Triplet chemotherapy with or without bevacizumab as first line treatment for metastatic colorectal cancer: An AGEO multicenter real-world study.

BACKGROUND: Prior trials validated triplet chemotherapy (Tri-CT) with bevacizumab as first line treatment for metastatic colorectal cancer (mCRC) but real-world data are scarce and practices remain heterogeneous. AIMS: To evaluate Tri-CT +/- bevacizumab efficacy and safety, and to identify factors influencing treatment decisions. METHODS: The COLOTRIP retrospective study enrolled mCRC patients treated from 2014 to 2019 in 14 French centers. RESULTS: Of 299 patients (81% PS 0-1, 58% RAS-mutated and 19% BRAF-mutated), 51% received Tri-CT and 49% Tri-CT + bevacizumab. Metastatic disease was classified as resectable (6.5%), potentially resectable (40%), and unresectable (54%). Bevacizumab use was associated with primary tumor location, mutational status and number of metastases. Median overall survival was 33.5 months in the Tri-CT group and 23.9 months in the Tri-CT + bevacizumab group, with median progression-free survival being 14.5 and 11.4 months. After adjusting for initial characteristics, no difference in survival was noted. Around 30% of patients experienced grade ≥3 adverse events. CONCLUSIONS: This study highlights several factors influencing Tri-CT use +/- bevacizumab decision and confirms the real-world good oncological outcomes and tolerability of these regimens in mCRC patients. Our results suggest that Tri-CT alone may by an appropriate option for specific subgroups of patients.

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.

Surgery in reference centers improves survival of sarcoma patients: a nationwide study.

BACKGROUND: NETSARC (netsarc.org) is a network of 26 sarcoma reference centers with specialized multidisciplinary tumor boards (MDTB) aiming to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and expert pathological review are mandatory for sarcoma patients nationwide. In the present work, the impact of surgery in a reference center on the survival of sarcoma patients investigated using this national NETSARC registry. PATIENTS AND METHODS: Patients' characteristics and follow-up are prospectively collected and data monitored. Descriptive, uni- and multivariate analysis of prognostic factors were conducted in the entire series (N = 35 784) and in the subgroup of incident patient population (N = 29 497). RESULTS: Among the 35 784 patients, 155 different histological subtypes were reported. 4310 (11.6%) patients were metastatic at diagnosis. Previous cancer, previous radiotherapy, neurofibromatosis type 1 (NF1), and Li-Fraumeni syndrome were reported in 12.5%, 3.6%, 0.7%, and 0.1% of patients respectively. Among the 29 497 incident patients, 25 851 (87.6%) patients had surgical removal of the sarcoma, including 9949 (33.7%) operated in a NETSARC center. Location, grade, age, size, depth, histotypes, gender, NF1, and surgery outside a NETSARC center all correlated to overall survival (OS), local relapse free survival (LRFS), and event-free survival (EFS) in the incident patient population. NF1 history was one of the strongest adverse prognostic factors for LRFS, EFS, and OS. Presentation to an MDTB was associated with an improved LRFS and EFS, but was an adverse prognostic factor for OS if surgery was not carried out in a reference center. In multivariate analysis, surgery in a NETSARC center was positively correlated with LRFS, EFS, and OS [P < 0.001 for all, with a hazard ratio of 0.681 (95% CI 0.618-0.749) for OS]. CONCLUSION: This nationwide registry of sarcoma patients shows that surgical treatment in a reference center reduces the risk of relapse and death.

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/).

Liver hypertrophy: Underlying mechanisms and promoting procedures before major hepatectomy.

Various procedures can promote hypertrophy of the future liver remnant (FLR) before major hepatectomy to prevent postoperative liver failure. The pathophysiological situation following portal vein embolization (PVE), hepatic artery ligation/embolization or hepatectomy remains unclear. On one hand, the main mechanisms of hepatic regeneration appear to be driven by hepatic hypoxia (involving the hepatic arterial buffer response), an increased portal blood flow inducing shear stress and the involvement of several mediators (inflammatory cytokines, vasoregulators, growth factors, eicosanoids and several hormones). On the other hand, several factors are associated with impaired liver regeneration, such as biliary obstruction, malnutrition, diabetes mellitus, male gender, age, ethanol and viral infection. All these mechanisms may explain the varying degrees of hypertrophy observed following a surgical or radiological procedure promoting hypertrophy the FLR. Radiological procedures include left and right portal vein embolization (extended or not to segment 4), sequential PVE and hepatic vein embolization (HVE), and more recently combined PVE and HVE. Surgical procedures include associated liver partition and portal vein ligation for staged hepatectomy, and more recently the combined portal embolization and arterial ligation procedure. This review aimed to clarify the pathophysiology of liver regeneration; it also describes radiological or surgical procedures employed to improve liver regeneration in terms of volumetric changes, the feasibility of the second step and the benefits and drawbacks of each procedure.

[Analysis of the 2015 British guidelines on the prevention and management of tumor lysis syndrome]. / Analyse des recommandations britanniques 2015 sur la prévention et la prise en charge du syndrome de lyse tumorale.

Whether it appears spontaneously or is induced by therapy, the tumor lysis syndrome is responsible for a massive release of ions and puric bases degradation of products in the circulation exceeding the renal excretion capacity. Some, such as uric acid, xanthine, and calcium phosphate, can precipitate in the renal tubules or parenchyma. It must be known to any practitioner supporting patients with hematologic malignancies, mainly high-grade but also some solid tumors. The 2015 publication of the British recommendations pertaining to patients suffering from hematological diseases should be broadcast. The main goal of treatment is to prevent the occurrence of renal dysfunction associated with heavy morbidity and mortality, either for his own conduct or consequences on obtaining a good tumor response. Some items proposed for the care, whether curative or preventive, should be discussed or detailed, which is the subject of this paper.

Effects of clamping procedures on central venous pressure during liver resection.

BACKGROUND: Various clamping procedures are used to decrease bleeding during liver resections but their effect on central venous pressure (CVP) remains unclear. The aim of this study was to assess the variations of the CVP during two different clamping procedures. METHODS: We retrospectively reviewed 29 patients (19 males, 10 females) who had Pringle maneuver (PM) and clamping of the inferior vena cava below the liver (IVCC) during major liver resections. RESULTS: Mean decrease of the CVP after PM, IVCC, and PM+IVCC was 0.84 ± 1.37, 2.17 ± 2.13 and 3.17 ± 2.56 cmH20, respectively (P=0.02, P<0.0001 and P<0.0001, respectively). IVCC was more effective in inducing a decrease of the CVP than PM alone (P<0.05). The combination of both PM and IVCC induced the greatest decrease but not to a level of significance compared to IVCC alone (P=0.25). CONCLUSION: IVCC remains the more efficient procedure to lower the CVP. However, although PM is commonly used to control vascular inflow within the liver its significant influence on the CVP could participate to the reduction of bleeding during liver resections.

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.

Retroperitoneal nodal metastases from colorectal cancer: Curable metastases with radical retroperitoneal lymphadenectomy in selected patients.

BACKGROUND: Retroperitoneal nodal metastases (RNM) represent 1-2% of metastases from colorectal cancer (CRC). Non-surgical treatments achieve 5-year overall survival (OS) of 0-12%. Radical retroperitoneal lymphadenectomy (RRL) in this setting remains controversial, but most published series do not distinguish local retroperitoneal recurrences from RNM. We specifically report outcomes after RRL for RNM from CRC. METHODS: We analyzed prospectively recorded data from patients who underwent standardized RRL for RNM from CRC between January 1997 and August 2012 in our institution. Local retroperitoneal recurrences were excluded. RESULTS: Twenty-five patients underwent RRL for synchronous (n = 19) or metachronous (n = 6) RNM from CRC. Fifteen patients had extra-retroperitoneal metastases. Median hospital stay was 16 [7-23] days. Grade ≥ III morbidity was 8% with no perioperative deaths. Median follow-up was 85 [4-142] months. Median OS and progression free survival (PFS) were 60 [4-142] and 14 [1-116] months. One, three- and 5-year OS were 92%, 64% and 47%. One, three- and 5-year PFS were 51%, 26% and 26%. Retroperitoneal nodal metastases from stage III CRC were associated with better median OS compared to those from stage IV CRC (p = 0.02). This variable did not impact on PFS. Subject to substantial risk of type II error on small samples data statistical analysis, survivals were not affected by timing and location of RNM, extra-retroperitoneal metastasis, nodal disruption, neoadjuvant nor adjuvant chemotherapy. CONCLUSIONS: To our knowledge, this is the largest series yet reported which specifically studied outcomes of RRL for RNM from CRC. RRL allows favorable outcomes in selected patients with acceptable morbidity.

Validation of a score for the early diagnosis of anastomotic leakage following elective colorectal surgery.

INTRODUCTION-AIM: Anastomotic leakage (AL) is the most feared complication after colorectal surgery. Its prognosis is related to early recognition and post-operative management and should be based on the concept of "failure to rescue". The aim of the present study was to validate the "DULK" diagnostic score for AL, developed in The Netherlands. MATERIAL AND METHOD: From June 2012 to June 2013, 100 consecutive patients were included in a prospective study according to the post-operative care protocol developed by den Dulk et al. The score is based on several laboratory and clinical items recorded daily. RESULTS: Among the 100 patients, 12 developed a post-operative AL (12%) with a specific mortality rate of 16.6% (2 patients). A DULK-score>3 was good criteria for early diagnosis of AL with a sensitivity of 91.7%, a specificity of 55.7%, a positive predictive value of 22%, a negative predictive value of 98%, and an area under the ROC curve of 0.83. If used routinely, the DULK-score would allow diagnosis of AL 3.5 days earlier than clinical judgment alone. The DULK-score was superior to common diagnostic criteria described in the literature such as the C-reactive protein or procalcitonin, in terms of both sensitivity and specificity. CONCLUSION: The DULK-score is, at present, the most reliable instrument for early diagnosis of AL after colorectal surgery and should be integrated into risk management health policies aiming to improve the quality of care according to the "failure to rescue" concept.

Radiofrequency ablation for colorectal liver metastases.

The management of hepatic metastases from colorectal cancer (HMCRC) is multimodal including chemotherapy, surgical resection, radiation therapy, and focused destruction technologies. Radiofrequency ablation (RFA) is the most commonly used focused destruction technology. It represents a therapeutic option that may be potentially curative in cases where surgical excision is contra-indicated. It also increases the number of candidates for surgical resection among patients whose liver metastases were initially deemed unresectable. This article explains the techniques, indications, and results of radiofrequency ablation in the treatment of hepatic colorectal metastases.

Excitatory action of vasopressin in the brain of the rat: role of cAMP signaling.

Brain vasopressin plays a role in behavioral and cognitive functions and in pathological conditions. Relevant examples are pair bonding, social recognition, fear responses, stress disorders, anxiety and depression. At the neuronal level, vasopressin exerts its effects by binding to V1a receptors. In the brainstem, vasopressin can excite facial motoneurons by generating a sustained inward current which is sodium-dependent, tetrodotoxin-insensitive and voltage-gated. This effect is independent of intracellular calcium mobilization and is unaffected by phospholipase Cß (PLCß) or protein kinase C (PKC) inhibitors. There are two major unsolved problems. (i) What is the intracellular signaling pathway activated by vasopressin? (ii) What is the exact nature of the vasopressin-sensitive cation channels? We performed recordings in brainstem slices. Facial motoneurons were voltage-clamped in the whole-cell configuration. We show that a major fraction, if not the totality, of the peptide effect was mediated by cAMP signaling and that the vasopressin-sensitive cation channels were directly gated by cAMP. These channels appear to exclude lithium, are suppressed by 2-aminoethoxydiphenylborane (2-APB) and flufenamic acid (FFA) but not by ruthenium red or amiloride. They are distinct from transient receptor channels and from cyclic nucleotide-regulated channels involved in visual and olfactory transduction. They present striking similarities with cation channels present in a variety of molluscan neurons. To our knowledge, the presence in mammalian neurons of channels having these properties has not been previously reported. Our data should contribute to a better knowledge of the neural mechanism of the central actions of vasopressin, and may be potentially significant in view of clinical applications.

Deciphering the H-Ras pathway in Xenopus oocyte.

Xenopus oocytes are arrested in prophase of the first meiotic division. In response to progesterone, they re-enter meiosis and arrest again in metaphase of the second meiotic division. This process, called meiotic maturation, is under the control of the Cyclin B-Cdc2 complex, M phase promoting factor (MPF). Injection of a constitutively active Xenopus H-Ras protein activates MPF, suggesting that Ras proteins could be implicated in the progesterone transduction pathway. The aim of this study was (1) to elucidate the pathway triggered by H-Ras leading to MPF activation in Xenopus oocytes and (2) to investigate whether endogenous H-Ras is involved in the physiological process of meiotic maturation. We generated three constitutively active double mutants, each of them recruiting a single effector in mammalian cells, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) or RalGDS. Our results show that the activation of a PI3K-related enzyme is crucial for H-Ras-induced MPF activation, whereas the recruitment of either MAPK or RalGDS is not. However, although the H-Ras/PI3K pathway is functional in Xenopus oocytes, it is not the physiological transducer of progesterone responsible for meiotic resumption.

From progesterone to active Cdc2 in Xenopus oocytes: a puzzling signalling pathway.

Since almost two decades, it is known that progesterone is responsible of the release of the prophase I arrest of amphibian oocytes and leads to the activation of the universal MPF, through a puzzling transduction pathway. It involves negative regulation of the cAMP-dependent protein kinase (PKA) and synthesis of new proteins, among them the c-Mos protooncogene product. The implication of the Mos/mitogenic activated protein kinase (MAP kinase) pathway in Cdc2 activation has been extensively studied and is now at the centre of a controversial debate. In this paper, we discuss the current progress and our recent results on the molecular mechanisms allowing progesterone to activate MPF and propose a model to partly resolve the long-standing inconsistencies concerning the role of Mos/MAP kinase during this process.