Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-associated Steatohepatitis Development.

BACKGROUND & AIMS: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood. METHODS: We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis. RESULTS: Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild-type mice. Hepatocyte-specific RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. In vitro mechanistic studies linked RECK induction to reduced ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation. CONCLUSION: Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlights its potential as a novel therapeutic in MASH.

Expression Analysis of Early Metastatic Seeding of Colorectal Cancer.

BACKGROUND: Distant metastasis is the leading cause of death in patients with colorectal cancer (CRC). Tumor dissemination for metastasis formation occurs in advanced cancers and also during early stages of tumorigenesis. Here, we investigated the genes involved in early metastatic seeding of CRC using gene expression analysis. PATIENTS AND METHODS: We performed a cDNA microarray using specimens resected from stages I-II CRC with and without metachronous metastatic recurrence. For the candidate genes, we immunohistochemically validated protein expression using a tissue microarray of stages I-III CRC. RESULTS: The expression of TROP2, VWCE, and BMP7 was upregulated in the recurrence group rather than in the non-recurrence group. Protein expression analysis revealed significant association of these genes with distant metastatic recurrence. The specimens with high expression of BMP7 showed worse recurrence-free survival (RFS; p = 0.02). Those with high expression of TROP2 and VWCE showed worse overall survival (OS) and RFS (TROP2: p = 0.01 and p = 0.03; VWCE: p < 0.05 and p < 0.001, respectively). In the multivariate analysis, high expression of VWCE and BMP7 was an independent predictor of recurrence [VWCE: hazard ratio (HR) 3.41, p < 0.001; BMP7: HR 2.93, p = 0.005]. In contrast, TROP2 was an independent prognostic factor for OS (HR 4.58, p = 0.03). CONCLUSIONS: Gene expression analysis revealed that TROP2, VWCE, and BMP7 were involved in early metastatic seeding. The high expression of these genes may warrant careful surveillance or adjuvant therapy, even in stages I-II CRC cases.

A Study of risk factors of postoperative ileus after laparoscopic colorectal resection.

Aim: Postoperative ileus (POI) is a common complication after abdominal surgery. However, the risk factors for POI after laparoscopic colorectal resection are unclear. We therefore investigated the risk factors for POI after laparoscopic colorectal surgery. Methods: This retrospective study involved 484 patients who underwent laparoscopic surgery for primary colorectal cancer at Hokkaido University Hospital. We categorized the patients into a POI group (n = 19) and non-POI group (n = 465). We compared sex, age, smoking, chronic obstructive pulmonary disease (COPD), diabetes mellitus, body mass index (BMI), cardiac disorder, serum albumin, American Society of Anesthesiologists-physical status, tumor location, tumor stage, operative duration, stoma formation, lymph node dissection, operator, and bleeding as potential risk factors for POI between the POI group and non-POI group by univariate and multivariate analyses. Results: The univariate analysis results showed that the POI group had a higher incidence of male sex (P = 0.036), COPD (P = 0.029), and a BMI of <20 kg/m2 (P = 0.0487) as well as a higher bleeding volume (P = 0.014). The multivariate analysis results showed that male sex (odds ratio [OR], 0.2799; 95% confidence interval [CI], 0.089-0.993; P = 0.0298), COPD (0.2866; 0.095-0.862; P = 0.0262), and a BMI of <20 kg/m2 (0.2985; 0.112-0.794; P = 0.0154) were independent risk factors for POI after laparoscopic colorectal resection. Conclusion: Our findings suggest that male sex, COPD, and a BMI of <20 kg/m2 are independent risk factors for POI after laparoscopic colorectal surgery for treatment of colorectal cancer.

Feasibility of Laparoscopic and Robotic Total Proctocolectomy for Ulcerative Colitis-related Colorectal Cancer.

BACKGROUND/AIM: To evaluate the feasibility of laparoscopic and robotic total proctocolectomy (TPC) for ulcerative colitis-associated colorectal cancer (UC-CRC). PATIENTS AND METHODS: We retrospectively analyzed the postoperative outcomes of TPC in 13 patients with UC-CRC between January 2011 and December 2021. Laparoscopic TPC was performed in 10 patients. TPC consisted of two procedures: ileal pouch-anal anastomosis (IAA) and TPC with end ileostomy. Using the da Vinci Xi platform with six ports, robotic TPC and abdominal perineal resection (APR) were performed in two and one patients, respectively. Transanal total mesorectal excision (TaTME) was performed using the perineal approach in five patients. RESULTS: UC-CRC was located in the transverse colon, sigmoid colon, rectum, and anal canal in 1, 1, 10, and 1 patients, respectively. IAA, TPC with end ileostomy, and APR were performed in nine, three, and one patients, respectively. Postoperative complications included colitis, portal vein thrombosis, and liver dysfunction, without mortality. The pathological stages were 0, I, IIa, IIIb, and IIIc in five, four, one, two, and one patients, respectively. The tumors were completely resected in all cases. Eleven patients with pStages 0, I, and II survived without recurrence; however, two patients with pStage III died of cancer recurrence. CONCLUSION: This study demonstrated the feasibility of laparoscopic and robotic TPC in patients with UC-CRC. However, long-term outcomes in terms of oncology and patient quality of life must be investigated in future large-scale studies.

Early-stage sigmoid colon cancer resection followed by liver metastasis recurrence 1 year later and mesenteric recurrence more than 5 years later: a case report.

BACKGROUND: Early-stage colorectal cancer (CRC) is often treated endoscopically, but additional surgical resection may be considered depending on pathological findings. CASE PRESENTATION: A 73-year-old man was found to have early-stage sigmoid colon cancer by colonoscopy during a medical examination, and endoscopic mucosal resection (EMR) was performed. The lesion was a 7-mm-sized sessile polyp, and the pathological diagnosis was well-differentiated tubular adenocarcinoma, pT1 (submucosal invasion of 400 µm), with no lymphovascular invasion, low budding grade, and negative horizontal and vertical margins. Therefore, the patient was observed without postoperative treatment. One year later, a computed tomography (CT) scan showed multiple liver metastases. After five courses of preoperative chemotherapy with folinic acid, 5-fluorouracil and oxaliplatin (FOLFOX) and panitumumab, liver metastases were reduced. The patient underwent extended right hepatic lobectomy. The pathological finding was well-to-moderately differentiated tubular adenocarcinoma, and immunohistochemistry findings were consistent with liver metastases from sigmoid colon cancer. Postoperatively, the patient received five courses adjuvant chemotherapy with FOLFOX. Although the patient had been recurrence-free for 5 years after liver resection, a CT scan revealed a nodular lesion in the sigmoid mesentery. Positron emission tomography (PET) showed abnormal accumulation in the same lesion. Therefore, the mesenteric nodules diagnosed as lymph metastasis and recurrence of sigmoid colon cancer and performed laparoscopic sigmoid colon resection with lymph node dissection. The pathological findings showed that the recurrent lesion in the mesentery formed a nodular infiltrate with venous, lymphatic, and neural invasion, but lymph node structures were not found, and it was assumed to be metastasis or recurrence due to lymphovascular invasion. The pathologic specimen of the sigmoid colon had no neoplastic lesions, which are considered to be a local recurrence on the mucosal surface. After sigmoid colectomy, adjuvant chemotherapy with CapeOX was conducted, and the patient has been recurrence-free for 13 months at present. CONCLUSION: Even early-stage CRCs that have no pathological indications for additional resection have risks of metastases and recurrences, and we may need to consider that the criteria for additional resection should not be limited to pathological findings alone.

Identification of tumor-related genes via RNA sequencing of tumor tissues in Xenopus tropicalis.

Cancer treatment is still challenging because the disease is often caused by multiple mutations. Although genomic studies have identified many oncogenes and tumor suppressor genes, gene sets involved in tumorigenesis remain poorly understood. Xenopus, a genus of aquatic frogs, is a useful model to identify gene sets because it can be genetically and experimentally analyzed. Here, we analyzed gene expression in tumor tissues of three individuals in Xenopus tropicalis and identified 55 differentially expressed genes (DEGs). Gene ontology (GO) analysis showed that the upregulated genes in the tumor tissues were enriched in GO terms related to the extracellular matrix and collagen fibril organization. Hierarchical clustering showed that the gene expression patterns of tumor tissues in X. tropicalis were comparable to those of human connective, soft, and subcutaneous tissue-derived cancers. Additionally, pathway analysis revealed that these DEGs were associated with multiple pathways, including the extracellular matrix, collagen fibril organization, MET signaling, and keratan sulfate. We also found that the expression tendency of some DEGs that have not been well analyzed in the cancer field clearly determines the prognosis of human cancer patients. This study provides a remarkable reference for future experimental work on X. tropicalis to identify gene sets involved in human cancer.

Preoperative mechanical bowel preparation using conventional versus hyperosmolar polyethylene glycol-electrolyte lavage solution before laparoscopic resection for colorectal cancer (TLUMP test): a phase III, multicenter randomized controlled non-inferiority trial.

BACKGROUND: A hyperosmolar ascorbic acid-enriched polyethylene glycol-electrolyte (ASC-PEG) lavage solution ensures excellent bowel preparation before colonoscopy; however, no study has demonstrated the efficacy of this lavage solution before surgery. This study aimed to establish the non-inferiority of ASC-PEG to the standard polyethylene glycol-electrolyte solution (PEG-ELS) in patients undergoing laparoscopic resection for colorectal cancer. METHODS: This was a prospective, single-blind, multicenter, randomized, controlled, non-inferiority clinical trial. Overall, 188 patients scheduled for laparoscopic colorectal resection for single colorectal adenocarcinomas were randomly assigned to undergo preparation with different PEG solutions between August 2017 and April 2020 at four hospitals in Japan. Participants received ASC-PEG (Group A) or PEG-ELS (Group B) preoperatively. The primary endpoint was the ratio of successful bowel preparations using the modified Aronchick scale, defined as "excellent" or "good." RESULTS: After exclusion, 86 and 87 patients in Groups A and B, respectively, completed the study, and their data were analyzed. ASC-PEG was not inferior to PEG-ELS in terms of effective bowel preparation prior to laparoscopic colorectal resection (0.93 vs. 0.92; 95% confidence interval, - 0.078 to 0.099, p = 0.007). The total volume of cleansing solution intake was lower in Group A than in Group B (1757.0 vs. 1970.1 mL). Two and three severe postoperative adverse events occurred in Groups A and B, respectively. Patient tolerance of the two solutions was almost equal. CONCLUSIONS: ASC-PEG is effective for preoperative bowel preparation in patients undergoing laparoscopic resection for colorectal cancer and is non-inferior to PEG-ELS.

Impact of Adipose Tissue Depot Harvesting Site on the Multilineage Induction Capacity of Male Rat Adipose-Derived Mesenchymal Stem Cells: An In Vitro Study.

Recently, substantial attention has been paid toward adipose-derived mesenchymal stem cells (AdMSCs) as a potential therapy in tissue engineering and regenerative medicine applications. Rat AdMSCs (r-AdMSCs) are frequently utilized. However, the influence of the adipose depot site on the multilineage differentiation potential of the r-AdMSCs is still ambiguous. Hence, the main objective of this study was to explore the influence of the adipose tissue harvesting location on the ability of r-AdMSCs to express the stem-cell-related markers and pluripotency genes, as well as their differentiation capacity, for the first time. Herein, we have isolated r-AdMSCs from the inguinal, epididymal, peri-renal, and back subcutaneous fats. Cells were compared in terms of their phenotype, immunophenotype, and expression of pluripotency genes using RT-PCR. Additionally, we investigated their potential for multilineage (adipogenic, osteogenic, and chondrogenic) induction using special stains confirmed by the expression of the related genes using RT-qPCR. All cells could positively express stem cell marker CD 90 and CD 105 with no significant in-between differences. However, they did not express the hematopoietic markers as CD 34 and CD 45. All cells could be induced successfully. However, epididymal and inguinal cells presented the highest capacity for adipogenic and osteogenic differentiation (21.36-fold and 11.63-fold for OPN, 29.69-fold and 26.68-fold for BMP2, and 37.67-fold and 22.35-fold for BSP, respectively, in epididymal and inguinal cells (p < 0.0001)). On the contrary, the subcutaneous cells exhibited a superior potential for chondrogenesis over the other sites (8.9-fold for CHM1 and 5.93-fold for ACAN, (p < 0.0001)). In conclusion, the adipose tissue harvesting site could influence the differentiation capacity of the isolated AdMSCs. To enhance the results of their employment in various regenerative cell-based therapies, it is thus vital to take the collection site selection into consideration.

Effect of Continuous Box-trainer Training on Laparoscopic Skills of Surgical Residents: A Prospective, Observational Study.

BACKGROUND/AIM: As opportunities for hands-on surgical training during residency have decreased, off-the-job training before surgery is gaining importance. We developed a training program using a box-trainer for surgical residents. This study aimed to verify the effectiveness of the program. Using task-achievement time, we demonstrated the learning curve through continuous task training and verified the efficiency of our training tasks. In addition, we examined the circularity of the cut circle to evaluate the task accuracy and summarized the questionnaire results. PATIENTS AND METHODS: A prospective, observational study was conducted at a single center with five trainees from April 2019 to March 2020. The training consisted of four tasks based on the Fundamentals of Laparoscopic Surgery module. The trainees had to achieve expert proficiency time targets. The task-achievement time and circularity of the cut circle were used for objective assessment; subjective evaluation was done using a questionnaire. RESULTS: Although the learning curves of the task-achievement time seemed to reach a plateau between the third and the fifth skills lab, all the trainees achieved expert proficiency times for the three tasks. Circularity of the cut circle tended to be more accurate after training. All trainees perceived an improvement in their skills after the training program. The level of satisfaction of the training program was rated as 'very satisfied' or 'satisfied'. CONCLUSION: Continuous box-trainer training for 1 year may be effective for improvement in preoperative laparoscopic surgical skills of surgical residents.

Insulin-like growth factor 1 reduces coronary atherosclerosis in pigs with familial hypercholesterolemia.

Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque's fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis, consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress, and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis showed that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1's effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.

Interischial Spine Distance Is a Simple Index of the Narrow Pelvis That Can Predict Difficulty During Laparoscopic Low Anterior Resection.

BACKGROUND: A narrow pelvis makes laparoscopic rectal resection difficult. This study aimed to evaluate whether a simple measurement on computed tomography can predict procedural difficulty. METHODS: A total of 62 patients with low rectal cancer underwent conventional laparoscopic low anterior resection. The interischial spine (IS) distance (ie, the distance between the ischial spines) was measured on an axial computed tomography slice. The operative time, blood loss, and time from the insertion of linear staplers to completion of clamping on the distal end of the rectum (clamp time) were compared between patients with narrow or wide pelvises. RESULTS: Overall, 42 men and 20 women with low rectal cancer were assessed. The mean tumor size was 34.5 mm. Total or tumor-specific mesorectal excisions were performed in all cases; high ligation and resection of the inferior mesenteric arteries were carried out in 92% of patients. The mean operative time and blood loss were 206 minutes and 15 mL, respectively. Four patients (6.5%) experienced postoperative complications, including 2 anastomotic leaks (3.2%). The mean IS distance was 93.3 mm. In simple linear regression analysis, a shorter IS distance correlated with a longer operative time ( R2 =0.08, P =0.030) and the clamp time ( R2 =0.07, P =0.046). Using a receiver operating characteristic curve, a narrow pelvis was defined as an IS distance <94.7 mm. Multivariate regression analysis revealed that an IS distance <94.7 mm (odds ratio: 3.51; P =0.04) was independently associated with a longer clamp time. CONCLUSIONS: The IS distance is a simple and useful measurement for predicting the difficulty of laparoscopic low anterior resection.

Exploration of the advantages of minimally invasive surgery for clinical T4 colorectal cancer compared with open surgery: A matched-pair analysis.

The indications of minimally invasive surgery (MIS) for T4 colorectal cancer are controversial because the advantages of MIS are unclear. Therefore, we compared overall survival (OS) and recurrence-free survival (RFS) as the primary endpoint, and short-term outcome, alteration in perioperative laboratory data, and the interval of postoperative chemotherapy from operation as secondary endpoints, between MIS and open surgery (OPEN) using a matched-pair analysis. We explored the advantages of MIS for T4 colorectal cancer. In this retrospective single-institution study, we included 125 patients with clinical T4 colorectal cancer who underwent curative-intent surgery of the primary tumor between October 2010 and September 2019. Conversion cases were excluded. MIS patients were matched to OPEN patients (ratio of 1:2) according to tumor location, clinical T stage, and preoperative treatment. We identified 25 and 50 patients who underwent OPEN and MIS, respectively, including 31 with distant metastasis. Both groups had similar background characteristics. The rate of major morbidities (Clavien-Dindo grade > III) was comparable between the 2 groups (P = .597), and there was no mortality in either group. MIS tended to result in shorter postoperative hospitalization than OPEN (P = .073). Perioperative alterations in laboratory data revealed that MIS suppressed surgical invasiveness better compared to OPEN. Postoperative chemotherapy, especially for patients with distant metastasis who underwent primary tumor resection, tended to be started earlier in the MIS group than in the OPEN group (P = .075). OS and RFS were comparable between the 2 groups (P = .996 and .870, respectively). In the multivariate analyses, MIS was not a significant prognostic factor for poor OS and RFS. MIS was surgically safe and showed similar oncological outcomes to OPEN-with the potential of reduced invasiveness and enhanced recovery from surgery. Therefore, patients undergoing MIS might receive subsequent postoperative treatments earlier.

STAT1-mediated induction of Ly6c-expressing macrophages are involved in the pathogenesis of an acute colitis model.

BACKGROUND: The development of inflammatory bowel diseases is thought to be multifactorial, but the exact steps in pathogenesis are poorly understood. In this study, we investigated involvement of the activation of STAT1 signal pathway in the pathogenesis of an acute colitis model. METHODS: A dextran sulfate sodium-induced acute colitis model was established by using wild-type C57BL/6 mice and STAT1-deficient mice. Disease indicators such as body weight loss and clinical score, induction of cytokines, chemokines, and inflammatory cells were evaluated in the acute colitis model. RESULTS: Disease state was significantly improved in the acute colitis model using STAT1-deficient mice compared with wild-type mice. The induction of Ly6c-highly expressing cells in colorectal tissues was attenuated in STAT1-deficient mice. IL-6, CCL2, and CCR2 gene expressions in Ly6c-highly expressing cells accumulated in the inflamed colon tissues and were significantly higher than in Ly6c-intermediate-expressing cells, whereas TNF-α and IFN-α/ß gene expression was higher in Ly6c-intermediate-expressing cells. Blockade of CCR2-mediated signaling significantly reduced the disease state in the acute colitis model. CONCLUSIONS: Two different types of Ly6c-expressing macrophages are induced in the inflamed tissues through the IFN-α/ß-STAT1-mediated CCL2/CCR2 cascade and this is associated with the pathogenesis such as onset, exacerbation, and subsequent chronicity of acute colitis.

Transabdominal Ultrasonography for Preoperative Diagnosis of Lymph Node Metastasis in Colon Cancer: A Retrospective Cohort Study.

Background/Aim: Although computed tomography (CT) is the standard modality for diagnosing lymph node metastasis (LNM), transabdominal ultrasonography (US) can be useful due to its high spatial resolution and use of Doppler signals to precisely analyse lymph nodes. This study aimed to evaluate the accuracy of US for lymph node assessment, establish US-based diagnostic criteria for LNM, and compare the capability of US with that of CT for the diagnosis of LNM. Patients and Methods: This retrospective, single-institution, cohort study included patients who underwent radical surgery for clinical stage 0-III colon cancer, between March 2012 and February 2019. Results: Overall, 34.9% (66/189) of patients had pathological LNM. The optimal US diagnostic criteria were 1) short axis ≥7 mm and short/long ratio ≥0.75 and 2) at least two of the following: the absence of hilar echoes, expansive appearance, or peripheral/mixed vascularity by the colour Doppler and/or contrast-enhanced method. Compared to CT, US showed a higher diagnostic sensitivity (54.5% vs. 43.9%; p=0.296), higher concordance with the number of pathological LNM (correlation coefficient: US, 0.42; CT, 0.27) and pathological N diagnosis (weighted ĸ: US, 0.35; CT, 0.18), and higher sensitivity for advanced LNM, including multiple LNMs (47.4% vs. 18.4%; p=0.014) and N2 stage (27.8% vs. 5.6%; p=0.177). Conclusion: US has higher sensitivity than CT for diagnosing LNM in colon cancer, along with a more accurate preoperative diagnosis of the N stage. Additionally, US may be more helpful than CT alone for preoperatively deciding the appropriateness of neoadjuvant treatment in colon cancer with advanced LNM.

Heterogeneity of adipose stromal vascular fraction cells from the different harvesting sites in rats.

In both veterinary and human health, regenerative medicine offers a promising cure for various disorders. One of the rate-limiting challenges in regenerative medicine is the considerable time and technique required to expand and grow cells in culture. Therefore, the stromal vascular fraction (SVF) shows a significant promise for various cell therapy approaches. The present study aimed to define and investigate the optimal harvest site of freshly isolated SVF cells from various adipose tissue (AT) depot sites in the female Sprague-Dawley (S.D.) rat. First, hematoxylin and eosin (H&E) were used to analyze the morphological variations in AT samples from peri-ovarian, peri-renal, mesenteric, and omental sites. The presence of putative stromal cells positive CD34 was detected using immunohistochemistry. Then, the isolated SVF cells were examined for cell viability and cellular yield differences. Finally, the expression of mesenchymal stem cells and hematopoietic markers in the SVF cells subpopulation was studied using flow cytometry. The pluripotent gene expression profile was also evaluated. CD34 staining of the omental AT was substantially higher than those of other anatomical sites. Despite having the least quantity of fat, omental AT has the highest SVF cell fraction and viable cells. Along with CD90 and CD44 higher expression, Oct4, Sox2, and Rex-1 genes levels were higher in SVF cells isolated from the omental AT. To conclude, omental fat is the best candidate for SVF cell isolation in female S.D. rats with the highest SVF cell fraction with higher MSCs phenotypes and pluripotency gene expression.

The survival impact of preoperative FOLFOX for resectable locally advanced rectal cancer: the R-NAC-01 study.

PURPOSE: In this follow-up of the R-NAC-01 study, we assessed the long-term oncological benefit of four courses of modified leucovorin, 5-fluorouracil (FU), and oxaliplatin (mFOLFOX6) chemotherapy before rectal surgery. METHODS: In this prospective, multicenter study (UMIN 000012559) involving 11 hospitals in Japan, patients with lower rectal cancer underwent four cycles of mFOLFOX6 chemotherapy and subsequent surgery within four to six weeks. The 3-year recurrence-free survival and local recurrence rates were then reported. RESULTS: Of 41 patients (36 males, 5 females; mean age: 60.8 years old) who received 4 courses of chemotherapy, 40 underwent total mesorectal excision, and 1 underwent total pelvic exenteration. R0 resection was achieved in 40 patients, but none showed a pathological complete response. Twenty-nine patients received adjuvant chemotherapy for an average of 4 months. The 3 year recurrence-free survival and local recurrence rates in patients undergoing curable resection were 72.8% and 8.5%, respectively. cStage III patients with adjuvant chemotherapy had a significantly higher 3 year recurrence-free survival than those without adjuvant chemotherapy (76.6 vs. 40.0%, log-rank p = 0.03). CONCLUSION: Four courses of mFOLFOX6 chemotherapy before surgery may be a promising treatment strategy for locally advanced rectal cancer. Adjuvant chemotherapy might be needed for cStage III patients, even after four courses of neoadjuvant mFOLFOX6.

Macrophage-Specific IGF-1 Overexpression Reduces CXCL12 Chemokine Levels and Suppresses Atherosclerotic Burden in Apoe-Deficient Mice.

OBJECTIVE: IGF-1 (insulin-like growth factor 1) exerts pleiotropic effects including promotion of cellular growth, differentiation, survival, and anabolism. We have shown that systemic IGF-1 administration reduced atherosclerosis in Apoe-/- (apolipoprotein E deficient) mice, and this effect was associated with a reduction in lesional macrophages and a decreased number of foam cells in the plaque. Almost all cell types secrete IGF-1, but the effect of macrophage-derived IGF-1 on the pathogenesis of atherosclerosis is poorly understood. We hypothesized that macrophage-derived IGF-1 will reduce atherosclerosis. Approach and Results: We created macrophage-specific IGF-1 overexpressing mice on an Apoe-/- background. Macrophage-specific IGF-1 overexpression reduced plaque macrophages, foam cells, and atherosclerotic burden and promoted features of stable atherosclerotic plaque. Macrophage-specific IGF1 mice had a reduction in monocyte infiltration into plaque, decreased expression of CXCL12 (CXC chemokine ligand 12), and upregulation of ABCA1 (ATP-binding cassette transporter 1), a cholesterol efflux regulator, in atherosclerotic plaque and in peritoneal macrophages. IGF-1 prevented oxidized lipid-induced CXCL12 upregulation and foam cell formation in cultured THP-1 macrophages and increased lipid efflux. We also found an increase in cholesterol efflux in macrophage-specific IGF1-derived peritoneal macrophages. CONCLUSIONS: Macrophage IGF-1 overexpression reduced atherosclerotic burden and increased features of plaque stability, likely via a reduction in CXCL12-mediated monocyte recruitment and an increase in ABCA1-dependent macrophage lipid efflux.

Lateral lymph node recurrence of rectal cancer with a pathological complete response to chemotherapy confirmed by laparoscopic lateral lymph node dissection: A case report.

Lateral lymph node (LLN) metastasis is one of the forms of local recurrence after surgery for lower rectal cancer. We here present a case of LLN recurrence of rectal cancer that was shown by laparoscopic lateral lymph node dissection (LLND) to have a complete pathological response to chemotherapy. A 58-year-old man underwent open low anterior resection for lower rectal cancer. After detection of right LLN recurrence 43 months after the operation, 11 cycles of capecitabine, oxaliplatin, and bevacizumab chemotherapy were administered. Laparoscopic right LLND was performed 55 months after the first operation. Pathological examination revealed no viable tumor cells in the dissected lymph nodes. The patient remains alive without recurrence 61 months after the first surgery and 6 months after laparoscopic LLND. Laparoscopic LLND for LLN recurrence of rectal cancer is feasible and should be considered a valid treatment option.

Long-term efficacy and safety of iron-based phosphate binders, ferric citrate hydrate and sucroferric oxyhydroxide, in hemodialysis patients.

PURPOSE: Iron-based phosphate binders, including ferric citrate hydrate (FCH) and sucroferric oxyhydroxide (SFOH), have been used for the treatment of hyperphosphatemia in end-stage renal disease patients on dialysis. However, the long-term efficacy and safety of these agents have not yet been clearly elucidated. METHODS: Laboratory data of 56 hemodialysis patients who had been prescribed either FCH (n = 33) or SFOH (n = 23) were retrospectively examined. RESULTS: We showed that both FCH and SFOH significantly and consistently decreased serum phosphate concentrations in the patients undergoing maintenance hemodialysis during the 36-month observation period. Serum levels of calcium, intact parathyroid hormone, as well as hemoglobin levels were unaltered. No overshoot of parameters of iron metabolism, such as transferrin saturation and serum ferritin levels, was observed, and serum ferritin level remained under 300 ng/mL in most patients. A trend towards decrease in the doses of erythropoiesis-stimulating agents used and frequency of intravenous iron use was observed in both treatment groups. No severe adverse drug reactions were observed in either the patients receiving FCH or SFOH. CONCLUSION: The results of the present study suggest that the iron-based phosphate binders, FCH and SFOH, decrease serum phosphate concentrations consistently and are safe to use over the long-term in maintenance hemodialysis patients.

Modified complete mesocolic excision with central vascular ligation by the squeezing approach in laparoscopic right colectomy.

PURPOSE: Complete mesocolic excision (CME) and central vascular ligation (CVL) are becoming the standard procedure in laparoscopic right-sided colectomy. However, the approach to CME and CVL has not been established, although several useful approaches have been reported. The squeezing approach described herein is a novel procedure to perform modified CME and CVL in laparoscopic right colectomy. METHODS: The squeezing approach features retroperitoneal mobilization followed by cranial mesocolic mobilization and lymph node dissection using a cranial approach followed by a caudal approach. Dissection of the regional lymph nodes along with central vascular ligation was performed along the anterior wall of the superior mesenteric vein. In total, 177 patients (mean age, 70.6 years; male-to-female ratio, 90:87) who underwent laparoscopic right-sided colectomy were retrospectively assessed. Descriptive statistics for patient characteristics were calculated. RESULTS: The mean operative time and blood loss were 169 min and 37 mL, respectively. Seven patients (4.0%) required conversion to open surgery, and major postoperative complications occurred in five patients (2.8%) with no anastomotic leakage. Histological R0 resection was achieved in all cases of stages 0-III colon cancer. The 5-year recurrence-free survival rates were 100% (n = 19), 100% (n = 40), 87% (n = 46), and 81% (n = 43) in pathological stages 0, I, II, and III, respectively. Node recurrence occurred in one case near the root of the middle colic artery. CONCLUSION: The novel squeezing approach in laparoscopic right colectomy could be safely performed in terms of the technical and oncological aspects.