Evaluation of the early use of norepinephrine in major abdominal surgery on medical and surgical postoperative complications: study protocol for a randomised controlled trial (EPON STUDY).

BACKGROUND: Post-induction anaesthesia often promotes intraoperative hypotension (IOH) that can worsen postoperative outcomes. This study aims to assess the benefit of norepinephrine versus ephedrine at the induction of anaesthesia to prevent postoperative complications following major abdominal surgery by preventing IOH. METHODS AND ANALYSIS: The EPON STUDY is a prospective single-centre randomised controlled trial with the planned inclusion of 500 patients scheduled for major abdominal surgery at the Amiens University Hospital. The inclusion criteria are patients aged over 50 years weighing more than 50 kg with an American Society of Anesthesiologists physical status score of ≥2 undergoing major abdominal surgery under general anaesthesia. Patients are allocated either to the intervention group (n=250) or the standard group (n=250). In the intervention group, the prevention of post-induction IOH is performed with norepinephrine (dilution to 0.016 mg/mL) using an electric syringe pump at a rate of 0.48 mg/h (30 mL/h) from the start of anaesthesia and then titrated to achieve the haemodynamic target. In the control group, the prevention of post-induction IOH is performed with manual titration of ephedrine, with a maximal dose of 30 mg, followed by perfusion with norepinephrine. In both groups, the haemodynamic target to maintain is a mean arterial pressure (MAP) of 65 mm Hg or 70 mm Hg for patients with a medical history of hypertension. An intention-to-treat analysis will be performed. The primary outcome is the Clavien-Dindo score assessed up to 30 days postoperatively. The secondary endpoints are the length of hospital stay and length of stay in an intensive care unit/postoperative care unit; postoperative renal function; postoperative cardiovascular, respiratory, neurological, haematological and infectious complications at 1 month; and volume of intraoperative vascular filling and mortality at 1 month. ETHICS AND DISSEMINATION: Ethical approval was obtained from the committee of protection of the persons of Ile de France in May 2021 (number 21 05 41). The authors will be involved in disseminating the research findings (through attending conferences and co-authoring papers). The results of the study will be disseminated via peer-reviewed publications and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT05276596.

S erratus anterior plane block alone, paravertebral block alone and their combination in video-assisted thoracoscopic surgery: the THORACOSOPIC double-blind, randomized trial.

OBJECTIVES: Serratus anterior plane block (SAPB) and paravertebral block (PVB) are well known to reduce pain levels after video-assisted thoracoscopic surgery (VATS). However, the relative efficacies of each block and a combination of the 2 have not been fully characterized. The objective of the present study was to assess the efficacy of PVB alone, SAPB alone and the combination of PVB and SAPB with regard to the occurrence and intensity of pain after VATS. METHODS: We conducted the THORACOSOPIC single-centre, double-blind, randomized trial in adult patients due to undergo elective VATS lung resection. The participants were randomized to PVB only, SAPB only and PVB + SAPB groups. The primary end-point was pain on coughing on admission to the postanaesthesia care unit. The secondary end-points were postoperative pain at rest and on coughing at other time points and the cumulative opioid consumption. Pain was scored on a visual analogue scale. RESULTS: One-hundred and fifty-six patients (52 in each group) were included. On admission to the postanaesthesia care unit, the 3 groups did not differ significantly with regard to the pain on coughing: the visual analogue scale score was 3 (0-6), 4 (0-8) and 2 (0-6) in the PVB, SAPB and PVB + SAPB groups, respectively (P = 0.204). During postoperative care, the overall pain score was significantly lower in the SABP + PVP group at rest and on cough. CONCLUSIONS: The combination of SABP + PVB could be beneficial for pain management in VATS in comparison to SABP or PVB alone.

Effectiveness of golimumab intensification in ulcerative colitis: A multicentric prospective study.

INTRODUCTION: Loss of response to golimumab occurs in nearly 40% of patients with ulcerative colitis (UC). Unlike others anti-TNF, no study has reported a correlation between serum golimumab level and response to drug intensification. The objective of this study was to evaluate the effectiveness and safety of golimumab intensification and to identify the best threshold of serum golimumab before drug intensification predictive of response. PATIENTS AND METHODS: We included all consecutive patients with active UC with loss of response to golimumab in a prospective multicentric cohort study. Patients with loss of response at 50 mg q4 weeks (W) and 100 mg q4W underwent therapeutic intensification at 100 mg q4W and 100 mg q2W, respectively. Effectiveness and safety were assessed between Weeks 2 and 4 (visit 2) and between Weeks 4 and 8 (visit 3) after intensification. Serum level and anti-golimumab antibodies were evaluated at each medical visit (Lisa Tracker, Theradiag France). RESULTS: A total of 47 UC patients (Female, 50%; median age, 39 years (IQR, 27-52)) treated with golimumab for a median of 20.4 weeks (IQR, 10.7-38.3) were included. The median partial Mayo score was 6 (IQR, 5-7), and the median endoscopic Mayo score was 3 (IQR, 2-3). The median golimumab serum level before intensification was 2.23 µg/mL (IQR, 1.02-3.96) and only one patient (2.1%) had anti-drug antibodies. At Visit 2 (Week 2-4), 40% patients experienced clinical response, 10% clinical remission, 33% endoscopic response and 23% endoscopic remission. At Visit 3 (Week 4-8), 44% of patients had clinical response, 22% of patients had clinical remission, 45% of patients had endoscopic response, and 41% of patients had endoscopic remission. The median golimumab levels before intensification do not differ between responders and non-responders (2.13 µg/ml (0.76-2.76) and 3.37 µg/ml (IQR, 1.08-4.67), respectively; p = 0.14) assessed at Visit 3. Golimumab intensification to 100 mg q4W (vs q2W) (OR 1.98, 95% CI [1.06-3.70]; p = 0.032) was significantly associated with clinical remission at Visit 3. Serum drug level at baseline or the presence of antidrug antibodies were not associated with clinical or endoscopic remission/response. Two serious adverse events (one infection and one UC flare) were reported during the 24-week follow-up. CONCLUSION: In this prospective multicentric study, half of patients recaptured response following golimumab intensification in UC. Therapeutic drug monitoring did not predict response after optimisation of golimumab.

Lymphatic drainage of lung cancer follows an intersegmental pathway within the visceral pleura.

OBJECTIVES: Lung cancer tumors are known to be highly lymphophilic. There are two different pattern of lymphatic drainage of the lung: one peribronchial lymphatic pathway, and another one within the visceral pleura which appears to be more intersegmental than the peribronchial pathway. We aimed to assess the prevalence of an intersegmental pathway in the lymphatic drainage of lung tumors within the visceral pleura and determine potential influential factors. METHODS: In this prospective study, we included all patients for whom a major pulmonary resection (lobar) was indicated and performed for suspected or proven lung cancer. An immediate ex-vivo evaluation of the surgical specimen after resection was conducted by trans-pleural injection of blue dye within the tumor. The pathways followed by the lymphatic vessels under the visceral pleura were assessed to define the occurrence of an intersegmental pathway, which was defined by the presence of blue dye within the lymphatic vessel crossing to a neighboring pulmonary segment, distinct from the tumorous segment. RESULTS: Fifty-three patients met the inclusion criteria and were assessed over a three-year period. Lymphatic drainage within the visceral pleura followed an intersegmental pathway in 35 of 53 patients (66 %). When the lymphatic drainage of the tumor was intersegmental, it drained in a single other segment in 21/35 cases and two or more in 14/35 cases. Logistic regression with multivariate analysis showed a peripheral location of the tumor to be a risk factor for the intersegmental pathway of visceral pleura lymphatic drainage (OR = 0.87 [079-0.95], p = 0.003). CONCLUSION: These results confirm that lymphatic drainage of lung cancer in the visceral pleura appears to largely follow an intersegmental pathway, especially when the tumor is peripheral, close to the visceral pleura.

Intraoperative conversion during video-assisted thoracoscopy resection for lung cancer does not alter survival.

OBJECTIVES: The aim of this study was to assess the long-term outcomes of patients treated by anatomical pulmonary resection with the video-assisted thoracoscopic surgery (VATS) approach, VATS requiring intraoperative conversion to thoracotomy or an upfront open thoracotomy for lung cancer surgery. METHODS: We performed a retrospective single-centre study that included consecutive patients between January 2011 and December 2018 treated either by VATS (with or without intraoperative conversion) or open thoracotomy for non-small-cell lung cancer (NSCLC). Patients treated for a benign or metastatic condition, stage IV disease, multiple primary lung cancer or by resection, such as pneumonectomies or angioplastic/bronchoplastic/chest wall resections, were excluded. RESULTS: Among 1431 patients, 846 were included: 439 who underwent full-VATS, 94 who underwent VATS-conversion (21 emergent, 73 non-emergent) and 313 treated with upfront open thoracotomy. The median follow-up was 37 months. There were no statistical differences in stage-specific overall survival between the full-VATS, VATS-conversion, and open thoracotomy groups, with 5-year OS for stage I NSCLC of 76%, 72.3% and 69.4%, respectively (P = 0.47). There was a difference in disease-free survival for stage I NSCLC, with 71%, 60.2% and 53%, respectively at 5 years (P = 0.013). Fewer complications occurred in the full-VATS group (pneumonia, arrhythmia, length of stay), but complication rates were similar between the VATS-conversion and thoracotomy groups. CONCLUSIONS: VATS resection for NSCLC with intraoperative conversion does not appear to alter the long-term oncological outcome relative to full-VATS or open upfront thoracotomy. Postoperative complications were higher than for full-VATS and comparable to those for thoracotomy. VATS should be favoured when possible.

Outcomes after Contralateral Anatomic Surgical Resection in Multiple Lung Cancer.

BACKGROUND: Patients treated surgically for lung cancer may present synchronous or metachronous lung cancers. The aim of this study was to evaluate outcomes after a second contralateral anatomic surgical resection for lung cancer. METHODS: We performed a retrospective two-center study, based on a prospective indexed database. Included patients were treated surgically by bilateral anatomic surgical resection for a second primary lung cancer. We excluded nonanatomic resections, benign lesions, and ipsilateral second surgical resections. RESULTS: Between January 2011 and September 2018, 55 patients underwent contralateral anatomic surgical resections for lung cancer, mostly for metachronous cancers. The first surgical resection was a lobectomy in most cases (45 lobectomies: 81.8%, 9 segmentectomies: 16.4%, and 1 bilobectomy: 1.8%), and a video-assisted thoracic surgery (VATS) procedure was used in 23 cases (41.8%). The mean interval between the operations was 38 months, and lobectomy was less frequent for the second surgical resection (35 lobectomies: 63.6% and 20 segmentectomies: 36.4%), with VATS procedures performed in 41 cases (74.5%). Ninety-day mortality was 10.9% (n = 6), and 3-year survival was 77%. Risk factor analysis identified the number of resected segments during the second intervention or the total number of resected segments, extent of resection (lobectomy vs. segmentectomy), surgical approach (thoracotomy vs. VATS), tumor stage, and nodal involvement as potential prognostic factors for long-term survival. CONCLUSION: A second contralateral anatomic surgical resection for multiple primary lung cancer is possible, with a higher early mortality rate, but acceptable long-term survival, and should be indicated for carefully selected patients.

No Benefit of Concomitant Immunomodulator Therapy on Efficacy of Biologics That Are Not Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases: A Meta-analysis.

BACKGROUND & AIMS: There is debate over whether patients with inflammatory bowel diseases (IBD) treated with biologics that are not tumor necrosis factor antagonists (such as vedolizumab or ustekinumab) should receive concomitant treatment with immunomodulators. We conducted a meta-analysis to compare the efficacy and safety of concomitant immunomodulator therapy vs vedolizumab or ustekinumab monotherapy. METHODS: In a systematic search of publications, through July 31, 2019, we identified 33 studies (6 randomized controlled trials and 27 cohort studies) of patients with IBD treated with vedolizumab or ustekinumab. The primary outcome was clinical benefit, including clinical remission, clinical response, or physician global assessment in patients who did vs did not receive combination therapy with an immunomodulator. Secondary outcomes were endoscopic improvement and safety. We performed random-effects meta-analysis and estimated odds ratio (OR) and 95% CIs. RESULTS: Overall, combination therapy was not associated with better clinical outcomes in patients receiving vedolizumab (16 studies: OR, 0.84; 95% CI, 0.68-1.05; I2=13.9%; Q test P = .17) or ustekinumab (15 studies: OR, 1.1; 95% CI, 0.87-1.38; I2 = 11%; Q test P = .28). Results were consistent in subgroup analyses, with no difference in clinical remission or response in induction vs maintenance studies or in patients with Crohn's disease vs ulcerative colitis in studies of vedolizumab. Combination therapy was not associated with better endoscopic outcomes in patients receiving vedolizumab (3 studies: OR, 1.13; 95% CI, 0.48-2.68; I2 = 0; Q test P=.96) or ustekinumab (2 studies: OR, 0.58; 95% CI, 0.21-1.16; I2 = 47%; Q test P = .17). Combination therapy was not associated with an increase in adverse events during vedolizumab therapy (4 studies: OR, 1.17; 95% CI, 0.75-1.84; I2 = 0; Q test P = .110). CONCLUSIONS: In a meta-analysis of data from studies of patients with IBD, we found that combining vedolizumab or ustekinumab with an immunomodulator is no more effective than monotherapy in induction or maintenance of remission.

Intraoperative conversion during video-assisted thoracoscopy does not constitute a treatment failure†.

OBJECTIVES: Intraoperative conversion may be required during video-assisted thoracoscopic surgery (VATS) for lung cancer. We evaluated the morbidity and mortality rates associated with VATS for anatomical pulmonary resection with conversion to thoracotomy and compared this technique with full VATS and an open thoracotomic approach. METHODS: We performed a retrospective, single-centre study between January 2011 and January 2017 and included 610 consecutive patients having undergone either VATS (with or without intraoperative conversion) or open thoracotomy for anatomical pulmonary resection. Pneumonectomies and angioplastic/bronchoplastic/chest wall resections were excluded. After propensity score adjustment, we assessed the 90-day mortality and determined whether the surgical approach was a risk factor for mortality. RESULTS: Of the 610 patients, 253 patients underwent full VATS, 56 patients underwent VATS + conversion and 301 patients underwent up-front open thoracotomy. Relative to the open thoracotomy group, the VATS + conversion group had a higher incidence of cardiac or respiratory comorbidities and was more likely to have an early-stage tumour. Following adjustment, the 90-day postoperative mortality rate was 5.4% (n = 3/56) in the VATS + conversion group and 3.7% (n = 11/301) in the open thoracotomy group (P = 0.58). Likewise, the morbidity rate was similar in these 2 groups. In a multivariable analysis, the surgical approach was not a risk factor for postoperative mortality. CONCLUSIONS: Following anatomical resection for lung cancer, VATS with conversion and open thoracotomy were associated with similar early postoperative morbidity and mortality rates. When in doubt, VATS should be preferred to thoracotomy; it potentially provides the patient with benefits of a fully VATS-based resection but is not disadvantageous when intraoperative conversion is required.

[Venous invasions in colonic adenocarcinoma: Value of elastic stain]. / Invasions veineuses dans l'adénocarcinome colique : intérêt d'une coloration des fibres élastiques.

The aim of our study was to assess the value of Elastic stain in the diagnosis of venous invasion (VI) in colonic adenocarcinoma. MATERIAL AND METHODS: All patients who undergone surgery for colonic adenocarcinoma at the University Hospital of Amiens, between 2004 and 2007, were included. Hematein-phloxin-saffron (HPS) stained slides of colectomy specimens were reviewed by two pathologists. Tumor blocks were stained with Elastic Stain (Roche - Ventana®). The presence or absence of VI, their number and localization were correlated with overall survival. RESULTS: Two hundred and thirty-one cases were investigated and 3274 slides were examined. VI were more often diagnosed by Elastic Stain than HPS stain (66% vs. 40%). Ninety percent of VI were revealed within the first 6 HPS slides, and from the first 5 in Elastic Stain. The presence of VI revealed by Elastic Stain and/or HPS was significantly associated with decreased overall survival in multivariate analysis (P=0.029), especially for stage IIA tumors (P=0.016). Tumor differentiation (P=0.006) and pTNM stage (P=0.001) were also independent prognostic factors. The localization and the number of VI were not prognostic factors. CONCLUSION: Our study confirms the prognostic value of VI, revealed by an elastic stain, in colonic adenocarcinoma. A systematic elastic stain of all tumor blocks (number at least 5) could be considered in the future, during pathological examination of colectomy for adenocarcinoma.

Paradoxical articular manifestations in patients with inflammatory bowel diseases treated with infliximab.

INTRODUCTION: Articular involvement is the most common extraintestinal manifestation associated with inflammatory bowel diseases (IBDs). Manifestations are 'paradoxical' when they occur during treatment, notably with anti-tumor necrosis factor (anti-TNF) drugs, which are expected to prevent or treat them. The aim of this study was to assess the frequency, characteristics, and associated factors of paradoxical articular manifestations in patients with IBD treated with anti-TNF. PATIENTS AND METHODS: In this prospective single-center study, an examination by a rheumatologist was systematically offered to all patients with IBD treated with infliximab (IFX) to assess the prevalence of articular manifestations and distinguish between those related to treatment and those associated with intestinal disease. Paradoxical manifestations were defined as the occurrence of articular manifestations (excluding induced lupus and hypersensitivity reactions) during anti-TNF therapy in patients with intestinal remission. Measures of biological inflammatory, immunological markers, HLA-B27 allele, IFX trough levels, and anti-IFX antibody (Ab) were performed for all patients. RESULTS: Between May 2013 and April 2014, 65 patients with Crohn's disease and 15 with patients ulcerative colitis treated with IFX were included. The median duration of anti-TNF therapy was 66 months [quartile (Q)1=23 months-Q3=81 months]. Articular manifestations were observed in 50 (62%) patients treated with IFX. Eleven percent (n=9) were considered to be associated with IBD and 16% (n=13) to be associated with anti-TNF therapy. Among articular manifestations associated with anti-TNF therapy, nine (11%) patients were considered paradoxical, two (2%) as drug-induced lupus, and two (2%) as a hypersensitivity reaction. Among the nine patients with paradoxical manifestations, all had Crohn's disease in clinical remission, three patients presented a spondyloarthropathy, and three developed associated paradoxical psoriasis. No patient discontinued anti-TNF because of the articular manifestations. Methotrexate was effective on articular symptoms in two of the three treated patients with paradoxical manifestations. No clinical or biological factors, including IFX trough levels, were associated with the occurrence of paradoxical manifestations. CONCLUSION: Paradoxical articular manifestations in IBD patients treated by anti-TNF are common, affecting more than 10% of patients. These events are generally mild and do not need discontinuation of anti-TNF therapy.

Bone complications of mastocytosis: a link between clinical and biological characteristics.

OBJECTIVES: Mastocytosis is a heterogeneous group of clonal mast cell disorders in which bone manifestations are frequently seen, but poorly understood. In this study, we analyzed correlation of clinical findings in mastocytosis patients with bone mineral density and bone turnover markers. METHODS: Serum levels of bone turnover markers were measured in mastocytosis patients and healthy volunteers. Bone disease was evaluated using radiographic imaging, and measurement of bone mineral density. RESULTS: Of 45 adult mastocytosis patients, bone abnormalities were detected in 34 (75%). Bone lesions were documented on radiographic imaging in 16 patients (36%), and bone mineral density in 24 patients (53%), of which 9 patients (20%) had osteoporosis and 15 (33%) had osteopenia. Serum levels of bone turnover markers that evaluate bone resorption (C-telopeptide, deoxypyridinoline), bone formation (bone-specific alkaline phosphatase), and bone remodeling (osteoprotegerin) were significantly higher in the patient population than in the control population (n=28). Levels of C-telopeptide and osteoprotegerin were higher in patients with advanced systemic mastocytosis than in patients with cutaneous or indolent systemic mastocytosis. Moreover, C-telopeptide and osteoprotegerin levels were significantly correlated with those of serum tryptase, a diagnostic marker of mastocytosis. CONCLUSION: The observed bone turnover markers variations indicate a complex process of bone turnover in mastocytosis-related bone manifestations. The highly significant correlation between serum tryptase and serum bone turnover markers levels, and the positive correlation of levels of bone turnover markers with advanced disease, support the existence of a link between bone remodeling and mast cell burden.