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Usefulness of various nutritional indices for management of patients with esophageal squamous cell carcinoma (ESCC) has been reported. Although Controlling Nutritional Status (CONUT) score is among promising indices to predict outcome, the optimal timing for its measurement during the perioperative period remains unknown. Here the prognostic value of the CONUT score was assessed among patients with ESCC.We analyzed 464 patients who underwent subtotal esophagectomy of ESCC, of which 276 patients were treated with neoadjuvant treatment (NAT). The significance of the associations between candidate parameters including the CONUT score and postoperative prognosis were evaluated.Among the 25 candidate predictors, the preoperative CONUT score had the highest correlation with overall survival (OS) after surgery. Patients were categorized as follows: normal, mild, and moderate or severe, on the basis of the preoperative CONUT score. OS was significantly shortened as the CONUT score worsened. Multivariable analysis revealed that the CONUT scores of the subgroups mild (Hazard ratio [HR] 1.69) and moderate or severe (HR 2.18) were independent predictors of poor prognosis for OS. Furthermore, in an analysis limited to patients who underwent NAT, OS was significantly shortened as the preoperative CONUT score worsened. On the contrary, there was no significant difference in RFS among patient groups stratified by the CONUT score determined before NAT.Our study indicates that the preoperative CONUT score serves as a prognosticator in resectable ESCC. The preoperative CONUT value was more useful than that before NAT in patients administered NAT.

Novel therapeutic targets are needed to improve the poor prognosis of patients with advanced gastric cancer. The aim of this study was to identify a novel therapeutic target for the treatment of GC and to investigate the potential therapeutic value of an antibody raised against the target.We identified gamma-aminobutyric acid type A receptor subunit delta as a candidate therapeutic target by differential transcriptome analysis of metastatic GC tissue and adjacent nontumor tissues. GABRD mRNA levels were analyzed in 230 pairs of gastric tissue by quantitative reverse-transcription polymerase chain reaction. GABRD function was assessed in proliferation, invasion, and apoptosis assays in human GC cell lines expressing control or GABRD-targeting small interfering RNA (siRNA). Mouse anti-human polyclonal GABRD antibodies were generated and assessed for inhibition of GC cell growth in vitro and in a mouse xenograft model of peritoneal GC dissemination.High GABRD mRNA expression level in primary human GC tissue was associated with poor prognosis. Expression of siGABRD in GC cell lines significantly decreased cell proliferation and invasion and increased apoptosis compared with control siRNA expression. Anti-GABRD polyclonal antibodies inhibited GC cell proliferation in vitro and decreased peritoneal tumor nodule size in the mouse xenograft model.We identified GABRD as novel regulator of GC cell growth and function. GABRD is upregulated in GC tissue and is associated with poor prognosis, suggesting that it may be a potential therapeutic target for GC.

The regimen of nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (Nal-IRI/FL) was approved in Japan as second-line chemotherapy after gemcitabine-based treatment for pancreatic ductal adenocarcinoma (PDAC) in 2020. We examined the difference in outcome between patients treated with second-line folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) and those treated with nal-IRI/FL after first-line gemcitabine and nab-paclitaxel (GnP).The outcomes of 34 patients with PDAC who received second-line FOLFIRINOX (n=21) or nal-IRI/FL (n=13) after GnP at our Department from January 2016 to June 2021 were reviewed retrospectively.Patient backgrounds did not differ between the groups. Dose reduction was more frequently required for treatment with FOLFIRINOX than with nal-IRI/FL (86% vs. 46%, p=0.022). Pegfilgrastim and aprepitant were used more frequently in the FOLFIRINOX group (both p0.01). Progression-free survival (5.9 vs. 8.3 months) and overall survival (9.1 vs. 11.2 months) did not differ significantly between the groups. The frequency of grade 3 (Common Terminology Criteria for Adverse Events) or higher adverse events was similar between the groups. All-grade peripheral neuropathy was more common in the FOLFIRINOX group (100% vs. 77%, p=0.048).FOLFIRINOX and nal-IRI/FL as second-line therapy after GnP provided similar prognoses, although supportive treatment and dose reduction were more frequently required for FOLFIRINOX.

The axon guidance gene family, SLIT/ROBO pathway, controls neural network formation, which correlates with the development of several cancers.We found through analysis of the public database that ROBO4, one of the axon guidance molecules among the SLIT/ROBO family, is significantly downregulated in primary pancreatic cancer tissues compared with adjacent normal tissues. We carried out transfection experiments using three pancreatic cancer cell lines (MiaPaCa-2, BxPC-3, and SW1990) and one pancreatic duct epithelial cell line (HPDE6c7). A total of 51 clinical samples were then examined by immunohistochemical staining to find an association between ROBO4 expression at the protein level, clinical characteristics, and surgical outcomes.ROBO4 overexpression suppressed the invasion and migration abilities in MiaPaCa-2 and BxPC-3, while ROBO4 siRNA transfection to SW1990 and HPDE6c7 enhanced those activities. PCR-based profiling detected MMP-9 as a candidate downstream target of ROBO4, which was validated by decreased MMP-9 activity after the ROBO4 overexpression assay. High ROBO4 expression clinical samples had significantly better overall survival rather than low ROBO4 cases (P = 0.048).These findings suggest that decreased ROBO4 expression activates malignant phenotypes in cancer cells and is correlated with poor survival outcomes in pancreatic cancer.

This is a file of "Supplementary Data".

Background. Neoadjuvant treatment is currently the gold standard for advanced esophageal squamous cell carcinoma (ESCC). Several studies have examined the value of blood count-based indexes for predicting short- and long-term outcomes after esophagectomy for ESCC, but the relative predictive value of pretreatment, preoperative, and postoperative indexes has not yet been examined. Methods. This study included 320 patients with thoracic ESCC who underwent subtotal esophagectomy after neoadjuvant chemotherapy or chemoradiotherapy at our institution. A total of 19 candidate blood parameters were measured before neoadjuvant treatment as well as preoperatively and postoperatively. The ability of the parameters to predict postoperative complications, overall survival (OS), and relapse-free survival (RFS) were assessed using receiver operating characteristic (ROC) curve analysis and Cox regression analysis. Results. ROC curve analysis indicated that the preoperative platelet to lymphocyte ratio (PLR) had the best predictive value with an optimal cutoff value of 166. Patients with high preoperative PLR (≥166) had significantly shorter OS and RFS and significantly higher incidences of hematogenous recurrence and postoperative pneumonia compared with patients with low preoperative PLR (

The albumin-bilirubin (ALBI) score was originally developed to assess the severity of liver dysfunction in patients with hepatocellular carcinoma and has subsequently been used as a prognostic marker for that disease. Here, we examined the value of the preoperative ALBI score as a prognostic marker for patients with esophageal squamous cell carcinoma (ESCC) after radical esophagectomy.We retrospectively analyzed data from 449 patients who underwent curative resection for ESCC. The ALBI score was calculated as (logOf the 449 ESCC patients, 232 and 217 were assigned to mALBI Grade 1 or Grade 2 groups based on preoperative ALBI scores of ≤ - 3.33 or- 3.33, respectively. Preoperative mALBI grade was significantly associated with age, excessive alcohol consumption, squamous cell carcinoma antigen level, and clinical disease stage. The mALBI Grade 2 group had significantly shorter disease-specific and recurrence-free survival than the mALBI Grade 1 group. Multivariate analysis demonstrated that mALBI Grade 2 was an independent prognostic factor for disease-specific survival (hazard ratio 1.86, 95% confidence interval 1.18-2.93, P = 0.0074). In most subgroup analyses, mALBI Grade 2 was associated with a greater risk of disease-specific death.mALBI grade serves as a simple and useful prognostic marker for disease-specific survival in patients with ESCC after radical esophagectomy.

Background HPV-positive oropharyngeal squamous cell carcinomas (OPSCCs) are sensitive to chemo-radiation therapy and have favorable survival outcomes compared with HPV-negative cancers. These tumors are usually not related to tobacco and alcohol exposure. Therefore, it is crucial to diagnose HPV-positive OPSCCs for the appropriate management of the disease, and no suitable markers are available for HPV-positive tumors. In this study, we attempt to find HPV-specific epigenetic biomarkers for OPSCCs. Methods A total of 127 surgical samples were analyzed for HPV positivity and promoter methylation of a panel of genes. HPV detection was performed by PCR detection of HPV E6 and E7 viral oncoproteins. In addition, promoter methylation of a total of 8 genes (DAPK, FHIT, RASSF1A, TIMP3 AGTR1, CSGALNACT2, GULP1 and VGF) was analyzed by quantitative-methylation specific PCR (QMSP), and their associations with HPV positivity or RB/p16 expressions were evaluated. Results AGTR1and FHIT were frequently methylated in HPV positive OPSCC samples with a good area under the curve (AUC over 0.70). In addition, these genes promoter methylation significantly associated with p16 positive and RB negative cases, which were the characteristics of OPSCC cases with favorable survival outcomes. Either of AGTR1and FHIT methylated cases were significantly associated with HPV-positive cancers with 92.0% sensitivity (P AGTR1 and FHIT methylation demonstrated a suitable detection marker of OPSCCs derived from the HPV-infected field, which were familiar with p16-positive and RB-negative phenotypes.

To improve the outcome of gastric cancer, novel markers that predict postoperative prognosis are required. For this purpose, the function of cellular retinoic acid binding protein 1 (

448 Background: Despite advances in multimodality treatment of esophageal squamous cell carcinoma (ESCC), the recurrence rate after curative resection remains high. Assessment of the risk of disease recurrences after curative resection of ESCC will be helpful for optimization of individual patient management. The close association between coagulation status and progression of malignant tumors has been previously reported. We herein sought to identify sensitive prognostic factors in ESCC by combining multiple coagulation markers. Methods: A total of 200 patients who underwent curative subtotal esophagectomy after neoadjuvant treatment for ESCC between January 2012 and December 2020 were included in the analysis. We retrospectively evaluated the correlation of preoperative plasma D-dimer (upper limit of normal, 1.0 μg/mL), fibrinogen (upper limit of normal, 350 mg/dL) levels and the coagulation score, which is calculated by combining levels of D-dimer and fibrinogen, with postoperative prognosis. The coagulation score was determined as follows. 0, neither D-dimer nor fibrinogen were elevated; 1, either D-dimer or fibrinogen was above the upper limit of normal; 2, both were elevated. Results: There was no significant difference in postoperative recurrence-free survival between the high and low groups for either preoperative D-dimer alone or preoperative fibrinogen alone. 59 patients (29.5%), 99 patients (49.5%) and 42 patients (21%) were categorized into coagulation score 0, 1 and 2, respectively. Patients in the coagulation score 1-2 group had a significantly shorter recurrence-free survival time than those in the coagulation score 0 group (hazard ratio 1.99, P = 0.0223). Conclusions: The coagulation score combining with plasma D-dimer and fibrinogen levels was suggested to be a simple predictor of postoperative recurrences in patients undergoing curative subtotal esophagectomy after neoadjuvant treatment for ESCC.

811 Background: Little knowledge is available for postsurgical changes in cognitive and physical functions that may be useful for considering indication for surgery in elderly patients with gastric cancer. We therefore conducted a prospective study aimed to determine the influence of gastrectomy on these patients. Methods: We recruited patients older than 75 years for whom gastrectomy for gastric cancer had been planned, and assessed their cognitive and physical functions, daily activities, episodes of depression, confusion, and delirium before surgery (baseline), upon discharge, and at 6 months after surgery (POM 6). Results: Among 54 elderly patients registered between February 2017 and February 2020. There were no significant decreases in MMSE scores between baseline and at POM 6, nor were there significant differences in physical function and indicators of depression and confusion between these time points. As many as 20% of patients were found to have the functional decline on the basic activities of daily living scores (BADL) after surgery compared with the baseline. The only variable significantly associated with a functional decline in BADL was postoperative complications. Conclusions: Postoperative cognitive functions did not significantly decline when compared with the baseline scores, although postoperative BADL scores of patients who experienced postoperative complications were significantly lower than those who did not.

Metastatic gastric cancer (GC) has a poor prognosis, and elucidating the molecular mechanisms involved in metastasis may lead to the development of novel therapeutic modalities.Transcriptome analysis of surgically resected metastatic tissue from GC patients and noncancerous tissue was performed to identify novel metastasis-related genes. Analyses of in vitro cell function, apoptosis, the cell cycle and cancer stemness were performed using GC cell lines with a stable knockout of a candidate gene. In vivo percutaneous, peritoneal dissemination and liver metastasis xenograft models were also generated. PCR array and proteome analyses were performed. Expression of the candidate gene was analyzed in GC tissues from 300 patients.Lysosomal Associated Membrane Protein Family Member 5 (LAMP5) was upregulated in the metastatic tissues. LAMP5 knockout significantly suppressed proliferation, invasion, and migration of GC cells and increased apoptosis, cell cycle arrest and cancer stemness. LAMP5 knockout virtually suppressed tumor growth in in vivo percutaneous, peritoneal dissemination and liver metastasis models. EMT- and autophagy-related genes were associated with LAMP5. High LAMP5 mRNA levels were significantly associated with a worse prognosis.LAMP5 plays a vital role in metastasis formation and may be a promising novel target of drug development for metastatic GC in the future.

In Japan, esophagectomy after two courses of 5-fluorouracil plus cisplatin is regarded a standard strategy for treating resectable stage II or III esophageal squamous cell carcinoma (ESCC). However, 5-fluorouracil plus cisplatin does not benefit cohorts with clinical stage III ESCC, suggesting the requirement for a more effective regimen. We are conducting a single-arm phase II study to assess the safety and efficacy of neoadjuvant docetaxel, oxaliplatin plus S-1 (DOS) for treating patients with clinical stage III ESCC. The primary endpoint is the pathological response rate, and the target number is 45 patients. Safety, response rate, R0 resection rate, and survival are secondary endpoints. This trial is registered in the Japan Registry of Clinical Trials as jRCTs041210023. We are conducting a prospective phase II trial to evaluate the safety and efficacy of three courses of neoadjuvant DOS treatment followed by radical esophagectomy for clinical stage III ESCC.