Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial.

BACKGROUND: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. PATIENTS AND METHODS: Women (N = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240 mg/day or placebo for 12 months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). RESULTS: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N = 1171; placebo, N = 1236) and 2427 patients for EQ-5D (neratinib, N = 1186; placebo, N = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. CONCLUSIONS: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709.

[Algorithms for early mobilization in intensive care units]. / Algorithmen zur Frühmobilisierung auf Intensivstationen.

Immobility of patients in intensive care units (ICU) can lead to long-lasting physical and cognitive decline. During the last few years, bundles for rehabilitation were developed, including early mobilization. The German guideline for positioning therapy and mobilization, in general, recommends the development of ICU-specific protocols. The aim of this narrative review is to provide guidance when developing a best practice protocol in one's own field of work. It is recommended to a) implement early mobilization as part of a bundle, including screening and management of patient's awareness, pain, anxiety, stress, delirium and family's presence, b) develop a traffic-light system of specific in- and exclusion criteria in an interprofessional process, c) use checklists to assess risks and preparation of mobilization, d) use the ICU Mobility Scale for targeting and documentation of mobilization, e) use relative safety criteria for hemodynamic and respiratory changes, and Borg Scale for subjective evaluation, f) document and evaluate systematically mobilization levels, barriers, unwanted safety events and other parameters.

[Early mobilization. Competencies, responsibilities, milestones]. / Frühmobilisierung. Zuständigkeiten, Verantwortungen, Meilensteine.

BACKGROUND: Early mobilization is an evident, interprofessional concept to improve the outcome of intensive care patients. It reduces psychocognitive deficits and delirium and attenuates a general deconditioning, including atrophy of the respiratory pump and skeletal muscles. In this regard the interdisciplinary approach of early mobilization, taking into account different levels of mobilization, appears to be beneficial. The purpose of this study was to explore opinions on collaboration and tasks between different professional groups. METHOD: During the 25th Bremen Conference on Intensive Medicine and Nursing on 20 February 2015, a questionnaire survey was carried out among the 120 participants of the German Early Mobilization Network meeting. RESULTS: In all, 102 questionnaires were analyzed. Most participants reported on the interdisciplinarity of the approach, but none of the tasks and responsibilities concerning early mobilization can be assigned to a single professional group. The practical implementation of mobilizing orally intubated patients may require two registered nurses as well as a physical therapist. Implementation in daily practice seems to be heterogeneous. CONCLUSIONS: There is no consensus regarding collaboration, competencies, and responsibilities with respect to early mobilization of intensive care patients. The approach to date has been characterized by a lack of interprofessional communication, which may lead to an inefficient use of the broad and varied base of knowledge and experienceof the different professions.

Cost-effectiveness of pneumococcal conjugate vaccination in Croatia.

OBJECTIVE: Pneumococcus is a known cause of meningitis, pneumonia, sepsis, and acute otitis media in children and adults globally. Two new vaccines for children have the potential to prevent illness, disability, and death, but these vaccines are expensive. The Croatian Ministry of Health has considered introducing the vaccine in the past, but requires economic evidence to ensure that the limited funds available for health care will be used in the most effective way. METHODOLOGY: Croatia appointed a multidisciplinary team of experts to evaluate the cost-effectiveness of introducing pneumococcal conjugate vaccination (PCV) into the national routine child immunization program. Both 10-valent and 13-valent PCV (PCV10 and PCV13) were compared to a scenario assuming no vaccination. The TRIVAC decision-support model was used to estimate cost-effectiveness over the period 2014-2033. We used national evidence on demographics, pneumococcal disease incidence and mortality, the age distribution of disease in children, health service utilization, vaccine coverage, vaccine timeliness, and serotype coverage. Vaccine effectiveness was based on evidence from the scientific literature. Detailed health care costs were not available from the Croatian Institute for Health Insurance at the time of the analysis so assumptions and World Health Organization (WHO) estimates for Croatia were used. We assumed a three-dose primary vaccination schedule, and an initial price of US$ 30 per dose for PCV10 and US$ 35 per dose for PCV13. We ran univariate sensitivity analyses and multivariate scenario analyses. RESULTS: Either vaccine is estimated to prevent approximately 100 hospital admissions and one death each year in children younger than five in Croatia. Compared to no vaccine, the discounted cost-effectiveness of either vaccine is estimated to be around US$ 69,000-77,000 per disability-adjusted life-years (DALYs) averted over the period 2014-2033 (from the government or societal perspective). Only two alternative scenarios were borderline cost-effective (US$ per DALY averted less than 3×GDP per capita of approximately US$ 40,000). The first was a scenario based primarily on the WHO 2008 pneumococcal disease burden estimates for Croatia. The second was a scenario that assumed a fairly dramatic drop in the price of the vaccine over the period. Both vaccines would need to be priced at approximately US$ 20 per dose or less to be considered cost-effective under base-case assumptions. PCV10 would be more cost-effective than PCV13 with base-case assumptions, but this is sensitive to the price of each vaccine. CONCLUSION: Based on estimated health and economic benefits in children alone, PCV is unlikely to be cost-effective in Croatia. Both vaccines would need to be priced at less than US$ 20 per dose to be considered cost-effective for children. Further analyses should be conducted to estimate the health and economic burden of pneumococcal disease in older age groups, and to assess the influence on cost-effectiveness results when short-term and long-term indirect effects are included for older individuals. While there are important uncertainties around the price and effectiveness of both vaccines, our analysis suggests there is insufficient evidence to warrant a significant difference in the price of the two vaccines.

Influenza vaccine effectiveness estimates in Croatia in 2010-2011: a season with predominant circulation of A(H1N1)pdm09 influenza virus.

This is a retrospective study using the test-negative case-control method to estimate seasonal 2010-2011 influenza vaccine effectiveness (VE) in Croatia. Of patients consulting a physician for influenza-like illness (ILI) and for whom a swab was taken, we compared RT-PCR influenza-positive and RT-PCR influenza-negative patients. We used a structured questionnaire and physicians' records to obtain information on vaccination status and potential confounders. We conducted a complete case analysis using logistic regression to measure adjusted VE overall, against A(H1N1)pdm09 and in age groups. Out of 785 interviewed patients, 495 eligible patients were included in the study, after applying exclusion criteria [217 cases, of which 92·6% were A(H1N1)pdm09 positive, 278 controls]. Crude VE was 31·9% [95% confidence interval (CI) -40·9 to 67·1] and adjusted VE was 20·7% (95% CI -71·4 to 63·3), with higher VE in youngest and oldest age groups. Results from this first VE study in Croatia suggest a low to moderate VE for the 2010-2011 season. Studies year on year are needed with a greater sample size to provide more precise estimates, and also by age group and risk groups for vaccination.

First evidence of simultaneous occurrence of West Nile virus and Usutu virus neuroinvasive disease in humans in Croatia during the 2013 outbreak.

PURPOSE: We report on first evidence of simultaneous occurrence of West Nile virus (WNV) and Usutu virus (USUV) neuroinvasive infection in humans in Croatia during the transmission season 2013. METHODS: From June to December 2013, a total of 95 patients with clinically suspected WNV infection (WNV fever and neuroinvasive disease) were tested for WNV IgM/IgG antibodies using enzyme-linked immunosorbent assay. Twenty-six reactive samples were further tested by virus neutralization test for confirmation. RESULTS: WNV neuroinvasive infection was confirmed in 20 patients, while in three patients USUV neutralizing antibodies were detected. Cases occurred during the 11-week interval (from 24 July to 07 October 2013). Both WNV and USUV cases were distributed in three north-western Croatian counties. In addition to human cases, recent asymptomatic WNV infection (detection of IgM antibodies) was recorded in 9/3,460 (0.3 %) tested sentinel horses. Infected animals were recorded in two eastern and one north-western county. CONCLUSIONS: Our results indicate co-circulation of WNV and USUV in Croatia. WNV infection could be misdiagnosed with other emerging infectious diseases presenting with neurological symptoms such as USUV infection.

Safety and efficacy of addition of bevacizumab to oxaliplatin-based preoperative chemotherapy in colorectal cancer with liver metastasis- a single institution experience.

PURPOSE: To evaluate the safety and efficacy of the addition of bevacizumab to oxaliplatin-based preoperative chemotherapy in metastatic colorectal cancer (mCRC) patients. METHODS: Between August 2008 and December 2011, 51 patients with histologically documented CRC and liver metastases were treated with first-line oxaliplatin-based therapy plus bevacizumab: FOLFOX 4 (oxaliplatin, folinic acid and 5-FU) plus bevacizumab or OXFL mod.Mayo (folinic acid, oxaliplatin and 5-FU) plus bevacizumab. RESULTS: The mean patient age was 59.69+ 9.38 years (range 38-78) and 34 (66.67%) were male. Complete response (CR) was achieved in 7 (13.73%) patients, partial response (PR) in 29 (56. 86%) and stable disease (SD) in 6 (11.76%); progressive disease (PD) was registered in 9 (17.65%) patients. Disease control rate was 82.36% (42 patients). Liver resections were performed in 37 (72.55%) patients vs those without resection (p<0.01). The same regimen without bevacizumab was administered postoperatively to 18 (42. 86%) patients. The mean progression free survival (PFS) was 9.90±7.07 months (range 3-26) and was significantly longer in patients with postoperative therapy (p<0.001). Treatment-related toxicity appeared in 28 (54. 90%) patients vs those who did not (p<0.001) Independent of grade, nausea (19.61%), leucopenia (17.65%) and peripheral neuropathy (17.65%) were the most frequent toxicities. Chemotherapy was postponed in 9 (17.65%) patients due to grade 3-4 toxicities. The most frequent grade 3 or 4 toxicities were leucopenia (5.88%) and hypertension (3.92%). CONCLUSION: Bevacizumab plus oxaliplatin-based treatment is safe and efficient as preoperative treatment of mCRC with primarily unresectable liver metastases. Liver resection could offer a possibility for long-term survival in these patients.

Transcranial magnetic stimulation of degenerating brain: a comparison of normal aging, Alzheimer's, Parkinson's and Huntington's disease.

Although the brain's ability to change constantly in response to external and internal inputs is now well recognized the mechanisms behind it in normal aging and neurodegeneration are less well understood. To gain a better understanding, transcranial magnetic stimulation (TMS) has been used extensively to characterize non-invasively the cortical neurophysiology of the aging and degenerating brain. Furthermore, there has been a surge of studies examining whether repetitive TMS (rTMS) can be used to improve functional deficits in various conditions including normal aging, Alzheimer's and Parkinson's disease. The results of these studies in normal aging and neurodegeneration have emerged reasonably coherent in delineating the main pathology in spite of considerable technical limitations, omnipresent methodological variability, and extraordinary patient heterogeneity. Nevertheless, comparing and integrating what is known about TMS measurements of cortical excitability and plasticity in disorders that predominantly affect cortical brain structures with disorders that predominantly affect subcortical brain structures may provide better understanding of normal and abnormal brain aging fostering new. The present review provides a TMS perspective of changes in cortical neurophysiology and neurochemistry in normal aging and neurodegeneration by integrating what is revealed in individual TMS measurements of cortical excitability and plasticity in physiological aging, Alzheimer's, Parkinson's, and Huntington's, disease. The paper also reflects on current developments in utilizing TMS as a physiologic biomarker to discriminate physiologic aging from neurodegeneration and its potential as a method of therapeutic intervention.

Current and future anti-HER2 therapy in breast cancer.

The therapeutic strategy for breast cancer with the use of targeted drugs is, at present, mainly focused on coping with HER2. Currently, lapatinib and trastuzumab are in widespread use. Virtually all completed and in progress clinical trials have demonstrated a significant enhancement in the rate of pathologic complete response (pCR), the primary endpoint in these studies, in cases of patients with HER2-positive breast cancer that received trastuzumab in the neoadjuvant setting. Use of lapatinib in the neoadjuvant setting should be considered experimental. When a 12-month course of trastuzumab was added to adjuvant chemotherapy, the disease-free survival (DFS) was greater and the overall survival (OS) was also greater. Although trastuzumab is approved as single-agent therapy, most patients are treated with trastuzumab plus cytotoxic agents. Trastuzumab, administered as single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Dual targeting approach with a combination of trastuzumab and lapatinib improved progression-free survival (PFS) as compared with lapatinib alone in patients with metastatic breast cancer who have not had a response to trastuzumab. The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged PFS. Novel anti-HER2 targeted therapies are needed to utilise novel approaches to combat trastuzumab resistance.

Effect of obesity on patient-reported outcomes in sarcoidosis.

OBJECTIVES: To assess the impact of high body mass index (BMI) on patient-reported outcomes in sarcoidosis patients and healthy persons. METHODS: In this case-control study, we investigated symptoms of fatigue and dyspnoea, health status, BMI and spirometric tests in 184 sarcoidosis patients and the same number of sex- and age-matched healthy subjects. Fatigue was assessed using the fatigue scale (FS), dyspnoea was determined by the baseline dyspnoea index (BDI) and health status was measured using the respiratory-specific St George's Respiratory Questionnaire (SGRQ). RESULTS: There were significantly more subjects with increased BMI (≥25 kg/m(2)) among the sarcoidosis patients than among the healthy volunteers ((2) 37.675, P < 0.01). Sarcoidosis patients also had a greater probability of having a higher BMI (P < 0.01, OR 1.18, 95%CI 1.071.3). We found significantly lower BDI scores and forced expiratory volume in 1 s/forced vital capacity, as well as higher total SGRQ and total FS scores in sarcoidosis patients than in healthy individuals (P < 0.01 for all differences). CONCLUSION: Sarcoidosis significantly reduces patients' health status, both independently and also due to increased BMI. Reduction in BMI may contribute to improved spirometry results and health status of patients with sarcoidosis.

History of exposure to dopaminergic medication does not affect motor cortex plasticity and excitability in Parkinson's disease.

OBJECTIVE: Little is known whether and how chronic exposure to dopaminergic treatment alters physiological mechanisms in Parkinson's disease (PD). METHODS: Two clinically similar groups of PD patients, one consisting of drug-naïve patients and another of patients already on chronic dopaminergic medication (when off medication), were compared to each other and to a control group. Plasticity and excitability of the hand primary motor cortex of the more affected side were evaluated using transcranial magnetic stimulation (TMS) techniques. RESULTS: There was little difference between two patient groups, and both groups showed similar differences in comparison to controls: decreased facilitatory sensory-motor plasticity (as measured by paired associative stimulation [PAS] protocol), impaired short-interval intracortical inhibition (SICI), and diminished slope of input-output curves at higher TMS intensities. The exception was that 30 min after PAS, intracortical facilitation (ICF) was significantly reduced in drug-naïve patients, whereas it changed much less in other two groups. CONCLUSIONS: Chronic exposure to dopaminergic drugs does not affect substantially the features of motor cortex excitability and plasticity in PD. There is little interaction between plasticity and excitability features of motor cortex in PD. SIGNIFICANCE: Reduced response to facilitatory PAS protocol, reduced SICI, and reduced slope of the input-output curve at higher TMS pulse intensities, seem to be physiological markers for the presence of the pathological disease process in PD. Long term treatment does not seem to change the underlying physiology of the disease.

Case-control design as investigative approach to assessing cancer etiology: development and future perspectives.

The case-control method evolved out of analyses of series of cases. The analytic form of the case-control study can be found in the 19th century medical literature, but did not appear to be viewed as a special or distinct methodology. The first modern case-control study was the Janet Lane-Claypon's study of breast cancer in 1926, but the design was used only sporadically in medicine until 1950, when 4 published casecontrol studies linked smoking and lung cancer. These 1950s studies synthesized the essential elements of the case-control comparison, produced a conceptual shift within epidemiology, and laid the foundation for the rapid development of the case-control design in the subsequent half century. The powerful consistency of these case-control studies, and the replication of their findings in later prospective studies, promoted the general acceptance of the case-control study as a scientific tool in clinical research. Newer case-control studies have benefited from the advances in design, execution and analysis since 1950s. These advances include more rigorous selection and matching of case and control population, improved interviewing techniques, location of the design within a general framework of epidemiologic strategies for relating exposure to disease, understanding of the measures of effect, and application of increasingly sophisticated statistical procedures to findings. This review traces the development and future perspectives of the case-control design to assessing cancer etiology. With illustrations drawn primarily from the literature on its use and the value of its results to unravelling the etiology of malignant diseases, we tried to explore if the case-control approach firmly ensconced in epidemiology as investigational tool and rivals in importance the more straightforward cohort approach.

The application of magnetic resonance imaging in preoperative evaluation of patients with endometrial carcinoma.

PURPOSE: The aim of this paper was to assess the usefulness of the preoperative application of magnetic resonance (MRI) imaging in patients with confirmed endometrial carcinoma. METHODS: This prospective study included 50 patients with endometrial cancer. MRI was used for preoperative disease staging and in planning the operative treatment. The parameters monitored by MRI were compared with the findings of curettage pathological examination. Estimated were the depth of myometrial invasion, the involvement of the cervix by the tumor, the presence of adnexal metastases and regional lymph nodes. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of the MRI in relation to the aforementioned clinicopathological parameters were assessed. RESULTS: The presence of myometrial invasion was estimated with 100% specificity, 86% sensitivity, 100% PPV and 40% NPV. The estimation of the depth of myometrial invasion (>or<50%) was defined with 89% sensitivity, 54% specificity, 83% PPV and 60% NPV. MRI provided valuable data about cervical invasion (100% PPV for the presence of cervical invasion and 55% PPV for the depth of cervical invasion), thereby helping to decide on the kind of surgical intervention, the choice of approach (open or laparoscopic surgery) and the choice of the surgeon. CONCLUSION: MRI is useful and reliable in preoperative evaluation. The information obtained by MRI provides space and time for planning the treatment modality.

Recurrence of cervical intraepithelial neoplasias with negative cone margins: risk factors.

PURPOSE: The percent of young patients treated for cervical intraepithelial neoplasias (CIN) has been increasing, thus it is very important to define patients in high risk for relapse. The aim of this study was to establish any possible association of persistent human papillomavirus (HPV) infection, age, smoking, parity, use of oral contraceptives, and Chlamydia infection, with relapse of CIN. METHODS: Between March 2006 and March 2009 a prospective clinical study was performed at the Clinic of Obstetrics and Gynecology in Nis, with the study group comprising the first 35 patients with disease relapse after conization and the control group consisting of 30 patients with more than one year after treatment without relapse. HPV typization was done at the Laboratory for Molecular Biology and Cytogenetics of the Clinical Centre Nis using polymerase chain reaction (PCR). RESULTS: A statistically significant higher percentage of recurrences with lower pathologic stage (CIN I) was found in younger women (below 29 years) (p<0.01). Women in the control group were more commonly non smokers (56.66 vs. 40%) but without statistical significance (p>0.05). The distribution of smoked cigarettes in the study and control subjects showed no statistically significant difference (p>0.05). Patients with recurrences were more commonly HPV-positive compared to controls (68.57 vs. 6.66%; p <0.05). In the study group, HPV-positive smokers recurred with more advanced grades (CIN III and microinvasive carcinoma/MIC; p<0.01). In non smokers, the severity of recurrence was not statistically correlated with HPV positivity. CONCLUSION: Persistent HPV infection, smoking associated with HPV infection and more advanced age were demonstrated to be of statistical significance for CIN recurrence. Parity, use of oral contraceptives, Chlamydia infection, and smoking as independent etiologic factors were not significantly associated with CIN relapse.

Paired-associative stimulation can modulate muscle fatigue induced motor cortex excitability changes.

The aim of this study was to examine whether the changes of the motor cortex excitability induced by muscle fatigue could be affected by prior or subsequent intervention protocol supposed to induce opposing excitability changes. For this purpose we used paired associative stimulation (PAS) method, where peripheral nerve stimuli were associated with transcranial magnetic stimulation (TMS) of the motor cortex at a fixed interstimulus interval of 25 ms. The PAS protocol used is known to produce a long lasting, long-term potentiation (LTP) like change of cortical plasticity manifested by significant increase in motor evoked potentials (MEPs) amplitude. In this study, we confirmed significant MEP size reduction following fatigue, which had been already reported in the literature. When PAS was applied either immediately before or after muscle fatigue protocol, the excitability changes were largely occluded and MEP sizes remained close to baseline levels. However, in spite of the effects on cortical excitability, conditioning with PAS did not cause any change in target fatigue measure, the endurance point, which remained the same as when fatiguing protocol was applied alone. The present results demonstrate that fatigue-related changes in cortical excitability can be modulated by either prior or subsequent excitability promoting activity. They also suggest that muscle fatigue associated changes in motor cortical excitability probably represent non-specific activity-related plasticity, rather than a direct expression of the so-called central fatigue.

Autochthonous dengue fever in Croatia, August-September 2010.

After information about a dengue case in Germany acquired in Croatia, health professionals and the public in Croatia were alerted to assess the situation and to enhance mosquito control, resulting in the diagnosis of a second case of autochthonous dengue fever in the same area and the detection of 15 persons with evidence of recent dengue infection. Mosquito control measures were introduced. The circumstances of dengue virus introduction to Croatia remain unresolved.

Effects of anthocyanins and anthocyanin-rich extracts on the risk for cancers of the gastrointestinal tract.

Anthocyanins are the largest group of water-soluble pigments in the plant kingdom. Anthocyanins are responsible for most of the red, blue, and purple colors of fruits, vegetables, flowers, and other plant tissues or products. In recent years, numerous studies have shown that anthocyanins display a wide range of biological activities. This review summarises recent literature evidence on the association of anthocyanins and anthocyanin-rich extracts consumption with the risk for gastrointestinal tract cancer, concentrating on the results from in vivo animal model tumor systems, as well as data from human epidemiological studies. Potential cancer chemopreventive activities of anthocyanins were revealed from in vitro studies. In vivo animal model tumor systems showed that dietary anthocyanins inhibit cancers of the gastrointestinal tract. Some epidemiological studies have revealed protective effects of anthocyanins consumption on gastrointestinal cancer risk in humans. Pharmacokinetic data indicate that absorption of anthocyanins into the bloodstream of rodents and humans is minimal, suggesting that they may have little efficacy in tissues other than the gastrointestinal tract and skin. Future studies should be undertaken to determine if the anticancer effects of anthocyanins are due to the parent compounds and/or to their metabolites.