Low skeletal muscle radiodensity is a risk factor for adjuvant chemotherapy discontinuation in colorectal cancer.

BACKGROUND: Previously, we reported SMR (skeletal muscle radiodensity) as a potential prognostic marker for colorectal cancer. However, there have been limited studies on the association between SMR and the continuation of adjuvant chemotherapy in colorectal cancer. METHODS: In this retrospective study, 143 colorectal cancer patients underwent curative surgery and adjuvant chemotherapy using the CAPOX regimen. Patients' SMRs were measured from preoperative CT images and divided into low (bottom quarter) and high (top three quarters) SMR groups. We compared chemotherapy cycles, capecitabine and oxaliplatin doses, and adverse effects in each group. RESULTS: The low SMR group had significantly fewer patients completing adjuvant chemotherapy compared to the high SMR group (44% vs. 68%, P < 0.01). Capecitabine and oxaliplatin doses were also lower in the low SMR group. Incidences of Grade 2 or Grade 3 adverse effects did not differ between groups, but treatment discontinuation due to adverse effects was significantly higher in the low SMR group. Logistic regression analysis revealed Stage III disease (odds ratio 18.09, 95% CI 1.41-231.55) and low SMR (odds ratio 3.26, 95% CI 1.11-9.56) as factors associated with unsuccessful treatment completion. Additionally, a higher proportion of low SMR patients received fewer than 2 cycles of chemotherapy (50% vs. 12%). CONCLUSION: The low SMR group showed higher treatment incompletion rates and received lower drug doses during adjuvant chemotherapy. Low SMR independently contributed to treatment non-completion in colorectal cancer patients.

Clinical practice guidelines for molecular tumor markers, 2nd edition review part 1.

With advances in gene and protein analysis technologies, many target molecules that may be useful in cancer diagnosis have been reported. Therefore, the "Tumor Marker Study Group" was established in 1981 with the aim of "discovering clinically" useful molecules. Later, the name was changed to "Japanese Society for Molecular Tumor Marker Research" in 2000 in response to the remarkable progress in gene-related research. Currently, the world of cancer treatment is shifting from the era of representative tumor markers of each cancer type used for tumor diagnosis and treatment evaluation to the study of companion markers for molecular-targeted therapeutics that target cancer cells. Therefore, the first edition of the Molecular Tumor Marker Guidelines, which summarizes tumor markers and companion markers in each cancer type, was published in 2016. After publication of the first edition, the gene panel testing using next-generation sequencing became available in Japan in June 2019 for insured patients. In addition, immune checkpoint inhibitors have been indicated for a wide range of cancer types. Therefore, the 2nd edition of the Molecular Tumor Marker Guidelines was published in September 2021 to address the need to revise the guidelines. Here, we present an English version of the review (Part 1) of the Molecular Tumor Marker Guidelines, Second Edition.

Less demand on stem cell marker-positive cancer cells may characterize metastasis of colon cancer.

BACKGROUND: CD44 and CD133 are stem cell markers in colorectal cancer (CRC). CD44 has distinctive isoforms with different oncological properties like total CD44 (CD44T) and variant CD44 (CD44V). Clinical significance of such markers remains elusive. METHODS: Sixty colon cancer were examined for CD44T/CD44V and CD133 at mRNA level in a quantitative PCR, and clarified for their association with clinicopathological factors. RESULTS: (1) Both CD44T and CD44V showed higher expression in primary colon tumors than in non-cancerous mucosas (p<0.0001), while CD133 was expressed even in non-cancerous mucosa and rather decreased in the tumors (p = 0.048). (2) CD44V expression was significantly associated with CD44T expression (R = 0.62, p<0.0001), while they were not correlated to CD133 at all in the primary tumors. (3) CD44V/CD44T expressions were significantly higher in right colon cancer than in left colon cancer (p = 0.035/p = 0.012, respectively), while CD133 expression were not (p = 0.20). (4) In primary tumors, unexpectedly, CD44V/CD44T/CD133 mRNA expressions were not correlated with aggressive phenotypes, but CD44V/CD44T rather significantly with less aggressive lymph node metastasis/distant metastasis (p = 0.040/p = 0.039, respectively). Moreover, both CD44V and CD133 expressions were significantly decreased in liver metastasis as compared to primary tumors (p = 0.0005 and p = 0.0006, respectively). CONCLUSION: Our transcript expression analysis of cancer stem cell markers did not conclude that their expression could represent aggressive phenotypes of primary and metastatic tumors, and rather represented less demand on stem cell marker-positive cancer cells.

Short-term outcomes of robot-assisted versus conventional laparoscopic surgery for mid and low rectal cancer after neoadjuvant chemoradiotherapy: a propensity score-matched analysis.

The benefits of robot-assisted laparoscopic surgery (RALS) for rectal cancer remain controversial. Only a few studies have evaluated the safety and feasibility of RALS following neoadjuvant chemoradiotherapy (NCRT). This study aimed to compare the short-term outcomes of RALS versus conventional laparoscopic surgery (CLS) after NCRT for rectal cancer. Propensity score matching of 111 consecutive patients who underwent RALS or CLS after NCRT for rectal adenocarcinoma between February 2014 and February 2022 was performed. Among them, 60 matched patients were enrolled and their short-term outcomes were compared. Although operative time, conversion rate to open laparotomy and blood loss were comparable, the incidence of postoperative complications, including anastomotic leakage, was significantly lower, urinary retention tended to be lower, and the days to soft diet intake and postoperative hospital stay were significantly shorter in the RALS than the CLS group. No postoperative mortality was observed in either group, and there were no significant differences in terms of resection margins and number of lymph nodes dissected. RALS after NCRT for rectal cancer is safe and technically feasible, and has acceptable short-term outcomes. Further studies are required for validation of the long-term oncological outcomes.

Short- and long-term outcomes of robotic-assisted laparoscopic surgery for rectal cancer: A single-center retrospective cohort study.

INTRODUCTION: Whether rectal cancer surgery by robotic-assisted laparoscopic surgery provides beneficial advantages remains controversial. Although favorable outcomes in terms of the safety and technical feasibility of robotic-assisted laparoscopic surgery have been demonstrated for rectal cancer, long-term oncological outcomes for robotic-assisted laparoscopic surgery have only been examined in a few studies. This retrospective study of subjects who underwent robotic-assisted laparoscopic surgery evaluated short- and long-term outcomes of consecutive rectal cancer patients. METHODS: Between November 2016 and January 2020, we analyzed the records of 62 consecutive patients who underwent robotic-assisted laparoscopic surgery for rectal adenocarcinoma without distant metastasis to evaluate short- and long-term outcomes. RESULTS: Tumors were located in the lower or mid-rectum (88.7%) in most patients. The median operative time was 357 min. No patient received transfusions, and the median blood loss was 10.5 ml. Open laparotomy was not required in any patient. A Clavien-Dindo classification of all grades was observed in 12 patients (19.4%). Positive radial margin was not observed in any patient. Duration of median follow-up was 40.5 mo, while 3-y overall survival and 3-y relapse-free survival rates were 96.8% and 85.0%, respectively. The local recurrence rate was 3.4%. CONCLUSION: Favorable short- and long-term outcomes demonstrated robotic-assisted laparoscopic surgery was safe and technically feasible for rectal cancer.

Comparison of short-term outcomes of robotic-assisted and conventional laparoscopic surgery for rectal cancer: A propensity score-matched analysis.

INTRODUCTION: The advantages of robotic-assisted laparoscopic surgery (RALS) for rectal cancer remain controversial. This study clarified and compared the short-term outcomes of RALS for rectal cancer with those of conventional laparoscopic surgery (CLS). METHODS: The records of 303 consecutive patients who underwent RALS or CLS for rectal adenocarcinoma between November 2016 and November 2021 were analyzed using propensity score-matched analysis. After matching, 188 patients were enrolled in our study to compare short-term outcomes, such as operative results, postoperative complications, and pathological findings, in each group. RESULTS: After matching, baseline characteristics were comparable between groups. Although operative time in the RALS group was significantly longer than in the CLS group (p < 0.0001), the conversion rate to open laparotomy and the postoperative complication rate in the RALS group were significantly lower than in the CLS group (p = 0.0240 and p = 0.0109, respectively). Blood loss was comparable between groups. In the RALS group, postoperative hospital stay and days to soft diet were significantly shorter than those in the CLS group (p = 0.0464 and p < 0.0001, respectively). No postoperative mortality was observed in either group and significant differences were observed in resection margins and number of lymph nodes harvested. CONCLUSION: Robotic-assisted laparoscopic surgery for rectal cancer was safe, technically feasible, and had acceptable short-term outcomes. Further studies are required to validate long-term oncological outcomes.

Skeletal Muscle Changes Assessed by Preoperative Computed Tomography Images Can Predict the Long-Term Prognosis of Stage III Colorectal Cancer.

Background: Myopenia and myosteatosis are reported to be long-term prognostic factors in patients with colorectal cancer (CRC). However, the established parameters are unsuitable for the Japanese population because their body composition is different from that of the Western population. Objective: We aimed to elucidate the effect of skeletal muscle changes among Japanese adults, measured using preoperative computed tomography (CT) as a prognostic factor in patients with stage III CRC. Patients: We retrospectively analyzed 341 patients diagnosed with stage III CRC. The cross-sectional area (skeletal muscle index: SMI) and mean radiodensity of skeletal muscle (skeletal muscle radiodensity: SMR) were measured using preoperative CT. The optimal sex-specific cutoff value, which was used to divide the patients according to the risk of recurrence, was set for SMI and SMR. Univariate and multivariate analysis were performed to determine the prognostic factors for recurrence-free survival (RFS). Results: The cutoff values of SMI for men and women were set as 48.5 and 41.4, respectively, and those of SMR were 35.0 and 21.7, respectively. Univariate analysis identified low SMI and SMR in men and low SMR in women as the worst prognostic factors for RFS. Multivariate analysis identified low SMI in men and low SMR in women as independent poor prognostic factors for RFS (hazard ratio [HR] = 1.87, 95% confidence interval [CI], 1.08-3.47, P = .03 and HR = 2.49, CI, 1.21-4.95, P = .01). Conclusion: Low SMI in men and low SMR in women were the independent prognostic factors for patients with stage III CRC.

Verifying the M1c category of CRC: analysis of the data from a Japanese multi-institutional database.

BACKGROUND/AIMS: In the TNM classification 8th edition, colorectal cancer (CRC) with peritoneal metastasis, one of the most poor prognostic factors, is classified as M1c (stage IVC), regardless of the presence/absence of other distant metastasis. Several cases with peritoneal metastasis have been successfully managed by surgical treatment; therefore, there is need to give more consideration for uniform differentiation of peritoneal metastasis. This study was aimed at verifying the classification of M1c in CRC. MATERIALS AND METHODS: Data from a multi-institutional retrospective cohort of 2929 CRC patients who were diagnosed as having stage IV CRC from 1997 to 2007 were analyzed. Peritoneal metastasis alone was defined as M1c1 and peritoneal metastasis with other organ metastasis was defined as M1c2. RESULTS: The 3-year OS of patients with M1c1 was significantly higher than that of patients with M1b (25.6% vs. 18.1%; HR 0.77; 95% confidence interval (CI) 0.65-0.92; p = 0.005); in particular, the prognosis of patients with M1c1 with localized peritoneal metastasis and R0 resection was equivalent to that of patients with M1a (3-year OS 40.5% vs. 39.2%, p = 0.41). On the other hand, among the stage IV cases, patients with M1c2 had a low R0 resection rate (5.9%) and the worst prognosis (3-year OS, 9.1%). CONCLUSIONS: The prognosis of M1c1 with localized peritoneal metastasis is relatively good, and can be further improved by surgical intervention. Combined evaluation of the M1c1/2 classification with the peritoneal metastasis grade may help in establishing more individualized treatment strategies.

Comprehensive Exploration to Identify Predictive DNA Markers of ΔNp63/SOX2 in Drug Resistance in Human Esophageal Squamous Cell Carcinoma.

BACKGROUND: OBP-801 is a novel histone deacetylase inhibitor being developed as an anticancer drug. In this study, we explored genes to predict drug resistance in human cancer. METHODS: OBP-801 resistance was assessed in 37 strains of human cancer cell lines. Expression microarrays harboring 54,675 genes were used to focus on candidate genes, which were validated for both functional and clinical relevance in esophageal squamous cell carcinoma (ESCC). RESULTS: OBP-801 is sensitive to esophageal, gastric, and thyroid cancer, and resistant to some esophageal and colorectal cancers. We therefore used ESCC to explore genes. Comprehensive exploration focused on ΔNp63/SOX2, which were both genetically and epigenetically overexpressed in ESCC. Genomic amplifications of ΔNp63/SOX2 were tightly correlated each other (r = 0.81). Importantly, genomic amplification of ΔNp63/SOX2 in the resected tumors after neoadjuvant chemotherapy was significantly associated with histological grade of response (G1). Forced expression of either of these two genes did not induce each other, suggesting that their functional relevances were independent and showed robust drug resistance in OBP-801, as well as 5-fluorouracil. Furthermore, ΔNp63 could exert a potent oncogenic potential. RNA interference of ΔNp63 supported its oncological properties, as well as drug resistance. CONCLUSION: Comprehensive exploration of genes involved in anticancer drug residence could identify critical oncogenes of ΔNp63/SOX2 that would predict chemotherapy response in ESCC.

Prediction of onset of remnant gastric cancer by promoter DNA methylation of CDO1/HOPX/Reprimo/E-cadherin.

BACKGROUND: Early detection of remnant gastric cancer (RGC) is required to reduce the risk of death, but long-term endoscopic surveillance is difficult after gastrectomy. In this study, data for the methylation status of 4 methylation genes (CDO1, HOPX, Reprimo, and E-cadherin) to predict the onset of RGC are presented. RESULTS: The 4 genes showed hypermethylation in RGC tumors in contrast to the corresponding non-cancerous mucosa tissues. The methylation level in the non-cancerous mucosa tissues of the initial surgery was obviously high in initial malignant disease for CDO1 (P = 0.0001), while in initial benign one for E-cadherin (P = 0.003). Promoter DNA methylation status in the remnant non-cancerous mucosa tissues together with the basic clinical data in turn predicted either initial malignant disease or initial benign disease with a high AUC score of 0.94, suggesting that methylation events are differentially recognized between the initial malignant and benign disease. We then finally confirmed that 4 genes hypermethylation of the non-cancerous tissues by biopsy prior to onset of RGC could predict terms until RGC occurred (P < 0.0001). METHODS: A total of 58 RGC patients were used to establish the model. The 4 genes promoter methylation were analyzed for DNA obtained from the patient's specimens using quantitative methylation specific polymerase chain reaction. CONCLUSIONS: This risk model would help provide guidance for endoscopic surveillance plan of RGC after gastrectomy.

Comprehensive Genetic Search to Clarify the Molecular Mechanism of Drug Resistance Identifies ASCL2-LEF1/TSPAN8 Axis in Colorectal Cancer.

BACKGROUND: Treatment-resistance genes limiting anticancer therapy have not been well clarified in colorectal cancer (CRC). We explored gene expression profiles to identify biomarkers for predicting treatment resistance to an anticancer drug in CRC. METHODS: Six CRC cell lines were treated with phenylbutyrate (PB). The gene expression profiles were then compared using microarrays (harboring 54,675 genes), and genes associated with PB resistance were identified. Candidate genes were functionally examined in cell lines and clinically validated for treatment resistance in clinical samples. RESULTS: Both DLD1 and HCT15 cells were PB resistant, while HCT116 cells were identified as PB sensitive. On microarray analysis, among the PB resistance-related genes, the expression of the genes ASCL2, LEF1, and TSPAN8 was clearly associated with PB resistance. PB-sensitive cells transfected with one of these three genes exhibited significant (P < 0.001) augmentation of PB resistance; ASCL2 induced expression of both LEF1 and TSPAN8, while neither LEF1 nor TSPAN8 induced ASCL2. RNA interference via ASCL2 knockdown made PB-resistant cells sensitive to PB and inhibited both genes. ASCL2 knockdown also played a critical role in sensitivity to treatment by 5-fluorouracil and radiotherapy in addition to PB. Finally, ASCL2 expression was significantly correlated with histological grade of rectal cancer with preoperative chemoradiation therapy. CONCLUSIONS: ASCL2 was identified as a causative gene involved in therapeutic resistance against anticancer treatments in CRC.

Critical relevance of genomic gains of PRL-3/EGFR/c-myc pathway genes in liver metastasis of colorectal cancer.

The PRL-3 gene is involved in the liver metastasis of colorectal cancer (CRC) and oncogene addiction to anticancer therapy. In the present study genomic gains in PRL-3 and its pathway genes, c-myc and EGFR, were investigated in order to determine their clinical relevance during metastatic formation in primary CRC and corresponding liver metastases. The genomic gain statuses of PRL-3, EGFR, and c-myc were investigated using quantitative polymerase chain reaction (qPCR) analysis in 35 samples of CRC and corresponding liver metastases. In the primary CRC specimens, genomic gains in PRL-3, c-myc, and EGFR were observed in 4, 4, and 13 cases, respectively. A genomic gain in one gene was observed in 18 cases, and these genomic gains were mutually exclusive. In the liver metastasis specimens, genomic gains were observed in 14, 8, and 13 cases, respectively. The copy numbers of PRL-3 and c-myc were significantly higher in the liver metastases than in the primary CRC specimens (P=0.03, P=0.009, respectively). A genomic gain in PRL-3 was the most frequent gain in the liver metastases (P=0.004) and was partially redundant with a c-myc genomic gain. EGFR genomic gains were consistent between the primary CRC and the liver metastases (P=0.0000008). In addition, a genomic gain in any of the 3 genes was observed in 23 cases (66%). Among the clinicopathological factors that were assessed, an EGFR genomic gain was significantly associated with tumour size in the primary CRC and the liver metastases (P=0.04). A c-myc genomic gain was also significantly associated with the v factor of the primary tumours in the liver metastases (P<0.01). In conclusion, the genomic copy numbers of PRL-3, c-myc and EGFR were frequently characterised by aberrations in genomic gain in liver metastases from CRC; thus, these gene statuses exhibit potential for the identification of patients who are likely to respond positively to anticancer therapies.

Dissected peripancreatic tissue margin is a critical prognostic factor and is associated with a K-ras gene mutation in pancreatic ductal adenocarcinoma.

We previously reported that the dissected pancreatic tissue margin (DPM) and the preoperative serum level of carbohydrate antigen 19-9 (preCA19-9) were independent prognostic factors in pancreatic ductal adenocarcinoma (PDAC). In the current study, the prognostic relevance of these factors, including their molecular associations, were validated. A total of 161 patients with PDAC underwent a pancreatectomy between 1986 and 2013, and a multivariate Cox proportional hazards model and a propensity score-based model validated the prognostic importance of DPM. The prognostic factors were compared with the mutation profiles of the K-ras and TP53 genes. Univariate prognostic analysis of disease-specific survival (DSS) demonstrated that DPM (P<0.0001), preCA19-9 (P<0.0001) and Union for International Cancer Control (UICC) stage (P<0.0001), were all significantly associated with poor outcome in PDAC. A multivariate Cox proportional hazards model confirmed that preCA19-9 (P=0.0002) and DPM (P=0.0002) remained as prognostic factors independent of UICC stage (P=0.0015). The combination of preCA19-9 and DPM to predict prognosis could accurately identify the long-term survivors of PDAC (70% 5-year DSS), and a multivariate logistic regression model identified that DPM was the most effective predictor of mortality. The prognostic relevance of DPM was also confirmed (P=0.0008) through propensity score-based background adjustment of patient bias. K-ras gene mutation was significantly associated with DPM (P=0.0002), and DPM-positive patients demonstrated recurrence of distant metastasis in 67% of cases. Therefore, DPM is a critical prognostic indicator in PDAC. In combination with preCA19-9, DPM may be useful to identify long-term survivors of PDAC. Furthermore, to the best of our knowledge, the current study was the first to discover that DPM can represent a poor prognosis based putatively on its association with the K-ras gene mutation.

Clinical significance of cancer specific methylation of the CDO1 gene in small bowel cancer.

Although small bowel cancer (SBC) is extremely rare, its prognosis is poor, and molecular mechanism of the SBC development remains unclear. The aim of our study is to elucidate whether DNA methylation of the promoter region of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in SBC. The study group comprised patients with 53 patients with SBC, 107 colorectal cancer (CRC), and other rare tumors of the small intestine such as 4 malignant lymphomas, 2 leiomyosarcomas, and 9 gastrointestinal stromal tumors. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1. Significantly higher CDO1 methylation was observed in cancer tissues compared with non-cancerous mucosa of the small intestine (ROC = 0.96). Among the various clinicopathological factors, positive correlation of CDO1 methylation with tumor diameter was observed (R = 0.31, p = 0.03), and the CDO1 methylation level was a possible prognostic factor for relapse-free survival (p = 0.09). Compared with CRC, SBC had a significantly poorer prognosis (p = 0.007) and displayed a significantly higher CDO1 methylation level (p < 0.0001). Intriguingly, especially in pStage I/II, there were robust prognostic difference between SBC and CRC (p = 0.08 / p < 0.0001), which may reflect CDO1 methylation status (p = 0.02 / p = 0.001). Among small bowel tumors, CDO1 methylation in SBC was higher in order of malignant lymphoma, cancer, and leiomyosarcoma/GIST (p = 0.002) by ANOVA. The CDO1 gene shows extremely cancer-specific hypermethylation, and it can be a prognostic marker in SBC.

Epigenetic Status of CDO1 Gene May Reflect Chemosensitivity in Colon Cancer with Postoperative Adjuvant Chemotherapy.

BACKGROUND: Cysteine dioxygenase type 1 (CDO1) acts as a tumor suppressor gene, and its expression is regulated by promoter DNA methylation in human cancer. The metabolic product mediated by CDO1 enzyme increases mitochondrial membrane potential (MMP), putatively representing chemoresistance. The aim of this study is to investigate the functional relevance of CDO1 gene in colon cancer with chemotherapy. PATIENTS AND METHODS: We investigated 170 stage III colon cancer patients for CDO1 methylation by using quantitative methylation-specific polymerase chain reaction (PCR). To elucidate the functional role of CDO1 gene in colorectal cancer (CRC) biology, we established cell lines that stably express CDO1 gene and evaluated chemosensitivity, MMP, and tolerability assay including anaerobic environment. RESULTS: Hypermethylation of CDO1 gene was an independent prognostic factor for stage III colon cancer on multivariate prognostic analysis. Surprisingly, patients with CDO1 hypermethylation exhibited better prognosis than those with CDO1 hypomethylation in stage III colon cancer with postoperative chemotherapy (P = 0.03); however, a similar finding was not seen in those without postoperative chemotherapy. In some CRC cell lines, forced expression of CDO1 gene increased MMP accompanied by chemoresistance and/or tolerance under hypoxia. CONCLUSION: CDO1 methylation may be a useful biomarker to increase the number of stage III colon cancer patients who can be saved by adjuvant therapy. Such clinical relevance may represent the functionally oncogenic property of CDO1 gene through MMP activity.

Cysteine dioxygenase type 1 (CDO1) gene promoter methylation during the adenoma-carcinoma sequence in colorectal cancer.

BACKGROUND: Progression of colorectal cancer (CRC) has been explained by genomic abnormalities along with the adenoma-carcinoma sequence theory (ACS). The aim of our study is to elucidate whether the promoter DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in CRC. METHODS: The study group comprised 107 patients with CRC who underwent surgical resection and 90 adenomas treated with endoscopic resection in the Kitasato University Hospital in 2000. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1. RESULTS: The methylation level increased along with the ACS process (p < 0.0001), and statistically significant differences were found between normal-appearing mucosa (NAM) and low-grade adenoma (p < 0.0001), and between low-grade adenoma and high-grade adenoma (p = 0.01), but not between high-grade adenoma and cancer with no liver metastasis. Furthermore, primary CRC cancers with liver metastasis harbored significantly higher methylation of CDO1 than those without liver metastasis (p = 0.02). As a result, the area under the curve by CDO1 promoter methylation was 0.96, 0.80, and 0.67 to discriminate cancer from NAM, low-grade adenoma from NAM, and low-grade adenoma from high-grade adenoma, respectively. CONCLUSIONS: CDO1 methylation accumulates during the ACS process, and consistently contributes to CRC progression.

Potential therapeutic targets of TP53 gene in the context of its classically canonical functions and its latest non-canonical functions in human cancer.

In normal tissue, p53 protein has a wide range of functions involving cell homeostasis; its mutation, however, permits a carcinogenic acquisition of function. TP53 gene mutation is a major genomic aberration in various human cancers and is a critical event in the multi-step carcinogenesis process. TP53 mutation is clinically relevant for the molecular classification of carcinogenesis, as most recently described rigorously by the Cancer Genome Atlas Research Network. TP53 gene mutation has been considered to work as a tumor suppressor gene through the loss of its transcriptional activity, which is designated as a canonical function. However, in cancer patients with mutant TP53, mutated p53 protein is frequently overexpressed, suggesting the activation of an oncogenic process through a gain of function (GOF). As part of this GOF, molecular mechanisms explaining the non-canonical function of TP53 gene abnormality have been reported, in which mutant p53 unconventionally binds with various critical molecules suppressing oncogenic properties, such as p63 and p73. Moreover, mutant TP53 gene-targeted therapy has been rigorously developed, and promising clinical trials have been started. In this study, we summarize the novel aspects of mutant p53 and describe its prominent therapeutic potentials in human cancer.

Patients' preoperative background causes gastric stasis after laparoscopy-assisted pylorus-preserving gastrectomy.

INTRODUCTION: Despite technical improvements in laparoscopic gastrectomy, gastric stasis is still a serious problem in laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG). The aim of this study was to investigate the factors that might cause gastric stasis in LAPPG. METHODS: From April 2004 through November 2012, 85 patients with cT1N0 middle-third gastric cancer who underwent LAPPG at Kitasato University Hospital; these patients were included in the present study. Infra-pyloric vein (IPV)-preserving LAPPG was performed in 41 patients. We compared the rate of gastric stasis in the IPV-preserving and the IPV-non-preserving groups, and analyzed the clinicopathological factors that might have caused gastric stasis. RESULTS: We did not demonstrate that preservation of the IPV could prevent gastric stasis in the early and late postoperative periods. Symptoms of gastric stasis were most frequently recognized 1 year after surgery. A significantly higher proportion of preoperative ASA class 2 patients had gastric stasis than did not (80.0% [12/15] vs 48.6% [34/70], P=0.02). Among the ASA class 2 patients, a significantly greater proportion of those with depressed activities of daily living than those with normal activities of daily living had gastric stasis (66.7% [4/6] vs 20.0% [8/40], P = 0.015). CONCLUSIONS: The clinical significance of the IPV preservation in LAPPG could not be demonstrated. LAPPG should be performed for ASA class 1 patients or those with maintained preoperative activities of daily living.

The H19-PEG10/IGF2BP3 axis promotes gastric cancer progression in patients with high lymph node ratios.

We previously demonstrated that the lymph node ratio (LNR) is a prognostic factor associated with EGFR expression, among first priority genes amplified or overexpressed in cancer. Here, we investigated the associations between high LNR and second, third, and fourth priority genes. We performed mRNA expression microarray analysis of tumor tissue from patients with stage III gastric cancer and high or low LNRs. Candidate high LNR-associated genes were further evaluated in 39 patients with stage III gastric cancer. The functional relevance of these genes was evaluated in gastric cancer cell lines. We focused on five genes: H19,PEG10, IGF2BP3, CD177, and PGA3. H19 and PEG10 were confirmed as high LNR-associated genes. H19, PEG10, and IGF2BP3 were found to promote each other's expression. Knocking down H19 or PEG10 using RNAi decreased cell proliferation, invasion, anchorage-independent growth, and chemoresistance. These genes had a mutual relationship in MKN7 cells. H19 knockdown decreased expression of epithelial-mesenchymal transition-associated genes in MKN74 cells to suppress transformation. Thus, H19 promotes epithelial-mesenchymal transition in gastric cancer and is a potential therapeutic target.