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The aim of this study was to evaluate the feasibility and perioperative safety of high-pressure/high-dose pressurized intraperitoneal aerosol chemotherapy (HP/HD-PIPAC) to manage peritoneal surface malignancies (PSM).Retrospective analysis of a prospective database of about 130 consecutive patients scheduled for HP/HD-PIPACs for PSM. Doxorubicin plus cisplatin (PIPAC-C/D) or oxaliplatin (PIPAC-Ox) were nebulized into a constant capnoperitoneum of 20 mmHg at doses of 6, 30, or 120 mg/mThe median age of patients was 62 years (range 9-82), and the primary tumor site was of colorectal (CRC), upper gastrointestinal tract (UGI), unknown primary (CUP), malignant epithelioid mesothelioma of the peritoneum (MPM), hepato-pancreatic-biliary tract (HPB), and other origin in 30 (23.1%), 27 (20.8%), 16 (12.3%), 16 (12.3%), 6 (4.6%), and 35 (26.9%) patients, respectively. Abdominal access failed for a first, second, third, and fourth or more HP/HD-PIPAC in 12/130 (9.2%), 4/64 (6.3%), 6/40 (15.0%), and 2/33 (6.1%) patients. A total of 243 procedures were performed in 118 patients. No intraoperative complications related to increased capnoperitoneal pressure occurred, but an intraoperative bleeding complication was observed in 1/243 (0.4%) patients. The overall rate of postoperative procedure-related complications was 19.3% (47/243), while 15.3% (37/243), 1.6% (6/243), 1.6% (1/243), 0.4% (1/243), and 0.4% (1/243) were Grade I, II, III, IV, and V complications, respectively.Perioperative complications of HP/HD-PIPAC are comparable with standard pressure/dose PIPAC treatment protocols. Prospective studies are warranted to examine potential improvement in therapy outcomes.

A stoma exposes patients to several complications which could impair their quality of life (QoL). In the last decade, the market for stoma therapy in France has evolved, with a significant increase in the activities of home health providers, meeting a need for patient follow-up and companionship. International studies have demonstrated the impact of the stoma therapist (ST) follow-up on the improvement of an ostomy patient's QoL. However, the impact of home stoma nurse management has not been analysed. In this context we would like to assess the added value on health-related QoL from the enhanced follow-up of ostomy patients by STs.This is a randomized, controlled, open, national and multicentre trial (12 centres) which includes patients with an ostomy who benefit from either standard follow-up or from an enhanced and personalized follow-up with, in particular, regular consultations with an ST after discharge. The primary end-point is the 3-month QoL score obtained from the Stoma-QoL questionnaire. The secondary end-points are satisfaction of the care, comparison of QoL scores (Stoma-QoL and EuroQuol EQ-5D) and the economic gains by calculating the consumption of resources between the two arms. There will be a modified intention-to-treat analysis with 6-month follow-up in both study arms.The StomaCare trial will be the first randomized controlled study in France to evaluate the impact on QoL of an enhanced follow-up at home of ostomy patients by an ST.

International audience; Background: Identifying the 30% of adhesive small bowel obstructions (aSBO) for which conservative management will require surgery is essential. The association between the previously described radiological score and failure of the conservative management of aSBO remains to be confirmed in a large prospective multicentric cohort. Our aim was to assess the risk factors of failure of the conservative management of aSBO considering the radiological score.Material and methods: This prospective observational study took place in 15 French centers over 3 months. Consecutive patients experiencing aSBO with no early surgery were included. The six radiological features from the Angers radiological computed tomography (CT) score were noted (beak sign, closed loop, focal or diffuse intraperitoneal liquid, focal or diffuse mesenteric haziness, focal or diffuse mesenteric liquid, and diameter of the most dilated small bowel loop > 40 mm).Results: Two hundred and seventy nine patients with aSBO were screened. Sixty patients (21.5%) underwent early surgery, and 219 (78.5%) had primary conservative management. In the end, 218 patients were included in the analysis of the risk factors for conservative treatment failure. Among them, 162 (74.3%) had had successful management while for 56 (25.7%) management had failed. In multivariate analysis, a history of surgery was not a significant risk factor for the failure of conservative treatment (OR = 0.11; 95%CI = 0-1.23). A previous episode of aSBO was protective against the failure of conservative treatment (OR = 0.36; 95%CI = 0.15-0.85) and an Angers CT score ≥ 5 as the only individual risk factor (OR = 2.39; 95%CI = 1.01-5.69).Conclusion: The radiological score of aSBO is a promising tool in improving the management of aSBO patients. A first episode of aSBO and/or a radiological score ≥5 should lead physicians to consider early surgical management.

Amalysis of Akt/Stat3 signaling induction following LIF stimulation. We measured the induction of STAT3 (A) and Akt (B) phosphorylation by western blot in sNF96.2 after incubation with LIF recombinant protein. We confirmed the specificity of induction triggered by LIF using LIFR blocking antibody or AG490 inhibitor.

We have shown that the 16D10 antigen located on the mucin-like COOH-terminal domain of the feto-acinar pancreatic protein (FAPP) is expressed at the surface of human pancreatic tumor cell lines such as SOJ-6 cell line. Furthermore, an in vivo study indicates that targeting this cell-membrane glycopeptide by the use of the monoclonal antibody (mAb) 16D10 inhibits the growth of SOJ-6 xenografts in nude mice. To validate the potential use of the mAb16D10 in immune therapy, this study examined the expression of 16D10 antigens at the surface of human pancreatic adenocarcinomas versus control tissues. We examined the reactivity of mAb16D10 and mAb8H8 with pancreatic ductal adenocarcinomas (PDAC) compared with controls by using immunohistochemistry and confocal laser scanning microscopy. mAb8H8 does react with control or nontumoral human pancreatic tissues. mAb16D10 has a strong and specific reactivity with PDAC and does not react with other cancers of epithelia or normal tissues tested. Notable, mAb16D10 mostly recognizes membrane of tumoral cells. Furthermore, mAb8H8 and mAb16D10 recognized a protein of 110 to 120 kDa in homogenates of nontumoral and tumoral human pancreatic tissues, respectively. This size correlates with that of FAPP or with that of the normal counterpart of FAPP, the so-called bile salt-dependent lipase. The results suggest that mAb16D10 presents a unique specificity against PDAC; consequently, it could be effective in immune therapy of this cancer. Furthermore, mAb16D10 and mAb8H8 pair might be useful for diagnosis purpose in discriminating tumoral from nontumoral human pancreatic tissues. [Mol Cancer Ther 2009;8(2):282–91]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell–promoting factor LIF supports PDAC-associated neural remodeling (PANR). LIF was overexpressed in tumor tissue compared with healthy pancreas, but its receptors LIFR and gp130 were expressed only in intratumoral nerves. Cancer cells and stromal cells in PDAC tissues both expressed LIF, but only stromal cells could secrete it. Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling. LIF also induced neuronal plasticity in dorsal root ganglia neurons by increasing the number of neurites and the soma area. Notably, injection of LIF-blocking antibody into PDAC-bearing mice reduced intratumoral nerve density, supporting a critical role for LIF function in PANR. In serum from human PDAC patients and mouse models of PDAC, we found that LIF titers positively correlated with intratumoral nerve density. Taken together, our findings suggest LIF as a candidate serum biomarker and diagnostic tool and a possible therapeutic target for limiting the impact of PANR in PDAC pathophysiology and metastatic progression.Significance: This study suggests a target to limit neural remodeling in pancreatic cancer, which contributes to poorer quality of life and heightened metastatic progression in patients. Cancer Res; 78(4); 909–21. ©2017 AACR.

Supplementary Fig. S1 from Monoclonal antibody 16D10 to the COOH-terminal domain of the feto-acinar pancreatic protein targets pancreatic neoplastic tissues

Supplementary methods and Figure legends

ObjectiveTechnical ex-vivo comparison of commercial nebulizer nozzles used for Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).MethodsThe performance of four different commercial nebulizer nozzles (Nebulizer; HurriChem™; MCR-4 TOPOL®; QuattroJet) was analysed concerning: i) technical design and principle of operation, ii) operational pressure as function of the liquid flow rate, iii) droplet size distribution via laser diffraction spectrometry, iv) spray cone angle, spray cone form as well as horizontal drug deposition by image-metric analyses and v) chemical resistance via exposing to a cytostatic solution and chemical composition by means of spark optical emission spectral analysis.ResultsThe Nebulizer shows quasi an identical technical design and thus also a similar performance (e.g., mass median droplet size of 29 µm) as the original PIPAC nozzles (MIP/ CapnoPen). All other nozzles show more or less a performance deviation to the original PIPAC nozzles. The HurriChem™ has a similar design and principle of operation as the Nebulizer, but provides a finer aerosol (22 µm). The principle of operation of MCR-4 TOPOL®and QuattroJet differ significantly from that of the original PIPAC nozzle technology. The MCR-4 TOPOL®offers a hollow spray cone with significantly larger droplets (50 µm) than the original PIPAC nozzles. The QuattroJet generates an aerosol (22 µm) similar to that of the HurriChem™ but with improved spatial drug distribution.ConclusionThe availability of new PIPAC nozzles is encouraging but can also have a negative impact if their performance and efficacy is unknown. It is recommended that PIPAC nozzles that deviate from the current standard should be subject to bioequivalence testing and implementation in accordance with the IDEAL-D framework prior to routine clinical use.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is increasingly used to manage gastric cancer peritoneal metastasis (GCPM). This study analyzed a prospective database of GCPM patients treated with cisplatin and doxorubicin PIPAC (PIPAC-C/D). The outcome criteria were adverse events, pathologic response [peritoneal regression grading score (PRGS)], and overall survival (OS). The PIPAC-C/D procedure was scheduled for 144 patients with a median age of 57 years (range 22–88 years). Access to the abdominal cavity for the first PIPAC failed in 11 patients (7.7 %). A total of 296 procedures were performed for 131 patients. Of the 144 patients, 52 (36.1%) underwent one PIPAC, 32 (22.2%) underwent two PIPACs, 24 (16.7%) underwent three PIPACs, and 21 (14.6%) underwent four or more PIPACs. The overall morbidity/mortality was grade 1 for 22 patients (15.3%), grade 2 for 32 patients (22.2%), grade 3 for 7 patients (4.9%), grade 4 for no patients (0%), and grade 5 for 2 patients (1.4%). Of the 37 patients who had three or more PIPACs eligible for histopathologic response analysis, 27 (73%) had major or complete regression (PRGS 1/2). A median OS of 11 months (range 0–61 months) for the total study population and 16 months (range 2–61 months) for the patients with three or more PIPACs was observed. For 10 patients (7%) who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, the median OS was 15 months (minimum, 4 months; maximum, 27 months). Multivariate analysis showed three or more PIPACs to be an independent prognostic factor for improved OS (hazard ratio, 0.36; p

The optimal elective colectomy in patients with splenic flexure tumor is debated.This study aimed to compare splenic flexure colectomy, left hemicolectomy, and subtotal colectomy for perioperative, histological, and survival outcomes in this setting.This is a multicenter retrospective cohort study.Patients diagnosed with nonmetastatic splenic flexure tumor who underwent elective colectomy were included.Between 2006 and 2014, 313 consecutive patients were operated on in 15 French Research Group of Rectal Cancer Surgery centers.Propensity score weighting was performed to compare short- and long-term outcomes.The primary end point was disease-free survival. Secondary end points included overall survival, quality of surgical resection, overall postoperative morbidity, surgical postoperative morbidity, and rate of anastomotic leakage.The most performed surgery was splenic flexure colectomy (59%), followed by subtotal colectomy (23%) and left hemicolectomy (18%). Subtotal colectomy was more often performed by laparotomy compared with splenic flexure colectomy and left hemicolectomy (93% vs 61% vs 56%, p0.0001), and was associated with a longer operative time (260 minutes (120-460) vs 180 minutes (68-440) vs 217 minutes (149-480), p0.0001). Postoperative morbidity was similar between the 3 groups, but the median length of hospital stay was significantly longer after subtotal colectomy (13 days (5-56) vs 10 (4-175) vs 9 (4-55), p = 0.0007). The median number of harvested lymph nodes was significantly higher after subtotal colectomy compared with splenic flexure colectomy and left hemicolectomy (24 (8-90) vs 15 (1-81) vs 16 (3-52), p0.0001). The rate of stage III disease and the number of patients treated by adjuvant chemotherapy were similar between the 3 groups. There was no difference in terms of disease-free survival and overall survival between the 3 procedures.The study was limited by its retrospective design.In the elective setting, splenic flexure colectomy is safe and oncologically adequate for patients with nonmetastatic splenic flexure tumor. However, given the oncological clearance after splenic flexure colectomy, it seems that the debate is not completely closed. See Video Abstract at http://links.lww.com/DCR/B703.ANTECEDENTES:La colectomía electiva óptima en pacientes con tumores del ángulo esplénico continua en debate.OBJETIVO:Comparar la colectomía de ángulo esplénico, hemicolectomía izquierda y colectomía subtotal para los resultados perioperatorios, histológicos y de supervivencia en este escenario.DISEÑO:Estudio de cohorte retrospectivo multicéntrico.ESCENARIO:Se incluyeron pacientes diagnosticados de tumores del ángulo esplénico no metastásicos que se sometieron a colectomía electiva.PACIENTES:Entre 2006 y 2014, 313 pacientes consecutivos fueron intervenidos en 15 centros GRECCAR.INTERVENCIONES:Se realizó una ponderación del puntaje de propensión para comparar los resultados a corto y largo plazo.PRINCIPALES MEDIDAS DE RESULTADO:El criterio de valoración principal fue la supervivencia libre de enfermedad. Los criterios de valoración secundarios incluyeron la supervivencia general, la calidad de la resección quirúrgica, la morbilidad posoperatoria general, la morbilidad posoperatoria quirúrgica y la tasa de fuga anastomótica.RESULTADOS:La cirugía más realizada fue la colectomía del ángulo esplénico (59%), seguida de la colectomía subtotal (23%) y la hemicolectomía izquierda (18%). La colectomía subtotal se realizó con mayor frecuencia mediante laparotomía en comparación con la colectomía de ángulo esplénico y la hemicolectomía izquierda (93% frente a 61% frente a 56%, p0.0001), y se asoció con un tiempo quirúrgico más prolongado (260 min [120-460] frente a 180 min [68-440] frente a 217 min [149-480], p0.0001). La morbilidad posoperatoria fue similar entre los tres grupos, pero la duración media de la estancia hospitalaria fue significativamente más prolongada después de la colectomía subtotal (13 días [5-56] frente a 10 [4-175] frente a 9 [4-55], p = 0.0007). La mediana del número de ganglios linfáticos extraídos fue significativamente mayor después de la colectomía subtotal en comparación con la colectomía del ángulo esplénico y la hemicolectomía izquierda (24 [8-90] frente a 15 [1-81] frente a 16 [3-52], p0.0001). La tasa de enfermedad en estadio III y el número de pacientes tratados con quimioterapia adyuvante fueron similares entre los 3 grupos. No hubo diferencias en términos de supervivencia libre de enfermedad y supervivencia general entre los 3 procedimientos.LIMITACIONES:El estudio estuvo limitado por su diseño retrospectivo.CONCLUSIONES:En un escenario electivo, la colectomía del ángulo esplénico es segura y oncológicamente adecuada para pacientes con tumores del ángulo esplénico no metastásicos. Sin embargo, dado el aclaramiento oncológico tras la colectomía del ángulo esplénico, parece que el debate no está completamente cerrado. Consulte Video Resumen en http://links.lww.com/DCR/B703.

Colorectal cancer (CRC) is the second leading cause of death worldwide, with 0.9 million deaths per year. The metastatic stage of the disease is identified in about 20% of cases at the first diagnosis and is associated with low patient-survival rates. Voltage-gated sodium channels (Na

The benefit of neoadjuvant (chemo) radiotherapy for locally advanced upper rectal tumors remains controversial. Thus, we aimed to evaluate the outcome of patients with stage II or-III upper rectal cancer undergoing neoadjuvant (chemo) radiotherapy followed by total mesorectal excision in our institution.From April 2004 to October 2019, all patients with stage II or III upper rectal cancer treated with neoadjuvant (chemo) radiotherapy followed by total mesorectal excision were identified from our database. Overall survival, progression-free survival, and local recurrence were assessed using the Kaplan-Meier method. Acute and late treatment-related toxicities were recorded according to the CTCAE-5 version.The study group consisted of 106 patients. Respectively, 36% and 61% of patients had stage II and stage III upper rectal cancer. The median follow-up period was 4.4 ± 3.4 years. Five-year overall survival and progression-free survival were respectively 78% [95% confidence interval (CI)=69.2-88] and 76.8% (95%CI=68.4-86.2). The rate of local recurrence at 5 years was 3.78% (95%CI=0-7.98). Forty-two percent of patients presented early toxicities and 27.4% of patients experienced early surgical complications. Late toxicities and surgical complications occurred in 24.5% and 9.4% of patients, respectively.Neoadjuvant (chemo) radiotherapy followed by total mesorectal excision of stage II-III upper rectal cancer is effective and safe.

The benefit of repetitive PIPAC specifically in CPM patients has yet to be demonstrated in terms of oncological and functional outcomes. The aim of this study was to evaluate the outcome of patients with non-resectable colorectal peritoneal metastases (CPM) treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). We conducted an analysis of a prospective single-center database of all CPM patients who underwent PIPAC with oxaliplatin 92 mg/m2 body surface (PIPAC-Ox). The outcome criteria were adverse events (Common Terminology Criteria for Adverse Events version 4.0), Peritoneal Regression Grading Score (PRGS), and survival. Overall, 102 patients with a median age of 64 years (33–88) were scheduled for PIPAC-Ox. Access to the abdominal cavity for the first application failed in 22/102 (21.6%) patients. A total of 185 PIPACs were performed, with 26/102 (25.5%), 20/102 (19.6%), 17/102 (16.7%), and 17/102 (16.7%) patients undergoing one, two, three, and four or more PIPACs, respectively. Perioperative overall morbidity/mortality Grade I–V occurred in 14 (7.6%), 29 (15.8%), 6 (3.2%), 1 (0.5%), and 1 (0.5%) patient without significant differences between each cycle. Of 27 patients who underwent three or more PIPACs, 20/102 (19.6%) had major/complete CPM regression (PRGS 1–2). In a multivariate analysis, independent predictive factors for > 12 months’ survival following the first PIPAC-Ox administration were three or more PIPACs (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.35–15.2; p = 0.014) and younger patient age (OR 1.058, 95% CI 1.00–1.12; p = 0.039). Repetitive PIPAC-Ox for CPM patients, alone or combined with perioperative systemic chemotherapy, is feasible. Our data suggest that three or more consecutive PIPAC-Ox cycles for advanced CPM can improve survival.

Colorectal cancer (CRC) is associated with high mortality worldwide and new targets are needed to overcome treatment resistance. Recent evidences highlight a role of the mitochondria calcium homeostasis in the development of CRC. In this context, we aimed to evaluate the role of the mitochondrial sodium-calcium-lithium exchanger (NCLX) and its targeting in CRC. We also identified curcumin as a new potential inhibitor of NCLX.In vitro, curcumin exerted strong anti-tumoral activity through its action on NCLX with mtCa2+ and reactive oxygen species overload associated with a mitochondrial membrane depolarization, leading to reduced ATP production and apoptosis through mitochondrial permeability transition pore opening concomitant with G2/M cell cycle arrest. NCLX inhibition with either CGP37157 (a benzodiazepine derivative), small interfering RNA-mediated knock-down or knockout approaches reproduced the effects of curcumin. Altered mitochondrial respiration, cellular aerobic glycolysis and endoplasmic reticulum–mitochondria membrane perturbations participated in these mechanisms. In a xenograft mouse model, NCLX inhibitors decreased CRC tumor growth. Both transcriptomic analysis of The Cancer Genome Atlas dataset and immunohistochemical analysis of tissue microarrays from 381 patients with microsatellite instability (MSI)-driven CRC demonstrated that higher NCLX expression was associated with MSI status and for the first time NCLX expression was significantly associated with recurrence-free survival in MSI CRC patients.Our findings provide strong evidence that blocking NCLX inhibits CRC in vitro and in vivo. We highlight a novel anti-tumoral mechanism of curcumin through its action on NCLX and mitochondria calcium overload that could benefit for therapeutic treatment of patients with MSI CRC.

International audience; BackgroundBladder invasion by colon cancer is rare; however, its management is still controversial. Our objective was to report outcomes and identify risk factors for local recurrence in colon cancer with clinically suspected bladder invasion.MethodsWe conducted a retrospective study in 23 centers in France. All patients who underwent colon surgery with bladder resection (2010–2017) were included. Metastatic and recurrent colon cancers were excluded.ResultsOne hundred and seventeen patients (men = 73) were included. Partial cystectomy occurred in 108 patients (92.3%), with a total cystectomy occurring in 9 patients (7.7%). Neoadjuvant treatment was given to 31 patients (26.5%). Major morbidity was 20.5%. R0 resection rates were 87.2%. Histologically confirmed bladder invasion was present in 47%. Thirty-four patients were pN+, while 60 patients (51.3%) received adjuvant chemotherapy. Mean follow-up was 33.8 months. Three-year overall survival and disease-free survival were 82.9% and 59.5%. Rates of local recurrence and distant recurrence were 14.5% and 18.8%, respectively; the local recurrences (11/17; 65%) were in the bladder, while 4 of these patients had a bladder recurrence despite not having histologically confirmed bladder invasion at the index surgery. The rate of bladder recurrence after histologic bladder invasion was 13% (7/55), while the rate of bladder recurrence without primary bladder invasion was 7% (4/62) (P = .343). Neoadjuvant therapy, type of cystectomy, and adjuvant therapy did not influence local recurrence (P > .445 each). R1 bladder resections, when compared with a R0 bladder resections, were associated with an increased rate of local recurrence (63% vs 10%; P < .0001).ConclusionClinically suspected bladder invasion increases local recurrence even in the absence of histologically confirmed bladder invasion. Only complete resections with R0 margins decrease local recurrence. Careful, detailed postoperative surveillance is required, even without pathologic bladder invasion.

Neoadjuvant chemoradiation/radiation therapy in locally advanced (LA) upper rectal adenocarcinoma management remains unclear. The aim of this study was to compare outcomes between neoadjuvant chemoradiation therapy (CRT) and upfront surgery (US).A total of 127 patients were retrospectively included from 5 centers (79 treated with US and 48 with CRT). CRT and US groups were compared in terms of postoperative complications and long-term oncological and functional results.Total mesorectal excision (TME) was more frequent in CRT (58% vs. 20% in US, p0.001). CRT was associated with more overall and severe postoperative complications (60% vs. 30%, p0.001 and 17% vs. 1%, p=0.002, respectively), and was the only risk factor [OR=18.8 (2.2-160.2), p=0.007]. Five-year overall survival and 5-year recurrence-free survival were similar between CRT and US (96% vs. 91% p=0.256 and 85.4% vs. 85%, p=0.495). The functional results were similar between the two groups.CRT did not improve long-term oncological outcomes in patients with LA upper rectal adenocarcinoma, but increased postoperative complications compared with US.

Introduction This study aimed to externally evaluate the accuracy of four predictive scores for conversion to open surgery after rectal laparoscopic resection. None of the four scores achieved external validation previously. Methods This was a retrospective analysis of two prospectively maintained databases from two academic centers in France and Morocco. All consecutive patients who underwent laparoscopic resection for rectal adenocarcinoma between 2005 and 2020 were included. Logistic regression was used to assess the association between the factors present in the four scores and conversion. The accuracy of each score was assessed using the area under the curve (AUC). Observed and predicted conversion rates were compared for each score using the Chi-square goodness-of-fit test. Results Four hundred patients were included. There were 264 men (66%) with a mean age of 65.95 years (standard deviation 12.2). The median tumor height was 7 cm (quartiles 4–11) and 29% of patients had low rectal tumors. Conversion rate was 21.75%. The accuracy to predict conversion was low with an AUC lower than 0,62 for the four models. The observed conversion rates were significantly different from the predicted rates, except for one score. Conclusions The four models had low accuracy in predicting the conversion to open surgery for laparoscopic rectal resection. There is a need for new well-designed studies, analyzing more specific variables, in a multicentric design to ensure generalizability of the results for daily surgical practice.

Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC.All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence-free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS.A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98).In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC.

To determine the safety of performing an anastomosis after rectal cancer (RC) resection in patients with a previously treated prostate cancer (PC).Patients with a previously treated PC who underwent rectal resection from 2008 to 2018 were retrospectively included. Outcomes were compared between patients who underwent rectal resection with anastomosis (restorative surgery, RS+ group) and those with a definitive stoma (RS- group). In the RS+ group, anastomotic leak (AL) rates were assessed according to the type of reconstruction.A total of 126 patients underwent rectal surgery for mid-low RC after a previous PC treated by radiotherapy (RT) and/or radical prostatectomy. Overall, 80 patients (63%) underwent a RS and 46 patients (37%) underwent rectal surgery with a definitive stoma. There was no statistical difference between the two groups in terms of intraoperative data, except for the type of resection with more multivisceral resection in the RS- group (p 0.01). In the RS+group, a diverting stoma was performed in 74% of cases. No difference between the two groups in terms of overall morbidity was found. In the RS+group (n = 80), 17 patients (21%) experienced AL. Of these, none was observed when delayed coloanal anastomosis was performed (p = 0.16). Long-term permanent stoma in the RS+ group was 16% (n = 13).Restorative surgery after resection for RC in patients with a previous history of RT and/or radical prostatectomy for PC is safe without additional morbidity. In selected patients for restorative surgery, performing delayed coloanal anastomosis may represent a promising option.

Background Colorectal cancer is the third most common cancer in France and by the time of the diagnosis, 15–25% of patients will suffer from synchronous liver metastases. Surgery associated to neoadjuvant treatment can cure these patients, but few studies focus only on rectal cancer. This study was meant to compare the outcomes of patients who underwent a simultaneous resection to those who underwent a staged resection (rectum first or liver first) in the University Hospital of Tours, France. Methods We assessed retrospectively a prospective maintained data base about the clinical, pathological and survival outcomes of patients who underwent a simultaneous or a staged resection in our center between 2010 and 2018. A propensity score matching was used, considering the initial characteristics of our groups. Results There were 70 patients (55/15 males, female respectively) with median age 60 (54–68) years. After matching 48 (69%) of them underwent a staged approach and 22 (31%) a simultaneous approach were compared. After PSM, there were 22 patients in each group. No differences were found in terms of morbidity (p = 0.210), overall survival (p = 0.517) and disease-free survival (p = 0.691) at 3 years after matching. There were significantly less recurrences in the simultaneous group (50% vs 81.8%, p = 0.026). Conclusions Simultaneous resection of the rectal primary cancer and synchronous liver metastases is safe and feasible with no difference in terms of survival.

Background/aim To develop and validate a nebulizer device for anti-cancer research on pressurized intraperitoneal aerosol supply in a preclinical peritoneal metastases (PM) rat model. Material and methods For aerosol generation, an ultrasonic nebulizer (USN) was modified. Aerosol analyses were performed ex-vivo by laser diffraction spectrometry (LDS). Intraperitoneal (IP) 99mtechnetium sodium pertechnetate (99mTc) aerosol distribution and deposition were quantified by in-vivo single photon emission computed tomography (SPECT/CT) and compared to liquid IP instillation of equivalent volume/doses of 99mTc with and without capnoperitoneum. PM was induced by IP injection of HCT116-Luc2 human colon cancer cells in immunosuppressed RNU rats. Tumor growth was monitored by bioluminescence imaging (BLI), 18F-FDG positron emission tomography (PET) and tissues examination at necropsy. Results The USN was able to establish a stable and reproducible capnoperitoneum at a pressure of 8 to 10 mmHg. LDS showed that the USN provides a polydisperse and monomodal aerosol with a volume-weighted diameter of 2.6 μm. At a CO2 flow rate of 2 L/min with an IP residence time of 3.9 s, the highest drug deposition efficiency was found to be 15 wt.-%. In comparison to liquid instillation, nebulization showed the most homogeneous IP spatial drug deposition. Compared to BLI, 18F-FDG-PET was more sensitive to detect smaller PM nodules measuring only 1–2 mm in diameter. BLI, 18F-FDG PET and necropsy analyses showed relevant PM in all animals. Conclusions The USN together with the PM rat model are suitable for robust and species-specific preclinical pharmacological studies regarding intraperitoneal delivery of pressurized aerosolized drugs and cancer research.

Background Colorectal cancer is a major public concern, being the second deadliest cancer in the world. Whereas survival is high for localized forms, metastatic colorectal cancer has showed poor prognosis, with a 5-year survival barely surpassing 11%. Conventional chemotherapies against this disease proved their efficiency and remain essential in first-line treatment. However, the large number of authorized protocols complexifies treatment decision. In common practice, such decision is made on an empirical basis, by assessing benefits and risks for the patient. In other words, there is currently no efficient means of predicting the efficacy of any chemotherapy protocol for metastatic colorectal cancer. Methods/design The use of a chemosensitivity assay, the Oncogramme®, should help clinicians administer the best chemotherapy regimen to their patients. We hypothesize it would ultimately improve their survival. In this multicentred, prospective trial (ONCOGRAM), eligible patients with metastatic colorectal cancer are randomized to determine whether they will receive an Oncogramme®. For clinicians whose patients benefited from the assay (arm A), results are used as a decision support tool. Patients not undergoing the Oncogramme® procedure are treated according to current practice, without the assistance of the assay (arm B). Primary outcome is 1-year progression-free survival. Secondary outcomes include response rates, as well as 6-month and 1-year survival rates. Discussion This study aims at investigating the clinical utility of the Oncogramme® as a decision support tool for the treatment of patients with metastatic colorectal cancer. If the Oncogramme® positively influenced patient overall survival and/or progression-free survival, it would be of great value for clinicians to implement this assay within the current landscape of personalized medicine tools, which include genomics and biomarker assays. Trial registration ClinicalTrials.gov identifier NCT03133273. Registered on April 28, 2017.

International audience; Background/Aim: Preoperative radiochemotherapy (RCT) followed by total mesorectum excision has become the gold standard for locally advanced carcinoma of the low and middle rectum. The aim of the study is to evaluate the short and long-term outcomes of patients in complete pathological response (PR) following this treatment sequence. Patients and Methods: One hundred and thirty patients were retrospectively included between 2005 and 2017 in an expert centre, with 3 groups formed, according to the PR: i) complete PR (absence of tumour cells on the surgical specimen ypT0N0), ii) partial PR (T or N downsizing) and iii) without PR. Results: The complete PR rate was 13.1%. The complete PR group tended to develop less symptomatic fistulas compared to partial PR and without PR groups (5.8% versus 13.5% versus 18.7, respectively; p=0.607). The 5-year disease-free survival was increased for complete-PR patients (93% versus 79% versus 47%, respectively; p=0.0003) without an improvement in overall survival. Conclusion: Complete PR is associated with an improvement in survival without recurrence and without an improvement in the overall survival at 5 years.

Objective The present study analyzes nutrition support in a group of patients undergoing colorectal surgery managed by nutritional requirement software compared to a group of consecutive patients undergoing colorectal surgery with conventional nutrition Materials and Methods A total of 485 patients were treated between January 2000 and January 2013 with colorectal resection. Outcomes (mortality, morbidity according to Clavien classification, length of hospital stay, type of colorectal disease) in a group of patients who received nutrition support through software (SG) were compared to those in a previous series, control group (CG) with conventional nutrition support Results Of the patients, 59.6% were men and the median age of the population was 68.2 years (range, 19–95 years), with no difference between the 2 groups. There were significantly more malnourished patients in the SG group (SG 63.8% versus 45.2% CG; P < 0.0001). The overall mortality was 2.1% lower in the SG group, but without a significant difference (SG 0.7% versus 2.7% CG). There were more severe stage III to IV complications according to Clavien classification in the SG group (SG 10.7 GC versus 17% NS), with significantly greater collections (SG 8% versus 16.9% CG; P = 0.015) and greater anastomotic leaks (SG 4% versus 13.9% CG; P < 0.001). The median hospital stay was lower in the SG group (SG 12 days versus 15 days CG; P = 0.049). Conclusion The proposed software could contribute to optimizing the strategy of nutritional support in hospitalized patients.

Simple Summary Intraperitoneal chemotherapy (IPC) is a locoregional treatment option in patients with peritoneal metastases (PM). Small animal models are valuable research tools allowing for rapid, reproducible, and inexpensive study and optimization of different forms of IPC. Here, we present a mouse model of ovarian cancer-derived PM and demonstrate its suitability for various modes of IPC, including pressurized intraperitoneal chemotherapy (PIPAC) using a micro-nozzle for aerosolized drug delivery. Abstract Intraperitoneal chemotherapy (IPC) is a locoregional treatment option in patients with peritoneal metastases (PM). Here, we present an ovarian cancer (OC)-derived PM mouse model for the study of different forms of IPC. Xenograft cell proliferation (luciferase-transfected OVCAR3 and SKOV3 clones) and growth kinetics were assessed using PET scan, bioluminescence imaging (BLI), and histological tumor analysis. Liquid IPC was achieved by intraperitoneal injection with/without capnoperitoneum (6–7 mmHg). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was mimicked using an intratracheal drug aerosol administration system (micro-nozzle), which, as demonstrated by ex vivo granulometric analysis using laser diffraction spectrometry, produced a polydisperse, bimodal aerosol with a volume-weighted median diameter of (26.49 ± 2.76) µm. Distribution of Tc-99m-labeled doxorubicin in mice was characterized using SPECT and was dependent on the delivery mode and most homogeneous when the micro-nozzle was used. A total of 2 mg doxorubicin per kg body weight was determined to be the optimally effective and tolerable dose to achieve at least 50% tumor reduction. Repeated PIPAC (four times at seven-day-intervals) with doxorubicin in SKOV3-luc tumor-bearing mice resulted in halted tumor proliferation and tumor load reduced after the second round of PIPAC versus controls and the number of tumor nodules was significantly reduced (27.7 ± 9.5 vs. 57.3 ± 9.5; p = 0.0003). Thus, we established the first mouse model of OC PM for the study of IPC using a human xenograft with SKOV3 cells and an experimental IPC setup with a miniaturized nozzle. Repeated IPC was feasible and demonstrated time-dependent anti-tumor activity.

Intraperitoneal chemotherapy (IPC) is a locoregional treatment option in patients with peritoneal metastases (PM). Here, we present an ovarian cancer (OC)-derived PM mouse model for the study of different forms of IPC. Xenograft cell proliferation (luciferase-transfected OVCAR3 and SKOV3 clones) and growth kinetics were assessed using PET scan, bioluminescence imaging (BLI), and histological tumor analysis. Liquid IPC was achieved by intraperitoneal injection with/without capnoperitoneum (6–7 mmHg). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was mimicked using an intratracheal drug aerosol administration system (micro-nozzle), which, as demonstrated by ex vivo granulometric analysis using laser diffraction spectrometry, produced a polydisperse, bimodal aerosol with a volume-weighted median diameter of (26.49 ± 2.76) µm. Distribution of Tc-99m-labeled doxorubicin in mice was characterized using SPECT and was dependent on the delivery mode and most homogeneous when the micro-nozzle was used. A total of 2 mg doxorubicin per kg body weight was determined to be the optimally effective and tolerable dose to achieve at least 50% tumor reduction. Repeated PIPAC (four times at seven-day-intervals) with doxorubicin in SKOV3-luc tumor-bearing mice resulted in halted tumor proliferation and tumor load reduced after the second round of PIPAC versus controls and the number of tumor nodules was significantly reduced (27.7 ± 9.5 vs. 57.3 ± 9.5; p = 0.0003). Thus, we established the first mouse model of OC PM for the study of IPC using a human xenograft with SKOV3 cells and an experimental IPC setup with a miniaturized nozzle. Repeated IPC was feasible and demonstrated time-dependent anti-tumor activity.

The acquisition of invasive capacities by carcinoma cells, i.e. their ability to migrate through and to remodel extracellular matrices, is a determinant process leading to their dissemination and to the development of metastases. these cancer cell properties have often been associated with an increased Rho-ROCK signalling, and ROCK inhibitors have been proposed for anticancer therapies. In this study we used the selective ROCK inhibitor, Y-27632, to address the participation of the Rho-ROCK signalling pathway in the invasive properties of SW620 human colon cancer cells. Contrarily to initial assumptions, Y-27632 induced the acquisition of a pro-migratory cell phenotype and increased cancer cell invasiveness in both 3- and 2-dimensions assays. This effect was also obtained using the other ROCK inhibitor Fasudil as well as with knocking down the expression of ROCK-1 or ROCK-2, but was prevented by the inhibition of NaV1.5 voltage-gated sodium channel activity. Indeed, ROCK inhibition enhanced the activity of the pro-invasive NaV1.5 channel through a pathway that was independent of gene expression regulation. In conclusions, our evidence identifies voltage-gated sodium channels as new targets of the ROCK signalling pathway, as well as responsible for possible deleterious effects of the use of ROCK inhibitors in the treatment of cancers.

International audience; Background: Lymph node recurrences (LNR) from colorectal cancer (CRC) still represent a therapeutic challenge, as standardized recommendations have yet to be established. The aim of this study was to analyze short- and long-term oncological outcomes following resection of LNR from CRC.Methods: All patients with previously resected CRC who underwent histopathologically confirmed LNR resection in 3 tertiary referral centers between 2010 and 2017 were reviewed. Short- and long-term outcomes were analyzed, mainly recurrence-free and overall survival. Further recurrences following LNR resection were also analyzed.Results: Overall, 18 patients were included. Primary CRC was left-sided in 16 (89%) patients, staged T3-4 in 15 (83%), N+ in 14 (78%) and presented with synchronous metastases in 8 (43%). Median time interval between primary CRC and LNR resections was 31 months. Performed lymphadenectomies were aortocaval (n = 10), pelvic (n = 7), in hepatic pedicle (n = 3) and mesenteric (n = 1). Four patients had associated liver metastases resection. Three (17%) presented with postoperative complications, of which one Clavien-Dindo 3. Fourteen (78%) patients presented with further recurrences after a mean delay of 9 months, with 36% of patients presenting with early (

International audience; Exocrine pancreatic ductal adenocarcinoma, simply referred to as pancreatic cancer (PC) has the worst prognosis of any malignancy. Despite recent advances in the use of adjuvant chemotherapy in PC, the prognosis remains poor, with fewer than 8% of patients being alive at 5 years after diagnosis. The prevalence of PC has steadily increased over the past decades, and it is projected to become the second-leading cause of cancer-related death by 2030. In this context, optimizing and integrating supportive care is important to improve quality of life and survival. Venous thromboembolism (VTE) is a common but preventable complication in PC patients. VTE occurs in one out of five PC patients and is associated with significantly reduced progression-free survival and overall survival. The appropriate use of primary thromboprophylaxis can drastically and safely reduce the rates of VTE in PC patients as shown from subgroup analysis of non-PC targeted placebo-controlled randomized trials of cancer patients and from two dedicated controlled randomized trials in locally advanced PC patients receiving chemotherapy. Therefore, primary thromboprophylaxis with a Grade 1B evidence level is recommended in locally advanced PC patients receiving chemotherapy by the International Initiative on Cancer and Thrombosis clinical practice guidelines since 2013. However, its use and potential significant clinical benefit continues to be underrecognized worldwide. This narrative review aims to summarize the main recent advances in the field including on the use of individualized risk assessment models to stratify the risk of VTE in each patient with individual available treatment options.

Laparoscopy for colorectal cancer treatment is widely accepted. However, there is no consensus as to whether or not laparoscopy can be considered the preferred treatment strategy in octogenarian and nonagenarian patients with colon cancer. The aim of this study was to compare operative and postoperative outcomes of laparoscopic right colectomy between oldest-old (≥80 years) and younger (80 years) patients with colon cancer.The study population was sampled from the CLIMHET Study Group cohort. Between January 2005 and December 2015, data were retrieved for all patients who had undergone elective laparoscopic right colectomy for colon cancer in five University Hospital centers in France (CHU of Clermont-Ferrand, Hôpital Civil of Strasbourg-IRCAD, Hôpital Henri-Mondor of Créteil, Hôpital Européen Georges Pompidou of Paris, and CHRU of Tours).Overall, 473 cancer patients were selected and analyzed. There were 156 oldest-old patients (median age: 84.1 years, range: 80-96) and 317 younger patients (median age: 67 years, range: 25-79). After adjusting based on propensity score on gender, obesity, American Society of Anesthesiologists score, smoking, arteriopathy, coronaropathy, comorbidity, and American Joint Committee on Cancer staging, no significant difference was found in operative and postoperative outcomes, except for time to resume a regular diet (3.6 days versus 3.0 days, P = .008) and length of hospital stay (12.1 days versus 9.1 days, P = .03), which were longer for oldest-old patients. Overall and disease-free survival rates were also equivalent between groups.These findings support that laparoscopic right colectomy can be safely performed in cancer patients aged 80 and older, and its outcomes are similar in oldest-old and younger patients.

Postoperative ileus (POI) is associated with an elevated risk of other complications and increases the economic impact on healthcare services. The aim of this study was to identify pre-, intra- and postoperative risk factors associated with the development of POI following elective laparoscopic right colectomy. Between 2004 and 2016, 637 laparoscopic right colectomies were performed. Data were analysed retrospectively thanks to the CLIHMET database. Potential contributing factors were analysed by logistic regression. Patients with POI (n = 113, 17.7%) were compared to those without postoperative ileus (WPOI) (n = 524, 82.3%). In the POI group, there were more men (62 vs 49%; p = 0.012), more use of epidural anaesthesia (19 vs 9%; p = 0.004), more intraoperative blood transfusion requirements (7 vs 3%; p = 0.018) and greater perioperative intravenous fluid administration (2000 vs 1750 mL; p

Background About 25% of patients with acute diverticulitis require emergency intervention. Currently, most patients with diverticular peritonitis undergo a Hartmann's procedure. Our objective was to assess whether primary anastomosis (PA) with a diverting stoma results in lower mortality rates than Hartmann's procedure (HP) in patients with diverticular peritonitis. Study Design We conducted a multicenter randomized controlled trial conducted between June 2008 and May 2012: the DIVERTI (Primary vs Secondary Anastomosis for Hinchey Stage III-IV Diverticulitis) trial. Follow-up duration was up to 18 months. A random sample of 102 eligible participants with purulent or fecal diverticular peritonitis from tertiary care referral centers and associated centers in France were equally randomized to either a PA arm or to an HP arm. Data were analyzed on an intention-to-treat basis. The primary end point was mortality rate at 18 months. Secondary outcomes were postoperative complications, operative time, length of hospital stay, rate of definitive stoma, and morbidity. Results All 102 patients enrolled were comparable for age (p = 0.4453), sex (p = 0.2347), Hinchey stage III vs IV (p = 0.2347), and Mannheim Peritonitis Index (p = 0.0606). Overall mortality did not differ significantly between HP (7.7%) and PA (4%) (p = 0.4233). Morbidity for both resection and stoma reversal operations were comparable (39% in the HP arm vs 44% in the PA arm; p = 0.4233). At 18 months, 96% of PA patients and 65% of HP patients had a stoma reversal (p = 0.0001). Conclusions Although mortality was similar in both arms, the rate of stoma reversal was significantly higher in the PA arm. This trial provides additional evidence in favor of PA with diverting ileostomy over HP in patients with diverticular peritonitis. ClinicalTrials.gov Identifier: NCT 00692393.