Epithelial overexpression of IL-33 induces eosinophilic esophagitis dependent on IL-13.

BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium-derived cytokine IL-33 is associated with type 2 immune responses and elevated in esophageal biopsy specimens from patients with EoE. OBJECTIVE: We hypothesized that overexpression of IL-33 by the esophageal epithelium would promote the immunopathology of EoE. METHODS: We evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL-33 in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2-/-, eosinophil-deficient, and IL-13-/- mice. Finally, EoE33 mice were treated with dexamethasone. RESULTS: EoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and TH2 cells. Marked increases in levels of type 2 cytokines, including IL-13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL-13 in EoE33 mice abrogated pathologic changes in vivo. EoE33 mice were responsive to steroids. CONCLUSIONS: IL-33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL-33 may play a pivotal role in the etiology of EoE by activating the IL-13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery.

TYRO3 promotes chemoresistance via increased LC3 expression in pancreatic cancer.

Pancreatic cancer (PC) is an aggressive malignancy with few treatment options, and improved treatment strategies are urgently required. TYRO3, a member of the TAM receptor tyrosine kinase family, is a known oncogene; however, the relationship between TYRO3 expression and PC chemoresistance remains to be elucidated. We performed gain- and loss-of-function experiments on TYRO3 to examine whether it is involved in chemoresistance in PC cells. TYRO3 knockdown decreased cell viability and enhanced apoptosis following treatment of PC cells with gemcitabine and 5-fluorouracil (5-FU). In contrast, no such effects were observed in TYRO3-overexpressing PC cells. It is known that autophagy is associated with cancer chemoresistance. We then examined effects of TYRO3 on autophagy in PC cells. TYRO3 overexpression increased LC3 mRNA levels and induced LC3 puncta in PC cells. Inhibition of autophagy by chloroquine mitigated cell resistance to gemcitabine and 5-FU. In a xenograft mouse model, TYRO3 silencing significantly increased sensitivity of the cells to gemcitabine and 5-FU. To further investigate the involvement of autophagy in patients with PC, we immunohistochemically analyzed LC3 expression in the tissues of patients who underwent pancreatectomy and compared it with disease prognosis and TYRO3 expression. LC3 expression was negatively and positively correlated with prognosis and TYRO3 expression, respectively. Furthermore, LC3- and TYRO3-positive patients had a significantly worse prognosis among patients with PC who received chemotherapy after recurrence. These results indicated that the TYRO3-autophagy signaling pathway confers PC resistance to gemcitabine and 5-FU, and could be a novel therapeutic target to resolve PC chemoresistance.

GPX4 Regulates Tumor Cell Proliferation via Suppressing Ferroptosis and Exhibits Prognostic Significance in Gastric Cancer.

BACKGROUND/AIM: Gastric cancer (GC) is the fourth leading cause of cancer-related death worldwide. Glutathione peroxidase 4 (GPX4) is a glutathione-dependent antioxidant enzyme known to regulate ferroptosis, which is a non-apoptotic form of cell death accompanied by iron-dependent accumulation of reactive oxygen species (ROS). This study evaluated the expression and function of GPX4 in GC. MATERIALS AND METHODS: The expression of GPX4 was examined in five human GC cell lines (KATO-III, MKN-1, MKN-28, MKN-45, and MKN-74) using real-time quantitative PCR and western blotting. The role of GPX4 in GC was examined using small interference RNA and cell proliferation and ROS assays. Finally, we analyzed GPX4 expression in tumor tissues from 106 patients who underwent GC surgery using immunohistochemistry and evaluated the relationship between GPX4 levels and clinical outcomes of GC. RESULTS: GPX4 was expressed in all GC cell lines at various levels. GPX4 silencing and inhibition significantly reduced cell proliferation and increased ROS generation. Furthermore, the mRNA levels of prostaglandin-endoperoxide synthase 2, a known biomarker of ferroptosis, were increased after GPX4 silencing. GPX4 expression was found to be an independent prognostic factor for overall and disease-specific survival in GC patients. CONCLUSION: GPX4 can regulate cancer cell death via ferroptosis in GC cell lines and represents a significant risk factor for survival in patients with GC.

Surgical Administration of Indocyanine Green in Hepatectomy for Improved Bile Leakage Detection.

BACKGROUND/AIM: Biliary fistulas (BFs) following hepatic resection are a complication of concern, and methods to completely prevent BFs after hepatic resection have yet to be developed. Our aim was to study the use of systemically administered indocyanine green (ICG) for preventing bile leakage (BL) from the cut surface of the liver. PATIENTS AND METHODS: The study sample comprised 26 patients who underwent hepatectomy without ICG (conventional observation group; CO-G) and 23 hepatectomy patients who underwent intraoperative detection of BL using systemically administered ICG (ICG observation group; IO-G). We compared the bilirubin levels in drainage effluent between patients in whom BL from the resected liver was observed using conventional assessment with the naked eye and those in whom ICG leakage was used as an indicator of BL. In the IO-G, we also compared the number of BL spots on the resected plane visible to the naked eye with the number of visible spots on an ICG camera. RESULTS: Three days after surgery, the bilirubin levels in the drainage fluid of the IO-G were significantly lower than those in the CO-G (1.3 vs. 1.9 mg/dl, p=0.019). Two cases (7.7%) of International Study Group of Liver Surgery (ISGLS) grade B biliary fistula occurred in the CO-G, but none in the IO-G. In the IO-G, the number of BL spots detected just after hepatectomy was significantly higher using ICG camera observation than the naked eye observation (0.22 vs. 0.91 spots, p<0.001). CONCLUSION: Observation with systemically administered ICG can detect BLs with more sensitivity than conventional observation with the naked eye. This enables rapid repair and may prevent biliary fistula.

The Barthel Index for Predicting Postoperative Complications in Elderly Patients Undergoing Abdominal Surgery: A Prospective Single-center Study.

BACKGROUND/AIM: The Barthel index and Katz index are useful in assessing the physical function status of patients. We prospectively evaluated the relationship between the Barthel and Katz indices and postoperative complications in older patients undergoing gastrointestinal surgery. PATIENTS AND METHODS: We enrolled 250 patients aged ≥65 years who underwent gastrointestinal surgery between September 2018 and April 2020. Postoperative complications within 30 days after surgery were categorized using the Clavien-Dindo classification. The primary endpoint was the incidence of postoperative complications of Clavien-Dindo grade ≥II. RESULTS: Of the 250 patients (age, 74.1±6.2 years), 149 (59.6%) were male and 101 (40.4%) were female. The Barthel index was <100 in 49 patients (19.6%), and the Katz index was B-G in 23 patients (9.2%). Seventy-five patients (30%) developed postoperative complications of Clavien-Dindo grade ≥I, and 72 patients (28.8%) developed complications of Clavien-Dindo grade ≥II within 30 days after surgery. A Barthel index of <100 was more common in the group with complications, while the Katz index did not differ. A Barthel index of <100 was also a significant multivariate predictor of complications of Clavien-Dindo grade ≥II. CONCLUSION: The Barthel index is a useful predictor of postoperative complications in older individuals undergoing gastrointestinal surgery.

Influence of the water jet system vs cavitron ultrasonic surgical aspirator for liver resection on the remnant liver.

BACKGROUND: Several methods, such as finger fracture, Pean crush, cavitron ultrasonic surgical aspirator (CUSA), and water jet (WJ), are used for hepatic parenchymal dissection in liver surgery. CUSA is the conventional method in Japan. WJ is a relatively novel method for parenchymal dissection. Although it has several advantages, such as lower volume of blood loss and shorter operative time, the effect of the WJ system for hepatic dissection on the remnant liver has not yet been investigated. AIM: To investigate and compare the effect of the WJ method vs CUSA on the remnant liver cut surface. METHODS: This observational study compared the two types of parenchymal transection methods (WJ vs CUSA) in liver surgery. In total, 24 and 40 patients who underwent hepatectomy using the WJ method and CUSA, respectively, were included in the analysis. Accordingly, the clinicopathological characteristics and clinical outcomes of 24 and 40 patients were compared. Furthermore, postoperative contrast-enhanced computed tomography (CT) scan was performed to assess the cut surface length of the remnant liver and the degenerative thickness of the areas with a reduced contrast effect in the dissected plane. Then, the two groups were compared. RESULTS: On CT scan, the median areas of denaturation in the liver dissection planes were 522 (range: 109.5-1242) mm2 in the CUSA group and 324 (range: 93.6-1529) mm2 in the WJ group. The area did not significantly differ between the two groups; however, the denaturation thickness of the WJ group was significantly lower than that of the CUSA group [5.8 (range: 0.7-11.1) mm vs 3.3 (range: 1.7-10.4) mm, P < 0.001]. CONCLUSION: The WJ group had significantly thinner contrast-enhanced areas in the post hepatectomy detached section than the CUSA group.

Modified geriatric nutritional risk index in patients with pancreatic cancer: a propensity score-matched analysis.

BACKGROUND: The modified nutritional geriatric risk index (mGNRI) was developed as a novel index and provides a more appropriate prognostic index than the original GNRI, which was reported to be a useful index for predicting prognoses for various malignancies. This study investigated the prognostic significance of the mGNRI compared with that of the GNRI in patients with pancreatic cancer and the association with psoas muscle volume (PMV) for survival outcomes. METHODS: This retrospective study included 137 patients who had undergone pancreatectomy for pancreatic cancer. The enrolled patients were grouped as high mGNRI (≥ 85.3) or low mGNRI (< 85.3), and high GNRI (≥ 92) or low GNRI (< 92) for prognostic analysis based on cutoff values. A propensity-matched analysis was performed in this study. RESULTS: The 5-year overall survival of patients in the high mGNRI group or high GNRI group was significantly longer than those in the low mGNRI group or low GNRI group. Statistically significant differences for the 5-year OS were observed in the three groups with respect to the combination of mGNRI and PMV. Patients with low mGNRI/low PMV had a worse 5-year OS rate compared with patients with high GNRI/high PMV or those with high GNRI or high PMV, but not both. The concordance index of the mGNRI to predict the 5-year overall survival was greater than that of the GNRI or the combination of the GNRI and PMV, but lower than that of the combination of the mGNRI and PMV. Multivariate analysis revealed that the mGNRI was an independent prognostic factor for patients with pancreatic cancer (P = 0.005). CONCLUSIONS: The mGNRI might be a more useful prognostic factor than the GNRI for patients with pancreatic cancer, and might predict prognostic outcomes more accurately when combined with PMV.

Geriatric nutritional risk index as a prognostic factor in patients with recurrent pancreatic cancer.

The aim of this study is to investigate the prognostic significance of geriatric nutritional risk index (GNRI) at the time of recurrence in patients with recurrent pancreatic cancer, and the relationship between GNRI and skeletal muscle mass for survival outcomes after recurrence. This study enrolled 77 patients who developed postoperative recurrence. The skeletal muscle mass index (SMI) was used in this study. The patients were divided into a high-GNRI group (n = 36) and a low-GNRI group (n = 41) for the GNRI, and were divided into a high-SMI group (n = 38) and a low-SMI group (n = 39) for SMI. The 2-year post-recurrence overall survival of patients in the high-GNRI group was significantly longer than that of patients in the low-GNRI group (P = 0.001). No significant difference for the 2-year post-recurrence OS curves between the high-SMI group and the low-SMI group was observed (P = 0.125). Upon stratifying the patients with high GNRI or low GNRI according to SMI, There was no significant difference in the 2-year post-recurrence OS curves between the patients with both high GNRI and high SMI and the patients with high GNRI and low SMI (P = 0.399). Similarly, There was no significant difference in the 2-year post-recurrence OS curves between the patients with low GNRI and high SMI and the patients with both low GNRI and low SMI (P = 0.256). Multivariate analysis revealed that the GNRI at the time of recurrence was an independent prognostic risk factor in patients with recurrent pancreatic cancer (P = 0.019). The GNRI at the time of recurrence is useful for predicting the prognosis in patients with recurrence pancreatic cancer. Skeletal muscle mass at the time of recurrence is not contributed to predict post-recurrence survival of patients with recurrent pancreatic cancer.

Molecular mechanisms underlying the promotion of wound repair by coenzyme Q10: PI3K/Akt signal activation via alterations to cell membrane domains.

Coenzyme Q10 (CoQ10) promotes wound healing in vitro and in vivo. However, the molecular mechanisms underlying the promoting effects of CoQ10 on wound repair remain unknown. In the present study, we investigated the molecular mechanisms through which CoQ10 induces wound repair using a cellular wound-healing model. CoQ10 promoted wound closure in a dose-dependent manner and wound-mediated cell polarization after wounding in HaCaT cells. A comparison with other CoQ homologs, benzoquinone derivatives, and polyisoprenyl compounds suggested that the whole structure of CoQ10 is required for potent wound repair. The phosphorylation of Akt after wounding and the plasma membrane translocation of Akt were elevated in CoQ10-treated cells. The promoting effect of CoQ10 on wound repair was abrogated by co-treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor. Immuno-histochemical and biochemical analyses showed that CoQ10 increased the localization of caveolin-1 (Cav-1) to the apical membrane domains of the cells and the Cav-1 content in the membrane-rich fractions. Depletion of Cav-1 suppressed CoQ10-mediated wound repair and PI3K/Akt signaling activation in HaCaT cells. These results indicated that CoQ10 increases the translocation of Cav-1 to the plasma membranes, activating the downstream PI3K/Akt signaling pathway, and resulting in wound closure in HaCaT cells.

Laparoscopic cholecystectomy after percutaneous transhepatic gallbladder drainage for acute cholecystitis in a patient with a left ventricle assist device: A case report and brief review of the literature (with video).

For acute cholecystitis in patients with left ventricular assist devices, the use of percutaneous transhepatic gallbladder drainage to calm inflammation before planned laparoscopic cholecystectomy may be helpful in safely adjusting anticoagulation and in performing safe laparoscopic cholecystectomy, as demonstrated in this case.

Circular stapling anastomosis with indocyanine green fluorescence imaging for cervical esophagogastric anastomosis after thoracoscopic esophagectomy: a propensity score-matched analysis.

BACKGROUND: Thoracoscopic esophagectomy has been extensively used worldwide as a curative surgery for patients with esophageal cancer; however, complications such as anastomotic leakage and stenosis remain a major concern. Therefore, the objective of this study was to evaluate the efficacy of circular stapling anastomosis with indocyanine green (ICG) fluorescence imaging, which was standardized for cervical esophagogastric anastomosis after thoracoscopic esophagectomy. METHODS: Altogether, 121 patients with esophageal cancer who underwent thoracoscopic esophagectomy with radical lymph node dissection and cervical esophagogastric anastomosis from November 2009 to December 2020 at Tottori University Hospital were enrolled in this study. Patients who underwent surgery before the anastomotic method was standardized were included in the classical group (n = 82) and patients who underwent surgery after the anastomotic method was standardized were included in the ICG circular group (n = 39). The short-term postoperative outcomes, including anastomotic complications, were compared between the two groups using propensity-matched analysis and the risk factors for anastomotic leakage were evaluated using logistic regression analyses. RESULTS: Of the 121 patients, 33 were included in each group after propensity score matching. The clinicopathological characteristics of patients did not differ between the two groups after propensity score matching. In terms of perioperative outcomes, a significantly higher proportion of patients who underwent surgery using the laparoscopic approach (P < 0.001) and narrow gastric tube (P = 0.003), as well as those who had a lower volume of blood loss (P = 0.009) in the ICG circular group were observed after matching. Moreover, the ICG circular group had a significantly lower incidence of anastomotic leakage (39% vs. 9%, P = 0.004) and anastomotic stenosis (46% vs. 21%, P = 0.037) and a shorter postoperative hospital stay (30 vs. 20 days, P < 0.001) than the classical group. According to the multivariate analysis, the anastomotic method was an independent risk factor for anastomotic leakage after thoracoscopic esophagectomy (P = 0.013). CONCLUSIONS: Circular stapling anastomosis with ICG fluorescence imaging is effective in reducing complications such as anastomotic leakage and stenosis.

The Significance of Surgical Intervention for Metasynchronous Liver Metastasis in Gastric Cancer: A Single-centre Analysis.

BACKGROUND/AIM: This study investigated the influence of surgery for metasynchronous liver metastasis in gastric cancer on prognosis. PATIENTS AND METHODS: A retrospective study was conducted involving 21 consecutive patients with gastric cancer with metasynchronous distant metastasis only in the liver after curative gastrectomy. The patients were divided into two groups: those who underwent hepatic resection and those who did not. The clinicopathological characteristics, recurrence-free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were analysed. RESULTS: Among 981 gastrectomies performed in Tottori University Hospital between 2005 and 2019, 930 were curative. Among 153 cases of recurrence during the follow-up, 21 consecutive cases involving the liver only and metasynchronous recurrent metastasis on imaging were included in this study. The study included 16 males and five females with a median age of 70 years. No statistical difference in RFS (237 vs. 201 days; p=0.788) was observed between the hepatectomy and non-hepatectomy groups; however, OS (1,564 vs. 608 days, p=0.008) and DSS (1,597 vs. 608 days, p=0.006) were significantly prolonged in the hepatectomy group. Univariate and multivariate analyses revealed that hepatectomy was the only independent prognostic factor (hazard ratio=0.33; p=0.042). CONCLUSION: Hepatic resection of heterogeneous liver metastases in gastric cancer seems to be a useful option that can be expected to cure the disease, which cannot be achieved by chemotherapy alone.

The impact of AMIGO2 on prognosis and hepatic metastasis in gastric cancer patients.

BACKGROUND: Gastric cancer (GC) is one of the most common malignancies, and the liver is the most common site of hematogenous metastasis of GC. AMIGO2 is a type I transmembrane protein that has been implicated in tumour cell adhesion in adenocarcinomas; however, its importance in GC remains undetermined. METHODS: We analyzed AMIGO2 expression by immunohistochemistry using the specific monoclonal antibody for human AMIGO2 in 128 patients who underwent GC surgery to evaluate its relationship between various metastatic and clinical outcomes in GC. RESULTS: Immunohistochemistry revealed that AMIGO2 expression was an independent prognostic factor for overall survival, disease-specific survival, and liver metastasis in GC patients. CONCLUSIONS: This study showed that AMIGO2 is induced in GC tissues and can mediate hepatic metastasis. Determining AMIGO2 expression in GC will help predict patient prognosis and the incidence of liver metastasis.

Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids.

Esophageal squamous cell carcinoma (ESCC) is prevalent worldwide, accounting for 90% of all esophageal cancer cases each year, and is the deadliest of all human squamous cell carcinomas. Despite recent progress in defining the molecular changes accompanying ESCC initiation and development, patient prognosis remains poor. The functional annotation of these molecular changes is the necessary next step and requires models that both capture the molecular features of ESCC and can be readily and inexpensively manipulated for functional annotation. Mice treated with the tobacco smoke mimetic 4-nitroquinoline 1-oxide (4NQO) predictably form ESCC and esophageal preneoplasia. Of note, 4NQO lesions also arise in the oral cavity, most commonly in the tongue, as well as the forestomach, which all share the stratified squamous epithelium. However, these mice cannot be simply manipulated for functional hypothesis testing, as generating isogenic mouse models is time- and resource-intensive. Herein, we overcome this limitation by generating single cell-derived three-dimensional (3D) organoids from mice treated with 4NQO to characterize murine ESCC or preneoplastic cells ex vivo. These organoids capture the salient features of ESCC and esophageal preneoplasia, can be cheaply and quickly leveraged to form isogenic models, and can be utilized for syngeneic transplantation experiments. We demonstrate how to generate 3D organoids from normal, preneoplastic, and SCC murine esophageal tissue and maintain and cryopreserve these organoids. The applications of these versatile organoids are broad and include the utilization of genetically engineered mice and further characterization by flow cytometry or immunohistochemistry, the generation of isogeneic organoid lines using CRISPR technologies, and drug screening or syngeneic transplantation. We believe that the widespread adoption of the techniques demonstrated in this protocol will accelerate progress in this field to combat the severe burden of ESCC.

Impact of skeletal muscle mass in patients with unresectable gastric cancer who received palliative first-line chemotherapy based on 5-fluorouracil.

BACKGROUND: The mortality rate of patients with unresectable gastric cancer (UGC) has decreased with the development of chemotherapies and surgical techniques. However, the survival rate remains low. We retrospectively examined the prognostic significance of the pretreatment skeletal muscle mass index (SMI) and nutritional and inflammatory factors in patients with UGC. METHODS: This study included 83 patients diagnosed with UGC at Tottori University Hospital who received palliative chemotherapy based on 5-fluorouracil. Pretreatment computed tomography (CT) measured overall skeletal muscle mass (SMM) and cross-sectional SMM at the third lumbar vertebra (L3). We focused on the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein-to-albumin ratio (CAR), prognostic nutritional index (PNI), and platelet-to-lymphocyte ratio (PLR) as nutritional and inflammatory factors. RESULTS: Receiver operating characteristic curve analysis was performed for median survival time (MST) after palliative chemotherapy. SMIs for males and females (43.9 cm2/m2 and 34.7 cm2/m2, respectively) were the cutoff values, and patients were divided into high (SMIHigh; n = 41) and low SMI groups (SMILow; n = 42). Body mass index (BMI) was significantly higher in patients in the SMIHigh group than in the SMILow group (p < 0.001). The number of patients who received third-line chemotherapy was significantly higher in the SMIHigh group than in the SMILow group (p = 0.037). The MST was significantly higher in the SMIHigh group than in the SMILow group (17.3 vs. 13.8 months; p = 0.008). The incidence of grade 3 or 4 side effects was significantly higher in patients with SMILow UGC (p = 0.028). NLR was significantly higher in patients with SMILow than it was in those with SMIHigh. (p = 0.047). In the univariate analysis, performance status, SMI, histological type, lines of chemotherapy, and NLR were prognostic indicators. The multivariate analysis identified SMI (p = 0.037), NLR (p = 0.002), and lines of chemotherapy (p < 0.001) as independent prognostic factors. CONCLUSIONS: The SMILow group had significantly more grade 3 or 4 side effects, were related to high NLR, and had a significantly worse prognosis than the SMIHigh group. TRIAL REGISTRATION: Retrospectively registerd.

Preoperative white blood cell count predicts anastomotic leakage in patients with left-sided colorectal cancer.

To determine whether preoperative white blood cell (WBC) counts reflect risk of anastomotic leak (AL) for patients with colorectal cancer (CRC), we retrospectively examined data from records of 208 consecutive patients who had undergone resections for left-sided CRC, including their clinicopathological parameters and preoperative laboratory data. The diagnostic value of WBC count for AL was evaluated and compared with those of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio and platelet count × C-reactive protein level multiplier (P-CRP) value; optimal cut-off values were derived from receiver operating characteristic curves. AL was observed in 11 of the 208 patients (5.3%). Compared with the no-AL group, the AL group had a significantly higher mean WBC count and smoking rate. In multivariate analysis, WBC count and smoking were independent risk factors for AL. Compared with the other tested inflammatory indicators, the cut-off value for WBC (6,200/µL) had the highest sensitivity (81.8%) and negative predictive value (98.4%), as well as the lowest likelihood ratio (0.289). Preoperative WBC count could therefore be a convenient predictor of AL in patients with left-sided CRC.

Platelet-to-Lymphocyte Ratio Multiplied by the Cytokeratin-19 Fragment Level as a Predictor of Pathological Response to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.

BACKGROUND: The standard treatment for resectable advanced esophageal squamous cell carcinoma in Japan is surgery followed by neoadjuvant chemotherapy, and it is important to predict the effect of neoadjuvant chemotherapy before treatment. Therefore, this study aims to extract conventional blood examination data, such as tumor markers and/or inflammatory/nutritional index levels, that can predict the pathological response of patients with esophageal squamous cell carcinoma to neoadjuvant chemotherapy. METHODS: We retrospectively analyzed the medical records of 66 patients with thoracic esophageal squamous cell carcinoma who received neoadjuvant chemotherapy, followed by curative esophagectomy at Tottori University Hospital between June 2009 and December 2019. RESULTS: We demonstrated that the product of the platelet-to-lymphocyte ratio (PLR) multiplied by the cytokeratin-19 fragment (CYFRA) level, which was termed "PLR-CYFRA," is the most accurate indicator that predicts the pathological response to neoadjuvant chemotherapy, with the highest area under the curve [0.795 (95% confidence interval: 0.665-0.925), P < 0.001] in receiver operating characteristic analyses. Therefore, we divided patients into the PLR-CYFRALow (< 237.6, n = 21) and PLR-CYFRAHigh (≥ 237.6, n = 45) groups and found that the percentage of PLR-CYFRALow was significantly higher in patients with a better pathological response (P < 0.001). Furthermore, patients with good pathological response had significantly better prognoses in terms of disease-specific survival (P = 0.014), recurrence-free survival (P = 0.014), and overall survival (P = 0.032). In the multivariate analysis, PLR-CYFRA was an independent predictor of the pathological response of patients with esophageal squamous cell carcinoma to neoadjuvant chemotherapy (P = 0.002). CONCLUSION: Pretreatment PLR-CYFRA might be a useful and simple tool that predicts the pathological effect of neoadjuvant chemotherapy in esophageal squamous cell carcinoma.

Human chromosome 3p21.3 carries TERT transcriptional regulators in pancreatic cancer.

Frequent loss of heterozygosity (LOH) on the short arm of human chromosome 3 (3p) region has been found in pancreatic cancer (PC), which suggests the likely presence of tumor suppressor genes in this region. However, the functional significance of LOH in this region in the development of PC has not been clearly defined. The human telomerase reverse transcriptase gene (hTERT) contributes to unlimited proliferative and tumorigenicity of malignant tumors. We previously demonstrated that hTERT expression was suppressed by the introduction of human chromosome 3 in several cancer cell lines. To examine the functional role of putative TERT suppressor genes on chromosome 3 in PC, we introduced an intact human chromosome 3 into the human PK9 and murine LTPA PC cell lines using microcell-mediated chromosome transfer. PK9 microcell hybrids with an introduced human chromosome 3 showed significant morphological changes and rapid growth arrest. Intriguingly, microcell hybrid clones of LTPA cells with an introduced human chromosome 3 (LTPA#3) showed suppression of mTert transcription, cell proliferation, and invasion compared with LTPA#4 cells containing human chromosome 4 and parental LTPA cells. Additionally, the promoter activity of mTert was downregulated in LTPA#3. Furthermore, we confirmed that TERT regulatory gene(s) are present in the 3p21.3 region by transfer of truncated chromosomes at arbitrary regions. These results provide important information on the functional significance of the LOH at 3p for development and progression of PC.

Clinical Significance of Serum Antithrombin III Activity After Hepatectomy for Hepatocellular Carcinoma.

BACKGROUND: As antithrombin III (AT-III) is produced in the hepatocytes, its serum activity decreases at the time of liver failure, in addition to ischemia reperfusion injury, vascular endothelial dysfunction, and disseminated intravascular coagulation (DIC). Here, we examined whether the serum AT-III value after hepatectomy could be a prognostic factor for hepatocellular carcinoma (HCC). METHODS: Of 141 patients who underwent hepatectomy for HCC, data for 101 patients in whom serum AT-III activity was measured on the first postoperative day were extracted. Patients with serum AT-III activity > 50% and ≤ 50% were assigned to high value (72 cases) and low value (29 cases) groups, respectively. We examined the clinical and prognostic differences between these two groups. RESULTS: The average age of enrolled patients (83 men and 18 women) was 68.0 years. The 5-year overall survival rate was 88% and 60% in the high and low value groups, respectively (P < 0.01). Furthermore, the 2-year relapse-free survival rate was 71% and 54% in the high and low value groups, respectively (P = 0.03). CONCLUSION: This is the first study to demonstrate that serum AT-III levels on the first postoperative day may serve as a prognostic factor in HCC patients.

Evaluation of Blood Supply with Indocyanine Green Fluorescence in Resection for Concurrent Gastric and Pancreatic Cancer: A Case Report.

We present a rare case of concurrent resection of pancreatic and gastric cancer in which indocyanine green (ICG) fluorescence was used to evaluate the remnant stomach. An 80-year-old man was referred with a tumor in the distal pancreas. Computed tomography showed a 25-mm mass in the pancreatic tail; endoscopic ultrasound-guided fine-needle aspiration revealed adenocarcinoma. Upper gastrointestinal endoscopy and subsequent upper gastrointestinal series revealed advanced gastric cancer in the mid-stomach. Concurrent resection of the pancreatic and gastric tumors was performed. After distal pancreatectomy and distal gastrectomy, ICG evaluation of the stomach showed fluorescence extending only 3 cm distal from the cardia. To avoid ischemic change at the remnant stomach, total gastrectomy was performed. Since remnant gastric necrosis and anastomotic leak following ischemia can lead to fatal outcomes, the use of ICG to evaluate blood supply at anastomotic sites can help determine the extent of safe resection in such cases.