Long-term survival and functional outcomes of laparoscopic surgery for clinical stage I ultra-low rectal cancers located within 5 cm of the anal verge: A prospective phase II trial (Ultimate trial).

OBJECTIVE: To clarify the long-term oncological outcomes and postoperative anal, urinary, and sexual functions after laparoscopic surgery for clinical stage I very low rectal carcinoma located near the anal canal. SUMMARY BACKGROUND DATA: Laparoscopic surgery is widely applied for rectal cancer; however, concerns remain, with some studies showing poorer outcomes compared to open surgery. METHODS: This single-arm, phase II trial included patients registered preoperatively from 47 institutions in Japan. The planned sample size was 300. The primary endpoint was the 3-year local recurrence rate. Anal, urinary, and sexual functions were evaluated using a prospective questionnaire. RESULTS: Three-hundred patients were registered between January 2014 and March 2017. Anus-preserving surgery was performed in 278 (93%), including 172 who underwent intersphincteric resection (58%) and 106 (36%) who underwent low anterior resection. The 3-year cumulative local recurrence rate was 6.3%. At 3 years postoperatively, 87% of patients used their own anus, and the median incontinence score improved from 12 at 3 months to 8 at 3 years. Only 5% of patients had severe incontinence (incontinence score of 16 points). Postoperative urinary function evaluation showed that International Prostate Symptom Score and Overactive Bladder Symptom Score decreased 1 week after surgery, but recovered to preoperative level 1 month after surgery. International Consultation on Incontinence Questionnaire-Sort Form remained almost stable after surgery. Sexual function evaluation using the International Index of Erectile Function-5 and International Index of Erectile Function-15 revealed that the patients had deteriorated 3 months after surgery but had recovered only slightly by 6 months. CONCLUSIONS: Laparoscopic surgery achieves feasible long-term oncological outcomes and a high rate of anus preservation with moderate anal function, and an acceptable incontinence score. While urinary function recovered rapidly, sexual function showed poor recovery.

Long-Term Outcomes of Additional Surgery After Endoscopic Resection Versus Primary Surgery for T1 Colorectal Cancer.

INTRODUCTION: There is considerable concern about whether endoscopic resection (ER) before additional surgery (AS) for T1 colorectal cancer (CRC) has oncologically potential adverse effects. Therefore, the aim of this study was to compare the long-term outcomes, including overall survival (OS), of patients treated with AS after ER vs primary surgery (PS) for T1 CRC using a propensity score-matched analysis from a large observational study. METHODS: This study investigated 6,105 patients with T1 CRC treated with either ER or surgical resection between 2009 and 2016 at 27 high-volume Japanese institutions, with those undergoing surgery alone included in the PS group and those undergoing AS after ER included in the AS group. Propensity score matching was used for long-term outcomes of mortality and recurrence analysis. RESULTS: After propensity score matching, 1,219 of 2,438 patients were identified in each group. The 5-year OS rates in the AS and PS groups were 97.1% and 96.0%, respectively (hazard ratio: 0.72, 95% confidence interval: 0.49-1.08), indicating the noninferiority of the AS group. Moreover, 32 patients (2.6%) in the AS group and 24 (2.0%) in the PS group had recurrences, with no significant difference between the 2 groups (odds ratio: 1.34, 95% confidence interval: 0.76-2.40, P = 0.344). DISCUSSION: ER before AS for T1 CRC had no adverse effect on patients' long-term outcomes, including the 5-year OS rate. ER is a viable first-line treatment option for endoscopically resectable T1 CRC.

Treatment Decision for Locally Resected T1 Colorectal Carcinoma-Verification of the Japanese Guideline Criteria for Additional Surgery Based on Long-Term Clinical Outcomes.

INTRODUCTION: To verify the value of the pathological criteria for additional treatment in locally resected pT1 colorectal carcinoma (CRC) which have been used in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines since 2009. METHODS: We enrolled 4,667 patients with pT1 CRC treated at 27 institutions between July 2009 and December 2016 (1,257 patients with local resection alone [group A], 1,512 patients with additional surgery after local resection [group B], and 1,898 patients with surgery alone [group C]). All 5 factors of the JSCCR guidelines (submucosal resection margin, tumor histologic grade, submucosal invasion depth, lymphovascular invasion, and tumor budding) for lymph node metastasis (LNM) had been diagnosed prospectively. RESULTS: Any of the risk factors were present in 3,751 patients. The LNM incidence was 10.4% (95% confidence interval 9.4-11.5) in group B/C patients with risk factors, whereas it was 1.8% (95% confidence interval 0.4-5.3) in those without risk factors ( P < 0.01). In group A, the incidence of recurrence was 3.6% in patients with risk factors, but it was only 0.4% in patients without risk factors ( P < 0.01). The disease-free survival rate of group A patients classified as risk positive was significantly worse than those of groups B and C patients. However, the 5-year disease-free survival rate in group A patients with no risk was 99.6%. DISCUSSION: Our large-scale real-world multicenter study demonstrated the validity of the JSCCR criteria for pT1 CRC after local resection, especially regarding favorable outcomes in patients with low risk of LNM.

Use of 3D-CT-derived psoas major muscle volume in defining sarcopenia in colorectal cancer.

BACKGROUND: Sarcopenia is characterized by reduced skeletal muscle volume and is a condition that is prevalent among elderly patients and associated with poor prognosis as a comorbidity in malignancies. Given the aging population over 80 years old in Japan, an understanding of malignancies, including colorectal cancer (CRC), complicated by sarcopenia is increasingly important. Therefore, the focus of this study is on a novel and practical diagnostic approach of assessment of psoas major muscle volume (PV) using 3-dimensional computed tomography (3D-CT) in diagnosis of sarcopenia in patients with CRC. METHODS: The subjects were 150 patients aged ≥ 80 years with CRC who underwent primary tumor resection at Juntendo University Hospital between 2004 and 2017. 3D-CT measurement of PV and conventional CT measurement of the psoas major muscle cross-sectional area (PA) were used to identify sarcopenia (group S) and non-sarcopenia (group nS) cases. Clinicopathological characteristics, operative results, postoperative complications, and prognosis were compared between these groups. RESULTS: The S:nS ratios were 15:135 for the PV method and 52:98 for the PA method. There was a strong positive correlation (r = 0.66, p < 0.01) between PVI (psoas major muscle volume index) and PAI (psoas major muscle cross-sectional area index), which were calculated by dividing PV or PA by the square of height. Surgical results and postoperative complications did not differ significantly in the S and nS groups defined using each method. Overall survival was worse in group S compared to group nS identified by PV (p < 0.01), but not significantly different in groups S and nS identified by PA (p = 0.77). A Cox proportional hazards model for OS identified group S by PV as an independent predictor of a poor prognosis (p < 0.05), whereas group S by PA was not a predictor of prognosis (p = 0.60). CONCLUSIONS: The PV method for identifying sarcopenia in elderly patients with CRC is more practical and sensitive for prediction of a poor prognosis compared to the conventional method.

Prognostic utility of circulating tumor DNA methylation analysis in stage IV colorectal cancer.

BACKGROUND AND OBJECTIVES: Our aim in this study was to investigate the usefulness of circulating tumor (ct) DNA methylation analysis for predicting long-term outcomes after resection in Stage IV colorectal cancer (CRC). METHODS: Methylation analyses were performed on 95 plasma samples from patients with CRC who underwent surgery. The methylation status (relative methylation value: RMV) of CpG within the promoter region of three genes (CHFR, SOX11, and CDO1) was assessed to quantitative methylation-specific PCR (qMSP) analysis. RESULTS: In the patients who had undergone resection of the primary tumor and metastatic organs with curative intent, the CHFR-RMV high group had significantly worse recurrence-free survival (RFS) compared with the CHFR-RMV low group (p = 0.001). Multivariate analysis revealed that CHFR-RMV was a significant independent prognostic factor (hazard ratio = 2.63 (1.29-5.36); p = 0.008). In the patients who had undergone resection of the primary tumor with metastatic organs with curative intent after neoadjuvant systemic chemotherapy, the SOX11-RMV high group had significantly worse RFS compared with the SOX11-RMV low group (p = 0.004). CONCLUSIONS: The current study showed the usefulness of ctDNA methylation analysis for predicting the possibility of curative resection and long-term outcomes after resection in Stage IV CRC. A future prospective study is needed to obtain more conclusive results.

Short- and long-term outcomes of surgical treatment for inguinal lymph node metastasis in rectal and anal canal adenocarcinoma.

AIM: The significance of lymphadenectomy and its indications in patients with inguinal lymph node metastasis (ILNM) of anorectal adenocarcinoma is unclear. This study aimed to clarify the surgical outcomes and prognostic factors of inguinal lymphadenectomy for ILNM. METHOD: This study included patients who underwent surgical resection for ILNM of rectal or anal canal adenocarcinoma with pathologically positive metastases between 1997 and 2011 at 20 participating centres in the Study Group for Inguinal Lymph Node Metastasis from Colorectal Cancer organized by the Japanese Society for Cancer of the Colon and Rectum. Clinicopathological characteristics and short- and long-term postoperative outcomes were retrospectively analysed. RESULTS: In total, 107 patients were included. The primary tumour was in the rectum in 57 patients (53.3%) and in the anal canal in 50 (46.7%). The median number of ILNMs was 2.34. Postoperative complications of Clavien-Dindo Grade III or higher were observed in five patients. The 5-year overall survival rate was 38.8%. Multivariate analysis identified undifferentiated histological type (P < 0.001), pathological venous invasion (P = 0.01) and pathological primary tumour depth T0-2 (P = 0.01) as independent prognostic factors for poor overall survival. CONCLUSION: The 5-year overall survival after inguinal lymph node dissection was acceptable, and it warrants consideration in more patients. Further larger-scale studies are needed in order to clarify the surgical indications.

Final analyses of the prospective controlled trial on the efficacy of uracil and tegafur/leucovorin as an adjuvant treatment for stage II colon cancer with risk factors for recurrence using propensity score-based methods (JFMC46-1201).

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. Using propensity score matching, we previously reported that the 3-year disease-free survival (DFS) rate was significantly higher in patients treated with uracil and tegafur plus leucovorin (UFT/LV) against surgery alone. We report the final results, including updated 5-year overall survival (OS) rates and risk factor analysis outcomes. METHODS: In total, 1902 high-risk stage II CC patients with T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and/or < 12 dissected lymph nodes were enrolled in this prospective, non-randomized controlled study based on their self-selected treatment. Oral UFT/LV therapy was administered for six months after surgery. RESULTS: Of the 1880 eligible patients, 402 in Group A (surgery alone) and 804 in Group B (UFT/LV) were propensity score-matched. The 5-year DFS rate was significantly higher in Group B than in Group A (P = 0.0008). The 5-year OS rates were not significantly different between groups. The inverse probability of treatment weighting revealed significantly higher 5-year DFS (P = 0.0006) and 5-year OS (P = 0.0122) rates in group B than in group A. Multivariate analyses revealed that male sex, age ≥ 70 years, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for DFS and/or OS. CONCLUSION: The follow-up data from our prospective non-randomized controlled study revealed a considerable survival advantage in DFS offered by adjuvant chemotherapy with UFT/LV administered for six months over surgery alone in individuals with high-risk stage II CC. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019), UMIN Clinical Trials Registry: UMIN000007783 (date of registration: 18/04/2012).

Two Surgical Cases of Colorectal Cancer in Patients With Immunoglobulin G4-Related Disease.

Immunoglobulin G4-related disease (IgG4RD) is a relatively new disease concept that is most common in Asia. It is a systemic chronic lymphoproliferative disease that is diagnosed by mass formation or thickened lesion, a high serum IgG4 level (≥135 mg/dL), and confirmation of lymphocytes and plasma cells by histopathological examination. The precise mechanism of this disease remains elusive; however, distinguishing IgG4RD from malignancy proves challenging due to its manifestation of swollen lymph nodes and retroperitoneal thickening and fibrosis. Malignancy is also 3.5 times more likely in cases with IgG4RD. In this study, we report two cases of colorectal cancer in patients with IgG4RD who underwent surgery. In both cases, excising the tumor from the retroperitoneal posed a challenge, and swollen lymph nodes were observed without evidence of cancer metastasis. We believe that these are very informative cases, and we report the cases with a literature review of IgG4RD.

A pilot study on the safety and efficacy of neoadjuvant chemo­adoptive immunotherapy for locally advanced rectal cancer.

The safety and efficacy of combination therapy of immune cell therapy and chemotherapy [chemo-adoptive immunotherapy (CAIT)] for patients with stage IV or recurrent colorectal cancer have been reported. In the present study, the safety and efficacy of neoadjuvant CAIT were investigated for preoperative therapy of locally advanced rectal cancer. The study included patients with cT3/T4 or cN (+) rectal adenocarcinoma scheduled for curative surgery. Six patients who consented to participate in the current study were selected as subjects. Neoadjuvant CAIT involves administration of activated autologous lymphocytes, αß T cells, and mFOLFOX6 every 2 weeks for six courses, followed by surgery 4-6 weeks thereafter. Common Terminology Criteria for Adverse Events grade 3 neutropenia was observed in one patient. Neoadjuvant CAIT and curative surgery were performed on all the patients. The confirmed response rate was 67%. Downstaging was confirmed in five patients (83%). Regarding histological effects, two patients were grade 1a and four were grade 2. Regarding immunological reactions, both CD4+ and CD8+ T cell infiltration rates increased after treatment in three patients on tumor-infiltrating lymphocyte (TIL) analysis. In peripheral blood analysis, the total lymphocyte count was maintained in all patients, and the CD8+ T cell count increased by ≥3 times on the pretreatment count in two patients but may not be associated with changes in TILs. During the median postoperative follow-up duration of 24 months, liver and lung metastases occurred in one patient, but all patients survived. In conclusion, neoadjuvant CAIT (αß T cells + mFOLFOX6) can be safely administered for the treatment of advanced rectal cancer. Verification of the efficacy of comprehensive immune cell therapy, especially the induction of antitumor immunity for the prevention of recurrence, will be maintained. The current study is registered with the Japan Registry of Clinical Trials (jRCT; ID, jRCTc030190248; January 21, 2019).

Impact of resection for ovarian metastases from colorectal cancer and clinicopathologic analysis: A multicenter retrospective study in Japan.

Aim: The aim of this study was to clarify the significance of resection of ovarian metastases from colorectal cancer and to identify the clinicopathologic characteristics. Methods: In this multicenter retrospective study, we evaluated data on ovarian metastases from colorectal cancer obtained from patients at 20 centers in Japan between 2000 and 2014. We examined the impact of resection on the prognosis of patients with ovarian metastases and examined prognostic factors. Results: The study included 296 patients with ovarian metastasis. The 3-y overall survival rate was 68.6% for solitary ovarian metastases. In all cases of this cohort, the 3-y overall survival rates after curative resection, noncurative resection, and nonresection were 65.9%, 31.8%, and 6.1%, respectively (curative resection vs noncurative resection [P < 0.01] and noncurative resection vs nonresection [P < 0.01]). In the multivariate analysis of prognostic factors, tumor size of ovarian metastasis (P < 0.01), bilateral ovarian metastasis (P = 0.01), peritoneal metastasis (P < 0.01), pulmonary metastasis (P = 0.04), liver metastasis (P < 0.01), and remnant of ovarian metastasis (P < 0.01) were statistically significantly different. Conclusion: The prognosis after curative resection for solitary ovarian metastases was shown to be relatively favorable as Stage IV colorectal cancer. Resection of ovarian metastases, not only curative resection but also noncurative resection, confers a survival benefit. Prognostic factors were large ovarian metastases, bilateral ovarian metastases, the presence of extraovarian metastases, and remnant ovarian metastases.

Feasibility of robotic-assisted surgery in advanced rectal cancer: a multicentre prospective phase II study (VITRUVIANO trial).

BACKGROUND: The potential benefits of robotic-assisted compared with laparoscopic surgery for locally advanced cancer have not been sufficiently proven by prospective studies. One factor is speculated to be the lack of strict surgeon criteria. The aim of this study was to assess outcomes for robotic surgery in patients with locally advanced rectal cancer with strict surgeon experience criteria. METHODS: A criterion was set requiring surgeons to have performed more than 40 robotically assisted operations for rectal cancer. Between March 2020 and May 2022, patients with rectal cancer (distance from the anal verge of 12 cm or less, cT2-T4a, cN0-N3, cM0, or cT1-T4a, cN1-N3, cM0) were registered. The primary endpoint was the rate positive circumferential resection margin (CRM) from the pathological specimen. Secondary endpoints were surgical outcomes, pathological results, postoperative complications, and longterm outcomes. RESULTS: Of the 321 registered patients, 303 were analysed, excluding 18 that were ineligible. At diagnosis: stage I (n = 68), stage II (n = 84) and stage III (n = 151). Neoadjuvant therapy was used in 56 patients. There were no conversions to open surgery. The median console time to rectal resection was 170 min, and the median blood loss was 5 ml. Fourteen patients had a positive CRM (4.6%). Grade III-IV postoperative complications were observed in 13 patients (4.3%). CONCLUSION: Robotic-assisted surgery is feasible for locally advanced rectal cancer when strict surgeon criteria are used.

NTRK2 expression in gastrointestinal stromal tumors with a special emphasis on the clinicopathological and prognostic impacts.

Gastrointestinal stromal tumors (GISTs) are typically characterized by activating mutations of the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type GIST. We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases, and all pan-trk positive cases showed diffuse and strong expression of c-kit. Interestingly, all of these cases showed only trkB but not trkA/trkC expression. Cap analysis of gene expression (CAGE) analysis identified increased number of genes whose promoters were activated in pan-trk/trkB positive GISTs. Imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in any of trkB positive GISTs, despite higher mRNA expression. TrkB expression was found in duodenal GISTs and more than half of small intestinal GISTs, and this subset of cases showed poor prognosis. However, there was not clear difference in clinical outcomes according to the trkB expression status in small intestinal GISTs. These findings may provide a possible hypothesis for trkB overexpression contributing to the tumorigenesis and aggressive clinical outcome in GISTs of duodenal origin.

Application of the Bioabsorbable Polyglycolic Acid Sheet in Colorectal Anastomosis in Animal Models.

Objectives: Anastomotic complications after colorectal surgery are one of the most serious outcomes. To address this issue, this study used the newly developed bioabsorbable polyglycolic acid (PGA) sheet to assess its usefulness and safety using two approaches of double stapling technique (DST) after laparoscopic anterior resection (AR) in pig models. Methods: Rectal intratissue pressure was assessed after DST anastomosis in two groups, i.e., with (PGA group) or without PGA sheet (nonPGA group), which was sandwiched between the anastomosis in the first approach. In the second approach, after laparoscopic DST anastomosis with PGA sheet attached at anvil side, the clinical short-term outcomes within 1 week and histological findings at 1 week after the surgery were evaluated. Results: Assessment of rectal intratissue pressure showed a mean pressure of 9.28 kPa in the PGA group versus 5.78 kPa in the nonPGA group (p = 0.39). The results of clinical short-term outcomes revealed that there were no anastomotic complications. The results of histological findings in anastomotic bowel tissues with PGA sheet were not significantly different from those of the control case. Conclusions: The bioabsorbable PGA sheet can be used for colorectal DST anastomosis in animal models and may be a valuable tool for this procedure.

Study of Purse-string Skin Closure Plus Negative-pressure Wound Therapy for Stoma Closure.

Background: Although purse-string skin closure (PSC) is an effective method for stoma closure considering wound infection, the period for scarring will be prolonged. The aim of this study was to assess whether negative-pressure wound therapy (NPWT) can reduce the wound-scarring period for PSC after stoma closure. Methods: Patients who underwent stoma closure between January 2015 and August 2020 at our department were retrospectively assessed. Patients in the control group received only PSC, and patients in the NPWT group received both PSC and NPWT using the VAC® or PICO®. The primary endpoint of this study was the short-term reduction ratio (RR). The RR is calculated by the length, width, and depth of the wound of the stoma closure site. The secondary endpoints were scarring period and wound-related complications such as surgical site infection, dermatitis, bleeding, enterocutaneous fistula, and ventral hernia. Results: Of the 53 patients included in this study, 21 had their stoma closed by PSC and 32 had their stoma closed by PSC plus NPWT. No significant differences were observed in patient characteristics or peri-operative states. The RR in the NPWT group was significantly smaller than that in the PSC group at 7 postoperative days (p=0.04). There was no difference in scarring period between the two groups (p=0.11).The rates of postoperative wound-related complications were similar in the two groups (control group: 4 (19%), NPWT group: 7 (21.9%), p=1.0). Conclusions: Our study suggests that PSC plus NPWT might be more effective for wound healing after stoma closure than only PSC.