Discovery of Pancreatic Cancer Biomarkers Using Non-Destructive OMICS Technology

Le cancer du pancréas est la quatrième cause de décès lié au cancer dans les pays occidentaux. Si la résection chirurgicale complète est le seul traitement curatif, moins de 30% des patients reséqués sont vivants à 5 ans. Le cancer du pancréas est souvent découvert à un stade avancé en termes d’extension et de retentissement pour le patient sans option thérapeutique curative. Ce constat est en partie lié à l’absence de biomarqueur sensible et spécifique permettant un diagnostic précoce de l’adénocarcinome du pancréas. Compte tenu des progrès de la technologie OMICS, plusieurs études ont identifié des biomarqueurs solubles (sanguins, urinaires, salivaires) via la spectrométrie de masse avec des résultants décevant en pratique clinique. Ces études ont concerné des échantillons tumoraux issus de pièces opératoires ou de biopsie de tumeur localement avancées ou métastatiques, non représentatifs du cancer du pancréas au stade précoce. L’analyse des tumeurs de tout stade impose l’accès aux échantillons issus de biopsie pancréatique lors du diagnostic qui demeurent indisponibles pour les chercheurs en raison d’une faible quantité de matériel et de son caractère précieux sur le plan clinique.Le Dr Turtoi a récemment co-développé une nouvelle méthode, conservatrice de l’échantillon sanitaire, nommée EXPEL, consistant en un rinçage sous pression d’un échantillon unique obtenu par biopsie fine, permettant au décours, un examen anatomopathologique standard et l’extraction des protéines, métabolites, ARN et ADN.En pratique clinique, la plupart des patients présentant une lésion suspecte du pancréas ont une écho-endoscopie avec biopsie fine à l’aiguille + aspiration. Le contenu de l’aiguille est ensuite rincé dans une solution de conservation nommée Preservcyt®. Apres extraction des biopsies/cellules du patient, ce liquide de conservation est systématiquement jeté.Mon travail de thèse a consisté, dans un premier, en l’étude PanEXPEL1, incluant 58 patients. Dans ce travail nous avons montré que ce Preservcyt® est riche en protéines ce qui nous a permis d’isoler une signature diagnostique de 19 protéines avec une sensibilité et une spécificité de 0.917 et 0.853 respectivement. Sa valeur prédictive positive du cancer du pancréas était de 100% chez les patients de plus de 54 ans.Dans un second temps, j’ai mis pu obtenir un financement et mettre en place l’étude clinico-biologique prospective PanEXPEL2 qui inclura 200 patients présentant une lésion suspecte du pancréas requérant une écho-endoscopie/biopsie avec analyse protéomique du Preservcyt® ainsi qu’une collection sérique appariée.Les perspectives de cette approche sont la mise en place de tests diagnostiques ou d’évaluation de la réponse à la chimiothérapie tout comme le développement de nouvelles thérapies (thérapies ciblées, immunothérapie).Pancreatic cancer is the 4th cause of cancer-related death in Western countries. While complete surgical resection is the only curative treatment, less than 30% of resected patients are alive at 5 years. Pancreatic cancer is often diagnosed at an advanced stage without any curative therapeutic option. This finding is linked to the absence of sensitive and specific biomarkers allowing early diagnosis of pancreatic cancer. Given the progress of OMICS technology, several studies have identified soluble biomarkers (blood, urine, saliva) via mass spectrometry, however none have been translated into clinical practice. These studies investigated tumor samples from surgical specimens or from locally advanced or metastatic tumor biopsies, not representative of early-stage pancreatic cancer. Analysis of tumors of early stage requires access to pancreatic biopsy specimens destined for diagnosis, which remain unavailable for research due to the small amount of tissue and its clinically valuable nature.Dr Turtoi (IRCM, Montpellier) recently co-developed a new method, conservative of the sanitary sample, called EXPEL, consisting of rinsing under pressure of a single sample obtained by fine needle biopsy, allowing in the course of a standard pathological examination and the extraction of proteins, metabolites, RNA and DNA.In clinical practice, most patients with a suspicious lesion of the pancreas have endoscopic ultrasound with fine needle/biopsy. This needle content is then rinsed in a preservative solution called Preservcyt®. After extraction of the patient's biopsies / cells, this conservation fluid is systematically discarded.My thesis work was in a first step, via the PanEXPEL1 study including 58 patients, to demonstrate that this Preservcyt® is rich in proteins and made it possible to isolate a diagnostic signature of 19 proteins with sensitivity and a specificity of 0.917 and 0.853 respectively. Its positive predictive value for pancreatic cancer was 100% in patients over 54 years of age.As a second step, I set up the prospective clinico-biological study PanEXPEL2 that will include more than 200 patients with a suspicious pancreatic lesion requiring endoscopic ultrasound/biopsy with proteomic analysis of Preservcyt® and matched serum collection.The perspectives for this approach are the development of diagnostic tests or evaluation of the response to chemotherapy as well as the development of targeted therapy (immunotherapy)

Cholangiocarinome interhépatique (étude bicentrique de 125 resections hépatiques à visée curative dans les CHU de Strasbourg et Montpellier)

Introduction Le cholangiocarcinome intrahépatique (CCI), dont l'incidence est en augmentation en occident, représente 6 % des cancers primitifs du foie. La chirurgie est le seul traitement à visée curative à ce jour avec une survie de l'ordre de 20 à 30 % à cinq ans. L'objectif principal de cette étude bicentrique était d'analyser les survies globale et sans récidive après traitement chirurgical pour cholangiocarcinome intrahépatique et d'en analyser les variables pronostiques. L'objectif secondaire était d'analyser la prise en charge des récidives après exérèse pour CCI. Méthodes et patients Les données clinico-pathologiques ainsi que les données relatives à la survie des patients qui ont été opérés d'un cholangiocarcinome intrahépatique dans les centres de Strasbourg et Montpellier, de décembre 1997 à décembre 2012, ont été recueillies de façon prospective et rétrospectivement analysées. Les variables clinico-pathologiques susceptibles d'influencer la probabilité de survie ont été étudiées par analyses uni- et multivariée. Résultats Dans cette étude, 125 patients ont été inclus (65H60F). L'âge médian était de 67 ans (28-80). Une hépatectomie majeure a été réalisée pour 70% des patients. La résection était élargie à la convergence biliaire, aux vaisseaux ou étendue aux organes voisins dans 21, 10 et 2,5% des cas respectivement. Des nodules satellites étaient présents pour 30% des patients. Une résection R0 a été effectuée dans la majorité des cas (90%). Un envahissement ganglionnaire était présent chez 33 malades ayant bénéficié d'un curage (n=88). Le foie non-tumoral était cirrhotique dans seulement 12% des cas. Les taux de morbi-mortalité postopératoire étaient respectivement de 34 et 5% et étaient influencés par la présence d'une résection biliaire, vasculaire ou étendue aux organes de voisinage (p 37U/L et une taille tumorale > 100 mm étaient facteurs de mauvais pronostic (p 100 mm a été identifiée comme facteur indépendant de récidive. La possibilité d'une ré intervention chirurgicale était significativement associée à une augmentation de la survie après récidive (p<0,05). Conclusion Une résection chirurgicale agressive à visée curative a permis d'obtenir des taux de survie globale et sans récidive relativement satisfaisant, comparables à ceux obtenus dans la littérature. Si les récidives locorégionales sont extrêmement fréquentes, une surveillance armée pour dépister les récidives et sélectionner les patients pouvant bénéficier d'une prise en charge chirurgicale est primordiale afin d'optimiser la survie globaleMONTPELLIER-BU Médecine UPM (341722108) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

How can I manage anaesthesia in obese patients?

International audienceThe obese patient is at risk of perioperative complications including difficult airway access (intubation, difficult or impossible ventilation), and postextubation acute respiratory failure due to the formation of atelectases or to airway obstruction. The association of obstructive sleep apnoea syndrome (OSA) with obesity is very common, and induces a high risk of per and postoperative complications. Preoperative OSA screening is crucial in the obese patient, as well as its specific management: use of continuous positive pre-, per- and postoperative pressure. For any obese patient, the implementation of difficult intubation protocols and the use of protective ventilation (low tidal volume 6–8 mL/kg of ideal body weight, moderate positive end-expiratory pressure of 10 cmH20, recruitment manoeuvres in absence of contra-indications), with morphine sparing and semi-seated positioning as much as possible are recommended, associated with a close postoperative monitoring. The dosage of anaesthetic drugs is usually based on the ideal body weight or the adjusted body weight and then titrated, except for succinylcholine that is dosed according to the total body weight. Monitoring of neuromuscular blockers should be used where appropriate, as well as monitoring of the depth of anaesthesia, especially when total intravenous anaesthesia is used in association with neuromuscular blockers. The occurrence of intraoperative awareness is indeed more frequent in the obese patient than in the non-obese patient. Appropriate prophylaxis against venous thromboembolism and early mobilisation are recommended, if possible included in an early rehabilitation protocol, to further reduce postoperative complications

Detection of soluble biomarkers of pancreatic cancer in endoscopic ultrasoundguided fine-needle aspiration samples

International audienceBackground: Biomarkers are urgently needed for pancreatic ductal adenocarcinoma (PDAC). Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the cornerstone for diagnosing PDAC. We developed a method for discovery of PDAC biomarkers using the discarded EUS-FNA liquid.Methods: This retrospective study included 58 patients with suspected pancreatic lesions who underwent EUS-FNA. Protein extracts from EUS-FNA liquid were analyzed by mass spectrometry. Proteomic and clinical data were modeled by supervised statistical learning to identify protein markers and clinical variables that distinguish PDAC.Results: Statistical modeling revealed a protein signature for PDAC screening that achieved high sensitivity and specificity (0.92, 95 % confidence interval [CI] 0.79-0.98, and 0.85, 95 %CI 0.67-0.93, respectively). We also developed a protein signature score (PSS) to guide PDAC diagnosis. In combination with patient age, the PSS achieved 100 % certainty in correctly identifying PDAC patients > 54 years. In addition, 3 /4 inconclusive EUS-FNA biopsies were correctly identified using PSS.Conclusions: EUS-FNA-derived fluid is a rich source of PDAC proteins with biomarker potential. The PSS requires further validation and verification of the feasibility of measuring these proteins in patient sera

Does Fungal Biliary Contamination after Preoperative Biliary Drainage Increase Postoperative Complications after Pancreaticoduodenectomy?

International audienceBackground: preoperative biliary drainage before pancreaticoduodenectomy (PD) is associated with bacterial biliary contamination (>85%) and a significant increase in global and infectious complications. In view of the lack of published data, the aim of our study was to investigate the impact of fungal biliary contamination after biliary drainage on the complication rate after PD.Methods: a multicentric retrospective study that included 224 patients who underwent PD after biliary drainage with intraoperative biliary culture.Results: the global rate of positive intraoperative biliary sample was 92%. Respectively, the global rate of biliary bacterial contamination and the rate of fungal contamination were 75% and 25%, making it possible to identify two subgroups: bacterial contamination only (B+, n = 154), and bacterial and fungal contamination (BF+, n = 52). An extended duration of preoperative drainage (62 vs. 49 days; p = 0.08) increased the risk of fungal contamination. The overall and infectious complication rates were not different between the two groups. In the event of postoperative infectious or surgical complications, the infectious samples taken did not reveal more fungal infections in the BF+ group.Conclusions: fungal biliary contamination, although frequent, does not seem to increase the rate of global and infectious complications after PD, preceded by preoperative biliary drainage

Chromosomal Aberrations Associated with Sequential Steps of the Metastatic Cascade in Colorectal Cancer Patients

International audienceBACKGROUND:Genomic information can help to identify colorectal tumors with high and low metastatic potential, thereby improving prediction of benefit of local and/or systemic treatment. Here we investigated chromosomal aberrations in relation to the different stages of the metastatic cascade: dissemination of tumor cells into the mesenteric vein, metastatic outgrowth in the liver, intravasation of the peripheral blood circulation, and development of further distant metastasis.METHODS:Peripheral and mesenteric blood from colorectal cancer patients (n = 72) were investigated for circulating tumor cells, and DNA extracted from their primary tumors was subjected to array comparative genomic hybridization profiling. The results were validated with an independent set of primary colorectal tumors (n = 53) by quantitative reverse transcription PCR.RESULTS:Mesenteric intravasation and liver metastasis were correlated with losses of chromosomes 16p (72%), 16q (27%), and 19 (54%), gain along 1q31 (45%) and 20q (60%), tumor cell infiltration into the peripheral blood circulation, and further distant metastasis with gain of chromosome 8q (59%) and 12 (47%, P < 0.01). Chromosome 12 gain was associated with poor overall survival in the initial (2.8 vs >7 years) and validation cohort (3.3 vs >6 years). The prospective study presented here is a hypothesis-generating study and confirmation with larger cohorts is required.CONCLUSIONS:This is the first study that investigated colorectal cancer in its different stages of metastasis in correlation with copy number changes of the primary tumor. This information might be helpful to identify patients with limited metastatic spread who may profit from liver metastasis resection and may lead to the discovery of new therapeutic targets.Microarray data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE82228

Liver venous deprivation versus portal vein embolization before major hepatectomy: future liver remnant volumetric and functional changes

International audienceBackground: We previously showed that embolization of portal inflow and hepatic vein (HV) outflow (liver venous deprivation, LVD) promotes future liver remnant (FLR) volume (FLR-V) and function (FLR-F) gain. Here, we compared FLR-V and FLR-F changes after portal vein embolization (PVE) and LVD.Methods: This study included all patients referred for liver preparation before major hepatectomy over 26 months. Exclusion criteria were: unavailable baseline/follow-up imaging, cirrhosis, Klatskin tumor, two-stage hepatectomy. 99mTc-mebrofenin SPECT-CT was performed at baseline and at day 7, 14 and 21 after PVE or LVD. FLR-V and FLR-F variations were compared using multivariate generalized linear mixed models (joint modelling) with/without missing data imputation.Results: Baseline FLR-F was lower in the LVD (n=29) than PVE group (n=22) (P<0.001). Technical success was 100% in both groups without any major complication. Changes in FLR-V at day 14 and 21 (+14.2% vs. +50%, P=0.002; and +18.6% vs. +52.6%, P=0.001), and in FLR-F at day 7, 14 and 21 (+23.1% vs. +54.3%, P=0.02; +17.6% vs. +56.1%, P=0.006; and +29.8% vs. +63.9%, P<0.001) differed between PVE and LVD group. LVD (P=0.009), age (P=0.027) and baseline FLR-V (P=0.001) independently predicted FLR-V variations, whereas only LVD (P=0.01) predicted FLR-F changes. After missing data handling, LVD remained an independent predictor of FLR-V and FLR-F variations.Conclusions: LVD is safe and provides greater FLR-V and FLR-F increase than PVE. These results are now evaluated in the HYPERLIV-01 multicenter randomized trial

Mesh Repair in Crohn’s Disease: A Case-Matched Multicenter Study in 234 Patients

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Stereotactic MR-Guided Adaptive Radiotherapy for Pancreatic Tumors: Updated Results of the Montpellier Prospective Registry Study

Introduction: Stereotactic MR-guided Adaptive RadioTherapy (SMART) is a novel process to treat pancreatic tumors. We present an update of the data from our prospective registry of SMART for pancreatic tumors. Materials and methods: After the establishment of the SMART indication in a multidisciplinary board, we included all patients treated for pancreatic tumors. Primary endpoints were acute and late toxicities. Secondary endpoints were survival outcomes (local control, overall survival, distant metastasis free survival) and dosimetric advantages of adaptive process on targets volumes and OAR. Results: We included seventy consecutive patients in our cohort between October 2019 and April 2022. The prescribed dose was 50 Gy in 5 consecutive fractions. No severe acute SMART related toxicity was noted. Acute and late Grade &le; 2 gastro intestinal were low. Daily adaptation significantly improved PTV and GTV coverage as well as OAR sparing. With a median follow-up of 10.8 months since SMART completion, the median OS, 6-months OS, and 1-year OS were 20.9 months, 86.7% (95% CI: (75&ndash;93%), and 68.6% (95% CI: (53&ndash;80%), respectively, from SMART completion. Local control at 6 months, 1 year, and 2 years were, respectively, 96.8 % (95% CI: 88&ndash;99%), 86.5 (95% CI: 68&ndash;95%), and 80.7% (95% CI: 59&ndash;92%). There was no grade &gt; 2 late toxicities. Locally Advanced Pancreatic Cancers (LAPC) and Borderline Resectable Pancreatic Cancers (BRPC) patients (52 patients) had a median OS, 6-months OS, and 1-year OS from SMART completion of 15.2 months, 84.4% (95% CI: (70&ndash;92%)), and 60.5% (95% CI: (42&ndash;75%)), respectively. The median OS, 1-year OS, and 2-year OS from initiation of induction chemotherapy were 22.3 months, 91% (95% CI: (78&ndash;97%)), and 45.8% (95% CI: (27&ndash;63%)), respectively. Twenty patients underwent surgical resection (38.7 % of patients with initially LAPC) with negative margins (R0). Conclusion: To our knowledge, this is the largest series of SMART for pancreatic tumors. The treatment was well tolerated with only low-grade toxicities. Long-term OS and LC rates were achieved. SMART achieved high secondary resection rates in LAPC patients

Stereotactic MR-Guided Adaptive Radiotherapy for Pancreatic Tumors: Updated Results of the Montpellier Prospective Registry Study

Introduction: Stereotactic MR-guided Adaptive RadioTherapy (SMART) is a novel process to treat pancreatic tumors. We present an update of the data from our prospective registry of SMART for pancreatic tumors. Materials and methods: After the establishment of the SMART indication in a multidisciplinary board, we included all patients treated for pancreatic tumors. Primary endpoints were acute and late toxicities. Secondary endpoints were survival outcomes (local control, overall survival, distant metastasis free survival) and dosimetric advantages of adaptive process on targets volumes and OAR. Results: We included seventy consecutive patients in our cohort between October 2019 and April 2022. The prescribed dose was 50 Gy in 5 consecutive fractions. No severe acute SMART related toxicity was noted. Acute and late Grade ≤ 2 gastro intestinal were low. Daily adaptation significantly improved PTV and GTV coverage as well as OAR sparing. With a median follow-up of 10.8 months since SMART completion, the median OS, 6-months OS, and 1-year OS were 20.9 months, 86.7% (95% CI: (75–93%), and 68.6% (95% CI: (53–80%), respectively, from SMART completion. Local control at 6 months, 1 year, and 2 years were, respectively, 96.8 % (95% CI: 88–99%), 86.5 (95% CI: 68–95%), and 80.7% (95% CI: 59–92%). There was no grade > 2 late toxicities. Locally Advanced Pancreatic Cancers (LAPC) and Borderline Resectable Pancreatic Cancers (BRPC) patients (52 patients) had a median OS, 6-months OS, and 1-year OS from SMART completion of 15.2 months, 84.4% (95% CI: (70–92%)), and 60.5% (95% CI: (42–75%)), respectively. The median OS, 1-year OS, and 2-year OS from initiation of induction chemotherapy were 22.3 months, 91% (95% CI: (78–97%)), and 45.8% (95% CI: (27–63%)), respectively. Twenty patients underwent surgical resection (38.7 % of patients with initially LAPC) with negative margins (R0). Conclusion: To our knowledge, this is the largest series of SMART for pancreatic tumors. The treatment was well tolerated with only low-grade toxicities. Long-term OS and LC rates were achieved. SMART achieved high secondary resection rates in LAPC patients