Toward liquid biopsies in cancer treatment: application of circulating tumor DNA

Circulating tumor DNA (ctDNA) refers to the fraction of cell‐free DNA in a patient's blood originating from tumor cells. Increased knowledge about tumor genomics, improvements in targeted therapies, and accompanying advances in DNA‐sequencing technologies have increased the interest in using ctDNA as a minimally invasive tool in cancer diagnostics and treatment. Especially, early tumor detection including identification of minimal residual disease and stratification of adjuvant therapy are promising approaches. Also, ctDNA showed to be reliable in treatment monitoring and can be used to assess therapy resistance due to the broad variety of tumor subclones captured in ctDNA. Therefore, using ctDNA in the clinical setting has the potential to improve therapeutic outcomes. In the present review, we summarize the status of ctDNA in oncology with focus of being an alternative to tissue biopsies in early detection and treatment monitoring.     

In vivo measurement of apparent diffusion coefficients of hyperpolarized 13C‐labeled metabolites

The combination of hyperpolarized MRS with diffusion weighting (dw) allows for determination of the apparent diffusion coefficient (ADC), which is indicative of the intra‐ or extracellular localization of the metabolite. Here, a slice‐selective pulsed‐gradient spin echo sequence was implemented to acquire a series of dw spectra from rat muscle in vivo to determine the ADCs of multiple metabolites after a single injection of hyperpolarized [1‐¹³C]pyruvate. An optimal control optimized universal‐rotation pulse was used for refocusing to minimize signal loss caused by B₁ imperfections. Non‐dw spectra were acquired interleaved with the dw spectra and these were used to correct for signal decay during the acquisition as a result of T₁ decay, pulse imperfections, flow etc. The data showed that the ADC values for [1‐¹³C]lactate (0.4–0.7 µm²/ms) and [1‐¹³C]alanine (0.4–0.9 µm²/ms) were about a factor of two lower than the ADC of [1‐¹³C]pyruvate (1.1–1.5 µm²/ms). This indicates a more restricted diffusion space for the former two metabolites consistent with lactate and alanine being intracellular. The higher ADC for pyruvate (similar to the proton ADC) reflected that the injected substance was not confined inside the muscle cells but also present extracellular. Copyright © 2014 John Wiley & Sons, Ltd.     

Adverse drug reactions in children reported by European consumers from 2007 to 2011

Background Information about medicines safety in children is very limited. Consumer adverse drug reaction (ADR) reports can provide information about serious and unknown ADRs from medicine use in children. Objective To characterize ADRs in children reported by consumers in Europe from 2007 to 2011. Methods We analysed ADRs reported to the European ADR database, EudraVigilance (EV) for individuals from birth to 17 years. Data were characterized with respect to age and sex of the child, type of ADR (system organ class and preferred term), seriousness and suspected medicines (anatomical therapeutic chemical classification system level 1 and 5). Results In total, 240 ADR reports corresponding to 670 ADRs were identified. The relatively largest share of ADRs were reported for infants below 1 year followed by teenagers, and 60 % of all ADRs were reported for girls. The majority of ADRs reported were of the general type (20 %) and nervous system disorders (15 %). The largest share of serious ADRs was of the type nervous system disorders (17 % of all serious). Three cases of death were reported. Vaccines and anti-infectives for systemic use contributed to 30 % of ADRs, antineoplastic and immunomodulating agents for 23 % and sex hormones for 13 %. Conclusion Only few paediatric ADR consumer reports were found in EudraVigilance. Many of these ADRs were serious, and fatal cases were reported, however also nonserious reports were present. The findings indicate that consumer reports may be of value in paediatric ADR signal detection.     

Development of a Real-Time Smartphone Solution for the Management of Women With or at High Risk of Gestational Diabetes

Gestational diabetes mellitus (GDM) is defined as new onset or recognition of glucose intolerance in pregnancy. Evidence supports tight blood glucose regulation to prevent adverse maternal and fetal outcomes. Finger-prick blood glucose (BG) testing with frequent clinic review remains the most common method of managing diabetes in pregnancy. The prevalence of GDM is rising globally, pressuring resource-limited services. We have developed an intuitive, interactive, reliable, and accurate management system to record BG measurements and deliver management of GDM remotely. Following an initial scoping phase, a prototype software application was developed using an Android smartphone with BG meter linkage via Bluetooth. A custom website was built for clinician review of the data transmitted by the smartphone. After system refinement, further evaluation was undertaken for usability and reliability in a 48-patient service development project. Women used the system for an average of 13.1 weeks. In all, 19 686 BG measures were transmitted, 98.6% of which had a meal tag. A total of 466 text messages were transmitted. A mean of 30 BG readings per woman per week were transmitted, and 85% of women submitted the minimum requirement of 18 readings per week. We have developed a novel, real-time, smartphone-based BG monitoring management system that allows clinician review of real-time patient-annotated BG results. Results indicate high usage and excellent compliance by women. Robust clinical, economic, and satisfaction evaluations are required. To address these requirements, we are currently conducting a randomized controlled pilot trial.     

Benefits and harms of mammography screening

Mammography screening for breast cancer is widely available in many countries. Initially praised as a universal achievement to improve women''s health and to reduce the burden of breast cancer, the benefits and harms of mammography screening have been debated heatedly in the past years. This review discusses the benefits and harms of mammography screening in light of findings from randomized trials and from more recent observational studies performed in the era of modern diagnostics and treatment. The main benefit of mammography screening is reduction of breast-cancer related death. Relative reductions vary from about 15 to 25% in randomized trials to more recent estimates of 13 to 17% in meta-analyses of observational studies. Using UK population data of 2007, for 1,000 women invited to biennial mammography screening for 20 years from age 50, 2 to 3 women are prevented from dying of breast cancer. All-cause mortality is unchanged. Overdiagnosis of breast cancer is the main harm of mammography screening. Based on recent estimates from the United States, the relative amount of overdiagnosis (including ductal carcinoma in situ and invasive cancer) is 31%. This results in 15 women overdiagnosed for every 1,000 women invited to biennial mammography screening for 20 years from age 50. Women should be unpassionately informed about the benefits and harms of mammography screening using absolute effect sizes in a comprehensible fashion. In an era of limited health care resources, screening services need to be scrutinized and compared with each other with regard to effectiveness, cost-effectiveness and harms.     

FOXP3 positive regulatory T-cells in cutaneous and systemic CD30 positive T-cell lymphoproliferations

The CD30-positive lymphoproliferations encompass a spectrum of disorders that share histological and phenotypic similarities but differ markedly in clinical behaviour. The basis for this diversity is not known, but it has been proposed that immune suppression by cytokines and/or regulatory T-cells (Tregs) may be implicated. In this study, skin biopsies from lymphomatoid papulosis (LyP) (n = 14), primary cutaneous anaplastic large cells lymphoma (C-ALCL) (n = 13) and systemic anaplastic large cells lymphoma (S-ALCL) with (n = 9) or without (n = 6) ALK expression were examined by immunohistology for FOXP3 expression in tumour cells and tumour infiltrating Tregs. Labelling of a majority of the neoplastic cells was seen in one case of C-ALCL. Another three cases (one LyP and two C-ALCL) displayed weak labelling of very occasional atypical T-cells. In the remaining 38 cases the atypical lymphoid infiltrate was FOXP3 negative. By contrast, all biopsies contained tumour infiltrating FOXP3-positive Tregs. Significant higher numbers were recorded in ALK negative S-ALCL and LyP than in C-ALCL and S-ALCL positive for ALK. In conclusion, it is shown that FOXP3 expression in cutaneous and systemic CD30-positive lymphoproliferations is generally confined to tumour infiltrating Tregs. These cells may have influence upon the clinical behaviour, possibly depending upon the net degree of Treg mediated immune suppression of tumour cells relative to tumour infiltrating, cytotoxic effector cells, thereby implicating the more favourable outcome of LyP compared to C-ALCL.     

Factors associated with mortality in human immunodeficiency virus type 1-infected adults initiating protease inhibitor-containing therapy: role of education level and of early transaminase level elevation (APROCO-ANRS EP11 study). The Antiprotéases Cohorte Agence Nationale de Recherches sur le SIDA EP 11 study

This study attempted to identify factors associated with mortality among human immunodeficiency virus (HIV)-infected adults starting a protease inhibitor (PI)-containing therapy. Among 1155 patients consecutively enrolled in the APROCO study between May 1997 and June 1998, clinical characteristics were as follows: median age, 36 years; median baseline CD4 cell count, 288 cells/mm(3); and median baseline plasma HIV RNA load, 4.4 log(10) copies/mL. After a median follow-up of 27 months, 48 deaths had occurred, of which 44% were related to acquired immune deficiency syndrome. The mortality rate was 2.9% at 12 months. When both data at baseline and data at 4 months after the start of PI therapy were considered, factors independently associated with mortality were (Cox model) low baseline plasma creatinine level, low school education level, low CD4 cell count at 4 months, low hemoglobin level, and elevated hepatic transaminase levels. Thus, social context plus clinical and biologic data, including the 4-month response to treatment, must be considered in treatment of HIV-infected patients.     

Multiple sclerosis: immunopathogenesis and controversies in defining the cause

PURPOSE OF REVIEW: Multiple sclerosis is a major cause of neurological disability in Western societies. The most important reason for the limited success obtained in the treatment and prevention so far is most likely related to the limited knowledge about its cause and pathogenesis. This paper discusses recent progress and controversies in the understanding of the pathogenesis and cause of multiple sclerosis. RECENT FINDINGS: Both T helper cells type 1 (Th1 cells), Th17 cells, cytotoxic T cells, B cells and regulatory T cells are involved in the inflammatory process. Axonal loss seems to be driven by inflammation during the early stages of disease but may become independent of inflammation at later stages. The target antigen of the immune response has not been identified. Weak genetic association has been established in two cytokine receptors, whereas increasing female: male ratio support the importance of environmental risk factors. A substantial proportion of intrathecal B cells are infected with Epstein-Barr virus. SUMMARY: Multiple sclerosis is a complex disease and calls for integrated efforts from immunology, epidemiology, neuroscience and genetics. In particular, the immunological implications of environmental risk factors such as vitamin D desufficiency, smoking and Epstein-Barr virus infection need to be explored.