Therapeutic Interval Research Articles

Reoperative central lymph node dissection for incidental papillary thyroid cancer can be performed safely: A retrospective review

BackgroundThis study compares the pathological outcomes and operative morbidity for papillary thyroid cancer (PTC) patients undergoing a primary total thyroidectomy (TT) with central lymph node dissection (CLND), to those undergoing an interval CLND following a previous thyroid operation, or for the unsuspected diagnosis of PTC. MethodsSingle-institution, retrospective review of PTC patients from 2000 to 2015 was performed. Three treatment groups were identified: primary TT/CLND, interval prophylactic CLND, and interval therapeutic CLND. Primary outcome measures were number of lymph nodes removed, hypoparathyroidism and recurrent laryngeal nerve (RLN) injury. ResultsResults for 30 prophylactic and 35 therapeutic interval CLND were compared with 218 patients undergoing primary TT/CLND. Interval CLND was associated with similar rates of cervical metastases, complications, and a trend towards decreased lymph node recovery. ConclusionReoperative CLND for incidental PTC frequently identifies cervical lymph node metastases, potentially reduces recurrence, and can be performed with similar morbidity to a primary lymphadenectomy.

Quality, origins and limitations of common therapeutic drug reference intervals.

Therapeutic drug monitoring (TDM) is used to manage drugs with a narrow window between effective and toxic concentrations. TDM involves measuring blood concentrations of drugs to ensure effective therapy, avoid toxicity and monitor compliance. Common drugs for which TDM is used include aminoglycosides for infections, anticonvulsants to treat seizures, immunosuppressants for transplant patients and cardiac glycosides to regulate cardiac output and heart rate. An essential element of TDM is the provision of accurate and clinically relevant reference intervals. Unlike most laboratory reference intervals, which are derived from a healthy population, TDM reference intervals need to relate to clinical outcomes in the form of efficacy and toxicity. This makes TDM inherently more difficult to develop as healthy individuals are not on therapy, so there is no "normal value". In addition, many of the aforementioned drugs are old and much of the information regarding reference intervals is based on small trials using methods that have changed. Furthermore, individuals have different pharmacokinetics and drug responses, particularly in the context of combined therapies, which exacerbates the challenge of universal TDM targets. This focused review examines the origins and limitations of existing TDM reference intervals for common drugs, providing targets where possible based on available guidelines.

Inconsistencies in dosage practice in children with overweight or obesity: A retrospective cohort study.

Obesity can affect the pharmacokinetics of most drugs, which may result in under‐ or overdosing if traditional pediatric dosing strategies are used. To investigate currently applied dosage strategies in children with overweight or obesity (overweight/obesity), in a clinical treatment facility. In particular, whether dosing guidelines were available and metrics of body size applied. A retrospective cohort study of 200 patients admitted to the Danish Children′s Obesity Clinic. Data were collected from 2007 to 2015. Overweight/obese children 3‐18 years were included if they had at least one drug prescription. Overall there were 658 prescriptions, primarily analgesics, psychotropics, asthma medications, and antibiotics. Except for one prescription, guidelines for dosage of overweight/obese children were not available in the clinic. In one prescription of gentamicin, the dose was adjusted by a metric body size. Otherwise dose was predominately prescribed either by total body weight or as fixed dose by age, in accordance with the recommendations of normal weight children. In drugs with a narrow therapeutic interval, we found large interindividual variations in dosing regimens, that is, for gentamicin, paracetamol, and prednisolone. Reduction of dose to the maximum recommended adult dose was common practice, when the dose calculated by total body weight (ie, mg/kg) exceeded this maximum. This study highlights the shortage of dosing guidelines in overweight/obese children. We found a large interindividual variability in dosage regimens, even in drugs with narrow therapeutic intervals. The clinicians rely on “best practice”, as evidence‐based dosage regimens are missing for many drugs prescribed during childhood.

Pharmacokinetics of Single Oral Dose Extended-Release Levetiracetam in Healthy Cats.

BackgroundRepeated PO dosing of anti‐epileptic drugs may contribute to poor compliance in treated cats. Intermediate‐release levetiracetam has been used safely in cats, but must be given q8h to maintain serum concentrations in the therapeutic interval for humans (5–45 μg/mL). Approved extended‐release levetiracetam (XRL) for human use may require less frequent dosing, but the large dosing unit has limited its use in cats.HypothesesIn healthy cats, serum levetiracetam concentration will remain above 5 μg/mL for at least 24 hours after administration of a single dose of XRL PO and will be well tolerated.Animals7 healthy cats.MethodsExtended‐release levetiracetam (500 mg) was administered PO. Blood was collected and neurologic examination findings recorded at scheduled times over 30 hours. Serum levetiracetam concentration was quantitated by an immunoassay validated in cats. Data were subjected to noncompartmental analysis. Descriptive statistics were reported.ResultsThe median dosage of 86.2 mg/kg, (range, 80–94.3) achieved a mean maximum concentration (C max) of 89.8 ± 25.8 μg/mL at 4.9 ±1.57 hours. Serum levetiracetam was >5 μg/mL in all cats by 90 minutes. Mean concentrations were 43.7 ± 18.4 and 4.9 ± 3.4 μg/mL at 12 and 24 hours, respectively. The half‐life was 4.1 ± 1.0 hours. The drug was well tolerated.Conclusions and Clinical ImportanceA single 500 mg PO dose of XRL safely maintained serum levetiracetam concentration ≥5 μg/mL in healthy cats for at least 21 hours. Clinical efficacy studies in epileptic cats receiving XRL are indicated; however, monitoring should be implemented for individual cats.

Abstract ID: 54 The application of the FLUKA Monte Carlo code in medical physics

Monte Carlo codes are increasingly spreading in medical physics community due to their capability of performing a detailed description of radiation transport and interaction with matter. This contribution will address the recent developments of the FLUKA code and its practical application in medical physics. FLUKA is being used in radiation therapy and nuclear medicine. At present, it is of particular interest in the context of particle therapy, thanks to the development of accurate and reliable physical models capable of handling all components of the expected radiation field. At the same time, the code can be interfaced to different radiobiological models. These features become extremely important for correctly performing not only physical but also biologically based dose calculations, especially in cases where ions heavier than protons are involved. At the same time, in order to support the application of FLUKA in hospital-based environments, the FLUKA graphical interface has been enhanced with the capability of translating CT DICOM images into voxel-based computational phantoms in a fast and well-structured way. The interface is capable of importing also radiotherapy treatment data described in DICOM RT standard. Therefore, the FLUKA code not only is a reliable instrument for the simulation of therapeutic beams, but it is also used in some of the leading European hadron therapy centers as an accurate tool for Treatment Planning verification and correction. In addition, it allows an accurate prediction of emerging secondary radiation and this is of the utmost importance in innovative areas of research aiming at in vivo treatment verification. Here we shall review the features of the FLUKA code, pointing out the recent refinements of the nuclear models, relevant for the therapeutic energy interval, which lead to an improved description of the mixed radiation field. Benchmarks against experimental data with both proton and ion beams will be shown. Examples of clinical application will be presented, together with a review of some results in medical physics research.

PP-14 Substandard prescription of drugs in a population of overweight and obese children. an observational retrospective cohort study

Background Obesity is a major area of public health concerns, since it is associated with a wide range of se-rious health complications, including diabetes type 2, musculoskeletal disorders, sleep apnea, depression, asthma, hypertension, and cancer. Consequently, obese children are more likely to receive drug treatment than their normal weight peers. Further, obesity is known to be associated with changes in pharmacokinetics of drugs (1–5). Dosing overweight (OW) and obese (OB) children by the use of traditional paediatric dosage strategies (e.g. mg per kilogram or fixed dose by age) may therefore result in a potential risk of sub-or supra-therapeutic doses. We aimed to investigate currently applied dosage strategies in OW/OB children, in a clinical treatment facility. In par-ticular, whether dosage guidelines were used and metrics of body size applied with special attention to drugs with a narrow therapeutic interval and/or loading dose of clin-ical importance. Methods A retrospective cohort study conducted at the Children’s Obesity Clinic in Denmark, in the period 2008–2015. OW/OB children≤18 years, having at least one drug prescribed, were included. 200 patient records were reviewed. The study was approved by the Data Protection Agency (BBH-2014–045, I-suite 03045) Drug treatments/prescriptions were registered with ref-erence to the Anatomical Therapeutic Chemical (ATC) Classification System. Dosage strategies were registered as dosage by total body weight (TBW), fixed dose by age (years), use of adjusted weight measures (e.g. IBW, ABW) or dose estimation by other strategies. Results A total number of 455 prescriptions were iden-tified, primarily distributed in ATC groups N, A, R and J. Guidelines for dosage of OW/OB children were not avail-able in the clinic, for any of the recorded drugs. Only one prescription of gentamicin was adjusted by weight (ABW) using metrics of body size. Otherwise, gentamicin was dosed after three different dosage regimens. In 35/455 prescriptions, dose was adjusted by an undocumented dosage strategy. Dose was primarily limited to the max-imum recommended adult dose, when dose (mg/kg) exceeded adult dose, i.e. acetaminophen. Conclusion This study highlights the shortage of dos-age guidelines in OW/OB children. We found as suspect-ed a large inter-individual variability in dosage regimens even in drugs with narrow therapeutic intervals or drugs which has loading doses important for clinical effects. The clinicians are left with ‘best practice’, as evidence based dosage regimens are missing for several drugs prescribed during childhood.

PP-36 Therapeutic indications for use of extemporaneous glucocorticoid formulations in children – the glufic study

Background The majority of young children with wheezing have transient symptoms typically associated with viral upper respiratory tract infections and do not have increased risks of asthma later in life. Episodes with severe respiratory symptoms are reported in these chil-dren too. How to diagnose these patients makes clear ev-idence based treatment guidelines unfeasible. Children aged 0–5 years with wheezing may be symptomatically treated with inhaled short-acting beta-2-adrenergic-ago-nist therapy. If no relief of symptoms or severe symptoms, treatment guidelines recommend oral or systemic gluco-corticoids. Since no exact therapeutic interval exists for oral glucocorticoids, there is inconsistency on the dosing recommendations. Moreover, currently the only licensed glucocorticoid preparations in Denmark are tablets or i.v. formulations. These formulations are not suitable, since young children are unable to swallow tablets, and i.v. ad-ministration is associated with unnecessary discomfort. In consequence, children younger than 5 years are treated with extemporaneous preparations, off-label, or unli-censed medications. Use of extemporaneous formula-tions prelude several drawbacks e.g. formulation diversity, differences in bioavailability, limited shelf-live, safety-pro-file, taste etc. Despite the wide therapeutic index of glu-cocorticoids, it is important that they are administrated at the lowest effective dose as a considerable number of dose dependent adverse events exist for these drugs. Objective To describe the use of extemporaneous glu-cocorticoids in children≤5 years of age diagnosed with acute symptoms of asthmatic bronchitis, compared to existing guidelines across three regional paediatric depart-ments. Second, to examine if high or low dose glucocor-ticoid influences the length of hospitalisation. Methods A descriptive, chart-based study including three paediatric departments in the Capital Region of Denmark. All patients 0–5 years of age diagnosed with acute symptoms of asthmatic bronchitis in 2013–2015 were eligible for inclusion at the day they received at least one extemporaneously prepared administration of pred-nisolone. Results During the three-year period almost 560 ad-missions were included, of which 70% were boys. The average age was 22,3 months±13,3, and the average weight 12,2 kg ±2,9. A priori, the paediatric wards used dif-ferent dosing regimens, which were reflected in the data, primarily varying from 1 mg/kg to 2 mg/kg for the first dose administrated. The patients received eight different kinds of extemporaneous formulations, with no obvious pattern of choice. For statistical analyses COX-regression were used. No coherence between dosing and length of hospitalisation were found. Conclusion This survey shows that the paediatric depart-ments used a variety of extemporaneous liquid prednis-olone formulations interchangeably. The degree of in-consistency raises issues concerning optimal dosing and potential toxicity. Since no association between higher doses and shorter length of hospitalisation were found we hope to encourage the paediatric departments to align the choice of formulation and dosing in order to select lowest effective dose.

Warfarin monitoring in nursing homes assessed by case histories. Do recommendations and electronic alerts affect judgements?

Purpose: Older adults treated with warfarin are prone to complications, and high-quality monitoring is essential. The aim of this case history based study was to assess the quality of warfarin monitoring in a routine situation, and in a situation with an antibiotic–warfarin interaction, before and after receiving an electronic alert.Materials and methods: In April 2014, a national web-based survey with two case histories was distributed among Norwegian nursing home physicians and general practitioners working part-time in nursing homes. Case A represented a patient on stable warfarin treatment, but with a substantial INR increase within the therapeutic interval. Case B represented a more challenging patient with trimethoprim sulfamethoxazole (TMS) treatment due to pyelonephritis. In both cases, the physicians were asked to state the next warfarin dose and the INR recall interval. In case B, the physicians could change their suggestions after receiving an electronic alert on the TMS-warfarin interaction.Results: Three hundred and ninety eight physicians in 292 nursing homes responded. Suggested INR recall intervals and warfarin doses varied substantially in both cases. In case A, 61% gave acceptable answers according to published recommendations, while only 9% did so for case B. Regarding the TMS-warfarin interaction in case history B, the electronic alert increased the percentage of respondents correctly suggesting a dose reduction from 29% to 53%. Having an INR instrument in the nursing home was associated with shortened INR recall times.Conclusions: Practical advice on handling of warfarin treatment and drug interactions is needed. Electronic alerts as presented in electronic medical records seem insufficient to change practice. Availability of INR instruments may be important regarding recall time.

Paroxetine concentrations in obsessive-compulsive disorder: Support for a therapeutic interval

IntroductionPrevious studies of concentrations of serotonin reuptake inhibitors (SRIs) versus therapeutic efficacy have yielded inconsistent results. Even if the relationships between the individual's serotonergic system and the clinical symptoms of obsessive-compulsive disorder (OCD) are poorly understood, the SRIs are consistently effective in OCD. However, studies on SRI concentrations in OCD treatment are rare.Objectives/aimsTo identify possible links between paroxetine concentrations and anti-obsessive response.MethodsIn a randomised, double-blind trial, comparing clomipramine, paroxetine and placebo in OCD treatment, serum paroxetine levels were measured after 1 week and after 4 weeks of treatment in 18 patients. Anti-obsessive response was assessed with Yale-Brown obsessive compulsive scale (Y-BOCS) and patients’ global evaluation (PGE), after 12 weeks of treatment.ResultsSerum paroxetine concentrations after 4 weeks suggested a therapeutic interval between 50 and 240 nmol/L (13–63 ng/mL). The mean Y-BOCS decrease was 54% inside versus 7% outside this interval (t = 3.96; P = 0.0011).ConclusionsParoxetine levels seemingly predicted clinical outcome. Studies with a greater number of patients are necessary in order to confirm this finding and to discern whether it is useful in clinical practice.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Developing equations to predict surface dose and therapeutic interval in bolused electron fields: A Monte Carlo Study

In this research, we aim to investigate the influence of different materials, as a bolus, on the low-energy electron beam dose distributions and to develop equations for predicting surface dose based on bolus thickness, as well as the therapeutic interval based on surface dose.All the Monte Carlo (MC) calculations and measurements were conducted on a Siemens PRIMUS linac. Based on EGSnrc MC code, BEAMnrc system was used to model a Siemens linac and generate phase-space files for three electron beams (6, 8, and 10MeV). The particles were transported from the phase-space files to the bolus materials and the simulated water phantom using DOSXYZnrc. Various materials with different thicknesses were examined as a bolus, and appropriate equations were determined for each material and electron beam.The comparison of percent depth dose (PDD) curves and beam profiles, using MC, with the measured data demonstrated that the calculated values properly matched with the measurements. The results indicated that the use of bolus materials with the density of higher than soft tissue can increase both surface dose and therapeutic interval simultaneously. This finding arises from the fact that the required bolus thickness for achieving the therapeutic surface dose decreases in the case of high-density materials.Two series of prediction equations were proposed for predicting the surface dose based on bolus thickness and the therapeutic interval based on surface dose. These equations are able to calculate properly the bolus thickness required for producing a therapeutic surface dose (above 90%) for any therapeutic interval.

Analytical model for ion stopping power and range in the therapeutic energy interval for beams of hydrogen and heavier ions

Many different approaches exist to calculate stopping power and range of protons and heavy charged particles. These methods may be broadly categorized as physically complete theories (widely applicable and complex) or semi-empirical approaches (narrowly applicable and simple). However, little attention has been paid in the literature to approaches that are both widely applicable and simple. We developed simple analytical models of stopping power and range for ions of hydrogen, carbon, iron, and uranium that spanned intervals of ion energy from 351 keV u−1 to 450 MeV u−1 or wider. The analytical models typically reproduced the best-available evaluated stopping powers within 1% and ranges within 0.1 mm. The computational speed of the analytical stopping power model was 28% faster than a full-theoretical approach. The calculation of range using the analytic range model was 945 times faster than a widely-used numerical integration technique. The results of this study revealed that the new, simple analytical models are accurate, fast, and broadly applicable. The new models require just 6 parameters to calculate stopping power and range for a given ion and absorber. The proposed model may be useful as an alternative to traditional approaches, especially in applications that demand fast computation speed, small memory footprint, and simplicity.

Therapeutic drug monitoring of isoniazid and rifampicin during anti-tuberculosis treatment in Auckland, New Zealand

There is uncertainty as to the optimal therapeutic concentrations of anti-tuberculosis drugs to achieve cure. To characterise the use of therapeutic drug monitoring (TDM), and identify risk factors and outcomes for those with concentrations below the drug interval. Patients treated for tuberculosis (TB) who had rifampicin (RMP) or isoniazid (INH) concentrations measured between 1 January 2005 and 31 December 2012 were studied retrospectively. Matched concentrations and drug dosing time were assessed according to contemporary regional drug intervals (RMP > 6 μmol/l, INH > 7.5 μmol/l) and current international recommendations (RMP > 10 μmol/l, INH > 22 μmol/l). Outcomes were assessed using World Health Organization criteria. Of 865 patients, 121 had concentrations of either or both medications. RMP concentrations were within the regional drug intervals in 106/114 (93%) and INH in 91/100 (91%). Concentrations were within international drug intervals for RMP in 76/114 (67%) and INH in 53/100 (53%). Low weight-based dose was the only statistically significant risk factor for concentrations below the drug interval. Of the 35 patients with low concentrations, 21 were cured, 9 completed treatment and 5 transferred out. There were no relapses during follow-up (mean 66.5 months). There were no clinically useful characteristics to guide use of TDM. Many patients had concentrations below international therapeutic intervals, but were successfully treated.

The FLUKA Code: An Accurate Simulation Tool for Particle Therapy.

Monte Carlo (MC) codes are increasingly spreading in the hadrontherapy community due to their detailed description of radiation transport and interaction with matter. The suitability of a MC code for application to hadrontherapy demands accurate and reliable physical models capable of handling all components of the expected radiation field. This becomes extremely important for correctly performing not only physical but also biologically based dose calculations, especially in cases where ions heavier than protons are involved. In addition, accurate prediction of emerging secondary radiation is of utmost importance in innovative areas of research aiming at in vivo treatment verification. This contribution will address the recent developments of the FLUKA MC code and its practical applications in this field. Refinements of the FLUKA nuclear models in the therapeutic energy interval lead to an improved description of the mixed radiation field as shown in the presented benchmarks against experimental data with both 4He and 12C ion beams. Accurate description of ionization energy losses and of particle scattering and interactions lead to the excellent agreement of calculated depth–dose profiles with those measured at leading European hadron therapy centers, both with proton and ion beams. In order to support the application of FLUKA in hospital-based environments, Flair, the FLUKA graphical interface, has been enhanced with the capability of translating CT DICOM images into voxel-based computational phantoms in a fast and well-structured way. The interface is capable of importing also radiotherapy treatment data described in DICOM RT standard. In addition, the interface is equipped with an intuitive PET scanner geometry generator and automatic recording of coincidence events. Clinically, similar cases will be presented both in terms of absorbed dose and biological dose calculations describing the various available features.

METHOD OF ASSESSMENT OF RADIOTHERAPEUTIC INTERVAL IN RADIATION THERAPY FOR CANCER CONSIDERING DOSE FRACTIONATION REGIMEN

The analysis of currently available definitions of the term «radiotherapeutic interval» (RTI) has showed that they contain significant uncertainties and do not take into account the dose fractionation regimen. The aim of the study was to analyze the current approaches to the definition of the term «radiotherapeutic interval» and to propose a new definition excluding uncertainties and taking into account the dose fractionation regi- men. materials and methods. A new approach to the assessment of radiotherapeutic interval was applied to superficial tumors treated with X-rays and fast electron beams. The features of dose distributions characteristic of X-ray and monoenergetic fast electron beams generated in radiotherapy of superficial malignant tumors 10 SIBERIAN JOURNAL OF ONCOLOGY. 2016. VOL. 15, № 3. Р. 5-11 в.а. лисин сПОсОб ОЦенКИ раДИОтераПевтИчесКОГО Интервала were studied. The relationship between radiotherapeutic interval and tumor size for Х-ray and monoenergetic fast electron beam radiotherapy was calculated. The algorithm of calculation was consistent with the new definition of the concept of «radiotherapeutic interval». Results. A new approach to the definition of «radio- therapeutic interval», which avoids the previous definition’s inherent uncertainties and contradictions and takes into account the dose fractionation regimen, has been proposed.

Long term sustained therapeutic effects of percutaneous posterior tibial nerve stimulation treatment of neurogenic overactive bladder in multiple sclerosis patients: 12-months results.

The aim of this study is to determine the sustained therapeutic efficacy and treatment intervals for PTNS in NOAB with MS, offering periodic additional treatments during 1 year in patients who completed an initial course of 12 consecutive weekly sessions. A total of 34 patients enrolled to the PTNS treatment and 21 patients completed the 1 year PTNS treatment with a tapering protocol of 6, 9, and 12 months of therapy, respectively. After 12 weeks of therapy, PTNS was applied at 14 day intervals for 3 months, 21 day intervals for 3 months, and 28 day intervals for 3 months. The patients completed a 3-day voiding diary at 3rd, 6th, 9th, and 12th month. The patients requested to complete validated questionnaires (ICIQ-SF, OAB-V8, OAB-q SF) were carried out within 3-month intervals thereafter during their enrolment in the study. A total of 21 patients were enrolled in the study. Of these 5 (23.8%) were men and 16 (76.2%) women. The improvements for all voiding diary parameters were significant in the 6th, 9th, and 12th months when compared with baseline. Mean values between baseline and 12 month parameters suggested that daytime frequency decreased by 5.4 voids daily, urge incontinence decreased by 3.4 episodes daily, urgency episodes decreased by 7.4 episodes daily, nocturia decreased by 2.6 voids, and voided volume improved by a mean of 72.1 cc. These results have demonstrated NOAB symptom improvement in MS patients can be achieved with 12 weekly PTNS treatments which show excellent durability over 12 months. Neurourol. Urodynam. 36:104-110, 2017. © 2015 Wiley Periodicals, Inc.

Fractionation and bioavailability of phosphorus in sediments of Huaihe River, China

<h3>Background</h3> Atrial fibrillation (AF) is one of the most common sustained cardiac arrhythmia. It is associated with significant morbidity, mortality and poor quality of life. This is the reason why it is very important to closely follow its treatment. Amiodarone is one of the most frequently used antiarrhythmic drugs in patients with AF both in prophylaxis and treatment. However, the treatment with this drug results in high healthcare resource use and costs due to its poor safety profile. <h3>Purpose</h3> The objective of this study was to assess the plasmatic concentration of amiodarone in patients with AF and also to identify possible factors that could influence it. The results were correlated with used doses, with concomitantly administered drugs, renal and liver function. <h3>Material and methods</h3> A prospective observational study was conducted in 27 consecutive patients treated with amiodarone from May to July 2017 in a Clinical University Hospital. The patients included met our inclusion criteria. HPLC-MS was the device used to determine the plasma concentration of amiodarone. <h3>Results</h3> The mean age of those 27 included patients was 65/6±11 years, 44.4% females. The used doses were 200 mg or 400 mg/day. In our patients, plasmatic concentration was given in a therapeutic interval (500–2,500 ng/ml) to 51.8%. In the patients with lower plasmatic concentrations of amiodarone, the drugs associated in the therapeutic plan belonged to: diuretics (furosemide), beta-blockers, statins, antiplatelets (clopidogrel), fluoroquinolones (ciprofloxacine) and non-steroidal anti-inflammatory drugs. It was observed that there was a statistically significant difference between the plasmatic concentrations of amiodarone in patients treated with furosemide vs patients treated concomitantly with other drugs. The interactions between other mentioned drugs and amiodarone were not registered. It was observed that an increase in transaminases or creatinine is correlated with an increase in amiodarone’s plasmatic concentration. <h3>Conclusion</h3> 48.2% of the patients with AF under chronic treatment with amiodarone had the plasmatic concentration of amiodarone out of the therapeutic range. We can report an underuse of amiodarone for these patients. It was found that there was a significant interaction between furosemide and amiodarone. In order to confirm this interaction, we need to continue the research on a larger sample. <h3>References and/or Acknowledgements</h3> Thanks to all the collaborators. No conflict of interest

A paradigm shift in imaging biomarkers in neovascular age-related macular degeneration

Neovascular age-related macular degeneration (AMD) has undergone substantial break-throughs in diagnostic as well as therapeutic respect, with optical coherence tomography (OCT) allowing to identify disease morphology in great detail, and intravitreal anti-vascular endothelial growth factor therapy providing unprecedented benefit. However, these two paths have yet not been combined in an optimal way, real-world outcomes are inferior to expectations, and disease management is largely inefficient in the real-world setting. This dilemma can be solved by identification of valid biomarkers relevant for visual function, disease activity and prognosis, which can provide solid guidance for therapeutic management on an individual level as well as on the population base. Qualitative and quantitative morphological features obtained by advanced OCT provide novel insight into exudative and degenerative stages of neovascular AMD. However, conclusions from structure/function correlations evolve differently from previous paradigms. While central retinal thickness was used as biomarker for guiding retreatment management in clinical trials and practice, fluid localization in different compartments offers superior prognostic value: Intraretinal cystoid fluid has a negative impact on visual acuity and is considered as degenerative when persisting through the initial therapeutic interval. Subretinal fluid is associated with superior visual benefit and a lower rate of progression towards geographic atrophy. Detachment of the retinal pigment epithelium was identified as most pathognomonic biomarker, often irresponsive to therapy and responsible for visual decline during a pro-re-nata regimen. Alterations of neurosensory tissue are usually associated with irreversible loss of functional elements and a negative prognosis. Novel OCT technologies offer crucial insight into corresponding changes at the level of the photoreceptor--retinal pigment epithelial--choriocapillary unit, identifying the biological limits of therapeutic interventions. To optimally benefit from high-resolution multi-modal imaging, an integrated analysis of all functional and structural features is required involving reliable automated algorithms and computational data analyses. Using innovative analysis methods, retinal biomarkers can be used to provide efficient personalized therapy for the individual patient, predictive disease- and population-based models for large-scale management and identifying promising targets for the development of novel therapeutic strategies.

Clinical intervals and diagnostic characteristics in a cohort of prostate cancer patients in Spain: a multicentre observational study.

BackgroundLittle is known about the healthcare process for patients with prostate cancer, mainly because hospital-based data are not routinely published. The main objective of this study was to determine the clinical characteristics of prostate cancer patients, the, diagnostic process and the factors that might influence intervals from consultation to diagnosis and from diagnosis to treatment.MethodsWe conducted a multicentre, cohort study in seven hospitals in Spain. Patients’ characteristics and diagnostic and therapeutic variables were obtained from hospital records and patients’ structured interviews from October 2010 to September 2011. We used a multilevel logistic regression model to examine the association between patient care intervals and various variables influencing these intervals (age, BMI, educational level, ECOG, first specialist consultation, tumour stage, PSA, Gleason score, and presence of symptoms) and calculated the odds ratio (OR) and the interquartile range (IQR). To estimate the random inter-hospital variability, we used the median odds ratio (MOR).Results470 patients with prostate cancer were included. Mean age was 67.8 (SD: 7.6) years and 75.4 % were physically active. Tumour size was classified as T1 in 41.0 % and as T2 in 40 % of patients, their median Gleason score was 6.0 (IQR:1.0), and 36.1 % had low risk cancer according to the D’Amico classification. The median interval between first consultation and diagnosis was 89 days (IQR:123.5) with no statistically significant variability between centres. Presence of symptoms was associated with a significantly longer interval between first consultation and diagnosis than no symptoms (OR:1.93, 95%CI 1.29–2.89). The median time between diagnosis and first treatment (therapeutic interval) was 75.0 days (IQR:78.0) and significant variability between centres was found (MOR:2.16, 95%CI 1.45–4.87). This interval was shorter in patients with a high PSA value (p = 0.012) and a high Gleason score (p = 0.026).ConclusionsMost incident prostate cancer patients in Spain are diagnosed at an early stage of an adenocarcinoma. The period to complete the diagnostic process is approximately three months whereas the therapeutic intervals vary among centres and are shorter for patients with a worse prognosis. The presence of prostatic symptoms, PSA level, and Gleason score influence all the clinical intervals differently.

Evaluation of protein drug stability with vitreous humor in a novel ex-vivo intraocular model

The stability of protein therapeutics during the residence time in the vitreous humor (VH) is an important consideration for intra ocular treatment and can possibly impact therapeutic efficacy and/or treatment intervals. Unavailability of the reliable Ex-vivo intravitreal (ExVit) model to estimate protein stability following IVT has driven the research focus to develop such model which can facilitate protein stability estimation before in-vivo experiments. In this manuscript, we have developed and evaluated three ExVit models, namely, ExVit static, semi-dynamic and dynamic. These models were utilized and compared when studying the in-vitro stability of model protein formulations under simulated intraocular conditions using porcine vitreous humor (VH). The ExVit static model exhibited significant precipitation and aggregation of proteins, most likely due to pH change occurred in the VH after isolation. The semi-dynamic model assessed was composed of two compartments i.e., VH- and buffer-compartment which has effectively stabilized the pH of the VH and facilitated the migration of VH degradation products. However, some limitations related to investigation of long-term protein stability were also observed with semi-dynamic model. The dynamic model developed, was comprised of three diffusion controlling barriers (two diffusion controlling membranes and a gel-matrix), which allowed modulation of the diffusion rate of macromolecules. The ability of dynamic model to modulate protein retention time in the VH will overcome the challenges faced by the semi-dynamic model such as long-term stability evaluation.

Percutaneous Treatment of Large Venous Malformations in the Oral and Maxillofacial Regions Using Electrochemical Therapy Combined With Pingyangmycin

The aim of the present study was to evaluate the therapeutic outcome of using electrochemical therapy (ECT) combined with a sclerosing agent, pingyangmycin (bleomycin A5 hydrochloride; PYM), for large (>3 cm in diameter) venous malformations (VMs) in the oral and maxillofacial regions. Thirty-five patients (15 male and 20 female; age range, 10 to 69 yr; mean age, 32 yr) with large VMs in the oral and maxillofacial region were treated with a combination of ECT and PYM under general anesthesia in the authors' department from June 2012 through May 2014. The size of the lesions varied from 3 × 3 to 12 × 15 cm. A repeated course of ECT and PYM was administered for larger VMs. The therapeutic interval was 3 months for ECT and 2 to 4 weeks for PYM. The dose of PYM for patients was 8 mg each time, and the injection concentration of PYM was 1.6 mg/mL. Patients were followed for 6 to 36 months. Therapeutic results were evaluated by clinical examination and Doppler ultrasonography before and after treatment. Of the 35 patients, 29 (82.9%) received 1 ECT treatment, 5 (14.3%) received 2 ECT treatments, and 1 (2.8%) received 3 ECT treatments. The number of PYM injection sessions was 1 to 5 (average, 2.5 times). According to the therapeutic criteria, the clinical outcome was excellent in 22 patients (62.9%), good in 10 patients (28.6%), and fair in 3 patients (8.5%). All patients (100%) had local swelling postoperatively that lasted approximately 1 to 2 weeks. Two patients (5.7%) had fever. No skin necrosis or nerve damage was found. Percutaneous treatment using ECT and PYM was a straightforward, safe, and reliable treatment modality for large VMs.