Development and validation of a childhood self-efficacy for functional constipation questionnaire

Abstract

Background

Children with functional constipation fear painful bowel movements leading to stool withholding behavior. Self-efficacy is the belief that an individual can accomplish a given goal. If children with constipation avoid defecation because they think that they are unable defecate comfortably, this low self-efficacy may prevent treatment success. The aim of the current study was to develop and validate a constipation specific self-efficacy scale.

Methods

The self-efficacy for functional constipation questionnaire (SEFCQ) was developed by the authors and evaluated by 10 children and seven experts. Ninety-nine healthy children and 122 children with functional constipation completed the SEFCQ and three other questionnaires measuring related constructs.

Key Results

Minor changes were made in wording based on feedback from experts and children. Factor analysis showed two scales, a 7 item Action scale (Cronbach's α = 0.88) and a 7 item Emotion scale (Cronbach α = 0.86). The SEFCQ total scale correlated positively with general self-efficacy (r = .32, P < .001) and quality of life (r = .20; P < .01) and negatively with anxiety (r = −.15; P < .05). Scores on the SEFCQ were higher in children without functional constipation compared to those with functional constipation (53.33 + 3.38 vs 39.34 + 7.19, P < .001).

Conclusions & Inferences

We developed a constipation specific self-efficacy questionnaire with good initial internal reliability, excellent face validity and adequate content validity. A low self-efficacy for defecation, may make the child resist their physical urge to defecate and hence, the need for further studies to assess its effect on treatment outcomes.

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The Correlation of Allergic Rhinitis with ABO Phenotype

Abstract

The aim of study the correlation of ABO phenotypes in patients of allergic rhinitis and controls and to compare our study with the previous studies to analyse the association of above. 100 patients with symptoms of allergic rhinitis and 100 controls individual were selected from same geographical region and paired by gender and age were enrolled in the study. Detailed history, examination and relevant radiological and hematological investigations were done. ABO phenotypes were identified in red blood cells using hemagglutination technique. This clinic-based observational study was conducted among the patients presenting with signs and symptoms of allergic rhinitis. Maximum no. of cases were seen in ABO phenotype O (52%), followed by A, B and AB (33, 12 and 3% respectively) and it was found to be statistically significant (p = 0.001). Also more number of male patients were found in B and O blood group which was statistically significant (OR 5.33, p = 0.017 and OR 3.63, p = 0.006 respectively). Controls showed marginalized difference in distribution among the basis of different ABO phenotypes. The O blood group phenotype of ABO histo-blood group system is associated with AR. This study contributes to the better understanding of the pathophysiology and clinical variability of this disease and may help to improve strategies towards its prevention and diagnosis. Additionally, ABO histo-blood group phenotyping, an inexpensive and easy to perform assay could be used to identify individuals at risk of developing allergic rhinitis.

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Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer

Abstract

Background

Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to first line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer.

Patients and Methods

83 patients on first line AI therapy for metastatic breast cancer were enrolled in a prospective study. Plasma samples were collected every 3 months to disease progression and ctDNA analysed by digital droplet PCR and enhanced tagged-amplicon sequencing (eTAm-Seq). Mutations identified in progression samples by sequencing were tracked back through samples prior to progression to study the evolution of mutations on therapy. The frequency of novel mutations were validated in an independent cohort of available baseline plasma samples in the SoFEA trial, which enrolled patients with prior sensitivity to AI.

Results

Of the 39 patients who progressed on first line AI, 56.4%(22/39) had ESR1 mutations detectable at progression, which were polyclonal in 40.9%(9/22) patients. In serial tracking, ESR1 mutations were detectable median 6.7 months (95%CI 3.7-NA) prior to clinical progression. Utilising eTAm-Seq ctDNA sequencing of progression plasma, ESR1 mutations were demonstrated to be sub-clonal in 72.2%(13/18) patients. Mutations in RAS genes were identified in 15.4%(6/39) of progressing patients (4 KRAS, 1 HRAS, 1 NRAS). In SoFEA, KRAS mutations were detected in 21.2%(24/113) patients, although there was no evidence that KRAS mutation status was prognostic for progression free or overall survival.

Conclusions

Cancers progressing on first line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic diversity of AI resistant cancers may limit subsequent targeted therapy approaches.

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Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors

Summary

Objective

New devices are needed for monitoring seizures, especially those associated with sudden unexpected death in epilepsy (SUDEP). They must be unobtrusive and automated, and provide false alarm rates (FARs) bearable in everyday life. This study quantifies the performance of new multimodal wrist-worn convulsive seizure detectors.

Methods

Hand-annotated video-electroencephalographic seizure events were collected from 69 patients at six clinical sites. Three different wristbands were used to record electrodermal activity (EDA) and accelerometer (ACM) signals, obtaining 5,928 h of data, including 55 convulsive epileptic seizures (six focal tonic–clonic seizures and 49 focal to bilateral tonic–clonic seizures) from 22 patients. Recordings were analyzed offline to train and test two new machine learning classifiers and a published classifier based on EDA and ACM. Moreover, wristband data were analyzed to estimate seizure-motion duration and autonomic responses.

Results

The two novel classifiers consistently outperformed the previous detector. The most efficient (Classifier III) yielded sensitivity of 94.55%, and an FAR of 0.2 events/day. No nocturnal seizures were missed. Most patients had <1 false alarm every 4 days, with an FAR below their seizure frequency. When increasing the sensitivity to 100% (no missed seizures), the FAR is up to 13 times lower than with the previous detector. Furthermore, all detections occurred before the seizure ended, providing reasonable latency (median = 29.3 s, range = 14.8–151 s). Automatically estimated seizure durations were correlated with true durations, enabling reliable annotations. Finally, EDA measurements confirmed the presence of postictal autonomic dysfunction, exhibiting a significant rise in 73% of the convulsive seizures.

Significance

The proposed multimodal wrist-worn convulsive seizure detectors provide seizure counts that are more accurate than previous automated detectors and typical patient self-reports, while maintaining a tolerable FAR for ambulatory monitoring. Furthermore, the multimodal system provides an objective description of motor behavior and autonomic dysfunction, aimed at enriching seizure characterization, with potential utility for SUDEP warning.

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Effectiveness of tip rotation in fibreoptic bronchoscopy under different experimental conditions: an in vitro crossover study

Abstract

Background

Proper manipulation of fibreoptic bronchoscopes is essential for successful tracheal intubation or diagnostic bronchoscopy. Failure of proper navigation and rotation of the fibrescope may lead to difficulties in advancing the fibrescope and might also be responsible for (unnecessary) difficulties and delays in fibreoptic tracheal intubation, with subsequent hypoxaemia. The present study, therefore, aimed to assess the effectiveness of tip rotation in flexible bronchoscopes in different experimental conditions.

Methods

Five differently sized pairs of fibrescopes (outer diameters of 2.2, 2.4, 3.5, 4.2, and 5.2 mm) were inserted into paediatric airway manikins via an appropriately sized laryngeal mask and were turned clockwise or anticlockwise at the fibrescope body or cord to 45, 90, and 180°, with the cord held either straight or bent. The primary outcome measure was the ratio of rotation measured at the tip over the rotation performed with the fibrescope body or cord.

Results

Overall, the 'body' turn was significantly less effective when a bent cord was present (mean difference ranging from 29.8% (95% confidence interval 8.8–50.9) to 117.4% (93.6–141.2). This difference was diminished when the 'cord' turn was performed. Smaller fibrescopes, with outer diameters of 2.2 and 2.4 mm, were inferior with respect to the transmission of 'body' rotation to the tip.

Conclusions

'Cord' turning of the fibrescope appears to be more effective in rotating the tip than a turn of the fibrescope 'body' only. Straightening the fibrescope cord and combined 'body' and 'cord' turning are recommended.

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Evidence-based medicine: the clue is in the name

Keane and Berg¹ have taken issue with the scientific basis of medicine. Their premise is built on the following three challenges: that 'science' (in particular, the randomized controlled trial) is fundamentally unsuited to complex health care; that the evolutionary processes described in economics are a better fit to health care; and that attempts to grade recommendations are unnecessary and unhelpful. Their editorial raises genuine concerns and merits careful reading. But this perhaps presents a Utopian fallacy; evidence-based medicine isn't perfect so it must be replaced. The term 'evidence-based medicine' is frequently misused, misapplied, and misunderstood. Evidence-based medicine (if it is to live up to its name) should be open to scrutiny and challenge. It is certainly not a religious creed that cannot be questioned. Unthinking misapplication of 'evidence' leads both directly and indirectly to poor patient outcomes. Evidence-based medicine has many definitions, but Masic and colleagues² described it well: 'Evidence based medicine is the conscientious, explicit, judicious and reasonable use of modern, best evidence in making decisions about the care of individual patients. Evidence based medicine integrates clinical experience and patient values with the best available research information.'

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An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers

Abstract

Background

There is a clinical need for potent opioids that produce little or no respiratory depression. In the current study we compared the respiratory effects of tapentadol, a mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and oxycodone, a selective mu-opioid receptor agonist. We hypothesize that tapentadol 100 mg has a lesser effect on the control of breathing than oxycodone 20 mg.

Methods

Fifteen healthy volunteers were randomized to receive oral tapentadol (100 and 150 mg), oxycodone 20 mg or placebo immediate release tablets in a crossover double-blind randomized design. The main end-point of the study was the effect of treatment on the ventilatory response to hypercapnia and ventilation at an extrapolated end-tidal P_CO2 of 7.3 kPa (55 mmHg, VE55); VE55 was assessed prior and for 6-h following drug intake.

Results

All three treatments had typical opioid effects on the hypercapnic ventilatory response: a shift to the right coupled to a decrease of the response slope. Oxycodone 20 mg had a significantly larger respiratory depressant effect than tapentadol 100 mg (mean difference −5.0 L min⁻¹, 95% confidence interval: −7.1 to −2.9 L min⁻¹, P<0.01), but not larger than tapentadol 150 mg (oxycodone vs. tapentadol 150 mg: P>0.05).

Conclusions

In this exploratory study we observed that both tapentadol and oxycodone produce respiratory depression. Tapentadol 100 mg but not 150 mg had a modest respiratory advantage over oxycodone 20 mg. Further studies are needed to explore how these results translate to the clinical setting.

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Guidelines on informed consent in anaesthesia: unrealistic, unethical, untenable….

'Informed consent' has become the primary paradigm for protecting the legal rights of patients and guiding the ethical practice of medicine.¹ The Association of Anaesthetists of Great Britain and Ireland (AAGBI) 'informed consent' guidelines have recently been updated in response to 'the changing ethical and legal background against which anaesthetists, intensivists and pain specialists, currently work'.² This guidance aims to advise its members (and others) how to provide information about anaesthesia that respects patient autonomy and stays within the law.³ This raises the question, are we really achieving the key principles of primum non nocere,⁴ respect for patient autonomy,⁵ and the need to provide adequate information?⁶ Current guidance has been almost solely based on medicolegal determinations around inadequate informed consent, focusing on the failure to disclose a 'material risk'.⁷⁸ This has led health authorities and many clinicians to interpret the guidelines as a directive, informing patients of an ever-increasing list of potential anaesthesia-related adverse events. Misguided attempts to include every possible 'material risk' are leaving patients bombarded with excessive amounts of largely irrelevant and incomprehensible information.⁹¹⁰ This practice is also leading to unnecessary alarm and confusion, not to mention exposure of patients to the adverse effects of nocebo communications (negative suggestion).¹¹

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Big data, small airways, big problems

Some of the earliest airway management interventions in humans occurred in neonates in the 18^th century. Small tubes were passed into the oropharynx of newborn children to support ventilation. Later in that century, the Royal Humane Society was developed in the United Kingdom to address adult drowning, and the first approaches to tracheal intubation were described. Airway management expanded from life-saving interventions such as these to the operating theatre to support surgical procedures with required ventilation. In the operating theatre, the focus of new approaches to airway management has been on adults. Unfortunately, this has left the paediatric provider with adult tools and techniques that have simply been downsized for paediatric airway management. Advancing our knowledge regarding the optimal airway management techniques in children is challenging because of the rare occurrence of difficult events and challenges surrounding enrolling children in clinical trials.

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Does pharmacokinetic/pharmacodynamic model-guided anaesthesia improve outcome after hip fracture surgery?

Hip fracture affects ∼628 000 patients annually and accounts for ∼200 000 deaths in Europe.¹ The EuroHOPE database, which includes seven European countries, revealed that the 30 day mortality rate after hip fracture surgery ranges from 4 to 12% and reaches up to 35% after 1 yr.² Postoperative complications, such as serious cardiac and pulmonary events, appear most frequently.¹³ Postoperative delirium occurs often and is associated with increased mortality.⁴ Improving outcomes for vulnerable elderly hip-fractured patients is a key goal for perioperative care.¹

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Is science the answer?

Nearly ten years ago, Tobin described the irony that evidence-based medicine (EBM) lacks a sound scientific basis.¹ A sentinel paper concluded that most results of medical research were false,² and now the same author, a well-lauded EBM proponent, argues that even if true, most clinical research is not useful³ and now concedes that EBM has been 'hijacked' by 'vested interests' including industry and researchers.⁴ The community expends vast resources on research, yet it has been estimated that there is an 85% 'waste in the production and reporting of research evidence'.⁵

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Surgical pleth index: prediction of postoperative pain in children?

Abstract

Background

. Surgical Pleth Index (SPI) is a non-invasive, dimensionless score (0–100) aimed to allow an estimate of intraoperative nociception. Thus, it may be a useful tool to guide intraoperative analgesia. However, no optimum SPI target range for the use in children has yet been defined. It was the aim of this study to define a clinically appropriate SPI target to predict moderate-severe postoperative pain in children.

Methods

. After ethics approval 105 children (2–16 yr) undergoing elective sevoflurane/opioid-based anaesthesia were included. SPI was recorded directly before the end of surgery and compared with acute postoperative pain (age appropriately assessed on different pain scales in the age groups two to three yr, four to eight yr and nine to16 yr) in the postoperative acute care unit (PACU).

Results

Data of 93 children were analysed. A significant negative correlation was found between age and SPI (r=−0.43; P=0.03). The SPI cut-off value with the highest sensitivity (76%) and specificity (62%) in all children combined was 40. The negative predictive value for SPI ≤ 40 to predict the absence of moderate-severe pain in PACU was 87.5%. The commonly used SPI cut-off (50) published in all related studies had neither any clinically relevant sensitivity nor specificity to predict the presence or absence of acute pain in PACU.

Conclusions

. The results suggest that a lower (≤ 40) than previously published (50) target for SPI may be more appropriate in studies investigating SPI guided anaesthesia in children, if the avoidance of moderate-severe postoperative pain is the main goal.

Clinical trial registration

ACTRN12616001139460.

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A high-resolution air pollutants emission inventory in 2013 for the Beijing-Tianjin-Hebei region, China

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Ji Qi, Bo Zheng, Meng Li, Fang Yu, Chuchu Chen, Fei Liu, Xiafei Zhou, Jing Yuan, Qiang Zhang, Kebin He
We developed a high-resolution Beijing-Tianjin-Hebei (BTH) regional air pollutants emission inventory for the year 2013. The inventory was established using a bottom-up approach based on facility-level activity data obtained from multiple data sources. The estimates from the BTH 2013 emission inventory show that the total emissions of SO2, NOX, PM2.5, PM10, CO, NMVOC, NH3, BC, and OC were 2,305, 2,686, 1,090, 1,494, 20,567, 2,207, 623, 160, and 254 Gg, respectively. The industry sector is the largest emissions source for SO2, NOX, PM2.5, PM10, CO, and NMVOC in the BTH region, contributing 72.6%, 43.7%, 59.6%, 64.7%, 60.3%, and 70.4% of the total emissions, respectively. Power plants contributed 11.8% and 23.3% of the total SO2 and NOX emissions, respectively. The transportation sector contributed 28.9% of the total NOX emissions. Emissions from the residential sector accounted for 31.3%, 21.5%, 46.6% and 71.7% of the total PM2.5, NMVOC, BC and OC emissions, respectively. In addition, more than 90% of the total NH3 emissions originate from the agriculture sector, with 44.2% from fertilizer use and 47.7% from livestock. The spatial distribution results illustrate that air pollutant emissions are mainly distributed over the eastern and southern BTH regions. Beijing, Tianjin, Shijiazhuang, Tangshan and Handan are the major contributors of air pollutants. The major NMVOC species in the BTH region are ethylene, acetylene, ethane and toluene. Ethylene is the biggest contributor in Tianjin and Hebei. The largest contributor in Beijing is toluene. There is relatively low uncertainty in SO2 and NOX emission estimates, medium uncertainty in PM2.5, PM10 and CO emission estimates, and high uncertainties in VOC, NH3, BC and OC emission estimates. The proposed policy recommendations, based on the BTH 2013 emission inventory, would be helpful to develop strategies for air pollution control.



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Development of an environmental chamber for evaluating the performance of low-cost air quality sensors under controlled conditions

Publication date: Available online 4 October 2017
Source:Atmospheric Environment
Author(s): Vasileios Papapostolou, Hang Zhang, Brandon J. Feenstra, Andrea Polidori
A state-of-the-art integrated chamber system has been developed for evaluating the performance of low-cost air quality sensors. The system contains two professional grade chamber enclosures. A 1.3 m³ stainless-steel outer chamber and a 0.11 m³ Teflon-coated stainless-steel inner chamber are used to create controlled aerosol and gaseous atmospheres, respectively. Both chambers are temperature and relative humidity controlled with capability to generate a wide range of environmental conditions. The system is equipped with an integrated zero-air system, an ozone and two aerosol generation systems, a dynamic dilution calibrator, certified gas cylinders, an array of Federal Reference Method (FRM), Federal Equivalent Method (FEM), and Best Available Technology (BAT) reference instruments and an automated control and sequencing software. Our experiments have demonstrated that the chamber system is capable of generating stable and reproducible aerosol and gas concentrations at low, medium, and high levels. This paper discusses the development of the chamber system along with the methods used to quantitatively evaluate sensor performance. Considering that a significant number of academic and research institutions, government agencies, public and private institutions, and individuals are becoming interested in developing and using low-cost air quality sensors, it is important to standardize the procedures used to evaluate their performance. The information discussed herein provides a roadmap for entities who are interested in characterizing air quality sensors in a rigorous, systematic and reproducible manner.

Graphical abstract

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Assessing Doping Prevalence is Possible. So What Are We Waiting For?

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Low Energy Availability in Athletes: A Review of Prevalence, Dietary Patterns, Physiological Health, and Sports Performance

Abstract

In a high-performance sports environment, athletes can present with low energy availability (LEA) for a variety of reasons, ranging from not consuming enough food for their specific energy requirements to disordered eating behaviors. Both male and female high-performance athletes are at risk of LEA. Longstanding LEA can cause unfavorable physiological and psychological outcomes which have the potential to impair an athlete's health and sports performance. This narrative review summarizes the prevalence of LEA and its associations with athlete health and sports performance. It is evident in the published scientific literature that the methods used to determine LEA and its associated health outcomes vary. This contributes to poor recognition of the condition and its sequelae. This review also identifies interventions designed to improve health outcomes in athletes with LEA and indicates areas which warrant further investigation. While return-to-play guidelines have been developed for healthcare professionals to manage LEA in athletes, behavioral interventions to prevent the condition and manage its associated negative health and performance outcomes are required.

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Does the type of renal artery anatomic variant determine the diameter of the main vessel supplying a kidney? A study based on CT data with a particular focus on the presence of multiple renal arteries

Abstract

Background

An in-depth knowledge of renal vascular anatomy is essential when planning many surgical procedures; however, a few data exists regarding renal artery diameter. The aim of this study was to assess this morphological feature and to investigate whether a correlation exists between renal artery diameter and the type of arterial supply, with a particular emphasis on variant anatomy and the presence of multiple renal arteries.

Materials and methods

Computed tomography angiography (CTA) studies of 248 patients, i.e., a total of 496 kidneys, were evaluated. The mean age of the patients was 66.4 ± 15.01 years. Renal artery diameter was measured based on the type of arterial blood supply.

Results

The frequency of occurrence of three anatomic variants of renal arterial supply was established: single renal artery (RA) 43.35%, single artery with prehilar branching (pRA) 37.30%, and multiple renal artery (mRA) 19.35%. The diameter of single renal arteries, with either prehilar or hilar branching, was significantly larger than when multiple arteries were present. A detailed analysis of just the mRA variant demonstrated that the diameter of the renal arteries in men was larger (p = 0.012) than those in women and that there was no difference in diameter with regard to the side of the body (p = 0.219).

Conclusions

The classification described in our study containing a detailed description of renal artery diameter. It may be helpful in clinical practice, especially for transplantologists, surgeons, and vascular surgeons.

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Organotypic brain explant culture as a drug evaluation system for malignant brain tumors

Abstract

Therapeutic options for malignant brain tumors are limited, with new drugs being continuously evaluated. Organotypic brain slice culture has been adopted for neuroscience studies as a system that preserves brain architecture, cellular function, and the vascular network. However, the suitability of brain explants for anticancer drug evaluation has been unclear. We here adopted a mouse model of malignant glioma based on expression of H-Ras^V12 in Ink4a/Arf^−/− neural stem/progenitor cells to establish tumor-bearing brain explants from adult mice. We treated the slices with cisplatin, temozolomide, paclitaxel, or tranilast and investigated the minimal assays required to assess drug effects. Serial fluorescence-based tumor imaging was sufficient for evaluation of cisplatin, a drug with a pronounced cytotoxic action, whereas immunostaining of cleaved caspase 3 (a marker of apoptosis) and of Ki67 (a marker of cell proliferation) was necessary for the assessment of temozolomide action and immunostaining for phosphorylated histone H3 (a marker of mitosis) allowed visualization of paclitaxel-specific effects. Staining for cleaved caspase 3 was also informative in the assessment of drug toxicity for normal brain tissue. Incubation of explants with fluorescently labeled antibodies to CD31 allowed real-time imaging of the microvascular network and complemented time-lapse imaging of tumor cell invasion into surrounding tissue. Our results suggest that a combination of fluorescence imaging and immunohistological staining allows a unified assessment of the effects of various classes of drug on the survival, proliferation, and invasion of glioma cells, and that organotypic brain slice culture is therefore a useful tool for evaluation of antiglioma drugs.

Establishment, culture, and analysis of tumor-bearing brain explants as a drug evaluation system for malignant brain tumors.

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Development and validation of a nomogram predicting the overall survival of stage IV breast cancer patients

Abstract

This study aimed to develop a nomogram to predict the overall survival (OS) of stage IV breast cancer patients. We searched the National Cancer Database (NCDB) for stage IV breast cancer patients diagnosed between 2010 and 2013. Predictors of OS were identified and a nomogram was developed and validated using concordance index (C-index), calibration plots, and risk group stratifications. A total of 7199 patients from the NCDB were included in the study. With a median follow-up of 25.7 months, the 1-year and 3-year OS rates were 80.6% and 52.5%, respectively. Race, age, comorbidity status, T-stage, grade, ER/PR/Her2 status, the presence of lung/liver/brain metastasis, surgery, radiotherapy, and chemotherapy were significantly associated with OS. The developed nomogram had a C-index of 0.722 (95% CI 0.710–0.734) and 0.725 (95% CI 0.713–0.736) in the training and the validation cohorts, respectively. The predicted survival using the nomogram is well correlated with actual OS. The nomogram was able to stratify patients into different risk groups, among which the survival benefit of local therapy varied. We developed a nomogram to predict the overall survival of stage IV breast cancer patients. Prospectively designed studies with international collaborations are needed to further validate our nomogram.

Nomogram to predict the overall survival stage IV breast cancer patients. This would be helpful to clinical decision-making.

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Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update

Abstract

Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging drugs have been tested in the last two decades within the context of phase I/II trials. In parallel, advances in genetic profiling have permitted to identify key molecular alterations for which new strategies are being developed. We performed a systematic review focused on the design and outcome of early-phase trials evaluating new agents in patients with relapsed medulloblastoma. PubMed, clinicaltrials.gov, and references from selected studies were screened to identify phase I/II studies with reported results between 2000 and 2015 including patients with medulloblastoma aged <18 years. A total of 718 studies were reviewed and 78 satisfied eligibility criteria. Of those, 69% were phase I; 31% phase II. Half evaluated conventional chemotherapeutics and 35% targeted agents. Overall, 662 patients with medulloblastoma/primitive neuroectodermal tumors were included. The study designs and the response assessments were heterogeneous, limiting the comparisons among trials and the correct identification of active drugs. Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies was 0% (0–100) and 6.5% (0–50), respectively. Temozolomide containing regimens had a median ORR of 16.5% (0–100). Smoothened inhibitors trials had a median ORR of 8% (3–8). Novel drugs have shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone for new combinations. Novel and more homogenous trial designs might facilitate the development of new drugs.

This systematic review in early-phase trials in patients with medulloblastoma summarizes the recent experience in therapeutic strategies in patients with relapsed and refractory medulloblastoma and highlights the strengths and pitfalls of current trials.

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Racial disparities in pancreatic neuroendocrine tumors survival: a SEER study

Abstract

Pancreatic neuroendocrine tumor (pancreatic NETs), is an important cause of cancer-related death worldwide. No study has rigorously explored the impact of ethnicity on pancreatic NETs. We aimed to demonstrate the relationship between ethnicity and the survival of patients with pancreatic NETs. We used the SEER database to identify patients with pancreatic NETs from 2004 to 2013. Kaplan–Meier methods and Cox proportional hazard models were used to evaluate the impact of race on survival in pancreatic NETs patients. A total of 3850 patients were included: 3357 Non-Blacks, 493 Blacks. We stratified races as "Black" and "White/Other." Blacks were more likely to be diagnosed with later stages of tumors (P = 0.021). As for the treatment, the access to surgery seemed to be more limited in Blacks than non-Black patients (P = 0.012). Compared with non-Black patients, Black patients have worse overall survival (OS) (HR = 1.17, 95% CI: 1.00–1.37, P = 0.046) and pancreatic neuroendocrine tumors specific survival (PNSS) (HR = 1.22, 95% CI: 1.01–1.48, P = 0.044). Multivariate Cox analysis identified that disease extension at the time of diagnosis and surgical status contributed to the ethnical survival disparity. Black patients whose stages at diagnosis were localized had significantly worse OS (HR = 2.09, 95% CI: 1.18–3.71, P = 0.011) and PNSS (HR = 3.79, 95% CI: 1.62–8.82, P = 0.002). As for the patients who did not receive surgery, Blacks also have a worse OS (HR = 1.18, 95% CI: 1.00–1.41, P = 0.045). The Black patients had both worse OS and PNSS compared to non-Black patients. The restricted utilization of surgery, and the advanced disease extension at the time of diagnosis are the possible contributors to poorer survival of Blacks with pancreatic NETs.

Our work demonstrates that Blacks with pancreatic neuroendocrine tumors have poor survival than non-Black patients. The possible contributors to this survival disparity may be later diagnosis, less access to surgery and genetic differences.

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Dynamic changes of urine proteome in a Walker 256 tumor-bearing rat model

Abstract

Despite advances in cancer treatments, early diagnosis of cancer is still the most promising way to improve outcomes. Without homeostatic control, urine reflects systemic changes in the body and can potentially be used for early detection of cancer. In this study, a tumor-bearing rat model was established by subcutaneous injection of Walker 256 cells. Urine samples from tumor-bearing rats were collected at five time points during cancer development. Dynamic urine proteomes were profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Several urine proteins that changed at multiple time points were selected as candidate cancer biomarkers and were further validated by multiple reaction monitoring (MRM) analysis. It was found that the urinary protein patterns changed significantly with cancer development in a tumor-bearing rat model. A total of 10 urinary proteins (HPT, APOA4, CO4, B2MG, A1AG, CATC, VCAM1, CALB1, CSPG4, and VTDB) changed significantly even before a tumor mass was palpable, and these early changes in urine could also be identified with differential abundance at late stages of cancer. Our results indicate that urine proteins could enable early detection of cancer at an early onset of tumor growth and monitoring of cancer progression.

Urine is a noninvasive and attractive biofluid for biomarker research, and has the potential to reflect early and small pathological changes in the body. Urine proteins changed significantly with cancer development in a tumor-bearing rat model. Our results indicate that urine proteins could enable early detection of cancer at an early onset of tumor growth and monitoring of cancer progression.

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Incidence, risk factors, and outcomes of central venous catheter-related thromboembolism in breast cancer patients: the CAVECCAS study

Abstract

Previous epidemiologic studies investigating central venous catheter (CVC)-related venous thromboembolism (CRT) were conducted in heterogenous cancer populations and data in breast cancer (BC) remain limited. To investigate the Doppler ultrasound (DUS)-CRT incidence, risk factors and outcomes in BC, we designed a prospective, multicenter cohort of nonmetastatic invasive BC patients undergoing insertion of a CVC for chemotherapy. All patients underwent double-blind DUS before, 7, 30, and 90 days after CVC insertion and a 6 months clinical follow-up. Symptomatic DUS-CRT were treated by anticoagulants. D-Dimers, thrombin generation, and platelet-derived microparticles were measured before and 2 days after CVC placement. In DUS-CRT patients, a nested case–control study analyzed the role of thrombophilia. Among 524 patients, the DUS-CRT (14 symptomatic, 46 asymptomatic) cumulative probability was 9.6% at 3 months and 11.5% at 6 months (overall incidence rate: 2.18/100 patient-months). Ten/14 symptomatic DUS-CRT were detected on double-blind DUS before the clinical symptoms, and 3/14 had a simultaneous pulmonary embolism. No clinical thrombotic event subsequently occurred in untreated asymptomatic DUS-CRT. Age >50 years (OR, 1.80; 95% CI, 1.01–3.22), BMI >30 kg/m² (OR, 2.64; 95% CI, 1.46–4.76) and comorbidities (OR, 2.05; 95% CI, 1.18–3.56) were associated with DUS-CRT. No biomarkers was found to predict DUS-CRT. In multivariate analysis, BMI >30 kg/m² (OR, 2.66; 95%CI, 1.46–4.84) and lobular carcinoma histology (OR, 2.56; 95%CI, 1.32–4.96) remained the only significant DUS-CRT risk factors. Thrombophilia did not account for DUS-CRT. Only clinical parameters identified high risk DUS-CRT patients who may be considered for thromboprophylaxis.

Data regarding central venous catheter-related thrombosis (CRT) in breast cancer (BC) patients are limited, although CVC placement for chemotherapy is common in this population and BC is the first cause of cancer in women worldwide. We conducted a large prospective multicentre study (9 cancer hospitals, 524 patients). The 6-months cumulative probability of symptomatic and asymptomatic CRT was 11.5%. BMI >30 kg/m² and lobular carcinoma histology were the main risk factors for CRT.

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Application of a novel prognostic invasive lesion index in ductal carcinoma in situ with minimal invasion of the breast

Abstract

Multiple invasive foci has been shown to increase the risk of lymph node metastasis (LNM) in early breast cancer, but its prognostic implication remains unknown. We aimed to identify the prognostic value of the number of invasive foci in ductal carcinoma in situ with minimal invasion of the breast (DCIS-MI), and further establish a prognostic invasive lesion index (ILI). A total of 193 patients with DCIS-MI (the invasive component was up to 10 mm in diameter) were included. Univariate and multivariate analysis (logistic regression) were used to evaluate the predictive value of the number of invasive foci in LNM. The Kaplan–Meier curve was used for survival analysis. More than five invasive foci was an independent predictor for LNM (OR, 2.67, 95% CI, 1.12–6.33, P = 0.026), and associated with significantly shorter disease-free survival (DFS) and overall survival (OS) compared with no more than five invasive foci (mean DFS 123.8 vs. 148.0 months, P = 0.002; and mean OS 133.5 vs. 151.4 months, P = 0.025). The ILI was established by the sum scores of the number of invasive foci and the invasive component size, having an optimal cut-off point of 5.5 scores. The high-ILI group (ILI >5 scores) had a higher incidence of LNM (23.6% vs. 6.9%) and worse prognosis than the low-ILI group (ILI ≤5 scores). In conclusion, more than five invasive foci was an independent predictor for LNM and an unfavorable prognostic parameter. The ILI could potentially be used to predict survival prognosis in patients with DCIS-MI.

Multiple invasive foci has been shown to increase the risk of lymph node metastasis (LNM) in early breast cancer, but its prognostic implication remains unknown. In this study, we found that more than five invasive foci is an independent predictor for LNM and an unfavorable prognostic parameter. Furthermore, the invasive lesion index, established by the number of invasive foci and the invasive component size, could potentially be used to predict survival prognosis in patients with DCIS-MI.

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Social determinants of stage IV anal cancer and the impact of pelvic radiotherapy in the metastatic setting

Abstract

Anal cancer is a relatively rare malignancy, and a minority of patients present with metastatic disease in the United States. The National Cancer Database (NCDB) was used to identify factors associated with metastatic disease at presentation and evaluate the role of pelvic radiotherapy in these patients. The NCDB was queried for patients with squamous cell cancer of the anus diagnosed between 2004 and 2013. Patients were stratified by clinical stage at diagnosis, and a binary logistic regression model was created to identify factors associated with metastatic disease at diagnosis. A secondary metastatic cohort was generated and a multivariable Cox proportional hazards model was created to identify factors associated with improved survival. To validate findings, propensity-score matching was performed to generate a 1:1 paired dataset stratified by receipt of pelvic radiotherapy. The primary analysis cohort consisted of 28,500 patients. Facility location, male gender, and lack of insurance were confirmed as independent risk factors for metastatic disease. The metastatic cohort consisted of 1264 patients. Multivariable analysis confirmed female sex, possession of a private or Medicare insurance plan, pelvic radiotherapy, and chemotherapy as independent predictors of improved survival. A propensity-score matched cohort of 730 patients was generated. The median survival was 17.6 months in patients who received radiotherapy versus 14.5 months in those who did not (P < 0.01). In this cohort, male gender and lack of insurance were associated with metastatic disease at presentation. Furthermore, a significant benefit was associated with the use of pelvic radiotherapy. Future prospective research is warranted to confirm these findings.

Using the National Cancer Database, male gender, facility location, and lack of insurance were associated with metastatic disease at presentation. Furthermore, a significant benefit was associated with the use of pelvic radiotherapy in these patients.

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Does the type of renal artery anatomic variant determine the diameter of the main vessel supplying a kidney? A study based on CT data with a particular focus on the presence of multiple renal arteries

Abstract

Background

An in-depth knowledge of renal vascular anatomy is essential when planning many surgical procedures; however, a few data exists regarding renal artery diameter. The aim of this study was to assess this morphological feature and to investigate whether a correlation exists between renal artery diameter and the type of arterial supply, with a particular emphasis on variant anatomy and the presence of multiple renal arteries.

Materials and methods

Computed tomography angiography (CTA) studies of 248 patients, i.e., a total of 496 kidneys, were evaluated. The mean age of the patients was 66.4 ± 15.01 years. Renal artery diameter was measured based on the type of arterial blood supply.

Results

The frequency of occurrence of three anatomic variants of renal arterial supply was established: single renal artery (RA) 43.35%, single artery with prehilar branching (pRA) 37.30%, and multiple renal artery (mRA) 19.35%. The diameter of single renal arteries, with either prehilar or hilar branching, was significantly larger than when multiple arteries were present. A detailed analysis of just the mRA variant demonstrated that the diameter of the renal arteries in men was larger (p = 0.012) than those in women and that there was no difference in diameter with regard to the side of the body (p = 0.219).

Conclusions

The classification described in our study containing a detailed description of renal artery diameter. It may be helpful in clinical practice, especially for transplantologists, surgeons, and vascular surgeons.

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Facilitating electroconvulsive therapy seizure induction: Lower pulse frequency or longer stimulus duration?

Publication date: Available online 4 October 2017
Source:Brain Stimulation
Author(s): Chittaranjan Andrade




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Improving cancer patient emergency room utilization: A New Jersey state assessment

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Anthony J. Scholer, Omar M. Mahmoud, Debopyria Ghosh, Jacob Schwartzman, Mohammed Farooq, Javier Cabrera, Robert Wieder, Nabil R. Adam, Ravi J. Chokshi
IntroductionDue to its increasing incidence and its major contribution to healthcare costs, cancer is a major public health problem in the United States. The impact across different services is not well documented and utilization of emergency departments (ED) by cancer patients is not well characterized. The aim of our study was to identify factors that can be addressed to improve the appropriate delivery of quality cancer care thereby reducing ED utilization, decreasing hospitalizations and reducing the related healthcare costs.MethodsThe New Jersey State Inpatient and Emergency Department Databases were used to identify the primary outcome variables; patient disposition and readmission rates. The independent variables were demographics, payer and clinical characteristics. Multivariable unconditional logistic regression models using clinical and demographic data were used to predict hospital admission or emergency department return.ResultsA total of 37,080 emergency department visits were cancer related with the most common diagnosis attributed to lung cancer (30.0%) and the most common presentation was pain. The disposition of patients who visit the ED due to cancer related issues is significantly affected by the factors of race (African American OR=0.6, p value=0.02 and Hispanic OR=0.5, p value=0.02, respectively), age aged 65 to 75years (SNF/ICF OR 2.35, p value=0.00 and Home Healthcare Service OR 5.15, p value=0.01, respectively), number of diagnoses (OR 1.26, p value=0.00), insurance payer (SNF/ICF OR 2.2, p value=0.02 and Home Healthcare Services OR 2.85, p value=0.07, respectively) and type of cancer (breast OR 0.54, p value=0.01, prostate OR 0.56, p value=0.01, uterine OR 0.37, p value=0.02, and other OR 0.62, p value=0.05, respectively). In addition, comorbidities increased the likelihood of death, being transferred to SNF/ICF, or utilization of home healthcare services (OR 1.6, p value=0.00, OR 1.18, p value=0.00, and OR 1.16, p value=0.04, respectively). Readmission is significantly affected by race (American Americans OR 0.41, standard error 0.08, p value=0.001 and Hispanics OR 0.29, standard error 0.11, p value=0.01, respectively), income (Quartile 2 OR 0.98, standard error 0.14, p value 0.01, Quartile 3 OR 1.07, standard error 0.13, p value 0.01, and Quartile 4 OR 0.88, standard error 0.12, p value 0.01, respectively), and type of cancer (prostate OR 0.25, standard error 0.09, p value=0.001).ConclusionWeb based symptom questionnaires, patient navigators, end of life nursing and clinical cancer pathways can identify, guide and prompt early initiation of treat before progression of symptoms in cancer patients most likely to visit the ED. Thus, improving cancer patient satisfaction, outcomes and reduce health care costs.



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Intentional partial odontectomy—a long-term follow-up study

Abstract

Background

The surgical extraction of the third molar is the most frequently encountered procedure in oral and maxillofacial surgery and is related with a variety of complications. This study examined the efficacy of intentional partial odontectomy (IPO) in the third molars which have no periapical lesions and are located near important anatomical structures such as inferior alveolar nerve.

Methods

Seven patients (four males, three females, 39.1 ± 11.6 years), who received IPO to reduce the risk of inferior alveolar nerve injury (IANI), were followed long-term. The treated teeth were horizontally impacted third molars in the mandibular left (n = 5) or mandibular right (n = 4) areas and were all ankylosed with the surrounding alveolar bone. During the IPO, the bone around the crown was removed to expose the crown, and then the tooth was resected at cement-enamel junction (CEJ). Any secondary trauma to the healthy root was minimized and remained intact after primary suture.

Results

The mean follow-up time was 63.2 ± 29.8 months, and all sites showed good bone healing after the crown removal. Also, sensory abnormality was not found in any patients after IPO. In one patient, the bone fragments erupted 4 months after IPO. In other patient, an implant placed on second molar site adjacent to the third molar that received IPO was explanted about 2 years after the patient's persistent discomfort.

Conclusions

In case where high risk of IANI exists, IPO may be chosen alternatively to surgical extraction to reduce the risk of nerve damage.

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Comparison of Circulating miRNAs Expression Alterations in Matched Tissue and Plasma Samples During Colorectal Cancer Progression

Abstract

MicroRNAs (miRNAs) have been found to play a critical role in colorectal adenoma-carcinoma sequence. MiRNA-specific high-throughput arrays became available to detect promising miRNA expression alterations even in biological fluids, such as plasma samples, where miRNAs are stable. The purpose of this study was to identify circulating miRNAs showing altered expression between normal colonic (N), tubular adenoma (ADT), tubulovillous adenoma (ADTV) and colorectal cancer (CRC) matched plasma and tissue samples. Sixteen peripheral plasma and matched tissue biopsy samples (N n = 4; ADT n = 4; ADTV n = 4; CRC n = 4) were selected, and total RNA including miRNA fraction was isolated. MiRNAs from plasma samples were extracted using QIAamp Circulating Nucleic Acid Kit (Qiagen). Matched tissue-plasma miRNA microarray experiments were conducted by GeneChip® miRNA 3.0 Array (Affymetrix). RT-qPCR (microRNA Ready-to-use PCR Human Panel I + II; Exiqon) was used for validation. Characteristic miRNA expression alterations were observed in comparison of AD and CRC groups (miR-149*, miR-3196, miR-4687) in plasma samples. In the N vs. CRC comparison, significant overexpression of miR-612, miR-1296, miR-933, miR-937 and miR-1207 was detected by RT-PCR (p < 0.05). Similar expression pattern of these miRNAs were observed using microarray in tissue pairs, as well. Although miRNAs were also found in circulatory system in a lower concentration compared to tissues, expression patterns slightly overlapped between tissue and plasma samples. Detected circulating miRNA alterations may originate not only from the primer tumor but from other cell types including immune cells.

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Metabolic characteristics of programmed cell death-ligand 1-expressing lung cancer on 18F-fluorodeoxyglucose positron emission tomography/computed tomography

Abstract

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have been identified as novel targets of immunotherapy of lung cancer. In present study, we evaluated the metabolic characteristics of lung cancer by using ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) with regard to PD-L1 protein expression. PD-L1 protein expression was evaluated by immunohistochemistry with the antibody clone SP142 in 579 surgically resected primary lung cancer patients. Cases with less than 5% tumor membrane staining were considered negative. We examined the association between the frequency of PD-L1 protein expression and the maximum standardized uptake value (SUVmax) in preoperative ¹⁸F-FDG PET/CT. The cut-off values for SUVmax were determined by receiver operating characteristic curve analyses. The SUVmax was significantly higher in nonsmall cell lung cancer (NSCLC) patients with PD-L1 protein expression compared with those without PD-L1 protein expression (P < 0.0001). However, there was no correlation between SUVmax and PD-L1 protein expression in patients with neuroendocrine tumors (P = 0.6545). Multivariate analysis revealed that smoking, the presence of pleural invasion, and high SUVmax were independent predictors of PD-L1 positivity. PD-L1-expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative ¹⁸F-FDG PET/CT was a predictor of PD-L1 protein expression in patients with NSCLC.

PD-L1-expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative 18F-FDG PET/CT was a predictor of PD-L1 protein expression in patients with NSCLC.

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Layer- and Subregion-Specific Differences in the Neurophysiological Properties of Rat Medial Prefrontal Cortex Pyramidal Neurons

Medial prefrontal cortex (mPFC) is critical for the expression of long term conditioned fear. However, the neural circuits involving fear memory acquisition and retrieval are still unclear. Two subregions within mPFC that have received a lot of attention are the prelimbic (PL) and infralimbic (IL) cortices (e.g., Santini et al. 2008; Song et al. 2015). Interestingly, PL and IL may play distinct roles during fear memory acquisition and retrieval but the underlying mechanism is poorly understood. One possibility is that the intrinsic membrane properties differ between these subregions. Thus, the current study was carried out to characterize the basic membrane properties of mPFC neurons in different layers and subregions. We found that pyramidal neurons in L2/3 were more hyperpolarized and less excitable than in L5. This was observed in both IL and PL and was associated with an enhanced h-current in L5 neurons. Within L2/3, IL neurons were more excitable than those in PL, which may be due to a lower spike threshold and higher input resistance in IL neurons. Within L5, the intrinsic excitability was comparable between neurons obtained in IL and PL. Thus, the heterogeneity in physiological properties of mPFC neurons may underlie the observed subregion-specific contribution of mPFC in cognitive function and emotional control, such as fear memory expression.

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Force illusions and drifts observed during muscle vibration

We explored predictions of a scheme that views position and force perception as a result of measuring proprioceptive signals within a reference frame set by ongoing efferent process. In particular, this hypothesis predicts force illusions caused by muscle vibration and mediated via changes in both afferent and efferent components of kinesthesia. Healthy subjects performed accurate steady force production tasks by pressing with the four fingers of one hand (the task hand) on individual force sensors with and without visual feedback. At various times during the trials, subjects matched the perceived force using the other hand. High-frequency vibration was applied to one or both of the forearms (over the hand and finger extensors). Without visual feedback, subjects showed a drop in the task hand force, which was significantly smaller under the vibration of that forearm. Force production by the matching hand was consistently higher than that of the task hand. Vibrating one of the forearms affected the matching hand in a manner consistent with the perception of higher magnitude of force produced by the vibrated hand. The findings were consistent between the dominant and non-dominant hands. The effects of vibration on both force drift and force mismatching suggest that vibration led to shifts in both signals from proprioceptors and the efferent component of perception, the referent coordinate and/or co-activation command. The observations fit the hypothesis on combined perception of kinematic-kinetic variables with little specificity of different groups of peripheral receptors that all contribute to perception of forces and coordinates.

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State-Dependent Rhythmogenesis and Frequency Control in a Half-Center Locomotor CPG

The spinal locomotor central pattern generator (CPG) generates rhythmic activity with alternating flexion and extension phases. This rhythmic pattern is likely to result from inhibitory interactions between neural populations representing flexor and extensor half-centers. However, it is unclear whether the flexor-extensor CPG has a quasi-symmetric organization with both half-centers critically involved in rhythm generation, features an asymmetric organization with flexor-driven rhythmogenesis, or comprises a pair of intrinsically rhythmic half-centers. There are experimental data that support each of the above concepts but appear to be inconsistent with the others. In this theoretical/modeling study, we present and analyze a CPG model architecture that can operate in different regimes consistent with the above three concepts depending on conditions, which are defined by external excitatory drives to CPG half-centers. We show that control of frequency and phase durations within each regime depends on network dynamics, defined by the regime-dependent expression of the half-centers' intrinsic rhythmic capabilities and the operating phase transition mechanisms (escape versus release). Our study suggests state-dependency in locomotor CPG operation and proposes explanations for seemingly contradictory experimental data.

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Calcium dynamics control K-ATP channel mediated bursting in substantia nigra dopamine neurons: a combined experimental and modeling study

Burst firing in medial substantia nigra dopamine (mSN DA) neurons has been selectively linked to novelty-induced exploration behavior in mice. Burst firing in mSN DA neurons, in contrast to lateral SN DA neurons, requires functional ATP-sensitive potassium channels (K-ATP) both in vitro and in vivo. However, the precise role of K-ATP channels in promoting burst firing is un-known. We show experimentally that L-type calcium channel activity in mSN DA neurons en-hances open probability of K-ATP channels. We then generated a mathematical model to study the role of Ca²⁺ dynamics driving K-ATP channel function in mSN DA neurons during bursting. In our model, Ca²⁺ influx leads to local accumulation of ADP due to Ca-ATPase activity, which in turn activates K-ATP channels. If K-ATP channel activation reaches levels sufficient to terminate spiking, rhythmic bursting occurs. The model explains the experimental observation that, in vitro, co-application of NMDA and a selective K-ATP channel opener, NN414, are required to elicit bursting as follows. Simulated NMDA receptor activation increases the firing rate and the rate of Ca²⁺ influx, which increases the activation of K-ATP. The model suggests that additional sources of hyperpolarization, such as GABAergic synaptic input, are recruited in vivo for burst termination or rebound burst discharge. The model predicts that NN414 increases the sensitivity of the K-ATP channel to ADP, promoting burst firing in vitro, and that that high levels of Ca²⁺ buffering, as might be expected in the calbindin-positive DA SN subpopulation, promote rhyth-mic bursting pattern, consistent with experimental observations in vivo.

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TRPC5 is required for the NO-dependent increase in dendritic Ca2+ and GABA release from chick retinal amacrine cells

GABAergic signaling from amacrine cells (ACs) is a fundamental aspect of visual signal processing in the inner retina. We have previously shown that nitric oxide (NO) can elicit release of GABA independently from activation of voltage-gated Ca²⁺ channels in cultured retinal ACs. This voltage-independent quantal GABA release relies on a Ca²⁺ influx mechanism with pharmacological characteristics consistent with the involvement of transient receptor potential canonical (TRPC) channels TRPC4 and/or TRPC5. To determine the identity of these channels, we evaluate the ability of NO to elevate dendritic Ca²⁺ and to stimulate GABA release from cultured ACs under conditions known to alter the function of TRPC4 and 5. We find that these effects of NO are phospholipase C-dependent, have a biphasic dependence on La³⁺ and are unaffected by moderate concentrations of the TRPC4 selective antagonist ML204. Together, these results suggest that NO promotes GABA release by activating TRPC5 channels in AC dendrites. To confirm a role for TRPC5, we knocked down the expression of TRPC5 using CRISPR/Cas9-mediated gene knockdown and found that both the NO-dependent Ca²⁺ elevations and increase in GABA release are dependent upon the expression of TRPC5. These results demonstrate a novel NO-dependent mechanism for regulating neurotransmitter output from retinal ACs.

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ACh-induced hyperpolarization and decreased resistance in mammalian type II vestibular hair cells.

In the mammalian vestibular periphery, electrical activation of the efferent vestibular system (EVS) has two effects on afferent activity: 1) increases background afferent discharge; and 2) decreases afferent sensitivity to rotational stimuli. While the cellular mechanisms underlying these two contrasting afferent responses remain obscure, we postulated that the reduction in afferent sensitivity was attributed, in part, to the activation of alpha9-containing nAChRs ( 9nAChRs) and small-conductance potassium channels (SK) in vestibular type II hair cells, as demonstrated in the peripheral vestibular system of other vertebrates. To test this hypothesis, we examined the effects of the predominant EVS neurotransmitter acetylcholine (ACh) on vestibular type II hair cells from wild type (wt) and α9nAChR-subunit knockout (α9-/-) mice. Immunostaining for choline acetyltransferase revealed there were no obvious gross morphological differences in the peripheral EVS innervation among any of these strains. ACh application onto wt type II hair cells, at resting potentials, produced a fast inward current followed by a slower outward current, resulting in membrane hyperpolarization and decreased membrane resistance. Hyperpolarization and decreased resistance were due to gating of SK channels. Consistent with activation of α9*nAChRs and SK channels, these ACh-sensitive currents were antagonized by the α9*nAChR blocker strychnine and SK blockers apamin and tamapin. Type II hair cells from α9-/- mice, however, failed to respond to ACh at all. These results confirm the critical importance of α9nAChRs in efferent modulation of mammalian type II vestibular hair cells. Application of exogenous ACh reduces electrical impedance thereby decreasing type II hair cell sensitivity.

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Figure-ground organization in the visual cortex: does meaning matter?

Figure-ground organization in the visual cortex is generally assumed to be based partly on general rules, and partly on specific influences of object recognition in higher centers as found in the temporal lobe. To see if shape familiarity influences figure-ground organization we tested border-ownership selective neurons in monkey V1-V2 with silhouettes of human and monkey face profiles and 'nonsense' silhouettes constructed by mirror-reversing the front part of the profile. We found no superiority of face silhouettes compared to nonsense shapes in eliciting border-ownership signals over all. However, in some neurons, border-ownership signals differed strongly between the two categories consistently across many different profile shapes. Surprisingly, this category selectivity appeared as early as 70 ms after stimulus onset, which is earlier than the typical latency of shape selective responses, but compatible with the earliest face selective responses in the inferior temporal lobe. While our results provide no evidence for a delayed top-down influence from object recognition centers, they indicate sophisticated shape categorization mechanisms that are much faster than generally assumed.

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Case Studies in Neuroscience: A Dissociation of Balance and Posture Demonstrated by Camptocormia

Upright stance in humans requires an intricate exchange between the neural mechanisms that control balance and those that control posture; however, the distinction between these control systems is hard to discern in healthy subjects. By studying balance and postural control of a participant with camptocormia - an involuntary flexion of the trunk during standing that resolves when supine - a divergence between balance and postural control was revealed. A kinematic and kinetic investigation of standing and walking showed a stereotyped flexion of the upper body by almost 80 degrees over a few minutes, and yet the participant's ability to control their center of mass within their base of support and to compensate for external perturbations remained intact. This unique case also revealed the involvement of automatic, tonic control of the paraspinal muscles during standing and the effects of attention. Although strength was reduced and MRI showed a reduction in muscle mass, there was sufficient strength to maintain an upright posture under voluntary control and when using geste antagoniste maneuvers or "sensory tricks" from visual, auditory and haptic biofeedback. Dual-tasks that either increased or decreased the attention given to postural alignment would decrease, or increase the postural flexion, respectively. The custom-made, 'twister' device that measured axial resistance to slow passive rotation revealed abnormalities in axial muscle tone distribution during standing. The results suggest that the disorder in this case was due to a disruption in the automatic, tonic drive to the postural muscles and myogenic changes were secondary.

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A murine model for quantitative, real-time evaluation of convection-enhanced delivery (RT-CED) using an 18[F]-positron emitting, fluorescent derivative of dasatinib

The blood brain barrier can limit the efficacy of systemically delivered drugs in treating neurological malignancies; therefore, alternate routes of drug administration must be considered. The Abl-kinase inhibitor, dasatinib, is modified to give compound 1 ([18F]-1) so that 18F-positron emission tomography (PET) and fluorescent imaging can both be used to observe drug delivery to murine orthotopic glioma. In vitro western blotting, binding studies (IC50 = 22 ± 5 nM), and cell viability assays (IC50 = 46 ± 30 nM) confirm nanomolar, in vitro effectiveness of [18F]-1, a dasatinib derivative that is visible by 18F-PET and fluorescence. [18F]-1 is used to image dynamic direct drug delivery via two different drug delivery techniques to orthotopic murine brainstem glioma (mBSG) bearing mice. Convection enhanced delivery (CED) delivers higher concentrations of drug to glioma-containing volumes vs. systemic, tail-vein delivery. Accurate delivery and clearance data pertaining to dasatinib are observed, providing personalized information that is important in dosimetry and redosing. Cases of missed drug delivery are immediately recognized by PET/CT, allowing for prompt intervention in the case of missed delivery.

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Pharmacological dual inhibition of tumor and tumor-induced functional limitations in transgenic model of breast cancer

Breast cancer progression is associated with systemic effects including functional limitations and sarcopenia without the appearance of overt cachexia. Autocrine/paracrine actions of cytokines/chemokines produced by cancer cells mediate cancer progression and functional limitations. The cytokine-inducible transcription factor NF-B could be central to this process, as it displays oncogenic functions and is integral to the Pax7:MyoD:Pgc-1β:miR-486 myogenesis axis. We tested this possibility using the MMTV-PyMT transgenic mammary tumor model and the NF-B inhibitor dimethylaminoparthenolide (DMAPT). We observed deteriorating physical and functional conditions in PyMT+ mice with disease progression. Compared to wild type mice, tumor-bearing PyMT+ mice showed decreased fat mass, impaired rotarod performance, and reduced grip strength as well as increased extracellular matrix (ECM) deposition in muscle. Contrary to acute cachexia models described in the literature, mammary tumor progression was associated with reduction in skeletal muscle stem/satellite-specific transcription factor Pax7. Additionally, we observed tumor-induced reduction in Pgc-1β in muscle, which controls mitochondrial biogenesis. DMAPT treatment starting at 6-8 weeks age prior to mammary tumor occurrence delayed mammary tumor onset and tumor growth rates without affecting metastasis. DMAPT overcame cancer-induced functional limitations and improved survival, which was accompanied with restoration of Pax7, Pgc-1β, and mitochondria levels and reduced ECM levels in skeletal muscles. In addition, DMAPT restored circulating levels of six out of 13 cancer-associated cytokines/chemokines changes to levels seen in healthy animals. These results reveal a pharmacological approach for overcoming cancer-induced functional limitations and the above noted cancer/drug-induced changes in muscle gene expression could be utilized as biomarkers of functional limitations.

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Gamma secretase inhibition by BMS-906024 enhances efficacy of paclitaxel in lung adenocarcinoma

Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor (GSI), and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin (mean CI value = 0.54 and 0.85, respectively, P = 0.01). On an extended panel of 31 NSCLC cell lines, 25 of which were adenocarcinoma, the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (mean CI = 0.43 vs. 0.90, respectively; P = 0.003). Paclitaxel-induced Notch1 activation was associated with synergy between BMS-906024 and paclitaxel in the KRAS- or BRAF-mutant group. Knockdown of mutant KRAS increased the synergy between BMS-906024 and paclitaxel in heterozygous KRAS-mutant cell lines. Among KRAS- or BRAF-mutant NSCLC, there was a significant correlation between synergy and mutant or null TP53 status, as well as between synergy and a low H2O2 pathway signature. Exogenous overexpression of activated Notch1 or Notch3 had no effect on the enhanced sensitivity of NSCLC to paclitaxel by BMS-906024. In vivo studies with cell line- and patient-derived lung adenocarcinoma xenografts confirmed enhanced antitumor activity for BMS-906024 plus paclitaxel versus either drug alone via decreased cell proliferation and increased apoptosis. These results show that BMS-906024 sensitizes NSCLC to paclitaxel, and that wildtype KRAS and BRAF status may predict better patient response to the combination therapy.

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Acquired resistance to FGFR inhibitor in diffuse-type gastric cancer through an AKT-independent PKC-mediated phosphorylation of GSK3{beta}

Preclinical models of diffuse type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish diffuse type gastric cancer patient-derived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the FGFR2 gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3β as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with PKC inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3β with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 in vitro synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multi-kinase inhibitor with PKC inhibiting activity in part reversed resistance of GAGA6-R tumor to AZD4547 in vivo. Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signalling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3β to gain a survival advantage.

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The irreversible covalent fibroblast growth factor receptor inhibitor PRN1371 exhibits sustained inhibition of FGFR after drug clearance

An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors.

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

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



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Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Teresa M. Petrella, Caroline Robert, Erika Richtig, Wilson H. Miller, Giuseppe V. Masucci, Euan Walpole, Celeste Lebbe, Neil Steven, Mark R. Middleton, Darcy Hille, Wei Zhou, Nageatte Ibrahim, Jonathan Cebon
ObjectiveReport results of patient-reported health-related quality of life (HRQoL) and symptoms from phase III KEYNOTE-006 study of pembrolizumab versus ipilimumab in patients with ipilimumab-naive advanced melanoma.Patients and methodsPatients received pembrolizumab 10 mg/kg every 2 (Q2W) or every 3 weeks (Q3W) for up to 2 years, or four cycles of ipilimumab 3 mg/kg Q3W. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was administered at baseline and throughout the study. Patient-reported outcome (PRO) analyses were pre-specified exploratory endpoints; the primary PRO assessment was the score change from baseline to week 12 in EORTC QLQ-C30 global health status (GHS)/HRQoL score between the arms using constrained longitudinal data analysis.ResultsThe PRO analysis population included 776 patients: pembrolizumab Q2W (n = 270); pembrolizumab Q3W (n = 266); ipilimumab (n = 240). Baseline GHS was similar across arms. QLQ-C30 compliance rates at week 12 were 87% (n = 214), 97% (n = 226), and 96% (n = 178), for the pembrolizumab Q2W, pembrolizumab Q3W, and ipilimumab arms, respectively. From baseline to week 12, GHS/HRQoL scores were better maintained with pembrolizumab than with ipilimumab (decrease of −1.9 and −2.5 for pembrolizumab versus −10.0 for ipilimumab; p < 0.001 for each pembrolizumab arm versus ipilimumab). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31% for pembrolizumab Q2W; 29% for Q3W and 44% for ipilimumab), with similar trends observed for individual functioning and symptoms scales.ConclusionsHRQoL was better maintained with pembrolizumab than with ipilimumab in patients with ipilimumab-naive advanced melanoma.ClinicalTrials.gov identifierNCT01866319.



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Insight in taste alterations during treatment with protein kinase inhibitors

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



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

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



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Outcomes for Umbilical Cord Blood Transplantation in Severe Combined Immunodeficiency Disorders: Ten-Year Experience

Pediatric Allergy, Immunology, and Pulmonology Sep 2017, Vol. 30, No. 3: 171-180.


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Inhaling Essential Oils: Purported Benefits and Harms

Pediatric Allergy, Immunology, and Pulmonology Sep 2017, Vol. 30, No. 3: 186-188.


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

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



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Comparison of the Effect of Dexamethasone and Tranexamic Acid, Separately or in Combination on Post-Rhinoplasty Edema and Ecchymosis

Abstract

Background

Dexamethasone and tranexamic acid are used to decrease post-rhinoplasty periorbital edema and ecchymosis. We compared the impact of each medication separately or in combination in this regard.

Methods

A prospective, randomized triple-blinded study was undertaken on 60 patients who underwent primary open rhinoplasty. They were divided into four groups: Group D (n = 15) received 8 mg dexamethasone, group T (n = 15) received 10 mg/kg tranexamic acid, group DT (n = 15) received both 8 mg dexamethasone and 10 mg/kg tranexamic acid, and group P (n = 15) received neither medication and served as the placebo control group. The medications were given intravenously (IV) 1 h before and three doses every 8 h postoperatively. Digital photographs were taken on the first, third and seventh postoperative days. One expert examiner blinded to the study evaluated the periorbital edema and ecchymosis on a scale of 0–4. Periorbital edema and ecchymosis were examined in all groups.

Results

In group D, group T and group DT, periorbital edema and ecchymosis ratings were significantly lower compared with the control group (p < 0.01). No statistically significant difference was seen in preventing or decreasing both periorbital edema and ecchymosis among group D, group T and group DT.

Conclusion

Tranexamic acid and dexamethasone, separately or in combination, had similar effects in reducing periorbital edema and ecchymosis in open rhinoplasty. Combined application did not show a significantly higher beneficial effect in this regard.

Level of Evidence III

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

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Outcomes of treatment with sandblasted implants. a long-term clinical study

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Sedation options for implant surgery

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Low-invasive implant therapy with individualized dental implants

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An in vitro investigation of human gingival fibroblast proliferation on dental titanium implants treated with selective laser melting technology

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The full digital workflow

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Single implant placement in the aesthetic area: immediate loading versus traditional delayed: surgical approach and 5 years long term evaluation

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Effects of Angelica Sinensis extract on proliferation and differentiation of rat bone marrow mesenchymal stem cells

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Improving biomechanics in removable partial dentures with implants. Clinical report -8 years follow-up

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Immediate and early loading of tapered implants in extraction sites: 10-year retrospective follow-up

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Impact of abutment material and soft tissue thickness on mucosa discoloration: a spectrophotometric in vitro study

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The effect of fibronectin derived fibrin-binding peptide fragments on periodontal ligament cell migration: an in vitro wound healing model

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Clinical outcome of dental implants in vascularized fibular osteoseptocutaneous flap as onlay graft on marginal mandibulectomy patients

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Advances in the Management of HER2-Positive Early Breast Cancer

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




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

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



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Should we be rethinking follow-up for oral cancer patients?

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Denosumab-related osteonecrosis of the jaw: a retrospective study

Abstract

Background

Osteonecrosis of the jaw is a very delicate side effect of Denosumab. The aim of this retrospective study is to assess the occurrence rate of Denosumab-related osteonecrosis of the jaw (DRONJ) at the Cancer Institute of Lorraine (ICL) and to highlight necrosis risk factors.

Methods

To that purpose we analyzed the medical records of 249 consecutive patients treated with Denosumab at the ICL during the past 5 years. Patients who received oro-facial radiotherapy or a previous treatment with a bisphosphonate were excluded. The p value was set at 0.005.

Results

141 patients treated at the ICL between January 2010 and December 2015 were included. All patients were treated with XGEVA^®. Of the 141 patients included in the study, 10 developed DRONJ. The incidence of DRONJ increases with the duration of follow-up: 3% at 1 year, 7% at 2 years and 8% from 30 months on. No risk factor for necrosis could be identified except the realization of prior dental extraction (p=0.025).

Conclusion

Our results raise important questions about the dental management of these patients, in particular concerning the healing period between dental extractions and the initiation of Denosumab.

This article is protected by copyright. All rights reserved.

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Need Surgery for Melanoma? Which Insurance Causes Delays?

When categorized by insurance type, Medicaid patients had longer delays for melanoma surgery than patients with Medicare and private insurance.
Medscape Medical News

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Reduction in harm from tracheostomy related incidents after implementation of the paediatric National Tracheostomy Safety Project resources: a retrospective analysis from a tertiary paediatric centre

Abstract

In the UK, patient safety issues related to adult tracheostomies are well recognised. A number of reports from the National Patient Safety Agency and National Confidential Enquiry into Patient Outcome and Death highlighted recurrent themes with deficiencies in staff education, resources, equipment provision and emergency guidance.^1,2. Similar patient safety concerns exist in the paediatric population. Studies report overall mortality rates in paediatric patients with tracheostomies varying from 2.2%³ to 58.8%,⁴ whilst tracheostomy-specific mortality is lower at 0.9%⁵ to 5.9%.⁴ Within our institution, concerns were noted regarding the risk of serious avoidable tracheostomy morbidity after merging three paediatric hospitals onto a single site in 2009.

This article is protected by copyright. All rights reserved.

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A collaborative in-situ simulation-based pediatric readiness improvement program for community emergency departments

Abstract

Background

More than 30 million children are cared for across 5,000 US emergency departments each year (ED). Most of these EDs are not facilities designed and operated solely for children. A web-based survey provided a national and state-by-state assessment of pediatric readiness and noted a national average score was 69 on a 100-point scale. This survey noted wide variations in ED readiness with scores ranging from 61 in low-pediatric-volume EDs to 90 in the high-pediatric-volume EDs. Additionally, the mean score at the state level ranged from 57 (Wyoming) to 83 (Florida) and for individual EDs ranged from 22 to 100. The majority of prior efforts made to improve pediatric readiness have involved providing web-based resources and online toolkits. This paper reports on the first year of a program that aimed to improve pediatric readiness across community hospitals in our state through in situ simulation-based assessment facilitated by our academic medical center. The primary aim was to improve the pediatric readiness scores in the ten participating hospitals. The secondary aim was to explore the correlation of simulation-based performance of hospital teams with pediatric readiness scores.

Methods

This interventional study measured the PRS prior to and after implementation of an improvement program. This program consisted of three components: (1) in-situ simulations; (2) report outs; and (3) access to online pediatric readiness resources and content experts. The simulations were conducted in situ (in the ED resuscitation bay) by multi-professional teams of doctors, nurses, respiratory therapists and technicians. Simulations and debriefings were facilitated by an expert team from a pediatric academic medical center. Three scenarios were conducted for all teams and include: a six-month-old with respiratory failure, an eight-year-old with diabetic ketoacidosis (DKA), and a six-month-old with supraventricular tachycardia (SVT). A performance score was calculated for each scenario. The improvement of PRS was compared before and after the simulation program. The correlation of the simulation performance of each hospital and the PRS was calculated.

Results

41 multi-professional teams from ten EDs in Indiana participated in the study, five were of medium pediatric volume and five were medium-high volume EDs. The PRS significantly improved from the first to the second on-site verification assessment (58.4±4.8 to 74.7±2.9, p=0.009). Total adherence scores to scenario guidelines were: 54.7%, 56.4% and 62.4% in the respiratory failure, DKA and SVT scenarios respectively. We found no correlation between simulation performance and PRS scores. Medium ED pediatric volume significantly predicted higher PRS scores compared to medium-high pediatric ED volume (β=8.7; CI: 0.72, 16.8, p=0.034).

Conclusion(s)

Our collaborative improvement program that involved simulation was associated with improvement in pediatric readiness scores in ten EDs participating statewide. Future work will focus on further expanding of the network and establishing a national model for pediatric readiness improvement.

This article is protected by copyright. All rights reserved.

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