Abdominal massage to prevent ileus after colorectal surgery. A single-center, prospective, randomized clinical trial: the MATRAC Trial.

BACKGROUND: There is scarce literature on the effect of mechanical abdominal massage on the duration of ileus after colectomy, particularly in the era of enhanced recovery after surgery (ERAS). The aim of this study was to determine whether abdominal massage after colorectal surgery with anastomosis and no stoma helps toward a faster return of intestinal transit. METHODS: This study was a superiority trial and designed as a prospective open-label, single-center, randomized controlled clinical trial with two parallel groups. Patients scheduled to undergo intestinal resection and follow an ERAS protocol were randomly assigned to either the standard ERAS group or the ERAS plus massage group. The primary endpoint was the return of intestinal transit, defined as the first passage of flatus following the operation. Secondary endpoints included time of the first bowel motion, maximal pain, 30 day complications, complications due to massage, anxiety score given by the Hospital Anxiety and Depression (HAD) questionnaire, and quality of life assessed by the EQ-5D-3L questionnaire. RESULTS: Between July 2020 and June 2021, 36 patients were randomly assigned to the ERAS group or the ERAS plus massage group (n = 19). Patients characteristics were comparable. There was no significant difference in time to passage of the first flatus between the ERAS group and the ERAS plus abdominal massage group (1065 versus 1389 min, p = 0.274). No statistically significant intergroup difference was noted for the secondary endpoints. CONCLUSION: Our study, despite its limitations, failed to demonstrate any advantage of abdominal massage to prevent or even reduce symptoms of postoperative ileus after colorectal surgery. TRIAL REGISTRATION NUMBER: 38RC20.021.

Oncological outcomes and hospitalization cost of hyperthermic intraperitoneal chemotherapy (HIPEC) open and closed abdomen techniques: Results from two French expert centers.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) associated with CC0 excision is performed using either an open (OPEN_HIPEC) or closed abdominal technique (CLOSED_HIPEC). However, little data is available on the costs of this treatment, as there is no code for HIPEC in the French Classification of Medical Acts. Oncological outcomes and the mean cost of hospitalization were compared. METHODS: Between 2017 and 2021, 144 patients with peritoneal carcinomatosis (all etiologies) were included (OPEN_HIPEC, n = 70; CLOSED_HIPEC, n = 74) in this retrospective two-center study. Morbi-mortality, overall survival (OS), recurrence-free-survival (RFS) and mean cost of hospitalization were compared. RESULTS: The median OS and RFS were 71.3 months [63-71.5] and 26.8 months [20-35.3] respectively, and were similar for both techniques; and after stratification by histology. Multivariate analysis adjusted on PCI score of OS identified mitomycin as a protective factor (HR = 0.31 [0.10-0.90], p = 0.032) and ASA score>2 (HR = 2.32 [1.32- 4.06], p = 0.003) and number of resection (HR = 1.21 [1.06-1.39], p = 0.006) as a risk factors of RFS. Complication rates at day 30 were similar between OPEN and CLOSED_HIPEC, 31 (44.3 %) vs 42 (56.8 %); p = 0.135. OPEN_HIPEC had more severe complications (11 (35.5 %) vs 6 (14.3 %); p = 0.034). The mean cost of hospitalization was estimated as €15,627 for OPEN_HIPEC and €14,211 for CLOSED_HIPEC for a mean length-of-stay of 12.7 and 16.7 days respectively. The mean amount received by the hospital per hospitalization was estimated at €16,399 and €15,536 respectively. CONCLUSIONS: OS and RFS were similar for open and closed HIPEC. Severe complications at day 30 were more frequent in OPEN_HIPEC group. The amount received by hospital for both HIPEC techniques is sufficient.

Early Evaluation of a New French Surgery Course in the Best Practice of Dealing With Major Incidents and Mass Casualty Events.

OBJECTIVE: The main objective of this study is to evaluate the impact of a nationwide 5-month course aimed to prepare surgeons for Major Incidents through the acquisition of key knowledge and competencies. Learners' satisfaction was also measured as a secondary objective. DESIGN: This course was evaluated thanks to various teaching efficacy metrics, mainly based on Kirkpatrick's hierarchy in medical education. Gain in knowledge of participants was evaluated by multiple-choice tests. Self-reported confidence was measured with 2 detailed pre and post training questionnaires. SETTING: Creation in 2020 of a nationwide, optional and comprehensive Surgical Training in War and Disaster Situation as part of the French surgery residency program. In 2021, data was gathered regarding the impact of the course on participants' knowledge and competencies. PARTICIPANTS: The study included 26 students in the 2021 cohort (13 residents and 13 practitioners). RESULTS: Mean scores were significantly higher in the post-test compared to the pre-test, showing significant increase in participants' knowledge during the course: 73,3% vs. 47,3% respectively (p ≤ 0.001). Average learners' confidence scores to perform technical procedures showed at least a +1-point increase on the Likert scale for 65% of items tested (p ≤ 0.001). 89% of items showed at least a +1-point increase on the Likert scale when it came to average learners' confidence score on dealing with complicated situations (p ≤ 0.001). Our post-training satisfaction survey showed that 92% of all participants have noticed the impact of the course on their daily practice. CONCLUSION: Our study shows that the third level of Kirkpatrick's hierarchy in medical education was reached. This course therefore appears to be meeting the objectives set by the Ministry of Health. Being only 2 years old, it is on the road to gathering momentum and further development.

Impact of Body Mass Index on Postoperative Pain and Opioid Administration After Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

PURPOSE: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique, developed for the treatment of peritoneal carcinomatosis (PC). In this retrospective observational study we assessed the impact of body mass index (BMI) on postoperative pain and opioid consumption. METHODS: We analyzed pain scores after 100 PIPAC procedures using either oxaliplatin or doxorubicin-cisplatin performed in 49 patients with PC between July 2016 and September 2020. The patients were divided into 3 groups (BMI <18.5, 18.5 ≥ BMI < 25, BMI≥25). Pain was self-rated on a visual analogue scale (VAS) from 0 to 10. RESULTS: Univariate logistic regression analysis identified oxaliplatin and PCI score to be associated with moderate to severe pain (VAS 4-10 at 8 am D1) after adjustment on BMI (OR [95% CI]; 3.26[1.00 - 10.65] p=0.050) and (OR [95% CI]; 1.09[1.01 - 1.17] p=0.019). The level of pain appeared significantly different between the treatment groups (median 2.5[0; 5] vs 0[0; 2.5] p=0.0017) irrespective of BMI (p =0.705 and p=0.118). Multivariate logistic regression analysis identified moderate to severe pain and synchronous PC to be associated with greater use of opioids (OR [95% CI]: 3.91 [1.24 - 12.32]) and (OR [95% CI]: 5.16 [1.71 - 15.58]; respectively. Opioids were administered after 45 procedures (45%) and was comparable between the treatment groups. Opioid administration and length-of-stay were similar among BMI bands. CONCLUSION: BMI is not related to postoperative pain or opioid use, howevermoderate to severe pain and synchronous PC are factors associated with requiring opioids.

Oncological Outcomes After Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in the Treatment of Peritoneal Carcinomatosis.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique for the treatment of initially unresectable peritoneal carcinomatosis (PC). Our objective was to assess its oncological outcomes. METHODS: Between July 2016 and September 2020, data from 100 PIPAC procedures with oxaliplatin or doxorubicin-cisplatin in 49 patients with PC (all etiologies) were analyzed. We studied the evolution of the peritoneal cancer index (PCI), the need for radical surgery (R0), and overall survival (OS). RESULTS: The patients' median age was 65 (59; 71) years, and 55.1% were women. Median PIPAC procedures per patient were 2 (1-3), and 28 (57.1%) underwent more than one PIPAC procedure. Median PCI at the first PIPAC was 19 (15-22). PCI decreased for 37%, remained stable for 29.6%, and increased for 33.4% patients. Four (8.3%) underwent radical R0 surgery after PIPAC. After a median follow-up of 16.1 months (1.5-90.1), the median overall survival from PC diagnosis was 29.1 months (14.8-34.3), with a median gastric and colorectal PC survival of 11.3 (7.2-34.3) and 29.1 months (16.1-31) respectively. Overall survival after the first PIPAC session was 11.6 months (6-17.3), with median survival after gastric and colorectal PCs being 6 (2.9-15.5) and 13.3 months (5-17.6), respectively. Stratification of patients according to the number of lines of systemic chemotherapy, PIPAC procedures, and the chronology of PC onset did not result in a significant difference in survival. CONCLUSION: The OS was in line with the literature. PIPAC could delay oncological progression and improve survival. These encouraging results justify the ongoing and future evaluations of PIPAC by prospective randomized trials.

Association between Enhanced Recovery After Surgery (ERAS) protocol, risk factors and 3-year survival after colorectal surgery for cancer in the elderly.

INTRODUCTION: As life expectancy is currently growing, more elderly and fragile patients need colorectal resection for cancer. We sought to assess the link between enhanced rehabilitation after surgery (ERAS), risk factors and overall survival at 3 years, in patients aged 65 and over. METHODS: Between 2005 and 2017, all patients undergoing colorectal resection for cancer were included. Overall survival at 3 years was compared for patients treated in following ERAS guidelines compared to conventional treatment (pre-ERAS). RESULTS: 661 patients were included (ERAS, n = 325; pre-ERAS, n = 336). The 3-year overall survival rate was significantly better regardless of age for ERAS vs pre-ERAS patients (73.1% vs 64.4%; p = 0.016). With overall survival rates of 83.2% vs 73.8%, 65.4% vs 62.8% and 59.6% vs 40% for the age bands 65-74, 75-84 and ≥ 85 years. The analysis of survival at 3 years by a multivariate Cox model identified ERAS as a protective factor with a reduction in the risk of death of 30% (HR = 0.70 [0.50-0.94], p = 0017) independently of other identified risk factors: age bands, ASA score > 2, smoking, atrial fibrillation and abdominal surgery. This result is confirmed by an analysis of the propensity score (HR = 0.67 [0.47-0.97], p = 0.032). CONCLUSIONS: Our study shows that ERAS is associated with better 3-year survival in patients undergoing colorectal resection for cancer, independent of risk factors. The practice of ERAS is effective and should be offered to patients aged 65 and over.

Hospitalization cost of Pressurized Intraperitoneal Aerosol chemotherapy (PIPAC).

INTRODUCTION: Pressurized Intraperitoneal Aerosol chemotherapy (PIPAC) is a new surgical technique for the treatment of unresectable peritoneal carcinomatosis. Very little data is available on the costs of this treatment in France as there is currently no code for PIPAC in the French Common Classification of Medical Acts (CCAM). Our objective was to estimate the mean cost of hospitalization for PIPAC in two French public teaching hospitals. METHODS: The mean cost of hospitalization was estimated from the mean fixed-rate remuneration paid to the hospital and the mean additional costs of treatment paid by the hospital. At discharge a patient's hospitalization is classified into a diagnosis related group, which determines the fixed-rate remuneration paid to the hospital (obtained from the national hospitals database - PMSI). Costs of medical devices and drug treatments specific to PIPAC, not covered by the fixed-rate remuneration, were obtained from the hospital pharmacies. RESULTS: Between July 2016 and November 2021, 205 PIPAC procedures were performed on 79 patients (mean procedures per patient = 2.6). Mean operating room occupancy was 165 min. The mean fixed-rate remuneration received by the hospitals per PIPAC hospitalization was €4031. The actual mean cost per hospitalization was €6562 for a mean length-of-stay of 3.3 days. Thus, each PIPAC hospitalization cost the hospital €2531 on average. CONCLUSION: The current reimbursement of PIPAC treatment by the national health system is insufficient and represents only 61% of the real cost. The creation of a new fixed-rate remuneration for PIPAC taking into account this cost differential is necessary.

Safety of use of the ENDOSWIR near-infrared optical imaging device on human tissues: prospective blind study.

Cancer surgery requires removing the tumor tissue in necessary and sufficient quantities. Spectral optical imaging in the short-wave infrared (900-1700 nm) could provide an intraoperative guidance to the surgeon based on the absorption of the tissues without contrast agent. Our objective was to ensure the safety of our ENDOSWIR device on human tissues. Histological analysis of fresh human tonsils exposed to the SWIR light or not was compared and showed no histological differences. This demonstrates the safety of using the SWIR device on human tissues and allows us to initiate a clinical study for the resection of tumors intraoperatively.

Assessment of postoperative pain after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in the treatment of peritoneal metastasis.

PURPOSE: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique, for the treatment of initially unresectable peritoneal metastasis (PM). Our objective was to assess postoperative pain and morbidity. METHODS: Between July 2016 and September 2020, data from 100 consecutive PIPAC procedures with oxaliplatin (PIPAC Ox) or doxorubicin-cisplatin (PIPAC C/D) in 49 patients with PM (all etiologies) were analyzed. Pain was self-assessed using a visual analog scale (VAS) of 0-10. RESULTS: The median PIPAC procedures per patient were 2 [1-3]. Patients indicated greatest pain at 4 pm on the day of the procedure (D0) and on postoperative D1 at 8 am and 4 pm. Postprocedural moderate-to-severe pain (VAS 4-10) was more frequent with PIPAC Ox than with PIPAC C/D, respectively 14 (36.8%) vs 7 (13.5%); p = 0.010. Hospitalization was longer for patients with moderate-to-severe pain than for others (median 4 days [3-7] vs 3 days [2-4], p = 0.004). Multivariate analysis identified oxaliplatin as a factor associated with greater pain (OR [95% CI], 2.95 [1.10-7.89]. Opiate administration was similar after PIPAC Ox and PIPAC C/D procedures, p = 0.477. CONCLUSION: PIPAC was well-tolerated, and pain was well-controlled in the majority of patients. Pain was greatest at 4 pm on D0 and 8 am and 4 pm on D1. PIPAC Ox is associated with greater pain than PIPAC C/D, independently of opiate treatment. Moderate-to-severe pain was associated with longer hospital stays.

Effect of implementation of enhanced recovery after surgery (ERAS) protocol and risk factors on 3-year survival after colorectal surgery for cancer-a retrospective cohort of 1001 patients.

PURPOSE: Several recent studies have shown that the enhanced recovery after surgery (ERAS) protocol reduces morbidity and mortality and shortens the length of stay compared to conventional recovery strategy (pre-ERAS). The aim of this study was to evaluate the effect of the implementation of this protocol on 3-year overall survival and postoperative outcome in patients undergoing colorectal resection for cancer. METHODS: This was a retrospective, single-center, comparative, and non-randomized study. Between January, 2005, and December, 2017, 1001 patients were included (ERAS, n = 497; pre-ERAS, n = 504). RESULTS: The 3-year overall survival rate was significantly better for ERAS than for pre-ERAS patients (76.1 vs 69.2%; p = 0.017). The length of hospital stay (median 10 days vs 15; p = ≤ 0.001) and the 90-day readmission rate (15 vs 20%; p = 0.037) were significantly lower in the ERAS group. Three-year recurrence-free survival (p = 0.398) and 90-day complications (p = 0.560) were similar in the two groups. Analysis of 3-year survival by a multivariate Cox model identified ERAS as a protective factor with a 30% reduction in the risk of death: (HR = 0.70 [0.55-0.90]). CONCLUSION: The implementation of the ERAS protocol was associated with an improvement in 3-year survival, a reduction of the length of hospital stay and the rate of readmission. ERAS is associated with better 3-year survival, independent of other commonly considered parameters. An ASA score > 2, smoking, a history of cancer, and atrial fibrillation are deleterious risk factors linked to earlier mortality.

Effect of Pressurized Intraperitoneal Aerosol Chemotherapy on the Survival Rate of Patients with Peritoneal Carcinomatosis of Gastric Origin.

INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique for the treatment of initially unresectable peritoneal carcinomatosis (PC). Our objective was to compare the results of PIPAC associated with systemic chemotherapy (PIPAC_CHEM) with those of systemic chemotherapy alone (ONLY_CHEM) in patients with gastric PC without metastasis other than peritoneal, and the WHO performance status < 3. METHODS: This was a retrospective, single center, comparative non-randomized study. Seventeen PIPAC_CHEM patients were compared to 29 ONLY_CHEM patients. The primary endpoint was overall survival at 6 months from diagnosis of PC. RESULTS: Ninety-eight patients were screened and 46 were included (PIPAC_CHEM, n = 17; ONLY_CHEM, n = 29). The PIPAC_ CHEM population was significantly younger (median 64 years [56; 68] vs 74 years [61; 79]; p = 0.0054). Median PIPAC session per patient is 2 [1-3]. Six-month survival was significantly higher in the PIPAC_CHEM group than in the ONLY_CHEM group 16/17 (94.1% [65-99.2]) vs 19/29 (65.5% [45.4-79.7]), respectively; p = 0.029. Over the entire follow-up, median survival [95% CI] was 12.8 months [7.2-34.3] with PIPAC vs 9.1 months [5.4-11.5] without, p = 0.056. At 6 months, median length of additional hospitalization was significantly less for PIPAC_CHEM (median 2 days [2-7]) than without PIPAC (median 11 days [3-21]) (p = 0.045). CONCLUSION: The overall survival at 6 months after the diagnosis of carcinomatosis was significantly better for PIPAC_CHEM patients. This difference appears to continue until at least 18 months. At 6 months, days of additional hospitalization was significantly less in the PIPAC_CHEM group. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT 04,879,953.

Liver Transplantation for Hepatocellular Carcinoma: A Real-Life Comparison of Milan Criteria and AFP Model.

PURPOSE: To compare the agreement for the criteria on the explant and the results of liver transplantation (LT) before and after adoption of the AFP (α-fetoprotein) model. METHODS: 523 patients consecutively listed in five French centers were reviewed to compare results of the Milan criteria period (MilanCP, n = 199) (before 2013) and the AFP score period (AFPscP, n = 324) (after 2013). (NCT03156582). RESULTS: During AFPscP, there was a significantly longer waiting time on the list (12.3 vs. 7.7 months, p < 0.001) and higher rate of bridging therapies (84 vs. 75%, p = 0.012) compared to the MilanCP. Dropout rate was slightly higher in the AFPscP (31 vs. 24%, p = 0.073). No difference was found in the histological AFP score between groups (p = 0.838) with a global agreement in 88% of patients. Post-LT recurrence was 9.2% in MilanCP vs. 13.2% in AFPscP (p = 0.239) and predictive factors were AFP > 2 on the last imaging, downstaging policy and salvage transplantation. Post-LT survival was similar (83 vs. 87% after 2 years, p = 0.100), but after propensity score analysis, the post-listing overall survival (OS) was worse in the AFPscP (HR 1.45, p = 0.045). CONCLUSIONS: Agreement for the AFP model on explant analysis (≤2) did not significantly change. AFP score > 2 was the major prognostic factor for recurrence. Graft allocation policy has a major impact on prognosis, with a post-listing OS significantly decreased, probably due to the increase in waiting time, increase in bridging therapies, downstaging policy and salvage transplantation.

Theranostic AGuIX nanoparticles as radiosensitizer: A phase I, dose-escalation study in patients with multiple brain metastases (NANO-RAD trial).

BACKGROUND AND PURPOSE: Brain metastasis impacts greatly on patients' quality of life and survival. The phase I NANO-RAD trial assessed the safety and maximum tolerated dose of systemic administration of a novel gadolinium-based nanoparticle, AGuIX, in combination with whole brain radiotherapy in patients with multiple brain metastases not suitable for stereotactic radiotherapy. MATERIALS AND METHODS: Patients with measurable brain metastases received escalating doses of AGuIX nanoparticles (15, 30, 50, 75, or 100 mg/kg intravenously) on the day of initiation of WBRT (30 Gy in 10 fractions) in 5 cohorts of 3 patients each. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events v4.03. RESULTS: Fifteen patients with 354 metastases were included. No dose-limiting toxic effects were observed up to AGuIX 100 mg/kg. Plasma elimination half-life of AGuIX was similar for all groups (mean 1.3 h; range 0.8-3 h). Efficient targeting of metastases (T1 MRI enhancement, tumor selectivity) and persistence of AGuIX contrast enhancement were observed in metastases from patients with primary melanoma, lung, breast, and colon cancers. The concentration of AGuIX in metastases after administration was proportional to the injected dose. Thirteen of 14 evaluable patients had a clinical benefit, with either stabilization or reduction of tumor volume. MRI analysis showed significant correlation between contrast enhancement and tumor response, thus supporting a radiosensitizing effect. CONCLUSION: Combining AGuIX with radiotherapy for patients with brain metastases is safe and feasible. AGuIX specifically targets brain metastases and is retained within tumors for up to 1 week; ongoing phase II studies will more definitively assess efficacy.

An innovative plasmacytoid dendritic cell line-based cancer vaccine primes and expands antitumor T-cells in melanoma patients in a first-in-human trial.

The efficacy of immune checkpoint inhibitors has been shown to depend on preexisting antitumor immunity; thus, their combination with cancer vaccines is an attractive therapeutic approach. Plasmacytoid dendritic cells (PDC) are strong inducers of antitumor responses and represent promising vaccine candidates. We developed a cancer vaccine approach based on an allogeneic PDC line that functioned as a very potent antigen-presenting cell in pre-clinical studies. In this phase Ib clinical trial, nine patients with metastatic stage IV melanoma received up to 60 million irradiated PDC line cells loaded with 4 melanoma antigens, injected subcutaneously at weekly intervals. The primary endpoints were safety and tolerability. The vaccine was well tolerated and no serious vaccine-induced side effects were recorded. Strikingly, there was no allogeneic response toward the vaccine, but a significant increase in the frequency of circulating anti-tumor specific T lymphocytes was observed in two patients, accompanied by a switch from a naïve to memory phenotype, thus demonstrating priming of antigen-specific T-cells. Signs of clinical activity were observed, including four stable diseases according to IrRC and vitiligoïd lesions. Four patients were still alive at week 48. We also demonstrate the in vitro enhancement of specific T cell expansion induced by the synergistic combination of peptide-loaded PDC line with anti-PD-1, as compared to peptide-loaded PDC line alone. Taken together, these clinical observations demonstrate the ability of the PDC line based-vaccine to prime and expand antitumor CD8+ responses in cancer patients. Further trials should test the combination of this vaccine with immune checkpoint inhibitors.

Treatment of multiple brain metastases using gadolinium nanoparticles and radiotherapy: NANO-RAD, a phase I study protocol.

INTRODUCTION: Occurrence of multiple brain metastases is a critical evolution of many cancers with significant neurological and overall survival consequences, despite new targeted therapy and standard whole brain radiotherapy (WBRT). A gadolinium-based nanoparticle, AGuIX, has recently demonstrated its effectiveness as theranostic and radiosensitiser agent in preclinical studies. The favourable toxicity profile in animals and its administration as a simple intravenous injection has motivated its use in patients with this first in human study. METHODS AND ANALYSIS: The NANO-RAD study is a phase I, first in human injection, monocentric, open-label, dose-escalation study to investigate the safety, the tolerability and the spectrum of side effects of AGuIX in combination with WBRT (30 Gy, 10 fractions of 3 Gy) for patients with multiple brain metastases. Five dose escalation cohorts are planned: 15, 30, 50, 75 and 100 mg/kg. A total of 15-18 patients will be recruited into this trial. The primary objective is to determine the maximum-tolerated dose of AGuIX nanoparticles combined with WBRT for the treatment of multiple brain metastases. Toxicity will be assessed using the National Cancer Institute Common Toxicity Criteria V.4.03. Secondary objectives are pharmacokinetic profile, distribution of AGuIX in metastases and surrounding healthy tissue visualised by MRI, intracranial progression-free survival and overall survival. Intracranial response will be determined according to Response Evaluation Criteria in Solid Tumour Criteria V.1.1 comparing MRI performed prior to treatment and at each follow-up visits. ETHICS AND DISSEMINATION: Approval was obtained from the ethics committee Sud Est V, France (Reference number 15-CHUG-48). The study was approved by the French National Agency for the Safety of Medicines and Health Products (ANSM) (Reference number 151519A-12). The results will be published in peer-reviewed journals or disseminated through national and international conferences. TRIAL REGISTRATION NUMBER: NCT02820454; Pre-results.

[How to predict the relapse after surgery or radiofrequency of liver metastases of colorectal cancer? Interest of the serum kinetic variation of a matrix metalloproteinase cluster]. / Cinétique de variation sérique des métalloprotéïnases matricielles (MMP-1, -2, -7 et -9) et de TIMP-1 : un facteur prédictif de récidive après traitement radical des métastases hépatiques de cancers colorectaux ?

INTRODUCTION: Recurrence after liver surgery or radiofrequency is a clinical and biological challenge because it worsens the colorectal cancer prognosis. To date, no biomarker is yet validated to predict the recurrence in order to intensify adjuvant therapy for patients with higher risk. Matrix metalloproteinases play a major role in the metastasis dissemination and tumoral microenvironment and could be a potential biomarker of interest. METHODS: Forty-four patients with liver metastasis treated by surgery or radiofrequency were enrolled in this study. Serum levels of MMP-1, MMP-2, MMP-7, MMP-9 and TIMP-1 were monitored in Elisa after therapy and correlated to the recurrence from January 2004 to December 2007. After the curative treatment, patients were assessed for the recurence for two years by CT-scan and examination. RESULTS: Post-operative serum level of MMP-9 was significantly higher between J0, J1 and J45 after liver surgery or radiofrequency (***P≤0.001). Level of MMP-2 was significantly increased at M3 and M6 (***P≤0.001) but does not appear to be a risk factor of liver recurrence. The level of TIMP-1 at J0 is a deleterious factor (HR=1.76, P=0.042*). CONCLUSION: This is the first study wich correlates the post-operative level of 4 MMPs and TIMP-1 with the risk of liver recurrence after surgery or radiofrequency. Serum TIMP-1 level at J0 could be helpful to identify patients with higher risk but these results need to be confirmed in a large-scale study.

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma.

BACKGROUND: Vascular endothelial (VE)-cadherin is an endothelial cell-specific protein responsible for endothelium integrity. Its adhesive properties are regulated by post-translational processing, such as tyrosine phosphorylation at site Y685 in its cytoplasmic domain, and cleavage of its extracellular domain (sVE). In hormone-refractory metastatic breast cancer, we recently demonstrated that sVE levels correlate to poor survival. In the present study, we determine whether kidney cancer therapies had an effect on VE-cadherin structural modifications and their clinical interest to monitor patient outcome. METHODS: The effects of kidney cancer biotherapies were tested on an endothelial monolayer model mimicking the endothelium lining blood vessels and on a homotypic and heterotypic 3D cell model mimicking tumour growth. sVE was quantified by ELISA in renal cell carcinoma patients initiating sunitinib (48 patients) or bevacizumab (83 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). RESULTS: Human VE-cadherin is a direct target for sunitinib which inhibits its VEGF-induced phosphorylation and cleavage on endothelial monolayer and endothelial cell migration in the 3D model. The tumour cell environment modulates VE-cadherin functions through MMPs and VEGF. We demonstrate the presence of soluble VE-cadherin in the sera of mRCC patients (n = 131) which level at baseline, is higher than in a healthy donor group (n = 96). Analysis of sVE level after 4 weeks of treatment showed that a decrease in sVE level discriminates the responders vs. non-responders to sunitinib, but not bevacizumab. CONCLUSIONS: These data highlight the interest for the sVE bioassay in future follow-up of cancer patients treated with targeted therapies such as tyrosine-kinase inhibitors.

Does continuous wound infiltration enhance baseline intravenous multimodal analgesia after posterior spinal fusion surgery? A randomized, double-blinded, placebo-controlled study.

PURPOSE: There has been a growing interest in continuous local anaesthetic wound infiltration as a non-opioid technique for postoperative pain relief. The impact of this modality on baseline analgesia after spinal fusion surgery has however been inconclusive. We tested whether continuous wound infiltration with ropivacaine can enhance postoperative analgesia compared to a baseline intravenous multimodal analgesia protocol after spinal fusion surgery. METHODS: In this randomized, double-blinded, placebo-controlled study, a multiholed 19-gauge catheter was placed at the end of the surgical procedure through the wound to permit the continuous administration (8 ml/h) of ropivacaine 0.2 % (ropivacaine group; n = 19 patients) or saline (control group; n = 20 patients) during the first 48 postoperative hours (H48). Both groups received intraoperative low-dose ketamine, a combination of acetaminophen, non-steroidal anti-inflammatory drug, and nefopam over the same postoperative period, and morphine delivered by a patient-controlled analgesia (PCA) device. RESULTS: Morphine consumption was comparable between the two groups both at H48, 38 mg (26:52) (median, 25th:75th percentile) (control group) versus 43 mg (19:74) (ropivacaine group), and at H24, 18 mg (16:22) versus 22 mg (9:35) respectively. Pain scores at rest and during mobilization, quality of postoperative sleep, and morphine-related side effects were comparable between the two groups at H24 and H48. CONCLUSION: Our findings indicate that no additional analgesia was provided with continuous wound infiltration of ropivacaine compared to a baseline intravenous multimodal analgesia protocol after spinal fusion surgery. TRIAL REGISTRATION: Clinicaltrials.gov #NCT01743794.

Vestibular results after intratympanic gentamicin therapy in disabling Menière's disease.

Intratympanic injection of gentamicin is increasingly used in the treatment of unilateral disabling Menière's disease (MD). Several objective functional and subjective tests have been developed to assess the control of vertigo after gentamicin treatment. The aim of this study was to show that subjective results require a vestibular deafferentation as profound as possible, evidenced with multifrequency vestibular assessment. Sixty four patients with intractable MD in situation of medical treatment failure longer than 6 months were included between 1998 and 2013 in this case control study. A 2-year follow-up was performed after the last intratympanic gentamicin performed with the titration technique. A vestibular assessment was applied before and after 2 years of treatment with a functional level score using the AAOHNS vertigo scale and multifrequency vestibular assessment: skull vibration-induced nystagmus test (SVINT), head-shaking test (HST) and caloric test (CaTe). The correlation between the results of the questionnaire and the level of the deafferentation as evaluated by the tests was analyzed with the Spearman test. Among the 64 included patients, 56 (87.5 %) described vertigo control. There was a correlation (=-0.33 [-0.53; -0.09], p = 0.008) between subjective improvement (AAO -HNS 1 or 2) and the degree of vestibular deafferentation as evidenced by a destructive nystagmus (beating toward the safe side) with the HST and the SVINT, as well as a caloric hypofunction >90 % with the CaTe. The present study demonstrates that a profound vestibular deafferentation confirmed with multifrequency test evaluation is needed to have a subjective improvement in the treatment of unilateral disabling MD with intratympanic gentamicin.