Effect of Treatment of Residual Disease After Immunotherapy-Based Combinations on Complete Response Rate of Patients With Metastatic Renal Cell Carcinomas.

INTRODUCTION: Immune checkpoint inhibitor (ICI)-based combinations have revolutionized the management of first-line metastatic renal cell carcinoma (mRCC) by improving patient survival. Large phase 3 randomized trials assessing ICI-based combinations have reported complete response (CR) rates of 10% to 18% in the first-line setting. However, there is a scarcity of data about the effect of treatment of residual disease regarding CR rates improvement. MATERIALS AND METHODS: We included retrospectively all consecutive mRCC patients treated in first-line setting at the Institut de Cancérologie Strasbourg Europe with an ICI-based combination involving ICI or TKI, either alone or with added local treatment of residual disease. Patients were characterized according to IMDC risk. Radiologic response was defined according to RECIST v1.1. RESULTS: We enrolled 80 mRCC patients treated with ICI-based combinations between May 2015 and May 2022. The median age was 63 years. Regarding IMDC risk, there were 12 favourable (15%), 50 intermediate (63%), and 18 poor-risk (22%) patients. Forty-seven patients (59%) received ICI + ICI, 24 (30%) received ICI + TKI, and 9 (11%) received another ICI-based therapy. In total, 8 achieved CR (10%), 36 patients (45%) achieved partial response, 23 (29%) achieved stable disease and 12 achieved progressive disease (15%) as the best response with systemic therapy alone. By adding local treatment of residual disease, 11 additional patients (14%) achieved radiological NED. Residual disease resected sites included kidney (n = 6), lymph nodes (n = 5), lung metastases (n = 2) and liver metastases (n = 1). CONCLUSIONS: The resection of residual disease after first-line ICI-based therapy is associated with improved CR rate (CR + NED) in patients with mRCC. These results need to be validated in prospective trial. PATIENT SUMMARY: In recent years, the advent of immunotherapy has radically changed the management of patients with metastatic kidney cancer. Approximately 10% to 18% of these patients using immune checkpoint inhibitor (ICI)-based combinations no longer have detectable disease on CT scans (complete response). There are currently few data on the use of treatment of residual disease to increase the number of patients in complete response. In this retrospective study, the complete response rate with ICI-based treatment was 10%. When local treatment was added, the number of patients with a complete response increased to 24%. This strategy could increase the number of patients with a prolonged complete response in the future.

Capecitabine efficacy after cycline-dependent-kinase 4/6 inhibitor plus endocrine therapy in metastatic hormone receptor-positive breast cancer.

BACKGROUND: The combination of endocrine treatment with cycline-dependent-kinase 4/6 inhibitor is the new standard of treatment in hormone receptor-positive HER2 negative metastatic breast cancer. The optimal subsequent treatment after CDK4/6 inhibitor remain unclear. As recommended by standard guidelines, capecitabine, an oral chemotherapy is a therapeutic option in endocrine resistant metastatic breast cancer. The objective of this study was to evaluate capecitabine efficacy after disease progression under combination of ET and CDK4/6 inhibitor in a hormone receptor positive metastatic breast cancer population. PATIENTS AND METHODS: Patients progressing under CDK 4/6 inhibitor plus ET and treated with capecitabine, between January 2016 and December 2020, were retrospectively included. Primary endpoint was time to treatment failure (TTF) on capecitabine. Logistic regression were used to identify predictive factors: exclusive bone versus visceral metastases, first-line versus ≥ 2 lines of combination therapy, aromatase inhibitor (AI) versus fulvestrant. RESULTS: Fifty-six patients with a 62-year median age (IC95% 42-81) were analyzed. The CDK 4/6 inhibitor and ET combination was prescribed in first-line setting in 26 patients (46%). Twenty-five patients (44%) had exclusive bone metastasis. Median TTF was 6.1 months. Six patients discontinued capecitabine due to toxicity. Outcomes were not significantly different regardless of metastases localization, ET, and treatment line of the combination of CDK 4/6 inhibitor and ET. Median PFS was 7.1 months. Median OS was 41.3 months. CONCLUSION: Compared to other data of capecitabine prescribed in patients with hormonal resistant MBC, this retrospective study suggests that capecitabine remains effective after CDK 4/6 inhibitor plus ET progression, regardless of therapeutic-line setting and metastases localization. MICRO ABSTRACT: Cycline dependant kinase 4/6 inhibitor plus endocrine therapy have become the standard of care in metastatic hormone receptor positive (HR+) breast cancer (BC). Few data reported the optimal subsequent therapy after progression under the combination. Capecitabine is a therapeutic option in endocrine resistant HR+/HER2- metastatic breast cancer. Data evaluating efficacy of capecitabine after disease progression on endocrine therapy plus cycline-dependant kinase 4/6 inhibitor are poor. This study showed a 6.1-month median time to treatment failure on capecitabine. Capecitabine remained effective regardless of therapeutic-line setting and metastases localization.

A propensity score-weighted study comparing a two- versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer.

PURPOSE: A 4-weekly schedule of pegylated liposomal doxorubicin (PLD) has been approved for the treatment of metastatic breast cancer (MBC). Phase II trials have suggested interest in a 2-weekly regimen. This study aimed to compare the efficacy and safety of these two schedules. METHODS: Data from MBC patients treated with PLD between 2011 and 2021 were retrospectively collected. The objective was to demonstrate the noninferiority of the 2-weekly versus the 4-weekly schedule in terms of 6-month progression-free survival (PFS). The prespecified noninferiority margin was calculated as 1.20. A propensity score to receive either schedule was estimated using a gradient boosting algorithm. Survival analyses using Cox regression models weighted by the propensity score were performed to compare the schedules. RESULTS: Among the 192 patients included, 96 (50%) underwent each schedule. The median number of previous systemic therapies was 4 (IQR, 3 to 6). Anthracyclines were previously given in early breast cancer in 63.9% of patients. The median follow-up was 10.0 months (IQR, 5.0 to 20.1). A comparable distribution of adverse events was observed. The median PFS was 3.2 months (95% CI, 2.9 to 3.9), and the median overall survival was 12.1 months (95% CI, 10.8 to 14.9). The weighted hazard ratio for PFS was 1.12 (90% CI, 0.82 to 1.54), including the noninferiority boundaries. CONCLUSION: PLD appeared to be a well-tolerated drug in this heavily pretreated MBC population. The efficacy and safety of the 2-weekly schedule did not provide any advantage, suggesting no interest in changing the registered regimen.

[How I TREAT AN ASYMPTOMATIC AORTIC STENOSIS?]. / COMMENT JE TRAITE... la sténose aortique asymptomatique.

Aortic stenosis (AS) is the most common valvular heart disease in adults. The most frequent aetiology is now degenerative AS. There is general agreement that, in the absence of serious co-morbidity, surgery must be recommended for patients with symptomatic disease. The management of asymptomatic patients with severe aortic disease remains controversial for several reasons: sudden death in asymptomatic patients has been reported with an incidence < 1 % per year. In addition, operative mortality is significantly higher in symptomatic, when compared with asymptomatic, patients. Patients should be carefully educated about the importance of follow-up and reporting symptoms as soon as they develop. Echocardiography confirms the diagnosis and the severity of aortic stenosis. Exercise testing may be helpful when the patient is asymptomatic. If the patient develops symptoms during test, he should be referred for surgery. The management of patients with AS in everyday practice is based on the guidelines developed by ESC in October 2012.

[Myocardial infarction on spontaneous coronary dissection caused by fibromuscular dysplasia]. / Le cas clinique du mois : Infarctus du myocarde sur dissection coronaire spontanée secondaire à une dysplasie fibromusculaire.

Spontaneous Coronary Artery Dissection (SCAD) is a non-traumatic and non-iatrogenic separation of the coronary arterial wall. Although uncommon, it should be suspected in any young patient with acute myocardial infarction especially without risk factor of cardiovascular disease. Early coronary angiography is essential in the diagnosis of SCAD. Fibromuscular dysplasia is a rare cause of SCAD, particularly encountered in young women. This is a nonatherosclerotic and noninflammatory vascular disease. Fibromuscular dysplasia may cause stenosis, aneurysm, dissection and / or occlusion of arteries. It most commonly affects the renal and cerebral arteries.

La dissection spontanée d'une artère coronaire est définie comme une séparation non traumatique et non iatrogène de la paroi artérielle coronaire. Bien que rare, elle devrait être suspectée chez tout jeune patient qui présente un infarctus aigu du myocarde, surtout s'il ne présente aucun facteur de risque cardio-vasculaire. Le diagnostic est posé lors de la coronarographie réalisée en urgence. La dysplasie fibromusculaire est une cause rare de dissection spontanée d'une artère coronaire, particulièrement rencontrée chez les jeunes femmes. Il s'agit d'une maladie de la paroi artérielle, dont l'origine n'est ni athéromateuse ni inflammatoire, entraînant des sténoses, anévrismes, dissections et/ou occlusions, touchant particulièrement les artères à visée cérébrale et rénale.

[ACUTE CORONARY SYNDROME AND LIPID-LOWERING THERAPY. DOES THE IMPROVE-IT STUDY MAKE ANY DIFFERENCE?]. / Syndrome coronarien aigu et traitement hypolipémiant. L'étude IMPROVE-IT change-t-elle la donne?

Statins reduce both LDL cholesterol (LDL-C) levels and the risk of cardiovascular events in patients with and without cardiovascular disease. Intensive statin therapy, compared with moderate-dose statin therapy, incrementally lowers LDL-C levels and rates of cardiovascular events in patients presenting with acute coronary syndrome. Ezetimibe, by diminishing the absorption of cholesterol from the intestine, additionally reduces LDL-C when added to statins. In this article, we discuss the potential benefits of the combination of simvastatin and ezetimibe for the long-term management of patients with acute coronary syndrome through an analysis of the IMPROVE-IT results (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial). This randomised double blind trial included 18,144 patients with a LDL-C of 50 to 100 (with statin) or 125 (without statin) mg/dl and had a median follow-up of 6 years. The objective of the study was to test the efficacy of simvastatin 40 mg versus simvastatin 40 mg and 10 mg ezetimibe. The primary endpoint included cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization. The addition of ezetimibe to simvastatin resulted in an incremental lowering of LDL-C (reached value 53.2 versus 69.9 mg/dl, p < 0.001) and a further improvement of the patient prognosis (relative reduction of primary endpoint: -6.4%, p = 0.016). In addition, the combined therapy showed no significant adverse effects, particularly regarding the risk of cancers, which confirms the safety of ezetimibe. In acute coronary syndrome, the prescription of ezetimibe should be considered (class HA, level of evidence B) in patients with a LDL-C a 70 mg/dl despite maximally tolerated dose of statin.

[Asymptomatic severe aortic stenosis with preserved left ventricular ejection fraction. Evaluation by exercise test: which results and which decision?]. / Sténose aortique sévère asymptomatique à fraction d'éjection ventriculaire gauche préservée. Évaluation à l'effort : quels résultats et quelles décisions ?

Aortic stenosis is the most common valvular heart disease in Europe and North America and it is a real public health problem. Its prevalence increases with population aging. Symptomatic patients require surgery (class I, level of evidence B). In asymptomatic patients, a stress test with or without imaging is recommended to unmask the false asymptomatic patients and refine risk stratification of occurrence of major events. This support remains difficult and makes the optimal timing for surgery controversial in the absence of prospective data on the determinants of aortic stenosis progression, multicenter studies on risk stratification or randomized studies on patient management. The complexity of care arises from the balance between the spontaneous disease risk (risk of sudden death and irreversible left ventricular dysfunction) and the risk of surgery and prosthetic complications. It is therefore crucial to identify subgroups of patients at risk of pejorative progression in whom prophylactic surgery may be considered. This article focuses on evaluating during exercise asymptomatic patients with severe aortic stenosis and preserved left ventricular ejection fraction. We will explain how to perform the test, determine which echocardiographic measurements should be obtained, focusing on the diagnostic and prognostic value of these measurements and discuss indications for surgery according to new practice guidelines.

[How I explore a case of suspected arrhythmogenic right ventricular dysplasia]. / Comment j'explore...une suspicion de dysplasie arythmogène du ventricule droit.

Arrhythmogenic right ventricular dysplasia is a rare, but not exceptional pathology combining the occurrence of potentially fatal arrhythmias with a gradual deterioration of the structure and function of the right ventricle. In this article, we discuss the etiopathology of the disease and emphasize the diagnostic approach.

[Perioperative management of direct oral anticoagulants: not much evidence but several different approaches]. / Gestion péri-opératoire des nouveaux anticoagulants oraux: peu de données mais plusieurs approches!

New oral anticoagulants (NOACs) are a major step forward in the field of anticoagulation. As a consequence, the number of patients treated with NOACs that have to undergo surgery constantly increases. The optimal management of such patients is not clearly determined so far as scientifically established data are lacking. A first proposal is to mimic the perioperative management of patients on vitamin-K antagonists. When the risk of perioperative bleeding is low, NOAC intake is stopped 24 hours before surgery. If the risk of postoperative hemorrhage is moderate or high, NOAC treatment is interrupted 5 days before surgery with a low molecular weight heparin bridging whenever necessary. A second option is based on pharmacokinetic data. When the risk of perioperative bleeding is low, NOAC intake is stopped the day before surgery. If the risk of perioperative bleeding is higher, NOAC intake is suspended for 5 half lives before surgery, 48-72 hours or more. This interruption should be for a longer period in the presence of renal failure. When an unforeseen surgery is needed, the procedure must be delayed as late as possible. In case of emergency, non specific pro-hemostatic agents such as prothrombin complexes or recombinant factor VIIa have not strongly proven useful and must only be used in last ditch effort.

[Cardiac amyloidosis, about an atypical case]. / Le cas clinique du mois. Amyloïdose cardiaque, a propos d'un cas atypique.

A 64 year old patient with heart failure due to primary cardiac amyloidosis is described. This case offers the opportunity to review the literature dealing with the cardiac involvement associated with this disorder and the differential diagnosis of restrictive heart disease.

[Primary mitral regurgitation: indications for surgery and recent advances]. / Insuffisance mitrate primaire: indications chirurgicales et dernières avancées.

Mitral regurgitation (MR) is, in Europe, the second most common valvular disease. Primary MR represents 61% of cases. The surgical indications for symptomatic patients with severe primary MR, are subject to a broad consensus with strong levels of recommendations. In asymptomatic patients, levels of recommendations are weaker despite the numerous publications. Exercise echocardiography has emerged as a useful tool for the management of the patients and appeared in the latest European recommendations. It continues to be the subject of numerous studies demonstrating its usefulness for risk stratification in asymptomatic patients. The next advances in this field will probably argue for an earlier surgery in these kinds of patients.

[Multimodal cardiovascular imaging before aortic valve transcatheter replacement]. / L'imagerie cardiovasculaire multimodalités avant l'implantation d'une prothèse valvulaire aortique par voie percutanée.

Calcified aortic valve stenosis is the most frequent valvular heart disease in developed countries with a very poor outcome when symptoms develop. However, several of these patients are denied for surgery. The main reasons are their advanced age (elderly patient), co-morbidities, technical limitations and a very high surgical risk. It is currently possible to propose a Transcatheter Aortic Valve Implantation (TAVI). After selection of candidates, the feasibility of the intervention is analysed. The size of the aortic bioprosthesis must be selected according to the cardiac anatomy. Several cardiac imaging modalities (echocardiography, computed tomography and cardiac MRI) can be used to identify unsuitable situations. Heavy calcifications or tortuosity can thwart the retrograde approach use. The sub-clavian arteries (for the CoreValve) and trans-apical approach (for the Edwards-Sapien) constitute alternatives ways.

[Inadvertent implantation of a defibrillation lead in the left ventricle through a patent foramen ovale]. / Le cas clinique du mois: Implantation fortuite d'une sonde de défibrillation dans le ventricule gauche au travers d'un foramen ovale perméable.

Inadvertent insertion of a defibrillation lead in the left ventricle is a rare complication generally underdiagnosed after device implantation. Management is not strictly codified due to the small number of observed cases. We report the case of a 78 year-old man in whom the diagnosis has been performed lately during an echocardiography.

[Assessment and management of aortic stenosis]. / Evaluation et traitement de la sténose aortique.

Surgical aortic valve replacement is the sole validated treatment of aortic stenosis. The indications for surgery rely on risk/benefit ratio and on the official recommendations. A symptomatic patient with severe aortic stenosis should be submitted to surgery. The indication of valve replacement is more difficult in asymptomatic patients. The decision should integrate a combination of an exercise test and prognostic parameters associated with poor outcome. Most of them are obtained by Doppler echocardiography. Patients presenting with severe aortic stenosis and low transvalvular gradient constitute a subgroup of patients who require appropriate echocardiographic assessment to determine the potential benefit and risk of surgery. Transluminal aortic valve implantation is a new modality for patients at high surgical risk.

[Update in the management of left valvular disease]. / Nouveautés dans la prise en charge des valvulopathies du coeur gauche.

In the last years, the management of left valvular disease has considerably evolved. The American guidelines of 1998 were recently reviewed. Since this year, we have European guidelines which are different in some points. The place of exercise testing in risk stratification of asymptomatic valvular disease is increasing and helps to make earlier decision regarding the need for surgery.

[New therapeutic guidelines in lower limb arteriopathy]. / Actualités thérapeutiques à propos de l'artériopathie des membres inférieurs.

This article describes the recent therapeutic options for lower limb arteriopathy and, as much as possible, analyzes the medical and surgical treatments according to the recommendations and levels of evidence.

[How I investigate... The coronary arteries in 2007: contributions of CT coronary angiography]. / Comment j'explore...Les artères coronaires en 2007: apports de la tomodensitomètrie.

Cardiac imaging has always been a challenge because of the continuous movement of the heart. Cardiac computed tomography (CT) has undergone an accelerated progression over the past decade, due to the combination of the high-speed rotation of the X-ray tube, the ECG-gating technique and the infra-millimeter spatial resolution. Multidetector CT allows visualisation of the coronary artery lumen and the detection of coronary stenosis after intravenous injection of contrast medium. Studies have demonstrated a high negative predictive value of CT coronary angiography (CTCA). CTCA may be reasonably used for the assessment of symptomatic patients, especially in the setting of equivocal treadmill or functional testing. Also, CTCA allows assessment of coronary bypass graft patency and recognition of aberrant coronary arteries. Limitations in the use of this technique exist: atrial fibrillation and other cardiac arrhythmias remain a contraindication; severe calcifications are the most frequent reason for impaired assessment of coronary arteries. High radiation doses prohibit the use of this test as a screening tool for asymptomatic patients.

[Ischemic mitral regurgitation]. / L'insuffisance mitrale ischémique.

Mitral regurgitation (MR) is a serious complication of coronary heart disease. The functional form is the most frequent, often presenting with a dynamic character. The presence, and in particular the severity of MR and its dynamic character have a major impact on the medium and long term prognosis. The mechanisms responsible for MR are complex and occur in a state of disequilibrium between traction forces and closing forces, for which the significance is partly affected by the presence of asynchrony in left ventricular contraction. The therapeutic management of these patients is difficult. In cases of proven asynchrony, implantation of a biventricular pacemaker is justified. A mitral surgical procedure may be envisaged in cases of severe MR where bypass surgery is planned. In cases of moderate MR at rest, an evaluation of its dynamic character on effort can assist with the decision to undertake combined surgery. Mitral regurgitation (MR) is a common and serious complication of ischemic heart disease. Three general forms are distinguished: MR related to acute rupture of the mitral pillar, ischemic MR and functional MR.

[Arrhythmogenic right ventricular dysplasia]. / Dysplasie arythmogène du ventricule droit.

Arrhythmogenic right ventricular dysplasia is an unfrequent disease that associates ventricular tachycardia with left bundle branch block morphology and right ventricular fibro-fatty degeneration. The etiology, pathogenesis, criteria for diagnosis and treatment are discussed.