Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. PATIENTS AND METHODS: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). RESULTS: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. CONCLUSIONS: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

Neonatal and pediatric ECMO organization in France: A national survey.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) in France has increased since the H1N1 pandemic in 2009. By contrast, neonatal and pediatric ECMO support in France was known to be limited to a few centers offering congenital cardiac surgery. The purpose of this survey conducted in 2017 was to identify the neonatal and pediatric ECMO centers in France as well as networks existing between ECMO and non-ECMO centers. RESULTS: Seventy-two neonatal or pediatric intensive care unit medical directors answered the survey (84% of the centers surveyed). Twenty were identified as ECMO centers, defined as a unit able to start ECMO with its own resources. ECMO centers ranged from 470,000 to 1,180,000 inhabitants (neonates or children under 18). Thirteen of them (65%) reported that they were affiliated with a congenital cardiac surgery department. A total of 187 patients were supported with ECMO in these centers in 2016. Only six of these centers estimated an activity greater than 15 cases per year over the last 5 years. Nearly 30% of ECMO runs were indicated before or after congenital heart surgery. Four of the ECMO centers offered off-site facilities (mobile team). Non-ECMO centers are likely to be neonatal intensive care units. Nine of them (18.7%) declared knowing an ECMO center that provided mobile care with predefined organization, 11 (22.9%) reported knowing an ECMO center providing a mobile activity without predefined organization, nine (18.%), and 18 (37.5%) ICUs declared they knew of the existence of an ECMO program but did not report any possibility of mobile care or any procedure for transfer. CONCLUSIONS: Of the centers reporting the highest case volumes, four offered mobile ECMO abilities. Well-organized networks for the most severe neonates and children were not identified in France.

Early detection of postoperative acute kidney injury by Doppler renal resistive index in cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Acute kidney injury (AKI) is common after cardiac surgery, affecting outcome. Early detection of an AKI marker is likely to speed diagnosis and implementation of measures to preserve renal function. In septic shock and unselected ventilated subjects, an increased Doppler renal resistive index (RRI) is a predictor of AKI. This study aims to determine whether RRI would act similarly in the postoperative setting of cardiac surgery. METHODS: This study included 65 subjects aged more than 60 yr undergoing elective heart surgery with cardiopulmonary bypass (CPB) and at risk of AKI. All presented at least one AKI risk factor [arteritis, diabetes, or serum creatinine (sCr) clearance of 30-60 ml min(-1)] and were haemodynamically stable without arrhythmia. Doppler RRI was measured in the immediate postoperative period (POP) while subjects were ventilated and sedated. AKI was assessed when sCr increased 30% above the preoperative baseline. RESULTS: Eighteen subjects developed AKI between days 1 and 4, with six requiring dialysis. RRI in the POP was increased in AKI [RRI: 0.79 (0.08) with AKI vs 0.68 (0.06) without AKI, P<0.001], correlating to AKI severity [0.68 (0.06) without AKI, 0.77 (0.08) with AKI but no dialysis, and 0.84 (0.03) with AKI and dialysis, P<0.001]. RRI was similar in subjects receiving catecholamines. RRI >0.74 in the POP predicted delayed AKI with high sensitivity and specificity (0.85 and 0.94, respectively). Multivariate analysis showed that AKI was associated with increased RRI and transfusion. CONCLUSIONS: RRI used in the immediate POP after cardiac surgery with CPB enabled prediction of delayed AKI and anticipation of its severity.

A non-invasively determined surrogate of cardiac power ('circulatory power') at peak exercise is a powerful prognostic factor in chronic heart failure.

OBJECTIVES: This study was designed to assess the prognostic value of a new variable derived from a cardiopulmonary exercise test, the circulatory power, a surrogate of cardiac power, at peak exercise, in patients with chronic heart failure. BACKGROUND: Peak exercise cardiac power and stroke work are invasive parameters with recently proven prognostic value. It is unclear whether these variables have better prognostic value than peak oxygen uptake (VO(2)). METHODS: The study population comprised 175 patients with chronic heart failure (ejection fraction <45%) who underwent a cardiopulmonary exercise test. Circulatory power and circulatory stroke work were defined as the product of systolic arterial pressure and VO(2) and oxygen pulse, respectively. Prognostic value was assessed by survival curves (Kaplan-Meier method) and uni- and multivariate Cox analyses. RESULTS: With a mean follow-up of 25+/-10 months, ejection fraction, heart rate, systolic arterial pressure, peak VO(2), VCO(2), the anaerobic threshold, minute ventilation, the ventilatory equivalents of oxygen and carbon dioxide, the half times of VO(2) and VCO(2) recoveries, and the circulatory stroke work and power predicted outcome. Multivariate analysis demonstrated that the peak circulatory power (chi-square=19.9, P<0.001) (but not peak circulatory stroke work) was the only variable predictive of prognosis. CONCLUSION: The prognostic value of cardiopulmonary exercise tests in heart failure patients can be improved by assessing a new variable, the circulatory power - a surrogate of cardiac power - at peak exercise.

Evidence of cardiac myolysis in severe nonischemic heart failure and the potential role of increased wall strain.

BACKGROUND: Myocyte death could play a role in heart failure (HF) irrespective of the presence of coronary artery disease. The study aimed to assess this hypothesis by use of the cardiac troponin I (cTnI) assay. METHODS AND RESULTS: Seventy-one patients with nonischemic HF, New York Heart Association (NYHA) class II-IV, with a normal coronary angiogram and after exclusion of myocardiopathies were evaluated in the study. The control group included 9 healthy subjects and 15 patients hospitalized for severe noncardiac dyspnea. Cardiac TnI concentrations were determined at admission with a research reagent (cTnIus) characterized by a detection limit of 0.026 ng/mL and a high analytic sensitivity of 0.002 ng/mL. cTnIus levels were more than 0.026 ng/mL in 19 HF patients, ranging between 0.027 and 0.463 ng/mL, whereas no cTnIus level was detectable in the control group. With use of a reference assay, only 2 HF patients had abnormal cTnI values. Severe HF was observed in 17 of these 19 patients, assessed by NYHA class IV or by the presence of pulmonary edema. Patients with an increased cTnIus level had a more restrictive mitral Doppler pattern (P <.001) and a more distinctive left ventricular (LV) concentric remodeling (P <.0001), whereas LV ejection fraction was similar in both HF groups. The increased cTnIus level was also associated with a LV wall strain biologic marker (ie, an increased brain natriuretic peptide plasma level) (P <.001). CONCLUSIONS: cTnI assay is a promising biochemical method for detecting cardiac myolysis in HF, independent of the presence of coronary artery disease. This subtle myolysis could be in part related to the severely increased LV wall strain.

[Management of severe acute pulmonary edema]. / Prise en charge de l'oedème aigu pulmonaire grave.

Acute cardiogenic pulmonary oedema is a medical emergency. It generally result from an acute left ventricular insufficiency, itself resulting from systolic or diastolic dysfunction (alteration in relaxation or distensibility). Clinical presentation may be atypical, especially in the elderly. Treatment is based on oxygen, diuretics and nitrates. In severe cases, mechanical ventilation may be required.

[Brain natriuretic peptide (BNP) in coronary insufficiency: relationship with left ventricular filling and exercise tolerance]. / Brain natriuretic peptide (BNP) dans l'insuffisance cardiaque: relations avec le remplissage ventriculaire gauche et la tolérance à l'effort.

Brain natriuretic peptide (BNP) is a recently discovered peptide, secreted by the atria and ventricles in response to parietal distension. It was recently proposed as a screening test for left ventricular failure. The authors assayed this peptide at rest in 37 patients with chronic heart failure due to left ventricular systolic dysfunction and another 20 patients with various diseases (respiratory failure, cirrhosis, heart transplantation, "diastolic" heart failure) but normal left ventricular systolic function. A significant increase compared to normal values was observed not only in the group of heart failure patients, but also in patients with all other diseases. BNP was significantly higher in NYHA class IV patients. The relationship between plasma BNP levels and ejection fraction was not significant. On the other hand, a good correlation was observed between BNP and left ventricular filling parameters evaluated by cardiac Doppler: E wave deceleration time (r = -0.53, p = 0.001), E/A ratio: r = 0.57 p = 0.005) or VO2 max (r = -0.55, p < 0.005).

[Use of carvedilol in daily practice]. / Utilisation du carvedilol en pratique quotidienne.

Studies conducted over recent years have definitively confirmed beta-blockers as the major treatment for heart failure. However, they are difficult to use and, to date, only carvedilol has been granted a Marketing Authorisation for this indication. The practical aspects of treatment with carvedilol in these patients are reviewed.

[A case of a dizygotic twin pregnancy where superfetation seems indisputable]. / A propos d'un cas de grossesse gémellaire dizygotique où la superfoetation paraît peu contestable.

A case of superfoetation is presented. Difference of age (3 weeks) between twins was established by ultrasound at 10 weeks, and persisted through subsequent echographic surveillance up to delivery at 39 of amenorrhea with twin 39 and 36 weeks old. Only three publications in recent international literature are related to superfoetation. An attempt is made to try to understand superfoetation and to clearly differentiate it from superovulation.

[The progesterone releasing I.U.D. Its indications in function of the menstrual disorders (author's transl)]. / Indications du stérilet progestatif en fonction des troubles du cycle menstruel.

Progesterone releasing I.U.D. improves dysmenorrhea and hypermenorrhea. This type of I.U.D. may be used whereas other I.U.D. are contra indicated. But over all it is a new kind of drug delivery system which could be used with other medications, for other purposes than contraception.