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Long-term survival data are lacking, and prognostic factors are not well-defined for patients with colorectal cancer and hepatic or lung metastases. This study evaluated the outcomes after resection of oligometastatic hepatic or lung metastases from colorectal cancer and sought to identify prognostic factors.We retrospectively investigated 1,123 patients with colorectal cancer and hepatic or pulmonary metastases who underwent curative surgery between January 1991 and December 2016.Of the 1,123 patients, 719 had hepatic metastases, 287 had pulmonary metastases, and 117 had both. The 5-year overall survival rate was 52.3% in the hepatic metastases group, 70.4% in the pulmonary metastases group, and 71.4% in the hepatic and pulmonary metastases group (P.001). In total, 1,045 patients had oligometastases (1-5 metastatic lesions in 1 or 2 organs) and 78 had polymetastases (≥6 metastases in 1 or 2 organs). Prognosis was significantly better in patients with oligometastases than in those with polymetastases. The 5-year overall survival rate was 59.0% in the oligometastases group and 35.3% in the polymetastases group (P.001); the respective 5-year relapse-free survival rates were 37.5% and 11.6% (P.001). Multivariable analysis identified predictors of both poor overall survival and relapse-free survival to be a high carcinoembryonic antigen level before the first metastasectomy, largest metastasis measuring ≥2 cm, polymetastases, and synchronous metastases.Prognosis after curative resection was better in patients with oligometastatic colorectal cancer in the liver or lung than in those with polymetastases. Multidisciplinary decision-making strategies, including about surgery, should be based on number of metastases rather than their site.

Although right-sided colon cancer is increasingly recognized as having a worse prognosis than left-sided colorectal cancer for colorectal liver metastases, little is known about the differences between the left-sided colon and rectum.This study evaluated the prognostic value of primary tumor location in patients with colorectal liver metastases by examining the left-sided colon and rectum separately.This was a retrospective study from 2003 to 2017.The study was conducted in a National Cancer Center Hospital.The study cohort included 489 patients with colorectal liver metastases from right-sided colon cancer (n=119, 24%), left-sided colon cancer (n=251, 51%), or rectal cancer (n=119, 24%) who underwent hepatic resection.Primary outcomes were relapse-free survival and overall survival.Five-year relapse-free survival rates for patients with right-sided colon cancer, left-sided colon cancer, and rectal cancer were 28.6%, 34.1%, and 26.4%, respectively, and 5-year overall survival rates were 53.9%, 70.3%, and 60.8%, respectively. Multivariable analysis revealed significant differences in relapse-free survival and overall survival between left-sided colon cancer and rectal cancer (relapse-free survival: HR=1.37, p=0.03; overall survival: HR=1.49, p=0.03) and between left-sided colon cancer and right-sided colon cancer (relapse-free survival: HR=1.39, p=0.02; overall survival: HR=1.60, p=0.01), but not between right-sided colon cancer and rectal cancer. In patients with recurrence (n=325), left-sided colon cancer had the lowest multiple-site recurrence rate and the highest surgical resection rate for recurrence (left-sided colon cancer, 20%/46%; right-sided colon cancer, 32%/30%; rectal cancer, 26%/39%).This study was retrospective in design.Rectal cancer was associated with worse relapse-free survival and overall survival compared with left-sided colon cancer in patients with colorectal liver metastases who underwent hepatic resection. Our findings suggest that the left-sided colon and rectum should be considered distinct entities in colorectal liver metastases. See Video Abstract at http://links.lww.com/DCR/B882 .

There is concern that the COVID-19 pandemic may cause people to refrain from undergoing examination resulting in delayed detection of colorectal cancer (CRC). The purpose of this study was to investigate whether there was a delay in CRC detection due to withholding of screening.The colonoscopy screening rate and the CRC detection rate were calculated for patients who underwent fecal immunochemical tests (FITs) from 2018 to 2021 in the longitudinal cohort. The stages of CRC cases detected as a result of positive FIT in each year were compared.A total of 39,521 patients were initially screened by FIT over a 4-year period. The FIT-positive rate was 4.7% (441 /9,349) in 2018, 4.6% (420 /9,156) in 2019, 4.9% (453 /9,255) in 2020, and 4.3% (504 /11,760) in 2021. The colonoscopy screening rate for positive FIT results was lower in 2020 than in 2019 (25.8% vs. 38.1%, P 0.001), and higher in 2021 than in 2020 (56.7% vs. 25.8%, P 0.001). The CRC detection rate among colonoscopy recipients was higher in 2021 than in 2020 (13% vs. 4%, P = 0.014). Stage 1 or higher CRC accounted for 25.0% (1/4) in 2020, and 78% (18/23) in 2021. Among the CRC cases detected each year, 1 (14%), 1 (25%), and 10 (43%) did not undergo colonoscopy despite positive FIT results in the previous year.The COVID-19 pandemic has reduced the detection of CRC by screening colonoscopy following FIT and might have led to a delay in the detection of CRC.

Background Treatment of brain metastases (BMs) from colorectal cancer (CRC) has transitioned with the expansion of indications for stereotactic radiotherapy. Our study aimed to assess changes in prognosis and prognostic factors associated with changes in treatment for BMs from CRC. Methods We retrospectively surveyed treatments for and outcomes of BMs from CRC in 208 patients treated during 1997–2018. Patients were divided into two groups according to time of BM diagnosis, i.e., 1997–2013 (“first period”) and 2014–2018 (“second period”). We compared overall survival between the periods and assessed how the transition impacted prognostic factors affecting overall survival, including the following prognostic factors such as Karnofsky performance status (KPS), volume-related factors (BM number and diameter), and BM treatment modalities as covariates. Results Of the 208 patients, 147 were treated in the first period and 61 in the second period. Whole-brain radiotherapy use decreased from 67 to 39% in the second period, and stereotactic radiotherapy use increased from 30 to 62%. Median survival after BM diagnosis improved from 6.1 to 8.5 months (p = 0.0272). Multivariate analysis revealed KPS, control of primary tumor, stereotactic radiotherapy use, and chemotherapy history as independent prognostic factors during the entire observation period. Hazard ratios of KPS, primary tumor control, and stereotactic radiotherapy were higher in the second period, whereas prognostic impact of chemotherapy history before BM diagnosis was similar in both periods. Conclusion Overall survival of patients with BMs from CRC improved since 2014, which can be attributed to advances in chemotherapy and the more widespread use of stereotactic radiotherapy.

Various prognostic factors have been reported for bone metastases from different primary tumor sites. However, bone metastases from colorectal cancer are very rare, and the prognostic factors have not been investigated in detail.To identify prognostic factors of bone metastases from colorectal cancer.Retrospective cohort study using data from a prospectively collected database.A single tertiary care cancer center in Japan.Patients who developed bone metastases from colorectal cancer during the study period among all patients who received initial treatment for colorectal cancer at our hospital between 2005 and 2016 (n = 4538) were targeted.Overall survival after diagnosis of bone metastases from colorectal cancer.Ninety-four patients developed bone metastases, accounting for 2.0% of all patients with colorectal cancer who started treatment during the study period. The 5-year overall survival rate was 11.0%. Multivariable analysis identified the following independent risk factors associated with poor prognosis: age ≥70 years at diagnosis of bone metastases (hazard ratio 2.48, 95% CI 1.24-4.95, p0.01), curative surgery not performed as initial treatment (hazard ratio 2.54, 95% confidence interval 1.24-5.19, p = 0.01), multiple bone metastases (hazard ratio 2.44, 95% CI 1.30-4.57, p0.01), albumin level3.7 g/dL (hazard ratio 3.80, 95% CI 1.95-7.39, p0.01), carcinoembryonic antigen ≥30 ng/mL (hazard ratio 1.94, 95% confidence interval 1.09-3.46, p = 0.02), and3 chemotherapy options remaining at diagnosis of bone metastases (hazard ratio 2.83, 95% CI 1.51-5.30, p0.01). The median survival times for patients with 0-2, 3, and 4-6 risk factors were 25.0, 8.8, and 4.3 months, respectively.Single-center, retrospective design.Our results may facilitate multidisciplinary decision-making in patients with bone metastases from colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B930.

Supplementary Figure 1 from Involvement of Sphingosine Kinase 2 in p53-Independent Induction of p21 by the Chemotherapeutic Drug Doxorubicin

Sphingosine-1-phosphate is a potent lipid mediator formed by phosphorylation of sphingosine, a metabolite of sphingolipids, catalyzed by two sphingosine kinase (SphK) isoenzymes, SphK1 and SphK2. Expression of SphK2, which is enriched in the nucleus of MCF7 human breast cancer cells, increased expression of the cyclin-dependent kinase inhibitor p21 but had no effect on p53 or its phosphorylation. The anticancer drug doxorubicin is known to increase p21 via p53-dependent and p53-independent mechanisms. Down-regulation of endogenous SphK2 with small interfering RNA targeted to unique mRNA sequences decreased basal and doxorubicin-induced expression of p21 without affecting increased expression of p53. Down-regulation of SphK2 also decreased G2-M arrest and markedly enhanced apoptosis induced by doxorubicin. Moreover, siSphK2 reduced doxorubicin-induced p21 expression in p53-inactivated MCF7 cells. Likewise, in human wild-type p53- and p21-expressing HCT116 colon carcinoma cells, as well as in p53-null counterparts, down-regulation of SphK2 markedly reduced p21 induction by doxorubicin. Knockdown of SphK2 sensitized HCT116 cells to apoptosis induced by doxorubicin with concomitant cleavage of poly(ADP-ribose) polymerase. Collectively, our results show that endogenous SphK2 is important for p53-independent induction of p21 expression by doxorubicin and suggest that SphK2 may influence the balance between cytostasis and apoptosis of human cancer cells. [Cancer Res 2007;67(21):10466–74]

The aim of this study was to evaluate the effect of biologics on the risk of advanced-stage inflammatory bowel disease (IBD)-associated intestinal cancer from a nationwide multicenter data set.The medical records of patients with Crohn's disease (CD) and ulcerative colitis (UC) diagnosed with IBD-associated intestinal neoplasia (dysplasia or cancer) from 1983 to 2020 were included in this study. Therapeutic agents were classified into 3 types: biologics, 5-aminosalicylic acid, and immunomodulators. The pathological cancer stage was compared based on the drug used in both patients with CD and UC.In total, 1,042 patients (214 CD and 828 UC patients) were included. None of the drugs were significantly associated with cancer stage in the patients with CD. In the patients with UC, an advanced cancer stage was significantly associated with less use of biologics (early stage: 7.7% vs advanced stage: 2.0%, P0.001), 5-aminosalicylic acid, and immunomodulators. Biologic use was associated with a lower incidence of advanced-stage cancer in patients diagnosed by regular surveillance (biologics [-] 24.5% vs. [+] 9.1%, P = 0.043), but this was not the case for the other drugs. Multivariate analysis showed that biologic use was significantly associated with a lower risk of advanced-stage disease (odds ratio = 0.111 [95% CI, 0.034-0.356], P0.001).Biologic use was associated with a lower risk of advanced IBD-associated cancer in patients with UC but not with CD. The mechanism of cancer progression between UC and CD may be different and needs to be further investigated.

JCOG-CCSG has been conducting several surgical trials and experienced several challenges. The first point is the appropriate timing of conducting the trial. Once a certain number of surgeons acquire the new technique and its utility is accepted, it suddenly becomes difficult to maintain ‘equipoise’ between the standard and new treatment, which may lead to poor patient accrual. Smooth preparation and commencement of the trial at an appropriate timing is necessary for its success. Second is the appropriate quality assurance of surgery. High-level quality assurance will strengthen the comparability of randomized control trials and minimize the heterogeneity among hospitals. On the other hand, it may impair the generalizability of the trial. Large observational studies help to bridge the gap of heterogeneity among hospitals. Third is the selection of an appropriate endpoint. Overall survival (OS) is the gold-standard primary endpoint; however, the number of events is much less due to more effective treatment. JCOG0212 and JCOG0404 were unable to demonstrate the non-inferiority of omission of lateral lymph node dissection and laparoscopic surgery partly due to a lack of power. Disease-free survival (DFS) is also a promising candidate for primary endpoint, but as in JCOG0603, special attention must be paid when DFS does not correlate with OS. Although careful discussion is required because the precision of the hazard ratio depends on the number of events, an alternative population-level summary of variables, including restricted mean survival time, can be considered as the primary endpoint. Future surgical trials should be planned considering these points.

Dysphonia has been reported with anti-angiogenic chemotherapy agents. Dysphonia in patients with cancer receiving chemotherapy tends to be overlooked in clinical practice since it is non-life-threatening. However, it reduces quality of life. Although inhibition of vascular endothelial growth factor receptor is the reported mechanism of dysphonia, it has not been elucidated. We report 6 cases of patients with dysphonia suspected to be due to panitumumab and nivolumab that have not been reported previously. Peripheral edema, a factor in dysphonia, can be seen with aflibercept, bevacizumab, panitumumab, and nivolumab. Therefore, chemotherapy drugs with peripheral edema may be related to dysphonia.

PURPOSE Adjuvant chemotherapy after hepatectomy is controversial in liver-only metastatic colorectal cancer (CRC). We conducted a randomized controlled trial to examine if adjuvant modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is superior to hepatectomy alone for liver-only metastasis from CRC. PATIENTS AND METHODS In this phase II or III trial (JCOG0603), patients age 20-75 years with confirmed CRC and an unlimited number of liver metastatic lesions were randomly assigned to hepatectomy alone or 12 courses of adjuvant mFOLFOX6 after hepatectomy. The primary end point of phase III was disease-free survival (DFS) in intention-to-treat analysis. RESULTS Between March 2007 and January 2019, 300 patients were randomly assigned to hepatectomy alone (149 patients) or hepatectomy followed by chemotherapy (151 patients). At the third interim analysis of phase III with median follow-up of 53.6 months, the trial was terminated early according to the protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy. With median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4 to 46.8) for hepatectomy alone compared with 49.8% (95% CI, 41.0 to 58.0) for chemotherapy (hazard ratio, 0.67; 95% CI, 0.50 to 0.92; one-sided P = .006). However, the updated 5-year overall survival (OS) was 83.1% (95% CI, 74.9 to 88.9) with hepatectomy alone and 71.2% (95% CI, 61.7 to 78.8) with hepatectomy followed by chemotherapy. In the chemotherapy arm, the most common grade 3 or higher severe adverse event was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after three courses of mFOLFOX6 administration. CONCLUSION DFS did not correlate with OS for liver-only metastatic CRC. Adjuvant chemotherapy with mFOLFOX6 improves DFS among patients treated with hepatectomy for CRC liver metastasis. It remains unclear whether chemotherapy improves OS.

Background Institutional variation in outcomes is a key factor to ascertain the generalizability of results and reliability of the clinical trial. This study evaluated institutional variation in survival and postoperative complications using data from JCOG0404 comparing laparoscopic colectomy (LAP) with open colectomy (OP). Methods Institutions with fewer than 10 registered patients were excluded from this analysis. Institutional variation was evaluated in terms of early postoperative complications, overall survival, and relapse‐free survival and estimated using a mixed‐effect model with institution as a random effect after adjusting for background factors. Results This analysis included 1028 patients in the safety analysis and 1040 patients in the efficacy analysis from 26 institutions. In the safety analysis, there was no variation in grades 3–4 early postoperative complications (in OP, median 6.3% [range 6.3%–6.3%]; in LAP, median 2.6% [range 2.6%–2.6%]), but some variation in grades 1–4 early postoperative complications was observed (in OP, median 20.8% [range 13.2%–31.8%]; in LAP, median 11.9% [range 7.2%–28.7%]), and that in grades 2–4 was observed only in LAP (median 8.8% [range 4.7%–24.0%]; in OP, median 12.7% [range 12.7%–12.7%]). Two specific institutions showed especially high incidences of postoperative complications in LAP. In the efficacy analysis, there was no institutional variation in OP, although a certain variation was observed in LAP. Conclusions Some institutional variations in safety and efficacy were observed, although only in LAP. We conclude that a qualification system, including training and education, is needed when new surgical techniques such as laparoscopic surgery are introduced in clinical practice., We evaluated institutional variation in survival and postoperative complications (PCs) using JCOG0404 data. Institutional variation was observed in laparoscopic surgery in grades 1–4 and 2–4 early PCs and 5‐y relapse‐free survival. A qualification system through training and education is needed when new surgeries, including laparoscopic surgery, are introduced.

This phase III trial evaluated whether the no touch was superior to the conventional in patients with cT3/T4 colon cancer.No touch involves ligating blood vessels that feed the primary tumor to limit cancer cell spreading. However, previous studies did not confirm the efficacy of the no touch.This open-label, randomized, phase III trial was conducted at 30 Japanese centers. The eligibility criteria were histologically proven colon cancer; clinical classification of T3-4, N0-2, andM0; and patients aged 20 to 80years. Patients were randomized (1:1) to undergo open surgery with conventional or the no touch. Patients with pathological stage III disease received adjuvant capecitabine chemotherapy. The primary endpoint was disease-free survival (DFS) according to the intention-to-treat principle.Between January 2011 and November 2015, 853 patients were randomized to the conventional group (427 patients) or the no touch group (426 patients). The 3-year DFS were 77.3% [95% confidence interval (CI) 73.1%-81.0%] and 76.2% (95% CI 71.9%-80.0%) in the conventional and no touch groups, respectively. The superiority of no touch was not confirmed: hazard ratio for DFS = 1.029 (95% CI 0.800- 1.324; 1-sided P = 0.59). Operative morbidity was observed in 31 of 427 conventional patients (7%) and 26 of 426 no touch patients (6%). All grade adverse events were similar between the conventional and no touch groups. No in-hospital mortality occurred in either group.The present study failed to confirm the superiority of the no touch.

The Wnt/β-catenin signaling pathway plays a key role in development and carcinogenesis. Although some target genes of this signaling have been identified in various tissues and neoplasms, the comprehensive understanding of the target genes and their roles in the development of human cancer, including hepatoma and colorectal cancer remain to be fully elucidated. In this study, we searched for genes regulated by the Wnt signaling in liver cancer using HuH-7 hepatoma cells. A comparison of the expression profiles between cells expressing an active form of mutant β-catenin and cells expressing enhanced green fluorescent protein (EGFP) identified seven genes upregulated by the mutant β-catenin gene (CTNNB1). Among the seven genes, we focused in this study on ODAM, odontogenic, ameloblast associated, as a novel target gene. Interestingly, its expression was frequently upregulated in hepatocellular carcinoma, colorectal adenocarcinoma, and hepatoblastoma. We additionally identified a distant enhancer region that was associated with the β-catenin/TCF7L2 complex. Further analyses revealed that ODAM plays an important role in the regulation of the cell cycle, DNA synthesis, and cell proliferation. These data may be useful for clarification of the main molecular mechanism(s) underlying these cancers.

Background In transitioning from the 7th edition of the tumor‐node‐metastasis classification (TNM‐7) to the 8th edition (TNM‐8), colorectal cancer with peritoneal metastasis was newly categorized as M1c. In the 9th edition of the Japanese Classification of colorectal, appendiceal, and anal carcinoma (JPC‐9), M1c is further subdivided into M1c1 (without other organ involvement) and M1c2 (with other organ involvement). This study aimed to compare the model fit and discriminatory ability of the M category of these three classification systems, as no study to date has made this comparison. Methods The study population consisted of stage IV colorectal cancer patients who were referred to the National Cancer Center Hospital from 2000 to 2017. The Akaike information criterion (AIC), Harrell's concordance index (C‐index), and time‐dependent receiver operating characteristic (ROC) curves were used to compare the three classification systems. Subgroup analyses, stratified by initial treatment year, were also performed. Results According to TNM‐8, 670 (55%) patients had M1a, 273 (22%) had M1b, and 279 (23%) had M1c (87 M1c1 and 192 M1c2 using JPC‐9) tumors. Among the three classification systems, JPC‐9 had the lowest AIC value (JPC‐9: 10546.3; TNM‐7: 10555.9; TNM‐8: 10585.5), highest C‐index (JPC‐9: 0.608; TNM‐7: 0.598; TNM‐8: 0.599), and superior time‐dependent ROC curves throughout the observation period. Subgroup analyses were consistent with these results. Conclusions While the revised M category definition did not improve model fit and discriminatory ability from TNM‐7 to TNM‐8, further subdivision of M1c in JPC‐9 improved these parameters. These results support further revisions to M1 subcategories in future editions of the TNM classification system., In transitioning from the TNM 7th edition to the TNM 8th edition, colorectal cancer with peritoneal metastasis was newly categorized as M1c, and in the Japanese Classification (9th edition), M1c is further subdivided into M1c1 (without other organ involvement) and M1c2 (with other organ involvement). To date, no study has compared the model fit and discriminatory ability of the M category of these three classification systems. In this study, with 1222 consecutive stage IV colorectal cancer patients, we clearly demonstrated that, by comparing AIC, Harrell's c‐index, and time‐dependent ROC curves between the three classification systems, while the revised M category definition did not improve model fit and discriminatory ability from TNM 7th edition to the TNM 8th edition, further subdivision of M1c in the Japanese Classification improved these parameters.

Background: Traditionally, adult intestinal intussusception is treated using Hutchinson’s maneuver, i.e., manual proximal bowel compression and reduction of intussusception. However, the lack of manual contact in laparoscopic surgery limits the application of Hutchinson’s maneuver. Moreover, when the lead point is located distal to the peritoneal refection, and the intussusception cannot be reduced prior to bowel resection, stoma construction (e.g., Hartmann surgery or abdominoperineal resection) becomes necessary. Here we report a case of sigmoidorectal intussusception treated laparoscopically using a modified Hutchinson’s maneuver.Case presentation: A 74-year-old man was diagnosed with sigmoidorectal intussusception caused by sigmoid colon cancer. Colonoscopy revealed a malignant-appearing obstructing mass telescoping into the rectum, with the lead point at 3 cm from the anal verge. During endoscopic examination, the lead point did not move. A biopsy of the mass showed adenocarcinoma, leading to a diagnosis of sigmoid cancer with sigmoidorectal intussusception. Since the patient had no symptoms of intestinal ischemia, and defecations were observed, elective laparoscopic surgery was planned. Intraoperatively, an attempt was made to pull out the intussuscepted segment proximally, but the presence of fibrous adhesions made the intussusception irreducible. Therefore, the rectum and mesorectum were mobilized completely up to the level of the levator ani so that the lower rectum could be wrapped with gauze on the anal side of the lead point of the intussusception. The gauze was then pulled up to the oral side and simultaneously, a surgeon pushed the distal end of the intussuscepted segment up using a laparoscopic bowel grasper, with another surgeon pushing the lead point through the anus with fingers. Thereby the intussusception was reduced to some extent, allowing for low anterior resection. The resected specimen contained an ulcerated moderately differentiated adenocarcinoma of the sigmoid colon measuring 3.5 cm × 3.0 cm, combined with circumferential ischemia with mucosal loss and necrosis over an 8-cm length on the distal side of the tumor. The tumor was stage III (T3 N1).Conclusion: We provide a laparoscopic approach for treating intussusception using a modified Hutchinson’s maneuver. This method will be useful in reducing the intussuscepted segment while avoiding stoma construction.

Introduction Currently, laparoscopic surgery generally relies on 2 K high-definition image quality. The National Cancer Center Hospital, Olympus Corporation, and NHK Engineering System Inc. recently developed a new laparoscopic system with an 8 K ultra-high-definition (UHD) camera that provides images with a high-resolution, wide color range, high frame rate, and high dynamic range. This study aimed to investigate the effectiveness and safety of a new laparoscopic system which uses an 8 K UHD camera system (8K UHD system). Methods This phase II study enrolled 23 patients with colon or rectosigmoid cancer who were indicated for radical resection with laparoscopic colectomy using the 8 K UHD system. The primary endpoint was the proportion of patients with ≥30 mL of intraoperative blood loss. Results Of the 23 patients, 22 completed laparoscopic surgery with the 8 K UHD system. One patient was converted to the 2 K high-definition laparoscopic system due to technical difficulties with the 8 K UHD system during surgery. The median amount of intraoperative blood loss was 14 mL (range, 2-71 mL), and number of patients with intraoperative blood loss ≥30 mL was four (17.4%). None of the patients had >100 mL of intraoperative blood loss. No intraoperative complications were noted, and four (17.4%) patients developed postoperative complications. Pathological complete resection was achieved in all patients, and no conversion to open surgery was required. Conclusions Laparoscopic surgery using the 8 K UHD system appears to be both safe and effective. However, further refinements may be necessary to improve usability.

A considerable number of elderly patients with colorectal cancer (CRC) die of non-CRC-related causes. The Controlling Nutritional Status (CONUT) score, American Society of Anesthesiologists Physical Status classification, Charlson Comorbidity Index, National Institute on Aging, and National Cancer Institute Comorbidity Index, and Adult Comorbidity Evaluation-27 score are all known predictors of survival in patients with CRC. However, the utility of these indices for predicting non-CRC-related death in elderly CRC patients is not known.The study population comprised 364 patients aged 80 years or more who received curative resection for stage I-III CRC between 2000 and 2016. The association of each index with non-CRC-related death was compared by competing-risks analysis such as the cumulative incidence function and proportional subdistribution hazards regression analysis as well as time-dependent receiver-operating characteristic (ROC) analysis.There were 85 deaths (40 CRC-related and 45 non-CRC-related) during a median observation period of 53.2 months. Cumulative incidence function analysis identified CONUT score as the most suitable for risk stratification for non-CRC-related death. In proportional subdistribution hazards regression, risk of non-CRC-related death increased significantly as CONUT score worsened (2/3/4 vs. 0/1, hazard ratio 1.73, 95% confidence interval [CI] 0.91-3.15; ≥5 vs. 2/3/4, hazard ratio 2.71, 95% CI 1.08-6.81). Time-dependent ROC curve analysis showed that CONUT score were consistently superior to other indices during the 5-year observation period.The majority of deaths in elderly patients with CRC were not CRC-related. CONUT score was the most useful predictor of non-CRC-related death in these patients.

Aberrant activation of the Wnt/β-catenin signaling pathway plays a crucial role in the development and progression of colorectal cancer. Previously, we identified a set of candidate genes that were regulated by this signaling pathway, and the present study focused on motile sperm domain containing 1 (MOSPD1). Immunohistochemical staining revealed that the expression of MOSPD1 was elevated in tumor cells from colorectal cancer tissues compared with in non-tumor cells. Using ChIP-seq data and the JASPAR database, the regulatory region(s) in the MOSPD1 gene as a target of the Wnt/β-catenin signaling pathway were searched, and a region containing three putative TCF-binding motifs in the 3′-flanking region was identified. Additional analyses using reporter assay and ChIP-quantitative PCR suggested that this region harbors enhancer activity through an interaction with transcription factor 7 like 2 (TCF7L2) and β-catenin. In addition, chromatin conformation capture assay revealed that the 3′-flanking region interacts with the MOSPD1 promoter. These data suggested that MOSPD1 was regulated by the β-catenin/TCF7L2 complex through the enhancer element located in the 3′-flanking region. These findings may be helpful for future studies regarding the precise regulatory mechanisms of MOSPD1.

BACKGROUND In Japan, total mesorectal excision plus lateral lymph node dissection without preoperative therapy is the standard treatment for advanced lower rectal cancer. Although long-term oncologic outcomes with preoperative therapy based on circumferential resection margin status in preoperative MRI has been reported, outcomes without preoperative therapy are unknown. OBJECTIVE This study evaluated long-term oncologic outcomes of radical surgery without preoperative therapy in advanced lower rectal cancer based on circumferential resection margin status in preoperative MRI, with the aim of defining appropriate patient populations for preoperative therapy. DESIGN This retrospective analysis compared long-term oncologic outcomes with preoperative MRI in patients with lower rectal cancer. SETTINGS Patients were identified through a database managed by our institute. PATIENTS In total, 338 patients with lower rectal cancer who underwent radical surgery between 2000 and 2014 at the National Cancer Center Hospital without preoperative therapy were included. MAIN OUTCOME MEASURES The main outcome was relapse-free survival. RESULTS The median follow-up period was 61.7 months (range, 3-153 months). Five-year relapse-free survival rates in MRI-predicted circumferential resection margin negative patients and positive patients were 76.0% and 55.6% (p < 0.001). Univariate and multivariate analyses revealed pN stage (HR, 2.35; 95% CI, 1.470-3.770; p < 0.001), lymphatic invasion (HR, 2.03; 95% CI, 1.302-3.176; p = 0.002), venous invasion (HR, 2.15; 95% CI, 1.184-3.9; p = 0.01), surgical procedure (HR, 1.72; 95% CI, 1.115-2.665; p = 0.01), and MRI-predicted circumferential resection margin (HR, 1.850; 95% CI, 1.206-2.838; p = 0.0051) to be independent risk factors for postoperative recurrence. LIMITATIONS This study was retrospective in design. CONCLUSIONS Magnetic resonance imaging-predicted circumferential resection margin was associated with relapse-free survival without preoperative therapy, indicating its potential for use in selecting optimal preoperative therapy. See Video Abstract at http://links.lww.com/DCR/B335. ESTADO DEL MARGEN DE RESECCION CIRCUNFERENCIAL COMO FACTOR PREDICTIVO DE RECURRENCIA EN LA RESONANCIA MAGNETICA PREOPERATORIA, PARA EL CANCER RECTAL BAJO AVANZADO SIN TERAPIA PREOPERATORIA: En Japon, la escision mesorrectal total con diseccion de ganglios linfaticos laterales y sin terapia preoperatoria, es el tratamiento estandar para el cancer rectal bajo avanzado. Aunque se han reportado resultados oncologicos a largo plazo con terapia preoperatoria, basada en el estado del margen de reseccion circunferencial en la resonancia magnetica preoperatoria, se desconocen los resultados sin terapia preoperatoria.Este estudio evaluo los resultados oncologicos a largo plazo de cirugia radical sin terapia preoperatoria, en cancer rectal bajo avanzado, basado en el estado del margen de reseccion circunferencial en la resonancia magnetica preoperatoria, con el objetivo de definir poblaciones de pacientes apropiadas para terapia preoperatoria.Este analisis retrospectivo comparo los resultados oncologicos a largo plazo con resonancia magnetica preoperatoria, en pacientes con cancer rectal bajo.Los pacientes fueron identificados a traves de una base de datos administrada por nuestro instituto.Se incluyeron un total de 338 pacientes con cancer rectal bajo, que se sometieron a cirugia radical entre 2000 y 2014 en el Hospital Nacional del Centro de Cancer, sin terapia preoperatoria.El resultado principal fue la supervivencia libre de recaidas.La mediana del periodo de seguimiento fue de 61,7 meses (rango, 3-153 meses). Las tasas de supervivencia sin recaidas a cinco anos, con margen de reseccion circunferencial predicho por resonancia magnetica, en pacientes negativos y pacientes positivos fueron 76.0% y 55.6% (p

Background Recent evidence suggests that both preoperative and postoperative inflammation-based prognostic markers are useful for predicting the survival of colorectal cancer (CRC) patients. However, associations between longitudinal changes in inflammation-based prognostic markers and prognosis are controversial. Methods The subjects of this study were 568 patients with stage III CRC between 2008 and 2014. Preoperative and postoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), C-reactive protein/albumin ratio (CAR) and lymphocyte-to-C-reactive protein ratio (LCR) were calculated to assess the inflammatory state of subjects. Subjects were stratified into three groups for each marker: preoperatively low inflammatory state (normal group), preoperatively high but postoperatively low inflammatory state (normalised group) and persistently high inflammatory state (elevated group). Multivariable analyses for overall survival (OS) and recurrence-free survival (RFS) were performed to adjust for well-established clinicopathologic factors. Results For all assessed markers, the normalised group had a significantly better prognosis than the elevated group and a similar prognosis as the normal group for both OS and RFS. Conclusions Postoperative, but not preoperative, inflammation-based prognostic markers more accurately predict OS and RFS in patients with stage III CRC.

In Japan, the standard treatment for advanced low rectal cancer has been total mesorectal excision (TME) + lateral pelvic lymph node dissection (LLND). On the other hand, in the West, preoperative chemoradiotherapy (CRT) + TME has been established as the standard. Japanese surgeons developed nerve-preserving LLND that could reduce complications associated with extended dissection. The Japan Clinical Oncology Group (JCOG)0212 trialinvestigated on the outcomes of so-called prophylactic LLND in patients without evident lateral lymph node metastasis in preoperative diagnostic imaging. Data from the JCOG0212 trial demonstrated scientific validity of the theory and practice of the Japanese approach. Data from the JCOG0212 trial supported the validity and safety of the Japanese approach, that is, TME + LLND for low rectal cancer without routine use of preoperative CRT. For future direction, modern approach for rectal cancer should involve both of the Eastern and Western strategies by combining LLND and CRT.

Previous studies investigating the impact of tumor location on colorectal cancer prognosis only compared two groups by location, e.g., ‘right-sided colon vs. left-sided colon,’ ‘colon vs. rectum,’ and ‘right-sided (right-sided colon) vs. left-sided (left-sided colon and rectum).’ This nationwide multicenter retrospective study aimed to clarify the prognostic impact of tumor location in patients with stage III colorectal cancer by classifying tumors into three groups: right-sided colon, left-sided colon, and rectum. Subjects were 9194 patients with stage III colorectal cancer who underwent curative surgery from 1997 to 2012. Relapse-free survival (RFS) after primary surgery and overall survival (OS) after recurrence were examined. Rectal cancer (n = 2922) was associated with worse RFS compared to right-sided colon cancer (n = 2362) (hazard ratio (HR) 0.65; 95% CI 0.59–0.72; p

OBJECTIVE This study aimed to investigate transitions of recurrence hazard and peak recurrence time in patients with nonmetastatic CRC using the hazard function. SUMMARY OF BACKGROUND DATA A postoperative surveillance period of 5 years is consistent across major guidelines for patients with nonmetastatic CRC, but surveillance intervals differ. Estimates of instantaneous conditional recurrence rate can help set appropriate intervals. METHODS The study population consisted of 4330 patients with stage I to III CRC who underwent curative resection at the National Cancer Center Hospital between January 2000 and December 2013. Hazard rates of recurrence were calculated using the hazard function. RESULTS Recurrence rates in patients with stage I, II, and III CRC were 4% (50/1432), 11% (136/1231), and 25% (424/1667), respectively. The hazard curve for stage I was relatively flat and hazard rates were consistently low (

Diagnosis of secondary ovarian tumors originating from colorectal cancer has previously been based upon history of malignancy and radiological findings of bilateral masses with a “stained glass appearance.” The purpose of this study was to perform a detailed investigation of the radiological and macroscopic features of ovarian metastases originating from colorectal cancer, which remain to be fully characterized. Study participants were 48 consecutive patients with ovarian metastases from colorectal cancer who underwent resection of ovarian tumors at the National Cancer Center Hospital between August 1998 and January 2019. Ovarian tumors were classified into subgroups using computed tomography (CT), magnetic resonance imaging (MRI), and macroscopic appearance. CT/MRI findings and macroscopic appearance were classified into the following four types: type 1 (oval, homogeneous-solid) (n = 5); type 2 (heterogeneous-solid, small in size with multinodular surface) (n = 3); type 3 (solid-cystic, predominantly solid) (n = 18); and type 4 (cystic-solid, multilocular with solid components) (n = 22). Type 1 mimics Krukenberg tumors, type 2 mimics ovarian metastases from breast cancer, type 3 mimics primary ovarian endometrioid cancer, and type 4 mimics primary ovarian mucinous cancer, with a “stained glass appearance”. Twenty-eight (58%) patients had bilateral metastases. Eleven patients (23%) underwent hysterectomy and/or pelvic lymph node dissection in addition to ovarian resection. We introduced a novel classification system for ovarian metastases originating from colorectal cancer, which may be beneficial for assessing ovarian metastases from colorectal cancer and avoiding unnecessary surgery due to misdiagnosis of primary ovarian tumors.