Pharmacokinetic/pharmacodynamic analysis of adjunctive perampanel in subjects with partial-onset seizures

Objectives

Explore perampanel pharmacokinetics (PK) in all subjects (aged ≥12 years) vs adolescents (aged ≥12 to ≤17 years) with partial-onset seizures (POS) and identify factors explaining between-subject variability in efficacy using a population PK/pharmacodynamic (PD) analysis.

Materials & methods

Population PK analysis was performed using nonlinear mixed-effect modeling with data from phase II/III randomized, double-blind, placebo-controlled studies of adjunctive perampanel in POS. Perampanel exposure was predicted for all subjects and adolescents. Population PK/PD analyses were performed using data from phase III studies to explore the relationship between perampanel exposure and 28-day average seizure frequency and responder probability.

Results

Pooled perampanel PK data from 1318 subjects were described by a one-compartment disposition model. In the absence of antiepileptic drugs (AEDs) affecting perampanel PK, estimated perampanel apparent clearance (CL/F) was 0.668 L/h (all subjects) and 0.682 L/h (adolescent subjects). Co-administration of carbamazepine and oxcarbazepine/phenytoin reduced perampanel exposure. Gender, Asian race (excluding Japanese or Chinese), and increasing alanine aminotransferase lowered perampanel CL/F, but differences were small and not considered clinically relevant. Adolescent outcomes were similar to the total population. Based on PK/PD data from 1748 subjects, percent reduction in 28-day average seizure frequency from baseline and responder probability increased with increasing perampanel exposure; concomitant CYP3A-inducing AEDs lowered perampanel exposure but did not impact the slope for responder probability.

Conclusions

These results are consistent with previous analyses but expand on these through inclusion of a larger number of patients from different ethnic groups, and demonstrate that outcomes were similar between adults and adolescents.

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Prognosis of status epilepticus in elderly patients

Purpose

To evaluate the clinical features and prognosis of status epilepticus (SE) in patients above 70 years old.

Methods

Retrospective analysis of all patients ≥70 years old with SE registered prospectively during 4 years. Follow-up after discharge was performed.

Results

Ninety patients were evaluated. Acute symptomatic etiology was the most prevalent. The mean number of antiepileptic drugs (AEDs) used was 2.7 ± 1.2, and 21% of the patients required sedation. A poor outcome was considered when death (31.1%) or developing of new neurological impairment at discharge (32.2%) occurred. After multivariate analysis, four variables predicted a poor outcome: acute symptomatic etiology (OR: 6.320; 95% CI: 1.976-20.217; P = .002), focal motor SE type (OR: 9.089; 95% CI: 2.482-33.283; P = .001), level of consciousness (OR: 4.596; 95% CI: 1.903-11.098; P = .001), and SE duration >12 hours (OR: 3.763; 95% CI: 1.130-12.530; P = .031). Independent predictive factors of mortality were SE duration >12 hours (OR: 4.306; 95% CI: 1.044-17.757; P = .043), modified Status Epilepticus Severity Score (mSTESS) (OR: 2.216; 95% CI: 1.313-3.740; P = .003), and development of complications (OR: 3.334; 95% CI: 1.004-11.070, P = .049). Considering long-term mortality, age (HR 1.036; 95% CI 1.001-1.071; P = .044), a potentially fatal underlying cause (HR 2.609; 95% CI 1.497- 4.548; P = .001), and mSTESS score >4 (HR 1.485; 95% CI 1.158-1.903; P = .002) remained as predictive factors. There was no association between sedation and the number of AEDs used with outcome at discharge or long-term mortality (P > .05). Conclusions: SE above 70 years old has a high morbimortality. Prognosis is not related to treatment aggressiveness.

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Seizures, CSF neurofilament light and tau in patients with subarachnoid haemorrhage

Objectives

Patients with severe subarachnoid haemorrhage (SAH) often suffer from complications with delayed cerebral ischaemia (DCI) due to vasospasm that is difficult to identify by clinical examination. The purpose of this study was to monitor seizures and to measure cerebrospinal fluid (CSF) concentrations of neurofilament light (NFL) and tau, and to see whether they could be used for predicting preclinical DCI.

Methods

We prospectively studied 19 patients with aneurysmal SAH who underwent treatment with endovascular coiling. The patients were monitored with continuous EEG (cEEG) and received external ventricular drainage (EVD). CSF samples of neurofilament light (NLF) and total tau (T-tau) protein were collected at day 4 and day 10. Cox regression analysis was applied to evaluate whether seizures and protein biomarkers were associated with DCI and poor outcome.

Results

Seven patients developed DCI (37%), and 4 patients (21%) died within the first 2 months. Six patients (32%) had clinical seizures, and electrographic seizures were noted in one additional patient (4.5%). Increased tau ratio (proportion tau10/tau4) was significantly associated with DCI and hazard ratio [HR=1.33, 95% confidence interval (CI) 1.055-1.680. P = .016].

Conclusion

Acute symptomatic seizures are common in SAH, but their presence is not predictive of DCI. High values of the tau ratio in the CSF may be associated with development of DCI.

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Serial electrophysiology in Guillain-Barré syndrome: A retrospective cohort and case-by-case multicentre analysis

Objectives

To assess the usefulness of serial electrophysiology in Guillain-Barré syndrome (GBS) in a multicenter setting and the reasons for change in electrodiagnostic subtypes with serial studies.

Methods

We retrospectively analysed serial electrophysiology of 51 patients with GBS from 4 European centres. Proportions of subtypes were determined at each timing. Individual case analyses were also performed where diagnostic changes occurred with either criteria, to ascertain if changes were due to disease progression or criteria inadequacy.

Results

At first study, comparing old vs new criteria, acute inflammatory demyelinating polyneuropathy (AIDP) was diagnosed in 70.6% vs 51%, axonal GBS in 15.7% vs 39.2%, equivocal forms in 11.8% vs 7.8%. At second study, AIDP was diagnosed in 72.5% vs 52.9%, axonal GBS in 9.8% vs 33.3%, equivocal forms in 15.7% vs 11.7%. Subtype proportions were unchanged, indicating serial studies did not, in the cohort, alter diagnostic rates for each subtype irrespective of criteria used. Individual review of cases where subtype electrodiagnosis changed indicated suboptimal specificity for AIDP/sensitivity for axonal GBS as main cause of diagnostic shifts with old criteria, whereas disease progression explained most changes with new criteria (55.6% vs 81.8%; P = .039).

Conclusions

Serial electrophysiology is unhelpful in GBS. Repeat studies cannot represent the gold standard as electrodiagnosis may alter due to disease progression. Changes in electrodiagnosis relate more often to disease progression with new criteria but are more frequently due to suboptimal sensitivity/specificity with old criteria. A single electrophysiological study using the most accurate available criteria appears sufficient in GBS.

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Vocational outcome in cerebral venous thrombosis: Long-term follow-up study

Abstract

Objectives

Few studies have investigated long-term functional outcome in patients with cerebral venous thrombosis (CVT). We aimed to evaluate return to work (RTW) after CVT and its association with self-reported life satisfaction, quality of life, health, participation, fatigue, depression, and anxiety.

Methods

From hospital records, we identified all patients diagnosed with CVT in Sahlgrenska University Hospital between 1996 and 2016 and invited all survivors to a clinical follow-up visit >1 year after onset. Primary outcome was RTW within the follow-up period which was defined as ≥50% of gainful work or equivalent activity. Patients that were >62 years when they developed CVT were excluded. Cox regression analyses identified associated factors to RTW and Mann-Whitney U tests compared distributions of self-reported questionnaires on life satisfaction and health.

Results

Of 62 eligible and consenting patients (median age: 41.5 years (28.75-51.0); 61.3% female), 44 (71.0%) did RTW within the follow-up period (median 135 months, IQR 64-197). Median time to RTW was 7.0 months (IQR 1.4-12.7). Female sex (HR = 0.50, 95% CI = 0.25-0.99, P = .049) and parenchymal lesion detected during acute hospital stay (HR = 0.45, 95% CI = 0.24-0.82, P = .009) were significantly associated with no RTW. Patients with RTW reported significantly higher life satisfaction, quality of life, health, participation and lesser impact of fatigue, depression, and anxiety.

Conclusions

Return to work after CVT is associated with higher life satisfaction, participation, and health. Parenchymal lesion in acute phase and female sex were associated with no RTW. Despite the young age of the patients, a significant portion did not regain working ability.

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Real-life clinical use of natalizumab and fingolimod in Austria

Objectives

To compare the efficacy of natalizumab or fingolimod in a nationwide observational cohort using prospectively collected data.

Materials and methods

We included all patients starting treatment with natalizumab or fingolimod documented in the Austrian MS Treatment Registry (AMSTR) from 2011 and staying on therapy for at least 24 months. We used propensity scores for several matching methods and as a covariate in multivariate models to correct for the bias of this non-randomized registry study.

Results

The study cohort includes 588 patients with RRMS. Ten patients did not produce a propensity score in the common support region, thus leaving 578 cases for final analyses, 332 in the fingolimod and 246 in the natalizumab group. Mean annualized relapse rates (ARR) during the 24 months observation period were 0.19 under fingolimod and 0.12 under natalizumab treatment (P = .005). No statistical significant differences were found analysing the log-transformed ARR, probability for experiencing a relapse, EDSS progression and EDSS regression. The hazard ratio for switching treatment from fingolimod comparing with natalizumab was 0.36 (95% CI: 0.247-0.523), P < .001.

Conclusions

The generalized linear model (GLM) for relapse count as Poisson distributed dependent variable and propensity score as covariate showed a statistically significant reduction for the mean relapse count in the natalizumab group compared with fingolimod. This effect was smaller in the analyses of log-transformed ARR with propensity score matching, loosing statistical significance although showing the same direction for the effect. We assume that the GLM was the more sensitive model analysing this question.

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Aneuploidy, TP53 mutation, and amplification of MYC correlate with increased intratumor heterogeneity and poor prognosis of breast cancer patients

Abstract

The clinical course of breast cancer varies from one patient to another. Currently, the choice of therapy relies on clinical parameters and histological and molecular tumor features. Alas, these markers are informative in only a subset of patients. Therefore, additional predictors of disease outcome would be valuable for treatment stratification. Extensive studies showed that the degree of variation of the nuclear DNA content, i.e., aneuploidy determines prognosis. Our aim was to further elucidate the molecular basis of aneuploidy. We analyzed five diploid and six aneuploid tumors with more than 20 years of follow-up. By performing FISH with a multiplexed panel of 10 probes to enumerate copy numbers in individual cells, and by sequencing 563 cancer-related genes, we analyzed how aneuploidy is linked to intratumor heterogeneity. In our cohort, none of the patients with diploid tumors died of breast cancer during follow-up in contrast to four of six patients with aneuploid tumors (mean survival 86.4 months). The FISH analysis showed markedly increased genomic instability and intratumor heterogeneity in aneuploid tumors. MYC gain was observed in only 20% of the diploid cancers, while all aneuploid cases showed a gain. The mutation burden was similar in diploid and aneuploid tumors, however, TP53 mutations were not observed in diploid tumors, but in all aneuploid tumors in our collective.

We conclude that quantitative measurements of intratumor heterogeneity by multiplex FISH, detection of MYC amplification and TP53 mutation could augment prognostication in breast cancer patients. This article is protected by copyright. All rights reserved.

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Functions of the multi-interacting protein KIDINS220/ARMS in cancer and other pathologies

Abstract

Development of an organ and subsequently the whole system from an embryo is a highly integrated process. Although there are evidence that different systems are interconnected during developmental stages, the molecular understanding of this relationship is either not known or only to a limited extent. Nervous system development, amongst all, is maybe the most crucial and complex process. It relies on the correct distribution of specific neuronal growth factors and hormones to the specific receptors. Among the plethora of proteins that are involved in downstream signalling of neuronal growth factors, we find the Kinase-D Interacting Substrate of 220 kDa (KIDINS220), also known as Ankyrin-rich Repeat Membrane Spanning (ARMS) protein. KIDINS220 has been shown to play a substantial role in the nervous system and vascular system development as well as in neuronal survival and differentiation. It serves as a downstream regulator for many important neuronal and vascular growth factors such as Vascular Endothelial Growth Factor (VEGF), the neurotrophin family, glutamate receptors and ephrin receptors. Moreover, activation and differentiation of B- and T-cells, as well as tumour cell proliferation has also shown to be related KIDINS220. This review comprehensively summarises the existing research data on this protein, with a particular interest in its role in cancer and in other pathologies. This article is protected by copyright. All rights reserved.

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Re: Should every medical student have exposure to robotic surgery?

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Measuring childhood cancer late effects: evidence of a healthy survivor effect

Abstract

Introduction

Given considerable focus on health outcomes among childhood cancer survivors, we aimed to explore whether survivor bias is apparent during long-term follow-up of childhood cancer survivors.

Methods

We identified all 1-year survivors of cancer diagnosed before 20 years of age in Denmark, Finland, Iceland, and Sweden. From the general population, we randomly sampled a comparison cohort. Study individuals were followed for hospitalizations for diseases of the gastroenterological tract, endocrine system, cardiovascular system, or urinary tract from the start of the cancer registries to 2010. We estimated cumulative incidence with death as competing risk and used threshold regression to compare the hazards of the diseases of interest at ages 20, 40, 60, and 75 years.

Results

Our study included 27,007 one-year survivors of childhood cancer and 165,620 individuals from the general population. The cumulative incidence of all four outcomes was higher for childhood cancer survivors during early adulthood, but for three outcomes, the cumulative incidence was higher for the general population after age 55 years. The hazard ratios (HRs) decreased for all outcomes with increasing age, and for two of the outcomes, the hazards were higher for the general population at older ages (endocrine diseases: age-specific HRs = 3.0, 1.4, 1.0, 0.87; Cardiovascular diseases: age-specific HRs = 4.1, 1.4, 0.97, 0.84).

Conclusions

Our findings provide empirical evidence that survivor bias attenuates measures of association when comparing survivors with the general population. The design and analysis of studies among childhood cancer survivors, particularly as this population attains older ages, should account for survivor bias to avoid misinterpreting estimates of disease burden.

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Phantom validation of quantitative Y-90 PET/CT-based dosimetry in liver radioembolization

Abstract

Background

PET/CT has recently been shown to be a viable alternative to traditional post-infusion imaging methods providing good quality images of ⁹⁰Y-laden microspheres after selective internal radiation therapy (SIRT). In the present paper, first we assessed the quantitative accuracy of ⁹⁰Y-PET using an anthropomorphic phantom provided with lungs, liver, spine, and a cylindrical homemade lesion located into the hepatic compartment. Then, we explored the accuracy of different computational approaches on dose calculation, including (I) direct Monte Carlo radiation transport using Raydose, (II) Kernel convolution using Philips Stratos, (III) local deposition algorithm, (IV) Monte Carlo technique (MCNP) considering a uniform activity distribution, and (V) MIRD (Medical Internal Radiation Dose) analytical approach. Finally, calculated absorbed doses were compared with those obtained performing measurements with LiF:Mg,Cu,P TLD chips in a liquid environment.

Results

Our results indicate that despite ⁹⁰Y-PET being likely to provide high-resolution images, the ⁹⁰Y low branch ratio, along with other image-degrading factors, may produce non-uniform activity maps, even in the presence of uniform activity. A systematic underestimation of the recovered activity, both for the tumor insert and for the liver background, was found. This is particularly true if no partial volume correction is applied through recovery coefficients. All dose algorithms performed well, the worst case scenario providing an agreement between absorbed dose evaluations within 20%. Average absorbed doses determined with the local deposition method are in excellent agreement with those obtained using the MIRD and the kernel-convolution dose calculation approach.

Finally, absorbed dose assessed with MC codes are in good agreement with those obtained using TLD in liquid solution, thus confirming the soundness of both calculation approaches. This is especially true for Raydose, which provided an absorbed dose value within 3% of the measured dose, well within the stated uncertainties.

Conclusions

Patient-specific dosimetry is possible even in a scenario with low true coincidences and high random fraction, as in ⁹⁰Y–PET imaging, granted that accurate absolute PET calibration is performed and acquisition times are sufficiently long. Despite Monte Carlo calculations seeming to outperform all dose estimation algorithms, our data provide a strong argument for encouraging the use of the local deposition algorithm for routine ⁹⁰Y dosimetry based on PET/CT imaging, due to its simplicity of implementation.

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Management of hereditary breast and ovarian cancer

Abstract

Hereditary breast and ovarian cancer (HBOC) syndrome represents 5−10% of all breast cancers. In Japan, the HBOC syndrome is frequently diagnosed in patients with breast cancer. Therefore, a treatment strategy combining a plan for existing breast cancer and for reduction of future breast and ovarian cancer risk is necessary. Breast cancer risk-reducing management involves three options—surveillance, chemoprevention, and risk-reducing mastectomy (RRM). RRM can prevent >90% of new breast cancers. Ovarian cancer risk management options are more limited, and risk-reduction salpingo-oophorectomy is the only option since there is no proven effective early detection method available. The local recurrence rate following breast-conserving surgery in BRCA1/2 mutation-associated breast cancer is not significantly higher than that in sporadic breast cancer. Furthermore, there is no difference in prognosis between surgical methods. Clinicians should inform patients that there are no data on long-term monitoring and fully discuss risks of re-developing breast cancer with patients when choosing the surgical method. In HBOC, BRCA1/2 mutations lead to failure of double-strand DNA break repair, with poly ADP-ribose polymerase (PARP) playing an important role in single-strand DNA nick repair. Use of PARP inhibitors in HBOC prevents DNA repair (synthetic lethality) leading to cell death. This review summarizes management of the HBOC syndrome based on recent evidence.

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Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer

Abstract

Background

In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (2 cycles of cisplatin 50 mg/m2 in week 1 and 4 of RT, followed by 4 cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required prior to patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation.

Patients and methods

A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n=395) and the United Kingdom (n=900), and for 1226/1295 (95%) matching review and original reports were available. 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the United Kingdom, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ).

Results

In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70).

Conclusion

Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved.This study is registered with ISRCTN (ISRCTN14387080, http://ift.tt/HkCGY7) and with ClinicalTrials.gov (NCT00411138).

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Quantitative CT assessment of a novel direction-modulated brachytherapy tandem applicator

Publication date: Available online 27 November 2017
Source:Brachytherapy
Author(s): Alyaa H. Elzibak, Petronella M. Kager, Abraam Soliman, Moti R. Paudel, Habib Safigholi, Dae Yup Han, Aliaksandr Karotki, Ananth Ravi, William Y. Song
PurposeThe purpose of this study was to quantitatively assess the CT metal-induced artifacts from a novel direction-modulated brachytherapy (DMBT) tandem applicator prototype, recently designed for cervical cancer treatments.Methods and materialsA water-based pelvic phantom was constructed for CT scanning. The DMBT applicator was imaged using our institutional protocol, one with higher kVp and mAs settings, and repetition of these protocols using 3-mm slices. A conventional stainless steel applicator was also scanned. In addition to the standard reconstructed images, applicator images were reconstructed using a commercial metal artifact-reduction (MAR) algorithm and an in-house–developed research algorithm. Subsequently, image quality and artifact severity were evaluated.ResultsArtifact severity, measured in terms of SDs in CT numbers, decreased asymptotically to background water levels with the distance away from the applicator. Artifact-reduction algorithms lead to significant and visible improvements in image quality, with >50% and >20% decrease in artifact severity achieved at a 10-mm distance for the DMBT and stainless steel applicators, respectively. Differences in artifact severity were minimal between the four imaging protocols. DMBT dimensions were the same on images with and without the commercial MAR algorithm, within <1 mm of the theoretical value. Both the commercial and in-house algorithms restored the CT numbers outside the applicator, albeit a better performance was achieved by the in-house algorithm.ConclusionsThe artifacts produced by both applicators were minimized with the use of MAR algorithms. Adoption of the DMBT and stainless steel applicators for CT-guided brachytherapy is anticipated as MAR algorithms are widely available on CT scanners.



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Tuberculosis in Pap Samples with Emphasis on LBC: Caught Only When Thought

Despite being a commonly encountered infection, the clinical diagnosis of tuberculosis of the uterine cervix is elusive. Though a straightforward diagnosis on tissue sections, identification of typical features of tubercular infection on cervical Pap samples is challenging. In our experience, the infrequent pale staining collections of epithelioid cells are difficult to pick up on Pap stained smears, particularly LBC samples. In this series, 2 of the three samples were reported as atypical squamous cells of undetermined significance while 1 was reported as inflammatory at the initial diagnosis. Scattered Langhans' type giant cells may be seen as a subtle clue which should prompt the search for epithelioid cell granulomas. These cases may have a mass lesion clinically while no obvious signs of malignancy on the cervical samples.

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Cysticercosis and cytodiagnosis

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Acknowledgment to reviewers

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Mycotic pseudoaneurysm of a pulmonary artery branch caused by Cladosporium

We report the case of a 53-year-old male with a history of acute myelogenous leukemia, who suffered the rupturing of a right-sided pulmonary artery pseudoaneurysm combined with pneumonia. He underwent a right-sided lower lobectomy. The resected lung tissue demonstrated a mycotic pseudoaneurysm of a pulmonary artery branch together with a filamentous fungal infection. Pseudoaneurysms are caused by the breaching of all layers of a blood vessel wall. The extravasated blood is trapped by the surrounding extravascular tissue or clots. Cladosporium was detected during a polymerase chain reaction-based analysis followed by DNA sequencing of formalin-fixed paraffin-embedded lung tissue samples. Although previous cases of pulmonary artery pseudoaneurysms caused by fungal infections, e.g., Candida or Aspergillus sp., have been reported, to the best of our knowledge this is the first case to involve cladosporiosis.

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Heterotopic Ossification During a Ventral Hernia Repair

In this report, a case of heterotopic ossification is observed in a patient who presented for ventral hernia repair.
ePlasty, Open Access Journal of Plastic Surgery

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Attelle nasale externe sur-mesure après rhinoplastie, introduction au concept de « tissu-modelage »

Publication date: Available online 27 November 2017
Source:Annales de Chirurgie Plastique Esthétique
Author(s): E. Auclair, W. Noel
Les auteurs rapportent leur expérience de 2 ans (43 patients) d'utilisation d'une attelle « sur-mesure » constituée de thermoplastique qui est moulée sur le nouveau nez au terme de la rhinoplastie, selon un procès comparable à celui utilisé par les dentistes pour fabriquer les gouttières. Cette attelle sera portée plusieurs semaines afin de guider la cicatrisation dans une direction désirée. Le moulage du nez peut-être re-sculpté pour guider la cicatrisation vers un meilleur résultat. Légère, lavable, discrète, notre attelle a l'avantage de pouvoir être portée plusieurs semaines sans inconfort dans le but d'améliorer l'efficacité de la contention.The authors report their experience of 2 years (43 patients) using a customized splint consists of thermoplastic which is molded on the new nose after rhinoplasty, according to a process comparable to that used by dentists to make the gutters. This splint will be applied several weeks to guide healing in a desired direction. The molding of the nose can be re-sculpted to guide the scarring to a better result. Lightweight, washable, discreet, our splint works to the advantage to be worn without discomfort for several weeks in order to improve the efficiency of contention.



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Fixation des greffes de peau mince dans les brûlures de l’enfant : étude des avantages de la colle de cyanoacrylate versus agrafes

Publication date: Available online 27 November 2017
Source:Annales de Chirurgie Plastique Esthétique
Author(s): P. Curings, P.-L. Vincent, R. Viard, P. Gir, J.-P. Comparin, D. Voulliaume
IntroductionLes brûlures de l'enfant posent des problèmes spécifiques en ce qui concerne les soins locaux et les suites postopératoires. Contrairement à l'adulte qui peut bénéficier d'anesthésies locorégionales, le geste chirurgical nécessite systématiquement une anesthésie générale. Pour diminuer la durée opératoire, on utilise des agrafes cutanées plutôt que des fils de suture ; cependant, leur ablation lors du pansement de vérification de greffe nécessite une analgésie importante voire une deuxième anesthésie générale. Nous étudions l'intérêt de la colle cutanée type cyanoacrylate pour la fixation des greffes.Matériel et méthodesUne étude comparative est réalisée de 2012 à 2016. Cent dix-huit enfants ont été inclus, présentant une brûlure concernant moins de 5 % de la surface corporelle totale. Soixante-douze enfants ont bénéficié d'une fixation par agrafage cutané, 46 par colle cutanée. Nous avons évalué la qualité de prise de la greffe, la sédation nécessaire au premier pansement, la durée d'hospitalisation après la greffe, la quantité de colle utilisée et les complications éventuelles.RésultatsIl existe des différences entre les deux groupes sur l'âge et la surface corporelle brûlée (le groupe agrafe présente des patients plus âgés et d'une surface brûlée plus étendue). Le taux de prise était de 100 % dans les deux groupes. Le pansement de vérification de greffe a pu être réalisé sans analgésie ou sous analgésie légère chez tous les enfants du groupe colle cutanée, alors qu'il a nécessité une anesthésie générale chez 64 % des patients du groupe agrafes. La durée moyenne d'hospitalisation après la greffe était de 4,9jours dans le groupe colle cutanée contre 6,5jours dans le groupe agrafes. Aucune complication n'a été observée.ConclusionL'utilisation de colle cutanée permet de positionner les greffes rapidement et ne nécessite pas de deuxième temps d'anesthésie. Elle réduit donc la durée de séjour jusqu'à 25 %. Le gain médico-économique est majeur par rapport à l'utilisation d'agrafes cutanées, pour un résultat final équivalent et sans inconvénient rencontré.IntroductionLocal postoperative care and burn wound management can present with a certain degree of difficulty in the pediatric population. While the use of skin staples as a method of skin graft fixation is a well-known, rapid and simple method, their removal can be painful and may necessitate some sedation or even general anesthesia. We studied in this article the advantages and economic value of using the cyanoacrylate glue as a fixation method for skin grafts.Materials and methodsA comparative study was carried out from 2012 to 2016. Hundred and eighteen infants with burns up to 5% of total body surface area were included in the study. Seventy-two infants had split thickness skin grafts fixed with skin staples. Forty-six infants had split thickness skin grafts fixed with cyanoacrylate glue. We compared the quality of graft, the sedation used during the first postoperative dressing, the length of hospital stay, the amount of glue used and the presence of complications.ResultsThere is a difference between the two groups studied in terms of age and total burn surface area. The rate of graft take was 100% in both groups. The first postoperative dressing was carried out without the use of powerful analgesia in the cyanoacrylate group, while it was necessary to use general anesthesia in 64% of the skin staples group. The average length of stay in hospital after skin grafting was 4.9 days for the cyanoacrylate glue versus 6.5 days in the skin staples group. No complications were noted in the 2 groups.ConclusionThe use of cyanoacrylate glue allows rapid fixation of skin grafts and avoid general anesthesia for postoperative cares. Subsequently the length of hospital stay is reduced within 25%. The medico-economic value of glue protocol is highly significant compared to skin staples, while having similar good results and without significant problems.



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Characteristics of the trace elements and arsenic, iodine and bromine species in snow in east-central China

Publication date: February 2018
Source:Atmospheric Environment, Volume 174
Author(s): Yunchuan Gao, Chao Yang, Jin Ma, Meixue Yin
Fifty-five snow samples were collected from 11 cities in east-central China. These sampling sites cover the areas with the most snowfall in 2014, there were only two snowfalls from June 2013 to May 2014 in east-central China. Twenty-three trace elements in the filtered snow samples were measured with inductively coupled plasma-mass spectrometry (ICP-MS). Statistical analysis of the results show that the total concentrations of elements in the samples from different cities are in the order of SJZ > LZ > XA > ZZ > GD > NJ > QD > JX > WH > HZ > LA, which are closely related to the levels of AQI, PM2.5 and PM10 in these cities, and their correlation coefficients are 0.93, 0.76 and 0.93. The concentration of elements in snow samples is highly correlated with air pollution and reflects the magnitude of the local atmospheric deposition. The concentrations of Fe, Al, Zn, Ba, and P are over 10.0 μg/L, the concentrations of Mn, Cu, Pb, As, Br and I are between 1.0 μg/L to 10.0 μg/L, the concentrations of V, Cr, Co, Ni, Se, Mo, Cd and Sb are less than 1.0 μg/L in snow samples in east-central China, and Rh, Pd, Pt, Hg were not detected. Iodine and bromine species in all samples and arsenic species (As(III), As(V), dimethylarsinic acid (DMA) and monomethyl arsenic (MMA)) in some samples were separated and measured successfully by HPLC-ICP-MS. The majority of arsenic in the snow samples is inorganic arsenic, and the concentration of As(III) (0.104–1.400 μg/L) is higher than that of As(V) (0.012–0.180 μg/L), while methyl arsenicals, such as DMA and MMA, were almost not detected. The concentration of I⁻ (Br⁻) is much higher than that of IO3⁻ (BrO3⁻). The mean concentration of soluble organic iodine (SOI) (1.64 μg/L) is higher than that of I⁻ (1.27 μg/L), however the concentration of Br⁻ (5.58 μg/L) is higher than that of soluble organic bromine (SOBr) (2.90 μg/L). The data presented here shows that SOI is the most abundant species and the majority of the total bromine is bromide in snow sampled at east-central China. Using Fe as the reference element to calculate the EFs, the enrichment factors of V, Cr, Co, Ni, Mn, Ba and P are between 12.3 and 82.8, and the enrichment factors of Cu, Pb, Mo, Zn, Cd, As, Sb, Br, I and Se are between 189.4 and 27667.9, indicating that these elements are contributed by artificial sources. Results of principal component analysis (PCA) on the elements showed that most of trace elements (e.g. V, Cr, Mn, Co, Ni, Cu, As, Mo, Sb, Se, Br, I, Ba and P)were from the combustion of fossil fuels, traffic and ocean sources and some other elements (e.g. Zn, Cd and Pb) were mainly originated from industrial activities.



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Variations of radon concentration in the atmosphere. Gamma dose rate

Publication date: February 2018
Source:Atmospheric Environment, Volume 174
Author(s): D.E. Tchorz-Trzeciakiewicz, A.T. Solecki
The purposes of research were following: observation and interpretation of variations of radon concentration in the atmosphere - vertical, seasonal, spatial and analysis of relation between average annual radon concentration and ground natural radiation and gamma dose rate. Moreover we wanted to check the occurrence of radon density currents and the possibility of radon accumulation at the foot of the spoil tip.The surveys were carried out in Okrzeszyn (SW Poland) in the area of the spoil tip formed during uranium mining that took place in 60's of 20th century. The measurements were carried out in 20 measurements points at three heights: 0.2 m, 1 m and 2 m a.g.l. using SSNTD LR-115. The survey lasted one year and detectors were exchanged at the beginning of every season. Uranium eU (ppm), thorium eTh (ppm) and potassium K (%) contents were measured using gamma ray spectrometer Exploranium RS-230, ambient gamma dose rate using radiometer RK-100.The average radon concentration on this area was 52.8 Bq m-3. The highest radon concentrations were noted during autumn and the lowest during winter. We observed vertical variations of radon concentration. Radon concentrations decreased with increase of height above ground level. The decrease of radon with increase of height a.g.l. had logarithmic character. Spatial variations of radon concentrations did not indicate the occurrence of radon density currents and accumulation of radon at the foot of the spoil tip.The analysis of relation between average radon concentrations and ground natural radiation (uranium and thorium content) or gamma dose rate revealed positive relation between those parameters. On the base of results mentioned above we suggested that gamma spectrometry measurements or even cheaper and simpler ambient gamma dose rate measurements can be a useful tool in determining radon prone areas. This should be confirmed by additional research.



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Effect of dendritic cell-cytokine-induced killer cells in patients with advanced colorectal cancer combined with first-line treatment

Abstract

Background

Surgical resection combined with adjuvant chemotherapy is considered as the gold-standard treatment for advanced colorectal cancer patients. These patients have a poor 5-year survival rate of 5% or less. Furthermore, a large dose of chemotherapy can produce adverse side effects and severe toxicity. Therefore, this retrospective study aimed to evaluate the efficacy of dendritic cell-cytokine-induced killer (DC-CIK) cell infusion as an adjuvant therapy in patients with advanced colorectal cancer combined with first-line treatment.

Methods

A total of 142 patients with stage III/IV colorectal carcinoma who had been treated with first-line therapy were included in this study. Among these patients, 71 patients received first-line treatment only (non-DC-CIK group), while the other 71 patients who had similar demographic and clinical characteristics received a DC-CIK cell infusion combined with first-line treatment (DC-CIK group). These patients were followed up until August 2014. Data were analyzed by Kaplan-Meier and Cox regression.

Results

Our results showed that the 5-year overall survival (OS) rate for the DC-CIK group versus the non-DC-CIK group was 41.3 versus 19.4% (p = 0.001) and the 5-year progression-free survival (PFS) rate for the DC-CIK group versus the non-DC-CIK group was 57.4 versus 33.6% (p = 0.022).

Conclusions

Our results showed that patients with advanced colorectal cancer might benefit from DC-CIK immunotherapy combined with first-line therapy by significantly prolonging 5-year OS and PFS.

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Life course evolution of body size and breast cancer survival in the E3N cohort

Abstract

Although adult obesity has been associated with poor breast cancer survival, data on adiposity at different periods in life and its lifelong evolution are scarce. Our aims were to assess the associations between breast cancer survival and body size during childhood, puberty, and early adulthood and body size trajectories from childhood to adulthood.

Self-assessed body size at age 8, at puberty, at age 20-25, and at age 35-40 and trajectories of body size of 4 662 breast cancer survivors from the prospective E3N cohort were studied in relation to risk of death from any cause, death from breast cancer and second invasive cancer event using multivariate Cox regression models.

Four trajectories of body size were identified (T1 "moderate increase", T2 "stable/low increase", T3 "increase at puberty", T4 "constantly high"). Compared with stable body size, an increase in body size during adult life was associated with an increased risk of death from any cause (HR T1 versus T2=1.27; 95% CI=1.01-1.60), and an increased risk of second invasive cancer event (HR T1 versus T2=1.25; 95% CI=1.06-1.47). Silhouettes at various ages were not associated with survival.

Our results suggest that the evolution of body size from childhood to adulthood has a long-term influence on breast cancer survival. Although these results need to be confirmed, this work sheds light on the need to combine lifelong approaches to current BMI to better identify breast cancer survivors who are at higher risk of recurrence or second primary cancer, or of death. This article is protected by copyright. All rights reserved.

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Postnatal myocardium remodelling generates inhomogeneity in the architecture of the ventricular mass

Abstract

Background

The 3D architecture of the ventricular mass is poorly known, although in vivo imaging techniques show the physiological inhomogeneity of ventricular walls mechanics. Polarized light imaging makes it possible to quantitatively analyse the myosin filament orientation.

Aims

In this paper, we focus on the study the 3D architecture and regional isotropy of myocardial cells.

Methods

Twenty normal human hearts, 10 from the perinatal period and 10 from the post-neonatal period were studied by polarized light microscopy. In each voxel of the ventricular mass (90 × 90 × 500 µm) the principal orientation segment was automatically and unambiguously extracted as well as a regional isotropy index (regional orientation tensor of the voxel neighbourhood).

Results

During the first months of postnatal age, the median regional isotropy values decreased in the ventricular mesh. This global decrease was not homogeneous across the ventricular walls. From the perinatal to the neonatal period, this decrease was more marked in the inner two-third of the lateral left ventricular wall and in the right part of the interventricular septum. There was a progressive post-neonatal appearance of a particularly inhomogeneous secondary arrangement of myocardial cells with alternation of thick low-RI and thin high-RI areas.

Conclusions

This study has shown a postnatal change in ventricular myocardial architecture, which became more inhomogeneous. The cell rearrangements responsible for the inhomogeneity in ventricular myocardial architecture are revealed by a variation of the regional isotropy index. These major changes are probably an adaptive consequence of the major haemodynamic changes occurring after birth during the neonatal period that generates major parietal stress variations and parietal remodelling.

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Postnatal myocardium remodelling generates inhomogeneity in the architecture of the ventricular mass

Abstract

Background

The 3D architecture of the ventricular mass is poorly known, although in vivo imaging techniques show the physiological inhomogeneity of ventricular walls mechanics. Polarized light imaging makes it possible to quantitatively analyse the myosin filament orientation.

Aims

In this paper, we focus on the study the 3D architecture and regional isotropy of myocardial cells.

Methods

Twenty normal human hearts, 10 from the perinatal period and 10 from the post-neonatal period were studied by polarized light microscopy. In each voxel of the ventricular mass (90 × 90 × 500 µm) the principal orientation segment was automatically and unambiguously extracted as well as a regional isotropy index (regional orientation tensor of the voxel neighbourhood).

Results

During the first months of postnatal age, the median regional isotropy values decreased in the ventricular mesh. This global decrease was not homogeneous across the ventricular walls. From the perinatal to the neonatal period, this decrease was more marked in the inner two-third of the lateral left ventricular wall and in the right part of the interventricular septum. There was a progressive post-neonatal appearance of a particularly inhomogeneous secondary arrangement of myocardial cells with alternation of thick low-RI and thin high-RI areas.

Conclusions

This study has shown a postnatal change in ventricular myocardial architecture, which became more inhomogeneous. The cell rearrangements responsible for the inhomogeneity in ventricular myocardial architecture are revealed by a variation of the regional isotropy index. These major changes are probably an adaptive consequence of the major haemodynamic changes occurring after birth during the neonatal period that generates major parietal stress variations and parietal remodelling.

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miR-221/222 cluster expression improves clinical stratification of non-muscle invasive bladder cancer (TaT1) patients' risk for short-term relapse and progression

Abstract

Clinical heterogeneity of bladder cancer prognosis requires the identification of bladder tumors' molecular profile to improve the prediction value of the established and clinically used markers. In the present study, we have analyzed miR-221/222 cluster expression in bladder tumors and its clinical significance for patients' prognosis and disease outcome. The study included 387 tissue specimens. Following extraction, total RNA was polyadenylated at 3΄-end and reversed transcribed. SYBR-Green based qPCR assays were performed for the quantification of miR-221/222 expression. Extensive statistical analysis was completed for the evaluation of miR-221/222 cluster's clinical significance. The expression of miR-221/222 is significantly downregulated in tumors compared to normal urothelium, while ROC curve and logistic regression analysis highlighted cluster's discriminatory ability. However, miR-222 levels were increased in muscle-invasive (T2-T4) compared to superficial tumors (TaT1), and in high compared to low-grade tumors. Kaplan-Meier survival curves and Cox regression analysis revealed the stronger risk of TaT1 patients overexpressing miR-222 for disease short-term relapse and progression following treatment. Moreover, multivariate Cox models highlighted the independent prognostic value of miR-222 overexpression for TaT1 patients' poor prognosis. Finally, the analysis of miR-222 expression improved significantly the positive prediction strength of the clinically used prognostic markers of tumor stage, grade, EORTC risk-stratification and recurrence at the first follow-up cystoscopy for TaT1 patients' outcome, and resulted to higher clinical net benefit following decision curve analysis. In conclusion, the expression of miR-221/222 cluster is deregulated in bladder tumors and miR-222 overexpression results to a superior positive prediction of TaT1 patients' short-term relapse and progression. This article is protected by copyright. All rights reserved.

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The Walking Dead: sequential nuclear and organelle destruction during hair development

Abstract

Background

Transition of hair shaft keratinocytes from actively respiring, nucleated cells to structural cells devoid of nucleus and cytoplasm, is key to hair production. This form of cell "death", or cornification, requires cellular organelle removal to allow the cytoplasm to become packed with keratin filament bundles that further require cross-linking to create a strong hair fibre. Although these processes are well described in epidermal keratinocytes, there is a lack of understanding of such mechanisms specifically in the hair follicle.

Objectives

To gain insights into cornification mechanisms within the hair follicle and thus improve our understanding of normal hair physiology.

Methods

Scalp biopsies and hair pluck samples were obtained from healthy human donors and analysed microscopically following immunohistochemical staining.

Results

A focal point of respiratory activity was evident in keratogenous zone cells within the hair shaft that also exhibited nuclear damage. Nuclear degradation occurred via both caspase-dependant and -independent pathways. Conversely, mitophagy was driven by Bnip3L and restricted to the boundary of the keratogenous zone at Adamson's Fringe.

Conclusions

We propose a model of stepwise living-dead transition within the first 1 mm of hair formation, whereby fully functional, nucleated cells first consolidate required functions by degrading nuclear DNA, yet continue to respire and provide the source of ROS required for keratin cross-linking. Finally, as the cells become packed with keratin bundles, Bnip3L expression triggers mitophagy to rid the cells of the last remaining "living" characteristic thus completing the march from "living" to "dead" within the hair follicle.

This article is protected by copyright. All rights reserved.

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Perioperative, spatiotemporally coordinated activation of T and NK cells prevents recurrence of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and NK cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells. Local T cell activation was confirmed by increased tumor infiltration with CD103+CD8+ T cells and neoantigen-specific CD8 T lymphocytes against the marker neoepitope LAMA4-G1254V. To achieve effective prevention of distant metastases in a complementary approach, we blocked the NK cell checkpoint CD96, an inhibitory NK cell receptor that binds CD155, which was abundantly expressed in primary PDAC and metastases of human patients. In gemcitabine-treated mice, neoadjuvant PD-1 blockade followed by adjuvant inhibition of CD96 significantly prevented relapse of PDAC, allowing for long-term survival. In summary, our results show in an aggressively growing transgenic mouse model of PDAC that the coordinated activation of both innate and adaptive immunity can effectively reduce the risk of tumor recurrence after surgery, facilitating long-term remission of this lethal disease.

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miR-139-5p modulates radiotherapy resistance in breast cancer by repressing multiple gene networks of DNA repair and ROS defense

Radiotherapy (RT) is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer (BC) via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both in vitro and in vivo, resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome, specifically in RT-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant BC xenografts highly amenable to sensitization by co-treatment with a miR-139-5p mimetic.

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A potent, metabolically stable tubulin inhibitor targets the colchicine binding site and overcomes taxane resistance

Antimitotics that target tubulin are among the most useful chemotherapeutic drugs, but their clinical activity is often limited by the development of multidrug resistance. We recently discovered the novel small molecule DJ101 as a potent and metabolically stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multidrug resistance of existing tubulin inhibitors. In this study, we determined the mechanism of action of this drug. The basis for its activity was illuminated by solving the crystal structure of DJ101 in complex with tubulin at a resolution of 2.8Å. Investigations of the potency of DJ101 in a panel of human metastatic melanoma cell lines harboring major clinically relevant mutations defined IC50 values of 7-10 nM. In cells, DJ101 disrupted microtubule networks, suppressed anchorage-dependent melanoma colony formation and impaired cancer cell migration. In melanoma-bearing mice, DJ101 administration inhibited tumor growth and reduced lung metastasis in the absence of observable toxicity. DJ101 also completely inhibited tumor growth in a paclitaxel-resistant xenograft mouse model of human prostate cancer (PC-3/TxR), where paclitaxel was minimally effective. Our findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation tubulin inhibitor for cancer therapy.

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Distinct TP63 isoform-driven transcriptional signatures predict tumor progression and clinical outcomes

TP63 is required to maintain stem cell pluripotency and suppresses the metastatic potential of cancer cells through multiple mechanisms. These functions are differentially regulated by individual isoforms, necessitating a deeper understanding of how the distinct transcriptional programs controlled by these isoforms affect cancer progression and outcomes. In this study, we conducted a pan-cancer analysis of The Cancer Genome Atlas (TCGA) to identify transcriptional networks regulated by TAp63 and ΔNp63 using transcriptomes derived from epidermal cells of TAp63-/- and ΔNp63-/- mice. Analysis of 17 cancer developmental and 27 cancer progression signatures revealed a consistent tumor suppressive pattern for TAp63. In contrast, we identified pleiotropic roles for ΔNp63 in tumor development and found that its regulation of Lef1 was crucial for its oncogenic role. ΔNp63 performed a distinctive role as suppressor of tumor progression by cooperating with TAp63 to modulate key biological pathways, principally cell cycle regulation, extra cellular matrix remodeling, epithelial-to-mesenchymal transition, and the enrichment of pluripotent stem cells. Importantly, these TAp63 and ΔNp63 signatures prognosticated progression and survival, even within specific stages, in bladder and renal carcinomas as well as low-grade gliomas. These data describe a novel approach for understanding transcriptional activities of TP63 isoforms across a large number of cancer types, potentially enabling identification of patient subsets most likely to benefit from therapies predicated on manipulating specific TP63 isoforms.

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New mechanisms of resistance to MEK inhibitors in melanoma revealed by intravital imaging

Targeted therapeutics that are initially effective in cancer patients nearly invariably engender resistance at some stage, an inherent challenge in the use of any molecular targeted drug in cancer settings. In this study, we evaluated resistance mechanisms arising in metastatic melanoma to MAPK pathway kinase inhibitors, as a strategy to identify candidate strategies to limit risks of resistance. To investigate longitudinal responses, we developed an intravital serial imaging approach that can directly visualize drug response in an inducible RAF-driven, autochthonous murine model of melanoma incorporating a fluorescent reporter allele (tdTomatoLSL). Using this system, we visualized formation and progression of tumors in situ starting from the single cell level longitudinally over time. Reliable reporting of the status of primary murine tumors treated with the selective MEK1/2 inhibitor (MEKi) trametinib illustrated a time-course of initial drug response and persistence followed by the development of drug resistance. We found that tumor cells adjacent to bundled collagen had a preferential persistence in response to MEKi. Unbiased transcriptional and kinome reprogramming analyses from selected treatment time points suggested increased c-Kit and PI3K/AKT pathway activation in resistant tumors, along with enhanced expression of epithelial genes and EMT downregulation signatures with development of MEKi resistance. Similar trends were observed following simultaneous treatment with BRAF and MEK inhibitors aligned to standard of care combination therapy, suggesting these re-programming events were not specific to MEKi alone. Overall, our results illuminate the integration of tumor-stroma dynamics with tissue plasticity in melanoma progression and provide new insights into the basis for drug response, persistence and resistance.

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Vitamin C sensitizes melanoma to BET inhibitors

Bromodomain and extra-terminal inhibitors (BETi) are promising cancer therapies, yet prominent side effects of BETi at effective doses have been reported in Phase I clinical trials. Here we screened a panel of small molecules targeting epigenetic modulators against human metastatic melanoma cells. Cells were pretreated with or without ascorbate (vitamin C), which promotes DNA demethylation and subsequently changes the sensitivity to drugs. Top hits were structurally unrelated BETi including JQ1, I-BET151, CPI-203, and BI-2536. Ascorbate enhanced the efficacy of BETi by decreasing acetylation of histone H4, but not H3, while exerting no effect on the expression of BRD proteins. Histone acetyltransferase 1 (HAT1), which catalyzes H4K5ac and H4K12ac, was downregulated by ascorbate mainly via the TET-mediated DNA hydroxymethylation pathway. Loss of H4ac, especially H4K5ac and H4K12ac, disrupted the interaction between BRD4 and H4 by which ascorbate and BETi blocked the binding of BRD4 to acetylated histones. Co-treatment with ascorbate and JQ1 induced apoptosis and inhibited proliferation of cultured melanoma cells. Ascorbate deficiency as modeled in Gulo-/- mice diminished the treatment outcome of JQ1 for melanoma tumorgraft. In contrast, ascorbate supplementation lowered the effective dose of JQ1 needed to successfully inhibit melanoma tumors in mice. Based on our findings, future clinical trials with BETi should consider ascorbate levels in patients. Furthermore, ascorbate supplementation might help reduce the severe side effects that arise from BETi therapy by reducing the dosage necessary for treatment.

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Utility of single cell genomics in diagnostic evaluation of prostate cancer

A distinction between indolent and aggressive disease is a major challenge in diagnostics of prostate cancer. As genetic heterogeneity and complexity may influence clinical outcome, we have initiated studies on single tumor cell genomics. In this study, we demonstrate that sparse DNA sequencing of single cell nuclei from prostate core biopsies is a rich source of quantitative parameters for evaluating neoplastic growth and aggressiveness. These include the presence of clonal populations, the phylogenetic structure of those populations, the degree of the complexity of copy number changes in those populations, and measures of the proportion of cells with clonal copy number signatures. The parameters all showed good correlation to the measure of prostatic malignancy, the Gleason score, derived from individual prostate biopsy tissue cores. Remarkably, a more accurate histopathological measure of malignancy, the surgical Gleason score, agrees better with these genomic parameters of diagnostic biopsy than it does with the diagnostic Gleason score and related measures of diagnostic histopathology. This is highly relevant since primary treatment decisions are dependent upon the biopsy and not the surgical specimen. Thus, single cell analysis has the potential to augment traditional core histopathology, improving both the objectivity and accuracy of risk assessment and inform treatment decisions.

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SHMT2 desuccinylation by SIRT5 drives cancer cell proliferation

The mitochondrial serine hydroxymethyltransferase SHMT2 which catalyzes the rate-limiting step in serine catabolism drives cancer cell proliferation, but how this role is regulated is undefined. Here we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2 which was crucial for activating its enzymatic activity. Conversely hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.

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MYC targeted long non-coding RNA DANCR promotes cancer in part by reducing p21 levels

The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here we report that MYC stimulates the transcription of DANCR, a long non-coding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell cycle inhibitor p21 (CDKN1A), and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR in vivo was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers.

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ER alpha binding by transcription factors NFIB and YBX1 enables FGFR2 signalling to modulate estrogen responsiveness in breast cancer

Two opposing clusters of transcription factors (TF) have been associated with the differential risks of estrogen receptor positive or negative breast cancers, but the mechanisms underlying the opposing functions of the two clusters are undefined. In this study, we identified NFIB and YBX1 as novel interactors of the estrogen receptor alpha (ESR1). NFIB and YBX1 are both risk TF associated with progression of ESR1-negative disease. Notably, they both interacted with the ESR1-FOXA1 complex and inhibited the transactivational potential of ESR1. Moreover, signaling through FGFR2, a known risk factor in breast cancer development, augmented these interactions and further repressed ESR1 target gene expression. We therefore show that members of two opposing clusters of risk associated with ESR1 positive and negative breast cancer can physically interact. We postulate that this interaction forms a toggle between two developmental pathways affected by FGFR2 signaling, possibly offering a junction to exploit therapeutically.

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Small molecule inhibition of Axl targets tumor immune suppression and enhances chemotherapy in pancreatic cancer

Activation of the receptor tyrosine kinase Axl is associated with poor outcomes in pancreatic cancer (PDA), where it coordinately mediates immune evasion and drug resistance. Here we demonstrate that the selective Axl kinase inhibitor BGB324 targets the tumor-immune interface to blunt the aggressive traits of PDA cells in vitro and enhance gemcitibine efficacy in vivo. Axl signaling stimulates the TBK1-NFκB pathway and innate immune suppression in the tumor microenvironment. In tumor cells, BGB324 treatment drove epithelial differentiation, expression of nucleoside transporters affecting gemcitabine response and an immune stimulatory microenvironment. Our results establish a preclinical mechanistic rationale for the clinical development of Axl inhibitors to improve the treatment of PDA patients.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2Ag1BJL

YAP1 and COX2 coordinately regulate urothelial cancer stem-like cells

Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here we report that the pro-inflammatory COX2/PGE2 pathway and the YAP1 growth regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSC. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with co-expression COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ztCOk9

Synthetic lethality of PARP inhibitors in combination with MYC blockade is independent of BRCA status in triple negative breast cancer

PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival. Combining MYC blockade with PARPi yielded synthetic lethality in MYC-driven TNBC cells. Using the cyclin-dependent kinase inhibitor dinaciclib, which downregulates MYC expression, we found that combination with the PARPi niraparib increased DNA damage and downregulated homologous recombination, leading to subsequent downregulation of the epithelial-mesenchymal transition (EMT) and cancer stem-like cell phenotypes. Notably, dinaciclib re-sensitized TBNC cells, which had acquired resistance to niraparib. We found that the synthetic lethal strategy employing dinaciclib and niraparib was also highly efficacious in ovarian, prostate, pancreatic, colon and lung cancer cells. Taken together, our results show how blunting MYC oncogene addiction can leverage cancer cell sensitivity to PARPi, facilitating the clinical use of c-myc as a predictive biomarker for this treatment.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2Ag27aF

The influence of family adaptability and cohesion on anxiety and depression of terminally ill cancer patients

Abstract

Purpose

This study investigated the effect of family members on terminally ill cancer patients by measuring the relationship of the presence of the family caregivers, visiting time by family and friends, and family adaptability and cohesion with patient's anxiety and depression.

Methods

From June, 2016 to March, 2017, 100 terminally ill cancer patients who were admitted to a palliative care unit in Seoul, South Korea, were surveyed, and their medical records were reviewed. The Korean version of the Family Adaptability and Cohesion Evaluation Scales III and Hospital Anxiety-Depression Scale was used. Chi-square and multiple logistic regression analyses were used.

Results

The results of the chi-square analysis showed that the presence of family caregivers and family visit times did not have statistically significant effects on anxiety and depression in terminally ill cancer patients. In multiple logistic regression, when adjusted for age, sex, ECOG PS, and the monthly average income, the odds ratios (ORs) of the low family adaptability to anxiety and depression were 2.4 (1.03–5.83) and 5.4 (1.10–26.87), respectively. The OR of low family cohesion for depression was 5.4 (1.10–27.20) when adjusted for age, sex, ECOG PS, and monthly average household income.

Conclusions

A higher family adaptability resulted in a lower degree of anxiety and depression in terminally ill cancer patients. The higher the family cohesion, the lower the degree of depression in the patient. The presence of the family caregiver and the visiting time by family and friends did not affect the patient's anxiety and depression.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2jp7wUQ

Management of bone health in postmenopausal women on aromatase inhibitors (AIs): a single health care system experience

Abstract

Introduction

Aromatase inhibitors (AIs) are the preferred therapy for postmenopausal women with early-stage estrogen receptor-positive breast cancers. However, their use causes bone loss and increased risks of osteoporosis and fractures.

Methods

This is a retrospective review of all postmenopausal women with breast cancer diagnosed and treated with AI between 2010 and 2015. Of the 564 women identified, 319 were eligible.

Results

The median age at AI initiation was 65 years (range 51–85 years), and the median duration of AI therapy was 28 months (1–72 months). The median number of DEXA scans per woman was 1 (0–4), performed at a median frequency of 24 months (1–48 months). Recommendations for calcium and vitamin D were in 66 and 59% of women, respectively. There were 52 (16%) women who received antiresorptive treatments with bisphosphonates (69%), denosumab (25%), or both drugs (6%). Based on guideline recommendations from six societies, starting antiresorptive treatment was unnecessary in 15–54% of women.

Conclusions

In this single health system experience, women start antiresorptive drugs that are unnecessary in 15–52%. These results highlight the nonuniformity in guideline recommendations, and this has implications for quality of care, cost-effectiveness, and value-of-care analyses for preventing fractures.

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Automatic referral to standardize palliative care access: an international Delphi survey

Abstract

Purpose

Palliative care referral is primarily based on clinician judgment, contributing to highly variable access. Standardized criteria to trigger automatic referral have been proposed, but it remains unclear how best to apply them in practice. We conducted a Delphi study of international experts to identify a consensus for the use of standardized criteria to trigger automatic referral.

Methods

Sixty international experts stated their level of agreement for 14 statements regarding the use of clinician-based referral and automatic referral over two Delphi rounds. A consensus was defined as an agreement of ≥70% a priori.

Results

The response rate was 59/60 (98%) for the first round and 56/60 (93%) for the second round. Twenty-six (43%), 19 (32%), and 11 (18%) respondents were from North America, Asia/Australia, and Europe, respectively. The panel reached consensus that outpatient palliative care referral should be based on both automatic referral and clinician-based referral (agreement = 86%). Only 18% felt that referral should be clinician-based alone, and only 7% agreed that referral should be based on automatic referral only. There was consensus that automatic referral criteria may increase the number of referrals (agreement = 98%), facilitate earlier palliative care access, and help administrators to set benchmarks for quality improvement (agreement = 86%).

Conclusions

Our panelists favored the combination of automatic referral to augment clinician-based referral. This integrated referral framework may inform policy and program development.

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Totally implantable venous access ports: a prospective long-term study of early and late complications in adult patients with cancer

Abstract

Purpose

Totally implantable venous access ports (TIVAP) have been widely used for many years in the management of patients suffering from cancer. The implantation and long-term use of TIVAPs are associated with mechanical, thrombotic, and infectious complications. This is the first exhaustive prospective study of all complications occurring in a whole population on long-term follow-up and therefore allows an objective assessment to be made of the safety of TIVAPs.

Methods

We carried out a prospective single-center observational study. All adult patients with cancer who had a TIVAP implanted between January 1 and December 31, 2006 were registered. Early and late complications were recorded until the removal of the device, the patient's death, or until December 31, 2013. Exhaustive data concerning patients and TIVAP was recorded at time of implantation.

Results

Four hundred and ninety-three TIVAPs were implanted in 483 adult cancer patients and were followed during a period from 1 to 94 months (median = 18 months) representing a global quantity of 367,359 catheter-days. Eighty-seven complications were recorded (0.237/1000 catheter-days), including 37 infections (0.101/1000 catheter-days), 17 thrombotic events (0.046/1000 catheter-days), and 9 extravasations. Out of the 87 events, 62 (71.3%) occurred during the first year after implantation. Events were therefore extremely rare after 1 year. Thromboembolic and infectious complications were rare and no risk factors for these were found.

Conclusions

This study demonstrates excellent tolerability, with only occasional complications. Most of these occurred during the year following implantation. A TIVAP may also be left in place for an extremely long time.

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Clinical equivalence with G-CSF biosimilars: methodologic approach in a (neo)adjuvant setting in non-metastatic breast cancer

Abstract

Biosimilars are biological medicines that have been shown to be similar to a reference biological medicine that has already been approved for use. Development of biosimilars is based on a "totality of evidence" approach that involves a series of steps by which biosimilars must demonstrate similarity to a reference product in all aspects of the drug and eliminate any remaining uncertainties. Clinical studies are then considered confirmatory and are performed to show that there are no clinically meaningful differences compared with the reference product in a sensitive patient population. The recombinant human granulocyte colony-stimulating factor (G-CSF) biosimilar EP2006/Zarxio® (filgrastim-sdnz) became the first FDA-approved biosimilar in 2015. This review evaluates how clinical equivalence can be demonstrated with G-CSF biosimilars through the identification of "sensitive" study populations and endpoints. Patients with non-metastatic breast cancer treated in the (neo)adjuvant setting represent a potentially homogenous population, making this a suitable sensitive indication for assessing filgrastim and pegfilgrastim biosimilars compared with reference products. This review includes clinical trials of G-CSF biosimilars in breast cancer, focusing on key aspects of the trials that were necessary to accurately demonstrate clinical equivalence and enable extrapolation to relevant indications, based on guidelines and biostatistical principles.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AdNdlo

Amisulpride in the prevention of nausea and vomiting induced by cisplatin-based chemotherapy: a dose-escalation study

Abstract

Purpose

The purpose of this study was to investigate the antiemetic effect of the dopamine D₂- and dopamine D₃-receptor antagonist, amisulpride, in patients receiving cisplatin-based chemotherapy.

Methods

This dose-finding, non-comparative study investigated the antiemetic effect and safety of increasing doses (2.5, 7.5 and 20 mg) of amisulpride against acute nausea and vomiting in the period 0–24 h after initiation of cisplatin-based chemotherapy. The 20 mg dose was also investigated in combination with the 5-HT₃-receptor antagonist, ondansetron. The primary parameter was complete response (0–24 h), defined as no emesis and no need for rescue antiemetics. Secondary parameters were number of emetic episodes, severity of nausea and time to first emetic episode and start of nausea.

Results

A total of 51 patients were enrolled and evaluable. None of the 10 patients in the 2.5 and 7.5 mg groups obtained a CR. In the 20 mg monotherapy cohort, two of the 18 subjects (11%) had a CR, 3/18 (17%) had no emesis and 12/18 (67%) had no significant nausea. Seven subjects (39%) had no nausea at all (a VAS score < 5 mm). In the combination (ondansetron plus amisulpride) cohort, 19/23 (83%; 90% confidence interval: 65–94%) had a CR and 14/23 (61%) had no nausea at all.

Conclusions

Amisulpride has antiemetic effect against cisplatin-induced acute nausea and vomiting. The effect against nausea is of particular interest. Randomised studies are warranted to further explore the effect and safety of amisulpride.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AaHuig

Impact of emotional competence on supportive care needs, anxiety and depression symptoms of cancer patients: a multiple mediation model

Abstract

Purpose

The aim of this study was to test the effect of intrapersonal and interpersonal emotional competence on cancer patients' supportive care needs, as mediated by anxiety and depression symptoms.

Methods

Cross-sectional design: 137 cancer patients (42% breast or ovarian cancer, 58% gastrointestinal cancer) in 4 French hospitals completed the Profile of Emotional Competence (PEC), the Hospital Anxiety and Depression Scale (HADS), and the Supportive Care Needs Survey Short Form (SCNS-SF). Bootstrap methods with PROCESS Macro were used to test multiple mediation models.

Results

Emotional competence presented a direct or indirect beneficial effect on the satisfaction of supportive care needs, anxiety and depression symptoms. As expected, anxiety and depression symptoms had also strong positive correlations with unmet needs. All multiple mediation models were significant, except for physical needs: intrapersonal and interpersonal emotional competence impacted anxiety and depression symptoms, which in turn impacted psychological, sexual, care/support, and information needs.

Conclusions

These innovative results show the important effect of patients' emotional competence on their supportive care need satisfaction, as mediated by anxiety and depression. Consequently, patients with high emotional competence may require less psychosocial input from medical clinicians. Thus, emotional competence may be integrated into health models and psychosocial interventions to improve patient adjustment. Further investigation is, however, needed to know which are the most beneficial specific emotional competences and at what point of the cancer pathway.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AdNhBE

A randomized phase II trial of geriatric assessment and management for older cancer patients

Abstract

Purpose

Geriatric assessment and management (GAM) can identify current health issues and recommend interventions to optimize well-being of older adults, but no randomized trial has yet been completed in oncology. Therefore, a randomized phase 2 trial was conducted.

Methods

A two-group parallel single-blinded randomized phase II trial (ClinicalTrials.gov Identifier: NCT02222259) enrolled patients aged ≥70 years, diagnosed with stage 2–4 gastrointestinal, genitourinary, or breast cancer within 6 weeks of commencing chemotherapy at Princess Margaret Cancer Centre. The coprimary feasibility outcomes were the proportion of eligible patients enrolled and retained. The coprimary clinical outcomes were quality of life (QOL) (EORTC QLQ C30) and modification of cancer treatment. Descriptive and regression analyses using intent-to-treat analysis were conducted.

Results

Sixty-one persons (64%) agreed to participate (31 allocated to intervention arm and 30 to control group). In the control group, more participants died and refused follow-up. The benefit of intervention over control on QOL at 3 months was greater for those who survived 6 months (difference 9.28; 95% CI −10.35 to 28.91) versus those who survived only 3 months (difference 6.55; 95% CI −9.63 to 22.73).

Conclusions

This trial showed that it was feasible to recruit and retain older adults for a GAM study. Those who survived at least 6 months seemed to receive a greater QOL benefit than those who died or withdrew.

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Predictive model of complexity in early palliative care: a cohort of advanced cancer patients (PALCOM study)

Abstract

Proposal

Model of early palliative care (PC) integrated in oncology is based on shared care from the diagnosis to the end of life and is mainly focused on patients with greater complexity. However, there is no definition or tools to evaluate PC complexity. The objectives of the study were to identify the factors influencing level determination of complexity, propose predictive models, and build a complexity scale of PC.

Patients and method

We performed a prospective, observational, multicenter study in a cohort of advanced cancer patients with an estimated prognosis ≤ 6 months. An ad hoc structured evaluation including socio-demographic and clinical data, symptom burden, functional and cognitive status, psychosocial problems, and existential-ethic dilemmas was recorded systematically. According to this multidimensional evaluation, investigator classified patients as high, medium, or low palliative complexity, associated to need of basic or specialized PC. Logistic regression was used to identify the variables influencing determination of level of PC complexity and explore predictive models.

Results

We included 324 patients; 41% were classified as having high PC complexity and 42.9% as medium, both levels being associated with specialized PC. Variables influencing determination of PC complexity were as follows: high symptom burden (OR 3.19 95%CI: 1.72–6.17), difficult pain (OR 2.81 95%CI:1.64–4.9), functional status (OR 0.99 95%CI:0.98–0.9), and social-ethical existential risk factors (OR 3.11 95%CI:1.73–5.77). Logistic analysis of variables allowed construct a complexity model and structured scales (PALCOM 1 and 2) with high predictive value (AUC ROC 76%).

Conclusion

This study provides a new model and tools to assess complexity in palliative care, which may be very useful to manage referral to specialized PC services, and agree intensity of their intervention in a model of early-shared care integrated in oncology.

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Making an informed decision of Korean cancer patients: the discrepancy between a patient’s recall of information and the information needed for acquisition of radiotherapy informed consent

Abstract

Introduction

To give informed consent, a patient needs to sufficiently understand the information provided by a physician to decide among treatment options. Although shared decision-making is becoming an important aspect of patient-centered care, little is known about decision-making by cancer patients in Korea.

Objectives

This study assessed Korean cancer patients' understanding of treatment goals and the need to obtain further information after a physician obtained informed consent for radiotherapy.

Methods

In this prospective study, doctors and patients completed questionnaires independently after informed consent for radiotherapy had been obtained. The questionnaires for the doctors and patients were comprised of matched items regarding treatment aims and the need for further information.

Results

The study enrolled 103 cancer patients scheduled for radiotherapy. The proportion of respondents who stated that the intent of treatment was to bring about a cure was 80.6% among the patients (83 of 103 patients) and 53.4% (55 of 103 patients) among the doctors (p = 0.000). The proportion of respondents who believed that the aim was prolongation of life was 16.5 and 1.9%, respectively (p = 0.000). Regarding the need for further information, 42.7% (44/103) of the patients did not want further information because they had faith in the physicians' medical expertise.

Conclusion

Many Korean cancer patients misunderstand the aims of treatment and half of participants do not want further information. Physicians should address whether specific interventions can solve these barriers so that Korean cancer patients can make truly autonomous treatment decisions.

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An optimal design for the study of palliative sedation—making somewhat better pictures

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Information service in head and neck cancer care—a qualitative study

Abstract

Aim

We aimed to understand how information was delivered to head and neck (H&N) cancer patients and describe the perceptions of the H&N patients concerning information delivery.

Methodology

This qualitative investigation was a part of our larger quantitative study that was conducted with H&N cancer patients at two academic hospitals in Montreal. After obtaining the ethical approval, a purposeful sample of participants was recruited from the main study until the content of the information gathered reached saturation. Data were collected by observing the information delivery and interviewing the study participants and Nurse Pivots. All observations and interviews were audiotaped. Data were transcribed verbatim; transcripts were developed, audited, and subjected to a thematic analysis.

Results

Eleven H&N patients participated in the study. We found that the doctors were the main source of information at both hospitals; one hospital delivered information systematically to every patient using a multimedia-based information disseminating tool while the second hospital delivered information verbally in an ad hoc manner. Those who received information using the multimedia tool understood what was said to them and were better prepared for the next step, while those who received information verbally did not retain much, were confused, and expressed dissatisfaction.

Conclusions

Although the doctors were the main source of information, patients experience difficulties in understanding what was said to them. Comprehensive information together with audiovisuals, when provided to H&N cancer patients based on their needs, seems to improve their understanding of their cancer and prepare them for their treatment.

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Efficacy of palonosetron to prevent delayed nausea and vomiting in non-Hodgkin’s lymphoma patients undergoing repeated cycles of the CHOP regimen

Abstract

Purpose

Few studies have investigated the effect of palonosetron on delayed chemotherapy-induced nausea and vomiting in lymphoma patients receiving the CHOP regimen. We conducted a prospective clinical trial to assess the efficacy of palonosetron in patients receiving the CHOP regimen.

Methods

Complete control (CC: emesis-free and mild nausea) during delayed phase (24–120 h) was the primary endpoint. The secondary endpoint was complete response (CR: emesis-free) during acute (0–24 h), delayed, and overall phases (0–120 h), and CC during acute and overall phases. Palonosetron (0.75 mg) was administered before chemotherapy on day 1 of both the first and second CHOP cycles.

Results

The efficacy of palonosetron in preventing emesis was evaluated in 40 patients. Across two cycles, over 85% of patients achieved CR. As the primary endpoint, the proportion of patients achieving CC in the delayed phase increased from 70% (cycle 1) to 85% (cycle 2). CR rate in the delayed phase increased from 85% (cycle 1) to 95% (cycle 2).

Conclusion

These results suggest that the antiemetic effects during the delayed phase were inferior to those in the acute phase during the first cycle. However, even at the same dose of palonosetron, CR and CC rates increased in the second cycle.

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Shared decision-making in palliative care: desires and facts

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AaGYRm

Barriers and enablers to implementing scalp cooling in Australia: a qualitative study of health professionals’ attitudes to and experience with scalp cooling

Abstract

Background

Chemotherapy-induced alopecia is a common and distressing adverse event for patients. Scalp cooling to reduce this alopecia has been available in Europe for more than a decade, but only recently introduced in Australia. The aim of this study was to qualitatively explore health professionals' perceptions of the barriers and enablers to the implementation of scalp cooling in Australian cancer centres.

Methods

Using a qualitative methodology, telephone interviews were conducted with 21 health professionals working in a tumour stream where chemotherapy-induced alopecia is an adverse event of treatment. Participants were recruited from five centres in Australia where scalp cooling is currently available and one centre without access to the technology.

Results

Four interrelated themes were identified: (1) health professional attitudes, (2) concerns for patient equity, (3) logistical considerations and (4) organisational support.

Conclusions

This qualitative study provides the first methodological exploration of Australian health professionals' perceptions of barriers and enablers to scalp cooling uptake. The results highlighted health professional support drives the introduction of scalp cooling. Integration of the technology requires adjustments to nursing practice to manage the increased time, workload and change in patient flow. Strategies to manage the change in practice and organisational support for change in work flow are essential for successful implementation into routine care.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2hXh7BW

Prevalence of hyponatremia in inpatients with incurable and life-limiting diseases and its association with physical symptoms—a retrospective descriptive study

Abstract

Purpose

Hyponatremia is a common electrolyte abnormality seen in hospitalized patients. It may cause a variety of symptoms and is associated with longer hospitalizations and higher mortality. However, to date, only little is known about the extent of hyponatremia in patients with incurable diseases and whether it is associated with physical symptoms in this patient group. This study aims to describe the prevalence of hyponatremia, associated symptoms, and symptom intensity in inpatients with hyponatremia receiving specialist palliative care (SPC).

Methods

This is a retrospective study. Demographic and clinical data as well as symptoms, scored symptom intensity, and laboratory values were collected. All inpatients of a large German University Hospital receiving SPC in 2013 with documented sodium values were included.

Results

In 2013, 789 inpatients received SPC of which 710 had documented sodium values. The prevalence of hyponatremia was 38.7% (275/710). A mild degree showed 220 (31,0%), 44 (6.2%) had a moderate, and 11 (1.6%) a severe form. Hyponatremia patients experienced significantly more symptoms than normonatremic patients (mean = 7.71 vs 6.63; p < 0.001). Breathlessness, depressiveness, nausea, vomiting, poor appetite, constipation, and weakness were significantly more frequent in patients with hyponatremia. Furthermore, hyponatremia severity was associated with higher symptom intensity (mean = 13.29 vs 11.28; p < 0.001).

Conclusions

More than one third of all SPC patients showed a hyponatremia, and the hyponatremia grade was associated with symptom burden and symptom intensity. A prospective analysis is needed to further examine this association and the possible influence of hyponatremia correction on symptom burden reduction.

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Palliative care needs in hospitalized cancer patients: a 5-year follow-up study

Abstract

Purpose

The aims of this study were to describe and compare diagnoses, symptoms, and care needs in palliative cancer patients in two medium-sized hospitals in a county council with no specialized palliative care available 24/7; to analyze the relationships between diagnosis and symptoms/care needs; and to compare results and trends from two datasets (from 2007 and 2012).

Methods

The study was population-based with a cross-sectional design and was conducted at two acute care hospitals. We performed 142 one-day inventories (n = 2972) in 2007 and 139 in 2012 (n = 2843) to register symptoms, care needs, and diagnosis based on a questionnaire. Multiple logistic regression models were used in the analysis.

Results

During 2007 and 2012 combined, 10% (n = 589) of hospitalized patients were assessed as having cancer in a palliative phase. Prostate (12%) and colorectal (12%) cancers were most common. Pain (42%) and deterioration (42%) were the most prevalent symptoms and were associated with pancreas cancer in our regression models (p = 0.003 and p = 0.019, respectively). Other cancers had different associations: hematologic malignancies were associated with infections and blood transfusions (p < 0.001), breast cancer with pleurocentesis (p = 0.002), and stomach/esophagus cancer with nausea (p < 0.001). Nausea was more common in women than in men (p < 0.01). The mean number of symptoms/care needs was 2.9; patients with stomach/esophagus cancer had the highest number of symptoms/care needs (3.5).

Conclusions

Acute care hospitals still play an important role for patients requiring palliative care. Symptoms and care needs were not strongly associated with specific diagnoses. Therefore, symptoms, rather than the specific cancer diagnoses, should be the focus of care.

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Is the addition of a neurokinin-1 receptor antagonist beneficial in moderately emetogenic chemotherapy?—a systematic review and meta-analysis

Abstract

Purpose

This systematic review evaluates the efficacy of neurokinin-1 receptor antagonists (NK1RAs) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy (MEC) excluding anthracycline-cyclophosphamide-based regimens.

Methods

A systematic review of MEDLINE (via PubMed and OVID) and Central databases, plus major oncology conferences, identified randomized trials evaluating NK1RAs in combination with a 5-HT₃ RA plus a glucocorticoid for management of CINV. Efficacy endpoints were complete response (CR), no emesis and no nausea rates. Data were analyzed using a random effects model.

Results

Sixteen trials (3848 patients) were identified. Results were separately analyzed for (a) pure MEC regimens (excluding regimens containing carboplatin or oxaliplatin), (b) carboplatin-based regimens, and (c) oxaliplatin-based regimens. (a) Two trials (abstracts) enrolled 715 patients. The odds ratio for overall CR with the addition of an NK1-RA was 1.46 (95% 1.06–2.02; p = 0.02) with an absolute risk difference (RD) of 8%. (b) Nine trials (1790 patients) were identified. The OR for achieving an overall CR was 1.96 (95% CI 1.57–2.45; p < 0.00001) in favor of the NK1RA containing regimen with an RD of 15%. (c) Three trials (1190 patients) were identified. The OR for achieving an overall CR was 1.34 (95% CI 0.88–2.04; p = 0.17) not reaching statistical significance with a RD of 4%.

Conclusion

Clear clinically significant benefit was seen with the addition of NK1RAs in carboplatin-based chemotherapy. A global benefit of an NK1RA containing regimen for the whole MEC category cannot be attested yet and warrants more randomized trials exclusively testing pure MEC regimens without carboplatin.

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A prospective study of docetaxel-associated pain syndrome

Abstract

Purpose

To investigate the natural history of taxane-associated acute pain syndrome (TAPS) in a docetaxel patient cohort and to examine the long-term manifestation of TAPS.

Patients and methods

For three consecutive treatment cycles, taxane-naive breast cancer patients completed diaries on days 1–7, 14, and 21 and telephone questionnaires 1, 3, 6, 9, and 12 months following treatment. Questionnaires to assess pain and interference were adapted from the Brief Pain Inventory. To examine the experience of arthralgia and myalgia as one syndrome, information on patient experiences with arthralgia or myalgia was elicited separately in order to determine how closely experiences of each toxicity correlated with each other. A ≥2 point increase from baseline was defined as an arthralgia or myalgia "pain flare," and only those with "flare" were included in calculations of incidence.

Results

A total of 278 patients were accrued. Thirty-eight patients were omitted due to missing information, and 24 patients were omitted due to metastatic disease, for a total of 216 patients overall and 188 in the docetaxel cohort. A total of 74.5% of docetaxel patients experienced joint pain flare, and 78.2% experienced muscle pain flare at some point in the overall course of three treatment cycles. Joint and muscle pain peaked on days 4–5 for each cycle, and median pain severity for both joint and muscle pain was 4/10 during the 21-day period. Median onset of joint pain flare was 3 days for cycle 1 and 4 days for cycles 2 and 3, with an average median duration of 4 days. Median onset of muscle pain flare was 4 days for all three cycles, with a median duration of 4 days for cycles 1 and 2, and 5 days for cycle 3. Both joint and muscle pain persisted 1 year after treatment in approximately half of responding patients.

Conclusion

This study documents the significant incidence of TAPS in patients treated with docetaxel chemotherapy and shows a long-term persistence of the syndrome.

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