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.

Respiratory variability of sinus node activation in humans: insights from ultra-high-density mapping.

PURPOSE: Experimental data suggest that shifts in the site of origin of the sinus node (SN) correlate with changes in heart rate and P wave morphology. The direct visualization of the effect of respiration on SN electrical activation has not yet been reported in humans. We aimed to measure the respiratory shifting of the SN activation using ultra-high-density mapping. METHODS: Sequential right atrial (RA) activation mapping during sinus rhythm (SR) was performed. Three maps were acquired for each patient: basal end-expiratory (Ex), end-inspiratory (Ins), and end-expiratory under isoproterenol (Iso). The earliest activation site (EAS) was defined as the earliest unipolar electrograms (EGM) with a QS pattern and was localized with respect to the ostium of the superior vena cava (SVC; negative values if EAS inside the SVC). RESULTS: In 20 patients, 49 maps in SR were acquired (20 Ex, 19 Ins, and 10 Iso). Expiratory (944 ± 227 ms) and inspiratory (946 ± 227 ms) SR cycle lengths were similar, but shortened under isoproterenol (752 ± 302 ms). Activation was unicentric in 33 maps and multicentric in 16: 4 during Ins, 10 during Ex, and 2 Iso. EAS location was significantly more cranial in expiration than in inspiration (0.27 ± 12.1 vs 5 ± 11.51 mm, p = 0.01). Iso infusion tends to induce a supplemental cranial shift (-4.07 ± 15.83 vs 0.27 ± 12.7 mm, p = 0.21). EAS were found in SVC in 22.7% of maps (30% Ex, 21% Ins, and 8% Iso). CONCLUSION: Inspiration induces a significant caudal shift of the earliest sinus activation. In one-third of the cases, sinus rhythm earliest activation is inside the SVC.

Accelerated idioventricular rhythm requiring catheter ablation in a child: The dark side of a benign arrhythmia.

A 12 year-old boy, with no history of cardiac disease, was referred to our department for evaluation of an incessant accelerated idioventricular rhythm (AIVR) complicated with severe left ventricular (LV) dysfunction and cardiogenic shock. Extensive diagnostic work-up failed to reveal any structural heart disease. During electrophysiological study, AIVR originated from the right ventricular endocardial anterior wall and was successfully ablated using remote magnetic navigation. LV function showed complete recovery four weeks after the procedure. This case highlights a life-threatening evolution of an arrhythmia generally presented as a benign entity in children.

[The use of transesophageal echocardiography to guide the trans-septal puncture. Practical guide, tips and tricks]. / Échocardiographie transœsophagienne pour guider la ponction transseptale. Guide pratique, astuces, particularités, pièges.

Transesophageal echocardiography is very useful to guide transseptal puncture for left atrial ablation procedures. This paper is a practical guide for the ultrasonographer who seeks to meet the expectations of the electrophysiologist, but also for young EP's in order to improve their understanding of the echocardiographical views and to ameliorate the communication between the two specialists. The tips and tricks of all the steps of the exam are presented.

[A non-fatal Nerium oleander self-poisoning: case report and discussion]. / Intoxication volontaire au laurier rose ; cas clinique et revue de la littérature.

Nerium oleander is potentially lethal plants after ingestion. We report a case of poisoning by these plants. Our patient complained of nausea, vomiting, and diarrhoea. He had bradycardia during first twelve hours. He was discharge after 3 days. All parts of these plants are toxic and contain a variety of cardiac glycosides including oleandrin. In most cases, clinical management of poisoning by N. oleander involves administration of activated charcoal and supportive care. Digoxin specific Fab fragments are an effective treatment.

[Usefulness of tricuspid annular displacement (TAD) to identify right ventricular dysfunction in normotensive patients with acute pulmonary embolism]. / Intérêt du tricuspid annular displacement (TAD) dans l'évaluation de la dysfonction ventriculaire droite au cours de l'embolie pulmonaire.

BACKGROUND: Echocardiographic criteria of right ventricular dysfunction (RVD) in acute pulmonary embolism (PE) differ among published studies. Assessment of RV systolic function remains difficult because of the RV's complex shape. We aimed to evaluate RV systolic function with TAD in patients (pts) with acute PE. TAD (QLAB, Philips Medical Imaging) was based on a tissue-tracking algorithm that is ultrasound beam angle independent for automated detection of tricuspid annular displacement. DESIGN: Prospective and observational study. METHODS: All adults' pts who were diagnosed with PE from December 2008 to December 2009 at Princess Grace Hospital, Monaco were eligible for this study after exclusion of history of heart failure. We evaluated 36 consecutive pts with PE (18 male, mean age 62.7 years), which underwent echocardiography, plasma BNP titration during the first day after admission, and a second echocardiography obtained within 48 hours before discharge. RESULTS: TAD value were significantly lower in pts with abnormal RV function by echocardiogram (15.9 ± 0.3 vs. 12.7 ± 0.2 ; P = 0.026). Pts with a normal BNP (<80 pg/ml) had an elevated TAD (16.4 ± 0.2 vs. 11.2 ± 0.3 mm ; P < 0.0001). At discharge, echocardiographic data were obtained from 33 pts (mean: 8.3 ± 3.5 days). RV end diastolic diameter, RV to LV diameter, pulmonary arterial systolic pressure, mean pulmonic valve acceleration time, RV FAC, Sa and TAD were significantly improved. There was no difference between TAD among pts with echocardiographic RVD at baseline vs. pts without RVD (14.9 ± 3.7 vs. 16.1 ± 2.9 mm ; P = 0.3). Four pts who deteriorated during short-term observation had substantially lower TAD values than those with uncomplicated courses (7.7 ± 0.4mm vs. 14.6 ± 0.2 mm ; P = 0.001). In conclusion, impaired TAD was associated with decreased RV systolic function in pts with acute PE. To identify the clinical meaning of decreased TAD, larger trials with longer follow-up periods are needed.

Magnetic navigation and voltage mapping guided implantation of a pacemaker atrial lead in a previously unpaceable patient.

We report successful implantation of the atrial pacing lead in a patient in whom such operation had previously failed with the manual approach. Right atrial (RA) electro-anatomical voltage mapping was used to identify an area suitable for pacing and magnetic navigation to allow exhaustive RA exploration leading to successful RA lead screwing.

[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.

[New concepts in the diagnosis and treatment of atrial flutter]. / Nouveaux concepts dans la prise en charge diagnostique et thérapeutique du flutter atrial.

Atrial flutter may now be very frequently and definitely cured in a single session of radiofrequency ablation. However, the very name of atrial flutter gives rise to a certain confusion. Clinical experience from everyday activity in ablation laboratories, especially since the introduction of new mapping techniques, has shown that this entity is in fact multiple. Flutters may be classified by their electrocardiographic appearance and/or their electrophysiological mechanism with as many prognostic as therapeutic implications. This article reviews diagnostic features of typical and atypical flutter and the different treatments which may be proposed in different clinical situations.

[Sinus-like tachycardias]. / Tachycardies d'allure sinusale.

Various tachycardias presenting with positive P waves in the standard leads are described in this article. Sinus tachycardia may occur as a normal adaptation reaction to the environment or in the setting of autonomic dysregulation. It may also be mimicked by various arrhythmias which share the earliest depolarisation in the sinus node area. The authors expose a review of these mechanisms.

[Ventricular tachycardia "in salvoes"]. / Les tachycardies ventriculaires en salves.

The term of ventricular tachycardia "in salvoes" describes electrophysiographic appearances of several consecutive ectopic ventricular beats without interposition of sinus rhythm. This is an intermediate arrhythmic state between isolated ventricular extrasystoles and sustained ventricular tachycardia. The generally accepted definition of the term "sustained" implies a duration of over 30 seconds or poor haemodynamic tolerance. Strictly speaking, the term "salvoe" has no precise definition in cardiology. In the 1996 edition of the Petit Robert French dictionary, the term is defined as the simultaneous discharge of guns or successive blasts of canons. The Delaware medical dictionary does not provide a French definition of the term "salvoe". In practice, we use the term tachycardia in salvoes in the same meaning as ventricular tachycardia. Schematically, in clinical practice, two situations may be encountered. In the first case, salvoes of VT are recorded in apparently normal hearts; they are not life-threatening and, though often nearly asymptomatic, they may pose therapeutic problems. In the second case, the arrhythmia occurs in a diseased heart, with a low ejection fraction, in which the essential problem is the vital prognosis.

[The best of arrhythmias in 2002]. / L'essentiel de 2002 en rythmologie.

In the era of evidence based medicine the year 2002 will be remembered principally for having brought the results of two large trials in areas of daily preoccupation for rhythmologists: those of atrial fibrillation and of prevention of rhythmic sudden death. The Atrial Fibrillation Following Investigation of Rhythm Management (AFFIRM) study compared strategies for controlling frequency and rhythm in atrial fibrillation for subjects aged over 65 years or having at least one risk factor for cerebral vascular accident. In an unexpected fashion, although in accordance with other recent results, the two strategies are equivalent in terms of mortality. It also underlined the necessity of continuing anticoagulation with an INR > 2. even when it is proposed to maintain the rhythm. In the matter of primary prevention of sudden coronary death, the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) had the originality of evaluating patients with no other risk factor than a severe alteration in left ventricular ejection fraction (30% Pounds). This "simple" selection of patients at risk allowed a mortality reduction of 30% to be demonstrated by the placement of a ventricular defibrillator, in addition to that brought about by optimal conventional treatment. In the chapter on syncope, the Framingham study delivers information in terms of incidence and long term prognosis, in a non selected population. Even if these results are difficult to compare with those recent studies using notably the inclination test, they remind us of the poor prognosis of cardiac origin syncope and the absence of excess mortality in patients affected by vagal syncope. The significance of these very wide series does not preclude drawing the greatest attention to the work by the Bordeaux team who have been able to provide evidence, in 27 patients with relapsing idiopathic ventricular fibrillation, of the initiator role of extra-systoles originating from the distal Purkinje network. A medium term cure was obtainable by ablation of these extra-systoles. This work of course allows the prospect of application to other types of malign ventricular arrhythmias.

[Sudden death and semi-automatic defibrillation]. / Mort subite et défibrillation semi-automatique.

While cardiac arrest in hospital poses few immediate management problems, this is not the case outside hospital. For this reason semi-automatic defibrillators are easy to handle devices designed to deliver an early electric shock in the context of usage by non-specialist people following minimum training. These devices have shown a clear improvement in survival compared to the exclusive use of a manual defibrillator by highly trained emergency services, especially in confined areas such as casinos or aircraft, or where a significant number of potential patients are concentrated, such as airports. It is now important to be able to improve public access to defibrillation by various means currently being studied, and probably by relaxing the rules which allow the use of these devices.

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.

[Nodal conduction]. / La conduction nodale.

The existence of a single atrio-ventricular fascicle had been suggested in the 19th century by Wilhelm His junior. In 1906, Sunao Tawara described in details the existence of a specific muscular fascicle in charge of the atrio-ventricular conduction. Since, it has remained famous under the name of atrio-ventricular node. It is located in the apical part of the Koch triangle. It is 5 to 7 mm long and 2 to 5 mm wide and includes often an enlargement of its compact portion along the fibrous annulus to the coronary sinus ostium which seems to be associated with the development of a intra- or atrio-nodal re-entry circuit. Its action potentials are qualified as "slow response" and propagate with a speed of 0.02 to 0.05 m/sec (which is comparable to that present in the sinus node). This propagation slowness explains the PR interval on surface EKG tracings and the AH interval in intra-cardiac electrogram. When AV node cells are requested by a rapid atrial rhythm, their physiological response is made under the mode of beatings group described by Luigi Luciani and Karel Wenckebach, prior to the EKG's invention. The atrio-ventricular physiological relationship during the atrial acceleration is made according to the Luciani-Wenckebach mode and then 2/1 mode as described in the non-linear dynamics theory. The most frequent pathological of the nodal conduction are the atrio-ventricular blocks and nodal duality. They are described and commented in this article. The nodal conduction disturbances are currently accessible to different therapeutic patterns such as cardiac pacing or ablative techniques. Nonetheless the innermost mechanism are still incompletely identified and will for sure be a matter of numerous studies in the future.

Myocardial connections between left atrial myocardium and coronary sinus musculature in man.

INTRODUCTION: Anatomic studies have shown that muscle morphologically identical to that of the atrial myocardium consistently surrounds the coronary sinus (CS). The CS musculature is connected to the left atrial (LA) myocardium in a variable fashion, with fewer connections in its distal portion. The aim of this study was to document the presence of connections between the LA myocardium and the CS musculature, using pacing maneuvers in man, and to study their potential association with natural atrial arrhythmia occurrence. METHODS AND RESULTS: Thirty patients (19 men; mean age 50.5 years) underwent electrophysiologic study, during which a decapolar catheter with 2-mm interelectrode spacing every 10 mm was inserted into the CS, with the proximal electrode pair positioned at the ostium. Associated atrial arrhythmias were paroxysmal atrial fibrillation in 5, typical atrial flutter in 13, LA flutter in 1, and other in 11. Baseline S1 and a single extrastimulus were delivered during distal and proximal CS pacing, while recordings were obtained from the four remaining bipoles. During distal CS pacing, double potentials with increasing interpotential interval from proximal to distal CS as a function of extrastimulus prematurity were detected in nine patients, suggesting block in a discrete local pathway distally connecting the CS to the LA and leading to reversion of low LA activation. Local delay in this pathway without complete CS-LA block resulting in LA activation fusion was observed in eight patients. A single nonfractionated potential at the distal CS, even at the shortest attainable S1-S2 coupling interval, which was interpreted as no block within distal CS-LA connection(s), was observed in the other 13 patients. History of atrial fibrillation or atypical atrial flutter was found in 8 of 9 patients with block at the distal CS-LA connection but in only 3 of 13 patients with no CS-LA connection block (P = 0.004). CONCLUSION: The ability to dissociate the LA from the distal CS suggests the presence of discrete connections between these structures in man. This observation appears to be associated with the clinical occurrence of atrial arrhythmias.

Classification of atrial flutter and regular atrial tachycardia according to electrophysiologic mechanism and anatomic bases: a statement from a joint expert group from the Working Group of Arrhythmias of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.

Regular atrial tachycardias classically are classified into flutter or tachycardia, depending on the rate and presence of a stable baseline on the ECG. However, current understanding of electrophysiology atrial tachycardias makes this classification obsolete, because it does not correlate with mechanisms. The proposed classification is based on electrophysiologic mechanisms, defined by mapping and entrainment. Radiofrequency ablation of a critical focus or isthmus can afford proof. Focal tachycardias are characterized by radial spread of activation and endocardial activation not covering the whole cycle. Ablation of the focus of origin interrupts the tachycardia. The mechanism of focal firing is difficult to ascertain by clinical methods. Macroreentrant tachycardias are characterized by circular patterns of activation that cover the whole cycle. Fusion can be shown during entrainment on the ECG or by multiple endocardial recordings. Ablation of a critical isthmus interrupts the tachycardia. Macroreentry can occur around normal structures (terminal crest, eustachian ridge) or around atrial lesions. The anatomic bases of these tachycardias must be defined, to guide appropriate treatment. Atrial flutter is a mere description of continuous undulation on the ECG, and only some strictly defined typical flutter patterns correlate with right atrial macroreentry bounded by the tricuspid valve, terminal crest, and caval vein orifices. This classification should be considered open, as some classically described tachycardias, such as reentrant sinus tachycardia, inappropriate sinus tachycardia, and type II atrial flutter, cannot be classified accurately. Furthermore, the possibility of fibrillatory conduction makes the limits with atrial fibrillation still ill defined.

[Atypical flutters]. / Flutters atypiques.

Typical atrial flutter may now be definitely treated in a single session. However, the very meaning of the term, atrial flutter, is confusing because it is a multiple entity. In fact, flutters may be classified with respect to their electrocardiographic and electrophysiological features. In addition to typical common atrial flutter with biphasic, predominantly negative F waves in the inferior leads and positive F waves in V1 due to an anticlockwise macro-reentry circuit localised to the right atrium, there are other forms which may be described as typical in that they pass through the cavo-tricuspid isthmus. They include typical flutter with inverted rotation, short loop inferior flutter and flutter with a double reentry circuit. In 2001, it would seem licit to call all flutters which do not pass through the cavotricuspid isthmus atypical, independently of their surface ECG appearances. The term flutter still refers to a continuous electrical activity with absence of an isoelectric line in at least one lead but with extremely variable ECG features. They may be classified as flutter on pre-existing lesions, with right or left atrial macro-reentry circuits. The ECG appearance is then that of very atypical flutter. More recently, flutters with circuits passing through the coronary sinus have been described. Ablation of the muscle of the coronary sinus seems to be able to treat this type of flutter, the prevalence of which is not yet known.