[An Abscopal Effect after Palliative Radiotherapy in a Patient with a Locally and Lymph Node Recurrent Gastric Cancer].

Radiotherapy is known to have a high local effect for cancer treatment. However, several reports that radiotherapy could stimulate the anti-tumor effect by releasing endogenous signals and cytokines, increasing the presentation of tumor associated antigens on dendritic cells, and proliferating tumor antigen-specific cytotoxic T lymphocytes have been shown. A tumor regression in both non-irradiated and irradiated fields have observed, which is called"abscopal effect". We report a case of the abscopal effect in adenocarcinoma of the stomach with locally and lymph node recurrence after surgery. A 59-year-old Japanese male was diagnosed with residual stomach cancer and underwent total gastrectomy and distal pancreatectomy. Three months after the surgery, a local recurrence and the involvement of para-aortic lymph node were diagnosed using computed tomography. The chemotherapy treatment(S-1, cisplatin, trastuzumab)was prescribed. However, the disease has progressed. Paclitaxel and ramucirumab were given for second-line, nivolumab for third-line and irinotecan for fourth-line. During that, tumor at local recurrent site invaded to the portal vein. The patients received 50 Gy in 25 fractions of radiotherapy. A remarkable reduction of the mass was shown. In addition to this, we observed that spontaneous shrinking of the para-aortic lymph node metastasis, which was located out of the radiation field. We observed a rare radiation-induced abscopal effect. Radiotherapy might represent a potential candidate for a combination with immunotherapy. A combination of immunotherapy as well as chemotherapy with radiotherapy represents a promising therapeutic strategy.

Clinical significance of serum anti-p53 antibody expression following curative surgery for colorectal cancer.

The aim of the present study was to investigate the usefulness of serum anti-p53 antibody (Ap53Ab) measurement for the diagnosis of colorectal cancer (CRC), and the clinical significance of the association between Ap53Ab expression and survival rate. Ap53Ab, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9 were measured by ELISA in 674 CRC patients and 115 healthy volunteers (control group). The half-life time of Ap53Ab and CEA was calculated. The association between positive Ap53Ab expression and clinicopathological characteristics, including survival rate, was analyzed. Of the 674 CRC patients, 195 (28.9%) were positive for Ap53Ab expression, while the positive rates of CEA and CA19-9 level were 39.9 and 16.9%, respectively. Positivity for Ap53Ab alone was observed in 94 patients (13.9%), whereas the positivity rate of any markers examined was 58.7%. The mean half-life of Ap53Ab and CEA was 30.7 and 11.3 days, respectively. Positive expression of Ap53Ab was significantly associated with the depth of tumor invasion (P<0.001), lymph node metastasis (P=0.024), stage (P<0.001) and CEA level (P=0.005). No significant correlation between Ap53Ab expression and poor survival rate was observed. The positive rate of Ap53Ab was higher compared with that of CEA and CA19-9 in early-stage CRC. The combination of these markers improved the diagnostic yield of CRC up to ~60%. Furthermore, Ap53Ab expression was associated with lymph node metastasis, but not with shorter survival. These results indicated that the measurement of Ap53Ab may contribute to increased rate of detection of CRC, particularly in patients with early-stage disease, in clinical practice.

Lower prevalence of Lynch syndrome in colorectal cancer patients in a Japanese hospital-based population.

PURPOSE: The aim of this study was to investigate the prevalence of Lynch syndrome among Japanese patients with surgically resected colorectal cancer at a single institution. METHODS: Of 616 colorectal cancer patients who underwent surgical operation in our institution from January 2005 to August 2010, immunohistochemistry analyses for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) and microsatellite instability (MSI) testing for surgically resected, formalin-fixed paraffin-embedded colorectal cancer specimens from 138 colorectal cancer patients under 60 years of age were undertaken. Hypermethylation of the MLH1 promoter and BRAF mutation were analyzed where necessary. RESULTS: Seven patients were identified as candidates for genetic testing by mismatch repair protein loss (n = 7) or MSI-H (n = 6). Methylation of MLH1 was detected in one case. Three patients were diagnosed with Lynch syndrome, comprising 2.2 % of the total colorectal cancer patients younger than 60 years of age. CONCLUSION: The prevalence of Lynch syndrome among hospital-based diagnosed cancer patients may therefore be lower than expected in Japan compared with Western populations.

Production of intraperitoneal interleukin-6 following open or laparoscopic assisted distal gastrectomy.

The interleukin (IL)-6 concentration in plasma or serum has been considered to represent the degree of stress resulting from surgery. However, IL-6 in peritoneal fluid has rarely been considered. The aim of this study was to assess the concentration and amount of IL-6 in peritoneal fluid as indicators of surgical stress. To obtain basic data on peritoneal release of IL-6 during gastric cancer surgery, we measured IL-6 in peritoneal drainage samples, stored for up to 72 hours postoperatively, from patients who had undergone conventional open (ODG group, n = 20) and laparoscopic-assisted (LADG group, n = 19) distal gastrectomy. Within 24 hours, 61 and 77% of the IL-6 was released into the peritoneal cavity in the LADG and ODG groups, respectively. In both groups, the concentration and amount of peritoneal fluid IL-6 were significantly correlated with each other (LADG group: Spearman's rank correlation test [rS] = 0.48, P = 0.04; ODG group: rS = 0.58, P = 0.01). The concentration and amount of IL-6 in peritoneal fluid was 2.8- and 3.6-fold higher in the ODG than in the LADG group, respectively (P < 0.01). With regard to the relationship between the serum C-reactive protein (CRP) peak and the concentration or amount of peritoneal fluid IL-6 released within 24 hours, only the concentration of peritoneal fluid IL-6 in the LADG group was significantly correlated (rS = 0.60, P = 0.01) with the serum CRP peak. Our findings suggest that the amount and concentration of IL-6 released into the peritoneal cavity for up to 24 hours after surgery can each be a reliable parameter for assessment of surgical stress.

Predicting the amount of intraperitoneal fluid accumulation by computed tomography and its clinical use in patients with perforated peptic ulcer.

The correlation between the amount of peritoneal fluid and clinical parameters in patients with perforated peptic ulcer (PPU) has not been investigated. The authors' objective was to derive a reliable formula for determining the amount of peritoneal fluid in patients with PPU before surgery, and to evaluate the correlation between the estimated amount of peritoneal fluid and clinical parameters. We investigated 62 consecutive patients who underwent emergency surgery for PPU, and in whom prediction of the amount of accumulated intraperitoneal fluid was possible by computed tomography (CT) using the methods described by Oriuchi et al. We examined the relationship between the predicted amount of accumulated intraperitoneal fluid and that measured during surgery, and the relationship between the amount of fluid predicted preoperatively or measured during surgery and several clinical parameters. There was a significant positive correlation between the amount of fluid predicted by CT scan and that measured during surgery. When patients with gastric ulcer and duodenal ulcer were analyzed collectively, the predicted amount of intraperitoneal fluid and the amount measured during surgery were each associated with the period from onset until CT scan, perforation size, the Mannheim peritoneal index, and the severity of postoperative complications according to the Clavien-Dindo classification. Our present results suggest that the method of Oriuchi et al is useful for predicting the amount of accumulated intraperitoneal fluid in patients with PPU, and that this would be potentially helpful for treatment decision-making and estimating the severity of postoperative complications.

[Significance of the granulocyte-to-lymphocyte ratio as a prognostic predictor in patients with stage IV colorectal cancer undergoing chemotherapy].

The aim of this study was to evaluate the clinical significance of the granulocyte-to-lymphocyte(G/L)ratio as a prognostic predictor in patients with Stage IV colorectal cancer. A total of 83 patients who underwent oxaliplatin-based chemotherapy for Stage IV colorectal cancer were enrolled in the study. Univariate analysis indicated that the G/L ratio; number of involved organs(more than one organ); performance status ≥1; noncurability; and levels of hemoglobin, C-reactive protein, albumin, alkaline phosphatase, carbohydrate antigen 19-9, and lactate dehydrogenase before chemotherapy were significant prognostic factors. Noncurability was identified to be an independent, unfavorable factor for survival on multivariate analysis. When patients were divided into 2 groups according to the G/L ratio(the median was considered the cut-off value), the median survival time of patients with a high G/L ratio(≥3.0)was significantly worse than that of patients with a low G/L ratio(<3.0; 16.1 months vs 25.4 months, p=0.03). Further studies with more patients are required to examine whether the G/L ratio is a convenient biomarker affecting survival in patients with Stage IV colorectal cancer.

[Significant prognostic factors in stage IV gastric cancer].

The aim of this study was to evaluate clinicopathological variables, including the granulocyte-to-lymphocyte ratio(G/L ratio), as prognostic factors for Stage IV gastric cancer patients. A total of 70 patients treated for Stage IV gastric cancer were enrolled in this study. Univariate analysis indicated that age ≥70 years, performance status >2, resection not being performed, chemotherapy not being administered, high C-reactive protein(CRP)levels, and carbohydrate antigen 19-9 levels were significantly associated with poor survival. Multivariate analysis of these factors identified resection not being performed, chemotherapy not being administered, and high CRP levels as independent unfavorable factors of survival. Although the G/L ratio was not a prognostic factor for Stage IV gastric cancer patients in this study, further studies with greater number of patients are required to determine whether the G/L ratio is a significant biomarker associated with survival.

Hemodynamics of the reconstructed gastric tube during esophagectomy: assessment of outcomes with indocyanine green fluorescence.

BACKGROUND: Construction of a gastric tube that is well perfused with blood during esophagectomy is the most important factor in avoiding anastomotic leakage. We clarified the hemodynamics of the reconstructed gastric tube with indocyanine green (ICG) fluorescence. METHODS: In 20 patients undergoing gastric tube reconstruction during esophagectomy, we evaluated blood flow in the gastric tube with ICG fluorescence imaging. We divided the patients into two groups according to the quality of blood flow to the gastric tube-"good" (n = 9) and "sparse or absent" (n = 11)-based on visual assessment of the anastomosis of the right and left gastroepiploic vessels. We measured the time from initial enhancement of the root of the right gastroepiploic artery until enhancement of the most cranial branch of the left gastroepiploic artery and tip of the gastric tube. RESULTS: The gastric tube was divisible into three zones according to the dominant arteries present in the greater curvature under ICG fluorescence. The left gastroepiploic artery was enhanced in a direction opposite that of physiological blood flow in all cases. The median period from initial enhancement of the root of the right gastroepiploic artery to the most cranial branch of the left gastroepiploic artery until perfusion up to the tip of the gastric tube did not differ significantly between the "good" and the "sparse or absent" groups (P = 0.24, 0.68) CONCLUSIONS: It is essential to preserve the whole vessel arcade of the greater curvature to achieve good blood perfusion in the gastric tube. The ICG fluorescence method has potential usefulness for evaluation of blood flow in the gastric tube.

[Efficacy of oxaliplatin-based adjuvant chemotherapy in stage II and III colorectal cancer with perforation].

This retrospective study evaluated the efficiency of oxaliplatin-based (Oxa-based) adjuvant chemotherapy for colorectal cancer with perforation. The study included 38 patients who underwent surgery for perforation associated with StageII and III colorectal cancer between April 1998 and March 2013. Patients with operative mortality were excluded from the study. The numbers of patients with StageII and III disease were 26 and 12, respectively. Adjuvant chemotherapy was received by 16 patients (62%) in the Stage II group. Seven patients (54%) in the Stage III group received adjuvant chemotherapy, of which 6 received Oxa-based adjuvant chemotherapy. The median relative dose intensity(range)of oxaliplatin was 83.3 (28.8- 100)%. Grade 3 adverse events were reported in 2 cases. The 3-year overall survival rates in the StageII and III groups were 60% and 79%, respectively. There was no significant difference in overall survival between the groups (p=0.28). Patients who received adjuvant chemotherapy had a 2.3-fold greater 3-year overall survival rate than those who did not receive adjuvant chemotherapy (80% vs 35%, p=0.01). The 3-year overall survival rates were 100% in patients who received Oxabased adjuvant chemotherapy (n=6), and 76%in patients who received adjuvant chemotherapy without oxaliplatin (n=17), with no significant difference between the groups (p=0.24). The Oxa-based adjuvant chemotherapy was tolerated equally well in Stage II and III colorectal cancer patients with or without perforation. Further studies are needed to compare the effect of oxaliplatin with other adjuvant chemotherapies.

C-reactive protein as a significant prognostic factor for stage IV gastric cancer patients.

BACKGROUND/AIM: We aimed to clarify the roles of CRP and albumin as independent prognostic factors for stage IV gastric cancer (stIVGC) patients. The optimal cut-off value for these two markers was investigated. PATIENTS AND METHODS: 123 stIVGC patients presented at our Medical Center from April, 2005 to March, 2011 were investigated. Clinicopathological, tumor-specific and treatment factors were analyzed. Univariate and multivariate Cox proportional regression models were used to identify for favorable factors affecting overall survival. The Receiver operating characteristic (ROC) curve was utilized to determine cut-off values. RESULTS: Multivariate analysis revealed CRP (hazard ratio (HR): 1.11; 95% confidence interval (CI): 1.03-1.18) to be an independent prognostic factor for survival. According to the results of the analysis albumin was excluded. ROC curve of the 3-month-prognosis patients revealed a maximum area under the curve of 0.85 and a cut-off value of 1.7 mg/dl. CONCLUSION: CRP can be considered an independent prognostic factor for survival of stIVGC patients and can be used for short-term survival prediction.

[Outcomes of patients with small bowel carcinoma treated with appropriate chemotherapy selected on the basis of genetic analysis findings].

Small bowel carcinoma is a rare tumor, for which a standardized chemotherapy regimen has not yet been established. Further, this tumor may belong to the group of Lynch syndrome-associated tumors, which are resistant to 5-fluorouracil (5-FU) -based chemotherapy. We investigated mismatch repair protein expression and K-ras gene mutation status in 8 patients with aggressive small bowel carcinoma and determined the chemotherapy regimen used in these patients. Immunohistochemical staining indicated normal mismatch repair protein expression in all surgical specimens. Of 8 patients, 4( 50%) had K-ras codon 12 mutations. Because small bowel carcinoma is not significantly associated with Lynch syndrome, 5-FU-based chemotherapy would be appropriate for the treatment of these patients. The prevalence of K-ras codon 12 mutations was relatively similar to that in patients with sporadic colorectal carcinoma, and the usefulness of anti- epidermal growth factor receptor (EGFR) antibody for the treatment of small bowel carcinoma should be evaluated in the future.

[Clinical differences between palliative gastrectomy and reduction surgery for gastrectomy in curatively unresectable gastric cancer].

Surgical treatments for curatively unresectable gastric cancer include reduction surgery and palliative surgery(palliative gastrectomy and bypass operation). Both palliative gastrectomy and reduction surgery reduce the tumor volume. In this study, the clinical significance of these treatment methods was investigated. The subjects were 58 patients with unresectable gastric cancer for which surgery was performed as the primary treatment. Of these patients, 38 patients underwent reduction surgery and 20 patients underwent palliative surgery. On univariate analysis, age and gender were not significant. Pre-operative performance status(PS) in patients treated with reduction surgery was favorable compared to that in patients receiving palliative surgery(PS 0: 65.8 vs 40.0%, p=0.06). The administration rate of post-operative chemotherapy in patients treated with reduction surgery was higher than that in patients with palliative surgery (92.1 vs 65.0%, p<0.01). The median survival time in patients treated with reduction surgery was 18.2 months, while that in patients with palliative surgery was 11.0 months (p<0.01). These results indicated that reduction surgery was clinically different compared to palliative surgery in terms of the administration rate of post-operative chemotherapy and prognosis.

Thymidylate synthase and thymidine phosphorylase mRNA expression in primary lesions using laser capture microdissection is useful for prediction of the efficacy of FOLFOX treatment in colorectal cancer patients with liver metastasis.

Chemotherapy with FOLFOX, which is a combination of 5-fluorouracil (5-FU)/leucovorin (LV) and oxaliplatin, has been used worldwide for the treatment of metastatic colorectal cancer patients. The aim of this study was to examine the candidates for predictors of the efficacy of the FOLFOX treatment regimen in colorectal cancer patients with liver metastasis, using formalin-fixed paraffin-embedded specimens. We investigated the mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT) and excision repair cross-complementing 1 (ERCC1) in 70 primary lesions and 30 liver metastatic lesions of colorectal cancer patients, using laser capture microdissection and real-time PCR methods. We then analyzed the correlation between their expression in primary lesions and those in corresponding liver metastatic lesions (n=30) and the relationship between their expression in the primary lesions and the efficacy of mFOLFOX6 in 45 colorectal cancer patients with unresectable liver metastasis. The gene expression in primary lesions positively correlated with those in corresponding liver metastatic lesions. The profiles of gene expression of primary lesions strongly correlated with those of synchronous liver metastatic lesions compared to that of metachronous liver metastatic lesions. TS and TP mRNA levels in the patients with complete response, partial response or stable disease (n=34) were significantly lower compared to those in the patients with progressive disease (n=11) (p=0.017 and p=0.04, respectively). Our results indicated that TS and TP mRNA expression profiles in primary lesions are sufficient to estimate the mRNA expression profiles in synchronous liver metastatic lesions compared to metachronous liver metastatic lesions. Additionally, these profiles may be useful predictors in the identification of eligible colorectal cancer patients with liver metastasis for FOLFOX treatment.

ALEX1 suppresses colony formation ability of human colorectal carcinoma cell lines.

Arm protein lost in epithelial cancers, on chromosome X (ALEX; also known as armadillo repeat containing, X-linked [ARMCX]) is a novel subgroup within the armadillo (ARM) family, which has several ARM repeat domains. The biological function of classical ARM family members such as ß-catenin is well understood, but that of the ALEX/ARMCX family members is largely unknown. Here we evaluate the effects of ALEX1 overexpression on in vitro colony formation ability and expression of ALEX1 mRNA in human colorectal tumor. Overexpression of ALEX1 suppressed the anchorage-dependent and -independent colony formation of human colorectal carcinoma cell lines by the study of stable clones of HCT116 cells expressing ALEX1 protein. Bisulfite genomic sequencing revealed that the promoter region of ALEX1 gene was highly methylated in both HCT116 and SW480 cells in comparison with PANC-1 and MCF-7 cells, which express endogenous ALEX1 mRNA, indicating the capability of promoter methylation to silence ALEX1 gene in HCT116 and SW480 cells. Our current findings suggest that overexpression of ALEX1 play a negative role in human colorectal tumorigenesis.

[Therapeutic effect of mFOLFOX6 for synchronous unresectable liver metastases from colorectal cancer].

The current chemotherapy for metastatic colon cancer has improved an overall survival. In this study, we retrospectively analyzed the efficacy of mFOLFOX6 in colorectal cancer patients with synchronous unresectable liver metastases and compared the prognosis between before and after the administration of mFOLFOX6. The subject was 28 patients of colorectal cancer with synchronous unresectable liver metastasis who received mFOLFOX6 as a first-line treatment from 2005 to 2010. The median frequency of mFOLFOX6 was 10 times( range, 2-24 times), relative dose intensity of oxaliplatin was 75.0% (range, 42 .9-100), response rate was 32%, and median progression-free survival was 9 . 9 months. Surgical resection of colorectal liver metastases was performed to 4 patients (14.3%) as a conversion therapy. The overall survival of the patients with mFOLFOX6 was significantly better than that of 31 patients who received the chemotherapy via hepatic artery or the chemotherapy before the administration of oxaliplatin (31.8 months vs. 15 .1 months, p<0.01). Our results suggested that mFOLFOX6 treatment for unresectable liver metastases of colorectal cancer was made not only the conversion therapy possible, but it has improved the prognosis when compared with previous treatment without oxaliplatin.