Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis.

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1-3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.

Implementable assay for monitoring minimum residual disease after radical treatment for colorectal cancer.

Considering the cost and invasiveness of monitoring postoperative minimal residual disease (MRD) of colorectal cancer (CRC) after adjuvant chemoradiotherapy (ACT), we developed a favorable approach based on methylated circulating tumor DNA to detect MRD after radical resection. Analyzing the public database, we identified the methylated promoter regions of the genes FGD5, GPC6, and MSC. Using digital polymerase chain reaction (dPCR), we termed the "amplicon of methylated sites using a specific enzyme" assay as "AMUSE." We examined 180 and 114 pre- and postoperative serial plasma samples from 28 recurrent and 19 recurrence-free pathological stage III CRC patients, respectively. The results showed 22 AMUSE-positive of 28 recurrent patients (sensitivity, 78.6%) and 17 AMUSE-negative of 19 recurrence-free patients (specificity, 89.5%). AMUSE predicted recurrence 208 days before conventional diagnosis using radiological imaging. Regarding ACT evaluation by the reactive response, 19 AMUSE-positive patients during their second or third blood samples showed a significantly poorer prognosis than the other patients (p = 9E-04). The AMUSE assay stratified four groups by the altered patterns of tumor burden postoperatively. Interestingly, only 34.8% of cases tested AMUSE-negative during ACT treatment, indicating eligibility for ACT. The AMUSE assay addresses the clinical need for accurate MRD monitoring with universal applicability, minimal invasiveness, and cost-effectiveness, thereby enabling the timely detection of recurrences. This assay can effectively evaluate the efficacy of ACT in patients with stage III CRC following curative resection. Our study strongly recommends reevaluating the clinical application of ACT using the AMUSE assay.

APC/PIK3CA mutations and ß-catenin status predict tankyrase inhibitor sensitivity of patient-derived colorectal cancer cells.

BACKGROUND: Aberrant WNT/ß-catenin signaling drives carcinogenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize AXINs, ß-catenin repressors. Tankyrase inhibitors block WNT/ß-catenin signaling and colorectal cancer (CRC) growth. We previously reported that 'short' APC mutations, lacking all seven ß-catenin-binding 20-amino acid repeats (20-AARs), are potential predictive biomarkers for CRC cell sensitivity to tankyrase inhibitors. Meanwhile, 'Long' APC mutations, which possess more than one 20-AAR, do not predict inhibitor-resistant cells. Thus, additional biomarkers are needed to precisely predict the inhibitor sensitivity. METHODS: Using 47 CRC patient-derived cells (PDCs), we examined correlations between the sensitivity to tankyrase inhibitors (G007-LK and RK-582), driver mutations, and the expressions of signaling factors. NOD.CB17-Prkdcscid/J and BALB/c-nu/nu xenograft mice were treated with RK-582. RESULTS: Short APC mutant CRC cells exhibited high/intermediate sensitivities to tankyrase inhibitors in vitro and in vivo. Active ß-catenin levels correlated with inhibitor sensitivity in both short and long APC mutant PDCs. PIK3CA mutations, but not KRAS/BRAF mutations, were more frequent in inhibitor-resistant PDCs. Some wild-type APC PDCs showed inhibitor sensitivity in a ß-catenin-independent manner. CONCLUSIONS: APC/PIK3CA mutations and ß-catenin predict the sensitivity of APC-mutated CRC PDCs to tankyrase inhibitors. These observations may help inform the strategy of patient selection in future clinical trials of tankyrase inhibitors.

Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer.

Cellular senescence causes a dramatic alteration of chromatin organization and changes the gene expression profile of proinflammatory factors, thereby contributing to various age-related pathologies through the senescence-associated secretory phenotype (SASP). Chromatin organization and global gene expression are maintained by the CCCTC-binding factor (CTCF); however, the molecular mechanism underlying CTCF regulation and its association with SASP gene expression remains unclear. We discovered that noncoding RNA (ncRNA) derived from normally silenced pericentromeric repetitive sequences directly impairs the DNA binding of CTCF. This CTCF disturbance increases the accessibility of chromatin and activates the transcription of SASP-like inflammatory genes, promoting malignant transformation. Notably, pericentromeric ncRNA was transferred into surrounding cells via small extracellular vesicles acting as a tumorigenic SASP factor. Because CTCF blocks the expression of pericentromeric ncRNA in young cells, the down-regulation of CTCF during cellular senescence triggers the up-regulation of this ncRNA and SASP-related inflammatory gene expression. In this study, we show that pericentromeric ncRNA provokes chromosomal alteration by inhibiting CTCF, leading to a SASP-like inflammatory response in a cell-autonomous and non-cell-autonomous manner and thus may contribute to the risk of tumorigenesis during aging.

Impaired tumor immune response in metastatic tumors is a selective pressure for neutral evolution in CRC cases.

A Darwinian evolutionary shift occurs early in the neutral evolution of advanced colorectal carcinoma (CRC), and copy number aberrations (CNA) are essential in the transition from adenoma to carcinoma. In light of this primary evolution, we investigated the evolutionary principles of the genome that foster postoperative recurrence of CRC. CNA and neoantigens (NAG) were compared between early primary tumors with recurrence (CRCR) and early primary tumors without recurrence (precancerous and early; PCRC). We compared CNA, single nucleotide variance (SNV), RNA sequences, and T-cell receptor (TCR) repertoire between 9 primary and 10 metastatic sites from 10 CRCR cases. We found that NAG in primary sites were fewer in CRCR than in PCRC, while the arm level CNA were significantly higher in primary sites in CRCR than in PCRC. Further, a comparison of genomic aberrations of primary and metastatic conditions revealed no significant differences in CNA. The driver mutations in recurrence were the trunk of the evolutionary phylogenic tree from primary sites to recurrence sites. Notably, PD-1 and TIM3, T cell exhaustion-related molecules of the tumor immune response, were abundantly expressed in metastatic sites compared to primary sites along with the increased number of CD8 expressing cells. The postoperative recurrence-free survival period was only significantly associated with the NAG levels and TCR repertoire diversity in metastatic sites. Therefore, CNA with diminished NAG and diverse TCR repertoire in pre-metastatic sites may determine postoperative recurrence of CRC.

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.

Head-to-head comparison of three chelates reveals DOTAGA promising for 225 Ac labeling of anti-FZD10 antibody OTSA101.

To select the most suitable chelate for 225 Ac radiolabeling of the anti-FZD10 antibody OTSA101, we directly compared three chelates: S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2,2',2″-(10-(1-carboxy-4-((4-isothiocyanatobenzyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (p-SCN-Bn-DOTAGA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DO3A-NHS-ester). We evaluated the binding affinity of the chelate-conjugated OTSA101 antibodies, as well as the labeling efficiency and stability in murine serum of 225 Ac-labeled OTSA101 as in vitro properties. The biodistribution, intratumoral distribution, absorbed doses, and therapeutic effects of the chelate-conjugated OTSA101 antibodies were assessed in the synovial sarcoma mouse model SYO-1. Of the three conjugates, DOTAGA conjugation had the smallest impact on the binding affinity (p < 0.01). The labeling efficiencies of DOTAGA-OTSA101 and DO3A-OTSA101 were 1.8-fold higher than that of DOTA-OTSA101 (p < 0.01). The stabilities were similar between 225 Ac-labeled DOTA-OTSA101, DOTAGA-OTSA101, and DO3A-OTSA101in serum at 37 and 4°C. The dosimetric analysis based on the biodistribution revealed significantly higher tumor-absorbed doses by 225 Ac-labeled DOTA-OTSA101 and DOTAGA-OTSA101 compared with 225 Ac-DO3A-OTSA101 (p < 0.05). 225 Ac-DOTAGA-OTSA101 exhibited the highest tumor-to-bone marrow ratio, with bone marrow being the dose-limiting tissue. The therapeutic and adverse effects were not significantly different between the three conjugates. Our findings indicate that among the three evaluated chelates, DOTAGA appears to be the most promising chelate to produce 225 Ac-labeled OTSA101 with high binding affinity and high radiochemical yields while providing high absorbed doses to tumors and limited absorbed doses to bone marrow.

Subclonal accumulation of immune escape mechanisms in microsatellite instability-high colorectal cancers.

BACKGROUND: Intratumor heterogeneity (ITH) in microsatellite instability-high (MSI-H) colorectal cancer (CRC) has been poorly studied. We aimed to clarify how the ITH of MSI-H CRCs is generated in cancer evolution and how immune selective pressure affects ITH. METHODS: We reanalyzed public whole-exome sequencing data on 246 MSI-H CRCs. In addition, we performed a multi-region analysis from 6 MSI-H CRCs. To verify the process of subclonal immune escape accumulation, a novel computational model of cancer evolution under immune pressure was developed. RESULTS: Our analysis presented the enrichment of functional genomic alterations in antigen-presentation machinery (APM). Associative analysis of neoantigens indicated the generation of immune escape mechanisms via HLA alterations. Multiregion analysis revealed the clonal acquisition of driver mutations and subclonal accumulation of APM defects in MSI-H CRCs. Examination of variant allele frequencies demonstrated that subclonal mutations tend to be subjected to selective sweep. Computational simulations of tumour progression with the interaction of immune cells successfully verified the subclonal accumulation of immune escape mutations and suggested the efficacy of early initiation of an immune checkpoint inhibitor (ICI) -based treatment. CONCLUSIONS: Our results demonstrate the heterogeneous acquisition of immune escape mechanisms in MSI-H CRCs by Darwinian selection, providing novel insights into ICI-based treatment strategies.

Spatiotemporal commonality of the TCR repertoire in a T-cell memory murine model and in metastatic human colorectal cancer.

Immune checkpoint inhibitors (ICIs) have shown superior clinical responses and significantly prolong overall survival (OS) for many types of cancer. However, some patients exhibit long-term OS, whereas others do not respond to ICI therapy at all. To develop more effective and long-lasting ICI therapy, understanding the host immune response to tumors and the development of biomarkers are imperative. In this study, we established an MC38 immunological memory mouse model by administering an anti-PD-L1 antibody and evaluating the detailed characteristics of the immune microenvironment including the T cell receptor (TCR) repertoire. In addition, we found that the memory mouse can be established by surgical resection of residual tumor following anti-PD-L1 antibody treatment with a success rate of > 40%. In this model, specific depletion of CD8 T cells revealed that they were responsible for the rejection of reinoculated MC38 cells. Analysis of the tumor microenvironment (TME) of memory mice using RNA-seq and flow cytometry revealed that memory mice had a quick and robust immune response to MC38 cells compared with naïve mice. A TCR repertoire analysis indicated that T cells with a specific TCR repertoire were expanded in the TME, systemically distributed, and preserved in the host for a long time period. We also identified shared TCR clonotypes between serially resected tumors in patients with colorectal cancer (CRC). Our results suggest that memory T cells are widely preserved in patients with CRC, and the MC38 memory model is potentially useful for the analysis of systemic memory T-cell behavior.

FZD10-targeted α-radioimmunotherapy with 225 Ac-labeled OTSA101 achieves complete remission in a synovial sarcoma model.

Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12-18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of ß-radioimmunotherapy (RIT) with the 90 Y-labeled anti-FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α-RIT with OTSA101 labeled with the α-emitter 225 Ac. Competitive inhibition and cell binding assays showed that specific binding of 225 Ac-labeled OTSA101 to SYO-1 synovial sarcoma cells was comparable to that of the imaging agent 111 In-labeled OTSA101. Biodistribution studies showed high uptake in SYO-1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225 Ac-labeled OTSA101 for tumors was 7.8 Bd higher than that of 90 Y-labeled OTSA101. 90 Y- and 225 Ac-labeled OTSA101 decreased tumor volume and prolonged survival. 225 Ac-labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225 Ac-labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90 Y-labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment-related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225 Ac-labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO-1. RIT with 225 Ac-labeled OTSA101 is a promising therapeutic option for synovial sarcoma.

Integration of human inspection and artificial intelligence-based morphological typing of patient-derived organoids reveals interpatient heterogeneity of colorectal cancer.

Colorectal cancer (CRC) is a heterogenous disease, and patients have differences in therapeutic response. However, the mechanisms underlying interpatient heterogeneity in the response to chemotherapeutic agents remain to be elucidated, and molecular tumor characteristics are required to select patients for specific therapies. Patient-derived organoids (PDOs) established from CRCs recapitulate various biological characteristics of tumor tissues, including cellular heterogeneity and the response to chemotherapy. Patient-derived organoids established from CRCs show various morphologies, but there are no criteria for defining these morphologies, which hampers the analysis of their biological significance. Here, we developed an artificial intelligence (AI)-based classifier to categorize PDOs based on microscopic images according to their similarity in appearance and classified tubular adenocarcinoma-derived PDOs into six types. Transcriptome analysis identified differential expression of genes related to cell adhesion in some of the morphological types. Genes involved in ribosome biogenesis were also differentially expressed and were most highly expressed in morphological types showing CRC stem cell properties. We identified an RNA polymerase I inhibitor, CX-5641, to be an upstream regulator of these type-specific gene sets. Notably, PDO types with increased expression of genes involved in ribosome biogenesis were resistant to CX-5461 treatment. Taken together, these results uncover the biological significance of the morphology of PDOs and provide novel indicators by which to categorize CRCs. Therefore, the AI-based classifier is a useful tool to support PDO-based cancer research.

Lymphocytes in tumor-draining lymph nodes co-cultured with autologous tumor cells for adoptive cell therapy.

BACKGROUND: Tumor-draining lymph nodes (TDLNs) are primary sites, where anti-tumor lymphocytes are primed to tumor-specific antigens and play pivotal roles in immune responses against tumors. Although adoptive cell therapy (ACT) using lymphocytes isolated from TDLNs were reported, characterization of immune activity of lymphocytes in TDLNs to tumor cells was not comprehensively performed. Here, we demonstrate TDLNs to have very high potential as cell sources for immunotherapy. METHODS: Lymphocytes from TDLNs resected during surgical operation were cultured with autologous-tumor cells for 2 weeks and evaluated tumor-reactivity by IFNγ ELISPOT assay. We investigated the commonality of T cell receptor (TCR) clonotypes expanded by the co-culture with tumor cells with those of tumor infiltrating lymphocytes (TILs). RESULTS: We found that that TCR clonotypes of PD-1-expressing CD8+ T cells in lymph nodes commonly shared with those of TILs in primary tumors and lymphocytes having tumor-reactivity and TCR clonotypes shared with TILs could be induced from non-metastatic lymph nodes when they were co-cultured with autologous tumor cells. CONCLUSION: Our results imply that tumor-reactive effector T cells were present even in pathologically non-metastatic lymph nodes and could be expanded in vitro in the presence of autologous tumor cells and possibly be applied for ACT.

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).

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.

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.

[A Case of Perforation of Unresectable Esophageal Cancer during Nivolumab Therapy].

A 46-year-old man visited our hospital complaining of dysphagia. He was diagnosed with unresectable esophageal cancer with multiple lung metastases(cStage Ⅳb)and gastric cancer(L, Gre, T3N+M0, cStage Ⅲ). The esophageal lesion and the lung metastatic lesions showed shrinkage initially with 5-FU, CDDP(FP)therapy but then re-grew; therefore, the therapy was changed to nivolumab therapy. After three courses of nivolumab therapy, the patient visited our hospital with a high fever. He was admitted as an emergency patient with a diagnosis of esophageal perforation and mediastinal abscess. CT- guided drainage was performed, and a self-expanding metal stent(SEMS)was placed. He was discharged on the 31st day of hospitalization and nivolumab therapy was resumed. We report the first case of esophageal perforation during immunotherapy with nivolumab therapy for esophageal cancer.

Safety of Small Circular Staplers in Double Stapling Technique Anastomosis for Sigmoid Colon and Rectal Cancer.

BACKGROUND: Although smaller circular staplers are easier to insert and less likely to involve the vagina and levator ani muscles when performing double stapling technique anastomosis, surgeons often consider that larger circular staplers would be safer in reducing the risk of postoperative anastomotic strictures. OBJECTIVE: This study aimed to investigate the safety of using 25-mm circular staplers compared with 28/29-mm staplers in the double stapling technique anastomosis regarding the development of anastomotic strictures and other complications. DESIGN: This is a retrospective observational study. SETTING: This study was conducted at a single comprehensive cancer center. PATIENTS: Consecutive patients undergoing curative colorectal resection with double stapling technique anastomosis for stage I to III sigmoid colon and rectal cancer between 2013 and 2016 were included. MAIN OUTCOME MEASURES: The incidence of anastomotic complications (strictures, leakage, and bleeding) was compared between the 25- and 28/29-mm circular staplers. Predictors for anastomotic strictures were investigated with multivariable logistic regression. RESULTS: Small (25-mm) staplers were used in 186 (22.8%) of 815 eligible patients. The 25-mm staplers were associated with use in female patients, splenic flexure take down, high tie of the inferior mesenteric artery, and low anastomosis. Overall anastomotic complications (11.8% vs 13.7%, p = 0.51), strictures (5.9% vs 3.3%, p = 0.11), leakage (2.7% vs 3.8%, p = 0.47), and bleeding (4.8% vs 7.6%, p = 0.19) were not different between the 25- and 28/29-mm staplers. From multivariable logistic regression, independent predictors of anastomotic strictures included diverting ostomy and anastomotic leakage, but not small circular stapler use. Most of the 32 anastomotic strictures were successfully treated without surgical intervention (finger dilation, n = 25; endoscopic intervention, n = 5). LIMITATIONS: This was a single-center retrospective study. CONCLUSIONS: Use of 25-mm circular staplers for double stapling technique anastomosis is safe and does not increase the risk of anastomotic strictures and other anastomotic complications in comparison with larger staplers. See Video Abstract at http://links.lww.com/DCR/B576. SEGURIDAD DE ENGRAPADORAS CIRCULARES PEQUEAS EN ANASTOMOSIS, CON TCNICA DE DOBLE ENGRAPADO PARA CNCER DE RECTO Y COLON SIGMOIDE: ANTECEDENTES:Aunque las engrapadoras circulares más pequeñas son más fáciles de insertar y menos probable que involucren a la vagina y los músculos elevadores del ano, cuando se realiza una anastomosis con técnica de doble engrapado, frecuentemente los cirujanos consideran que las engrapadoras circulares más grandes, serían más seguras para disminuir los riesgos de estenosis anastomóticas postoperatorias.OBJETIVO:El estudio se dirigió para investigar la seguridad en el uso de engrapadoras circulares de 25 mm, en comparación con engrapadoras de 28/29 mm, en anastomosis con técnica de doble engrapado, en relación al desarrollo de estenosis anastomóticas y otras complicaciones.DISEÑO:Estudio observacional retrospectivo.AJUSTE:Centro oncológico integral único.PACIENTES:Se incluyeron pacientes consecutivos sometidos a resección colorrectal curativa, con anastomosis y técnica de doble engrapado, para cáncer de recto y colon sigmoide en estadios I-III entre 2013 y 2016.PRINCIPALES MEDIDAS DE RESULTADO:Se compararon las incidencias de complicaciones anastomóticas (estenosis, fugas y sangrados) entre las engrapadoras circulares de 25 y 28/29 mm. Los predictores para estenosis anastomóticas se investigaron con regresión logística multivariable.RESULTADOS:Entre un total de 815 pacientes elegibles, se utilizaron engrapadoras de 25 mm en 186 (22,8%). Las engrapadoras de 25 mm se asociaron con el uso en pacientes femeninas, descenso del ángulo esplénico, ligadura alta de arteria mesentérica inferior y anastomosis baja. Complicaciones anastomóticas generales (11,8% vs. 13,7%, p = 0,51), estenosis (5,9% vs. 3,3%, p = 0,11), fugas (2,7% vs. 3,8%, p = 0,47) y sangrado (4,8% vs. 7,6%, p = 0,19). No hubo diferencia entre las engrapadoras de 25 y 28/29 mm. En la regresión logística multivariable, predictores independientes de estenosis anastomóticas incluyeron ostomía derivativa y fuga anastomótica, pero no incluyeron el uso de engrapadoras circulares pequeñas. La mayoría de las 32 estenosis anastomóticas se trataron con éxito sin intervención quirúrgica (dilatación del dedo, n = 25; intervención endoscópica, n = 5).LIMITACIONES:Fue un estudio retrospectivo de un solo centro.CONCLUSIONES:El uso de engrapadoras circulares de 25 mm para la anastomosis con técnica de doble engrapado, es seguro y no aumenta el riesgo de estenosis anastomóticas y de otras complicaciones anastomóticas, cuando son comparadas con engrapadoras más grandes. Consulte Video Resumen en http://links.lww.com/DCR/B576. (Traducción-Dr. Fidel Ruiz-Healy).

Adding Narrow-Band Imaging to Chromoendoscopy for the Evaluation of Tumor Response to Neoadjuvant Therapy in Rectal Cancer.

BACKGROUND: Endoscopic assessment is crucial in diagnosing clinical complete response after neoadjuvant therapy in rectal cancer. OBJECTIVE: The purpose of this research was to evaluate the benefits of adding narrow-band imaging endoscopy to conventional chromoendoscopy in predicting pathologic complete response in the surgical specimen. DESIGN: This was a prospective nonrandomized study. SETTINGS: This was an ad hoc study of a prospective phase II trial at a single comprehensive cancer center that evaluated oncologic outcomes of a neoadjuvant therapy for rectal cancer. PATIENTS: Patients with high-risk stage II to III low rectal cancer who received neoadjuvant modified folinic acid, fluorouracil, and oxaliplatin plus bevacizumab followed by chemoradiotherapy and surgery were included. INTERVENTION: Tumor response after neoadjuvant therapy was evaluated using conventional white light endoscopy plus chromoendoscopy then followed by using narrow-band imaging based on a predefined diagnostic protocol. MAIN OUTCOME MEASURES: Diagnostic accuracy for predicting pathologic complete response and inter-rater agreement between an expert and trainee endoscopists were compared between the assessments using conventional white light endoscopy plus chromoendoscopy and the assessment adding narrow-band imaging. RESULTS: In total, 61 patients were eligible for the study, and 19 had pathologic complete response (31.1%). Although the addition of narrow-band imaging correctly converted the diagnosis in 3 patients, overall diagnostic improvement in predicting pathologic complete response was limited (conventional chromoendoscopy vs adding narrow-band imaging: accuracy, 70.5% vs 75.4%; sensitivity, 63.2% vs 73.7%; specificity, 73.8% vs 76.2%; positive predictive value, 52.2% vs 58.3%; and negative predictive value, 81.6% vs 86.5%). A κ value for the inter-rater agreement improved from 0.599 to 0.756 by adding narrow-band imaging. LIMITATIONS: This was a single-center study with a relatively small sample size. CONCLUSIONS: Despite the limited improvement in diagnostic accuracy, adding narrow-band imaging to chromoendoscopy improved inter-rater agreement between the expert and nonexpert endoscopists. Narrow-band imaging is a reliable and promising modality for universal standardization of the diagnosis of clinical complete response. See Video Abstract at http://links.lww.com/DCR/B275. ADICIÓN DE IMÁGENES DE BANDA ESTRECHA A LA CROMOENDOSCOPÍA PARA LA EVALUACIÓN DE LA RESPUESTA TUMORAL A LA TERAPIA NEOADYUVANTE EN EL CÁNCER DE RECTO: La evaluación endoscópica es fundamental para valorar la respuesta clínica completa después de la terapia neoadyuvante en el cáncer de recto.Evaluar los beneficios de agregar endoscopia de imagen de banda estrecha a la cromoendoscopía convencional para predecir la respuesta patológica completa en la muestra quirúrgica.Estudio prospectivo no aleatorizado.Un estudio ad hoc de un ensayo prospectivo de fase II en un solo centro integral de cáncer que evaluó los resultados oncológicos de una terapia neoadyuvante para el cáncer rectal.Pacientes con cáncer rectal bajo de alto riesgo en estadio II-III que recibieron ácido folínico neoadyuvante modificado, fluorouracilo y oxaliplatino más bevacizumab seguido de quimiorradioterapia y cirugía.La respuesta tumoral después de la terapia neoadyuvante se evaluó mediante endoscopia de luz blanca convencional más cromoendoscopía, seguido de imágenes de banda estrecha basadas en un protocolo de diagnóstico predefinido.La precisión diagnóstica para predecir la respuesta patológica completa y el acuerdo entre evaluadores entre un experto y un endoscopista en entrenamiento se compararon entre las evaluaciones utilizando endoscopia de luz blanca convencional más cromoendoscopía y la evaluación agregando imágenes de banda estrecha.En total, 61 pacientes fueron elegibles para el estudio, y 19 tuvieron una respuesta patológica completa (31.1%). Aunque la adición de imágenes de banda estrecha convirtió correctamente el diagnóstico en 3 pacientes, la mejora diagnóstica general en la predicción de la respuesta patológica completa fue limitada (cromoendoscopía convencional versus adición de imágenes de banda estrecha: precisión, 70.5% versus 75.4%; sensibilidad, 63.2% versus 73.7%; especificidad, 73.8% versus 76.2%; valor predictivo positivo, 52.2% versus 58.3%; y valor predictivo negativo, 81.6% versus 86.5%). Un valor de kappa para el acuerdo entre evaluadores mejoró de 0.599 a 0.756 al agregar imágenes de banda estrecha.Un estudio de centro único con un tamaño de muestra relativamente pequeño.A pesar de la mejora limitada en la precisión diagnóstica, agregar imágenes de banda estrecha a la cromoendoscopía mejoró el acuerdo entre evaluadores entre los endoscopistas expertos y no expertos. La imagenología de banda estrecha es una modalidad confiable y prometedora para la estandarización universal del diagnóstico de respuesta clínica completa. Consulte Video Resumen en http://links.lww.com/DCR/B275.

Educational system for acquiring appropriate laparoscopic colorectal surgical skills: analysis in a Japanese high-volume cancer center.

BACKGROUND: Acquiring appropriate laparoscopic technique is necessary to safely perform laparoscopic surgery. The Endoscopic Surgical Skill Qualification System of the Japanese Society of Endoscopic Surgery, which was established to improve the quality of laparoscopic surgery in Japan, provides training to become an expert laparoscopic surgeon. In this study, we describe our educational system, in a Japanese highest volume cancer center, and evaluate the system according to the pass rate for the Endoscopic Surgical Skill Qualification System examination. METHODS: We assessed 14 residents who trained for more than 2 years from 2012 to 2018 in our department. All teaching surgeons, qualified by the Endoscopic Surgical Skill Qualification System, participated in all surgeries as supervisors. For the first 3 months, trainees learned as the scopist, then as the first assistant for 3 months, and then by performing laparoscopic surgery as an operator during ileocecal resection or sigmoidectomy. Trainees apply for this training in their second year of residency or later. All laparoscopic procedures in our department are standardized in detail. RESULTS: The cumulative pass rate was 75% (12/16), and 87% (12/14) of the trainees eventually passed, while the general pass rate was approximately 30%. On average, those who passed in their second or third year had experienced 94 procedures as the surgeon, 177 as the first assistant, and 199 as the scopist. The number of laparoscopic procedures and the learning curves did not differ between successful and failed applicants. CONCLUSIONS: Through our educational system, residents successfully acquired laparoscopic skills with a much higher pass rate in the Endoscopic Surgical Skill Qualification System examination than the general standard. Laparoscopic practice under supervision by experienced surgeons with standardized procedures and accurate understanding of the relevant anatomy is very helpful to achieving appropriate laparoscopic technique.

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.