Predictive and prognostic factors in colorectal cancer: a personalized approach.

It is an exciting time for all those engaged in the treatment of colorectal cancer. The advent of new therapies presents the opportunity for a personalized approach to the patient. This approach considers the complex genetic mechanisms involved in tumorigenesis in addition to classical clinicopathological staging. The potential predictive and prognostic biomarkers which have stemmed from the study of the genetic basis of colorectal cancer and therapeutics are discussed with a focus on mismatch repair status, KRAS, BRAF, 18qLOH, CIMP and TGF-β. © 2011 by the authors; licensee MDPI, Basel, Switzerland

Current status of 5α-reductase inhibitors in the management of lower urinary tract symptoms and BPH

Benign prostatic hyperplasia (BPH) is a progressive disease that is commonly associated with bothersome lower urinary tract symptoms (LUTS) and might result in complications, such as acute urinary retention and BPH-related surgery. Therefore, the goals of therapy for BPH are not only to improve LUTS in terms of symptoms and urinary flow, but also to identify those patients at a risk of unfavorable disease progression and to optimize their management. This article reviews the current status of therapy with 5 alpha-reductase inhibitors (5ARIs), namely fiasteride and dutasteride, for men with LUTS and BPH. Data from key randomized controlled trials (Oxford level 1b) on the use of 5ARIs are analyzed. The efficacy of 5ARIs either as monotherapy or in combination with alpha(1)-adrenoceptor antagonists in the management of LUTS and the impact of monotherapy and combined therapy on BPH progression are discussed. Further promises, including the withdrawal of the alpha-blocker from the combined medical treatment and the potential clinical implications from the use of 5ARIs for prostate cancer chemoprevention in patients receiving 5ARIs for symptomatic BPH are highlighted. Current evidence shows that 5ARIs are effective in treating LUTS and preventing disease progression and represent a recommended option in treatment guidelines for men who have moderate to severe LUTS and enlarged prostates

Large-scale synchrony of gap dynamics and the distribution of understory tree species in maple-beech forests

Large-scale synchronous variations in community dynamics are well documented for a vast array of organisms, but are considerably less understood for forest trees. Because of temporal variations in canopy gap dynamics, forest communities—even old-growth ones—are never at equilibrium at the stand scale. This paucity of equilibrium may also be true at the regional scale. Our objectives were to determine (1) if nonequilibrium dynamics caused by temporal variations in the formation of canopy gaps are regionally synchronized, and (2) if spatiotemporal variations in canopy gap formation aVect the relative abundance of tree species in the understory. We examined these questions by analyzing variations in the suppression and release history of Acer saccharum Marsh. and Fagus grandifolia Ehrh. from 481 growth series of understory saplings taken from 34 mature stands. We observed that (1) the proportion of stems in release as a function of time exhibited a U-shaped pattern over the last 35 years, with the lowest levels occurring during 1975–1985, and that (2) the response to this in terms of species composition was that A. saccharum became more abundant at sites that had the highest proportion of stems in release during 1975–1985. We concluded that the understory dynamics, typically thought of as a stand-scale process, may be regionally synchronized

Intestinal lesions in dogs with acute hemorrhagic diarrhea syndrome associated with netF-positive Clostridium perfringens type A

Acute hemorrhagic diarrhea syndrome (AHDS), formerly named canine hemorrhagic gastroenteritis, is one of the most common causes of acute hemorrhagic diarrhea in dogs, and is characterized by acute onset of diarrhea, vomiting, and hemoconcentration. To date, histologic examinations have been limited to postmortem specimens of only a few dogs with AHDS. Thus, the aim of our study was to describe in detail the distribution, character, and grade of microscopic lesions, and to investigate the etiology of AHDS. Our study comprised 10 dogs with AHDS and 9 control dogs of various breeds, age, and sex. Endoscopic biopsies of the gastrointestinal tract were taken and examined histologically (H&E, Giemsa), immunohistochemically (Clostridium spp., parvovirus), and bacteriologically. The main findings were acute necrotizing and neutrophilic enterocolitis (9 of 10) with histologic detection of clostridia-like, gram-positive bacteria on the necrotic mucosal surface (9 of 10). Clostridium perfringens isolated from the duodenum was identified as type A (5 of 5) by multiplex PCR (5 of 5). In addition, each of the 5 genotyped isolates encoded the pore-forming toxin netF. Clostridium spp. (not C. perfringens) were cultured from duodenal biopsies in 2 of 9 control dogs. These findings suggest that the pore-forming netF toxin is responsible for the necrotizing lesions in the intestines of a significant proportion of dogs with AHDS. Given that the stomach was not involved in the process, the term acute hemorrhagic diarrhea syndrome seems more appropriate than the frequently used term hemorrhagic gastroenteritis

Ileosigmoid fistula and delayed ileal obstruction secondary to blunt abdominal trauma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Abdominal trauma is a source of significant mortality and morbidity. Bowel injury as a result of blunt abdominal trauma is usually evident within hours or days of the accident.</p> <p>Case presentation</p> <p>A 38-year-old Caucasian Greek man presented with a subtle and delayed small bowel obstruction caused by a post-traumatic ileosigmoid fistula and ileal stricture four months after a road traffic accident.</p> <p>Conclusion</p> <p>Delayed occurrence of post-traumatic small bowel stricture and ileosigmoid fistula is an uncommon surgical emergency. General surgeons as well as emergency physicians should bear this manifestation in mind should a patient return to the hospital several weeks or even years after blunt abdominal trauma with symptoms or signs of bowel obstruction.</p

A systematic review of the association between emotions and eating behaviour in normal and overweight adult populations

A systematic review was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search of four electronic databases (2004–2015) yielded 60,017 articles, of which 29 met inclusion criteria. Included studies performed poorly on data quality analysis in terms of randomisation and controlling for confounding factors. Participant’s body mass index scores range from 19.73 (standard deviation?=?1.54) to 28.4 (standard deviation?=?1.4) kg/m2. Where positive and negative affects were compared, food was more likely to be consumed in response to positive affect. With regard to discrete emotions; stress, depression and sadness consistently elicited eating behaviours that fall outside of nutritional recommendations (e.g. increased food intake or poor nutritional food choices). The role of moderators including individual differences in dietary restraint and emotional eating, as well as methodological considerations, such as means of eliciting and measuring emotions, may account for equivocality with regard to some emotion and eating associations. This article concludes with recommendations for future research and implications for practice

Cost-effectiveness of oral alitretinoin in patients with severe chronic hand eczema - a long-term analysis from a Swiss perspective

BACKGROUND: The impact on patients suffering from chronic hand eczema (CHE) is enormous, as no licensed systemic treatment option with proven efficacy for CHE is available. Alitretinoin is a novel agent which showed high clinical efficacy in patients with severe, refractory CHE. We assessed the cost-effectiveness of alitretinoin for CHE patient treatment from a Swiss third party payer perspective. A further objective of this study was to determine the burden of disease in Switzerland. METHODS: A long-term Markov cohort simulation model was used to estimate direct medical costs (euro) and clinical effectiveness (quality adjusted life years, QALYs) of treating severe CHE patients with alitretinoin. Comparison was against the standard treatment of supportive care (optimised emollient therapy). Information on response rates were derived from a randomized controlled clinical trial. Costs were considered from the perspective of the Swiss health system. Swiss epidemiological data was derived from official Swiss Statistic institutions. RESULTS: Annual costs of alitretinoin treatment accounted for 2'212 euro. After a time horizon of 22.4 years, average remaining long-term costs accounted for 42'208 euro or 38'795 euro in the alitretinoin and the standard treatment arm, respectively. Compared with the standard therapy, the addition of alitretinoin yielded an average gain of 0.230 QALYs at the end of the simulation. Accordingly, the incremental cost-effectiveness ratio resulted in 14'816 euro/QALY gained. These results were robust to changes in key model assumptions. CONCLUSION: The therapy for CHE patients is currently insufficient. In our long-term model we identified the treatment with alitretinoin as a cost-effective alternative for the therapy of CHE patients in Switzerland

FMRFamide-Like Peptides (FLPs) Enhance Voltage-Gated Calcium Currents to Elicit Muscle Contraction in the Human Parasite Schistosoma mansoni

Schistosomes are amongst the most important and neglected pathogens in the world, and schistosomiasis control relies almost exclusively on a single drug. The neuromuscular system of schistosomes is fertile ground for therapeutic intervention, yet the details of physiological events involved in neuromuscular function remain largely unknown. Short amidated neuropeptides, FMRFamide-like peptides (FLPs), are distributed abundantly throughout the nervous system of every flatworm examined and they produce potent myoexcitation. Our goal here was to determine the mechanism by which FLPs elicit contractions of schistosome muscle fibers. Contraction studies showed that the FLP Tyr-Ile-Arg-Phe-amide (YIRFamide) contracts the muscle fibers through a mechanism that requires Ca2+ influx through sarcolemmal voltage operated Ca2+ channels (VOCCs), as the contractions are inhibited by classical VOCC blockers nicardipine, verapamil and methoxyverapamil. Whole-cell patch-clamp experiments revealed that inward currents through VOCCs are significantly and reversibly enhanced by the application of 1 µM YIRFamide; the sustained inward currents were increased to 190% of controls and the peak currents were increased to 180%. In order to examine the biochemical link between the FLP receptor and the VOCCs, PKC inhibitors calphostin C, RO 31–8220 and chelerythrine were tested and all produced concentration dependent block of the contractions elicited by 1 µM YIRFamide. Taken together, the data show that FLPs elicit contractions by enhancing Ca2+ influx through VOCC currents using a PKC-dependent pathway

Molecular classification improves risk assessment in adult BCR-ABL1–negative B-ALL

Genomic classification has improved risk assignment of pediatric but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (NCT00002514) trial accrued 1229 BCR-ABL1-negative adolescent/adult B-ALL patients (aged 14-65 years). While 93% of patients achieved remission, 41% relapsed at a median of 13 months (range 28 days to 12 years). Five-year overall survival (5yr-OS) was 42% (95% CI, 39, 44). Transcriptome sequencing (n=238), gene expression profiling (n=210), cytogenetics (n=197) and fusion PCR (n=274) enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients in the outcome analysis, 29.5% of cases had favorable outcomes with 5yr-OS of 65-80% and were deemed standard-risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5yr-OS of 0-27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); and 20.3% had intermediate-risk genotypes with 5yr-OS of 33-45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like and TP53 mutations occurred in low-hypodiploid (54%) and BCL2/MYC-rearranged patients (33%), but were not independently associated with outcome. Of patients considered high-risk for relapse based on presenting age and WBC count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses which may translate into future therapeutic benefits

Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, ‘epigenetic’ drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.National Institutes of Health (U.S.) (Grant R37-HD04502