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Background: Signal regulatory protein alpha (SIRPα) inhibits phagocytosis by macrophages by interacting with CD47. Despite its known role in various cancers, the clinical significance of SIRPα in gastric cancer (GC) remains unclear. This study aimed to elucidate the clinical implications of SIRPα in GC, exploring its relevance to immunotherapy efficacy and the tumor microenvironment., Methods: Two cohorts were studied: a gastrectomy cohort (137 patients) and an immune checkpoint inhibitor (ICI)-treated cohort (19 patients with unresectable advanced GC who received nivolumab). Immunohistochemistry was used to assess SIRPα, CD80, CD163, CD8, and PD-L1 expressions. Kaplan-Meier curves and Cox models were used to analyze the clinical outcomes. In vitro experiments used peripheral blood mononuclear cells and THP-1 macrophage cell lines to examine SIRPα responses to interferon-γ (IFN-γ)., Results: In the gastrectomy cohort, high SIRPα expression correlated with advanced tumor invasion, distant metastasis, and poor recurrence-free and overall survival. SIRPα expression was also significantly associated with macrophage and CD8 + T cells infiltration and PD-L1 expression. In the ICI-treated cohort, high SIRPα expression was associated with better overall survival after nivolumab induced. Moreover, in vitro IFN-γ stimulation upregulated SIRPα expression on monocytes in peripheral blood mononuclear cells and THP-1 cells, suggesting high SIRPα expression may reflect an active immune microenvironment., Conclusion: SIRPα expression is not only a poor prognostic factor for GC, possibly through inhibition of the CD47-SIRP⍺ pathway, but may also be involved in the efficacy of ICI therapy in GC., Competing Interests: Declarations. Conflict of interest: The authors have no conflict of interest. Ethical approval: Approval of the research protocol by an Institutional Reviewer Board: The protocol was approved by the Clinical Research Ethical Committee of our Institutional Review Board (Kyushu University, IRB NO.22152-00). Informed consent: Informed consent to be included in the study, or the equivalent, was obtained from all patients., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Management of patients with colorectal liver metastases (CRLMs) requires a multidisciplinary approach. For patients with progression of RAS mutant tumors, the choice of angiogenesis inhibitors can be controversial. Here, we report a patient with RAS mutant CRLMs achieving long-term disease-free survival with repeated R0 resections and perioperative treatment, especially aflibercept + FOLFIRI (5-fluorouracil, levofolinate, irinotecan), which may have prevented long-term recurrence., Case Presentation: The patient was a 37 year-old woman diagnosed with RAS mutant transverse colon cancer with 19 LMs. As the metastases were limited to the liver, we introduced systemic chemotherapy aiming at conversion surgery. After six cycles of bevacizumab + FOLFOXIRI (5-fluorouracil, levofolinate, oxaliplatin, irinotecan), we performed partial hepatectomy for all LMs, and left hemicolectomy for the primary tumor after another four cycles of bevacizumab + FOLFIRI. Three months after surgery, the patient presented with massive ovarian metastases with carcinomatous ascites. We conducted bilateral oophorectomy, and initiated aflibercept + FOLFIRI therapy considering the possibility of resistance to bevacizumab. The patient was recurrence-free for 2 years during aflibercept + FOLFIRI treatment. After its discontinuation, two distant metastases developed. Both were resectable and the patient achieved recurrence-free survival of 2 years and 3 months after the last operation (6 years since initiation of treatment), without additional chemotherapy., Conclusions: We believe that multidisciplinary treatment aimed at complete resection could lead to long-term survival even in patients with repeated recurrence of CRLMs. Aflibercept + FOLFIRI could be effective in controlling metastasis of RAS mutant colon cancer even after treatment with bevacizumab., (© 2024. The Author(s).)

Purpose: Few studies have investigated the impact of the surgical proximal and distal margins on colon cancer recurrence. We conducted this study to investigate the effect of resection margins on the prognosis of resectable colon cancer., Methods: We analyzed data on 1458 patients who underwent colorectal resection in our institute between January, 2004 and March, 2020, including 579 patients with resectable colon cancer. The association between the resection margin and recurrence for each oncological status was assessed and the value of the resection length that influenced recurrence was analyzed., Results: Patients who had pT4 colon cancer with margins of more than 7 cm had a trend of fewer recurrences and longer relapse-free survival (RFS) than those with colon cancer of other stages (P = 0.033; hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.20-0.89). Multivariate analysis identified a margin of < 7 cm as an independent risk factor for RFS in patients with pT4 colon cancer (P = 0.023; HR, 2.65; 95% CI 1.013-6.17). No correlation was found between resection margins and recurrence, depending on the extent of lymph node metastasis and tumor location., Conclusion: A resection margin of at least 7 cm should be maintained for patients with pT4 colon cancer., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background/aim: The efficacy of neoadjuvant chemotherapy (NAC) for colon cancer remains unestablished. This study aimed to investigate the outcomes of NAC in patients with locally advanced T4b or obstructive T4a colon cancers (LACC)., Patients and Methods: Data of patients with LACC who underwent colon surgery between 2010 and 2022 after NAC at our institution were retrospectively reviewed. Patient characteristics, surgical outcomes, tumor features, and prognosis were analyzed., Results: Among 800 patients with LACC who underwent radical resection, 11 received NAC because of cT4b or cT4a with mechanical obstruction. NAC, administered as a doublet regimen, had a median duration of three months, without grade ≥3 adverse events. R0 resection was achieved in all patients and downstaging was observed in eight patients. One patient developed a postoperative abdominal abscess, and adjuvant chemotherapy was administered to eight patients. Four patients experienced recurrence: liver metastasis in two, and local recurrence in two. Among these, three patients underwent resection of recurrent tumors. Median follow-up was 30 months., Conclusion: NAC is feasible for T4b or obstructive T4a colon cancer and may be a treatment option for LACC. Further large-scale studies are required to confirm the efficacy of NAC in these patients., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Insulin resistance and hyperglycemia are risk factors for periodontitis and poor wound healing in diabetes, which have been associated with selective loss of insulin activation of the PI3K/Akt pathway in the gingiva. This study showed that insulin resistance in the mouse gingiva due to selective deletion of smooth muscle and fibroblast insulin receptor (SMIRKO mice) or systemic metabolic changes induced by a high-fat diet (HFD) in HFD-fed mice exacerbated periodontitis-induced alveolar bone loss, preceded by delayed neutrophil and monocyte recruitment and impaired bacterial clearance compared with their respective controls. The immunocytokines, CXCL1, CXCL2, MCP-1, TNFα, IL-1β, and IL-17A, exhibited delayed maximal expression in the gingiva of male SMIRKO and HFD-fed mice compared with controls. Targeted overexpression of CXCL1 in the gingiva by adenovirus normalized neutrophil and monocyte recruitment and prevented bone loss in both mouse models of insulin resistance. Mechanistically, insulin enhanced bacterial lipopolysaccharide-induced CXCL1 production in mouse and human gingival fibroblasts (GFs), via Akt pathway and NF-κB activation, which were reduced in GFs from SMIRKO and HFD-fed mice. These results provided the first report that insulin signaling can enhance endotoxin-induced CXCL1 expression to modulate neutrophil recruitment, suggesting CXCL1 as a new therapeutic direction for periodontitis or wound healing in diabetes., Article Highlights: The mechanism for the increased risks for periodontitis in the gingival tissues due to insulin resistance and diabetes is unclear. We investigated how insulin action in gingival fibroblasts modulates the progression of periodontitis in resistance and diabetes. Insulin upregulated the lipopolysaccharide-induced neutrophil chemoattractant, CXCL1, production in gingival fibroblasts via insulin receptors and Akt activation. Enhancing CXCL1 expression in the gingiva normalized diabetes and insulin resistance-induced delays in neutrophils recruitment and periodontitis. Targeting dysregulation of CXCL1 in fibroblasts is potentially therapeutic for periodontitis and may also improve wound healing in insulin resistance and diabetes., (© 2023 by the American Diabetes Association.)

Objective: To correlate inflammatory cytokines and vascular endothelial growth factor (VEGF) in vitreous and plasma with vitreous retinol binding protein 3 (RBP3), diabetic retinopathy (DR) severity, and DR worsening in a population with type 1 and type 2 diabetes., Research Design and Methods: RBP3, VEGF, and inflammatory cytokines were measured in plasma and vitreous samples (n = 205) from subjects of the Joslin Medalist Study and Beetham Eye Institute., Results: Higher vitreous RBP3 concentrations were associated with less severe DR (P < 0.0001) and a reduced risk of developing proliferative DR (PDR) (P < 0.0001). Higher RBP3 correlated with increased photoreceptor segment thickness and lower vitreous interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and TNF-β (P < 0.05). PDR was associated with lower vitreous interferon-γ and IL-10 and higher VEGF, IL-6, and IL-15 (P < 0.05), but was not associated with their plasma concentrations., Conclusions: Higher vitreous RBP3 concentrations are associated with less severe DR and slower rates of progression to PDR, supporting its potential as a biomarker and therapeutic agent for preventing DR worsening, possibly by lowering retinal VEGF and inflammatory cytokines., (© 2022 by the American Diabetes Association.)

Until the last decade, gentoo penguins were usually split into two subspecies, northern gentoo penguins (Pygoscelis papua papua) breeding in the Falkland Islands, South Georgia, and other subantarctic islands and southern gentoo penguins (P. papua ellsworthi) breeding in the South Sandwich, South Orkney and South Shetland islands, and Antarctic Peninsula. Recent genetics research, however, suggests that the population at South Georgia is much more closely related to those further south and should be included in P. papua ellsworthi. In Japanese zoos and aquariums, captive breeding of gentoo penguins is conducted separately in three populations: "Captive-South Georgia," originating from South Georgia, "Captive-South Shetlands," originating from South Shetlands, and "Captive-Unknown," originating from at least one founder of unknown subspecies. The aims of the present study were to investigate the genetic diversity and differentiation of these captive populations using microsatellite analysis. Genetic diversity in each captive population was similar to that found in the wild, although they had much lower contemporary effective population sizes. Pairwise genetic differentiation indexes (F ST ) among the three captive populations were as follows: 0.0309 ("Captive-South Georgia" and "Captive-Unknown"), 0.1094 ("Captive-South Georgia" and "Captive-South Shetlands"), and 0.1214 ("Captive-South Shetlands" and "Captive-Unknown"). Using Bayesian clustering, there was relatively high genetic differentiation between the "Captive-South Shetlands" group, which formed a distinct cluster, and individuals of the "Captive-Unknown" group, which were assigned to clusters in common with "Captive-South Georgia." The results from the present study are useful for future management of captive gentoo penguin populations in Japan., (© 2021 Wiley Periodicals LLC.)

Objective: The aim of this study is to identify biomarkers that predict efficacy of preoperative therapy and survival for esophageal squamous cell carcinoma (ESCC)., Background: It is essential to improve the accuracy of preoperative molecular diagnostics to identify specific patients who will benefit from the treatment; thus, this issue should be resolved with a large-cohort, retrospective observational study., Methods: A total of 656 patients with ESCC who received surgery after preoperative CDDP + 5-FU therapy, docetaxel + CDDP + 5-FU therapy or chemoradiotherapy (CRT) were enrolled. Immunohistochemical analysis of TP53, CDKN1A, RAD51, MutT-homolog 1, and programmed death-ligand 1 was performed with biopsy samples obtained before preoperative therapy, and expression was measured by immunohistochemistry., Results: In all therapy groups, overall survival was statistically separated by pathological effect (grade 3 > grade 2 > grade 0, 1, P < 0.0001). There was no correlation between TP53, CDKN1A, MutT-homolog 1, programmed death-ligand 1 expression, and pathological effect, whereas the proportion of positive RAD51 expression (≥50%) in cases with grade 3 was lower than that with grade 0, 1, and 2 (P = 0.022). In the CRT group, the survival of patients with RAD51-positive tumor was significantly worse than RAD51-negative expressors (P = 0.0119). Subgroup analysis of overall survival with respect to positive RAD51 expression indicated preoperative chemotherapy (CDDP + 5-FU or docetaxel + CDDP + 5-FU) was superior to CRT., Conclusions: In ESCC, positive RAD51 expression was identified as a useful biomarker to predict resistance to preoperative therapy and poor prognosis in patients who received preoperative CRT. Administration of preoperative chemotherapy may be warranted for patients with positive RAD51 expression., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The Stump classification is significantly correlated with a retear after arthroscopic rotator cuff repair. However, no study has evaluated whether or not the stump classification is correlated with retear in the suture-bridge or double-row repair techniques. The aim of this study was to evaluate the relationship between a retear and the stump classification in the suture-bridge and double-row repair techniques., Methods: Among 389 patients who underwent arthroscopic repairs of full-thickness rotator cuff tears using suture-bridge or double-row repair techniques, 326 patients (median age 67.0 years; range 25-85) were included. There were 51 small, 172 medium, 83 large, and 20 massive tears. Two hundred forty patients were treated with the suture-bridge technique, and 86 patients were treated with the double-row technique. The following variables were analyzed: age, sex, the Cofield classification, anteroposterior and mediolateral tear size on preoperative MRI, global fatty degeneration index, and the stump classification. Cuff integrity was evaluated on magnetic resonance imaging at 6 months after surgery. The patients were divided into the intact and retear groups and the relationship between the variables and retear was evaluated by multivariate logistic regression analysis., Results: The overall retear rate was 10.1%. In the multivariate logistic regression analysis, the independent predictors of a retear were the stump classification type 3 (Odds ratio: 4.71, p = 0.0246), global fatty degeneration index (Odds ratio: 3.87, p = 0.0030), and anteroposterior tear size (Odds ratio: 1.07, p = 0.0077) in the suture bridge technique. In the double-row technique, the independent predictors of retear were stump classification type 3 (Odds ratio: 7.82, p = 0.0348), and age (Odds ratio: 1.22, p = 0.0163)., Conclusion: The stump classification was significantly correlated with retear in the suture-bridge and double-row repair technique. Stump classification type 3 was indicated to be an important risk factor for predicting retear., Level of Evidence: III., (© 2021. European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Background: Acute mediastinitis is a rare disease that rapidly progresses with a high mortality rate. Its most common cause is direct injury of the mediastinum, including iatrogenic causes such as cardiac surgery or upper endoscopy. Enzymatic mediastinitis is a rare complication of a pancreatic fistula caused by the inflammatory digestion of the parietal peritoneum spreading to the mediastinum. Here, we present two cases of enzymatic mediastinitis caused by total gastrectomy with splenectomy. One of them was successfully treated and cured after early diagnosis and transabdominal drainage., Case Presentation: Case 1 was that of a 60-year-old man (body mass index [BMI] 27) with a medical history of diabetes and hypertension who was diagnosed with advanced gastric cancer in the upper body of the stomach. A total gastrectomy with splenectomy was performed. The patient experienced acute respiratory failure 24 h after surgery. Pulmonary embolism was suspected, so a computed tomography (CT) scan was performed; however, no relevant causes were found. Although he was immediately intubated and treated with catecholamine, he died in the intensive care unit (ICU) 40 h after surgery. Post-mortem findings revealed retroperitonitis caused by a pancreatic fistula spreading towards the mediastinum, causing severe mediastinitis; a review of the CT scan revealed pneumomediastinum. We concluded that the cause of death was enzymatic mediastinitis due to post-gastrectomy pancreatic fistula. Case 2 involved a 61-year-old man (BMI 25) with a medical history of appendicitis who was diagnosed with advanced gastric cancer at the gastric angle between the lesser curvature and the pylorus, spreading to the upper body of the stomach. A total gastrectomy with splenectomy was also performed. The patient had a high fever 3 days after the surgery, and a CT scan revealed pneumomediastinum, indicating mediastinitis. As the inflammation was below the bronchial bifurcation, we chose a transabdominal approach for drainage. The patient was successfully treated and discharged., Conclusion: Acute mediastinitis caused by gastrectomy is rare. The acknowledgment of abdominal surgery as a cause of mediastinitis is important. In treating mediastinitis caused by abdominal surgery, transabdominal drainage may be a minimally invasive yet effective method if the inflammation is mainly located below the bifurcation of the trachea.

Background: Ileostomy-related high-output syndrome has become a major cause of postoperative morbidity after rectal cancer surgery. This study aimed to clarify the predisposing factors and clinical impact of high-output syndrome., Methods: Clinical parameters that were associated with high-output syndrome and clinical impact of high-output syndrome on nutritional status, electrolyte abnormality and renal dysfunction were retrospectively investigated in consecutive patients with rectal cancer undergoing resection with covering ileostomy during 2016-2017., Results: High-output syndrome developed in 44/195 eligible patients (22.6%). Multivariable analysis revealed that neoadjuvant (chemo)radiotherapy [odds ratio (OR): 2.4; 95% confidence interval (CI) 1.1-5.2; P = 0.02], postoperative complications (OR: 2.2; 95% CI 1.0-4.6; P = 0.049), postoperative maximal white blood cell ≥ 10,000 cells/μl (OR: 4.0; 95% CI 1.9-8.8; P = 0.0004), and postoperative maximal C-reactive protein ≥ 10 mg/dl (OR: 2.4; 95% CI 1.1-5.2; P = 0.02) were independently associated with high-output syndrome. High-output syndrome was associated with increased renal dysfunction at the time of ostomy closure (29.6% versus 11.9%, patients with high-output syndrome vs. without high-output syndrome, P = 0.008), but not with nutritional imbalance or electrolyte abnormalities. High-output syndrome (OR: 2.5; 95% CI 1.1-5.9; P = 0.03) and postoperative maximal C-reactive protein ≥ 10 mg/dl (OR: 2.4; 95% CI 1.0-5.6; P = 0.04) were independently associated with renal dysfunction at ostomy closure., Conclusion: Preoperative (chemo)radiotherapy, postoperative inflammatory response, and postoperative complications predisposed to high-output syndrome, and it significantly impacted postoperative renal dysfunction. Active monitoring and early intervention are warranted to prevent renal dysfunction in patients with these factors.

New cancer characteristics can be discovered by focusing on the process of tumor formation. Cancer stem cells (CSCs) are a key subpopulation, as they are theorized to be at the apex of the tumor hierarchy. We can better understand their function in the tumor hierarchy by using sectioned samples to observe the growth of tumors from their origins as CSCs. In this study, we evaluated the growth of moderate differentiated colorectal cancer from LGR5-positive cells, which is a CSC marker of colorectal cancer, using xenograft and three-dimensional culture models spatiotemporally. These cells express LGR5 at high levels and show CSC phenotypes. To detect them, we used a previously generated antibody that specifically targets LGR5, and were therefore able to observe LGR5-positive cells aggregating into small clusters (sCLs) over the course of tumor growth. Because these LGR5-expressing sCLs formed continuously during growth mainly in the invasive front, we concluded that the structure must contribute significantly to the expansion of CSCs and to tumor growth overall. We confirmed the formation of sCLs from gland structures using a three-dimensional culture model. In addition, sCLs exhibited upregulated genes related to stress response and partial/hybrid epithelial-mesenchymal transition (EMT), as well as genes reported to be prognosis factors. Finally, sCLs with high LGR5 expression were identified in clinical samples. Based on these results, we elucidate how sCLs are an important contributors to tumor growth and the expansion of CSCs.

This study aims to evaluate the safety and efficacy of a poly lactic-co-glycolic acid (PLGA)-coated β-tricalcium phosphate (β-TCP) with N-methyl-2-pyrrolidone (NMP) liquid activator (PLGA/β-TCP) on alveolar ridge preservation after tooth extraction in dog mandible. Thirty-two extraction sites were prepared in eight dog mandibles. A distal root of the mandibular premolar was extracted and randomly grafted with one of the following bone substitutes: (1) PLGA/β-TCP, (2) β-TCP, or (3) left empty as a control, and wounds were closed with keratinized mucosa graft. Post-operative wound healing was observed and scored to evaluate safety. After 12 and 24 weeks, the bone regeneration was evaluated with micro-computed tomography (CT) images and histomorphometric analyses. Gingival epithelization progressed over time without complication or infection. Micro-CT images and histological observation revealed that both PLGA/β-TCP and β-TCP granules supported sufficient new bone formation. Although bone formation and substrate resorption were delayed slightly with the PLGA and the NMP-containing plasticizer as compared to those treated with conventional β-TCP, it can be concluded that the PLGA and the NMP-containing plasticizer that facilitated the in situ hardening properties of the material had no negative influence on the biocompatibility of the material.

Background: Adjuvant chemotherapy is generally recommended for patients with stage III colorectal cancer. Even with adjuvant chemotherapy, 20-30% of such patients develop recurrences; the risk factors for recurrence are currently unclear. The preoperative systemic inflammation index has been linked to poor prognoses in patients with colorectal cancer; however, the relationship between postoperative systemic inflammation index and recurrence is unclear. We aimed to evaluate the association between preoperative and postoperative systemic inflammation indexes and recurrence in patients with stage III colorectal cancer., Methods: The following laboratory data of 133 patients with stage III colorectal cancer were analyzed: preoperative and postoperative C-reactive protein/albumin ratios (CAR); neutrophil to lymphocyte ratios (NLR); and platelet to lymphocyte ratios (PLR) and their relationships with recurrence analyzed., Results: The optimal cutoff values for systemic inflammation indexes were determined by examining receiver operating characteristic curves. Multivariate analyses indicated that N-stage, postoperative complications, preoperative NLR, and postoperative CAR were independent predictors of recurrence-free survival (RFS). Postoperative CAR was also an independent predictor of overall survival (OS). Patients with postoperative CAR ≥ 0.035 who did not receive adjuvant chemotherapy had shorter RFS and OS than those who did. There were no significant differences in RFS and OS between patients with postoperative CAR < 0.035 who did and did not receive adjuvant chemotherapy., Conclusions: Postoperative CAR is strongly associated with poor prognosis in patients with stage III colorectal cancer and is a useful biomarker for determining whether adjuvant chemotherapy should be administered.

Nivolumab, an anti-programmed cell death-1 (PD-1) antibody, has attracted increasing attention as a new treatment modality for gastric cancer. Herein, a case of acute kidney injury in a 66-year-old man with gastric cancer treated with nivolumab is presented. Kidney biopsy revealed severe acute interstitial nephritis and mild immunoglobulin A nephropathy. The cause of acute kidney injury was considered as acute interstitial nephritis because the main site of the lesion was the tubulointerstitium. Cessation of nivolumab and oral prednisolone administration rapidly improved the patient's renal function. Nivolumab was then restarted without worsening of renal function. To the best of the authors knowledge, this is the first case in which reintroduction of nivolumab was successfully performed in a patient with gastric cancer. Further, the relevant literature was reviewed on nivolumab-induced acute interstitial nephritis., Competing Interests: Conflict of interestEiji Oki received honorarium from Ono Pharma., (© The Japan Society of Clinical Oncology 2020.)

Background: Postoperative changes in skeletal muscle and their influence on outcomes after esophagectomy for patients with esophageal cancer have not been fully investigated. This study aimed to confirm that postoperative skeletal muscle decrease influences long-term patient outcomes., Methods: Data were collected from 218 patients who underwent curative esophagectomy for esophageal cancer whose data were available before and 6 months after surgery. The skeletal muscle index (SMI) was measured at the level of the L3 vertebrae, and the postoperative change in the SMI compared with preoperative values was calculated as the delta SMI., Results: The mean SMI value was - 11.64%, and the median delta SMI value was - 11.88%. The first and third quartiles were defined as cutoffs, and 218 patients were classified as the mild-loss group (54 patients), moderate-loss group (110 patients), and severe-loss group (54 patients). The patients with a more severely reduced SMI had a worse prognosis (5-year overall survival rates: mild loss, 66.6%; moderate loss, 58.8%; and severe loss, 48.5%; p = 0.0314). This correlation between reduced SMI and prognosis also was observed for the patients with preoperative sarcopenia (p < 0.0001), but not for those without preoperative sarcopenia., Conclusions: Postoperative reduced SMI and worse prognosis were significantly associated in esophageal cancer patients.

Background: Hepatoid carcinoma (HC) is an extra-hepatic neoplasm that shares the morphological and immunohistochemical features of hepatocellular carcinoma. Pancreatic HC exists as either pure or combined type. Pure pancreatic HC is extremely rare, with only a few cases reported in the literature to date. Because of the rarity of pure pancreatic HC, its clinical features including incidence, behavior, and prognosis remain unclear. We herein report the case of a 56-year-old man who developed pure pancreatic HC treated with surgical resection. We also include a review of the existing literature., Case Presentation: A 56-year-old male patient was admitted to our hospital after a pancreatic cyst was identified by abdominal ultrasonography on a comprehensive medical examination. Endoscopic ultrasound revealed a cystic mass measuring 13 mm in size in the pancreatic head and a low-density mass measuring 16 mm in size in the pancreatic tail, which was partially enhanced on contrast-enhanced ultrasound. Contrast-enhanced computed tomography (CT) revealed a branch duct type intraductal papillary mucinous neoplasm in the pancreatic head and an early enhanced nodule measuring approximately 10 mm in size in the pancreatic tail. Endoscopic ultrasound-guided fine-needle aspiration of the hypervascular tumor was performed. The hypervascular tumor was suspected to be a solid pseudopapillary neoplasm. Laparoscopic spleen-preserving distal pancreatectomy was performed. Histology was identical to hepatocellular carcinoma of the liver. Immunohistochemically, the tumor cells were positive for hepatocyte paraffin 1, and a canalicular pattern was confirmed on the polyclonal carcinoembryonic antigen staining. The patient was diagnosed with a moderately differentiated pancreatic HC. The patient was followed up without adjuvant chemotherapy, and there was no evidence of recurrence at 6 months post-operatively., Conclusions: We present a case of moderately differentiated pure pancreatic HC. For the accurate preoperative diagnosis of pure pancreatic HC, biopsy is preferred to cytology or preoperative imaging studies such as CT. The prognosis of pure pancreatic HC depends on its differentiation.

Objectives: Programmed death 1 (PD-1) is an immunoinhibitory receptor and has been identified as a new target for immunotherapy in cancer. Here we report the expression of PD-1 ligand 1 (PD-L1) in surgically resected gastric cancer., Materials and Methods: We examined formalin-fixed tumor samples from 144 gastric cancer patients with a primary diagnosis of gastric carcinoma. Immunohistochemistry was used to detect PD-L1. Human epidermal growth factor receptor 2 (HER2) expression and phosphatase and tensin homolog (PTEN) loss of heterozygosity were investigated in these patients. RNA interference was used to downregulate HER2 expression, and PD-L1 protein expression was assessed by flow cytometry using the gastric cancer cell line MKN45., Results: Overexpression of PD-L1 was significantly correlated with tumor invasion (p = 0.011) and associated with poor survival. The number of PD-L1-positive cases increased according to the HER2 score in clinical samples. siRNA-mediated downregulation of HER2 significantly decreased PD-L1 protein expression in MKN45 cells., Conclusions: PD-L1 expression was associated with poor survival of gastric cancer, and HER2 signaling affects the expression of PD-L1 in gastric cancer. In gastric cancer, PTEN and HER2 are potential candidate biomarkers for developing human antibodies that block PD-L1., (© 2017 S. Karger AG, Basel.)

Recent studies have shown that infection with Porphyromonas gingivalis, a major periodontal pathogen, hastens the progression of non-alcoholic fatty liver disease (NAFLD). However, the intracellular fate of P. gingivalis in hepatocytes remains unknown. Here, using oleic-acid-induced HepG2 cells as an in vitro model for NAFLD, we found that lipid droplets increased the existence of P. gingivalis in the cells at an early phase of infection. Confocal microscopic analysis revealed that lipid droplets affected the formation of autolysosomes in infected cells. Thus, lipid droplets affect the elimination of P. gingivalis in HepG2 cells by altering the autophagy-lysosome system., (Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Background/aim: Neuroendocrine carcinoma (NEC) of the esophagus is rare and aggressive. We herein report a case of a patient who showed NEC conversion from squamous cell carcinoma (SCC) of the esophagus in the recurrent lesion after definitive chemoradiotherapy., Case Report: The patient was a 57-year-old Japanese male with mid-thoracic esophageal carcinoma diagnosed as SCC with invasion of the submucosal layer. After definitive chemoradiotherapy, the esophageal tumor completely disappeared. Two months later, local recurrence was recognized at the same location and salvage surgery was performed. An immunohistochemical examination of the resected specimen revealed that most of the recurrent tumor had neuroendocrine (NE) differentiation, although a retrospective review of the initial biopsy specimen showed no involvement of NE differentiation., Conclusion: This case is significant not only in bringing attention to the possibility of NEC conversion from SCC after chemoradiotherapy, but also in discussing tumors originating in the esophagus., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The significance of neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) remains controversial with regard to the pathological response and long-term survival. We herein review the current status of and future perspectives regarding NACRT followed by esophagectomy for locally advanced ESCC. Some studies have suggested that a pathological complete response with NACRT is more common in patients with ESCC than in those with adenocarcinoma and that NACRT provided a survival benefit limited to patients with ESCC. However, NACRT may increase the risk of postoperative complications after esophagectomy. It is obvious that a favorable pathological response is the most important factor for obtaining a survival benefit, although no established parameters have been implemented clinically to predict the response to NACRT. Prospective clinical studies and basic research studies to identify predictive biomarkers for the response to NACRT are needed to aid in the development of NACRT treatment strategies for patients with ESCC.

Introduction: 2-Isopropyl-5-[methyl-(2-phenylethyl)amino]-2-phenylpentanenitrile (emopamil; EMP) is a calcium channel blocker of the phenylalkylamine class, with weak substrate properties for P-glycoprotein (P-gp). A weak substrate for P-gp would be suitable for measuring enhanced P-gp function. This study was performed to synthesise (R)- and (S)-[(11)C]EMP and characterise their properties as P-gp tracers., Methods: We synthesised (R)- and (S)-[(11)C]EMP and compared their biodistribution, peripheral metabolism, and effects of the P-gp inhibitor cyclosporine A (CsA, 50 mg/kg). We compared the brain pharmacokinetics of (R)-[(11)C]EMP and (R)-[(11)C]verapamil [(R)-[(11)C]VER] at baseline and CsA pretreatment with small animal positron emission tomography (PET)., Results: (R)- and (S)-[(11)C]EMP were synthesised from (R)- and (S)-noremopamil, respectively, by methylation with [(11)C]methyl triflate in the presence of NaOH at room temperature. (R)- and (S)-[(11)C]EMP yields were ~30%, with specific activity>74 GBq/μmol and radiochemical purity>99%. (R)-[(11)C]EMP showed significantly greater uptake in the mouse brain than (S)-[(11)C]EMP. Both showed homogeneous non-stereoselective regional brain distributions. (R)- and (S)-[(11)C]EMP were rapidly metabolised to hydrophilic metabolites. Unchanged plasma (S)-[(11)C]EMP level was significantly lower than that of (R)-[(11)C]EMP 15 minutes post-injection, whilst>88% of radioactivity in the brain was intact at 15 minutes post-injection and was non-stereoselective. CsA pretreatment increased brain activity ~3-fold in mice, but was non-stereoselective. The baseline area-under-the-curve (AUC) of brain radioactivity (0-60 minutes) of (R)-[(11)C]EMP was 2-fold higher than that of (R)-[(11)C]VER, but their AUCs after CsA pretreatment were comparable., Conclusions: (R)-[(11)C]EMP is a novel tracer for imaging P-gp function with higher baseline uptake than (R)-[(11)C]VER., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Adjuvant chemotherapy (ACT) may prevent recurrence in patients with stage III colorectal cancer (CRC). However, only 10% of patients benefit from ACT and no effective indicators exist to predict which patients are likely to benefit. The present study validated metastatic lymph node (MLN) number as a new indicator for ACT., Patients and Methods: We retrospectively reviewed 173 patients with stage III CRC, who were classified by Union for International Cancer Control (UICC) stage or N category, and analyzed their overall survival (OS) and disease-free survival (DFS) according to stage, number of MLNs and ACT use., Results: Among 173 patients, we found 65 with only one MLN (N1a). For N1a patients treated with ACT, the 5-year OS rate was 100%; the 3-year DFS rate was 92.7% for those treated with oral ACT., Conclusion: The number of MLNs is a simple indicator for ACT in patients with stage III CRC. For patients with only one MLN, oral chemotherapy is a good option., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Leucine-rich repeat-containing G-protein coupled receptor 5, or LGR5, is a molecule that recognizes stem cells in multiple organs and also in colon cancer. Previously, we have developed monoclonal antibodies specific to LGR5 protein that can be used for immunofluorescence staining, but because a very low level of LGR5 protein is expressed, the visualization technique needed to be enhanced. To develop procedures to detect LGR5 protein in various specimens by immunofluorescence staining, we evaluated the Alexa-labeled streptavidin biotin (LSAB), the Qdot, and the tyramide methods. The detection sensitivity was highest in the tyramide method followed by the Qdot method, whereas subcellular localization of the protein was most clear in the Qdot method, because the Qdot method gave a high S/N ratio that could show a low background. Thus, the tyramide method is superior to the Q-dot method for intensifying the signal of a low expression protein, and the Qdot method is superior to the tyramide method for identifying the subcellular localization of the target protein. The results of the present study will be helpful in providing more insight into the pathophysiological roles of LGR5-positive cancer stem cells and in developing therapeutic approaches for targeting cancer stem cells.

Surgery is a major treatment option for rectal cancer, and total mesorectal excision has been demonstrated to be advantageous in terms of oncological outcome and thus has been the standard surgical approach. Radiotherapy before or after radical surgery is the optimal treatment to control local recurrence of advanced rectal cancer. To date, in many countries, the combination of neoadjuvant concurrent chemotherapy and radiotherapy is considered the standard therapy. A more recent interest in neoadjuvant therapy has been the use of oxaliplatin or targeted agents for neoadjuvant chemoradiotherapy. However, despite many trials of oxaliplatin and targeted agents, 5-FU-based concurrent chemoradiotherapy has remained the only standard treatment option. Postoperative adjuvant chemotherapy with neoadjuvant chemoradiotherapy or induction chemotherapy with neoadjuvant chemoradiotherapy may further improve patient survival, as some clinical studies recently indicated. In Japan, neoadjuvant therapy is not the standard treatment method, because surgery with lateral lymph node dissection is usually performed and this type of surgery may reduce recurrence rate as does radiation therapy. The phase III study to evaluate the oncological effect of the Japanese standard operation (mesorectal excision, ME) with lateral lymph node dissection in comparison with ME alone for clinical stage II and III lower rectal cancer is currently ongoing.

Siglecs, sialic acid-recognizing Ig-superfamily lectins, regulate various aspects of immune responses, and have also been shown to induce the endocytosis of binding materials such as anti-Siglec antibodies or sialic acid-harboring bacteria. In this study, we demonstrated that the expression of Siglec-9 enhanced the transfection efficiency of several cell lines such as macrophage RAW264 and non-hematopoietic 293FT cells. We applied this finding to the production of a lentiviral vector in which cells were transfected simultaneously with multiple vectors, and achieved a twice increase in viral production levels. Furthermore, 293FT cells expressing lectin-defective Siglec-9 produced three- to seven-fold higher titer of viral vector compared with parental 293FT cells. These results suggest that Siglec-9 enhanced lentiviral vector production in a lectin-independent manner.

Unlabelled: Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression., Implications: Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer., (©2015 American Association for Cancer Research.)

Background/aim: Definitive chemoradiotherapy (dCRT) is frequently administered in oesophageal cancer. We carried out hyperthermochemotherapy (HCT) for residual or recurrent cases after dCRT for oesophageal cancer. The aim of this study was to elucidate the usefulness of salvage HCT for these patients., Patients and Methods: Salvage HCT after dCRT was performed in 11 patients with residual or recurrent oesophageal cancer. We used an 8-MHz radiofrequency capacitive heating system for hyperthermia. The combined chemotherapy comprised of cisplatin/5-fluorouracil, an oral fluoropyrimidine and irinotecan., Results: There were no severe adverse events caused by hyperthermia. Complete response and stable disease was achieved in three and five patients, respectively; symptoms were improved in the remaining three patients. The median survival time after HCT was 12 (range=3-88) months., Conclusion: HCT is a feasible and potent salvage therapy for patients with residual or recurrent oesophageal cancer after dCRT, unless salvage surgery is indicated., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objective: PTEN (the encoding phosphate and tensin homolog) is a well-known cancer suppressor gene and its mutation and loss of heterozygosity (LOH) occurs in various types of carcinomas. This study aimed to examine the association between LOH of PTEN and prognosis in HER2-expressing and nonexpressing gastric cancer patients., Methods: Fresh-frozen tumor samples of 221 gastric cancer patients with a primary diagnosis of gastric carcinoma were examined for LOH of PTEN. The results were compared with pathological parameters and the HER2 status. To elucidate the role of LOH of PTEN, the activation of the PI3K/AKT pathway was examined immunohistochemically using a phosphorylation-specific antibody., Results: LOH of PTEN was observed in 20% of the patients (39 of 195 cases). LOH of PTEN was associated with vascular involvement (25 of 39 cases; p = 0.0083), equivocal to positive staining for HER2 (p = 0.0080), and phospho-Akt expression (p = 0.0067). Patients with HER2-expressing gastric cancer with LOH of PTEN had a significantly worse prognosis (p = 0.0050)., Conclusions: Although HER2 expression itself was not a prognostic factor, the combination of HER2 expression and LOH of PTEN exacerbates the malignant potential of gastric cancer through its proliferative function., (© 2014 S. Karger AG, Basel.)

Purpose: The aim of this study was to clarify the usefulness of two-stage operation for the patients with esophageal cancer who have liver dysfunction., Methods: Eight patients with esophageal cancer concomitant with liver dysfunction who underwent two-stage operation were analyzed. The patients initially underwent an esophagectomy, a cervical esophagostomy and a tube jejunostomy, and reconstruction with gastric tube was performed after the recovery of patients' condition., Results: The average time of the 1(st) and 2(nd) stage operation was 410.0 min and 438.9 min, respectively. The average amount of blood loss in the 1(st) and 2(nd) stage operation was 433.5 ml and 1556.8 ml, respectively. The average duration between the operations was 29.8 days. The antesternal route was selected for 5 patients (62.5%) and the retrosternal route was for 3 patients (37.5%). In the 1(st) stage operation, no postoperative complications were observed, while, complications developed in 5 (62.5%) patients, including 4 anastomotic leakages, after the 2(nd) stage operation. Pneumonia was not observed through two-stage operation. No in-hospital death was experienced., Conclusion: A two-stage operation might prevent the occurrence of critical postoperative complications for the patients with esophageal cancer concomitant with liver dysfunction.