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.

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.

Catheter-related bloodstream infection caused by Lacticaseibacillus paracasei: A case report and literature review.

Catheter-related bloodstream infections (CRBSIs) caused by Lactobacillus spp. and Lacticaseibacillus spp. are rare, and their clinical course and optimal treatment remain uncertain. In this report, we present a 46-year-old male patient who experienced clinically diagnosed Lacticaseibacillus paracasei CRBSI on four separate occasions, despite receiving systemic administration of antibiotics and antimicrobial lock therapy. The patient did not develop L. paracasei bacteremia after catheter removal. This case report furthers our knowledge of CRBSI caused by Lactobacillus and related genera and highlights the need for further research.

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.

Impact of obstructive ventilatory impairment on intraoperative bleeding during laparoscopic hepatectomy.

PURPOSE: An animal model of laparoscopic hepatectomy showed that bleeding from the hepatic vein is influenced by airway pressure. However, there are little research reports on how airway pressure leads to risks in clinical practice. The main objective of this study was to investigate the impact of preoperative forced expiratory volume % in 1 s (FEV1.0%) on intraoperative blood loss in laparoscopic hepatectomy. METHODS: All patients who underwent pure laparoscopic or open hepatectomy from April 2011 to July 2020 were classified into two groups by preoperative spirometry: those with obstructive ventilatory impairment (obstructive group; FEV1.0% < 70%) and those with normal respiratory function (ormal group; FEV1.0% ≥ 70%). Massive blood loss was defined as 400 mL for laparoscopic hepatectomy. RESULTS: In total, 247 and 445 patients underwent pure laparoscopic and open hepatectomy, respectively. Regarding laparoscopic hepatectomy group, blood loss was significantly greater in the obstructive group (122 vs. 100 mL, P = 0.042). Multivariate analysis revealed that high IWATE criteria which classify the surgical difficulty of laparoscopic hepatectomy (≥ 7, odds ratio (OR): 4.50, P = 0.004) and low preoperative FEV1.0% (< 70%, OR: 2.28, P = 0.043) were independent risk factors for blood loss during laparoscopic hepatectomy. In contrast, FEV1.0% did not affect the blood loss (522 vs. 605 mL, P = 0.113) during open hepatectomy. CONCLUSION: Obstructive ventilatory impairment (low FEV1.0%) may affect the amount of bleeding during laparoscopic hepatectomy.

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.

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.

G-protein subunit gamma-4 expression has potential for detection, prediction and therapeutic targeting in liver metastasis of gastric cancer.

BACKGROUND: The liver is the most common site for haematogenous metastasis of gastric cancer, and liver metastasis is fatal. METHODS: We conducted a transcriptomic analysis between metastatic foci in the liver, primary tumour and adjacent tissues from gastric cancer patients with metastasis limited to the liver. We determined mRNA expression levels in tumour tissues of 300 patients with gastric cancer via quantitative RT-PCR. The oncogenic phenotypes of GNG4 were determined with knockdown, knockout and forced expression experiments. We established and compared subcutaneous and liver metastatic mouse xenograft models of gastric cancer to reveal the roles of GNG4 in tumorigenesis in the liver. RESULTS: GNG4 was upregulated substantially in primary gastric cancer tissues as well as liver metastatic lesions. High levels of GNG4 in primary cancer tissues were associated with short overall survival and the likelihood of liver recurrence. Functional assays revealed that GNG4 promoted cancer cell proliferation, the cell cycle and adhesiveness. Tumour formation by GNG4-knockout cells was moderately reduced in the subcutaneous mouse model and strikingly attenuated in the liver metastasis mouse model. CONCLUSIONS: GNG4 expression may provide better disease monitoring for liver metastasis, and GNG4 may be a novel candidate therapeutic target for liver metastasis.

Pancreatic Fat and Body Composition Measurements by Computed Tomography are Associated with Pancreatic Fistula After Pancreatectomy.

OBJECTIVES: Postoperative pancreatic fistula (POPF) is the most threatening complication after pancreatectomy. This study aimed to directly assess pancreatic fatty infiltration with preoperative computed tomography (CT) imaging and to investigate whether a preoperative analysis of patient variables, including CT characteristics and clinical factors, can predict POPF. METHODS: We enrolled 150 consecutive patients who underwent curative pancreatectomy. Radiographic factors, including pancreatic fat volume, were measured using preoperative CT imaging and the predictive factors were explored using univariate and multivariate analyses. RESULTS: POPF developed in 30 patients (20.0%). The ratio of pancreatic fat (RPF) ≥ 4.83% was associated with a risk of POPF, high body mass index (BMI), and obese body habitus. Patients with POPF were significantly more likely to have high BMI (≥ 25 kg/m2), obese body habitus, and an RPF ≥ 4.83% than patients without POPF. In the multivariate analysis, visceral fat area/skeletal muscle index (VFA/SMI) ≥ 1.94 (odds ratio [OR] 4.28, 95% confidence interval [CI] 1.43-12.9, p = 0.0095) was the sole independent predictive factor for POPF. For patients with a soft pancreas, VFA/SMI ≥ 1.94 (OR 5.67, 95% CI 2.05-15.7, p = 0.0008) was again the sole independent predictive factor for POPF. CONCLUSION: Preoperative CT images can examine pancreatic fatty infiltration, and patients who had POPF were significantly associated with a high RPF. Among several parameters, VFA/SMI was the only independent predictive factor for clinically relevant POPF. Preoperative evaluation of these body composition variables and the pancreatic configuration could be useful for predicting POPF.

miR-23b-3p Plays an Oncogenic Role in Hepatocellular Carcinoma.

BACKGROUND: Reports show miR-23b to be a cancer-related biomarker in various cancer types. Interestingly, it has a dual role of oncogenic and tumor-suppressive functions, depending on the cancer type. This study focused on the unknown association of miR-23b-3p with hepatocellular carcinoma (HCC). METHODS: Expression of miR-23b-3p was measured in nine HCC cell lines and 125 resected human HCC samples by TaqMan microRNA assays. To detect its downstream target, miR-23b-3p mimic and inhibitor constructs were transfected and analyzed. RESULTS: HepG2, a high miR-23b-3p-expressing cell line, was transfected with a miR-23b-3p inhibitor construct, whereas SK-Hep1, a low miR-23b-3p-expressing cell line, was transfected with a mimic construct. Proliferation of HCC cells was activated by miR-23b-3p overexpression and diminished by its knockdown. Then, 125 clinical HCC samples were examined to measure miR-23b-3p expression. Tumor expression of miR-23b-3p was upregulated in 48 cases (38%) and downregulated in 77 cases (62%). The upregulated cases were correlated with elderly patients (P = 0.015). These patients also showed significantly poor overall survival [hazard ratio (HR), 3.10; 95% conflidence interval (CI), 1.57-6.29; P = 0.001] in a multivariate analysis. Furthermore, mitochondrial metabolism-related genes (MICU3 and AUH) were detected as specific binding targets. CONCLUSION: The study showed that miR-23b-3p functions as an oncogenic microRNA in HCC cell lines. Its overexpression in resected HCC tissues was a significant prognostic factor of overall survival. Both MICU3 and AUH may be candidate gene targets of miR-23b-3p.

Peritoneal Lavage Tumor DNA as a Novel Biomarker for Predicting Peritoneal Recurrence in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The clinical role of peritoneal lavage cytology (CY) in pancreatic ductal adenocarcinoma (PDAC) remains controversial, partly due to its low sensitivity. This study aimed to develop a new biomarker, defined as peritoneal lavage tumor DNA (ptDNA), using DNAs extracted from peritoneal lavage samples from patients with PDAC. METHODS: Samples were collected intraoperatively from 89 PDAC patients who underwent pancreatectomy between 2012 and 2017. Droplet digital polymerase chain reaction (PCR) was used to measure ptDNA for detection of KRAS mutations. The ptDNA status and clinical characteristics were retrospectively evaluated. RESULTS: Positive ptDNA was found in 41 patients, including all 9 patients positive for CY (CY+) and 32 patients negative for CY (CY-). The mutant allele frequency was significantly higher in the CY+ patients than in the CY- patients. The disease-free survival (DFS) and overall survival (OS) were significantly poorer in the high-ptDNA group than in the low-ptDNA group (median DFS, 11.0 vs. 18.8 months; p = 0.007; median OS, 28.7 vs not reached; p = 0.001). The survival curves of DFS and OS in the CY+ group were almost equal to those in the CY- and high-ptDNA group. In a multivariable analysis, ptDNA was an independent predictive factor for DFS (p = 0.025) and OS (p = 0.047). The estimated cumulative incidence of peritoneal recurrence was 45.5% in the high-ptDNA group. The ptDNA biomarker had a much higher sensitivity for peritoneal recurrence than CY, whereas CY had higher specificity. CONCLUSIONS: As a promising biomarker, ptDNA may predict poor prognosis and peritoneal recurrence in PDAC, resolving the controversy surrounding CY.

Randomized phase II study comparing the efficacy and safety of SOX versus mFOLFOX6 as neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer (KSCC1301).

BACKGROUND: Preoperative chemoradiotherapy (CRT), the current standard of care for locally advanced rectal cancer (LARC), is associated with many radiotherapy (RT)-related side effects. We aimed to evaluate whether S-1 and oxaliplatin (SOX) or folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) can be as effective as neoadjuvant chemotherapy (NAC) regimens for LARC without RT. METHODS: Patients with untreated resectable LARC were randomly assigned to receive SOX or mFOLFOX6. The NAC protocol period was 3 months. The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints included pathological effects, surgical completion rate, 3-year survival, and safety. RESULTS: From September 2013 to October 2015, 56 and 54 patients were enrolled in the SOX and mFOLFOX6 arms, respectively. The 3-year DFS rates were 69.4% (95% confidence interval [CI] 54.9-83.6) and 73.4% (95% CI 58.7-83.6) in the SOX and mFOLFOX6 arms, respectively; no significant differences were found between the arms (log-rank test; P = 0.5315, hazard ratio: 0.808, 95% CI 0.414-1.578). The 3-year survival rates were 92.3 and 91.8% in the SOX and mFOLFOX6 arms, respectively. The surgical completion rate was 98.1% overall, 100% in the SOX arm, and 96.0% in the mFOLFOX6 arm. The incidences of pathological response rates ≥grade 1b were 41.5 and 43.8% in the SOX and mFOLFOX6 arms, respectively. Both treatments were manageable and tolerable. CONCLUSION: We demonstrated the effectiveness and safety of SOX and mFOLFOX6, both of which may be new neoadjuvant treatment candidates in previously untreated LARC cases. TRIAL REGISTRATION: Date of enrolment of the first participant to the trial: 3rd Oct 2013; This study was registered in the UMIN clinical trials registry on 14th Aug, 2013. (Prospectively registered, UMIN-CTR number UMIN000011486). https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&recptno=R000013441&language=J.

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.