Evaluation of two-stage hepatectomy using portal vein embolization for colorectal liver metastasis: a retrospective nationwide cohort survey in Japan.

INTRODUCTION: Two-stage hepatectomy (TSH) enables patients to undergo surgery for colorectal liver metastasis (CRLM) which one-stage hepatectomy cannot remove. Although the outcome of TSH has been reported, there is no original report from Japan. The aim of this retrospective study was to evaluate the outcome of TSH in Japanese patients with CRLM. METHODS: We conducted a retrospective cohort study using the nationwide database that included clinical information of 12,519 patients treated with CRLM between 2005 and 2017 in Japan. The primary outcome measure was overall survival. The second outcome measure was progression-free survival. Fisher's exact test, chi-squared test and Mann-Whitney U test were conducted to examine an intergroup difference. Univariate and multivariate analyses were performed using Cox regression model. Survival analysis was performed by Kaplan-Meier method and log-rank test. RESULTS: Of the database, 53 patients undergoing TSH using portal vein embolization (PVE) were identified and analyzed. Their morbidity and in-hospital mortality rate at the second hepatectomy were 26.4% and 0.0%. The mean observation period was 21.8 months. The estimated 1-, 3- and 5-year overall survival rate were 92.5%, 70.8% and 34.7%. Multivariate analyses showed that more than 10 liver nodules significantly increased the mortality risk by 4.2-fold (95%CI 1.224-14.99, P= 0.023). Survival analysis revealed that repeat hepatectomy for disease progression after TSH was superior to chemotherapy in overall survival (mean: 49.6 vs. 18.7, months, P= 0.004). CONCLUSION: In the Japanese cohort, TSH was confirmed to be a safety procedure with acceptable survival outcome. More than 10 liver nodules may be a predictor for unfavorable outcome of patients with CRLM undergoing TSH. Furthermore, repeat hepatectomy can be a salvage treatment for resectable intrahepatic recurrence after TSH.

Laparoscopy-Assisted Restorative Proctocolectomy with Ileal Pouch-Anal Anastomosis in Middle Colic Artery Ligation Immediately before Specimen Removal.

Introduction: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure for ulcerative colitis (UC). Intestinal ischemia may occur if the main blood vessels are ligated at an early stage of this surgery. Considering that the blood flow in the large intestine can be maintained by preserving the middle colic artery, we have used a new IPAA method: ligating the middle colic artery immediately before removal of the specimens ("M-method"). Here, we evaluated the M-method's clinical outcomes. Methods: Between April 2009 and December 2021, 13 patients underwent a laparoscopy-assisted IPAA procedure at our institution. The conventional method was used for 6 patients, and the M-method was used for the other 7 patients. We retrospectively analyzed the cases' clinical notes. Results: The M-method's rate of postoperative complications (Clavien-Dindo classification grade II or more) was significantly lower than that of the conventional method (14.2% vs. 83.3%). The M-method group's postoperative stay period was also significantly shorter (average 16.4 days vs. 55.5). There were significant differences in the albumin value and the ratio of the modified GPS score 1 or 2 on the 7th postoperative day between the M- and conventional methods (average 3.15 vs. 2.5, average 4/7 vs. 6/6). However, it is necessary to consider the small number of cases and the uncontrolled historical comparison. Conclusion: Late ligation of the middle colic artery may be beneficial for patients' post-surgery recovery and can be recommended for IPAAs in UC patients.

Ceramide synthase CERS4 gene downregulation is associated with KRAS mutation in colorectal cancer.

Ceramide, the central molecule in sphingolipid synthesis, is a bioactive lipid that serves as a regulatory molecule in the anti-inflammatory responses, apoptosis, programmed necrosis, autophagy, and cell motility of cancer cells. In particular, the authors have reported differences in sphingolipid content in colorectal cancer tissues. The associations among genetic mutations, clinicopathological factors, and sphingolipid metabolism in colorectal cancer (CRC) have not been investigated. The objective of this study is to investigate the association between genes associated with sphingolipid metabolism, genetic variations in colorectal cancer (CRC), and clinicopathological factors in CRC patients. We enrolled 82 consecutive patients with stage I-IV CRC who underwent tumor resection at a single institution in 2019-2021. We measured the expression levels of genes related to sphingolipid metabolism and examined the relationships between CRC gene mutations and the clinicopathological data of each individual patient. The relationship between CRC gene mutations and expression levels of ceramide synthase (CERS), N-acylsphingosine amidohydrolase (ASAH), and alkaline ceramidase (ACER) genes involved in sphingolipid metabolism was examined CRES4 expression was significantly lower in the CRC KRAS gene mutation group (p = 0.004); vascular invasion was more common in colorectal cancer patients with high CERS4 expression (p = 0.0057). By examining the correlation between sphingolipid gene expression and clinical factors, we were able to identify cancer types in which sphingolipid metabolism is particularly relevant. CERS4 expression was significantly reduced in KRAS mutant CRC. Moreover, CRC with decreased CERS4 showed significantly more frequent venous invasion.

A proposed new Japanese classification of synchronous peritoneal metastases from colorectal cancer: A multi-institutional, prospective, observational study conducted by the Japanese Society for Cancer of the Colon and Rectum.

Aim: To establish a new Japanese classification of synchronous peritoneal metastases from colorectal cancer. Methods: This multi-institutional, prospective, observational study enrolled patients who underwent surgery for colorectal cancer with synchronous peritoneal metastases. Overall survival rates were compared according to the various models using objective indicators. Each model was evaluated by Akaike's information criterion (AIC). The region of peritoneal metastases was evaluated by the peritoneal cancer index (PCI). Results: Between October 2012 and December 2016, 150 patients were enrolled. The AIC of the present Japanese classification was 1020.7. P1 metastasis was defined as confined to two regions. The minimum AIC was obtained with the cutoff number of 10 or less for P2 metastasis and 11 or more for P3 metastasis. As for size, the best discrimination ability between P2 and P3 metastasis was obtained with a cutoff value of 3 cm. The AIC of the proposed classification was 1014.7. The classification was as follows: P0, no peritoneal metastases; P1, metastases localized to adjacent peritoneum (within two regions of PCI); P2, metastases to distant peritoneum, number ≤10 and size ≤3 cm; P3, metastases to distant peritoneum, number ≥11 or size >3 cm; P3a, metastases to distant peritoneum, number ≥11 and size ≤3 cm, or number ≤10 and size >3 cm; P3b, metastases to distant peritoneum, number ≥11 and size >3 cm. Conclusion: This objective classification could improve the ability to discriminate prognosis in patients with synchronous peritoneal metastases from colorectal cancer.

Development of a Diagnostic Artificial Intelligence Tool for Lateral Lymph Node Metastasis in Advanced Rectal Cancer.

BACKGROUND: Metastatic lateral lymph node dissection can improve survival in patients with rectal adenocarcinoma, with or without chemoradiotherapy. However, the optimal imaging diagnostic criteria for lateral lymph node metastases remain undetermined. OBJECTIVE: To develop a lateral lymph node metastasis diagnostic artificial intelligence tool using deep learning, for patients with rectal adenocarcinoma who underwent radical surgery and lateral lymph node dissection. DESIGN: Retrospective study. SETTINGS: Multicenter study. PATIENTS: A total of 209 patients with rectal adenocarcinoma, who underwent radical surgery and lateral lymph node dissection at 15 participating hospitals, were enrolled in the study and allocated to training (n = 139), test (n = 17), or validation (n = 53) cohorts. MAIN OUTCOME MEASURES: In the neoadjuvant treatment group, images taken before pretreatment were classified as baseline images and those taken after pretreatment as presurgery images. In the upfront surgery group, presurgery images were classified as both baseline and presurgery images. We constructed 2 types of artificial intelligence, using baseline and presurgery images, by inputting the patches from these images into ResNet-18, and we assessed their diagnostic accuracy. RESULTS: Overall, 124 patients underwent surgery alone, 52 received neoadjuvant chemotherapy, and 33 received chemoradiotherapy. The number of resected lateral lymph nodes in the training, test, and validation cohorts was 2418, 279, and 850, respectively. The metastatic rates were 2.8%, 0.7%, and 3.7%, respectively. In the validation cohort, the precision-recall area under the curve was 0.870 and 0.963 for the baseline and presurgery images, respectively. Although both baseline and presurgery images provided good accuracy for diagnosing lateral lymph node metastases, the accuracy of presurgery images was better than that of baseline images. LIMITATIONS: The number of cases is small. CONCLUSIONS: An artificial intelligence tool is a promising tool for diagnosing lateral lymph node metastasis with high accuracy. DESARROLLO DE UNA HERRAMIENTA DE INTELIGENCIA ARTIFICIAL PARA EL DIAGNSTICO DE METSTASIS EN GANGLIOS LINFTICOS LATERALES EN CNCER DE RECTO AVANZADO: ANTECEDENTES:Disección de nódulos linfáticos laterales metastásicos puede mejorar la supervivencia en pacientes con adenocarcinoma del recto, con o sin quimiorradioterapia. Sin embargo, aún no se han determinado los criterios óptimos de diagnóstico por imágenes de los nódulos linfáticos laterales metastásicos.OBJETIVO:Nuestro objetivo fue desarrollar una herramienta de inteligencia artificial para el diagnóstico de metástasis en nódulos linfáticos laterales mediante el aprendizaje profundo, para pacientes con adenocarcinoma del recto que se sometieron a cirugía radical y disección de nódulos linfáticos laterales.DISEÑO:Estudio retrospectivo.AJUSTES:Estudio multicéntrico.PACIENTES:Un total de 209 pacientes con adenocarcinoma del recto, que se sometieron a cirugía radical y disección de nódulos linfáticos laterales en 15 hospitales participantes, se inscribieron en el estudio y se asignaron a cohortes de entrenamiento (n = 139), prueba (n = 17) o validación (n = 53).PRINCIPALES MEDIDAS DE RESULTADO:En el grupo de tratamiento neoadyuvante, las imágenes tomadas antes del tratamiento se clasificaron como imágenes de referencia y las posteriores al tratamiento, como imágenes previas a la cirugía. En el grupo de cirugía inicial, las imágenes previas a la cirugía se clasificaron como imágenes de referencia y previas a la cirugía. Construimos dos tipos de inteligencia artificial, utilizando imágenes de referencia y previas a la cirugía, ingresando los parches de estas imágenes en ResNet-18. Evaluamos la precisión diagnóstica de los dos tipos de inteligencia artificial.RESULTADOS:En general, 124 pacientes se sometieron a cirugía solamente, 52 recibieron quimioterapia neoadyuvante y 33 recibieron quimiorradioterapia. El número de nódulos linfáticos laterales removidos en los cohortes de entrenamiento, prueba y validación fue de 2,418; 279 y 850, respectivamente. Las tasas metastásicas fueron 2.8%, 0.7%, y 3.7%, respectivamente. En el cohorte de validación, el área de recuperación de precisión bajo la curva fue de 0.870 y 0.963 para las imágenes de referencia y antes de la cirugía, respectivamente. Aunque tanto las imágenes previas a la cirugía como las iniciales proporcionaron una buena precisión para diagnosticar metástasis en los nódulos linfáticos laterales, la precisión de las imágenes previas a la cirugía fue mejor que la de las imágenes iniciales.LIMITACIONES:El número de casos es pequeño.CONCLUSIÓN:La inteligencia artificial es una herramienta prometedora para diagnosticar metástasis en los nódulos linfáticos laterales con alta precisión. (Traducción-Dr. Aurian Garcia Gonzalez ).

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.

Enhanced Clinical Utility of Molecular Budding Signature as a Recurrence Risk Determinant in Stage II and III Colon Cancer Patients.

BACKGROUND: A molecular budding signature (MBS), which consists of seven tumor budding-related genes, was recently presented as a prominent prognostic indicator in colon cancer (CC) using microarray data acquired from frozen specimens. This study aimed to confirm the predictive power of MBS for recurrence risk based on formalin-fixed, paraffin-embedded (FFPE) materials. METHODS: This research utilized the same microarray data from a prior multicenter study using FFPE whole tissue sections, which retrospectively reviewed 232 stage II CC patients without adjuvant chemotherapy and 302 stage III CC patients with adjuvant chemotherapy. All patients underwent upfront curative surgery without neoadjuvant therapy between 2009 and 2012. An MBS score was calculated using the mean of log2 [each signal] of seven genes (MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3, and FOXC1) as described before. RESULTS: The MBS-low group exhibited a better relapse-free survival (RFS) than the MBS-high group in stage II (P = 0.0077) and in stage III CC patients (P = 0.0003). Multivariate analyses revealed that the MBS score was an independent prognostic factor in both stage II (P = 0.0257) and stage III patients (P = 0.0022). Especially among T4, N2, or both (high-risk) stage III patients, the MBS-low group demonstrated markedly better RFS compared with the MBS-high group (P = 0.0013). CONCLUSIONS: This study confirmed the predictive power of the MBS for recurrence risk by employing FFPE materials in stage II/III CC patients.

Is Low Volume Drainage of Ascites Associated With Improved Survival in Digestive System Cancer Patients With Malignant Ascites?-A Retrospective Cohort Study.

Objectives: To determine whether the volume of paracentesis for malignant ascites in acute care hospital wards is associated with survival and symptom relief. Methods: Patients with malignant ascites caused by digestive system cancer who underwent paracentesis between January 2010 and April 2022 were retrospectively analyzed from medical records. Collected data included the drainage volume per paracentesis procedure, survival time from the first paracentesis procedure, symptoms, and adverse events. According to the volume per paracentesis procedure, we divided the patients into the "small-drainage" (≤1500 mL) and "standard-drainage" (>1500 mL) groups. Results: The median age of the 144 patients was 69 years, 33% were female, and 64% had gastrointestinal cancer. The median survival from the first paracentesis procedure was 36 days. Eighty-nine (61.8%) and 55 (38.2%) patients were allocated to the small-drainage and standard-drainage groups, respectively. The median number of paracentesis procedures in the small-drainage and standard-drainage groups was 12 and 7, respectively (P=.001). The median survival in the small-drainage and standard-drainage groups was 50 and 44 days, respectively (P=.76). The multivariate analysis showed that the amount of drainage per session was not significantly associated with survival. Symptoms improved similarly in the 2 groups. No serious adverse events were observed. Conclusions: Paracentesis was demonstrated to be effective and safe, irrespective of the amount of fluid drained, for patients with malignant ascites in an acute care hospital. Thus, a strategy of limiting the amount of drainage is not associated with longer survival.

Prognostic Value of KRAS Exon-specific Mutations in Patients With Colorectal Cancer.

BACKGROUND/AIM: The clinical significance of many RAS-family mutations in colorectal cancer (CRC) remains unclear. The purpose of this study was to investigate the relationship of RAS mutations on an exon basis (i.e., mutations in KRAS exons 2, 3, and 4 and in NRAS) with clinicopathological features and prognosis in CRC. PATIENTS AND METHODS: We performed a retrospective cohort study of the medical records and frozen tissue samples of 268 consecutive patients with stage I-III CRC who underwent curative resection at a single institution between 2014 and 2018. RESULTS: The RAS mutation rate was significantly associated with age and histology. Patients with KRAS exon 2 mutations exhibited shorter recurrence-free survival compared to those with KRAS wild-type, KRAS exon 3 mutations, KRAS exon 4 mutations, and NRAS mutations (73.0% vs. 85.5%, 86.7%, 85.7%; p=0.031). Age and histology were independent risk factors for RAS mutations. RAS mutations were independent prognostic factors with respect to recurrence-free survival in patients with stage I-III CRC. CONCLUSION: In stage I-III CRC patients, KRAS exon 2 mutations had the worst prognosis, whereas KRAS wild type, exon 3 mutations, exon 4 mutations, and NRAS mutations had better prognoses.

Analysis of Circulating DNA to Assess Prognoses for Metastatic Colorectal Cancer Patients Treated with Regorafenib Dose-Escalation Therapy: A Retrospective, Exploratory Analysis of the RECC Trial.

INTRODUCTION: Regorafenib is a multi-kinase inhibitor approved for patients with metastatic colorectal cancer (mCRC) who were previously treated with standard therapies. A few reports showed the impact of KRAS mutation on therapeutic efficacy of regorafenib. Only one study reported poor prognoses for patients treated with regorafenib who had large amounts of circulating cell-free DNA (cfDNA). In the present study, we evaluated the impact of KRAS mutations in tissue or plasma and amounts of cfDNA on prognoses of mCRC patients treated with regorafenib. METHOD: This is a biomarker investigation of the RECC study, which evaluated efficacy of regorafenib dose-escalation therapy. Plasma samples were obtained just before initiation of treatment with regorafenib. KRAS mutations were evaluated using tissue and plasma samples. cfDNA was extracted from plasma samples and quantified. RESULTS: Forty-five patients were enrolled in this biomarker study. Median progression-free survival (PFS) and overall survival (OS) of patients without KRAS mutations in tissues were 1.9 months (95% confidence interval [CI] 1.7-2.0) and 8.9 months (95% CI: 6.5-11.2), and those of patients with KRAS mutations were 1.4 months (95% CI: 1.3-1.5) and 6.8 months (95% CI: 5.0-8.5). Median PFS and OS of patients with plasma KRAS mutations were 1.9 months (95% CI: 1.8-1.9) and 7.0 months (95% CI: 5.3-8.7), respectively. Median PFS and OS of patients without plasma KRAS mutations were 1.7 months (95% CI: 1.1-2.3) and 8.9 months (95% CI: 6.7-11.2), respectively. Prior to administration of regorafenib, KRAS mutations were detected in 6 of 16 (37.5%) patients who had no tissue KRAS mutations. Median OS of patients with high cfDNA concentration (>median) was significantly poorer than that of patients with low cfDNA. CONCLUSION: KRAS mutations in the tissue or plasma have no impact on efficacy of regorafenib. KRAS emerging mutations were observed in quite a few patients. Large amounts of cfDNA may indicate poorer prognoses for patients receiving late-line regorafenib chemotherapy.

Comprehensive data of 4502 patients newly diagnosed with colorectal liver metastasis between 2015 and 2017, and prognostic data of 2427 patients newly diagnosed with colorectal liver metastasis in 2013 and 2014: Third report of a nationwide survey in Japan.

To improve treatment outcomes in patients with colorectal liver metastasis (CRLM), the Joint Committee for Nationwide Survey on CRLM was established by the Japanese Society for Cancer of the Colon and Rectum and the Japanese Society of Hepato-Biliary-Pancreatic Surgery. The aim of the study was to evaluate transition in the characteristics and treatment strategy in CRLM patients and analyze prognostic factors using large-scale data. The present study summarizes the data of patients newly diagnosed between 2015 and 2017 and presents prognostic data of patients newly diagnosed in 2013 and 2014. Survival curves were generated by the Kaplan-Meier method and compared by log-rank test. Multivariate analyses were carried out using Cox proportional hazard modeling. The data of 4502 patients newly diagnosed with CRLM between 2015 and 2017 and the prognostic data of 2427 patients diagnosed in 2013 and 2014 are included. Regarding the 2013 and 2014 prognostic data, the 5-year overall survival (OS) rates of patients who underwent hepatectomy alone was 59.8%. Multivariate analyses identified age at diagnosis of CRLM ≥70 years, concomitant extrahepatic metastasis at diagnosis of CRLM, tumor depth of primary lesion ≥subserosa/pericolic or perirectal tissue, mutant KRAS status, number of CRLM ≥5, maximum diameter of CRLM >5 cm, and surgical curability R1/R2 as independent predictors of OS. Analysis of the latest nationwide database of patients diagnosed with CRLM revealed changes in patients and oncological characteristics, a transition in treatment strategy, and different independent prognosticators to those reported previously.

Validation study of the JSHBPS nomogram for patients with colorectal liver metastases who underwent hepatic resection in the recent era - a nationwide survey in Japan.

BACKGROUND: The Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) nomogram was developed to predict disease-free survival in patients with colorectal liver metastases (CRLM) undergoing upfront hepatectomy. However, the utility of the nomogram in patients with resected CRLM remains unknown in the current situation in which treatment strategies are changing with advances in drugs. METHODS: Patients in the initial nomogram cohort (n = 727) and validation cohort (n = 2225) were divided into the upfront hepatectomy and preoperative chemotherapy groups. The nomogram was validated by measuring calibration and discrimination in the two cohorts. Calibration curves were plotted, and survival probabilities were compared. Finally, to quantify the discrimination power, we estimated the concordance index (C-index). RESULTS: In the upfront hepatectomy group, the C-index was 0.63, the suitable cutoff value of the Beppu score was 7, and adjuvant chemotherapy was significantly effective limited to high-risk patients (Beppu score ≥7). The C-index was 0.56 in the preoperative chemotherapy group. CONCLUSIONS: The JSHBPS nomogram remains beneficial for patients undergoing upfront hepatectomy in the recent era but is less effective for patients undergoing hepatectomy after chemotherapy. Patients with a Beppu score ≥7 showed high-risk recurrence, and adjuvant chemotherapy should be recommended for these patients.

Impact of early tumor shrinkage on quality of life in patients treated with first-line cetuximab plus chemotherapy for unresectable metastatic colorectal cancer: results of Phase II QUACK trial.

PURPOSE: Although early tumor shrinkage (ETS) is a predictor of improved overall survival (OS), the association between ETS and health-related quality of life (HRQOL) remains unclear for patients with metastatic colorectal cancer (mCRC) treated with first-line cetuximab plus chemotherapy. METHODS: The data were collected from a prospective trial that assessed HRQOL using the EORTC QLQ-C30. The impact of ETS on HRQOL was estimated using a linear mixed-effects model for repeated measures. RESULTS: ETS was achieved in 82 (64.1%) of 128 mCRC patients treated with first-line cetuximab plus chemotherapy, and these patients had a significantly longer OS than those without ETS (HR, 0.38; 95% CI, 0.20-0.72; P = .002). Asymptomatic patients with ETS had a favorable OS, while symptomatic patients without ETS had a worse OS (2-year OS rates, 77.8% vs. 42.5%). Symptomatic patients with ETS had similar outcomes as asymptomatic patients without ETS (2-year OS rates, 64.1% vs. 67.0%). For symptomatic patients, ETS was associated with improved HRQOL scores between baseline and 8 weeks: the mean changes for patients with and without ETS were 5.86 and -4.94 for global health status (GHS)/QOL, 26.73 and 3.79 for physical functioning, and 13.58 and -3.10 for social functioning, respectively. The improved HRQOL was comparable to that of asymptomatic patients without ETS. For asymptomatic patients, ETS showed a decreased deterioration in HRQOL. CONCLUSION: Our findings highlight the importance of ETS for HRQOL and prognostic estimates, and assessing ETS may provide clinically useful information for physicians and patients to make more informed decisions.

Efficacy and safety of regorafenib dose-escalation therapy for Japanese patients with refractory metastatic colorectal cancer (RECC study).

BACKGROUND: Regorafenib significantly improves overall survival in previously treated metastatic colorectal cancer patients. However, various toxicities, such as hand-foot skin reaction (HFSR), fatigue, and liver dysfunction have limited the use of regorafenib. These toxicities appear soon after treatment initiation. The ReDOS study demonstrated the effectiveness of a weekly dose-escalation therapy of regorafenib starting with a lower daily dose; however, its usefulness in Asian subjects is unknown. We conducted a phase II study to evaluate the safety and survival benefit of regorafenib dose-escalation therapy for Japanese patients. METHODS: Patients with sufficient organ function, who had previously received more than two lines of chemotherapy were included. Regorafenib was started at 80 mg/day and escalated to 120 mg/day in Week 2 and 160 mg/day in Week 3, if no severe drug-related toxicities were observed. The primary endpoint was cancer progression-free survival (PFS). Tumor response and progression were assessed radiologically every 8 weeks. This study was registered in the University Hospital Medical Information Network (UMIN#UMIN000028933). RESULTS: 57 patients were enrolled and all started regorafenib at 80 mg/day. 32 patients (56.1%) were subsequently escalated to 120 mg/day and 19 (33.3%) to 160 mg/day. Only 8 patients (14.0%) discontinued treatment because of adverse events. Median PFS was 1.9 months. Median overall survival was 8.9 months, the response rate was 0%, and the disease control rate was 31.6%. The most frequent adverse event greater than grade 3 was hypertension (19.3%), followed by HFSR (14.0%). CONCLUSIONS: Regorafenib dose-escalation therapy is well tolerated with PFS-like regorafenib standard therapy.

The preoperative geriatric nutritional risk index (GNRI) is an independent prognostic factor in elderly patients underwent curative resection for colorectal cancer.

The world is becoming longer-lived, and the number of elderly colorectal cancer patients is increasing. It is very important to identify simple and inexpensive postoperative predictors in elderly colorectal cancer patients. The geriatric nutritional risk index (GNRI) is a marker of systemic nutrition and is associated with poor survival in various kinds of cancers. A few reports have investigated recurrence factors using preoperative GNRI with CRC (colorectal cancer) patients. This study aimed to investigate whether preoperative GNRI is associated with recurrence-free survival (RFS) and overall survival (OS) in elderly patients with CRC. This study retrospectively enrolled 259 patients with Stage I-III CRC who were more than 65 years old and underwent curative surgery at a single institution in 2012-2017. We classified them into low GNRI (RFS: ≤ 90.5, OS ≤ 101.1) group and high GNRI (RFS: > 90.5, OS > 101.1) group. Multivariable analyses showed low GNRI group was an independent risk factor for 3-year RFS (P = 0.006) and OS (P = 0.001) in the patients with CRC. Kaplan-Meier analysis showed 3-year RFS and 3-year OS were significantly worse in the low GNRI group than in high GNRI group (p = 0.001, 0.0037). A low-preoperative GNRI was significantly associated with a poor prognosis in elderly CRC patients.

Optimizing nodal and staging classification in low rectal cancers with lateral node metastasis: multicentre retrospective cohort study.

BACKGROUND: Patients with lateral node metastasis in low rectal cancers have a poor prognosis. However, variability in patient survival in terms of lateral metastatic status has not been thoroughly investigated. This study was conducted to assess the prognostic value of lateral node involvement and to review nodal classification. METHODS: Patients with stage III low rectal cancers who underwent lateral node dissection were retrospectively reviewed. Two cohorts were set: the first one (1995-2006) was selected using a Japanese multi-institutional database and was used for development of a new nodal system, and the second (2007-2013) was collected from referral institutions for validation of findings. Variables correlated with poor prognosis were investigated. Next, a modified classification of lateral-positive nodal cancers was created. Finally, this new classification was compared with TNM and Japanese classification-based systems according to the Akaike information criterion (AIC) and concordance index (c-index). RESULTS: Overall, 742 and 508 patients were selected for cohorts 1 and 2, respectively. Based on the analyses on cohort 1, patients with two or more lateral metastatic nodes partially spreading into regions outside of internal iliac area exhibited poor prognosis; accordingly, a modified N classification was created, where TNM-N1 and N2a cancers with this feature were upgraded, respectively, to N2a and N2b. The modified N classification yielded the most favourable indices (AIC = 2661.08; c-index = 0.6477) compared with the TNM (AIC = 2662.36; c-index = 0.6457) and Japanese classification-based systems (AIC = 2684.06; c-index = 0.6302). All findings were confirmed by analysing cohort 2. CONCLUSION: A modified nodal system is proposed to account for the significance of lateral node metastasis.

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.

Predicting Overall Survival Using Preoperative Nutritional and Inflammation Status for Colorectal Cancer.

AIM: It has been shown that nutritional status and inflammation correlate with survival in patients with various cancer types. In this study, we evaluated several kinds of nutritional and inflammation parameters in preoperative blood samples and constructed new risk model predicting survival in patients with colorectal cancer. PATIENTS AND METHODS: We retrospectively examined 286 patients with stage I-III colorectal cancer who had undergone curative resection at Teikyo University Hospital. The association between overall survival (OS) and nutritional status and inflammation factors were examined using Kaplan-Meier curves and log-rank tests. RESULTS: Serum albumin, cholesterol and C-reactive protein concentration, neutrophil count and platelet count were shown to be correlated with OS. We constructed a new risk model (nutrition inflammation status, NIS) using these factors, and compared it with other nutrition and inflammation models. CONCLUSION: NIS was useful as a new model for predicting OS in patients undergoing curative resection for colorectal cancer, compared with known models.

HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability.

BACKGROUND & AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability-high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.