Safety and pharmacokinetics of MM-302, a HER2-targeted antibody–liposomal doxorubicin conjugate, in patients with advanced HER2-positive breast cancer: A phase 1 dose-escalation study

BackgroundThis phase 1 dose-escalation trial studied MM-302, a novel HER2-targeted PEGylated antibody-liposomal doxorubicin conjugate, in HER2-positive locally advanced/metastatic breast cancer.MethodsPatients were enrolled in four cohorts: MM-302 monotherapy (8, 16, 30, 40, and 50 mg/m2 every 4 weeks [q4w]); MM-302 (30 or 40 mg/m2 q4w) plus trastuzumab (4 mg/kg q2w); MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m2) q3w.ResultsSixty-nine patients were treated. The most common adverse events (AEs) were fatigue and nausea. Grade 3/4 AEs of special interest included neutropenia, fatigue, mucosal inflammation, anemia, thrombocytopenia, febrile neutropenia, and palmar-plantar erythrodysesthesia. The MTD was not reached. With MM-302 ≥ 30 mg/m2, overall response rate (ORR) was 13% and median progression-free survival (mPFS) 7.4 months (95% CI: 3·5-10·9) in all arms. In 25 anthracycline-naïve patients, ORR was 28·0% and mPFS 10·9 months (95% CI: 1·8-15·3). Imaging with 64Cu-labeled MM-302 visualized tumor-drug penetrance in tumors throughout the body, including the brain.ConclusionMM-302 monotherapy, in combination with trastuzumab, or trastuzumab plus cyclophosphamide, was well tolerated and showed promising efficacy. The selected phase 2 MM-302 dose was 30 mg/m2 plus 6 mg/kg trastuzumab q3w

An open‐label, single‐arm, phase 2 study of single‐agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93582/1/bjh9232.pd

Computer-aided disease diagnosis in aquaculture: current state and perspectives for the future.

ABSTRACT. Automation of essential processes in agriculture is becoming widespread, especially when fast action is required. However, some processes that could greatly benefit from some degree of automation have such difficult characteristics, that even small improvements pose a great challenge. This is the case of fish disease diagnosis, a problem of great economic, social and ecological interest. Difficult problems like this often require a interdisciplinary approach to be tackled properly, as multifaceted issues can greatly benefit from the inclusion of different perspectives. In this context, this paper presents the most recent advances in research subjects such as expert systems applied to fish disease diagnosis, computer vision applied to aquaculture, and image-based disease diagnosis applied to agriculture, and discusses how those advances may be combined to support future developments towards more effective diagnosis tools. The paper finishes suggesting a possible solution to increase the degree of automation of fish disease diagnosis tools

Data mining as a tool for environmental scientists

Over recent years a huge library of data mining algorithms has been developed to tackle a variety of problems in fields such as medical imaging and network traffic analysis. Many of these techniques are far more flexible than more classical modelling approaches and could be usefully applied to data-rich environmental problems. Certain techniques such as Artificial Neural Networks, Clustering, Case-Based Reasoning and more recently Bayesian Decision Networks have found application in environmental modelling while other methods, for example classification and association rule extraction, have not yet been taken up on any wide scale. We propose that these and other data mining techniques could be usefully applied to difficult problems in the field. This paper introduces several data mining concepts and briefly discusses their application to environmental modelling, where data may be sparse, incomplete, or heterogenous

The NAME trial:a direct comparison of classical oral Navelbine versus metronomic Navelbine in metastatic breast cancer

Chemotherapy for metastatic breast cancer (MBC) is in general given in cycles of maximum tolerated doses to potentially maximize the therapeutic outcome. However, when compared with targeted therapies for MBC, conventional and dose intensified chemotherapy has caused only modest survival benefits during the recent decades, often compromising the quality of life considerably. Navelbine is an antineoplastic agent that has shown efficacy in the treatment of a variety of cancer types, including breast cancer. Early clinical trials involving both breast cancer and lung cancer patients suggest that metronomic dosing of Navelbine might be at least as effective as classical administration (once weekly, etc.). The NAME trial compares these two strategies of Navelbine administration in MBC patients

Efficacy and safety of T-DM1 in the 'common-practice' of HER2+ advanced breast cancer setting: a multicenter study

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (mBC). The aim of this 'field-practice' study was to investigate the efficacy and safety of T-DM1, focusing on treatment line, previous lapatinib treatment and patterns of metastasis. Three hundred and three patients with HER2-positive mBC who received T-DM1 were identified by reviewing the medical records of 24 Italian Institutions. One hundred fourty-nine (49%) and 264 (87%) had received prior hormonal treatment and/or anti-HER2 targeted therapy, respectively. Particularly, 149 patients had been previously treated with lapatinib. The objective response rate (ORR) was 36.2%, and 44.5% when T-DM1 was administrated as second-line therapy. Considering only patients with liver metastases, the ORR was 44.4%. The median progression-free survival (PFS) was 7.0 months in the overall population, but it reached 9.0 and 12.0 months when TDM-1 was administered as second- and third-line treatment, respectively.In conclusion, in this 'real-word' study evaluating the effects of T-DM1 in patients with HER2-positive mBC who progressed on prior anti-HER2 therapies, we observed a clinically-relevant benefit in those who had received T-DM1 in early metastatic treatment-line and in subjects previously treated with lapatini

Valproic Acid-Induced Teratogenesis in Japanese Rice Fish (Oryzias Latipes) Embryogenesis

Valproic acid (VPA) was introduced as an antiepileptic in 1967 in France and it has become the most prescribed anticonvulsive drug therapy worldwide since then. In the clinic, valproic acid is selected to treat absence seizures, myoclonic seizures, generalized tonic-clonic seizures, atonic attacks and partial seizures. Epilepsy is the second most comneurologic disorder that affects pregnant women (0.5%–1%). Approximately 1 out of 250 pregnant women are taking antiepileptic drugs. Valproic acid is designated as a human teratogen, which induces major congenital anomalies, facial dysmorphic features, and autistic-like behaviors, which affect verbal, cognitive, communicative, and social abilities of affected children. We are developing the Japanese rice fish (Oryzias latipes), also known as Japanese medaka, as an animal model to study valproate-induced teratogenesis during the period of embryogenesis. Fertilized embryos of Japanese rice fish at three developmental stages (group A: 0–2 dpf; group B: 1–3 dpf; group C: 4–6 dpf) were exposed to VPA (0–80 mM) for 48 hrs. The amounts of VPA to cause 50% mortality (LC50), which were observed on 14 day post fertilization (dpf), are found to be developmental stage-specific. The LC50 for group A (Iwamatsu developmental stage 4–10) is 1.68 ± 1.55 mM which is much lower than the LC50s for groups B (26.45 ±1.64 mM) and C (20.37 ± 3.3 mM) (Iwamatsu developmental stages 17–32). The development of the cardiovascular system was disrupted by VPA in each treatment group, displaying increased incidence of thrombus, reduced heart rates, and inhibited or delayed onset of circulation. The hatching efficiency was also reduced by VPA in each treatment group. The higher the concentration of VPA the embryos were treated with, the more severe the results were. The earlier developmental stages the treatments were targeted at, the more deleterious the effects of VPA were. VPA also caused malformation of neurocranial and splanchnocranial cartilages of hatchlings that had been exposed prenatally. The length of neurocranium, quadrate, ceratohyal and basibranchial 1–3 were all reduced in hatchlings of both groups E (0–2 pdf) and L (4–6 dpf). Trabeculae, epiphyseal bar, anterior orbital cartilage and basilar plate displayed reduction in length only in hatchlings of group E. In addition, the significant reduction in the linear length of polar cartilage and ceratobranchials 1–5 were manifested only in hatchlings of group L. Other cartilages remained unaltered in both groups E and L. It was indicated that the length of the neurocranium was reduced due to cumulative reduction of the component cartilages. mRNA analyses of nine genes demonstrated that the genes involved with oxidative stress remained unaltered after valproate exposure. However, the genes involved with neurogenesis (wnt1, otx2 and nlgn3b) and regulation of cell division (shh and ccna2) shodevelopmental stage-specific alteration after valproate exposure. This study indicates that valproate is able to induce some phenotypic features in Japanese rice fish which are analogous to human fetal valproate syndrome (FVS), and Japanese rice fish can be used as a unique alternatively non-mammalian vertebrate model to study valproate-induced teratogenesis, including FVS