Sex and gender perspectives in colorectal cancer.

Historically women were frequently excluded from clinical trials and drug usage to protect unborn babies from potential harm. As a consequence, the impact of sex and gender on both tumour biology and clinical outcomes has been largely underestimated. Although interrelated and often used interchangeably, sex and gender are not equivalent concepts. Sex is a biological attribute that defines species according to their chromosomal makeup and reproductive organ, while gender refers to a chosen sexual identity. Sex dimorphisms are rarely taken into account, in either preclinical or clinical research, with inadequate analysis of differences in outcomes according to sex or gender still widespread, reflecting a gap in our knowledge for a large proportion of the target population. Underestimation of sex-based differences in study design and analyses has invariably led to 'one-drug' treatment regimens for both males and females. For patients with colorectal cancer (CRC), sex also has an impact on the disease incidence, clinicopathological features, therapeutic outcomes, and tolerability to anticancer treatments. Although the global incidence of CRC is higher in male subjects, the proportion of patients presenting right-sided tumours and BRAF mutations is higher among females. Concerning sex-related differences in treatment efficacy and toxicity, drug dosage does not take into account sex-specific differences in pharmacokinetics. Toxicity associated with fluoropyrimidines, targeted therapies, and immunotherapies has been reported to be more extensive for females with CRC than for males, although evidence about differences in efficacy is more controversial. This article aims to provide an overview of the research achieved so far into sex and gender differences in cancer and summarize the growing body of literature illustrating the sex and gender perspective in CRC and their impact in relation to tumour biology and treatment efficacy and toxicity. We propose endorsing research on how biological sex and gender influence CRC as an added value for precision oncology.

Plasmatic BRAF-V600E allele fraction as a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments.

BACKGROUND: Combination of a BRAF inhibitor (BRAFi) and an anti-epidermal growth factor receptor (EGFR), with or without a MEK inhibitor (MEKi), improves survival in BRAF-V600E-mutant metastatic colorectal cancer (mCRC) over standard chemotherapy. However, responses are heterogeneous and there are no available biomarkers to assess patient prognosis or guide doublet- or triplet-based regimens. In order to better characterize the clinical heterogeneity observed, we assessed the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) for these combinations. PATIENTS AND METHODS: A prospective discovery cohort including 47 BRAF-V600E-mutant patients treated with BRAFi-anti-EGFR ± MEKi in clinical trials and real-world practice was evaluated. Results were validated in an independent multicenter cohort (n= 29). Plasmatic BRAF-V600E AF cut-off at baseline was defined in the discovery cohort with droplet digital PCR (ddPCR). All patients had tissue-confirmed BRAF-V600E mutations. RESULTS: Patients with high AF have major frequency of liver metastases and more metastatic sites. In the discovery cohort, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS [hazard ratio (HR) 2.97, 95% confidence interval (CI) 1.55-5.69; P = 0.001] and worse OS (HR 3.28, 95% CI 1.58-6.81; P = 0.001) than low-BRAF AF patients (<2%, n = 24). In the multivariable analysis, BRAF AF levels maintained independent significance. In the validation cohort, high BRAF AF was associated with worse PFS (HR 3.83, 95% CI 1.60-9.17; P = 0.002) and a trend toward worse OS was observed (HR 1.86, 95% CI 0.80-4.34; P = 0.15). An exploratory analysis of predictive value showed that high-BRAF AF patients (n = 35) benefited more from triplet therapy than low-BRAF AF patients (n = 41; PFS and OS interaction tests, P < 0.01). CONCLUSIONS: Plasmatic BRAF AF determined by ddPCR is a reliable surrogate of tumor burden and aggressiveness in BRAF-V600E-mutant mCRC treated with a BRAFi plus an anti-EGFR with or without a MEKi and identifies patients who may benefit from treatment intensification. Our results warrant further validation of plasmatic BRAF AF to refine clinical stratification and guide treatment strategies.

[Arrhythmia and sport]. / Arythmies du sportif.

Sports arrhythmia has gained wide attention with the mediatization of the death of famous sports stars. Sport strongly modifies the structure of the heart with the development of left ventricular hypertrophy which may be difficult to differentiate from that due to doping. Intense training modifies also the resting electrocardiogram with appearance of signs of left ventricular hypertrophy whereas resting sinus bradycardia and atrioventricular conduction disturbances usually reverts upon exertion. Accordingly, arrhythmia may develop ranging from extrasystoles to atrial fibrillation and even sudden death. Recent data suggest that if benign arrhythmia may be the result of the sole intense training and are reversible, malignant ventricular arrhythmia and sudden death mostly occur in unknown structural heart disease. Hypertrophic cardiomyopathy is amongst the most frequent post mortem diagnosis in this situation. Doping is now present in many sports and further threatens the athlete in the safe practice of sport.

Atypical atrial flutters.

Typical atrial flutter is due to a counterclockwise macro-re-entry circuit localized in the right atrium with a surface ECG pattern showing predominantly negative F waves in the inferior leads and positive F waves in V1. Recently it has been proposed to classify atrial flutter on the basis of its cavo-tricuspid isthmus dependence rather than on the ECG pattern. Therefore some atrial flutters are considered typical even if the ECG does not exhibit a typical pattern. This is the case for reverse typical atrial flutter, lower loop re-entry and partial-isthmus-dependent short circuit flutter. The term atypical flutter refers to a non-isthmus dependent flutter. Usually these patients have had previous cardiac surgery with a right or left atriotomy. Flutter involving a spontaneous right atrial scar is not uncommon.

Randomized comparison of two targets in typical atrial flutter ablation.

Typical atrial flutter ablation has become anatomically guided to 2 separate sites within the isthmus at the inferior right atrium: (1) between the inferior vena cava and the tricuspid annulus (anterior side of the isthmus [A]), (2) between the eustachian crest, the coronary sinus ostium and tricuspid annulus (posterior side of the isthmus [P]). We prospectively compared ablation results at these sites in 72 consecutive patients. Patients were randomized in group P or A according to the initial target site. If ablation failed at 1 site after 15 radiofrequency (RF) pulses, the other side of the isthmus was targeted. Before 15 RF pulses, complete bidirectional isthmus block was achieved in 30 of 36 group A patients and in 25 of 36 group P patients, with similar mean RF pulses number, procedure time, and fluoroscopy time. After shifting to the other target, success was finally obtained at P in 2 of 6 group A patients, and at A in 8 of 11 group P patients before a maximum of 30 RF pulses. Among successful patients, number of RF pulses, procedure time, and fluoroscopy time were significantly lower in group A (7.2 +/- 5.4 vs 11.0 +/- 8.1 pulses, p = 0.03; 131 +/- 44 vs 163 +/- 66 minutes, p = 0.03; 31 +/- 19 vs 46 +/- 24 minutes, p = 0.01, respectively). Impairment of atrioventricular (AV) nodal conduction occurred in 5 patients only during ablation at P. AV block was transient in 4 patients and permanent in 1. Although atrial flutter ablation is equally effective at P and A, success seems easier to obtain when A is first targeted. Ablation at P is associated with a significant risk of AV block.

High incidence of left atrial thrombus detected by transoesophageal echocardiography in heart transplant recipients.

The aim of the study was the detection of spontaneous echo contrast (SEC) and left atrial thrombus by transoesophageal echocardiography (TEE) in patients who had undergone orthotopic heart transplantation. TEE was prospectively performed in 64 heart transplant recipients (53 males, 11 females, mean age 51 years). Since surgery (mean time: 31 months), all heart transplant recipients had received either aspirin (39), or dipyridamole (22), or both (3). Despite the antiplatelet treatment, an acute arterial embolism (two strokes, one popliteal and one mesenteric ischaemia) occurred in four patients who subsequently received an oral anticoagulant therapy. TEE was performed with a biplane high-frequency transducer after lidocaine pharyngeal anaesthesia, midazolam intravenous injection and antibiotic prophylaxis. Mean ejection fraction was 63 +/- 10%. None had evidence of rejection at endomyocardial biopsy performed on the same day as TEE and analysed in a blinded fashion. All were in sinus rhythm. Left atrial SEC was found in 35 patients (55%) and was associated with left atrial thrombus in 18 patients (28%). These thrombi were localized in the donor left atrial appendage in 10 cases, on the posterior wall of the left atrium in six cases, on the donor part of inter-atrial septum in one case and on the suture line in one case. They were not detected by transthoracic echocardiography (TTE). When compared with patients without thrombus, no difference was found concerning left atrial size, left ventricular ejection fraction, pulmonary artery pressure and number of previous episodes of rejection. However, cardiac index was significantly lower in patients with left atrial thrombus.(ABSTRACT TRUNCATED AT 250 WORDS)

[Prevalence of intra-auricular thrombi detected by transesophageal echocardiography in patients with cardiac transplants]. / Fréquence des thrombus intra-auriculaires détectés par l'échocardiographie transoesophagienne chez les transplantés cardiaques.

The aim of this study was to determine the prevalence of intra-atrial thrombi or spontaneous contrast by transoesophageal echocardiography in patients who underwent cardiac transplantation by Lower and Shumway's technique. Transoesophageal echocardiography was performed in 52 transplant patients (43 men, 9 women: average age 51 years) with a high frequency biplane transducer. After surgery, all patients received platelet antiaggregant therapy. Despite this treatment, 4 patients had a sudden systemic embolic episode and were then placed on oral anticoagulants. All patients were in sinus rhythm at the time of the examination and some had signs of acute rejection on endomyocardial biopsy performed the same day. Spontaneous contrast was observed in 27 patients (52%) and was associated with thrombosis in 15 patients (29%). These thrombi were located in the left atrial appendage in 8 cases, on the left atrial posterior wall in 5 cases and on the left atrial sutures in 2 cases. None of these thrombi had been detected by transthoracic echocardiography. No significant difference was observed between those with and those without thrombosis with respect to left atrial dimensions, left ventricular ejection fraction, cardiac index, pulmonary pressures and the number of episodes of acute rejection. The 4 patients with a history of arterial embolism all had an intra-atrial thrombus. This study demonstrates a high incidence of spontaneous contrast and intracardiac thrombi in the dilated left atrium of patients transplanted by Lower and Shumway's technique. It also underlines the value of transoesophageal echocardiography in the follow-up of transplant patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic basis of catheter ablation in atrial flutter.

A reentrant mechanism is believed to be responsible for atrial flutter. The recent development of the entrainment criteria further supports this theory, and there is a general consensus that circus movement is the underlying abnormality that supports this arrhythmia. In most clinical studies, abnormal fragmented (or double spike) electrograms, suggesting the presence of areas of localized slowing of conduction or block, have been reported. They are almost always recorded in the lower and posterior portion of the right interatrial septum, but also frequently in the high lateral portion of the right atrium. The determination of their involvement in the reentry pathway is important for designing curative procedures such as surgery or ablation. The low atrial septal area surrounding the mouth of the coronary sinus was suspected as being the critical area of slow conduction in atrial flutter. Rapid pacing at that site can yield a surface electrocardiographic pattern similar to the clinically occurring arrhythmias. Additionally, the flutter circuit can be accelerated during atrial pacing at fixed and slightly faster rates than the intrinsic tachycardia rate--the so-called entrainment phenomenon. When entrainment criteria are fulfilled, tachycardia termination being by definition ruled out, any concomitant recorded local type II block identifies an area that must be outside the circuit. Such local block may be recorded either spontaneously or during entrainment and therefore helps in identifying atrial slow conduction areas that do not belong to the reentrant path. This approach was applied to identify the optimal ablation site in 8 patients with long-standing drug resistant atrial flutter. In 7 of 8 patients, we were able to identify a fragmented potential in the low posteroseptal area during sustained atrial flutter.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacological bases of the treatment of cardiac insufficiency]. / Bases pharmacologiques du traitment de l'insuffisance cardiaque.

Congestive heart failure is a complex physiopathological state where both myocardial hypo-contraction and excessive peripheral vasoconstriction lead to lower cardiac output. The increase in cytosolic calcium concentration triggers the contractile processus. Digitalis inhibits the Na+/K+ ATPase enzyme and indirectly increases intracellular calcium concentration. beta 1 agonists increase the synthesis of cAMP-dependent protein kinase and hence the recruitment of new receptor-operated calcium channels which increase the calcium influx and the mobilization from its intracellular storage sites. Vascular smooth muscle contraction occurs with calcium influx into the cell resulting from various receptor activation. In congestive heart failure, activation of the sympathetic nervous system and of the renin-angiotensin system leads to neurohumoral-induced peripheral vasoconstriction. Renal effects of angiotensin II and aldosterone are responsible for sodium and water retention. alpha 1-blocking agents are drugs that block competitively the catecholamines effects on vascular receptors. Angiotensin I-converting-enzyme inhibitors block the formation of the key-element of the system: angiotensin II. Both alpha 1-blocking agents and converting-enzyme inhibitors show vasodilatator effects and acutely improve hemodynamic status of patients with congestive heart failure. Converting-enzyme inhibitors exhibit specific improvement of intrarenal hemodynamics and do not induced sodium and water retention in longterm therapy.

Percutaneous transluminal balloon valvuloplasty of adult aortic stenosis: report of 92 cases.

Percutaneous transluminal balloon valvuloplasty was attempted in 92 adult patients with severe calcific aortic stenosis. The mean age was 75 +/- 11 years (range 38 to 91) and 35 patients were more than 80 years old. Most of the patients were severely disabled; 66 were in New York Heart Association functional class III or IV, 27 had syncopal attacks and 21 had severe angina pectoris. Because of unacceptably high surgical risk or contraindication to thoracic surgery, 42 patients could not be considered for valve replacement. Other patients either were in a category of high operative risk or refused the surgical intervention. Valvuloplasty was performed by way of the femoral route (82 patients) or the brachial route (10 patients). Catheters of size 15, 18 and 20 mm were successively placed across the aortic valve and three inflations were usually done with each of them, lasting 80 seconds on average, until a decrease in peak to peak systolic pressure gradient to 40 mm Hg or less was attained, a result considered satisfactory. The inflated balloons were not totally occlusive in most cases and clinical tolerance of inflation was good. Valvuloplasty resulted in a reduction of mean systolic gradient from 75 +/- 26 to 30 +/- 13 mm Hg (p less than 0.001); the final gradient was less than 40 mm Hg in 78 patients. Mean calculated aortic valve area increased from 0.49 +/- 0.17 to 0.93 +/- 0.36 cm2 (p less than 0.001). Immediately after the procedure, ejection fraction increased from 48 +/- 16 to 51 +/- 16% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Percutaneous transluminal valvuloplasty of acquired aortic stenosis in elderly patients: an alternative to valve replacement?

Percutaneous transluminal balloon catheter aortic valvuloplasty (PTAV) was carried out in three elderly patients with acquired severe aortic valve stenosis. Transvalvular systolic pressure gradient was considerably decreased at the end of the procedure, during which there were no complications. Increased valve opening was confirmed by angiography and echocardiography. Subsequent clinical course showed a pronounced functional improvement. PTAV is recommended as a simple alternative to aortic valve replacement in elderly and/or high-risk patients.

[Aortic stenosis with low preoperative ejection fraction. Long-term postoperative hemodynamic and angiographic studies]. / Rétrécissement aortique à fraction d'éjection pré-opératoire basse. Etude hémodynamique et angiographique à distance de l'intervention.

Twenty-two patients underwent aortic valve replacement for aortic stenosis with a preoperative ejection fraction less than 45%. Three patients died peroperatively and a fourth patient died 18 months later before the haemodynamic control. The other 18 patients were systematically reinvestigated, on average 16 months after surgery. Sixteen had a remarkable functional improvement and a significant increase in ejection fraction at haemodynamic control: 32 +/- 6% to 61 +/- 8%, p less than 0.001. They were surgical successes (Group I). In this group, the 7 patients with the most severe alteration of ventricular function and an average ejection fraction of: 26 +/- 3%, also improved to near normal function with a postoperative fraction of 62 +/- 11%. There was no significant improvement of the ejection fraction in 2 patients, and they were classified with the fatalities as surgical failures (Group II). The clinical, electrocardiographic, radiological, haemodynamic and angiographic data of these two populations were compared to try and identify preoperative indices of prognostic value. Only the angiographic left ventricular myocardial mass index (LVMI) was significantly higher in Group II (253 +/- 98 g/m2) than in Group I (156 +/- 56 g/m2, p less than 0.05). A discriminating analysis showed that the most important parameters to separate the 2 groups of patients were the LVMI and the thickness of the left ventricular wall. The marked increase of the postoperative ejection fraction in 3/4 of our patients confirmed the clinical value of valvular replacement justifying the indication for surgery in patients with severe aortic stenosis in spite of a severe alteration of left ventricular function.