[Surgical Outcomes of Colorectal Cancer for Over 90-Year-Old Patients in Our Hospital].

The aim of this study was to investigate the short-term outcomes of surgery for colorectal cancer(CRC)in the elderly aged over 90 years old. We retrospectively analyzed 1,043 patients with stage Ⅰ-Ⅳ CRC who underwent curative surgery in our institutions between 2013 and 2022. The patients were divided into the super older(aged ≥90 years, 20 patients) and non-super older groups(aged 80-89 years, 243 patients). The short-term outcomes were compared between the 2 groups. There were no significant differences in tumor location, stage, surgical approach, duration of operation and blood loss. The incidence of severe postoperative complications did not differ between the 2 groups. In conclusion, our study suggested that surgery for colorectal cancer could be as safely performed in super elderly patients as in non-super elderly patients.

Impact of severe postoperative complications on the prognosis of older patients with colorectal cancer: a two-center retrospective study.

BACKGROUND: The occurrence of postoperative complications may affect short-term outcomes and prognosis of patients with various malignancies. However, the prognostic impact of these complications in older patients with colorectal cancer (CRC) remains unclear. Therefore, this study aimed to investigate the impact of severe postoperative complications on the oncological outcomes of older (aged ≥ 80 years) and non-older (aged < 80 years) patients with CRC. METHODS: We retrospectively analyzed 760 patients with stage I-III CRC who underwent curative surgery in two institutions between 2013 and 2019. The patients were categorized into older (aged ≥ 80 years, 191 patients) and non-older (aged < 80 years, 569 patients) groups. Short- and long-term outcomes were compared between the two groups. RESULTS: The incidence of severe postoperative complications did not differ between the two groups (p = 0.981). Cancer-specific survival (CSS) was significantly worse in older patients with severe complications than in those without severe complications (p = 0.007); meanwhile, CSS did not differ between the non-older patients with severe complications and those without severe complications. Survival analysis revealed that the occurrence of severe postoperative complications was an independent prognostic factor for CSS in older patients (hazard ratio = 4.00, 95% confidence interval: 1.27-12.6, p = 0.017). CONCLUSION: CRC surgery can be safely performed in older and non-older patients. Moreover, the occurrence of severe postoperative complications might more strongly affect the prognosis of older patients than that of non-older patients.

CACNA2D1 regulates the progression and influences the microenvironment of colon cancer.

BACKGROUND: Calcium voltage-gated channel auxiliary subunit alpha 2/delta 1 (CACNA2D1), a gene encoding a voltage-gated calcium channel, has been reported as an oncogene in several cancers. However, its role in colon cancer (CC) remains unclear. This study aimed to investigate the function of CACNA2D1 and its effect on the microenvironment in CC. METHODS: Immunohistochemistry (IHC) analysis was performed on samples collected from 200 patients with CC who underwent curative colectomy. Knockdown experiments were performed using CACNA2D1 siRNA in the human CC cell lines HCT116 and RKO, and cell proliferation, cycle, apoptosis, and migration were then analyzed. The fibroblast cell line CCD-18Co was co-cultured with CC cell lines to determine the effect of CACNA2D1 on fibroblasts and the relationship between CACNA2D1 and the cancer microenvironment. Gene expression profiles of cells were analyzed using microarray analysis. RESULTS: IHC revealed that high CACNA2D1 expression was an independent poor prognostic factor in patients with CC and that CACNA2D1 expression and the stroma are correlated. CACNA2D1 depletion decreased cell proliferation and migration; CACNA2D1 knockdown increased the number of cells in the sub-G1 phase and induced apoptosis. CCD-18Co and HCT116 or RKO cell co-culture revealed that CACNA2D1 affects the cancer microenvironment via fibroblast regulation. Furthermore, microarray analysis showed that the p53 signaling pathway and epithelial-mesenchymal transition-associated pathways were enhanced in CACNA2D1-depleted HCT116 cells. CONCLUSIONS: CACNA2D1 plays an important role in the progression and the microenvironment of CC by regulating fibroblasts and may act as a biomarker for disease progression and a therapeutic target for CC.

[Laparoscopic Surgery for Delayed Chylous Ascites in Unresectable Gastric Cancer Patient-A Case Report].

Chylous ascites is a rare post operative complication after gastrectomy, which commonly occurs in early postoperative period. Here, we successfully treated a patient with unresectable gastric cancer who occurred chylous ascites 9 months after first surgery and underwent laparoscopic surgery for chylous ascites. Since prolonged chylous ascites may cause malnutrition, surgical treatment should be considered for refractory chylous ascites.

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.

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.

Cancer Stem Cells of Hepatocellular Carcinoma Are Suppressed by the Voltage-gated Calcium Channel Inhibitor Amlodipine.

BACKGROUND/AIM: The membrane transporters activated in cancer stem cells (CSCs) are the target of novel cancer therapies for hepatocellular carcinoma (HCC). The present investigation demonstrated the expression profiles of ion channels in CSCs of HCC. MATERIALS AND METHODS: Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from HepG2 cells, a human HCC cell line, by fluorescence-activated cell sorting, and CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were investigated using microarray analysis. RESULTS: Among HepG2 cells, ALDH1A1 messenger RNA level was 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, such as calcium voltage-gated channel auxiliary subunit gamma 4 (CACNG4). The cytotoxicity of the CACNG4 inhibitor amlodipine was higher at lower concentrations in CSCs than in non-CSCs, and markedly decreased the number of tumorspheres. The cell population among HepG2 cells that highly expressed ALDH1A1 was also significantly reduced by this inhibitor. CONCLUSION: CACNG4 plays a role in maintaining CSCs, and its inhibitor, amlodipine, could potentially be a targeted therapeutic agent against HCC.

Laparoscopic Surgery for Elderly Colorectal Cancer Patients With High American Society of Anesthesiologists Scores.

BACKGROUND/AIM: To evaluate the safety of colorectomy in elderly colorectal cancer patients with high American Society of Anesthesiologists (ASA) scores compared to those with low scores. PATIENTS AND METHODS: Two hundred patients with stage I-IV colorectal cancer aged ≥80 years were retrospectively analyzed. Short- and long-term outcomes were compared between 136 patients with ASA scores ≤2 (low ASA group) and 64 patients with scores ≥3 (high ASA group). RESULTS: The incidence of postoperative complications, duration of postoperative hospital stay, and 5-year overall and cancer-specific survival rates did not differ significantly between the groups. Laparoscopic surgery was significantly associated with a lower incidence of postoperative complications than open surgery in the high ASA score group (p=0.041), whereas no difference was observed in the low ASA score group (p=0.639). In the high ASA group, open surgery (p=0.024) and higher body mass index (p=0.040) were independent risk factors for postoperative complications. CONCLUSION: Colorectal cancer resection can be safely performed in elderly patients with high ASA scores. Moreover, laparoscopic surgery may have a stronger contribution to the reduction of postoperative complications in elderly patients with colorectal cancer with high ASA scores than in those with low ASA scores.

Differences of clinical features and outcomes between male and female elderly patients in gastric cancer.

Although the average life span differs between males and females, little is known about differences in clinical features and short and long-term outcomes between elderly male and female gastric cancer patients. This study was designed to clarify these issues to identify the possibility for sex-based treatment strategies in elderly gastric cancer patients. This study included 295 consecutive elderly gastric cancer patients (75 years or older) who underwent curative gastrectomy between 1997 and 2016. We defined postoperative complications as Clavien-Dindo classification grade II or higher. Comorbidities were present in 67% of all patients. Males tended to have more comorbidities than females (P = 0.077). Male patients had significantly more upper gastric cancers (P = 0.001), a higher incidence of postoperative complications (P = 0.045), and poorer prognoses than females (P = 0.003). Multivariate analysis revealed that being male was an independent risk factor for postoperative complications (Odds ratio 2.5, P = 0.045) and a poor prognostic factor (Hazard ratio 1.81, P = 0.008). Patients who underwent limited surgery without postoperative complications tended to have a better prognosis than patients receiving standard surgery with postoperative complications (3-year overall survival: 78% vs. 55%, P = 0.156). Male was an independent risk factor for postoperative complications and an independent poor prognostic factor in elderly gastric cancer patients. To avoid postoperative complications, the limited surgery might be justified for high-risk elderly male patients.

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.

Roles of miR-4442 in Colorectal Cancer: Predicting Early Recurrence and Regulating Epithelial-Mesenchymal Transition.

Early recurrence in patients with colorectal cancer (CRC) is associated with a poor prognosis. We aimed to identify circulating microRNAs that are biomarkers of early CRC recurrence and elucidate their functions. We identified miR-4442 as a candidate biomarker by microRNA array analysis comparing preoperative and postoperative plasma levels in patients with CRC, with and without recurrence. The association between preoperative plasma miR-4442 levels, clinicopathological features, and recurrence-free survival was analyzed in 108 patients with CRC after curative surgery. Furthermore, cell-function analyses were performed, and the involvement of miR-4442 in regulating epithelial-mesenchymal transition (EMT) was examined. Preoperatively plasma miR-4442 levels were associated with CRC recurrence and exhibited an incremental increase with earlier recurrence dates. Moreover, miR-4442 demonstrated high sensitivity and specificity as a potential biomarker for early CRC recurrence. The expression of miR-4442 in cancer tissues of patients with metastatic liver cancer from CRC was higher than in normal liver, CRC, and normal colorectal tissues. The overexpression of miR-4442 promoted the proliferative, migratory, and invasive activities of CRC cells, decreased levels of RBMS1 and E-cadherin, and increased levels of N-cadherin and Snail1. Plasma miR-4442 is a clinically useful biomarker for predicting the early recurrence of CRC. Furthermore, miR-4442 regulates EMT in CRC by directly targeting the messenger RNA of RBMS1.

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.

Obesity paradox as a new insight from postoperative complications in gastric cancer.

The obesity paradox is reported to exist in various diseases. However, obesity is a pivotal issue in gastric cancer (GC) patients because of the surgical difficulty related to postoperative abdominal infectious complications (PAIC). This study clarified the existence of the obesity paradox in GC. Between 1997 and 2015, 1536 consecutive patients underwent curative gastrectomy. Of all patients, 18.6% (285/1536) were obese and tended to have a better prognosis (P = 0.073). In patients without PAIC, obesity was a significant prognostic factor for 5-year overall survival (P = 0.017). PAIC was an independent poor prognostic factor in both obese and non-obese patients (P < 0.001; hazard ratio [HR] 4.22 and 1.82). In pStage II-III patients, there was a large and significant prognostic difference between non-PAIC and PAIC obese patients (P = 0.006; 5-year overall survival: 69.7% vs. 43.8%) related to the higher incidence of peritoneal recurrence in PAIC obese patients (P = 0.035; 31% vs. 10%). Whereas, there was a small prognostic difference between non-PAIC and PAIC non-obese patients (P = 0.102; 5-year overall survival: 56.5% vs. 51.9%). Although the obesity paradox is present in GC, PAIC had a more negative prognostic impact through peritoneal recurrence in obese GC 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.

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 Case in Which a Distal Pancreatectomy Was Performed for Pancreatic Metastasis of Renal Cell Carcinoma after Nephrectomy, and a Total Pancreatectomy Was Performed for Residual Pancreatic Recurrence].

We reported a case in which a pancreatic resection was performed for pancreatic metastasis of renal cell carcinoma 24 years after nephrectomy, and a residual pancreatectomy was performed 4 years later for residual pancreatic recurrence. The patient was a 72-year-old. In 1991, he underwent right nephrectomy for right renal cell carcinoma. During follow-up, in 2015, mass lesions were noted in the pancreatic tail and distal pancreatectomy was performed on suspicion of pancreatic neuroendocrine tumor(NET). Pathological examination diagnosed metastasis of renal cell carcinoma. In 2019, mass lesions were noted in the residual pancreas and total pancreatectomy was performed. Pathological examination diagnosed metastasis of renal cell carcinoma. There was 5 cases in Japan, including an our case, in which pancreatectomy was performed again after pancreatectomy for pancreatic metastasis of renal cancer, and the average time until the first pancreatic metastasis was pointed out was 11.8 years, and the average time until pancreatic recurrence was 9.4 years. Pancreatic metastasis of renal cell carcinoma shows heterochronic and multiple metastasis occurs, requiring long-team follow-up. When determining the extent of resection, it was suggested that the minimum number of repetitions necessary may lead to a long-term prognosis, taking into account the patient's age, background.