Clinicopathological features and prognosis of primary small bowel adenocarcinoma: a large multicenter analysis of the JSCCR database in Japan.

BACKGROUND: The clinicopathological features and prognosis of primary small bowel adenocarcinoma (PSBA), excluding duodenal cancer, remain undetermined due to its rarity in Japan. METHODS: We analyzed 354 patients with 358 PSBAs, between January 2008 and December 2017, at 44 institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum. RESULTS: The median age was 67 years (218 males, 61.6%). The average tumor size was 49.9 (7-100) mm. PSBA sites consisted of jejunum (66.2%) and ileum (30.4%). A total of 219 patients (61.9%) underwent diagnostic small bowel endoscopy, including single-balloon endoscopy, double-balloon endoscopy, and capsule endoscopy before treatment. Nineteen patients (5.4%) had Lynch syndrome, and 272 patients (76.8%) had symptoms at the initial diagnosis. The rates for stages 0, I, II, III, and IV were 5.4%, 2.5%, 27.1%, 26.0%, and 35.6%, respectively. The 5-year overall survival rates at each stage were 92.3%, 60.0%, 75.9%, 61.4%, and 25.5%, respectively, and the 5-year disease-specific survival (DSS) rates were 100%, 75.0%, 84.1%, 59.3%, and 25.6%, respectively. Patients with the PSBA located in the jejunum, with symptoms at the initial diagnosis or advanced clinical stage had a worse prognosis. However, multivariate analysis using Cox-hazard model revealed that clinical stage was the only significant predictor of DSS for patients with PSBA. CONCLUSIONS: Of the patients with PSBA, 76.8% had symptoms at the initial diagnosis, which were often detected at an advanced stage. Detection during the early stages of PSBA is important to ensure a good prognosis.

Outcomes of Metastatic and Unresectable Small Bowel Adenocarcinoma in Japan According to the Treatment Strategy: A Nationwide Observational Study.

PURPOSE: Limited information is available regarding the characteristics and outcomes of stage IV small bowel adenocarcinoma (SBA) in Japan. This study examined the clinical and pathological characteristics and outcomes according to the treatment strategies in patients with stage IV SBA. METHODS: This retrospective observational study used the data of patients with jejunal or ileal adenocarcinoma collected by the Small Bowel Malignant Tumor Project of the Japanese Society for Cancer of the Colon and Rectum. Descriptive statistics were expressed as the mean (standard deviation) or median (range). Survival analysis was performed using Kaplan-Meier curves and pairwise log-rank tests. RESULTS: Data from 128 patients were analyzed. The treatment strategies were chemotherapy alone (26 of 128, 20.3%), surgery alone (including palliative surgery; 21 of 128, 16.4%), surgery + chemotherapy (74 of 128, 57.8%), and best supportive care (7 of 128, 5.5%). The median (range) overall survival was 16 (0-125) months overall, and 11 (1-38) months, 8 (0-80) months, 18 (0-125) months, and 0 (0-1) months for the chemotherapy, surgery, surgery + chemotherapy, and best supportive care groups, respectively. Three main categories of chemotherapeutic regimen were used: a combination of fluoropyrimidine and oxaliplatin (F + Ox), fluoropyrimidine and irinotecan (F + Iri), and single-agent fluoropyrimidine. Among patients treated with chemotherapy, the median (range) OS was 16 (1-106) months overall, and 17 (1-87) months, 29 (7-39) months, and 16 (1-106) months in patients treated with fluoropyrimidine, F + Iri, and F + Ox, respectively. CONCLUSION: Patients treated with surgery, chemotherapy, or both had a better prognosis than those who received best supportive care. Among patients who received chemotherapy, survival did not differ according to the chemotherapeutic regimen.

Prognostic factors of para-aortic lymph node metastasis from colorectal cancer in highly selected patients undergoing para-aortic lymph node dissection.

PURPOSE: We investigated the surgical outcomes of para-aortic lymph node (PALN) dissection in patients with colorectal cancer and assessed the prognostic factors related to the survival. METHODS: This single-center retrospective study included 31 patients with synchronous or metachronous PALN metastasis from colorectal cancer who underwent PALN dissection between January 2006 and December 2018. RESULTS: Twenty-one patients had synchronous PALN metastasis, and 10 had metachronous PALN metastasis. Seven patients had either simultaneous distant metastasis or a history of distant metastasis other than PALN metastasis at the time of PALN dissection. Eighteen patients underwent adjuvant chemotherapy. The 5-year overall and recurrence-free survival rates were 54.2 and 17.2%, respectively. A multivariable analysis revealed that rectal cancer, metachronous PALN metastasis, and three or more pathological PALN metastases were significantly poor prognostic factors for the recurrence-free survival. Among patients with rectal cancer, lower rectal cancer and lateral pelvic lymph node metastasis were poor prognostic factors for the overall survival. CONCLUSION: Curative PALN dissection for PALN metastasis from colorectal cancer is feasible with favorable long-term outcomes. A multidisciplinary approach, including surgery and chemotherapy, is needed for colorectal cancer with PALN metastasis to improve the long-term outcomes.

Negative impact of behavior restriction amidst a clustered COVID-19 infection on immobility syndrome in older patients negative for COVID-19: report from a chronic care hospital in Japan.

Previous studies have reported on associations between immobility syndrome and the COVID-19 pandemic. However, little is known about the aggravation of this syndrome in older patients negative for COVID-19 infection amidst behavior restriction due to a clustered COVID-19 infection. Patients hospitalized one month before a clustered COVID-19 infection occurred in our hospital were recruited. Rehabilitation therapy was suspended for 25 days during behavior restriction. The ability of daily living of the patients was evaluated with the functional independence measure and Barthel index. Chronological changes in the functional independence measure and Barthel index scores were evaluated monthly, beginning one month before the clustered COVID-19 infection to one month after re-initiation of rehabilitation therapy. Patients with minimum scores in the functional independence measure (18) and Barthel index (0) prior to the clustered COVID-19 infection were excluded. Functional independence measure scores of 73 older patients and the Barthel index scores of 48 patients were analyzed. The mean total functional independence measure score amidst the behavior restriction significantly changed from 36.3 to 35.1 (p = 0.019), while statistical significance was not detected in the mean motor subtotal (from 21.6 to 20.9 with p = 0.247) or cognitive subtotal functional independence measure scores (from 14.6 to 14.2 with p = 0.478). During the behavior restriction, the mean Barthel index scores declined from 25.8 to 23.2 without statistical significance (p = 0.059). Behavior restriction due to a clustered COVID-19 infection may aggravate immobility syndrome in older patients who are negative for COVID-19.

Correction to: Clinical Impact of Inferior Mesenteric Lymph Node Metastasis in Patients with Cancer of the Sigmoid Colon or Rectum.

[This corrects the article DOI: 10.1007/s13193-021-01389-3.].

Non-operative management after chemoradiotherapy plus consolidation or sandwich (induction with bevacizumab and consolidation) chemotherapy in patients with locally advanced rectal cancer: a multicentre, randomised phase II trial (NOMINATE trial).

INTRODUCTION: Total mesorectal excision (TME) and postoperative adjuvant chemotherapy following neoadjuvant chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer (LARC). However, neoadjuvant CRT has no recognised impact on reducing distant recurrence, and patients suffer from a long-lasting impairment in quality of life (QOL) associated with TME. Total neoadjuvant therapy (TNT) is an alternative approach that could reduce distant metastases and increase the proportion of patients who could safely undergo non-operative management (NOM). This study is designed to compare two TNT regimens in the context of NOM for selecting a more optimal regimen for patients with LARC. METHODS AND ANALYSIS: NOMINATE trial is a prospective, multicentre, randomised phase II selection design study. Patients must have clinical stage II or III (T3-T4Nany) LARC with distal location (≤5 cm from the anal verge or for those who are candidates for abdominoperineal resection or intersphincteric resection). Patients will be randomised to either arm A consisting of CRT (50.4 Gy with capecitabine) followed by consolidation chemotherapy (six cycles of CapeOx), or arm B consisting of induction chemotherapy (three cycles of CapeOx plus bevacizumab) followed by CRT and consolidation chemotherapy (three cycles of CapeOx). In the case of clinical complete response (cCR) or near cCR, patients will progress to NOM. Response assessment involves a combination of digital rectal examination, endoscopy and MRI. The primary endpoint is the proportion of patients achieving pathological CR or cCR≥2 years, defined as the absence of local regrowth within 2 years after the start of NOM among eligible patients. Secondary endpoints include the cCR rate, near cCR rate, rate of NOM, overall survival, distant metastasis-free survival, locoregional failure-free survival, time to disease-related treatment failure, TME-free survival, permanent stoma-free survival, safety of the treatment, completion rate of the treatment and QOL. Allowing for a drop-out rate of 10%, 66 patients (33 per arm) from five institutions will be accrued. ETHICS AND DISSEMINATION: The study protocol was approved by Wakayama Medical University Certified Review Board in December 2020. Trial results will be published in peer-reviewed international journals and on the jRCT website. TRIAL REGISTRATION NUMBER: jRCTs051200121.

Characteristics of anal canal cancer in Japan.

Anal canal cancer (ACC) has been reported to be an uncommon cancer in Japan, as in the USA, Europe, and Australia. This retrospective multi-institutional study was conducted to clarify the characteristics of ACC in Japan. First, the histological ACC type cases treated between 1991 and 2015 were collected. A detailed analysis of the characteristics of anal canal squamous cell carcinoma (SCC) cases was then conducted. The results of the histological types revealed that of the 1781 ACC cases, 435 cases (24.4%) including seven cases of adenosquamous cell carcinomas were SCC and 1260 cases (70.7%) were adenocarcinoma. However, the most common histological type reported in the USA, Europe, and Australia is SCC. Most ACC cases are adenocarcinomas and there is a low incidence of SCC in Japan which is different from the above-mentioned countries. Moreover, we reclassified T4 into the following two groups based on tumor size: T4a (tumor diameter of 5 cm or less) and T4b (tumor diameter of more than 5 cm). The results of the TNM classification of SCC revealed that the hazard ratio (HR) to T1 of T2, T3, T4a, and T4b was 2.45, 2.28, 2.89, and 4.97, respectively. As T4b cases had a worse prognosis than T4a cases, we propose that T4 for anal canal SCC in Japan be subclassified into T4a and T4b.

Lymph Node Mapping in Transverse Colon Cancer Treated Using Laparoscopic Colectomy With D3 Lymph Node Dissection.

BACKGROUND: Laparoscopic surgery for transverse colon cancer has been excluded from 7 randomized trials for various reasons. The optimal procedure for transverse colon cancer remains controversial. OBJECTIVE: This study aimed to analyze the patterns of lymph node metastasis in transverse colon cancer and to report short- and long-term outcomes of the treatment procedures. DESIGN: This was a single-center retrospective study. SETTINGS: This study was conducted at Cancer Institute Hospital, Tokyo, Japan. PATIENTS: We enrolled 252 patients who underwent laparoscopic surgery for transverse colon cancer. INTERVENTIONS: The transverse colon was divided into 3 segments, and the procedures for transverse colon cancer were based on these segments, as follows: right hemicolectomy, transverse colectomy, and left hemicolectomy. MAIN OUTCOME MEASURES: Postoperatively, the surgeons identified and mapped the lymph nodes from specimens and performed formalin fixation separately to compare the results of the pathological findings. RESULTS: For right-sided, middle-segment, and left-sided transverse colon cancers, the frequency of lymph node metastases was 28.2%, 19.2%, and 19.2%. Skipped lymph node metastasis occurred in right-sided and left-sided transverse colon cancers but not in middle-segment transverse colon cancers. The pathological vascular invasion rate was significantly higher in right and left hemicolectomy than in transverse colectomy. For right hemicolectomy, transverse colectomy, and left hemicolectomy, 5-year overall survival rates were 96.3%, 92.7%, and 93.7%, and relapse-free survival rates were 92.4%, 88.3%, and 95.5%. In multivariate analysis, the independent risk factor for relapse-free survival was lymph node metastasis. LIMITATIONS: Selection bias and different backgrounds may have influenced surgical and long-term outcomes. CONCLUSION: Laparoscopic surgery for transverse colon cancer may be a feasible technique. Harvested lymph node mapping after laparoscopic resection based on D3 lymphadenectomy may help guide the field of dissection when managing patients who have transverse colon cancer. The only independent prognostic factor for relapse-free survival was node-positive cancer. See Video Abstract at http://links.lww.com/DCR/B706.MAPEO DE GANGLIOS LINFÁTICOS EN CÁNCER DE COLON TRANSVERSO TRATADO MEDIANTE COLECTOMÍA LAPAROSCÓPICA CON LINFADENECTOMÍA D3ANTECEDENTES:La cirugía laparoscópica en casos de cáncer de colon transverso fué excluida de siete estudios randomizados mayores por diversas razones. El procedimiento más idóneo en casos de cáncer de colon transverso, sigue siendo controvertido.OBJETIVO:Analizar los patrones de las metástasis en los ganglios linfáticos en casos de cáncer de colon transverso y reportar los resultados a corto y largo plazo de los diferentes procedimientos para su tratamiento.DISEÑO:Estudio retrospectivo en un solo centro de referencia.AJUSTE:Estudio llevado a cabo en el Hospital del Instituto del Cancer, Tokio, Japón.PACIENTES:Fueron incluidos 252 pacientes, sometidos a cirugía laparoscópica por cáncer de colon transverso.INTERVENCIONES:El colon transverso fué dividido en tres segmentos y los procedimientos en casos de cáncer se basaron sobre estos segmentos del tranverso, de la siguiente manera: hemicolectomía derecha, colectomía transversa y hemicolectomía izquierda.PRINCIPALES MEDIDAS DE RESULTADO:En el postoperatorio, los cirujanos identificaron y mapearon los ganglios linfáticos de las piezas quirúrgicas y las fijaron con formaldehido por separado para así poder comparar los resultados con los hallazgos histopatológicos.RESULTADOS:En los cánceres de colon transverso del segmento derecho, del segmento medio y del segmento izquierdo, la frecuencia de metástasis en los ganglios linfáticos fue del 28,2%, 19,2% y 19,2%, respectivamente. Las metástasis en los ganglios linfáticos omitidos se produjo en los cánceres de colon transverso del lado derecho y del lado izquierdo, pero no en los cánceres de colon transverso del segmento medio. La tasa de invasión vascular patológica fue significativamente mayor en la hemicolectomía derecha e izquierda que en la colectomía transversa. Para la hemicolectomía derecha, colectomía transversa y hemicolectomía izquierda, las tasas de supervivencia general a cinco años fueron del 96,3%, 92,7% y 93,7%, y las tasas de supervivencia sin recaída fueron del 92,4%, 88,3% y 95,5%, respectivamente. En el análisis multivariado, el factor de riesgo independiente para la sobrevida sin recidiva fue la metástasis en los ganglios linfáticos.LIMITACIONES:El sesgo de selección y los diferentes antecedentes pueden haber influido en los resultados quirúrgicos a largo plazo.CONCLUSIONES:La cirugía laparoscópica en casos de cáncer de colon transverso puede ser una técnica factible. El mapeo de los ganglios linfáticos recolectados después de la resección laparoscópica basada en la linfadenectomía D3 puede ayudar a guiar el campo de la disección en el manejo de pacientes con cáncer de colon transverso. El único factor pronóstico independiente para el SLR fue el cáncer con ganglios positivos. Consulte Video Resumen en http://links.lww.com/DCR/B706. (Traducción-Dr. Xavier Delgadillo).

Decision-making in postoperative chemotherapy for ovarian metastasis from colorectal cancer: a retrospective single-center study.

BACKGROUND: Ovarian metastases from colorectal cancer are relatively uncommon, and no consensus has been reached regarding resection of metastases or chemotherapy before and after surgery. We evaluated the clinicopathological characteristics of ovarian metastases from colorectal cancer and the impact of metastatic resection. We also performed a comparative analysis to clarify the prognostic impact of metastatic resection and the choice of chemotherapy before and after surgery. METHODS: Between 2006 and 2014, 38 patients at our institution underwent resection of ovarian metastases from colorectal cancer. Clinicopathological data were extracted from the patients' records and evaluated with respect to the long-term outcome. For 15 patients with metachronous ovarian metastases who received chemotherapy until immediately before resection, we compared the prognosis with and without changes in the regimen after resection. RESULTS: The 5-year overall survival rate was 19.9%, and the median survival duration was 27.2 months. The survival rate in the R0 resection group (n = 8) was significantly better than that in the R1/2 resection group (n = 30) (P = 0.0004). Patients without peritoneal dissemination (n = 15) or extra-ovarian metastases (n = 31) had a significantly better prognosis than those with peritoneal dissemination (n = 23) or extra-ovarian metastases (n = 7) (P = 0.040 and P = 0.0005, respectively). The progression-free survival and median survival times of patients who resumed chemotherapy after resection without a change in their preoperative regimen were 10.2 months and 26.2 months, respectively, while those among patients with a change in their regimen before resection versus after resection were 11.0 months and 18.1 months, respectively. The difference between the two groups was not statistically significant (progression-free survival time and median survival time: P = 0.52 and P = 0.48, respectively). CONCLUSIONS: Patients who underwent R0 resection of ovarian metastases clearly had a better prognosis than those who underwent R1/2 resection. Additionally, a poor prognosis was associated with the presence of peritoneal dissemination and extra-ovarian metastases. The data also suggested that resumption of chemotherapy without changing the regimen after resection could preserve the next line of chemotherapy for future treatment and improve the prognosis.

Tumor-informed or tumor-agnostic circulating tumor DNA as a biomarker for risk of recurrence in resected colorectal cancer patients.

Introduction: Circulating tumor DNA (ctDNA) has been increasingly recognized as a promising minimally-invasive biomarker that could identify patients with minimal residual disease and a high risk of recurrence after definitive treatment. In this study, we've compared the clinical utility and sensitivity of 2 different approaches to ctDNA analyses: tumor-informed and tumor-agnostic in the management of colorectal (CRC) patients. The clinical benefits of a single timepoint ctDNA analysis compared to serial ctDNA monitoring after definitive treatment were also evaluated to uncover the ideal surveillance protocol. Methods: Patient-paired resected tumor tissues, peripheral blood cells, and a total of 127 pre-operative and serial plasma cell-free DNA (cfDNA) samples after definitive treatment from 38 CRC patients that had undergone curative intent surgery were analyzed using a commercial NGS cfDNA panel. Results: Up to 84% (32/38) of the recruited patients were detected with at least 1 genomic alteration from the tumor tissues that could be monitored using the tumor-informed ctDNA approach and none of the detected alterations were clonal hematopoiesis (CH) related. In contrast, 37% (14/38) of patients were detected with at least 1 monitoring alteration after exclusion of CH mutations using the tumor-agnostic approach. Serial plasma samples after definitive therapy were available for 31 patients. In the landmark ctDNA analysis, 24% (7/29) of patients had detectable ctDNA and were more likely to relapse than ctDNA-negative patients (p < 0.05). The landmark analysis sensitivity and specificity for recurrence were 67% and 87%, respectively. The incorporation of longitudinal ctDNA analysis at 6-months intervals improved the sensitivity to 100%. The median variant allele frequency (VAF) of the ctDNA mutations detected during surveillance was 0.028% (range: 0.018-0.783), where up to 80% (8/10) of the mutations were detected at VAF lower than the tumor-agnostic detection limit of 0.1%. Utilizing the tumor-agnostic approach reduced the recurrence detection sensitivity to 67% (4/6). Serial ctDNA analyses predicted disease recurrence at a median of 5 months ahead of radiological imaging. Conclusion: Longitudinal monitoring using tumor-informed ctDNA testing shows high analytical sensitivity, low probability of false-positive results due to CH mutations, and improved sensitivity in detecting recurrence which may modify the clinical management of CRC.

Short- and long-term outcomes of laparoscopic surgery with extracorporeal anastomosis for transverse colon cancer: comparison of triangulating anastomosis with functional end-to-end anastomosis.

BACKGROUND: We compared triangulating anastomosis (TRI) with functional end-to-end anastomosis (FEEA) in terms of patient demographics, clinicopathological features, and short- and long-term outcomes in this study. METHODS: From November 2005 to May 2016, 315 patients with transverse colon cancer underwent laparoscopic resection. TRI was performed in 62 patients and FEEA in 253 patients. Patients with another concomitant cancer, who received neoadjuvant chemotherapy, and/or who underwent another operation at the same time were excluded. RESULTS: The patients' backgrounds were comparable in each group. Transverse colectomy was selected more frequently in TRI and right hemicolectomy in FEEA. The operation time was shorter in TRI. The rate of anastomotic leakage was comparable (1.6% in TRI vs. 0.8% in FEEA). Stricture was more common in TRI (8.1% vs. 0%) and bleeding was more common in FEEA (1.6% vs. 10.6%). The rate of long-term complications was comparable in each group. Overall survival of stage 0-III patients was comparable in each group (94.7% in TRI vs. 93.7% in FEEA). 5-year disease-free survival of stage 0-III, stage II, and stage III patients was also comparable in each group (94.8% vs. 93.0%, 100% vs. 92.1%, and 80.3% vs. 79.2% in TRI and FEEA, respectively). CONCLUSION: The short- and long-term outcome rates were acceptable in both groups. Specific attempts to prevent complications are required for each anastomotic procedure.

Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion.

Emerging evidence is revealing that alterations in gut microbiota are associated with colorectal cancer (CRC). However, very little is currently known about whether and how gut microbiota alterations are causally associated with CRC development. Here we show that 12 faecal bacterial taxa are enriched in CRC patients in two independent cohort studies. Among them, 2 Porphyromonas species are capable of inducing cellular senescence, an oncogenic stress response, through the secretion of the bacterial metabolite, butyrate. Notably, the invasion of these bacteria is observed in the CRC tissues, coinciding with the elevation of butyrate levels and signs of senescence-associated inflammatory phenotypes. Moreover, although the administration of these bacteria into ApcΔ14/+ mice accelerate the onset of colorectal tumours, this is not the case when bacterial butyrate-synthesis genes are disrupted. These results suggest a causal relationship between Porphyromonas species overgrowth and colorectal tumourigenesis which may be due to butyrate-induced senescence.

Oncologic impact of lateral lymph node metastasis at the distal lateral compartment in locally advanced low rectal cancer after neoadjuvant (chemo)radiotherapy.

INTRODUCTION: The frequency and oncologic outcomes of lateral lymph node (LLN) metastasis at the most distal lateral compartment (DLC) among clinical stage II-III low rectal cancer patients treated with neoadjuvant (chemo)radiotherapy (nCRT) are poorly understood. The aim was to investigate the oncologic impact of LLN metastasis in the DLC versus the proximal lateral compartment (PLC). MATERIALS AND METHODS: Consecutive patients with low rectal cancer treated with nCRT followed by total mesorectal excision and selective LLN dissection including the DLC were analyzed retrospectively. DLC was defined as the area distal to the infra-piriformis foramen on axial MRI images. Size and location of LLN metastasis on MRI, and survival were retrospectively assessed. RESULTS: Of the 718 patients, 72 (10.0%) had pathological LLN metastasis. Thirty-two (44.4%) had metastasis in the DLC (DLC group), while 40 (55.6%) had metastasis in the PLC without metastasis in the DLC (PLC group). The proportion of ypN2 category tended to be lower in the DLC group (15.6% vs 35.0%, P = 0.105). The median number of metastatic LLN was similar (1 vs. 1, P = 0.691). The median short-axis size of metastatic LLN was smaller in the DLC group than in the PLC group on pre-treatment (P < 0.001) and re-staging (P = 0.004) MRI. By multivariable analysis, LLN metastasis in the DLC was predictive of better disease-free survival (HR, 0.412; 95% CI, 0.159-0.958, P = 0.039). CONCLUSION: LLN metastasis in the DLC is frequent and has favorable oncologic outcomes after surgical dissection with nCRT.

Postoperative Nutritional Status is Predictive of the Survival Outcomes in Patients Undergoing Resection of Stage III Colorectal Cancer.

BACKGROUND: Preoperative nutritional status is reportedly associated with the clinical outcomes in patients with colorectal cancer (CRC), although it remains inconclusive whether the preoperative nutritional status that may improve after surgery is truly predictive of the survival outcomes of patients with CRC. METHODS: Clinical records of patients with stage III CRC (n = 821) in whom curative resection had been achieved were retrospectively reviewed and the prognostic impact of nutritional status, determined by the controlling nutritional status (CONUT) score, was analyzed. RESULTS: The CONUT undernutrition grade was significantly associated with the overall survival rate (OS) in the original population (P < 0.0001). By adopting a cut-off value of CONUT score of ≥ 2 and adjustment for clinical variables using the inverse probability treatment weighting methods, the group with a preoperative CONUT score of ≥ 2 showed a worse OS as compared to the groups with a preoperative CONUT score of < 2 (P = 0.037). However, sub-analysis based on the dynamic changes in the CONUT score revealed that sustained malnutrition in the postoperative period was more frequent among patients with preoperative CONUT score of ≥ 2, and that the OS and recurrence-free survival rate (RFS) were significantly correlated with the "postoperative" nutritional status, irrespective of the preoperative nutritional status. Patients who showed improvements of the nutritional status after surgery showed a significantly longer OS and RFS. CONCLUSIONS: Sustained undernutrition or worsening of the nutritional status after colectomy may be associated with a worse OS and RFS after curative resection in patients with stage III CRC.

Systemic Inflammatory Markers Combined with Tumor-Infiltrating Lymphocyte Density for the Improved Prediction of Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer.

BACKGROUND: Previous studies have reported the utility of systemic inflammatory markers and CD8+ tumor-infiltrating lymphocyte (TIL) separately in predicting response to chemoradiotherapy (CRT) in rectal cancer; however, the efficacy of combining these markers remains unclear. OBJECTIVE: This study aimed to elucidate the predictive efficacy of systemic inflammatory markers combined with CD8+ TIL density on response to neoadjuvant CRT in locally advanced rectal cancer. METHODS: Ten systemic inflammatory markers and CD8+ TIL density were assessed in 267 patients with rectal cancer using pretreatment clinical data and biopsy samples. Response to CRT was determined using the Dworak tumor regression grade (TRG), with good responders classified as TRG3-4. RESULTS: Receiver operating characteristic curve analysis showed high areas under the curve for the lymphocyte-to-C-reactive protein ratio (LCR) and neutrophil × monocyte (N × M) value (0.58 and 0.62, respectively). In the multivariate analysis, LCR, N × M value, and CD8+ TIL density were independently associated with good responders (p = 0.016, 0.005, and 0.002, respectively). Stratified analysis with these three markers showed a positive correlation between TRG3-4 ratio and the number of positive predictive factors (8.2%, 20.0%, 34.2%, and 59.1% in patients with 0, 1, 2, and 3 predictors, respectively). Overall and disease-free survival were significantly worse in patients with zero factors present compared with those with one to three factors present. CONCLUSIONS: LCR, N × M value, and CD8+ TIL density are independently associated with response to CRT. Assessing local TIL density along with systemic inflammatory markers may be useful for selecting a multimodal neoadjuvant approach in rectal cancer therapy.

Comparative Analysis of Patient-Matched PDOs Revealed a Reduction in OLFM4-Associated Clusters in Metastatic Lesions in Colorectal Cancer.

Metastasis is the major cause of cancer-related death, but whether metastatic lesions exhibit the same cellular composition as primary tumors has yet to be elucidated. To investigate the cellular heterogeneity of metastatic colorectal cancer (CRC), we established 72 patient-derived organoids (PDOs) from 21 patients. Combined bulk transcriptomic and single-cell RNA-sequencing analysis revealed decreased gene expression of markers for differentiated cells in PDOs derived from metastatic lesions. Paradoxically, expression of potential intestinal stem cell markers was also decreased. We identified OLFM4 as the gene most strongly correlating with a stem-like cell cluster, and found OLFM4+ cells to be capable of initiating organoid culture growth and differentiation capacity in primary PDOs. These cells were required for the efficient growth of primary PDOs but dispensable for metastatic PDOs. These observations demonstrate that metastatic lesions have a cellular composition distinct from that of primary tumors; patient-matched PDOs are a useful resource for analyzing metastatic CRC.

Improved oncologic outcomes with increase of laparoscopic surgery in modified complete mesocolic excision with D3 lymph node dissection for T3/4a colon cancer: results of 1191 consecutive patients during a 10-year period: a retrospective cohort study.

BACKGROUND: Laparoscopic modified complete mesocolic excision (mCME) with D3 lymph node dissection has been performed with increasing frequency, but the oncological safety remains unclear. This study investigated the oncological safety of laparoscopic modified CME with D3 dissection for pT3/4a M0 colon cancer. PATIENTS: Consecutive patients with pT3/4a M0 colon cancer undergoing curative colectomy at a comprehensive cancer center between 2004 and 2013 were included. Outcomes were compared between early (2004-2008, n = 450) and late (2009-2014, n = 741) periods. Prognostic factors were investigated by multivariate analysis. RESULTS: A total of 1191 patients were eligible. Median follow-up was 57 months. Laparoscopic surgeries were more common in the late period (early vs late: 53.6% vs. 91.8%, p < 0.01). Patients in the late period showed lower blood loss (20 mL vs. 10 mL, p < 0.01), higher number of harvested lymph nodes (18.1 vs. 21.6, p < 0.01) and fewer patients with < 12 harvested nodes (13.6% vs. 5.8%, p < 0.01). Postoperative complication rates were similar between periods (2.7% vs. 2.7%, p = 0.97). Five-year relapse-free survival rate (RFS) (75.3% vs. 82.7%, p < 0.01) and overall survival rate (OS) (86.9% vs. 91.7%, p = 0.01) were higher in the late period. Multivariate analysis revealed laparoscopic surgery as an independent favorable prognostic factor for both RFS (hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.54-0.99, p = 0.03) and OS (HR = 0.56, 95% CI 0.37-0.83, p < 0.01). CONCLUSION: Improved oncologic outcomes and more frequent laparoscopic surgery during the 10-year period of the study were demonstrated for modified CME with D3 dissection, suggesting the safety of this procedure performed by experienced surgeons for pT3/4a M0 colon cancer.

T-cell complexity and density are associated with sensitivity to neoadjuvant chemoradiotherapy in patients with rectal cancer.

Emerging evidence suggests that an increased density of pre-treatment CD8+ tumor-infiltrating lymphocytes (TILs) is associated with good response to chemoradiotherapy (CRT) in patients with locally advanced rectal cancer. However, the significance of T-cell complexity in the clinical setting remains unknown. High-throughput T-cell receptor (TCR) ß sequencing was applied to quantify the TCR repertoire of pre-treatment biopsies from 67 patients with advanced rectal cancer receiving preoperative CRT. Diversity index was used to represent the complexity of the TCR repertoire in a tumor. Pre-treatment CD8+ TIL densities were assessed by immunohistochemistry. Changes in TCR repertoire before and after CRT were also analysed in 23 patients. Diversity indices were significantly higher for good responders than for non-responders (P = 0.031). The multivariate analysis revealed that both CD8+ TIL density and TCR diversity index were independently associated with good response to CRT (P < 0.001 and P = 0.049, respectively). Patients who were high for both CD8+ TIL density and TCR diversity (double-high) had markedly better responses to CRT than double-low patients (84.2% vs 16.7%, P < 0.0001). Larger changes in TCR repertoires before and after CRT were correlated with better recurrence-free survival (P = 0.027). The complexity and dynamic change in the TCR repertoire might serve as a useful indicator of response to CRT in combination with CD8+ TIL density in patients with rectal cancer.

Clinical Impact of Inferior Mesenteric Lymph Node Metastasis in Patients with Cancer of the Sigmoid Colon or Rectum.

The aim of this study was to clarify the clinical impact of inferior mesenteric lymph node (IMLN) metastasis from cancer of the sigmoid colon or rectum. A total of 952 patients underwent curative surgery with IMLN dissection for either sigmoid colon cancer or rectal cancer from January 2000 to August 2018. Of these, 26 (2.7%) were pathologically diagnosed with IMLN metastasis. Excluding 1 patient, 25 patients were retrospectively investigated for clinicopathological characteristics and long-term outcomes. Specifically, the clinical course of patients with recurrence was meticulously scrutinised. Of the 25 patients, 14 (56%) had recurrence during the follow-up period. The 5-year recurrence-free survival was 31.2%, and 5-year overall survival was 59.7%. No serious morbidity, such as anastomotic leakage, was observed. Of the 14 patients with recurrence, 6 underwent secondary surgery with curative intent and 5 of the 6 patients remained cancer-free. In contrast, 8 patients were treated with chemotherapy, radiotherapy or best supportive care. Although IMLN metastasis was strongly associated with recurrence, long-term survival could be expected in most cases. Furthermore, there could be a chance for complete cure in patients with recurrence if secondary surgery is successfully carried out.

Long-term outcomes of needlescopic surgery in patients with colon cancer: a retrospective cohort study.

BACKGROUND: Laparoscopic surgery is a minimally invasive and frequently performed surgical procedure that has become the standard surgery for colorectal cancer. Needlescopic surgery (NS) for colon cancer has also been performed and reported as a less invasive technique. In this study, we investigated the long-term outcomes of NS in comparison with those of conventional surgery (CS). METHODS: The data of 1122 patients without distant metastasis who underwent laparoscopic surgery between 2011 and 2014 were retrospectively analyzed. In this study, NS was defined as a laparoscopic procedure performed with the use of 3-mm ports and forceps with one 5-mm port for an energy device, as well as with clips. One 12-mm port was placed in the umbilicus for specimen extraction from the abdominal cavity. RESULTS: A total of 241 patients underwent NS. There was no significant difference between the 5-year recurrence rate and the 5-year total mortality rate (NS: 10.0% and 5.4% vs. CS: 10.3% and 3.5%, p = 0.86/0.23). In the multivariate analysis, NS was not found to be an independent prognostic factor. In terms of the distribution of recurrence sites, there was no significant difference between the two groups. CONCLUSIONS: NS for colon cancer was not inferior to CS in terms of short-term and long-term outcomes.