Suprapubic versus transurethral catheterization for bladder drainage in male rectal cancer surgery (GRECCAR10), a randomized clinical trial.

BACKGROUND: Bladder drainage is systematically used in rectal cancer surgery; however, the optimal type of drainage, transurethral catheterization (TUC) or suprapubic catheterization (SPC), is still controversial. The aim was to compare the rates of urinary tract infection on the fourth postoperative day (POD4) between TUC and SPC, after rectal cancer surgery regardless of the day of removal of the urinary drain. METHODS: This randomized clinical trial in 19 expert colorectal surgery centers in France and Belgium was performed between October 2016 and October 2019 and included 240 men (with normal or subnormal voiding function) undergoing mesorectal excision with low anastomosis for rectal cancer. Patients were followed at postoperative days 4, 30, and 180. RESULTS: In 208 patients (median age 66 years [IQR 58-71]) randomized to TUC (n = 99) or SPC (n = 109), the rate of urinary infection at POD4 was not significantly different whatever the type of drainage (11/99 (11.1%) vs. 8/109 (7.3%), 95% CI, - 4.2% to 11.7%; p = 0.35). There was significantly more pyuria in the TUC group (79/99 (79.0%) vs. (60/109 (60.9%), 95% CI, 5.7-30.0%; p = 0.004). No difference in bacteriuria was observed between the groups. Patients in the TUC group had a shorter duration of catheterization (median 4 [2-5] vs. 4 [3-5] days; p = 0.002). Drainage complications were more frequent in the SPC group at all followup visits. CONCLUSIONS: TUC should be preferred over SPC in male patients undergoing surgery for mid and/or lower rectal cancers, owing to the lower rate of complications and shorter duration of catheterization. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02922647.

Prognosis of poorly cohesive gastric cancer after complete cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (CYTO-CHIP study).

BACKGROUND: The incidence of gastric poorly cohesive carcinoma (PCC) is increasing. The prognosis for patients with peritoneal metastases remains poor and the role of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is controversial. The aim was to clarify the impact of gastric PCC with peritoneal metastases treated by CRS with or without HIPEC. METHODS: All patients with peritoneal metastases from gastric cancer treated with CRS with or without HIPEC, in 19 French centres, between 1989 and 2014, were identified from institutional databases. Clinicopathological characteristics and outcomes were compared between PCC and non-PCC subtypes, and the possible benefit of HIPEC was assessed. RESULTS: In total, 277 patients were included (188 PCC, 89 non-PCC). HIPEC was performed in 180 of 277 patients (65 per cent), including 124 of 188 with PCC (66 per cent). Median overall survival (OS) was 14.7 (95 per cent c.i. 12.7 to 17.3) months in the PCC group versus 21.2 (14.7 to 36.4) months in the non-PCC group (P < 0.001). In multivariable analyses, PCC (hazard ratio (HR) 1.51, 95 per cent c.i. 1.01 to 2.25; P = 0.044) was associated with poorer OS, as were pN3, Peritoneal Cancer Index (PCI), and resection with a completeness of cytoreduction score of 1, whereas HIPEC was associated with improved OS (HR 0.52; P < 0.001). The benefit of CRS-HIPEC over CRS alone was consistent, irrespective of histology, with a median OS of 16.7 versus 11.3 months (HR 0.60, 0.39 to 0.92; P = 0.018) in the PCC group, and 34.5 versus 14.3 months (HR 0.43, 0.25 to 0.75; P = 0.003) in the non-PCC group. Non-PCC and HIPEC were independently associated with improved recurrence-free survival and fewer peritoneal recurrences. In patients who underwent HIPEC, PCI values of below 7 and less than 13 were predictive of OS in PCC and non-PCC populations respectively. CONCLUSION: In selected patients, CRS-HIPEC offers acceptable outcomes among those with gastric PCC and long survival for patients without PCC.

Prospective Assessment of First-Year Quality of Life After Pelvic Exenteration for Gynecologic Malignancy: A French Multicentric Study.

BACKGROUND: Pelvic exenteration remains one of the most mutilating procedures, with important postoperative morbidity, an altered body image, and long-term physical and psychosocial concerns. This study aimed to assess quality of life (QOL) during the first year after pelvic exenteration for gynecologic malignancy performed with curative intent. METHODS: A French multicentric prospective study was performed by including patients who underwent pelvic exenteration. Quality of life by measurement of functional and symptom scales was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (version 3.0) and the EORTC QLQ-OV28 questionnaires before surgery, at baseline, and 1, 3, 6, and 12 months after the procedure. RESULTS: The study enrolled 97 patients. Quality of life including physical, personal, fatigue, and anorexia reported in the QLQ-C30 was significantly reduced 1 month postoperatively and improved at least to baseline level 1 year after the procedure. Body image also was significantly reduced 1 month postoperatively. Global health, emotional, dyspnea, and anorexia items were significantly improved 1 year after surgery compared with baseline values. Unlike younger patients, elderly patients did not regain physical and social activities after pelvic exenteration. CONCLUSIONS: Therapeutic decision on performing a pelvic exenteration can have a severe and permanent impact on all aspects of patients' QOL. Deterioration of QOL was most significant during the first 3 months after surgery. Elderly patients were the only group of patients with permanent decreased physical and social function. Preoperative evaluation and postoperative follow-up evaluation should include health-related QOL instruments, counseling by a multidisciplinary team to cover all aspects concerning stoma care, sexual function, and long-term concerns after surgery.

Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial.

BACKGROUND: For patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5-fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting. PATIENTS AND METHODS: OLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m(2), folinic acid 400 mg/m(2), 5-fluorouracil 400 mg/m(2) (bolus) then 2400 mg/m(2) (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m(2), irinotecan 165 mg/m(2), folinic acid 200 mg/m(2), 5-fluorouracil 3200 mg/m(2) (46-h infusion)] every 2 weeks. Unresectability was defined as ≥1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis. RESULTS: In patients assigned to bevacizumab-FOLFOXIRI (n = 41) or bevacizumab-mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI -11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab-FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab-mFOLFOX-6. Median progression-free survival (PFS) was 18·6 (95% CI 12.9-22.3) months and 11·5 (95% CI 9.6-13.6) months, respectively. The most common grade 3-5 adverse events were neutropenia (bevacizumab-FOLFOXIRI, 50%; bevacizumab-mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively). CONCLUSIONS: Bevacizumab-FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab-mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab-FOLFOXIRI. CLINICALTRIALSGOV: NCT00778102.

Associating portal embolization and artery ligation to induce rapid liver regeneration in staged hepatectomy.

BACKGROUND: Insufficient volume of the future liver remnant (FLR) is a major cause of unresectability in patients with bilobar colorectal liver metastases (CLM). The objective of this study was to evaluate the safety and efficacy of the novel associating portal embolization and artery ligation (APEAL) technique before extended right hepatectomy during a two-stage procedure for CLM. METHODS: All patients who had undergone extended right hepatectomy during two-stage surgery for CLM between 2012 and 2014 were identified retrospectively from a prospectively maintained database. In the first stage, right portal vein embolization, partial right hepatic artery ligation and devascularization of segment IVb along the round ligament without parenchymal transection were associated with clearance of the FLR and/or primary tumour resection. Liver volumetry was performed using OsiriX software on postoperative day (POD) 7 and 30. RESULTS: Ten patients underwent the APEAL procedure. During the first stage, APEAL was combined with colorectal resection in seven patients. The median (range) interval between the two stages was 45 (31-71) days. The FLR volume increased from 327 (214-537) cm(3) before surgery to 590 (508-1072) cm(3) on POD 7 and 701 (512-1018) cm(3) on POD 30. This corresponded to a FLR regeneration rate of 104 (42-185) and 134 (53-171) per cent respectively. There were no deaths. The overall morbidity rate was 60 per cent (6 of 10) after each procedure, with severe morbidity occurring in two and three of ten patients after the first and second procedures respectively. CONCLUSION: APEAL induces fast, safe, reproducible and effective FLR growth when an extended right hepatectomy is scheduled in patients with multiple bilobar CLM.

Assisted hepatic resection using a toroidal HIFU device: an in vivo comparative study in pig.

PURPOSE: Bleeding is the main cause of postoperative complications during hepatic surgery. Blood loss and transfusions increase tumor recurrence in liver metastases from colorectal cancer. A high intensity focused ultrasound (HIFU) device with an integrated ultrasound imaging probe was developed for the treatment of colorectal liver metastasis. METHODS: The HIFU toroidal-shaped transducer contains 256 elements (working frequency: 3 MHz) and can create a single conical lesion of 7 cm3 in 40 s. Then, the volume of treatment can be significantly increased by juxtaposing single lesions. Presented here is the use of this device in an animal model as a complementary tool to improve surgical resection in the liver. Before transecting the liver, a wall of coagulative necrosis was performed using this device in order to minimize blood loss and dissection time during hepatectomy. Resection assisted by HIFU was compared to classical dissections with clamping [intermittent Pringle maneuver (IPM) group] and without clamping (control group). For each technique, 14 partial liver resections were performed in seven pigs. Blood loss per dissection surface area and resection time were the main outcome parameters. RESULTS: Conserving liver blood inflow during hepatic resection assisted by HIFU did not increase total blood loss (7.4 +/- 3.3 ml cm(-2)) compared to hepatic resection performed during IPM and controlled blood inflow (11.2 +/- 2.2 ml cm(-2)). Lower blood loss was measured on average when using HIFU, even though difference with clamping (IPM) was not statistically significant (p = 0.09). Resection assisted by HIFU reduced blood loss by 50% compared to control group (14.0 +/- 3.4 ml cm(-2), p = 0.03). The duration of transection when using HIFU (13 +/- 3 min) was significantly lower compared to clamping (23 +/- 4 min, p < 0.01) and control (18 +/- 3 min, p = 0.02). Precoagulation also resulted in sealing blood vessels with a diameter of less than 5 mm, and therefore the number of clips needed in the HIFU group was significantly lower (0.8 +/- 0.2 cm(-2)) when compared to clamping (1.6 +/- 0.2 cm(-2), p < 0.01) and control (1.8 +/- 0.4 cm(-2), p < 0.01). CONCLUSIONS: This method holds promise for future clinical applications in resection of liver metastases.

Early and late morbidity of local excision after chemoradiotherapy for rectal cancer.

BACKGROUND: Local excision (LE) after chemoradiotherapy is a new option in low rectal cancer, but morbidity has never been compared prospectively with total mesorectal excision (TME). Early and late morbidity were compared in patients treated either by LE or TME after neoadjuvant chemoradiotherapy for rectal cancer. METHOD: This was a post-hoc analysis from a randomized trial. Patients with clinical T2/T3 low rectal cancer with good response to the chemoradiotherapy and having either LE, LE with eventual completion TME, or TME were considered. Early (1 month) and late (2 years) morbidities were compared between the three groups. RESULTS: There were no deaths following surgery in any of the three groups. Early surgical morbidity (20 per cent LE versus 36 per cent TME versus 43 per cent completion TME, P = 0.025) and late surgical morbidity (4 per cent versus 33 per cent versus 57 per cent, P < 0.001) were significantly lower in the LE group than in the TME or the completion TME group. of LE, was associated with the lowest rate of early (10 versus 18 versus 21 per cent, P = 0.217) and late medical morbidities (0 versus 7 versus 7 per cent, P = 0.154), although this did not represent a significant difference between the groups. The severity of overall morbidity was significantly lower at 2 years after LE compared with TME or completion TME (4 versus 28 versus 43 per cent grade 3-5, P < 0.001). CONCLUSION: The rate of surgical complications after neoadjuvant chemoradiotherapy in the LE group was half that of TME group at 1 month and 10 times lower at 2 years. LE is a safe approach for organ preservation and should be considered as an alternative to watch-and-wait in complete clinical responders and to TME in subcomplete responders.

Immune checkpoint inhibitor treatment of a first cancer is associated with a decreased incidence of second primary cancer.

BACKGROUND: Second primary cancers (SPCs) are diagnosed in over 5% of patients after a first primary cancer (FPC). We explore here the impact of immune checkpoint inhibitors (ICIs) given for an FPC on the risk of SPC in different age groups, cancer types and treatments. PATIENTS AND METHODS: The files of the 46 829 patients diagnosed with an FPC in the Centre Léon Bérard from 2013 to 2018 were analyzed. Structured data were extracted and electronic patient records were screened using a natural language processing tool, with validation using manual screening of 2818 files of patients. Univariate and multivariate analyses of the incidence of SPC according to patient characteristics and treatment were conducted. RESULTS: Among the 46 829 patients, 1830 (3.9%) had a diagnosis of SPC with a median interval of 11.1 months (range 0-78 months); 18 128 (38.7%) received cytotoxic chemotherapy (CC) and 1163 (2.5%) received ICIs for the treatment of the FPC in this period. SPCs were observed in 7/1163 (0.6%) patients who had received ICIs for their FPC versus 437/16 997 (2.6%) patients receiving CC and no ICIs for the FPC versus 1386/28 669 (4.8%) for patients receiving neither CC nor ICIs for the FPC. This reduction was observed at all ages and for all histotypes analyzed. Treatment with ICIs and/or CC for the FPC are associated with a reduced risk of SPC in multivariate analysis. CONCLUSION: Immunotherapy with ICIs alone and in combination with CC was found to be associated with a reduced incidence of SPC for all ages and cancer types.

Multicentre validation of a clinical prognostic score integrating the systemic inflammatory response to the host for patients treated with curative-intent for colorectal liver metastases: The Liverpool score.

BACKGROUND: This study aimed to create a new prognostic score integrating the systemic inflammatory response to predict survival in patients treated with curative intent for colorectal liver metastases (CLM). METHODS: We identified independent prognostic factors in patients who underwent liver surgery for CLM in a tertiary centre in the United Kingdom (UK) between 2010 and 2015. A pre- and a postoperative score (Liverpool score) were created by combining these factors to stratify patients into different risk groups. These new scores were validated in an international cohort of 219 patients from China and France. RESULTS: Multivariate cox regression analysis of the 364 patients of the UK cohort identified 6 preoperative and 1 postoperative prognostic factors for overall survival (OS): American society of anaesthesiologists (ASA) score, location and node status of the primary tumour, number and size of CLM, neutrophil-to-lymphocyte ratio (NLR) and resection margin. Both pre- and postoperative scores can be calculated with an online calculator at https://jscalc.io/calc/PXatrmjfrEFpYy2t. Using the pre-operative model on the UK cohort, median OS was 61.22 (50.23, not reached) months in the low-risk group (n = 162) and 30.36 (23.68, 35.95) months in the high-risk group (n = 162, p < 0.0001). The same difference was observed in the validation cohort. The Liverpool score outperformed previously published scoring system with a c-index of 0.619 pre-operatively and of 0.637 post-operatively. CONCLUSION: We developed a new prognostic score based on clinicopathologic characteristics including the site of the primary tumour location and on measurement of the systemic inflammatory response which could help to tailor patients' management.

Contrast-enhanced intra-operative ultrasound as a clinical decision making tool during surgery for colorectal liver metastases: The ULIIS study.

BACKGROUND: Detecting more colorectal liver metastases (CRLMs) during surgery may help optimise strategy and improve outcomes. Our objective was to determine clinical utility (CU) of contrast-enhanced intra-operative ultrasound (CE-IOUS) using sulphur hexafluoride microbubbles during CRLM surgery. METHOD: A prospective phase II trial performed at two comprehensive cancer research centres. Patients operated for CRLMs were eligible and assessable if intra-operative ultrasound (IOUS) and CE-IOUS had been performed and pathological results were available and/or 3-month imaging. CU was defined as the justified change in planned surgical strategy or procedure using CE-IOUS. RESULTS: Out of the 68 patients enrolled, 54 were eligible and assessable. 43 patients underwent pre-operative chemotherapy. The median number of CRLMs was 2 (range, 1-11). Pre-operative staging was performed using MRI. IOUS allowed identification of 45 new CRLMs in 13 (24.7%) patients. Compared to IOUS, CE-IOUS allowed identification of 10 additional CRLMs in 9 (16.7%) patients. Surgery was altered and justified in 4 patients only, leading to a CU rate of 7.70% (95 CI, [3.2, 18.6]). No missing CRLMs were identified by CE-IOUS. CONCLUSIONS: Although the primary endpoint was not met for one protocol violation, secondary endpoints indicate that CE-IOUS has an intermediate added-value for surgeons treating CRLMs. TRIAL REGISTRATION: NCT01880554 (https://clinicaltrials.gov/).

European Society of Surgical Oncology's strategy for clinical research: Paving the way for a culture of research in cancer surgery.

As part of its mission to promote the best surgical care for cancer patients, the European Society of Surgical Oncology (ESSO) has been developing multiple programmes for clinical research along with its educational portfolio. This position paper describes the different research activities of the Society over the past decade and an action plan for the upcoming five years to lead innovative and high quality surgical oncology research. ESSO proposes to consider pragmatic research methodologies as a complement to randomised clinical trials (RCT), advocates for increased funding and operational support in conducting research and aims to enable young surgeons to be active in research and establish partnerships for translational research activities.

Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases.

PURPOSE: To assess the rate of R(0) resection of liver metastases achieved after chemotherapy with FOLFIRINOX. PATIENTS AND METHODS: Patients with histologically proven primary colorectal cancer and bidimensionally measurable liver metastasis, not fully resectable based on technical inability to achieve R(0) resection, but potentially resectable after tumor reduction, were given FOLFIRINOX: oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), bolus fluorouracil 400 mg/m(2) and fluorouracil 46-h continuous IV infusion 2,400 mg/m(2), every 2 weeks for a maximum of 12 cycles. RESULTS: Thirty-four patients were enrolled. Response rate before surgery was 70.6% (95%CI: 52.5-84.9). Twenty-eight patients (82.4%) underwent hepatic resection and nine achieved R(0) resection [26.5% (95% CI: 12.9-44.4%)]. The rate of clinical complete remission after surgery was 79.4%. Two-year overall survival was 83%. The most frequent grade 3 or 4 toxicities were neutropenia (64.8%), diarrhea (29.4%), fatigue (23.5%), abdominal cramps (14.7%), neuropathy and nausea (11.8% each), and AST/ALT elevation (14.7/11.8%). Only one patient experienced febrile neutropenia, four patients withdrew due to toxicity and no toxic death was observed. CONCLUSION: FOLFIRINOX, with an acceptable toxicity profile, shows a high response rate in liver metastases from colorectal cancer. The rate of hepatic resection in patients initially not resectable, is attractive and warrants further assessment of this regimen in randomized studies compared to standard regimens.

[Pseudo-Meigs syndrome: particular management of ovarian metastases in colorectal cancer]. / Le pseudosyndrome de Meigs, particularité dans la prise en charge des métastases ovariennes de cancer colorectal.

Ascites and/or pleural effusion with ovarian metastases in colorectal cancer are usually related to peritoneal carcinomatosis. Pseudo-Meigs syndrome is a characterized by non-malignant ascites and/or pleural effusion caused by pelvic tumors other than solid benign ovarian tumors. We treated two patients who developed this syndrome in a context of colorectal cancer. After ovarian metastasis resection, ascites and pleural diffusion disappeared. In the presence of acellular ascites with ovarian metastases from colorectal cancer, diagnosis of pseudo-Meigs syndrome may allow surgical treatment with curative intent.

Alu RNA accumulation induces epithelial-to-mesenchymal transition by modulating miR-566 and is associated with cancer progression.

Alu sequences are the most abundant short interspersed repeated elements in the human genome. Here we show that in a cell culture model of colorectal cancer (CRC) progression, we observe accumulation of Alu RNA that is associated with reduced DICER1 levels. Alu RNA induces epithelial-to-mesenchymal transition (EMT) by acting as a molecular sponge of miR-566. Moreover, Alu RNA accumulates as consequence of DICER1 deficit in colorectal, ovarian, renal and breast cancer cell lines. Interestingly, Alu RNA knockdown prevents DICER1 depletion-induced EMT despite global microRNA (miRNA) downregulation. Alu RNA expression is also induced by transforming growth factor-ß1, a major driver of EMT. Corroborating this data, we found that non-coding Alu RNA significantly correlates with tumor progression in human CRC patients. Together, these findings reveal an unexpected DICER1-dependent, miRNA-independent role of Alu RNA in cancer progression that could bring mobile element transcripts in the fields of cancer therapeutic and prognosis.

[A tumour-mimic pig liver model for guiding focused ultrasound thermal ablation]. / Modèle de pseudotumeur pour guider l'ablation thermique par ultrasons focalisés: étude sur le porc.

There is no established liver tumour model in pigs to study the efficacy of ablative treatment options available for the treatment of liver tumours by physical agents. A tumour-mimic model visible with high contrast on sonograms and on gross pathology has been studied at mid-term on 20 pigs. The aim was to determine if these tumour-mimics are well tolerated and can be used to validate the use of thermal therapies at a preclinical stage. The dimensions of the tumour-mimics measured on sonograms were reproducible (diameter: 9.6 +/- 1.9 mm) and correlated with those performed in gross pathology (R(2)=0.73). The accuracy of focused ultrasound thermal therapy can be evaluated preclinically using these tumour-mimics.