First-line therapy in HER2 positive metastatic breast cancer. Is the mosaic fully completed or are we missing additional pieces?

The discovery of human epidermal growth factor receptor 2 (HER2) and its role in the biology of breast cancer and the subsequent development of HER2-targeted therapies, have dramatically improved clinical outcomes for women with early-stage and advanced HER2-positive breast cancer (BC). HER-2 targeted therapies represent a major step forward in achieving the goal of delivering individualized targeted therapy for BC, and trastuzumab was the first anti-HER-2 strategy to be approved for treatment of HER-2 positive BC. This review discusses the treatment of metastatic HER2-positive BC and describes efficacy and safety of novel anti-HER2 target therapies in first-line metastatic settings and the future challenges include refining such treatments, reducing toxicity and simultaneously developing innovative therapies. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described. In the next future will be possible to use an ample armamentarium of combination therapies directed against HER2 and key signaling components integrated in the HER network. This approach will allow clinicians to tailor the management of the individual patient on the basis of tumor- specific biomarker profiles. There is an urgent need for prospective biomarker-driven trials to identify patients for whom targeting is cost-effective

R & D Planning Involving Multicriteria Decision Analytic Methods at the Branch Level

This series of papers are a product of collaborative research coordinated through IIASA's Management and Technology Area. The collaborating institutions are Hungarian State Office of Technical Development (Personnel: Anna Vari, Janos Vecsenyi, Laszlo David); Decision Analysis Unit, Brunel University, England (Personnel: Patrick Humphreys, Lawrence D. Phillips); All-Union Research Institute of Systems Studies, USSR (Personnel: Oleg. I Larichev). The papers report case studies prepared by the personnel from the collaborating institutions based on their own, and their colleagues' work in their own institutions. They worked together as a team in developing the methods for the analysis of these case studies which are described in the first paper in the series. IIASA provided support for this work through its telecenter for communication between the investigations, and provided facilities for short term meetings between the investigations at IIASA for development of case studies and their comparative analysis. Particular MMT staff were Ronald M. Lee, Nora Avedisians, and Miyoko Yamada, who is the editor of this series. A summary of this comparative analysis, based on the first four case studies in this series was presented at the IFIP/IIASA Conference on "Processes and Tools for Decision Support", Laxenburg, Austria, July, 1982. The paper presented at the IFIP/IIASA conference will be published as Humphreys, P.C., O.I. Larichev, A. Vari, and J. Vecsenyi, Comparative analysis of decision support systems in R&D decisions, in H.G. Sol (ed.), "Processes and Tools for Decision Support", Amsterdam: North Holland, 1982. Another study in this series was published separately as L.D. Phillips: Requisite decision modeling: a case study. "Journal of the Operations Research Society, 1982, 33:303-311

Commentary- Increasing abuse of anabolic steroids and chemsex drugs as performance and image-enhancing agents

Anabolic Androgenic Steroids (AAS) are a family of synthetic “Appearance and Performance Enhancing Drugs” (APED) derived from natural sex hormones, such as testosterone and its derivatives or precursors (e.g., dihydrotestosterone)1 . Whereas testosterone is the androgen responsible for the development of male secondary sex characteristics and elicits both anabolic and androgenic effects, AAS mostly simulate the anabolic effect of endogenous testosterone, and induce only partial androgenic effects2 . In the 1930s, anabolic steroids were shown to facilitate muscular growthhand consequently became rapidly popular among bodybuilders and other athletes, and were already widespread in the 1960s. AAS have been and still are among the doping agents most frequently misused by athletes, regardless of the type of sport, both in preparations containing natural anabolic drugs [e.g., testosterone and dehydroepiandrosterone (DHEA)] and in those with synthetic substances (e.g., dianazole, nandrolone, stanozolol and tetrahydrogestrinone

Design of Flood-loss Sharing Programs in the Upper Tisza Region, Hungary: A dynamic multi-agent adaptive Monte Carlo approach

Losses from human-made and natural catastrophes are rapidly increasing. The main reason for this is the clustering of people and capital in hazard-prone areas as well as the creation of new hazard-prone areas, a phenomenon that may be aggravated by a lack of knowledge of the risks. This alarming human-induced tendency calls for new integrated approaches to catastrophic risk management. This paper demonstrates how flood catastrophe model and adaptive Monte Carlo optimization can be linked into an integrated Catastrophe Management Model to give insights on the feasibility of a flood management program and to assist in designing a robust program. As a part of integrated flood risk management, the proposed model takes into account the specifics of the catastrophic risk management: highly mutually dependent losses, the lack of information, the need for long-term perspectives and geographically explicit models, the involvement of various agents such as individuals, governments, insurers, reinsurers, and investors. Therefore, the integrated catastrophe management model turns out to be an important mitigation measure in comprehending catastrophes. As a concrete case we consider a pilot region of the Upper Tisza river, Hungary. Specifically, we analyze the demand of the region in a multipillar flood-loss sharing program involving a partial compensation by the central government, a voluntary private property insurance, a voluntary private risk-based insurance GIS-based catastrophe models and specific stochastic optimization methods are used to guide policy analysis with respect to location-specific risk exposures. To analyze the stability of the program, we use economically sound risk indicators

Cognitive enhancing drugs: a future challenge for the workplace?

In medical practice, cognitive enhancers (also called nootropics) are defined as therapeutic drugs treating specific cognition impairments in patients with attention deficit hyperactivity disorder, Alzheimer’s disease, stroke schizophrenia or aging. However, the non-medical use of cognitive enhancers with the aim of increasing mental alertness and concentration, improving memory, fighting wakefulness and boosting energy has been spreading worldwide2. In this concern, scarce investigations have been carried out on the possible risks of chronic non-medical use of nootropics, and these risks seem to be largely overlooked, especially among students3. Considering the ever more competitive nature of modern societies, which also reverberates into workplaces, cognitive enhancers are reasonably expected to become even more common over time4. Nonetheless, long-term consequences are as yet unknown. Cognitive enhancers, used by healthy individuals, are widely known as nootropics: they consist of drugs, supplements and other substances that are allegedly known to improve cognitive function, particularly executive functions, and to strengthen memory, creativity or even motivation. Pharmaceutical substances and compounds known as ‘cognitive-enhancers’ allegedly boost mental performance and the ability to focus and keep concentration. In broader terms, such drugs are often claimed to heighten and foster the acquisition of motor capabilities and affective skills (i.e., one’s ability to deal with anxiety stemming from performing certain work tasks or eliciting feelings of trust and affiliation). It is worth noting, however, that no drugs are licensed by medical authorities to be recommended and prescribed as ‘cognitive enhancers’. Thus, the definition of ‘performance-enhancing drug’ is usually linked to the off-label use of drugs prescribed for specific medical conditions. These substances are usually stimulants that preferentially target the catecholamines of the prefrontal cortex of the brain to induce their effects5. Historically, amphetamines have been the first drugs used off-label for the purpose of fostering memory consolidation and increasing concentration6. Since these substances are legally controlled as drugs of abuse, they can only be obtained on illegal markets. This purchase channel is also used to obtain methylphenidate, which is undoubtedly the most misused drug as cognitive enhancer5,7. Mostly prescribed for treating Attention Deficit Hyperactive disorder (ADHD) and narcolepsy, methylphenidate has been scheduled as an illegal drug in many countries for its abuse liability and side effects, resulting in a rapid expansion of methylphenidate legal analogs onto the drug market. Alternative prescription drugs for the treatment of narcolepsy and ADHD, such as modafinil and armodafinil, are also used as cognitive enhancers8. Finally, two last drugs should be mentioned among nootropics: atomoxetine, a selective nor-adrenaline reuptake inhibitor licensed for the treatment of children with methylphenidate-resistant ADHD or undergoing methylphenidate side effects9, and donepezil, a second-generation acetylcholinesterase inhibitor licensed for the treatment of mild to moderately severe symptoms of Alzheimer-related dementia10. At the same time, there has been renewed interest in older prescription drugs (e.g., beta blockers, to decrease performance anxiety) and illicit psychostimulants (e.g., cocaine, amphetamines), sometimes in different forms or doses. Whereas there is still little consensus on the actual effectiveness and nature of the cognitive benefits of the above-mentioned drugs in healthy subjects13, their use to enhance the level of performance in specific workplaces has been reported for decades14. In fact, cognitive enhancement has been a mainstay of military research in the US since the Second World War with the use of amphetamines, modafinil and other cognitive enhancers in the most recent military operations (e.g., Vietnam war, Korean war, operations Desert Shield and Desert Storm in Iraq, later sustained military operations in the Middle East)15,16. Whereas the military use of cognitive enhancers has been known for many years, not only in the US but internationally. More recent studies reported that other occupations present a high prevalence of use: medical doctors and health professionals (e.g., surgeons, surgical technicians’ anesthetists), transportation workers (e.g., truck drivers, car drivers, taxi drivers), financial traders, clinical investigators, research managers and lawyers. Finally, the increase of precarious and part-time home works has been recently associated to psychological discomfort and an increase in prescriptions of psychotropic drugs, and a rise in the misuse of cognitive enhancers can be hypothesized17-19. Another important factor to be taken into account is the role of the internet as a source of information through web forums and as a way of obtaining those substances. Such dynamics also constitute a cultural shift in the way drugs are obtained and consumed: they are anonymously received and safer than street drugs trafficking, although the actual composition and nature of the substances cannot be precisely ascertained. This latter fact creates a gap of information on the diagnosis of misuse in cases of possible intoxications and fatalities, since neither analytical screening nor confirmation methodologies are currently available for documenting exposure to those profuse and chemically diverse substances. In addition, apart from intoxications and fatalities, it has to be reminded that several of these substances present a potential for abuse liability and abstinence symptoms, which, instead of improving work pressure and overload, can worsen the environmental situation. In conclusion, we wish to draw the attention of the whole scientific community and policy makers to the increasing importance of the misuse of cognitive enhancers, and to improve public awareness of the phenomenon and contextual political strategies to stop this incoming threat for the health of current and future worker

Prospective study on nanoparticle albumin-bound paclitaxel in advanced breast cancer. Clinical results and biological observations in taxane-pretreated patients

Background: There is a deep need to improve the care of metastatic breast cancer (MBC) patients, since even today it remains an incurable disease. Taxanes are considered the most effective cytotoxic drugs for the treatment of MBC, both in monotherapy and in combined schedules, but the need for synthetic solvents contributes to the severe toxicities and may have a negative impact on the efficacy. Nanoparticle albumin-bound paclitaxel (Nab-paclitaxel) is a colloidal suspension of paclitaxel and human serum albumin initially developed to avoid the toxicities associated with conventional taxanes. Patients and methods: The aim of this prospective, single-center open-label, noncomparative study was to evaluate the efficacy and safety of nab-paclitaxel in MBC patients pretreated with taxanes. The patients were treated with nab-paclitaxel as a single agent, 260 mg/m2 on day 1 of each 3-week cycle or 125 mg/m2 weekly. The primary endpoint was the overall response rate (ORR). Secondary objectives were duration of response, clinical benefit rate, progression-free survival (PFS), overall survival, and safety. Results: A total of 42 patients (median age 48 years, median Eastern Cooperative Oncology Group performance status 0, triple-negative MBC 19%, all pretreated with a taxane-based therapy, mainly in advanced disease) were enrolled in the study. The ORR was 23.8%, including one complete response (2.4%) and nine partial responses (21.4%); the disease control rate was 50%. The median duration of response was 7.2 months. After a median follow-up of 9 months, the median PFS was 4.6 months. ORR and PFS were similar irrespective of the previous chemotherapy lines, metastatic sites, and biomolecular expression. Nab-paclitaxel was well tolerated, and the most frequent treatment-related toxicities were mild to moderate (grades 1–2). Conclusion: This real-life study shows that nab-paclitaxel has a significant antitumor activity and a manageable safety profile in patients pretreated with taxanes and experiencing a treatment failure after at least one line of chemotherapy