Long-term Outcome After Surgical Resection of Paraaortic Lymph Node Metastasis of Colorectal Cancer: A Multicenter Retrospective Study.

BACKGROUND: The significance of resection of paraaortic lymph node metastasis in colorectal cancer is controversial. OBJECTIVE: To clarify the prognosis of colorectal cancer after paraaortic lymph node metastasis resection. DESIGN: Multicenter retrospective study. SETTINGS: Thirty-six institutions in Japan participated in this study. PATIENTS: Patients with resected and pathologically proven paraaortic lymph node metastasis of CRC between 2010 and 2015. DATA SOURCES: Database and medical records at each institution. MAIN OUTCOME MEASURES: Overall survival after paraaortic lymph node metastasis resection, recurrence-free survival, and recurrence patterns after R0 resection of paraaortic lymph node metastasis. RESULTS: A total of 133 patients were included in the primary analysis population in this study. The 5-year overall survival rate (95% confidence interval [CI]) was 41.0% (32.0, 49.8), and the median survival (95% CI) was 4.1 (3.4, 4.7) years. Independent prognostic factors for overall survival were the pathological T stage (pT4 vs. pT1- 3, adjusted hazard ratio [aHR]: 1.91, p = 0.006), other organ metastasis (present vs. absent, aHR: 1.98, p = 0.005), time to metastases (synchronous vs. metachronous, aHR: 2.02, p = 0.02), and number of paraaortic lymph node metastasis (≥3 vs. <3, aHR: 2.13, p = 0.001). The 5-year recurrence-free survival rate (95% CI) was 21.1% (13.5, 29.7), with a median (95% CI) of 1.2 (0.9, 1.4) years. The primary tumor location (left- vs. right-sided colon, aHR: 4.77, p = 0.01; rectum vs. right-sided colon, aHR: 5.27, p = 0.006), other organ metastasis (present vs. absent, aHR: 1.90, p = 0.03), number of paraaortic lymph node metastasis (≥3 vs. <3, aHR: 2.20, p = 0.001), and hospital volume (<10 vs. ≥10, aHR: 2.18, p = 0.02) were identified as independent prognostic factors for recurrence-free survival. Paraaortic lymph node recurrence was the most common at 33.3%. LIMITATIONS: Selection bias cannot be ruled out because of the retrospective nature of the study. CONCLUSIONS: Less than three paraaortic lymph node metastasis was a favorable prognostic factor for both overall survival and recurrence-free survival. However, paraaortic lymph node metastases were considered to be a systemic disease and the significance of resection was limited. See Video Abstract.

SLC7A11 and the glutathione pathway as novel prognostic markers in resectable pancreatic ductal adenocarcinoma: A metabolomics study of clinical specimens.

BACKGROUND/OBJECTIVES: Despite the poor prognosis associated with pancreatic ductal adenocarcinoma (PDAC), there remains a lack of clarity regarding the metabolic pathways and their significant impact on its phenotype. Therefore, we aimed to utilize metabolomics to capture changes in clinical PDAC tissues and elucidate the significant metabolic pathways close to its phenotypes. METHODS: This basic research was retrospectively validated using database research, immunohistochemistry, and protein analysis based on the findings obtained from metabolomics using clinical tissues collected from prospectively registered patients with PDAC. mRNA expression analysis using a database and protein analysis using archived clinical specimens was performed to validate the candidate pathways identified using metabolomics. Between-group comparisons were analyzed using paired t-tests and log-rank test, and Kaplan-Meier curves illustrated survival times. RESULTS: Patients subjected to metabolomics revealed a significant increase in glutathione disulfide levels in PDAC tissues when compared to normal pancreatic tissues. The Cancer Genome Atlas database analysis revealed significant changes in glutathione pathway-related mRNAs in PDAC compared to that in the normal pancreas. Protein analysis of previously resected specimens demonstrated a significant increase in SLC7A11 expression in PDAC tissues. The abundance ratio of SLC7A11 isoforms was associated with the post-operative prognosis in resectable PDAC. CONCLUSION: Glutathione disulfide levels were significantly increased in clinical PDAC metabolomics. Additionally, increased mRNA and protein expression in SLC7A11 was observed in PDAC. Furthermore, the SLC7A11 isoform abundance ratio may be a valuable prognostic marker in patients with resectable PDAC.

Effects of neoadjuvant chemotherapy for patients with obstructive colon cancer: A multicenter propensity score-matched analysis (YCOG2101).

Aim: Obstructive colon cancer is locally advanced colon cancer with poor prognosis. However, the effect of neoadjuvant chemotherapy (NAC) on obstructive colon cancer remains unclear. Therefore, this study aimed to investigate the safety and efficacy of NAC in patients with obstructive colon cancer. Methods: From January 2012 to December 2017, we collected patient data for clinical stage II/III obstructive colon cancer at seven Yokohama Clinical Oncology Group (YCOG) institutions. The long-term outcomes of the NAC and non-NAC groups were analyzed retrospectively after adjusting for patients' background characteristics using propensity score matching. Results: Among the 202 eligible patients, propensity score matching extracted 51 patients each for the NAC and non-NAC groups. After matching, the groups showed no marked differences in the background factors. All the patients in the NAC group underwent diverting stoma construction. Nineteen patients (37.3%) experienced grade 3-4 adverse events during NAC. The incidence of postoperative complications was similar between groups. The 5-year progression-free survival rates were 75.8% in the NAC group and 63.0% in the non-NAC group (p = 0.22, log-rank test). The 5-year overall survival rates were 88.5% in the NAC group and 78.8% in the non-NAC group (p = 0.09, log-rank test). Conclusion: Although NAC was feasible for obstructive colon cancer after diverting stoma construction, its effects on long-term outcomes could not be proven.

Multicenter randomized phase II study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases (YCOG1001).

PURPOSE: The high recurrence rate of colorectal cancer liver metastasis (CRCLM) after surgery remains a crucial problem. However, adjuvant chemotherapy after hepatectomy for CRCLM has not yet been established. This study evaluated the efficacy of adjuvant therapy with S-1 and oxaliplatin (SOX). METHODS: In a multicenter, randomized, phase II study, patients undergoing curative resection of CRCLM were randomly enrolled in a 1:1 ratio to either the low- or high-dose group. S-1 and oxaliplatin were administered from days 1 to 14 of a 3-week cycle as a 2-h infusion every 3 weeks. The dose of S-1 was fixed at 80 mg/m2. The doses in the low- and high-dose oxaliplatin groups were 100 mg/m2 (low-dose group) and 130 mg/m2 (high-dose group), respectively. This treatment was repeated eight times. The primary endpoint was the rate of discontinuation owing to toxicity. The secondary endpoints were the relapse-free survival (RFS) and frequency of adverse events (AEs). RESULTS: Between August 2010 and March 2015, 44 patients (low-dose group: 31 patients and high-dose group: 13 patients) were enrolled in the study. Of these, one patient was excluded from the efficacy analysis. In the high-dose group, five of nine patients were unable to continue the study due to toxicity in February 2013. At that time, recruitment to the high-dose group was stopped from the protocol. The relative dose intensity (RDI) for S-1 in the low- and high-dose groups were 49.8 and 48.7% (p = 0.712), and that for oxaliplatin was 75.9 and 73.0% (p = 0.528), respectively. The rates of discontinuation due to toxicity were 60 and 53.8% in the low- and high-dose groups, respectively, with no marked difference noted between the groups (p = 0.747). The frequency of grade ≥ 3 common adverse events was neutropenia (23.3%/23.1%), diarrhea (13.3%/15.4%), and peripheral sensory neuropathy (6.7%/7.7%). The disease-free survival (DFS) at 3 years was 52.9% in the low-dose group, which was not significantly different from that in the high-dose group (46.2%; p = 0.705). CONCLUSIONS: SOX regimens as adjuvant therapy after hepatectomy for CRCLM had high rates of discontinuation due to toxicity in both groups. In particular, the RDI of S-1 was < 50%. Therefore, the SOX regimen is not recommended as adjuvant chemotherapy after hepatectomy for CRCLM.

Surgical outcomes of a prospective, phase 2 trial of robotic surgery for resectable right-sided colon cancer (the ROBOCOLO trial).

Aim: We evaluated the safety of robotic surgery for right-sided colon cancer in Japan. Methods: This was a prospective, open-label, single-arm phase II trial conducted at two institutions. Patients ≥20 years old with stage I-III right-sided colon cancer and scheduled for radical resection with ≥D2 lymph node dissection were eligible. The criterion for surgeons was experience performing robot-assisted rectal resection in ≥40 cases. The primary endpoint was the postoperative complication rate ≤30 days after surgery. Results: From August 2021 to February 2023, 42 patients were enrolled; three were excluded, with 39 analyzed as the full analysis set. The median age was 72 years, and the median body mass index was 23.2. The tumor was located in the cecum in 13 cases (33.3%), ascending colon in 20 cases (51.3%), and transverse colon in six cases (15.4%). Ileocolic resection was performed in 17 cases (43.5%) and right hemicolectomy in 22 cases (56.5%), both with D3 lymph node dissection. The median console time was 109 min, and the operative time was 170 min. The mean blood loss was 7.7 mL. Intracorporeal anastomosis was performed in 28 patients (71.8%). There were no conversions and no intraoperative adverse events. The median postoperative stay was 5 days. Postoperative complications occurred in four patients (10.2%; paralytic ileus [n = 3] and pneumonia [n = 1]). All postoperative complications were grade 1 or 2, with no mortalities noted. R0 resection was achieved in all patients. Conclusions: This study demonstrated the safety and feasibility of robotic surgery for right-sided colon cancer.

Short-term and Mid-term Outcomes of Indocyanine Green Fluorescence Imaging-Guided Laparoscopic Right-Sided Colectomy: A Propensity Score-Matched Cohort Study.

BACKGROUND: With the use of indocyanine green fluorescence imaging, intraoperative lymphatic flow assessment is possible. However, no report has indicated mid-term outcomes of indocyanine green fluorescence imaging-guided laparoscopic right-sided colectomy. OBJECTIVE: To analyze the mid-term outcomes of indocyanine green fluorescence imaging-guided laparoscopic right-sided colectomy. DESIGN: This was a retrospective, multi-institutional study that used propensity score matching. SETTINGS: We conducted this study within the framework of the Yokohama Clinical Oncology Group in Japan. PATIENTS: A total of 921 patients who underwent laparoscopic right-sided colectomy with lymph node dissection for colon cancer with clinical stages I to III between January 2009 and December 2020 were included. The patients were divided into 2 groups: 233 patients who underwent the lymphatic flow evaluation (indocyanine green group) and 688 patients who did not undergo lymphatic flow evaluation (non-indocyanine green group). MAIN OUTCOMES MEASURES: The 3-year relapse-free survival after laparoscopic right-sided colectomy with and without indocyanine green fluorescence imaging were compared. RESULTS: After propensity score matching, 231 patients were matched in each group. The numbers of dissected central lymph nodes (6 vs 4, p < 0.001), intermediate lymph nodes (7 vs 6, p = 0.03), and the total number of dissected lymph nodes (31 vs 27, p = 0.047) were significantly higher in the indocyanine green group. The median follow-up was 36.9 months. The estimated respective 3-year relapse-free survival and overall survival rates were 88.8% and 94.5% in the indocyanine green group and 89.4% and 94.7% in the non-indocyanine green group ( p = 0.721 and 0.300), respectively, with no difference between the 2 groups. LIMITATIONS: Retrospective design of the study. CONCLUSIONS: Indocyanine green fluorescence imaging-guided laparoscopic right-sided colectomy could increase the number of total, intermediate, and central lymph nodes. However, there was no difference in mid-term outcomes. See Video Abstract. RESULTADOS A CORTO Y MEDIO PLAZO DE LA COLECTOMA LAPAROSCPICA DEL LADO DERECHO GUIADA POR IMGENES DE FLUORESCENCIA CON VERDE DE INDOCIANINA UN ESTUDIO DE COHORTE EMPAREJADO POR PUNTAJE DE PROPENSIN: ANTECEDENTES:Con el uso de imágenes de fluorescencia verde de indocianina, es posible la evaluación del flujo linfático intraoperatorio. Sin embargo, no hay ningún reporte que indique los resultados a medio plazo de la colectomía laparoscópica del lado derecho guiada por imágenes de fluorescencia con verde de indocianina.OBJETIVO:Examinar los resultados a mediano plazo de la colectomía laparoscópica del lado derecho guiada por imágenes de fluorescencia con verde de indocianina.DISEÑO:Estudio multiinstitucional retrospectivo con emparejamiento de puntuación de propensión.CONFIGURACIÓN:Realizado en el marco del Grupo de Oncología Clínica de Yokohama en Japón.PACIENTES:Un total de 921 pacientes sometidos a colectomía laparoscópica del lado derecho con disección de ganglios linfáticos por cáncer de colon con estadio clínico I a III entre enero de 2009 y diciembre de 2020. Los pacientes se dividieron en dos grupos: 233 pacientes sometidos a la evaluación del flujo linfático (grupo con verde de indocianina) y 688 pacientes que no sometidos a la evaluación del flujo linfático (grupo sin verde de indocianina).PRINCIPALES MEDIDAS DE RESULTADOS:Se comparó la supervivencia libre de recaídas a los 3 años después de la colectomía laparoscópica del lado derecho con y sin imágenes de fluorescencia con verde de indocianina.RESULTADOS:Después de emparejar el puntaje de propensión, 231 pacientes fueron emparejados en cada grupo. El número de ganglios linfáticos centrales disecados (6 frente a 4, p < 0,001) y de ganglios linfáticos intermedios (7 frente a 6, p = 0,03) y el número total de ganglios linfáticos disecados (31 frente a 27, p = 0,047) fueron significativamente mayor en el grupo verde de indocianina. La mediana de seguimiento fue de 36,9 meses. Las tasas respectivas estimadas de supervivencia libre de recaídas y supervivencia general a los 3 años fueron del 88,8 % y el 94,5 % en el grupo con verde de indocianina y del 89,4 % y el 94,7 % en el grupo sin verde de indocianina ( p = 0,721 y 0,300), sin diferencias entre los dos grupos.LIMITACIONES:Estudio de diseño retrospectivo.CONCLUSIONES:La colectomía laparoscópica del lado derecho guiada por imágenes de fluorescencia con verde de indocianina puede aumentar el número de ganglios linfáticos totales, intermedios y centrales. Sin embargo, no hubo diferencias en los resultados a medio plazo. (Traducción-Dr. Fidel Ruiz Healy ).

Exploratory randomized phase II trial for optimizing treatment dosage and duration of adjuvant S-1 plus oxaliplatin in patients with stage III colon cancer: YCOG1402 (SOAP trial).

Introduction: Conventionally, the recommended duration of adjuvant chemotherapy of colon cancer had been 6 months. The IDEA Collaboration suggested that shortening capecitabin and oxaliplatin (CAPOX) adjuvant chemotherapy may be possible. S-1 and oxaliplatin (SOX) treatment is standard treatment in metastatic colorectal cancer in Japan. The aim of this study was to optimize treatment dosage and duration of adjuvant SOX in stage III colon cancer. Methods: This trial was as open-label multi-center randomized phase II study. Patients with stage III colon cancer were randomly assigned to 3 months or 6 months of adjuvant SOX treatment in different doses: 130 mg/m2 (3 months) or 100 mg/m2 (6 months) of oxaliplatin. The primary endpoint was 3-year disease-free survival (DFS) and the null hypothesis for the primary endpoint was that the 3-year DFS was ≤72% in each arm and was tested with a one-sided significance level of 10%. Results: Eighty-two patients were assigned to the 6 months arm and 81 to the 3 months arm. The 3-year DFS was 75.0% (80% CI 67.95-80.72, p = 0.282) in the 6 months arm and 76.9% (80% CI 70.1-82.38, p = 0.171) in the 3 months arm. Treatment completion rate and relative dose intensity (RDI) were higher in 3 months than 6 months arm. The adverse events (AE) were similar in both arms. Conclusions: The 3-year DFS was not significantly superior to null hypothesis in both 3 months and 6 months arms for the stage III colon cancer. Primary endpoint was not achieved. The SOX regimen was not feasible in long-term outcomes.

Elucidating colorectal cancer-associated bacteria through profiling of minimally perturbed tissue-associated microbiota.

Sequencing-based interrogation of gut microbiota is a valuable approach for detecting microbes associated with colorectal cancer (CRC); however, such studies are often confounded by the effect of bowel preparation. In this study, we evaluated the viability of identifying CRC-associated mucosal bacteria through centimeter-scale profiling of the microbiota in tumors and adjacent noncancerous tissue from eleven patients who underwent colonic resection without preoperative bowel preparation. High-throughput 16S rRNA gene sequencing revealed that differences between on- and off-tumor microbiota varied considerably among patients. For some patients, phylotypes affiliated with genera previously implicated in colorectal carcinogenesis, as well as genera with less well-understood roles in CRC, were enriched in tumor tissue, whereas for other patients, on- and off-tumor microbiota were very similar. Notably, the enrichment of phylotypes in tumor-associated mucosa was highly localized and no longer apparent even a few centimeters away from the tumor. Through short-term liquid culturing and metagenomics, we further generated more than one-hundred metagenome-assembled genomes, several representing bacteria that were enriched in on-tumor samples. This is one of the first studies to analyze largely unperturbed mucosal microbiota in tissue samples from the resected colons of unprepped CRC patients. Future studies with larger cohorts are expected to clarify the causes and consequences of the observed variability in the emergence of tumor-localized microbiota among patients.

Optimal bowel resection margin in colon cancer surgery: prospective multicentre cohort study with lymph node and feeding artery mapping.

Background: There are no standardised criteria for the 'regional' pericolic node in colon cancer, which represents a major cause of the international uncertainty regarding the optimal bowel resection margin. This study aimed to determine 'regional' pericolic nodes based on prospective lymph node (LN) mapping. Methods: According to preplanned in vivo measurements of the bowel, the anatomical distributions of the feeding artery and LNs were determined in 2996 stages I-III colon cancer patients who underwent colectomy with resection margin >10 cm at 25 institutions in Japan. Findings: The mean number of retrieved pericolic nodes was 20.9 (standard deviation, 10.8) per patient. In all patients except seven (0.2%), the primary feeding artery was distributed within 10 cm of the primary tumour. The metastatic pericolic node most distant from the primary tumour was within 3 cm in 837 patients, 3-5 cm in 130 patients, 5-7 cm in 39 patients and 7-10 cm in 34 patients. Only four patients (0.1%) had pericolic lymphatic spread beyond 10 cm; all of whom had T3/4 tumours accompanying extensive mesenteric lymphatic spread. The location of metastatic pericolic node did not differ by the feeding artery's distribution. Postoperatively, none of the 2996 patients developed recurrence in the remaining pericolic nodes. Interpretation: The pericolic nodes designated as 'regional' were those located within 10 cm of the primary tumours, which should be fully considered when determining the bowel resection margin, even in the era of complete mesocolic excision. Funding: Japanese Society for Cancer of the Colon and Rectum.

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%.

Randomized controlled trial evaluating the effect of the use of a laparoscopic lens-cleaning device during laparoscopic colorectal surgery on the multidimensional workload (YCOG1903).

BACKGROUND: OpClear® is a newly developed laparoscopic lens-cleaning device that can be attached to a laparoscope. The present study determined whether or not the use of a OpClear® reduces the multidimensional surgery-specific workload of the operator during laparoscopic colorectal surgery for colorectal cancer compared with the reference technique (warm saline) by a randomized controlled trial. METHODS: Patients diagnosed with colorectal cancer and scheduled for laparoscopic colorectal surgery were randomly allocated to the warm saline arm or Opclear® arm. The primary endpoint was the multidimensional workload of the first operator (value of SURG-TLX). The secondary endpoints were the operative time and total number of lens washes outside the abdominal cavity. RESULTS: Between March 2020 and January 2021, a total of 120 patients were enrolled in this study. A total of 4 patients were excluded from the full analysis set. A total of 116 patients (warm saline arm: 59 patients, Opclear® arm: 57 patients) were therefore analyzed. The baseline factors were well-balanced between the two arms. Regarding SURG-TLX, there was no significant difference in the overall workload between the two arms. Operators in the Opclear® arm required significantly less physical demand than in the warm saline arm (Opclear® arm: 6, warm saline arm: 7; p = 0.046). The operative time was similar between the two arms. The total number of lens washes outside the abdominal cavity in the Opclear® arm was significantly lower than that in the warm saline arm (Opclear® arm: 2, warm saline arm: 10; p < 0.001). CONCLUSIONS: There was no significant difference in the overall workload, but the physical demand and total number of lens washes outside the abdominal cavity were significantly lower in the Opclear® arm than in the warm saline arm. The use of this device may thus help reduce operator stress in terms of physical demand. The study was registered with the Japanese Clinical Trials Registry as UMIN0000038677.

Curable leakage in stapled IPAA has little effect on the long-term pouch function.

PURPOSE: This study aimed to evaluate the frequency and grade of anastomotic leakage (AL) in stapled ileal pouch-anal anastomosis (IPAA) and its long-term impact on the pouch functions. METHODS: A longitudinal cohort study was conducted on UC patients who underwent stapled IPAA at Yokohama City University Medical Center between 2007 and 2018. The diagnosis and grading of AL were performed in accordance with the recommendations of the International Study Group of Rectal Cancer. We assessed the functional pouch rate, late complication, pouch survival rate, bowel function (bowel movements per day, soiling, spotting, difficulty in distinguishing feces from flatus) and pouch inflammation (pouchitis disease activity index; PDAI) in the long-term period. RESULTS: Two hundred seventy-six patients were analyzed. Twenty-three (8.3%; grade B/C; 13/10) patients were diagnosed with AL, but a functional pouch was achieved in all the twenty-three patients. Anastomotic stricture was significantly more common in patients with AL (AL group) than in patients without AL (non-AL group; AL/non-AL: 13.0/3.2%, p = 0.020). There were no differences in other late complications. Furthermore, the pouch survival rate did not differ between the AL and non-AL groups (100.0/97.9%/10 years, p = 0.494). There were no differences between the groups in bowel movements per day, spotting, soling, difficulty in distinguishing feces from flatus, or PDAI postoperatively. CONCLUSIONS: Curable AL may not affect late complications (except anastomotic stricture), pouch survival, the bowel function, or pouch inflammation over the long term. Perioperative management to prevent the severity of AL is as important as preventing its occurrence.

Inflammatory bowel disease-specific findings are common morphological changes in the ileal pouch with ulcerative colitis.

Why inflammation is common in ileal pouches with ulcerative colitis (UC) is unclear. We therefore clarified the morphological changes in pouches and afferent limbs (AL) of patients with UC and explored the relationship between these findings. We evaluated the morphological findings (histological and endoscopic inflammation as the Pouchitis Disease Activity Index [PDAI] histology subscore [hPDAI] and endoscopy subscore [ePDAI], inflammatory bowel disease [IBD]-specific findings using the IBD score [SIBD], colonic metaplasia using the colonic metaplasia score [CMS], and goblet cell [GC] ratio) in the pouch and AL of patients with UC. A total of 261 pouchoscopies were analyzed. The pouch body had a higher hPDAI (p < 0.001), SIBD (p < 0.001), CMS (p < 0.001), GC ratio (p < 0.001), and ePDAI (p < 0.001) than the AL. The hPDAI was correlated with the SIBD (Spearman's coefficient r = 0.538; p < 0.001), CMS (r = 0.687; p < 0.001), and the ePDAI (r = 0.552; p < 0.001), but not with GC ratio (r = 0.175; p < 0.001) or the pouch usage duration (r = -0.057; p = 0.107). The incidence of histological inflammation was higher in specimens showing basal plasmacytosis with severe mononuclear cell infiltration (BP) than in those without BP (odds ratio [OR] 6.790, p < 0.001), BP was commonly found with crypt hyperplasia (OR 3.414, p < 0.001) and the crypt length correlated with neutrophil infiltration (r = 0.469; p < 0.001). Histological inflammation, colonic metaplasia, the GC ratio, endoscopic inflammation, and IBD-specific findings were commonly present in the pouch than in the AL. Histological inflammation occurs with IBD-specific findings and colonic metaplasia, and these signify endoscopic inflammation.

Safety, efficacy, and operability of a newly developed absorbable adhesion barrier (GM142) in patients with primary rectal cancer scheduled for diverting ileostomy during laparoscopic surgery: Randomized controlled trial.

Aim: The aim of this study was to compare the outcomes of GM142, a newly developed gelatin film with a concave and convex structure to a commercially available conventional film, hyaluronate-carboxymethylcellulose. Methods: Patients with primary rectal cancer who were scheduled for diverting ileostomy during laparoscopic surgery were eligible for this study. Patients were randomized before surgery and an antiadhesion film was applied under the umbilical incision. The primary outcome was the incidence of adhesion under the midline incision confirmed by second-look surgery for diverting ileostomy closure. The secondary outcomes were the adhesion severity score, the extent of adhesion score, the presence of intestinal obstruction, and the success of all patching. Results: A total of 146 patients were enrolled. A total of 123 patients were included in the full analysis set. The primary outcome of "no adhesion" was observed in 66.1% in the GM142 group and 55.7% in the conventional film group. The noninferiority of GM142 to conventional film was confirmed (P = .0005). The secondary outcomes were similar between the groups. For the safety evaluation, there were no safety concerns regarding allergic reactions to gelatin or increased gelatin-specific IgE antibody titers. Conclusions: The noninferiority of GM142 to conventional film was shown. GM142 showed no major safety issues. The clinical safety profiles of GM142 suggested certain physiological benefits of the gelatin film as an adhesion barrier.

Intratumoral density of regulatory T cells is a predictor of host immune response and chemotherapy response in colorectal cancer.

Regulatory T cells (Tregs) are a subset of CD4+ T lymphocytes known to dampen the host immune response against cancer cells. Within the tumor microenvironment, Tregs are potent facilitators of immune tolerance, and a higher proportion of Tregs compared to cytotoxic T cells predicts a worse outcome in most solid tumors. We studied the association between Treg density, and cancer biology and clinical outcome in colorectal cancer (CRC). We used xCell to estimate intratumoral Tregs in total of 898 CRC patients in the Cancer Genome Atlas (TCGA) and GCE39582 cohorts. High-Treg CRCs enriched immune response-related gene sets; inflammatory response, IFN-γ and IFN-α response, IL2/IL6 signaling, and allograft rejection, and had significantly high infiltration of CD8, CD4, M1 and M2 macrophage, and dendritic cells in both cohorts. While high-Treg CRCs enriched multiple pro-cancer signaling pathways compared to low-Treg CRCs, such as Epithelial Mesenchymal Transition, K-ras, Hypoxia, TGF-ß, TNF-α, and angiogenesis, Treg infiltration was surprisingly associated with earlier CRC stage in TCGA. Notably, in two separate cohorts a higher proportion of Tregs predicted an improved response to chemotherapy. In the GSE28702 cohort, metastatic CRCs with more Tregs showed a significantly better response to mFOLFOX6 versus low-Treg CRC metastases (88.9% response vs. 16.7%, P<0.001). In the GSE72970 cohort, high-Treg CRCs were found to have a 68.8% response to FOLFOX/FOLFIRI without bevacizumab, compared to 44% response in the low-Treg CRCs. Additionally, high-Treg CRCs were associated with increased expression of immune checkpoint molecules PD-L1/PD-L2, CTLA4, TIGIT and BTLA, implying susceptibility to immunotherapy. We also found that CRCs with higher proportions of Tregs were associated with lower amounts of three microorganisms in the tumor: Lachnoclostridium, flavivirus, and Ornithobacterium. In conclusion, we show that amount of Treg in the tumor is a predictor of host immune response and chemotherapy response in CRC.

The prognostic significance of apical lymph node metastasis in patients with high-risk stage III colon cancer.

The effect of apical lymph node (APN) metastasis on the prognosis of colon cancer is unknown. The present study investigated the impact of APN metastasis on the prognosis of the patients with high-risk stage III colon cancer. This retrospective multi-institutional study included patients with pathological high-risk stage III colon cancer who underwent surgery between April 2009 and December 2014. Clinicopathological factors were examined by univariate and multivariate analyses to clarify independent risk factors for overall survival (OS) and relapse-free survival (RFS). A total of 185 patients were collected. The 5-year OS rates of patients with and without APN metastasis were 35.0% and 72.1%, respectively (p = 0.0014). The 5-year RFS rates of patients with and without APN metastasis was 16.2% and 57.2%, respectively (p = 0.0002). The rate of distant metastasis in patients with APN metastasis was significantly higher than that in patients without APN metastasis (68.8% vs. 36.7%, p = 0.012). The univariate analysis revealed that the differentiation, lymph node ratio, and APN metastasis were significantly associated with 5-year OS, and the preoperative CEA and CA19-9 levels and APN metastasis were significantly associated with 5-year RFS. The multivariate analysis showed that APN metastasis was an independent risk factor for 5-year OS and RFS. APN metastasis may be independently associated with the prognosis of patients with high-risk Stage III colon cancer.

A Prospective, Single-arm, Multicenter Trial of Diverting Stoma Followed by Neoadjuvant Chemotherapy Using mFOLFOX6 for Obstructive Colon Cancer: YCOG 1305 (PROBE Study).

OBJECTIVE: We conducted the first prospective clinical trial of neoadjuvant chemotherapy for patients with obstructive colon cancer. BACKGROUND: Obstructive colorectal cancer is locally advanced colorectal cancer with a poor prognosis. The effect of neoadjuvant chemotherapy for obstructive colon cancer is unclear. METHODS: We conducted a single arm, multicenter trial involving patients from the Yokohama Clinical Oncology Group with obstructive colon cancer. All eligible patients underwent diverting stoma formation before neoadjuvant chemotherapy. Patient received 6 cycles of mFOLFOX6 followed by primary tumor surgery and then 6 cycles of adjuvant chemotherapy. The primary endpoint was the objective response rate of all intended neoadjuvant therapy. The study was registered with the Japanese Clinical Trials Registry as UMIN000013198. RESULTS: Between April 2014, and July 2016, 50 patients were registered, and 46 received neoadjuvant chemotherapy. The objective response rate as the primary endpoint was 67.4%. The most common grade >3 adverse event associated with neoadjuvant chemotherapy was neutropenia (28.3%). Forty-five patients underwent surgical resection of the primary lesion (R0 resection in all cases). Grade >2 surgery-related complications occurred in 7 patients (15.6%). The downstaging rate was 48.9%, and the moderate or greater regression rate was 52.2%; no cases showed pathological complete response. Adjuvant chemotherapy with mFOLFOX6 was performed in 34 patients (75.6%). The 3-year relapse-free and overall survival rates were 76.5% and 95.4%, respectively. CONCLUSION: Neoadjuvant chemotherapy using mFOLFOX6 was feasible and might be a treatment option for patients with obstructive colon cancer. Further large-scale studies are warranted to confirm the present findings.

Pathological Changes in the Lymphatic System of Patients with Secondary Lower Limb Lymphedema Based on Single Photon-Emission Computed Tomography/Computed Tomography/Lymphoscintigraphy Images.

Background: In patients with secondary upper limb lymphedema, positive correlations have been observed between the dermal back flow (DBF) type and visualization of lymph nodes around the clavicle, between the former and the lymph flow pathway type, and between the latter and the visualization of lymph nodes around the clavicle when using single photon-emission computed tomography/computed tomography/lymphoscintigraphy (SPECT-CT LSG). Methods and Results: We analyzed the associations between the visualization of inguinal lymph nodes, the lymph flow pathway type, and the DBF type using SPECT-CT LSG in 81 patients with unilateral secondary lower limb lymphedema by statistical analysis using Fisher's exact test. We revealed that the lymph flow pathways in the lower limb can be classified into nine types because the type in the lower leg is not always equal to the type in the thigh. Associations were observed between the visualization of inguinal lymph nodes and types of DBF (p < 0.01), between the types of lymph flow pathway in the thighs and visualization of the inguinal lymph nodes (p = 0.02), and between the lymph flow pathway types in the thighs and lower legs (p < 0.01). Conclusion: Detriment to the superficial lymph flow pathways in the lower limb appears to usually start from the proximal side, and deep pathways are considered to become dominant from a compensatory perspective as lymphedema severity increases.

Preoperative risk factors of incisional surgical site infection in severe or intractable ulcerative colitis.

PURPOSE: The present study explored preoperative risk factors (predictors) of incisional surgical site infection (I-SSI) in severe or intractable ulcerative colitis (UC). METHODS: This was a retrospective study of 230 consecutive patients who underwent primary surgery for UC. Patients whose surgical indications were UC with cancer or dysplasia were excluded. SSI was defined as an infection according to the Centers for Disease Control and Prevention Guidelines. Preoperative variables were examined by univariate, receiver operating characteristic curve, and multivariate analyses. RESULTS: We analyzed 208 patients in this study. In a multivariate logistic analysis, C-reactive protein (CRP) ≥ 1.7 mg/dl [odds ratio (OR) 5.35; 95% confidence interval (CI) 1.50-19.06; p = 0.01), albumin ≤ 2.4 g/dl (OR 5.77; 95% CI 1.41-23.57; p = 0.02), and preoperative blood transfusion (OR 3.21; 95% CI 1.04-9.96; p = 0.04) were predictors of I-SSI. Patients with all predictors had a more than 50% incidence of I-SSI, a higher incidence of all severe complications (13.6% vs. 3.2%; p = 0.02), and a longer postoperative hospital stay (19.5 vs. 17.0 days, p = 0.04) than the other patients. CONCLUSIONS: CRP ≥ 1.7 mg/dl, albumin ≤ 2.4 g/dl, and transfusion are predictors of I-SSI in severe or intractable UC. Clinician should carefully evaluate the surgical options before these predictors appear.

Relationship between stromal regulatory T cells and the response to neoadjuvant chemotherapy for locally advanced rectal cancer.

BACKGROUND: In addition to the direct power of anticancer drugs, the effectiveness of anticancer therapy depends on the host immune function. The present study investigated whether or not the reduction rate and histological response of preoperative chemotherapy were related to the immune microenvironment surrounding a primary tumor of the rectum. METHODS: Sixty-five patients received preoperative chemotherapy followed by resection from 2012 to 2014; all of these patients were retrospectively analyzed. CD3, CD8, and FoxP3 were immunohistochemically examined as markers for T lymphocytes, cytotoxic T lymphocytes, and regulatory T lymphocytes (Treg), respectively. The correlation between the tumor-infiltrating lymphocyte composition and the tumor reduction rate and histological response to neoadjuvant chemotherapy was investigated. RESULTS: The average tumor reduction rate was 41.5% ± 18.8%. According to RECIST, 47 patients (72.3%) achieved a partial response (PR), and 1 patient (1.5%) achieved a complete response (CR). Eight patients (12.3%) showed a grade 2 histological response, and 2 (3.1%) showed a grade 3 response. A multivariate analysis demonstrated that a low Treg infiltration in stromal cell areas was significantly associated with the achievement of a PR or CR [odds ratio (OR) 7.69; 95% confidence interval (CI) 1.96-33.33; p < 0.01] and a histological grade 2 or 3 response (OR 11.11; 95% CI 1.37-98.04; p = 0.02). CONCLUSION: A low Treg infiltration in the stromal cell areas may be a marker of a good response to neoadjuvant chemotherapy in patients with locally advanced rectal cancer.