Clinical Case Seminar: Post-menopausal ovarian androgen excess: challenges in diagnostic work-up and management of ovarian thecosis

Abstract

A 72 year old female was referred to the Department of Endocrinology with a 20-year history of hirsutes, mostly affecting her face and torso, the initial onset of which dated shortly after menopause age 52 years. There was no history of subfertility, menstrual irregularity, or hyperandrogenism during reproductive life to suggest prior polycystic ovary syndrome (PCOS), with three live births, two miscarriages and one still-birth.

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Prognostic scores for sorafenib-treated hepatocellular carcinoma patients: A new application for the hepatoma arterial embolisation prognostic score

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): J. Edeline, J.-F. Blanc, B. Campillo-Gimenez, Y.-T. Ma, J. King, O. Faluyi, J. Mathurin, S. Ghazi, D.H. Palmer, T. Meyer
BackgroundNo prognostic classification is currently used for patients treated with systemic therapies for Hepatocellular Carcinoma (HCC).MethodsWe retrospectively analysed data from patients treated with sorafenib for HCC from five centres in France and in the United Kingdom (UK). The training set comprised data from two centres and the validation set from three. Variables independently associated with Overall Survival (OS) in the training set were used to build the SAP (Sorafenib Advanced HCC Prognosis) score. The score was tested in the validation set, then compared with other prognostication systems.ResultsThe training set and validation set included 370 and 468 patients respectively. In the training set, variables independently associated with OS in multivariable analysis were: performance status (PS) >0, alpha-fetoprotein (AFP) >400 ng/ml, tumour size >7 cm, bilirubin >17 μmol/l and albumin <36 g/l. The SAP score was built giving one point to each abnormal variable, and three classes were constructed. The SAP score was significantly associated with OS in the training set, with median OS of 14.9 months for SAP A, 7.2 months for SAP B and 2.5 months for SAP C (P < 0.001). In the validation set, the SAP score was significantly associated with OS, and showed greater discriminative abilities than Barcelona Clinic Liver Cancer (BCLC) and albumin-bilirubin (ALBI) scores. However, the hepatoma arterial embolisation prognostic (HAP) score showed greater discriminative abilities than the SAP score.ConclusionIn European patients treated with sorafenib, the HAP was the most discriminant prognostic score and may facilitate stratification in trials and inform clinical decision making.



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Insight in taste alterations during treatment with protein kinase inhibitors

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): A. van der Werf, M. Rovithi, J.A.E. Langius, M.A.E. de van der Schueren, H.M.W. Verheul
The role of Protein Kinase Inhibitors (PKI) in the treatment of various types of cancer is increasingly prominent. Their clinical application is accompanied by the development of side effects, among which patient-reported taste alterations. These alterations are missed frequently, but impair nutritional intake, are associated with weight loss and often result in significant morbidity, especially in the context of chronic administration. Accurate reporting of taste alterations is hampered by lack of modules for symptom objectification and inadequate understanding on the underlying mechanisms. In this review we initially describe the physiology of taste and smell and the mechanism of action of PKIs. We proceed to summarize taste related side effects as reported in major clinical trials and describe possible causal factors. Lastly, an in-depth analysis is given on potential molecular pathways responsible for the PKI-induced taste alterations. Objectification of patient-reported symptoms and universal reporting, along with a better understanding of the underlying mechanisms, will lead to early recognition and optimized treatment, ultimately improving patient adherence and quality of life.



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‘Mind the gap’ between the development of therapeutic innovations and the clinical practice in oncology: A proposal of the European Organisation for Research and Treatment of Cancer (EORTC) to optimise cancer clinical research

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Emmanuelle Kempf, Jan Bogaerts, Denis Lacombe, Lifang Liu
In Europe, most of the cancer clinical research dedicated to therapeutic innovations aims primarily at regulatory approval. Once an anticancer drug enters the common market, each member state determines its real-world use based on its own criteria: pricing, reimbursement and clinical indications. Such an innovation-centred clinical research landscape might neglect patient-relevant issues in real-world setting, such as comparative effectiveness of distinct treatment options or long-term safety monitoring.The European Organisation for Research and Treatment of Cancer (EORTC) advocates reforming the current 'innovation-centred' system to a truly 'patient-centred' paradigm with systematically coordinated applied clinical research in conjunction with drug development, featuring the following strategy:(1) An interconnected partnership among key-stakeholders involved in the care delivery system, namely patients, health professionals, academia, pharmaceutical industry, regulators, payers and policy-makers, to optimise the transition from research to clinical practice and vice versa;(2) An independent research infrastructure host and coordination ensuring independent, high quality and sustainable research.



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Towards assessing corticospinal excitability bilaterally: Validation of a double-coil TMS method

Publication date: 1 January 2018
Source:Journal of Neuroscience Methods, Volume 293
Author(s): Julien Grandjean, Gerard Derosiere, Pierre Vassiliadis, Louise Quemener, Ysaline de Wilde, Julie Duque
BackgroundFor several decades, Transcranial magnetic stimulation (TMS) has been used to monitor corticospinal excitability (CSE) changes in various contexts. Habitually, single-coil TMS is applied over one primary motor cortex (M1), eliciting motor-evoked potentials (MEPs) in a contralateral limb muscle, usually a hand effector. However, in many situations, it would be useful to obtain MEPs in both hands simultaneously, to track CSE bilaterally. Such an approach requires stimulating both M1 concurrently while avoiding interference between the two descending stimuli.New methodWe examined MEPs obtained at rest using a double-coil TMS approach where the two M1 are stimulated with a 1ms inter-pulse interval (double-coil1ms). MEPs were acquired using double-coil1ms (MEPdouble) or single-coil (MEPsingle) TMS, at five different intensities of stimulation (100, 115, 130, 145 or 160% of the resting motor threshold, rMT). Given the 1ms inter-pulse interval in double-coil1ms trials, MEPdouble were either evoked by a 1st (MEPdouble-1) or a 2nd (MEPdouble-2) TMS pulse.ResultsAll MEPTYPE (MEPTYPE=MEPsingle, MEPdouble-1 and MEPdouble-2) were equivalent, regardless of the hand within which they were elicited, the intensity of stimulation or the pulse order.Comparison with existing methodThis method allows one to observe state-related CSE changes for the two hands simultaneously on a trial-by-trial basis.ConclusionThese results infer the absence of any neural interactions between the two cortico-spinal volleys with double-coil1ms TMS. Hence, this technique can be reliably used to assess CSE bilaterally, opening new research perspectives for scientists interested in physiological markers of activity in the motor output system.



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The Global Bioequivalence Harmonization Initiative: Summary report for EUFEPS international conference

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Mei-Ling Chen, Henning Blume, Gerald Beuerle, Barbara Davit, Mehul Mehta, Henrike Potthast, Barbara Schug, Yu Chung Tsang, Ralph-Steven Wedemeyer, Werner Weitschies, Jan Welink
Bioequivalence (BE) is considered one of the key questions in new and generic drug product development and registration worldwide. However, the regulations and jurisdiction vary from country to country and continent to continent. Harmonization of regulatory requirements and criteria for BE determination may avoid unnecessary repetition of BE studies and minimize drug exposure to humans. Harmonization around the globe may be achieved by a better understanding of scientific principles and expectations from different regulatory authorities. To facilitate global harmonization, the Network on Bioavailability and Biopharmaceutics (BABP) under the European Federation for Pharmaceutical Sciences (EUFEPS) launched a Global Bioequivalence Harmonization Initiative (GBHI) several years ago. This international conference was the first in a series of workshops organized by EUFEPS/BABP under GBHI. The workshop provided a forum for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on selected BE issues in the hope of identifying common ground and arriving at a harmonized view on these topics.

Graphical abstract

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Investigation of novel supersaturating drug delivery systems of chlorthalidone: The use of polymer-surfactant complex as an effective carrier in solid dispersions

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Maria Terezinha França, Rafael Pereira Nicolay, Manoela Klüppel Riekes, Juliana Munari Oliveira Pinto, Hellen Karine Stulzer
Supersaturating drug delivery systems (SDDS), as solid dispersions (SDs), stand out among strategies to enhance bioavailability of poorly soluble drugs. After oral administration, their dissolution in gastrointestinal fluids often leads to supersaturation, which drives to a rapid and sustained absorption. Polymers and surfactants play important roles in SDs through inhibiting precipitation caused by transitions from amorphous into crystalline form, in supersaturated solutions, and also through improving SDs physical stability. Novel chlorthalidone SDs, a BCS IV drug, were developed using polymeric and non-polymeric carriers, specially a polymer-surfactant complex. SDs drug releases were evaluated using sink and non-sink conditions in water and biorelevant medium. Their physical stability was also monitored under different storage conditions. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL), sodium lauryl sulfate (SLS) and a combination of both showed promising results in apparent solubility studies, and therefore they were selected to compose the spray dried SDs. Dissolution studies demonstrated the SOL-SLS complex potential for providing chlorthalidone fast release (>80% in 15min), producing and maintaining in vitro supersaturation. This formulation comprising high drug loading (75%) reached a high supersaturation degree under non-sink condition (up to 6-fold the equilibrium solubility) once maintained for 6h in biorelevant medium. In addition, this SD presented better physical stability when compared to the chlorthalidone neat amorphous. The SOL-SLS complex impacts positively on chlorthalidone release and physical stability, highlighting its potential as carrier in SDDS of a poorly soluble drug.

Graphical abstract

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Hand-foot skin reaction with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: A systematic review and meta-analysis

Publication date: Available online 3 October 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Jing Li, Jian Gu
A meta-analysis was conducted to systematically review the risk of hand-foot skin reaction (HFSR) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with cancer. The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with VEGFR-TKIs were retrieved and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published till May 2017. Twenty-one RCTs and 9552 patients were included. The current analysis suggested that the use of VEGFR-TKIs increased the risk of all-grade HFSR (7.04;95%CI, 5.33-9.30;p<0.00001) and high-grade (≥grade 3) HFSR (21.62;95%CI, 15.19-30.78;p<0.00001). On subgroup analyses, the risk ratio (RR) of all-grade HFSR varies significantly according to cancer type, whereas the RR of high-grade HFSR did not. The risk of all-grade and high-grade HFSR did not affect by drug types, treatment line, median age and treatment duration.



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Interaction between municipal solid waste leachate and Bauru aquifer system: a study case in Brazil

Abstract

Leachate contamination is a chronic and urgent problem present in municipal solid waste (MSW) landfill. Geochemical mathematical models in this work was suitable to study the dynamics of the leachate from an MSW landfill located in the Midwest of Sao Paulo, Brazil, a region with high precipitation and temperature and rich in chalcophile compounds and lithophile compounds, despite contamination with nitrogenous compounds. After 13 years of local aquifer monitoring, some groundwater samplings in Feb. 2004, Aug. 2007, Nov. 2009, and Feb. 2014 were chosen to be simulated. The hydrolysis is the main process at the landfill, together with absorption, adsorption, complexation, dilution, cation exchange, and oxidation, besides nitrification, reoxidation, and reduction.

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Photodegradative fate and potential phototoxic products of bromocarbazoles and chlorocarbazoles in water

Abstract

Bromocarbazoles and chlorocarbazoles are emerging environmental contaminants that have been reported to be persistent and possessing dioxin-like toxicity; however, their photodegradative fate in water is unknown. The photodegradation of 3-bromocarbazole, 3-chlorocarbazole, and 3,6-dichlorocarbazole was determined in ultrapure water. They proceeded by direct photolysis and followed first-order kinetics. The rate constants (k) were 0.4838, 0.3454, and 0.4422 h⁻¹ corresponding to half-lives (t _1/2) 1.81, 2.01, and 1.62, while the quantum yields (Ф) were 0.232, 0.180, and 0.295 respectively. The maximum wavelengths of absorption (λ _max) were in the near ultraviolet region (295, 296, 299, and 301 nm) implying these compounds are likely to degrade slowly under sunlight in natural aquatic environment. The molar extinction coefficients (ε) determined in acetonitrile were 18,573, 17,028, 13,385, and 14,010 L mol⁻¹ cm⁻¹, respectively, the latter being 3,6-dibromocarbazole. A bathochromic shift was observed with halogen addition on their respective mono-substituted congeners. Bromocarbazoles were observed to degrade faster in water than chlorocarbazoles. In addition, photodegradation was estimated to proceed faster in summer than in winter, in natural water system at 50° N latitude. In the absence of light, hydrolytic degradation occurred but proceeded very slowly. Hexahydroxybenzene and trihydroxycarbazole were positively identified as the likely photoproducts with the former being a known toxic compound. Dehalogenation, oxidative cleavage, hydroxylation, and hydrolysis are suggested as the major photodegradation mechanisms in water, yielding phototoxic products that may be of enhanced toxicity than the parent compounds.

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Neuroprotective effects of curcumin against acetamiprid-induced neurotoxicity and oxidative stress in the developing male rat cerebellum: biochemical, histological, and behavioral changes

Abstract

Curcumin is a molecule found in turmeric root that has anti-inflammatory, antioxidant, and anti-tumor properties and has been widely used as both an herbal drug and a food additive to treat or prevent neurodegenerative diseases. This study aimed to investigate the effect of curcumin on neurobehavioral and neuropathological alterations induced by acetamiprid on male rats. Three groups of ten male Wistar rats each were used for the study: the first was a control group (CTR) that did not consume acetamiprid (ACE); the second was an experimental group (ACE) that consumed 40 mg/kg body weight/day of acetamiprid; and the third group (CUR) received curcumin (100 mg/kg) and acetamiprid (40 mg/kg) in combination. Neurobehavioral evaluations including inclined plane performance and forepaw grip time were studied. Treatment with CUR significantly prevented ACE-treated rats from impairments in the performance of neurobehavioral tests, indicating the presence of deficits on sensorimotor and neuromuscular responses. In addition, Curcumin administration protects rats against acetamiprid-induced cerebellum toxicity such as increase in AChE and BChE activities, decrease on cells viability, oxidative stress, and an increase of intracellular calcium. Taken together, these results demonstrate for the first time that ACE treatment substantially impairs the survival of primary neuronal cells through the induction of necrosis concomitantly with the generation of an oxidative stress. Additionally, curcumin reduced histopathological changes caused by ACE.

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Advances in the Management of HER2-Positive Early Breast Cancer

Publication date: Available online 4 October 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): José Baselga, Robert E. Coleman, Javier Cortés, Wolfgang Janni




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Experimental verification of dose enhancement effects in a lung phantom from inline magnetic fields

Publication date: Available online 3 October 2017
Source:Radiotherapy and Oncology
Author(s): Bradley M. Oborn, Maegan A. Gargett, Trent J. Causer, Sarah J. Alnaghy, Nicholas Hardcastle, Peter E. Metcalfe, Paul J. Keall
Background and purposeTo present experimental evidence of lung dose enhancement effects caused by strong inline magnetic fields.Materials and methodsA permanent magnet device was utilised to generate 0.95T–1.2T magnetic fields that encompassed two small lung-equivalent phantoms of density 0.3g/cm³. Small 6MV and 10MV photon beams were incident parallel with the magnetic field direction and Gafchromic EBT3 film was placed inside the lung phantoms, perpendicular to the beam (experiment 1) and parallel to the beam (experiment 2). Monte Carlo simulations of experiment 1 were also performed.ResultsExperiment 1: The 1.2T inline magnetic field induced a 12% (6MV) and 14% (10MV) increase in the dose at the phantom centre. The Monte Carlo modelling matched well (±2%) to the experimentally observed results. Experiment 2: A 0.95T field peaked at the phantom centroid (but not at the phantom entry/exit regions) details a clear dose increase due to the magnetic field of up to 25%.ConclusionsThis experimental work has demonstrated how strong inline magnetic fields act to enhance the dose to lower density mediums such as lung tissue. Clinically, such scenarios will arise in inline MRI-linac systems for treatment of small lung tumours.



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Effects of biodegradable hydrogel spacer injection on contralateral submandibular gland sparing in radiotherapy for head and neck cancers

Publication date: Available online 3 October 2017
Source:Radiotherapy and Oncology
Author(s): Avani D. Rao, Stephanie Coquia, Robert De Jong, Christine Gourin, Brandi Page, Diane Latronico, Samson Dah, Lin Su, Stephen Clarke, Jeffrey Schultz, Lauren M. Rosati, Carole Fakhry, John Wong, Theodore L. DeWeese, Harry Quon, Kai Ding, Ana Kiess
Xerostomia is the most common late toxicity after head and neck radiation. We demonstrate injection of a hydrogel spacer anteriorly displacing the submandibular gland. This procedure enables reduced dose to the displaced submandibular gland in cadaveric models of oropharynx cancer treated with IMRT, with potential implications in reducing xerostomia risk.



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Unrelated umbilical cord stem cell transplantation in an eleven-month-old male infant with Wiskott-Aldrich syndrome

Publication date: Available online 3 October 2017
Source:The Kaohsiung Journal of Medical Sciences
Author(s): Chih-Yu Chen, Yee-Hsuan Chiou, Hung-Wen Su, Yu-Hsiang Chang




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Adult-to-adult living donor liver transplantation preoperative survey using MDCT, a single medical center experience in Taiwan

Publication date: Available online 3 October 2017
Source:The Kaohsiung Journal of Medical Sciences
Author(s): Te-Cheng Su, Siu-Wan Hung, Ming-Cheng Liu, Yen-Ting Lin, Jeon-Hor Chen, Shao-Bin Cheng, Clayton Chi-Chang Chen
This study evaluated multi-detector computed tomography (MDCT) scans performed on potential living donors for adult-to-adult liver transplantation (LDLT), with the aim of identifying significant findings that could be used to exclude potential transplantation donors. We retrospectively reviewed the medical records of 151 consecutive potential adult donors for LDLT from May 2007 to January 2015. Liver parenchyma steatosis, focal hepatic mass or intraabdominal malignancy, vascular variations, and donor liver volume were evaluated via MDCT. Grounds for excluding potential donors were also recorded and analyzed. Of the 151 potential donors, nine (6.0%) had moderate to severe fatty liver, 37 (24.5%) had hepatic arterial variants, 22 (14.6%) had significant portal venous variants, and more than half were found to have right accessory inferior hepatic vein. No intraabdominal malignancies were found. Eighty-eight potential donors were rejected, with the most common cause being insufficient recipient volume or remnant donor volume (47.7%), moderate to severe parenchymal steatosis (10.2%), and recipient expiration prior to transplantation (8.0%). An additional 16 potential donors were excluded by the surgical team due to the complexity of their portal venous variations. The rate of exclusion by pre-transplant imaging evaluation with MDCT was 33.8%. MDCT can provide accurate quantification of donor liver volume and steatosis severity along with precise demonstration of vascular variants, which are crucial for the preoperative evaluation of LDLT. However, MDCT may be ineffective for evaluating the biliary system without hepatobiliary-excreted contrast agent and has the disadvantage of ionizing radiation.



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Response to ‘Serological diagnostics in the detection of IgG autoantibodies against human collagen VII in epidermolysis bullosa acquisita – a multicenter analysis’

Abstract

In a recent retrospective serological study in 95 sera from epidermolysis bullosa acquisita (EBA) patients Schmidt et al. conclude that Col7A-NC1/NC2 ELISA (MBL, Japan) is superior to NC1 ELISA, Western blot and indirect immunofluorescence (IIF) on salt-split skin (SSS) with the highest sensitivity of 97.9%.¹ This sensitivity is an overestimation from a biased sample, since the sera had been preselected from patients with IgG reactivity fitting EBA by at least one of the immune serological assays indirect immunofluorescence, ELISA, and Western blot. The deficiency in study design with an incorrect reference standard creates a bias in estimated test accuracy.

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HLA class II alleles of susceptibility and protection in Brazilian and Dutch pemphigus foliaceus

Abstract

Pemphigus foliaceus (PF) is a worldwide chronic autoimmune bullous disease targeting desmoglein 1 (Dsg 1) on epithelial cell surface of skin and mucous membranes, causing lesions in skin but sparing mucosa, since the latter contain compensating desmoglein 3¹. Several environmental triggers for the autoimmune reaction have been imputed, such as drugs, ultraviolet radiation and mercurium. Human leucocyte antigens class II (HLA-DR4) alleles were linked to the disease in Ashkenazi Jews and other populations². For endemic pemphigus foliaceus in Brazil, named fogo selvagem (FS), HLA-DRB1*04 was shown to have a relative risk >14 for the disease³.

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Enhanced strain sensitivity in magnetostrictive spinel ferrite Co1−xZnxFe2O4

Publication date: 1 February 2018
Source:Journal of Magnetism and Magnetic Materials, Volume 447
Author(s): Shekhar D. Bhame, P.A. Joy
We report the magnetic and magnetoelastic properties of spinel oxide system Co1−xZnxFe2O4 (CZF series) where x = 0.0, 0.1, 0.2, 0.3, 0.4, and 0.5. All the composition were prepared by conventional solid state synthesis method and exhibited pure spinel phase formation. The lattice parameters showed gradual increase indicating uniform distribution Zn ions in cobalt ferrite lattice. The magnetic properties such as saturation magnetization and coercive field were drastically affected with Zn substitution showing enhanced saturation magnetization and a sharp decrease in the coercivity. The room temperature magnetostrictive properties showed a promising 30% enhancement in the slope of magnetostriction curve for x = 0.2 composition and a reasonable magnetostrictive strain of 110 ppm indicating its suitability as a promising magnetostrictive material.



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Disagreement in normative IGF-I levels may lead to different clinical interpretations and GH dose adjustments in GH deficiency

Summary

Introduction and Background

Normative data for the iSYS IGF-I assay have been published both in the VARIETE cohort and by Bidlingmaier et al.

Aim of the study

To investigate whether normative data of the VARIETE cohort lead to differences in Z-Scores for total IGF-I and clinical interpretation compared to normative data of Bidlingmaier et al.

Methods

We used total IGF-I values previously measured by the IDS-iSYS assay in 102 GH deficient subjects before starting GH treatment and after 12 months of GH treatment. Z-scores were calculated for all samples by using the normative data of the VARIETE cohort and by the normative data reported by Bidlingmaier et al.

Results

Before GH treatment Z-scores calculated by using the normative data of the VARIETE cohort were significantly lower than those calculated by the normative data of Bidlingmaier et al.: -2.40 (-4.52 to +1.31) (mean (range)) vs. -1.41 (-3.14 to +1.76); p<0.001). After 12 months of GH treatment again the Z-scores based on the normative data of the VARIETE cohort were significantly lower than those based on the normative data of Bidlingmaier et al.: -0.65 (-4.32 to +2.79) vs. 0.21 (-3.00 to +3.28); p<0.001).

Conclusions

IGF-I Z-scores in 102 GH deficient subjects differed significantly when normative data from two different sources were used. In daily clinical practice this would most likely have led to different clinical interpretations and GH dose adjustments.

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