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Objectives: Due to their mechanism of action, most classical cytostatic drugs have carcinogenic, mutagenic and/or reprotoxic properties. Therefore, occupational exposure of healthcare staff to these drugs should be prevented. Our objective was to lay out European legislation on this topic and reflect on the process of revising the European CM-directive. We summarise independent European and Dutch studies, and give a concise set of basic recommendations for safe working with cytotoxic drugs in healthcare facilities., Methods: We were directly involved in the process of revising the CM-directive: first, through an EU commissioned workshop in the Netherlands, and after that by contributing to the pan-European stakeholder symposium. For this aim, we had to gather the relevant study data from the Netherlands and from Europe. We analysed all relevant industry-independent studies and collated a set of basic recommendations., Results: Independent studies show that the development of measures in recent years can lead to a safe work environment. Standardising the cleaning process leads to a significant improvement in environmental contamination in the majority of hospitals. In the Netherlands, exposure of workers was shown to be well beneath the limit value of 0.74 µg cyclophosphamide per week, therefore showing that the measures taken in recent years are adequate., Conclusions: The safety of healthcare workers is of the utmost importance. Current practice in the Netherlands show that measures taken in recent years are adequate. European legislation should be based on independent scientific research and practice. The first goal should be to bring countries with less safe working levels to a higher level instead of introducing measures that only increase healthcare budgets but not healthcare safety., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

A relevant number of cancer patients who receive potentially neurotoxic cytostatic agents develop a chemotherapy-induced peripheral neuropathy over time. Moreover, the increasing use of immunotherapies and targeted agents leads to a raising awareness of treatment-associated peripheral neurotoxicity, e.g., axonal and demyelinating neuropathies such as Guillain-Barré-like syndromes. To date, the differentiation of these phenomena from concurrent neurological co-morbidities or (para-)neoplastic nerve affection as well as their longitudinal monitoring remain challenging. Neuromuscular ultrasound (NMUS) is an established diagnostic tool for peripheral neuropathies. Performed by specialized neurologists, it completes clinical and neurophysiological diagnostics especially in differentiation of axonal and demyelinating neuropathies. No generally approved biomarkers of treatment-induced peripheral neurotoxicity have been established so far. NMUS might significantly extend the repertoire of diagnostic and neuromonitoring methods in this growing patient group in short term. In this article, we present enlargements of the dorsal roots both in cytostatic and in immunotherapy-induced neurotoxicity for the first time. We discuss related literature regarding new integrative applications of NMUS for cancer patients by reference to two representative case studies. Moreover, we demonstrate the integration of NMUS in a diagnostic algorithm for suspected peripheral neurotoxicity independently of a certain cancer treatment regimen emphasizing the emerging potential of NMUS for clinical routine in this interdisciplinary field and prospective clinical trials., (© 2023. The Author(s).)

Introduction: Advances in treatment have resulted in a significant increase in survival rates for patients cured of malignant diseases such as neuroblastoma (NBL) and extracranial germ cell tumor (GCT). NBL is one of the pediatric cancers during which potentially ototoxic cytostatic drugs (cisplatin and carboplatin) are used for treatment. Other cancers include germinal tumors, hepatoblastoma, sarcomas, and brain tumors. Often, this very aggressive treatment has a high risk of causing long-term side effects, including hearing loss. Hence, the present study aimed to evaluate the usefulness of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Brock, Chang, and International Society of Pediatric Oncology (SIOP) Boston scales in terms of detecting the high-frequency nature of hearing loss induced by ototoxic drugs and monitoring hearing status in children after completion of oncological treatment. Additionally, the frequency of hearing loss in children treated for NBL and extracranial GCT was assessed, and the principles of monitoring hearing in these patients were indicated., Methods: The study group consisted of 78 patients diagnosed with NBL (n = 47) and GCT (n = 31). There were 23 boys and 24 girls in the NBL group, aged 0-16 years, and 21 boys and 10 girls in the GCT group, aged 0-18 years. The control group consisted of 54 patients who had never received oncological treatment, were not taking potentially ototoxic drugs, and appeared socially efficient in the subjective audiological assessment. Audiometric examinations and DP-acoustic otoemission measurements were performed. Additionally, impedance audiometry tests were done to exclude a possible conductive component of the hearing loss., Results: The analysis shows that ototoxicity-induced hearing loss was observed in 13.8-65.5% of children. 75.9% of patients showed hearing loss in the 16 kHz frequency range, and at least 56.8% of patients showed hearing loss in the frequency range above 12.5 kHz. Hearing impairment, relevant to speech understanding, was displayed by more than 40% of children treated for NBL and GCT., Conclusions: The confirmation of hearing loss in nearly 65% of cases in both patients indicates the necessity to monitor the long-term side effects of anticancer treatment. Acoustic otoemission measurements, the adoption of articulatory indices based on an audiogram, or the use of arbitrary ototoxicity assessment scales such as Brock, Chang, or SIOP Boston are fully justified techniques for studying ototoxicity induced by cytostatic drugs. However, they all require continuous improvement to increase their sensitivity and specificity, especially in the pediatric group., (© 2022 S. Karger AG, Basel.)

Background: Every year the number of cases of colorectal cancer increases. Chemotherapy is one of the main methods of treating cancer. However, chemotherapeutic treatment of colorectal cancer is inextricably linked to hepatotoxic reactions., Objective: The aim of this study was to investigate the effect of the cytostatic vincristine on the background of previous enterosorption correction with the drug aut-m in adenocarcinoma of the colon., Material and Methods: To simulate carcinogenesis, dimethylhydrazine (DMH) was administered subcutaneously to 77 rats for 30 weeks at a dose of 7.2 mg/kg body weight. After simulation of colon cancer, the animals were intragastricly administered entorosorbent at a dose of 1 ml of suspension (corresponding to 0.2 g of net weight of the drug) per 100 g of body weight of the animal, daily for 21 days. After detoxification therapy, rats with simulated carcinogenesis were administered the daily cytostatic vincristine at a dose of 0.23 mg/kg for 14 days., Results: It was found that prolonged administration of dimethylhydrazine is accompanied by destructive changes in plasma membranes, as evidenced by increased activity of enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and serum urea., Conclusions: The used sorbent aut-m showed an effective effect on reducing the manifestations of cytolytic processes in induced carcinogenesis, as indicated by the normalization of the studied parameters. The cytostatic vincristine, which was used in rats with induced colorectal cancer after enterosorption therapy, did not significantly affect the enhancement of cytolytic processes, which confirms the effectiveness of previous sorption measures under these conditions., Competing Interests: The authors report no financial or any other conflicts of interest in this work, (© Copyright by the National Institute of Public Health NIH - National Research Institute.)

Objective: To analyse the genotoxic risk of cytostatic drugs in health professionals after occupational exposure., Method: Literature was searched for the databases PubMed, Lilacs, The Cochrane Library and Scopus with free and controlled language (MeSH terms) using boolean operators AND and OR. The research was limited to articles published between 2005-2016., Results: 11 articles were selected depending on their relevancy to this review's aim. Nine of the 11 articles proved the existence of damage to genetic material (DNA) of health workers, who were exposed to cytostatics. Furthermore, current security practices do not eliminate the chance of exposure completely. Therefore, the creation of new clinical trials is required., Conclusions: Handling cytostatic drugs can cause a genotoxic risk to health workers who are exposed to these substances. This exposure may cause damage on the workers' DNA. There are not enough data to prove a cause-effect relationship between the genotoxic risk and adverse reactions on individuals. Health education will be the main way to raise the awareness and prevention this problem., (Copyright © 2019 Elsevier España, S.L.U. All rights reserved.)

Molecular targeted therapy with lenvatinib is commonly offered to advanced hepatocellular carcinoma (HCC) patients, although it is often interrupted by adverse effects which require a reduction in the initial dose. Thus, an alternative lenvatinib-based therapy to compensate for dose reduction is anticipated. This study aimed to assess the effect of combination of low-dose of lenvatinib and the angiotensin-II (AT-II) receptor blocker losartan on human HCC cell growth. In vitro studies found that losartan suppressed the proliferation by inducing G1 arrest and caused apoptosis as indicated by the cleavage of caspase-3 in AT-II-stimulated HCC cell lines (Huh-7, HLE, and JHH-6). Losartan attenuated the AT-II-stimulated production of vascular endothelial growth factor-A (VEGF-A) and interleukin-8 and suppressed lenvatinib-mediated autocrine VEGF-A production in HCC cells. Moreover, it directly inhibited VEGF-mediated endothelial cell growth. Notably, the combination of lenvatinib and losartan augmented the cytostatic and angiostatic effects of the former at a low-dose, reaching those achieved with a conventional dose. Correspondingly, a HCC tumor xenograft assay showed that the oral administration of losartan combined with lenvatinib reduced the subcutaneous tumor burden and intratumor vascularization in BALB/c nude mice. These findings support that this regimen could be a viable option for patients intolerant to standard lenvatinib dosage.

Introduction: The use of cytostatic drugs such as Mitomycin C and 5-Fluorouracil is well-known in glaucoma filtering surgery, as well as the management of its complications. However, there is a lack of information regarding the preventive measures to be taken by the professional that handles these types of substances., Objective: Raise awareness among professionals of the risks associated with the use of cytostatic drugs without adequate prevention measures., Results: Review of the available literature and legislation on preventive measures in the management of cytostatic drugs in the medical and ophthalmological field., Conclusions: The prevention and awareness of the risks of the qualified professionals that handle these substances is the most important measure to prevent the possible risks. Coordination is necessary with the Occupational Health teams of the Hospital, as well as the professionals and staff involved in the different phases of the process, from the preparation in Hospital Pharmacy to its elimination., (Copyright © 2020 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Hyperthermic intraperitoneal chemotherapy (HIPEC)-heated, intra-abdominal chemotherapy-has become the treatment of choice for treating peritoneal metastases from ovarian, stomach or colorectal cancers. HIPEC has several advantages and disadvantages. The major benefit is minimal systemic toxicity for the patient, but there is a risk of occupational exposure for operating room staff. We have not found any reports of workers with chronic aplastic anaemia as a result of exposure to cytostatic fumes during HIPEC. The aim of this case report is to raise the awareness of potential negative health effects of inhalation exposure to cytostatic drugs. We present a rare case of a 43-year-old woman, suffering from aplastic anaemia as a long-term consequence of exposure to cytostatics. During the HIPEC procedure, surgical revision of the peritoneal cavity was undertaken which resulted in release of cytostatic fumes. Despite awareness of the health effects of occupational exposure to cytostatic drugs and well-developed procedures for safely handling them, unexpected exposure may occur causing serious medical conditions. These may develop in sensitive subjects although accidental high-level exposure may lead to unexpected long-term consequences in all workers. Medical staff need to be informed of the risks of HIPEC and safety guidelines to reduce the risk of exposure., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Due to growing long-term survival rate of oncologic patients, there is increased interest in cardiotoxicity of oncologic treatment among medical professionals. It is concerning both paediatric and adult patients. When prescribing oncologic treatment, there should be focus on the efficacy and safety of the used drugs. Nowadays, the main problem is early dia-gnosis of cardiotoxicity., Purpose: In our work we wanted to investigate whether the increase in bio-markers after the cytostatic therapy with anthracyclines can predict further increase in the left ventricular volume and decrease of the left ventricular ejection fraction., Materials and Methods: We were monitoring 36 patients with the dia-gnosis of non-Hodgkins lymphoma who received therapy with anthracyclines. After the therapy we were measuring the cardiac bio-markers NT-proBNP and high-sensitivity troponin I and performed echocardiography., Results: In our group of patients there is a statistically significant correlation between increased levels of troponin I, NT-proBNP and increment of the left ventricular volume measured before the treatment and 3 months after the treatment. There is also a significant inverse correlation between the left ventricular volume and left ventricular ejection fraction. There was no relationship between higher cumulative doses of anthracyclines and the increment of the left ventricular volume. There is a significant correlation between higher cumulative doses of anthracyclines and higher levels of troponin I., Conclusion: The measurement of bio-markers troponin I and NT-proBNP should be considered for an early dia-gnosis of cardiotoxicity in oncologic patients. Echocardiography is also beneficial for the dia-gnosis in these patients. All efforts after the dia-gnosis should be focused on the therapy with cardioprotective drugs, which can prevent the development of severe heart failure.

Cytostatics not only induce significant side-effects in patients treated oncologically but also pose a threat to the health of occupationally exposed healthcare workers: pharmacists, physicians, nurses and other personnel. Since the 1970s numerous reports from various countries have documented the contamination of working areas with cytostatics and the presence of drugs/metabolites in the urine or blood of healthcare employees, which directly indicates the occurrence of occupational exposure to these drugs. In Poland the significant scale of occupational exposure to cytostatics is also confirmed by the data collected in the central register of occupational carcinogens/mutagens kept by the Nofer Institute of Occupational Medicine. The assessment of occupational exposure to cytostatics and health risks constitutes employers' obligation. Unfortunately, the assessment of occupational risk resulting from exposure to cytostatics raises a number of concerns. Provisions governing the problem of workers' health protection are not unequivocal because they derive from a variety of law areas, especially in a matter of hazard classification and safety data sheets for cytostatics. Moreover, no legally binding occupational exposure limits have been set for cytostatics or their active compounds, and analytical methods for these substances airborne and biological concentrations are lacking. Consequently, the correct assessment of occupational exposure to cytostatics, the evaluation of health hazards and the development of the proper preventive strategy appear difficult. The authors of this article described and discussed the amendments to the European provisions concerning chemicals in the light of employers' obligations in the field of employees' heath protection against the consequences of exposure to cytostatics. Some modifications aimed at a more effective health protection of workers occupationally exposed to cytostatics were also proposed. Int J Occup Med Environ Health. 2019;32(2):141-59., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

Purpose of Review: The current review will focus on drug hypersensitivity reactions to chemotherapy specifically to those drugs most used in children. We know that potentially all chemotherapeutic agents can cause infusion reactions, generally defined as adverse drug reactions. Of these, some are Type A, defined as expected and described in the characteristics of the drug and others, and Type B, defined as unexpected reactions which cannot be explained by the known toxicity profile of the drug. When an unexpected reaction occurs, drugs we can refer as hypersensitivity reactions (HSRs). Some of these (HSRs) are allergic reactions as they have an underlying immunologic mechanism. In general, the cytotoxic agents most commonly associated with HSRs are the platinum salts derivatives, taxanes, pegylated liposomal doxorubicin, L-asparaginase, procarbazine, etoposide, bleomycin, and cytarabin., Recent Findings: HSRs may also occur in children with cancer, during the treatment with chemotherapeutic drugs. The most used drugs of this group in children to cause HSRs are: carboplatin, L-asparaginase, and methothrexate. The aim of this review is to summarize the incidence and the clinical features of HSRs occurring with these drugs in children., Summary: The aim of this review is to summarize the incidence and the clinical features of HSRs occurring with these drugs in children. The current review will focus on the most involved drugs in children, the type of reactions, the mechanisms involved, and the best way to manage them.

No causal treatment for chemotherapy-induced peripheral neuropathy (CIPN) is known. Therefore, there is an urgent need to develop a therapy for CIPN. Only scarce clinical data are available concerning magnetic field therapy (MFT) in this context. We conducted a unicentric, randomized, double-blind, placebo-controlled phase-III trial of an MFT device versus placebo. In this study, we randomized 44 patients with CIPN to two treatment groups, where 21 patients were treated with MFT (Group 1) and 23 patients received placebo (Group 2). We evaluated the efficacy of MFT at baseline (T 1 ), after 3 weeks of study treatment (T 2 ), and after 3 months of study treatment (T 3 ). The primary endpoint was nerve conduction velocity (NCV), while secondary endpoints were the Common Toxicity Criteria (CTCAE) score and the Pain Detect End Score at T 3 . Seventeen of the patients in Group 1 and 14 patients in Group 2 completed the respective study treatment. The primary endpoint, significant improvement of NCV at T 3 , was achieved by MFT (P = 0.015), particularly for sensory neurotoxicity of the peroneal nerve. Also, in respect to the secondary endpoints, significant improvement (P = 0.04) was achieved in terms of the patients' subjectively perceived neurotoxicity (CTCAE score), but not of neuropathic pain (P = 0.11). From data in the randomized study presented here, a positive effect on the reduction of neurotoxicity can be assumed for the MFT device. Patients with sensory neurotoxicity in the lower limbs, especially, should therefore be offered this therapy. Bioelectromagnetics. 38:85-94, 2017. © 2016 The Authors. Bioelectromagnetics published by Wiley Periodicals, Inc., (© 2016 The Authors. Bioelectromagnetics published by Wiley Periodicals, Inc.)

Objective: Provide updated evidence and learn about the actions that must be implemented in order to prevent the occupational exposure to cytostatic drugs., Method: A bibliographic search was carried out on the MEDLINE, COCHRANE PLUS and WEB OF SCIENCE databases, with the terms "surface contamination", "cytostatic drug", "drug preparation", "occupational exposure", "safe handling" and "closed-system transfer device", within the 2010-2015 period., Results: Thirteen articles were selected for review. These articles are from hospitals in U.S.A., Canada, Japan, Australia, Spain, Portugal and Germany. In all of them, surface contamination by cytostatic agents was found in over 15 different surfaces, with concentrations ranging from 1.69 ng/cm2 to 4-784 μg/cm2. The specific drugs were cyclophosphamide, ifosfamide, 5-fluorouracil, methotrexate, paclitaxel, cisplatin, gemcitabine, and docetaxel. Closed-system transfer devices can reduce the contamination in work surfaces significantly, but do not eliminate it., Conclusions: Presence of contamination by cytostatic drugs was confirmed in many hospitals across all 5 continents. In all cases, contamination was found in the cabinet, on the floor in front of the cabinet, and in other places of the Hospital Pharmacy. The drug most frequently found was cyclophosphamide. The most effective action used to reduce contamination was the closed-system transfer devices (CSTDs)., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Erlotinib (Tarceva®) is a chemotherapeutic drug approved for the treatment of pancreatic cancer and non-small cell lung cancer. Its primary mode of action is the inhibition of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK). Recently, RTK-inhibiting polyphenols have been reported to interact synergistically with erlotinib. Furthermore some anthocyanidins and anthocyanin-rich berry extracts have been reported to inhibit tyrosine kinases, including the EGFR, which raises the question of potential interactions with erlotinib. Polyphenol-rich preparations such as berry- or soy-based products are commercially available as food supplements. In the present study we tested a bilberry extract, its major anthocyanin and potential intestinal degradation products, as well as genistein, with respect to possible interactions with erlotinib. Cell growth inhibition was assessed using the sulforhodamine B assay, while interactions with EGFR phosphorylation were analyzed by SDS-PAGE/western blotting with subsequent immunodetection. Genistein, bilberry extract, delphinidin-3-O-glucoside and delphinidin were found to antagonize erlotinib whereas phloroglucinol aldehyde was found to enhance cytostatic effects of the drug on human epithelial A431 cells. Genistein also antagonized the EGFR inhibitory effects of erlotinib, whereas bilberry anthocyanins showed no significant interactions in this regard. Our data indicate that different polyphenols are potentially able to impair the cytostatic effect of erlotinib in vitro. Genistein interacts via the modulation of erlotinib-mediated EGFR inhibition whereas bilberry anthocyanins modulated the growth-inhibitory effect of erlotinib without affecting EGFR phosphorylation, thus indicating a different mechanism of interference.

Objective: The therapeutic use of ototoxic drugs is relatively common, particularly in patients with severe diseases. It is likely that disturbances of balance in these patients are underestimated by clinicians., Materials and Methods: The purpose of this study was to identify drugs involved in the vestibulotoxic origin of instability in a group of 18 patients., Results: Six patients showed both cochlear and vestibular damage, while 12 were affected only by posterior labyrinthine damage. Four groups of drugs were identified: antibiotics (nine patients), cytostatics (four), anti-tuberculosis medicinal products (three), and other drugs (two). Cytostatics were involved in many cases studied, a fact scarcely reported before., Conclusion: It is important to ensure an early diagnosis to prevent ototoxic effects induced by drugs. We propose that patients receiving potential ototoxic drugs undergo cochlear and vestibular assessments. Further, we recommend that patients with instability undergo vestibular rehabilitation.

Objective: To investigate the relationship between cardiovascular morbidity and exposure to cytostatic drugs., Materials and Methods: A descriptive analytical study was conducted with 74 nurses exposed to cytostatic drugs in oncology and 215 unexposed. A medical questionnaire was applied. Exposure to cytostatic drugs was estimated by the exposure time and the index of cytostatic contact (ICC). The statistical tests used are: relative risk, odds ratio, multivariate analysis: descriptive (ACM) and predictive (AIC system)., Results: It is a young population; the average age is 42±9.9years with a female predominance (81%). The average length was 18.4±11.11years. The average of the ICC ranged from 0.60 to 12.6 with a highly significant difference. For morbidity, there was no difference for most cardiovascular disease (RR, 1.03; 95% CI [0.59; 1.82]) outside of hypertension and venous thrombosis. ACM objectified separation between the terms and the comments of the two groups for HTA. The interpretation of results at alpha=0.05 showed an association with cardiovascular disease. The study of the association between cardiovascular morbidity and exposure to cytostatic objectified association with seniority and the ICC with a statistically significant difference (P=0.01)., Conclusion: Multivariate analysis helped to eliminate confounding factors and retain the ICC and length of exposure to cytostatic in the onset of cardiovascular morbidity., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Various plant polyphenols have been recognized as redox active molecules. This review discusses some aspects of polyphenols' modes of redox action, corresponding structure-activity relationships and their potential to be applied as adjuvants to conventional cytostatic drugs. Polyphenols' antioxidative capacity has been discussed as the basis for targeting oxidative stress and, consequently, for their chemopreventive and anti-inflammatory activities, which may alleviate side-effects on normal cells arising from oxidative stress caused by cytostatics. Some polyphenols may scavenge various free radicals directly, and some of them are found to suppress free radical production through inhibiting NADPH oxidases and xanthine oxidase. Additionally, polyphenols may increase antioxidative defense in normal cells by increasing the activity of NRF2, transcription factor for many protective proteins. The activation of the NRF2-mediated signaling pathways in cancer cells results in chemoresistance. Luteolin, apigenin and chrysin reduce NRF2 expression and increase the chemosensitivity of cancer cells to cytostatic drugs. Their common 5,7-dihydroxy-4H-chromen-4-one moiety, may represent a starting pharmacophore model for designing novel, non-toxic compounds for overcoming chemoresistance. However, prooxidative activity of some polyphenols (quercetin, EGCG) may also provide a basis for their use as chemotherapeutic adjuvants since they may enhance cytotoxic effects of cytostatics selectively on cancer cells. However, considerable caution is needed in applying polyphenols to anticancer therapy, since their effects greatly depend on the applied dose, the cell type, exposure time and environmental conditions.

Background: Patients with chronic diseases often receive multiple medications and are associated with increased vulnerability to medication errors. Identifying high-alert medications for them would help to prioritize the interventions with greatest impact for improving medication safety. The aim of this study was to develop a list of high-alert medications for patients with chronic illnesses (HAMC list) that would prove useful to the Spanish National Health Service strategies on chronicity., Methods: The RAND/UCLA appropriateness method was used. Drug classes/drugs candidates to be included on the HAMC list were identified from a literature search in MedLine, bulletins issued by patient safety organizations, incidents recorded in Spanish incident reporting systems, and previous lists. Eighteen experts in patient/medication safety or in chronic diseases scored candidate drugs for appropriateness according to three criteria (evidence, benefit and feasibility of implementing safety practices). Additionally they rated their priority of inclusion on a Likert scale., Results: The final HAMC list includes 14 drug classes (oral anticoagulants, narrow therapeutic range antiepileptics, antiplatelets - including aspirin -, antipsychotics, β-blockers, benzodiazepines and analogues, corticosteroids long-term use, oral cytostatics, oral hypoglycemic drugs, immunosuppressants, insulins, loop diuretics, nonsteroidal anti-inflammatory drugs, and opioid analgesics), and 4 drugs or pairs of drugs (amiodarone/ dronedarone, digoxin, oral methotrexate and spironolactone/eplerenone)., Conclusions: An initial list of high-alert medications for patients with chronic diseases has been developed, which can be built into the medication management strategies for chronicity to guide the implementation of efficient safety strategies and to identify those patients at greater risk for preventable adverse drug events., (Copyright © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: In head-to-head comparisons of coronary drug-eluting stents, the primary endpoint is traditionally assessed after 9-12 months. However, the optimum timepoint for this assessment remains unclear. In this study, we assessed clinical outcomes at up to 5 years' follow-up in patients who received two different types of drug-eluting stents., Methods: We undertook this multicentre, open-label, randomised superiority trial at five percutaneous coronary intervention centres in Denmark. We randomly allocated 2332 eligible adult patients (≥18 years of age) with an indication for drug-eluting stent implantation to the zotarolimus-eluting Endeavor Sprint stent (Medtronic, Santa Rosa, CA, USA) or the sirolimus-eluting Cypher Select Plus stent (Cordis, Johnson & Johnson, Warren, NJ, USA). Randomisation of participants was achieved by computer-generated block randomisation and a telephone allocation service. The primary endpoint of the SORT OUT III study was a composite of major adverse cardiac events-cardiac death, myocardial infarction, and target vessel revascularisation-at 9 months' follow-up. In this study, endpoints included the occurrence of major adverse cardiac events and definite stent thrombosis at follow-up times of up to 5 years. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00660478., Findings: We randomly allocated 1162 patients to receive the zotarolimus-eluting stent and 1170 to the sirolimus-eluting stent. At 5-year follow-up, rates of major adverse cardiac events were similar in patients treated with both types of stents (zotarolimus-eluting stents 197/1162 [17.0%] vs sirolimus-eluting stents 182/1170 [15.6%]; odds ratio [OR] 1.10, 95% CI 0.88-1.37; p=0.40). This finding was indicative of the directly contrasting results for rates of major adverse cardiac events at 1-year follow up (zotarolimus 93/1162 [8.0%] vs sirolimus 46/1170 [3.9%]; OR 2.13, 95% CI 1.48-3.07; p<0.0001) compared with those at follow-up between 1 and 5 years (104 [9.0%] vs 136 [11.6%]; OR 0.78, 95% CI 0.59-1.02; p=0.071). At 1-year follow-up, definite stent thrombosis was more frequent after implantation of the zotarolimus-eluting stent (13/1162 [1.1%]) than the sirolimus-eluting stent (4/1170 [0.3%]; OR 3.34, 95% CI 1.08-10.3; p=0.036), whereas the opposite finding was recorded for between 1 and 5 years' follow-up (zotarolimus-eluting stent 1/1162 [0.1%] vs sirolimus-eluting stent 21/1170 [1.8%], OR 0.05, 95% CI 0.01-0.36; p=0.003). 26 of 88 (30%) target lesion revascularisations in the zotarolimus-eluting stent group occurred between 1 and 5 years' follow-up, whereas 54 of 70 (77%) of those in the sirolimus-eluting stent group occurred during this follow-up period., Interpretation: The superiority of sirolimus-eluting stents compared with zotarolimus-eluting stents at 1-year follow-up was lost after 5 years. The traditional 1-year primary endpoint assessment therefore might be insufficient to predict 5-year clinical outcomes in patients treated with coronary drug-eluting stent implantation., Funding: Cordis and Medtronic., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the impact of anti-B-cell therapy on the clinical and immunological parameters of systemic lupus erythematosus (SLE) activity, on the time course of changes in these parameters during long-term follow-up, and on the tolerability of repeated rituximab (RTM) therapy cycles., Subjects and Methods: RTM was given to 97 patients with high activity of SLE refractory to treatment with glucocorticosteroids (GCS) and cytostatics. The follow-up lasted 18 (12-36) months. The most common clinical manifestations of SLE were lupus nephritis (LN) (62%) and skin (33%) and nervous system (22.7%) involvements. Clinical SLE activity was assessed applying the SLE disease activity index 2000 (SLEDAI2K); therapeutic effectiveness was evaluated using indicators, such as partial response (PR), complete response (CR) and exacerbation. The exacerbation was classified as moderate and severe using the Selena-Sledai Flare index (SFI)., Results: Depletion was identified in 78% of the patients with SLE immediately after RTM therapy. During 3.5 years of follow-up, the effect of RTM was seen in 82% of the patients after repeated RMT therapy cycles (CR 56% and PR 28%). Exacerbations were observed in a total of 24 (24.7%) patients; the exacerbation lasted 12 (12-24) months after RTM therapy: of them 17.5% with LN and 7.2% with extrahepatic manifestations of SLE (exacerbations occurred 12 (12-24) and 18 (6-48) months after RMT therapy). In 24 exacerbated patients, B cells recovered at 6 (3-12) months. A year after RMT therapy, a group of 35 patients who were observed to have complete B cell depletion achieved CR statistically significantly more frequently than a group of 20 patients who had B-cell recovery (65.7 and 30% respectively, p = 0.03). CR was observed significantly more often in patients after repeated RTM therapy cycles than those who had received only one RTM therapy cycle (p = 0.02). The long-term follow-up showed a reduction in SLEDAI2K, normalization of laboratory values, and a decrease in the daily dose of GCS. Most patients tolerated well both the first and repeated RTM therapy cycles., Conclusion: According to the results of the long-term follow-up, RTM therapy is a highly effective treatment option for SLE patients in whom the previous standard therapy with GCS and cytostatics was previously ineffective. The 3.5-year follow-up showed a good tolerability of RTM and revealed no increase in the risk of infectious complications or adverse reactions.

The function of liver and synthesized by it components of blood coagulation were studied on sampling of 25 patients with acute lymphoblastic leucosis in the debut of disease and under implementation of induction of remission. Before treatment the hepatotoxicity was detected in 40% of patients. The reliable correlation between level of aspartataminotransferase and number of leucocytes and blasts (rs = 0.401 and rs = 0.406 correspondingly) testifies the role of leucosis cells in functional disorders of liver during this period of disease. Against the background of cytostatic therapy the signs of liver damage were presented in 76% of patients. The maximum expressed hepatotoxicity was observed at 9-14 day of treatment. The decrease of components of hemostasis synthesized in liver was observed at 16-21 day of treatment. During this time the synthesis of factors of thrombin complex, antithrombin III and plasminogen was disordered. The plasminogen also decreased at the expense of its consumption as a result of fibrinolysis activation validated by decreased level of D-dimers. It is proved that in the debut and under treatment acute lymphoblastic leucosis the danger of development of thrombotic hemorrhagic complications is related both with derangement of synthesis of procoagulants, antithrombin III and plasminogen and with their consumption in case of activation of intravascular coagulation with leucosis process and cytostatic.

Background: Extravasation is a devastating complication of intravenous therapy that develops when a drug infiltrates the interstitial tissue surrounding the vein. Due to the uncertain and possibly dramatic outcome, early recognition and adequate treatment with the aid of a standardized protocol are needed., Methods: A pubmed literature search was conducted and all relevant articles were reviewed for the development of an extravasation treatment protocol., Results: An overview of current treatment guidelines and clinical experience is provided. The extravasation treatment protocol was implied during 1 year in this university hospital with satisfactory outcome., Conclusion: Treatment starts with prevention. In case of an established extravasation injury, early recognition, assessment of severity, and treatment with medical and/or surgical therapies are recommended.

Errors involving cytotoxic drugs have the potential of being fatal and should therefore be prevented. The objective of this article is to identify the characteristics of medication errors involving parenteral cytotoxic drugs in Sweden. A total of 60 cases reported to the national error reporting systems from 1996 to 2008 were reviewed. Classification was made to identify cytotoxic drugs involved, type of error, where the error occurred, error detection mechanism, and consequences for the patient. The most commonly involved cytotoxic drugs were fluorouracil, carboplatin, cytarabine and doxorubicin. The platinum-containing drugs often caused serious consequences for the patients. The most common error type were too high doses (45%) followed by wrong drug (30%). Twenty-five of the medication errors (42%) occurred when doctors were prescribing. All of the preparations were delivered to the patient causing temporary or life-threatening harm. Another 25 of the medication errors (42%) started with preparation at the pharmacies. The remaining 10 medication errors (16%) were due to errors during preparation by nurses (5/60) and administration by nurses to the wrong patient (5/60). It is of utmost importance to minimise the potential for errors in the prescribing stage. The identification of drugs and patients should also be improved., (© 2012 Blackwell Publishing Ltd.)

In modern oncology chemotherapy (CT), along with the surgical technique and radiotherapy is a leader in the treatment of cancer patients. More than 60% of patients receiving chemotherapy at different stages of treatment. Recently, modern chemotherapy has become more urgent personal approach to the choice of drugs and their doses, aimed at reducing the toxicity of chemotherapy. Complications of chemotherapy significantly degrade the effectiveness of the treatment of patients with malignant tumors, because they require lower doses of anticancer drug, or lengthening the intervals between cycles of chemotherapy, which affects treatment outcomes and quality of life. This paper presents a literature review of toxic effects of cytostatic drugs on the gastrointestinal tract.

Acute kidney injury is a common complication in hospitalized patients and is associated with substantially increased morbidity and mortality. Frequently, it is caused by impaired renal perfusion, ischemia and reperfusion injury, sepsis or urinary tract obstruction, but often its etiology is multifactorial. In this context, the contribution of nephrotoxic medications to the development of AKI plays an important role. This review begins with an attempt to evaluate the importance of drug-related acute kidney injury in general. Then, a selected list of 7 classes of drugs or compounds, namely aminoglycosides, aristolochic acid, cytostatic drugs, nonsteroidal anti-inflammatory drugs, osmotic agents, radiocontrast, and phosphate salts are discussed in depth, including their epidemiology, pathophysiology, clinical features and treatment. While not attempting to be exhaustive, this review attempts to provide an overview with additional in-depth information on certain classes of drugs that are either of general importance or have recently emerged in the literature.

Objective: To present current developments in the specific management of extravasations of antineoplastic agents after the extravasation., Method: We conducted a search in PubMed, Medline and IDIS-Iowa to identify papers written in English or Spanish that described new specific measures for the management of extravasations. We also reviewed the references given in these papers and recent tertiary sources related to oncology or cytostatic agents. The search covered the period between 1997 and 2010., Results: There are only specific measures for the treatment of extravasations of 22 cytostatic agents. These measures are presented for each cytostatic agent, according their drug group., Conclusions: Although currently there is no general consensus on the specific management of antineoplastic agents after extravasation, this review outlines the information collected and published so far, so that it may be of use to any national health centre where cytostatic drugs are prescribed, handled or administered., (Copyright © 2010 SEFH. Published by Elsevier Espana. All rights reserved.)

The aim of our study was to investigate the immunotoxicity of occupational cytostatic drug exposure, and to assess the possible effect of confounding factors, such as age and smoking. In this human study, the immunotoxic effect of antineoplastic drugs was investigated among 306 nurses working in oncology chemotherapy units. Results were compared to 98 non-exposed women. The immune status of the subjects was characterized by immune phenotyping of peripheral blood lymphocytes by flow cytometry, using monoclonal antibodies against surface antigens (CD3, CD4, CD8, CD19, CD25, CD45, CD56 and CD71). The killing ability of neutrophil leukocytes was assessed by the measurement of reactive oxygen intermediate production. Occupational exposure to antineoplastic drugs caused shifts in the major lymphocyte subpopulations, resulting in a statistically significant increase in the ratio of B cells. Cytostatic drug exposure also manifested itself in a decreased frequency of CD25 positive, activated T lymphocytes, and increased oxidative burst of neutrophil granulocytes, both of which may have a functional impact on the immune system of exposed subjects. In the younger subjects exposure also caused a shift in T cell subpopulations: a reduction in the cytotoxic T cell population lead to an elevated Th/Tc ratio. In the exposed group, smoking increased activation of T lymphocyte subpopulations. In conclusion, we have demonstrated that low dose occupational cytostatic drug exposure is immunotoxic, and age and smoking modify the effect of exposure.

Background: A characteristic cutaneous eruption related to the use of cytostatic chemotherapeutic drugs has been described in the literature. This condition appears to be characterized by an erythematous eruption, primarily affecting the intertriginous areas bilaterally, together with eccrine squamous syringometaplasia as the main histologic feature., Objective: We sought to establish the epidemiologic, clinical, and histologic characteristics of this poorly defined chemotherapy drug-related eruption., Methods: Retrospective data were collected from 21 consecutive patients with this clinical and histopathologic pattern who attended an oncology center between January 1999 and September 2009. Two skin biopsy specimens were obtained from all patients, with the first being taken within 24 hours of onset, and the second 72 to 96 hours after onset., Results: The patients analyzed were predominantly female (72%), with a mean age of 52 years (range 10-69 years). The lesions presented clinically as bilateral erythematous plaques affecting both axillae (95%), groin (88%), and side aspects of the neck (48%). The main histologic feature in all cases was eccrine squamous syringometaplasia, characterized by the transformation of the eccrine cuboidal epithelium into two or more layers of squamous cells with intercellular bridges. The onset of the eruption appeared within 30 days (range 2-30 days) after the initiation of the cytostatic agent infusion. The lesions resolved with desquamation and postinflammatory hyperpigmentation. The same cutaneous pattern recurred in up to 50% of patients in whom the oncologist reintroduced the cytostatic treatment., Limitations: Small sample size was a limitation., Conclusions: We suggest the term "chemotherapy-related bilateral dermatitis associated with eccrine squamous syringometaplasia" to describe this distinctive entity, which is primarily associated with pegylated liposomal doxorubicin infusions and chemotherapeutic regimens used in autologous bone-marrow transplantation., (Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

When validating oral chemotherapy, pharmacists should confirm the suitability and correctness of the prescription, applying the same safety standards as those used for parenteral cytostatic drugs. There are an increasing number of cancers for which orally administered drugs are available, which increases patient satisfaction as these drugs can be taken at home without the need to visit a hospital. As oral cytostatic treatments increase, so does the importance of ensuring optimal treatment compliance. The new oral cytostatic agents are less toxic, reduce indirect costs and imply less loss of time for patients and their families. However, the cost of these agents should be below a threshold acceptable for society. As an aid to decision making, pharmacoeconomic tools should be used., (Copyright © 2011 Sociedad Española de Farmacia Hospitalaria. Published by Elsevier Espana. All rights reserved.)

Objective: To measure and provide an economic assessment of the preparations returned to a centralised cytostatic drug preparation unit, analyse reasons for their return, propose measures for minimising returns and assess their impact on the Medical Oncology division's outpatient services., Methods: This prospective study contained two phases. During the first, we registered all returns, motives, cases of reuse and costs. In the second phase, we analysed returns at the Oncology outpatient division after having adopted measures to minimise the returns., Results: During the first phase, 218 preparations (worth € 51,131) were returned. The Oncology Day Hospital returned 1% of the preparations worth 1% of the total value; during the second phase, these figures were 0.56% of the preparations and 0.14% of the total value., Conclusions: Favouring reporting on and identifying expensive treatments with little stability and using returned preparations as a quality indicator for Oncology has improved management of the central cystostatic preparation unit., (Copyright © 2009 SEFH. Published by Elsevier Espana. All rights reserved.)

Extravasation of cytostatics occurs when an infusion containing a cytotoxic drug leaks into the surrounding perivascular and subcutaneous tissues. Incidence of cytostatic extravasation is found to be 0.1-6% according to the literature. Depending on the severity of complications, pain, loss of function in the extremities, or in extreme cases tissue necrosis necessitating an amputation may develop, drawing consequences like delay or interruption of the chemotherapy. Extent of complications is greatly influenced by the type of medication administered, general condition of the patient, and professional preparedness of staff providing the oncological health service. The protocol recently implemented in the National Institute of Oncology is a short, compact guidance for physicians and nurses providing oncological care, so by quick and adequate management of extravasation cases, severe complications could be prevented. More complex practical guidelines including algorithms could be created as a result of a wider collaboration, with the help of which oncological health professionals could easily cope with this rare problem. The authors describe in their review the implementation of the use of dry warm and cold packs, dymethylsulfoxide and hyaluronidase and their function within the algorithm of extravasation treatment.

Paravasation of cytostatic drugs during peripheral intravenous administration is a well known complication. In the United States of America it occurs in seven percent of cases with different severity and consequences. Although methods to completely avoid this complication are still unavailable, we are able to decrease the risks by identifying the patient- and procedure-related factors. The educated patient is a good indicator of paravasation in case he or she can cooperate and call the nurse. When the patient is unable to cooperate, the risks of extravasation is higher and closer nursing surveillance is indicated. The extent of injury depends mainly on the chemical structure of the extravasant substance (vesicant, irritant or non-vesicant) which may be modified by other factors. There is no strong evidence-based guidance for the management of complication. Abrupt cessation of the infusion and drawing back on the inserted venous catheter as well as elevating and resting the affected limb are necessary measures. In the available literature cooling or warming of the affected area is controversial. Similarly there are still open questions regarding the value of using antidotes as dexrazoxane, dimethylsulfoxide, thiosulfate and hyaluronidase (which is not registered as medicament in Hungary). In the event of extravasation early multidisciplinary dermatological and surgical assessment is essential for definitive diagnosis and setting the optimal management.

Purpose: The premise for phase I trials for cytostatic agents is different from that of cytotoxic agents. For cytostatic agents, toxicity and efficacy do not necessarily increase monotonically with increasing dose levels, but likely plateau after they reach maximal toxicity or efficacy. Here, we propose a phase I-II trial design to assess both toxicity and efficacy to find the best dose as well as a good dose., Experimental Design: We propose a 2-step dose-finding trial for assessing both toxicity and efficacy for a targeted agent. The 1st step uses a traditional phase I trial design. This step only assesses toxicity and finds the maximal tolerated dose (MTD). For the 2nd step, we propose a modified phase II selection design for 2 or 3 dose levels at and below the MTD to determine efficacy and evaluate each dose level by both efficacy and toxicity., Results and Conclusion: Simulation studies are done on several combinations of toxicity and efficacy scenarios to assess the operating statistics of our proposed trial design. We then compare our results with a traditional phase I trial followed by a single-arm phase II trial using the same total sample size. The proposed design does better in most cases than a traditional design using the same overall sample size. This design allows assessing a few dose levels more closely for both efficacy and toxicity and provides greater certainty of having correctly determined the best dose level before launching into a large efficacy trial., (©2010 AACR.)

The effect of cytostatic drug cyclophosphamide (CY) on lingual epithelium was studied in 90 female mice using histological, morphometric, quantitative histochemical and immunohistochemical methods. CY (400 mg/kg) was injected intraperitoneally three times with a 48 h interval. Material was obtained 2 days after injections and 10-20 days after their discontinuation. CY treatment was shown to result in the damage of both surface epithelium of the tongue and the epithelium of minor lingual salivary glands. Damage to the surface epithelium was more pronounced on the ventral surface of the tongue and was associated mainly with the disturbances of its proliferation. Changes were less severe on the dorsal surface and were seen as the disturbances of epithelial differentiation and desquamation. Glandular epithelium was damaged to a lesser extent than the surface one, with serocytes being more sensitive to the cytotoxic injury than mucocytes. After cytostatic drug discontinuation, the tendency for the normalization of the epithelial characteristics was noted. Most persistent changes in the surface epithelium were found on the dorsal surface of the tongue and in the glandular epithelium--in the serous secretory portions of the salivary glands.

In the preceding work ("Morphology", 2011, issue 2), the regularities of oral mucosal (OM) epithelium injury after the cytostatic drug (CSD) treatment and its further regeneration, were reviewed. This paper presents the systematized summary of current literature data and the authors' own findings on the regularities of CSD effect on non-epithelial OM cell populations and their interactions with each other and the epithelium. The changes of intraepithelial tissue homeostasis, associated with CSD effect on intraepithelial lymphocytes, granulocytes, dendritic antigen presenting cells and melanocytes, interacting with epitheliocytes, are described. The data are presented, indicating that along with the epithelium, the cell populations of lamina propria and submucosal connective tissue, as well as the small blood vessels, are important targets of CSD in the OM tissues. The concept of a unifying model, describing tissue, cellular and molecular mechanisms of the oral mucositis development after CSD treatment, is reviewed.

This paper presents the systematized summary of current literature data and the authors' own findings on the regularities of human and animal surface oral mucosal epithelium (OME) injury caused by cytostatic drugs (CSD) administration, and on the ways of its regeneration after the cytostatic chemotherapy (CSCT) discontinuation. Tissue, cell and molecular mechanisms of CSCT effects on OME, are described. The direct effects of CSD included the epithelial layer attenuation with the derangement of its architecture, epitheliocyte proliferation suppression, apoptosis activation, and differentiation disturbances (involving the broad spectrum of cytological, cytochemical, ultrastructural and molecular-biological changes). In severe cases, these processes resulted in the loss of the epithelial layer integrity with the development of ulceration. Complete epithelial regeneration requires a long period after the CSCT discontinuation. Indirect effects of CSD on OME are associated with the microbial invasion and the diffusion of microbial vital activity products into the epithelium with concurrent leukopenia, immunosuppression and decreased salivary secretion.

The number of drugs used for the treatment of different types of cancers is constantly increasing and actually exceeds 100 distinct chemical formulations. The use of most cytotoxic agents is associated with potential hypersensitivity reactions, and the constant increase of their administration has caused an increase in incidence of these adverse effects, thus becoming a relevant problem for clinicians. Hypersensitivity reactions are common with platinum compounds, L-asparaginase, taxanes, procarbazine, and epipodophyllotoxins, whereas they are unusual, but always possible, with the other chemotherapeutic drugs. Reactions associated with individual drugs are discussed in detail. The mechanism underlying these hypersensitivity reactions involves IgE-mediated hypersensitivity reactions, nonallergic hypersensitivity reactions, and a few pathogenetically unclear reactions. More studies are needed to better understand, diagnose, treat, and prevent these reactions. To achieve this goal, a multidisciplinary approach to treat patients with cancer who have potential allergies is needed., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

This paper reports a 43-year-old patient who had a large, mobile, worm-like thrombus in the left main coronary artery after receiving a chemotherapy regimen containing cisplatin, bleomycin and etoposide for a nonseminomatous testes tumor. The patient was successfully treated with thrombolytic therapy. Physicians should be aware that thrombotic events may be observed after the administration of certain chemotherapeutic agents, particularly cisplatin.

The effect of the cyclophosphane and amino acids with side charge radicales (basic--lysine, arginine, acid--asparagine and glutamic acid) on the cell proliferation and apoptosis development in lymphoide tissue explants in young rats (at age 3 months old) and old rats (at age 24 months old) was investigated in organotypic tissue culture. All amino acids in concentration of 10(-12) M stimulated proliferation in explants' growth zone of young rats and two amino acids (arginine, glutamic acid)--of old rats. Cyclophosphane in concentration of 1 mg/ml inhibited the explant cell proliferation. A delay of the cyclophosphane inhibitory effect was observed under the combined administration into the culture of cyclophosphane with each of the amino acids having a stimulated effect. Thus, the amino acids can possess a protective effect by action of DNA synthesis inhibitors both in young and old rats.

Goals of Work: Empirical antibiotic therapy usually started in patients who are neutropenic following treatment with cytostatic chemotherapy for a haematological malignancy as soon as fever develops to forestall fulminant sepsis. Hence, accurate and timely detection of fever is crucial to the successful management of infectious complications in these patients. We report an investigation of the feasibility and validity of continuous non-invasive body temperature measurement., Patients and Methods: The feasibility of non-invasive continuous measurement of the skin temperature was investigated using the Propaq(R) device in a cohort of 33 patients receiving an allogeneic HSCT who were all at risk of developing a febrile episode. Non-invasive continuous measurement of the skin temperature (CST) was compared with a standard episodic axillary temperature measurement (EAT) five times daily using a Terumo(R) device. The study period entailed monitoring during the 10 or 12 days that profound neutropenia was expected to be present., Main Results: Measuring the skin temperature continuously and accurately by using the Propaq(R) was feasible. The CST correlated well with the EAT measurements (Pearson r = 0.782). Compared to EAT, the start of empirical therapy could be started 2.5 h earlier when relying on continuous measurements than was possible with EAT., Conclusion: Continuous skin temperature measurements are feasible and valid compared to the conventional temperature measurement and may improve the management of infections by earlier detection of fever in neutropenic patients.

Cytotoxic agents like Hydroxyurea, Busulfan and Interferon-alpha are to date the most commonly used therapeutic approaches in Essential Thrombocythemia (ET). However, few data on the efficacy and safety of these agents in the long-term are currently available. We report a retrospective analysis of the long-term outcome of 386 consecutive ET patients, followed at single Institution for a median follow-up of 9.5 years (range, 3-28.5). Cytoreductive therapy was administered to 338 patients (88%), obtaining a response in 86% of cases. Forty-five patients (12%) experienced a thrombosis. Among baseline characteristics, only history of vascular events prior to ET diagnosis predicted a higher incidence of thrombosis. Evolution in acute leukemia/myelofibrosis occurred in 6 (1,5%) and 20 (5%) patients, and was significantly higher in patients receiving sequential cytotoxic agents. Overall survival was 38% at 19 years and was poorer for patients older than 60 years, with higher leukocytes count (>15 x 10(9)/L), hypertension and mellitus diabetes at ET diagnosis and for patients experiencing a thrombotic event during follow-up. Cytoreductive therapy was effective in decreasing platelet number with negligible toxicity; however, thrombocytosis control did not reduce the incidence of thrombosis and, for patients who received sequential therapies, the probability of disease evolution was higher and survival was poorer., (Copyright 2008 Wiley-Liss, Inc.)

Despite the introduction of many targeted therapies, a wide variety of cytostatic agents are still frequently used in dermato-oncology. In order to avoid further morbidity in tumor patients, prevention of extravasation reactions is of highest importance. The optimal management of extravasation requires an early diagnosis, the application of specific antidotes and a well-trained oncology team.

Studies aimed on evaluation of possibility for correction of cyclophosphan-induced immunosuppression in BALB/c mice by using acellular staphylococcal vaccine "Staphylovac" (SV). Cyclophosphan (CP) administered to mice four times with 24 hours intervals decreased levels of T-, B-, T-regulatory (T-reg CD4/CD25/Foxp3) lymphocytes, increased quantity of cells expressing early activation marker CD25 (assessment after 4 hours). Administration of SV along side with cytostatic does not influenced significantly on characteristics of CP-induced immunosuppression at the moment of its assessment. Twenty four hours after administration of CP or SV with CP level of cells expressing CD3 and MHC I continued to decrease as compared with control. Compared with administration of CP only or with control group, SV administered along side with CP increased expression of MHC II on 38- and 1.8-fold respectively. Levels of CD4, CD25, CD8, and CD19 cells in these groups were already closer to control values that points to the beginning of restoration of some disturbances in mechanisms of immunoregulation. Five days after administration of CP or CP+SV levels of CD3, MHC I, and CD8 lymphocytes significantly increased, although were lower than in the control group in 3.3- and 2.3-fold (CD3), 12- and 4-fold (MHC I), and in 2.8- and 1.8-fold (CD8) respectively. Levels of NK, NKT were higher as compared to control. CP continued to decrease levels of CD4 and CD19 cells and simultaneously increased level of T-regulatory cells, which play key role in suppression of immune response. Administration of SV during CP course corrected levels of cells expressing these markers. It was established that under the influence of SV, cytotoxic potential of NK cells and proliferative activity of lymphocytes were restored.

Many different drugs and agents may cause nephrotoxic acute kidney injury (AKI) in children. Predisposing factors such as age, pharmacogenetics, underlying disease, the dosage of the toxin, and concomitant medication determine and influence the severity of nephrotoxic insult. In childhood AKI, incidence, prevalence, and etiology are not well defined. Pediatric retrospective studies have reported incidences of AKI in pediatric intensive care units (PICU) of between 8% and 30%. It is widely recognized that neonates have higher rates of AKI, especially following cardiac surgery, severe asphyxia, or premature birth. The only two prospective studies in children found incidence rates of 4.5% and 2.5% of AKI in children admitted to PICU, respectively. Nephrotoxic drugs account for about 16% of all AKIs most commonly associated with AKI in older children and adolescents. Nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, amphotericin B, antiviral agents, angiotensin-converting enzyme (ACE) inhibitors, calcineurin inhibitors, radiocontrast media, and cytostatics are the most important drugs to indicate AKI as significant risk factor in children. Direct pathophysiological mechanisms of nephrotoxicity include constriction of intrarenal vessels, acute tubular necrosis, acute interstitial nephritis, and-more infrequently-tubular obstruction. Furthermore, AKI may also be caused indirectly by rhabdomyolysis. Frequent therapeutic measures consist of avoiding dehydration and concomitant nephrotoxic medication, especially in children with preexisting impaired renal function.