Graphene Quantum Dots Downregulate Multiple Multidrug-Resistant Genes via Interacting with Their C-Rich Promoters

Multidrug resistance (MDR) is the major factor in the failure of many forms of chemotherapy, mostly due to the increased efflux of anticancer drugs that mediated by ATP-binding cassette (ABC) transporters. Therefore, inhibiting ABC transporters is one of effective methods of overcoming MDR. However, high enrichment of ABC transporters in cells and their broad substrate spectra made to circumvent MDR are almost insurmountable by a single specific ABC transporter inhibitor. Here, this study demonstrates that graphene quantum dots (GQDs) could downregulate the expressions of P-glycoprotein, multidrug resistance protein MRP1, and breast cancer resistance protein genes via interacting with C-rich regions of their promoters. This is the first example that a single reagent could suppress multiple MDR genes, suggesting that it will be possible to target multiple ABC transporters simultaneously with a single reagent. The inhibitory ability of the GQDs to these drug-resistant genes is validated further by reversing the doxorubicin resistance of MCF-7/ADR cells. Notably, GQDs have superb chemical and physical properties, unique structure, low toxicity, and high biocompatibility; hence, their capability of inhibiting multiple drug-resistant genes holds great potential in cancer therapy.

Graphene quantum dots (GQDs) downregulate multiple multidrug-resistant (MDR) genes via interacting with C-rich regions of their promoters. The inhibitory ability of the GQDs to MDR genes is validated by reversing doxorubicin resistance of MCF-7/ADR cells.

http://ift.tt/2uzBXyt

Intravitreal aflibercept for choroidal neovascularization associated with chorioretinitis: a pilot study

http://ift.tt/2va1WOi

Optimising the surgical outcome in a case of post-traumatic cataract using ultrasound biomicroscopy

A 12-year-old boy was brought with the chief complaint of diminution of vision in his left eye for the past 1 month. History revealed a blunt trauma to his left eye with a wooden stick 6âweeks ago.Visual acuity was 20/20 and hand movement close to face in right and left eye, respectively, without any relative afferent pupillarydefect. Slit-lamp examination showed a total cataractous lens with signs suggestive of suspected posterior capsular (PC) defect. The PC defect was screened initially using B-scan ultrasound of the posterior segment, followed by confirmation of the same using ultrasound biomicroscopy. Left eye lens aspiration along with limited anterior vitrectomy followed by placement of multipiece intraocular lens in the sulcus was performed. Best-corrected visual acuity at 6 months of follow-up was 20/20.

http://ift.tt/2uzPYMM

Giant oesophageal gastrointestinal stromal tumour presenting with dyspnoea and clubbed fingers

Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms of the gastrointestinal tract originating from the interstitial cells of Cajal. Giant oesophageal GISTs are rare since the oesophagus is rarely the primary site of GISTs, and they are usually diagnosed early due to complaints such as dysphagia. We present the case of a giant oesophageal GIST presenting with prominent clubbing. The case underlined the diagnostic importance of clubbing and the careful consideration of chemotherapy. Although clubbed fingers associated with GISTs are rare, our experience demonstrates the importance of physicians' recognition of clubbing as a paraneoplastic phenomenon for early diagnosis of malignancies since patients seldom notice their own clubbing by themselves. Chemotherapy using imatinib, an Bcr-Abl kinase inhibitor, is the standard option for unresectable giant GISTs. However, careful consideration must be made of the risk of complications associated with rapid mass reduction due to imatinib such as bleeding, oesophageal perforation and mediastinitis.

http://ift.tt/2vKTulV

Type I talon cusp on mandibular incisor

Description

Talon cusp is a comparably rare developmental dental anomaly assumed to arise because of evagination on the surface of a tooth crown during tooth calcification stage. Talon cusp also called as Eagle's is a well-defined extra cusp like structure located on lingual or palatal surface of deciduous or permanent anterior teeth. Its occurrence may be either unilateral or bilateral, single or multiple teeth in males or females. Prevalence of talon's cusp is reported to be between 0.06% to 7.7%. Eagle's talon is most commonly seen in maxillary lateral incisor >maxillary central incisor> maxillary canine> mandibular incisor.1

Mandibular talon cusp is a rare entity to occur. Mandibular talon cusps are more prevalent in men than women. Occurrence in talon cusp is more common in permanent dentition. Most of the mandibular talon cusp shows unilateral presentation. Talon cusp associated with permanent central incisor and primary lateral incisor...

http://ift.tt/2uzucJ0

Between fire and ice: refractory hypothermia and warmth-induced pain in inherited erythromelalgia

Inherited erythromelalgia (IEM) is a well-described pain disorder caused by mutations of sodium channel Na_v1.7, a peripheral channel expressed within dorsal root ganglion and the sympathetic ganglion neurons. Clinically, IEM is characterised by paroxysmal attacks of severe pain, usually in the distal extremities, triggered by warmth or exercise. Pain is not adequately treated by existing pharmacological agents. Individuals with IEM classically cool their limbs for relief, in some cases resulting in tissue injury. We describe a patient from a family with IEM due to the L858F mutation of Na_v1.7 who presented with refractory hypothermia due to overcooling. This presentation of refractory hypothermia necessitating warming strategies, complicated by severe warmth-induced pain, posed a substantial therapeutic challenge. We report our experience in overcoming hypothermia lasting 3 weeks in a child with IEM, discuss possible pathophysiological mechanisms underlying this unusual complication and suggest potential therapeutic interventions.

http://ift.tt/2vKB7h1

Depression and anxiety in multiple system atrophy

Background

It has been noticed that the patients with multiple system atrophy (MSA) can accompany with depression and anxiety. This study aimed to establish the incidence and determinants of depression and anxiety symptoms in Chinese MSA patients.

Methods

A total of 237 MSA patients were enrolled in the study. Neuropsychological assessment was performed using Hamilton Depression Rating Scale-24 items and Hamilton Anxiety Rating Scale.

Results

We found that 62.0% and 71.7% patients had at least mild depression and anxiety symptoms, respectively. The severity of depression of MSA patients was associated with lower educational years (P=.024), longer disease duration (P<.001), and disease severity (P<.001). The severity of anxiety was associated with increased disease duration (P<.001), disease severity (P=.013), and orthostatic hypotension (P=.005). Binary logistic regression showed the determinants of depression and anxiety were female gender, longer disease duration, and disease severity.

Conclusion

Depression and anxiety symptoms are common in patients with MSA. Neurologists should pay attention to depression and anxiety in patients with MSA, especially in female patients and those with longer disease duration and severe disease condition.

http://ift.tt/2uEgSkU

Dynamic value assessments in oncology supported by the PACE Continuous Innovation Indicators

Future Oncology, Ahead of Print.


http://ift.tt/2h4EMCQ

Guideline recommendations and antimicrobial resistance: the need for a change

Objectives

Antimicrobial resistance has become a global burden for which inappropriate antimicrobial use is an important contributing factor. Any decisions on the selection of antibiotics use should consider their effects on antimicrobial resistance. The objective of this study was to assess the extent to which antibiotic prescribing guidelines have considered resistance patterns when making recommendations for five highly prevalent infectious syndromes.

Design

We used Medline searches complemented with extensive use of Web engine to identify guidelines on empirical treatment of community-acquired pneumonia, urinary tract infections, acute otitis media, rhinosinusitis and pharyngitis. We collected data on microbiology and resistance patterns and identified discrete pattern categories. We assessed the extent to which recommendations considered resistance, in addition to efficacy and safety, when recommending antibiotics.

Results

We identified 135 guidelines, which reported a total of 251 recommendations. Most (103/135, 79%) were from developed countries. Community-acquired pneumonia was the syndrome mostly represented (51, 39%). In only 16 (6.4%) recommendations, selection of empirical antibiotic was discussed in relation to resistance and specific microbiological data. In a further 69 (27.5%) recommendations, references were made in relation to resistance, but the attempt was inconsistent. Across syndromes, 12 patterns of resistance with implications on recommendations were observed. 50% to 75% of recommendations did not attempt to set recommendation in the context of these patterns.

Conclusion

There is consistent evidence that guidelines on empirical antibiotic use did not routinely consider resistance in their recommendations. Decision-makers should analyse and report the extent of local resistance patterns to allow better decision-making.

http://ift.tt/2vKWkr3

Associations of anthropometry since birth with sagittal posture at age 7 in a prospective birth cohort: the Generation XXI Study

Objectives

Adult sagittal posture is established during childhood and adolescence. A flattened or hypercurved spine is associated with poorer musculoskeletal health in adulthood. Although anthropometry from birth onwards is expected to be a key influence on sagittal posture design, this has never been assessed during childhood. Our aim was to estimate the association between body size throughout childhood with sagittal postural patterns at age 7.

Design

Prospective cohort study.

Setting and participants

A subsample of 1029 girls and 1101 boys taking part in the 7-year-old follow-up of the birth cohort Generation XXI (Porto, Portugal) was included. We assessed the associations between anthropometric measurements (weight, height and body mass index) at birth, 4 and 7 years of age and postural patterns at age 7. Postural patterns were defined using latent profile analysis, a probabilistic model-based technique which allows for simultaneously including anthropometrics as predictors of latent profiles by means of logistic regression.

Results

Postural patterns identified were sway, flat and "neutral to hyperlordotic"in girls, and "sway to neutral", flat and hyperlordotic in boys; with flat and hyperlordotic postures representing a straightened and a rounded spine, respectively. In both girls and boys, higher weight was associated with lower odds of a flat pattern compared with a sway/"sway to neutral"pattern, with stronger associations at older ages: for example, ORs were 0.68 (95% CI 0.53 to 0.88) per SD increase in birth weight and 0.36 (95% CI 0.19 to 0.68) per SD increase in weight at age 7 in girls, with similar findings in boys. Boys with higher ponderal index at birth were more frequently assigned to the hyperlordotic pattern (OR=1.44 per SD; p=0.043).

Conclusions

Our findings support a prospective sculpting role of body size and therefore of load on musculoskeletal spinopelvic structures, with stronger associations as children get older.

http://ift.tt/2uzjPVB

Profiles of children's social-emotional health at school entry and associated income, gender and language inequalities: a cross-sectional population-based study in British Columbia, Canada

Objectives

Early identification of distinct patterns of child social–emotional strengths and vulnerabilities has the potential to improve our understanding of child mental health and well-being; however, few studies have explored natural groupings of indicators of child vulnerability and strengths at a population level. The purpose of this study was to examine heterogeneity in the patterns of young children's social and emotional health and investigate the extent to which sociodemographic characteristics were associated.

Design

Cross-sectional study based on a population-level cohort.

Setting

All kindergarten children attending public schools between 2004 and 2007 in British Columbia (BC), Canada.

Participants

35 818 kindergarten children (age of 5 years) with available linked data from the Early Development Instrument (EDI), BC Ministry of Health and BC Ministry of Education.

Outcome measure

We used latent profile analysis (LPA) to identify distinct profiles of social–emotional health according to children's mean scores across eight social–emotional subscales on the EDI, a teacher-rated measure of children's early development. Subscales measured children's overall social competence, responsibility and respect, approaches to learning, readiness to explore, prosocial behaviour, anxiety, aggression and hyperactivity.

Results

Six social–emotional profiles were identified: (1) overall high social–emotional functioning, (2) inhibited-adaptive (3) uninhibited-adaptive, (4) inhibited-disengaged, (5) uninhibited-aggressive/hyperactive and (6) overall low social–emotional functioning. Boys, children with English as a second language (ESL) status and children with lower household income had higher odds of membership to the lower social–emotional functioning groups; however, this association was less negative among boys with ESL status.

Conclusions

Over 40% of children exhibited some vulnerability in early social–emotional health, and profiles were associated with sociodemographic factors. Approximately 9% of children exhibited multiple co-occurring vulnerabilities. This study adds to our understanding of population-level distributions of children's early social–emotional health and identifies profiles of strengths and vulnerabilities that can inform future intervention efforts.

http://ift.tt/2vKJFEB

Respiratory syncytial virus: a systematic scientometric analysis of the global publication output and the gender distribution of publishing authors

Objective

Worldwide, the respiratory syncytial virus (RSV) represents the predominant viral agent causing bronchiolitis and pneumonia in children. To conduct research and tackle existing healthcare disparities, RSV-related research activities around the globe need to be described. Hence, we assessed the associated scientific output (represented by research articles) by geographical, chronological and socioeconomic criteria and analysed the authors publishing in the field by gender. Also, the 15 most cited articles and the most prolific journals were identified for RSV research.

Design

Retrospective, descriptive study.

Setting

The NewQIS (New Quality and Quantity Indices in Science) platform was employed to identify RSV-related articles published in the Web of Science until 2013. We performed a numerical analysis of all articles, and examined citation-based aspects (eg, citation rates); results were visualised by density equalising mapping tools.

Results

We identified 4600 RSV-related articles. The USA led the field; US-American authors published 2139 articles (46.5%% of all identified articles), which have been cited 83 000 times. When output was related to socioeconomic benchmarks such as gross domestic product or Research and Development expenditures, Guinea-Bissau, The Gambia and Chile were ranked in leading positions. A total of 614 articles on RSV (13.34% of all articles) were attributed to scientific collaborations. These were primarily established between high-income countries. The gender analysis indicated that male scientists dominated in all countries except Brazil.

Conclusions

The majority of RSV-related research articles originated from high-income countries whereas developing nations showed only minimal publication productivity and were barely part of any collaborative networks. Hence, research capacity in these nations should be increased in order to assist in addressing inequities in resource allocation and the clinical burden of RSV in these countries.

http://ift.tt/2uyUYRu

Herbal medications for surgical patients: a systematic review protocol

Introduction

Postoperative nausea and vomiting (PONV) affect approximately 80% of surgical patients and is associated with increased length of hospital stay and systemic costs. Preoperative and postoperative pain, anxiety and depression are also commonly reported. Recent evidence regarding their safety and effectiveness has not been synthesised. The aim of this systematic review is to evaluate the efficacy and safety of herbal medications for the treatment and prevention of anxiety, depression, pain and PONV in patients undergoing laparoscopic, obstetrical/gynaecological and cardiovascular surgical procedures.

Methods and analysis

The following electronic databases will be searched up to 1 October 2016 without language or publication status restrictions: CENTRAL, MEDLINE, EMBASE, CINAHL, Web of Science and LILACS. Randomised clinical trials enrolling adult surgical patients undergoing laparoscopic, obstetrical/gynaecological and cardiovascular surgeries and managed with herbal medication versus a control group (placebo, no intervention or active control) prophylactically or therapeutically will be considered eligible. Outcomes of interest will include the following: anxiety, depression, pain, nausea and vomiting. A team of reviewers will complete title and abstract screening and full-text screening for identified hits independently and in duplicate. Data extraction, risk of bias assessments and evaluation of the overall quality of evidence for each relevant outcome reported will be conducted independently and in duplicate using the Grading of Recommendations Assessment Development and Evaluation classification system. Dichotomous data will be summarised as risk ratios; continuous data will be summarised as standard average differences with 95% CIs.

Ethics and dissemination

This is one of the first efforts to systematically summarise existing evidence evaluating the use of herbal medications in laparoscopic, obstetrical/gynaecological and cardiovascular surgical patients. The findings of this review will be disseminated through peer-reviewed publications and conference presentations.

Systematic review registration

PROSPERO CRD42016042838.

http://ift.tt/2vLmmdB

Medication incidents in primary care medicine: a prospective study in the Swiss Sentinel Surveillance Network (Sentinella)

Objectives

To describe the type, frequency, seasonal and regional distribution of medication incidents in primary care in Switzerland and to elucidate possible risk factors for medication incidents.

Design

Prospective surveillance study.

Setting

Swiss primary healthcare, Swiss Sentinel Surveillance Network.

Participants

Patients with drug treatment who experienced any erroneous event related to the medication process and interfering with normal treatment course, as judged by their physician. The 180 physicians in the study were general practitioners or paediatricians participating in the Swiss Federal Sentinel reporting system in 2015.

Outcomes

Primary: medication incidents; secondary: potential risk factors like age, gender, polymedication, morbidity, care-dependency, previous hospitalisation.

Results

The mean rates of detected medication incidents were 2.07 per general practitioner per year (46.5 per 1 00 000 contacts) and 0.15 per paediatrician per year (2.8 per 1 00 000 contacts), respectively. The following factors were associated with medication incidents (OR, 95% CI): higher age 1.004 per year (1.001; 1.006), care by community nurse 1.458 (1.025; 2.073) and care by an institution 1.802 (1.399; 2.323), chronic conditions 1.052 (1.029; 1.075) per condition, medications 1.052 (1.030; 1.074) per medication, as well as Thurgau Morbidity Index for stage 4: 1.292 (1.004; 1.662), stage 5: 1.420 (1.078; 1.868) and stage 6: 1.680 (1.178; 2.396), respectively. Most cases were linked to an incorrect dosage for a given patient, while prescription of an erroneous medication was the second most common error.

Conclusions

Medication incidents are common in adult primary care, whereas they rarely occur in paediatrics. Older and multimorbid patients are at a particularly high risk for medication incidents. Reasons for medication incidents are diverse but often seem to be linked to communication problems.

http://ift.tt/2uzcLYR

Ability to join the workforce and work productivity among drug users under methadone maintenance treatment in a mountainous area of Northern Vietnam: a cross-sectional study

Objectives

A major measure of treatment success for drug users undergoing rehabilitation is the ability to enter the workforce and generate income. This study examines the absenteeism and productivity among people who inject drugs (PWID) enrolled in methadone maintenance treatment (MMT) in Northern Vietnam.

Setting

We conducted a cross-sectional study in two clinics in Tuyen Quang province.

Participants

A total of 241 patients enrolled in MMT.

Primary and secondary outcome measures

Patients' work productivity was measured using the WPAI-GH instrument (Work Productivity and Activity Impairment Questionnaire: General Health V2.0). We also collected additional characteristics about participants' employment history, such as proficient jobs, whether they actively found a new job and be accepted by employers.

Results

Most of the participants (>90%) were employed at the time of the study. Rates of absenteeism (missed work), presenteeism (impairment while working) and overall loss of productivity were 15.8%, 5.6% and 11.2%, respectively, as measured by the WPAI-GH questionnaire. The most proficient job was 'freelancer' (17.5%), followed by 'blue-collar worker' (10.6%) and 'farmer' (10.2%). Only 26.8% of patients reported that they actively sought jobs in the past. About half of them had been refused by employers because of their drug use history and/or HIV status. We found no statistically significant difference between patients enrolled in MMT for <1 year and those who had been enrolled >1 year. Factors associated with higher work productivity included not endorsing problems in mobility, self-care or pain; being HIV-negative and having greater MMT treatment adherence.

Conclusion

Our study highlights the high employment rate and work productivity among PWID in MMT programmes in remote areas of Northern Vietnam. The results can help to improve the quality and structure of MMT programmes across Vietnam and in other countries.

http://ift.tt/2vL0AXk

Common attributes in retired professional cricketers that may enhance or hinder quality of life after retirement: a qualitative study

Objectives

Retired professional cricketers shared unique experiences and may possess specific psychological attributes with potential to influence quality of life (QOL). Additionally, pain and osteoarthritis can be common in retired athletes which may negatively impact QOL. However, QOL in retired athletes is poorly understood. This study explores the following questions from the personal perspective of retired cricketers: How do retired cricketers perceive and experience musculoskeletal pain and function in daily life? Are there any psychological attributes that might enhance or hinder retired cricketers' QOL?

Design

A qualitative study using semistructured interviews, which were subject to inductive, thematic analysis. A data-driven, iterative approach to data coding was employed.

Setting

All participants had lived and played professional cricket in the UK and were living in the UK or abroad at the time of interview.

Participants

Eighteen male participants, aged a mean 57±11 (range 34–77) years had played professional cricket for a mean 12±7 seasons and had been retired from professional cricket on average 23±9 years.

Results

Fifteen participants reported pain or joint difficulties and all but one was satisfied with their QOL. Most retired cricketers reflected on experiences during their cricket career that may be associated with the psychological attributes that these individuals shared, including resilience and a positive attitude. Additional attributes included a high sense of body awareness, an ability to self-manage pain and adapt lifestyle choices to accommodate physical limitations. Participants felt fortunate and proud to have played professional cricket, which may have further contributed to the high QOL in this group of retired cricketers.

Conclusions

Most retired cricketers in this study were living with pain or joint difficulties. Despite this, all but one was satisfied or very satisfied with their QOL. This may be partly explained by the positive psychological attributes that these retired cricketers shared.

http://ift.tt/2uzflhL

Recruitment and retention in a 10-month social network-based intervention promoting diabetes self-management in socioeconomically deprived patients: a qualitative process evaluation

Objectives

Socioeconomically deprived patients with type 2 diabetes often face challenges with self-management, resulting in more diabetes-related complications. However, these groups are often under-represented in self-management interventions. Evidence on effective recruitment and retention strategies is growing, but lacking for intensive self-management interventions. This study aims to explore recruitment, retention and effective intervention strategies in a 10-month group-based intervention among Dutch, Moroccan, Turkish and Surinamese patients from socioeconomically deprived neighbourhoods.

Methods

Participants were recruited through general practitioners (GPs) and participated in a 10-month social network-based intervention (10 groups, n=69): Powerful Together with Diabetes. This intervention also targeted the significant others of participants and aimed to increase social support for self-management and to decrease social influences hindering self-management. A qualitative process evaluation was conducted. Retention was measured using log books kept by group leaders. Further, we conducted 17 in-depth interviews with participants (multiethnic sample) and 18 with group leaders. Interviews were transcribed, coded and analysed using framework analyses.

Results

The GP's letter and reminder calls, an informational meeting and the intervention's informal nature facilitated recruitment. During the first months, positive group atmosphere, the intervention's perceived usefulness, opportunities to socialise and a reduction in practical barriers facilitated retention. After the first months, conflicting responsibilities and changes in the intervention's nature and planning hindered retention. Calls from group leaders and the prospect of a diploma helped participants overcome these barriers.

Conclusion

To promote retention in lengthy self-management interventions, it seems important that patients feel they are going on an outing to a social gathering that is enjoyable, recreational, useful and easy to attend. However, rewards and intensive personal recruitment and retention strategies remained necessary throughout the entire intervention period.

Trial registration number

Dutch Trial Register NTR1886; Results.

http://ift.tt/2vL9q7M

Respiratory muscle endurance training reduces the O2 cost of cycling and perceived exertion in obese adolescents.

In obesity the increased O₂ cost of breathing negatively affects the O₂ cost of exercise and exercise tolerance. The purpose of the study was to determine whether, in obese adolescents, the addition of respiratory muscle endurance training (RMET) (isocapnic hyperpnea) to a standard body mass reduction program decreases the O₂ cost of exercise and perceived exertion and increases exercise tolerance. 9 male obese adolescents (16.0±1.4 years [x±SD], body mass 114.4±22.3 kg) underwent 3 weeks of RMET (5 days/week); 8 age-and sex- matched obese adolescents underwent the standard body mass reduction program (CTRL). Before and after interventions patients performed on a cycle ergometer: incremental exercise; 12-min constant work-rate exercises (CWR) at 65% and 120% of gas exchange threshold (GET) determined before the intervention. Breath-by-breath pulmonary ventilation (V'E) and O₂ uptake (V'O₂), heart rate (HR) and ratings of perceived exertion for dyspnea/respiratory discomfort (RPE_R) and leg effort (RPE_L) were determined. Body mass decreased (by ~3.0 kg) after both RMET and CTRL (P=0.001; GLM for repeated measures). Peak O₂ and peak work rate were not affected by both interventions. During CWR<GET no changes were observed after both interventions. During CWR>GET the O₂ cost of cycling (P=0.014), the slope of V'O₂ vs. time (P=0.012), RPE_R (P=0.012), RPE_L (P=0.016) and HR (P=0.001) decreased following RMET but not following CTRL, whereas V'E did not change. In obese adolescents RMET, superimposed on a standard body mass reduction program, lowered the O₂ cost of cycling and perceived exertion during constant heavy-intensity exercise.

http://ift.tt/2eOZ6rn

Chronic Hindbrain Administration of Oxytocin is Sufficient to Elicit Weight Loss in Diet-Induced Obese Rats

Oxytocin (OT) administration elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates and humans by both reducing energy intake and increasing energy expenditure (EE). Although the neurocircuitry underlying these effects remains uncertain, OT neurons in the paraventricular nucleus are positioned to control both energy intake and sympathetic nervous system outflow to interscapular brown adipose tissue (IBAT) through projections to both the hindbrain nucleus of the solitary tract and spinal cord. The current work was undertaken to examine whether central OT increases BAT thermogenesis, whether this effect involves hindbrain OT receptors (OTRs), and whether such effects are associated with sustained weight loss following chronic administration. To assess OT-elicited changes in BAT thermogenesis, we measured the effects of intracerebroventricular administration of OT on IBAT temperature (TIBAT) in both rats and mice. Because fourth ventricular (4V) infusion targets hindbrain OTRs, whereas third ventricular (3V) administration targets both forebrain and hindbrain OTRs, we compared responses to OT following chronic 3V infusion in DIO rats and mice with chronic 4V infusion in DIO rats. We report that chronic 4V infusion of OT into two distinct rat models recapitulates the effects of 3V OT to ameliorate diet-induced obesity by reducing fat mass. While reduced food intake contributes to this effect, our finding that 4V OT also increases BAT thermogenesis suggests that increased EE may contribute as well. These findings collectively support the hypothesis that in DIO rats, OT action in the hindbrain evokes sustained weight loss by both reducing energy intake and increasing BAT thermogenesis.

http://ift.tt/2h4gtVS

Spot Urine Protein Measurements in Normotensive Pregnancies, Pregnancies with Isolated Proteinuria and Preeclampsia

We performed a prospective, longitudinal study of pregnant women presenting to their first obstetrics visits to characterize the changes in spot urine protein-to-creatinine (UPCR) and albumin-to-creatinine ratios (UACR) in normotensive pregnancies, as well as identify clinical characteristics associated with isolated proteinuria and preeclampsia. We measured spot urinary albumin, protein, and creatinine at the first prenatal visit, end of the second trimester, and at delivery. In normotensive pregnancy (n=142), we found that from the beginning of pregnancy to delivery, UACR increased by a median (interquartile range (IQR)) of 14.7 mg/g Cr (3.74-51.8) and UPCR by 60 mg/g Cr (30-130) (p<0.001 for both changes). Isolated proteinuria (defined as UPCR > 300 mg/g Cr in the absence of hypertension) was identified in 19 /142 (13.4%) normotensive pregnancies. Increases in systolic and diastolic blood pressure from early pregnancy to delivery, and increases in UACR from early to mid-pregnancy were associated with isolated proteinuria at delivery. Twelve women developed preeclampsia. Nulliparity, early and mid-pregnancy diastolic blood pressures were strongly associated with the development of preeclampsia, but early changes in UACR were not. In conclusion, women who develop isolated proteinuria at delivery have a larger increase in blood pressure than women without proteinuria and have a 'microalbuminuric' phase earlier in gestation, unlike women who develop preeclampsia. These findings suggest a different mechanism of urine protein excretion in women with isolated proteinuria as compared to women with preeclampsia, where proteinuria has a more abrupt onset.

http://ift.tt/2ePlWPj

Using pharmacogenetics to prevent severe adverse reactions to capecitabine

Pharmacogenomics, Ahead of Print.


http://ift.tt/2h3Vx14

Prospect for immune checkpoint blockade: dynamic and comprehensive monitorings pave the way

Pharmacogenomics, Ahead of Print.


http://ift.tt/2eP8IlS

Low-dose decitabine enhances chidamide-induced apoptosis in adult acute lymphoblast leukemia, especially for p16-deleted patients through DNA damage

Pharmacogenomics, Ahead of Print.


http://ift.tt/2h4p8HF

Use of exome sequencing to determine the full profile of genetic variants in the fluoropyrimidine pathway in colorectal cancer patients affected by severe toxicity

Pharmacogenomics, Ahead of Print.


http://ift.tt/2eP8DP6

Association of CYP2C19*2 polymorphism with clopidogrel response and 1-year major adverse cardiovascular events in a multiethnic population with drug-eluting stents

Pharmacogenomics, Ahead of Print.


http://ift.tt/2h3VkLk

Prior opioid exposure influences parents’ sharing of their children's CYP2D6 research results

Pharmacogenomics, Ahead of Print.


http://ift.tt/2ePzqL4

Institutional profile of pharmacogenetics within University of Michigan College of Pharmacy

Pharmacogenomics, Ahead of Print.


http://ift.tt/2eP8xac

Anaplastic lymphoma kinase-rearrangements in non-small-cell lung cancer: novel applications in diagnostics and treatment

Pharmacogenomics, Ahead of Print.


http://ift.tt/2h4lMUX

CYP2C19-guided antiplatelet therapy: a cost–effectiveness analysis of 30-day and 1-year outcomes following percutaneous coronary intervention

Pharmacogenomics, Ahead of Print.


http://ift.tt/2eP8jzS

Pharmacogenomic considerations in the treatment of muscle-invasive bladder cancer

Pharmacogenomics, Ahead of Print.


http://ift.tt/2h4740i

Early health technology assessments in pharmacogenomics: a case example in cardiovascular drugs

Pharmacogenomics, Ahead of Print.


http://ift.tt/2ePquoQ

Advanced cancer pain: the search for genetic factors correlated with interindividual variability in opioid requirement

Pharmacogenomics, Ahead of Print.


http://ift.tt/2h4lsFJ

The effect of rs5758550 on CYP2D6*2 phenotype and formation of endoxifen in breast cancer patients using tamoxifen

Pharmacogenomics, Ahead of Print.


http://ift.tt/2ePkyw9

Simultaneous occurrence of fibroblastic osteosarcoma and hypertrophic osteopathy (Marie’s disease) in a German shepherd dog

Abstract

Osteosarcoma, as a progressive tumor, accounts for approximately 80% of malignant bone tumors in dogs. Since it is a highly metastatic tumor, it develops pulmonary metastasis in the majority of cases. The considerable site preference of the tumor in dogs and the possibility of hypertrophic osteopathy in a number of cases must be considered. Clinical examination of a 12-year female German shepherd dog with lameness, weakness, and cachexia revealed an abnormal thickening in the left forelimb and a severe swelling in the left proximal humerus. Radiographic examinations showed severe swelling in the arm's soft tissue, proximal humerus osteolysis, and irregular and palisade periosteal reaction in most bones of thoracic and pelvic limbs as well as soft-tissue masses in the thoracic cavity. In postmortem examination, a semi-hard destructive mass extended from the central cavity of humerus to the surrounding soft tissue, pulmonary and splenic metastases were observed. According to microscopic features, the tumoric bone lesion was diagnosed as fibroblastic osteosarcoma. Hypertrophic osteopathy (Marie's disease) was also diagnosed due to gross characteristics of the forearm and palm along with radiographic findings of the forearm and tibia. This is the first report of simultaneous occurrence of fibroblastic osteosarcoma and Marie's disease in Iranian dogs.

http://ift.tt/2v0W5Kv

Clinical Significance of Four Molecular Subtypes of Gastric Cancer Identified by The Cancer Genome Atlas Project

Purpose: The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein–Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer.

Experimental Design: Gene expression data from a TCGA cohort (n = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (n = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed.

Results: EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (P = 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor [HR, 1.5; 95% confidence interval (CI), 1.2–1.9; P = 0.001]. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16–0.94; P = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36–1.89; P = 0.65).

Conclusions: Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted. Clin Cancer Res; 23(15); 1–9. ©2017 AACR.

http://ift.tt/2uz05RL

Defining Standards in Experimental Microsurgical Training: Recommendations of the European Society for Surgical Research (ESSR) and the International Society for Experimental Microsurgery (ISEM)

Background: Expectations towards surgeons in modern surgical practice are extremely high with minimal complication rates and maximal patient safety as paramount objectives. Both of these aims are highly dependent on individual technical skills that require sustained, focused, and efficient training outside the clinical environment. At the same time, there is an increasing moral and ethical pressure to reduce the use of animals in research and training, which has fundamentally changed the practice of microsurgical training and research. Various animal models were introduced and widely used during the mid-20th century, the pioneering era of experimental microsurgery. Since then, high numbers of ex vivo training concepts and quality control measures have been proposed, all aiming to reduce the number of animals without compromising quality and outcome of training. Summary: Numerous microsurgical training courses are available worldwide, but there is no general agreement concerning the standardization of microsurgical training. The major aim of this literature review and recommendation is to give an overview of various aspects of microsurgical training. We introduce here the findings of a previous survey-based analysis of microsurgical courses within our network. Basic principles behind microsurgical training (3Rs, good laboratory practice, 3Cs), considerations around various microsurgical training models, as well as several skill assessment tools are discussed. Recommendations are formulated following intense discussions within the European Society for Surgical Research (ESSR) and the International Society for Experimental Microsurgery (ISEM), based on scientific literature as well as on several decades of experience in the field of experimental (micro)surgery and preclinical research, represented by the contributing authors. Key Messages: Although ex vivo models are crucial for the replacement and reduction of live animal use, living animals are still indispensable at every level of training which aims at more than just a basic introduction to microsurgical techniques. Modern, competency-based microsurgical training is multi-level, implementing different objective assessment tools as outcome measures. A clear consensus on fundamental principles of microsurgical training and more active international collaboration for the sake of standardization are urgently needed.
Eur Surg Res 2017;58:246–262

http://ift.tt/2u0MGhI

The (Continued) Challenges of Out-of-Hospital Rapid Sequence Intubation

SEE RELATED ARTICLE, P. ■■■.

http://ift.tt/2tLyNJ5

What Is the Utility of End-Tidal Capnography for Procedural Sedation and Analgesia in the Emergency Department?

The search parameters identified 3,311 total studies, of which 3 studies (n=1,272 participants) met the inclusion criteria for this review. The participants in these studies included both pediatric and adult patients. The studies were all performed at single-center academic EDs in the United States and Canada. All studies excluded critically ill patients and one study excluded pediatric patients receiving supplemental oxygen at baseline. The definitions of the primary outcome of oxygen desaturation varied by study, including less than 93% for greater than 15 seconds (n=132),2 less than 90% for greater than 30 seconds (n=986),3 and less than 95% for any duration (n=154).

http://ift.tt/2u0rcBB

Provider and Practice Factors Associated With Emergency Physicians’ Being Named in a Malpractice Claim

We examine the association between emergency physician characteristics and practice factors with the risk of being named in a malpractice claim.

http://ift.tt/2tLmIUs

Bolus-Dose Vasopressors in the Emergency Department: First, Do No Harm; Second, More Evidence Is Needed

SEE RELATED ARTICLE, P. ■■■.

http://ift.tt/2u0Ltam

“Futile Care”—An Emergency Medicine Approach: Ethical and Legal Considerations

Futility often serves as a proposed reason for withholding or withdrawing medical treatment, even in the face of patient and family requests. Although there is substantial literature describing the meaning and use of futility, little of it is specific to emergency medicine. Furthermore, the literature does not provide a widely accepted definition of futility, and thus is difficult if not impossible to apply. Some argue that even a clear concept of futility would be inappropriate to use. This article will review the origins of and meanings suggested for futility, specific challenges such cases create in the emergency department (ED), and the relevant legal background.

http://ift.tt/2tKMLuO

Managing Patients With Transient Ischemic Attack

Approximately 300,000 patients are treated annually in US emergency departments (EDs) for cerebral transient ischemic attack.1 Their management is variable.1,2 Created in 1975, the historical definition3—focal neurologic symptoms with a vascular cause, lasting less than 24 hours—no longer makes sense in a world of magnetic resonance imaging (MRI), fibrinolytic treatment for ischemic stroke, and a better understanding of the ultraearly stroke risk after transient ischemic attack. The new definition of transient ischemic attack is "a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia without acute infarction."4

http://ift.tt/2u0SS9G

Does the Use of Video Laryngoscopy Improve Intubation Outcomes?

The authors included 64 randomized controlled trials reporting outcomes for 7,044 subjects. Only 3 of these studies included patients requiring emergency airway management: one based in an ICU,5 one in a trauma center,6 and one in an out-of-hospital setting.7 The small number of emergency intubations identified precluded subgroup analysis of this population. The remaining 61 studies took place in an operating room setting and comprised elective surgical participants. The most commonly studied video laryngoscopy devices included GlideScope (Verathon, Bothwell, WA) (29 studies), Pentax AWS (Ambu Inc, Ballerup, Denmark) (20 studies), C-MAC (Karl Storz GmbH & Co KG, Tuttlingen, Germany) (9 studies), and McGrath (Aircraft Medical Limited, Edinburgh, UK) (8 studies).

http://ift.tt/2tLhqrN

Unilateral Headache Status after Intra-Aortic Balloon Pump Placement

Introduction. Intra-aortic balloon pump (IABP) counterpulsation is a catheter-based treatment for coronary artery disease and decompensated heart failure to increase coronary blood flow and improve cardiac output. IABP is generally well tolerated, and complications are usually related to peripheral vasculature or red blood cell and platelet consumption. The usual insertion site via femoral artery renders the patient bedbound. Recently, axillary artery has been used in patients with atherosclerotic peripheral vascular disease and documented small arteries or in those awaiting transplant to ensure ambulation and prevent deconditioning. Case Report. We present a patient with ischemic cardiomyopathy and severe left ventricular dysfunction, awaiting Orthotropic Heart Transplant. His worsening intractable angina and dyspnea necessitated IABP placement via left axillary artery, significantly improving his condition. He subsequently experienced migraine-type persistent unilateral headache refractory to standard pain management. Multiple strategies were utilized to treat his pain, but the patient insisted that his pain commenced after IABP placement. Ultimately, the removal of the pump led to complete resolution with no recurrence. Conclusion. The authors hypothesize that the unilaterally directed blood flow and direct increase in cerebral perfusion from the intra-aortic balloon pump may have caused vasodilation of the extracranial arteries, leading to a persistent and debilitating headache in this susceptible patient.

http://ift.tt/2tEBJmF

Intraoperative subdural low-noise EEG recording of the high frequency oscillation in the somatosensory evoked potential

Pathological high frequency oscillations (pHFOs, 80-500 Hz) recorded in the pre and intra-operative ECoG of epilepsy patients have been proposed as a biomarker for the identification of the epileptogenic zone (Jacobs et al., 2012). Particularly for epilepsy surgery, it has been demonstrated that residual fast ripples (FR, > 250 Hz) are a reliable predictor of seizure outcome (Fedele et al., 2017; van 't Klooster et al., 2015; Wu et al., 2010). While faster oscillations have higher clinical relevance, they suffer from a poor signal-to-noise ratio (SNR).

http://ift.tt/2w1vV7F

Expression of MicroRNA-146a and MicroRNA-155 in Placental Villi in Early- and Late-Onset Preeclampsia

We studied the expression of microRNA-146a and microRNA-155 in placental villi from 18 women (26-39 weeks of gestation) of reproductive age with early- or late-onset preeclampsia. The reference group consisted of women with physiological pregnancy and full-term gestation and with preterm birth after caesarian section on gestation week 26-31. MicroRNA-146a and microRNA-155 were detected by in situ hybridization with digoxigenin on paraffin sections. It was found that the expression of microRNA-146a in both syncytiotrophoblast of the intermediate villi and syncytial knots was lower at late-onset preeclampsia than at physiologic pregnancy of full-term period (p=0.037 and p=0.001 respectively). The expression of microRNA-155 in syncytiotrophoblast of intermediate placental villi in early-onset preeclampsia was higher than in group with preterm delivery (p=0.003). However, in syncytiotrophoblast of intermediate villi and in syncytial knots, the expression of microRNA-155 was lower at late-onset preeclampsia in comparison with full-term physiological pregnancy (p=0.005). In addition, the expression of microRNA-146a and microRNA-155 did not increase in the later terms in preeclampsia, while in the reference groups demonstrating gradual increase in the expression of these markers with increasing gestational age. Expression microRNA-146a and microRNA-155 little differed in early- and late-onset preeclampsia. These findings suggest that different variants of preeclampsia are probably characterized by common pathogenetic pathways. Damaged trophoblast cannot maintain of microRNAs synthesis at the required level, which determines the formation of a vicious circle in preeclampsia and further progression of the disease.

http://ift.tt/2v0Rub0

HDL Cholesterol, LDL Cholesterol, and Triglycerides as Risk Factors for CKD: A Mendelian Randomization Study

High-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride concentrations are heritable risk factors for vascular disease, but their role in the progression of chronic kidney disease (CKD) is unclear.

http://ift.tt/2uZthCA

Lung Function and Incident Kidney Disease: The Atherosclerosis Risk in Communities (ARIC) Study

Reduced lung function is associated with clinical outcomes such as cardiovascular disease. However, little is known about its association with incident end-stage renal disease (ESRD) and chronic kidney disease (CKD).

http://ift.tt/2uDEl5K

Comparative efficacy of various endoscopic techniques for the treatment of common bile duct stones: A network meta-analysis

Although various endoscopic techniques have been introduced for successful removal of common bile duct (CBD) stones, the optimal method is not yet clear. We aimed to compare the efficacy of different endoscopic techniques for CBD stone removal.

http://ift.tt/2tE9che

FABP1 and Hepar expression levels in Barrett's Oesophagus and Associated Neoplasia in an Asian Population

Barrett's oesophagus (BE) is a premalignant condition associated with oesophageal adenocarcinoma (EAC). Evidence highlights that EAC is associated with an estimated 5-year survival of approximately 10-15%. Therefore, there is a need to determine which biomarkers are of value in the diagnosis of BE and beyond. The aim of our study was to evaluate the clinical significance of markers known to be expressed across BE and associated neoplasia.

http://ift.tt/2vJYJSN

Manipulation of Gut Microbiota Reveals Shifting Community Structure Shaped by Host Developmental Windows in Amphibian Larvae

Abstract

Exploration of the importance of developmental windows for microbial colonization in diverse animal taxa, and tests of how these shape both animal microbiomes as well as host phenotypes promise to shed needed light on host-microbe interactions. The aims of this study were to explore how gut microbiota diversity of larval amphibians varies among species and across ontogeny, and to test if manipulation of gut colonization can reveal how microbiomes develop. We found that gut microbiomes differ among species and change across larval ontogeny, with distinctive differences between larvae, metamorphic animals, and juvenile frogs. Through applying a gnotobiotic protocol to eggs and cross-inoculating gut microbiomes between species, we demonstrated that microbiota can be transplanted among species and developmental stages. These results also demonstrated that microbial colonization at hatching is potentially formative for long term composition and function of amphibian gut microbiomes, suggesting that hatching may be a critical developmental window for colonization, similar to the effects of birth mode on human microbiomes. Specifically, our results suggest that either the egg jelly and/or capsules surrounding amphibian eggs are likely important sources for initial microbiome inoculation. Furthermore, we speculate these results suggest that vertical transmission may be important to amphibian microbiome establishment and development, as is common among many animal taxa. Taken together, our results suggest that explicit tests of how host developmental windows influence microbial colonization, and shape amphibian microbiomes across life stages promise to provide insight into the ecological and evolutionary dynamics of host-microbe interactions.

http://ift.tt/2uySbrA

Trade-offs Influencing the Physiological Ecology of Hibernation in Temperate-Zone Bats

Abstract

Seasonality of temperature and food availability can lead to trade-offs between the benefits of immediate reproduction and costs associated with mortality risk from starvation, inclement weather, or predation. Hibernating mammals exhibit an enormous seasonal shift in physiology and behavior and provide a useful system to examine the effect of this trade-off on key events in the annual cycle. Most of what we understand about the ecological energetics and phenology of hibernation comes from studies of rodent hibernators such as ground squirrels, chipmunks, and dormice. Temperate-zone, insectivorous bats, however, provide another useful model system to examine trade-offs influencing seasonal change within individuals. Here, I review recent studies from my laboratory on little brown bats (Myotis lucifugus) from central Canada to understand the interplay between capacity for energy storage, energy expenditure during hibernation, and the timing of key events in the annual cycle of hibernating mammals. These studies have relied on measurements of body condition to assess energetic status, biologging of skin temperature using temperature telemetry, and use of passive transponders (i.e., PIT tags) to quantify emergence timing. In general, these studies suggest that, in part due to constraints associated with flight, bats exhibit unique, or at least unusual, adaptations for extreme energy savings during winter. The results also support the optimization hypothesis that current energetic status and future energy requirements influence energy expenditure during hibernation and the timing of emergence from hibernation in spring. Taken together, this work provides insight into the influence of reproductive timing and energy availability on hibernation behavior and physiology. It also has implications for understanding responses of bat populations to anthropogenic impacts like climate change and white-nose syndrome.

http://ift.tt/2vKtIOI

An Introductory “How-to” Guide for Incorporating Microbiome Research into Integrative and Comparative Biology

Abstract

Research on host-associated microbial communities has grown rapidly. Despite the great body of work, inclusion of microbiota-related questions into integrative and comparative biology is still lagging behind other disciplines. The purpose of this paper is to offer an introduction into the basic tools and techniques of host-microbe research. Specifically, what considerations should be made before embarking on such projects (types of samples, types of controls)? How is microbiome data analyzed and integrated with data measured from the hosts? How can researchers experimentally manipulate the microbiome? With this information, integrative and comparative biologists should be able to include host-microbe studies into their research and push the boundaries of both fields.

http://ift.tt/2uyQMkX

Who Are the “Lazy” Ants? The Function of Inactivity in Social Insects and a Possible Role of Constraint: Inactive Ants Are Corpulent and May Be Young and/or Selfish

Abstract

Social insect colonies are commonly thought of as highly organized and efficient complex systems, yet high levels of worker inactivity are common. Although consistently inactive workers have been documented across many species, very little is known about the potential function or costs associated with this behavior. Here we ask what distinguishes these "lazy" individuals from their nestmates. We obtained a large set of behavioral and morphological data about individuals, and tested for consistency with the following evolutionary hypotheses: that inactivity results from constraint caused by worker (a) immaturity or (b) senescence; that (c) inactive workers are reproducing; that inactive workers perform a cryptic task such as (d) acting as communication hubs or (e) food stores; and that (f) inactive workers represent the "slow-paced" end of inter-worker variation in "pace-of-life." We show that inactive workers walk more slowly, have small spatial fidelity zones near the nest center, are more corpulent, are isolated in colony interaction networks, have the smallest behavioral repertoires, and are more likely to have oocytes than other workers. These results are consistent with the hypotheses that inactive workers are immature and/or storing food for the colony; they suggest that workers are not inactive as a consequence of senescence, and that they are not acting as communication hubs. The hypotheses listed above are not mutually exclusive, and likely form a "syndrome" of behaviors common to inactive social insect workers. Their simultaneous contribution to inactivity may explain the difficulty in finding a simple answer to this deceptively simple question.

http://ift.tt/2vKkvFY

Cardiopulmonary Exercise Testing in Adult Congenital Heart Disease

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S93-S101, July 2017.


http://ift.tt/2u0Ay0m

Exercise Testing, Supplemental Oxygen, and Hypoxia

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S140-S148, July 2017.


http://ift.tt/2tKUxVn

Cardiopulmonary Exercise Testing

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S1-S2, July 2017.


http://ift.tt/2u0kKuI

Measuring Cardiac Output during Cardiopulmonary Exercise Testing

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S48-S52, July 2017.


http://ift.tt/2u04rxP

Exercise Prescriptions for Training and Rehabilitation in Patients with Heart and Lung Disease

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S59-S66, July 2017.


http://ift.tt/2tKOUqs

Graphical Data Display for Clinical Cardiopulmonary Exercise Testing

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S12-S21, July 2017.


http://ift.tt/2u0jFmv

Ventilatory Inefficiency and Exertional Dyspnea in Early Chronic Obstructive Pulmonary Disease

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S22-S29, July 2017.


http://ift.tt/2tLjyjt

Cardiopulmonary Exercise Testing: Basics of Methodology and Measurements

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S3-S11, July 2017.


http://ift.tt/2u0zGJ3

Cardiopulmonary Exercise Testing and Surgery

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S74-S83, July 2017.


http://ift.tt/2tZUNLK

Cardiopulmonary Exercise Test as a Tool to Choose Therapy in Heart Failure

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S67-S73, July 2017.


http://ift.tt/2tKNlcb

Mechanisms That Modulate Peripheral Oxygen Delivery during Exercise in Heart Failure

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S40-S47, July 2017.


http://ift.tt/2u019uk

Cardiopulmonary Exercise Test in Hypertrophic Cardiomyopathy

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S102-S109, July 2017.


http://ift.tt/2tKUw3L

Cardiopulmonary Exercise Testing in Pediatrics

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S123-S128, July 2017.


http://ift.tt/2u0nGaw

The Link between Reduced Inspiratory Capacity and Exercise Intolerance in Chronic Obstructive Pulmonary Disease

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S30-S39, July 2017.


http://ift.tt/2tL5gPQ

Prognostic Role of Cardiopulmonary Exercise Testing in Clinical Practice

Annals of the American Thoracic Society, Volume 14, Issue Supplement_1, Page S53-S58, July 2017.


http://ift.tt/2tEMSny

Identical TP53 mutations provide evidence that late recurring tubo-ovarian high grade serous carcinomas do not represent new peritoneal primaries

Abstract

Tubo-ovarian high-grade serous carcinoma (HGSC) is the most common female adnexal malignancy and by far the most lethal. There is now compelling evidence that most of these neoplasms arise from the distal fallopian tube from a precursor referred to as serous tubal intraepithelial carcinoma (STIC) (1-5). Most cases present at advanced stage (FIGO stages III-IV) and the overall prognosis is poor (6). While most cases respond well initially to chemotherapy, early recurrence (within a few years) is common and most patients will eventually succumb to their disease (6)

This article is protected by copyright. All rights reserved.

http://ift.tt/2v064j9

Digital image analysis of HER2 immunohistochemistry in gastric- and oesophageal adenocarcinoma: a validation study on biopsies and surgical specimens

Abstract

Aims

to test the validity of diagnostics incorporating digital image analysis (DIA) for human epidermal growth factor 2 (HER2) immunohistochemistry (IHC) in gastro-oesophageal adenocarcinomas, as an alternative to current standard diagnostics using manual scoring.

Methods and results

we included 319 consecutive gastro-oesophageal adenocarcinomas (232 biopsies and 87 surgical specimens). DIA was applied to determine HER2 IHC classification, using both standard breast cancer (BC) and modified gastro-oesophageal cancer (GEC) cutoffs. Consensus manual scores were established by four independent observers. Chromogenic in situ hybridization (CISH) was performed on all 2+ cases by manual scoring, DIA or both. HER2 status was considered positive in 3+ and CISH positive 2+ cases. Overall agreement between DIA and consensus manual scores was 76.5% (weighted κ=0.66, BC cutoffs) and 85.6% (weighted κ=0.80, GEC cutoffs). Agreement was similar for biopsies and surgical specimens. All disagreement occurred in the manual IHC equivocal cases. DIA resulted in a reduction of 2+ cases: 75.8% with BC cutoffs and 46.5% with GEC cutoffs. HER2 status was positive in 48 cases (15%) with standard diagnostics and DIA using GEC cutoffs, and 46 cases (14.4%) using BC cutoffs (all with CISH in 2+ cases). Considering standard diagnostics as a reference, DIA showed 93.8% sensitivity and 99.6% specificity (BC cutoffs) or 97.9% sensitivity and 99.6% specificity (GEC cutoffs).

Conclusions

DIA is a reliable and feasible alternative to manual HER2 IHC scoring in gastro-oesophageal adenocarcinoma, both in biopsies and surgical specimens, leading to a reduction of 2+ cases for which subsequent ISH testing is required.

This article is protected by copyright. All rights reserved.

http://ift.tt/2v0EkL8

The association between clinical outcome and CD8+ lymphocytic infiltration in advanced stages of colorectal cancer differs by latent virus infection in the tumour tissue

Abstract

Aims

In near future, an immunoscore based on the quantification of lymphocytic populations can be expected as fundamental supplement of colorectal cancer (CRC) classification. This study explored, whether latent viral infection has an influence on prognostic relevant host immunity in CRC.

Methods and Results

CD8+ lymphocytic infiltration in three tumour compartments of 121 CRC was compared with clinical data and occurrence of latent infection with HSV1, HSV2, CMV, EBV, HPV16, and HPV18 in the tumour tissue, which was determined by PCR. Intraepithelial CD8+ lymphocytic infiltration (IE_CD8+) showed a trend towards correlation with clinical stage (p = 0.073), significant differences between CRC with metastases and without metastases (p = 0.001), and a significant correlation with overall survival (OS, p = 0.001). Each of these three clinical parameters showed a significant link to IE_CD8+ in the virus DNA-negative (p-values: 0.001 – 0.036), but no significant differences in the virus DNA-positive subgroup, which is consistent with a moderating effect of virus DNA on these associations. A significant correlation of CD8+ infiltration in the invasive margin (IM_CD8+) with OS (p = 0.016) was also moderated by virus DNA.

Conclusion

Our data hint at a possible influence of latent viral infection on the association between clinical outcome and CD8+ lymphocytic infiltration in CRC tissue. After confirmation of these results by large cohort studies, a potential interaction between microbial pathogens and host immunity in CRC and its impact on prognostic immunoscores and/or new therapeutic strategies should be further investigated.

This article is protected by copyright. All rights reserved.

http://ift.tt/2tEou5B

Cholangiohepatitis with extensive intrahepatic choledocholithiasis

http://ift.tt/2h4d9tH

Efficacy of Over the Scope Clips in Management of High-risk Gastrointestinal Bleeding

Standard endoscopic therapies do not control bleeding or produce complications in as many as 20% of patients with non-variceal gastrointestinal bleeding. Most bleeding comes from ulcers with characteristics such as high-risk vascular territories and/or large vessels. We evaluated the efficacy of using over the scope clips (OTSCs) as primary or rescue therapy for patients with bleeding from lesions that have a high-risk for adverse outcomes.

http://ift.tt/2eOYcLm

An unusual diagnosis for a bile duct mass: eosinophilic cholangitis diagnosed by digital cholangioscopy

http://ift.tt/2h4gokK

Towards More Efficient Dietary Elimination Therapy for EoE: The Fantastic 4?

http://ift.tt/2eOSRnj

'Patients with Ulcerative Colitis and Primary Sclerosing Cholangitis Frequently Have Subclinical Inflammation in the Proximal Colon'

Primary sclerosing cholangitis (PSC) patients with ulcerative colitis (UC) have a high risk of colonic neoplasia. As histologic inflammation is an independent risk factor for the development of neoplasia, we hypothesized that patients with UC and PSC have more subclinical disease activity than patients with UC alone.

http://ift.tt/2h40gjv

Definitive Stereotactic Body Radiotherapy (SBRT) for Extracranial Oligometastases: An International Survey of >1000 Radiation Oncologists

Purpose: Stereotactic body radiotherapy (SBRT) is often used to treat patients with oligometastases (OM). Yet, patterns of SBRT practice for OM are unknown. Therefore, we surveyed radiation oncologists internationally, to understand how and when SBRT is used for OM. Methods: A 25-question survey was distributed to radiation oncologists. Respondents using SBRT for OM were asked how long they have been treating OM, number of patients treated, organs treated, primary reason for use, doses used, and future intentions. Respondents not using SBRT for OM were asked reasons why SBRT was not used and intentions for future adoption. Data were analyzed anonymously. Results: We received 1007 surveys from 43 countries. Eighty-three percent began using SBRT after 2005 and greater than one third after 2010. Eighty-four percent cited perceived treatment response/durability as the primary reason for using SBRT in OM patients. Commonly treated organs were lung (90%), liver (75%), and spine (70%). SBRT dose/fractionation schemes varied widely. Most would offer a second course to new OM. Nearly all (99%) planned to continue and 66% planned to increase SBRT for OM. Of those not using SBRT, 59% plan to start soon. The most common reason for not using SBRT was lack of clinical efficacy (48%) or lack of necessary image guidance equipment (34%). Conclusions: Radiation oncologists are increasingly using SBRT for OM. The main reason for not using SBRT for OM is a perceived lack of evidence demonstrating clinical advantages. These data strengthen the need for robust prospective clinical trials (ongoing and in development) to demonstrate clinical efficacy given the widespread adoption of SBRT for OM.

http://ift.tt/2w1nFon

Oral Platelet Gel Supernatant Plus Supportive Medical Treatment Versus Supportive Medical Treatment in the Management of Radiation-induced Oral Mucositis: A Matched Explorative Active Control Trial by Propensity Analysis

Objectives: In this active control trial, the rate of radio-induced WHO grade 3/4 oral mucositis and the change in quality of life, assessed by OMWQ-HN, were measured in subjects with head and neck cancer treated by platelet gel supernatant (PGS) and supportive medical treatment versus subjects treated by supportive medical treatment alone. Materials and Methods: Eighty patients with nonmetastatic head and neck cancer underwent curative or adjuvant radiotherapy. All patients underwent supportive medical treatment and/or PGS at the beginning and during radiotherapy. Sixteen patients received PGS in association with supportive medical treatment. To obtain 2 groups virtually randomized for important clinical characteristics subjects were matched, by propensity analysis, with a group of subjects (64 patients) treated with supportive medical treatment alone. Results: Subjects treated with standard supportive treatment experienced significant higher WHO grade 3/4 toxicity (55%; 35/64) than subjects treated by PGS (13%; 3/16). The reduced toxicity found in PGS group paralleled with the evidence that they developed later symptoms with respect to controls. The Cox proportional hazard model indicated that patients treated with standard supportive medical treatment experienced 2.7-fold increase (hazard ratio=2.7; 95% confidence interval, 1.3-5.7) in the occurrence of WHO grade 3/4 toxicity. PGS group significantly experienced higher quality of life than control groups as measured by OMWQ-HN. A significant decrease in the opioid analgesics usage was found in the PGS group. Conclusions: These preliminary data should be interpreted with caution and could serve as a framework around which to design future trials.

http://ift.tt/2w1s3DL

Hematologic Toxicity of Concurrent Administration of Radium-223 and Next-generation Antiandrogen Therapies

Purpose/Objectives: Radium-223 is a first-in-class radiopharmaceutical recently approved for the treatment of castration-resistant prostate cancer in patients with symptomatic bone metastases. Initial studies investigating Radium-223 primarily used nonsteroidal first-generation antiandrogens. Since that time, newer antiandrogen therapies have demonstrated improved survival in patients with castration-resistant prostate cancer. It has been suggested that the rational combination of these newly approved agents with Radium-223 may lead to improved response rates and clinical outcomes. Currently, there is lack of information regarding the safety of concurrent administration of these agents with radiopharmaceuticals. Here, we report on hematologic toxicity findings from our institution in patients receiving concurrent Radium-223 and next-generation antiandrogen therapies with either enzalutamide or abiraterone. Materials/Methods: In a retrospective study, we analyzed patients who received Radium-223 as part of an early-access trial, and following FDA approval in May 2013, patients receiving Radium-223 as part of standard care. Radium-223 was given at standard dosing of 50 kBq/kg each month for 6 total cycles. Complete blood counts were performed before treatment monthly and following each injection. Blood counts from patients receiving Radium alone and concurrently with next-generation antiandrogens were compared. To date, 25 total patients were analyzed, with a median of 5 monthly doses received per patient. Fourteen patients received concurrent therapy during monthly Radium-223 with either enzalutamide (n=8) or abiraterone (n=6). Results: Six patients expired due to disease progression. Two patients discontinued treatment due to grade 3 myelosuppression. For patients receiving either Radium alone and with concurrent next-generation antiandrogen therapy, there did not appear to be any statistically significant differences between initial and nadir blood counts. Mean change from initial neutrophil count to nadir was 1.9×106/L in patients receiving Radium alone, versus 2.3×106/L in patients receiving concurrent therapy (P=0.77). Mean change from initial hemoglobin value to nadir was 1.5 g/L in patients receiving Radium alone, versus 1.8 g/L in patients receiving concurrent therapy (P=0.31). Mean change from initial platelet count to nadir was 52.3×109 cells/L in patients receiving Radium alone versus 70.6×109 cells/L in patients receiving concurrent therapy (P=0.39). Individual blood counts for each measured laboratory are included in the supplemental data. PSA was stable or decreased in 22% of patients receiving Radium alone versus 35% of patients receiving combination treatment (P=0.24). Conclusions: Concurrent administration of Radium-223 and next-generation antiandrogen therapies appears to be well tolerated with similar toxicities to standard administration of Radium-223 alone. This particular cohort of patients represents a high-risk, heavily pretreated group of patients with advanced metastatic disease and significant marrow burden. Despite these risk factors, hematologic toxicity was modest and was in the range expected for this risk group based on previous trials. To date, this is the first study investigating the toxicity of combination treatment. Further studies investigating the safety and efficacy of combination treatments are warranted.

http://ift.tt/2w1my7W

Phase I Study of Amrubicin and Cyclophosphamide in Patients With Advanced Solid Organ Malignancies: HOG LUN 07-130

Objectives: Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC. Materials and Methods: The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m2 on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m2 with increments of 5 mg/m2 per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response. Results: Thirty-six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m2, AMR 30 mg/m2) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response. Conclusions: AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.

http://ift.tt/2w1sqhn

The Prognostic Significance of Pretreatment Hematologic Parameters in Patients Undergoing Resection for Colorectal Cancer

Objectives: The prognostic value of several hematologic parameters, including platelet, lymphocyte, and neutrophil counts, has been studied in a variety of solid tumors. In this study, we examined the significance of inflammatory markers and their prognostic implications in patients with colorectal cancer (CRC). Materials and Methods: Patients with stage I-III CRC who underwent surgical resection at the Stanford Cancer Institute between 2005 and 2009 were included. Patients were excluded if they did not have preoperative complete blood counts performed within 1 month of surgical resection, underwent preoperative chemotherapy or radiation, had metastatic disease at diagnosis, or had another previous malignancy. We included 129 eligible patients with available preoperative complete blood counts in the final analysis. Results: A preoperative neutrophil-to-lymphocyte ratio of>3.3 was significantly associated with worse disease-free (DFS) and overall survival (OS) (P=0.009, 0.003), as was a preoperative lymphocyte-to-monocyte ratio of ≤2.6 (P=0.01, 0.002). Preoperative lymphopenia (P=0.002) was associated with worse OS but not DFS (P=0.09). In addition, preoperative thrombocytosis was associated with worse DFS (P=0.006) and OS (P=0.010). Preoperative leukocytosis was associated with worse OS (P=0.048) but not DFS (P=0.49). Preoperative hemoglobin was neither associated with OS (P=0.24) or DFS (P=0.15). Conclusions: Pretreatment lymphopenia, thrombocytosis, a decreased lymphocyte-to-monocyte ratio, and an elevated neutrophil-to-lymphocyte ratio independently predict for worse OS in patients with CRC.

http://ift.tt/2w1GKXw

Metformin Does Not Predict for Prostate Cancer Diagnosis, Grade, or Volume of Disease After Transperineal Template-guided Mapping Biopsy

Objectives: Previous studies have evaluated whether metformin is associated with prostate cancer incidence and outcomes with conflicting conclusions. In this study, we evaluate the incidence of prostate cancer in diabetic patients treated with and without metformin compared with nondiabetic patients. Materials and Methods: One thousand thirty-four patients underwent transperineal template-guided mapping biopsy secondary to either an elevated prostate-specific antigen (PSA) or a prior biopsy finding of atypical small acinar proliferation/prostatic intraepithelial neoplasia. The cohort included 881 nondiabetic men, 65 diabetic men treated with metformin, and 88 diabetic men not receiving metformin. In metformin-treated patients, the median duration of usage was 6.0 years. Differences in prostate cancer diagnosis, histologic grade, and tumor volume were compared across the 3 cohorts. Results: There was no statistically significant differences discerned between the 3 cohorts in patient age, prebiopsy PSA, prostate volume, PSA density, PSA doubling time, PSA velocity, or the total number of prior transrectal ultrasound biopsy sessions. Five hundred eighty-four patients were diagnosed with prostate cancer. There was no difference in prostate cancer diagnosis (P=0.153), Gleason score (P=0.960), the number of positive biopsy cores (P=0.764), or risk group stratification (P=0.877) between the 3 cohorts. In multivariate analysis, only older age predicted for prostate cancer diagnosis. In terms of Gleason score ≥7, patient age, PSA velocity, and body mass index predicted for more aggressive histology. Neither diabetes, metformin use or duration was of statistical consequence. Conclusion: Metformin did not impact incidence of prostate cancer diagnosis, Gleason score distribution, or volume of disease.

http://ift.tt/2w1iODt

Surgery and Adjuvant Radiation for High-risk Skin Adnexal Carcinoma of the Head and Neck

Objectives: Skin adnexal carcinoma (SAC) is a rare cutaneous malignancy that arises from sebaceous and sweat glands. These carcinomas are believed to behave more aggressively than cutaneous squamous cell carcinomas (SCC) with a propensity for local recurrence. The role of adjuvant radiotherapy in SAC is undefined. Methods: We retrospectively reviewed all cases of head and neck SAC treated with surgery and adjuvant radiation from 2000 to 2012 at a single institution. Results: Nine cases were identified. Median age was 67 (range, 52 to 88) years. The histologies were: adnexal carcinoma (n=1), adnexal carcinoma with sebaceous differentiation (n=1), adnexal carcinoma with squamous differentiation (n=1), skin appendage carcinoma (n=1), sclerosing sweat duct carcinoma (n=1), mucinous carcinoma (n=1), ductal eccrine adenocarcinoma (n=1), porocarcinoma (n=1), and trichilemmal carcinoma (n=1). All tumors were reviewed by a dermatopathologist to confirm the SAC diagnosis. All patients had undergone surgery. Indications for adjuvant radiation included involved lymph nodes (n=4), perineural invasion (n=2), nodal extracapsular extension (n=2), positive margin (n=1), high-grade histology (n=6), multifocal disease (n=2), and/or recurrent disease (n=5). Radiation was delivered to the primary site alone (n=3), to the draining lymphatics alone (n=2), or to both (n=4). One patient received concurrent cisplatin. Median dose to the primary site was 60 Gy and to the neck was 50 Gy. Median follow-up was 4.0 years (range, 0.6 to 11.4 y). Locoregional control was 100%. Five-year progression-free survival was 89%. There was 1 acute grade 3 toxicity and no greater than or equal to grade 2 late toxicities were recorded. Conclusions: Surgery and adjuvant radiation for high-risk SAC offers excellent locoregional control with acceptable toxicity.

http://ift.tt/2w1GiZg

Stage I Lung SBRT Clinical Practice Patterns

Objectives: Stereotactic body radiation therapy (SBRT) has become increasingly utilized over the last decade in the treatment of inoperable stage I non–small cell lung cancer (NSCLC) patients, although no standardized dosing guidelines exist. In this retrospective study, we investigated the dose prescription pattern use in the United States for patients receiving SBRT. Methods: Patients with stage I NSCLC treated with SBRT between 2004 and 2011 were identified within the National Cancer Database (NCDB). Trends in SBRT use and dose prescriptions were analyzed. Results: A total of 5246 patients met criteria as receiving SBRT. The overall mean and median BED10 were 134.5 and 132 Gy, respectively. Of these patients, 94.5% were prescribed a regimen with a BED10≥100 Gy. The most common prescriptions overall were 60 Gy in 3 fractions (24.1%), 48 Gy in 4 fractions (17.8%), 50 Gy in 5 fractions (13.0%), and 54 Gy in 3 fractions (12.8%). Analysis of prescription trends revealed decreased utilization of 54 to 60 Gy in 3 fractions (47.9% in 2006 to 27.9% in 2011, combined) and increased utilization of 50 Gy in 5 fractions (3.1% in 2006 to 20.4% in 2011). Conclusions: Our findings suggest increasing use of SBRT over the last decade with a majority of patients being treated with regimens employing a BED10≥100 Gy. Since 2006, there has been a decline in the use of 54 to 60 Gy in 3 fractions, with an increase in the use of 50 Gy in 5 fractions. Possible explanations include concern for increased toxicity with higher BED regimens and increasing treatment of centrally located tumors.

http://ift.tt/2w1ld12

Comparison of Toxicity and Treatment Outcomes in HIV-positive Versus HIV-negative Patients With Squamous Cell Carcinoma of the Anal Canal

Purpose: To compare the toxicity and treatment outcomes in human immunodeficiency virus (HIV)-positive versus HIV-negative patients with squamous cell carcinoma of the anal canal who underwent definitive concurrent chemoradiation at a single institution. Materials and Methods: Fifty-three consecutive HIV-positive patients treated between 1987 and 2013 were compared with 205 consecutive HIV-negative patients treated between 2003 and 2013. All patients received radiotherapy at a single regional facility. The median radiation dose was 54 Gy (range, 28 to 60 Gy). Concurrent chemotherapy consisted of 2 cycles 5-FU with mitomycin-C given on day 1±day 29). After treatment, patients were closely followed with imaging studies, clinical examinations, and rigid proctoscopies. Outcomes assessed were toxicity rates, progression-free survival, colostomy-free survival, cancer-specific survival, and overall survival. Results: Median follow-up was 34 months. Compared with HIV-negative patients, HIV-positive patients were younger (median age, 48 vs. 62 y) and predominantly male sex (98% of HIV-positive patients were male vs. 22% of HIV-negative patients). Of the HIV-positive patients, 37 (70%) were on highly active antiretroviral therapy, 26 (65%) had an undetectable viral load at the time of treatment, and 36 (72%) had a CD4 count>200 (mean CD4 count, 455). There were no significant differences in acute or late nonhematologic or hematologic toxicity rates between the 2 groups. At 3 years, there was no significant difference between HIV-positive and HIV-negative patients in regards to progression-free survival (75% vs. 76%), colostomy-free survival (85% vs. 85%), or cancer-specific survival (79% vs. 88%, P=0.36), respectively. On univariate analysis, there was a trend toward worse overall survival in HIV-positive patients (72% vs. 84% at 3 y, P=0.06). For the entire cohort, on multivariate analysis only male sex and stage were predictive of worse survival outcomes. HIV status was not associated with worse outcomes in Cox models. Conclusions: In the highly active antiretroviral therapy era, HIV-positive patients with anal cancer treated with standard definitive chemoradiation have equivalent toxicity and cancer-specific survival compared with HIV-negative patients.

http://ift.tt/2w1Ahvr

The Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer Harboring Wild-type Epidermal Growth Factor Receptor: A Meta-analysis of 25 RCTs

Objective: To determine the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non–small cell lung cancer (NSCLC) patients with wild-type (WT) EGFR tumors, we performed an indirect meta-analysis to assess the treatment effects of EGFR-TKIs in such patients. Methods: We searched for randomized controlled trials in Medline, Embase, the Cochrane controlled trials register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Effect measures used were hazard ratios (HR) for progression-free survival (PFS) and overall survival. Results: Out of 2134 retrieved articles, 25 randomized controlled trials including more than 4467 patients were identified. This pooled analysis showed the inferior efficacy of TKI over chemotherapy among patients with WT EGFR NSCLC in terms of PFS (HR, 1.37; 95% confidence interval [CI]: 1.10, 1.72; P=0.006). When used as first-line treatment, TKIs have also fared worse than chemotherapy when compared with standard platinum doublet regimens in patients with WT EGFR in terms of PFS (HR, 2.15; 95% CI: 1.68, 2.76; P

http://ift.tt/2w1iN2n

Contemporary Patterns and Survival Outcome of Adjuvant Systemic Therapy for Localized Gastrointestinal Stromal Tumors

Objectives: To describe contemporary patterns of and factors associated with adjuvant therapy use and survival outcome after resection of localized gastrointestinal stromal tumors (GISTs) using a large contemporary clinical database. Methods: We queried the National Cancer Data Base to identify localized GIST cases diagnosed from 2004 to 2011, and used descriptive and logistic regression analyses to determine patterns of and factors associated with adjuvant therapy. Kaplan-Meier and Cox proportional-hazard model were utilized to generate survival probabilities and hazard ratios (HRs). Results: Of 4694 patients, 73.5% received surgery alone, and 26.5% received adjuvant therapy during 2004 to 2011. Receipt of adjuvant therapy more than doubled between 2006 (13.2%) and 2007 (30.5%), peaked to 37.9% in 2009, and then decreased to 25.6% in 2011 (P for trend10 cm) than those with smaller tumor size (≤5 cm) (44.1% vs. 15.8%; P10 cm tumor size (HR=0.42; 95% confidence interval, 0.20-0.89; P=0.02). Conclusions: In a large nationwide dataset, we showed that the use of adjuvant therapy for localized GISTs has significantly increased over time and patients treated with adjuvant therapy have better survival than patients treated with surgery alone.

http://ift.tt/2w1fkkj

Influence of NSAID Use Among Colorectal Cancer Survivors on Cancer Outcomes

Purpose: Colorectal cancer (CRC) is the third most common cancer diagnosed in men and women in the United States. Given the availability of effective screening, most tumors are found early enough to offer patients substantial long-term survival. Thus there is a resulting significant population of CRC survivors for whom modifiable risk factors for recurrence and survival would be of interest. Methods: We conducted a population-based retrospective cohort study among patients enrolled in 2 large Midwestern health plans for which claims data, including pharmacy fill data, and medical record data were available. Men and women who were 40 years of age or older at the time of CRC diagnosis with disease less than stage IV and no history of Crohn disease, ulcerative colitis, and irritable bowel syndrome were included. CRC cases diagnosed between January 1, 1990 and December 31, 2000 were included if they met the inclusion criteria. Adjusted Cox proportional hazard models were used with exposure modeled as a time-dependent covariate. We assessed progression-free survival, defined as an aggressive polyp or invasive disease, and overall survival. Results: After adjustment for age at diagnosis, sex, race, body mass index, stage, side of initial tumor, and tumor histology, we found that current users of nonsteroidal anti-inflammatory drugs had a 3-fold decreased risk of recurrence and a >7-fold decreased risk of death. Our results are statistically significant with P-values

http://ift.tt/2w1qIN8

Thyroid V50 Highly Predictive of Hypothyroidism in Head-and-Neck Cancer Patients Treated With Intensity-modulated Radiotherapy (IMRT)

Objectives: Radiation-induced hypothyroidism affects a significant number of patients with head-and-neck squamous cell cancer (HNSCC). We examined detailed dosimetric and clinical parameters to better determine the risk of hypothyroidism in euthyroid HNSCC patients treated with intensity-modulated radiation therapy (IMRT). Materials and Methods: From 2006 to 2010, 75 clinically euthyroid patients with HNSCC were treated with sequential IMRT. The cohort included 59 men and 16 females with a median age of 55 years (range, 30 to 89 y) who were treated to a median dose of 70 Gy (range, 60 to 75 Gy) with concurrent chemotherapy in nearly all (95%) cases. Detailed thyroid dosimetric parameters including maximum dose, mean dose, and other parameters (eg, V50—percent volume receiving at least 50 Gy) were obtained. Freedom from hypothyroidism was evaluated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using Cox regression. Results: After a median follow-up period of 50 months, 25 patients (33%) became hypothyroid. On univariate analysis, thyroid V50 was highly correlated with developing hypothyroidism (P=0.035). Other dosimetric paramaters including mean thyroid dose (P=0.11) and maximum thyroid dose (P=0.39) did not reach statistical significance. On multivariate analysis incorporating patient, tumor, and treatment variables, V50 remained highly statistically significant (P=0.037). Regardless of other factors, for V50>60%, the odds ratio of developing hypothyroidism was 6.76 (P=0.002). Conclusions: In HNSCC patients treated with IMRT, thyroid V50 highly predicts the risk of developing hypothyroidism. V50>60% puts patients at a significantly higher risk of becoming hypothyroid. This can be a useful dose constraint to consider during treatment planning.

http://ift.tt/2w1HmfF

Lymph Node Burden as a Predictive Factor for Selective Chemoradiotherapy in Patients With Locally Advanced Gastric Cancer After a D2 Dissection: A Retrospective Study

Objectives: The role of adjuvant radiation in locally advanced gastric cancer after a D2 lymph node dissection is not well defined. The Adjuvant Chemoradiation Therapy in Stomach Cancer trial demonstrated a benefit in selected patients with positive lymph nodes. This study further defines lymph node burden as a predictive factor for adjuvant radiation in locally advanced gastric cancer after radical D2 lymph node dissection. Materials and Methods: One hundred eighty-six patients with locally advanced gastric cancer and D2 dissections were retrospectively investigated. Patients were divided into 2 equal and well-balanced groups based on clinicopathologic characteristics, with half receiving chemoradiation and the other half chemotherapy alone. Clinical outcomes and recurrence patterns were compared. Lymph node ratio (LNR) was defined as ratio of positive to examined nodes. Chemotherapies were fluorouracil-based regimens. Radiation was prescribed to 45 Gy (range, 45 to 50.4 Gy) using 3-dimensional conformal or intensity-modulated radiation therapy techniques. Results: There was no difference between patients treated with or without radiation in 3-year disease-free survival (DFS) (57.0% vs. 62.0%, P=0.30) or 3-year overall survival (72.8% vs. 77.4%, P=0.23). However, patients with LNR>0.65 or 3 to 6 positive nodes (N2) had improved 3-year DFS and 3-year distant metastasis-free survival (DMFS) in the chemoradiation group (LNR>0.65 vs. LNR≤0.65: 3-y DFS: 35.8% vs. 0%, P=0.052, 3-y DMFS: 75.2% vs. 0%, P=0.026; N2 vs. non-N2: 3-y DFS: 84.7% vs. 57.1%, P=0.046, 3-y DMFS: 100.0% vs. 65.3%, P=0.036). Conclusions: N2 or LNR>0.65 may be indications for adjuvant chemoradiotherapy. Further randomized studies are needed for validation.

http://ift.tt/2w1mwNm

Long-term Outcomes and Complications in Pediatric Ewing Sarcoma

Objectives: The objective of this study was to determine treatment outcomes and long-term complications in pediatric patients with Ewing Sarcoma treated at the British Columbia Cancer Agency (BCCA). Methods: A retrospective chart review of 101 pediatric patients (

http://ift.tt/2w1so9f

Resection of Colorectal Cancer With Versus Without Preservation of Inferior Mesenteric Artery

Objective: To assess the clinical significance of preservation of the inferior mesenteric artery (IMA) in comparison with IMA ligation in surgery for sigmoid colon or rectal (colorectal) cancer. Methods: Consecutive patients (n=862) with colorectal cancer who underwent intended surgical resection of the main tumor between 1986 and 2011 were retrospectively analyzed. The patients were divided into 2 groups: IMA preserved (n=745) and IMA ligated (n=117). Results: No significant difference was observed in incidence of advanced stage III or IV disease between the 2 groups (P=0.56 and 0.51, respectively), whereas a longer operation time (287 [95 to 700] vs. 215 [60 to 900] min, respectively; P

http://ift.tt/2w1AX3W

Favorable Outcome of Hurthle Cell Carcinoma of the Thyroid Treated With Total Thyroidectomy, Radioiodine, and Selective Use of External-Beam Radiotherapy

Objectives: There is controversy about the prognosis of Hurthle cell carcinoma of the thyroid. The purpose of this project is to report the outcome of a well-defined group of patients treated at a single institution in the modern era. Methods: Sixteen patients met the following inclusion criteria: Treatment with curative intent at our institution between January 1, 1997, and December 31, 2010. Primary treatment with total thyroidectomy with or without neck dissection. Age >18 years at the time of thyroidectomy. Confirmation by a pathologist of the diagnosis of a primary Hurthle cell carcinoma of the thyroid based on ≥75% Hurthle cells with extension through the tumor capsule. No areas of poorly differentiated (insular) or undifferentiated (anaplastic) carcinoma. Stage T1-3, NX-1b, M0. All patients received radioiodine immediately after thyroidectomy (remnant ablation, n=14) or as adjuvant for a recurrence (n=2). External-beam radiotherapy to the neck as adjuvant therapy after thyroidectomy was used in 2 patients and after resection of a neck recurrence in 1 patient. Results: Five-year actuarial rates with a median 6 years of follow up on surviving patients were as follows: Overall and cancer-specific survival: 92% (1 death from Hurthle cell carcinoma). Relapse-free survival (no visible tumor and unstimulated thyroglobulin ≤1.0): 65%. Conclusions: Our experience suggests that the outcome of Hurthle cell carcinoma of the thyroid is favorable in adults with stage T1-3 NX-1b M0 disease who are managed with total thyroidectomy, radioiodine, and—in selected cases—external-beam radiotherapy. We do not have the ability to compare our results to other management strategies.

http://ift.tt/2w1qJka

Diagnostic application of BAP1 immunohistochemistry to differentiate pleural mesothelioma from metastatic pleural tumors

Abstract

Malignant pleural mesothelioma (MPM) is the most common primary pleural tumor and an aggressive neoplasm that arises from mesothelium of the pleura. The prognosis is poor with the overall median survival of 9-11 months¹. For the diagnosis of MPM, differentiating MPM from pleural metastatic tumors is important.

This article is protected by copyright. All rights reserved.

http://ift.tt/2uCvhhr

Short-term and long-term clinical outcomes of uncommon types of invasive breast cancers

Abstract

Background

Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are predominant and well-documented types of invasive breast cancers (IBC). However, clinical outcomes of other types of IBC (i.e., uncommon IBC), which collectively account for about 20% of all IBC cases, are largely unknown.

Methods

We identified all IBC cases diagnosed in 2004-2006 (n=159,293) and 2010-2011 (n=118,822) from the Surveillance, Epidemiology and End Results (SEER) database. Uncommon IBC included mixed IDC and ILC (MDLC), IDC mixed with other types of carcinoma (IDC-MO), ILC mixed with other types of carcinoma (ILC-MO), and other-type of breast cancers (OC). We estimated overall survivals (OS) and cancer-specific survivals in multivariate regression models.

Results

Compared with IDC, MDLC was associated with a better OS (adjusted hazard ratio [aHR]=0.92, P<0.001 at approximately 10-year follow-up; aHR=0.88, P=0.01 at approximately 4-year follow-up) while OC had a worse OS (aHR=1.06, P=0.005 at approximately 10-year follow-up; aHR=1.23, P<0.001 at approximately 4-year follow-up). Other uncommon IBCs had an OS similar to IDC. Heterogeneity in survivals was observed in some subtypes of OC, with better OS in MDLC and tubular carcinoma. Radiotherapy extended OS for all types of IBC in older women (50+ years). For younger women (<50 years), radiotherapy improved OS in women with IDC, but not ILC or uncommon IBC. Radiotherapy did not change cancer-specific survival of any IBC in younger women.

Conclusions

Uncommon IBCs have distinct patterns in prognosis and survival. Effectiveness of radiotherapy in women with uncommon IBC may differ by age. The underlying mechanisms warrant further studies.

This article is protected by copyright. All rights reserved.

http://ift.tt/2v0amHp

Preoperative genetic testing impacts surgical decision making in BRCA mutation carriers with breast cancer: a retrospective cohort analysis

Abstract

Background

The impact of timing of genetic testing on surgical decision making in women with breast cancer and BRCA mutation is not well known.

Methods

Women who were found to carry a deleterious BRCA mutation and had been diagnosed with breast cancer were identified from a database at Beaumont Health. Women who had received BRCA positive results at least a day prior to their index surgery were considered to be aware of their mutation status prior to surgery. Baseline characteristics and surgical choices were compared between women who were aware of their mutation status prior to surgery and those who were not. Fischer's exact test was used for categorical variables and Mann–Whitney U-Test was used for continuous variables.

Results

A total of 220 patients were included in the final analysis, 208 (94.5%) with unilateral breast cancer and 12 (5.5%) with bilateral breast cancer. Out of the 208 patients with unilateral breast cancer, 106 (51.0%) patients were aware of their mutation status prior to index surgery while 102 (49%) were not. A significantly (p < 0.05) higher proportion of women underwent contralateral prophylactic mastectomy in the group that was aware of their mutation status prior to index surgery compared to the group that was not (76.4% vs 14.7%).

Conclusions

Our study demonstrates that knowledge of BRCA mutation status impacts surgical decision making in favor of bilateral mastectomy in patients who are aware of their results prior to index surgery. This finding supports the practice of preoperative genetic testing in patients with newly diagnosed breast cancer.

http://ift.tt/2w19DDa

Combined interventions to reduce HIV incidence in KwaZulu-Natal: a modelling study

Combined prevention interventions, including early antiretroviral therapy initiation, may substantially reduce HIV incidence in hyperendemic settings. Our aim was to assess the potential short-term impact of c...

http://ift.tt/2v8SUBo

Knowledge and perceptions about Zika virus in a Middle East country

Zika virus, an emerging serious infectious disease, is a threat to persons living or travelling to regions where it is currently endemic, and also to contacts of infected individuals. The aim of this study was...

http://ift.tt/2w10XfL

A Standardized Method for Measuring Internal Lung Surface Area via Mouse Pneumonectomy and Prosthesis Implantation

Internal lung surface area (ISA) is a critical criterion for assessing lung morphology and physiology in lung diseases and injury-induced alveolar regeneration. We describe here a standardized method that can minimize the measurement bias for ISA in both lung pneumonectomy and prosthesis implantation mouse models.

http://ift.tt/2h30YNR

EKG interpretation checklists

For cardiac rhythm strip evaluation the EKG Club expert panel recommends paramedics, EMTs and students follow a repeatable pattern or process. Although not diagnostic, in many case examining each of these characteristics can help direct appropriate prehospital patient treatment: Heart rate P wave (Normal shape" Present" Followed by QRS") PR interval (Normal" Short" Long" Irregular") QRS interval (Normal" ...

http://ift.tt/2eOsQV7

Life inside a gall: closeness does not favour horizontal transmission of Rickettsia between a gall wasp and its parasitoid

Abstract

The incidence of horizontal transmission as a route for spreading symbiont infections is still being debated, but a common view is that horizontal transfers require intimate between-species relationships. Here we study a system that meets ideal requirements for horizontal transmission: the gall wasp Leptocybe invasa and its parasitoid Quadrastichus mendeli (Hymenoptera: Eulophidae). These wasps belong to the same subfamily, spend most of their lives inside the same minute gall and are both infected by Rickettsia, a maternally inherited endosymbiotic bacteria that infects several arthropods, sometimes manipulating their reproduction, like inducing thelytokous parthenogenesis in L. invasa. Despite intimate contact, close phylogenetic relationship and the parasitoid's host specificity, we show that host and parasitoid do not share the same Rickettsia. We provide indirect evidence that Rickettsia infecting Q. mendeli may be inducing thelytokous parthenogenesis, as the symbiont is densely present in the reproductive apparatus and is vertically transmitted. Phylogenetic analyses based on 16S and gltA placed this symbiont in the leech group. The confirmed and presumed parthenogenesis-inducing Rickettsia discovered so far only infect eulophid wasps, and belong to three different groups, suggesting multiple independent evolution of the parthenogenesis inducing phenotype. We also show some degree of cospeciation between Rickettsia and their eulophid hosts.

http://ift.tt/2tR21FG