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Background/aim: Regulatory T cells (Tregs) suppress various anti-tumor immune responses in the tumor microenvironment (TME) and their control is considered essential to enhancing efficacy of cancer immunotherapy. The purpose of the study was to evaluate the strategy to regulate Tregs through the vascular endothelial growth factor (VEGF) pathway., Materials and Methods: We evaluated VEGF receptor (VEGFR) expression in subtypes of Tregs by analysis of public databases and through flow cytometry by investigating surgically resected specimens and peripheral blood mononuclear cells (PBMCs) from 26 patients with advanced colorectal cancer (CRC)., Results: Analysis of The Cancer Genome Atlas colorectal adenocarcinoma dataset (n=592) showed that mRNA expression of both FLT1 (VEGFR1) and KDR (VEGFR2) was positively correlated with mRNA expression of FOXP3 as well as Treg signature. Clinical specimens revealed abundant VEGFR2 expression on Tregs, but very marginal VEGFR1 expression. The frequency of effector Tregs, the most immunosuppressive fraction of Tregs, was significantly higher in the tumor than in the PBMC and normal mucosa, and the majority of effector Tregs expressed VEGFR2. Furthermore, by using in vitro generated Tregs, the proportion of Tregs expressing IL-10 or TGF-β1 was significantly inhibited by a VEGFR2 inhibitor., Conclusion: A therapeutic strategy targeting the VEGFR2 axis may have a potential to control effector Tregs in the CRC-TME., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

TIM-3 was originally identified as a negative regulator of helper T cells and is expressed on dendritic cells (DCs). Since the inhibition of TIM-3 on DCs has been suggested to enhance T cell-mediated anti-tumor immunity, we examined its expression on DCs within the tumor microenvironment (TME) in colorectal cancer (CRC) using transcriptomic data from a public database ( n = 592) and immunohistochemical evaluations from our cohorts of CRC ( n = 115). The expression of TIM-3 on DCs in vitro was examined by flow cytometry, while the expression of its related molecules, cGAS and STING, on immature and mature DCs was assessed by Western blotting. The expression of HAVCR2 (TIM-3) was strongly associated with the infiltration of DCs within the TME of CRC. Immunohistochemical staining of clinical tissue samples revealed that tumor-infiltrating DCs expressed TIM-3; however, their number at the tumor-invasive front significantly decreased with stage progression. TIM-3 expression was higher on immature DCs than on mature DCs from several different donors ( n = 6). Western blot analyses showed that the expression of STING was higher on mature DCs than on immature DCs, which was opposite to that of TIM-3. We demonstrated that TIM-3 was highly expressed on tumor-infiltrating DCs of CRC and that its expression was higher on immature DCs than on mature DCs.

Hemoglobin vesicles (HbVs), considered as red blood cell substitutes, are liposomes encapsulating purified hemoglobin, with a phospholipid bilayer membrane (diameter: 250 nm; P50, 28 Torr). In this study, we aimed to investigate HbV function during hemorrhagic shock in lung resection and analyze the details of oxygen delivery. Left pneumonectomy was performed in dogs under mechanical ventilation, followed by rapid exsanguination of approximately 30% of the total circulating blood volume, which led to shock, reducing the mean arterial pressure (MAP) by approximately 60% of baseline. Subsequently, either 5% human serum albumin (HSA) or HbVs suspended in 5% HSA were infused for resuscitation. The MAP only recovered to 75% of baseline after HSA administration, but fully recovered (100%) after HbV administration, with significant differences between the groups (P < 0.005). Oxygen delivery was restored in the HbV group and was significantly higher than that in the HSA group (P < 0.0001). The infusion of HbVs dispersed in a 5% HSA solution compensated for the rapid loss of approximately 30% of the total circulating blood volume in a dog pneumonectomy model, even with impaired lung function. Thus, HbVs can be used for resuscitation from hemorrhagic shock during thoracic surgery.

Hemoglobin wrapped covalently with poly(2-ethyl-2-oxazoline)s (POx-Hb) is characterized physicochemically and physiologically as an artificial O 2 carrier for use as a red blood cell (RBC) substitute. The POx-Hb is generated by linkage of porcine Hb surface-lysines to a sulfhydryl terminus of the POx derivative, with the average binding number of the polymers ascertained as 6. The POx-Hb shows moderately higher colloid osmotic activity and O 2 affinity than the naked Hb. Human adult HbA conjugated with POx also possesses equivalent features and O 2 binding properties. The POx-Hb solution exhibits good hemocompatibility, with no influence on the functions of platelets, granulocytes, and monocytes. Its circulation half-life in rats is 14 times longer than that of naked Hb. Hemorrhagic shock in rats is relieved sufficiently by infusion of the POx-Hb solution, as revealed by improvements of circulatory parameters. Serum biochemistry tests and histopathological observations indicate no acute toxicity or abnormality in the related organs. All results indicate that POx-Hb represents an attractive alternative for RBCs and a useful O 2 therapeutic reagent in transfusion medicine.

M2 tumor-associated macrophages (M2-TAMs) promote cancer cell proliferation and metastasis in the TME. Our study aimed to elucidate the mechanism of increased frequency of M2-TAMs infiltration in the colorectal cancer (CRC)-TME, focusing on the resistance to oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we evaluated the correlation between M2-TAM signature and mRNA expression of antioxidant related genes using public datasets, and the expression level of antioxidants in M2-TAMs by flow cytometry and the prevalence of M2-TAMs expressing antioxidants by immunofluorescence staining using surgically resected specimens of CRC (n = 34). Moreover, we generated M0 and M2 macrophages from peripheral blood monocytes and evaluated their resistance to oxidative stress using the in vitro viability assay. Analysis of GSE33113, GSE39582, and The Cancer Genome Atlas (TCGA) datasets indicated that mRNA expression of HMOX1 (heme oxygenase-1 (HO-1)) was significantly positively correlated with M2-TAM signature (r = 0.5283, r = 0.5826, r = 0.5833, respectively). The expression level of both Nrf2 and HO-1 significantly increased in M2-TAMs compared to M1- and M1/M2-TAMs in the tumor margin, and the number of Nrf2 + or HO-1 + M2-TAMs in the tumor stroma significantly increased more than those in the normal mucosa stroma. Finally, generated M2 macrophages expressing HO-1 significantly resisted to oxidative stress induced by H 2 O 2 in comparison with generated M0 macrophages. Taken together, our results suggested that an increased frequency of M2-TAMs infiltration in the CRC-TME is related to Nrf2-HO-1 axis mediated resistance to oxidative stress., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment, thereby contributing to a more favorable response to immune checkpoint inhibitors (ICI) in colorectal cancer (CRC). However, the impact of the expression of cGAS-STING in tumor cells on the infiltration of CD8 + T cells and clinical outcomes in mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC remains largely unknown. Our findings reveal that 56.8% of all pMMR CRC cases were cGAS-negative/STING-negative expressions (cGAS - /STING - ) in tumor cells, whereas only 9.9% of all pMMR CRC showed cGAS-positive/STING-positive expression (cGAS + /STING + ) in tumor cells. The frequency of cGAS + /STING + cases was reduced in the advanced stages of pMMR/MSS CRC, and histone methylation might be involved in the down-regulation of STING expression in tumor cells. Since the expression level of cGAS-STING in tumor cells has been associated with the infiltration of CD8 + and/or CD4 + T cells and the frequency of recurrence in pMMR/MSS CRC, decreased expression of cGAS-STING in tumor cells might lead to poor immune cell infiltration and worse prognosis in most pMMR/MSS CRC patients. Our current findings provide a novel insight for the treatment of patients with pMMR/MSS CRC.

This paper describes the synthesis and O 2 binding properties of core-shell structured hemoglobin (Hb) nanoparticles (NPs), artificial O 2 carriers of five types, as designed for use as red blood cell (RBC) substitutes. Human adult Hbs were polymerized using α-succinimidyl-ω-maleimide and dithiothreitol in spheroidal shapes to create parent particles. Subsequent covalent wrapping of the sphere with human serum albumin (HSA) yielded 100 nm-diameter Hb nanoparticles (HbNPs). The HbNP showed higher O 2 affinity than that of RBC, but NPs prepared under a N 2 atmosphere exhibited low O 2 affinity. Entirely synthetic particles comprising recombinant human adult Hb and recombinant HSA were also fabricated. Using a recombinant Hb (rHb) variant in which Leu-β28 of the heme pocket had been replaced with Phe, we found somewhat low O 2 affinity of rHb(βL28F)NP. Particles made of stroma-free Hb (SFHb) containing natural antioxidant enzyme catalase (SFHbNP) formed a very stable O 2 complex, even in aqueous H 2 O 2 solution. The SFHbNP showed good blood compatibility and did not affect the blood cell component functionality. The circulation half-life of SFHbNP in rats was considerably longer than that of naked Hb. All results indicate these Hb-based NPs as useful alternative materials for RBC and as a useful O 2 therapeutic reagent in diverse medical scenarios.

Deficient mismatch repair (dMMR)/microsatellite instability (MSI) colorectal cancer (CRC) has high immunogenicity and better prognosis compared with proficient MMR (pMMR)/microsatellite stable (MSS) CRC. Although the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered to contribute to the high number of CD8 + TILs, its role in dMMR/MSI CRC is largely unknown. In this study, to examine the role of the cGAS-STING pathway on the recruitment of CD8 + TILs in dMMR/MSI CRC, we used public datasets and clinical tissue samples in our cohorts to evaluate the expression of cGAS, STING, and CD8 + TILs in pMMR/MSS and dMMR/MSI CRCs. According to the analysis of public datasets, the expression of cGAS-STING, CD8 effector gene signature, and CXCL10-CCL5, chemoattractants for CD8 + TILs which regulated by the cGAS-STING pathway, was significantly upregulated in dMMR/MSI CRC, and the expression of cGAS-STING was significantly associated with the expression of CD8 effector gene signature. Immunohistochemistry staining of the clinical tissue samples (n = 283) revealed that cGAS-STING was highly expressed in tumor cells of dMMR CRC, and higher expression of cGAS-STING in tumor cells was significantly associated with the increased number of CD8 + TILs. Moreover, we demonstrated that the downregulation of MMR gene in human CRC cell lines enhanced the activation of the cGAS-STING pathway. Taken together, for the first time, we found that dMMR/MSI CRC has maintained a high level of cGAS-STING expression in tumor cells, which might contribute to abundant CD8 + TILs and immune-active TME., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: SARC-F, a sarcopenia screening tool, has limited use but may be beneficial for detecting sarcopenia in frail older people. This study aimed to clarify the validity of the SARC-F questionnaire in older people., Methods: In this validation study, 74 (36 men; age, 81.9 ± 6.7 years, 38 women; age, 83 ± 6.2 years) community-dwelling older people who attended a daycare facility participated in our study. Participants completed the SARC-F and SARC-calf circumference (SARC-CalF) questionnaires, and their body composition, walk speed and grip strength were measured. Sarcopenia was determined using the Asian Working Group for Sarcopenia criteria, and the participants were divided into non-sarcopenia and sarcopenia groups. SARC-F and SARC-CalF scores were evaluated using receiver operating characteristic curve analysis for sarcopenia considering the area under the curve. Internal consistency was evaluated using Cronbach's alpha., Results: The prevalence of sarcopenia, defined by physical characteristics, was 60.0% in men and 48.1% in women. The area under the curve of the SARC-F for sarcopenia was 0.703 (95% confidence interval [CI]: 0.585-0.821, P = 0.001). Cronbach's alpha was 0.81, and the internal consistency was high. SARC-F had lower sensitivity (0.47; 95% CI: 0.31-0.64) but higher specificity (0.78; 95% CI: 0.60-0.89) than the sensitivity and specificity of SARC-CalF, respectively, and the sensitivity of SARC-F was higher than that reported in previous studies., Conclusion: The SARC-F questionnaire is more sensitive in assessing sarcopenia in low-functioning populations and can be used as a screening tool for sarcopenia in long-term daycare facilities for older people rather than in community-based healthcare activities. Geriatr Gerontol Int 2022; 22: 889-893., (© 2022 Japan Geriatrics Society.)

Background: The standard strategy in Japan for locally advanced rectal cancer is total mesorectal excision plus adjuvant chemotherapy. However, large tumors significantly restrict pelvic manipulation of the distal side of the tumor during surgery;therefore, from an oncological point of view, it is better to shrink the tumor as much as possible preoperatively to optimize the circumferential resection margin. In recent years, advances in systemic chemotherapy have significantly improved the tumor reduction effect, enabling such drug therapy prior to surgery for locally advanced rectal cancer. We herein retrospectively evaluated the clinical, short-term outcomes of patients treated by neoadjuvant chemotherapy (NAC) using capecitabin and oxaliplatin (CAPOX), focusing on overall safety as well as clinical and pathological staging responses to NAC., Methods: We applied the preoperative chemotherapy protocol to T3-4, any N, M0 or M1a (with resectable metastases) (UICC 8 th ) Ra/Rb rectal cancers. The chemotherapy regimen consisted of four cycles of CAPOX. After NAC, curative intent surgery with total mesorectal excision/tumor-specific mesorectal excision with/without metastasectomy was performed. Adverse effects (AEs) and compliance with NAC, surgical complications, clinical and pathological staging were evaluated. All patients undergoing the protocol between January 2017 and June 2021 at Fukushima Medical University were enrolled., Results: Twenty cases were enrolled. No severe AEs were observed either preoperatively or perioperatively. Preoperative assessment of NAC showed no cases of progressive disease (PD). Radical resection was achieved in all cases. Histological therapeutic grading after NAC revealed one grade 3, four grade 2, three grade 1b, eleven grade 1a and one grade 0 among all cases., Conclusion: This study suggests that NAC for locally advanced rectal cancer is likely to be acceptable because there were no severe AEs pre- or perioperatively, radical resection was achieved in all cases, and there were no cases of PD.

A bovine hemoglobin (HbBv) or human adult hemoglobin (HbA) wrapped covalently by human serum albumins (HSAs), hemoglobin-albumin clusters (HbBv-HSA 3 and HbA-HSA 3 ), are artificial O 2 carriers used as a red blood cell substitute. This article describes the physicochemical properties of the HbBv-HSA 3 and HbA-HSA 3 solutions, and their abilities to restore the systemic condition after resuscitation from hemorrhagic shock in anesthetized rats. The HbBv-HSA 3 and HbA-HSA 3 , which have high colloid osmotic activity, showed equivalent solution characteristics and O 2 binding parameters. Shock was induced by 50% blood withdrawal. Rats exhibited hypotension and significant metabolic acidosis. After 15 min, the rats were administered shed autologous blood (SAB), HbBv-HSA 3 , HbA-HSA 3 , or Ringer's lactate (RL) solution. Survival rates, circulation parameters, hematological parameters, and blood gas parameters were monitored during the hemorrhagic shock and for 6 h after administration. All rats in the SAB, HbBv-HSA 3 , and HbA-HSA 3 groups survived for 6 h. The HbBv-HSA 3 and HbA-HSA 3 groups restored mean arterial pressure after the resuscitation. No remarkable difference was observed in the time courses of blood gas parameters in any resuscitated group except for the RL group. Serum biochemical tests showed increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the HbBv-HSA 3 and HbA-HSA 3 groups compared to the SAB group. Therefore, we observed other rats awakened after resuscitation with HbA-HSA 3 for 7 days. The blood cell count, AST, and ALT recovered to the baseline values by 7 days. All the results implied that HbBv-HSA 3 and HbA-HSA 3 clusters provide restoration from hemorrhagic shock as an alternative material for SAB transfusion., (© 2022 Wiley Periodicals LLC.)

Introduction and Importance: Juvenile polyposis of the stomach (JPST) is a very rare disease and has been reported to have malignant potential. Total gastrectomy has been recommended as a standard treatment. Recently, the usefulness of laparoscopic surgery for this disease has been reported; however, in laparoscopic surgery, maintaining the surgical space is difficult because of the distended and thickened stomach wall that polyposis causes., Case Presentation: A 64-year-old woman was admitted to our hospital because she became malnourished due to loss of appetite. She had no family history of gastrointestinal polyposis and was diagnosed with gastric polyposis and polyp-related anemia eight years previously. She received endoscopic submucosal dissection of early gastric cancer twice in another hospital. Thereafter, the patient received an annual upper gastrointestinal endoscopy and took iron supplements for anemia due to occasional bleeding from polyps. However, the number of polyps increased over time. Enhanced computed tomography showed gastric wall thickening and multiple gastric polyps. She was diagnosed as having JPST and underwent laparoscopic total gastrectomy. She was discharged on postoperative Day 10., Clinical Discussion: In the present case, similar to previous cases, standard laparoscopic surgery could be performed although the patient had excessive distention and congestion of the stomach. This report suggests that laparoscopic surgery is a safe and feasible option for patients with JPST and is preferable because of better cosmetic effects, especially for young female patients., Conclusion: We successfully performed laparoscopic surgery to treat a rare case of JPST., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Claw nail deformity is common in patients with fingertip injury. The optimal reconstruction remains unclear. We devised a unique strategy for reconstruction of claw nail deformity. We divided the approach into three parts: soft tissue reconstruction, bone graft and nail bed graft. In the soft-tissue reconstruction, a reverse digital arterial finger flap for the finger or an extended palmar flap advancement with V-Y plasty for the thumb was selected. A part of the distal phalanx of the second toe including periosteum was harvested as a bone graft. A nail bed graft from the big toe was performed. We reconstructed in 11 cases of claw nail deformity using our strategy. All cases achieved significant improvement with no recurrence of the claw nail deformity. Moreover, there was no donor site morbidity.

Background: Colorectal cancer (CRC) develops through chromosomal instability (CIN) or microsatellite instability (MSI) due to deficient mismatch-repair (dMMR). We aimed to characterise novel cancer-associated genes that are downregulated upon malignant transformation in microsatellite stable (MSS) CRCs, which typically exhibit CIN with proficient mismatch-repair (pMMR)., Methods: Comprehensive screening was conducted on adenomas, MSI/MSS CRCs and cell lines, followed by copy number analysis, and their genetic and prognostic relevance was confirmed in microarray and RNA-seq cohorts (n = 3262, in total). Immunohistochemistry for SH2D4A was performed in 524 specimens of adenoma, carcinoma in situ and dMMR/pMMR CRC. The functional role of SH2D4A was investigated using CRC cell lines., Results: A set of 11 genes, including SH2D4A, was downregulated during the adenoma-carcinoma sequence in MSS/CIN CRCs, mainly due to chromosome 8p deletions, and their negative prognostic impact was validated in independent cohorts. All adenomas were SH2D4A positive, but a subset of CRCs (5.3%) lacked SH2D4A immunohistochemical staining, correlating with poor prognosis and scarce T cell infiltration. SH2D4A depletion did not affect cell proliferation or IL-6-induced STAT3 phosphorylation., Conclusions: Our findings suggest that downregulation of multiple genes on chromosome 8p, including SH2D4A, cooperatively contribute to tumorigenesis, resulting in the immune cold tumour microenvironment and poor prognosis., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Upper extremity deep vein thrombosis (UEDVT) is relatively rare but cannot be negligible because it can cause fatal complications. Although it is reported that the occurrence rate of UEDVT has increased due to central venous catheter (CVC), cancer, and surgical invasion, there is still limited information for esophagectomy. The aim of this study was to evaluate the clinical factors, including CVC placement and thromboprophylaxis approach, as well as retrosternal space's width as a predictive factor for UEDVT in patients receiving esophagectomy., Methods: This study included 66 patients who underwent esophagectomy with retrosternal reconstruction using a gastric tube. All patients routinely underwent contrast-enhanced computed tomography (CT) on the 4th postoperative day. Low-molecular-weight-heparin (LMWH) was routinely administered by the 2nd postoperative day. To evaluate retrosternal space's width, (a) The distance from sternum to brachiocephalic artery and (b) the distance from sternum to vertebra were measured by preoperative CT, and the ratio of (a) to (b) was defined as the width of retrosternal space., Results: Among all patients, 11 (16.7%) suffered from UEDVT, and none was preoperatively received CVC placement, while 7 were inserted in non-UEDVT cases. Retrosternal space's width in patients with UEDVT was significantly smaller than that in patients without UEDVT (0.17 vs. 0.26; P < 0.0001). A cutoff value of the width was 0.21, which has high sensitivity (87%) and specificity (82%) for UEDVT prediction, respectively., Conclusion: The existence of CVC may not affect the development of UEDVT, but preoperative evaluation of retrosternal ratio may predict the occurrence of UEDVT., (© 2022. The Author(s).)

Hemoglobin vesicles (HbVs), liposomes containing concentrated hemoglobin extracted from outdated human red blood cells (RBC), are artificial oxygen carriers with a small particle size. To evaluate the reperfusion of capillaries with HbVs in a tracheal transplant model and compare it with that of RBC. Isogenic mice were used as donors and recipients in a parallel trachea transplant model. Both ends of the donor trachea were anastomosed end-laterally to the recipient trachea to form in parallel. After transplantation, 0.3 mL of HbV solution (Hb concentration, 10 g/dL) was administered via the tail vein. The recipients were euthanized 1, 4, 6, and 8 h after surgery (n = 5 in each group). The tracheas were harvested, and tracheal subepithelial capillaries (SEC) reperfusion was histologically evaluated. A significant number of particles defined as HbV by electron microscopy were observed in the SEC of the grafted tracheas 4 h after the transplant surgery and HbV administration when no RBC were found in the SECs. The number increased 6 and 8 h later. Our findings suggest that HbVs, which are smaller than RBC, can reperfuse the capillaries of grafts earlier than RBCs after transplantation and contribute to the oxygenation of transplanted tissues.

Background/aim: The limited efficacy of immune checkpoint inhibitors in colorectal cancer (CRC) is likely due to immunosuppressive mechanisms including T cell exhaustion caused by inhibitory immune checkpoints in the tumor microenvironment., Materials and Methods: We investigated the expression status of the inhibitory immune checkpoint receptors on tumor-infiltrating T cells and their ligands on tumor cells by flow cytometry and immunohistochemistry, using surgically-resected specimens of CRC., Results: Flow cytometry analysis indicated that TIM-3, TIGIT, and PD-1 were expressed on tumor-infiltrating CD4+ (8.3%, 56.0%, 26.1%) and CD8+ T cells (8.2%, 51.6%, 23.5%), and CRC cells abundantly expressed PD-L1, CEACAM-1, and CD155 (2.2%, 77.0%, 46.8%). Immunohistochemical analysis revealed that the tumor proportional score of PD-L1, CEACAM-1, and CD155 was 42.4%, 54.2%, and 52.1%, respectively., Conclusion: PD-1, TIM-3, and TIGIT axes may reduce T cell function in the CRC tumor microenvironment., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is widely used for patients with locally advanced rectal cancer. However, response to nCRT varies substantially among patients, highlighting the need for predictive biomarkers that can distinguish non-responsive from responsive patients before nCRT. This study aimed to build novel multi-gene assays for predicting nCRT response, and to validate our signature and previously-reported signatures in multiple independent cohorts., Methods: Three microarray datasets of pre-therapeutic biopsies containing a total of 61 non-responders and 53 responders were used as the discovery cohorts to screen for genes that were consistently associated with nCRT response. The predictive values of signatures were tested in a meta-analysis using six independent datasets as the validation cohorts, consisted of a total of 176 non-responders and 99 responders., Results: We identified four genes, including BRCA1 , GPR110 , TNIK, and WDR4 in the discovery cohorts. Although our 4-gene signature and nine published signatures were evaluated, they were unable to predict nCRT response in the validation cohorts., Conclusions: Although this is one of the largest studies addressing the validity of gene expression-based classifiers using pre-treatment biopsies from patients with rectal cancer, our findings do not support their clinically meaningful values to be predictive of nCRT response.

The patient was a 66-year-old male who had undergone an operation for lung cancer and solitary brain metastases. Follow- up PET-CT after 1 year detected FDG accumulation in the stomach. We performed esophagogastroscopy and found an approximately 20 mm-sized Type 2 tumor on the greater curvature of the upper stomach. A pathological diagnosis of lung adenocarcinoma metastasis in the stomach was made. Laparoscopic surgery was performed on the metastatic lesion to prevent bleeding and perforation, and resection was achieved with minimal invasion. The current development of chemotherapy, including immunotherapy, has contributed to the improved prognosis of cancer patients, including those with lung metastasis in the stomach. Considering these backgrounds, preventive surgical resection under laparoscopy may be an effective approach for improving prognosis and preventing acute life-threatening adverse events. We report this case along with a literature review.

Objectives: The standard strategy for advanced rectal cancer (RC) is preoperative short-course radiotherapy (SCRT)/chemoradiotherapy (CRT) plus total mesorectal excision (TME) in Western countries; however, the survival benefit of adding chemotherapy to radiotherapy remains unclear. There is accumulating evidence that either SCRT/CRT or lateral pelvic lymph node dissection (LPND) alone may not be sufficient for local control of advanced RC. We herein retrospectively evaluated the clinical outcomes of patients who were treated by SCRT/CRT+TME+LPND, particularly focusing on the prognostic impact of lateral pelvic lymph node metastasis (LPNM)., Methods: Patients diagnosed as having clinical Stage II and III lower RC who received SCRT/CRT+TME+LPND between 1999 and 2012 at our hospital were enrolled. Adverse events (AEs), surgery-related complications (SRC), and therapeutic effects were retrospectively analyzed., Results: Fifty cases (SCRT:25, CRT:25) were analyzed. No significant differences were observed in overall survival (OS), relapse-free survival (RFS), local recurrence (LR), AE, and SRC between the SCRT and CRT groups, although the pathological therapeutic effect was higher in the CRT group. The patients with LPNM showed significantly inferior 5-year OS and 5-year RFS than those without LPNM., Conclusions: There were no significant differences in OS, RFS, or LR between SCRT and CRT, although CRT had a significantly greater histological therapeutic effect. The prognosis of the pathological LPNM-positive cases was significantly poorer than that of pathological LPNM-negative cases., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2021 by The Japan Society of Coloproctology.)

Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) encodes an enzyme that catalyzes de novo purine biosynthesis. Although PAICS has been implicated as a potential therapeutic target in several cancers, its clinical and prognostic significance in colorectal cancer (CRC) is not fully understood. To elucidate the roles of PAICS in CRC, we investigated PAICS expression in four cohorts consisting of a total of 1659 samples based on quantitative RT-PCR, microarray and RNA-seq analysis. Despite upregulated PAICS levels in tumor compared to those of normal mucosa, we found a decreasing trend of PAICS expression during tumor progression and metastasis. We conducted immunohistochemistry on 252 specimens, showing that PAICS protein was strongly expressed in the majority of CRCs, but not in adjacent mucosa. Notably, 29.0% of tumors lacked PAICS staining, and PAICS-negative expression in tumor had significant prognostic impact on poor cancer-specific survival in stage III CRC. Correspondingly, decreased levels of PAICS transcript were also correlated with poor relapse-free survival particularly in stage III patients, and this finding was robustly confirmed in three microarray datasets of a total of 802 stage II-III patients. Bioinformatics analysis of CRC tissues and cell lines consistently indicated a correlation between decreased PAICS expression and copy number loss of chromosome arm 4q. In conclusion, our results suggest that PAICS expression is downregulated during tumor progression due to genetic deletion of chromosome 4q in microsatellite stable but chromosomally unstable tumors. Furthermore, decreased expression of PAICS transcript or loss of PAICS protein may provide prognostic stratification for postoperative patients with stage III CRC., Competing Interests: The authors have declared that no competing interests exist.

AT-rich interactive domain 1A (ARID1A), which is a tumor suppressor gene, is frequently mutated in Epstein-Barr virus-positive gastric cancer [EBV (+) GC]. While most ARID1A mutations in GC are truncating mutations, leading to loss of ARID1A protein expression, epigenetic modifications appear to contribute to ARID1A deficiency in EBV (+) GC harboring wild-type ARID1A. Based on the significant role of epigenetic modifications in EBV (+) GC that contributes to ARID1A deficiency, the methylation status of ARID1A was evaluated in EBV-infected cells and GC patients using a publicly available microarray and the Cancer Genome Atlas (TCGA) database. EBV-encoded miRNAs that potentially target ARID1A were identified as an additional epigenetic modulator by computational prediction. In vitro experiments were conducted to evaluate how EBV-encoded miRNAs affected ARID1A mRNA and protein levels. In clinical GC samples, the expression of predicted miRNAs and ARID1A and the mutation status of ARID1A was evaluated. As results, ARID1A was not hypermethylated in EBV (+) GC samples or EBV-infected GC cells. EBV infection did not alter ARID1A mRNA levels, suggesting that ARID1A protein deficiency was caused by post-transcriptional gene silencing in ARID1A-WT EBV (+) GC. Overexpression of miR-BART11-3p and miR-BART12, which were identified as miRNAs that potentially bind ARID1A, suppressed ARID1A protein expression in MKN7 and NCI-N87 cells. Highly expressed miR-BART11-3p and miR-BART12 were correlated with decreased ARID1A levels in GC tumors which did not harbor ARID1A mutations. The present findings revealed that ARID1A expression was epigenetically regulated by miR-BART11-3p and miR-BART12 in EBV (+) GC., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Epstein-Barr virus-positive gastric cancer [EBV (+) GC] is a distinct GC subtype with unique genetic and epigenetic aberrations. Here, we examined resected GC samples and publicly available microarray data and The Cancer Genome Atlas (TCGA) database to identify the mechanism underlying overexpression of PD-L1 in EBV (+) GC. We found that high levels of PD-L1 overexpression in EBV (+) GC were caused by focal amplification of CD274. By contrast, relatively high expression of PD-L1 in tumor tissue and infiltrating immune cells correlated with CD8 lymphocyte infiltration and IFN-γ expression via IRF3 activation. Since we reported previously that PD-L1 expression is associated both with the presence of CD8 T cells in the tumor microenvironment and with IFN-γ expression in GC, we examined a database to see whether IFN-γ-associated overexpression of PD-L1 plays a significant role in EBV (+) GC. Immunohistochemical staining showed that expression of the IRF3 signature in clinical GC samples was higher in EBV (+) than in EBV (-) cases. The data presented herein reveal a unique dual mechanism underlying PD-L1 overexpression in EBV (+) GC: high focal amplification of CD274 or IFN-γ-mediated signaling via activation of IRF3.

Background: AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene that is frequently mutated in gastric cancer (GC). Although ARID1A mutations are not a druggable target for conventional treatments, novel therapeutic strategies based on a synthetic lethal approach are effective for ARID1A-deficient cancers. The histone methyltransferase EZH2 acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer, although its role in GC remains unknown., Methods: The selective sensitivity of the EZH2 inhibitors for ARID1A-deficient GC cells was evaluated using cell viability and colony formation assays. The expression of PI3K/AKT signaling genes were investigated using TCGA's cBioPortal database to determine whether the homeostasis between ARID1A and EZH2 is related to cell proliferation and survival via the PI3K/AKT signaling pathway. We also evaluated the phosphorylation of PI3K/AKT signaling proteins in ARID1A knock downed ARID1A-WT GC cells., Results: EZH2 inhibitors decreased the viability of ARID1A-deficient cells in a dose-dependent manner and demonstrated the selective sensitivity to ARID1A-deficient cells in vitro experiment system. Bioinformatics approach revealed that the PI3K/AKT signaling was tended to be activated in ARID1A-deficient GC enhancing cell viability and, furthermore, down-regulation of EZH2 in ARID1A-deficient GC was related to normalization of PI3K/AKT signaling pathway. The cell experiment revealed that phosphorylated AKT was upregulated in ARID1A-deficent GC cells., Conclusions: The present findings provide a rationale for the selective sensitivity of EZH2 inhibitors against ARID1A-deficient GC and suggest the potential efficacy of targeted therapy using EZH2 inhibitors in this patient population.

Surgical resection is the most effective treatment for liposarcoma, a retroperitoneal malignant soft tissue tumor, and a reliable negative margin is required because of the high risk of local recurrence. We reported a case of pelvic liposarcoma that could be resected by laparoscopic and transsacral hybrid approach. A 60's-man had a mixed liposarcoma occupying the right rear of the pelvis in the rectum. The operation was preceded by a laparoscopic operation, and the right internal iliac artery and vein and the superior rectal artery were dissected. The tumor was separated along the right pelvic wall. The oral rectum was transected and the colon was elevated by the extraperitoneal route. After conversion to the Jackknife position, the anterior sacrum was exfoliated with the right transsacral approach, the coccyx was resected, and the rectal anus, tumor, and surrounding fatty tissue were removed as an en bloc fasion. Histopathological examination showed mixed type of liposarcoma and negative margin of the stump. The patient is alive without recurrence 8 months after the surgery.

Tyrosine kinase inhibitors are used as first-line treatment for non-small cell lung cancer (NSCLC) patients harboring driver mutations in EGFR, ALK, ROS1, and BRAF. Currently, standard molecular testing approaches help identify single genes for such targetable driver mutations in NSCLC; however, next-generation sequencing (NGS)-based genetic profiling provides a more comprehensive approach and is hence strongly recommended. This case study aimed to highlight the benefits of NGS-based tests for the diagnosis of complex EGFR L858R mutations. A patient was diagnosed with stage IVB NSCLC using a government-approved in vitro diagnostic test and was noted to have a high programmed death-ligand 1 tumor proportion score. This patient was treated with pembrolizumab monotherapy followed by cisplatin and pemetrexed owing to the lack of actionable driver gene mutations, including EGFR mutations. After treatment failure, a sample harvested from the same transbronchial lung biopsy specimen (formalin-fixed and paraffin-embedded) used for the initial EGFR test was subjected to NGS-based broad genetic profiling. The NGS-based test identified an EGFR L858R-K860I cis doublet mutation; however, neither of these mutations was identified upon initial molecular testing. The patient was then successfully treated with a third-generation EGFR-tyrosine kinase inhibitor, osimertinib. In this study, we delved deeper into the realm of L858R and K860I mutations in NSCLC and discuss the potential causes underlying our initial negative diagnosis. Furthermore, this study highlighted the additional benefits of replacing typical molecular tests with NGS-based broad profiling approaches. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: The EGFR L858R-K860I cis doublet mutation was not detected by a PCR-based EGFR test. A next generation sequencing (NGS)-based test was able to identify the L858R-K860I cis doublet mutation. WHAT THIS STUDY ADDS: Osimertinib was effective in an NSCLC patient with EGFR L858R and K860I mutations., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Colorectal cancer (CRC) cells often express Tn antigen, a tumor-associated truncated immature O-glycan (GalNAcα-O-Ser/Thr) that can promote tumor progression. Immunotherapies against Tn antigen have been developed and are being evaluated in clinical trials. Tn antigen can also be considered a novel immune checkpoint that induces immunosuppressive signaling through glycan-biding lectins to lead effector T cell apoptosis. We evaluated the correlation of Tn antigen expression by immunohistochemistry with mismatch-repair (MMR) status, tumor-infiltrating lymphocytes, tumor cell PD-L1 expression, and clinicopathological characteristics in 507 CRC patients. Although 91.9% of CRCs showed negative or weak Tn antigen staining (Tn-negative/weak), we identified a small subset of CRCs (8.1%) that displayed particularly intense and diffuse distribution of Tn antigen immunoreactivity (Tn-strong) that closely related to deficient MMR (dMMR). Moreover, 40 dMMR CRCs were stratified into 24 Tn-negative/weak dMMR tumors (60.0%) exhibiting dense CD8+ lymphocyte infiltrate concomitant with a high rate of PD-L1 positivity, and 16 Tn-strong dMMR tumors (40.0%) that demonstrated CD8+ T cell exclusion and a lack of PD-L1 expression, which was comparable to those of proficient MMR. Our finding suggests that the immune cold subset of patients with Tn-strong dMMR CRC may be effectively treated with immune checkpoint blockade therapy or cellular immunotherapy targeting Tn antigen.

Background: Haemoglobin vesicles (HbVs) are red blood cell (RBC) substitutes with a phospholipid bilayer membrane and a polyethylene modified surface (diameter=250 nm; P 50 =28 Torr). They can be preserved for years and can be used in patients of all blood types without the risk of infection. Their oxygen affinity can be modified by changing the allosteric effectors., Methods: Left pneumonectomy was performed under mechanical ventilation on rats, followed by rapid exsanguination of ~30% of the total circulating blood volume. Rat RBCs shed in 5% human serum albumin (HSA) solution (rat RBC), HbV with high oxygen affinity in 5% albumin solution (low-P 50 HbV, P 50 =9 Torr), normal HbV suspended in 5% albumin (HbV, P 50 =28 Torr) or 5% HSA was infused for resuscitation. Haemodynamics and oxygenation were evaluated., Results: Systemic arterial blood pressure significantly decreased after exsanguination and increased after each infusion. In the HbV, low-P 50 HbV and rat RBC groups, all rats were liberated from mechanical ventilation and blood pressure was stabilised, whereas 50% of the rats in the HSA group died within 1 hour after weaning from mechanical ventilation. The PaO 2 in arterial blood for 1 hour after liberation from mechanical ventilation in the rat RBC, HbV and low-P 50 HbV groups was 59.4±12.5, 58.3±10.1 and 70.5±14.5 mm Hg, respectively. The PaO 2 in the low-P 50 HbV group was significantly higher than those in the rat RBC and HbV groups (p=0.05 for both). Serum lactate elevations due to hypoxic damage were minimised by HbV, low-P 50 HbV as well as rat RBCs., Conclusions: The oxygen-carrying ability of HbV was comparable to that of rat RBCs, even under impaired lung function after pneumonectomy. HbVs with high oxygen affinity may have more beneficial effects on oxygenation in pulmonary resection., Competing Interests: Competing interests: HS is an inventor on patents related to the production and utilisation of haemoglobin vesicles., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Epithelial-mesenchymal transition (EMT) is an important step leading to invasion and migration of various cancer cells, and are characterized by decreased E-cadherin as an epithelial marker, and increased vimentin as a mesenchymal marker. The present study focused on the clinicopathological significance of E-cadherin and vimentin expression in lung squamous cell carcinoma (SqCC). Immunohistochemically, E-cadherin expression patterns were classified into two types: preserved or reduced; and vimentin expression patterns were also divided into two types: positive or negative. The univariate analyses showed six factors associated with increased mortality: tumor size (P = 0.031), lymph node metastasis (P < 0.001), lymphatic invasion (P < 0.001), histological differentiation (P = 0.036), E-cadherin reduced expression (P < 0.001), and vimentin positive expression (P = 0.004). Multivariate analysis demonstrated that E-cadherin reduced expression (P < 0.001), vimentin positive expression (P = 0.028), lymph node metastasis (P < 0.001), and age (P = 0.020) were independent predictors of patient mortality. There may be some correlation between E-cadherin and vimentin expression (P = 0.017), but the correlation coefficient was 0.235. The complete EMT and the incomplete EMT type were associated with a poor prognosis (p < 0.001 and p=0.036, respectively). The overall survival rate after curative resection was significantly lower in patients with the complete EMT type (reduced E-cadherin / positive vimentin). In conclusion, both E-cadherin and vimentin are independent predictors of mortality, and the EMT phenotype is a significant indicator of poor prognosis in lung SqCC.

Homeobox A (HOXA) cluster genes, members of the HOX family, perform an important role in normal organ development. It has previously been reported that HOXA gene expression in various types of cancer is associated with poor patient outcomes. However, the role of HOXA genes, as well as their expression, in colorectal cancers (CRC) remains unknown. Therefore, the present study investigated HOXA gene expression in patients with CRC and revealed that HOXA9 expression was significantly increased in tumor tissues compared with non-tumor tissues. Additionally, the functional role of HOXA9 was assessed by knocking down the HOXA9 gene in CRC cells and by evaluating cell growth. Regarding gene expression, cases with positive HOXA9 expression (as detected by immunohistochemical staining) were significantly associated with higher TNM stage and positive lymph node metastasis, although no association was observed between increased HOXA9 levels and the rate of overall survival in the present cohort. Regarding the functional role, HOXA9 expression was demonstrated to be upregulated in patients with CRC and was associated with lymph node metastasis.

Solute carrier (SLC) drug transporters exchange various molecules without energy from adenosine triphosphate hydrolysis, indicating an association with anticancer drug resistance. However, the expression and role of SLC transporters in malignant tumors has not yet been fully elucidated. Therefore, in the current study, the expression of SLC37A family genes was evaluated in patients with colorectal cancer (CRC), and it was revealed that SLC family 37 member 1 (SLC37A1) expression was significantly increased in tumorous tissues compared with that in non-tumorous tissues. The cases with upregulated expression of SLC37A1 by immunohistochemical staining were significantly associated with positive venous invasion and liver metastasis. Furthermore, upregulated SLC37A1 expression was associated with poor overall survival time in the present cohort. These results indicated that SLC37A1 is involved in the hematogenous metastasis of CRC. To investigate whether SLC37A1 is associated with hematogenous metastasis and glycolipid metabolism, SLC37A1 was knocked down in colon cancer cells, and the expression of sialyl Lewis A and sialyl Lewis X was observed to be decreased. In summary, upregulation of SLC37A1 was observed in patients with CRC, and was associated with poor patient outcomes and survival. To the best of our knowledge, the present study is the first to propose a key role of SLC37A1 in CRC, and additional studies are warranted to reveal the functional role of SLC37A1 in CRC development.

Kinesin family member 4A (KIF4A) is a member of the kinesin 4 subfamily of kinesin-related proteins and serves an important role in cell division. The expression levels of KIF4A have been investigated in numerous types of cancer, including cervical, lung, oral, and breast cancer, and are established to be associated with poor patient prognosis. However, the role of KIF4A, as well as its expression in colorectal cancer (CRC), remains to be elucidated. Therefore, the current study investigated KIF4A expression levels in patients with CRC and demonstrated that its levels were increased in tumor tissues compared with non-tumor tissues. To investigate the functional role of KIF4A, KIF4A was knocked down in CRC cells and cell viability was evaluated. CRC cells with KIF4A knockdown exhibited lower cell proliferation compared with control cells. In addition, KIF4A expression levels, as determined by immunohistochemistry, were compared with the expression of Ki-67, but no significant associations were observed in the patients with CRC. Therefore, KIF4A was found to be upregulated in patients with CRC and downregulation of KIF4A reduced cell proliferation in CRC cells. These results suggest that KIF4A may be a potential therapeutic target, which may improve the outcomes of patients with CRC.

Resistance to 5-fluorouracil (5‑FU), a key drug in the treatment of colorectal cancer, is one of the major reasons for poor patient prognosis during cancer treatment. Annexin A1 (ANXA1) is a calcium‑dependent phospholipid‑linked protein that is associated with drug resistance, anti‑inflammatory effects, regulation of cellular differentiation, proliferation and apoptosis. Although there have been several studies investigating ANXA1 expression in drug resistant cells, the role of ANXA1 is yet to be fully understood. We therefore, in this study, generated SW480 cells resistant to 5‑FU (SW480/5‑FU) to evaluate ANXA1 expression. When compared to the control cells, ANXA1 expression was significantly induced in the SW480/5‑FU cells. We then revealed the role of ANXA1 expression in 5‑FU resistance by using overexpression and knockdown methods in colon cancer cells. Overexpression of ANXA1 induced a significant increase of cell viability to 5‑FU, whereas ANXA1 knockdown induced a significant decrease of cell viability to 5‑FU. Further experiments revealed that ANXA1 expression was induced by hypoxia in colon cancer cells. These results suggest that ANXA1 expression may play a critical role in 5‑FU resistance and may be induced by hypoxia during cancer progression. Our results provide a possible strategy to overcome 5‑FU resistance by modulating ANXA1 expression.

Primary malignant melanoma of the gallbladder is a rare disease, and 37 cases have been reported in the literature.The current patient was a 78-year-old man who was admitted with a pelvic tumor and left leg edema due to compression of the external iliac vein by the pelvic tumor.The edema improved following resection of the tumor, which was diagnosed at pathology as a malignant melanoma.After surgery, the patient became anorexic and complained of discomfort in the upper right abdomen.A whole body FDG-PET scan demonstrated significant uptake in the gallbladder and in the lymph nodes of the lower abdomen.The patient underwent open cholecystectomy, and the pathological diagnosis was malignant melanoma. Junctional activity was seen in the gallbladder, suggesting that this was the primary site.No melanocytic lesions of the skin or eyes were detected, further supporting the diagnosis of primary malignant melanoma of the gallbladder.Chemotherapy was initiated, but the patient died on February 28, 2016.

Purpose: To validate the usefulness of sennoside as a substitute for polyethylene glycol (PEG) as a mechanical bowel preparation (MBP) for elective colon cancer surgery., Methods: We performed a prospective randomized non-inferiority trial comparing the use of sennoside and PEG in MBP for elective colon cancer surgery, in terms of the risk of surgical site infection (SSI) and the feasibility of surgery., Results: The overall incidence of SSIs was 2.9 % in the sennoside group (n = 68) and 6.3 % in the PEG group (n = 63) with a difference of 3.4 % (95 % confidence interval 6.9-10.6 %). The intraoperative spillage of the stool materials in the sennoside and PEG groups was 4.4 and 3.1 %, respectively, and was not significantly different (p = 0.71), even the upstream stool consistency, was more frequently observed to be non-stool in the PEG group (65.1 vs. 30.9 %, p < 0.01)., Conclusion: MBP with sennoside could be a substitution for PEG in elective colon cancer surgery.

A 21-year-old woman who underwent laparoscopic total colectomy for familial adenomatous polyposis (FAP) 1 year 3 months previously presented with a mass larger than 10 cm around the ileostomy. Multiple tumors in the mesentery around the ileostomy and anterior to the sacrum, accompanied by bilateral hydronephrosis, were detected by computed tomography. The patient was diagnosed with intraabdominal desmoid tumors, stage Ⅳ according to the Church's classification. The desmoid tumor (15×9 cm) around the ileostomy was completely resected surgically, whereas another desmoid tumor (5×4 cm) was incompletely resected. We found a desmoid tumor of more than 10 cm in size and many fibromatous plaques in the mesentery. We then performed 4 courses of systemic chemotherapy with dacarbazine and doxorubicin in for the residual desmoid tumors after surgery. There was no growth of the residual desmoid tumors for 12 months after chemotherapy. Genetic tests detected a pathogenic germline mutation of the APC gene in the high-risk region of the desmoid tumor. We also confirmed somatic mutations in the resected specimens.

We retrospectively investigated clinical outcome and treatment strategies in Stage Ⅲcolorectal cancer patients who underwent emergency surgery because of tumor-related perforation. We compared the clinical outcome of 6 patients (perforation group) who underwent emergency surgery for colonic perforation due to Stage Ⅲ colorectal cancer with 12 matched patients (matching group) who underwent elective colorectal surgery, between April 1998 and March 2012. Patients in the perforation group underwent colostomy procedures more frequently (p=0.02), had longer operative times (p=0.02), and more bleeding (p=0.04) than those in the matching group. There was no significant difference between the groups in terms of the introduction rate of chemotherapy, recurrence rate, or recurrence pattern. The 3-year disease-free survival rate was 44% in the perforation group and 81% in the matching group, resulting in no significant differences between these groups (p=0.28). The 3-year disease-free survival rates in the perforation and the matching groups were 44% and 81%, respectively (p=0.07). The 3-year overall survival rates in the perforation and the matching groups were 17% and 81%, respectively (p<0.01). The 3-year overall survival rate of patients who received adjuvant chemotherapy was 50% in the perforation group and 88%in the matching group (p=0.03). We concluded that patients with perforated Stage Ⅲ colorectal cancer had a significantly poorer prognosis compared with patients with non-perforated Stage Ⅲ colorectal cancer.

The clinical outcome and efficacy of postoperative chemotherapy in patients with Stage Ⅳ colorectal cancer with perforation were investigated. We compared the clinical outcomes between 11 patients with Stage Ⅳ colorectal cancer (perforation group), who underwent emergency surgery for colonic perforation between September 2005 and March 2012, and 22 matched patients (matching group) who underwent elective colorectal surgery during the same period. The colostomy rate in the perforation group was significantly higher than that of the matching group: patients with perforation received stoma construction surgery more frequently (p<0.01). Seven patients (64%) in the perforation group received postoperative chemotherapy, while 20 patients (91%) in the matching group received chemotherapy (p=0.15). Oxaliplatin-based chemotherapy was administered to all patients in both groups. There was no difference in the median relative dose intensity of oxaliplatin between these groups (p=0.37). No significant difference was observed between the cumulative 3-year overall survival rate in the perforation group and that of the matching group (35% and 54%, respectively; p=0.35). Moreover, the 3-year overall survival rates of patients who received oxaliplatin-based chemotherapy were 51%in the perforation group and 57% in the matching group (p=0.74). Our results suggest that postoperative oxaliplatin-based chemotherapy may improve the prognosis of patients with Stage Ⅳ colorectal cancer with perforation.

When we perform stapled ileal pouch anal anastomosis (IPAA) for familial adenomatous polyposis (FAP), some rectal mucosa persists. There is no consensus on surgical treatment when cancer develops at the residual mucosa. We report the case of a 43-year-old woman who repeatedly underwent endoscopic resection for intramucosal cancer that developed in the residual rectal mucosa 6 years after stapled IPAA, which she received at age 33. She was referred to our department for surgical treatment. We performed mucosectomy for the residual rectum mucosa, including a 0-Ⅱa lesion at the anterior wall. Two months later, stenosis was observed at the anastomotic site. We repeatedly conducted balloon expansion of the stenotic lesion. Six months later, the resected lesion was covered with white epithelium, and columnar epithelium was confirmed by step biopsy of the epithelium from the dentate line to the ileoanal pouch anastomotic site. This finding indicated that the regenerating epithelium was derived from the epithelium from the anal side. The patient remains well after 2 year 4 months with no complaints.

Annexin A1 (ANXA1) is a calcium-dependent phospholipid-linked protein, involved in anti-inflammatory effects, regulation of cellular differentiation, proliferation and apoptosis. While many studies have investigated the ANXA1 expression in various tumor types, the role of ANXA1 is not fully understood. Therefore, in the present study, we evaluated the ANXA1 expression in 211 breast cancer patients and compared the levels with clinicopathological factors. ANXA1 was positively expressed in 31 (14.7%) of the 211 cases in our cohort, and these positive cases were associated with triple-negative breast cancer (TNBC) (P=0.007) and venous invasion (P=0.028). The in vitro cell experiment found that the MDA-MB-231 cell line, which is a TNBC cell line, highly expressed ANXA1. Using this cell line, the functional role of ANXA1 in breast cancer was revealed and the knockdown of ANXA1 by specific siRNA demonstrated a significant reduction in cellular invasion. Further experiments indicated that ANXA1 was induced by hypoxia with hypoxia-inducible factor-1α induction. These results suggested that ANXA1, which enhanced breast cancer invasion and metastasis under hypoxia, were significantly associated with the worst patient outcome. This is particularly noted in TNBC, the group of breast cancer with the worst outcome for which new therapeutic implications are required.