Low blood level of tumour suppressor miR-5193 as a target of immunotherapy to PD-L1 in gastric cancer.

BACKGROUND: Recent studies have identified that low levels of some tumour suppressor microRNAs (miRNAs) in the blood contribute to tumour progression and poor outcomes in various cancers. However, no study has proved these miRNAs are associated with cancer immune mechanisms. METHODS: From a systematic review of the NCBI and miRNA databases, four tumour suppressor miRNA candidates were selected (miR-5193, miR-4443, miR-520h, miR-496) that putatively target programmed cell death ligand 1 (PD-L1). RESULTS: Test-scale and large-scale analyses revealed that plasma levels of miR-5193 were significantly lower in gastric cancer (GC) patients than in healthy volunteers (HVs). Low plasma levels of miR-5193 were associated with advanced pathological stages and were an independent prognostic factor. Overexpression of miR-5193 in GC cells suppressed PD-L1 on the surface of GC cells, even with IFN-γ stimulation. In the coculture model of GC cells and T cells stimulated by anti-CD3/anti-CD28 beads, overexpression of miR-5193 increased anti-tumour activity of T cells by suppressing PD-L1 expression. Subcutaneous injection of miR-5193 also significantly enhanced the tumour-killing activity and trafficking of T cells in mice. CONCLUSIONS: Low blood levels of miR-5193 are associated with GC progression and poor outcomes and could be a target of nucleic acid immunotherapy in GC patients.

Minimally Invasive transCervical oEsophagectomy (MICE) for oesophageal cancer: prospective cohort study (IDEAL stage 2A).

BACKGROUND: Minimally invasive transcervical oesophagectomy is a surgical technique that offers radical oesophagectomy without the need for transthoracic access. The aim of this study was to evaluate the safety and feasibility of the minimally invasive transcervical oesophagectomy procedure and to report the refinement of this technique in a Western cohort. METHODS: A single-centre prospective cohort study was designed as an IDEAL stage 2A study. Patients with oesophageal cancer (cT1b-4a N0-3 M0) who were scheduled for oesophagectomy with curative intent were eligible for inclusion in the study. The main outcome parameter was the postoperative pulmonary complication rate and the secondary outcomes were the anastomotic leakage, recurrent laryngeal nerve palsy, and R0 resection rates, as well as the lymph node yield. RESULTS: In total, 75 patients underwent minimally invasive transcervical oesophagectomy between January 2021 and November 2023. Several modifications to the surgical technique were registered, evaluated, and implemented in the context of IDEAL stage 2A. A total of 12 patients (16%) had postoperative pulmonary complications, including pneumonia (4 patients) and pleural effusion with drainage or aspiration (8 patients). Recurrent laryngeal nerve palsy was observed in 33 of 75 patients (44%), with recovery in 30 of 33 patients (91%). A total of 5 of 75 patients (7%) had anastomotic leakage. The median number of resected lymph nodes was 29 (interquartile range 22-37) and the R0 resection rate was 96% (72 patients). CONCLUSION: Introducing minimally invasive transcervical oesophagectomy for oesophageal cancer in a Dutch institution is associated with a low rate of postoperative pulmonary complications and a high rate of temporary recurrent laryngeal nerve palsy.

Urinary microRNA-210-3p as a novel and non-invasive biomarker for the detection of pancreatic cancer, including intraductal papillary mucinous carcinoma.

BACKGROUND: This study aims to explore novel microRNAs in urine for screening and predicting clinical characteristics in pancreatic cancer (PC) patients using a microRNA array-based approach. METHODS: We used the Toray® 3D-Gene microRNA array-based approach to compare urinary levels between PC patients and healthy volunteers. RESULTS: (1) Four oncogenic microRNAs (miR-744-5p, miR-572, miR-210-3p, and miR-575) that were highly upregulated in the urine of PC patients compared to healthy individuals were identified by comprehensive microRNA array analysis. (2) Test-scale analysis by quantitative RT-PCR for each group of 20 cases showed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P = 0.009). (3) Validation analysis (58 PC patients and 35 healthy individuals) confirmed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P < 0.001, area under the receiver operating characteristic curve = 0.79, sensitivity: 0.828, specificity: 0.743). We differentiated PC patients into invasive ductal carcinoma (IDCa) and intraductal papillary mucinous carcinoma (IPMC) groups. In addition to urinary miR-210-3p levels being upregulated in IDCa over healthy individuals (P = 0.009), urinary miR-210-3p levels were also elevated in IPMC over healthy individuals (P = 0.0018). Urinary miR-210-3p can differentiate IPMC from healthy individuals by a cutoff of 8.02 with an AUC value of 0.762, sensitivity of 94%, and specificity of 63%. (4) To test whether urinary miR210-3p levels reflected plasma miR-210-3p levels, we examined the correlation between urinary and plasma levels. Spearman's correlation analysis showed a moderate positive correlation (ρ = 0.64, P = 0.005) between miR-210-3p expression in plasma and urine. CONCLUSIONS: Urinary miR-210-3p is a promising, non-invasive diagnostic biomarker of PC, including IPMC. TRIAL REGISTRATION: Not applicable.

Risk assessment for pancreatic fistula by intraoperative image analysis of laparoscopic and robotic gastrectomy.

BACKGROUND: Pancreatic fistula (PF) is one of the most serious postoperative complications of gastrectomy. Misidentification of the boundary between the pancreas and the dissected fat is a primary concern. In this study, we focused on differences in the appearance of the pancreas and the dissected fat in actual surgical images and statistically analyzed the relationship between the pancreas and the dissected fat. METHODS: We analyzed data from 109 gastric cancer patients who underwent curative gastrectomy between November 2018 and March 2023. Intraoperative images were taken from videos of lymph node dissections of Nos.6 and 8a regions, and the mean gray value of the areas was measured using ImageJ software for analysis. The visceral fat area (VFA) was evaluated by preoperative axial CT at the umbilical level using Ziostation software. RESULTS: A significant correlation was observed between the fat/pancreas gray value ratio in the No.8a lymph node region and the drain/serum amylase ratio (P < 0.001). The fat/pancreas gray value ratio in the No.6 lymph node region correlated with VFA (P < 0.001). The VFA and drain/serum amylase ratio were significantly higher in the group with intra-abdominal complications (P = 0.004). CONCLUSIONS: We revealed significant relationships between the fat/pancreas gray value ratio with drain/serum amylase and VFA. Detecting differences in gray values between the pancreas and the dissected fat may lead to a decrease in the drain/serum amylase ratio and PF.

Evaluation of ventral branches of segment VI portal vein relative to the right hepatic vein in laparoscopic right anterior sectionectomy.

INTRODUCTION: The right intersectional plane and the right hepatic hilum were noted too often exhibit anatomical variations, making difficult the laparoscopic right anterior sectionectomy (LRAS). METHODS: We analyzed the anatomical features employing 3D-CT images of 55 patients, and evaluated these features according to the course of ventral branches of segment VI of the portal vein (PV, P6a) relative to the right hepatic vein (RHV). RESULTS: P6a run on the dorsal side of RHV in 32 patients (58%, Dorsal-P6a) and the ventral side of RHV in 23 (42%, Ventral-P6a). Ventral-P6a had more patients with S6 partially drained by middle hepatic vein (MHV, 39% vs. 0%, P < 0001), the narrower angle between the anterior and posterior branches of PV (73.1° vs. 93.8°, P = 0.006), the wider angle between the RHV and inferior vena cava  (54.3° vs. 44.3°, P < 0.001), and more steeply pitched angle between S6 and S7 along the RHV (140.6° vs. 162.0°, P < 0.001) compared to Dorsal-P6a. CONCLUSION: In LRAS for Dorsal-P6a patients, the transection surface was relatively flat. In LRAS for Ventral-P6a patients, the narrow space between anterior and posterior glissons makes difficult the glissonean approach. The transection plane was steeply pitched, and RHV was partially exposed. S6 was often partially drained to MHV in 39% of the Ventral-P6a patients, which triggers congestion during liver transection of a right intersectional plane after first splitting the confluence of this branch.

Lymphovascular invasion is associated with poor long-term outcomes in patients with pT1N0-3 or pT2-3N0 remnant gastric cancer: a retrospective cohort study.

BACKGROUND: Lymphovascular invasion (LVI) is a poor prognostic factor in various malignancies. However, its prognostic effect in remnant gastric cancer (RGC) remains unclear. We examined the correlation between LVI and disease prognosis in patients with T1N0-3 or T2-3N0 RGC in whom adjuvant chemotherapy was not indicated and a treatment strategy was not established. METHODS: We retrospectively analyzed patients with T1N0-3 and T2-3N0 RGC who underwent curative surgery at the Kyoto Prefectural University of Medicine between 1997 and 2019 and at the Kyoto Chubu Medical Center between 2009 and 2019. RESULTS: Fifteen of 38 patients (39.5%) with RGC were positive for LVI. Patients with LVI had a significantly poorer prognosis for both overall survival ([OS]: P = 0.006) and recurrence-free survival ([RFS]: P = 0.001) than those without LVI. Multivariate analyses using the Cox proportional hazards model revealed LVI as an independent prognostic factor affecting OS (P = 0.024; hazard ratio 8.27, 95% confidence interval:1.285-161.6) and RFS (P = 0.013; hazard ratio 8.98, 95% confidence interval:1.513-171.2). CONCLUSIONS: LVI is a prognostic factor for patients with T1N0-3 or T2-3N0 RGC. Evaluating LVI may be useful for determining treatment strategies for RGC.

The impact of preoperative skeletal muscle loss on the completion of S-1 adjuvant chemotherapy for gastric cancer.

PURPOSE: Body weight loss after surgery for gastric cancer is related to S-1 compliance and it also affects the prognosis. However, it is unclear whether the preoperative skeletal muscle mass affects S-1 completion for gastric cancer. We investigated the impact of preoperative skeletal muscle mass loss on the completion of S-1 adjuvant chemotherapy for gastric cancer. METHODS: We retrospectively analyzed data from 53 patients who underwent curative gastrectomy followed by adjuvant S-1 monotherapy for pStage II-III gastric cancer between 2012 and 2021 at our hospital. The psoas muscle mass index (PMI) was used as the index for preoperative skeletal muscle mass. RESULTS: Thirty-six patients completed S-1 treatment and 17 discontinued treatment. The patients who completed S-1 treatment had a longer overall survival than those who discontinued treatment (log-rank test, p = 0.043). According to a univariate analysis, the patients in the discontinuation group had a significantly lower preoperative body mass index (< 22.9 kg/m2, p = 0.005) and a higher rate of adverse events (grade 2 or higher, p < 0.001) than those in the completion group. According to a multivariate analysis, preoperative PMI (HR 3.563, p = 0.030) was an independent predictive factor for S-1 completion. CONCLUSION: Preoperative skeletal muscle loss might therefore prevent the completion of adjuvant chemotherapy S-1 in patients with gastric cancer.

Impact of hypoglycemia after gastrectomy on Global Leader Initiative on Malnutrition-defined malnutrition: a retrospective study.

PURPOSE: The Global Leader Initiative on Malnutrition (GLIM) criteria were developed in 2018 as a global indicator of malnutrition, and the term 'malnutrition-sarcopenia syndrome' was established. Recently, it has been reported that fluctuations in blood glucose are related to sarcopenia. In this study, we investigated the effects of glucose fluctuations on malnutrition after gastrectomy using a continuous glucose monitoring (CGM) device. METHODS: We analyzed the data of 69 patients with gastric cancer (GC) who underwent curative gastrectomy between November 2017 and December 2020. CGM was performed over a 2-week period at 1 month and 1 year after surgery. The GLIM criteria included weight loss, the body mass index (BMI), and the psoas muscle mass index (PMI). RESULTS: One year after surgery, 25 and 35 patients had severe and moderate malnutrition, respectively. The time below range (TBR) (percent of time the glucose concentration was < 70 mg/dL) and nocturnal (00:00-06:00) TBR were significantly higher in the severe malnutrition group than in the other groups (TBR: normal/moderate 17.9% vs. severe 21.6%, P = 0.039, nocturnal TBR; normal/moderate 30.6% vs. severe 41.1%, P = 0.034). CONCLUSIONS: Post-gastrectomy hypoglycemia, including long nocturnal hypoglycemia, was higher in severely malnourished patients than in other patients even 1 year after surgery. Prevention of nocturnal hypoglycemia may be the key to improving malnutrition following gastrectomy.

Plasma microRNA-192-5p can predict the response to neoadjuvant chemotherapy and prognosis in esophageal cancer.

Esophageal cancer (EC) is the sixth leading cause of cancer-related death worldwide. Recently, neoadjuvant chemotherapy (NAC) before curative surgery has become a standard treatment for clinical stage II or III EC patients. Some EC patients receive a complete response (CR) by NAC; thus, curative surgery may be unnecessary for such patients. MicroRNA levels in plasma have the potential to be a predictor of response to NAC. In the present study, we focused on miR-192-5p, which is highly expressed in EC tissue. The purpose was to investigate the correlations between levels of plasma miR-192-5p and the response to NAC. Furthermore, molecular functions of miR-192-5p associated with chemosensitivity were examined using EC cell lines. The levels of miR-192-5p in plasma before surgery were evaluated in 113 EC patients. Sixty-nine patients received NAC. miR-192-5p levels in the CR group were significantly higher than in the other groups (p = 0.002). The downregulation of miR-192-5p in the EC cell line inhibited sensitivity to cisplatin, and the overexpression of miR-192-5p in the EC cell line promoted sensitivity to cisplatin. miR-192-5p regulated sensitivity to cisplatin by targeting ERCC3 and ERCC4. Plasma miR-192-5p could be used as a predictor of response to chemotherapy and prognosis in EC patients.

Plasma miR-1254 as a predictive biomarker of chemosensitivity and a target of nucleic acid therapy in esophageal cancer.

This study investigated novel tumor suppressor microRNAs (miRNAs) that decrease in plasma and predict chemosensitivity to neoadjuvant chemotherapy (NAC) for esophageal squamous cell carcinoma (ESCC) and revealed their usefulness as novel therapeutic agents. We selected four miRNA candidates (miR-323, 345, 409, and 1254) based on the microRNA microarray comparing pre-treatment plasma levels in ESCC patients with high and low histopathological responses to NAC and an NCBI database review. Among these miRNA candidates, miR-1254 was more highly elevated in pre-treatment plasma of ESCC patients with a high histopathological response than in those with a low histopathological response (P = 0.0021, area under the receiver-operating characteristic curve 0.7621). High plasma miR-1254 levels tended to correlate with the absence of venous invasion (P = 0.0710) and were an independent factor predicting a higher response to chemotherapy (P = 0.0022, odds ratio 7.86) and better prognosis (P = 0.0235, hazard ratio 0.23). Overexpressing miR-1254 in ESCC cells significantly enhanced chemosensitivity to cisplatin through the transcriptional regulation of ABCC1 in vitro. Moreover, increased plasma miR-1254 levels by subcutaneous injection significantly improved responses to cisplatin in mice. Plasma miR-1254 might be a useful biomarker for predicting responses to NAC, and the restoration of plasma miR-1254 levels might improve chemosensitivity in ESCC.

Cancer Stem Cells of Esophageal Adenocarcinoma are Suppressed by Inhibitors of TRPV2 and SLC12A2.

BACKGROUND: The potential of membrane transporters activated in cancer stem cells (CSCs) as new therapeutic targets for cancer is attracting increasing interest. Therefore, the present study examined the expression profiles of ion transport-related molecules in the CSCs of esophageal adenocarcinoma (EAC). METHODS: Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from OE33 cells, a human Barrett's EAC cell line, by fluorescence-activated cell sorting. CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were examined by a microarray analysis. RESULTS: Among OE33 cells, ALDH1A1 messenger RNA levels were higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels/transporters, such as transient receptor potential vanilloid 2 (TRPV2) and solute carrier family 12 member 2 (SLC12A2). The cytotoxicities of the TRPV2 inhibitor tranilast and the SLC12A2 inhibitor furosemide were higher at lower concentrations in CSCs than in non-CSCs, and both markedly reduced the number of tumorspheres. The cell population among OE33 cells that highly expressed ALDH1A1 also was significantly decreased by these inhibitors. CONCLUSIONS: Based on the present results, TRPV2 and SLC12A2 are involved in the maintenance of CSCs, and their specific inhibitors, tranilast and furosemide, respectively, have potential as targeted therapeutic agents for EAC.

Effects of TRPV2 on the Expression of PD-L1 and Its Binding Ability to PD-1 in Gastric Cancer.

BACKGROUND: Transient receptor potential vanilloid 2 (TRPV2) is a member of the TRP superfamily of non-specific cation channels with functionally diverse roles. We herein investigated the effects of TRPV2 on the expression of programmed cell death-ligand 1 (PD-L1) and its binding ability to programmed cell death-1 (PD-1) in gastric cancer (GC). METHODS: Knockdown (KD) experiments were performed on human GC cell lines using TRPV2 small-interfering RNA. The surface expression of PD-L1 and its binding ability to PD-1 were analyzed by flow cytometry. Eighty primary tissue samples were assessed by immunohistochemistry (IHC), and the relationships between IHC results, clinicopathological factors, and patient prognosis were analyzed. The molecular mechanisms underlying the effects of TRPV2 on the intracellular ion environment were also investigated. RESULTS: TRPV2-KD decreased the expression level of PD-L1 in NUGC4 and MKN7 cells, thereby inhibiting its binding to PD-1. A survival analysis revealed that 5-year overall survival rates were significantly lower in the TRPV2 high expression and PD-L1-positive groups. In IHC multivariate analysis of GC patients, high TRPV2 expression was identified as an independent prognostic factor. Furthermore, a positive correlation was observed between the expression of TRPV2 and PD-L1. An immunofluorescence analysis showed that TRPV2-KD decreased the intracellular concentration of calcium ([Ca2+]i). Treatment with ionomycin/PMA (phorbol 12-myristate 13-acetate), which increased [Ca2+]i, upregulated the protein expression of PD-L1 and promoted its binding to PD-1. CONCLUSIONS: The surface expression of PD-L1 and its binding ability to PD-1 in GC were regulated by TRPV2 through [Ca2+]i, indicating the potential of TRPV2 as a biomarker and target of immune checkpoint blockage for GC.

Functional Analysis and Clinical Importance of ATP1A1 in Colon Cancer.

BACKGROUND: Na+/K+-ATPase α1 subunit (ATP1A1) exhibits aberrant expression in various types of cancer. Moreover, its levels in specific tissues are associated with the development of cancer. Nevertheless, the mechanism and signaling pathways underlying the effects of ATP1A1 in colon cancer (CC) have not been elucidated, and its prognostic impact remains unknown. METHODS: Knockdown of ATP1A1 expression was performed in human CC cell lines HT29 and Caco2 using small interfering RNA. The roles of ATP1A1 in various biological processes of cells (i.e., proliferation, cell cycle, apoptosis, migration, and invasion) were assessed. Microarray analysis was utilized for gene expression profiling. Samples obtained from 200 patients with CC who underwent curative colectomy were analyzed through immunohistochemistry. RESULTS: ATP1A1 knockdown suppressed cell proliferation, migration, and invasion and induced apoptosis. The results of the microarray analysis revealed that the upregulated or downregulated gene expression in ATP1A1-depleted cells was related to the extracellular signal-regulated kinase 5 (ERK5) signaling pathway [epidermal growth factor receptor (EGFR), mitogen-activated protein kinase kinase 5 (MAP2K5), mitogen-activated protein kinase 7 (MAPK7), FOS, MYC, and BCL2 associated agonist of cell death (BAD)]. Immunohistochemical analysis demonstrated a correlation between ATP1A1 expression and pathological T stage (p = 0.0054), and multivariate analysis identified high ATP1A1 expression as an independent predictor of poor recurrence-free survival in patients with CC (p = 0.0040, hazard ratio: 2.807, 95% confidence interval 1.376-6.196). CONCLUSIONS: ATP1A1 regulates tumor progression through the ERK5 signaling pathway. High ATP1A1 expression is associated with poor long-term outcomes in patients with CC.

Evaluating prognostic value and stage migration effects using a positive lymph node ratio in adenocarcinoma of the esophagogastric junction.

BACKGROUND: Adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide. Lymph node metastasis is an important clinical issue in AEG patients. This study investigated the usefulness of a positive lymph node ratio (PLNR) to stratify prognosis and evaluate stage migration. METHODS: We retrospectively analysed 117 consecutive AEG patients (Siewert type I or II) who received a lymphadenectomy between 2000 and 2016. RESULTS: A PLNR cut-off value of 0.1 most effectively stratified patient prognosis into two groups (P < 0.001). Also, prognosis could be clearly stratified into four groups: PLNR = 0, 0 < PLNR < 0.1, 0.1 ≤ PLNR < 0.2, and 0.2 ≤ PLNR (P < 0.001, 5-year survival rates (88.6%, 61.1%, 34.3%, 10.7%)). A PLNR ≥ 0.1 significantly correlated with tumour diameter ≥ 4 cm (P < 0.001), tumour depth (P < 0.001), greater pathological N-status (P < 0.001), greater pathological Stage (P < 0.001), and oesophageal invasion length ≥ 2 cm (P = 0.002). A PLNR ≥ 0.1 was a poor independent prognostic factor (hazard ratio 6.47, P < 0.001). The PLNR could stratify prognosis if at least 11 lymph nodes were retrieved. A 0.2 PLNR cut-off value discriminated a stage migration effect in pN3 and pStage IV (P = 0.041, P = 0.015) patients; PLNR ≥ 0.2 might potentially diagnose a worse prognosis and need meticulous follow-up post-surgery. CONCLUSION: Using PLNR, we can evaluate the prognosis and detect higher malignant cases who need meticulous treatments and follow-up in the same pStage.

A shorter distal resection margin is a surrogate marker of nodal metastasis and poor prognosis in distal gastrectomy for advanced gastric cancer.

BACKGROUND: Although a 3-5 cm surgical margin distance is recommended for advanced gastric cancer (GC) in Japanese guidelines, little is known about the clinical effects of the surgical margin, especially the distal resection margin (DM). This study aims to clarify the clinical significance of DM in GC. METHODS: A total of 415 GC patients who underwent curative distal gastrectomy between 2008 and 2018 were analyzed retrospectively. RESULTS: The DM significantly stratified recurrence-free survival (P = 0.002), and a DM < 30 mm was an independent factor of a poor prognosis (P = 0.023, hazard ratio: 1.91). Lymphatic recurrence occurred significantly more frequently in the DM < 30 mm group than in the DM ≥ 30 mm group (P = 0.019, 6.9% vs. 1.9%). Regarding the station No.6 lymph node metastases in advanced GC (DM < 30 mm vs. 30 mm ≤ DM ≤ 50 mm vs. DM > 50 mm), the number (P < 0.001, 1.42 ± 1.69 vs. 1.18 ± 1.80 vs. 0.18 ± 0.64), the positive rate (P < 0.001, 59.0% vs. 46.7% vs. 11.3%) and therapeutic value index (43.3 vs. 14.5 vs. 8.0) were significantly higher in the DM < 30 mm group. By subdivision using the DM distance of 30 mm, more segmented prognostic stratifications were possible (P < 0.001). CONCLUSIONS: A DM of less than 30 mm could be a surrogate marker of poor RFS, especially increasing nodal recurrence. More intensive treatment strategies, including lymphadenectomy and chemotherapy, are needed for patients with this condition.

Value of the Tumor-Stroma Ratio and Structural Heterogeneity Measured by a Novel Semiautomatic Image Analysis Technique for Predicting Survival in Patients With Colon Cancer.

BACKGROUND: The tumor-stroma ratio and intratumor stromal heterogeneity have been identified as prognostic factors for several carcinomas. Recent advancements in image analysis technologies and their application to medicine have enabled detailed analysis of clinical data beyond human cognition. OBJECTIVE: This study aimed to investigate the tumor-stroma ratio and intratumor stromal heterogeneity measured using a novel objective and semiautomatic method with image analysis. DESIGN: A retrospective cohort design. SETTINGS: Single institution. PATIENTS: This study included patients who underwent curative colectomy for colon cancer. MAIN OUTCOME MEASURES: The survival analyses between tumor-stroma ratio or intratumor stromal heterogeneity high and low groups after colectomy were assessed in multivariate analyses. RESULTS: Two hundred patients were divided into 2 groups based on the median tumor-stroma ratio and intratumor stromal heterogeneity values. The 5-year overall survival and relapse-free survival rates after colectomy significantly differed between the high and low tumor-stroma ratio or intratumor stromal heterogeneity groups. Multivariate analysis identified low tumor-stroma ratio (HR: 1.90, p = 0.03) and high intratumor stromal heterogeneity (HR: 2.44, p = 0.002) as independent poor prognostic factors for relapse-free survival. The tumor-stroma ratio and intratumor stromal heterogeneity correlated with the duration from curative surgery to recurrence. Furthermore, postoperative recurrence within 2 years was predicted with higher accuracy by using the tumor-stroma ratio or intratumor stromal heterogeneity than by using the pathological stage. In a validation cohort, interobserver agreement was assessed by 2 observers, and Cohen's κ coefficient for the tumor-stroma ratio (κ value: 0.70) and intratumor stromal heterogeneity (κ value: 0.60) revealed a substantial interobserver agreement. LIMITATIONS: This study was limited by its retrospective, single-institution design. CONCLUSIONS: Tumor-stroma ratio and intratumor stromal heterogeneity calculated using image analysis software have potential as imaging biomarkers for predicting the survival of patients with colon cancer after colectomy. See Video Abstract at http://links.lww.com/DCR/C114 . VALOR DE LA PROPORCIN DE ESTROMA TUMORAL Y LA HETEROGENEIDAD ESTRUCTURAL MEDIDOS POR UNA NUEVA TCNICA DE ANLISIS DE IMGENES SEMIAUTOMTICA PARA PREDECIR LA SUPERVIVENCIA EN PACIENTES CON CNCER DE COLON: ANTECEDENTES:La proporción de estroma tumoral y la heterogeneidad del estroma intratumoral han sido identificados como factores pronósticos para varios tipos de carcinomas. Los avances recientes en cuanto a las tecnologías de análisis de imágenes y sus aplicaciones en la medicina, han permitido un análisis detallado de los datos clínicos más allá del conocimiento humano.OBJETIVO:Investigar la relación del estroma tumoral y la heterogeneidad del estroma intratumoral calculados mediante un nuevo método objetivo y semiautomático para el análisis de imágenes.DISEÑO:Diseño de cohorte retrospectivo.AJUSTES:Institución única.PACIENTES:Pacientes sometidos a colectomía curativa por cáncer de colon.PRINCIPALES MEDIDAS DE RESULTADO:Los análisis de supervivencia entre la relación del estroma tumoral o la heterogeneidad del estroma intratumoral entre los grupos con valores altos y bajos tras la colectomía, fueron evaluados en análisis multivariados.RESULTADOS:Fueron divididos 200 pacientes en dos grupos basados en la mediana de la proporción con respecto a los valores del estroma tumoral y la heterogeneidad del estroma intratumoral. Las tasas de supervivencia general a los 5 años y de supervivencia libre de recaídas después de la colectomía, difirieron significativamente entre los grupos con índice de estroma tumoral o heterogeneidad del estroma intratumoral altos y bajos. El análisis multivariante identificó una proporción de estroma tumoral baja (cociente de riesgos instantáneos: 1.90, p = 0.03) y una heterogeneidad estromal intratumoral alta (cociente de riesgos instantáneos: 2.44, p = 0.002) como factores independientes de mal pronóstico para la supervivencia libre de recaídas. La proporción de estroma tumoral y la heterogeneidad del estroma intratumoral se correlacionaron con la duración de la recurrencia desde la cirugía.Además, la recurrencia posoperatoria dentro de los 2 años se predijo con mayor precisión mediante el uso del índice de estroma tumoral o la heterogeneidad del estroma intratumoral que mediante el uso del estadio patológico. En una cohorte de validación, la concordancia interobservador fue evaluada por dos observadores, y el coeficiente Kappa de Cohen para la proporción de estroma tumoral y la heterogeneidad estromal intratumoral reveló una concordancia interobservador sustancial (valor Kappa: 0.70, 0.60, respectivamente).LIMITACIONES:Este estudio estuvo limitado por su diseño retrospectivo de una sola institución.CONCLUSIONES:La proporción del estroma tumoral y la heterogeneidad del estroma intratumoral calculadas mediante software de análisis de imágenes tienen potencial como biomarcadores de imagen para predecir la supervivencia de los pacientes con cáncer de colon tras la colectomía. Consulte Video Resumen en http://links.lww.com/DCR/C114 . (Traducción-Dr. Osvaldo Gauto ).

Postoperative liver dysfunction is associated with poor long-term outcomes in patients with colorectal cancer: a retrospective cohort study.

BACKGROUND: Postoperative hepatobiliary enzyme abnormalities often present as postoperative liver dysfunction in patients with colorectal cancer. This study aimed to clarify the risk factors of postoperative liver dysfunction and its prognostic impact following colorectal cancer surgery. METHODS: We retrospectively analyzed data from 360 consecutive patients who underwent radical resection for Stage I-IV colorectal cancer between 2015 and 2019. A subset of 249 patients with Stage III colorectal cancer were examined to assess the prognostic impact of liver dysfunction. RESULTS: Forty-eight (13.3%) colorectal cancer patients (Stages I-IV) developed postoperative liver dysfunction (Common Terminology Criteria for Adverse Events version 5.0 CTCAE v5.0 ≥ Grade 2). Univariate and multivariate analyses identified the liver-to-spleen ratio on preoperative plain computed tomography (L/S ratio; P = 0.002, Odds ratio 2.66) as an independent risk factor for liver dysfunction. Patients with postoperative liver dysfunction showed significantly poorer disease-free survival than patients without liver dysfunction (P < 0.001). Univariate and multivariate analyses using Cox's proportional hazards model revealed that postoperative liver dysfunction independently was a poor prognostic factor (P = 0.001, Hazard ratio 2.75, 95% CI: 1.54-4.73). CONCLUSIONS: Postoperative liver dysfunction was associated with poor long-term outcomes in patients with Stage III colorectal cancer. A low liver-to-spleen ratio on preoperative plain computed tomography images was an independent risk factor of postoperative liver dysfunction.

Impact of the preoperative clinical N stage on the prognosis of patients with colon cancer.

AIM: Although preoperative clinical staging (cStage) is performed for most cancer patients, limited information is currently available on the relationship with postoperative prognosis. We herein investigated the relationship between cStage and prognosis of colon cancer (CC) patients, particularly focusing on the presence or absence of clinical lymph node (LN) metastasis. METHOD: This was a retrospective study on 840 consecutive patients with colon adenocarcinoma who underwent radical resection at our institution between January 2007 and December 2018. A Kaplan-Meier curve was used to analyse the prognosis of two groups: cN(+)pN(-); a group preoperatively diagnosed with clinical LN metastasis positive, but with no pathological LN metastasis postoperatively, and cN(-)pN(-); a group without clinical and pathological LN metastasis. We also investigated whether a clinical diagnosis is a more accurate prognostic factor than other clinical factors. RESULTS: Among pN(-) cases, the 5-year recurrence-free survival rate was significantly lower in preoperatively diagnosed cN(+) cases than in cN(-) cases (79.4% vs. 95.6%, 3.04 years vs. 3.85 years, p < 0.01). In a multivariate analysis of various preoperative clinical factors in pStage II cases, including high risk factors for pStage II CC, cN(+) was identified as an independent prognostic factor (hazard ratio: 2.06, 95% CI: 1.02-4.27, p = 0.04). CONCLUSION: Preoperatively over-staged cN cases had a poorer prognosis than cases without over-staging, indicating its potential as a prognostic factor. In addition to already known high risk factors in pStage II cases, the preoperative cStage may be an indication for adjuvant chemotherapy.

Predictors of the difficulty of transcervical subcarinal lymph node dissection for esophageal cancer.

BACKGROUND: Transmediastinal radical esophagectomy (TME) is a new minimally invasive approach without thoracotomy. However, the transcervical dissection of subcarinal lymph nodes (SCLN) is challenging. The shape or narrowness of the mediastinal space, particularly around the aortic arch to the tracheal bifurcation, may increase the difficulty of this procedure. The present study aimed to clarify predictors of the difficulty of transcervical SCLN dissection. METHODS: Patients who underwent TME between 2016 and 2019 were included (n = 126). Four indicators, the cervical angle, carina distance, aorta distance, and sternum distance, were defined as indicators of mediastinal narrowness by 3D-CT. The relationships between the difficulty of transcervical SCLN dissection and clinicopathological features, including the above indicators, were investigated. RESULTS: In a univariate analysis, the cervical angle (p = 0.023), aorta distance (p = 0.002), and middle thoracic tumor (p = 0.040) correlated with difficulty. The median cervical angle and aorta distance were 15° and 33 mm in difficult cases and 19° and 43 mm in easy cases, respectively. In a multivariate analysis, the short aorta distance (odds ratio: 7.96, p = 0.002) and middle thoracic tumor (odds ratio: 3.35, p = 0.042) were independent predictive factors. CONCLUSIONS: The cervical angle, aorta distance, and middle thoracic tumor may predict the difficulty of transcervical SCLN dissection. In difficult cases, a transhiatal approach should be combined for complete SCLN dissection.

Overexpression of Tetraspanin31 contributes to malignant potential and poor outcomes in gastric cancer.

Tetraspanin has important functions in many cancers by aggregating with various proteins that interact with intracellular signaling proteins. The molecular function of Tetraspanin31 (TSPAN31), located in the 12q14 amplified region in various cancers, remains unclear in gastric cancer (GC). We tested whether TSPAN31 acts as a cancer-promoting gene through its activation or overexpression in GC. We analyzed seven GC cell lines and 189 primary tumors, which were curatively resected in our hospital between 2011 and 2013. Overexpression of the TSPAN31 protein was frequently detected in three GC cell lines (42.9%) and 62 primary GC specimens (32.8%). Overexpression of TSPAN31 was significantly correlated with lymphatic invasion, venous invasion, more advanced pT and pN stages, and a higher recurrence rate. Moreover, TSPAN31 positivity was an independent factor predicting worse patient outcomes (p = 0.0283, hazard ratio 3.97). Ectopic overexpression of TSPAN31 facilitated cell proliferation of GC cells, and knockdown of TSPAN31 inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition of GC cells through the PI3K-Akt pathway and increased cell apoptosis in a TP53 mutation-independent manner. In vivo analysis also revealed knockdown of TSPAN31 suppressed tumor progression. In addition, knockdown of TSPAN31 improved chemosensitivity to cisplatin through the suppression of ABCC2. These findings suggest that TSPAN31 plays a crucial role in tumor-malignant potential through overexpression, highlighting its utility as a prognostic factor and a potential therapeutic target in GC.