Blood Perfusion Assessment by Indocyanine Green Fluorescence Imaging for Minimally Invasive Rectal Cancer Surgery (EssentiAL trial): A Randomized Clinical Trial.

OBJECTIVE: The aim of the present randomized controlled trial was to evaluate the superiority of indocyanine green fluorescence imaging (ICG-FI) in reducing the rate of anastomotic leakage in minimally invasive rectal cancer surgery. BACKGROUND: The role of ICG-FI in anastomotic leakage in minimally invasive rectal cancer surgery is controversial according to the published literature. METHODS: This randomized, open-label, phase 3, trial was performed at 41 hospitals in Japan. Patients with clinically stage 0-III rectal carcinoma less than 12 cm from the anal verge, scheduled for minimally invasive sphincter-preserving surgery were preoperatively randomly assigned to receive a blood flow evaluation by ICG-FI (ICG+ group) or no blood flow evaluation by ICG-FI (ICG- group). The primary endpoint was the anastomotic leakage rate (grade A+B+C, expected reduction rate of 6%) analyzed in the modified intention-to-treat population. RESULTS: Between December 2018 and February 2021, a total of 850 patients were enrolled and randomized. After the exclusion of 11 patients, 839 were subject to the modified intention-to-treat population (422 in the ICG+ group and 417 in the ICG- group). The rate of anastomotic leakage (grade A+B+C) was significantly lower in the ICG+ group (7.6%) than in the ICG- group (11.8%) (relative risk, 0.645; 95% confidence interval 0.422-0.987; P =0.041). The rate of anastomotic leakage (grade B+C) was 4.7% in the ICG+ group and 8.2% in the ICG- group ( P =0.044), and the respective reoperation rates were 0.5% and 2.4% ( P =0.021). CONCLUSIONS: Although the actual reduction rate of anastomotic leakage in the ICG+ group was lower than the expected reduction rate and ICG-FI was not superior to white light, ICG-FI significantly reduced the anastomotic leakage rate by 4.2%.

Robot-assisted low anterior resection for a rectal cancer patient with ileal conduit: A case report.

Surgery for rectal cancer patients with an ileal conduit after total cystectomy is difficult because adhesions in the pelvis and around the ileal conduit are expected. In the present case, we performed robot-assisted low anterior resection of the rectum in a 69-year-old male patient with rectal cancer who underwent ileal conduit diversion after total cystectomy. In this procedure, the port was inserted into the left upper abdomen as a first step, and two additional ports were added on the left side. Low anterior resection was performed using two left hands to create more space in the abdominal cavity for the ileal conduit. We present this minimally invasive robotic procedure that is extremely useful for dissection of adhesions in a narrow pelvic cavity.

Robot-assisted surgery for rectal cancer with solitary sacrococcygeal metastasis after neoadjuvant chemoradiotherapy: A case report.

An 81-year-old man was referred to our hospital for anal bleeding. Colonoscopy revealed a type 3 tumor at the upper rectum and biopsy showed adenocarcinoma. An enhanced circumferential lesion at the upper rectum and a solitary soft-tissue shadow at the fifth sacral vertebra to the coccyx were detected on abdominal magnetic resonance imaging. Fluorodeoxyglucose uptake was observed at the same sites on positron emission tomography. The patient was diagnosed with rectal cancer with isolated sacrococcygeal metastasis and was treated with neoadjuvant chemoradiotherapy followed by robotic surgery. Hartmann's operation was performed in the lithotomy position. The left internal iliac artery and vein were then divided. The internal pudendal artery and vein, the piriformis muscle, and sacrospinous ligament were also divided while preserving the lumbosacral trunk. The scheduled transection line of the sacral surface was fully exposed to prevent massive bleeding during sacrectomy. The dorsal surface of the sacrum was then exposed in the prone position and communicated with the pelvic space. The sacrum was transected at the superior margin of S3 and a specimen was extracted. Pathological findings revealed the infiltration of cancer cells in the sacrococcygeal specimen. The postoperative course was uneventful and the patient was discharged on postoperative day 13.

Japanese multicenter prospective study investigating laparoscopic surgery for locally advanced rectal cancer with evaluation of CRM and TME quality (PRODUCT trial).

Aim: In Japan, we have not been able to validate the results of laparoscopic surgery for locally advanced rectal cancer using the universal index "circumferential resection margin (CRM)." Previously, we established a semi-opened circular specimen processing method and validated its feasibility. In the PRODUCT trial, we aimed to assess CRM in patients with locally advanced rectal cancer who underwent laparoscopic rectal resection. Methods: This was a multicenter, prospective, observational study. Eligible patients had histologically confirmed rectal adenocarcinoma located at or below 12 cm above the anal verge with clinical stage II or III and were scheduled for laparoscopic or robotic surgery. The primary endpoint was pathological CRM. CRM ≤1 mm was defined as positive. Results: A total of 303 patients operated on between August 2018 and January 2020 were included in the primary analysis. The number of patients with clinical stage II and III was 139 and 164, respectively. Upfront surgery was performed for 213 patients and neoadjuvant therapy for 90 patients. The median CRM was 4.0 mm (IQR, 2.1-8.0 mm), and CRM was positive in 26 cases (8.6%). Univariate and multivariate analyses demonstrated that a predicted CRM from the mesorectal fascia of ≤1 mm on MRI was the significant factor for positive CRM (P = .0012 and P = .0045, respectively). Conclusion: This study showed the quality of laparoscopic rectal resection based on the CRM in Japan. Preoperative MRI is recommended for locally advanced rectal cancer to prevent CRM positivity.

Robot-assisted anterior resection for rectal cancer with double inferior vena cava: A case report.

Double inferior vena cava (DIVC) is a rare but generally asymptomatic condition that is often detected incidentally by radiological examinations such as computed tomography (CT). Here, we describe the case of a 73-year-old woman with DIVC, who underwent robot-assisted surgery (RS) for rectal cancer. In this case, 3D CT angiography showed DIVC with an interiliac vein from the left common iliac vein and a tortuous aorta. Intraoperatively, we identified the presence of the left IVC in addition to the inferior mesenteric vein, gonadal vein, and ureter, which require meticulous attention during vascular processing. By optimizing the port placement, we were able to ensure mobility of the robotic arm and sufficient field of view to safely perform a robot-assisted anterior resection with lymph node dissection. Careful preoperative assessment and development of a strategy for port placement using CT imaging are essential in avoiding iatrogenic injury and performing safe RS.

Robotic low anterior resection of rectal metastasis from small bowel adenocarcinoma: A case report.

A 69-year-old female underwent laparoscopic ileal partial resection for ileal adenocarcinoma. Pathological diagnosis was moderately differentiated tubular adenocarcinoma (UICC 8th; T4N0M0 StageIIB). The patient received adjuvant chemotherapy with modified 5-fluorouracil/leucovorin/oxaliplatin. Fourteen months after surgery, computed tomography revealed a mass in the upper rectum. Colonoscopy detected a submucosal protruding mass and a biopsy specimen showed moderately differentiated tubular adenocarcinoma. Robotic low anterior resection was performed. The tumor was located in the upper rectum and there was no macroscopic invasion or peritoneal dissemination. Pathologically, the tumor was moderately differentiated tubular adenocarcinoma located within the rectal wall with little evidence of a carcinoma component in the mucosal lining. Immunohistochemistry showed the same pattern as the previous ileal adenocarcinoma: negativity for cytokeratin 7 and positivity for cytokeratin 20 and caudal-type homeobox 2. In combination with the rectum showing no abnormalities in colonoscopy performed 15 mo previously, the mass was considered hematogenous metastasis from small bowel adenocarcinoma.

Laparoscopic resection of a gastrointestinal stromal tumor that recurred more than 15 years after surgery using lighted ureteral catheters: A case report.

A 69-year-old woman underwent abdominoperineal resection for a gastrointestinal stromal tumor (GIST) of the rectum 15 years ago. She received adjuvant chemotherapy for 8 years. Seven years later, abdominal computed tomography revealed a soft-tissue shadow in the left lower abdomen, and fluorodeoxyglucose uptake was observed at the same site on positron emission tomography. The recurrence of GIST was suspected, and laparoscopic resection was performed. Laparoscopy showed that the tumor was located at the retroperitoneum near to the descending colon and invaded the left ovarian vessels. It also made contact with the left ureter; however, lighted ureteral catheters enabled us to identify and preserve the left ureter. An immunohistochemical examination revealed the recurrence of GIST. Recurrence may become apparent 15 years or more after GIST surgery, and, thus, a long-term follow-up is required. Lighted ureteral catheters were useful for identifying the ureter and preventing ureteral injury in a recurrent case suspected of invading the ureter.

Thymidylate synthase locus LOH in combination with genotype has prognostic and predictive significance in colorectal cancer.

The aim of the current study was to investigate the prognostic and predictive significance of polymorphisms in the thymidylate synthase (TS) gene, alongside the loss of heterozygocity (LOH) at this gene locus in patients with colorectal cancer. Genotyping was carried out for a variable number tandem repeat (VNTR) polymorphism in the TS 5'-untranslated region, a G/C single nucleotide polymorphism (SNP) located within this VNTR, and for TS LOH status in 246 colorectal cancer and paired normal DNA samples. The results were analyzed in relation to clinicopathological features, including the prognostic and predictive significance of TS genotype in patients who underwent curative surgery. Complete VNTR, SNP and LOH information for TS was obtained in 226 cases. No significant associations were observed between normal tissue TS genotype status and clinicopathological features. LOH of TS was observed in 58% of tumor samples and was associated with poor prognosis independently of clinical stage. Cases exhibiting TS LOH were classified into the three groups of 2R/loss, 3G/loss and 3C/loss. Patients with 3C/loss genotype status had poor outcomes when treated by surgery alone, but their survival was similar to patients with other genotypes following Fluorouracil (5-FU)-based adjuvant chemotherapy. The results suggested that LOH of the TS locus may be a significant prognostic factor in colorectal cancer, with the genotype of the residual allele also demonstrating an influence on prognosis. In conclusion, LOH status should be considered when TS genotype is explored as a potential prognostic and predictive marker for 5-FU-based adjuvant chemotherapy in colorectal cancer.

Combination therapy of bevacizumab with either S-1 and irinotecan or mFOLFOX6/CapeOX as first-line treatment of metastatic colorectal cancer (TRICOLORE): Exploratory analysis of RAS status and primary tumour location in a randomised, open-label, phase III, non-inferiority trial.

AIM: The TRICOLORE trial previously demonstrated that S-1 and irinotecan plus bevacizumab was non-inferior, based on progression-free survival (PFS), to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)/capecitabine and oxaliplatin (CapeOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC). Overall survival (OS) data were immature at the time of the primary analysis. METHODS: In total, 487 patients from 53 institutions with previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6/CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; 3- or 4-week regimen). The final OS data were analysed from follow-up data collected until 30th September 2017. RESULTS: With a median follow-up period of 48.7 months, median survival times were 32.6 and 34.3 months (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.72-1.10, P = 0.293) and median PFS durations were 10.8 and 14.0 months in the control and experimental groups, respectively (HR: 0.86, 95% CI: 0.71-1.04, P < 0.0001 for non-inferiority). In patients with left-sided RAS wild-type tumours, median PFS durations were 11.4 and 16.9 months in the control and experimental groups, respectively (HR: 0.68, 95% CI: 0.48-0.96, P = 0.028). CONCLUSION: S-1 and irinotecan plus bevacizumab resulted in comparable OS and non-inferior PFS with that of mFOLFOX6/CapeOX plus bevacizumab treatment as first-line chemotherapy for patients with mCRC. We recommend the use of S-1 and irinotecan plus bevacizumab as a standard first-line regimen independent of tumour sidedness or RAS status in mCRC. TRIAL REGISTRATION: UMIN-CTR: 000007834.

Laparoscopic treatment for celiac artery stenosis caused by median arcuate ligament compression with Adachi V type vascular anomaly: a case report.

BACKGROUND: Median arcuate ligament syndrome (MALS), which results from compression of the median arcuate ligament (MAL), is a rare cause of abdominal pain and weight loss. Treatment is dissection of the MAL; however, the laparoscopic procedure is not yet established and it involves the risk of major vascular injury, especially in cases with an anomaly. CASE PRESENTATION: A 47-year-old man was evaluated at the hospital for epigastric pain. Contrast computed tomography scan revealed stenosis of the celiac artery origin due to the MAL. An Adachi V type vascular anomaly was also observed. Laparoscopic treatment was performed to release pressure on the celiac artery. Laparoscopic ultrasonography was used to less invasively confirm the release of the MAL. Despite a concomitant Adachi V type vascular anomaly, surgery was safely performed using the laparoscopic magnification view and intraoperative ultrasonography. Follow-up ultrasonography confirmed the celiac artery stenosis has not recurred. CONCLUSIONS: A rare case of MALS with an Adachi V type vascular anomaly is presented and the laparoscopic treatment is detailed.

Advanced colorectal cancer subtypes (aCRCS) help select oxaliplatin-based or irinotecan-based therapy for colorectal cancer.

Oxaliplatin (OX) and irinotecan (IRI) are used as key drugs for the first-line treatment of metastatic colorectal cancer (mCRC). However, no biomarkers have been identified to decide which of the drugs is initially used. In this translational research (TR) of the TRICOLORE trial, the advanced colorectal cancer subtype (aCRCS) was analyzed as a potential biomarker for the selection of OX or IRI. We collected 335 (68.8%) formalin-fixed, paraffin-embedded (FFPE) primary tumor specimens from 487 patients registered in the TRICOLORE trial and performed direct sequencing and immunohistochemical staining of CRC-related genes, comprehensive gene-expression analysis, and genome-wide methylation analysis. The progression-free survival (PFS) of the IRI group was significantly better compared with the OX group in BRAF wild-type (WT), PTEN-positive, and aCRCS A1 patients. Among the molecular factors, aCRCS were only associated with the PFS of OX and IRI groups. The PFS of the IRI group was significantly better compared with the OX group in aCRCS A1 + B1 (hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.41-0.82; P = .0023). In contrast, the OX group had better PFS compared with the IRI group in aCRCS B2, although this was not statistically significant (HR = 1.66; 95% CI = 0.94-2.96; P = .083). Nearly half of patients with mCRC (46.8%, aCRCS A1 + B1) respond well to IRI, while only about 18.5% (aCRCS B2) of patients with mCRC responded well to OX. In conclusion, the aCRCS might be a predictive factor for the clinical outcomes of OX-based and IRI-based therapies.

Prospective Multicenter Study on the Prognostic and Predictive Impact of Tumor Budding in Stage II Colon Cancer: Results From the SACURA Trial.

PURPOSE: The International Union Against Cancer highlighted tumor budding as a tumor-related prognostic factor. International assessment criteria for tumor budding were recently defined by the 2016 International Tumor Budding Consensus Conference (ITBCC2016). This study aimed to clarify the prognostic and predictive values of tumor budding in a randomized controlled trial evaluating the superiority of adjuvant chemotherapy with oral tegafur-uracil over surgery alone for stage II colon cancer (SACURA trial; ClinicalTrials.gov identifier: NCT00392899). PATIENTS AND METHODS: Between 2006 and 2010, we enrolled 991 patients from 123 institutions with stage II colon cancer. Tumor budding was diagnosed by central review on the basis of the criteria adopted in the ITBCC2016. We prospectively recorded all clinical and pathologic data, including the budding grade, and performed prognostic analyses after 5 years of completing the patients' registration. RESULTS: Of 991 tumors, 376, 331, and 284 were classified as BD1, BD2, and BD3, respectively; the 5-year relapse-free survival (RFS) rate was 90.9%, 85.1%, and 74.4%, respectively (P < .001), and ranged widely in T4 tumors (86.6% to 53.3%). The budding grade significantly correlated with recurrence in the liver, lungs, lymph nodes, and peritoneum (P < .001 to .01). Multivariable analysis revealed that budding and T stage exerted an independent impact on RFS, and on the basis of the Harrell concordance index, these two factors substantially contributed to the improvement of the Cox model for predicting RFS. Both the BD2 and BD3 groups demonstrated greater improvement in the 5-year recurrence rate in the adjuvant chemotherapy group than the surgery-alone group by approximately 5%, but the difference was statistically nonsignificant. CONCLUSION: Tumor budding grade on the basis of the ITBCC2016 criteria should be routinely evaluated in pathologic practice and could improve the benefit of adjuvant chemotherapy for stage II colon cancer.

A randomised-controlled trial of 1-year adjuvant chemotherapy with oral tegafur-uracil versus surgery alone in stage II colon cancer: SACURA trial.

BACKGROUND: Efficacy of adjuvant chemotherapy in patients with stage II colon cancer is still controversial. The SACURA trial is a randomised-controlled study evaluating the superiority of 1-year adjuvant treatment with oral tegafur-uracil (UFT) to surgery alone for stage II colon cancer. METHODS: Patients were randomly assigned to the surgery-alone group or UFT group (UFT at 500-600 mg/day for 5 days, followed by 2-day rest, for 1 year). The primary end-point was disease-free survival (DFS). Target sample size was 2000, determined with one-sided alpha of 0.05, power of 0.9 and assumed hazard ratio (HR) 0.729. RESULTS: A total of 1982 patients (997 in the surgery-alone group and 985 in the UFT group) were analysed. Median follow-up was 69.5 months, median age was 66 years and for stage IIA/IIB/IIC, the distribution was 84%/13%/3%. The 5-year DFS rate was 78.4% in the surgery-alone group and 80.2% in the UFT group. The HR for DFS was 0.91 (95% confidence interval [CI], 0.75-1.10; p = 0.31); superiority of UFT was not demonstrated. Approximately 9% of patients experienced second cancers, which consist 40.7% of the DFS events. The 5-year relapse-free and overall survival rates of the surgery-alone and UFT group were 84.6% and 87.2% (HR, 0.82; 95% CI, 0.65-1.04) and 94.3% and 94.5% (HR, 0.93; 95% CI, 0.66-1.31), respectively. Subgroup analysis failed to disclose superiority in prognosis of adding UFT to the patients with risk factors for recurrence. CONCLUSIONS: Superiority of 1-year adjuvant UFT over surgery alone was not demonstrated in stage II colon cancer. Patients with risk factors for recurrence did not benefit from UFT. TRIAL REGISTRATION: ClinicalTrials. Gov. #NCT00392899.

Anticipation of umbistoma in laparoscopic anterior rectal resection: Ileostomy and ostomy closure.

OBJECTIVE: The use of laparoscopic surgery for rectal disease is expected to provide good cosmetic benefits for patients postoperatively. However, this expectation is significantly reduced when a diverting ileostomy is created. We present a new technique that reduces the size of the skin wound by constructing a diverting ileostomy in the umbilicus. This procedure, diverting umbilical ileostomy (umbistoma) does not require special tools for its construction and closure. METHODS: Twenty-nine patients underwent treatment with umbilical diverting stoma, including five women and 24 men, with a mean age of 70 years (range: 40-88 years). At the time of ostomy closure, a new umbilicus was formed by subcutaneously suturing the wound to the fascia. In addition, we did not close the new umbilical upper and lower spaces, so as to allow open drainage of the healing wound. RESULTS: All procedures were completed successfully without any perioperative complications. CONCLUSIONS: Our findings suggest that the umbilical diverting stoma could provide improved safety and cosmetic advantages in laparoscopic rectal resection.

A case of a mucin-producing bile duct tumor diagnosed over the course of 6 years.

We report a case of a mucin-producing intraductal papillary neoplasm of the intrahepatic bile duct (M-IPNB) diagnosed over a period of 6 years. A 64-year-old man underwent follow-up evaluations for an abdominal aortic aneurysm at our hospital. In 2009, a computed tomography (CT) scan revealed a simple hepatic cyst in segment 3 of the liver. Annual CT scans initially showed almost no change in the size or shape of the cyst. The cystic lesion, which measured 5 cm in 2014, had increased to 11 cm by 2015, and a solid component was detected within the cyst. A biliary cystic tumor was suspected and we performed a left lateral hepatectomy. Pathological examination showed that the papillary lesion in the cyst included adenocarcinoma and adenoma components. We diagnosed M-IPNB in 2015. Identification of the solid component of the cyst, as well as an increase in cyst diameter in the image analyses, was critical for diagnosis of M-IPNB.

Laparoscopic pelvic lymph node dissection for malignant foot melanoma.

A 39 year-old woman with malignant foot melanoma underwent wide excision of the primary tumor with a safety margin and sentinel lymph node biopsy (SLNB) for the right inguinal lymph node. SLNB was positive and a computed tomography (CT) scan revealed right iliac lymph node swelling. Positron emission tomography computed tomography (PET-CT) scan of the lymph nodes revealed abnormal uptake of fluorodeoxyglucose (FDG). We performed a laparoscopic pelvic lymph node obturator, iliac lymph node) dissection. During the operation, several black lymph nodes were observed in the iliac lymph node. Pathologically, the iliac lymph node consisted of metastasized atypical melanocytes. This surgical method for pelvic lymph node dissection is not a standard procedure among institutions. There have been no reported cases of malignant melanoma with pelvic lymph node metastasis treated by laparoscopic surgery. However, due to the minimally invasive technique, this method is worth considering to be used for pelvic lymph node dissection in malignant melanoma as well as other cancers in the field of urology or gynecology.

Multicenter phase II study of infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin, plus biweekly cetuximab as first-line treatment in patients with metastatic colorectal cancer (CELINE trial).

The current phase II study investigated the efficacy and safety of biweekly cetuximab combined with standard oxaliplatin-based chemotherapy [infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX-6)] in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Sixty patients with a median age of 64 years (range, 38-82 syears) received a biweekly intravenous infusion of cetuximab (500 mg/m2 on day 1) followed by FOLFOX-6 (2-hour oxaliplatin 85 mg/m2 infusion on day 1 in tandem with a 2-h leucovorin 200 mg/m2 infusion on days 1 and 2, and 5-FU as a 400 mg/m2 bolus followed by a 46-hour 2,400 mg/m2 infusion on days 1-3). Patient response rate was 70%, with 95% disease control rates. The median progression-free survival was 13.8 months. Thirteen patients (21.7%) were able to undergo resection of previously unresectable metastases, with the aim of curing them. The median follow-up was 22.7 months, and median overall survival was 31.0 months. Cetuximab did not increase FOLFOX-6 toxicity and was generally well tolerated. The results of the current study demonstrate that the combination of biweekly cetuximab with FOLFOX-6 was well tolerated and had a manageable safety profile for the first-line treatment of KRAS wild-type metastatic colorectal cancer. Efficacy was comparable to other treatment regimens. The results support the administration of biweekly cetuximab in combination with FOLFOX-6, which may be more convenient and provide treatment flexibility in this setting for patients with metastatic colorectal cancers.

Laparoscopic versus Open stoma creation: A retrospective analysis.

OBJECTIVES: This study aimed to compare open stoma (OS) creation with laparoscopic stoma (LS) creation considering the operation time, blood loss, time of oral intake, and complications. We also compared multiport LS and single-incision laparoscopic stoma (SILS) creation. METHODS: We reviewed the demographic data, diagnosis, indications, operation time, blood loss, time of oral intake, operative procedure, and complications of 50 patients who underwent stoma creation between April 2014 and April 2016. RESULTS: The mean blood loss was significantly lower in the LS group (7.85±18.4 ml) than in the OS group (38.1±73.2 ml; P=0.02). There were no statistical differences between the groups in terms of the operation time (LS, 72.1±32.7 min; OS, 61.2±31.2 min; P=0.23) or time of oral intake (LS, 1.0±0 days; OS, 1.91±2.71 days; P=0.17). Peristomal skin problems occurred in 11 patients (47.8%) in the OS group and 5 patients (18.5%) in the LS group. There were no statistically significant differences between the SILS and multiport LS groups, considering the operation time, amount of bleeding, and time of oral intake. CONCLUSIONS: LS is comparable with OS in terms of operation time and time of oral intake and may cause lesser blood loss. Considering its advantages, LS is a useful approach for patients requiring biopsies or intra-abdominal inspection. SILS is a minimally invasive technique, suitable for patients in whom the stoma site is preoperatively decided.

Prognostic and predictive significance of long interspersed nucleotide element-1 methylation in advanced-stage colorectal cancer.

BACKGROUND: Hypomethylation of Long Interspersed Nucleotide Element-1 (LINE-1) is associated with worse prognosis in colorectal cancer (CRC). However, little is known about the relevance of this marker for the prognosis and response to chemotherapy of metastatic and recurrent (advanced-stage) CRC. Our aim was therefore to investigate whether tumor LINE-1 hypomethylation correlates with patient survival and with response to 5-fluorouracil (5-FU)/ oxaliplatin (FOLFOX) chemotherapy in advanced-stage CRC. METHODS: The study included 40 CRC patients who developed metastasis or local recurrence after surgery and subsequently underwent FOLFOX therapy. Progression-free and overall survival were estimated using the Kaplan-Meier method. LINE-1 methylation levels in formalin-fixed and paraffin-embedded primary tumor tissues were measured by MethyLight assay and correlated with patient survival. In vitro analyses were also conducted with human colon cancer cell lines having different LINE-1 methylation levels to examine the effects of 5-FU and oxaliplatin on LINE-1 activity and DNA double-strand-breaks. RESULTS: Patients with LINE-1 hypomethylation showed significantly worse progression-free (median: 6.6 vs 9.4 months; P = 0.02) and overall (median: 16.6 vs 23.2 months; P = 0.01) survival following chemotherapy compared to patients with high methylation. LINE-1 hypomethylation was an independent factor for poor prognosis (P = 0.018) and was associated with a trend for non-response to FOLFOX chemotherapy. In vitro analysis showed that oxaliplatin increased the LINE-1 score in LINE-1-expressing (hypomethylated) cancer cells, thereby enhancing and prolonging the effect of 5-FU against these cells. This finding supports the observed correlation between tumor LINE-1 methylation and response to chemotherapy in CRC patients. CONCLUSIONS: Tumor LINE-1 hypomethylation is an independent marker of poor prognosis in advanced-stage CRC and may also predict non-response to combination FOLFOX chemotherapy. Prospective studies are needed to optimize the measurement of tumor LINE-1 methylation and to confirm its clinical impact, particularly as a predictive marker.

Laparoscopic total pelvic exenteration using transanal minimal invasive surgery technique with en bloc bilateral lymph node dissection for advanced rectal cancer.

A 59-year-old man presenting with fecal occult blood visited our hospital. He was diagnosed with advanced lower rectal cancer, which was contiguous with the prostate and the left seminal vesicle. There were no metastatic lesions with lymph nodes or other organs. We performed laparoscopic total pelvic exenteration (LTPE) using transanal minimal invasive surgery technique with bilateral en bloc lateral lymph node dissection for advanced primary rectal cancer after neoadjuvant chemoradiotherapy. The total operative time was 760 min, and the estimated blood loss was 200 ml. LTPE is not well established technically, but it has many advantages including good visibility of the surgical field, less blood loss, and smaller wounds. A laparoscopic approach may be an appropriate choice for treating locally advanced lower rectal cancer, which requires TPE.