[A Case of Intrahepatic Cholangiocarcinoma in Contact with the Gastroduodenal Anastomosis in Which Proton Beam Therapy Was Performed after Placement of an Absorbable Spacer].

Chemotherapy is the standard therapy for unresectable intrahepatic cholangiocarcinoma(ICC), but chemotherapy is not efficacious. Proton beam therapy(PBT)has been covered by Japanese health insurance for ICC since 2022, and the number of cases is expected to increase. In some cases, irradiation is difficult due to the close proximity of the gastrointestinal tract to the tumor. We report our management of a patient with ICC close to the gastrointestinal tract. The patient was a 69-year- old woman with a history of distal gastrectomy and Billroth-Ⅰ reconstruction for gastric cancer. A CT scan showed a tumor in liver S3; a biopsy revealed ICC. Because the tumor was in contact with the gastroduodenal anastomosis, we placed an absorbable spacer and performed PBT. After the treatment, the tumor shrank slightly. Although the liver is anatomically adjacent to the digestive tract, the placement of absorbable spacers facilitates performing PBT without adverse events, and is thus considered a useful treatment.

The expression of carcinoembryonic antigen mRNA in the lavage of the dissected area of the lateral lymph nodes influences the lateral recurrence of lower rectal cancer.

PURPOSE: To determine whether or not migrating cancer cells are present on the surgical plane after lateral lymph node dissection (LLND) for lower rectal cancer and related to lateral recurrence (LR), we evaluated the lavage of LLND areas by reverse-transcription polymerase chain reaction (RT-PCR) to check the expression of CEA mRNA in the residual cancer cells. METHODS: Thirty patients who underwent curative LLND were enrolled. Lavage was collected after LLND and subjected to RT-PCR to detect CEA mRNA. The median follow-up to check for recurrence was 31.4 months. RESULTS: CEA mRNA was detected in 9 of the 46 dissected areas. Based on the receiver operating characteristic curves, the cut-off value of PCR was set at 0.025. This cut-off point classified five patients into the high-expression group for CEA mRNA. During follow-up, LR developed in 1 of 40 low-expression areas of CEA mRNA and 3 of 6 high-expression areas. The LR rate was higher in the high-expression group than in the low-expression group (p = 0.015). A multivariate analysis showed that the high expression of CEA mRNA was likely an independent prognostic factor of LR. CONCLUSION: The expression of CEA mRNA in the lavage of LLND areas indicates the presence of residual cancer cells that cause LR.

Efficacy of intraoperative ICG fluorescence imaging evaluation for preventing anastomotic leakage after left-sided colon or rectal cancer surgery: a propensity score-matched analysis.

BACKGROUND: Intestinal perfusion at the anastomotic site is thought to be one of the most influential risk factors for postoperative anastomotic leakage (AL). We evaluated the efficacy of indocyanine green (ICG) fluorescence imaging at the stump of the proximal colon in left-sided colectomy or rectal resection in terms of decreasing the incidence of AL. METHODS: Prospectively collected data were retrospectively evaluated. Patients who underwent left-sided colectomy or rectal resection were enrolled (ICG group; n = 197), and patients who had undergone a similar procedure before the ICG group were enrolled from the charts as historical controls (HC group; n = 187). After ICG evaluation, anastomosis was performed where fluorescence was sufficient. The incidence of AL was compared between the ICG and HC groups. Propensity score (PS)-matched data were analyzed to clarify the risk of AL. RESULTS: AL occurred in 6 patients (3.3%) in the ICG group and 17 (10.7%) in the HC group. ICG evaluation revealed 179 patients with good fluorescence and 18 with poor/none perfusion (9.1%). The transection line was changed in all patients with poor/none fluorescence. Three of these 18 patients developed AL (16.7%), though transection line was changed at which is thought to be good. We hope AL in poor/none fluorescence can be prevented at the same rate of cases with good fluorescence. Actually, the rate of that was significantly higher compared with good fluorescence patients (P = 0.038). 93 patients in each group were compared by PS-matched data analysis, which showed the AL rate in the ICG group was significantly lower than that in the HC group (3.2% vs 10.8%, respectively; P = 0.046). CONCLUSIONS: Even though this study has limitations of comparison of data prospectively collected and retrospectively analyzed, intraoperative ICG fluorescence imaging evaluation could significantly decrease the incidence of AL.

Accurate localization of rectal cancer using near infrared ray-guided surgery with intra-operative colonoscopy and da Vinci Firefly technology.

Accurate localization of the tumor during robot-assisted laparoscopic surgery for rectal cancer is crucial. Several techniques have been described, but each has its shortcomings. We developed a new technique of near infrared ray-guided surgery (NIRGS) to localize the tumor accurately, using intra-operative colonoscopy and da Vinci Firefly technology. After clamping the oral side of the tumor, the colonoscope was inserted. In the normal visible light mode, we could not recognize the endoscopic light; however, after changing to the Firefly mode, the endoscopic light was seen clearly. Using this simple and new technique, we could locate the tumor easily and accurately. We performed this technique in 12 patients and detected the location of the tumor clearly in all, without any procedure-related complications. Based on these findings, NIRGS is a useful and safe technique for detecting tumor location during robot-assisted laparoscopic surgery for rectal cancer.

Laparoscopic extraperitoneal sigmoid colostomy using the totally extraperitoneal hernia repair technique after abdominoperineal resection for rectal cancer.

Stoma creation through the extraperitoneal route reportedly reduces the risk of parastomal hernia and stomal prolapse after abdominoperineal resection (APR) for rectal cancer. We describe a new technique for laparoscopic extraperitoneal sigmoid colostomy following APR. After the rectus abdominis muscle is separated, Lap ProtectorTM and EZ AccessTM devices are placed. An extraperitoneal stoma tunnel is created laparoscopically as much as possible. Next, the peritoneum is separated from the inside of the abdominal cavity, and the extraperitoneal tunnel is opened. At the time of writing, we had performed laparoscopic extraperitoneal sigmoid colostomy in eight patients, without any complications or conversion to the conventional procedure. Thus, laparoscopic extraperitoneal sigmoid colostomy is a useful and safe technique for the laparoscopic creation of an extraperitoneal stoma tunnel after APR.

No inflammatory benefit obtained by single-incision laparoscopic surgery for right hemicolectomy compared with conventional laparoscopy.

PURPOSE: We evaluated the perioperative inflammatory mediators in a right hemicolectomy performed with single-incision laparoscopic surgery (SILS) and traditional multi-port laparoscopic surgery (MLS) to compare the postoperative inflammatory response and feasibility of SILS with that of MLS. METHODS: In this retrospective study, we enrolled 56 consecutive colorectal cancer patients who underwent right hemicolectomy prospectively. Twenty patients underwent SILS, and 36 underwent MLS. The preoperative and postoperative levels of plasma vascular endothelial growth factor (VEGF), serum interleukin-6 (IL-6), and C-reactive protein (CRP) as well as the number of platelet cells were measured in all patients. The operation duration, number of harvested lymph nodes, length of the resected bowel, blood loss, and duration of hospital stay were also compared between the two groups. RESULTS: Neither SILS nor MLS had any conversion cases. The operation duration was longer for MLS than for SILS. Blood loss tended to be lower among patients who underwent SILS than among those who underwent MLS. However, the number of harvested LNs was significantly lower with SILS than with MLS. In both pre- and postoperative blood examinations, there was no marked difference in inflammatory mediators between MLS and SILS. CONCLUSION: There was no systemic inflammatory advantage associated with SILS compared with MLS.

[Review of High-Risk Factors and Adjuvant Chemotherapy Indication in T4-pStage â ¡ Colon Cancer].

BACKGROUND: T4 is one of the high-risk factors, but the efficacy of adjuvant chemotherapy for T4-Stage Ⅱ colon cancer are unclear. METHOD: We retrospectively reviewed 211 patients with primary pStage Ⅱ colon cancer who underwent radical resection between 2004 and 2015. RESULTS: The 5-year overall survival rate(OS)of Stage ⅡA/ⅡB/ⅡC were 90.2/83.4/ 59.2%, and the 5-year recurrence-free survival rate(RFS)were 87.3/73.3/42.8%. Multivariate analysis of OS as a high-risk factor of T4 revealed male, ly2/3, no adjuvant chemotherapy, and in RFS, male, ly2/3. However, compared the cases with or without adjuvant chemotherapy, 5-year OS was no difference. There were no cases used oxaliplatin-based adjuvant chemotherapy. CONCLUSION: An adjuvant chemotherapy without oxaliplatin were not enough to improve the prognoses of T4-Stage Ⅱcolon cancer, so the oxaliplatin based regimen might be recommended.

High serum levels of interleukin-6 in patients with advanced or metastatic colorectal cancer: the effect on the outcome and the response to chemotherapy plus bevacizumab.

PURPOSE: We evaluated the relationship of the pretreatment serum IL-6 levels with the outcome and treatment response in patients with advanced or metastatic colorectal cancer (CRC) who underwent bevacizumab-containing chemotherapy. METHODS: In this retrospective study, the pretreatment serum IL-6 and plasma vascular endothelial growth factor (VEGF) levels were measured in 113 patients with metastatic CRC. The cut-off values for these measurements, as determined by a receiver operating characteristic curve analysis, were 4.3 and 66 pg/mL, respectively. The median follow-up period was 19 months (range 1-40 months). Sixty-three patients had primary cancer, and 38 had a metachronous recurrence. Thirty patients underwent curative resection, and 71 underwent chemotherapy, 53 of whom received bevacizumab-containing chemotherapy. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier and multivariate Cox proportional hazards regression analyses. RESULTS: The plasma VEGF levels and positive KRAS mutation status were not associated with the outcomes. However, high serum IL-6 levels were significantly associated with poorer OS and PFS in comparison to low serum IL-6 levels. A Cox proportional hazards regression analysis showed that high serum IL-6 levels were an independent risk factor for a poor outcome. CONCLUSION: In patients with metastatic CRC, high pretreatment serum IL-6 levels were associated with a poor outcome and bevacizumab resistance.

Robotic-assisted surgery for rectal adenocarcinoma: short-term and midterm outcomes from 200 consecutive cases at a single institution.

BACKGROUND: Although robotic surgery is increasingly used in the management of rectal cancer, its oncologic safety remains uncertain. OBJECTIVE: We aimed to evaluate the feasibility and safety of robotic-assisted rectal cancer resection in terms of short-term and midterm outcomes. DESIGN: A prospectively collected set of samples was retrospectively evaluated. SETTINGS: Data included in this study were collected at a single institution from 2007 to 2011. PATIENTS: The study included 200 consecutive rectal cancer patients. INTERVENTION: The patients underwent robotic-assisted resection surgery performed by a single surgeon. MAIN OUTCOME MEASURES: The short-term (surgical outcome and pathologic data) and midterm outcomes (local pelvic control and overall and disease-free survival) were evaluated and compared with those in the published literature. RESULTS: The median patient age was 60 years, and the male:female ratio was 2:1. The median distance of rectal tumors from the anal verge was 6 cm. Preoperative radiotherapy was performed in 55 patients. The median operation time was 270 minutes, and the median blood loss was 190 mL. Grade 3 to 5 complications, according to the Clavien-Dindo classification, were observed in 15 patients (7.5%). The circumferential resection margin was positive in 5 patients (2.5%). During the median follow-up period of 29.8 months, recurrence occurred in 27 patients (distant metastasis, 18 patients; local recurrence, 7 patients; and both local recurrence and distant metastases, 2 patients). The local pelvic control and overall and disease-free survival rates of stage III patients at 5 years were 93.0%, 88.6%, and 76.6%. LIMITATIONS: This was a retrospective, uncontrolled study of selected patients by a single surgeon. CONCLUSIONS: Our results demonstrated an acceptable morbidity and a low rate of positive circumferential resection margin with effective local control. We also achieved excellent survival data. The midterm oncologic safety justifies the practice of robotic rectal cancer resection to further investigate its role on long-term outcomes.

The multiphasic learning curve for robot-assisted rectal surgery.

BACKGROUND: Robotic rectal surgery is gaining in popularity. We aimed to define the learning curve of an experienced laparoscopic colorectal surgeon in performing robot-assisted rectal surgery. We hypothesized that there are multiple phases in this learning process. METHODS: We performed a retrospective analysis. Consecutive patients who underwent robot-assisted rectal surgery between July 2007 and August 2011 were identified. Operating times were analyzed using the CUSUM (cumulative sum) technique. CUSUMs were model fitted as a fourth-order polynomial. χ(2), Fisher's exact, two independent samples t test, one-way ANOVA, Kruskal-Wallis, and Mann-Whitney tests were used. A p value of <0.05 was considered statistically significant. RESULTS: We identified 197 patients. The median (range) total operative, robot, console, and docking times (min) were 265 (145-515), 140 (59-367), 135 (50-360), and 5 (3-40), respectively. CUSUM analysis of docking time showed a learning curve of 35 cases. CUSUM analysis of total operative, robot, and console times demonstrated three phases. The first phase (35 patients) represented the initial learning curve. The second phase (93 patients) involved more challenging cases with increased operative time. The third phase (69 patients) represented the concluding phase in the learning curve. There was increased complexity of cases in the latter two phases. Of phase 1 patients, 45.7% had tumors ≤7 cm from the anal verge compared to 64.2% in phases 2 and 3 (p = 0.042). Of phase 1 patients, 2.9% had neoadjuvant chemoradiotherapy compared to 32.7% of patients in phases 2 and 3 (p < 0.001). Splenic flexure was mobilized in 8.6% of phase 1 patients compared to 56.8% of patients in phases 2 and 3 (p < 0.001). Median blood loss was <50 ml in all three phases. The patients in phases 2 and 3 had a longer hospital stay compared to those in phase 1 (9 vs. 8 days, p = 0.002). There were no conversions. CONCLUSION: At least three phases in the learning curve for robot-assisted rectal surgery are defined in our study.

Carcinoembryonic antigen elevation in post-hepatectomy patients with colorectal cancer liver metastasis indicates recurrence with high accuracy.

BACKGROUND/AIMS: We aimed to retrospectively determine the accuracy of postoperative serum carcinoembryonic antigen (CEA) monitoring to detect or rule out recurrence in post-hepatectomy colorectal cancer patients by using a new statistical technique, likelihood ratio and post-test probability. METHODS: A total of 110 colorectal cancer patients who underwent curative hepatectomy were enrolled. A serum CEA assay and radiological examination were performed routinely for 5 years after surgery or until recurrence was detected. Yearly recurrence rates, sensitivities, specificities, and likelihood ratios were calculated. Post-test probabilities were calculated using these values. RESULTS: All episodes of recurrence occurred within 3 years after hepatectomy. The most frequent recurrence site was the liver, with a recurrence rate of 61.4% of all recurrence. The post-test probabilities of recurrence in post-hepatectomy colorectal cancer patients with positive and negative serum CEA were approximately 70-90% and 10%, respectively. CONCLUSIONS: CEA elevation in colorectal cancer patients who underwent curative resection indicated recurrence with high accuracy because of the high recurrence rate in the liver, in which CEA elevation is more frequent than in other recurrent sites. The elevation of CEA in post-hepatectomy patients necessitates frequent examination using imaging techniques to reveal undetected metastasis as soon as possible.

Curatively resected isolated inguinal lymph node metastasis from cecum cancer: report of a case.

We herein report the case of a curatively resected solitary inguinal lymph node metastasis from cecum cancer. Our patient was a 67-year-old male with cecum cancer with abdominal wall invasion. Three years after surgery, inguinal lymph node swelling was detected by a computed tomography examination. Further examination revealed no other metastases. Surgical resection was performed to remove the lesion, and microscopic examination revealed that cancer cells had metastasized. No recurrence was detected 3 years after the salvage surgery. Inguinal lymph node metastasis of cecum cancer has not been reported in the literature, but in our case salvage surgery resulted in a good outcome.

Establishment of a simple predictive scoring system for pancreatic fistula after laparoscopy-assisted gastrectomy.

BACKGROUND: The potential severity of postoperative pancreatic fistula (POPF) after laparoscopy-assisted gastrectomy (LAG) necessitates efforts to identify predictive factors for POPF. The aim of the present study was to identify predictive factors for POPF and to establish a predictive scoring system for POPF after LAG. PATIENTS AND METHODS: Between June 2004 and March 2011, 277 gastric cancer patients who underwent curative resection with LAG were enrolled. POPF was defined according to the International Study Group for Pancreatic Fistula grading system. Risk factors for POPF were evaluated using logistic regression analysis, and a scoring system for POPF was established. RESULTS: In the derivation cohort, multivariate analysis revealed the risk factors for POPF as patient age ≤70 years (5 points), amylase level of postoperative day 1 drainage fluid >454 IU/L(5 points), total number of retrieved lymph nodes >21 (5 points), body mass index >21.45 kg/m(2) (4 points), and operating time >337 min (2 points). In the validation cohort, at the cut-off point for high risk (score ≥15), the model had a negative predictive value of 94.5%, a positive predictive value of 57.4%, a sensitivity of 88.6%, and a specificity of 75.0% (C statistic = 0.857). CONCLUSION: This study demonstrated that POPF after LAG is associated with specific preoperative and postoperative factors. With a simple predictive scoring system, patients at high risk for POPF can be accurately identified. This simple predictive scoring system will be useful for many clinicians to assess the risk of POPF after LAG and start treating at-risk patients earlier.

Elevated Preoperative Serum Vascular Endothelial Growth Factor Does Not Predict Poor Outcomes in Curatively Resected Non-metastatic Colorectal Cancer Treated Without Neoadjuvant Therapy.

BACKGROUND/AIM: Vascular endothelial growth factor (VEGF) influences colorectal cancer (CRC) progression and is a key target in the treatment for metastatic CRC. However, the oncological impact of preoperative circulating VEGF in non-metastatic CRC (non-mCRC) has not been clearly elucidated. Herein, we have investigated the prognostic significance of elevated preoperative serum VEGF concentration in curatively resected non-mCRC without neoadjuvant therapy. PATIENTS AND METHODS: A total of 474 patients with pStage I-III CRC who underwent curative resection without neoadjuvant therapy were included. The relationship between preoperative serum VEGF concentration and clinicopathologic characteristics, overall survival (OS), and recurrence-free survival (RFS) were investigated. RESULTS: The median follow-up duration was 47.4 months. No significant relationship between preoperative VEGF and clinicopathologic characteristics including tumor markers, pStage, and lymphovascular invasion was identified; however, VEGF values were wide-ranged in every pStage. Patients were categorized into four groups as follows: VEGF < median, median to 75th percentile, 75th percentile to 90th percentile, and ≥90th percentile. A tendency for a difference in 5-year OS (p=0.064) and RFS (p=0.089) was observed among the groups; however, OS and RFS were not correlated with VEGF elevation. In multivariate analyses, VEGF ≥90th percentile was paradoxically associated with better RFS. CONCLUSION: Preoperative elevated serum VEGF concentration was associated with neither worse clinicopathological characteristics nor worse long-term outcomes in curatively resected non-mCRC. The prognostic value of preoperative circulating VEGF in initially resectable non-mCRC remains limited.

Transvaginal resection of a rectal gastrointestinal stromal tumor.

We herein report a case in which a rectal gastrointestinal stromal tumor (GIST) was resected transvaginally. The patient, a 45-year-old female, had a rectal GIST on the anterior wall of the lower rectum. The tumor was within 6 cm of the anal verge, a location which would normally require performing an ultra-low anterior resection using the Double Staple Technique, and a diverting stoma. To minimize the invasiveness of treatment and to reduce the postoperative morbidity, a transvaginal resection was performed. Under general anesthesia, the posterior vaginal mucosa was incised vertically. The tumor was then excised en bloc with the overlying rectovaginal septum and rectal mesenchymal tissue. The defect was repaired primarily, and a diverting stoma was not required. The procedure was uncomplicated, and the patient was discharged home with an intact anal sphincter function and no abdominal incisions. In female patients, transvaginal resection of low anterior rectal lesions may provide a minimally invasive alternative to the traditional ultra-low anterior resection.

PDGFRα+ Interstitial Cells are Effector Cells of PACAP Signaling in Mouse and Human Colon.

BACKGROUND & AIMS: Platelet-derived growth factor receptor α (PDGFRα)-positive interstitial cells (PIC) are interposed between enteric nerve fibers and smooth muscle cells (SMCs) in the tunica muscularis of the gastrointestinal tract. PIC have robust expression of small conductance Ca2+ activated K+ channels 3 (SK3 channels) and transduce inhibitory inputs from purinergic and sympathetic nerves in mouse and human colon. We investigated whether PIC also express pituitary adenylate cyclase-activating polypeptide (PACAP) receptors, PAC1 (PAC1R), and are involved in mediating inhibitory regulation of colonic contractions by PACAP in mouse and human colons. METHODS: Gene expression analysis, Ca2+ imaging, and contractile experiments were performed on mouse colonic muscles. Ca2+ imaging, intracellular electrical recordings, and contractile experiments were performed on human colonic muscles. RESULTS: Adcyap1r1 (encoding PAC1R) is highly expressed in mouse PIC. Interstitial cells of Cajal (ICC) and SMCs expressed far lower levels of Adcyap1r. Vipr1 and Vipr2 were expressed at low levels in PIC, ICC, and SMCs. PACAP elicited Ca2+ transients in mouse PIC and inhibited spontaneous phasic contractions via SK channels. In human colonic muscles, PAC1R agonists elicited Ca2+ transients in PIC, hyperpolarized SMCs through SK channels and inhibited spontaneous phasic contractions. CONCLUSIONS: PIC of mouse and human colon utilize PAC1R-SK channel signal pathway to inhibit colonic contractions in response to PACAP. Effects of PACAP are in addition to the previously described purinergic and sympathetic inputs to PIC. Thus, PIC integrate inhibitory inputs from at least 3 neurotransmitters and utilize several types of receptors to activate SK channels and regulate colonic contractile behaviors.

Chitinase 3-like 1 secreted from cancer-associated fibroblasts promotes tumor angiogenesis via interleukin-8 secretion in colorectal cancer.

The cancer­stromal interaction has been demonstrated to promote tumor progression, and cancer-associated fibroblasts (CAFs), which are the main components of stromal cells, have attracted attention as novel treatment targets. Chitinase 3-like 1 (CHI3L1) is a chitinase-like protein, which affects cell proliferation and angiogenesis. However, the mechanisms through which cells secrete CHI3L1 and through which CHI3L1 mediates tumor progression in the cancer microenvironment are still unclear. Accordingly, the present study assessed the secretion of CHI3L1 in the microenvironment of colorectal cancer and evaluated how CHI3L1 affects tumor angiogenesis. CAFs and normal fibroblasts (NFs) established from colorectal cancer tissue, and human colon cancer cell lines were evaluated using immunostaining, cytokine antibody array, RNA interference, reverse transcription-quantitative PCR (RT-qPCR), ELISA, western blotting and angiogenesis assays. The expression and secretion of CHI3L1 in CAFs were stronger than those in NFs and colorectal cancer cell lines. In addition, interleukin-13 receptor α2 (IL-13Rα2), a receptor for CHI3L1, was not expressed in colorectal cancer cell lines, but was expressed in fibroblasts, particularly CAFs. Furthermore, the expression and secretion of IL-8 in CAFs was stronger than that in NFs and cancer cell lines, and recombinant CHI3L1 addition increased IL-8 expression in CAFs, whereas knockdown of CHI3L1 suppressed IL-8 expression. Furthermore, IL-13Rα2 knockdown suppressed the enhancement of IL-8 expression induced by CHI3L1 treatment in CAFs. For vascular endothelial growth factor-A (VEGFA), similar results to IL-8 were observed in an ELISA for comparison of secretion between CAFs and NFs and for changes in secretion after CHI3L1 treatment in CAFs; however, no significant differences were observed for changes in expression after CHI3L1 treatment or IL-13Rα2 knockdown in CAFs assessed using RT-qPCR assays. Angiogenesis assays revealed that tube formation in vascular endothelial cells was suppressed by conditioned medium from CAFs with the addition of human CHI3L1 neutralizing antibodies compared with control IgG, and also suppressed by conditioned medium from CAFs transfected with CHI3L1, IL-8 or VEGFA small interfering RNA compared with negative control small interfering RNA. Overall, the present findings indicated that CHI3L1 secreted from CAFs acted on CAFs to increase the secretion of IL-8, thereby affecting tumor angiogenesis in colorectal cancer.

The clinical impact of robot-assisted laparoscopic rectal cancer surgery associated with robot-assisted radical prostatectomy.

INTRODUCTION: Robot-assisted laparoscopic surgery has been performed in various fields, especially in the pelvic cavity. However, little is known about the utility of robot-assisted laparoscopic rectal cancer surgery associated with robot-assisted radical prostatectomy (RARP). We herein report the clinical impact of robot-assisted laparoscopic rectal cancer surgery associated with RARP. METHODS: We experienced five cases of robot-assisted laparoscopic rectal cancer surgery associated with RARP. One involved robot-assisted laparoscopic abdominoperineal resection with en bloc prostatectomy for T4b rectal cancer, and one involved robot-assisted laparoscopic intersphincteric resection combined with RARP for synchronous rectal and prostate cancer. The remaining three involved robot-assisted laparoscopic low anterior resection (RaLAR) after RARP. For robot-assisted laparoscopic rectal cancer surgery, the da Vinci Xi surgical system was used. RESULTS: We could perform planned robotic rectal cancer surgery in all cases. The median operation time was 529 min (373-793 min), and the median blood loss was 307 ml (32-1191 ml). No patients required any transfusion in the intra-operative or immediate peri-operative period. The circumferential resection margin was negative in all cases. There were no complications of grade ≥III according to the Clavien-Dindo classification and no conversions to conventional laparoscopic or open surgery. CONCLUSION: Robot-assisted laparoscopic surgery associated with RARP is feasible in patients with rectal cancer. The long-term surgical outcomes remain to be further evaluated.

Cancer cell­induced tissue inhibitor of metalloproteinase­1 secretion by cancer­associated fibroblasts promotes cancer cell migration.

Cancer­associated fibroblasts (CAFs) are one of the major components of the cancer stroma in the tumor microenvironment. The interaction between cancer cells and CAFs (cancer­stromal interaction; CSI) promotes tumor progression, including metastasis. Recently, the tissue inhibitor of metalloproteinase­1 (TIMP­1) was reported to promote cancer cell migration and metastasis, which is contrary to its anticancer role as an inhibitor of matrix metalloproteinase. Moreover, CAF­derived TIMP­1 is reported to regulate CAF activity. In the present study, we investigated the effect of TIMP­1 on colon cancer cell migration in vitro. The TIMP­1 secretion levels from the CAFs and cancer cell lines were comparatively measured to determine the main source of TIMP­1. Furthermore, the effect of CSI on TIMP­1 secretion was investigated using the Transwell co­culture system. Cancer cell migration was evaluated using the wound­healing assay. The results demonstrated that TIMP­1 promoted the migration of LoVo cells, a colon cancer cell line, whereas TIMP­1 neutralization inhibited the enhanced migration. The TIMP­1 levels secreted from the cancer cells were approximately 10 times less than those secreted from the CAFs. TIMP­1 secretion was higher in CAFs co­cultured with cancer cells than in monocultured CAFs. Furthermore, the migration of LoVo cells increased upon co­culturing with the CAFs. TIMP­1 neutralization partially inhibited this enhanced migration. These results suggest that CAFs are the primary source of TIMP­1 and that the TIMP­1 production is enhanced through CSI in the tumor microenvironment, which promotes cancer cell migration.

The Interaction Between Cancer-associated Fibroblasts and Cancer Cells Enhances Bcl-xL and Mcl-1 in Colorectal Cancer.

BACKGROUND/AIM: The acquisition of resistance to apoptosis is one of the biggest problems in colorectal cancer (CRC) treatment. This study aimed to elucidate the mechanisms of resistance to apoptosis with a focus on interleukin (IL)-6 produced by the interaction between cancer cells and cancer-associated fibroblasts (CAFs). MATERIALS AND METHODS: DLD-1 and HCT116 cell lines were treated with IL-6 and furthermore co-cultured with CAFs. The expression levels of Bcl-xL, Mcl-1 and phosphorylation of STAT3 were evaluated by western blotting. We also performed immunostaining for CRC specimens and evaluated the correlation between CAFs invasion and Bcl-xL/Mcl-1 expression. RESULTS: Both IL-6 and co-culturing enhanced Bcl-xL, Mcl-1 and the phosphorylation of STAT3. Immunohistochemistry showed a positive correlation between CAFs and Bcl-xL/Mcl-1. These results showed that the interaction between CAFs and cancer cells enhances Bcl-xL and Mcl-1 through the IL-6/STAT3 signaling pathway. CONCLUSION: Our findings provide new potential therapeutic targets and strategies for CRC treatment.