Timing the initiation of multiple myeloma

The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2nd-3rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection

Long-range epigenetic silencing at 2q14.2 affects most human colorectal cancers and may have application as a non-invasive biomarker of disease

Large chromosomal regions can be suppressed in cancer cells as denoted by hypermethylation of neighbouring CpG islands and downregulation of most genes within the region. We have analysed the extent and prevalence of long-range epigenetic silencing at 2q14.2 (the first and best characterised example of coordinated epigenetic remodelling) and investigated its possible applicability as a non-invasive diagnostic marker of human colorectal cancer using different approaches and biological samples. Hypermethylation of at least one of the CpG islands analysed (EN1, SCTR, INHBB) occurred in most carcinomas (90%), with EN1 methylated in 73 and 40% of carcinomas and adenomas, respectively. Gene suppression was a common phenomenon in all the tumours analysed and affected both methylated and unmethylated genes. Detection of methylated EN1 using bisulfite treatment and melting curve (MC) analysis from stool DNA in patients and controls resulted in a predictive capacity of, 44% sensitivity in positive patients (27% of overall sensitivity) and 97% specificity. We conclude that epigenetic suppression along 2q14.2 is common to most colorectal cancers and the presence of a methylated EN1 CpG island in stool DNA might be used as biomarker of neoplastic disease

Reducing length of stay for acute diabetic foot episodes: employing an extended scope of practice podiatric high-risk foot coordinator in an acute foundation trust hospital

BACKGROUND: To enhance the acute management of people with diabetic foot disease requiring admission, an extended scope of practice, podiatric high-risk foot coordinator position, was established at the Great Western Hospital, Swindon in 2010. The focus of this new role was to facilitate more efficient and timely management of people with complex diabetic foot disease. The aim of this project was to investigate the impact of the podiatric high-risk foot coordinator role on length of stay, rate of re-admission and bed cost. METHOD: This study evaluated the difference in length of stay and rate of re-admission between an 11- month pre-pilot period (November 2008 to October 2009) and a 10-month pilot period (August 2010 to June 2011). The estimated difference in bed cost between the pre-pilot and pilot audits was also calculated. Inclusion criteria were restricted to inpatients admitted with a diabetic foot ulcer, gangrene, cellulitis or infection as the primary cause for admission. Eligible records were retrieved using ICD-10 (V9) coding via the hospital clinical audit department for the pre-pilot period and a unique database was used to source records for the pilot phase. RESULTS: Following the introduction of the podiatric high-risk foot coordinator, the average length of stay reduced from 33.7 days to 23.3 days (mean difference 10.4 days, 95% CI 0.0 to 20.8, p = 0.050). There was no statistically significant difference in re-admission rate between the two study periods, 17.2% (95% CI 12.2% to 23.9%) in the pre-pilot phase and 15.4% (95% CI 12.0% to 19.5%) in the pilot phase (p = 0.820). The extrapolated annual cost saving following the implementation of the new coordinator role was calculated to be £234,000 for the 2010/2011 year. CONCLUSIONS: This audit found that the extended scope of practice coordinator role may have a positive impact on reducing length of stay for diabetic foot admissions. This paper advocates the role of a podiatric high-risk foot coordinator utilising an extended scope of practice model, although further research is needed

Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (SCOUT) in metastatic colorectal cancer

Tegafur–uracil (UFT) plus leucovorin® (LV, folinic acid) with alternating irinotecan and oxaliplatin were effective and well tolerated in patients with metastatic colorectal cancer (mCRC) in a phase I study. This study expanded the maximum tolerated dose group. Patients aged ⩾18 years had histologically confirmed, inoperable, previously untreated, measurable mCRC. Patients received irinotecan 180 mg m−2 on day 1, oxaliplatin 100 mg m−2 on day 15 and UFT 250 mg m−2 plus LV 90 mg on days 1–21 every 28 days. The phase I/II study comprised 45 patients, 29 at the maximum tolerated dose (MTD). The response rate in 38 evaluable patients was 63% (95% confidence interval (CI): 49–80). Median time to progression and overall survival were 8.7 months (95% CI: 7.9–10.4) and 16.8 months (95% CI: 9.6–25.3), respectively. In the MTD group, one patient had grade 3 leucopaenia; one had grade 3 neutropaenia; three had grade 3 diarrhoea; and one had grade 3 neurotoxicity. No hand–foot syndrome grade >1 was seen. In total, 67% of eligible patients received second-line therapy. UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for mCRC, with minimal neurotoxicity and hand–foot syndrome

Meanings given to algebraic symbolism in problem posing

Some errors in the learning of algebra suggest students have difficulties giving meaning to algebraic symbolism. In this paper, we use problem posing in order to analyze the students’ capacity to assign meaning to algebraic symbolism and the difficulties that students encounter in this process depending on the characteristics of the algebraic statements given. We designed a written questionnaire composed of eight closed algebraic statements expressed symbolically, which was administered to 55 students who had finished their compulsory education and that had some previous experience in problem posing. In our analysis of the data, we examine both syntactic and semantic structures of the problem posed. We note that in most cases students posed problems with syntactic structures different to those given. They did not include computations within variables, and changed the kinds of relationships connecting variables. Students easily posed problems for statements with additive structures. Other differences in the type of problems posed depend on the characteristics of the given statements

Effectiveness of influenza vaccine against laboratory-confirmed influenza, in the late 2011-2012 season in Spain, among population targeted for vaccination

Background: In Spain, the influenza vaccine effectiveness (VE) was estimated in the last three seasons using the observational study cycEVA conducted in the frame of the existing Spanish Influenza Sentinel Surveillance System. The objective of the study was to estimate influenza vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza-like illness (ILI) among the target groups for vaccination in Spain in the 2011-2012 season. We also studied influenza VE in the early (weeks 52/2011-7/2012) and late (weeks 8-14/2012) phases of the epidemic and according to time since vaccination. Methods: Medically attended patients with ILI were systematically swabbed to collect information on exposure, laboratory outcome and confounding factors. Patients belonging to target groups for vaccination and who were swabbed 4 months, respectively, since vaccination. A decrease in VE with time since vaccination was only observed in individuals aged ≥ 65 years. Regarding the phase of the season, decreasing point estimates were only observed in the early phase, whereas very low or null estimates were obtained in the late phase for the shortest time interval. Conclusions: The 2011-2012 influenza vaccine showed a low-to-moderate protective effect against medically attended, laboratory-confirmed influenza in the target groups for vaccination, in a late season and with a limited match between the vaccine and circulating strains. The suggested decrease in influenza VE with time since vaccination was mostly observed in the elderly population. The decreasing protective effect of the vaccine in the late part of the season could be related to waning vaccine protection because no viral changes were identified throughout the season

Lymphatic mapping and sentinel node biopsy in gynecological cancers: a critical review of the literature

Although it does not have a long history of sentinel node evaluation (SLN) in female genital system cancers, there is a growing number of promising study results, despite the presence of some aspects that need to be considered and developed. It has been most commonly used in vulvar and uterine cervivcal cancer in gynecological oncology. According to these studies, almost all of which are prospective, particularly in cases where Technetium-labeled nanocolloid is used, sentinel node detection rate sensitivity and specificity has been reported to be 100%, except for a few cases. In the studies on cervical cancer, sentinel node detection rates have been reported around 80–86%, a little lower than those in vulva cancer, and negative predictive value has been reported about 99%. It is relatively new in endometrial cancer, where its detection rate varies between 50 and 80%. Studies about vulvar melanoma and vaginal cancers are generally case reports. Although it has not been supported with multicenter randomized and controlled studies including larger case series, study results reported by various centers around the world are harmonious and mutually supportive particularly in vulva cancer, and cervix cancer. Even though it does not seem possible to replace the traditional approaches in these two cancers, it is still a serious alternative for the future. We believe that it is important to increase and support the studies that will strengthen the weaknesses of the method, among which there are detection of micrometastases and increasing detection rates, and render it usable in routine clinical practice

Targeted therapies in colorectal cancer: an integrative view by PPPM

In developed countries, colorectal cancer (CRC) is the third most common malignancy, but it is the second most frequent cause of cancer-related death. Clinicians are still faced with numerous challenges in the treatment of this disease, and future approaches which target the molecular features of the disorder will be critical for success in this disease setting. Genetic analyses of many solid tumours have shown that up to 100 protein-encoding genes are mutated. Within CRC, numerous genetic alterations have been identified in a number of pathways. Therefore, understanding the molecular pathology of CRC may present information on potential routes for treatment and may also provide valuable prognostic information. This will be particularly pertinent for molecularly targeted treatments, such as anti-vascular endothelial growth factor therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy. As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response. Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches