Mickaël Schaeffer

Incidence and prevalence of inflammatory myopathies: a systematic review

OBJECTIVES . The aims of this study were to determine the incidence and prevalence of inflammatory myopathies (IMs), their epidemiological tendencies over time and their possible key determinants. METHODS . All original articles in English or French regarding the prevalence and/or incidence of IMs were searched. The methods of case ascertainment, epidemiological analysis and diagnostic criteria were systematically analysed. RESULTS . Forty-six articles published between 1966 and 2013 were found in which the incidence of IMs as a whole ranged from 1.16 to 19/million/year and their prevalence ranged from 2.4 to 33.8 per 100 000 inhabitants. Methodological heterogeneities limited comparisons, although certain epidemiological tendencies were highlighted. The relative incidence of DM may follow a latitudinal gradient in the northern hemisphere that may be explained by the immunomodulatory action of ultraviolet radiation. The prevalence of sporadic inclusion body myositis (sIBM) was correlated with the frequency of HLA-DR3. Juvenile myositis onset was non-random over seasons and/or time, consistent with a role of infectious diseases, although other environmental factors may be involved. Disparities according to sex, age and geographical origin were also found. The frequency of IM increased over time, which may reflect progress in diagnostic performance, although there is still a need to increase the level of awareness with regard to these diseases, especially sIBM, as attested by its considerably delayed diagnosis. CONCLUSION . This first systematic literature review confirms the rarity of IM and may highlight certain genetic and environmental determinants of IM. There is a need for uniformity in diagnostic and classification criteria as well as more exhaustive case ascertainment to refine IM epidemiology.

Synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C.

Objective Although direct-acting antiviral agents (DAAs) have markedly improved the outcome of treatment in chronic HCV infection, there continues to be an unmet medical need for improved therapies in difficult-to-treat patients as well as liver graft infection. Viral entry is a promising target for antiviral therapy. Design Aiming to explore the role of entry inhibitors for future clinical development, we investigated the antiviral efficacy and toxicity of entry inhibitors in combination with DAAs or other host-targeting agents (HTAs). Screening a large series of combinations of entry inhibitors with DAAs or other HTAs, we uncovered novel combinations of antivirals for prevention and treatment of HCV infection. Results Combinations of DAAs or HTAs and entry inhibitors including CD81-, scavenger receptor class B type I (SR-BI)- or claudin-1 (CLDN1)-specific antibodies or small-molecule inhibitors erlotinib and dasatinib were characterised by a marked and synergistic inhibition of HCV infection over a broad range of concentrations with undetectable toxicity in experimental designs for prevention and treatment both in cell culture models and in human liver-chimeric uPA/SCID mice. Conclusions Our results provide a rationale for the development of antiviral strategies combining entry inhibitors with DAAs or HTAs by taking advantage of synergy. The uncovered combinations provide perspectives for efficient strategies to prevent liver graft infection and novel interferon-free regimens.

Plasma fibrinogen level on admission to the intensive care unit is a powerful predictor of postoperative bleeding after cardiac surgery with cardiopulmonary bypass

INTRODUCTION Evidence regarding the behavior of fibrinogen levels and the relation between fibrinogen levels and postoperative bleeding is limited in cardiac surgery under cardiopulmonary bypass (CPB). To evaluate perioperative fibrinogen levels as a predictor of postoperative bleeding in patients undergoing cardiac surgery with CPB. MATERIALS AND METHODS In this prospective, single-center, observational cohort study of 1956 patients following cardiac surgery with CPB, fibrinogen level was measured perioperatively. Excessive bleeding group was defined as patients with a 24-h chest tube output (CTO) exceeded the 90th percentile of distribution. RESULTS The median 24-h CTO was 728.6±431.1ml. A total of 189 patients (9.7%) were identified as having excessive bleeding. At admission to the intensive care (Day 0), the fibrinogen levels were 2.5±0.8g/l and 2.1±0.8g/l in the control and excessive bleeding groups, respectively (P<0.0001). The fibrinogen level on Day 0 was significantly correlated with the 24-h CTO (rho=-0.237; P<0.0001). Multivariate analysis demonstrated that the fibrinogen level at Day 0 was the best perioperative standard laboratory test to predict excessive bleeding (P=0.0001; odds ratio, 0.5), whereas preoperative fibrinogen level was not a predictor. Using receiver operating characteristics curve analyses, the best Day 0 fibrinogen level cutoff to predict postoperative bleeding was 2.2g/l. CONCLUSIONS In this large prospective study, the fibrinogen level upon admission to the intensive care unit after CPB predicted the risk of postoperative bleeding. Our data add to the concern regarding the fibrinogen level threshold that might require fibrinogen concentrate infusion to reduce postoperative blood loss.

Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases

Background:Identifying patients who will experience lung cancer recurrence after surgery remains a challenge. We aimed to evaluate whether mutant forms of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (mEGFR and mKRAS) are useful biomarkers in resected non-small cell lung cancer (NSCLC).Methods:We retrospectively reviewed data from 841 patients who underwent surgery and molecular testing for NSCLC between 2007 and 2012.Results:mEGFR was observed in 103 patients (12.2%), and mKRAS in 265 (31.5%). The median overall survival (OS) and time to recurrence (TTR) were significantly lower for mKRAS (OS: 43 months; TTR: 19 months) compared with mEGFR (OS: 67 months; TTR: 24 months) and wild-type patients (OS: 55 months; disease-free survival (DFS): 24 months). Patients with KRAS G12V exhibited worse OS and TTR compared with the entire cohort (OS: KRAS G12V: 26 months vs Cohort: 60 months; DFS: KRAS G12V: 15 months vs Cohort: 24 months). These results were confirmed using multivariate analyses (non-G12V status, hazard ratio (HR): 0.43 (confidence interval: 0.28–0.65), P<0.0001 for OS; HR: 0.67 (0.48–0.92), P=0.01 for TTR). Risk of recurrence was significantly lower for non-KRAS G12V (HR: 0.01, (0.001–0.08), P<0.0001).Conclusions:mKRAS and mEGFR may predict survival and recurrence in early stages of NSCLC. Patients with KRAS G12V exhibited worse OS and higher recurrence incidences.

Specific KRAS amino acid substitutions and EGFR mutations predict site-specific recurrence and metastasis following non-small-cell lung cancer surgery

Background:We aimed to evaluate whether EGFR mutations (mEGFR) and KRAS amino acid substitutions can predict first site of recurrence or metastasis after non-small-cell lung cancer (NSCLC) surgery.Methods:Data were reviewed from 481 patients who underwent thoracic surgery for NSCLC between 2007 and 2012.Results:Patients with KRAS G12C developed significantly more bone metastases compared with the remainder of the cohort (59% vs 16%, P<0.0001). This was confirmed in multivariate analysis (MA) (odds ratio (OR): 0.113 (95% confidence interval (CI): 0.055–0.231), P<0.0001). Significantly, more patients with mEGFR developed liver and brain metastases compared with the remainder of the cohort (30% vs 10%, P=0.006; 59% vs 1%, P<0.0001, respectively). These were confirmed in MA (OR: 0.333 (95% CI: 0.095–0.998), P=0.05; OR: 0.032 (95% CI: 0.008–0.135), P<0.0001, respectively). Patients with KRAS G12V developed significantly more pleuro-pericardial metastases compared with the remainder of the cohort (94% vs 12%, P<0.0001). This was confirmed in MA (OR: 0.007 (95% CI: 0.001–0.031), P<0.0001). Wild-type patients developed significantly more lung metastases (35% vs 10%, P<0.0001). This was confirmed in MA (OR: 0.383 (95% CI: 0.193–0.762), P=0.006).Conclusion:Epidermal growth factor receptor mutation and KRAS amino acid substitutions seem to predict site-specific recurrence and metastasis after NSCLC surgery.

Impact of EGFR mutations and KRAS amino acid substitution on the response to radiotherapy for brain metastasis of non-small-cell lung cancer

BACKGROUND Our study aimed to evaluate response rate (RR) to brain metastasis radiotherapy (RT), depending on the genomic status of non-small-cell lung cancer. MATERIAL & METHODS We retrospectively reviewed 1971 non-small-cell lung cancer files of patients with EGFR and KRAS testing and focused on 157 patients who had undergone RT for brain metastasis. RESULTS A total of 16 patients (10.2%) harbored EGFR mutations (mEGFR) and 45 patients (28.7%) KRAS (mKRAS). In univariate analysis, RR was significantly higher for mEGFR compared with wild-type EGFR/KRAS (odds ratio [OR]: 4.96; p = 0.05) or mKRAS (OR: 1.81; p = 0.03). In multivariate analysis, KRAS G12V or G12C status was associated with both poor RR (OR: 0.1; p < 0.0001) and overall survival (OR: 3.41; p < 0.0001). CONCLUSION mEGFR are associated with higher RR to brain RT than wild-type EGFR/RAS or mKRAS.

The intrathoracic lymph node ratio seems to be a better prognostic factor than the level of lymph node involvement in lung metastasectomy of colorectal carcinoma

OBJECTIVES Data on thoracic lymph node involvement (LNI) in lung metastasis of colorectal cancer (CRC) are conflicting, with a 5-year overall survival (OS) ranging from 6 to 40%. We aimed to evaluate whether there are subgroups of patients according to the lymph node ratio (LNR). METHODS We retrospectively reviewed the data from 106 patients who underwent a thoracic procedure for CRC lung metastasis with pathologically proven thoracic LNI. RESULTS In the univariate analysis, the median OS was significantly poorer for a pN2 location of LNI (26 vs 16 months, P = 0.04), LNR ≥50% (30 vs 17 months, P = 0.005), high preoperative CEA (32 vs 16 months, P = 0.02), hepatic metastases (27 vs 11 months, P <0.0001) and disease-free survival < 24 months (32 vs 17 months, P = 0.05). When pN1 and pN2 patients were staged according to the LNR, the median OS was significantly better for an LNR <50% (27 vs 17 months for pN1, 32 vs 12 months for pN2, P = 0.01). In the multivariate analysis, a high preoperative CEA [hazard ratio (HR): 2.256 (1.051-4.841), P = 0.04], pN1 status [HR: 0.337 (0.162-0.7), P = 0.004] and the absence of hepatic metastases [HR: 0.395 (0.180-0.687), P = 0.02] remained significant prognostic factors. There was an upward trend for patients with LNR <50% [HR: 0.565 (0.296-1.082), P = 0.08]. Otherwise, low LNR was significantly associated with a decreased risk of loco-regional recurrence (HR: 0.36, 95% confidence intervals: 0.14-0.96, P = 0.04). CONCLUSIONS The LNR seems to be a more reliable prognostic factor than LNI for CRC lung metastasis. Prospective studies are necessary.

The prothrombotic paradox of severe obesity after cardiac surgery under cardiopulmonary bypass

BACKGROUND Obesity is suggested to reduce postoperative bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) but perioperative hemostasis variations have not been studied. Therefore, we investigated the effects of severe obesity (body mass index [BMI] ≥35kg/m(2)) on chest tube output (CTO) and hemostasis in patients undergoing cardiac surgery with CPB. MATERIALS AND METHODS We prospectively investigated 2799 consecutive patients who underwent coronary and/or valve surgery using CPB between 2008 and 2012. 204 patients (7.3%) presented a severe obesity. RESULTS In the severe obesity group, the 6-h and 24-h CTO were significantly reduced by -21.8% and -14.8% respectively (P<0.0001) compared with the control group. A significant reduction of the mean number of red blood cell units transfused at 24h was observed in the severe obesity groups (P=0.01). On admission to the intensive care unit, a significant increase of platelet count (+9.2%; P<0.0001), fibrinogen level (+12.2%; P<0.0001) and prothrombin time (+4.1%; P<0.01) and a significant decrease of the activated partial thromboplastin time (-4.2%; P<0.01) were observed in the severe obesity group compared with the control group. In multivariate analysis, severe obesity was significantly associated to a decreased risk of excessive bleeding (24-h CTO >90th percentile; Odds ratio: 0.37, 95% CI: 0.17 to 0.82). No significant differences were observed regarding postoperative thromboembolic events between the two groups. CONCLUSIONS Severe obesity is associated with a prothrombotic postoperative state that leads to a reduction of postoperative blood loss in patients undergoing cardiac surgery with CPB.

KRAS exon 2 codon 13 mutation is associated with a better prognosis than codon 12 mutation following lung metastasectomy in colorectal cancer

Introduction The utilization of molecular markers as routinely used biomarkers is steadily increasing. We aimed to evaluate the potential different prognostic values of KRAS exon 2 codons 12 and 13 after lung metastasectomy in colorectal cancer (CRC). Results KRAS codon 12 mutations were observed in 116 patients (77%), whereas codon 13 mutations were observed in 34 patients (23%). KRAS codon 13 mutations were associated with both longer time to pulmonary recurrence (TTPR) (median TTPR: 78 months (95% CI: 50.61–82.56) vs 56 months (95% CI: 68.71–127.51), P = 0.008) and improved overall survival (OS) (median OS: 82 months vs 54 months (95% CI: 48.93–59.07), P = 0.009). Multivariate analysis confirmed that codon 13 mutations were associated with better outcomes (TTPR: HR: 0.40 (95% CI: 0.17–0.93), P = 0.033); OS: HR: 0.39 (95% CI: 0.14–1.07), P = 0.07). Otherwise, no significant difference in OS (P = 0.78) or TTPR (P = 0.72) based on the type of amino-acid substitutions was observed among KRAS codon 12 mutations. Materials and Methods We retrospectively reviewed data from 525 patients who underwent a lung metastasectomy for CRC in two departments of thoracic surgery from 1998 to 2015 and focused on 150 patients that had KRAS exon 2 codon 12/13 mutations. Conclusions KRAS exon 2 codon 13 mutations, compared to codon 12 mutations, seem to be associated with better outcomes following lung metastasectomy in CRC. Prospective multicenter studies are necessary to fully understand the prognostic value of KRAS mutations in the lung metastases of CRC.

Ability of pulmonary function decline to predict death in amyotrophic lateral sclerosis patients

Abstract Objectives: Objectives were to evaluate the relative risk of death associated with lung function decline in patients with amyotrophic lateral sclerosis (ALS), and to examine the ability of ALS patients to perform volitional pulmonary function tests (PFTs). Methods: The PFTs of 256 consecutive patients referred to the Strasbourg University Hospital ALS Centre over an eight-year period were reviewed. Slow vital capacity (VC), maximal inspiratory and expiratory pressures (MIP, MEP), sniff nasal inspiratory pressure (SNIP), and peak cough flow (PCF) were performed at diagnosis and then every four months. The instantaneous risk of death associated with PFTs deterioration was calculated using time-dependent covariate Cox models. The changes of each PFT over time were examined and compared. Results: A total of 985 acceptable PFT sessions were recorded. The risk of death was significantly associated with the decline in pulmonary function, regardless of the PFT parameter and its expression. When VC, MIP/SNIP and MEP (% of predicted) decreased by 10%, or PCF decreased by 50 L/min, the risk of death was multiplied by 1.31 (95% CI 1.21–1.41), 1.48 (1.32–1.66), 1.54 (1.32–1.79), and 1.32 (1.19–1.75), respectively. MIP, SNIP and MEP were decreased earlier in the course of disease and plunged deeper than VC within months before death, but were more affected by learning effect. Conclusions: This study provides tools to calculate the increase in risk of death from a PFT decline. At an individual level, since each test showed some flaws, the use of a combination of PFTs for ALS respiratory monitoring is recommended.