[The effects of targeted therapies on bones]


DECEMBER 10, 2012

LAM KID - 2012;2(04)

[Arthritis is associated with local as well as generalised bone loss. It is likely that similar inflammatory/immunological factors contribute to both types of bone loss. Today, the main targets of arthritis therapy are proinflammatory citokines (TNF-alpha, IL-1, IL-6, in the future IL-17) and the inhibition of B and T cells. All biological therapies have been proved to slow down the development of focal joint destruction. TNF-inhibitors in particular have been demonstrated to have a beneficial effect on generalised osteoporosis. In ankylosing spondylitis, generalised osteoporosis and locally increased bone formation occur at the same time, creating a controversial situation. Further studies are needed for a better understanding of the effects of targeted therapy on bones.]



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[Effect of zoledronic acid treatment on pain and quality of life in patients with metastatic bone disease suffering from breast and prostate cancer - Multicenter, prospective, observational study]

PÁPAI Zsuzsanna, LANDHERR László, SPEER Gábor

[INTRODUCTION - Metastatic bone disease is frequently associated with breast and prostate cancer. Bisphosphonate treatment of bone metastases is palliative: its primary goal is to relieve pain, while it's also important to decrease the risk of bone fractures, prolong survival and maintain physical activity of the patients. Pain is the most common symptom of bone metastases. PATIENTS AND METHODS - In total 845 patients were enrolled in our open, multicenter, prospective, observational study, the first of its kind in Hungary. The agent tested was zoledronic acid (Zometa®). Duration of the study was 20 months and its primary goal was to assess the correlation between pain and quality of life during the treatment of patients with bone metastases from breast or prostate carcinoma. RESULTS - During the 18 months of the study, the average intensity of pain, measured on the visual analog scale showed a 42% reduction (p<0.0001). By the end of the 18. month, the ratio of patients free of symptoms has increased by 15% and the number of patients with substantial complaints has decreased by 73%. CONCLUSION - Our study supports the observation published in the international literature that in patients with bone metastases from breast and prostate cancer, zoledronic acid treatment is beneficial for reducing pain and thus for improving quality of life.]


[The importance of balneotherapy in osteology]


[The authors overview the role of hydro-and balneotherapy in osteology. AsHungary is very rich in thermal-mineralwater, this kind of therapy has a greatimportance in the rehabilitation of locomo-tor diseases. In the past years, an increasingnumber of data have been published aboutthe immunomodulatory, metabolic andanalgesic role of hydro- and balneothera-py. Although balneotherapy’s mechanismof action has not been clarified yet, a num-ber of reviews and metaanalyses havefound that hydro- and balneotherapy havea beneficial effect on locomotor diseases.The majority of these articles - many ofthem written by Hungarian authors - dis-cusses the treatment of arthrosis. Further-more, an increasing amount of data isavailable on calcium supplementation withmineral water. In this paper, we discuss therole of hydro- and balneotherapy in thetherapy of osteological diseases, on thebasis of the available evidence. ]


[Stop at one - Make your first break your last!]



[Adherence of Hungarian postmenopausal women with osteoporosis]

LAKATOS Péter, TÓTH Emese, LANG Zsolt, NAGY Bence, SZEKERES László, TAKÁCS István

[INTRODUCTION - Osteoporosis is defined as a loss of bone tissue and bone mass that leads to a compromised trength and quality of bones and thus to an increased risk of fractures. In many women, menopausal hormonal changes are associated with an increased bone loss. This population has postmenopausal osteoporosis. The essence of osteporosis treatment is the adequate calcium and vitamin D supplementation, which, if needed, might be combined with drug therapy to inhibit the process of bone loss. METHODS - We assessed the adherence to therapy of Hungarian patients and its effect on the risk of bone fractures, using data recorded by the National Health Insurance Fund Administration between 2004 and 2010 (n=223068, mean age: 69.9 years). We performed a statistical analyses of the available data. Medication possession ratio (MPR) for each treatment and the ratio of patients receiving continuous treatment in the study period (for 12, 18 and 24 months) were estimated. Medication persistence was investigated using Kaplan-Meier survival analysis. A multivariate Cox proportional hazard model was used to determine the factors influencing the risk of fracture. RESULTS, CONCLUSION - The results of our study show that medication adherence to treatment is low among Hungarian patients [mean MPR: 57.9%; 95% CI (57.7%- 58.0%) and persistence rate: 32.4%; 95% CI (32.2%-32.6%) in the first year]. These parameters are substantially influenced by the administration route and the frequency of treatments [mean MPR ranged 41.5%- 100% and persistence rates ranged 18.8%- 100% in the first year, differences between subgroups were significant (p<0,05)]. Our compliance as well as persistance studies showed that parenteral administration had more beneficial effects. Confirming our preliminary hypotheses, the improvement of patient compliance significantly reduced fracture risk (good compliance was defined as MPR>80%, which was associated with RR: 0.57, p<0.05 for fracture risk). Further improvement might be achieved by parenteral administration [RR for fracture risk 0.60 compared with non-compliant patients and 0.44 compared with compliant subgroups treated with oral and parenteral medications (p<0.05)].]

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Lege Artis Medicinae



[Rheumatoid arthritis is an autoimmune rheumatic condition of unknown origin. Due to its high prevalence, incompletely solved therapy, significant impact on mortality and morbidity, and the psychological and economic burden it puts on the patient, family and society, rheumatoid arthritis has a major public health significance. Although its importance is still underestimated both by the public and the medical community, today an improving tendency can be observed. The past decade has seen important breakthroughs in terms of increased recognition of the significance of the disease, as well as in its pathogenesis, diagnosis and therapy. The introduction of new diagnostic and prognostic markers and early aggressive treatment, the establishment of early arthritis clinics, and, most importantly, the successful use of biological therapy have revolutionized the management of rheumatoid arthritis. The paper reviews the modern therapy of the disease, touching on the options available in Hungary.]

Clinical Oncology

[Cell cycle as therapeutic target – CDK4/6 inhibition]


[One of the most important decision of a cell: to live or die. If survival is the choice, there are three options: proliferate, to stay in sleeping state for a while, or differentiate in order to perform its specifi c function. These decisions are under a very strict molecular regulation infl uenced by internal and external factors. Tumor cells more and more disregard the regulations, and move into independency for a continuous proliferation, which has a very similar program in normal and tumor cells. The main route towards mitosis is the cell cycle, under the supervision of positive and negative regulators, forming checkpoints, telling to the cell - under the infl uence of mitogenic signals - to go or to stop. The most critical checkpoint is at the border of G1 and S phases where the main players are cyclinD, CDK4/6 and RB1. It turned out that the best targets to inhibit cell proliferation are the CDKs, but this approach, when used unselected targets, was unsuccessful due to the toxicity. To improve the clinical results, the selection of CDK4/6 as a therapeutic target seems to fulfi l most of the hopes. Today three drugs are the most promising: palbociclib (with an acceptance by FDA and EMA to treat breast cancer patients), abemaciclib and ribociclib (underclinical trials). Now, most of the data concern breast cancer, especially the combinations of CDK4/6 inhibitors and endocrine therapy, but many other malignancies are studied (e.g. liposarcoma, mantel cell lymphoma, melanoma, renal cancer, lung cancer, pancreatic cancer, ovarian cancer, teratomas etc.). The key points are the side-effects, the most frequently observed is neutropenia, but so far it is managed without serious toxicity.]

Clinical Oncology

[Molecular profi les in therapeutic strategy]

PETÁK István, SCHWAB Richárd

[In 2013, 10 years after the completion of the human genome, the cancer genome project has identifi ed almost all possible cancer genes, which could be responsible for the malignant transformation and progression. These genes are called „driver” genes, and the pathogenic mutations to be „driver” mutations. The census of „driver genes” in 2013 counted 138 genes and 1.5 million mutations. The situation is further complicated by the fact that up to 8 „driver” gene can be activated simultaneously in the same tumor, furthermore, the profi le may change during tumor growth and metastatization. 2013 was a turning point also because several targeted therapies were registered. Currently there are about 30 targeted drugs in clinical use and more than 200 targeted compounds in clinical development. This means that in 3-4 years the number of drugs will at least double. Most of the current patients can only access these compounds in clinical trials. But, patient already benefi t signifi cantly more even from phase I clinical trials, if they are selected based on the molecular profi le of the tumor. Fortunately, the advancements of next generation sequencing technologies provide the opportunity to identify all „driver” genes, - the whole molecular profi le, - in the patient’s tumor for the cost of one month targeted therapy. But the information generated can be only used in clinical practice if the results are processed by „molecular info-bionics”.]

Clinical Oncology

[MEK and ERK - against RAS and RAF ]


[In most cases, the targeted therapy is able to produce clinical response, but after a certain interval it turns to be ineffective due to secondary resistance against the therapy. One of the most demanding challenge in treatment of cancer is to prevent or inhibit such resistance, which could have several forms, e.g. appearance of new driver activating mutations in the treated tumor, clon(s) existed in minority with different mutations (targets) can grow and replace the temporarely sensitive tumor cells (on the basis of tumor heterogeneity); another pathway takes over the role in cancer progression, etc. Such problems are very common in the RAS-RAF-MEK-ERK pathway. These are very important proteins to collect extracellular signals in order to regular different cell functions, especially proliferation. With activating mutations make the RAS-pathway independent from the normal .regulation. To inhibit the consequence of the mutations is largely still an unsolved problem, with few exceptions (e.g. inhibition of BRAF mutations). Theoretically, the inhibition of the next steps of the pathway, MEK and ERK, may stop the pathologically activated signals, partly due to their inhibition, and party to effi ciently decrease the feedback inside the pathway. This review discusses aspects of this possibilities, especially to overcome resistance and prolong the effectiveness of therapy.]

Clinical Oncology

[Radiochemotherapy - questions/answers]

PIKÓ Béla, LACZÓ Ibolya

[During chemoradiotherapy the two main non-surgical anticancer methods are combined to improve the treatment outcomes. The theoretical possibilities of interactions and the most frequently used drugs will be presented here, emphasizing that although both the radiation therapy and the drugs need to be administered in full dose in practice considering the summarization of side effects we often have to make compromises. The treatments of the most frequent indications (brain, head and neck, oesophagus, lung, stomach, pancreas, rectum, bladder, cervix, soft tissue sarcoma) will be demonstrated. Since there are several drugs and drug combinations that are not included in the Hungarian registered anticancer therapies, for their off-label use the permission of the National Institute of Pharmacy and Nutrition is required. To choose the optimal treatment (during planning the optimal place of chemoradiotherapy, agents and doses) the opinion of a multidisciplinary team is necessary]