Therapeutic antibody targeting natriuretic peptide receptor 1 inhibits gastric cancer growth via BCL-2-mediated intrinsic apoptosis.

Despite recent advances in the development of therapeutic antibodies, the prognosis of unresectable or metastatic gastric cancer (GC) remains poor. Here, we searched for genes involved in the malignant phenotype of GC and investigated the potential of one candidate gene to serve as a novel therapeutic target. Analysis of transcriptome datasets of GC identified natriuretic peptide receptor 1 (NPR1), a plasma membrane protein, as a potential target. We employed a panel of human GC cell lines and gene-specific small interfering RNA-mediated NPR1 silencing to investigate the roles of NPR1 in malignancy-associated functions and intracellular signaling pathways. We generated an anti-NPR1 polyclonal antibody and examined its efficacy in a mouse xenograft model of GC peritoneal dissemination. Associations between NPR1 expression in GC tissue and clinicopathological factors were also evaluated. NPR1 mRNA was significantly upregulated in several GC cell lines compared with normal epithelial cells. NPR1 silencing attenuated GC cell proliferation, invasion, and migration, and additionally induced the intrinsic apoptosis pathway associated with mitochondrial dysfunction and caspase activation via downregulation of BCL-2. Administration of anti-NPR1 antibody significantly reduced the number and volume of GC peritoneal tumors in xenografted mice. High expression of NPR1 mRNA in clinical GC specimens was associated with a significantly higher rate of postoperative recurrence and poorer prognosis. NPR1 regulates the intrinsic apoptosis pathway and plays an important role in promoting the GC malignant phenotype. Inhibition of NPR1 with antibodies may have potential as a novel therapeutic modality for unresectable or metastatic GC.

Absence of Hypercoagulation Status after Neoadjuvant Treatment is Associated with Favorable Prognosis in Patients Undergoing Subtotal Esophagectomy for Esophageal Squamous Cell Carcinoma.

BACKGROUND: Abnormal activation of the coagulation system is associated with malignant tumor progression. Although neoadjuvant treatment (NAT) for resectable esophageal squamous cell carcinoma (ESCC) is the standard of care, the correlation between coagulation status and prognosis of patients undergoing preoperative treatment is insufficiently understood. METHODS: Patients (n = 200) who underwent radical subtotal esophagectomy after preoperative treatment for ESCC between January 2012 and December 2021were included in the analysis. Plasma D-dimer and fibrinogen levels and their combined indices (non-hypercoagulation; D-dimer and fibrinogen levels within the upper normal limit, or hypercoagulation; D-dimer or fibrinogen levels above the upper normal limit) were determined before and after NAT and correlated to clinicopathological factors and prognosis. RESULTS: The nonhypercoagulation group achieved superior overall survival (OS) than the hypercoagulation group (5-year OS rates = 89% vs. 55%; hazard ratio 3.62, P = 0.0008) when determined according to coagulation status after NAT. Multivariate analysis showed that hypercoagulation after NAT served as an independent factor for poor postoperative OS (hazard ratio 3.20; P = 0.0028). The nonhypercoagulation group achieved significantly better disease-free survival (76% vs. 54%; P = 0.0065) than the hypercoagulation group that experienced a significantly higher rate of hematogenous metastasis as an initial recurrence (P = 0.0337). CONCLUSIONS: Hypercoagulation state after NAT served as a valid indicator correlating with postoperative outcomes of patients with ESCC who underwent NAT followed by radical subtotal esophagectomy.

Therapeutic Potential of Antibody Targeting Neuronal Pentraxin Receptor in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis despite advances in multidisciplinary treatments and immune checkpoint inhibitors. We previously reported that neural pentraxin receptor (NPTXR), a transmembrane protein mainly expressed in the brain and involved in synaptic transmission, is implicated in gastric cancer malignancy. This study evaluated the expression and function of NPTXR in ESCC, the therapeutic potential of monoclonal antibody (mAb) against NPTXR, and its prognostic value in ESCC patients. METHODS: The study involved analyzing the NPTXR expression in 21 ESCC cell lines and total 371 primary ESCC tissue samples using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. The impact of NPTXR on the malignant behavior of ESCC was examined using small interfering RNA-mediated knockdown and a subsequent assessment of cell proliferation, apoptosis, and adhesion. This study further investigated the efficacy of anti-NPTXR mAb in vitro and associations between the expression of NPTXR messenger RNA (mRNA) and protein with clinicopathological factors and the prognosis. RESULTS: NPTXR was overexpressed in several ESCC cell lines and primary ESCC tissues. Knockdown of NPTXR in ESCC cells resulted in reduced proliferation, increased apoptosis, and decreased cell adhesion. The mAb against NPTXR significantly inhibited ESCC cell proliferation in vitro. A high NPTXR expression in patient tissues was correlated with a worse overall survival, suggesting its potential as a prognostic biomarker. CONCLUSIONS: NPTXR influences the malignant behavior of ESCC cells. Anti-NPTXR mAb may be a promising therapeutic agent, and its expression in ESCC tissues may serve as a prognostic biomarker.

Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways.

BACKGROUND: Advanced gastric cancer (GC) has a poor prognosis. This study aimed to identify novel GC-related genes as potential therapeutic targets. METHODS: Killer cell lectin-like receptor G2 (KLRG2) was identified as a candidate gene by transcriptome analysis of metastatic GC tissues. Small interfering RNA-mediated KLRG2 knockdown in human GC cell lines was used to investigate KLRG2 involvement in signaling pathways and functional behaviors in vitro and in vivo. Clinicopathological data were analyzed in patients stratified according to tumor KLRG2 mRNA expression. RESULTS: KLRG2 knockdown in GC cells decreased cell proliferation, migration, and invasion; caused cell cycle arrest in G2/M phase; induced apoptosis via caspase activation; suppressed JAK/STAT and MAPK-ERK1/2 pathway activities; and upregulated p53 and p38 MAPK activities. In mouse xenograft models of peritoneal metastasis, the number and weight of disseminated GC nodules were decreased by KLRG2 knockdown. High tumor levels of KLRG2 mRNA were significantly associated with lower 5-year overall survival (OS) and relapse-free survival (RFS) rates in patients with Stage I-III GC (5-year OS rate: 64.4% vs. 80.0%, P = 0.009; 5-year RFS rate: 62.8% vs. 78.1%, P = 0.030). CONCLUSIONS: KLRG2 knockdown attenuated the malignant phenotypes of GC cells via downregulation of JAK/STAT and MAPK-ERK1/2 pathway activity and upregulation of p38 MAPK and p53. Targeted suppression of KLRG2 may serve as a new treatment approach for GC.

Gamma-aminobutyric Acid Type A Receptor Subunit Delta as a Potential Therapeutic Target in Gastric Cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Albumin-Globulin Ratio Indicates the Survival Outcome of Pancreatic Cancer Cases Who Underwent Preoperative Treatment and Curative Surgical Resection.

BACKGROUND: The pretreatment albumin-globulin ratio (AGR) is a frequently used inflammation-associated factor that has been reported to have associations with the survival outcomes of various malignancies. METHODS: We retrospectively analyzed 162 patients with pancreatic cancer who underwent preoperative treatment followed by curative surgery at Nagoya University Hospital between April 2010 and December 2020. Representative nutritional status indicators of neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), and albumin-globulin ratio (AGR) were calculated for each case. RESULTS: Among pretreatment blood examination parameters, only AGR (cutoff: 1.33) showed a significant difference in overall survival time (OS) and progression-free survival time (PFS) from the beginning of the preoperative treatment. Median PFS was 22.3 mo, in high AGR cases and 17.1 mo, in low AGR cases (P = 0.019). Median OS was 48.7 mo, in high AGR cases and 32.9 mo, in low AGR cases (P = 0.043). CONCLUSION: High pretreatment AGR may be a favorable prognostic factor for pancreatic cancer patients who received preoperative multimodal therapy followed by curative cancer resection. It may imply that nutritional status and inflammation control before the multimodal treatment affect the survival outcomes of pancreatic cancer cases and needs to be optimized.

Controlling Nutritional Status Score Serves as a Prognosticator in Esophageal Squamous Cell Carcinoma: Optimal Timing of Evaluation of Patients Undergoing Neoadjuvant Treatment.

BACKGROUND: 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. METHODS: 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. RESULT: 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. CONCLUSIONS: 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.

High Preoperative Platelet to Lymphocyte Ratio Is Associated with a Greater Risk of Postoperative Complications and Hematogenous Recurrences in Esophageal Squamous Cell Carcinoma Patients Receiving Neoadjuvant Treatment.

INTRODUCTION: 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) was assessed using receiver operating characteristic (ROC) curve analysis and Cox regression analysis. RESULTS: ROC curve analysis indicated that 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 (<166). In multivariate analysis, high preoperative PLR and high preoperative serum carcinoembryonic antigen level were independent predictors of poor prognosis. CONCLUSION: Preoperative PLR is a good predictor of short- and long-term prognosis in patients with advanced ESCC who receive neoadjuvant treatment followed by radical resection.

The preoperative systemic immune-inflammation index is associated with an unfavorable prognosis for patients undergoing curative resection of esophageal squamous cell carcinoma after neoadjuvant therapy.

PURPOSES: Systemic inflammation and immune status play a critical role in the development and progression of cancers. We evaluated the clinical significance of the preoperative systemic immune-inflammation index (SII) for predicting the long-term outcomes of patients who received neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC). METHODS: The subjects of this study were 277 patients who underwent curative resection of ESCC after neoadjuvant therapy. The SII was calculated as follows: SII = neutrophil × platelet/lymphocyte counts. Patients were stratified into high and low preoperative SII groups according to the cut-off value calculated by a receiver operating characteristic curve analysis. The Kaplan-Meier method and Cox proportional regression analysis were used to evaluate the correlation of SII to prognosis. RESULTS: The optimal cutoff of the preoperative SII was set at 700. Patients were categorized into preoperative SII-low (n = 203) and SII-high (n = 74) groups. The preoperative SII was significantly associated with tumor size. The relapse-free survival of patients in the SII-high group was significantly shorter (P = 0.0087) and preoperative SII-high was identified as an independent prognostic factor (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.06-2.28, P = 0.0229). The prevalence of hematogenous recurrence was significantly higher in the SII-high group. When we stratified patients into three groups with an additional cutoff value of 1200, we observed an incremental decrease in relapse-free survival rates. CONCLUSIONS: High preoperative SII was associated with shorter relapse-free survival times for ESCC patients who underwent curative resection after neoadjuvant therapy.

Prognostic Value of a Modified Albumin-Bilirubin Score Designed for Patients with Esophageal Squamous Cell Carcinoma After Radical Resection.

BACKGROUND: 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. METHODS: We retrospectively analyzed data from 449 patients who underwent curative resection for ESCC. The ALBI score was calculated as (log10 serum bilirubin [µmol/l] × 0.66) + (serum albumin [g/l] × - 0.0852). Receiver operating characteristic curve analysis was used to define a preoperative modified ALBI (mALBI) score for patient stratification. RESULTS: Of 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. CONCLUSIONS: mALBI grade serves as a simple and useful prognostic marker for disease-specific survival in patients with ESCC after radical esophagectomy.

Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9.

BACKGROUND: The axon guidance gene family, SLIT/ROBO pathway, controls neural network formation, which correlates with the development of several cancers. METHODS: 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. RESULTS: 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). CONCLUSION: These findings suggest that decreased ROBO4 expression activates malignant phenotypes in cancer cells and is correlated with poor survival outcomes in pancreatic cancer.

Lysosomal-associated membrane protein family member 5 promotes the metastatic potential of gastric cancer cells.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: LAMP5 plays a vital role in metastasis formation and may be a promising novel target of drug development for metastatic GC in the future.

Drain Amylase Concentrations at 3 h After Gastrectomy Enhance Early Prediction of Postoperative Peripancreatic Inflammatory Fluid Collection.

BACKGROUND: Despite numerous studies of peripancreatic inflammatory fluid collection (PIFC) that report on the relevance of the drain amylase concentration (D-AMY), early prediction using this assay is problematic. This study aimed to investigate the clinical significance of measuring the D-AMY at 3 h after gastrectomy (POD0) for gastric cancer. METHODS: This retrospective analysis included consecutive patients who underwent gastrectomy combined with peripancreatic lymph node dissection. The predictive value of D-AMY on POD0 and postoperative day 1 (POD1) for clinically relevant PIFC was evaluated together or individually. RESULTS: Analyses were performed in 204 patients. Twenty (9.8%) patients experienced PIFC. D-AMY cutoffs of 721 IU/L on POD0 and 1695 IU/L on POD1 were determined using the receiver operating characteristic curve analysis for predicting PIFC. The D-AMY on POD0 had higher sensitivity (80%) but lower specificity (66.3%) for prediction of PIFC, compared with those of D-AMY on POD1 (65%, 89.1%, respectively). When combination marker analysis was performed, the highest risk group (D-AMY ≥ the cutoff values of POD0 and POD1) were associated with an elevated rate of occurrence (44%) and a high positive likelihood ratio (7.36) compared with those of the single cutoff group. The lowest risk group (D-AMY < the cutoff values on POD0 and POD1) was associated with a low rate of occurrence (2.5%) and low negative likelihood ratio (0.24) compared with those of the single cutoff group. CONCLUSIONS: Combined measurements of D-AMYs on POD0 and POD1 enhanced early prediction of PIFC after gastrectomy.

Hepatic metastasis of gastric cancer is associated with enhanced expression of ethanolamine kinase 2 via the p53-Bcl-2 intrinsic apoptosis pathway.

BACKGROUND: Gastric cancer (GC) with hepatic metastasis has a poor prognosis. Understanding the molecular mechanisms involved in hepatic metastasis may contribute to the development of sensitive diagnostic biomarkers and novel therapeutic strategies. METHODS: We performed transcriptome analysis of surgically resected specimens from patients with advanced GC. One of the genes identified as specifically associated with hepatic metastasis was selected for detailed analysis. GC cell lines with knockout of the candidate gene were evaluated in vitro and in vivo. Expression of the candidate gene was analysed in GC tissues from 300 patients. RESULTS: Ethanolamine kinase 2 (ETNK2) was differentially upregulated in GC patients with hepatic metastasis. ETNK2 expression was elevated in GC cell lines derived from haematogenous metastases. ETNK2 knockout significantly suppressed proliferation, invasion, and migration; increased apoptosis; reduced Bcl-2 protein expression; and increased phosphorylated p53 expression. In mouse xenograft models, ETNK2 knockout virtually abolished hepatic metastasis. Stratification of GC patients based on ETNK2 mRNA level revealed significant associations between high ETNK2 tumour expression and both hepatic recurrence and worse prognosis. CONCLUSIONS: Upregulation of ETNK2 in GC enhances hepatic metastasis, possibly via dysregulation of p53-Bcl-2-associated apoptosis. ETNK2 expression may serve as a biomarker for predicting hepatic recurrence and a therapeutic target.

High Serum Uric Acid Levels Could Be a Risk Factor of Hepatocellular Carcinoma Recurrences.

BACKGROUND: The Apolipoprotein-related MORtality RISk (AMORIS) study in Sweden revealed that serum uric acid (SUA) was significantly associated with hepatobiliary cancer occurrence. However, the association with postoperative hepatocellular carcinoma (HCC) recurrence has not been reported. METHODS: A total of 256 surgically resected HCC patients were included (from January 2003 to December 2017) in this study. Comparisons in terms of clinicopathologic factors and long-term outcomes were made between patients with high SUA (>6.1 mg/dl) at the time of hepatectomy and low SUA. Besides, SUA data at one postoperative year (1POY) of the same cohort were collected and analyzed in the same manner. RESULTS: About 88.8% of tumor relapse sites were the remnant liver. High SUA levels were associated with male and well-differentiated HCCs. Recurrence-free survival (RFS) of high SUA patients was significantly inferior to low SUA patients [median survival time (MST): 22.7 vs. 28.5 mo, P = 0.033], whereas no difference was observed in overall survival (MST: both not reached, P = 0.771). RFS of high SUA patients at 1POY also showed significantly poorer outcomes than low SUA patients (MST: 29.3 vs. 57.0 mo, P = 0.049). CONCLUSIONS: High SUA implies a significant risk factor of activating hepatocarcinogenesis. Keeping the SUA level low may be recommended after HCC resections.

The significance of the time to arterial perfusion in intraoperative ICG angiography during colorectal surgery.

BACKGROUND: Intraoperative indocyanine green angiography (ICG-A) is a promising tool to confirm blood supply; however, the assessment is difficult without clear demarcation. In this study, the clinical impact of the time to arterial perfusion (TAP) on anastomotic leakage (AL) was evaluated, especially in patients without ICG demarcation. METHODS: The TAP was assessed using ICG-A during colorectal surgery in 110 patients. ICG demarcation required changing the transection line, and the TAP was measured at the new stump. The patients were divided into marginal flow (MF) and direct flow (DF) groups according to the arterial route. Delayed TAP was defined as the third quartile or slower TAP in each group. RESULTS: Sixty-six patients (60%) were classified into the MF group, including 64 patients who underwent rectal or sigmoid resection with high ligation of the inferior mesenteric artery. The cut-off value of the delayed TAP in the MF group was significantly slower than that in the DF group (30 and 22 s, respectively, p < 0.001). In the entire cohort, the transection line was changed in 2 patients, resulting in no AL. Nevertheless, AL still developed in 6 patients (5.4%), 5 of whom were in the MF group, and delayed TAP was found in 5 of 6 patients. Delayed TAP was significantly associated with AL in the MF group (p = 0.046). CONCLUSIONS: In patients without ICG demarcation, delayed TAP might be helpful for predicting the high-risk patients with AL in the MF group; however, performing diverting stoma or strictly careful observation might be a realistic reaction.

The carcinoembryonic antigen ratio is a potential predictor of survival in recurrent colorectal cancer.

BACKGROUND: The carcinoembryonic antigen (CEA) "value" itself is often useless in patients with a normal CEA level at initial presentation and those with tumor-irrelevant elevated CEA. Although the unified marker using CEA has been desirable for recurrent tumor staging as well as for primary tumor staging, little is known concerning its relationship with the survival of patients with recurrent colorectal cancer in particular. METHODS: This retrospective historical study included patients who experienced disease relapse after curative surgery for stage I-III colorectal cancer between 2006 and 2018. A total of 129 patients with recurrent disease after curative surgery for colorectal cancer were included. We focused on the CEA "ratio" (CEA-R: the ratio of the CEA level at the time of recurrence to that measured 3 months before recurrence) and aimed to evaluate the correlation between CEA-R and survival in recurrent colorectal cancer. RESULTS: Patients with a high CEA-R (≥ 2) exhibited significantly worse 2 year survival than those with a low CEA-R (< 2) (88.1% vs. 44.9%, P < 0.001), irrespective of the CEA value before primary resection. Multivariate analyses demonstrated that the CEA-R (HR; 3.270, 95% CI 1.646-6.497, P = 0.001) was a significant prognostic factor. CONCLUSION: The CEA-R is a potential marker stratifying the survival of patients with disease relapse who exhibit aggressive biology at recurrent disease foci. As a novel marker, the CEA-R would serve as a clinical guide for tailoring treatment strategies at the time of disease relapse in patients with colorectal cancer.

Newly developed primary malignancies in long-term survivors who underwent curative esophagectomy for squamous cell carcinoma of the esophagus.

PURPOSE: We evaluated the efficacy of the long-term follow-up of patients who underwent radical esophagectomy for esophageal squamous cell carcinoma (ESCC) to screen for recurrence and new primary malignancies. METHODS: We retrospectively collected 448 ESCC patients who underwent radical esophagectomy. Esophagogastroduodenoscopy, computed tomography, a stool test and the assessment of the serum concentration of squamous cell carcinoma antigen and carcinoembryonic antigen were performed annually, even over 5 years after esophagectomy. The incidence of ESCC recurrence and new primary malignancies was investigated. RESULTS: We enrolled 222 patients who survived at least 5 years after esophagectomy. A total of 104 new primary malignancies occurred in 82 patients (36.9%) after esophagectomy. Twenty-one malignancies were in the head and neck region, 14 in the residual esophagus, 13 in the prostate and 11 in the gastric tube and lung. Patients who developed new primary malignancies after esophagectomy had a significantly higher Brinkman index than those without new malignancies. An endoscopic approach successfully treated 92.9% of carcinomas in the residual esophagus, 90.9% of cancers in the gastric tube and 42.9% of carcinomas in the head and neck region. CONCLUSION: The incidence of new primary malignancies was higher than the age-standardized incidence. Long-term follow-up and systemic screening may increase the probability of an early diagnosis and subsequent low-invasive treatment.

An Open-Label Single-Arm Phase II Study of Treatment with Neoadjuvant S-1 Plus Cisplatin for Clinical Stage III Squamous Cell Carcinoma of the Esophagus.

LESSONS LEARNED: Two courses of neoadjuvant therapy using S-1 plus cisplatin for clinical stage III esophageal squamous cell carcinoma did not achieve expected response rate according to endoscopic evaluation of primary tumors. Subsequent esophagectomy was safely performed. BACKGROUND: In Japan, esophagectomy after two courses of 5-fluorouracil plus cisplatin is regarded a standard strategy for treating 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 need for a more effective regimen. METHODS: A single-arm, open-label phase II trial was conducted to evaluate the safety and efficacy of two courses of neoadjuvant chemotherapy using S-1 plus cisplatin (NAC-SP) for clinical stage III ESCC. The primary endpoint was overall response rate as defined by endoscopic evaluation of primary tumors. RESULTS: We enrolled 26 patients. The completion rate for the two courses of NAC-SP was 61.5%. Grade 3 or higher adverse events were experienced by 38.4% of patients. The treatment response rate according to endoscopic findings, acquired before the second course, was 34.6% and below the expected level (55.0%). The morbidity rate of patients who underwent radical subtotal esophagectomy (96.2%) was 32.0%. Repeat surgery was unnecessary, and surgery-associated deaths did not occur. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 84.6% and 92.2%, respectively. CONCLUSION: We demonstrate safety of NAC-SP, but not its efficacy, for patients with clinical stage III ESCC. Subsequent esophagectomy was safely performed.

Characteristics Associated with Nodal and Distant Recurrence After Radical Esophagectomy for Squamous Cell Carcinoma of the Thoracic Esophagus.

BACKGROUND: Recurrence after radical resection of esophageal squamous cell carcinoma (ESCC) is common. Limited evidence is available about the differences in clinical characteristics, risk factors, and prognostic significance between nodal and distant recurrence of thoracic ESCC. PATIENTS AND METHODS: We retrospectively analyzed 341 patients who underwent radical resection of thoracic ESCC and experienced (1) initial recurrence only in lymph nodes (n = 39), (2) recurrence only at distant organs (n = 57), or (3) no recurrences (n = 245) after follow-up ≥ 24 months. Clinicopathological characteristics, survival times, and risk factors were compared between the nodal and distant recurrence groups. RESULTS: The median follow-up time was 57.8 months. Metastasectomy as initial treatment for the recurrence was performed for six (15.4%) patients in the nodal recurrence group and one patient in the distant recurrence group. Compared with the nodal recurrence group, patients with distant recurrence had significantly shorter disease-free survival [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.10-2.57, P = 0.0169], postrecurrence survival (HR 1.77, 95% CI 1.01-3.10, P = 0.0476), and overall survival (HR 1.98, 95% CI 1.12-3.51, P = 0.0193). The distant recurrence group had significantly larger macroscopic tumor size and more advanced pathological T stage than the nodal recurrence group, whereas preoperative treatment, tumor location, number of fields dissected, tumor differentiation, lymphatic involvement, and vessel invasion were not significantly different between the two groups. CONCLUSIONS: Survival times and recurrence risk factors differed between patients with nodal and distant recurrence after radical resection of thoracic ESCC.