MODUL cohort 2: an adaptable, randomized, signal-seeking trial of fluoropyrimidine plus bevacizumab with or without atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer.

BACKGROUND: MODUL is an adaptable, signal-seeking trial designed to test novel agents in predefined patient subgroups in first-line metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with measurable, unresectable, previously untreated mCRC received induction with ≤8 cycles of FOLFOX + bevacizumab followed by randomization to maintenance treatment comprising control [fluoropyrimidine (FP)/bevacizumab: 5-fluorouracil 1600-2400 mg/m2 46-h intravenous (i.v.) infusion day 1 q2 weeks plus leucovorin 400 mg/m2 2-h infusion i.v. day 1 q2 weeks or capecitabine 1000 mg/m2 b.i.d. orally days 1-14 every 21 days; bevacizumab 5 mg/kg 15-30-min i.v. infusion q2 weeks] or experimental treatment in one of four biomarker-driven cohorts. In patients with BRAF wild-type (BRAFwt) tumors (cohort 2), experimental treatment was FP/bevacizumab + atezolizumab (800 mg 60-min i.v. infusion q2 weeks). Primary efficacy endpoint was progression-free survival (PFS; intent-to-treat population). Enrollment is complete; efficacy and safety findings from cohort 2 are presented. RESULTS: Four hundred and forty-five patients with BRAFwt mCRC were randomized (2 : 1) to maintenance in cohort 2. At a median follow-up of 10.5 months, PFS outcome hypothesis was not met [hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.72-1.17; P = 0.48]; overall survival (OS) was immature. At a median follow-up of 20.3 months (2-year survival follow-up), PFS benefit was also not met (HR 0.95; 95% CI 0.77-1.18; P = 0.666); OS HR with nearly two-thirds of patients with events was 0.83 (95% CI 0.65-1.05; P = 0.117). No new safety signals were identified. The most common grade ≥3 treatment-emergent adverse events (TEAEs) for experimental versus control arms were hypertension (6.1% versus 4.2%), diarrhea (3.1% versus 2.1%), and palmar-plantar erythrodysesthesia syndrome (1.0% versus 2.5%). Four patients experienced TEAEs with fatal outcome, two were study treatment-related: hepatic failure (experimental arm) and large intestine perforation (control arm; bevacizumab-related). CONCLUSIONS: Adding atezolizumab to FP/bevacizumab as first-line maintenance treatment after FOLFOX + bevacizumab induction for BRAFwt mCRC did not improve efficacy outcomes.

Environmental Effects of Temperature and Water Potential on Mycelial Growth of Neocosmospora solani and Fusarium spp. Causing Dry Root Rot of Citrus.

This study aimed at evaluating the effect of environmental factors temperature and water potential (Ψw) on the growth of Neocosmospora (Fusarium) solani and three Fusarium species (F. oxysporum, F. equiseti and F. brachygibbosum) associated with citrus dry root rot and to determine the optimum and marginal rate for their growth. The effects of incubation temperature (5-40 °C), water potentials (Ψw) (- 15.54; - 0.67 MPa) (0.89-0.995 aw) and their interaction (5-30 °C) was evaluated on the in vitro radial growth rates of Fusarium spp. and on their lag phase. Secondary models were used to model the combined effect of these factors on radial growth rate. The results underlined a highly significant effects (P < 0.001) of Ψw and temperature and their interactions on radial growth rates and lag phases (λ). The Four studied species were shown tolerant to a temperature of 35 °C with an optimum mycelial growth at 30 for N. solani and F. oxysporum and at 25 °C for F. equiseti and F. brachygibbosum. However, no growth was observed at both temperatures 5 and 40 °C and at Ψw of - 9.68 MPa (0.93 aw). The optimum water potential for growth was ≥- 2.69 MPA (>0.98 aw). The results from the polynomial model and response surface showing good agreement between observed and predicted values. The external validation on citrus fruit indicated slight differences between predicted and observed values of radial growth. The results of this study will be beneficial for understanding the ecological knowledge of these species and thereby limited preventively their occurrence.

The typical RB76 recombination breakpoint of the invasive recombinant tomato yellow leaf curl virus of Morocco can be generated experimentally but is not positively selected in tomato.

TYLCV-IS76 is an unusual recombinant between the highly recombinogenic tomato yellow leaf curl virus (TYLCV) and tomato yellow leaf curl Sardinia virus (TYLCSV), two Mediterranean begomoviruses (Geminiviridae). In contrast with the previously reported TYLCV/TYLCSV recombinants, it has a TYLCSV derived fragment of only 76 nucleotides, and has replaced its parental viruses in natural conditions (Morocco, Souss region). The viral population shift coincided with the deployment of the popular Ty-1 resistant tomato cultivars, and according to experimental studies, has been driven by a strong positive selection in such resistant plants. However, although Ty-1 cultivars were extensively used in Mediterranean countries, TYLCV-IS76 was not reported outside Morocco. This, in combination with its unusual recombination pattern suggests that it was generated through a rare and possibly multistep process. The potential generation of a recombination breakpoint (RB) at locus 76 (RB76) was investigated over time in 10 Ty-1 resistant and 10 nearly isogenic susceptible tomato plants co-inoculated with TYLCV and TYLCSV clones. RB76 could not be detected in the recombinant progeny using the standard PCR/sequencing approach that was previously designed to monitor the emergence of TYLCV-IS76 in Morocco. Using a more sensitive PCR test, RB76 was detected in one resistant and five susceptible plants. The results are consistent with a very low intra-plant frequency of RB76 bearing recombinants throughout the test and support the hypothesis of a rare emergence of TYLCV-IS76. More generally, RBs were more scattered in resistant than in susceptible plants and an unusual RB at position 141 (RB141) was positively selected in the resistant cultivar; interestingly, RB141 bearing recombinants were detected in resistant tomato plants from the field. Scenarios of TYLCV-IS76 pre-emergence are proposed.

Monitoring the dynamics of emergence of a non-canonical recombinant of Tomato yellow leaf curl virus and displacement of its parental viruses in tomato.

Recombinant viruses are increasingly being reported but the dynamics of their emergence is rarely documented. A new recombinant Tomato yellow leaf curl virus (TYLCV-IS76) was detected for the first time in 2010 in Southern Morocco (Souss). An original diagnostic tool was needed to fit its unusual recombination profile. Although IS76 was detected following the appearance of Tylc symptoms on tolerant tomato plants, symptoms could not be associated to IS76 or to a synergy with criniviruses. According to infection profiles of Tylc-associated viruses determined on 879 plant samples collected between 1998 and 2014 and a Bayesian inference applied to genomic sequences of representatives of TYLCV, IS76 emerged in Southern Morocco at the end of the 1990s, replaced the parental viruses between 2004 and 2012 in Souss and is spreading towards the North of Morocco. The emergence of IS76 coincides with the increasing use of tolerant cultivars in the 2000s.

[Pulmonary arterial hypertension and porto-caval fistula in a 17 year old patient]. / Hypertension artérielle pulmonaire et fistule porto-cave découverte chez un jeune de 17 ans.

The authors report the case of a 17 year old patient with severe pulmonary arterial hypertension accompanied with a congenital porto-caval shunt. This patient had been admitted with dyspnoea on exertion with signs of pulmonary arterial hypertension on clinical examination. Echocardiography revealed a systolic pulmonary arterial pressure of 80 mmHg with no left heart anomaly or intracardiac shunt. Pulmonary investigations, as well as immunology, clotting, liver function and retroviral serology were all negative. A routine abdominal ultrasound showed a 10 mm proximal porto-caval fistula with no sign of portal hypertension. This case shows that anomalies of the portal system can cause pulmonary arterial hypertension even in the absence of any symptoms suggestive of hepatic disorder.

[Cardiac hydatid cysts: report of 10 cases]. / Kyste hydatique du coeur. A propos de 10 cas.

Authors report 10 observations of cardiac hydatid cyst collected to cardiovascular unit of Ibn Rochd hospital in Casablanca during last 7 years. Clinical investigation included in all cases chest X ray, ECG and ultrasonography (US). A computed tomography (CT) scan was performed in 6 cases, magnetic resonance imaging in four cases, transoesophageal US in two cases. Examination for other hydatic sites was realized in all cases, and brain CT was performed in 5 cases. The hydatid cyst was variably localized in the left ventricle in 6 cases, the pericardium in 4 cases, the interventricular septum in 2 cases, the right auricle in 2 cases and multiple locations in one case. The existence of other cardiac hydatid sites was found in 7 cases. Seven patients have been operated (2 cases to closed heart). Outcome was favorable in 6 cases with a mean of three years survey. Two patients died and 2 others have been lost of view. The diagnosis of the cardiac hydatid cyst has benefits from the combination USCT scan that allowed a precise topographical inventory, reducing the need for MRI to the complicated cases and to the rare cases of inconclusive results by US-CT scan.

[Hypertrophic cardiomyopathy disclosing Friedreich's disease. Report of a case]. / Cardiomyopathie hypertrophique révélant une maladie de Friedreich. A propos d'un cas.

The authors report the case of a 21 year old woman admitted to hospital for congestive cardiac failure due to concentric hypertrophic cardiomyopathy. Echocardiography showed severe systolo-diastolic left ventricular dysfunction without obstruction to ejection. Neurological examination showed a stato-kinetic cerebellar syndrome, a posterior radiculo-cordonal syndrome and a dysmorphic syndrome which characterise Friedreich's disease. In the light of this case and a review of the literature, the authors underline the rarity of cardiomyopathy in Friedreich's disease, its particular presentation and its poor prognostic significance in this disease.

[False aneurysm complicating ligation of patent ductus arteriosus operated on successfully]. / Faux anévrisme après ligature d'un canal artériel opéré avec succès.

Postoperative aneurysm of ductus arteriosus is a rare complication but may be lethal without treatment. It is less frequent than spontaneous aneurysm of ductus arteriosus. We report the case of 5 years-old girl who underwent a ligation of patent ductus arteriosus complicated, 6 months later, with a false aneurysm of ductus arteriosus and endocarditis of the ductus and the aortic valve. The diagnosis of the aneurysm was suspected on the anteroposterior chest X-ray which showed a left superior mediastinal opacity and confirmed by echocardiography. Through bilateral thoracotomy, an anevrismorraphy and aortic repair was carried out without problem. The postoperative course was unremarkable.

[Cardiovascular abnormalities of the antiphospholipid antibody syndrome]. / Anomalies cardiovasculaires révélatrices du syndrome des anticorps anti-phospholipides.

The antiphospholipid antibody syndrome (APS) may present with serious cardiovascular complications which should be recognised by the cardiologist. The authors report a series of 6 cases of APS diagnosed after thrombotic events and the finding of antiphospholipid antibodies. The APS was primary in 5 cases and associated with tuberculous lymphadenitis in 1 case. There was cardiac involvement in 5 patients with pericardial effusion in 3 cases, complicated by tamponade as the presenting sign of primary APS in the other 2, valvular disease in one case (moderate mitral stenosis with aortic valve disease) and pulmonary embolism in one case. Five patients developed recurrent deep vein thrombosis of the legs. One patient had a transient ischaemic cerebral attack.

[Malignant non-Hodgkin's lymphoma presenting with cardiac tamponade]. / Tamponnade cardiaque révélatrice d'un lymphome malin non hodgkinien.

Malignant non-Hodgkin's lymphoma rarely involves the heart. However, all cardiac structures may be invaded, although the myocardium and pericardium are affected more often than the valvular structures. Diagnosis is important because treatment must be adapted. The cardiac signs are usually non-specific and lymphomas presenting in this way have only occasionally been reported. The authors report two cases in which malignant non-Hodgkin's lymphoma presented with cardiac tamponade.

[Obstructive left triatrial heart in the adult. Echocardiographic appearances]. / Coeur triatrial obstructif gauche chez l'adulte. Aspects échocardiographiques.

The authors report the case of a 23-year old man who presented with signs of pulmonary hypertension due to an obstructive left triatrial heart in adulthood. Transthoracic and transoesophageal echocardiography showed a partially calcified intra-left atrial membrane perforated in its centre. Doppler analysis of flow through the membrane showed continuous systolo-diastolic flow at high velocity indicating haemodynamic obstruction. The systolic pulmonary artery pressure was estimated at 80 mmHg. The patient was treated by surgical excision of the intra-left atrial membrane.

[Hypocalcemic dilated cardiomyopathy: rare cause of heart failure]. / Une cause rare d'insuffisance cardiaque: la cardiomyopathie dilatée hypocalcémique.

Hypocalcemic dilated cardiomyopathy is a rare cause of heart failure in adults. We report a case in a 19-year-old woman who developed congestive heart failure induced by severe chronic hypocalcemia disclosing primary hypoparathyroidism. Complete regression of the clinical signs was achieved with vitamin-calcium treatment, but left ventricular systolic dysfunction persisted eight months after treatment.

[Aneurysm of the posterior sinus of Valsalva ruptured into right atrium]. / Anévrisme du sinus de Valsalva postérieur rompu dans l'oreillette droite.

Sinus of Valsalva aneurysm is rare malformation, which takes origin from one of the three aortic sinuses. Diagnosis of this abnormality is usually made when rupture has occurred. Our observation underlines the severity of the posterior sinus of Valsalva aneurysm ruptured into right atrium, and emphasizes the utility of transthoracic and transoesophageal echocardiography for diagnosis.

Electroporation-mediated delivery of 3'-protected phosphodiester oligodeoxynucleotides to the skin.

The feasibility of topical delivery in the skin of 3' end modified phosphodiester oligonucleotides using electroporation was investigated. Experiments were performed in vitro, using hairless rat skin. Five pulses of (200 V, 450 ms) were applied. The 3' end modifications of the 15 mer oligonucleotide were: (1) 3'-aminohexyl, (2) biotin, with a triethyleneglycol arm, (3) methylphosphonate links between nucleotides 13, 14 and 15, and (4) 2-O-methyl nucleotides at 13, 14 and 15 positions. All the modifications were efficient to protect the oligonucleotides against degradation in the skin. Electroporation increased the topical delivery of the 3' end-modified phosphodiesters by two orders of magnitude compared to passive diffusion, without significant differences between the derivatives. Oligonucleotide concentrations in the range of 1 microm could be achieved in the viable skin. The delivery of a phosphorothioate congener was lower than phosphodiester delivery due to the interaction of phosphorothioate with the stratum corneum. Consequently, 3' end-protected phosphodiesters could be an interesting alternative to phosphorothioate oligonucleotides for topical treatment of cutaneous diseases.

[Malignant mediastinal schwannoma in Recklinghausen's disease presenting as cardiac tamponade. Report of two cases]. / Tamponnade cardiaque révélatrice de schwannome malin médiastinal au cours de la maladie de Recklinghausen. A propos de deux observations.

The authors report two cases of Recklinghausen's disease admitted for cardiac tamponade. Two-dimensional echocardiography showed a pericardial tumour in addition to a compressive pericardial effusion. After pericardial drainage, the outcome was rapidly fatal. Histological examination confirmed the diagnosis of a malignant intrapericardial schwannoma. A review of the literature revealed the scarcity of mediastinal malignant schwannoma. Associated with Von Reckinghausen's disease in 2 to 13% of cases, the prognosis is poor. The presentation of malignant mediastinal schwannoma with cardiac tamponade remains very rare.

[Horton's disease presenting as a myocardial infarction]. / Infarctus du myocarde révélant une maladie de Horton.

The authors report the case of a 60-year-old man admitted for uncomplicated acute myocardial infarction. The history of persistent fronto-occipital headaches and palpation of bilateral tortuous temporal arteries with a decreased pulse suggested the diagnosis of temporal arteritis, particularly in the presence of marked laboratory signs of inflammation and the coronary angiograph findings. The diagnosis was confirmed by temporal artery biopsy. Treatment consisted of corticosteroid therapy, with a satisfactory outcome at three months. The diagnosis of temporal arteritis should be systematically suggested in patients over the age of 50 years, presenting with a marked inflammatory syndrome and recent-onset arterial disease. Similarly, any form of arterial disease occurring during treated temporal arteritis should initially be considered to be a secondary site of the arteritis, requiring intensification of corticosteroid therapy.

[Approach of Moroccan cardiologists to arterial hypertension]. / Les cardiologues marocains face à l'hypertension artérielle.

The authors conducted a survey among 300 cardiologists in order to evaluate their knowledge of HT. Most of the 200 cardiologists answering the survey considered that systolic HT was defined by a systolic blood pressure greater than 160 mmHg (75%). Only 14 cardiologists (7%), defined systolic HT as a blood pressure greater than 140 mmHg. 121 cardiologists (60.5%) defined diastolic HT as a pressure greater than 95 mmHg. 2/3 of cardiologists were not familiar with the conclusions of the JNCV for the detection, evaluation and treatment of HT. All cardiologists agreed that treatment of HT should start with single-agent therapy. In the case of insufficient control, 11% doubled the dose, 5% changed the drug in the same class, 53% changed therapeutic category and 30% prescribed two-agent therapy. Once BP was stabilized, one half of cardiologists reviewed their patients once every 3 months, and 22.5% reviewed their patients once every six months. These results demonstrate that cardiologists do not correctly follow the rules of management of HT recently defined by the various working parties. The authors propose a number of points to remedy some of the deficiencies revealed by this survey.

[Cardiac tamponade and transient ischemia revealing a syndrome of primary antiphospholipid antibodies]. / Tamponnade cardiaque et accident ischémique transitoire révélant un syndrome des anticorps antiphospholipides primitif.

The authors report a case of echocardiographically confirmed cardiac tamponade, which required emergency pericardial aspiration, and a transient ischaemic attack revealing an underlying primary antiphospholipid antibody syndrome in a 29-year-old patient. The test for antiphospholipid antibodies was positive on 2 occasions (IgG > 91.41 micrograms/l). The diagnosis of systemic lupus erythematosus was eliminated. A favourable course was observed after 3 months of corticosteroids and platelet antiaggregants. Any case of cardiac tamponade or transient ischaemic attack with an unexplained aetiology in a young patient must suggest the diagnosis of antiphospholipid antibody syndrome.

[Hypertension and Takayasu disease. Report of 8 cases]. / HTA et maladie de Takayasu. A propos de 8 cas.

In this paper, the authors report 8 cases of Takayasu disease presenting in the form of hypertension, observed in the Cardiology of Ibn Rochd University Hospital in Casablanca between 1983 and 1995. The majority of cases presented with renovascular HT, secondary to unilateral or bilateral renal artery stenosis. More rarely, the patients presented proximal hypertension secondary to coarctation of the aorta. Medical treatment was prescribed all 8 cases, associated with surgery in 8 cases.