Tumour biology, metastatic sites and taxanes sensitivity as determinants of eribulin mesylate efficacy in breast cancer: results from the ERIBEX retrospective, international, multicenter study.

BACKGROUND: Our retrospective, international study aimed at evaluating the activity and safety of eribulin mesylate (EM) in pretreated metastatic breast cancer (MBC) in a routine clinical setting. METHODS: Patients treated with EM for a locally advanced or MBC between March 2011 and January 2014 were included in the study. Clinical and biological assessment of toxicity was performed at each visit. Tumour response was assessed every 3 cycles of treatment. A database was created to collect clinical, pathological and treatment data. RESULTS: Two hundred and fifty-eight patients were included in the study. Median age was 59 years old. Tumours were Hormone Receptor (HR)-positive (73.3 %) HER2-positive (10.2 %), and triple negative (TN, 22.5 %). 86.4 % of the patients presented with visceral metastases, mainly in the liver (67.4 %). Median previous metastatic chemotherapies number was 4 [1-9]. Previous treatments included anthracyclines and/or taxanes (100 %) and capecitabine (90.7 %). Median number of EM cycles was 5 [1-19]. The relative dose intensity was 0.917. At the time of analysis (median follow-up of 13.9 months), 42.3 % of the patients were still alive. The objective response rate was 25.2 % (95 %CI: 20-31) with a 36.1 % clinical benefit rate (CBR). Median time to progression (TTP) and overall survival were 3.97 (95 %CI: 3.25-4.3) and 11.2 (95 %CI: 9.3-12.1) months, respectively. One- and 2-year survival rates were 45.5 and 8.5 %, respectively. In multivariate analysis, HER2 positivity (HR = 0.29), the presence of lung metastases (HR = 2.49) and primary taxanes resistance (HR = 2.36) were the only three independent CBR predictive factors, while HR positivity (HR = 0.67), the presence of lung metastases (HR = 1.52) and primary taxanes resistance (HR = 1.50) were the only three TTP independent prognostic factors. Treatment was globally well tolerated. Most common grade 3-4 toxicities were neutropenia (20.9 %), peripheral neuropathy (3.9 %), anaemia (1.6 %), liver dysfunction (0.8 %) and thrombocytopenia (0.4 %). Thirteen patients (5 %) developed febrile neutropenia. CONCLUSION: EM is an effective new option in heavily pretreated MBC, with a favourable efficacy/safety ratio in a clinical practice setting. Our results comfort the use of this new molecule and pledge for the evaluation of EM-trastuzumab combination in this setting. Tumour biology, primary taxanes sensitivity and metastatic sites could represent useful predictive and prognostic factors

Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study.

PurposeOsteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI.MethodsUsing data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves.ResultsIn children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05).ConclusionFrom the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves

Identifying chondroprotective diet-derived bioactives and investigating their synergism

Osteoarthritis (OA) is a multifactorial disease and nutrition is a modifiable factor that may contribute to disease onset or progression. A detailed understanding of mechanisms through which diet-derived bioactive molecules function and interact in OA is needed. We profiled 96 diet-derived, mainly plant-based bioactives using an in vitro model in chondrocytes, selecting four candidates for further study. We aimed to determine synergistic interactions between bioactives that affected the expression of key genes in OA. Selected bioactives, sulforaphane, apigenin, isoliquiritigenin and luteolin, inhibited one or more interleukin-1-induced metalloproteinases implicated in OA (MMP1, MMP13, ADAMTS4, ADAMTS5). Isoliquiritigenin and luteolin showed reactive oxygen species scavenging activity in chondrocytes whereas sulforaphane had no effect and apigenin showed only a weak trend. Sulforaphane inhibited the IL-1/NFκB and Wnt3a/TCF/Lef pathways and increased TGFβ/Smad2/3 and BMP6/Smad1/5/8 signalling. Apigenin showed potent inhibition of the IL-1/NFκB and TGFβ/Smad2/3 pathways, whereas luteolin showed only weak inhibition of the IL-1/NFκB pathway. All four bioactives inhibited cytokine-induced aggrecan loss from cartilage tissue explants. The combination of sulforaphane and isoliquiritigenin was synergistic for inhibiting MMP13 gene expression in chondrocytes. We conclude that dietary-derived bioactives may be important modulators of cartilage homeostasis and synergistic relationships between bioactives may have an anti-inflammatory and chondroprotective role

Iron status in the elderly: a review of recent evidence

A comprehensive literature review of iron status in the elderly was undertaken in order to update a previous review (Fairweather-Tait et al, 2014); 138 papers were retrieved that described research on the magnitude of the problem, aetiology and age-related physiological changes that may affect iron status, novel strategies for assessing iron status with concurrent health conditions, hepcidin, lifestyle factors, iron supplements, iron status and health outcomes (bone mineral density, frailty, inflammatory bowel disease, kidney failure, cancer, cardiovascular, and neurodegenerative diseases). Each section concludes with key points from the relevant papers. The overall findings were that disturbed iron metabolism plays a major role in a large number of conditions associated with old age. Correction of iron deficiency/overload may improve disease prognosis, but diagnosis of iron deficiency requires appropriate cut-offs for biomarkers of iron status in elderly men and women to be agreed. Iron deficiency (with or without anemia), anemia of inflammation, and anemia of chronic disease are all widespread in the elderly and, once identified, should be investigated further as they are often indicative of underlying disease. Management options should be reviewed and updated, and novel therapies, which show potential for treating anemia of inflammation or chronic disease, should be considered

Mechanisms of proteoglycan aggregate degradation in cytokine-stimulated cartilage

Aggrecan is one of the most important structural components of the extracellular matrix (ECM) of articular cartilage, where it contributes to the hydration of the tissue and its ability to resist compressive loads during joint movement. Increased aggrecan degradation and loss occurs in joint diseases and is thought to be mediated by enzymes such as the matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS). It has also been proposed that aggrecan release from the cartilage can be mediated by a non-proteolytic mechanism which involves the degradation of hyaluronan (RA) to which the aggrecan is bound. As aggrecan degradation and loss is known to be induced by pro-inflammatory cytokines, IL-1, TNFalpha, IL-6, IL-17 and OSM were used to investigate the mechanisms involved in proteoglycan catabolism in organ cultures of bovine articular cartilage. Irrespective of the cytokine, all aggrecan fragments generated were characteristic of aggrecanase action, and no additional aggrecan-degrading enzymatic activity was detected. In the presence of OSM, more rapid aggrecan release was observed, due to both proteolysis and fragmentation of HA by hyaluronidase activity. Moreover, addition of OSM resulted in the cleavage of aggrecan at a non-canonical aggrecanase site near its carboxy-terminal globular domain. Such cleavage could be reproduced in vitro by the action of either ADAMTS-4 or ADAMTS-5. Gene expression analysis revealed that both aggrecanases were highly induced by the cytokines, and while ADAMTS-4 was the major aggrecanase to be stimulated in all conditions, ADAMTS-5 remains the predominant aggrecanase to be expressed in cartilage. Thus, the present study shows that aggrecanase activity is primarily responsible for aggrecan degradation in the early stages of cytokine stimulation, and that in the presence of OSM, aggrecanase substrate specificity can be differentially modulated and hyaluronidase-mediated RA degradation can be induced

Bilan martial et anémie dans la prise en charge médicale du cancer du sein localisé (rôle du récepteur soluble de la transferrine)

Objectifs: décrire la prévalence de l'anémie avant l'initiation de la chimiothérapie, l'évolution des taux d'hémoglobine, l'incidence de l'anémie et son grade en cours de chimiothérapie, le type et la fréquence du traitement spécifique de l'anémie, le statut martial et le rôle du récepteur soluble de la transferrine (RsT) dans une population de 347 patientes traitées par une chimiothérapie adjuvante ou néoadjuvante séquentielle pour un cancer du sein localisé. Déterminer les facteurs cliniques, histologiques et biologiques associés à la carence martiale et à la survenue d'une anémie en cours de chimiothérapie. Patients et méthodes: 347 patientes ont reçu 3 ou 4 cures de FEC100 et 3 ou 4 cures de taxane. Un recueil rétrospectif des données cliniques, histologiques et biologiques pré-thérapeutiques a été réalisé. L'hémoglobine a été relevée à chaque cure de chimiothérapie. La carence martiale a été définie par une ferritinémie basse ou une capacité totale de saturation de la transferrine haute associée au coefficient de saturation de la transferrine bas. Un dosage du RsT par imlnunoturbidimétrie a été réalisé à partir du sérum prélevé avant la chiIniothérapie. Résultats: 21 patientes (6,1 %) présentaient une anémie avant le début de la chimiothérapie. 89 patientes (25,6%) ont bénéficié d'un traitement spécifique de l'anémie,~37 patientes (17%) par EPO, 37 patientes (17%) par fer, 3 patientes par transfusion sanguine. 35 patientes (10,2%) ont présenté une carence martiale. Le RsT était élevé chez 19 patientes (6,30/0). 299 patientes (86,2%) ont présenté en cours de traitement une Hb < 12 gldl, 168 patientes (48,4%) une Hb < Il gldl et 41 patientes (11,8%) une Hb < 10 g/d!. En analyse multiparamétrique, le RsT élevé et l'absence de ménopause étaient associés à la carence martiale, seule Hb < 13 gldl avant le début de la chimiothérapie était associée à la survenue d'une anémie en cours de chimiothérapie. Conclusion: La carence martiale ne joue pas de rôle prédominant dans l'apparition d'une anémie en cours de chimiothérapie. Le RsT permet de diagnostiquer une carence martiale mais la standardisation de la technique reste nécessaire. Ni la carence martiale, ni le RsT ne permettent de prédire la survenue d'une anémie en cours de chimiothérapie. Le facteur prédictif majeur de l'apparition d'une anémie en cours de chiIniothérapie est un taux d'hémoglobine inférieur à 13g/dl à l'initiation du traitement.MONTPELLIER-BU Médecine UPM (341722108) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

MMPs are less efficient than ADAMTS5 in cleaving aggrecan core protein.

Aggrecan degradation in articular cartilage occurs predominantly through proteolysis and has been attributed to the action of members of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) families. Both families of enzymes cleave aggrecan at specific sites within the aggrecan core protein. One cleavage site within the interglobular domain (IGD), between Glu(373-374)Ala and five additional sites in the chondroitin sulfate-2 (CS-2) region of aggrecan were characterized as "aggrecanase" (ADAMTS) cleavage sites, while cleavage between Ser(341-342)Phe within the IGD of bovine aggrecan is attributed to MMP action. The objective of this study was to assess the cleavage efficiency of MMPs relative to ADAMTS and their contribution to aggrecan proteolysis in vitro. The analysis of aggrecan IGD degradation in bovine articular cartilage explants treated with catabolic cytokines over a 19-day period showed that MMP-mediated degradation of aggrecan within the IGD can only be observed following day 12 of culture. This delay is associated with the lack of activation of proMMPs during the first 12 days of culture. Analysis of MMP1, 2, 3, 7, 8, 9, 12, 13 and ADAMTS5 efficiencies at cleaving within the aggrecan IGD and CS-2 region in vitro was carried out by the digestion of bovine aggrecan with the various enzymes and Western blot analysis using aggrecan anti-G1 and anti-G3 antibodies. Of these MMPs, MMP12 was the most efficient at cleaving within the aggrecan IGD. In addition to cleavage in the IGD, MMP, 3, 7, 8 and 12 were also able to degrade the aggrecan CS-2 region. MMP3 and MMP12 were able to degrade aggrecan at the very C-terminus of the CS-2 region, cleaving the Glu(2047-2048)Ala bond which was previously shown to be cleaved by ADAMTS5. However, in comparison to ADAMTS5, MMP3 was about 100 times and 10 times less efficient at cleaving within the aggrecan IGD and CS-2 regions, respectively. Collectively, our results showed that the delayed activation of proMMPs and the relatively low cleavage efficiency of MMPs can explain the minor contribution of these enzymes to aggrecan catabolism in vivo. This study also uncovered a potential role for MMPs in the C-terminal truncation of aggrecan

Iron homeostasis and anemia markers in early breast cancer

Iron plays a fundamental role in cell life and its concentration in living organisms is precisely regulated. Different molecules for iron storage and transport are used to maintain its intracellular homeostasis which is often altered in cancer cells. Specifically, recent studies have demonstrated that in breast cancer cells, the expression/activity of several iron-related proteins, such as ferritin, hepcidin and ferroportin, is deregulated and that these alterations may have a prognostic impact in patients with breast cancer. Moreover, molecules that regulate iron metabolism could become therapeutic targets. This review focuses on recent findings on iron metabolism particularly in breast cancer and on the development of new biomarkers that may be used in the clinical routine for the diagnosis, prognosis and management of cancer-associated anemia as well as for monitoring personalized treatments

Involvement of ADAMTS5 and hyaluronidase in aggrecan degradation and release from OSM-stimulated cartilage.

The relative contribution of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)4 and ADAMTS5 to aggrecan degradation under oncostatin M (OSM) stimulation, the role of the ancillary domains of the aggrecanases on their ability to cleave within the chondroitin sulfate (CS)-2 region, the role of hyaluronidases (HYAL) in stimulating aggrecan release in the absence of proteolysis, and the identity of the hyaluronidase involved in OSM-mediated cartilage breakdown were investigated. Bovine articular cartilage explants were cultured in the presence of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha) and/or OSM, or treated with trypsin and/or hyaluronidase. Aggrecan was digested with various domain-truncated isoforms of ADAMTS4 and ADAMTS5. Aggrecan and link protein degradation and release were analyzed by immunoblotting. Aggrecanase and HYAL gene expression were determined. ADAMTS4 was the most inducible aggrecanase upon cytokine stimulation, whereas ADAMTS5 was the most abundant aggrecanase. ADAMTS5 was the most active aggrecanase and was responsible for the generation of an OSM-specific degradation pattern in the CS-2 region. Its ability to cleave at the OSM-specific site adjacent to the aggrecan G3 region was enhanced by truncation of the C-terminal thrombospondin domain, but reduced by further truncation of both the spacer and cysteine-rich domains of the enzyme. OSM has the ability to mediate proteoglycan release through hyaluronan degradation, under conditions where HYAL-2 is the predominant hyaluronidase being expressed. Compared to other catabolic cytokines, OSM exhibits a unique potential at degrading the proteoglycan aggregate, by promoting early robust aggrecanolysis, primarily through the action of ADAMTS5, and hyaluronan degradation