Aesthetic reconstruction of retroauricular keloid: Creating a keystone flap from the mastoid-helix area

Abstract

Advances in aesthetic rhinoplasty using conchal cartilage grafts have led to a high occurrence of retroauricular keloids. The purpose of this study is to introduce our surgical experiences using a keystone flap in retroauricular keloids following conchal cartilage grafts. The present study is a retrospective review of patients with pathologically confirmed retroauricular keloids following conchal cartilage grafts. These cases were surgically excised and we covered the defect with a keystone flap followed by one-time steroid injection at postoperative day 14 and silicone gel sheeting application for 3 months. Treatment outcome was recorded as recurrence or non-recurrence. In all patients, a follow-up period of minimum 12 months was required. Of these patients, 90.0% had successful treatment of their auricular keloids, whereas 10.0% had recurrences. The postoperative course was uneventful. In conclusion, our aesthetic reconstruction using a keystone flap created from the mastoid-helix area is a useful treatment strategy in terms of retroauricular keloids following conchal cartilage grafts.

Effect of Diabetes Sleep Education for T2DM Who Sleep After Midnight: A Pilot Study from China

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.

The Association Between Sleeping Time and Metabolic Syndrome Features, Among Older Adults Living in Mediterranean Region: The MEDIS Study

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.

Clinical study to evaluate the performance of a noninvasive focused ultrasound device for thigh fat and circumference reduction compared to control

Summary

Background and objectives

An FDA-cleared focused ultrasound device (UltraShape, Syneron Candela^®, Yokneam, Israel) for noninvasive abdominal fat reduction produces localized mechanical cellular membrane disruption in adipocytes. This study seeks to determine the safety and efficacy of this device for use on the thighs.

Study designs/Materials and methods

Fourteen women aged 33-60 were selected to receive 3 biweekly treatments to one thigh with the other thigh serving as an internal control. The subjects had a BMI range of 18-30 kg/m² and a weight range of 54-83 kg. After the third treatment, patients were followed at 4, 8, and 16 weeks. Fat thickness was measured by both caliper and ultrasound. In addition, thigh circumference and the patient's weight were measured. Pain, edema, erythema, and adverse events as well as investigator and patient overall satisfaction were recorded at all visits.

Results

In comparison with the control, there was a statistically significant average reduction in fat thickness measured by calipers at all time points with a 22.20% (P = .0165) improvement in 16 weeks. By ultrasound, there was a 19.23% (4.03 mm P = .0051) reduction in fat thickness at 16 weeks with statistically significant improvement at the other follow-up visits. At 16 weeks, thigh circumference improved, on average, 2.8 cm (P = .0059) at the midline. 90.0% of the subjects were satisfied with the results at 16 weeks, and the investigator was 100% satisfied. No adverse events were reported; no edema was observed in any subject. All subjects experienced mild erythema. All reported zero pain on a 0-10 scale.

Conclusion

Focused ultrasound is safe, effective, and well tolerated to improve the circumference and fat thickness of the thighs without significant side effects. There were no significant adverse events. Investigators and subjects were highly satisfied with the results.

Multi-perspective comparisons and mitigation implications of SO 2 and NO x discharges from the industrial sector of China: a decomposition analysis

Abstract

This study is the first attempt to investigate the drivers of Chinese industrial SO₂ and NO_x emissions from both periodic and structural perspectives through a decomposition analysis using the logarithmic mean Divisia index (LMDI). The two pollutants' emissions were decomposed into output effects, structural effects, clean production effects, and pollution abatement effects. The results showed that China's industrial SO₂ discharge increased by 1.14 Mt during 2003–2014, and the contributions from the four effects were 23.17, − 1.88, − 3.80, and − 16.36 Mt, respectively. Likewise, NO_x discharge changed by − 3.44 Mt over 2011–2014, and the corresponding contributions from the four effects were 2.97, − 0.62, − 1.84, and − 3.95 Mt. Thus, the output effect was mainly responsible for the growth of the two discharges. The average annual contribution rates of SO₂ and NO_x from output were 14.33 and 5.97%, respectively, but pollution abatement technology presented the most obvious mitigating effects (− 10.11 and − 7.92%), followed by the mitigating effects of clean production technology (− 2.35 and − 3.7%), and the mitigation from the structural effect was the weakest (− 1.16 and − 1.25%, respectively), which meant pollutant reduction policies related to industrial structure adjustment should be a long-term measure for the two discharges. In addition, the sub-sectors of I20 (manufacture of raw chemical materials and chemical products), I24 (manufacture of non-metallic mineral products), and I26 (smelting and pressing of non-ferrous metals) were the major contributors to both discharges. Thus, these sub-sectors should be given priority consideration when designing mitigation-related measures. Last, some particular policy implications were recommended for reducing the two discharges, including that the government should seek a technological discharge reduction route.

Phytoremediation of a petroleum-polluted soil by native plant species in Lorestan Province, Iran

Abstract

Petroleum hydrocarbons are potentially toxic for organisms due to the inherent properties, such as solubility, volatility, and biodegradability. The petroleum materials released from corroded old pipelines would pollute soils, shallow groundwater and air as a consequence, and threat the health of human and environment. Therefore, the removal of these compounds from environment is vital. The stability of these pollutants at the soil and their gradual accumulation over time would disrupt the normal function of the soil, such as reduced agricultural capability. In this research, the influence of two plant species (Bromus tectorum L. and Festuca arundinacea) with different amendments including arbuscular mycorrhizal fungi, alfalfa residues, and nutrient solution on the degradation rate of petroleum hydrocarbons in soil was studied. The results showed that the most effective treatment for petroleum remediation was related to B. tectorum L. plant when treated with mycorrhizal fungi and nutrient solution. The degradation rate during 40 days was about 83.27% when compared to the control. Arbuscular mycorrhizal associations are important in the restoration of degraded ecosystems because of the benefits to their symbiotic partners. This fungal phytotechnological mechanism is still in its infancy and there has been little research on aged-contaminated soils.

Water treatment by new-generation graphene materials: hope for bright future

Abstract

Water is the most important and essential component of earth's ecosystem playing a vital role in the proper functioning of flora and fauna. But, our water resources are contaminating continuously. The whole world may be in great water scarcity after few decades. Graphene, a single-atom thick carbon nanosheet, and graphene nanomaterials have bright future in water treatment technologies due to their extraordinary properties. Only few papers describe the use of these materials in water treatment by adsorption, filtration, and photodegradation methods. This article presents a critical evaluation of the contribution of graphene nanomaterials in water treatment. Attempts have been made to discuss the future perspectives of these materials in water treatment. Besides, the efforts are made to discuss the nanotoxicity and hazards of graphene-based materials. The suggestions are given to explore the full potential of these materials along with precautions of nanotoxicity and its hazards. It was concluded that the future of graphene-based materials is quite bright.

Investigating Psychosocial Causes of the Tendency for Facial Cosmetic Surgery

Abstract

Introduction

Despite the importance of cosmetic surgery in improving body image and promoting individuals' physical and mental health, it is accompanied with some physical, mental, and economic problems, because it is an invasive procedure. Considering such extensive consequences and given the rising demand for performing such surgeries, it is essential to consider programs for reducing such requests. The present study aimed to investigate the psychosocial causes of the tendency for facial cosmetic surgery in patients referred to medical centers in Ahvaz in 2016–2017.

Materials and Methods

This study was conducted on 385 facial cosmetic surgery applicants referred to medical centers in Ahvaz and were selected using a sequential non-probability sampling method. The data collection tool was a questionnaire divided into two sections namely: (1) demographic questions and (2) a questionnaire on the psychosocial causes of the tendency for facial cosmetic surgery.

Results

The mean scores of the psychological and social causes of the tendency for facial cosmetic surgery were 4.46 (SD = 1.67) and 3.44 (SD = 2.57), respectively. "Being interested in being beautiful" was the most frequent positive response of the participants regarding the cause of tending to undergo facial cosmetic surgery (88.6%) and the least frequent response was estimated to be 35.1% for the "inappropriate psychological state" cause.

Conclusion

The results of this study showed that psychological factors affected the participants' tendency for facial cosmetic surgery more than social factors. Determining and identifying such psychological pressures and providing individual training and psychological support can prevent individuals from undergoing facial cosmetic surgery.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Analysis of Symmetry Stability Following Implant-Based Breast Reconstruction and Contralateral Management in 582 Patients with Long-Term Outcomes

Abstract

Introduction

This study aimed to analyse the long-term outcomes following breast reconstruction and contralateral management to evaluate the stability of breast symmetry and patient satisfaction.

Materials and Methods

The study population consisted of women who had undergone implant-based monolateral breast reconstruction and contralateral management. Patients answered the BREAST-Q reconstruction module. Two reviewers analysed the post-operative outcomes of the patients included and compiled the Kroll Scale. Patients were divided into three groups: implant-based contralateral management, breast reduction and mastopexy tendency between the groups. The Fisher's exact test was applied to the results.

Results

From the BREAST-Q analysis, the group of patients undergoing contralateral breast augmentation (Figs. 1, 2) achieved significantly better results regarding the ability to wear clothing (p ≪ 0.001), symmetry (p ≪ 0.001), psychosocial well-being (p ≪ 0.001) and physical well-being (p ≪ 0.001). From the analysis of the Kroll Scale, the group of implant-based contralateral management received the highest score for symmetry (p ≪ 0.001), shape (p ≪ 0.001) and aesthetic result overall (p ≪ 0.001). Fig. 1

Patient submitted to right mastectomy and implant-based breast reconstruction with contralateral symmetrisation with implant. Preoperative (a, c) and three years post-operative (b, d) views

Fig. 2

Patient submitted to left mastectomy and implant-based breast reconstruction with contralateral symmetrisation with implant. Preoperative (a, c) and five years post-operative (b, d) views

Conclusions

This study was the first to use BREAST-Q to analyse the stability of breast symmetry following breast reconstruction with long-term results. The implant-based contralateral management was the most effective procedure for achieving a stable and lasting result to obtain the high satisfaction of patients.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Neonicotinoids thiamethoxam and clothianidin adversely affect the colonisation of invertebrate populations in aquatic microcosms

Abstract

Surface waters are sometimes contaminated with neonicotinoids: a widespread, persistent, systemic class of insecticide with leaching potential. Previous ecotoxicological investigations of this chemical class in aquatic ecosystems have largely focused on the impacts of the neonicotinoid imidacloprid; few empirical, manipulative studies have investigated the effect on invertebrate abundances of two other neonicotinoids which are now more widely used: clothianidin and thiamethoxam. In this study, we employ a simple microcosm semi-field design, incorporating a one-off contamination event, to investigate the effect of these pesticides at field-realistic levels (ranging from 0 to 15 ppb) on invertebrate colonisation and survival in small ephemeral ponds. In line with previous research on neonicotinoid impacts on aquatic invertebrates, significant negative effects of both neonicotinoids were found. There were clear differences between the two chemicals, with thiamethoxam generally producing stronger negative effects than clothianidin. Populations of Chironomids (Diptera) and Ostracoda were negatively affected by both chemicals, while Culicidae appeared to be unaffected by clothianidin at the doses used. Our data demonstrate that field-realistic concentrations of neonicotinoids are likely to reduce populations of invertebrates found in ephemeral ponds, which may have knock on effects up the food chain. We highlight the importance of developing pesticide monitoring schemes for European surface waters.

Headache following head injury: a population-based longitudinal cohort study (HUNT)

Headache is the most frequent symptom following head injury, but long-term follow-up of headache after head injury entails methodological challenges. In a population-based cohort study, we explored whether sub...

A grey DEMATEL-based approach for modeling enablers of green innovation in manufacturing organizations

Abstract

Incorporating green practices into the manufacturing process has gained momentum over the past few years and is a matter of great concern for both manufacturers as well as researchers. Regulatory pressures in developed countries have forced the organizations to adopt green practices; however, this issue still lacks attention in developing economies like India. There is an urgent need to identify enablers of green innovation for manufacturing organizations and also to identify prominent enablers among those. This study is an attempt to first identify enablers of green innovation and then establish a causal relationship among them to identify the enablers that can drive others. Grey DEMATEL (Decision Making Trial and Evaluation Laboratory) methodology is used for establishing the causal relationship among enablers. The novelty of this study lies in the fact that no study has been done in the past to identify the enablers of green innovation and then establishing the causal relationship among them. A total of 21 enablers of green innovation have been identified; research indicates developing green manufacturing capabilities, resources for green innovation, ease of getting loans from financial institutions, and environmental regulations as the most influential enablers of green innovation. Managerial and practical implications of the research are also presented to assist managers of the case company in adopting green innovation practices at their end.

Does finance affect environmental degradation: evidence from One Belt and One Road Initiative region?

Abstract

This paper explores the effects of finance on environmental degradation and investigates environmental Kuznets curve (EKC) of each country among 52 that participate in the One Belt and One Road Initiative (OBORI) using the latest long panel data span (1980–2016). We utilized panel long run econometric models (fully modified ordinary least square and dynamic ordinary least square) to explore the long-run estimates in full panel and country level. Moreover, the Dumitrescu and Hurlin (2012) causality test is applied to examine the short-run causalities among our considered variables. The empirical findings validate the EKC hypothesis; the long-run estimates point out that finance significantly enhances the environmental degradation (negatively in few cases). The short-run heterogeneous causality confirms the bi-directional causality between finance and environmental degradation. The empirical outcomes suggest that policymakers should consider the environmental degradation issue caused by financial development in the One Belt and One Road region.

Anesthesia Technique for Cosmetic Breast Augmentation: Does One Size Fit All?

Pediatric low-grade gliomas: a brave new world

See the article by Jones et al. on pages 160–173.

The siren song of bevacizumab: swan song or clarion call?

Bevacizumab burst onto the neuro-oncology scene in 2005 based upon dramatic responses in recurrent glioblastoma patients receiving this agent with the ineffective drug irinotecan. Acceptable toxicity and superior radiographic response rates compared with standard salvage therapy, confirmed in pivotal uncontrolled phase II trials,^1,2 led to accelerated FDA approval in 2009. Moreover, many patients were able to reduce their corticosteroid dose, suggesting steroid-sparing properties.³ Nonetheless, these reports, which focused on progression-free survival (PFS) and radiographic response, did not suggest seismic improvement in overall survival (OS). Thus, concerns persisted that the agent's apparent activity might principally or wholly reflect anti–vascular endothelial growth factor mediated stabilization of the blood–brain barrier, creating a "pseudoresponse."

Ritanserin, a novel agent targeting the mesenchymal subtype of glioblastomas

See the article by Olmez et al on pages 192–202.

Highlights from the Literature

Forthcoming Meetings

Meeting Update—Society for Neuro-Oncology 2017 Annual Meeting

Standard chemoradiation in combination with VEGF targeted therapy for glioblastoma results in progressive gray and white matter volume loss

brain atrophychemoradiationglioblastomaneuroimagingneurotoxicity

Corrigendum

Corrigendum to Jones et al. Pediatric low-grade gliomas: next biologically driven steps. Neuro-Oncology, (https://doi.org/10.1093/neuonc/nox141) first published online August 02, 2017.

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy

Abstract

Background

Cabozantinib is a potent, multitarget inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2). This open-label, phase II trial evaluated cabozantinib in patients with recurrent or progressive glioblastoma (GBM).

Methods

Patients were initially enrolled to a starting cabozantinib dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of safety concerns. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, glucocorticoid use, and safety.

Results

Among 222 patients enrolled, 70 had received prior antiangiogenic therapy. Herein, we report results in this subset of 70 patients. The objective response rate was 4.3%, and the median duration of response was 4.2 months. The proportion of patients alive and progression free at 6 months was 8.5%. Median progression-free survival was 2.3 months, and median overall survival was 4.6 months. The most common adverse events reported in all patients, regardless of dose group, included fatigue (74.3%), diarrhea (47.1%), increased alanine aminotransferase (37.1%), headache (35.7%), hypertension (35.7%), and nausea (35.7%); overall, 34 (48.6%) patients experienced adverse events that resulted in dose reductions.

Conclusions

Cabozantinib treatment appeared to have modest clinical activity with a 4.3% response rate in patients who had received prior antiangiogenic therapy for GBM.

Clinical Trials Registration Number

NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288)

Is the blood–brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data

Abstract

The blood–brain barrier (BBB) excludes the vast majority of cancer therapeutics from normal brain. However, the importance of the BBB in limiting drug delivery and efficacy is controversial in high-grade brain tumors, such as glioblastoma (GBM). The accumulation of normally brain impenetrant radiographic contrast material in essentially all GBM has popularized a belief that the BBB is uniformly disrupted in all GBM patients so that consideration of drug distribution across the BBB is not relevant in designing therapies for GBM. However, contrary to this view, overwhelming clinical evidence demonstrates that there is also a clinically significant tumor burden with an intact BBB in all GBM, and there is little doubt that drugs with poor BBB permeability do not provide therapeutically effective drug exposures to this fraction of tumor cells. This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated.

Identification of time-to-peak on dynamic 18F-FET-PET as a prognostic marker specifically in IDH1/2 mutant diffuse astrocytoma

Abstract

Background

Stratification of glioma according to isocitrate dehydrogenase 1/2 (IDH1/2) mutation and 1p/19q codeletion status has gained major importance in the new World Health Organization (WHO) classification. Parameters derived from uptake dynamics of ¹⁸F-fluoro-ethyl-tyrosine PET (¹⁸F-FET-PET) such as minimal time-to-peak (TTP_min) allow discrimination between different prognostic glioma subgroups, too. The present study is aimed at exploring whether TTP_min analysis provides prognostic information beyond the WHO classification.

Methods

Three hundred patients with newly diagnosed WHO 2007 grades II–IV gliomas with ¹⁸F-FET-PET imaging at diagnosis were grouped into 4 subgroups (IDH1/2 mut–1p/19q codel; IDH1/2 mut–1p/19q non-codel; IDH1/2 wildtype WHO grade II and III tumors; and glioblastoma). Clinical and imaging factors such as age, Karnofsky performance score, treatment, TTP_min, and maximal tumor-to-brain ratio (TBR_max) were analyzed with regard to progression-free and overall survival (PFS and OS) via univariate and multivariate regression analysis.

Results

PFS and OS were longest in the IDH1/2 mut–1p/19q codel subgroup, followed by IDH1/2 mut–1p/19q non-codel, IDH1/2 wildtype, and GBM (P < 0.001). Further, outcome stratified by TTP_min with a cutoff of 17.5 minutes revealed significantly longer PFS and OS in patients with TTP_min >17.5 minutes (P < 0.001 for PFS and OS). Lower TBR_max values or the absence of ¹⁸F-FET uptake was also associated with favorable outcome in the entire group. In the subgroup analyses, longer median TTP_min was associated with improved outcome specifically in the IDH1/2 mut–1p/19q non-codel group.

Conclusion

¹⁸F-FET-PET–derived dynamic analysis defines prognostically distinct subgroups of IDH1/2 mutant–1p/19q non-codel gliomas which cannot be distinguished as yet by molecular marker analysis.

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy

Abstract

Background

Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM).

Methods

Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety.

Results

Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome.

Conclusions

Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions.

Clinical Trials Registration Number

NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288)

Brain volume reduction after whole-brain radiotherapy: quantification and prognostic relevance

Abstract

Background

Recent studies have questioned the value of adding whole-brain radiotherapy (WBRT) to stereotactic radiosurgery (SRS) for brain metastasis treatment. Neurotoxicity, including radiation-induced brain volume reduction, could be one reason why not all patients benefit from the addition of WBRT. In this study, we quantified brain volume reduction after WBRT and assessed its prognostic significance.

Methods

Brain volumes of 91 patients with cerebral metastases were measured during a 150-day period after commencing WBRT and were compared with their pretreatment volumes. The average daily relative change in brain volume of each patient, referred to as the "brain volume reduction rate," was calculated. Univariate and multivariate Cox regression analyses were performed to assess the prognostic significance of the brain volume reduction rate, as well as of 3 treatment-related and 9 pretreatment factors. A one-way analysis of variance was used to compare the brain volume reduction rate across recursive partitioning analysis (RPA) classes.

Results

On multivariate Cox regression analysis, the brain volume reduction rate was a significant predictor of overall survival after WBRT (P < 0.001), as well as the number of brain metastases (P = 0.002) and age (P = 0.008). Patients with a relatively favorable prognosis (RPA classes 1 and 2) experienced significantly less brain volume decrease after WBRT than patients with a poor prognosis (RPA class 3) (P = 0.001). There was no significant correlation between delivered radiation dose and brain volume reduction rate (P = 0.147).

Conclusion

In this retrospective study, a smaller decrease in brain volume after WBRT was an independent predictor of longer overall survival.

Pediatric low-grade gliomas: next biologically driven steps

Abstract

Despite the fact that they are not typically life-threatening, low-grade gliomas (LGGs) remain a significant clinical challenge in pediatric neuro-oncology due to comorbidities associated with these tumors and/or their treatments, and their propensity to multiply recurs. LGGs, in total the most common brain tumors arising in childhood, can often become a chronic problem requiring decades of management. The Second International Consensus Conference on Pediatric Low-Grade Gliomas held in Padua, Italy in 2016 was convened in an attempt to advance the pace of translating biological discoveries on LGGs into meaningful clinical benefit. Topics discussed included: the implications of our growing biological understanding of the genomics underlying these tumors; the assessment of the model systems available; the implications of the molecular and histopathologic differences between adult and pediatric diffuse gliomas; and steps needed to expedite targeted therapy into late-stage clinical trials for newly diagnosed cases. Methods for the diagnostic assessment of alterations in the Ras/mitogen-activated protein kinase pathway, typical for these tumors, were also considered. While the overall tone was positive, with a consensus that progress is being and will continue to be made, the scale of the challenge presented by this complex group of tumors was also acknowledged. The conclusions and recommendations of the meeting panel are provided here as an outline of current thinking and a basis for further discussion.

Divergent evolution of temozolomide resistance in glioblastoma stem cells is reflected in extracellular vesicles and coupled with radiosensitization

Abstract

Background

Glioblastoma (GBM) is almost invariably fatal due to failure of standard therapy. The relapse of GBM following surgery, radiation, and systemic temozolomide (TMZ) is attributed to the ability of glioma stem cells (GSCs) to survive, evolve, and repopulate the tumor mass, events on which therapy exerts a poorly understood influence.

Methods

Here we explore the molecular and cellular evolution of TMZ resistance as it emerges in vivo (xenograft models) in a series of human GSCs with either proneural (PN) or mesenchymal (MES) molecular characteristics.

Results

We observed that the initial response of GSC-initiated intracranial xenografts to TMZ is eventually replaced by refractory growth pattern. Individual tumors derived from the same isogenic GSC line expressed divergent and complex profiles of TMZ resistance markers, with a minor representation of O⁶-methylguanine DNA methyltransferase (MGMT) upregulation. In several independent TMZ-resistant tumors originating from MES GSCs we observed a consistent diminution of mesenchymal features, which persisted in cell culture and correlated with increased expression of Nestin, decline in transglutaminase 2 and sensitivity to radiation. The corresponding mRNA expression profiles reflective of TMZ resistance and stem cell phenotype were recapitulated in the transcriptome of exosome-like extracellular vesicles (EVs) released by GSCs into the culture medium.

Conclusions

Intrinsic changes in the tumor-initiating cell compartment may include loss of subtype characteristics and reciprocal alterations in sensitivity to chemo- and radiation therapy. These observations suggest that exploiting therapy-induced changes in the GSC phenotype and alternating cycles of therapy may be explored to improve GBM outcomes.

microRNA-7 upregulates death receptor 5 and primes resistant brain tumors to caspase-mediated apoptosis

Abstract

Background

MicroRNAs (miRs) are known to play a pivotal role in tumorigenesis, controlling cell proliferation and apoptosis. In this study, we investigated the potential of miR-7 to prime resistant tumor cells to apoptosis in glioblastoma (GBM).

Methods

We created constitutive and regulatable miR-7 expression vectors and utilized pharmacological inhibition of caspases and genetic loss of function to study the effect of forced expression of miR-7 on death receptor (DR) pathways in a cohort of GBM with established resistance to tumor necrosis factor apoptosis inducing ligand (TRAIL) and in patient-derived primary GBM stem cell (GSC) lines. We engineered adeno-associated virus (AAV)–miR-7 and stem cell (SC) releasing secretable (S)-TRAIL and utilized real time in vivo imaging and neuropathology to understand the effect of the combined treatment of AAV–miR-7 and SC–S-TRAIL in vitro and in mouse models of GBM from TRAIL-resistant GSC.

Results

We show that expression of miR-7 in GBM cells results in downregulation of epidermal growth factor receptor and phosphorylated Akt and activation of nuclear factor-kappaB signaling. This leads to an upregulation of DR5, ultimately priming resistant GBM cells to DR-ligand, TRAIL-induced apoptotic cell death. In vivo, a single administration of AAV–miR-7 significantly decreases tumor volumes, upregulates DR5, and enables SC-delivered S-TRAIL to eradicate GBM xenografts generated from patient-derived TRAIL-resistant GSC, significantly improving survival of mice.

Conclusions

This study identifies the unique role of miR-7 in linking cell proliferation to death pathways that can be targeted simultaneously to effectively eliminate GBM, thus presenting a promising strategy for treating GBM.

Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma

Abstract

Background

Combined immunotherapy approaches are promising cancer treatments. We evaluated anti–programmed cell death protein 1 (PD-1) treatment combined with gene-mediated cytotoxic immunotherapy (GMCI) performed by intratumoral injection of a prodrug metabolizing nonreplicating adenovirus (AdV-tk), providing in situ chemotherapy and immune stimulation.

Methods

The effects of GMCI on PD ligand 1 (PD-L1) expression in glioblastoma were investigated in vitro and in vivo. The efficacy of the combination was investigated in 2 syngeneic mouse glioblastoma models (GL261 and CT-2A). Immune infiltrates were analyzed by flow cytometry.

Results

GMCI upregulated PD-L1 expression in vitro and in vivo. Both GMCI and anti–PD-1 increased intratumoral T-cell infiltration. A higher percentage of long-term survivors was observed in mice treated with combined GMCI/anti–PD-1 relative to single treatments. Long-term survivors were protected from tumor rechallenge, demonstrating durable memory antitumor immunity. GMCI led to elevated interferon gamma positive T cells and a lower proportion of exhausted double positive PD1+TIM+CD8+ T cells. GMCI also increased PD-L1 levels on tumor cells and infiltrating macrophages/microglia. Our data suggest that anti–PD-1 treatment improves the effectiveness of GMCI by overcoming interferon-induced PD-L1–mediated inhibitory signals, and GMCI improves anti–PD-1 efficacy by increasing tumor-infiltrating T-cell activation.

Conclusions

Our data show that the GMCI/anti–PD-1 combination is well tolerated and effective in glioblastoma mouse models. These results support evaluation of this combination in glioblastoma patients.

Selective BCL-XL inhibition promotes apoptosis in combination with MLN8237 in medulloblastoma and pediatric glioblastoma cells

Abstract

Background

CNS tumors, including medulloblastoma and pediatric glioblastoma (pGBM) account for the majority of solid pediatric malignancies. There remains an unmet need to identify novel treatment approaches in poor prognosis and relapsed pediatric brain tumors, where therapeutic options are limited. Small-molecule B-cell lymphoma 2 (BCL-2) family inhibitors may enhance tumor cell killing when combined with conventional and targeted chemotherapeutic agents. We investigated the effect of disrupting BCL-2 and B cell lymphoma-extra large (BCL-X_L) protein function using ABT-263, ABT-199 and WEHI-539 in medulloblastoma and pGBM cells following treatment with MLN8237, an Aurora kinase inhibitor under investigation as a novel agent for the treatment of malignant brain tumors.

Methods

Tumor cell growth and viability were determined by MTT/WST-1 assays and flow cytometry. Effects on cell phenotype, cell cycle progression, and ploidy were determined by live cell imaging and DNA content analysis. Apoptosis was determined by annexin V/propidium iodide staining and time-lapse microscopy and confirmed by measuring caspase-3/7 activity and western blotting and by short interfering RNA (siRNA) knockdown of BCL-2 associated X protein/BCL-2 antagonist killer (BAX/BAK).

Results

ABT-263, in combination with MLN8237, reduced mitotic slippage and polyploidy and promoted the elimination of mitotically defective cells via a BAX/BAK-dependent, caspase-mediated apoptotic pathway. The BCL-X_L antagonist, WEHI-539, significantly augmented tumor cell killing when used in combination with MLN8237, as well as sensitized resistant brain tumor cells to a novel BAX activator, SMBA1. In addition, siRNA-mediated knockdown of BCL-X_L sensitized pGBM and medulloblastoma cells to MLN8237 and mimicked the effect of combination drug treatment.

Conclusion

Selective small-molecule inhibitors of BCL-X_L may enhance the efficacy of MLN8237 and other targeted chemotherapeutic agents.

Glioblastoma in elderly patients: solid conclusions built on shifting sand?

Abstract

Management of glioblastoma in the elderly population is challenging. In the near future, more than half of patients with this tumor will be over the age of 65. Clinicians have been historically reluctant to treat such patients with the same intensity as younger patients. Due to upper age limits or poor accrual of elderly patients in clinical trials, randomized data for this patient population have been relatively sparse until recently. In this review, we will discuss the concept of an elderly patient population, describe evidence for molecular differences in glioblastoma of elderly versus young patients, evaluate recent first-line trials studying glioblastoma in elderly patients, and discuss best therapeutic practices including the value of molecular testing.

Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha

Abstract

Background

The mesenchymal phenotype in glioblastoma (GBM) and other cancers drives aggressiveness and treatment resistance, leading to therapeutic failure and recurrence of disease. Currently, there is no successful treatment option available against the mesenchymal phenotype.

Methods

We classified patient-derived GBM stem cell lines into 3 subtypes: proneural, mesenchymal, and other/classical. Each subtype's response to the inhibition of diacylglycerol kinase alpha (DGKα) was compared both in vitro and in vivo. RhoA activation, liposome binding, immunoblot, and kinase assays were utilized to elucidate the novel link between DGKα and geranylgeranyltransferase I (GGTase I).

Results

Here we show that inhibition of DGKα with a small-molecule inhibitor, ritanserin, or RNA interference preferentially targets the mesenchymal subtype of GBM. We show that the mesenchymal phenotype creates the sensitivity to DGKα inhibition; shifting GBM cells from the proneural to the mesenchymal subtype increases ritanserin activity, with similar effects in epithelial-mesenchymal transition models of lung and pancreatic carcinoma. This enhanced sensitivity of mesenchymal cancer cells to ritanserin is through inhibition of GGTase I and downstream mediators previously associated with the mesenchymal cancer phenotype, including RhoA and nuclear factor-kappaB. DGKα inhibition is synergistic with both radiation and imatinib, a drug preferentially affecting proneural GBM.

Conclusions

Our findings demonstrate that a DGKα–GGTase I pathway can be targeted to combat the treatment-resistant mesenchymal cancer phenotype. Combining therapies with greater activity against each GBM subtype may represent a viable therapeutic option against GBM.

Decreased Superficial Surgical Site Infections, Shortened Hospital stay and Improved Quality of Live due to Incisional Negative Pressure Wound Therapy after Reversal of Double Loop Ileostomy

Abstract

This single-center prospective, controlled observational study investigates the impact of incisional negative pressure wound therapy on wound healing processes and its potency to prevent superficial surgical site infections after reversal of a double loop ileostomy. Furthermore, this study gains insight in socio-economic aspects, like duration of hospital stay and, for the first time, patient's quality of life during the incisional negative pressure wound treatment. To address this question, an interventional group of 24 patients treated with incisional negative pressure wound therapy (Prevena® incisional wound management system, KCI, Germany) and a respective control cohort of 25 patients treated with a standard sterile dressing were observed for 30 days in the post-operative course. Postoperative incisional negative pressure wound therapy resulted in statistically significant decreasing duration of hospital stay (6 days vs. 9 days, p= 0.019) and lower rates of superficial surgical site infections (12.5% vs. 20.0%, p= 0.478) in accordance with a not statistically significant decreased necessity of postoperative antibiotic therapy (12.5% vs. 36%, p= 0.051). To survey subjective items of well-being and quality of life, all patients were asked to answer a questionnaire. Patients of both groups noticed increasing quality of life after reversal of their ileostomy. However, patients treated with an incisional negative pressure wound therapy had a superior improvement of a variety of subjective items, resulting in an overall much better satisfaction with the course of wound healing. Our findings suggest, that incisional negative pressure wound therapy seems to be a reasonable therapeutic option to reduce incidence of superficial surgical site infections and to have a beneficial impact to patient's quality of life, as well as, socio-economic aspects. This article is protected by copyright. All rights reserved.

Utility of perioperative skin perfusion pressure measurement for treatment of ulcers caused by arteriovenous access ischaemic steal

Arteriovenous access ischaemic steal is a serious complication following arteriovenous fistula (AVF) construction. The aim of treatment is to improve distal circulation without impairing the function of the fistula. Therefore, any repair should be performed with intraoperative monitoring. We report 2 cases of this disorder treated using perioperative measurement of skin perfusion pressure (SPP) for preoperative surgical planning and intraoperative guidance.

A 73-year-old woman with a left cubital AVF developed gangrene of the tip of the left little finger. Arteriovenous access ischaemic steal was suspected. The SPP of the little finger was 18 mm Hg, which increased to 65 mm Hg after manual occlusion of the fistula. A 58-year-old woman with a left antebrachial AVF had gangrene of the tip of the left middle finger. The SPP was 19 mm Hg, and steal syndrome was suspected based on angiography and the SPP with manual occlusion of the fistula.

In both cases, serial plication of the fistula was performed based on intraoperative perfusion pressure monitoring, leading to the successful resolution of the ischaemic steal syndrome. In both cases, haemodialysis could be continued through the repaired fistula.

Metataxonomic approach to decipher the polymicrobial burden in diabetic foot ulcer and its biofilm mode of infection

Chronic diabetic foot is a global burden affecting millions of people, and the chronicity of an ulcer is directly linked to the diverse bacterial burden and its biofilm mode of infection. The bacterial diversity of 100 chronic diabetic ulcer samples was profiled via traditional culturing method as well as metagenomic approach by sequencing the 16S rRNA V3 hyper-variable region on Illumina Miseq Platform (Illumina, Inc., San Diego, CA). All the relevant clinical metadata, including duration of diabetes, grade of ulcer, presence of neuropathy, and glycaemic level, were noted and correlated with the microbiota. The occurrence and establishment of bacterial biofilm over chronic wound tissues was revealed by Fluorescent in situ Hybridization and Scanning Electron Microscopy. The biofilm-forming ability of predominant bacterial isolates was studied via crystal violet assay and Confocal Laser Scanning Microscopy. The dominant phyla obtained from bacterial diversity analysis were Firmicutes, Proteobacteria, and Actinobacteria. The dominant aerobic pathogens identified by culture method are Pseudomonas, Proteus, Enterococcus, and Staphylococcus, whereas high-throughput sequencing revealed heightened levels of Streptococcus and Corynebacterium along with 22 different obligate anaerobes. The biofilm occurrence in chronic diabetic ulcer infection is well analysed. Herein, we illustrate the comprehensive pattern of bacterial infection and identify the community composition of chronic wound pathogenic biofilm.

Assessment of the efficacy of a new complex antisensitive skin cream

Summary

Background

Sensitive skin is frequently complaint in dermatology consultation with cutaneous manifestations such as stinging, redness, dryness, and burning sensation that affect the quality of life. Its pathogenesis is mainly related to dysfunction of neurosensory, skin barrier, and also immune activity. The treatment is generally based on continuous and topical therapy by nonirritating complex.

Objective

To evaluate the antisensitive function of a new complex cream composed by Yunnan Portulaca oleracea extract, Prinsepia utilis oil, beta-glucan, and sodium hyaluronate extracted from mushroom.

Methods

A randomized double-blind and self-control study was conducted on 20 selected volunteers with sensitive skin. Subjects applied the test cream to 1 side of the face, and the control cream (tolerance-extreme cream) to the other side of the face, twice daily over 28 days. Evaluations were performed at baseline and at 28 days. Expert clinical grading of facial skin including dryness, roughness, desquamation, and erythema was assessed. Subject self-assessment questionnaires, digital photography and noninvasive bioinstrumentation of hydration, transepidermal water loss, lipid index, skin texture, and wettability were also included in the study.

Results

Products were well tolerated. For all parameters studied, no significant difference was observed between test and control creams. Results showed that test cream provided a statistically significant improvement in clinical grading scores for dryness, roughness, and erythema at 28 days compared to baseline. In addition, statistically significant improvement of skin hydration and texture parameters (eg, smoothness and roughness) was demonstrated. Volunteers' questionnaire revealed self-perceived benefits consistent with expert visual grading.

Conclusion

This study confirmed the effectiveness and tolerance of the new complex cream in subjects with sensitive skin. The test cream could serve as a daily care moisturizer for face.

Type of Menopause, Age at Menopause, and Risk of Developing Obstructive Sleep Apnea in Postmenopausal Women

Abstract

Despite established sex differences and longstanding hypotheses of sex hormones in obstructive sleep apnea (OSA) etiology, no studies have evaluated type of menopause and age at menopause, which affect postmenopausal hormonal milieu, in relation to OSA risk in women. We followed 50,473 postmenopausal women from the Nurses' Health Study (NHS) between 2002-2012 and 53,827 postmenopausal women from the NHSII between 1995-2013, with 1,712 and 2,560 incident OSA diagnoses, respectively. Compared with natural menopause, the pooled HR for OSA was 1.27 (95% CI: 1.17, 1.38) for surgical menopause by hysterectomy/oophorectomy. The association remained the same after further accounting for age at menopause (HR=1.26; 95% CI: 1.15, 1.38). The risk associated with surgical menopause was higher in non-obese women as well as women who never used hormone therapy (P-interaction<0.05). Earlier menopause was associated with higher OSA risk prior to adjustment for type of menopause (HR comparing <40 years versus 50-54 years=1.21; 95% CI: 1.08, 1.35; p=0.008 for trend), although no association was observed after the adjustment. Surgical as compared with natural menopause was independently associated with higher OSA risk in postmenopausal women. Our results provide additional evidence for a role of sex hormones, particularly abrupt hormonal changes, in modulating OSA risk.

Oral prednisolone versus non-steroidal anti-inflammatory drugs in the treatment of acute gout: a meta-analysis of randomized controlled trials

Abstract

Objectives

To evaluate the efficacy and safety of oral prednisolone in the treatment of acute gout compared with non-steroidal anti-inflammatory drugs (NSAIDs).

Methods

A comprehensive search of databases in both Chinese and English was performed. Data from the selected studies were extracted and analyzed independently by two authors.

Results

Three double-blind, randomized, controlled trials were included in the final analysis, with a total of 584 patients. Regarding the efficacy, oral prednisolone (30–35 mg/day) was comparable with NSAIDs (naproxen at 500 mg/day or indomethacin at 50–100 mg/day) on the pain relief scale, both in activity (difference in means 0.259, 95% CI − 1.532 to 2.050, P = 0.777) and at rest (difference in means − 0.502, 95% CI − 4.961 to 3.956, P = 0.825) during the first 2–6 h. During the following 4 to 6 days, prednisolone acted with comparable efficacy either in activity (difference in means − 0.552, 95% CI − 1.364 to 0.260, P = 0.183) or at rest (difference in means − 0.164, 95% CI − 0.463 to 0.134, P = 0.281). Regarding safety, prednisolone did not increase the total adverse events (AEs) (risk ratios [RR] 0.765, 95% CI 0.473 to 1.238, P = 0.275) and reduced the withdrawal rate because of the AEs (RR 0.127, 95% CI 0.021–0.763, P = 0.024). Prednisolone decreased the risks of several AEs (including indigestion: RR 0.544, 95% CI 0.311–0.952, P = 0.033; nausea: RR 0.296, 95% CI 0.136–0.647, P = 0.002; and vomiting: RR 0.155, 95% CI 0.033–0.722, P = 0.018) but increased the risk of skin rashes (RR 4.049, 95% CI 1.241–13.158, P = 0.021).

Conclusions

Oral prednisolone may be of similar efficacy and a slightly safer strategy for treatment of active, acute gout compared with NSAIDs. Further clinical studies are still warranted to investigate its long-term efficacy and safety.

The views of children and young people on the use of silk garments for the treatment of eczema: a nested qualitative study within the CLOTHing for the relief of Eczema Symptoms (CLOTHES) randomized controlled trial

Summary

This study reports on a trial from the U.K. to find out if specialised silk clothing improved eczema in children. Eczema is a common skin condition. It affects around one in five children and can cause sore and itchy skin, poor sleep and reduced quality of life. As part of this work the researchers wanted to find out what the children who wore the garments in the study thought of them. They invited 18 children aged between five and 15 years to take part, meeting in small groups and using stories and play to help the children tell the researchers about the garments. All the children and young people had high hopes that the garments would make their skin much better. They expected the garments to feel soft and smooth and were disappointed when they were not like this. They reported that they mostly wore them at night as it was embarrassing to wear them during the day. Some said that the garments were see through. Garments tended to go grey and start to fall apart when they had been worn and washed. A few children found that the garments made their skin more comfortable and helped them sleep better. They were disappointed that the miracle cure they hoped for did not happen. It is important and possible to involve children in studies like this so we can understand what they think about possible treatments for eczema.

Efficacy and adverse events of oral isotretinoin for acne: a systematic review

Summary

Acne vulgaris, usually just referred to as acne, is the most common skin disease. It causes red spots, pus-filled spots and blackheads and can vary in severity from mild to severe. Because it can be very visible, it can cause anxiety, reduced self-esteem and stigma. In cases of more severe acne that hasn't improved with other treatments, a powerful drug taken orally (by mouth) called isotretinoin can be prescribed by doctors. This study, from Canada, reviewed evidence from randomized controlled trials (RCTs) to assess the efficacy and safety of isotretinoin. RCTs are studies in which a number of patients are randomly allocated to two or more test groups, one of which will be a 'control' group (who typically receive either no treatment, standard care or a placebo), while the other groups will receive the specific treatments being tested. The different groups of patients are then monitored in the exact same way, allowing for direct comparison between different treatments. Eleven trials were identified, involving a total of 760 patients - mostly males. Across all trials, isotretinoin reduced acne lesion counts (number of spots), and always by a greater amount than controls, which were either placebo, oral antibiotics, or another control type. The frequency of adverse events, meaning unwanted side effects, was twice as high with isotretinoin (751 events) compared to control (388 events). More than half of all adverse events related to skin dryness. Adverse events caused 12 of the 760 participants to withdrawal from trials, due to the development of Stevens-Johnson Syndrome, cheilitis, xerosis, acne flare, photophobia, elevated liver enzymes, decreased appetite, headaches and depressed mood. This review suggests that isotretinoin is effective in reducing acne lesion counts, but adverse events are common.

脂溢性皮炎在中老年人群中的发病率及决定因素:鹿特丹研究

Summary

脂溢性皮炎是一种常见的皮肤病,见于头皮、面部及胸部,主要表现为炎症和脂性鳞屑。虽然尚不清楚脂溢性皮炎的病因,但研究者认为马拉色氏酵母菌的过度生长是脂溢性皮炎的部分原因。若干其他因素也与此类疾病有关;年龄、性别、肥胖、肤色、压力、沮丧、教育程度、高血压、气候、皮肤干燥、饮酒以及吸烟等因素都与脂溢性皮炎有关,但相关性证据通常并无定论。该研究旨在确定与脂溢性皮炎有关的生活方式及生理因素。该研究中的数据来自针对荷兰中老年人群开展的鹿特丹研究,旨在研究这些之前报告的因素。研究依据在于,了解决定因素可以在脂溢性皮炎的病理生理学方面提供新的见解,以便采取预防策略和/或新的治疗方案。在鹿特丹研究中,5,498 位参与者进行了全身皮肤检查,其中 788 位罹患脂溢性皮炎。作者发现,男性、肤色浅、冬季以及全身干燥皮肤可增加脂溢性皮炎发病率,其他因素则与脂溢性皮炎无关。此外,作者分析了研究性别差异能否通过激素差异来解释,但他们发现激素与脂溢性皮炎之间并无关联。在已发现的关联中,干燥皮肤似乎最容易带来影响。因此,增强皮肤屏障可以作为脂溢性皮炎治疗中的一个目标。

Image Gallery: A case of malignant syphilis in an HIV-infected patient mimicking fungal infection

Novel clinical and molecular findings in Spanish patients with nevoid basal cell carcinoma syndrome

Summary

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin Syndrome, affects only 1 in 56 000 people. It is usually inherited from a parent with the condition and affects both males and females equally (autosomal dominant inheritance). People with NBCCS may show characteristic features such as extra fingers or toes, irregular ribs, an unusually shaped face and large head. Tumours sometimes develop, particularly jaw cysts and basal cell carcinomas (BCCs) of the skin from which the syndrome is named. NBCCS is caused by mistakes (mutations) in a gene called PTCH1 located on the long arm of chromosome 9. PTCH1 acts as a brake on a set of chemical processes in cells called the Hedgehog (HH)/GLI signalling pathway. In NBCCS, mutations inactivate PTCH1 allowing excessive Hedgehog signalling. This loss of control results in the abnormal bones and tumours. Within an affected family, people with the same genetic mutation can have very different abnormalities. This group from Spain studied 22 unrelated Spanish people with NBCCS to see if they could discern any relationship between specific clinical abnormalities and specific genetic mutations. BCCs were very common, occurring in 96% of patients with 43% having more than 50; 77% had jaw cysts. Two abnormalities had not previously been recognised in NBCCS: double uterus and a benign nerve tumour. They found 19 PTCH1 mutations that had not previously been reported. However, they could not find any pattern relating the type of mutation to the clinical abnormalities. Presumably other factors besides the PTCH1 mutation causes the clinical features.

British Association of Dermatologists’ guidelines for the investigation and management of generalized pruritus in adults without an underlying dermatosis, 2018

Summary

Pruritus (or itch) is a common and distressing symptom of many skin diseases, systemic illnesses and psychological disorders. Itch is perhaps the commonest presenting symptom of skin disorders. In any two week period, 8 to 9% of the population suffer from significant pruritus. The focus of this guideline is not itchy rashes, but rather the situation where itch is present without rash. The guidelines also do not cover itch in children, in pregnancy, nor do they detail the science of the cause of itch. The study group consist mostly of dermatologists (skin specialists) from a number of hospitals in the U.K., but a number of other hospital doctors, a nurse and a general practitioner (GP) are also part of the team. There may be an underlying cause of pruritus, such as blood disorders, iron deficiency or excess, kidney problems, liver problems, cancer, infections, medications, behavioural factors, dry skin or any combination of these with old age. This can be significant in 20 to 30% of cases of itchy skin without rash. There remain a small number of individuals with itch and no apparent underlying cause or rash. It is always important to look for an underlying causative condition, as the most effective management of pruritus without rash depends on the treatment of any underlying disease. The management of itch appears to be very situation specific, even if the underlying cause cannot be treated. The management of true pruritus of unknown cause is different again.

Corrigenda

Advances in the diagnosis of pigmented skin lesions

通过电子皮镜观察到在后天性痣亚型中常见 BRAF 和 NRAS 突变,表现出组成型 MAPK 通路活化

Summary

大多数人的皮肤上都有几个褐斑,我们称之为黑素细胞痣或痣。痣对人体无害,但偶尔可能转化为潜在致死性肿瘤,也就是恶性黑色素瘤。在放大镜(电子皮镜)下,皮肤科专家通过外观确定了不同类型的痣。广义上:"球状"痣在早年出现,并且可能转化为黑色素瘤;"网状"痣在成年期出现,并且可能与未长痣部位出现的黑色素瘤有关;带"外围球状体"(PG) 的网状痣会生长,但非恶性。良性痣及癌性痣(恶性黑色素瘤)中都可能出现 BRAF 和 NRAS 基因突变(变异)。这些基因是在肿瘤形成中起重要作用的 MAPK 通路的成分。为说明这些基因的作用,这些来自澳大利亚的研究人员探讨了电子皮镜下外观与良性痣中的 NRAS 和 BRAF 突变之间的关系。他们通过电子皮镜检查了 27 人的 40 个后天性(非先天性)痣,然后去痣以进行分析。在显微镜下,研究人员观察到大多数网状痣中的细胞结构无序,但这种情况在球状痣以及 PG 痣中很少见。研究人员使用了一种能够检测单细胞突变的新型高灵敏度方法("微滴式数字 PCR"),他们发现大多数球状痣以及所有 PG 痣都出现 BRAF 突变,网状痣则出现 BRAF 或 NRAS 突变。研究人员得出结论,所有痣具有 MAPK 基因突变,证明 MAPK 通路在黑素细胞痣及黑色素瘤的形成中起基础性作用。

A new era in holistic care: bridging the gap between dermatologists and oncologists for the treatment of malignant melanoma

Morphological characteristics and human papillomavirus genotype predict the treatment response in cutaneous warts

Summary

Skin warts are highly prevalent in both children and adults. They are caused by a virus called 'human papilloma virus' (HPV). Only around half of skin warts disappear after treatment. This study was performed to predict the type of HPV in warts and more importantly, to predict which warts are likely to disappear after treatment. Therefore, features both of patients and their warts were studied. A new standard tool for warts (the CWARTS diagnostic tool) was used to score the appearance of the wart and 23 different virus types were tested. The treatments that were used were monochloroacetic acid, cryotherapy or a combination of cryotherapy and salicylic acid. In total, 311 warts of 159 patients were studied. Black dots in a wart suggested presence of HPV. If warts contained HPV2, HPV27 or HPV57 they responded less often to most treatments. However this did not apply to warts located on the hands or body if they were treated with cryotherapy. Warts that show callus or are deeper located on the skin were less responsive to cryotherapy. To summarize, the appearance of warts and the type of HPV they contain influence the chance of healing. Therefore, in the future it might be important for medics to take this into account when choosing a treatment option for common and plantar warts.

When to switch biologics: some answers, but lots of questions too

Linked Article: Langley et al. Br J Dermatol 2018; 178:114–123.

Vitiligo and quality of life: the dark face of whiteness

Linked Article: Bae et al. Br J Dermatol 2018; 178:238–244.

受孕和妊娠期使用生物疗法:系统综述

Summary

生物疗法可以有效治疗银屑病,并且通常在育龄期女性中使用。监管部门表示,由于没有充分的研究评估在受孕或妊娠期使用生物制剂的安全性,因此建议在此期间禁用。但事实上,这实施起来很有挑战,因为临床上治疗银屑病需要持续进行。为评估受孕和/或者妊娠期使用生物疗法的安全性,该研究的作者(来自英国)对有关女性在受孕和/或妊娠期使用生物疗法治疗银屑病的相关研究进行了系统综述。作者确定了四项研究,共涉及 1,300 名在孕前 3 个月或孕期前 3 个月使用 TNFi 生物制剂的女性。这些研究表明具有不同炎症(不仅仅是银屑病)的女性在使用 TNFi 后容易出现药物特定的损害,而且其中三项研究表明先天畸形风险增加,一项研究表明早产风险增加。但是,风险很低且不确定是否因 TNFi 所致。作者得出结论,生物制剂对妊娠结局(特别是女性银屑病患者)的潜在影响尚缺乏充分研究,无法准确量化。有关在其他病例中的生物制剂使用数据十分有限。通常建议有生育能力的女性使用常规避孕,但在备孕的情况下,应视具体情况讨论继续或停止生物治疗的风险及好处。大规模研究是必需的,并且应考虑其他可能影响妊娠的因素,比如疾病活动性、其他疗法及母体人口统计特征。

Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial

Summary

Psoriasis is a chronic disease causing red and scaling skin lesions. Current treatments, especially biologics, which are either given by injection or intravenous infusion (IV), are very effective in the treatment of moderate to severe plaque psoriasis. However, most patients look to achieve clear skin, so there is room for improvement. One approved biologic, ustekinumab, blocks two of the body's internal proteins, interleukin (IL)-12 and IL-23. Blocking these proteins prevents signals that cause inflammation in psoriasis. While ustekinumab is effective in many patients, most will not achieve complete skin clearance. Because recent scientific evidence shows that IL-23 may be more important than IL-12 in causing psoriasis, guselkumab, a new treatment that specifically targets IL-23, but not IL-12, has been developed and was recently approved in the U.S. to treat moderate to severe psoriasis. In the NAVIGATE trial, 871 patients with moderate-to-severe plaque psoriasis received ustekinumab and if, after 16 weeks, patients were not clear or almost clear, they were randomly assigned to either continue ustekinumab or start treatment with guselkumab until week 44. From week 16 until week 40, the average number of visits (maximum = 4) at which patients were clear or almost clear was significantly greater in patients treated with guselkumab (1.5) than with ustekinumab (0.7). In addition, at week 28, twice the proportion of patients on guselkumab (31.1%) were clear or almost clear than on ustekinumab (14.3%). Infections were the most commonly reported adverse event among patients on either guselkumab or ustekinumab. The authors conclude that for patients who do not achieve clear or almost clear skin after ustekinumab treatment, switching to guselkumab could be an effective treatment strategy and did not raise safety concerns.

Corrigenda

Experiences of rosacea and its treatment: an interpretative phenomenological analysis

Summary

Rosacea is a skin disorder which causes flushing and redness of the face. Relatively few people with rosacea receive specialist dermatology treatment or psychological support. Despite this, individuals with rosacea can experience social anxiety, depression and embarrassment, and decreased quality of life. Whilst questionnaire based studies have been used to investigate the type of distress that people living with rosacea might experience, there are no studies that have sought to gain an in-depth understanding of the experiences of living with this visible skin condition. Therefore, this study used face-to-face interviews to learn about participants' complex, individual experience of life with rosacea. A qualitative approach called interpretative phenomenological analysis (IPA) was used to guide the interviews and analysis. This approach to research focuses on individual accounts and has been extensively used to investigate illness experience. In this study nine participants took part in detailed semi-structured interviews. Three overarching themes were gleamed from these interviews; self-consciousness, which focused on the fear of others assigning blame to participants for having caused their own symptoms; avoidance, concealment, and hiding emotions, referring to the coping strategies participants employed in response to rosacea; and inconsistencies in treatment, which focused on the need for medical professionals to assess the emotional wellbeing of patients with rosacea. The findings are consistent with qualitative findings from patients with other skin conditions that demonstrate that self-conscious emotions can be a significant part of the experience of life with a skin condition. Healthcare professionals need to take care to assess for the presence of such concerns in rosacea, and where unhelpful thoughts or beliefs are reported, patients may benefit from dermatology specific psychological support.

Sustained Psoriasis Area and Severity Index, Dermatology Life Quality Index and EuroQol-5D response of biological treatment in psoriasis: 10 years of real-world data in the Swedish National Psoriasis Register

Summary

Patients with mild disease are usually treated with topical treatments, meaning applied to the skin, while patients with moderate to severe disease require systemic treatments (taken inside the body), which includes drugs called biologics. PsoReg is the Swedish national register established in 2006 to monitor the long term effectiveness and safety of biologics. PsoReg records patients' Psoriasis Area and Severity Index (PASI), which is a way of measuring how severe and widespread a patient's psoriasis is at a given time, allowing doctors to see if symptoms are worsending or improving. PsoReg also records patients' Health-Related Quality of Life (HRQoL), which takes into account how the disease is affecting their daily activities and emotional wellbeing. This study used data from 583 patients to see how switching to a biologic treatment, having not previously taken biologics, impacts on their PASI and HRQoL. PASI and HRQoL values were analysed at 3–5 months, 6–11 months, and at least once more after a year or more, up to 9 years after switch to biological treatment. The data showed significant improvement in these scores 3–5 months after the switch, and this improvement lasted the whole observation period. The results from this study may support clinicians in starting and continuing biological treatment for patients with disappointing results with other types of treatment.

What can we learn from psoriasis pharmacogenomics research?

Linked Article: van Vugt et al. Br J Dermatol 2018; 178:86–94.

How breakthroughs in translational research have impacted treatment strategies for melanoma

Association of circulating resistin, leptin, adiponectin and visfatin levels with Behçet disease: a meta-analysis

Summary

Background

Behçet disease (BD) is a chronic inflammatory disease. Adipokines are synthesized in adipose tissue, and have been reported to play important roles in the pathogenesis of autoimmune and inflammatory diseases, including BD.

Aim

To evaluate the relationship between circulating blood adipokine levels and BD.

Methods

We conducted a meta-analysis of papers reporting on serum/plasma resistin, leptin, adiponectin and visfatin levels in patients with BD and in healthy controls (HCs). We identified 82 relevant studies using electronic and manual search methods, and selected 16 studies for full-text review based on the title and abstract. Two of these were later excluded (one was a review, one had no data), leaving 14 articles that met the inclusion criteria for this meta-analysis.

Results

The 14 included studies assessed 637 patients with BD and 520 HCs. Compared with the HCs, the BD group had significantly higher levels of leptin [standardized mean difference (SMD) = 0.68, 95% CI 0.15–1.21, P = 0.01]. Levels of resistin (SMD = 0.51, 95% CI 0.92–0.918, P = 0.02) and adiponectin (SMD = 0.31, 95% CI 0.06–0.56, P = 0.02) were significantly higher in the BD group after adjustment for age, sex and body mass index (BMI), but not without such adjustment (resistin: (SMD = 0.38, 95% CI −0.18 to 0.93, P = 0.19; adiponectin: SMD = −0.59, 95% CI −2.23 to 1.06, P = 0.48). A significantly lower visfatin level was found in the BD group with adjustment (SMD = −1.70, 95% CI −2.14 to −1.25, P < 0.001) but not without adjustment (SMD = 0.31, 95% CI −0.21 to 0.82, P = 0.24).

Conclusions

Our meta-analysis revealed significantly higher circulating resistin, leptin and adiponectin levels and lower visfatin levels in patients with BD than in HCs, indicating that adipokines probably play an important role in BD pathogenesis.

Noonan syndrome with multiple lentigines and associated craniosynostosis

Hypopigmented patches on the buttocks of a 7-year-old boy

Patient Perspectives: What are hives?

Asymptomatic bands on an infant's extremity

Nancy B. Esterly, MD: The mother of pediatric dermatology

Dr. Nancy Lee Burton Esterly 4/14/1935–10/8/2017

Congenital scalp tumor with ulceration

Polarized transilluminating dermoscopy

Rapidly spreading subcutaneous nodules in a 2-year-old boy

Congenital sacral mass in a newborn

In memoriam: Dr. Ramón Ruiz Maldonado (November 7, 1937-April 5, 2017)

A Note from the Journal's Editors-in-Chief

A newborn with significant white hyperkeratotic plaques

Issue Information

Comment on “Hidradenitis suppurativa in children treated with finasteride—A case series”

Itchy bumps with new-onset bullae

Chronic pruritic warty papules on the buttocks

A case of paraneoplastic elastosis perforans serpiginosa associated with ovarian malignancy

Abstract

Elastosis perforans serpiginosa (EPS) is a rare skin disorder in which there is transepithelial elimination of elastin fibers. It belongs to a group of perforating disorders of which there are four classic types. The EPS type is extremely rare. There have been no previous reports of elastosis perforans serpiginosa occurring as a paraneoplastic phenomenon. We report a case of paraneoplastic elastosis perforans serpiginosa in the setting of stage 4 ovarian cancer.

Radiotherapy regimens in patients with nonmelanoma head and neck skin cancers

Abstract

Background

To assess the effectiveness and outcomes of adjuvant radiotherapy regimens for nonmelanoma skin cancers (NMSC) of the head and neck, particularly for elderly patients.

Methods

A retrospective review of patients with head and neck NMSC was conducted. Radiotherapy dose per fraction regimens included ≤200, 240–250, 300–400, and 500–600 cGy. Demographics, tumor characteristics, local control (LC), regional control (RC), and survival outcomes were analyzed.

Results

Of the 90 patients with 140 disease sites, 76.6% were squamous cell carcinoma, 15.5% were basal cell carcinoma, and 7.7% were other histologies. The mean age at diagnosis was 72.1 years old. The most common location was preauricular (20.0%), followed by temple, scalp, cheek, and forehead. The overall LC and RC rates were 88.8% and 88.8%, respectively by patients, and 92.8% and 86.4%, respectively by treatment sites. Age, primary tumor location, T classification, N classification, overall stage, perineural invasion, comorbid disease, skull base invasion, and radiotherapy subgroup were significantly associated with disease-free and overall survival (P < 0.05). LC and RC were not significantly different among the radiotherapy dose subgroups. The mean survival was longer in patients treated with 240–250 cGy/fraction (50.3 months). There was no significant difference in radiotherapy toxicity between the subgroups.

Conclusion

Short-term radiotherapy regimens for patients with locally or regionally advanced head and neck NMSC appear feasible and effective, particularly in elderly patients or those that cannot tolerate the length of standard regimens.

IgG from atopic dermatitis patients induces IL-17 and IL-10 production in infant intrathymic TCD4 and TCD8 cells

Abstract

Introduction

Our group recently demonstrated that IgG modulates αβT cell cytokine production during the maturation process in the human thymus. The effects of this modulation are IgG repertoire dependent and can exert a systemic and long-term impact.

Objective

To investigate whether IgG from atopic dermatitis (AD) patients can modulate cytokine production of infant intrathymic TCD4 and TCD8 cells in vitro.

Methods

Thymic tissues were obtained from newborn children from nonatopic mothers, and thymocytes were cultured for 6 days with purified IgG from AD patients or with intravenous immunoglobulin (IVIG) or mock conditions as controls. Cells were gated as double positive T cells (TDP⁻CD4⁺CD8⁺), TCD4 cells (CD4⁺CD8⁻), or TCD8 cells (CD4⁻CD8⁺), and intracellular levels of IL-17A, IFN-γ, TNF-α, IL-4, IL-10, and TGF-β were evaluated by flow cytometry.

Results

Compared to mock and IVIG culture conditions, IgG of AD individuals induced in vitro intracellular production of IL-17 and IL-10 by intrathymic TDP, TCD4, and TCD8 cells of infants. TGF-β was also detected at a higher frequency in response to AD IgG in TDP and TCD8 cells compared to mock and IVIG cultured conditions. An opposite effect was detected upon IFN-γ production in TCD4 cells, such that AD IgG reduced IFN-γ production compared to production under mock conditions but not under IVIG conditions.

Conclusion

IgG of AD patients can stimulate cytokine production in infant thymocytes and thus resembles the peripheral profile observed in adults. These findings suggest a novel mechanism that can contribute to AD pathogenesis.

Sensory improvement of leprosy peripheral neuropathy in patients treated with perineural injection of platelet-rich plasma

Generalized reactions during skin testing with clindamycin in drug hypersensitivity: a report of 3 cases and review of the literature

Summary

Background

The diagnostic approach to drug hypersensitivity includes a detailed medical history, clinical examination, and skin testing and/or oral challenge with a culprit or alternative drug, depending on the type of reaction and the suspected drugs. Although skin testing is considered to be rather safe, cutaneous and systemic, including fatal, reactions have been described.

Objectives

To report 3 cases with generalized delayed reactions after skin testing with clindamycin, and to review the existing literature.

Methods

Thorough clinical examination, blood tests and prick, intradermal and patch tests were performed in 3 patients.

Results

All patients experienced generalized maculopapular exanthema after intradermal and patch testing with clindamycin and amoxicillin in the first patient, and clindamycin alone in the second and third patients. None of the patients showed immediate reactions to skin tests, while positive intradermal reactions after 24 h to amoxicillin and clindamycin were observed in the first patient, and positive intradermal reactions after 24 h to clindamycin were observed in the second and third patients.

Conclusions

Skin testing with clindamycin in the diagnosis of drug hypersensitivity carries some risk of adverse reactions. A stepwise and individual diagnostic work-up, considering potential risk factors, and testing in a specialized centre with emergency equipment available is highly recommended.

Progressive Tightening of Pulley Sutures for Primary Repair of Large Scalp Wounds

Summary: Scalp defects greater than 2 cm in diameter are not usually amenable to primary closure and require local tissue rearrangement, grafting, tissue expansion, or prolonged second intention healing. Scalp flap reconstruction is a significant undertaking that requires elevation of a total flap surface area that is 3–6 times the size of the defect, often involves profuse bleeding, and can be challenging to perform without conscious sedation or general anesthesia. Anticoagulated and medically complex patients pose additional challenges and limit options for treatment. The pulley suture uses the mechanical advantage of the pulley to distribute tension across a wound and is useful in areas of high tension such as scalp wounds. For scalp wounds greater than 2 cm, pulley sutures are placed along the length of the wound. An assistant exerts equal tension on the pulley sutures, and the surgeon sequentially ties the sutures. The sutures are tightened and retied weekly until complete scalp closure is achieved. The pulley sutures can be used for rapid primary closure of scalp wounds up to 2.5–3.0 cm in diameter under local anesthesia. For scalp wounds larger than 3 cm, we have also found that pulley sutures can be progressively tightened yielding additional tissue expansion every week. Scalp wounds greater than 3.0 cm can be easily closed via primary repair and weekly tightening of pulley sutures without the need for flap reconstruction, traditional tissue expander placement, or second intention healing.

Guideline compliant prescription of biologicals and possible barriers in dermatological practices in Bavaria

Abstract

Introduction

Psoriasis and urticaria are chronic inflammatory skin diseases, which account for a substantial socio-economic burden and severely affect patients' quality of life. According to the respective German guidelines, biologicals can be used for the treatment of severe forms of these diseases. However, only a minority of patients receive this advised treatment.

Objective

To analyse the prescription of biologicals according to German national guidelines for psoriasis and chronic spontaneous urticaria and to assess possible barriers to prescription.

Material/methods

Cross-sectional, questionnaire based study including all Bavarian dermatologists based in private practices. Linear and logistic regression models were used to identify significant influencing factors on the perception of possible barriers.

Results

Between 01/2017 and 02/2017 a total of 137 (out of 499) dermatologists participated. Of all patients with moderate to severe psoriasis and chronic spontaneous urticaria, participating dermatologists indicated treating 14.2% and 6.9% with biologicals, respectively. The most prevalent barriers to prescription were the high cost of the therapy, the low reimbursement and the fear of recourse. Analysis showed that age, years spent working in a dermatological hospital and the number of patients treated with moderate to severe psoriasis affect the perception of many barriers. Furthermore, age and barriers related to physician factors and external factors were identified as modifiers to the prescription scheme of dermatologists.

Conclusions

The role of clinical education and the importance of external and economic barriers in comparison to medical barriers have to be emphasised. Guideline-compliant use of biologicals has to be optimised. Further research is needed to ascertain not only a barrier pattern for Bavaria, but also for wider settings. Actions based on this for psoriasis are needed to achieve the goal of the WHO Global Psoriasis Report to strengthen the role of patient-centred care and improve the quality of life of affected patients. Analogue, this applies also for urticaria.

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Pigmented fungiform lingual papillae: dermoscopic and clinical features

Abstract

Background

The tongue is covered by fungiform, filiform and circumvallate papillae. Fungiform papillae may be mainly pigmented in dark-skinned individuals.

Objective

A single-center study aimed to examine the clinical and dermoscopic features of pigmented fungiform papulae of the tongue (PFPT) in children, and a concise review of the literature has been performed.

Methods

The clinical and anamnestic data of 8 children affected by PFPT visited at the Pediatric Dermatology Unit of Bologna between 2010 and 2017, and a sistemic review of all studies of PFPT published on Pubmed up to August 31, 2017 have been collected and analyzed.

Results

The results of our data were consistent with the literature review: dark brown to black colored pinhead papules or bumps were observed in all cases of PFPT and three types of clinical patterns have been detected. Moreover the dermoscopic examination showed a cobblestone-like distribution and rose petal pattern. PFPT could be associated with hyperpigmentation of other sites such as the proximal nail folds and gums and an intra-familiar transmission is also possible.

Conclusion

Clinical and dermoscopic features of PFPT may help clinicians to recognize this ethnic, acquired, and benign condition.

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Picosecond Alexandrite Laser for Nevus of Ota Treatment in Chinese

Abstract

Nevus of Ota, also known as nevus fusco-caeruleus ophthalmo-maxillaris, is a benign dermal melanocytosis that typically affects the Asians. The patients experience psychosocial distress related to disfigurement and often seek for treatments. Q-switched lasers have demonstrated positive clinical results.

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Acute vascular reaction due to lipo-prostaglandin E1

Abstract

Lipo-prostaglandin E1 (Lipo-PGE1) is a PGE1 product in lipid microspheres and acts as a vasodilator. Injection of Lipo-PGE1 is used clinically for chronic skin ulcers caused by collagen diseases, diabetes mellitus and impaired blood circulation. Erythema, vascular pain, and phlebitis of the injected sites are recognized as cutaneous manifestations of the side effects of PGE1. Here we present the first case of acute vascular reaction along veins injected with Lipo-PGE1.

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Therapy response was not altered by HLA-Cw6 status in psoriasis patients treated with secukinumab: a retrospective case series

Abstract

Physicians can treat psoriasis patients with several effective treatments, however the response is individual and even the most effective therapies do sometimes not lead to a success of treatment. Currently, possible genetic markers that can predict individual therapy response are investigated. Up to now 45 genes have been identified to be associated with psoriasis [1].

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