Tolerance and Efficacy of Regorafenib according to UGT Pharmacogenetical Status in the Treatment of Metastatic Refractory Colorectal Cancer

Introduction: Regorafenib is a multi tyrosin-kinase inhibitor prescribed in metastatic refractory colorectal cancer treatment. Its toxicity is significant but inconstant. The metabolism of regorafenib includes oxydation via cytochrome P3A4, then glucuroconjugation. A pharmacogenetical approach of mutational status of Uridine-Diphospho-Glucuronosyltransfersase (UDP-glucuronosyl-transferase, UGT) could be a strategy to optimise the use of regorafenib. Patients and Method: This is a restrospective, unicentric study. All adult patients treated with regorafenib for a metastatic colorectal cancer in our center between 2013 and 2017 were analysed. UGT1A1 polypmorphism was previously researched in the laboratory after written informed consent. Results: Thirty-five patients received regorafenib during the study period. A TA repetition in UGT1A1 gene was present for 16 patients including two Gilbert syndrome. There were no more adverse events on patients with a heterozygous TA repetition or with a Gilbert syndrome compared with patients without UGT polymorphism, whatever the dosage at initiation of regorafenib. Adverse events grade 2 or superior, and grade 3 or superior tended to be more noticeable when the starting dose was 120 or 160 mg per day compared to 80 mg per day, but not statistically significant. No difference was observed on progression-free survival neither depending on UGT status nor depending on initating dose of regorafenib. Conclusion: This is a preliminary study evaluating safety of regorafenib according to UGT1A1 polymorphism. Larger and prospective studies are needed to evaluate dose-escalation strategy in patients with variable activity of glucuroconidation, especially Gilbert syndrome, or with abnormalities in other UGT enzymes such as UGT1A9.     

Persistent Left Superior Vena Cava in Cardiac Congenital Surgery

Persistent left superior vena cava (LSVC) is a relatively frequent finding in congenital cardiac malformation. The scope of the study was to analyze the timing of diagnosis of persistent LSVC, the timing of diagnosis of associated anomalies of the coronary sinus, and the global impact on morbidity and mortality of persistent LSVC in children with congenital heart disease after cardiac surgery. Retrospective analysis of a cohort of children after cardiac surgery on bypass for congenital heart disease. Three hundred seventy-one patients were included in the study, and their median age was 2.75 years (IQR 0.65–6.63). Forty-seven children had persistent LSVC (12.7 %), and persistent LSVC was identified on echocardiography before surgery in 39 patients (83 %). In three patients (6.4 %) with persistent LSVC, significant inflow obstruction of the left ventricle developed after surgery leading to low output syndrome or secondary pulmonary hypertension. In eight patients (17 %), persistent LSVC was associated with a partially or completely unroofed coronary sinus and in two cases (4 %) with coronary sinus ostial atresia. Duration of mechanical ventilation was significantly shorter in the control group (1.2 vs. 3.0 days, p = 0.04), whereas length of stay in intensive care did not differ. Mortality was also significantly lower in the control group (2.5 vs. 10.6 %, p = 0.004). The results of study show that persistent LSVC in association with congenital cardiac malformation increases the risk of mortality in children with cardiac surgery on cardiopulmonary bypass. Recognition of a persistent LSVC and its associated anomalies is mandatory to avoid complications during or after cardiac surgery.     

Long-term results of continuous subcutaneous recombinant PTH (1-34) infusion in children with refractory hypoparathyroidism

Hypoparathyroidism in children is most often due to mutations in genes involved in parathyroid development and calcium homeostasis signaling. Some rare cases result from autoimmune attack on the parathyroid glands as a part of the type 1 polyglandular failure syndrome (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). The majority of cases of pediatric hypoparathyroidism are well controlled under conventional treatment with calcium and vitamin D analogs. However, this treatment may be difficult to manage, especially in two situations: 1) in the context of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and 2) activating mutations in the calcium-sensing receptor. We successfully treated three patients with hypoparathyroidism with continuous subcutaneous administration of rhPTH(1-34) (recombinant human PTH(1-34)), two of which were refractory to conventional therapy.     

Comparisons among external resistive loading,drug-induced bronchospasm,and dense gas breathing in cats: Roles of vagal and spinal afferents

In anesthetized cats, breathing spontaneously, increase in lung resistance (RL) was induced by either external resistive loads (ERL) or internal loading produced by dense gas breathing (sulfur hexafluoride, SF₆) or serotonin (5-HT)-induced bronchoconstriction. The 3 test agents were used in each animal. Arterial blood gases were maintained in the normal range. Ventilatory and cardiovascular responses were studied in 3 groups of animals: intact, vagotomized, or spinalized at C8 level, a condition that preserved diaphragmatic afferents. In intact or spinal animals, ERL as well as SF₆ inhalation lengthened the inspiratory and/or the expiratory periods, whereas 5-HT injections elicited rapid shallow breathing. The changes in ventilatory timing with either type of load were not observed in vagotomized cats. In all animals, ERL breathing or 5-HT injections increased the moving-time average of diaphragmatic EMG measured at constant time (Edi 0.1 and 0.5 secs), but this was not observed during SF₆ inhalation, a condition in which the magnitude of Rl increase was less than in the 2 other situations. The changes in systemic arterial blood pressure and/or cardiac frequency were mostly associated with 5 HT-induced bronchoconstriction. They persisted in spinalized cats, but were not observed or reversed in vagotomized ones. These observations demonstrate that vagal afferents play a major role in the changes in ventilatory timing and cardiovascular function in response to both external or internal moderate resistive loading. The existence of Edi changes in the 3 groups of cats suggests also that diaphragmatic afferents, preserved in both situations, are involved in this response. Offprint requests to: S. Delpierre     

Measurement of pulsatile motion with millisecond resolution by MRI

We investigated a technique based on phase-contrast cine MRI combined with deconvolution of the phase shift waveforms to measure rapidly varying pulsatile motion waveforms. The technique does not require steady-state displacement during motion encoding. Simulations and experiments were performed in porcine liver samples in view of a specific application, namely the observation of transient displacements induced by acoustic radiation force. Simulations illustrate the advantages and shortcomings of the methods. For experimental validation, the waveforms were acquired with an ultrafast ultrasound scanner (Supersonic Imagine Aixplorer), and the rates of decay of the waveforms (relaxation time) were compared. With bipolar motion-encoding gradient of 8.4 ms, the method was able to measure displacement waveforms with a temporal resolution of 1 ms over a time course of 40 ms. Reasonable agreement was found between the rate of decay of the waveforms measured in ultrasound (2.8 ms) and in MRI (2.7-3.3 ms).     

Annual conversion to Alzheimer disease among patients with memory complaints attending an outpatient memory clinic: the influence of amnestic mild cognitive impairment and the predictive value of neuropsychological testing

Summary OBJECTIVE: The goals of this study were to determine the annual conversion rate to Alzheimer disease (AD) among patients reporting memory problems, including a subgroup with amnestic mild cognitive impairment (aMCI), and to investigate the predictive value of neurocognitive testing for future dementia. METHODS: A prospective study was carried out in an outpatient memory clinic. One hundred and seven patients underwent a clinical examination and completed a battery of standard cognitive tests at study entry and two years later. The conversion rate to clinically manifested AD two years later was investigated, and sensitivity, specificity, receiver operating characteristics (AUC), positive predictive value and negative predictive value for each neuropsychological test were determined. RESULTS: We found an annual rate of conversion to AD of 6.5% among patients reporting memory decline in the setting of our clinic. Specifically, patients with aMCI had an annual conversion rate of approximately 20%. The annual conversion rate for patients reporting memory problems but showing no memory deficit at memory testing was approximately 3%. Receiver operating characteristics (AUC) of the neuropsychological tests ranged from 0.60 to 0.94. CONCLUSIONS: Patients with aMCI have 8.6-fold higher odds of developing AD compared with patients without evident memory impairment on neuropsychological testing. Although the risk of developing AD among patients without objective memory decline is small, some patients in this group still convert to AD, and therefore, close clinical monitoring of patients is necessary.

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J?hrliche Konversionsrate von Patienten mit Ged?chtnisbeeintr?chtigung zur Alzheimerkrankheit: Der Einfluss von amnestischer MCI und die pr?diktive Aussagekraft der neuropsychologischen Testung

Zusammenfassung ZIEL: Ziel der vorliegenden Studie war die Bestimmung der j?hrlichen Konversionsrate von Patienten mit subjektiver Ged?chtnisbeeintr?chtigung zur Alzheimerkrankheit unter Berücksichtigung der amnestischen Milden Kognitiven St?rung (aMCI). Die Wertigkeit zur Vorhersage der Konversion durch einzelne neuropsychologische Testverfahren wurde ebenfalls untersucht. METHODIK: Im Rahmen einer Ged?chtnisambulanz wurde eine prospektive Studie durchgeführt. 107 Patienten wurden in die Studie inkludiert. Alle Patienten durchliefen eine neurologische und eine neuropsychologische Untersuchung am Beginn der Studie und nach zwei Jahren am Ende der Studie. Einerseits wurde die Konversionsrate zur Alzheimerkrankheit untersucht, und anderseits wurden einige Kennwerte der Kriteriumsvalidit?t (Sensitivit?t, Spezifit?t, Receiver Operating Characteristics [AUC], Positive Predictive Value, Negative Predictive Value) einzelner neuropsychologischer Testverfahren zur Vorhersage der Alzheimerkrankheit bestimmt. RESULTAT: Wir fanden eine j?hrliche Konversionsrate von 6,5 % für Patienten, die eine Beeintr?chtigung der Ged?chtnisfunktionen berichteten. Patienten mit aMCI hatten eine j?hrliche Konversionsrate von ungef?hr 20 %. Die j?hrliche Konversionsrate von Patienten mit subjektiver Ged?chtnisbeeintr?chtigung ohne testpsychologisch nachweisbare Ged?chtnist?rung lag bei ungef?hr 3 %. Receiver operating characteristics (AUC) für einzelne neuropsychologische Verfahren lagen zwischen 0,60 und 0,94. KONKLUSION: Patienten mit aMCI haben, im Vergleich zu Patienten ohne neuropsychologisch fassbare Ged?chtnisst?rung, eine 8,6-fache Wahrscheinlichkeit, innerhalb von zwei Jahren eine klinisch manifeste Alzheimerkrankheit zu entwickeln. Obwohl die Wahrscheinlichkeit für Patienten ohne neuropsychologisch fassbare Ged?chtnisst?rung, innerhalb von zwei Jahren eine Alzheimerkrankheit zu entwickeln, gering ist, konvertieren einige wenige Patienten doch zur Alzheimerkrankheit. Engmaschige Kontrolluntersuchungen sind deshalb notwendig.

     

Adenylate cyclase responsiveness to hormones in various portions of the human nephron.

The action sites for parathyroid hormone (PTH), salmon calcitonin (SCT), and arginine-vasopressin (AVP) were investigated along the human nephron by measuring adenylate cyclase activity, using a single tubule in vitro microassay. Well-localized segments of tubule were isolated by microdissection from five human kidneys unsuitable for transplantation. PTH (10 IU/ml) increased adenylate cyclase activity in the convoluted and the straight proximal tubule, in the medullary and cortical portions of the thick ascending limb, and in the early portion of the distal convoluted tubule (corresponding stimulated:basal activity ratios were 64, 19, 10, 18, and 22, respectively). SCT (10 ng/ml) increased adenylate cyclase activity in the medullary and cortical portions of the thick ascending limb, in the early portion of the distal convoluted tubule, and, to a lesser extent, in the cortical and the medullay collecting tubule (activity ratios were 7, 14, 15, 3, and 3, respectively). AVP (1 microM) stimulated adenylate cyclase activity in the terminal nephron segments only, i.e., the late portion of the distal convoluted tubule, the cortical and medullary portions of the collecting tubule (activity ratios 81, 51, and 97, respectively). As measured in one experiment, nearly one-half maximal responses were obtained with 0.1 IU/ml PTH or 0.3 ng/ml SCT in thick ascending limbs and with 1 nM AVP in collecting tubules, suggesting that enzyme sensitivity to hormones as well preserved under the conditions used in this study.