Multicenter phase III randomized trial comparing laparoscopy and laparotomy for colon cancer surgery in patients older than 75 years: the CELL study, a Fédération de Recherche en Chirurgie (FRENCH) trial.

BACKGROUND: Several multicenter randomized controlled trials comparing laparoscopy and conventional open surgery for colon cancer have demonstrated that laparoscopic approach achieved the same oncological results while improving significantly early postoperative outcomes. These trials included few elderly patients, with a median age not exceeding 71 years. However, colon cancer is a disease of the elderly. More than 65% of patients operated on for colon cancer belong to this age group, and this proportion may become more pronounced in the coming years. In current practice, laparoscopy is underused in this population. METHODS: The CELL (Colectomy for cancer in the Elderly by Laparoscopy or Laparotomy) trial is a multicenter, open-label randomized, 2-arm phase III superiority trial. Patients aged 75 years or older with uncomplicated colonic adenocarcinoma or endoscopically unresectable colonic polyp will be randomized to either colectomy by laparoscopy or laparotomy. The primary endpoint of the study is overall postoperative morbidity, defined as any complication classification occurring up to 30 days after surgery. The secondary endpoints are: 30-day and 90-day postoperative mortality, 30-day readmission rate, quality of surgical resection, health-related quality of life and evolution of geriatric assessment. A 35 to 20% overall postoperative morbidity rate reduction is expected for patients operated on by laparoscopy compared with those who underwent surgery by laparotomy. With a two-sided α risk of 5% and a power of 80% (ß = 0.20), 276 patients will be required in total. DISCUSSION: To date, no dedicated randomized controlled trial has been conducted to evaluate morbidity after colon cancer surgery by laparoscopy or laparotomy in the elderly and the benefits of laparoscopy is still debated in this context. Thus, a prospective multicenter randomized trial evaluating postoperative outcomes specifically in elderly patients operated on for colon cancer by laparoscopy or laparotomy with curative intent is warranted. If significant, such a study might change the current surgical practices and allow a significant improvement in the surgical management of this population, which will be the vast majority of patients treated for colon cancer in the coming years. TRIAL REGISTRATION: ClinicalTrials.gov NCT03033719 (January 27, 2017).

Impact of Combination Chemotherapy in Peritoneal Mesothelioma Hyperthermic Intraperitoneal Chemotherapy (HIPEC): The RENAPE Study.

BACKGROUND: The introduction of cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) improved the prognosis of selected patients with peritoneal mesothelioma (PM). OBJECTIVE: The objective of our study was to evaluate whether different HIPEC agents were associated with different outcomes in patients with PM. METHODS: From the RENAPE database, we selected all patients with histology-proven PM who underwent CRS + HIPEC from 1989 to 2014. Inclusion criteria were age ≤ 80 years, performance status ≤ 2, and no extraperitoneal metastases. RESULTS: Overall, 249 patients underwent CRS + HIPEC for PM. The HIPEC regimen included five chemotherapeutic agents (CAs), consisting of cisplatin, doxorubicin, mitomycin-C, oxaliplatin, and irinotecan. When considering all CAs (alone or in combination), there was no significant statistical difference in regard to postoperative overall survival (OS). However, OS was better when using two CAs (group 2 drugs) versus one CA (group 1 drug) (p = 0.03). The different CA regimens were equally distributed between the two groups. This association between OS and HIPEC agent, as well as a trend for better progression-free survival, were both observed in the two-drug group versus the one-drug group (p = 0.009) for patients undergoing complete cytoreductive surgery (CC-0) with an epithelioid subtype. CONCLUSIONS: This large study seems to show improved OS when combined CAs, especially with platinum-based regimens, are used for HIPEC in patients with PM, but needs to be confirmed by a randomized controlled trial.

A feasibility study of the use of computed virtual chromoendoscopy for laparoscopic evaluation of peritoneal metastases.

BACKGROUND: Detection of an incipient peritoneal carcinomatosis (PC) is still challenging, and there is a crucial need for technological improvements in order to diagnose and to treat early this condition. Fujinon Intelligent Chromo Endoscopy (FICE) is a spectral image processing technology that enhances the contrast of the target tissue. The aim of this study is to investigate the usefulness of FICE system during peritoneal endoscopy and to establish the optimal FICE preset(s) for peritoneal exploration and PC detection. METHODS: A total of 561 images corresponding to 51 different areas of PC nodules and normal peritoneum were recorded during peritoneal endoscopies (For each area, one white light endoscopy (WLE) image and 10 FICE images). Three groups of 5 evaluators each: senior surgeons, surgical residents and medical students assessed these images. In a first questionnaire, the evaluators gave a score ranging from 1 to 10 to each image, and the three best FICE channels were determined. In a second questionnaire, five criteria were studied specifically: contrast, brightness, vascular architecture, differentiation between organs and detection of PC. The evaluators ranked the WLE and the three best FICE channel images according to these criteria. RESULTS: The three best FICE channels were channels 6, 2 and 9 with mean scores of 6.21 ± 1.59, 6.17 ± 1.48 and 6.06 ± 1.52, respectively. FICE Channel 2 was superior to WLE and other FICE channels, in terms of contrast (p < 10-4), visualization of vascular architecture (p < 10-4), differentiation between organs (p < 10-4) and detection of PC (p < 10-4); and ranked first in 38.8, 41.5, 31 and 46.9 % of the cases, respectively. CONCLUSION: FICE system provides adequate illumination of the abdominal cavity and a unique contrast that enhances the vascular architecture. FICE Channel 2 is the optimal channel for peritoneal exploration and could be a useful tool for the diagnosis of PC during peritoneal explorations.

Natural History of Pneumoperitoneum After Laparotomy: Findings on Multidetector-Row Computed Tomography.

BACKGROUND: Postoperative pneumoperitoneum after abdominal surgery represents a diagnostic challenge. This study was designed to analyze the appearance of pneumoperitoneum on computed tomography after uncomplicated abdominal surgery through laparotomy. METHODS: The database of the department of digestive surgery was retrospectively queried to identify all patients who underwent abdominal surgery through laparotomy during a 13-month period. This initial search retrieved a total of 384 consecutive patients. Criteria for inclusion in this study were: (a) the operation was performed in our institution, (b) the patient had computed tomography examination postoperatively, and (c) the patient had no postoperative grade ≥3 complication. RESULTS: Postoperative pneumoperitoneum was visible in 38/80 patients (47.5 %), with a mean volume of 15 ± 22.8 (SD) cm3 and multiple locations in 32/38 patients (84 %). Postoperative pneumoperitoneum was observed in 22/26 patients (85 %) until day 5 postoperative, 14/34 patients (41 %) between day 6 and day 15 postoperative, and in 2/21 patients (9.5 %) after day 15 postoperative. Its volume decreased when the time interval between surgery and computed tomography increased. Results of multivariate analysis showed that the time interval between surgery and computed tomography was the single independent variable that was associated with the presence of postoperative pneumoperitoneum. CONCLUSIONS: Postoperative pneumoperitoneum is a frequent finding on computed tomography in the early period following abdominal surgery and commonly with multiple locations. Although commonly observed before day 5 postoperative, its presence must be considered as an alarming finding after day 7 postoperative, if present in a single location with a volume >20 cm3.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis in the Elderly: A Case-Controlled, Multicenter Study.

OBJECTIVE: This study was designed to identify factors associated with morbidity and mortality in patients older than 70 years who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC). BACKGROUND: Major surgery is associated with higher morbidity and mortality in elderly patients. For PC, CRS and HIPEC is the only current potential curative therapy, but the risks inherent to this patient population have called its benefits into question. METHODS: We retrospectively analyzed a multi-center database from 1989 to 2015. All patients who underwent CRS and HIPEC for PC were selected and patients older than 70 years were matched 1:4 with a younger cohort according to cancer origin, peritoneal cancer index (PCI), and completeness of cytoreduction. Major morbidity and mortality were analyzed. RESULTS: Of 2328 patients, 188 patients older than aged 70 years were matched with 704 younger patients. Patients older than aged 70 years demonstrated a higher American Society of Anesthesiologist score (≥ASA III 10.8 vs. 6.6 %, p = 0.008). There was no difference in overall 90-day morbidity (≥70: 45.7 % vs. <70: 44.5 %; p = 0.171); however, patients older than 70 years had significantly more cardiovascular complications (13.8 vs. 9.2 %, p = 0.044). Differences between the older and younger cohorts failed to reach significance for 90-day mortality (5.4 and 2.7 %, respectively; p = 0.052), and failure-to-rescue (11.6 and 6.1 %, respectively; p = 0.078). In multivariate analysis, PCI > 7 (95 % CI 1.051-5.798, p = 0.038) and HIPEC duration (95 % CI 1.106-6.235, p = 0.028) were independent factors associated with morbidity in elderly patients. CONCLUSIONS: CRS and HIPEC appear feasible for selected patients older than aged 70 years, albeit with a higher risk of medical complications associated with increased mortality.

Single-incision flexible endoscopy (SIFE) for detection and staging of peritoneal carcinomatosis.

OBJECTIVE: To show the feasibility and the safety of peritoneal carcinomatosis (PC) evaluation by single-incision flexible endoscopy (SIFE) and to compare it to single-incision rigid endoscopy (SIRE). BACKGROUND: Direct peritoneal visualization, either by laparotomy or laparoscopy, continues to be the gold standard in diagnosing PC. We reported, in animal study, that combining single-incision laparoscopic surgery and flexible endoscopy improved evaluation of the peritoneal cavity in a live porcine model and in four human cadavers. METHODS: Patients, undergoing surgical exploration for diagnosis and staging of PC, were included in a prospective study. Using a superiority design a sample size of 47 patients was determined. Through a single incision, a standardized peritoneoscopy was conducted with rigid (SIRE) and with flexible endoscope (SIFE). Primary outcome was the access success rates for the 13 regions of the Peritoneal Carcinomatosis Index (PCI). RESULTS: Overall access to the 13 regions of PCI was successful in 83 % of the cases with SIRE and in 91.1 % with SIFE (p < 10(-10)). SIFE access rates were superior to SIREs' in the regions: R1 (87.2 vs. 61.7 %, p = 0.002), R2 (87.2 vs. 66 %, p = 0.004), R3 (85.1 vs. 59.6 %, p = 0.001) and R6 (80.9 vs. 61.7 %, p = 0.008). The mean PCI was higher (p < 10(4)) with SIFE 12.77 (±11.97) than with SIRE 11.77 (±11.63). CONCLUSION: This prospective, comparative study shows that SIFE was significantly superior to SIRE in the exploration of some difficult-to-access peritoneal areas, located in regions 1, 2, 3 and 6. These two minimally invasive staging procedures are safe, feasible and have to be seen as complementary rather than competing.

Insertion of a Stent in Obstructive Colon Cancer Can Induce a Metastatic Process in an Experimental Murine Model.

BACKGROUND: Colonic self-expanding metallic stents (SEMS) are used in obstructive colorectal cancer patients as a bridge to surgery. However, its oncologic safety remains uncertain. Therefore, we attempted to clarify this further with an experimental study and constructed a mouse model of colonic cancer. METHODS: CT26 cells were injected in the rectal wall, and to mimic SEMS, a cardiac stent was inserted under endoscopy in occlusive (75 % lumen occlusion) tumors. We set up a control group (n = 22) and a stent group (n = 16), and the findings were compared. We focused on serum lactate dehydrogenase (LDH) concentrations, circulating tumor cells, survival time, peritoneal carcinomatosis, liver metastases, and bioluminescence. RESULTS: One week after stent insertion, the serum LDH concentrations were significantly higher in the stent group (506 ± 203 IU/L) compared to the controls (229 ± 52 IU/L) (P = 0.005). The average survival time before sacrifice was significantly lower in the stent group (15.2 ± 1 days) compared to the controls (20 ± 5 days) (P = 0.005). The presence of a peritoneal carcinomatosis was more frequently observed in the stent group (75 %) than in the controls (50 %). Liver metastases were observed in 19 % of the stent group compared to the controls (4.5 %) (P = 0.29). After multivariate analysis, the stent group was still found to be associated with significantly lower survival time (P = 0.002). CONCLUSIONS: These observations led us to conclude that in our mouse model, SEMS resulted in an increased metastatic process and a shorter survival time. We suggest, therefore, that the utmost caution be exercised when opting for a stent as a bridge to surgery.

Enhanced recovery after surgery (ERAS) implementation in cytoreductive surgery (CRS) and hyperthermic IntraPEritoneal chemotherapy (HIPEC): Insights from Italian peritoneal surface malignancies expert centers.

BACKGROUND: Cytoreductive surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is a complex procedure that involves extensive peritoneal and visceral resections followed by intraperitoneal chemotherapy. The Enhanced Recovery After Surgery (ERAS) program aims to achieve faster recovery by maintaining pre-operative organ function and reducing the stress response following surgery. A recent publication introduced dedicated ERAS guidelines for CRS and HIPEC with the aim of extending the benefits to patients with peritoneal surface malignancies. METHODS: A survey was conducted among 21 Italian centers specializing in peritoneal surface malignancies (PSM) treatment to assess adherence to ERAS guidelines. The survey covered pre/intraoperative and postoperative ERAS items and explored attitudes towards ERAS implementation. RESULTS: All centers completed the survey, demonstrating expertise in PSM treatment. However, less than 30 % of centers adopted ERAS protocols despite being aware of dedicated guidelines. Preoperative optimization was common, with variations in bowel preparation methods and fasting periods. Intraoperative normothermia control was consistent, but fluid management practices varied. Postoperative practices, including routine abdominal drain placement and NGT management, varied greatly among centers. The majority of respondents expressed an intention to implement ERAS, citing concerns about feasibility and organizational challenges. CONCLUSIONS: The study concludes that Italian centers specialized in PSM treatment have limited adoption of ERAS protocols for CRS ± HIPEC, despite being aware of guidelines. The variability in practice highlights the need for standardized approaches and further evaluation of ERAS applicability in this complex surgical setting to optimize patient care.

Kallikrein-Related Peptidase 6 (KLK6) as a Contributor toward an Aggressive Cancer Cell Phenotype: A Potential Role in Colon Cancer Peritoneal Metastasis.

Kallikrein-related peptidases (KLKs) are implicated in many cancer-related processes. KLK6, one of the 15 KLK family members, is a promising biomarker for diagnosis of many cancers and has been associated with poor prognosis of colorectal cancer (CRC) patients. Herein, we evaluated the expression and cellular functions of KLK6 in colon cancer-derived cell lines and in clinical samples from CRC patients. We showed that, although many KLKs transcripts are upregulated in colon cancer-derived cell lines, KLK6, KLK10, and KLK11 are the most highly secreted proteins. KLK6 induced calcium flux in HT29 cells by activation and internalization of protease-activated receptor 2 (PAR2). Furthermore, KLK6 induced extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation. KLK6 suppression in HCT-116 colon cancer cells decreased the colony formation, increased cell adhesion to extracellular matrix proteins, and reduced spheroid formation and compaction. Immunohistochemistry (IHC) analysis demonstrated ectopic expression of KLK6 in human colon adenocarcinomas but not in normal epithelia. Importantly, high levels of KLK6 protein were detected in the ascites of CRC patients with peritoneal metastasis, but not in benign ascites. These data indicate that KLK6 overexpression is associated with aggressive CRC, and may be applied to differentiate between benign and malignant ascites.

Impact of laparoscopy on oncological outcomes after colectomy for stage III colon cancer: A post-hoc multivariate analysis from PETACC8 European randomized clinical trial.

BACKGROUND: In colon cancer (CC), surgery remains the mainstay of treatment with curative intent. Despite several clinical trials comparing open and laparoscopic approaches, data on long-term outcomes for stage III CC are lacking. METHODS: This post-hoc analysis of the European PETACC8 randomized phase 3 trial included patients from 340 sites between December 2005 and November 2009, with long follow-up (median 7.56 years). Patients were randomly assigned to FOLFOX or FOLFOX+cetuximab after colonic resection. The surgical approach was left to the referring surgeon's discretion. RESULTS: Among 2555 patients included, 1796 (70.29%) were operated on by open surgery and 759 (29.71%) by laparoscopy. The 5-year OS rate was better after laparoscopic resection (85.4%, 95%CI 82.5-87.7) than after open surgery (80.2%, 95%CI 78.2-82.0; p = 0.002). The 5-year DFS rate was also better after laparoscopy (p = 0.016). However, in multivariate analysis using a propensity matching, the surgical approach was not found to be an independent prognostic factor for OS or DFS. OS (p = 0.0243) and DFS (p = 0.035) were increased after laparoscopic surgery in KRAS/BRAF WT sub-group CONCLUSION: We showed that laparoscopic resection has comparable long-term outcomes to open surgery in patients with stage III CC. For those with RAS and BRAF WT CC, laparoscopic colectomy may favorably impact survival.

Bidirectional chemotherapy combining intraperitoneal docetaxel with intravenous 5-fluorouracil and oxaliplatin for patients with unresectable peritoneal metastasis from gastric cancer: the first study in Western countries.

BACKGROUND: A new treatment using bidirectional intraperitoneal (IP) and intravenous (IV) chemotherapy developed by Asiatic surgeons improves outcomes in patients with synchronous peritoneal metastasis (PM) from gastric cancer (GC). METHODS: We enrolled six consecutive patients with unresectable PM from GC who underwent bidirectional chemotherapy using IP docetaxel and IV FOLFOX or LV5FU2. In one course, IP docetaxel 30 mg/m2 was administrated on days 1, 8 and 15, and IV FOLFOX or LV5FU2 was administered on days 1 and 15, followed by 7 days of rest. Before and after a complete bidirectional cycle of three courses, the peritoneal cancer index (PCI) was evaluated by laparoscopy. The primary endpoint was to evaluate the feasibility and safety of bidirectional chemotherapy. Secondary endpoints were overall survival (OS), and the success of the therapeutic strategy was reflected by a decrease of 25% of the initial PCI. RESULTS: All patients completed one bidirectional cycle. The regimen was well tolerated. The median OS was 13 months [range 5-18], and the 1-year OS rate was 67%. After the first bidirectional cycle, the PCI decrease ≥25% of the initial value in four patients. A major histological response was observed in four patients. CONCLUSIONS: This is the first Western study and confirms the feasibility and safety of bidirectional treatment using IP and IV chemotherapy for patients with unresectable PM from GC, resulting in a 13-month median OS with limited morbidity. The decrease in PCI after one bidirectional cycle is promising.

Impact of preoperative chemotherapy on the histological response of patients with peritoneal metastases from colorectal cancer according to peritoneal regression grading score (PRGS) and TRG.

BACKGROUND: This study evaluated the histologic response after preoperative systemic therapy (pST) using the Peritoneal Regression Grading Score (PRGS) and tumor regression grade (TRG) classifications for patients with peritoneal metastases (PM) from colorectal cancer (CRC). METHODS: Twenty-three patients were selected from a prospective database of 196 patients who underwent CRS followed by HIPEC for synchronous PM from CRC. In all study patients, biopsies of the PM obtained before pST (during the first laparoscopy) and after pST (during cytoreductive surgery) were compared. RESULTS: Complete (PRGS 1), Major (PRGS 2), Minor (PRGS 3) and no histological responses (PRGS 4) were obtained in 17,5%, 52% and 13% and 17,5% of patients, respectively. Major (TRG 1-2), partial (TRG3), and no (TRG4-5) histological tumor regression were observed in 61%, 9% and 30% of patients, respectively. Regardless of the classification applied, median OS was significantly higher in patients with a "complete or major" response than in those with a "minor/partial or no" response (54 vs. 26 months, p < 0.05). CONCLUSIONS: The PRGS and TRG can be used in clinical practice to evaluate the histological response after pST. This study demonstrated that a complete histologic response of PM from CRC can be obtained after pST.

Evaluation of a new histological grading system for assessing the response to chemotherapy of peritoneal metastases from colorectal cancer: A mouse model study.

This experimental study evaluated the histological response of peritoneal metastases (PM) from colorectal cancer (CRC) after preoperative systemic chemotherapy (pCT). The results demonstrated that the Peritoneal Regression Grade Score could be used in medical practice. AIM: The aim was to evaluate the histological criteria used by the tumour regression grade (TRG) and Peritoneal Regression Grade Score (PRGS) for determining the response to chemotherapy (CT), in a mouse model of peritoneal metastases (PM) from colorectal cancer (CRC). METHODS: Twenty immunocompetent BALB/c mice were randomized into four groups at day (D) 10 after intraperitoneal (ip) injection with bioluminescent CRC tumour cells (CT26-luc). A histology before treatment group was obtained by sacrifice on D10; the other groups all received one of the following ip treatments over 15 days: 5% glucose (control, G5); 5-fluorouracil (5FU, 0.03 mg/g); or 5FU with oxaliplatin (Ox, 0.006 mg/g). The histological response (HR) was analysed by comparing the histology of PM before and after treatment, using both scores: TRG and PRGS. RESULTS: All mice showed limited PM as visualised by bioluminescence and confirmed at the time of sacrifice in the histology before treatment group. The mean peritoneal carcinomatosis index (PCI) was = 8 [6-10], The rate of complete HR was significantly higher in the Ox-5FU group (83.3%) than 5FU group (0%) and G5 group (0%) (p = 0.016). Fibrosis was present only in CT-treated groups (p = 0.05). PCI, ascites volume and haemorrhagic ascites were significantly higher in the G5 group than CT groups (p < 0.05). CONCLUSIONS: The TRG score can be used in practice when we want to compare the HR between the primary tumour and the PMs. The PRGS is a good measure of HR and is correlated with the efficacy of CT.

Post-operative wall shear stress in the superior mesenteric artery: Biomarker of long term outcome in patients with residual disease after incomplete cytoreductive surgery for pseudomyxoma peritonei.

BACKGROUND: After incomplete cytoreductive surgery (CRS), the assessment of pseudomyxoma peritonei (PMP) progression remains challenging. The objective was to assess the efficacy of wall shear stress (WSS) measured in superior mesenteric artery (SMA) to predict PMP progression in the postoperative setting to propose additional treatments. METHODS: In a prospective study, 52 patients with PMP had Doppler-ultrasound examination of the SMA with WSS calculation within one year after CRS with a mean follow-up of 43.3 ±â€¯18.3 months. Patients were categorized according to the completeness of CRS and clinical outcome: Group-1 (n = 19): complete CRS and no recurrence, group-2 (n = 20): incomplete CRS with slowly progressive disease (alive at 2 years without severe clinical symptoms), group-3 (n = 13): incomplete CRS and severe clinical symptoms or dead within two years. Results of WSS were compared between groups and to 24 healthy subjects. RESULTS: WSS measured in the SMA was superior in Group-3 (19.6 ±â€¯8.2 dynes/cm2) than in Group-2 (9.2 ±â€¯1.8 dynes/cm2, p = 1.10-6), Group-1 (10.4 ±â€¯2.8 dynes/cm2, p = 8.10-5), and healthy patients (8.7 ±â€¯2.8 dynes/cm2, p = 9.10-7). One year after surgery, among patients with incomplete CRS a cut-off value of 12.1dynes/cm2 allowed distinguishing patients without from those with severe disease progression with a sensitivity of 100% and a specificity of 100% (p < 1.10-4) AUC = 1.000 [95%CI: 0.897-1.000]. CONCLUSION: Post-operative assessment of the WSS in the SMA in patients with incomplete CRS for PMP should be considered as biomarker of tumor progression in the postoperative setting. Therefore, WSS could be useful to target patients needing adjuvant systemic chemotherapy one year after CRS.

The location of the primary colon cancer has no impact on outcomes in patients undergoing cytoreductive surgery for peritoneal metastasis.

BACKGROUND: The impact of the location of colorectal cancer on patient outcomes has been reported in several settings. The objective of this study was to assess the prognostic impact of the location of the primary colon cancer among patients with colorectal cancer peritoneal metastases undergoing complete cytoreductive surgery. METHODS: Using the prospectively maintained clinical and biological digestive peritoneal metastasis database of the BIG-RENAPE network, we identified 796 patients treated by a complete cytoreductive surgery between January 2004 and January 2017 for colorectal cancer peritoneal metastases in 16 different institutions. The 2 primary endpoints were overall survival and progression-free survival. To evaluate the impact on overall survival and progression-free survival of potential prognostic factors (including the location of the primary colorectal cancer), these factors were included in univariate and multivariate Cox proportional hazard models. RESULTS: Right-sided colorectal cancers were more often BRAF mutated and had microsatellite instability, whereas the frequency of RAS mutation was similar between right-sided and left-sided colorectal cancers. After a median follow-up time of 3.3 years, there was no significant difference in overall survival or progression-free survival according to tumor side. The lack of effect of tumor location on overall survival and progression-free survival was consistent across subgroups. CONCLUSION: Among patients undergoing complete cytoreductive surgery for peritoneal metastases, the site of the primary colorectal cancer was not associated with differences in progression-free survival or overall survival. Tumor side should not be used as a stratification factor in trials of colorectal cancer peritoneal metastases and should not be used in the selection process of patients for cytoreductive surgery.

Preoperative detection of malignant liver tumors: Comparison of 3D-T2-weighted sequences with T2-weighted turbo spin-echo and single shot T2 at 1.5 T.

PURPOSE: To assess the performances of three-dimensional (3D)-T2-weighted sequences compared to standard T2-weighted turbo spin echo (T2-TSE), T2-half-Fourier acquisition single-shot turbo spin-echo (T2-HASTE), diffusion weighted imaging (DWI) and 3D-T1-weighted VIBE sequences in the preoperative detection of malignant liver tumors. METHODS: From 2012 to 2015, all patients of our institution undergoing magnetic resonance imaging (MRI) examination for suspected malignant liver tumors were prospectively included. Patients had contrast-enhanced 3D-T1-weighted, DWI, 3D-T2-SPACE, T2-HASTE and T2-TSE sequences. Imaging findings were compared with those obtained at follow-up, surgery and histopathological analysis. Sensitivities for the detection of malignant liver tumors were compared for each sequence using McNemar test. A subgroup analysis was conducted for HCCs. Image artifacts were analyzed and compared using Wilcoxon paired signed rank-test. RESULTS: Thirty-three patients were included: 13 patients had 40 hepatocellular carcinomas (HCC) and 20 had 54 liver metastases. 3D-T2-weighted sequences had a higher sensitivity than T2-weighted TSE sequences for the detection of malignant liver tumors (79.8% versus 68.1%; P < 0.001). The difference did not reach significance for HCC. T1-weighted VIBE and DWI had a higher sensitivity than T2-weighted sequences. 3D-T2-weighted-SPACE sequences showed significantly less artifacts than T2-weitghted TSE. CONCLUSION: 3D-T2-weighted sequences show very promising performances for the detection of liver malignant tumors compared to T2-weighted TSE sequences.

The close relationship between heparanase and epithelial mesenchymal transition in gastric signet-ring cell adenocarcinoma.

Heparanase (HPSE), a heparan sulfate-specific endo-ß-D-glucuronidase, plays an important role in tumor cell metastasis through the degradation of extracellular matrix heparan sulfate proteoglycans. Suramin, a polysulfonated naphthylurea, is an inhibitor of HPSE with suramin analogues. Our objective was to analyze the HPSE involvement in gastric signet ring cell adenocarcinoma (SRCA) invasion. High expression of HPSE mRNA and protein was found in the tumor and in ascites of SRCA as well as in KATO-III cell line. Beside of collagen-I, growth factors (TGF-ß1 and VEGF-A, except FGF-2) and epithelial mesenchymal transition (EMT) markers (Snail, Slug, Vimentin, α-SMA and Fibronectin, except E-cadherin) were found higher in main nodules of SRCA as compared to peritumoral sites. Among MDR proteins, MDR-1 and LRP (lung resistance protein) were highly expressed in tumor cells. The formation of 3D cell spheroids was found to be correlated with their origin (adherent or non-adherent KATO-III). After treatment of KATO-III cells with a HPSE inhibitor (suramin), cell proliferation and EMT-related markers, besides collagen-1 expression, were down regulated. In conclusion, in SRCA, HPSE via an autocrine secretion is involved in acquisition of mesenchymal phenotype and tumor cell malignancy. Therefore, HPSE could be an interesting pharmacological target for the treatment of SRCA.

Hepatectomy increases metastatic graft and growth in an immunocompetent murine model of peritoneal metastases.

BACKGROUND: Curative surgery of synchronous peritoneal metastases (PM) and colorectal liver metastases (LM) has been recently investigated as feasible option. When synchronous peritoneal and liver resection is not achievable, the sequence of the surgery remains unknown. Our hypothesis was that liver resection (LR) promotes peritoneal growth resulting in a non-resectable PM. We sought to analyse the effects of major LR and liver regeneration after hepatectomy in a murine model of PM and the associated angiogenesis. METHODS: Murine model of colorectal PM in Balb/C mice was developed by intraperitoneal injection of different CT-26 tumour cell concentrations. Five days after the injection, mice were randomized into three groups: 68% hepatectomy group, sham laparotomy and control group without surgery. On post-operative days 1, 5 and 20, PM was evaluated macroscopically, tumour growth and liver regeneration by immunohistochemistry, and angiogenesis by immunofluorescence. Circulating progenitor cells, plasmatic cytokines and digestive arterial blood flow velocity measurements were also analysed. RESULTS: Reproducible murine model of limited colorectal PM was obtained. Surgery induced PM increases and promoted neo-angiogenesis. Major hepatectomy influence the tumour growth in the late phase after surgery, the extent of extra-peritoneal metastasis and the increase of Ki-67 expression in the remnant liver. CONCLUSIONS: This animal model confirms the pro-tumoural and pro-angiogenic role of surgery, laparotomy and major LR, which promotes the increase of angiogenic factors and their participation in PM growth. These results suggest that peritoneal resection should be first step in the case of two-step liver and peritoneal surgery for patients with colorectal PM and LM.