MIWI2 targets RNAs transcribed from piRNA-dependent regions to drive DNA methylation in mouse prospermatogonia.

Argonaute/Piwi proteins can regulate gene expression via RNA degradation and translational regulation using small RNAs as guides. They also promote the establishment of suppressive epigenetic marks on repeat sequences in diverse organisms. In mice, the nuclear Piwi protein MIWI2 and Piwi-interacting RNAs (piRNAs) are required for DNA methylation of retrotransposon sequences and some other sequences. However, its underlying molecular mechanisms remain unclear. Here, we show that piRNA-dependent regions are transcribed at the stage when piRNA-mediated DNA methylation takes place. MIWI2 specifically interacts with RNAs from these regions. In addition, we generated mice with deletion of a retrotransposon sequence either in a representative piRNA-dependent region or in a piRNA cluster. Both deleted regions were required for the establishment of DNA methylation of the piRNA-dependent region, indicating that piRNAs determine the target specificity of MIWI2-mediated DNA methylation. Our results indicate that MIWI2 affects the chromatin state through base-pairing between piRNAs and nascent RNAs, as observed in other organisms possessing small RNA-mediated epigenetic regulation.

Posttranscriptional regulation of gene expression by Piwi proteins and piRNAs.

Piwi proteins and Piwi-interacting RNAs (piRNAs) are essential for gametogenesis, embryogenesis, and stem cell maintenance in animals. Piwi proteins act on transposon RNAs by cleaving the RNAs and by interacting with factors involved in RNA regulation. Additionally, piRNAs generated from transposons and psuedogenes can be used by Piwi proteins to regulate mRNAs at the posttranscriptional level. Here we discuss piRNA biogenesis, recent findings on posttranscriptional regulation of mRNAs by the piRNA pathway, and the potential importance of this posttranscriptional regulation for a variety of biological processes such as gametogenesis, developmental transitions, and sex determination.

Duration of Adjuvant Chemotherapy for Stage III Colon Cancer.

BACKGROUND: Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. METHODS: We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. RESULTS: After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). CONCLUSIONS: Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

Changes in disease characteristics of primary biliary cholangitis: An observational retrospective study from 1982 to 2016.

AIM: Disease characteristics of primary biliary cholangitis have changed recently. However, detailed studies on the subject have been limited. Therefore, we aimed to clarify disease characteristics of patients with recent primary biliary cholangitis using the cohort from Niigata University and 21 affiliated hospitals. METHODS: Overall, 508 patients were enrolled in this study from 1982 to 2016, divided into three cohorts according to their year of diagnosis: ≤1999, 2000-2009 and ≥2010. We compared differences in clinical characteristics, response to ursodeoxycholic acid and prognosis. RESULTS: The male-to-female ratio increased incrementally from 1:16.4 (≤1999) to 1:3.8 (≥2010) (P < 0.001). In women, the median age at diagnosis increased incrementally from 54.0 years (≤1999) to 60.5 years (≥2010) (P < 0.001) and serum albumin decreased gradually (P = 0.001), which might have affected the increase in the Fibrosis-4 Index and albumin-bilirubin score. The ursodeoxycholic acid response rate according to the Barcelona criteria increased incrementally from 26.7% (≤1999) to 78.4% (≥2010) (P < 0.010), and those according to other criteria (Paris-I, Rotterdam and Toronto) were approximately ≥80% in all cohorts. Ten-year survival rate in the ≤1999 and 2000-2009 cohorts were 98.6% and 95.6%, respectively. These earlier cohorts were also characterized by a higher rate of asymptomatic state and mild histology (83.5% [≤1999] and 84.7% [2000-2009], and 93.6% [≤1999] and 91.1% [2000-2009]). CONCLUSIONS: Patients with primary biliary cholangitis were characterized by older age at diagnosis and an increase in male to female ratio as well as higher response rates of ursodeoxycholic acid and longer survival, resulting from the early recognition of primary biliary cholangitis.

Highly efficient induction of primate iPS cells by combining RNA transfection and chemical compounds.

Induced pluripotent stem (iPS) cells hold great promise for regenerative medicine and the treatment of various diseases. Before proceeding to clinical trials, it is important to test the efficacy and safety of iPS cell-based treatments using experimental animals. The common marmoset is a new world monkey widely used in biomedical studies. However, efficient methods that could generate iPS cells from a variety of cells have not been established. Here, we report that marmoset cells are efficiently reprogrammed into iPS cells by combining RNA transfection and chemical compounds. Using this novel combination, we generate transgene integration-free marmoset iPS cells from a variety of cells that are difficult to reprogram using conventional RNA transfection method. Furthermore, we show this is similarly effective for human and cynomolgus monkey iPS cell generation. Thus, the addition of chemical compounds during RNA transfection greatly facilitates reprogramming and efficient generation of completely integration-free safe iPS cells in primates, particularly from difficult-to-reprogram cells.

Mouse GTSF1 is an essential factor for secondary piRNA biogenesis.

The piRNA pathway is a piRNA-guided retrotransposon silencing system which includes processing of retrotransposon transcripts by PIWI-piRNAs in secondary piRNA biogenesis. Although several proteins participate in the piRNA pathway, the ones crucial for the cleavage of target RNAs by PIWI-piRNAs have not been identified. Here, we show that GTSF1, an essential factor for retrotransposon silencing in male germ cells in mice, associates with both MILI and MIWI2, mouse PIWI proteins that function in prospermatogonia. GTSF1 deficiency leads to a severe defect in the production of secondary piRNAs, which are generated from target RNAs of PIWI-piRNAs. Furthermore, in Gtsf1 mutants, a known target RNA of PIWI-piRNAs is left unsliced at the cleavage site, and the generation of secondary piRNAs from this transcript is defective. Our findings indicate that GTSF1 is a crucial factor for the slicing of target RNAs by PIWI-piRNAs and thus affects secondary piRNA biogenesis in prospermatogonia.

A MicroRNA Signature Associated With Metastasis of T1 Colorectal Cancers to Lymph Nodes.

Most T1 colorectal cancers treated by radical surgery can now be cured by endoscopic submucosal dissection. Although 70%-80% of T1 colorectal cancers are classified as high risk, <16% of these patients actually have lymph node metastases. Biomarkers are needed to identify patients with T1 cancers with the highest risk of metastasis, to prevent unnecessary radical surgery. We collected data from The Cancer Genome Atlas and identified 5 microRNAs (MIR32, MIR181B, MIR193B, MIR195, and MIR411) with significant changes in expression in T1 and T2 colorectal cancers with vs without lymph node metastases. Levels of the 5 microRNAs identified patients with lymph node invasion by T1 or T2 cancers with an area under the receiver operating characteristic curve (AUROC) value of 0.84. We validated these findings in 2 cohorts of patients with T1 cancers, using findings from histology as the reference. The 5-microRNA signature identified T1 cancers with lymph node invasion in cohort 1 with an AUROC value of 0.83, and in cohort 2 with an AUROC value of 0.74. When we analyzed biopsy samples from untreated patients, the 5-microRNA signature identified cancers with lymph node metastases with an AUROC value of 0.77. The 5-microRNA therefore identifies high-risk T1 colorectal cancers with a greater degree of accuracy than currently used pathologic features.

Separation-Based Enzymomics Assay for the Discovery of Altered Peptide-Metabolizing Enzymatic Activities in Biosamples.

We have developed a novel method to globally monitor the enzymatic activities of biological samples based on performing the global activity analysis on a proteome separated by native electrophoresis. The study of the alteration in peptide-metabolizing enzymatic activity in colorectal tumor specimens led us to the discovery of elevated thimet oligopeptidase activity, which contributed to the faster consumption of immune-stimulating peptide neurotensin.

Short- and Long-term Outcomes of Minimally Invasive Versus Open Multivisceral Resection for Locally Advanced Colorectal Cancer.

BACKGROUND: Colorectal cancer invading the adjacent organs/structures is detected in 5% to 20% of all surgical interventions performed for the management of colorectal cancer. OBJECTIVE: Our purpose is to verify the safety and feasibility of laparoscopic surgery for the treatment of locally advanced colorectal cancer invading the adjacent organs. DESIGN: This is a retrospective study. SETTINGS: The study was conducted at a single institution in Japan. PATIENTS: We compared the morbidity, appropriate oncological resection, and disease-free survival of laparoscopic and open multivisceral resection in patients with colorectal carcinoma in the period between 2007 and 2015. MAIN OUTCOME MEASURES: The primary outcome measures were curative resection rate, morbidity rate, and recurrence of laparoscopic and open multivisceral resection in patients with colorectal cancer. RESULTS: Thirty-one patients received laparoscopic surgery, and 50 received open surgery. The amount of blood loss was smaller in the laparoscopic group than in the open group (60 vs 595 mL, p < 0.01). Curative surgery was performed in 46 patients of the open group (92.0%) and in 30 patients of the laparoscopic group (96.8%). Days until oral intake (5 vs 7 days, p < 0.01) and postoperative hospital stay (14 vs 19 days, p < 0.01) were shorter in the laparoscopic group. Overall morbidity was not different between the groups (22.5% vs 40.0%). Three-year disease-free survival rates were 62.7% in the open group and 56.7% in the laparoscopic group (p = 0.5776). LIMITATION: This study was a retrospective small study conducted at a single institute. CONCLUSION: Laparoscopic multivisceral resection may be a safe, less invasive alternative to open surgery, with less blood loss and shorter hospital stay, and was not inferior to open surgery based on long-term oncological end points. See Video Abstract at http://links.lww.com/DCR/A785.

Impact of Primary Tumor Location on Postoperative Recurrence and Subsequent Prognosis in Nonmetastatic Colon Cancers: A Multicenter Retrospective Study Using a Propensity Score Analysis.

OBJECTIVE: We aimed to clarify the prognostic impact of primary tumor location on recurrence after curative surgery and subsequent survival in patients with nonmetastatic colon cancer. SUMMARY OF BACKGROUND DATA: Right and left colon cancers are suggested to be oncologically different; however, their prognostic differences have been conflictingly reported. METHODS: A total of 5664 patients with curatively resected stage II-III colon cancer were reviewed, retrospectively. Relapse-free survival (RFS) after primary surgery and cancer-specific survival (CSS) after recurrence were compared between patients with right and left colon cancer. Patients' backgrounds were matched using propensity scores. RESULTS: Although patients with right colon cancer had more advanced disease, their 5-year RFS rate was significantly superior compared with that in those with left colon cancer (83.9% vs 81.1%, P = 0.019). However, the 5-year CSS after recurrence rate was significantly inferior in patients with right colon cancer compared with that in those with left colon cancer (30.6% vs 43.6%, P = 0.016). CONCLUSIONS: The primary tumor location of nonmetastatic colon cancer might have different prognostic implications for the rates of recurrence after curative resection and cancer-specific mortality after recurrence.

Retrotransposons and pseudogenes regulate mRNAs and lncRNAs via the piRNA pathway in the germline.

The eukaryotic genome has vast intergenic regions containing transposons, pseudogenes, and other repetitive sequences. They produce numerous long noncoding RNAs (lncRNAs) and Piwi-interacting RNAs (piRNAs), yet the functions of the vast intergenic regions remain largely unknown. Mammalian piRNAs are abundantly expressed from the spermatocyte to round spermatid stage, coinciding with the widespread expression of lncRNAs in these cells. Here, we show that piRNAs derived from transposons and pseudogenes mediate the degradation of a large number of mRNAs and lncRNAs in mouse late spermatocytes. In particular, they have a large impact on the lncRNA transcriptome, as a quarter of lncRNAs expressed in late spermatocytes are up-regulated in mice deficient in the piRNA pathway. Furthermore, our genomic and in vivo functional analyses reveal that retrotransposon sequences in the 3' UTR of mRNAs are targeted by piRNAs for degradation. Similarly, the degradation of spermatogenic cell-specific lncRNAs by piRNAs is mediated by retrotransposon sequences. Moreover, we show that pseudogenes regulate mRNA stability via the piRNA pathway. The degradation of mRNAs and lncRNAs by piRNAs requires PIWIL1 (also known as MIWI) and, at least in part, depends on its slicer activity. Together, these findings reveal the presence of a highly complex and global RNA regulatory network mediated by piRNAs with retrotransposons and pseudogenes as regulatory sequences.

Nine primary malignant neoplasms-involving the esophagus, stomach, colon, rectum, prostate, and external ear canal-without microsatellite instability: a case report.

BACKGROUND: Although cases of multiple primary malignant neoplasms are increasing, reports of more than three or four primary metachronous malignant neoplasms are extremely rare. Moreover, very few publications have provided a genetic mutational analysis or have evaluated risk factors associated with such neoplasms. We present an extremely rare case of nine primary malignant lesions in a man who was successfully treated. We also report on microsatellite stability status, analyze risk factors, and discuss the relevant literature. CASE PRESENTATION: Between 67 and 73 years of age, a male patient developed nine primary metachronous malignant lesions: Three were located in the esophagus, two in the stomach, two in the colorectum, one in the prostate gland, and one in the external ear canal. The patient's clinical history included hypertension, atrial fibrillation, an acoustic schwannoma, and heavy smoking. The lesions were diagnosed during regular screening over a six-year period. He was successfully treated with surgery (both open surgical and endoscopic resection of lesions) and adjuvant chemotherapy. Immunohistochemistry and mutational analysis showed that the lesions were microsatellite stable, and the KRAS, BRAF, p53, and nuclear ß-catenin status was not uniform among the lesions. CONCLUSIONS: Given that the presence of more than three or four neoplasms is extremely rare, the present case of nine primary malignancies with no associated microsatellite instability and no apparent predisposing hereditary conditions, is extraordinary. Our case study shows that it is possible for up to nine sporadic neoplasms to occur, and efficient disease management requires diligent screening and early detection.

Prominent Information of jN3 Positive in Stage III Colorectal Cancer Removed by D3 Dissection: Retrospective Analysis of 6866 Patients From a Multi-institutional Database in Japan.

BACKGROUND: The presence of main or lateral lymph node metastasis in colorectal cancer is classified as jN3 by the Japanese Society for Cancer of the Colon and Rectum. Whether information on jN3 status adds value to the TNM classification remains unclear. OBJECTIVE: We aimed to assess the prognostic relevance of colorectal cancer nodal staging through the Japanese jN3 categorization compared with that through TNM. DESIGN: This was a retrospective study. SETTING: The study used the multi-institutional database of the Japanese Society for Cancer of the Colon and Rectum. PATIENTS: Clinical and pathological data of 6866 patients with histologically proven stage III colorectal cancer who underwent curative surgery (R0) with D3 dissection between 1995 and 2006 were derived from the database. MAIN OUTCOME MEASURES: We investigated the prognostic significance of jN3 status in each TNM N class (N1/N2a/N2b) and stage (IIIA/IIIB/IIIC) based on cancer-specific survival. RESULTS: Comparison of cancer-specific survival rates revealed significant differences between jN3+ and jN3- colorectal cancer patient groups according to the TNM N status (5-year cancer-specific survival; N1, 70.4% (jN3+) vs 85.5% (jN3-), p < 0.001; N2a, 59.2% vs 77.0%, p < 0.001; N2b, 39.2% vs 68.7%, p < 0.001) and the TNM stage (stage IIIA, 72.5% vs 94.9%, p < 0.001; stage IIIB, 67.9% vs 84.0%, p < 0.001; stage IIIC, 42.4% vs 70.6%, p < 0.001). LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: Assessment and inclusion of jN3 status are of clinical importance for patients with stage III colorectal cancer with D3 dissection, because it contributes to improved understanding of recurrence risk and subsequent decision-making for follow-up procedures and adjuvant therapy. See Video Abstract at http://links.lww.com/DCR/A506.

Nomogram Predicting Survival After Recurrence in Patients With Stage I to III Colon Cancer: A Nationwide Multicenter Study.

BACKGROUND: Although a number of studies have been conducted to investigate factors affecting colon cancer recurrence and patient overall survival after surgical treatment, no prognostic risk models have been proposed for predicting survival specifically after postsurgical recurrence. OBJECTIVE: We aimed to identify factors affecting the survival of the patients with recurrent colon cancer and to construct a nomogram for predicting their survival. DESIGN: This was a retrospective study. SETTINGS: This study used the Japanese Study Group for Postoperative Follow-Up of Colorectal Cancer database, which contains retrospectively collected data of all consecutive patients with stage I to III colorectal cancer who underwent surgical curative resection between 1997 and 2008 at 23 referral institutions. PATIENTS: A total of 2563 patients with stage I to III colon cancer who experienced recurrence after surgery were included in the present study. MAIN OUTCOME MEASURES: A nomogram predicting survival was constructed using a training cohort composed of patients from 15 hospitals (n = 1721) using a Cox regression hazard model analysis. The clinical applicability of this nomogram was validated in patients from the 8 remaining hospitals (the validation cohort; n = 842). RESULTS: Eight factors (age, location of the primary tumor, histopathological type, positive lymph node status, presence of peritoneal metastasis, number of organs involved in the first recurrence, treatment for recurrence, and the interval between initial surgery and recurrence) were identified as nomogram variables. Our nomogram showed good calibration, with concordance indexes of 0.744 in the training cohort and 0.730 in the validation cohort. The survival curves stratified by the risk score calculated by the nomogram were almost identical for the training and validation cohorts. LIMITATIONS: The study was conducted using the data until 2008, and more advanced chemotherapeutic agents and multidisciplinary therapies that might have improved the outcomes predicted by our nomogram were not available. In addition, treatment strategies for recurrence might differ between countries. CONCLUSIONS: Our nomogram, which is based on a nationwide multicenter study, is the first statistical model predicting survival after recurrence in patients with stage I to III colon cancer. It promises to be of use in postoperative colon cancer surveillance. See Video Abstract at http://links.lww.com/DCR/A687.

Value of FDG-PET/CT Volumetry After Chemoradiotherapy in Rectal Cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by an optimal surgery is the standard treatment for patients with locally advanced rectal cancer. FDG-PET/CT is commonly used as the modality for assessing the effect of chemoradiotherapy. OBJECTIVE: The purpose of this study was to investigate whether PET/CT-based volumetry could contribute to the prediction of pathological complete response or prognosis after neoadjuvant chemoradiotherapy. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted at a single research center. PATIENTS: Ninety-one consecutive patients with locally advanced rectal cancer were enrolled between January 2005 and December 2015. INTERVENTION: Patients underwent PET/CT before and after neoadjuvant chemoradiotherapy. MAIN OUTCOME MEASURES: Maximum standardized uptake value and total lesion glycolysis on PET/CT before and after neoadjuvant chemoradiotherapy were calculated using isocontour methods. Correlations between these variables and clinicopathological factors and prognosis were assessed. RESULTS: PET/CT-associated variables before chemoradiotherapy were not correlated with either clinicopathological factors or prognosis. Maximum standardized uptake value was associated with pathological complete response, but total lesion glycolysis was not. Maximum standardized uptake value correlated with ypT, whereas total lesion glycolysis correlated with both ypT and ypN. High total lesion glycolysis was associated with a considerably poorer prognosis; the 5-year recurrence rate was 65% and the 5-year mortality rate 42%, whereas in lesions with low total lesion glycolysis, these were 6% and 2%. On multivariate analysis, high total lesion glycolysis was an independent risk factor for recurrence (HR = 4.718; p = 0.04). LIMITATIONS: The gain in fluoro-2-deoxy-D-glucose uptake may differ between scanners, thus the general applicability of this threshold should be validated. CONCLUSIONS: In patients with locally advanced rectal cancer, high total lesion glycolysis after neoadjuvant chemoradiotherapy is strongly associated with a worse prognosis. Total lesion glycolysis after chemoradiotherapy may be a promising preoperative predictor of recurrence and death. See Video Abstract at http://links.lww.com/DCR/A464.

LMR predicts outcome in patients after preoperative chemoradiotherapy for stage II-III rectal cancer.

BACKGROUND: Recently, lymphocyte-to-monocyte ratio (LMR) has attracted attention as a new marker of the chronic systemic inflammatory response and has been associated with patient prognosis in those who underwent chemoradiotherapy (CRT) for several solid cancers. This study aimed to evaluate the association between LMR and the prognosis of patients with rectal cancer. METHODS: A total of 183 stage II-III rectal cancer patients who underwent preoperative CRT followed by surgical R0 resection were retrospectively reviewed. The LMR was calculated from pre- and post-CRT blood samples. To determine the optimal cutoff value for pre- and post-CRT LMR for predicting relapse-free survival (RFS) and overall survival (OS), a receiver operator characteristic curve was used. Cox's proportional hazard models were applied to identify risk factors for recurrence and overall mortality. RESULTS: Low LMR was observed in 54 patients (pre-CRT <4.0) and 29 patients (post-CRT <1.5). Although pre-CRT LMR correlated with tumor size and ypT stage, post-CRT LMR showed no correlation to any pathologic features. Median follow-up term was 66.3 months; the 5-year RFS and OS of all patients were 72.5% and 88.7%, respectively. We found that a low pre-CRT LMR was an independent risk factor for OS (hazard ratio, 2.83; 95% confidence interval 1.03-8.13; P = 0.043). CONCLUSIONS: In rectal cancer patients who have undergone preoperative CRT, a low pre-CRT LMR is a poor prognostic factor for OS.

The short-term outcomes of robotic sphincter-preserving surgery for rectal cancer: comparison with open and laparoscopic surgery using a propensity score analysis.

PURPOSE: The aim of this study is to clarify the short-term outcomes of robotic sphincter-preserving surgery for rectal cancer in a retrospective study. METHODS: The short-term outcomes of robotic sphincter-preserving surgery (n = 130) were retrospectively compared to open (n = 234) and laparoscopic surgery (n = 318) by a propensity score analysis. RESULTS: Robotic surgery was performed more frequently for patients with lower rectal cancer (55%) than open (30%, p < 0.0001) or laparoscopic surgery (36%, p < 0.0001). None of the robotic surgery cases were converted to open surgery. After propensity score matching, robotic surgery was found to be associated with a longer operation time (342 vs. 230 min, p < 0.0001) and less blood loss (7 vs. 420 mL, p < 0.0001) than open surgery. The overall complication rate of robotic surgery was lower than that of open surgery (13 vs. 28%, p = 0.032). Robotic surgery was associated with a lower incidence of surgical site infections (SSIs) than laparoscopic surgery (0 vs. 7%, p = 0.028). There were no cases of anastomotic leakage after robotic surgery. The circumferential resection margin was involved in 0.8% of the patients who underwent robotic surgery; the incidence did not differ among the treatment groups. CONCLUSIONS: Although robotic surgery for rectal cancer was associated with a longer operation time, it was associated with a very low incidence of SSIs. The degree of safety was comparable to both open and laparoscopic surgery.

Comparison of Prognostic Abilities Among Preoperative Laboratory Data Indices in Patients with Resectable Gastric and Esophagogastric Junction Adenocarcinoma.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), modified Glasgow prognostic score (mGPS) and prognostic nutritional index (PNI) are simple indices determined employing laboratory data alone and have been used to predict the clinical outcomes of patients with esophagogastric tumors. However, prior results were generally based on analyzing dichotomous data with arbitrary cutoff values. This retrospective study aims to assess prognostic utilities of preoperative NLR, PLR, LMR, mGPS and PNI, as continuous variables, in gastric cancer (GC) and adenocarcinoma of esophagogastric junction (AEG). METHODS: Preoperative data from 1363 patients who underwent surgery for GC/AEG were retrospectively examined. Survival time was evaluated applying the Cox proportional hazard model to both univariate and multivariate estimates of clinicopathological factors and the aforementioned indices as continuous variables. RESULTS: Preoperatively, each index value was significantly associated with T and N stages, as well as lymphatic involvement and venous involvement. On univariate Cox regression analysis, preoperative NLR, PLR, LMR and PNI were significantly associated with overall survival (OS) and relapse-free survival (RFS). Preoperative mGPS was associated only with RFS. On multivariate Cox regression analysis, preoperative PNI was independently associated with OS and RFS (hazard ratio [HR] 0.62 per 10-unit increase, 95% CI 0.47-0.82, p < 0.001; HR 0.60, 95% CI 0.46-0.78, p < 0.001, respectively), as age, gender, tumor location, T and N stages and venous involvement, while other indices lost independence on multivariate analysis. CONCLUSIONS: Preoperative PNI, a score related to nutritional status, is of importance for predicting long-term outcomes in patients with GC and AEG.

Successful Management of a Positive Air Leak Test during Laparoscopic Colorectal Surgery.

BACKGROUND/AIMS: Anastomotic leakage remains the most serious complications of colorectal surgery. To prevent colorectal anastomotic leakage (CAL), an air leak test (ALT) with intraoperative colonoscopy (IOCS) is performed to detect mechanically insufficient colorectal anastomoses. The approaches to an intraoperative anastomotic air leak (IOAL) have not been fully investigated. This study aimed to clarify the safe management of an IOAL in laparoscopic colorectal surgery. METHODS: One hundred forty-eight consecutive patients who underwent laparoscopic resection with double-stapling technique (DST) anastomosis for left-sided colorectal cancer between April 2015 and June 2016 were included and retrospectively reviewed. RESULTS: Intraoperative anastomotic ALT yielded positive results in 7 patients. In all 7 patients, reanastomoses were performed, and diverting stomas were constructed to protect the anastomosis in 2 patients whose reanastomosis sites were close to the anus. Three of the revised DST anastomoses showed air leakage on the repeat ALT; these sites underwent suturing repair and were confirmed to be airtight. None of the patients with a positive intraoperative ALT had postoperative CAL. The overall CAL rate was 1.4%. CONCLUSIONS: Combination management using DST revision, direct suturing repair, and a diverting stoma is recommended for intraoperative repair of anastomotic defects detected by IOCS.

Different Impacts of Preoperative Radiotherapy and Chemoradiotherapy on Oncological Outcomes in Patients with Stages II and III Lower Rectal Cancer: A Propensity Score Analysis.

BACKGROUND/AIMS: The neoadjuvant therapy for locally advanced rectal cancer has been changed from radiotherapy (RT) to chemoradiotherapy (CRT). This study is aimed at evaluating the benefit of CRT in patients with stage II or III lower rectal cancer, with regard to the impact on recurrence. METHODS: A total of 474 patients with clinical stage II or III lower rectal cancer who received either preoperative RT (n = 221) or CRT (n = 253) followed by total mesorectal excision were identified from our institutional database. Propensity score analysis was performed to mitigate selection biases. RESULTS: Among stage II patients, the CRT group showed a significantly lower 5-year local recurrence rate than the RT group (3.0 vs. 14.8%, p = 0.002). In contrast, among stage III patients, the CRT group showed a significantly lower 5-year distant recurrence rate than the RT group (27.8 vs. 42.6%, p = 0.04) and also a better 5-year recurrence-free survival (64.2 vs. 48.3%, p = 0.03). CONCLUSIONS: Addition of concurrent chemotherapy to preoperative RT significantly enhanced the local control in stage II patients and decreased distant recurrence in stage III patients. The oncological benefit of CRT may differ between patients with stage II or III rectal cancer.