: The preoperative C-reactive protein-to-albumin ratio is a novel inflammation-based prognostic marker in various cancers. However, its prognostic role in biliary tract cancer is unknown. We conducted a systematic review and meta-analysis to evaluate the prognostic value of preoperative C-reactive protein-to-albumin ratio in biliary tract cancer. METHODS: A systematic search of the literature for studies evaluating the prognostic value of C-reactive protein-to-albumin ratio in patients undergoing surgery for biliary tract cancer was conducted, and a random effects meta-analysis of overall survival and recurrence-free survival was performed. RESULTS: Nine studies with 1292 participants were included. The preoperative C-reactive protein-to-albumin ratio negatively correlated with overall survival (hazard ratio, 2.44 [95% confidence interval: 1.98-2.90]; P < .001) and recurrence-free survival (hazard ratio, 2.73 [95% confidence interval: 2.01-3.70]; P < .001). Subgroup analysis showed that an elevated preoperative C-reactive protein-to-albumin ratio predicted poor overall survival, regardless of the cutoff value, sample size, histological type, and treatment. CONCLUSION: An elevated preoperative C-reactive protein-to-albumin ratio is significantly associated with poor prognosis in patients undergoing surgery for biliary tract cancer. The C-reactive protein-to-albumin ratio may be an independent prognostic biomarker for overall survival and recurrence-free survival in patients undergoing surgery for biliary tract cancer.

C-reactive Protein-to-Albumin Ratio Predicts Conversion from Laparoscopic to Open Cholecystectomy in Acute Cholecystitis.

BACKGROUND/AIM: The aim of this study was to identify predictors of conversion from laparoscopic to open cholecystectomy, and to determine whether pre-operative C-reactive protein-to-albumin ratio (CAR) can predict conversion from laparoscopic to open cholecystectomy, in patients with acute cholecystitis diagnosed according to the Tokyo Guidelines 2018. PATIENTS AND METHODS: We retrospectively analysed 231 patients who underwent laparoscopic cholecystectomy for acute cholecystitis between January 2012 and March 2022. Two hundred and fifteen (93.1%) patients were included in the laparoscopic cholecystectomy group; sixteen (6.9%) patients were included in the conversion from laparoscopic to open cholecystectomy group. RESULTS: In univariate analysis, significant predictors of conversion from laparoscopic to open cholecystectomy included the interval between symptom onset and surgery (>72 h), C-reactive protein (≥15.0 mg/l) and albumin (<3.5 mg/l) levels, pre-operative CAR (≥5.54), gallbladder wall thickness (≥5 mm), pericholecystic fluid collection, and pericholecystic fat hyperdensity. In multivariate analysis, elevated pre-operative CAR (≥5.54) and the interval between symptom onset and surgery (>72 h) were independent predictors of conversion from laparoscopic to open cholecystectomy. CONCLUSION: Pre-operative CAR as a predictor of conversion from laparoscopic to open cholecystectomy may be useful for pre-operative risk assessment and treatment planning.

Lymphocyte-to-C-Reactive Protein Ratio Predicts Prognosis in Patients With Colorectal Liver Metastases Post-hepatic Resection: A Retrospective Study.

BACKGROUND/AIM: Preoperative systemic inflammation has been reported to predict survival in patients with various cancer types. In patients with colorectal liver metastasis (CRLM), the prognosis is poor despite therapeutic advances in the field. Here, we aimed to evaluate the prognostic role of the lymphocyte-to-C-reactive protein (CRP) ratio (LCR) in patients with CRLM after hepatic resection. PATIENTS AND METHODS: This retrospective study included 104 patients who underwent hepatic resection for CRLM between October 2010 and 2021 at the National Hospital Organization Fukuyama Medical Center, Hiroshima, Japan. The association between clinicopathological variables, including various inflammatory biomarkers [LCR, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), CRP-to-albumin ratio (CAR), and prognostic nutritional index (PNI)], and overall survival of the patients was investigated using univariate and multivariate analyses. RESULTS: The optimal cut-off values for each biomarker by receiver-operating characteristic analysis were as follows: LCR: 12,720; PLR: 150; NLR: 4; CAR: 0.023; and PNI: 44.8. The 1-, 3-, and 5-year overall survival rates were 97.0%, 71.3%, and 56.8%, respectively. On univariate analysis, LCR<12, 720, PLR<0.14, body mass index <24 kg/m2, carbohydrate antigen 19-9 ≥37 U/ml, multiple tumours, and largest hepatic tumour ≥5 cm were significant factors predictive of poorer survival. The multivariate analysis revealed that LCR<12, 720 (hazard ratio=2.156, 95% confidence interval=1.060-4.509, p=0.034) and multiple tumours (HR=2.336, 95% CI=1.125-4.925, p=0.023) were independent predictors of poor overall survival. CONCLUSION: LCR may be an independent prognostic predictor in patients after hepatic resection for CRLM. Therefore, the assessment of LCR as a biomarker may help in treatment planning.

Preoperative lymphocyte-to-C-reactive protein ratio predicts hepatocellular carcinoma recurrence after surgery.

Purpose: This study was performed to determine the prognostic value of lymphocyte-to-CRP ratio after curative resection for hepatocellular carcinoma. Methods: Between July 2010 and October 2021, 173 consecutive patients (144 male, 29 female) who underwent surgical resection for pathologically confirmed hepatocellular carcinoma were included in this retrospective study. Cox regression analysis was used to evaluate the relationship between clinicopathological characteristics and recurrence-free survival (RFS) and overall survival (OS). A P-value of <0.05 was considered statistically significant. Results: The patients (mean age, 71 years) were stratified into high (≥9,500, n = 108) and low (<9,500, n = 65) lymphocyte-to-CRP ratio groups. The low lymphocyte-to-CRP ratio group had significantly worse RFS and OS. Low lymphocyte-to-CRP ratio (hazard ratio [HR], 1.865; 95% confidence interval [CI], 1.176-2.960; P = 0.008), multiple tumors (HR, 3.333; 95% CI, 2.042-5.343; P < 0.001), and microvascular invasion (HR, 1.934; 95% CI, 1.178-3.184; P = 0.009) were independently associated with RFS, whereas low albumin-to-globulin ratio (HR, 2.270; 95% CI, 1.074-4.868; P = 0.032), α-FP of ≥25 ng/mL (HR, 2.187; 95% CI, 1.115-4.259; P = 0.023), and poor tumor differentiation (HR, 2.781; 95% CI, 1.041-6.692; P = 0.042) were independently associated with OS. Lymphocyte-to-CRP ratio had a higher area under the curve (0.635) than other inflammation-based markers (0.51-0.63). Conclusion: Lymphocyte-to-CRP ratio is superior to other inflammation-based markers as a predictor of RFS in patients with surgically resected hepatocellular carcinoma.

C-reactive protein to albumin ratio predicts difficult laparoscopic cholecystectomy in patients with acute cholecystitis diagnosed according to the Tokyo Guidelines 2018.

INTRODUCTION: Difficult laparoscopic cholecystectomy (DLC) may increase the risk of complications and extend the duration of hospitalization. The aims of this study were to evaluate the predictive value of C-reactive protein/albumin ratio (CAR) for DLC in patients with acute cholecystitis (AC) diagnosed according to the Tokyo Guidelines 2018 and to develop a preoperative predictive model for DLC. METHODS: We retrospectively analyzed 205 patients who had laparoscopic cholecystectomy for AC between January 2012 and December 2020. We defined DLC cases as having one of the following factors: blood loss ≥50 mL, operative time ≥150 minutes, or conversion to open surgery. We classified the remaining cases into the non-DLC group. RESULTS: Overall, 127 (62.0%) and 78 (38.0%) patients were grouped into the DLC and non-DLC groups, respectively. Patients in the DLC group had: higher severity grade, which was assessed using the Tokyo Guidelines 2018; higher incidence of postoperative complications; and more hospitalization days than those in the non-DLC group. Multivariate analysis revealed that male, CAR (≥3.20), and pericholecystic fat hyperdensity on computed tomography (CT) were independent predictors of DLC. We developed a predictive scoring system for DLC based on these three factors (cutoff value, 2.0; area under the curve, 0.75; sensitivity, 71.7%; and specificity, 70.5%). CONCLUSION: CAR could predict DLC independently in AC patients. We identified male gender, CAR, and pericholecystic fat hyperdensity on CT as predictive factors for DLC and established a preoperative prediction system based on these three factors.

A combined prediction model for biliary tract cancer using the prognostic nutritional index and pathological findings: a single-center retrospective study.

BACKGROUND: The prognostic nutritional index, a marker of nutritional status and systemic inflammation, is a known biomarker for various cancers. However, few studies have evaluated the predictive value of the prognostic nutritional index in patients with biliary tract cancer. Therefore, we investigated the prognostic significance of the prognostic nutritional index, and developed a risk-stratification system to identify prognostic factors in patients with biliary tract cancer. METHODS: Between July 2010 and March 2021, 117 patients with biliary tract cancer were recruited to this single-center, retrospective study. The relationship between clinicopathological variables, including the prognostic nutritional index, and overall survival was analyzed using univariate and multivariate analyses. A P < 0.05 was considered statistically significant. RESULTS: The median age was 75 (range 38-92) years. Thirty patients had intrahepatic cholangiocarcinoma; 29, gallbladder carcinoma; 27, distal cholangiocarcinoma; 17, ampullary carcinoma; and 13, perihilar cholangiocarcinoma. Curative (R0) resection was achieved in 99 patients. In univariate analysis, the prognostic nutritional index (< 42), lymph node metastasis, carbohydrate antigen 19-9 level (> 20 U/mL), preoperative cholangitis, tumor differentiation, operation time (≥ 360 min), and R1-2 resection were significant risk factors for overall survival. The prognostic nutritional index (P = 0.027), lymph node metastasis (P = 0.040), and tumor differentiation (P = 0.006) were independent prognostic factors in multivariate analysis. A combined score of the prognostic nutritional index and pathological findings outperformed each marker alone, in terms of discriminatory power. CONCLUSIONS: The prognostic nutritional index, lymph node metastasis, and tumor differentiation were independent prognostic factors after surgical resection in patients with biliary tract cancer. A combined prediction model using the prognostic nutritional index and pathological findings accurately predicted prognosis, and can be used as a novel prognostic factor in patients with biliary tract cancer.

Preoperative Albumin-to-Globulin Ratio Predicts Prognosis in Hepatocellular Carcinoma: A Cohort Study Including Non-Hepatitis Virus-Infected Patients.

INTRODUCTION: We evaluated the prognostic significance of the preoperative albumin-to-globulin ratio (AGR) in patients with hepatocellular carcinoma (HCC) with various liver etiologies. METHODS: We retrospectively analyzed 157 patients with HCC between July 2010 and February 2021. The relationship between clinicopathological variables was investigated using univariate and multivariate analyses. Statistical significance was set at p < 0.05. RESULTS: The mean overall survival (OS) was 24.5 months. The 1-, 3-, and 5-year OS rates were 90.4%, 81.2%, and 68.7%, respectively. Patients were classified into 2 groups: AGR <1.16 (low-AGR group; n = 43) and AGR ≥1.16 (high-AGR group; n = 114). In univariate analysis, OS was significantly reduced in patients with a low AGR (AGR <1.16), an alpha-fetoprotein level ≥25 ng/mL, a tumor size ≥3.5 cm, microvascular invasion, and poor tumor differentiation. In multivariate analysis, a low AGR (hazard ratio [95% confidence interval]) (2.394 [1.092-5.213]; p = 0.030) and microvascular invasion (2.268 [1.019-5.169]; p = 0.045) were independent predictors of OS. DISCUSSION/CONCLUSION: A low AGR was significantly associated with poor OS in patients with HCC, regardless of liver etiology. This may assist in treatment stratification and better management of patients with HCC.

Comparison of Inflammation-based Prognostic Scores in Patients With Biliary Tract Cancer After Surgical Resection.

BACKGROUND/AIM: Inflammation-based prognostic scores are proven prognostic biomarkers in various cancers. This study aimed to identify a useful prognostic score for patients with biliary tract cancer (BTC) after surgical resection. PATIENTS AND METHODS: This retrospective study recruited 115 patients with BTC during 2010-2020. The relationship between clinicopathological variables, including various prognostic scores and overall survival (OS), was investigated using univariate and multivariate analyses. RESULTS: BTC included 58 cholangiocarcinoma, 29 gallbladder carcinoma, 16 ampullary carcinoma, and 12 perihilar cholangiocarcinoma cases. A significant difference was detected in OS of patients with a Japanese modified Glasgow prognostic score (JmGPS) 0 (n=62) and JmGPS 1 or 2 (high JmGPS) (n=53). In the multivariate analysis, tumour differentiation (p=0.014) and a high JmGPS (p=0.047) were independent prognostic factors. CONCLUSION: The high JmGPS was an independent prognostic predictor after surgical resection and was superior to other prognostic scores.

[Anastomotic Recurrence after Curative Resection for Transverse Colon Cancer-A Case Report].

The rate of local and anastomotic recurrence after curative resection for colon cancer is quite low, at 2.1%. We describe an anastomotic recurrence that rapidly increased after transverse colon cancer resection. An 80-year-old man underwent laparoscopic- assisted transverse colon resection with D3 lymph node dissection. The pathological diagnosis was pT4aN1bM0, pStage Ⅲb. We diagnosed the patient with anastomotic recurrence and liver metastasis 4 months after the procedure based on PET-CT findings. Partial colon resection(small intestine and stomach combined)was performed at 6 months after the procedure. The patient's quality of life(QOL)was reduced by complications after the second procedure and continuing with chemotherapy became difficult. Although the prognosis of curative resection of local and anastomotic recurrence after transverse colon cancer surgery can be good, combined resection of an adjacent organ can result in a decline in patient QOL. Surgical intervention should be minimally invasive and neo-adjuvant chemotherapy might offer 1 option.

[Local Recurrence of Rectal Cancer under Perineal Skin after Abdominoperineal Resection].

A woman in her early 50s underwent abdominoperineal resection with left lateral lymph node resection for advanced rectal cancer. The pathological diagnosis was RC, RbP, well-differentiated, type 5, 65×47mm, pT3(A), pN0(0/40), M0, pStage Ⅱ. The local recurrence discovered under the perineal skin 2 months later was treated by resecting the tumor and both inguinal lymph nodes. Adjuvant chemotherapy containing UFT plus LV was also initiated for 6 months. She remains free of recurrence 1 year after resection of the local recurrence.

TOP2A, GGH, and PECAM1 are associated with hematogenous, lymph node, and peritoneal recurrence in stage II/III gastric cancer patients enrolled in the ACTS-GC study.

BACKGROUND: To identify factors related to relapse sites, we carried out an exploratory biomarker analysis of data from the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer study, which is a randomized, controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer. PATIENTS AND METHODS: Surgical specimens from 829 patients were retrospectively examined, and 63 genes involved in a variety of biological processes were analyzed by quantitative real-time PCR. Gene expression normalized to reference genes was categorized as lower or higher than the median, and association with relapse sites was analyzed based on 5-year relapse-free survival. RESULTS: Hematogenous, lymph node, and peritoneal recurrence developed in 72, 105, and 138 of the 829 patients, respectively; hazard ratios were 0.79 (95% confidential interval: 0.54-1.16), 0.51 (0.31-0.82), and 0.60 (0.42-0.84), respectively. Expression of platelet/endothelial cell adhesion molecule 1 (PECAM1) and topoisomerase II alpha (TOP2A) was strongly correlated with hematogenous recurrence and peritoneal recurrence, respectively (false discovery rate = 7.7×10-5 and 0.002, respectively). Gamma-glutamyl hydrolase (GGH) expression was moderately correlated with lymph node recurrence (false discovery rate = 0.34). Relapse-free survival was worse in patients expressing high levels of PECAM1 (hazard ratio = 2.37, 1.65-3.41), TOP2A (hazard ratio = 2.35, 1.55-3.57), or GGH (hazard ratio = 1.87, 1.13-3.08), respectively. A multivariate analysis revealed that these were stronger independent risk factors than tumor histological type. CONCLUSION: In patients with stage II/III gastric cancer, TOP2A, GGH, and PECAM1 levels in primary tumors are linked to high risk of hematogenous, lymph node, and peritoneal recurrence, respectively.

Impact of insulin-like growth factor-1 receptor and amphiregulin expression on survival in patients with stage II/III gastric cancer enrolled in the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer.

BACKGROUND: Exploratory biomarker analysis was conducted to identify factors related to the outcomes of patients with stage II/III gastric cancer using data from the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer, which was a randomized controlled study comparing the administration of an orally active combination of tegafur, gimeracil, and oteracil with surgery alone. METHODS: Formalin-fixed paraffin-embedded surgical specimens from 829 patients were retrospectively examined, and 63 genes were analyzed by quantitative real-time RT-PCR after TaqMan assay-based pre-amplification. Gene expression was normalized to the geometric mean of GAPDH, ACTB, and RPLP0 as reference genes, and categorized into low and high values based on the median. The impact of gene expression on survival was analyzed using 5-year survival data. The Benjamini and Hochberg procedure was used to control the false discovery rate. RESULTS: IGF1R and AREG were most strongly correlated with overall survival, which was significantly worse in high IGF1R patients than low IGF1R patients, but better in high AREG patients than low AREG patients. The hazard ratio for death in the analysis of overall survival (S-1 vs. surgery alone) was reduced in the high IGF1R group compared with the low IGF1R group and in the low AREG group compared with the high AREG group. There were no significant interaction effects. CONCLUSION: IGF1R gene expression was associated with poor outcomes after curative resection of stage II/III gastric cancer, whereas AREG gene expression was associated with good outcomes. No significant interaction effect on survival was evident between S-1 treatment and gene expression.

Impact of the expression of thymidylate synthase and dihydropyrimidine dehydrogenase genes on survival in stage II/III gastric cancer.

BACKGROUND: The efficacy of 5-fluorouracil (5FU)-based therapy, which remains the cornerstone of gastrointestinal cancer treatment, depends upon the expression of enzymes involved in pyrimidine metabolism, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase (OPRT). We analyzed the expression of these genes in patients enrolled in the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) and their possible roles as biomarkers for treatment outcomes. METHODS: Formalin-fixed, paraffin-embedded specimens were available for 829 of a total of 1,059 (78.3 %) patients. TS, DPD, TP, and OPRT expression was measured by RT-PCR in manually microdissected tumor specimens and normalized to the reference gene, ß-actin. The expression level of each gene was categorized as low or high using cutoffs at the 33.3rd, 50th, or 66.7th percentiles. RESULTS: The hazard ratio (HR) for overall survival (OS) after S-1 treatment versus surgery alone was significantly lower in high (>66.7th percentile; HR = 0.370; 95 % CI 0.221-0.619) compared to low (<66.7th percentile; HR = 0.757; 95 % CI 0.563-1.018) TS expression groups (P = 0.015). Similarly, the HR for OS after S-1 therapy versus surgery alone was significantly lower in high (>33.3rd percentile; HR = 0.520, 95 % CI 0.376-0.720) compared to low (<33.3rd percentile; HR = 0.848, 95 % CI 0.563-1.276) DPD expression groups (P = 0.065). There was no interaction between TP or OPRT expression and OS. CONCLUSIONS: This large biomarker study showed that high TS and DPD gene expression in tumors was associated with enhanced benefit from postoperative adjuvant S-1 treatment in gastric cancer. There was no interaction between TP and OPRT expression and S-1 treatment.

Evaluation of HER2-based biology in 1,006 cases of gastric cancer in a Japanese population.

BACKGROUND: The ToGA trial demonstrated the beneficial effect of trastuzumab in gastric cancer patients with human epidermal growth factor receptor 2 (HER2)-overexpressing tumors. Therefore, evaluation of the relationship between HER2 expression and gastric cancer biology using a validated system has become an even more important task. Herein, we verified the correlation between HER2 overexpression in the tumor and the clinical course of gastric cancer patients. METHODS: A total of 1,006 consecutive patients with gastric cancer who underwent surgery at the National Cancer Center Hospital East between January 2003 and July 2007 were examined using the tissue microarrays approach. HER2 expression was determined based on an immunohistochemistry score of 3+, or an immunohistochemistry score of 2+ plus HER2 gene amplification as detected by double-color fluorescent in situ hybridization. A retrospective review of the medical records was conducted to determine the correlation between the presence of HER2 overexpression and clinicopathological factors. Then, in 948 patients who had undergone curative resection, HER2 status was compared with the survival. RESULTS: HER2 overexpression was detected in 118 (11.7 %) patients. HER2 overexpression was correlated with age, gender, grade of differentiation, expanding growth pattern, and nodal status. In the survival analysis, HER2 overexpression was not found to be correlated with either disease-specific survival or recurrence-free survival. CONCLUSIONS: HER2 overexpression in the tumor was not identified as a significant prognostic factor in patients with operable gastric cancer. The HER2-targeted therapy may be beneficial in a proportion of cases.