Q-switched 532nm laser energy causes significant vascular damage in the capillary plexus – how does this affect laser tattoo removal?

Abstract

Tattoos can be effectively removed using Q-switched and picosecond lasers at four wavelengths – 1064, 755, 694 and 532nm^1,2,3,4. However, there are two particular problems with the 532nm line. Firstly, it is well absorbed by the melanin in the epidermis, due to its relatively high absorption coefficient⁵, (μ_{a_mel} = 56 cm⁻¹ for typical Caucasian skin). Secondly, 532nm is also strongly absorbed in the haemoglobin located in the capillary plexus⁵ (μ_{a_HbO} = 260 cm⁻¹).

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How well are reporting guidelines and trial registration used by dermatology journals to limit bias? A meta-epidemiological study

Abstract

Reporting guidelines were created to ensure research is reported in a transparent, complete manner that minimizes reporting bias. Further, these guidelines assist editors and peer reviewers when reviewing manuscripts for publication and readers when critically appraising published articles ¹. Though reporting guidelines and trial registration have been associated with improved reporting quality, the full effect of these guidelines has yet to manifest because many journals do not require their use ².

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The expanding spectrum of clinical phenotypes associated with PSTPIP1 mutations: from PAPA to PAMI syndrome and beyond

Abstract

Mutations in the PSTPIP1 gene encoding proline-serine-threonine-phosphatase interactive protein 1 were first identified in an autosomal dominant syndrome called PAPA associated with pyogenic sterile arthritis, pyoderma gangrenosum (PG) and cystic acne.^1,2. We report a patient with an autoinflammatory syndrome called PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome.³ A 23-year-old man had a 3-year-history of skin ulcerations.

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Response to ‘Clinical presentation of terbinafine-induced severe liver injury and the value of laboratory monitoring: a critically appraised topic’

Abstract

We read with interest the article by Kramer et al entitled "Clinical presentation of terbinafine-induced severe liver injury and the value of laboratory monitoring: a critically appraised topic". ¹ We would like to bring to focus our experience in this regard. With increasing concerns of reduced susceptibility to terbinafine² and an upsurge of recalcitrant cutaneous dermatophytoses, dermatologists in India have been using higher doses of terbinafine for cutaneous dermatophytoses, as used in the early literature with this drug (upto 500mg/day in single or divided doses) ³; and for longer periods of time.

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Response to “IL-36 in hidradenitis suppurativa: Evidence for a distinctive pro-inflammatory role and a key factor in the development of an inflammatory loop”

Abstract

we read with interest the recent paper of Hessam et al.¹ regarding the involvement of IL-36 in hidradenitis suppurativa (HS). They have showed that agonist members of IL-36 were significantly overexpressed in HS lesional skin.

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Chronic sun exposure is associated with distinct histone acetylation changes in human skin

Abstract

Background

Photoaging is attributed to continuous sunlight or artificial UV exposure and manifests the clinical and histological changes of skin. Epigenetic changes have been found to be involved in the pathogenesis of photoaging. However, the underlying mechanisms are unclear.

Objectives

To analyse histone modification patterns in sun-exposed and non-exposed skins, and identify the abnormally histone modified-genes related to photoaging.

Methods

Skin biopsies were collected both from the outer forearm (sun-exposed area) and the buttock (sun-protected area) in 20 healthy middle-aged female volunteers. Global histone H3/H4 acetylation and H3K4/H3K9 methylation statuses were assessed by ELISA. Expression levels of HATs and HDACs were measured by RT-qPCR and western blot. ChIP-chip assay with anti-acetyl-histone H3 antibody in sun-exposed Pool (combining six sun-exposed skin samples) and non-exposed Pool (combining six non-exposed skin samples) was conducted to explore the abnormal histone H3 acetylation genes related to photoaging, then ChIP-qPCR was followed to verify the results of ChIP-chip.

Results

We observed higher global histone H3 acetylation level, increased P300 and decreased HDAC1 and SIRT1 expression in sun-exposed skins, compared with matched non-exposed skins. Further, ChIP-chip assay results showed that 227 genes displayed significant hyperacetylation of histone H3, and 81 genes displayed significant hypoacetylation of histone H3 between the two groups. Histone H3 acetylations levels on the promoters of PDCD5, ITIH5, MMP1 and AHR were positively correlated with the mRNA expression of the corresponding gene.

Conclusions

Chronic sun exposure induced histone H3 hyperacetylation may play a critical role in the pathogenesis of skin photoaging.

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Aprepitant improves refractory pruritus in primary cutaneous T-cell lymphomas: experience of the Spanish Working Group on Cutaneous Lymphomas

Abstract

Aprepitant has shown a promising anti-itch activity in several cases of cutaneous T-cell lymphomas (CTCLs)^1-8. We sought to determine its antipruritic efficacy in a large multicenter series of CTCLs patients with refractory pruritus and, secondarily, to define possible clinical predictors of response.A retrospective, analytical review of the Spanish Working Group on Cutaneous Lymphoma database was designed to collect patients with CTCLs and refractory pruritus, treated with aprepitant from 2009 to 2013.

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Strengthening the Healthy Start Workforce: A Mixed-Methods Study to Understand the Roles of Community Health Workers in Healthy Start and Inform the Development of a Standardized Training Program

Abstract

Introduction Healthy Start (HS) is dedicated to preventing infant mortality, improving birth outcomes, and reducing disparities in maternal and infant health. In 2014, the HS program was reenvisioned and standardization of services and workforce development were prioritized. This study examined how HS community health workers (CHW), as critical members of the workforce, serve families and communities in order to inform the development of a CHW training program to advance program goals. Methods In 2015, an online organizational survey of all 100 HS programs was conducted. Ninety-three sites (93%) responded. Three discussion groups were subsequently conducted with HS CHWs (n = 21) and two discussion groups with HS CHW trainers/supervisors (n = 14). Results Most (91%) respondent HS programs employed CHWs. Survey respondents ranked health education (90%), assessing participant needs (85%), outreach/recruitment (85%), and connecting participants to services (85%) as the most central roles to the CHW's job. Survey findings indicated large variation in CHW training, both in the amount and content provided. Discussion group findings provided further examples of the knowledge and skills required by HS CHWs. Conclusions The study results, combined with a scan of existing competencies, led to a tailored set of competencies that serve as the foundation for a HS CHW training program. This training program has the capacity to advance strategic goals for HS by strengthening HS CHWs' capacity nationwide to respond to complex participant needs. Other maternal and child health programs may find these results of interest as they consider how CHWs could be used to strengthen service delivery.

Correction to: A bibliometric analysis of research on haze during 2000–2016

Abstract

The original version of this article unfortunately contains mistakes.

Patient-reported health outcomes in patients with non-melanoma skin cancer and actinic keratosis: Results from a large scale observational study analysing effects of diagnoses and disease progression

Abstract

Background

Non-melanoma skin cancer (NMSC) and actinic keratosis (AK) are very common among fair-skinned individuals. A disease continuum from AK to squamous cell carcinoma (SCC) has been frequently postulated. AK and NMSC may influence quality of life (QL) of patients, and it can be suspected that disease progression entails a QL reduction. The purpose of this study was to document QL in patients with NMSC and AK using the health-outcome questionnaire EQ-5D-5L.

Methods

The study was designed as a non-interventional, prospective, cross-sectional study. Patients with AK, SCC, basal cell carcinoma (BCC) or multiple diagnoses were enrolled in this study in 29 dermatological centres across Germany. Patients were asked to complete the EQ-5D-5L (compromising EQ Index and EQ VAS), and the dermatologists provided diagnosis, disease history and treatment data.

Results

A total of 1,184 patients were enrolled and diagnosed as follows: 73% AK, 49% BCC and 17% SCC. 66% had a single diagnosis, 28% two different diagnoses and 6% three different diagnoses. QL was strongly associated with patients' diagnosis. Patients with a single AK diagnosis had significantly higher mean EQ VAS (78) than patients with BCC (74), SCC (72), and BCC plus SCC (69), p < .050. When the effects of disease progression were calculated, patients with AK plus SCC reported significantly less mean EQ VAS (71) than patients with a single AK diagnosis (78), p < .011.

Conclusions

While rarely being imminently life-threatening, NMSC and AK have an impact on QL as quantified by the EQ-5D-5L. This impact is associated with diagnosis (AK vs. NMSC) and clinical progression (AK vs. AK plus SCC). Both lead to a clear decline in QL. This shows that disease progression is perceived and judged as detrimental by patients and that AK and NMSC should be diligently treated to preserve and restore QL.

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Metabolic Profile in Patients with Mild Obstructive Sleep Apnea

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

Victimization and Human Immunodeficiency Virus-Related Risk Among Transgender Women in India: A Latent Profile Analysis

Violence and Gender , Vol. 0, No. 0.

Patients with Spitz nevi in the Greek population: Epidemiologic, Clinical, and histopathological characteristics

Abstract

Background

Spitz nevi may present with clinical and histopathological atypical features that do not affect patient prognosis, but may become worrisome for patients ≥40 years presenting with newly appearing SN.

Objective

Patient characteristics and sun behavior patterns were investigated in correlation with age. SN characteristics and histopathological attributes were also investigated in correlation with age.

Methods

Patients with histopathologicaly confirmed diagnosis of SN were invited for a clinical examination. Data such as skin type, number of banal/atypical nevi, sun exposure patterns, personal/family history etc., were collected. Histopathology preparations were re-examined by two different histopathologists and characteristics were collected based on a prespecified checklist. Patients were afterwards followed-up every 6 months.

Results

110 patients with SN were identified and assigned to 3 age groups. The most common area of presentation was the trunk, for the ≥40 years age group, and the limbs for the other age groups. Patients ≥40 years had a higher possibility of presenting with a nevus count ≥50 and at least one atypical nevus compared to the other age groups. Patients ≥40 years presented more commonly with a history of painful sunburn (100%) before the appearance of the SN, used less sunscreen, had higher sun exposure times and more clinical signs of solar skin damage compared to the other age groups. Finally, patients ≥40 years presented more commonly with signs of histopathological atypia such as presence of mitoses, cellular atypia and prominent nucleolus.

Conclusion

Patients ≥40 were more likely to report a history of longer sun exposure times, of never using a sunscreen and of having a history of painful sunburn. However, the importance of this observation remains to be elucidated since these patients also presented more commonly with lesions located on non-sun exposed areas (trunk), and higher nevus/atypical nevus counts.

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Acute and Recurrent Facial Pustulosis: A Unique Clinical Entity?

We report a series of three patients encountered in a tertiary referral center that share a rare constellation of clinical and histopathologic findings. In each case, a healthy female patient reported recurrent episodes of rapidly-appearing, tightly-clustered, fine pustules on a background of light erythema involving the chin, forehead, cheeks, and neck (Figure 1). These episodic eruptions, which occurred approximately 4-6 episodes per year, were associated with mild pruritus, and relapsed and remitted within 5 days without therapeutic intervention.

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A Slowly Developed Severe Cutaneous Adverse Reaction to Idelalisib

Intracellular signal mediator phosphatidylinositol-3-kinase (PIK3K) –δ, an isoform of PIK3K, is expressed in hematopoietic cells especially in lymphoid lineage 1. Idelalisib is a novel PIK3K-δ targeted kinase inhibitor which is approved for relapsed follicular B-cell non-Hodgkin lymphoma as a monotherapy and in combination with rituximab, an anti-CD20 antibody, for relapsed chronic lymphocytic leukemia (CLL) 2. Only one case describing the clinical features of severe cutaneous adverse reaction (SCAR) of idelalisib in detail has been previously published 3. Here we expand the clinical picture of SCAR caused by idelalisib with its histological profile.

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Plantar Eumycetoma by Madurella mycetomatis in a heart-transplanted patient living in Portugal

Eumycetoma is a chronic granulomatous fungal infection of dermal and subcutaneous tissue rarely seen in Europe. It is characterized by a painless subcutaneous mass with drainage of macroscopic grains through sinus tracts,^1,2 spreading with severe tissue destruction, including fascia and bone.

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Finding the needle in the haystack is teledermoscopy's task

We read with interest the recent letter in this journal by Kukutsch et al. as to the opinion of an international group of experts on dermoscopy about the practice of teledermoscopy (TDC) between primary care physicians (PCPs) and a remote dermatologist.

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Recognizing the haystack is the task of the primary care physician

In a reply to our letter Ferrandiz and colleagues wondered why dermoscopy experts did not already fully embrace teledermoscopy (TD) for suspicious pigmented skin lesions.¹ Our study showed that the structure of the health systems that were investigated differed, with countries where primary care physicians (PCP) hold a gate keeper function and others with direct access to a dermatologist. Significant differences in waiting time and travel distance were observed.² Since we believe that there is enough evidence that the addition of high quality dermoscopic pictures to a teleconsultation leads to higher accuracy of the diagnosis we did not investigate this question in our survey.

Using Citrus aurantifolia essential oil for the potential biocontrol of Colocasia esculenta (taro) leaf blight caused by Phytophthora colocasiae

Abstract

The aim of this work was to evaluate the antimicrobial activities of leaves and epicarp of Citrus aurantifolia essential oil against Phytophthora colocasiae, the causative agent of taro leaf blight. Oils were extracted by hydrodistillation, and their chemical composition was determined by gas chromatography and gas chromatography coupled with mass spectrometry. Antimicrobial activities of oils were tested in vitro against mycelium growth and sporangium production. In situ tests were done on healthy taro leaves, and the necrosis symptoms were evaluated. Results showed that the essential oil extraction yields from leaves and epicarp were 0.61 and 0.36%, respectively. Limonene (48.96%), bornyl acetate (14.18%), geraniol (10.53%), geranial (3.93%), and myrcene (3.14%) were the main components in leaf oil, while limonene (59.09%), cis-hydrate sabinene (7.53%), geranial (5.61%), myrtenol (5.02%), and terpinen-4-ol (3.48%) were the main components in epicarp oil. Both oils exhibited antimicrobial activities with total inhibition of the mycelium growth at 500 and 900 ppm for leaf and epicarp, respectively. The highest inhibitory concentration of sporangium production was 400 (72.84%) and 800 ppm (80.65%) for leaf and epicarp oil, respectively. For the standard fungicide (metalaxyl), the total inhibition value of mycelial growth and sporangium production was 750 ppm. In situ tests showed that, at 5000 ppm, total inhibition (100%) was obtained for a preventive test, while 50% of the inhibition was observed for a curative test when leaf oil was applied. When epicarp essential oil was applied at 5000 ppm, 47.5 and 16.66% of the reduction of leaf necrosis were observed for the preventive and curative test, respectively. There were positive correlations between both the oil concentration and the reduction of necrosis caused by P. colocasiae. These findings suggest that the C. aurantifolia essential oil could serve as an eco-friendly biocontrol for the management of taro leaf blight.

An Appraisal of the Cephalic Index in Sagittal Craniosynostosis, and the Unseen Third Dimension.

No abstract available

“Reply: Outpatient circumferential lower Body Lift is the Lipo-Body Lift an ideal method?

No abstract available

Outpatient circumferential lower Body Lift: Is the Lipo-Body Lift an ideal method?

No abstract available

Comparison of Steroid and Botox Monotherapy with Combination Therapy for Treating Human Hypertrophic Scars in an Animal Model

No abstract available

“Predictors of Autologous Free Fat Graft Retention in the Management of Craniofacial Contour Deformities.”

No abstract available

Authors´ response: Parry-Romberg syndrome shows greater fat graft retention after a complementary fat grafting

No abstract available

Re: Autologous Fat Transfer for Thumb Carpometacarpal Joint Osteoarthritis A Prospective Study

No abstract available

Autologous Fat Transfer for Thumb Carpometacarpal Joint Osteoarthritis: A Prospective Study

No abstract available

Ion-imprinted electrospun nanofibers of chitosan/1-butyl-3-methylimidazolium tetrafluoroborate for the dynamic expulsion of thorium (IV) ions from mimicked effluents

Abstract

The present study explores the innocuous, biocompatible, and extremely competent molecularly imprinted chitosan/RTIL electrospun nanofibers having average diameter of 30 nm for the expulsion of thorium (IV) ions from the mimicked effluent waste. The extended Flory–Huggins theory and three-dimensional molecular modeling have been effectively premeditated via Materials Studio software for enumerating the inter-miscibility and compatibility (Chi parameter (χ) = 1.019, mixing energy (E_mix) = 0.603 kcal/mol) of the chitosan/RTIL (1-butyl-3-methylimidazolium tetrafluoroborate). The maximum adsorption efficiency is found to be 90% at a neutral pH of 7, and a temperature of 298 K within 120 min. The adsorption process was extensively studied by two-parameter adsorption isotherms like Langmuir, Freundlich, Temkin, and Dubinin–Radushkevich (D–R) and three-parameter models like Redlich–Paterson and Sips isotherm. Pseudo-second-order kinetics model (R² = 0.982) and Langmuir isotherm (R² = 0.994) bestowed the best fitting on chitosan/RTIL nanofibers for the adsorption of Th (IV) ions. The thermodynamic study reveals the spontaneity and exothermic nature of the reaction. The experimental analysis conjoint with isotherm and kinetic models, and simulation study establish the applicability of chitosan/RTIL nanofibers for the expulsion of Th (IV) and other toxic metal ions from the effluents.

Graphical abstract

Ion-imprinted electrospun nanofiber for expulsion of thorium (IV) ion

Comprehensive study of the mountainous lake sediments in relation to natural and anthropogenic processes and time (Mały Staw Lake, Poland)

Abstract

The Sudety Mts. form a chain of mountains in the South of Poland and during the last 200 years were subjected to strong industrial and agricultural pressure. The records of these human-induced changes are stored in natural archives like lake sediments. For the comprehensive study, three sediment cores taken from Mały Staw Lake (Sudety Mts.) were analyzed for the concentration of K, Na, Mn, Fe, Cu, Mg, Zn, Cd, Cr, Ni, Pb and radioactivity of ¹³⁷Cs and ²¹⁰Pb. As a result of the studies, the bathymetry map was developed and the sources of solid material supplied to the lake were identified. The geochronology studies of the cores were performed using ²¹⁰Pb method, to evaluate model of time changes in the sediment. Radioactivity of ²¹⁰Pb_uns (determined indirectly by ²¹⁰Po) ranged from 1051 ± 64 to 12 ± 8 Bq kg⁻¹. The ¹³⁷Cs radioactivity was determined directly by gamma spectrometry and varied from 525 ± 37 Bq kg⁻¹ for top layers to 9.80 ± 5.40 Bq kg⁻¹ for the bottom of the core. Two characteristic peaks of ¹³⁷Cs radioactivity related to the global fallouts after nuclear weapons testing and the Chernobyl accident were observed and used to confirm ²¹⁰Pb dating method. Chemometrics analysis of the chosen metal's concentrations combined with sample dating showed distinct imprint of human activity on the studied area.

Outcomes Comparison for Microsurgical Breast Reconstruction in Specialty Surgery Hospitals Versus Tertiary Care Facilities

Background: Postoperative monitoring is crucial in the care of free flap breast reconstruction patients. Tertiary care facilities (TCFs) provide postoperative monitoring in an ICU after surgery. Specialty surgery hospitals (SSHs) do not have ICUs, but these facilities perform free flap breast reconstruction as well. Are outcomes comparable between the 2 facilities in terms of flap reexploration times and overall success? Methods: Retrospective study including 163 SSH and 157 TCF patients. Primary predictor was facility in which the procedure was performed. Secondary predictors included operative, demographic, and comorbidity data. Primary outcomes were flap take back rate and flap failures. Secondary outcomes were total time from adverse event noticed in the flap to returning to the operating room (OR) and total time from decision made to return to the OR to returning to the OR (decision made). Tertiary outcomes were length of stay, operative times, and blood loss. Results: Patients at the TCF were generally less healthy than SSH patients. Salvage rates and failure rates were similar between the 2 institutions. Adverse event noticed and decision made times did not differ between the 2 facilities. Overall flap success rate was 98.22% at SSH and 98.81% at TCF. No primary or secondary predictors had a significant correlation with increased odds for flap failure. Conclusion: SSHs can offer similar outcomes in free flap breast reconstruction with just as effective clinical response times to endangered flaps as found in a TCF. However, surgery at an SSH may best be reserved for healthier patients.

An Algorithmic Approach to Operative Management of Complex Pediatric Dog Bites: 3-Year Review of a Level I Regional Referral Pediatric Trauma Hospital

Background: Incidence of dog bites continues to rise among the pediatric population and serves as a public health threat for the well-being of children. Plastic surgeons are at the forefront of initial management and eventual outcome of these devastating injuries. This study set out to determine the nature of dog bite injuries treated over a 3-year period at a large level 1 pediatric trauma center. Methods: A retrospective review of emergency room records of all pediatric patients (age, 0–18 years old) who sustained dog bites between January 2012 and December 2014 were gathered. All details about age of patient, location and severity of dog bites, type of dog breed, antibiotics given, and emergency versus operative treatment were recorded and analyzed. Results: One hundred eight patients aged 5 months to 18 years old were treated in the emergency department after suffering dog bite injuries during the study period. The highest incidence of dog bites occurred in preschool children. The mean age for patients who required operative repair was lower than the mean age for patients who underwent primary closure in the emergency department. The location of injury was most commonly isolated to the head/neck region. Of the 56 cases that had an identified dog breed, pit bulls accounted for 48.2% of the dog bites, and 47.8% of pit bull bites required intervention in the operating room. Conclusion: Children with large dog bite injuries require more immediate care in a level 1 pediatric trauma hospitals in order to optimize their hospitalization course and eventual outcome.

Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is frequently upregulated in prostate cancer, and its overexpression conveys tumor growth and angiogenesis by metabolizing asymmetric dimethylarginine (ADMA)

Abstract

Tissue microarray analysis confirmed higher dimethylarginine dimethylaminohydrolase-1 (DDAH1) expression in prostate cancer (PCa) compared to benign and normal prostate tissues. DDAH1 regulates nitric oxide (NO) production by degrading endogenous nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA). This study examined whether DDAH1 has any physiological role in PCa progression. Using overexpression of DDAH1 in PCa (PC3 and LNCaP) cell lines, we found that DDAH1 promotes cell proliferation, migration and invasion by lowering ADMA levels, as well as increasing NO production. VEGF, HIF-1α and iNOS were upregulated in DDAH1 expressing cells as result of elevated NO. DDAH1 increased secretion of pro-angiogenic signals bFGF and IL-8, into conditioned media. Treatment of DDAH1-positive PCa cells with NOS inhibitors (L-NAME and 1400 W) attenuated DDAH1 activity to promote cell growth. Xenografts derived from these cells grew significantly faster (> twofold) than those derived from control cells. Proliferation rate of cells stably expressing mutant DDAH1 was same as control cells unlike wild-type DDAH1-positive PCa cells. Xenograft tumors derived from mutant-positive cells did not differ from control tumors. VEGF, HIF-1α and iNOS expression did not differ in DDAH1 mutant-positive tumors compared to control tumors, but was upregulated in wild-type DDAH1 overexpressing tumors. Furthermore, CD31 immunostaining on xenograft tissues demonstrated that DDAH1 tumors had high endothelial content than mutant DDAH1 tumors. These data suggest that DDAH1 is an important mediator of PCa progression and NO/DDAH pathway needs to be considered in developing therapeutic strategies targeted at PCa.

Soil physical properties response to tillage practices during summer fallow of dryland winter wheat field on the Loess Plateau

Abstract

Soil physical properties are a greatly important part of the soil and indicator of soil quality, which can directly affect soil nutrient turnover and crop yields in dryland. This study was carried out with three tillage practices during the summer fallow season since 2011, including no tillage (NT), plow tillage (PT), and subsoiling (ST) in dryland winter wheat fields of the Loess Plateau. Results showed that soil tillage during the summer fallow had a small effect on soil bulk density (ρ _b) in the 0–50-cm soil profile before sowing and after harvesting of winter wheat. Soil ρ _b under NT at a depth of 20–30 cm was significantly greater than those under PT in both seasons. Both soil gravimetric water content (θ _g) and volumetric moisture content (θ _v) after harvesting increased by 28.8–78.6% and 37.5–87.3%, respectively, compared with those before sowing. Adoption of PT significantly increased soil θ _g and θ _v in the entire 0–50-cm profile before sowing compared with NT and ST (P < 0.05). In addition, there was a small effect on soil porosity (e.g., total porosity, air-filled porosity, and capillary porosity) in the profile of 0–50 cm both before sowing and after harvesting. Overall, short-term tillage during summer fallow mainly affected soil water content in the 0–50-cm soil profile, and it had a slight effect on other physical soil properties.

Facial reanimation surgery in Möbius syndrome: Experience from 76 cases from a tertiary referral hospital in Latin America

Publication date: Available online 15 November 2017
Source:Annales de Chirurgie Plastique Esthétique
Author(s): A. Cardenas-Mejia, D. Palafox
IntroductionMöbius syndrome is defined as a combined congenital bilateral facial and abducens nerve palsies. The main goal of treatment is to provide facial reanimation by means of a dynamic surgical procedure. The microneurovascular transfer of a free muscle transplant is the procedure of choice for facial animation in a child with facial paralysis.ObservationBetween January 2008 and January 2017, 124 patients with the syndrome have been approached at our institution. Distribution according to Möbius Syndrome classification presents as follows: Complete Möbius syndrome (n=88), Incomplete Möbius syndrome (n=28), Möbius-Like syndrome (n=8). Seventy-nine female and 45 male patients. Sixty-one percent have undergone a microsurgical procedure (n=76), in all of them, a free gracilis flap transfer was performed.DiscussionOur proposed treatment protocol for complete Möbius syndrome is determined by the available donor nerves. We prefer to use the masseteric nerve as first choice, however, if this nerve is not available, then our second choice is the spinal accesory nerve. For this purpose, all patients have an electromyography performed preoperatively. Overall, dynamic facial reanimation obtained through the microvascular transfer of the gracilis muscle have proved to improve notoriously oral comissure excursion and speech intelligibility.ConclusionThe free gracilis flap transfer is a reproducible procedure for patients with Möbius syndrome. It is of utmost importance to select the best motor nerve possible, based on an individualized preoperative clinical and electromyographic evaluation. To our best knowledge, this is the largest series of patients with Möbius syndrome globally, treated at a single-institution.

On Tacit Knowledge for Philosophy of Education

Abstract

This article offers a detailed reading Gascoigne and Thornton's book Tacit Knowledge (2013), which aims to account for the tacitness of tacit knowledge (TK) while preserving its status as knowledge proper. I take issue with their characterization and rejection of the existential-phenomenological Background—which they presuppose even as they dismiss—and their claim that TK can be articulated "from within"—which betrays a residual Cartesianism, the result of their elision of conceptuality and propositionality. Knowledgeable acts instantiate capacities which we might know we have and of which we can be aware, but which are not propositionally structured at their "core". Nevertheless, propositionality is necessary to what Robert Brandom calls, in Making It Explicit (1994) and Articulating Reasons (2000), "explicitation", which notion also presupposes a tacit dimension, which is, simply, the embodied person (the knower), without which no conception of knowledge can get any purchase. On my view, there is no knowledgeable act that can be understood as such separately from the notion of skilled corporeal performance. The account I offer cannot make sense of so-called "knowledge-based" education, as opposed to systems and styles which supposedly privilege "contentless" skills over and above "knowledge", because on the phenomenological and inferentialist lines I endorse, neither the concepts "knowledge" nor "skill" has any purchase or meaning without the other.

Co-Transplantation of Nanofat Enhances Neovascularization and Fat Graft Survival in Nude Mice

Abstract

Background

Autologous fat grafting is commonly used for soft-tissue augmentation and reconstruction. However, this technique is limited by a high rate of graft absorption. Thus, approaches to improve fat graft survival that promote neovascularization are of great interest. Nanofat has several beneficial features that may render it more suitable for clinical applications than other stem-cell based approaches.

Objectives

We aimed to determine whether nanofat could enhance new vessel formation and improve the long-term retention of fat grafts.

Methods

Nanofat was processed via mechanical emulsification and filtration. Fat grafts were transplanted subcutaneously under the scalps of nude mice with different nanofat volumes or without nanofat. The grafted fat was dissected 12 weeks after transplantation. Graft weight and volume were measured, and histological evaluations, including capillary density measurement, were performed.

Results

The co-transplantation of fat with nanofat showed higher graft weight and volume retention, better histological structure, and higher capillary density compared to that in controls. However, there were no significant differences between the two nanofat volumes utilized.

Conclusions

Nanofat can enhance neovascularization and improve fat graft survival, providing a potential clinically viable approach to fat graft supplementation in plastic and reconstructive surgery.

The influences of separators on capacitive deionization systems in the cycle of adsorption and desorption

Abstract

This research focused on the influence of different separator compartments on the performance of capacitive deionization (CDI) cells in terms of brackish water treatment. For comparison, different separators including filter paper(FP), carbon nanotube (CNT), and stainless steel fiber (SSF) on deionization and desorption rate of salt were examined. The best performance was obtained when the CNT separator was packed, followed by SSF and FP. Reducing the cell voltage from 1.2 to 0.4 V decreased the salt removal and electrode regeneration rate of SSF-CDI. Electrochemical impedance spectrometry (EIS) analysis revealed that the resistance and specific capacitance of separator materials are essential to the desalination and desorption performance of CDI. The electric double layers (EDLs) accelerated the ion transfer in the flow chamber due to storing excess ions, therefore increasing the desalination and electrode regeneration rate.

Morphology, molecular structure, and stable carbon isotopic composition of black carbon (BC) in urban topsoils

Abstract

Urban soils contain significant amounts of black carbon (BC) from biomass and fossil fuel combustion and regard to be a pool of BC. BC in urban soils has multiple effects on environmental processes in urban system, such as global climate change, air quality, and public health. Urban topsoil samples (0–10 cm) were collected from Anshan, Liaoning Province, northeast China, which is one of the most important old steel industrial bases in China. The BC in urban topsoils was extracted using the density method. Their chemical composition, morphology, molecular structure, and stable carbon isotopic composition were examined using elemental analysis, scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDS), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and stable carbon isotope (δ¹³C). Elemental analysis shows that carbon content in the BC of studied soils ranged from 64.5 to 78.4%, with the average more than 70%. The O/C atomic ratio of BC is on average 0.18. The BC particle displays different morphology, including porous spherical, irregular porous fragmentary, and blocky shapes. The porous spherical BC particles has atomic molar O/C ratio determined by SEM-EDS ranging from 0.04 to 0.37. XRD indicates that BC exists in mainly combining with mineral phases hematite (Fe₂O₃), kaolinite (Al₂Si₂O₅(OH)₄), quartz (SiO₂), and calcite (CaCO₃). The FTIR spectra of BC particles show major bands at approximately 3400 cm⁻¹ (O–H), 2920 cm⁻¹ (C = H), 1600 cm⁻¹ (C = C), 1230 cm⁻¹ (C = O), and 1070 cm⁻¹ (C = O). The stable carbon isotope (δ¹³C) of BC ranges from −24.48 to −23.18‰ with the average of −23.79 ± 0.39‰. The concentration of BC in the industrial area is significantly (p < 0.05) higher than that in the roadside area. The BC of industrial area is characterized by porous spherical structure, suggesting that they are mainly derived from fossil fuel combustion. Results indicated that a combination of atomic O/C ratio, porous structure, and stable carbon isotopic (δ¹³C) of BC could reflect effectively the origin of BC in urban topsoils. It could conclude that BC in Anshan urban topsoil was mainly from fossil fuel combustion.

Interest in tanning beds and sunscreen in German-speaking countries

Summary

Background

The growing incidence of nearly all types of skin cancer can be attributed to increased exposure to natural or artificial ultraviolet (UV) radiation. However, there is a scarcity of statistical data on risk behavior or sunscreen use, which would be important for any prevention efforts.

Methods

Using the search engine Google^®, we analyzed search patterns for the terms Solarium (tanning bed), Sonnencreme (sunscreen), and Sonnenschutz (sun protection) in Germany, Austria, and Switzerland between 2004 and 2016, and compared it to search patterns worldwide. For this purpose, "normalized search volumes" (NSVs) were calculated for the various search queries. The corresponding polynomial functions were then compared with each other over the course of time.

Results

Since 2001, there has been a marked worldwide decrease in the search queries for tanning bed, whereas those for sunscreen have steadily increased. In German-speaking countries, on the other hand, there have – for years – consistently been more search queries for tanning bed than for sunscreen. There is an annual periodicity of the queries, with the highest NSVs for tanning bed between March and May and those for sunscreen in the summer months around June. In Germany, the city-states of Hamburg and Berlin have particularly high NSVs for tanning bed.

Conclusions

Compared to the rest of the world, German-speaking countries show a strikingly unfavorable search pattern. There is still great need for education and prevention with respect to sunscreen use and avoidance of artificial UV exposure.

Mat-like telangiectasias

Multi-Institutional Competing Risks Analysis of Distant Brain Failure and Salvage Patterns after Upfront Radiosurgery without Whole Brain Radiotherapy for Brain Metastasis

Background

In this study we use a competing risks analysis to assess factors predictive of early salvage whole brain radiotherapy (WBRT) and early death after upfront stereotactic radiosurgery (SRS) alone for brain metastases in an attempt to identify populations that benefit less from upfront SRS.

Patients and methods

Patients from eight academic centers were treated with SRS for brain metastasis. Competing risks analysis was performed for distant brain failure (DBF) vs. death prior to DBF as well as for salvage SRS vs. salvage WBRT vs. death prior to salvage. Linear regression was used to determine predictors of the number of brain metastases at initial DBF (nDBF).

Results

A total of 2,657 patients were treated with upfront SRS alone. MVA identified an increased hazard of DBF associated with increasing number of brain metastases (p < 0.001), lowest SRS dose received (p < 0.001), and melanoma histology (p < 0.001), while there was a decreased hazard of DBF associated with increasing age (p < 0.001), KPS < 70 (p < 0.001), and progressive systemic disease (p = 0.004). MVA for first salvage SRS vs. WBRT vs. death prior to salvage revealed an increased hazard of first salvage WBRT seen with increasing number of brain metastases (p < 0.001) and a decreased hazard with widespread systemic disease (p = 0.002) and increasing age (p < 0.001). Variables associated with nDBF included age (p = 0.02), systemic disease status (p = 0.03), melanoma histology (p = 0.05), and initial number of brain metastases (p < 0.001).

Conclusions

Patients with a higher initial number of brain metastases were more likely to experience DBF, have a higher nDBF, and receive early salvage WBRT, while patients who were older, had lower KPS, or had more systemic disease were more likely to experience death prior to DBF or salvage WBRT.

Improved survival in metastatic germ-cell cancer

Abstract

Background

The prognostic score of the International Germ Cell Cancer Collaborative Group (IGCCCG) in metastatic germ-cell cancers (mGCC) relies on treatments delivered before 1990. It is unclear, if this score is still relevant to contemporary cohorts of patients who receive modern-type chemotherapy and supportive care.

Patients and Methods

All patients who underwent cisplatin/etoposide based first-line chemotherapy for mGCC at the University Hospital Zurich (USZ) between 1991 and 2016 were identified retrospectively. Clinical characteristics were extracted from medical charts and patients classified according to the IGCCCG score (J Clin Oncol 1997;15:594). Progression-free survival (PFS) and overall survival (OS) probabilities at 5 years served as outcome parameters.

Results

The study cohort consisted of 204 patients at a median age of 32 years and a median follow-up of 4.2 years. According to the IGCCCG score, PFS in the contemporary USZ cohort was 71% overall; 83% for good risk, 69% for intermediate risk and 30% for poor risk patients, p < 0.001. OS for the entire cohort was 88%. In respect to OS, we observed no difference between good risk and intermediate risk patients (94% vs. 91%, p = 0.62), but a statistically significant difference between those two risk groups and poor risk patients, who had an OS of only 65%, p < 0.001.

Conclusions

Within the contemporary USZ cohort of mGCC patients no improvements in PFS probabilities were observed compared to the ones predicted by the IGCCCG score for any prognostic category, but marked improvements in OS probabilities for intermediate risk and poor risk patients, possibly due to better salvage treatments.

Reply to: Re-Aligning the ASCO and ESMO Clinical Benefit Frameworks or Modern Cancer Therapies

Age at diagnosis and prostate cancer treatment and prognosis: a population-based cohort study

Abstract

Background

Old age at prostate cancer diagnosis has been associated with poor prognosis in several studies. We aimed to investigate the association between age at diagnosis and prognosis, and if it is independent of tumor characteristics, primary treatment, year of diagnosis, mode of detection and comorbidity.

Patients and methods

We conducted a nation-wide cohort study including 121,392 Swedish men aged 55-95 years in Prostate Cancer data Base Sweden (PCBaSe) 3.0 diagnosed with prostate cancer in 1998-2012 and followed for prostate cancer death through 2014. Data were available on age, stage, grade, PSA-level, mode of detection, comorbidity, educational level and primary treatment. We used Cox regression to calculate hazard ratios (HR) and 95% confidence intervals (CIs).

Results

With increasing age at diagnosis, men had more comorbidity, fewer PSA detected cancers, more advanced cancers and were less often treated with curative intent. Among men with high-risk or regionally metastatic disease, the proportion of men with unknown M stage was higher among old men versus young men. During a follow-up of 751,000 person-years, 23,649 men died of prostate cancer. In multivariable Cox-regression analyses stratified by treatment, old age at diagnosis was associated with poorer prognosis among men treated with deferred treatment (HR_{age 85+ vs. 60-64}: 7.19; 95% CI: 5.61-9.20), androgen deprivation therapy (HR_{age 85+ vs. 60-64}: 1.72; 95% CI: 1.61-1.84) or radical prostatectomy (HR_{age 75+ vs. 60-64}: 2.20; 95% CI: 1.01-4.77), but not radiotherapy (HR_{age 75+ vs. 60-64}: 1.08; 95% CI: 0.76-1.53).

Conclusion

Our findings argue against a strong inherent effect of age on risk of prostate cancer death, but indicate that in current clinical practice, old men with prostate cancer receive insufficient diagnostic work-up and subsequent curative treatment.

Novel treatment options for refractory GCT: Back to the bench!

Nivolumab in non-small cell lung cancer with EGFR mutation

LTBK-03 MULTICENTER RANDOMIZED PLACEBO CONTROLLED TRIAL OF AUTOLOGOUS FORMALIN FIXED TUMOR VACCINE FOR NEWLY DIAGNOSED GLIOBLASTOMAS

Abstract

BACKGROUND

Unlike immune checkpoint inhibitors, various vaccines have failed to demonstrate sufficient evidence in phase III studies due to the multiple antigenicity of neoplasms. Autologous formalin-fixed tumor vaccine (AFTV) from paraffin-embedded tissue is stable, and contains multiple tumor peptides, which are designed to induce killer lymphocytes in vivo (Nat Med 1995, 1996). We conducted three AFTV trials of Phase Ib or IIa for recurrent and newly-diagnosed glioblastoma (ndGBM), which demonstrate promising results. (Clin Cancer Res 2004; J Neurosurg 2011, 2013). In addition, a multicenter double-blind Phase IIb/III trial has been initiated.

METHODS

Patients from 16 to 75 years of age with supratentorial ndGBM, extensive resection, KPS of at least 60, and no prolonged steroids, were eligible. Planned patient enrollment was 120. AFTV or placebo, including for adjuvant treatment, was administered intradermally 3 times preceding (1) temozolomide chemoradiotherapy, (2) first and (3) second courses of adjuvant temozolomide.

RESULTS

In 30 months, 63 patients were registered for phase IIb and 61 cases were analyzed (mean age, 61 years). Median resection rate was 95%, median KPS was 80. In the whole cohort, median OS and progression-free survival (PFS) was 31.5 and 14.5 months, respectively. Comparison of the AFTV group (median OS, 25.6 months; 3-year OS rate, 38%) and the placebo group (median OS, 31.5 months; 3-year OS rate, 41%) did not reveal a significant difference in OS (HR, 1.19; 95% CI, 0.57 - 2.47; P = 0.64). Median PFS was 13.5 months in both groups (P = 0.98). According to a subgroup analysis of tumors with negative p53 immunostaining, 3-year OS of AFTV and placebo was 79% and 43%, respectively (P = 0.072). Surprisingly, for patients undergoing total resection of tumors, 3-year PFS of AFTV and placebo was 81% and 46%, respectively (P = 0.067). There were no severe adverse effects.

CONCLUSIONS

Phase IIb of AFTV trial for ndGBM did not demonstrate obvious survival impact in the whole cohort. However, subgroup analyses of tumors with negative p53 immunostaining or after total resection revealed possible better outcomes after AFTV therapy. These results will be investigated further in the Phase III part of the study.

LTBK-04 FIRST RESULTS OF THE RANDOMIZED PHASE II STUDY ON DEPATUX –M ALONE, DEPATUX-M IN COMBINATION WITH TEMOZOLOMIDE AND EITHER TEMOZOLOMIDE OR LOMUSTINE IN RECURRENT EGFR AMPLIFIED GLIOBLASTOMA: FIRST REPORT FROM INTELLANCE 2/EORTC TRIAL 1410

Abstract

BACKGROUND

Depatux-m is a tumor-specific antibody-drug-conjugate consisting of antibody (ABT-806) bound to the toxin monomethylauristatin-F. We investigated depatux-m in EGFR-amplified recurrent glioblastoma (40–50% of glioblastoma).

METHODS

EORTC-1410-BTG (NCT02343406) is a randomized open label phase II study. Eligible were patients with centrally confirmed EGFR-amplified glioblastoma at first recurrence after temozolomide chemo-irradiation, occurring ≥3 months after radiotherapy. After stratification for WHO status and time of relapse (<16 or ≥16 weeks after the first day of the last temozolomide cycle), patients were randomized to either a) treatment with depatux-m 1.0 mg/kg every 2 weeks intravenously, or b) the same treatment combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, or c) either lomustine or temozolomide (TMZ/LOM) depending on the time of relapse. Primary endpoint was overall survival (OS); 240 patients/170 events were needed to detect a HR reduction of 0.54 in the depatux-m arms.

RESULTS

Between March 2015 and July 2016 260 patients were randomized. With 199 events observed, for the primary comparison of depatux-m in combination with TMZ versus TMZ/LOM a HR of 0.71 was observed (95%CI [0.50, 1.02]; p = 0.031 one-sided; median OS 9.6 months versus 8.2 months, 1-year OS rate 39.7% versus 28.2%). No OS difference was observed between depatux-m monotherapy (median OS 7.9 months) and TMZ/LOM (HR 1.04; 95%CI [0.73, 1.48]. In patients with relapse ≥16 weeks after end of 1stline TMZ treatment, combined depatux-m/TMZ was associated with improved OS (HR 0.45, 95%CI [0.23, 0.87]; median OS 14.9 months versus 9.5 months). The main toxicity observed in depatux-m treated patients was ocular (grade 3: 27.9%, grade 4: 1%).

CONCLUSION

Although the primary endpoint was not met, depatux-m in combination with TMZ might improve OS in EGFR amplified recurrent glioblastoma. Outcome for depatux-m monotherapy was similar to LOM/TMZ control. Ocular events observed were consistent with earlier studies.

CMET-26. DIAGNOSTIC VALUE OF FDG-PET/CT FOR PATIENTS WITH BRAIN METASTASIS FROM UNKNOWN PRIMARY SITE

Abstract

OBJECTIVE

In 30% of patients with brain metastasis (BM), BM are the first clinical manifestation of systemic malignancy, referred to as BM from cancer of unknown primary site (BM-CUPS). The value of 18F-fluordesoxyglucose positron emission tomography (FDG-PET)/CT in the work-up of BM-CUPS patients remains to be defined.

METHODS

We screened 566 patients operated for BM at the University Hospital Zurich between 2004 and 2014 and identified 127 BM-CUPS patients. A validation cohort from two independent centers (n=100 and 120 patients) was available.

RESULTS

FDG-PET/CT was not superior to CT in localizing the primary lesion (FDG-PET/CT: 73/78, 93.6%; CT: n=70/78, 89.7%; p=0.25, McNemar's test). Thirty-six of 64 patients (56.3%) showed the same result in spotting the primary tumor. FDG-PET/CT identified additional lesions suspicious for extracranial metastases in 28 patients (43.7%). The graded prognostic assessment (GPA) score was determined post-hoc to objectify clinical relevance of additional findings. Information from CT only or FDG-PET/CT was used to assess extracranial metastases. Median GPA was 3 for CT vs. 2.5 for PET/CT (p= 3.8x10-5, McNemar's test), resulting in a predicted survival of 5.3 vs. 3.8 months (p= 6.1x10-5; Wilcoxon's test). Sensitivity of CT and FDG-PET/CT and staging capabilities were comparable in all cohorts.

CONCLUSION

FDG-PET/CT shows similar sensitivity to detect the primary tumor in BM-CUPS patients as CT, but may improve the accuracy of staging by detecting of more metastases. GPA scores and predicted survival differ significantly when calculated based on CT versus FDG-PET/CT. FDG-PET/CT should be prioritized for planning the diagnostic algorithm of BM-CUPS patients and redundant CT imaging should be avoided. Further, randomized trials on BM patients should standardize the methods when stratifying for GPA.

ACTR-01. RETROSPECTIVE ANALYSIS OF OLIGODENDROGLIOMA TREATMENT AT A SINGLE INSTITUTION

Abstract

BACKGROUND

Recently published results of randomized prospective clinical trials have demonstrated benefit from sequential radiation and chemotherapy after surgery for oligodendroglial tumors (RTOG 9802, 9402; EORTC 26951). We aimed to investigate whether such a benefit could be demonstrated in a retrospective cohort treated at our institution.

METHODS

Patients were identified from the quality control database in the Section of Neuro-Oncology, Yale Cancer Center. Histologic, clinical, imaging, treatment, and outcome data was reviewed. Patients who were 18 to 39 years old and had undergone gross total resection of a WHO II lesion were deemed low-risk (LR). High-risk patients were those ≥40 years old or who had undergone an incomplete resection or those with anaplastic tumors. Primary outcome measure is progression-free survival (PFS). Secondary outcome measure is overall survival (OS). PFS and OS are analyzed in high-risk patients who at initial diagnosis received sequential therapy (HR-SEQ) compared to individuals who only underwent surgery alone or combined with one adjuvant treatment modality (HR-DEL). Survival estimates are based on Kaplan Meier method and survival distributions are compared using the log-rank test.

RESULTS

We identified 150 consecutive biopsy-confirmed oligodendroglioma cases who were treated at Yale Cancer Center between 2002 and 2016. Forty-one patients (27%) are deceased. Thirty patients were considered low risk (1p/19q intact, n=14; co-deletion, n=14; 1p-deleted, n=2). Amongst the high-risk patients, 99 were in the SEQ group (1p/19q intact, n=46; co-deletion, n=47; 1p-deleted, n=2; 19q-deleted, n=4) and 21 in the DEL group (1p/19q intact, n=9; co-deletion, n=8; 1p-deleted, n=3; 19q-deleted, n=1). Median OS was 15.1 years for LR, 6.75 years for HR-SEQ, and 16.95 years for HR-DEL.

CONCLUSIONS

PFS and subgroup analysis based on molecular markers is ongoing. We reserve our conclusions until the analysis is complete. The cohort is likely too small for detailed subgroup analysis.

TMOD-48. SNAIL1 REGULATES GLIOMAGENESIS INDEPENDENT OF ITS MESENCHYMAL TRANSFORM FUNCTION

Abstract

BACKGROUND

Master mesenchymal factors such as Snail1 have long been implicated in local invasion and metastasis of various cancers including malignant brain tumors such as glioblastoma (GBM). However, mesenchymal factors are expressed early in tumorigenesis, well before first evidence of metastatic cells, suggesting that these factors have other critical functions independent of their mesenchymal regulation.

METHODS

We used a highly penetrant, retrovirally-delivered, PDGFB-induced mouse model of gliomagenesis in a conditional PTEN and/or P53 knockout background to produce GBM tumors of the proneural subtype, in which Snail1 expression is much lower compared to the mesenchymal subtype. We then examined the effect of conditional KO of Snail1 in glial cells when PDGFB overexpression occurred, using in vitro and in vivo loss-of-function experiments augmented by RNAseq expression profiling and computational network analysis.

RESULTS

Snail1 expression peaked early in gliomagenesis although its expression is downregulated once PDGFB-induced proneural tumors are formed. In an immune intact background, Snail1-null GBM developed at a much slower pace. Snail1 cooperated with oncogene activity to promote higher transformative capacity and to influence the cancer stem cell compartment.

CONCLUSION

Our data confirms a dual role for Snail1 in GBM progression, in which it cooperates with oncogenes to promote early transformation while independently also regulating mesenchymal changes at later stages of tumor development. Our platform combining RNAseq expression profiling and computational network analysis with biological validation provides a potentially powerful tool to study mechanistic events as gliomagenesis and proneural subtype GBM transformed into mesenchymal subtype GBM.

SURG-11. LASER INTERSTITIAL THERMOTHERAPY (LITT) FOR NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA: ASSOCIATION BETWEEN TIME TO INITIATION OF CHEMOTHERAPY POST-PROCEDURE AND OUTCOME

Abstract

BACKGROUND

LITT is used for cytoreduction of unresectable glioblastoma and is associated with blood brain barrier disruption with an increased permeability peak at 2 weeks. We investigated if time to initiation of chemotherapy post-LITT was associated with progression free survival (PFS) and overall survival (OS).

METHODS

Records of glioblastoma patients who underwent LITT at our institution between 2013-2017 were reviewed. Patients with inadequate follow-up or no further treatment after LITT were excluded. A time-to-event analysis was performed to investigate the association between PFS, OS and the time to initiation of chemotherapy after LITT.

RESULTS

The study included 21 patients; 17 recurrent glioblastoma (rGBM) (6 secondary glioblastoma), 4 newly diagnosed glioblastoma (nGBM). Median age was 53.6 (19.8-64.9) years. Three patients (14%) had isocitrate dehydrogenase (IDH)-1 mutation by immunohistrochemistry and two patients had unknown IDH status. Pre- and post-operative median KPS were 90 (60-100) and 80 (40-100) respectively. Eleven patients had difficulty weaning steroids (4 patients initiated steroids peri-operatively, 7 patients prior to surgery). For rGBM post-LITT median PFS was 3.36 months (95% CI (0.21, 0.51)) and median OS was 18.48 months (95% CI (0.66,NA)) with 5 deaths. Median PFS and OS for nGBM has not been reached. Eighteen patients (86%) received post-LITT chemotherapy of which eight initiated treatment >3 weeks post-LITTdue to poor functionality (6), pregnancy (1), and patient choice (1). Among the patients receiving chemotherapy, time to initiation of chemotherapy was not associated with PFS or OS. Chemotherapy in rGBM cohort included lomustine (6), temozolomide (5), bevacizumab (3), bevacizumab + lomustine (1), lapatinib (1), and Novo-TTF (1). Median time to initiation ofi bevacizumab (4 patients) after LITT was 30.5 (17-45) days, without complications.

CONCLUSIONS

LITT may be an effective cytoreductive treatment for glioblastoma. Timing of onset of chemotherapy after LITT for glioblastoma is not associated with PFS or OS.

EPID-13. A SINGLE INSTITUTION ANALYSIS: DETERMINING GENETIC VARIATION AND SURVIVAL OUTCOMES AMONG ASIAN AND NON-ASIAN NEUROSURGERY PATIENTS

Abstract

BACKGROUND

Globally, brain cancer compromises 2% of all total emerging cancers, yet has one of the lowest survival five-year survival rates. Differences in clinical outcomes between brain tumor patients of different races remains poorly understood.

METHODS

A retrospective chart review was performed on brain tumor resection patients 18 years old. Demographics, treatment variables, and survival outcomes were collected. Primary outcomes were recurrence rate, progression free survival (PFS), and overall survival (OS).

RESULTS

A total of 666 patients were included in final analysis. Females and males had nearly a 1:1 ratio (n = 345 and n = 321, respectively). Mean age was 51.3 (± 17.2) years. Females composed 64.3% (n = 54) of Asians patients; males constituted 35.7% (n = 30). Mean age of the Asians was 53.5 (± 16.5) years. Tumor pathologies included meningioma (n = 210 total) and glioblastoma (n = 192 total). There were 210 meningioma patients, of which Non-Asian patients comprised 81.43% of the group (n = 171) and Asian patients composed 18.57% (n = 39). We identified 192 glioblastoma patients in total. Non-Asian patients made up 92.7% of the glioblastoma cohort (n = 178) with the remaining 7.3% (n = 14) composed of Asian patients. There were no statistically significant differences between these groups in both cohorts in recurrence (P = .9052 and P = .7894, respectively), PFS (P = .6953 and P = .845, respectively), or OS (P = 1.0 and P = .9126, respectively).

CONCLUSION

Studies evaluating the survival between patients of different racial backgrounds against several tumor varieties are rare. Patients of certain racial backgrounds may need additional care consideration despite the same mutational composition as their counterparts. Repeated studies using national databases, such as the SEER database, may yield more conclusive results.

TMIC-36. CROSSTALK OF GLIOMA STEM CELLS WITH VASCULAR ENDOTHELIAL CELLS PERSISTS THEIR PRONEURAL PHENOTYPE AND THERAPY RESISTANCE VIA ENDOCAN-CD11A INTERACTION

Abstract

GBM cells tend to invade into adjacent normal brain tissues and cannot be completely resected surgically. These remaining tumor cells are the "seeds" to escape post-surgical therapies, hence contributing to tumor recurrence. The exact mechanisms by which these seeds confer to therapy resistance remains elusive. Several studies have shown the functional contribution of tumor microenvironment to glioma stemness and highlighted the importance of vascular endothelial(VE) cells in tumor initiation and progression. Here, we aim to determine the role of crosstalk of VE cells with glioma stem cells (GSCs) to develop GBM recurrence. We first assessed the effect of VE conditioned media (VE-CM) on patient-derived GBM neurospheres in vitro and in vivo. Culturing GBM neurospheres with VE-CM or their coculturing with VE cells promoted growth and migration of GBM neurospheres. Mice coinjected with VE cells and GBM neurospheres resulted in an increase of tumor growth compared to the injection of GBM neurospheres alone. To understand the mechanism of action, we performed RNA sequencing with CD31+ VE cells and A2B5+ GSCs directly isolated from patients with therapy-refractory epilepsy or GBM to identify factors secreted by these cells. We identified that Endocan is upregulated in VE cells, whereas CD11a – a receptor for Endocan, is upregulated in GSCs. Preferential expression of CD11a in perivascular region of GBM tissues was observed by immunohistochemistry. Irradiating VE cells substantially increased ESM1, by which VE cells provide extrinsic signals for elevated malignancy of GSCs after radiation therapy. Functionally, adding VE-CM or recombinant ESM1 protected GBM neurospheres from undergoing irradiation induced apoptosis and mesenchymal transition. We are currently investigating exact mechanism by which Endocan secretion from VE cells promotes GSC malignancy after radiation. Taking these data together, targeting ESM1 in VE cells or CD11a in GBM cells may provide a novel and effective strategy for preventing GBM recurrence.

ATIM-20. CLINICAL OUTCOMES WITH IPILIMUMAB IN COMBINATION WITH BEVACIZUMAB IN PATIENTS WITH RECENTLY DIAGNOSED GLIOBLASTOMA - A RETROSPECTIVE COHORT REVIEW

Abstract

BACKGROUND

Median survival for patients with glioblastoma remains under a year. Whilst there is accumulating interest in the role of checkpoint inhibitors in newly diagnosed glioblastoma, the results of clinical trials are awaited to establish clinical efficacy. We have previously presented clinical outcomes in patients with relapsed glioblastoma treated with the anti-CTLA-4 monoclonal antibody ipilimumab in combination with the anti-VEGF monoclonal antibody bevacizumab.

METHODS

We retrospectively identified patients with newly diagnosed WHO grade IV glioma who received treatment with ipilimumab and bevacizumab at our centre between March 2015 and March 2017. Baseline demographics, tumour characteristics, concurrent therapy, radiological responses, and survival data were analysed.

RESULTS

Nineteen patients were identified, 18 with glioblastoma and one with a glioneuronal tumour (Grade IV). Median age was 52 years (range 22–85) and 79% were male. 5% (1/19) had an IDH mutation, and 38% (6/16) had MGMT promotor methylation. Ipilimumab (3mg/kg, 3 weekly, 4 cycles) and bevacizumab (10mg/kg 2 weekly), given with concurrent G-CSF or GM-CSF were commenced after radiotherapy (except in one patient who did not receive radiotherapy). 58% of patients had prior surgical debulking (42% biopsy only), 79% had prior radical radiotherapy with concomitant temozolomide, 16% had short course radiotherapy, and 5% did not receive radiotherapy. 84% of patients received adjuvant temozolomide, and 89% received concurrent valganciclovir. In those with visible disease on pre-treatment MRI, 62% (8/13) had a radiological response. At time of analysis, 63% of patients remained alive, and 58% were alive and progression free. Median follow up was 15 months. Median survival in patients who had had debulking surgery was 23 months, and median survival in those who had a biopsy only was 16 months.

CONCLUSION

This combination requires prospective evaluation in clinical trials to formally determine efficacy. Data on this cohort continues to be collected and will be updated.

CSIG-41. UPREGULATED EXPRESSION OF THE ARYL HYDROCARBON RECEPTOR PATHWAY IN BRAIN METASTASES FROM MALIGNANT MELANOMA

Abstract

OBJECTIVE

The Aryl-hydrocarbon-receptor (AHR) is a ligand activated transcription factor linked to exogenic carcinogenic agents such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 2011, the tryptophan (TRP) catabolite kynurenine (KYN) was identified as an endogenous ligand for AHR. The AHR is involved in several crucial processes such as cell migration, tumorigenesis, and immune function. Dysregulation of AHR, its nuclear translocator (ARNT), its repressor AHRR and the KYN building Enzyme TRP-2,3-dioxygenase 2 (TDO) has been linked to poor survival in patients with Glioblastoma. We aimed to evaluate the AHR-pathway in brain metastases.

METHODS

Using qRT-PCR, gene expression was analyzed in 19 brain-metastases of melanoma patients, 10 control tissues from peritumoral brain and 10 glioblastoma (GBM) samples. Differences in the expression of AHR, ARNT, AHRR, TDO as well as the AHR/AHRR ratio between tumor tissue and control were analyzed. Results are depicted in mean values with standard deviation (SD) and in Arbitrary Units (AU). p<.05 was considered significant.

RESULTS

Both, AHR and ARNT were massively overexpressed in metastatic tissues (p<.01) (6- and 4.5-fold) in comparison to control (AHR: 3.64 ± 2.32 vs. .58 ±.50; p<0.01 and ARNT: 3.81 ± 2.25 vs. .83 ±.48, p<.01). AHRR and TDO where not significantly upregulated (.73 ±.88 vs. .41 ±.35; p=.31 and .37 ±.61 vs. .14 ±.09; p=.46). The ratio of AHR and its repressor AHRR (AHRR/AHR) was significantly different between metastases and control, hinting at a distinct regulatory imbalance (.55 ± 1.09 vs. .18 ± 1.60 p<.01). The difference of AHR expression in metastases and GBM did not quite reach significance (3.64 ± 2.32 vs. 1.27 ± 1.89; p=.055). ARNT was significantly elevated in metastases compared to GBM (3.81 ± 2.25 vs. 1.7 ±.1.15, p<.01).

CONCLUSION

The AHR pathway is significantly upregulated in melanoma brain metastases and might play a pathophysiological role in growth and progression of brain metastases.

EXTH-59. THE IDH1 MUTANT INHIBITOR AG-120 SHOWS STRONG INHIBITION OF 2-HG PRODUCTION IN AN ORTHOTOPIC IDH1 MUTANT GLIOMA MODEL IN VIVO

Abstract

Mutations in isocitrate dehydrogenase (IDH) 1 and 2 result in accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which drives multiple oncogenic processes, including increased histone and DNA methylation, leading to a block in cellular differentiation. IDH1/2 mutations occur in >70% of diffuse low-grade gliomas (LGG). Standard of care treatment for patients with diffuse LGG involves combined modality approaches including surgery, radiation, and chemotherapy. Here we present preclinical data from studies using AG-120, a potent, orally available inhibitor of the mIDH1 protein currently in clinical trials. In an orthotopic mouse xenograft model of a human mIDH1-R132H glioma, strong inhibition of 2-HG production in brain tumor samples (>77% inhibition) was observed when AG-120 was dosed orally at 150 mg/kg twice daily. Pharmacokinetic analysis revealed that AG-120 was detectable in the brain and brain-tumor tissues of the mice, although at much lower exposures than in the plasma, indicating that AG-120 is highly potent against the mIDH1-R132H protein in vivo. Results from ongoing preclinical studies testing the potential activity of AG-120 combined with radiation therapy in an orthotopic human mIDH1-R132H glioma model will also be shared.

STEM-21. CONTEXT-SPECIFIC TUMOR SUPPRESSIVE FUNCTION OF THE CANONICAL Wnt PATHWAY IN PEDIATRIC MEDULLOBLASTOMA HIGHLIGHTS A THERAPEUTIC STRATEGY FOR TREATMENT-REFRACTORY SUBGROUPS

Abstract

Current molecular subgroups of childhood medulloblastoma (MB) recognize distinct disease entities of which activated Wnt signaling is associated with a distinct subgroup and the best overall outcome. In contrast, non-Wnt MBs are characterized by metastatic disease, increased rate of recurrence, and poor overall survivorship. Given the excellent clinical outcome in Wnt-driven MB, we aimed to convert treatment-resistant MB subgroups 3 and 4 into an ostensibly benign tumor. Activated Wnt signaling by way of Wnt agonists decreased in vitro self-renewal of primary MB cells. Comparative RNA-sequencing of control and transgenic lines containing a stabilized beta-catenin mutant demonstrated a reduction in self-renewal genes following beta-catenin overexpression, including Sox2 and Bmi1. In order to validate the therapy-sensitive nature of Wnt-activated cells, we developed stable human Group 3 and 4 patient-derived lines containing a 7XTOPFlash reporter to determine the presence of endogenous Wnt signaling. Rare subclonal Wnt-active cells demonstrated a reduced self-renewal and tumor-initiating capacity through in vivo limiting dilution assays when compared to bulk Wnt-inactive cells from Group 3 and 4 MBs. The therapeutic relevance of these findings were demonstrated with an in vivo survival advantage in mice with orthotopic injections of cells containing stabilized beta-catenin overexpression or endogenous Wnt-active cells. Resulting xenograft tumors were smaller in size, maintained a lower rate of proliferation, and reduction in MB self-renewal genes. To develop a rationale clinical therapeutic, we used a novel substrate-competitive peptide inhibitor for GSK. Treatment with our peptide inhibitor showed a significant reduction in tumor burden and metastatic disease with a corresponding increase in survival of patient-derived Group 3 and 4 tumors that were otherwise treatment-resistant. Our work establishes activated Wnt signaling as a novel treatment paradigm in childhood MB, identifies a rationale therapeutic approach for recurrent MB, and provides evidence for the context-specific tumor suppressive function of the canonical Wnt pathway.

TMIC-06. IMMUNE MICROENVIRONMENT IN CYSTIC GBM

Abstract

The study objective was to characterize the immune microenvironment in cystic glioblastoma (GBM). We retrospectively reviewed the records of 298 consecutive newly diagnosed and recurrent adult GBM patients treated at our hospital from Jan 2011 to Jun 2017. 23 (7.7%) had cystic tumors and 17 had cystic tumor components. We were able to analyze 23 of these cystic GBM (cGBM) cases. We observed that overall survival in cGBM group is longer than in noncystic counterparts. In 17 samples, 16 were PTEN+, and all of these had TILS CD3, CD4, CD8 within the tumor and in surrounding vessels, 7/17 cGBM were PDL-1+ (>1%). T cells (CD8+, CD4+, and CD8+CD4+), B cells and NK cells were detected in the cystic fluid of cGBM cases. T memory cells (CD4+CD25-CD127+) but not Treg cells were also detected in the cystic fluid. The proportion of active T cells (CD69+) in the cystic fluid was higher than in control PBMC. Immunosuppressive cells Treg and MDSC populations were lower in the cystic fluid than in PBMC. The ProcartaPlex Human Cytokine Panel (34 plex) and IPA data analysis a variety of chemokines were detected in the GBM cyst fluid. IL-6, GRO-alpha, IL-8, IP-10, MCP-1, TNF-a, IL-4, IL-27 were higher in the peripheral blood serum cGBM patients versus non-cystic GBM patients; however, the inhibitory cytokine IL-10 is lower in cyst fluid or PB serum. These results suggest that the mechanism of cystic formation in cGBM could be due to activation of the host immune system. Higher levels of chemokines in the cystic fluid of cGBM patients could enhance recruitment of lymphocytes into the tumor. Intact PTEN status as observed in 16/17 cGBM patients in our study, is critical for anti-glioma immune function and may have played a role in improved survival in our study.

TMOD-19. SOMATIC GENOME EDITING WITH THE RCAS-CRISPR/Cas9 SYSTEM FOR PRECISION GLIOMA MODELING

Abstract

It has been gradually established that the vast majority of human tumors are extraordinarily heterogeneous at a genetic level. To accurately recapitulate this complexity, it is now evident that in vivo animal models of cancers will require to recreate not just a handful of simple genetic alterations, but possibly dozens and increasingly intricate. Here we have combined the RCAS/tv-a system with the CIRSPR/Cas9 genome editing tools to somatically target neural stem cells (NSCs) for precise modeling of human glioma. We show that deletion, both in pups and adult mice, of a variety of known tumor suppressor genes (Trp53, Cdkn2a and Pten), in combination with the expression of an oncogene driver, leads to high-grade glioma formation. Moreover, by simultaneously delivery into NSCs of pairs of gRNAs we show for the first time that the Bcan-Ntrk1 gene fusions, is able to induce high-grade gliomas. We further established that cells derived from Bcan-Ntrk1 tumors are remarkably sensitive to a Pan-Ntrk inhibitor. Lastly, using homology directed repair (HDR), we generated the Braf V600E mutation into NSCs and we demonstrated that it's sufficient to induce glioma tumor formation. In summary, we have developed an extremely powerful and versatile mouse model for in vivo somatic genome editing. Our system will elicit the generation of more accurate glioma models, particularly suitable for preclinical testing.

SCDT-30. SURGICAL IMPLANTATION OF AN OSMOTIC PUMP FOR CONVECTION ENHANCED DELIVERY INTO DIPG XENOGRAFT MURINE MODELS

Abstract

INTRODUCTION

Diffuse intrinsic pontine gliomas (DIPG) are fatal, high-grade tumors arising in the pons of children. Convection-enhanced delivery (CED) is a method for directly delivering agents into the tumor, bypassing the blood brain barrier. CED can achieve effective long-term continuous administration when connected to an osmotic pump filled with chemotherapeutic agents. Our objective is to optimize the technique for placement of the CED cannula carrying an osmotic pump into the tumor of preclinical DIPG mouse models.

METHODS

Using agarose gel, Evans blue dye (EBD) was injected at various rates to determine area of distribution. Then, an osmotic pump with a capacity to infuse 100ml over 28 days was used in two cohorts of mice. A cannula was stereotactically implanted into the pons in both cohorts and connected to a subcutaneously placed osmotic pump loaded with EBD or DII. The first cohort assessed the feasibility of implantation into the pons. The second cohort was transplanted with murine DIPG cells and allowed to develop pontine tumors before cannula implantation. The EBD/DII signal was evaluated and compared to tumor cell location to assess delivery to targeted site and distribution.

RESULTS

We have established a methodology for surgical implantation of a cannula attached to an osmotic pump into mouse pons, and assessed the distribution of EBD/DII in healthy as well as tumor bearing murine models of DIPG. We also show that CED cannula installation does not affect the overall survival of the mouse.

CONCLUSION

We show that precise pontine delivery of cargo (dye) has optimal distribution within the pons, tissue integrity is not compromised, and more importantly, does not alter overall survival. This technique will serve as a platform for rapid assessment of tumor response to therapeutic agents. An effective agent can then be translated in clinical setting through upcoming clinical trials.

CBIO-29. ACOT7 REGULATES COLONIZATION OF BREAST CANCER CELLS IN THE BRAIN BY REGULATING ENDOPLASMIC RETICULUM STRESS RESPONSE

Abstract

Colonization of cancer cells in a foreign organ is the key for establishment of metastases. To identify the genes that are responsible for colonization of breast cancer cells in the brain, we conducted an in silico analysis using a NKI dataset and identified ACOT-7 to be negatively correlated with patient survival. ACOT-7 is normally expressed in the brain and is responsible for maintaining the cellular pool of coenzyme-A by catalyzing the conversion of acyl-CoA to free fatty acid and CoA. The resulting CoA can be used for anabolic reactions. ACOT-7 was found to be overexpressed in microdissected brain metastases as compared to primary breast cancer tissues, and it was also upregulated in brain metastasis models CN34/CN34BrM2 and BT-474/BT-474BrM3. To understand the role of brain specific protein ACOT-7 in brain metastasis, ACOT-7 knockdown studies were conducted. ACOT7 knockdown in CN34Br cells reduced their ability to grow in the brain, which subsequently resulted in increased median survival by 60% in a preclinical mouse model. To understand the role of ACOT-7, we conducted a whole proteome analysis and found reduced expression of genes responsible for unfolded protein response (UPR)/Endoplasmic reticulum (ER)-stress. The results were confirmed using quantitative RT-PCR and western blotting. ACOT-7 knockdown cells also exhibited increased sensitivity to thapsigargin (an ER stress inducer). In conclusion, ACOT-7 is aberrantly expressed in brain metastases arising from breast cancer, and it regulates the ability of cells to counter ER stress. Hence unfolded protein response/ER stress proteins will be a novel therapeutic target for the treatment of breast cancer brain metastases.

CSIG-08. MUTANT IDH1 CO-OPERATES WITH ATRX LOSS TO DRIVE THE ALTERNATIVE LENGTHENING OF TELOMERE (ALT) PHENOTYPE IN GLIOMA

Abstract

A subset of human tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT activation. In these tumors, which include lower-grade astrocytomas (LGA) and secondary glioblastoma (sGBM), the ALT phenotype is associated with loss-of-function mutations in p53 and ATRX, although these mutations alone are insufficient to drive the process. Because LGA and sGBM also exhibit R132H IDH1 mutations, we examined the possible role of mutant IDH1 in driving ALT-based gliomagenesis. In p53/pRb-deficient human astrocytes, we found that neither expression of mutant IDH1 nor genetic deletion of ATRX was sufficient to drive the ALT phenotype. Combined expression of mutant IDH1 and loss of ATRX, however, resulted in the creation of tumorigenic cells with the ALT phenotype. The tumorigenic IDH1-mutant, ATRX-deficient ALT cells, as well as human IDH1-mutant LGA xenograft cells, consistently downregulated both RAP1 and XRCC1. Furthermore, exogenous re-expression of XRCC1 and/or RAP1 suppressed the ALT phenotype and tumor cell viability. Mechanistically, suppression of RAP1, a component of the telomere-capping shelterin complex, caused telomere dysfunction. Downregulation of XRCC1, a key component of the alternative non-homologous end joining (aNHEJ) pathway, suppressed aNHEJ-mediated lethal fusion of dysfunctional telomeres, and instead allowed IDH1-mutant, ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. These studies show that mutant IDH1 expression initiates telomeric dysfunction and alters DNA repair pathway preference at telomeres, and in doing so co-operates with p53 and ATRX loss to allow cells to overcome a critical bottleneck in gliomagenesis. Agents that alter the linkage between mutant IDH1 and DNA repair pathway preference may therefore be of particular interest in mutant IDH1 driven glioma.

DRES-05. IDENTIFYING DRIVERS OF CHEMORESISTANCE IN GROUP 3 MEDULLOBLASTOMA THROUGH A GENOME-WIDE CRISPR/Cas9 ACTIVATION SCREEN

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for nearly 20% of all pediatric brain cancers. Based on transcriptional profiling studies, MB has been characterized into four molecular subgroups--WNT, SHH, Group 3, and Group 4--that have distinct genetics, patient demographics, histology, and clinical outcomes. Group 3 MB carries the worst prognosis, with 5-year survival rates of 50%. Current therapy for MB consists of maximal safe surgical resection, radiation, and chemotherapy, with cisplatin and cyclophosphamide as mainstays in many chemotherapy regimens. However, Group 3 MB commonly develops resistance and becomes refractory to standard therapy. As these mechanisms of resistance remain poorly understood, I used the CRISPR/Cas9-based synergistic activation mediator (SAM) system to conduct a genome-wide, gain-of-function, positive selection screen to identify the specific drivers of chemoresistance in Group 3 MB. I cloned and sequenced a library consisting of 70,290 single-guide RNAs (sgRNAs) targeting each of the 23,430 coding isoforms from the human RefSeq database. I transduced this library into a Group 3 MB patient-derived model stably expressing the other SAM components (dCas9, VP64, MS2, p65, and HSF1) and then selected with cisplatin and 4-hydroperoxycyclophosphamide. Modulators of chemotherapy sensitivity will be prioritized by sgRNAs that have activated genes conferring chemoresistance, and I have performed next-generation sequencing to identify these sgRNAs. I will validate the top hits from our screen and also cross-reference them with recently published whole-genome sequencing data on six pairs of human diagnostic and post-therapy Group 3 MBs. These findings will provide insights into the mechanisms of resistance in Group 3 MB and inform novel therapeutic targets that may sensitize the tumor to chemotherapy and improve future treatment response.

EXTH-31. RNA NANOPARTICLE-BASED TARGETED GENE THERAPY FOR GLIOBLASTOMA

Abstract

Systemic administration of therapeutic siRNA/microRNA for targeted treatment of glioblastoma, one of the most deadly cancers, requires robust and efficient delivery platform without immunogenicity. Here we report newly emerged multivalent naked RNA nanoparticle (RNP), named FA-pRNA-3WJ, based on pRNA 3-way-junction (3WJ) from bacteriophage phi29 to target glioblastoma cells with folate (FA) ligand and deliver siRNA/microRNA for tumor cell killing. Systemically injected FA-pRNA-3WJ RNPs successfully targeted and delivered siRNA into brain tumor cells in mice, and efficiently reduced luciferase reporter gene expression (4-fold lower than control). The FA-pRNA-3WJ RNP also can target human patient-derived glioblastoma stem cells, thought to be responsible for tumor initiation and deadly recurrence, without accumulation in adjacent normal brain cells, nor other major internal organs. FA-3WJ-LNA-miR21 specifically targeted and delivered anti-miR-21 LNA and knocked down miR-21 expression in glioblastoma cells in vitro and in vivo with favorable biodistribution. Systemically injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glioblastoma cell apoptosis and tumor growth regression. This RNA nanotechnology was employed even to regulate the anchoring of nanoparticles on the surface of extracellular vesicles (EVs) for specific cancer targeting and intracellular trafficking. Taking advantage of the RNA aptamer ligand for specific targeting and EVs for efficient membrane fusion, EGFRapt-pRNA-3WJ RNP was constructed and anchored onto EVs loaded with survivin siRNA. In the preliminary animal tests, systemic administration of the EV-siSurvivin coated with EGFRapt-pRNA-3WJ RNP inhibited tumor growth in orthotopic breast cancer xenograft mouse model by successfully downregulating the Survivin expression. The studies are indicative of the clinical benefit of FA-3WJ RNP based tumor targeting and gene therapy for the successful targeted therapy of primary and recurrent glioblastoma.

GENE-04. COMPREHENSIVE GENOMIC CHARACTERIZATION OF AGGRESSIVE MENINGIOMAS IDENTIFIES MOLECULAR SIGNATURES THAT PREDICT CLINICAL OUTCOMES

Abstract

BACKGROUND

Current pathological grading schemes do not fully predict meningioma behavior, and the molecular basis for meningioma is incompletely understood. Here, we perform whole exome sequencing (WES), DNA methylation arrays, RNA-seq, NanoString (NS), and immunohistochemistry using tissue microarrays (TMAs) on meningiomas to elucidate molecular drivers of aggressive behavior and identify clinically relevant biomarkers.

METHODS

We constructed a database containing clinical data and tissue from 283 patients who underwent resection of meningioma between 1990 and 2015. Histology was re-evaluated using current grading criteria. We conducted WES (n=24), methylation arrays (n=26), and RNA-seq (n=42) in a discovery cohort composed of 14 grade I, 23 grade II and 5 grade III meningiomas. We further carried out NS profiling of 282 cancer-associated transcripts (n=96), and TMAs (n=241) in an independent validation cohort composed of 132 grade I, 87 grade II and 22 grade III meningiomas. WES data was analyzed via the bcbio pipeline with the ensemble method and CNVkit, methylation data was processed in the minfi Bioconductor package, and RNA-seq data was analyzed with the DESeq2 Bioconductor package. Hierarchical clustering and statistics were performed in R. 

RESULTS

WES demonstrated increased somatic mutation burden was associated with decreased overall survival (OS) (p=0.005). Unsupervised hierarchical clustering of methylation arrays segregated meningioma samples into three groups with significant differences in OS (p=0.0465) and age (p=0.0123). RNA-seq showed enrichment of a FOXM1 mediated transcriptional network with an overrepresentation of cell division genes. High FOXM1 mRNA expression was associated with decreased local recurrence free survival (LRFS) (p=0.004). Consistently, high FOXM1 mRNA expression in NS samples was associated with decreased LRFS (p=0.001) and OS (p=0.006), and high FOXM1 protein expression was associated with decreased LRFS in TMA samples (p=0.049).

CONCLUSION

Comprehensive genomic characterization of aggressive meningiomas identifies molecular signatures associated with poor outcomes, suggesting novel prognostic markers and therapeutic targets.

Exploring repositioning movements in sitting with ‘at risk’ groups using accelerometry and interface pressure mapping technologies

Publication date: Available online 15 November 2017
Source:Journal of Tissue Viability
Author(s): May Stinson, Rachel Ferguson, Alison Porter-Armstrong
BackgroundDespite high quality guidelines underpinning pressure ulcer care (EPUAP/NPUAP/PPPIA, 2014), pressure ulceration still poses a significant financial impact on health care services in treatment and staff costs as well as having a profound effect on the health and quality of life of individuals experiencing them. Repositioning is a key preventative technique recommended by occupational therapists and other health care professionals. The frequency and quality of repositioning movements performed by individuals, however, can be difficult to determine. This paper explores the use of technology in monitoring repositioning movements in sitting.ObjectiveTo explore the outputs of technologies such as interface pressure mapping systems and accelerometers in enabling the therapist to accurately monitor seated behaviour and enhance practice through targeted interventions to prevent sitting acquired pressure ulceration.MethodReviewing the findings of two recent research studies with 'at risk' cohorts (spinal cord injury; elderly orthopaedic), using accelerometry and seated interface pressures, this paper will highlight how useful this technology is in clinical practice to monitor weight shifts and repositioning behaviours.ResultBoth studies illustrated that the majority of individuals did not adhere to the frequency or magnitude of movements currently recommended to redistribute seating interface pressures. When repositioning was performed it was ineffective in reducing seated pressures.ConclusionIn an era of personalised medicine, technology has an important role to play in providing the service user, caregivers and healthcare staff with important biofeedback information about seated behaviours, particularly those that minimise the risk of developing sitting acquired pressure ulcers. This information can augment occupational therapists' clinical decision-making in maximising active pressure ulcer prevention.

A request for standardisation of publishing of blood culture processing interventions

Pleomorphic mastocytoma in an adult

A cutaneous mastocytoma (CM) is a clinical variant of cutaneous mastocytosis. It is defined as the presence of up to 3 isolated mast cell skin lesions. When only 1 lesion is observed, the patient is classified as having a solitary mastocytoma, and when 4 or more lesions are observed, the patient should be classified as having urticaria pigmentosa (1).

Issue Information

Guidelines for the use of flow cytometry

Soluble TAM receptor tyrosine kinases in rheumatoid arthritis: Correlation with disease activity and bone destruction

Summary

The TAM receptor tyrosine kinases (TAM RTK) are a subfamily of receptor tyrosine kinases, the role of which in autoimmune diseases such as systemic lupus erythematosus has been well-explored, while their functions in rheumatoid arthritis (RA) remain largely unknown. In this study, we investigated the role of soluble TAM receptor tyrosine kinases (sAxl/sMer/sTyro3) in the patients with RA. 306 RA patients, 100 osteoarthritis (OA) patients and 120 healthy controls (HCs) were enrolled in this study. The serum concentrations of sAxl/sMer/sTyro3 were measured by ELISA, then the associations between sAxl/sMer/sTyro3 levels and clinical features of RA patients were analyzed. And we also investigated whether sTyro3 could promote osteoclast differentiation in vitro in RA patients. The results showed that comparing with HCs, sTyro3 levels in the serum of RA patients were remarkably elevated and sMer levels were significantly decreased. Whereas there was no difference between HCs and RA patients on sAxl levels. The sTyro3 levels were weakly but positively correlated with WBC, IgM, RF, swollen joint counts, tender joint counts, total sharp scores and joint erosion scores. Conversely, there were no significant correlations between sMer levels and the above indices. Moreover, RA patients with high disease activity also showed higher sTyro3 levels. In vitro osteoclast differentiation assay further showed that TRAP⁺ osteoclasts were significantly increased in the presence of sTyro3. Collectively, our study indicated that sTyro3 levels were elevated in RA patients and positively correlated with disease activity and bone destruction, which may serve as an important participant in RA pathogenesis. This article is protected by copyright. All rights reserved.

The helsinki face transplantation: surgical aspects and one-year outcome

Publication date: Available online 15 November 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Patrik Lassus, Andrew Lindford, Jyrki Vuola, Leif Bäck, Sinikka Suominen, Karri Mesimäki, Tommy Wilkman, Tuija Ylä-Kotola, Erkki Tukiainen, Hannu Kuokkanen, Jyrki Törnwall
BackgroundSince 2005, at least 38 facial transplantations have been performed worldwide. We herein describe the surgical technique and one year clinical outcome in Finland's first face transplant case.MethodsA 34 year-old male who had a severe facial deformity following ballistic trauma in 1999 underwent facial transplantation in the Helsinki University Hospital on 8^th February 2016. Three-dimensional (3D) technology was used to manufacture donor and recipient patient specific osteotomy guides and a donor face mask. The facial transplant consisted of a Le Fort II maxilla, central mandible, lower ⅔ of the midface muscles, facial and neck skin, oral mucosa, anterior tongue and floor of mouth muscles, facial nerve (3 bilateral branches), and bilateral hypoglossal and buccal nerves.ResultsAt one-year follow-up there have thus far been no clinical nor histological signs of rejection. The patient has a good aesthetic outcome with symmetrical restoration of the mobile central part of the face with recovery of pain and light touch sensation to almost the entire facial skin and intraoral mucosa. Electromyography at 1 year has confirmed symmetrical muscle activity in the floor of the mouth and facial musculature and the patient is able to produce spontaneous smile. Successful social and psychological outcome has also been observed. Postoperative complications requiring intervention included: early (nasopalatinal fistula, submandibular sialocele, temporomandibular joint pain, and transient type 2 diabetes) and late (intraoral wound and fungal infection, renal impairment, and hypertension).ConclusionAt one year we report overall good functional outcome in Finland's first face transplant.

Targeted muscle reinnervation for pain control in an elective transradial amputation

Publication date: Available online 2 November 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): D. Nikkhah, D. Reissis, A. Sadri, P. Sadigh

Noninvasive induction of angiogenesis in tissues by external suction: sequential optimization for use in reconstructive surgery

Abstract

In reconstructive surgery, tissues are routinely transferred to repair a defect caused by trauma, cancer, chronic diseases, or congenital malformations; surgical transfer intrinsically impairs metabolic supply to tissues placing a risk of ischemia-related complications such as necrosis, impaired healing, or infection. Pre-surgical induction of angiogenesis in tissues (preconditioning) can limit postsurgical ischemic complications and improve outcomes, but very few preconditioning strategies have successfully been translated to clinical practice due to the invasiveness of most proposed approaches, their suboptimal effects, and their challenging regulatory approval. We optimized a method that adopts noninvasive external suction to precondition tissues through the induction of hypoxia-mediated angiogenesis. Using a sequential approach in a rodent model, we determined the parameters of application (frequency, suction levels, duration, and interfaces) that fine-tune the balance of enhanced angiogenesis, attenuation of hypoxic tissue damage, and length of treatment. The optimized repeated short-intermittent applications of intermediate suction induced a 1.7-fold increase in tissue vascular density after only 5 days of treatment (p < 0.05); foam interfaces showed the same effectiveness and caused less complications. In a second separate experiment, our model showed that the optimized technique significantly improves survival of transferred tissues. Here we demonstrate that noninvasive external suction can successfully, safely, and promptly enhance vascularity of soft tissues: these translational principles can help design effective preconditioning strategies, transform best clinical practice in surgery, and improve patient outcomes.

INSM1: A Novel Nuclear Marker in Merkel Cell Carcinoma (Cutaneous Neuroendocrine Carcinoma)

Merkel cell carcinoma (MCC) is a rare, clinically aggressive, cutaneous neuroendocrine (NE) neoplasm. As a tumor with small, round, blue cells, the histologic differential diagnosis for MCC can include melanoma, metastatic small cell carcinoma (SCC), nodular hematopoietic tumors, basal cell carcinoma (BCC), atypical variants of squamous carcinoma, and the uncommon occurrence of primary cutaneous Ewing sarcoma. In cases with atypical histology or without the classic immunophenotype the diagnosis can be challenging. Ultimately, immunohistochemistry (IHC) is essential to the definitive diagnosis of MCC, and in difficult cases the diagnosis may hinge entirely on the immunophenotype of the tumor cells. INSM1 is a transcription factor expressed in tissues undergoing terminal NE differentiation. As a nuclear protein tied both to differentiation and the cell-cycle, INSM1 may offer additional utility in comparison to traditional, cytoplasmic markers of NE differentiation.

Clinical patterns of Compositae dermatitis in Danish monosensitized patients

Summary

Background

Compositae dermatitis was originally described as airborne contact dermatitis. More recent studies have reported a wider clinical spectrum, but often in polysensitized patients.

Objective

To evaluate the clinical features of patients sensitized to Compositae only.

Patients/Methods

Consecutive Compositae-sensitive eczema patients, tested between 1990 and 2015, who, at the patch testing session diagnosing their Compositae allergy, were found to be sensitized only to the plant family, were included.

Results

Altogether, 529 of 13 139 patients tested (4.0%) were sensitized to Compositae, and 95 (18% of these) were monosensitized. The majority had hand eczema, and 39 (44%) had a vesicular volar pattern. Eighty-one patients were classified into one of three groups of similar size: localized eczema, eczema of exposed skin, and localized eczema turning into widespread eczema.

Conclusions

The prevalence of Compositae sensitization is continuously high in consecutive eczema patients. Sensitization may occur at any age. Clinical features in monosensitized patients vary, but, with continuing exposure, the patients may develop more widespread dermatitis similar to classic Compositae dermatitis. Avoidance may clear the exogenous part, but not endogenous aetiological factors such as vesicular hand eczema or possible photosensitivity. Thorough clinical assessment and patient education are important in reducing the impact of Compositae contact allergy.

Classification of consumer products under the EU CLP Regulation: what to consider when caring for contact dermatitis patients

Summary

Possibly hazardous chemical substances and mixtures need to be clearly and correctly classified and labelled, in order for their hazards to be properly identified and communicated. As dermatologists may encounter cases of harm to patients induced by chemicals, such as chemical burns, and irritant and allergic contact dermatitis, it is essential for them to be aware of the EU CLP Regulation and its potential pitfalls. Manufacturers are required by CLP to classify their products according to the rules given in the CLP Regulation. The enforcement duty lies with the Member States and their competent authorities. Dangerous non-food consumer products have to be reported to the European Commission to be entered into the Rapid Alert System for Dangerous Non-food Products (RAPEX) notifications. The sheer complexity of the CLP Regulation and lack of awareness of its ramifications by companies, competent authorities, consumer associations and the public at large may prevent efficient enforcement actions. When dermatologists become aware of inappropriately labelled chemicals, they should inform the competent authorities.