A phase 1 study of mTORC1/2 inhibitor BI 860585 as a single agent or with exemestane or paclitaxel in patients with advanced solid tumors

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5-300 mg/day; Arm A), BI 860585 (40-220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80-220 mg/day; Arm C) with 60-80 mg/m(2)/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n= 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n= 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel

Treatment landscape of metastatic prostate cancer: the role of radium-223.

The landscape of metastatic prostate cancer has changed recently with the availability of six new molecules showing an overall survival benefit. The development of compounds able to decrease the rate of complications from bone metastasis has also led to improvements in overall morbidity associated with this disease. In this paper, we briefly review the currently available drugs indicated in the treatment of metastatic prostate cancer, focusing on the place of the radiopharmaceutical agent radium-223 and its very unique mechanism of action and safety profile

Une anémie de Biermer se dissimulant sous les traits d’une anémie normocytaire

L’anémie mégaloblastique par carence en vitamine B12 ou en folate est bien connue. Son diagnostic est aisément posé par l’association d’une carence en vitamine et d’une macrocytose globulaire. Toutefois, diverses circonstances peuvent masquer la macrocytose et, donc, compliquer le diagnostic. Nous rapportons le cas d’une patiente se présentant pour une anémie hémolytique normocytaire qui s’avère être après mise au point, une anémie de Biermer associée à une alpha-thalassémie mineure.[A pernicious anemia masking itself under the guise of a normocytic anemia] Megaloblastic anemia due to vitamin B12 or folate deficiency is a well-known clinical entity. Diagnosis is easily made on the basis of vitamin deficiency associated with macrocytosis. Several conditions can, however, hide the conventional macrocytosis, rendering the diagnosis less straightforward. We report the case of a 45-year-old woman presenting with relatively well-tolerated severe anemia (7g/dL) and mild thrombocytopenia. The mean corpuscular volume (MCV) was normal (86,9 fL) with low reticulocytosis. Biology revealed signs of hemolysis and a low vitamin B12 level combined with anti-intrinsinc factor antibodies, which corroborated the diagnosis of pernicious anemia. To exclude a bicytopenia of central origine, a bone marrow aspiration was performed, which confirmed the megloblastosis. the normal MCV prompted us to search for a cause that could mask the classic macrocytosis observed in megaloblastic anemias. Ferritin and C-reactive protein levels were in the normal range, as was hemoglobin electrophoresis. We finally detected an α+thalassemia with 3,7 kb deletion while using molecular biology techniques. The patient recovered within a few weeks after being given intramuscular vitamin B12. This case of normocytic hemolytic anemia that turned out to be a pernicious anemia associated with an alpha-thalassemia minor illustrates that normal MCV does not suffice to rule out vitamin B12 deficiency. The major reasons for normocytic anemia under these circumstances are its combination with microcytic anemia, mostly due to iron deficiency and thalassemia, or its coexistence with macrocytic erythrocytes comprising erythrocyte fragment

Malnutrition with Low Muscle Mass Is Common after Weaning off Home Parenteral Nutrition for Chronic Intestinal Failure

The differences in outcomes after weaning off intravenous support (IVS) for chronic intestinal failure (IF) are unclear. Adult IF patients who are weaned off IVS at a tertiary care center (June 2019–2022) were included in this study, and nutritional and functional markers were assessed before, during, and after weaning. Short bowel syndrome (SBS) was present in 77/98 of the IF patients, with different outcomes according to the final anatomy. The body weight and the BMI increased during IVS in those with a jejunocolonic (JC) anastomosis (p p 60%, with a reduced muscle mass, which was found using bioelectrical impedance analysis (BIA), in >50% of SBS-JC patients. Although reduced hand-grip strength and sarcopenia were less common, the muscle quality, or phase angle (BIA), decreased during follow-up, also correlating with serum albumin and muscle mass (p ≤ 0.01). The muscle quality and albumin were low in the patients restarting IVS, which was only the case with ≤60 cm of small bowel. Closer follow-up and earlier treatment with teduglutide (TED) should be considered in these patients, as none of the TED-treated patients were malnourished or sarcopenic. Studies on the potential benefits of nutritional and physical interventions for low muscle mass and associations with outcomes are needed in chronic IF patients

599P R-IMMUNE: A phase Ib/II study to evaluate safety and efficacy of atezolizumab combined with radio-chemotherapy in a preoperative setting for patients with locally advanced rectal cancer (LARC)

BACKGROUND : There is a strong rationale to combine radiotherapy with immune checkpoint inhibitors (ICIs). This study evaluates this combination before surgery in locally advanced rectal cancer (LARC). [...

Le droit en transition

La croissance occupe aujourd’hui une place centrale dans la gouvernance publique. Parce qu’elle soutiendrait la création d’emplois, assurerait le financement de la sécurité sociale, allégerait le fardeau de la dette, favoriserait les investissements, l’augmentation constante du produit intérieur brut serait devenue indispensable à la prospérité collective. Dès son émergence cependant, cet « imaginaire croissanciel » - qui a su séduire à gauche comme à droite - s’est attiré des critiques d’ordre anthropologique (la croissance infinie du pouvoir d’achat ne signe pas l’épanouissement humain), écologique (la quête éperdue de points de croissance se heurte au mur des limites planétaires) et social (cinquante ans d’agenda croissanciel n’ont pas empêché les inégalités de se maintenir). La crise économique qui a éclaté en 2007 et les signes toujours plus tangibles des bouleversements climatiques à venir ont donné à ces critiques une acuité nouvelle. Et le droit dans tout cela ? Nos règles juridiques reflètent-elles l’emprise de l’imaginaire croissanciel ou autorisent-elles d’autres conceptions du progrès humain ? Et les juristes ? Ont-ils les moyens et la légitimité pour traduire dans les règles de droit les aspirations à une prospérité sans croissance ? Ce sont ces questions difficiles que cet ouvrage aborde, couronnant trois années de travaux au sein du Séminaire interdisciplinaire d’études juridiques. Gageons que le lecteur y trouvera une source d’inspiration et un programme de recherche à la hauteur des défis de notre époque

The PRSS3P2 and TRY7 deletion copy number variant modifies risk for chronic pancreatitis

Background PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition. Methods We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction. Results We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52–0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77–0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression. Conclusions The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection