Conditional ablation of heparan sulfate expression in stromal fibroblasts promotes tumor growth in vivo.

Heparan sulfate (HS) is a glycocalyx component present in the extracellular matrix and cell-surface HS proteoglycans (HSPGs). Although HSPGs are known to play functional roles in multiple aspects of tumor development and progression, the effect of HS expression in the tumor stroma on tumor growth in vivo remains unclear. We conditionally deleted Ext1, which encodes a glycosyltransferase essential for the biosynthesis of HS chains, using S100a4-Cre (S100a4-Cre; Ext1f/f) to investigate the role of HS in cancer-associated fibroblasts, which is the main component of the tumor microenvironment. Subcutaneous transplantation experiments with murine MC38 colon cancer and Pan02 pancreatic cancer cells demonstrated substantially larger subcutaneous tumors in S100a4-Cre; Ext1f/f mice. Additionally, the number of myofibroblasts observed in MC38 and Pan02 subcutaneous tumors of S100a4-Cre; Ext1f/f mice decreased. Furthermore, the number of intratumoral macrophages decreased in MC38 subcutaneous tumors in S100a4-Cre; Ext1f/f mice. Finally, the expression of matrix metalloproteinase-7 (MMP-7) markedly increased in Pan02 subcutaneous tumors in S100a4-Cre; Ext1f/f mice, suggesting that it may contribute to rapid growth. Therefore, our study demonstrates that the tumor microenvironment with HS-reduced fibroblasts provides a favorable environment for tumor growth by affecting the function and properties of cancer-associated fibroblasts, macrophages, and cancer cells.

Predictive Value of the Prognostic Nutritional Index in Neoadjuvant Chemoradiotherapy for Rectal Cancer.

Background/Aim: Prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) indicate nutritional status and host immunity. We used immunohistochemistry and apparent diffusion coefficient (ADC) values calculated using diffusion-weighted imaging (DWI) to investigate relationships of these factors with pathological and radiological characteristics in rectal cancer treated with neoadjuvant chemoradiotherapy (nCRT). Patients and Methods: We evaluated expression levels of VEGFA, CD8, CD33, and ADC values in tumors pre/post nCRT; and analyzed the relationships between those factors and PNI, NLR in 32 patients. Results: Pretreatment PNI negatively correlated with change in tumor stromal CD8 + T cells and positively correlated with ADC values. Pretreatment NLR and PNI change correlated with recurrence-free survival (RFS). Conclusion: Patients with higher pretreatment PNI had greater changes in ADC values and stromal CD8 + T-cell counts, and those with greater PNI reduction from nCRT had a worse prognosis. Proper nutritional management during nCRT benefits patients and may lead to better prognosis in rectal cancer.

Evaluation of the SYNAPSE VINCENT for lateral lymph node dissection in rectal cancer with robotic surgery: a preliminary report.

BACKGROUND: Even if 3D angiographic images of preoperative contrast-enhanced computed tomography (CT) are created, the coronal and axial sections can be unclear, and thus, it is difficult to achieve projection awareness similar to that of actual laparoscopic images. In recent years, the technology of analyzing and applying medical images has advanced, and surgical simulation and navigation have been widely used to improve the safety of surgical operations. It is important to understand pelvic anatomy in the area of rectal cancer, and use of the SYNAPSE VINCENT makes it possible to simulate the anatomy before surgery, which is very useful in educating surgeons and their assistants. MATERIALS AND METHODS: An important objective in surgery is to understand the anatomy of the external/internal iliac arteries and lymph nodes in lateral lymph node dissection (LLD) for rectal cancer. In this study, we explored the accuracy and usefulness of SYNAPSE VINCENT images of pelvic anatomy (especially vascular anatomy) analyzed preoperatively in two cases of LLD for rectal cancer in our department. RESULTS: The patients were two men aged 73 and 57 years, respectively. Both patients underwent robotic abdominal perineal resection and LLD with neoadjuvant chemoradiotherapy. The operating times for LLD were 138 and 106 min, estimated blood loss was less than 10 mL and 20 mL, and the harvested lymph nodes were nos. 21 and 22, respectively. The SYNAPSE VINCENT could be used for simulation and navigation before and during surgery. For experienced surgeons, the system helped them carry out operations more accurately. CONCLUSION: In the future, surgical support using virtual reality, augmented reality, and mixed reality based on medical images will be useful and is expected to improve the safety, accuracy, and efficiency of surgery, which is extremely useful for both young and skilled surgeons preparing for difficult operations.

Evaluation of histopathological heterogeneity of colorectal cancer liver metastasis sites after preoperative chemotherapy.

Patients with liver metastases from colorectal cancer (CRLMs) frequently receive chemotherapy prior to liver resection. Histopathological assessment of the resected specimen can evaluate the response to chemotherapy. The present study analyzed the association between histopathological changes in the primary site and liver metastases. The present study comprised 45 patients with resectable CRLMs at the Surgical Oncology Department of Gifu University School of Medicine (Gifu, Japan) between January 2006 and August 2015. The study included 24 men and 21 women. The primary colonic tumor was located in the right side in 13 (28.9%) patients and the left side in 32 (71.9%) patients. The present study evaluated patients with metastatic colorectal cancer (31/45) after excluding those in whom histopathological heterogeneity between the primary and liver metastasis changed to grade 3 after chemotherapy. The group that underwent hepatectomy after chemotherapy (n=25) was compared with the group that underwent hepatectomy alone (n=6). In 16 (53.3%) out of 25 patients, histopathological heterogeneity of the liver metastasis was lost (P=0.04). In conclusion, chemotherapy appeared to change histopathological heterogeneity. The present study suggested that the histopathological change of intratumoral heterogeneity is reflected by the response to chemotherapy.

Phase II Study of Preoperative Chemoradiotherapy With S-1 Plus Oxaliplatin for Locally Advanced Rectal Cancer (PerSeUS-RC01).

BACKGROUND/AIM: We report the end results of a study evaluating the safety and efficacy of preoperative chemoradiotherapy with S-1 plus oxaliplatin. PATIENTS AND METHODS: Eligible patients had histopathologically confirmed locally advanced rectal carcinoma (LARC; cT3-T4, any N). They received oral S-1 (80 mg/m2/day on days 1-5, 8-12, 22-26, and 29-33) and oxaliplatin by infusion (50 mg/m2/day on days 1, 8, 22, and 29) along with radiotherapy (1.8 Gy/day, total dose: 45 Gy/25 fractions). A chemotherapy gap was included in the third week of radiotherapy. The study endpoint was pathological response rate (Grade 2, 3). Secondary endpoints included rates of pathologic complete response (pCR), R0 resection, disease-free survival (DFS), overall survival (OS), local and distant recurrence, and safety and relative dose intensity. RESULTS: The study enrolled 23 patients at three Centres in Gifu, Japan. All patients received chemoradiotherapy, and 22 underwent surgery. Rates of pathological response, R0 resection, and pathological down-staging were 56.5% (13/23), 95.7% (22/23), and 63.6% (14/22), respectively. There were no grade 4 adverse events, but grade 3 events occurred in 21.7% of patients. The cumulative 3-year local recurrence rate was 8.7%. Distant metastasis occurred in 10 (43.5%) patients, 2 (8.7%) from local recurrence and 2 from secondary pancreatic cancer and lung cancer. There were 8 patients with lung metastasis, 2 with liver metastasis, one with ovarian metastasis, and one with bone metastasis. Three-year rates of DFS and OS were 51.1% (median follow-up 34.3 months) and 91.1% (45.2 months), respectively. CONCLUSION: The study showed high pathological response rate without severe toxicity and good follow-up results. Unexpectedly, however, this regimen could not control local recurrence and distant metastasis. Nevertheless, adding oxaliplatin to preoperative chemoradiotherapy with S-1 in patients with LARC appears feasible and may safely result in better local control than standard treatment. The study suggests adding treatment with induction chemotherapy in consideration of CEA level and N factor.

Short- and long-term outcomes after colonic self-expandable metal stent placement for malignant large-bowel obstruction as a bridge to surgery focus on the feasibility of the laparoscopic approach: a retrospective, single center study.

PURPOSE: Malignant large-bowel obstruction (MLBO) is a highly urgent condition in colorectal cancer with high complication rates. Self-expandable metal stent (SEMS) placement in MLBO is a new decompression treatment in Japan. Preoperative stent placement (bridge to surgery: BTS) avoids emergency surgery, but oncological influences of stent placement and post-BTS surgical approach remain unclear. We examined short- and long-term results of surgery for MLBO after SEMS placement in our hospital. METHODS: We retrospectively reviewed 75 patients with MLBO who underwent resection after SEMS placement at our hospital from June 2013 to December 2018. Postoperative morbidity and mortality were evaluated by comparison with the surgical approach. RESULTS: Tumor location was significantly higher in the left-side colon and rectum (n = 59, 78.7%) than right-side colon (n = 16, 21.3%). Technical and clinical success rates for SEMS placement were 97.3% and 96.0%, respectively. Laparoscopic surgery was performed in 54 patients (69.0%), and one-stage anastomosis was performed in 73 (97.3%). Postoperative complications were similar in the open surgery (open) group (n = 5, 23.8%) and laparoscopic surgery (lap) group (n = 7, 13.0%), with no severe complications requiring reoperation. Three-year overall survival (OS) and relapse-free survival (RFS) rates were not significantly different in the lap vs open group (67.5% vs 66.4%; 82.2% vs 62.5%). CONCLUSION: Preoperative stent treatment avoids stoma construction but allows anastomosis. One-time surgery was performed safely contributing to minimally invasive treatment and acceptable short- and long-term results.