Response to Induction Neoadjuvant Hormonal Therapy Using Upfront 21-Gene Breast Recurrence Score Assay-Results From the SAFIA Phase III Trial.

PURPOSE: Luminal, human epidermal growth factor receptor 2-negative breast cancer represents the most common subtype of breast malignancies. Neoadjuvant strategies of operable breast cancer are mostly based on chemotherapy, whereas it is not completely understood which patients might benefit from neoadjuvant hormone therapy (NAHT). MATERIALS AND METHODS: The SAFIA trial is a prospective multicenter, international, double-blind, neoadjuvant phase III trial, using upfront 21-gene Oncotype DX Breast Recurrence Score assay (recurrence score [RS] < 31) to select operable luminal human epidermal growth factor receptor 2-negative patients, for induction hormonal therapy HT (fulvestrant 500 mg with or without goserelin) before randomly assigning responding patients to fulvestrant 500 mg (with or without goserelin) plus either palbociclib (cyclin-dependent kinase 4/6 inhibitor) or placebo. The objectives of this interim analysis were to assess the feasibility of upfront RS determination on core biopsies in the Middle-East and North Africa region and evaluate the efficacy of induction NAHT in patients with an RS < 31. RESULTS: At the time of this interim analysis, 258 patients with relative risk were accrued, including 202 patients (RS < 31% to 78.3%) treated with induction NAHT and 182 patients evaluable so far for response. The feasibility of performing the Oncotype DX assays on core biopsy specimens was optimal in 96.4% of cases. Overall, 93.4% of patients showed hormone sensitivity and no difference in NAHT efficacy was noticed between RS 0-10, 11-25, and 26-30. Interestingly, patients with high RS (26-30) showed a trend toward a higher major response rate (P = .05). CONCLUSION: The upfront 21-gene assay performed on biopsies is feasible in our population and has allowed us to select patients with high hormone sensitivity (RS < 31). This approach could be an alternative to upfront surgery without significant risk of progression, particularly during pandemic times.

Toxicity profile of taxanes in Tunisian cancer patients: A retrospective study of 90 cases.

INTRODUCTION: Taxanes are widely used in medical oncology. The aim of our study was to report and analyze the toxicity features of these drugs in Tunisian patients and to determine their impact on treatment response. METHODS: Our retrospective study concerned 90 patients treated by taxanes in a medical oncology unit, from January 2014 to January 2017. We collected their epidemiologic and anatomo-clinical data and we detailed toxicity features including types grades and impact on tumor response. RESULTS: Median age was 46 years. 80% of patients had breast cancer. Tumors were metastatic in 23.3% of cases. Nail toxicity was observed in 100% of patients. Grade I-II digestive toxicity was observed in 54.4% of cases. Hematological toxicity was noted in 42.2% of patients and it reached grade III-IV in five patients. Neurological toxicity occurred in 31% of patients and was grade III-IV in 6 cases. Alopecia was observed in 60% of patients. Fatigue was noted in 57.8% of patients. Myalgia was observed in 42.2% of patients. Toxicity did not affect the response to treatment. CONCLUSION: The taxanes' toxicity profile in Tunisian patients is characterized by more frequent digestive and nail toxicities and less frequent hematological toxicities, dose reduction and treatment delays than other populations.

Identification of Novel BRCA1 and RAD50 Mutations Associated With Breast Cancer Predisposition in Tunisian Patients.

BACKGROUND: Deleterious mutations on BRCA1/2 genes are known to confer high risk of developing breast and ovarian cancers. The identification of these mutations not only helped in selecting high risk individuals that need appropriate prevention approaches but also led to the development of the PARP-inhibitors targeted therapy. This study aims to assess the prevalence of the most frequent BRCA1 mutation in Tunisia, c.211dupA, and provide evidence of its common origin as well as its clinicopathological characteristics. We also aimed to identify additional actionable variants using classical and next generation sequencing technologies (NGS) which would allow to implement cost-effective genetic testing in limited resource countries. PATIENTS AND METHODS: Using sanger sequencing, 112 breast cancer families were screened for c.211dupA. A set of patients that do not carry this mutation were investigated using NGS. Haplotype analysis was performed to assess the founder effect and to estimate the age of this mutation. Correlations between genetic and clinical data were also performed. RESULTS: The c.211dupA mutation was identified in 8 carriers and a novel private BRCA1 mutation, c.2418dupA, was identified in one carrier. Both mutations are likely specific to North-Eastern Tunisia. Haplotype analysis supported the founder effect of c.211dupA and showed its recent origin. Phenotype-genotype correlation showed that both BRCA1 mutations seem to be associated with a severe phenotype. Whole Exome Sequencing (WES) analysis of a BRCA negative family revealed a Variant of Unknown Significance, c.3647C > G on RAD50. Molecular modeling showed that this variant could be classified as deleterious as it is responsible for destabilizing the RAD50 protein structure. Variant prioritization and pathway analysis of the WES data showed additional interesting candidate genes including MITF and ANKS6. CONCLUSION: We recommend the prioritization of BRCA1-c.211dupA screening in high risk breast cancer families originating from the North-East of Tunisia. We also highlighted the importance of NGS in detecting novel mutations, such as RAD50-c.3647C > G. In addition, we strongly recommend using data from different ethnic groups to review the pathogenicity of this variant and reconsider its classification in ClinVar.

Oxaliplatin-induced peripheral neuropathy risk factors and management in Tunisian population.

The most important limits of oxaliplatin treatment is its peripheral neurotoxicity. The aim of our study was to evaluate the oxaliplatin-induced peripheral neuropathy, its impact on treatment and its management. One hundred chemo-naive patients treated with oxaliplatin-based regimen in the medical oncology department of the military hospital of Tunis between 2012 and 2017 were recruited retrospectively. Evaluation of neuropathy was done according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V4). Fifty-six patients were aged more than 60 years. The sex-ratio was 1.56. Twenty-seven patients were overweight, 17 were obese and 56 had a BMI inferior to 25 kg/m2. Two patients were consuming alcohol. Twenty-three patients had diabetes. Sixty-four patients developed chronic peripheral neuropathy because of oxaliplatin (grade 1-2 in 58 cases and grade 3 in 6 cases). Sex, BMI, diabetes and alcohol consumption were not associated with the development of peripheral neuropathy. No association was found between grades of neuropathy and sex, alcohol consumption and diabetes. The median cumulative dose of oxaliplatin that induced neuropathy was 432.4 mg/m2. The most prescribed treatment was gabapentin (81%) and carbamazepine (16.8%). The treatment was not sufficient to stop neuropathy in 82.6% of cases. Dose reduction was done in 64.2% of cases, treatment delay in 10.7% of cases and treatment interruption in 10.7% of cases. We didn't find any association between known risk factors and peripheral neuropathy. The cumulative dose is interesting to define or to predict the timing of neurotoxicity.

Diagnostic and prognostic value of 2D-Strain in Non-ST Elevation Myocardial Infarction.

BACKGROUND: Strain has shown a promising diagnostic and prognostic value in acute coronary syndromes. With, however, less data in non-ST elevation myocardial infarction (NSEMI). AIM: to evaluate in NSTEMI patients, the ability of strain to predict the severity of the disease, by assessing correlations to established prognostic parameters, and to predict culprit and occluded coronary arteries (CA). Secondary, to determine factors associated to strain changes during follow-up. METHODS: The study was prospective, NSTEMI patients with significant coronary lesion and without significant non-ischaemic disease were included. Angiographic and echocardiographic investigation including global (GLS) and territorial (TLS) longitudinal strain were performed within 24h from admission. Syntax I score was calculated. Severe coronary artery disease (CAD) was defined by left main of three-vessel disease. RESULTS: Seventy NSTEMI patients aged 60.2±10.1 years were enrolled; 61% were smokers, 54% diabetics and 46% hypertensive. 34% had a severe CAD, 7% had an acute coronary occlusion (ACO) and 14% a chronic coronary total occlusion (CTO). GLS >-15.3% predicted a left ventricular ejection fraction (LVEF) <50% with 80% Sensitivity (Se) and 78% Specificity (Sp). GLS was associated to CAD complexity and severity. GLS > -14.1% detected severe CAD with 83% Se and 80%Sp. TLS determined the culprit artery in 74% of cases and TLS > -9.2% predicted ACO with 85% Se and 85% Sp. TLS was also associated to CTO. At a 10 months median follow-up [3-12months], GLS significantly improved, baseline LVEF, GLS, wall motion score index and revascularization were the predictors of this improvement. CONCLUSION: In NSTEMI patients, GLS detected severe CAD and poor myocardial function. TLS predicted the culprit vessel and its occlusion. GLS improvement at midterm was predicted by baseline systolic LV function parameters and myocardial revascularization.

Oral anticoagulation therapy using acenocoumarol during the month of ramadan: a comparative study between fasting and non-fasting patients.

BACKGROUND AND OBJECTIVES: The effect of Ramadan fasting on anticoagulation by vitamin K antagonists has been previously investigated in small scale studies with controversial results. From this perspective, this study aimed to compare the fluctuations of anticoagulation in fasting and nonfasting patients taking Acenocoumarol and to identify the factors associated with such fluctuations. METHODS: The study, conducted between May and August 2018, was a comparative one. Three study periods were defined: before Ramadan (BR), Ramadan and after Ramadan (AR). Enrolment involved ambulatory patients aged over eighteen, without medical contraindications to fasting (for the fasting group) and whom international normalized ratio (INR) was within the therapeutic target range during the last three months BR. Anticoagulation monitoring consisted in five consecutive INR assays; INR0 (during the 14 days BR), INR1 (between the 1st and the 14th day of Ramadan), INR2 (between the 15th and the 28th day of Ramadan), INR3 (28 days after INR2) and INR4 (28 days after INR3). INR stability was assessed by calculating four percentages of time in therapeutic range (TTR); TTR0 (between INR0 and INR1), TTR1 (between INR0 and INR2), TTR2 (between INR2 and INR3) and TTR3 (between INR3 and INR4). The null hypothesis was the occurrence of an anticoagulation imbalance (evaluated by TTR) in fasting patients in comparison with non-fasting ones. RESULTS: One hundred and twenty-two patients (84 fasting patients), aged 60 ± 19 years, were included. In fasting patients, the average differences of INR1, 2, 3 and 4 compared with INR0 were statistically non-significant and accounted for +0.46, +0.34, +0.28 and +0.30 respectively. Among the three TTRs, only TTR2 significantly decreased in comparison with TTR0 in fasting group (50.3 ± 37.4 vs. 63.6 ± 39.3%, p=0.004). TTR1, 2 and 3 were comparable between fasting and non-fasting patients. CONCLUSIONS: The fluctuations of anticoagulation balance, assessed by TTR, were comparable between fasting and non-fasting patients taking Acenocoumarol.

Transformation of a prostatic adenocarcinoma into squamous cell carcinoma after luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy treatment.

Squamous cell carcinoma of the prostate is rare and represents 0.5% to 1% of prostatic carcinomas. Transformation of prostatic adenocarcinoma into squamous cell carcinoma after LH-RH agonist intake has been reported in only 8 cases in the literature. To our knowledge, our case is the second pure squamous cell carcinoma observed after hormonotherapy and radiotherapy. We reported a case of a patient with prostatic adenocarcinoma treated by radical prostatectomy followed by radiotherapy. Eleven years later, he had a vesical recurrence of prostatic adenocarcinoma. Our patient had an endoscopic resection followed by injections of Triptorelin. Six months later, he developed a local recurrence of a squamous cell carcinoma.

Left main coronary artery thrombosis revealing angio-Behçet syndrome.

Although acute myocardial infarction commonly results from coronary atherothrombosis, there are several other etiologies that should be taken initially into account, especially in young adults without significant atherosclerotic risk factors. Thrombophilia and coronary arteritis are, in this context, examples of etiologies that should be looked after. Through this article, we present a case of Behçet's disease with arterial involvement diagnosed after myocardial infarction resulting from thrombosis of the left main coronary artery in a 38-year-old young man without any particular past medical history.

[Circular shunt in the severe neonatal form of Ebstein's Anomaly. The prostaglandine infusion is it beneficial or harmful?] / Le shunt circulaire dans la forme néonatale sévère de la maladie d'Ebstein : effet bénéfique ou délétère des prostaglandines?

Ebstein's disease with functional pulmonary atresia is a severe neonatal presentation of Ebstein's anomaly where the therapeutic management is typically based on the prescription of prostaglandins. The circular shunt is a serious "hemodynamic" complication which is often undiagnosed leading to the discontinuation of prostaglandins. We report a severe neonatal form of Ebstein's anomaly with hemodynamic deterioration relatted to a circular shunt. The diagnosis of Ebstein's anomaly with functional pulmonary atresia was made prenatally at 36 weeks of pregnancy. The patient was born at 38 weeks of gestation by caesarean section. Postnatal ultrasound confirmed the diagnosis. Treatment with prostaglandins was originally created to maintain the vital ductus arteriosus patent. Despite this treatment, hemodynamic deterioration was observed. Ultrasound monitoring showed pictures for a circular shunt. Indeed, blood coming into the pulmonary artery by the wide ductus arteriosus, was "drawn" to the right ventricle and the right atrium due to tricuspid regurgitation and from there to the left heart via the fossa ovalis shunting right to left, when it was ejected into the aorta and the ductus arteriosus. Before this circular shunt, treatment with prostaglandin was discontinued and treatment to reduce pulmonary resistance was described. However, the patient died prior to initiation of treatment. The neonatal form of Ebstein's anomaly is a severe form that can be complicated by a circular shunt. This hemodynamic phenomenon encourages early closure of the ductus arteriosus against indicating the prescription of prostaglandins.

[Contrast-induced nephropathy after cardiac catheterization: a prospective study of 180 patients]. / Néphropathie induite par les produits de contraste iodés après cathétérisme cardiaque : Une étude prospective de 180 patients.

BACKGROUND: Contrast-induced nephropathy (CIN) is associated with an increased cardiovascular morbi-mortality. Little is known about the incidence and risk factors of CIN after cardiac catheterization in Tunisian patients. AIM: To determine the incidence of CIN and its predictors after coronary angiography as well as its prognostic and therapeutic repercussions in a Tunisian patients' cohort. METHODS: In this prospective single center study, 180 consecutive patients who underwent cardiac catheterization were enrolled; all patients were followed-up for 3 months. RESULTS: The incidence of CIN defined as an absolute increase in serum creatinine ³ 5 mg/l (44µmol/l) and/or a relative increase in serum creatinine ³ 25%, was 17.2%. In multivariate logistic regression, independent predictors of CIN were: diabetes mellitus (Odds Ratio (OR)=2.26 ; 95% confidence interval (95%CI) : 1.29- 3.98, p=0.005), creatinine clearance < 80ml/mn (OR=2.87 ; 95%CI : 1.59-5.19, p<0.001), left ventricular ejection fraction (LVEF) < 45% (OR=2.03 ; 95%CI : 1.22-3.39, p=0.007) and use of a volume of contrast media > 90ml (1.72 ; 95%CI : 0.99-2.99, p=0.05). Perprocedural hypotension was the strongest independent predictor of CIN in our study (OR=3.99; 95% CI: 1.65-9.66, p=0.002). CIN was totally regressive within one month in 27 patients (86.7%) while 3 patients (10%) had a residual renal dysfunction at the end of the follow-up period (3 months). CONCLUSION: More than one angiocoronarography on 6 resulted in CIN in our population. CIN affects cardiovascular prognosis even if renal function normalization is usually obtained within one month after the investigation. Besides identifying risk factors of CIN in order to apply preventive measures in risky patients, we stress the necessity of insuring a good hemodynamic status while achieving the procedure.

Acute myocardial infarction in a patient with hypofibrinogenemia: a case report.

INTRODUCTION: Congenital fibrinogen deficiency is a rare coagulation disorder usually responsible for hemorrhagic diathesis. However, it can be associated with thrombosis and there have been limited reports of arterial thrombotic complications in these patients. CASE PRESENTATION: A 42-year-old Tunisian man with congenital hypofibrinogenemia and no cardiovascular risk factors presented with new onset prolonged angina pectoris. An electrocardiogram showed features of inferior acute myocardial infarction. His troponin levels had reached 17 ng/L. Laboratory findings confirmed hypofibrinogenemia and ruled out thrombophilia. Echocardiography was not useful in providing diagnostic elements but did show preserved left ventricular function. Coronary angiography was not performed and our patient did not receive any anticoagulant treatment due to the major risk of bleeding. Magnetic resonance imaging confirmed myocardial necrosis. Our patient was managed with aspirin, a beta-blocker, an angiotensin-converting enzyme inhibitor and statin medication. The treatment was well tolerated and no ischemic recurrence was detected. CONCLUSION: Although coronary thrombosis is a rare event in patients with fibrinogen deficiency, this condition is of major interest in view of the difficulties observed in managing these patients.