Quality of life assessment in patients with nonmelanoma skin cancer – psychometric validation of the EORTC QLQ-C30 questionnaire

Summary

Background

Nonmelanoma skin cancer (NMSC) is a chronic and sometimes difficult-to-treat condition affecting the quality of life (QL). The present study was conducted to investigate whether the European Organization for Research and Treatment of Cancer (EORTC) core QL Questionnaire – Cancer (QLQ-C30) is a suitable tool for the assessment of QL in patients with NMSC.

Patients and methods

In order to define the psychometric properties of the questionnaire, the QLQ-C30 and the Dermatology Life Quality Index (DLQI) were handed out to 172 patients of the Department of Dermatology at the University Hospital Regensburg, Germany.

Results

Internal consistencies of all multi-item scales (except one) were acceptable, with Cronbach's alpha ranging from 0.71 to 0.93. The hypothesized scale structure was supported by item/scale and interscale correlations within the QLQ-C30. Related scales of the QLQ-C30 and the DLQI correlated significantly, thus establishing construct validity. At the same time, the proportion of substantial correlations (6 % ≥ 0.40) indicated that the two questionnaires assessed distinct components of QL. The QLQ-C30 significantly differentiated between clinically distinct patient groups, indicating that severe clinical conditions were associated with greater impairment in physical, role, and cognitive functioning (p ≤ 0.030).

Conclusions

These results confirm the QLQ-C30 to be a suitable tool for the assessment of QL in patients with NMSC.

Wege zum Verständnis neutrophiler Dermatosen

Beurteilung der Lebensqualität bei Patienten mit nicht-melanozytärem Hautkrebs – psychometrische Validierung des EORTC QLQ-C30-Fragebogens

Zusammenfassung

Hintergrund

Nicht-melanozytärer Hautkrebs (NMSC, nonmelanoma skin cancer) ist eine chronische und mitunter schwierig zu behandelnde Erkrankung, die die Lebensqualität (LQ) beeinträchtigt. Die vorliegende Studie wurde durchgeführt um zu prüfen, ob der Kernfragebogen Quality of Life Questionnaire - Cancer (QLQ-C30) der European Organization for Research and Treatment of Cancer (EORTC) ein geeignetes Instrument für die Beurteilung der LQ bei NMSC-Patienten ist.

Patienten und Methoden

Zur Bestimmung der psychometrischen Eigenschaften des Fragebogens wurden der QLQ-C30 und der Dermatology Life Quality Index (DLQI) an 172 Patienten der Klinik und Poliklinik für Dermatologie des Universitätsklinikums Regensburg, Deutschland, ausgegeben.

Ergebnisse

Die interne Konsistenz aller Multi-Item-Skalen (außer einer) war akzeptabel, wobei Cronbachs Alpha-Koeffizient zwischen 0,71 bis 0,93 lag. Die angenommene Skalenstruktur wurde durch Korrelationen zwischen Items und Skalen sowie Korrelationen zwischen Skalen innerhalb des QLQ-C30 bestätigt. Verwandte Skalen des QLQ-C30 und des DLQI korrelierten signifikant und belegten damit die Konstruktvalidität. Gleichzeitig wies der Anteil substanzieller Korrelationen (6 % ≥ 0,40) darauf hin, dass mit den beiden Fragebogen unterschiedliche Aspekte der LQ beurteilt werden. Der QLQ-C30 differenzierte signifikant zwischen Patienten mit verschiedenen Erkrankungsgraden. Eine schwere Erkrankung ging mit stärkeren Beeinträchtigungen der Körperlichen, Rollen- und Kognitiven Funktion einher (p ≤ 0,030).

Schlussfolgerungen

Diese Ergebnisse bestätigen, dass der QLQ-C30 ein geeignetes Instrument für die Beurteilung der LQ bei NMSC-Patienten darstellt.

Kopfhautnekrose an Stirn und Schläfe

Flächige Hyperpigmentierungen im Gesicht einer philippinischen Patientin

EXTH-15. RADIATION-INDUCED LATE MALIGNANT MENINGIOMA TRANSFORMATION: CDK 4/6 INHIBITOR THERAPY

Abstract

Meningiomas are the most common primary brain tumor reported in the United States each year and account for approximately 30% of primary neoplasms. Though in most cases the etiology of meningiomas is unclear, prior exposure to radiation is responsible for a subset of meningiomas. Some have speculated that there may be a relationship between pretreatment characteristics and radiotherapy parameters in the development of radiation-induced meningiomas (RIM). Compared with their sporadic counterparts, currently, the clinical treatment involves is similar with radiation used as a first line therapy. Novel therapeutic agents being investigated in the treatment of these tumors, rely on the direct or cell cycle-mediated induction of DNA damage to promote cellular apoptosis. Our pre-clinical data showed that disruption of p16INK4a-Cdk4-Rb (retinoblastoma) pathways plays a significant role in the development of RIM in Rb+ low-gradelow-grade meningioma cells. These observations highlight the critical role of the p16INK4a-Cdk4-Rb pathway in RIM and suggest that targeting this pathway might be a promising strategy to improve the therapeutic efficacy among RIM patients. Pretreatment characteristics and radiotherapy parameters which may influence the time interval for development of radiation-induced Rb+ meningiomas (RIM) were identified. Our results also demonstrated that CDK 4/6 Inhibitor, significantly suppresses radiation induced malignant transformation and prolonged survival in a cell-free, slice culture model and xenograft model of meningioma. Success of the proposed therapeutic strategies in both in vitro and in vivo models may form the basis for future research.

ACTR-02. DCC-2618, A NOVEL pan-KIT AND PDGFRa KINASE SWITCH CONTROL INHIBITOR, SHOWS ENCOURAGING SIGNAL IN A PATIENT (PT) WITH GLIOBLASTOMA (GBM)

Abstract

BACKGROUND

Non-clinical data suggest that PDGFRa plays an important role in the development and progression of human gliomas. To date, few PDGFRa inhibitors with CNS activity have been available. DCC-2618 was designed to potently inhibit the broadest range of mutations (mut) in KIT & PDGFRa kinases that emerge during tumor progession or on treatment.

METHODS

In a dose-escalation study (NCT# 02571036) of oral DCC-2618 (QD or BID q28 days), pts with advanced malignancies with a molecular rationale for activity were eligible. MRI scans were performed initially every 2 cycles then every 3 cycles.

RESULTS

We enrolled 4 GBM pts and 1 anaplastic astrocytoma (AA) pt with PDGFRa muts/ amplifications who had progressed after standard temozolomide chemoradiation (GBM) or temozolomide only (AA) and had received 0 to 5 salvage therapies. Three pts (2 GBM and 1 AA) had a triple amplification of PDGFRa, KIT and KDR (4q12 amplicon). Two GBM pts had activating PDGFRa mutations. Pts were treated at 20 mg (1 pt), 50 mg BID (2 pts) or 100 mg QD (2 pts). The per-protocol population (N=48) received doses up to 200 mg BID and DCC-2618 was well tolerated. One GBM pt with mut PDGFRa progressed after 6 weeks and one stopped treatment due to a tumor-related hemaorrhage on C1D12. Two of the three pts with triple amplifications progressed after 2 cycles while the third pt (GBM, 20 mg BID) achieved a PR per RANO after 9 cycles. This pt is currently in cycle 20 with a remarkable 94% tumor reduction.

CONCLUSIONS

The durable partial response of >18 months in a GBM patient (94% tumor reduction) warrants further evaluation of DCC-2618 in gliomas. An expansion cohort for pts with KIT- and PDGFRa driven tumors was initiated to be able to better select the patient population with a likely benefit.

SCDT-20. NEW THERAPEUTIC APPROACH FOR BRAINSTEM GLIOMA: INTRANASAL DELIVERY OF NANOLIPOSOMAL SN-38

Abstract

INTRODUCTION

Children with diffuse intrinsic pontine gliomas (DIPGs) die within 2 years after initial diagnosis. The infiltrative nature and anatomic location of DIPGs in an eloquent area of the brain preclude surgical resection, and the blood-brain barrier (BBB) reduces the availability of systemically administered agents. In order to improve outcomes for patients with DIPG, new drug delivery approach circumventing the BBB are greatly needed. Intranasal delivery (IND) is a practical, noninvasive method to deliver therapeutic agents into the brain along with the olfactory and trigeminal nerves pathway. With the advantages of reducing systemic side effects and convenient self-administration for patients, IND is an alternative to systemic (intravenous) and/ or direct invasive (intraparechymal) drug delivery.

METHODS

Two human DIPG cell lines were treated with hydrophobic fluorophore (DiI)-labeled nanoparticle liposomes containing CPT-11 (nanoliposomal CPT-11) and SN-38. Cell viability was determined by MTS assay and intracellular localization was imaged by confocal microscopy. For in vivo study, mice bearing human brainstem gliomas were randomly assigned to 3 groups: 1. empty nanoliposomes, 2. nanoliposomal CPT-11, 3. nanoliposomal SN-38, administrating by IND for 3 weeks. In vivo distribution was determined by DiI-labeled nanoliposomal SN-38 into the tumor bearing mice. Tumor growth and response to therapy were quantitatively measured by bioluminescence imaging, and efficacy was assessed by survival analysis.

RESULTS

DiI-fluorescence were detected at 30 minutes and peaked at 24 hours following treatment with DiI nanoliposomal SN-38. Nanoliposomal SN-38 induced dose dependent inhibition of the growth of DIPG cells, that is greater inhibition than nanoliposomal CPT-11. IND of nanoliposomal SN-38 showed significant reduction of the growth rate in compared to IND of empty nanoliposome. Results from animal survival will be reported at the meeting.

ACTR-03. INDUCING FACTORS OF MALIGNANT RECURRENCE IN LOW-GRADE GLIOMA

Abstract

Low-grade glioma patients have relatively long life expectancy for gliomas, but once they recur in malign, their prognosis can be poor. We analyzed factors corresponding to malignant recurrence by uni- and multi-variate analysis applying their treatment backgrounds. SUBJECTS: 261 newly diagnosed WHO grade 2 adults gliomas in 2004 to 2014. Malignant recurrence was determined by pathological diagnosis if the patient had a surgery (69% of the recurrent patients), otherwise contrast T1WI or 11C- methionine PET images if the patient was unable to undergo any surgery or biopsy.

RESULTS

Age average 41 years old, the 10-year survival rate in all patients was 75%, and the mean of progression-free survival time was 7.8 years. Relapse event occurred in 115 cases (44%), and 67 % of them developed malignant glioma sometime. The 10-year survival rate for the patients who relapsed in malign was 37%, on the contrary, the patients who had recurrence but staying in low grade was 71% (p=0.0389). When they were categorized by 1p19q deletion and IDH1 mutation status, IDH wild type diffuse astrocytoma patients had significantly developed malignant glioma compared to oligodendroglioma and IDH mutant type diffuse astrocytoma (p<0.0001). The factors related to malignant progression were extracted as; recurrence in 2 years, 6% and over in MIB-1 index, no intervention longer than 18 months since the disease revealed, 1p19q non-co-deletion, less than 90% of tumor resection rate, and IDH wild type. In the 1p19q non-deletion patients, who were provisionally defined as diffuse astrocytoma patients here, the factors were resection rate, MIB-1 index, and duration between discovered the disease and the first surgery, but not the IDH mutant status (p＜0.0001, p=0.0015, p=0.0478 respectively).

CONCLUSION

Recurrence in malign form low-grade glioma can be avoided by early intervention in 18 months from diagnosis and resection over 90% of volume of the tumor.

SURG-28. KYPHO-IORT: A NEW TREATMENT PARADIGM FOR PATHOLOGICAL FRACTURES

Abstract

OBJECTIVE

This is a prospective single institution study to assess the safety and efficacy of Kypho-intraoperative radiation therapy (Kypho-IORT) for potentially mechanically unstable metastatic disease to the spine in reducing pain.

METHODS

Patients with symptomatic osteolytic vertebral body metastasis underwent Kypho-IORT: kyphoplasty procedures and intraoperative radiotherapy with the ZEISS INTRABEAM System followed by cement augmentation. Tumors were limited to vertebral body using the International Spine Radiosurgery Consortium (ISRC) anatomic classification system, SINS scores of 7-12 (potentially unstable), and Bilsky grade 0. Intraoperative CT delineation of gross tumor volume, needle applicator tip, and OAR delineation were done with deformable image registration, integrating pre-operative CT and MRI images. 10 Gy was prescribed to a distance from the source tip to the distal boundary. The prescription was limited by a maximum dose limit to the spinal cord of 12 Gy. Preoperative and postoperative pain scores were assessed with the numerical rating pain scale (NRPS). The involved spine will be imaged at 3-month intervals up to one year.

RESULTS

7 vertebral levels were treated. All patients were discharged home within 12 hours of the Kypho-IORT procedure. There was a statistically significant reduction in patient reported NPRS scores from preoperative baseline within 2 weeks (6.57 ± 2.82 preoperative versus 4.00 ± 2.16 postoperatively; p=0.0349). After 3 months, one patient with metastatic rectal cancer suffered local progression. No patients experience neurological deterioration postoperatively.

CONCLUSIONS

Kypho-IORT is a safe treatment option for potentially unstable spinal metastases. Patient reported pain scores significantly improve within two weeks, enhancing the patient's quality of life. Long-term follow up is necessary to further evaluate efficacy.

ACTR-44. AUTOPSY STUDY ON THE EFFECTS OF TUMOR TREATMENT FIELDS IN RECURRENT GLIOBLASTOMA: PRELIMINARY RESULTS AND TRIAL DESIGN

Abstract

BACKGROUND

Optune therapy with tumor treatment fields (TTFields) is approved for the treatment of recurrent glioblastoma due to a recent clinical trial that showed better quality of life and comparable overall survival to conventional therapy. In the newly diagnosed setting, the addition of TTFields to standard therapy consisting of surgery, radiation and temozolomide has also been shown to prolong tumor progression and improve overall survival. TTFields are low-intensity, alternating frequency electric fields that have been shown to disrupt cell division and subsequently tumor growth. Apoptosis and cell cycle arrest have been seen in vitro, and shown in mice and rabbit tumor models. Though preclinical studies are ongoing, glioblastoma patients who have undergone TTFields therapy have not yet been assessed at autopsy to determine both the pathological signature of TTFields therapy, and the pattern of failure.

METHODS

Whole brain samples were acquired and analyzed pathologically from two recurrent GBM patients at autopsy. One patient served as a control and one considered a test patient who had undergone TTFields therapy. Tissue samples were acquired from regions suspicious of tumor and treatment effects. Samples were paraffin embedded and hematoxylin and eosin (H&E) stained, and pathologically reviewed by a board certified pathologist. Samples were then compared.

RESULTS

The patient who underwent TTFields therapy showed regions of necrosis and increased cellular debris compared to the control patient who had pseudo-palisading and radiation necrosis.

CONCLUSION

These findings suggest there is increased apoptosis in patients treated with TTFields compared to those on chemoradiation alone. Recruitment is ongoing for expansion of this study to include 10 patients treated with TTFields at recurrence and 10 at treated at initial diagnosis. Patients will be recruited from brain donation. Pathology will be compared to control patients naïve of TTFields therapy.

CMET-47. PRECLINICAL VALIDATION OF NOVEL THERAPEUTICS TARGETING A BMIC POPULATION IN HUMAN BRAIN METASTASES

Abstract

Brain Metastases (BM) are the most common neoplasm to affect the adult central nervous system, occurring at a rate 10 times greater than that of primary brain cancers. Despite the prevalence and severe lethality of BM, therapeutic strategies remain limited. Advancements in in vivo modelling of metastasis presents a useful platform to aid in the advance and screening of novel targeting therapeutics, though currently few models exist that properly recapitulate the clinical progression of brain metastasis. Utilizing primary patient samples of BMs, we have characterized a subpopulation of CSC-like cells, termed brain metastasis-initiating cells (BMICs), which are responsible for initiating BMs. Through injections of BMICs isolated from lung BMs into NOD-SCID mice, we have generated a novel patient-derived xeno-transplantation (PDXT) model of BM that allows for interrogation of each phase of the metastatic process from lung to brain. We then expanded our model to incorporate BMICs derived from breast and melanoma BMs. BMICs were harvested from primary sites and corresponding BMs, and RNA submitted for sequencing to identify metastatic and tissue-specific gene signatures. BMICs were found to possess a unique genomic profile as compared to BMICs isolated from full primary tumors and complete macro-metastases, exhibiting dysregulated expression in over 13,000 genes, including those involved in stem cell, epithelial-to-mesenchymal transition, and quiescence properties. In silico analysis was used to generate a list of therapeutics targeting this unique BMIC population. In vitro and in vivo screening has identified a subset of compounds with no previously known efficacy in cancer treatment that inhibits BMIC growth and metastasis. Ultimately, we aim to transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.

ACTR-45. A PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF MARIZOMIB (MRZ) WITH TEMOZOLOMIDE (TMZ) AND RADIOTHERAPY (RT) IN NEWLY DIAGNOSED WHO GRADE IV MALIGNANT GLIOMA (GLIOBLASTOMA, ndGBM)

Abstract

Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for ndGBM. MRZ -- an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma preclinical activity -- is being evaluated in ndGBM patients (NCT02903069). The phase 1 study (MRZ at 0.55, 0.7, 0.8, 1.0, and 1.2 mg/m²) is accruing in separate concomitant (MRZ+TMZ+RT) and adjuvant (MRZ+RT) treatment cohorts (3 + 3 design), followed by dose-expansion at the recommended phase 2 dose in concomitant followed by adjuvant treatment cohorts. Concomitant treatment (42 days (D)): MRZ (10 min IV infusion) D1, 8, 15, 29, 36; RT total dose 60 Gy; TMZ (75 mg/m², PO QD). Adjuvant treatment (28D-cycle): MRZ D1, 8, 15; TMZ (150–200 mg/m², PO QDX5). Tumor response (RANO criteria) measured at beginning and end of concomitant treatment, and every other cycle during adjuvant treatment; MRZ and TMZ PK in concomitant treatment D1-2, 8–9. Mean age 55 yrs (60% male) for 20 patients in 14Apr2017 interim analysis (cohorts 1–3 have completed accrual in concomitant treatment, cohorts 1 and 2 have completed accrual and 2 patients are enrolled in adjuvant cohort 3); one DLT (fatigue) in the 0.7 mg/m² adjuvant cohort. Most common treatment-related AEs (≥4 pts): fatigue, nausea, vomiting, decreased appetite, dizziness, hallucination; three Grade 3 SAEs (fatigue, hallucination, vomiting; all MRZ-related); two Grade 2 SAEs (nausea, confusional state, MRZ-related). Seventeen of the 20 patients included in this interim analysis remain on study: 7 of 9 concomitant patients are continuing in adjuvant treatment (longest beginning adjuvant cycle 7); of 11 adjuvant pts, two beginning cycle 9. The study is ongoing at 1.0 mg/m² for both concomitant and adjuvant dose-escalation cohorts. Together the data demonstrate that the combination of MRZ with standard of care in ndGBM is well tolerated and may provide novel therapeutic benefit in this unmet need.

STEM-11. A MAPK-DRIVEN miR-124-SOX9 AXIS IS CRITICAL FOR STEM CELL MAINTENANCE, PROGRESSION, AND THERAPY-RESISTANCE IN GLIOBLASTOMA

Abstract

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor. Genetic alterations in growth factor signaling pathways are found in 90% of GBMs. Advances in developmental and glioma biology suggest that common down-stream effector molecules in growth factor signaling pathways are critical for stem cell maintenance in the normal brain and GBM cells. It remains unclear whether differentiation therapies will be of therapeutic value for GBM patients. Here, we demonstrate that constitutive mitogen activated protein kinase (MAPK) activation in stem cells drives GBM formation and blocks neurogenesis in mice. Pharmacological inhibition of MAPK signaling restored neurogenesis in vivo and induced neuronal differentiation in GBM tumorspheres cultures established from murine GBMs and patient-derived tumors. Inhibition of MAPK signaling depleted SOX9 protein expression, and to a lesser extent SOX9 mRNA levels, in GBM cells. MicroRNA profiling experiments demonstrated that MAPK signaling regulates genome-wide expression of miRNAs, including the neuronal determinant miR-124. Pharmacological inhibition of MAPK signaling increased miR-124 levels in SOX9-expressing GBMs, but not SOX10-expressing proneural tumors. Using a doxycycline-inducible approach in vitro and in vivo, we demonstrated that miR-124 overexpression blocks SOX9 expression and induces neuronal differentiation in an EGFRvIII-driven GBM model and patient-derived xenografts. Neuronal differentiation resulted in apoptosis, reduced DNA repair capacity, and radiosensitized GBM cells. Doxycycline-mediated miR-124 overexpression resulted in complete regression for 1/3 of patient-derived xenografts. Mechanistic studies showed that SOX9 was a direct target of miR-124 and a major regulator of stem cell maintenance in GBM. Preliminary data showed that MAPK activation regulates transcriptional networks in SOX10-expressing proneural glioma, suggesting that distinct miRNAs regulate glioma aggressiveness in a subtype-specific manner. In conclusion, our results provide a mechanistic explanation for MAPK-dependent expansion of the stem cell pool during GBM initiation and demonstrate that enforcing neuronal differentiation represents a viable therapeutic strategy in glioma.

ACTR-46. AG-120, A FIRST-IN-class MUTANT IDH1 INHIBITOR IN PATIENTS WITH RECURRENT OR PROGRESSIVE IDH1 MUTANT GLIOMA: UPDATED RESULTS FROM THE PHASE 1 NON-ENHANCING GLIOMA POPULATION

Abstract

INTRODUCTION

Isocitrate dehydrogenase 1/2 (IDH1/2) mutations occur in >70% of low-grade gliomas (LGG) and lead to an altered metabolic state associated with production of D-2-hydroxyglutarate (2-HG), resulting in genetic/epigenetic dysregulation and oncogenesis. AG-120 is a potent oral inhibitor of mutant IDH1 (mIDH1) under clinical evaluation in an ongoing phase 1 study that treated 66 pretreated (median 2 prior systemic therapies) glioma patients in dose escalation and expansion cohorts. Safety and preliminary results were presented previously (SNO2016). We present updated results from the non-enhancing glioma patient population.

METHODS

Key eligibility: mIDH1 recurrent or progressive disease, ECOG 0–1, no surgery/radiation within 6 months. MRI response was assessed every 8 weeks using RANO and LGG-RANO criteria by local and independent central review. Exploratory analyses: change in tumor growth rate (FLAIR tumor volume, non-enhancing glioma expansion cohort) and pharmacodynamic evaluations of tissue and serum.

RESULTS

As of 10March2017, 35 patients with non-enhancing glioma were enrolled in dose escalation (n=11) and expansion (n=24), and 51% (n=18) remain on AG-120. M/F 23/12, median age 38 years, 1p19q intact in 54% (n=19) of patients, 74% reported anticonvulsant use. Frequent (≥5 patients) adverse events (AEs) grade 1–2: diarrhea (26%), headache (26%), nausea (20%), anemia (17%), neutrophil decrease (17%), and vomiting (17%). 7 (20%) patients experienced a grade 3–4 AE (hypophosphatemia most frequent, n=2, unrelated), with no dose reduction due to AEs. 73% and 88% of patients achieved stable disease as best response in the dose escalation (RANO) and expansion (LGG-RANO) cohorts, respectively. Median duration on AG-120 was 14.7 months (range 1.4–25.0); 63% remained on AG-120 for ≥1 year. Updated safety, response, and exploratory imaging analyses will be presented.

CONCLUSIONS

AG-120 monotherapy is associated with a favorable safety profile and prolonged stable disease in a previously treated non-enhancing mIDH1 glioma patient population, and warrants further clinical evaluation.

TMOD-04. A COMPREHENSIVE GENOMIC LANDSCAPE OF GLIOMA SPHEROID CULTURES RECAPITULATES THE HETEROGENEITY OF GLIOBLASTOMA AND IDENTIFIES DNA METHYLATION PREDICTORS OF RADIOTHERAPY RESPONSE

Abstract

Glioma sphere-forming cells (GSCs) are important in glioblastoma (GBM) initiation, maintenance, and treatment resistance. We performed whole exome and transcriptome sequencing, DNA methylation profiling, DNA copy number determination, and functional characterization of 43 GSCs and matching tumors. Comparative analyses revealed that GSCs recapitulate the molecular landscape of GBM and provide a unique means for discovering the inter- and intra-tumor heterogeneity of GBM. We performed clonogenic assays to explore the relationship between methylation status and radiation response in twelve IDH wild type GSCs irradiated with 2-, 4-, and 6-Gy ionizing radiation. The survival fraction at 4Gy and 6Gy (SF4 and SF6, respectively) were used to dichotomize GSCs as either radiation-sensitive or resistant. DNA CpG methylomes of the GSCs were profiled using Infinium 450K methylation beadchip arrays. We observed that 304,458 out of 465,844 methylation probes (65.4%) showed increased methylation in radiation-resistant relative to radiation-sensitive GSCs (Fisher's Exact Test, p < 1e-15). Using GSEA, we observed that fifteen of sixteen oxidative stress genes were methylated in radiation-resistant GSCs (p-value=0.019), suggesting an association between radiation-resistance and reactive oxygen species metabolism (ROS). To validate our finding, we derived a methylation signature differentiating the two GSC radiation response groups and used this to classify TCGA cases that received radiotherapy into a responder and non-responder group. We found that survival was significantly different between the two groups (median survival 84 vs. 61 weeks; HR 1.64 adjusting for patient age, p-value<0.008), suggesting that the methylation signature predicts clinical response to radiation treatment. This study identified a novel predictor of radiation response and confirms that the genomic landscape of GSCs can be used to determine clinical and functional properties of GBM.

GENE-36. ACCURATE DETECTION OF TERT PROMOTER MUTATION IN GLIOMAS USING INFINIUM DNA METHYLATION ARRAYS IDENTIFIES NOVEL EPIGENETIC ASSOCIATION

Abstract

The telomere reverse transcriptase promoter (TERTp) is frequently mutated in malignant gliomas, particularly glioblastomas (GBM, 85%), and is involved in maintaining telomere length. TERTp mutations are prognostic for patient survival. Given the evolving use of Infinium DNA methylation arrays in assaying biomarkers in glioma, we aimed to develop an accurate predictor of TERTp mutations in gliomas using this platform. We analyzed TCGA lower grade glioma (LGG) and GBM available with both TERTp sequencing and Infinium 450k data. Samples were split into training and testing set to determine predictor accuracy. Probes with potential quality issues were excluded and probe selection performed using an elastic net algorithm. Probes were selected across the genome, not limited to the TERTp locus. A logistic regression model with binomial distribution was built using the final optimized model, constructed based on 1000 CpG probes, all distinct from TERTp. Prediction accuracy was 100% (179/179, AUC=1) in the training set and 97.5% (116/119) in the test set. Comparison of the normalized frequency of selected probes by chromosome revealed enrichment for chromosomes 20 (0.4987%) and 18 (0.4859%). The majority of probes enriched in CpG islands (53.6%), followed by open sea (22.9%), shore (17.4%), and shelf (6.1%). Relative to known genes, probe enrichment occurred predominantly near transcriptional start sites (within 200–1500 bp, 31.0%), followed by gene bodies (26.3%) and intergenic regions (18.3%). Quite unexpectedly, probes within the predictor do not map near TERT or other telomere maintenance factors nor fell within known methylation signatures, such as G-CIMP, suggesting that TERTp mutation is associated with novel epigenetic changes. Moreover, this biomarker permits rapid and cost effective detection of TERTp mutation using the widely used Infinium platform.

CBIO-12. GTP METABOLIC SWITCH LEADS TO NUCLEOLAR TRANSFORMATION AND MALIGNANT GROWTH OF GLIOBLASTOMA

Abstract

Nucleolar mass is frequently increased in malignant cells, pointing to a prominent role for aberrant rRNA transcription in highly anabolic cells. ATP and GTP, fundamental energy currencies and building blocks for DNA and RNA, are synthesized by the energy-efficient salvage pathway and energy-demanding de novo pathway. While purine nucleotide biosynthesis is upregulated in malignant cancers, distinctive role(s) of de novo ATP and GTP biosynthesis in cancer cell proliferation remains elusive. Here, we show that the highly lethal brain cancer glioblastoma rewires purine metabolism to activate de novo GTP biosynthesis for rRNA transcription and nucleolar transformation, whereas de novo ATP biosynthesis is commonly utilized in glioblastoma and primary glial cells. Transcriptome screening followed by two cohort analyses identified upregulation of inosine monophosphate dehydrogenase-2 (IMPDH2) in glioblastoma patients. Pharmacological and genetic inhibition of IMPDH2 abolished de novo GTP biosynthesis and growth of glioblastoma cells in vitro and in vivo without affecting de novo ATP biosynthesis. This GTP metabolic switch in glioblastoma cells is critical for enhanced RNA Pol I-dependent nucleolar transcription, but not for RNA Pol II and Pol III transcription. Increased IMPDH2 expression correlates with enlarged nucleoli in human glioma patients, and inhibition of IMPDH2 leads to decreased nucleolar mass. Abnormal nucleolar morphology in many cancer types has long been recognized by pathologists and de novo purine biosynthesis was discovered in 1885. Our data connect these dots of long observed features in cancer by demonstrating a glioblastoma-specific shift in glucose flux to increase de novo GTP biosynthesis, which is required for enhanced ribosome biosynthesis and growth of tumor cells. Our results propose new strategies for the detection and treatment of the incurable glioblastoma, and perhaps other tumors, with minimum impact on normal tissues.

GENE-37. PATHWAY ANALYSIS OF RADIATION-INDUCED MENINGIOMAS REVEALS THAT TUMOURS WITH NF2-FUSION HAVE UPREGULATION OF INFLAMMATORY PATHWAYS

Abstract

INTRODUCTION

As more pediatric cancer patients are surviving into adulthood from improved oncological therapy there is an increase in the long-term sequelae of treatment. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate significantly different biology than sporadic meningiomas (SMs) and demonstrate clinically more aggressive behaviour. RIMs have been shown to not harbor mutations in common SM associated driver genes, such as NF2, TRAF7, KLF4, PIK3CA and SMO; however, a subset of RIMs have genomic rearrangements with NF2 gene fused to a reciprocal gene, which was previously not seen in SMs. We aimed to compare and contrast the gene expression in RIMs with and without the NF2-fusion event.

METHODS

A primary cohort of 7 RIMs with NF2-fusion and 12 RIMs with wildtype NF2 had RNA sequencing performed using the Illumina HiSeq platform. RNA-Seq expression profiles were analyzed using edgeR, available through BioConductor. Gene Set Enrichment Analysis was performed using Cytoscape®.

RESULTS

Principle component analysis of the RNA-Seq data showed that 5/7 RIMs with NF2-fusion were similar to one another. One of the outliers was the only NF2-fusion RIM without a 1p chromosomal arm loss. Significant differentially expressed genes included IGF-1 (log2 of fold change or logFC = 4.14, p=2.65E-05), MME (logFC = 3.03, p = 3.56E-03) and MMP16(logFC = 2.47, p=8.14E-03). Notably, the pathway analysis demonstrated that there was an upregulation of immune/inflammation pathways involving PD-1, STAT-4, IGF-1 and other genes in RIMs with NF2-fusion compared to RIMs with NF2 wildtype.

CONCLUSION

RIMs with the NF2-fusion event have a distinct gene expression profile, with upregulation of inflammatory pathways. Further studies need to be performed to validate these findings using immunohistochemistry. These results suggest that NF2-fusion RIMs may be candidates for immunotherapy.

DDIS-15. SYNERGISTIC INHIBITION OF GLIOMA CELL PROLIFERATION BY WITHAFERIN A AND TUMOR TREATING FIELDS

Abstract

BACKGROUND

Glioblastoma (GBM) is the most aggressive and lethal form of primary brain cancer. Standard therapies are non-specific and often of limited effectiveness; thus, efforts are underway to uncover novel, unorthodox therapies against GBM. In previous studies, we investigated Withaferin A, a steroidal lactone from Ayurvedic medicine that inhibits proliferation in cancers including GBM. Another novel approach, tumor treating fields (TTFields), is thought to disrupt mitotic spindle formation and stymie proliferation of actively dividing cells. We hypothesized that combining TTFields with Withaferin A would synergistically inhibit proliferation in glioblastoma.

METHODS

Human glioblastoma cells (GBM2, GBM39, U87-MG) and human breast adenocarcinoma cells (MDA-MB-231) were isolated from primary tumors. The glioma cell lines were genetically engineered to express firefly luciferase. Proliferative potential was assessed either by bioluminescence imaging or cell counting via hemocytometer.

RESULTS

TTFields (4 V/cm) significantly inhibited growth of the four cancer cell lines tested (n=3 experiments per time point, 4 measurements per sample, p<0.02 at least; 2-way ANOVA, control vs. treatment). The combination of Withaferin A (10–100 nM) with TTFields significantly inhibited the growth of the glioma cells to a degree beyond that of Withaferin A or TTFields alone. The interaction of the Withaferin A and TTFields on glioma cells was found to be synergistic in nature (p<0.01, n=3 experiments). These findings were validated by both bioluminescence and hemocytometric measurements.

CONCLUSIONS

The combination of Withaferin A with TTFields represents a novel approach to treat GBM in a manner that is likely better than either treatment alone and that is synergistic.

GENE-38. DISRUPTED ENDOTHELIAL CELL GENE EXPRESSION PROFILE PREDICTS GBM CLINICAL RESPONSE TO ANTI-ANGIOGENIC THERAPY

Abstract

Glioblastoma (GBM) is one of the most aggressive adult brain tumors, with the histopathologic hallmark of increased abnormal vasculature. While anti-angiogenesis therapy had shown value in pre-clinical and early clinical studies, in particular targeting vascular endothelial growth factor (VEGF), the durability of response to anti-angiogenic therapy varies and hence efficacy remains a limitation. There is data to suggest that certain subtypes of GBM however have a more effective response to anti-angiogenic therapy. Therefore, there is a need to identify prognostic markers that can determine the subpopulation of GBM patients that response to AA therapy. We established five genetic expression profiles (group A~E) by stimulating endothelial cells (ECs) with different combinations of ionizing radiation (IR) and mesenchymal stem cells (MSCs) before performing angiogenesis array analysis. Bioinformatics analysis of Group A~E identified the combination of HGF and CXCL10 alterations as the differentiators that separated the AVAglio patients into 3 groups (group 1~3). We found that GBM patients with high HGF and low CXCL10 levels had the worst clinical response to AA therapy. Further qPCR analysis of gene expression levels among different cell types revealed that GBM cells have the highest expression of HGF and the lowest expression of CXCL10 relative to ECs. Similar trend were detected in MSCs relative to ECs but to a lesser degree. Thus we propose that such genetic parameter in GBM could potentially be a prognostic marker for AA therapy.

ACTR-42. INITIAL EXPERIENCE OF BLOOD-BRAIN BARRIER OPENING FOR CHEMOTHERAPEUTIC-DRUG DELIVERY TO BRAIN TUMOURS BY MR-GUIDED FOCUSED ULTRASOUND

Abstract

INTRODUCTION

Magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly open the blood-brain barrier (BBB) for targeted drug delivery. Animal models have shown the feasibility of BBB opening for delivery of a broad range of compounds. We describe the first experience of focused ultrasound mediated BBB opening in malignant brain tumours.

METHODS

This phase-one clinical trial was approved by Health Canada and our Research Ethics Board. A modified clinical MRgFUS brain system was used with a 3T MR scanner. Prior to BBB opening patients received a single dose of IV liposomal doxorubicin (N=1) or temozolomide (N=2). Patients were positioned in the FUS array with a stereotactic frame. Two targets close to the posterior margin of the tumor were chosen based on T2 images. A bolus injection of Definity microbubbles was applied simultaneously with each sonication. Post sonication, Gd-enhanced images were acquired to verify BBB openings, and T2*-weighted GRE images were collected to detect hemorrhage.

RESULTS

All patients tolerated FUS procedures and BBB opening well, with no adverse events. T2* images demonstrated a small degree of RBC extravasation, with no overt hemorrhage on standard T1, no edema on T2 or DWI changes on treatment or follow-up scans. BBB was successfully opened in all patients at each targeted location, with clear Gd enhancement. All patients underwent safe maximal surgical resection at 24 hours post-sonication.

DISCUSSION

Our initial experience of FUS-mediated BBB opening in high-grade glioma demonstrates the safety and feasibility of this emerging adjuvant modality. We were able to open the BBB, as demonstrated with Gd enhancement, in several discrete brain regions surrounding the tumour, without adverse events. Patients tolerated the procedure well. Next steps will include sonication of larger tumour volumes, done in conjunction with standard of care prescriptions of chemotherapeutic agents, for which the BBB is a major challenge.

GENE-39. UNANTICIPATED GERMLINE CANCER SUSCEPTIBILITY MUTATIONS IDENTIFIED DURING ROUTINE NEXT GENERATION SEQUENCING OF PRIMARY CNS NEOPLASMS

Abstract

INTRODUCTION

Tumor genomic profiling is routinely performed on primary brain tumors to identify somatic mutations. Such testing may also identify clinically significant germline mutations. Several syndromes (neurofibromatosis, Li Fraumeni, Von Hippel Lindau and Turcot) are well known causes of primary CNS neoplasms but there is limited data on other germline cancer susceptibility mutations in CNS tumor patients. After a somatic mutation was unexpectedly found to be germline, we interrogated our database of somatic CNS tumor mutations.

METHODS

This IRB approved retrospective study reviewed patients at the Texas Oncology-Austin Brain Tumor Center from May 2013 through April 2017. Tumors underwent genomic profiling using a commercially available test which evaluates 315 genes using next generation sequencing. Patients' whose tumors carried a mutation which was concerning for a germline variant were tested further.

RESULTS

Tumor genomic profiling was performed on 291 CNS tumor patients. Five patients were found to carry unexpected germline variants (1.7%). Two patients had glioblastoma: 1 BRCA2 pathogenic mutation, 1 MLH1 variant of uncertain significance; 2 anaplastic astrocytomas: 1 BRCA2 pathogenic mutation, 1 with pathogenic APC and ATM mutations; 1 atypical meningioma: 1 BRCA2 pathogenic mutation. Median age was 42.2 (range 33–53). As a result of the incidental findings, medical management was altered and testing of numerous family members was recommended. Complete tumor genomic profiles, pedigrees, and additional pending germline testing will be presented.

CONCLUSIONS

In this series of primary brain tumor patients whose tumors were sequenced, unexpected germline variants were identified in the genes: BRCA2, MLH1, APC and ATM for an incidence of at least 1.7%. These results had life-saving implications for these patients and their families. This data is reasonably extrapolated to the brain tumor population at large and warrants further scrutiny of systematic approaches for identifying patients as candidates for germline testing based on tumor genomic profiling.

STEM-41. A SUBSET OF GBM BRAIN TUMOR STEM CELL LINES ARE UNIQUELY DEPENDENT ON GLUTAMINE METABOLISM FOR AMINO ACID SYNTHESIS

Abstract

Glioblastoma multiforme (GBM) is the most aggressive adult primary brain tumor. Despite a treatment regimen involving surgical resection, chemotherapy, and radiation, GBM patients have a median survival of approximately 15 months. This poor outcome highlights the need for improved therapeutic approaches for GBM patients. A subpopulation of cells that exhibit stem cell properties, termed brain tumor stem cells (BTSCs), are hypothesized to be the source of recurrence and resistance due to their inherent ability to resist treatment, invade into normal tissue, and re-populate a tumor. We have recently found that a subset of BTSC lines are uniquely dependent on glutamine metabolism for survival and maintenance of their stem cell properties. This dependence on glutamine differs from the more conventional view that cancer cells rely on increased glucose metabolism. Inhibiting glutamine metabolism in the sensitive subset of BTSC lines, by targeting the enzyme glutaminase (GLS) that deaminates glutamine to produce glutamate, results in decreased growth, viability, and self-renewal. We have found that inhibition of GLS decreases intracellular glutamate levels and leads to amino acid depletion. Replenishing the amino acid pool using bovine serum albumin rescues the decrease in BTSC growth following GLS inhibition. Intriguingly, the sensitive subset of BTSC lines have low expression of the glutamate transporter termed excitatory amino acid transporter 2 (EAAT2), limiting their glutamate uptake. We are exploring the relationship between reduced glutamate uptake and glutamine dependence; specifically, by asking whether GLS inhibition-resistant BTSC lines become glutamine-dependent after exposure to glutamate transport inhibitors. Taken together, our findings point to a unique dependence on glutamine metabolism for amino acid synthesis, in a subset of BTSC lines. Our long-term goal is to pursue this glutamine dependence as a novel therapeutic strategy to target the cells at the root of this aggressive and lethal disease.

GENE-40. CIRCULATING TUMOR DNA ANALYSIS IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA

Abstract

Extracellular tumor-derived DNA in body fluids (also known as circulating tumor DNA or ctDNA) is being widely studied for noninvasive tumor genotyping, tracking clonal evolution, monitoring treatment response and early detection of cancer. In patients with glioblastoma (GBM), ctDNA is more readily detectable in cerebrospinal fluid as compared to blood plasma. In literature, sensitivity for mutation detection in DNA from CSF is ~60% compared to ~10% in plasma DNA. However, CSF is difficult to sample and other body fluids need to be studied carefully. To develop new strategies for plasma ctDNA detection and increase tumor DNA shedding into plasma in patients with GBM, we sought to utilize body fluid samples form patient derived xenograft (PDX) models. In this context, any human DNA detectable in mouse plasma is derived from the tumor xenograft. Hence, we developed a human-specific multiplexed droplet digital PCR assay to detect and accurately quantify plasma ctDNA in PDX models derived from patients with GBM. This assay is composed of 8 paired primer/probe sets, fluorescently labeled, with careful design accounting for unique diploid amplification, variable regions, cross amplification between species, and most common genomic aberrations in GBM. We will share results demonstrating the analytical validity of the assay as well as utility in testing approaches for increasing ctDNA yield and shedding from GBM tumors.

Prevalence and clinicopathologic characteristics of multiple myeloma with cutaneous involvement: A case series from Korea

Publication date: Available online 6 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Yu Ri Woo, Jong Sic Kim, Ji Hong Lim, Sewon Hwang, Miri Kim, Jung Min Bae, Young Min Park, Chang-Ki Min, Dong-Wook Kim, Hyun Jeong Park
BackgroundMultiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of a clonal proliferation of tumor cells. Cutaneous involvement of MM is very rare and remains poorly understood.ObjectiveThe aim of this study was to examine the clinical and histopathologic characteristics of cutaneous involvement in MM and identify factors associated with overall survival of MM with cutaneous involvement.MethodsThe medical records of 1228 patients with MM were retrieved and analyzed. Of those patients, 14 with cutaneous involvement of MM (1.14%) were further evaluated for their clinical and histopathologic findings.ResultsPatients with cutaneous involvement showed significantly reduced overall survival compared with those without cutaneous involvement (median, 28 vs. 57 months; hazard ratio, 1.929; 95% confidence interval, 1.030-3.613). In subgroup analyses of patients with MM with cutaneous involvement, erythematous nodules (P = .004), multiple cutaneous lesions (P = .002), and absence of a grenz zone (P = .004) were clinicopathologic features associated with reduced overall survival after Bonferroni correction.LimitationsThe retrospective design and the small sample size are the limitations.ConclusionCutaneous involvement accounted for about 1.14% of patients with MM and was associated with reduced overall survival.

Depressive symptoms, depression, and the effect of biologic therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR)

Publication date: Available online 6 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Bruce Strober, Melinda Gooderham, Elke M.G.J. de Jong, Alexa B. Kimball, Richard G. Langley, Nikita Lakdawala, Kavitha Goyal, Fabio Lawson, Wayne Langholff, Lori Hopkins, Steve Fakharzadeh, Bhaskar Srivastava, Alan Menter
BackgroundPatients with psoriasis are at an increased risk for depression. However, the impact of treatment on this risk is unclear.ObjectiveEvaluate the incidence and impact of treatment on depression among patients with moderate-to-severe psoriasis.MethodsWe defined a study population within the Psoriasis Longitudinal Assessment and Registry and measured the incidence of depressive symptoms (Hospital Anxiety and Depression Scale–Depression score ≥8) and adverse events (AEs) of depression within cohorts receiving biologics, conventional systemic therapies, or phototherapy. Patients were evaluated at approximately 6-month intervals. Multivariate modeling determined the impact of treatment on risk.ResultsThe incidence rates of depressive symptoms were 3.01 per 100 patient-years (PYs) (95% confidence interval [CI], 2.73-3.32), 5.85 per 100 PYs (95% CI, 4.29-7.97), and 5.70 per 100 PYs (95% CI, 4.58-7.10) for biologics, phototherapy, and conventional therapy, respectively. Compared with conventional therapy, biologics reduced the risk for depressive symptoms (hazard ratio, 0.76; 95% CI, 0.59-0.98), whereas phototherapy did not (hazard ratio, 1.05; 95% CI, 0.71-1.54). The incidence rates for AEs of depression were 0.21 per 100 PYs (95% CI, 0.15-0.31) for biologics, 0.55 per 100 PYs (95% CI, 0.21-1.47) for phototherapy, and 0.14 per 100 PYs (95% CI, 0.03-0.55) for conventional therapy; the fact that there were too few events (37 AEs) precluded modeling.LimitationsIncomplete capture of depression and confounders in the patients on registry.ConclusionCompared with conventional therapy, biologics appear to be associated with a lower incidence of depressive symptoms among patients with psoriasis.

Pediatric severity of alopecia tool

Abstract

The Severity of Alopecia Tool serves as a tool for alopecia research and a clinical guideline for following progression of disease. The original Severity of Alopecia Tool score does not take into account pediatric age groups. As new clinical trials for alopecia areata include more children, a more accurate tool should be available for this population. By collecting images from patients 2-21 years of age and aligning the hair-bearing regions of the scalp, we created an adaptation of the Severity of Alopecia Tool for scoring hair loss percentage of the top, parietal, and occipital scalp in individuals 2-5, 6-11, and 12-21 years of age.

Wound culture isolated antibiograms and caregiver-reported skin care practices in children with epidermolysis bullosa

Abstract

Background/Objectives

Many patients with epidermolysis bullosa (EB) require intensive daily wound care and individualized treatment plans. Understanding patient's home skin care routines and emerging antibiotic resistance patterns in EB wounds is necessary to optimize treatment recommendations. The objective was to identify patterns of antimicrobial resistance in EB wounds and characterize patient's home practices of skin care and bathing.

Methods

This was an observational study of 23 children with EB at an outpatient pediatric dermatology practice in New York City from 2012 to 2014. Information on individual bathing and skin care practices and wound cultures was collected as part of routine examinations and an institutional review board–approved antibiogram protocol.

Results

Sixty wound cultures were collected from 23 patients. Eleven organisms were isolated, most commonly methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, Streptococcus species, and Pseudomonas aeruginosa. Six patients (26%) were colonized with methicillin-resistant S. aureus. Over the course of the study, 13 patients (56%) were found to have mupirocin-resistant S. aureus. More than half of participants reported mupirocin or bacitracin use. Fewer than half indicated that they regularly used dilute bleach or dilute vinegar as part of their bathing routine.

Conclusion

Numerous organisms, including resistant bacteria, are known to colonize the wounds of individuals with EB. Mupirocin resistance was prevalent and more than half of the participants reported its use. Testing for mupirocin resistance may be considered for certain patients. These observations may help guide questions for future longitudinal multicenter studies with the goal of optimizing EB wound care recommendations.

Do body build and composition influence striae distensae occurrence and visibility in women?

Summary

Background

Striae have been reported to be one of the most common skin changes and a commonly encountered esthetic problem.

Objectives

To analyze risk factors of striae not associated with pregnancy and verify if body build and composition influence striae distensae (SD) occurrence and visibility.

Methods

Eighty female students (40 with striae (the mean age 23.9 years, SD 2.05 years) and 40 without these lesions (24.7 years, SD 6.2 years)) were included in the study. The subjects were asked to fill out a questionnaire including questions concerning risk factors of SD. Body build and composition were examined using Tanita SC-331S Body Composition Analyzer.

Results

Women without striae more often reported a history of intended weight loss (P < .0001), less frequently had a history of contraceptives intake (P < .001) and more often their family history of striae was negative or unknown (P = .01). Multivariate analysis including body build and composition parameters indicated BMI as risk factor of SD (P = .021; OR =1.155, 95% CI 1.006; 1.325).

Conclusions

History of contraceptives intake and a family history of striae are risk factors of SD occurrence, while weight loss can reduce the risk of these lesions. BMI appeared to be the risk factor of striae visibility, especially in abdomen, but not on the buttocks. Further clinical researches are needed to examine the pathophysiology of this condition and to inform patients about the possibility to reduce the risk of striae occurrence.

A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: Results of NRG Oncology RTOG 0913

Abstract

Background

This Phase II study was designed to determine the efficacy of the mTOR inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma.

Methods

Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities.

Results

A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced both a significant increase in Grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared to control (median PFS time: 8.2 vs. 10.2 months, respectively; p=0.79). OS for patients randomized to receive everolimus was inferior to the control patients (median survival time (MST): 16.5 vs. 21.2 months, respectively; p=0.008). A similar trend was observed in both 06-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylated and unmethylated tumors.

Conclusion

Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and did not improve PFS in patients with newly diagnosed glioblastoma. Although the MST in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study.

Highly specific determination of IDH status using edited in vivo magnetic resonance spectroscopy

Abstract

Background

Mutations in the isocitrate dehydrogenase (IDH) enzyme affects 40% of gliomas and represent a major diagnostic and prognostic marker. The goals of this study were to evaluate the performance of noninvasive magnetic resonance spectroscopy (MRS) methods to determine the IDH status of patients with brain gliomas through detection of the oncometabolite 2-hydroxyglutarate (2HG), and to compare performance of these methods with DNA sequencing and tissue 2HG analysis.

Methods

Twenty-four subjects with suspected diagnosis of low grade glioma were included prospectively in the study. For all subjects, MRS data were acquired at 3 T using two MRS methods, edited MRS using MEGA-PRESS sequence and a PRESS sequence optimized for 2HG detection, using a volume of interest larger than 6 mL. IDH mutational status was determined by combination of automated immunohistochemical analysis (IHC) and Sanger sequencing. 2HG levels in tissue samples measured by gas chromatography-mass spectrometry (GC-MS) were compared to those estimated by MRS.

Results

Edited MRS provided 100% specificity and 100% sensitivity in the detection of 2HG. The 2HG levels estimated by this technique were in line with those derived from tissue samples. Optimized PRESS provided lower performance, in agreement with previous findings.

Conclusions

Our results suggest that edited MRS is one of the most reliable tools to predict IDH mutation noninvasively, showing high sensitivity and specificity for 2HG detection. Integrating edited MRS in clinical practice may be highly beneficial for noninvasive diagnosis of glioma, prognostic assessment, and treatment planning.

Eat this Book: A Carnivore’s Manifesto Taste as Experience. The Philosophy and Aesthetics of Food

Eat This Book: A Carnivore's Manifesto

Strange Tools: Art and Human Nature

Strange Tools: Art and Human Nature

Digging out the evidence – how strong is the IDSA recommendation against antibiotic prophylaxis in basilar skull fracture and cerebrospinal fluid leakage?

Reply to Kuehl et al.

What’s New in Imaging for Gynecologic Cancer?

Abstract

Magnetic resonance imaging (MRI) is the optimal modality for local staging of gynecological tumors. Advances in functional MRI with diffusion-weighted and dynamic contrast-enhanced sequences provide more detailed information regarding tumor cellularity, vascularity, and viability. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) now has an established role in imaging for gynecological cancers, particularly staging of locally advanced cervical cancers and pre-salvage exenterative therapy in relapsed gynecologic tumors. Novel PET tracers, targeting other aspects of tumor biology, are being evaluated although none are currently in routine clinical use. New PET/MR scanners have the potential to combine the strengths of both modalities in one sitting. This review covers advances in gynecologic imaging concentrating on cervical, endometrial, and ovarian cancers.

Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II

Abstract

Background

Anastrozole reduces breast cancer risk in women at high risk, but implementing preventive therapy in clinical practice is difficult. Here, we evaluate adherence to anastrozole in the International Breast Cancer Intervention Study (IBIS) II prevention and Ductal Carcinoma in Situ (DCIS) trials, and its association with early symptoms.

Patients and methods

In the prevention trial, 3864 postmenopausal women were randomized to placebo vs. anastrozole. 2980 postmenopausal women with DCIS were randomized to tamoxifen vs. anastrozole. Adherence to trial medication was calculated using the Kaplan-Meier method and all P-values were two-sided.

Results

In the prevention trial, adherence was 65.8% (anastrozole (65.7%) vs. placebo (65.9%); HR = 0.97 (0.87-1.09), p=0.6). Adherence was lower for those reporting arthralgia in the placebo group (p=0.02) or gynecological symptoms in the anastrozole group (P=0.003), compared with those not reporting these symptoms at 6 months. In the DCIS study, adherence was 66.7% (anastrozole (67.5%) vs. tamoxifen (65.8%); HR = 1.06 (0.94-1.20), p=0.4). Hot flashes were associated with greater adherence in the anastrozole arm (p=0.02). In both studies, symptoms were mostly mild or moderately severe, and adherence decreased with increasing severity for most symptoms. Drop-outs were highest in the first 1.5 years of therapy in both trials.

Conclusions

In the IBIS-II prevention and DCIS trials, over two-thirds of women were adherent to therapy, with no differences by treatment groups. Participants who reported specific symptoms in the IBIS-II prevention trial had a small but significant effect on adherence, which strengthened as severity increased. Strategies to promote adherence should target the first year of preventive therapy.

Impact of Neoadjuvant Chemoradiotherapy on Health Related Quality of Life In Long-Term Survivors of Esophageal or Junctional Cancer: Results from the Randomized Cross Trial

Abstract

Background

Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone.

Patients and methods

Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared to pre-treatment and 12-months-postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary endpoints. Predefined secondary endpoints were global quality of life and fatigue (both QLQ-C30).

Results

After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL-endpoints were found between both groups. Compared to one-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared to pre-treatment levels, eating problems had improved (Cohen's d -0.37, p = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pre-treatment levels in both groups (Cohen's d -0.56 and 0.51, resp., both p < 0.001).

Conclusion(s)

Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared to patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care.

CLINICAL TRIALS NUMBER

Trial registration number: Netherlands Trial Register NTR487

Infant Group B Streptococcal Disease Incidence and Serotypes Worldwide: Systematic Review and Meta-analyses

Abstract

Background

Group B Streptococcus (GBS) remains a leading cause of neonatal sepsis in high-income contexts, despite declines due to intrapartum antibiotic prophylaxis (IAP). Recent evidence suggests higher incidence in Africa, where IAP is rare. We investigated the global incidence of infant invasive GBS disease and the associated serotypes, updating previous estimates.

Methods

We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data regarding invasive GBS disease in infants aged 0–89 days. We conducted random-effects meta-analyses of incidence, case fatality risk (CFR), and serotype prevalence.

Results

We identified 135 studies with data on incidence (n = 90), CFR (n = 64), or serotype (n = 45). The pooled incidence of invasive GBS disease in infants was 0.49 per 1000 live births (95% confidence interval [CI], .43–.56), and was highest in Africa (1.12) and lowest in Asia (0.30). Early-onset disease incidence was 0.41 (95% CI, .36–.47); late-onset disease incidence was 0.26 (95% CI, .21–.30). CFR was 8.4% (95% CI, 6.6%–10.2%). Serotype III (61.5%) dominated, with 97% of cases caused by serotypes Ia, Ib, II, III, and V.

Conclusions

The incidence of infant GBS disease remains high in some regions, particularly Africa. We likely underestimated incidence in some contexts, due to limitations in case ascertainment and specimen collection and processing. Burden in Asia requires further investigation.

Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children: Why, What, and How to Undertake Estimates?

Abstract

Improving maternal, newborn, and child health is central to Sustainable Development Goal targets for 2030, requiring acceleration especially to prevent 5.6 million deaths around the time of birth. Infections contribute to this burden, but etiological data are limited. Group B Streptococcus (GBS) is an important perinatal pathogen, although previously focus has been primarily on liveborn children, especially early-onset disease. In this first of an 11-article supplement, we discuss the following: (1) Why estimate the worldwide burden of GBS disease? (2) What outcomes of GBS in pregnancy should be included? (3) What data and epidemiological parameters are required? (4) What methods and models can be used to transparently estimate this burden of GBS? (5) What are the challenges with available data? and (6) How can estimates address data gaps to better inform GBS interventions including maternal immunization? We review all available GBS data worldwide, including maternal GBS colonization, risk of neonatal disease (with/without intrapartum antibiotic prophylaxis), maternal GBS disease, neonatal/infant GBS disease, and subsequent impairment, plus GBS-associated stillbirth, preterm birth, and neonatal encephalopathy. We summarize our methods for searches, meta-analyses, and modeling including a compartmental model. Our approach is consistent with the World Health Organization (WHO) Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER), published in The Lancet and the Public Library of Science (PLoS). We aim to address priority epidemiological gaps highlighted by WHO to inform potential maternal vaccination.

Maternal Disease With Group B Streptococcus and Serotype Distribution Worldwide: Systematic Review and Meta-analyses

Abstract

Background

Infections such as group B Streptococcus (GBS) are an important cause of maternal sepsis, yet limited data on epidemiology exist. This article, the third of 11, estimates the incidence of maternal GBS disease worldwide.

Methods

We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data on invasive GBS disease in women pregnant or within 42 days postpartum. We undertook meta-analyses to derive pooled estimates of the incidence of maternal GBS disease. We examined maternal and perinatal outcomes and GBS serotypes.

Results

Fifteen studies and 1 unpublished dataset were identified, all from United Nations–defined developed regions. From a single study with pregnancies as the denominator, the incidence of maternal GBS disease was 0.38 (95% confidence interval [CI], .28–.48) per 1000 pregnancies. From 3 studies reporting cases by the number of maternities (pregnancies resulting in live/still birth), the incidence was 0.23 (95% CI, .09–.37). Five studies reported serotypes, with Ia being the most common (31%). Most maternal GBS disease was detected at or after delivery.

Conclusions

Incidence data on maternal GBS disease in developing regions are lacking. In developed regions the incidence is low, as are the sequelae for the mother, but the risk to the fetus and newborn is substantial. The timing of GBS disease suggests that a maternal vaccine given in the late second or early third trimester of pregnancy would prevent most maternal cases.

Neurodevelopmental Impairment in Children After Group B Streptococcal Disease Worldwide: Systematic Review and Meta-analyses

Group B Streptococcus (GBS) is a leading cause of invasive disease in infants, causing mortality and neurodevelopmental impairment (NDI) in survivors. This article estimates the percentage of survivors of infant GBS disease with NDI.

Background

Survivors of infant group B streptococcal (GBS) disease are at risk of neurodevelopmental impairment (NDI), a burden not previously systematically quantified. This is the 10th of 11 articles estimating the burden of GBS disease. Here we aimed to estimate NDI in survivors of infant GBS disease.

Methods

We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data on the risk of NDI after invasive GBS disease in infants <90 days of age. We did meta-analyses to derive pooled estimates of the percentage of infants with NDI following GBS meningitis.

Results

We identified 6127 studies, of which 18 met eligibility criteria, all from middle- or high-income contexts. All 18 studies followed up survivors of GBS meningitis; only 5 of these studies also followed up survivors of GBS sepsis and were too few to pool in a meta-analysis. Of meningitis survivors, 32% (95% CI, 25%–38%) had NDI at 18 months of follow-up, including 18% (95% CI, 13%–22%) with moderate to severe NDI.

Conclusions

GBS meningitis is an important risk factor for moderate to severe NDI, affecting around 1 in 5 survivors. However, data are limited, and we were unable to estimate NDI after GBS sepsis. Comparability of studies is difficult due to methodological differences including variability in timing of clinical reviews and assessment tools. Follow-up of clinical cases and standardization of methods are essential to fully quantify the total burden of NDI associated with GBS disease, and inform program priorities.

Stillbirth With Group B Streptococcus Disease Worldwide: Systematic Review and Meta-analyses

Abstract

Background

There are an estimated 2.6 million stillbirths each year, many of which are due to infections, especially in low- and middle-income contexts. This paper, the eighth in a series on the burden of group B streptococcal (GBS) disease, aims to estimate the percentage of stillbirths associated with GBS disease.

Methods

We conducted systematic literature reviews (PubMed/Medline, Embase, Literatura Latino-Americana e do Caribe em Ciências da Saúde, World Health Organization Library Information System, and Scopus) and sought unpublished data from investigator groups. Studies were included if they reported original data on stillbirths (predominantly ≥28 weeks' gestation or ≥1000 g, with GBS isolated from a sterile site) as a percentage of total stillbirths. We did meta-analyses to derive pooled estimates of the percentage of GBS-associated stillbirths, regionally and worldwide for recent datasets.

Results

We included 14 studies from any period, 5 with recent data (after 2000). There were no data from Asia. We estimated that 1% (95% confidence interval [CI], 0–2%) of all stillbirths in developed countries and 4% (95% CI, 2%–6%) in Africa were associated with GBS.

Conclusions

GBS is likely an important cause of stillbirth, especially in Africa. However, data are limited in terms of geographic spread, with no data from Asia, and cases worldwide are probably underestimated due to incomplete case ascertainment. More data, using standardized, systematic methods, are critical, particularly from low- and middle-income contexts where the highest burden of stillbirths occurs. These data are essential to inform interventions, such as maternal GBS vaccination.

Maternal Colonization With Group B Streptococcus and Serotype Distribution Worldwide: Systematic Review and Meta-analyses

Abstract

Background

Maternal rectovaginal colonization with group B Streptococcus (GBS) is the most common pathway for GBS disease in mother, fetus, and newborn. This article, the second in a series estimating the burden of GBS, aims to determine the prevalence and serotype distribution of GBS colonizing pregnant women worldwide.

Methods

We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus), organized Chinese language searches, and sought unpublished data from investigator groups. We applied broad inclusion criteria to maximize data inputs, particularly from low- and middle-income contexts, and then applied new meta-analyses to adjust for studies with less-sensitive sampling and laboratory techniques. We undertook meta-analyses to derive pooled estimates of maternal GBS colonization prevalence at national and regional levels.

Results

The dataset regarding colonization included 390 articles, 85 countries, and a total of 299924 pregnant women. Our adjusted estimate for maternal GBS colonization worldwide was 18% (95% confidence interval [CI], 17%–19%), with regional variation (11%–35%), and lower prevalence in Southern Asia (12.5% [95% CI, 10%–15%]) and Eastern Asia (11% [95% CI, 10%–12%]). Bacterial serotypes I–V account for 98% of identified colonizing GBS isolates worldwide. Serotype III, associated with invasive disease, accounts for 25% (95% CI, 23%–28%), but is less frequent in some South American and Asian countries. Serotypes VI–IX are more common in Asia.

Conclusions

GBS colonizes pregnant women worldwide, but prevalence and serotype distribution vary, even after adjusting for laboratory methods. Lower GBS maternal colonization prevalence, with less serotype III, may help to explain lower GBS disease incidence in regions such as Asia. High prevalence worldwide, and more serotype data, are relevant to prevention efforts.

Preterm Birth Associated With Group B Streptococcus Maternal Colonization Worldwide: Systematic Review and Meta-analyses

Abstract

Background

Preterm birth complications are the leading cause of deaths among children <5 years of age. Studies have suggested that group B Streptococcus (GBS) maternal rectovaginal colonization during pregnancy may be a risk factor for preterm delivery. This article is the fifth of 11 in a series. We aimed to assess the association between GBS maternal colonization and preterm birth in order to inform estimates of the burden of GBS.

Methods

We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data from investigator groups on the association of preterm birth (<37 weeks' gestation) and maternal GBS colonization (GBS isolation from vaginal, cervical, and/or rectal swabs; with separate subanalysis on GBS bacteriuria). We did meta-analyses to derive pooled estimates of the risk and odds ratios (according to study design), with sensitivity analyses to investigate potential biases.

Results

We identified 45 studies for inclusion. We estimated the risk ratio (RR) for preterm birth with maternal GBS colonization to be 1.21 (95% confidence interval [CI], .99–1.48; P = .061) in cohort and cross-sectional studies, and the odds ratio to be 1.85 (95% CI, 1.24–2.77; P = .003) in case-control studies. Preterm birth was associated with GBS bacteriuria in cohort studies (RR, 1.98 [95% CI, 1.45–2.69]; P < .001).

Conclusions

From this review, there is evidence to suggest that preterm birth is associated with maternal GBS colonization, especially where there is evidence of ascending infection (bacteriuria). Several biases reduce the chance of detecting an effect. Equally, however, results, including evidence for the association, may be due to confounding, which is rarely addressed in studies. Assessment of any effect on preterm delivery should be included in future maternal GBS vaccine trials.

Neonatal Encephalopathy With Group B Streptococcal Disease Worldwide: Systematic Review, Investigator Group Datasets, and Meta-analysis

Abstract

Background

Neonatal encephalopathy (NE) is a leading cause of child mortality and longer-term impairment. Infection can sensitize the newborn brain to injury; however, the role of group B streptococcal (GBS) disease has not been reviewed. This paper is the ninth in an 11-article series estimating the burden of GBS disease; here we aim to assess the proportion of GBS in NE cases.

Methods

We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data from investigator groups reporting GBS-associated NE. Meta-analyses estimated the proportion of GBS disease in NE and mortality risk. UK population-level data estimated the incidence of GBS-associated NE.

Results

Four published and 25 unpublished datasets were identified from 13 countries (N = 10436). The proportion of NE associated with GBS was 0.58% (95% confidence interval [CI], 0.18%–.98%). Mortality was significantly increased in GBS-associated NE vs NE alone (risk ratio, 2.07 [95% CI, 1.47–2.91]). This equates to a UK incidence of GBS-associated NE of 0.019 per 1000 live births.

Conclusions

The consistent increased proportion of GBS disease in NE and significant increased risk of mortality provides evidence that GBS infection contributes to NE. Increased information regarding this and other organisms is important to inform interventions, especially in low- and middle-resource contexts.

Intrapartum Antibiotic Chemoprophylaxis Policies for the Prevention of Group B Streptococcal Disease Worldwide: Systematic Review

Abstract

Background

Intrapartum antibiotic chemoprophylaxis (IAP) prevents most early-onset group B streptococcal (GBS) disease. However, there is no description of how IAP is used around the world. This article is the sixth in a series estimating the burden of GBS disease. Here we aimed to review GBS screening policies and IAP implementation worldwide.

Methods

We identified data through (1) systematic literature reviews (PubMed/Medline, Embase, Literature in the Health Sciences in Latin America and the Caribbean [LILACS], World Health Organization library database [WHOLIS], and Scopus) and unpublished data from professional societies and (2) an online survey and searches of policies from medical societies and professionals. We included data on whether an IAP policy was in use, and if so whether it was based on microbiological or clinical risk factors and how these were applied, as well as the estimated coverage (percentage of women receiving IAP where indicated).

Results

We received policy information from 95 of 195 (49%) countries. Of these, 60 of 95 (63%) had an IAP policy; 35 of 60 (58%) used microbiological screening, 25 of 60 (42%) used clinical risk factors. Two of 15 (13%) low-income, 4 of 16 (25%) lower-middle–income, 14 of 20 (70%) upper-middle–income, and 40 of 44 (91%) high-income countries had any IAP policy. The remaining 35 of 95 (37%) had no national policy (25/33 from low-income and lower-middle–income countries). Coverage varied considerably; for microbiological screening, median coverage was 80% (range, 20%–95%); for clinical risk factor–based screening, coverage was 29% (range, 10%–50%). Although there were differences in the microbiological screening methods employed, the individual clinical risk factors used were similar.

Conclusions

There is considerable heterogeneity in IAP screening policies and coverage worldwide. Alternative global strategies, such as maternal vaccination, are needed to enhance the scope of global prevention of GBS disease.

Estimates of the Burden of Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children

Abstract

Background

We aimed to provide the first comprehensive estimates of the burden of group B Streptococcus (GBS), including invasive disease in pregnant and postpartum women, fetal infection/stillbirth, and infants. Intrapartum antibiotic prophylaxis is the current mainstay of prevention, reducing early-onset infant disease in high-income contexts. Maternal GBS vaccines are in development.

Methods

For 2015 live births, we used a compartmental model to estimate (1) exposure to maternal GBS colonization, (2) cases of infant invasive GBS disease, (3) deaths, and (4) disabilities. We applied incidence or prevalence data to estimate cases of maternal and fetal infection/stillbirth, and infants with invasive GBS disease presenting with neonatal encephalopathy. We applied risk ratios to estimate numbers of preterm births attributable to GBS. Uncertainty was also estimated.

Results

Worldwide in 2015, we estimated 205000 (uncertainty range [UR], 101000–327000) infants with early-onset disease and 114000 (UR, 44000–326000) with late-onset disease, of whom a minimum of 7000 (UR, 0–19000) presented with neonatal encephalopathy. There were 90000 (UR, 36000–169000) deaths in infants <3 months age, and, at least 10000 (UR, 3000–27000) children with disability each year. There were 33000 (UR, 13000–52000) cases of invasive GBS disease in pregnant or postpartum women, and 57000 (UR, 12000–104000) fetal infections/stillbirths. Up to 3.5 million preterm births may be attributable to GBS. Africa accounted for 54% of estimated cases and 65% of all fetal/infant deaths. A maternal vaccine with 80% efficacy and 90% coverage could prevent 107000 (UR, 20000–198000) stillbirths and infant deaths.

Conclusions

Our conservative estimates suggest that GBS is a leading contributor to adverse maternal and newborn outcomes, with at least 409000 (UR, 144000–573000) maternal/fetal/infant cases and 147000 (UR, 47000–273000) stillbirths and infant deaths annually. An effective GBS vaccine could reduce disease in the mother, the fetus, and the infant.

Risk of Early-Onset Neonatal Group B Streptococcal Disease With Maternal Colonization Worldwide: Systematic Review and Meta-analyses

Abstract

Background

Early-onset group B streptococcal disease (EOGBS) occurs in neonates (days 0–6) born to pregnant women who are rectovaginally colonized with group B Streptococcus (GBS), but the risk of EOGBS from vertical transmission has not been systematically reviewed. This article, the seventh in a series on the burden of GBS disease, aims to estimate this risk and how it varies with coverage of intrapartum antibiotic prophylaxis (IAP), used to reduce the incidence of EOGBS.

Methods

We conducted systematic reviews (Pubmed/Medline, Embase, Latin American and Caribbean Health Sciences Literature (LILACS), World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data from investigator groups on maternal GBS colonization and neonatal outcomes. We included articles with ≥200 GBS colonized pregnant women that reported IAP coverage. We did meta-analyses to determine pooled estimates of risk of EOGBS, and examined the association in risk of EOGBS with IAP coverage.

Results

We identified 30 articles including 20328 GBS-colonized pregnant women for inclusion. The risk of EOGBS in settings without an IAP policy was 1.1% (95% confidence interval [CI], .6%–1.5%). As IAP increased, the risk of EOGBS decreased, with a linear association. Based on linear regression, the risk of EOGBS in settings with 80% IAP coverage was predicted to be 0.3% (95% CI, 0–.9).

Conclusions

The risk of EOGBS among GBS-colonized pregnant women, from this first systematic review, is consistent with previous estimates from single studies (1%–2%). Increasing IAP coverage was linearly associated with decreased risk of EOGBS disease.

Cover

Trust and Justice in Big Data Analytics: Bringing the Philosophical Literature on Trust to Bear on the Ethics of Consent

Abstract

Much bioethical literature and policy guidances for big data analytics in biomedical research emphasize the importance of trust. It is essential that potential participants trust so they will allow their data to be used to further research. However, comparatively, little guidance is offered as to what trustworthy oversight mechanisms are, or how policy should support them, as data are collected, shared, and used. Generally, "trust" is not characterized well enough, or meaningfully enough, for the term to be systematically applied in policy development. Yet points made in the philosophical literature on trust can help. They allow us, not only to better distinguish the different ways the term "trust" may be interpreted, but also to better determine how different approaches to trust can align with policy and governance—in what ways they may relate to key bioethical concepts and related laws, and in what ways they can help to balance individual and group interests in data sharing. This article draws from the philosophical literature on trust to identify a relationship among consent, trust, and justice. Specifically, parallels are drawn between "character-trustworthiness" and "natural justice," a set of widely held legal safeguards intended to ensure decision-makers follow a pattern of procedural fairness which protects the rights of the individual and thereby maintains public confidence in the decision-making process. Relevance to traditional bioethical principles, established laws, and consent procedures are addressed throughout. In conclusion, policy actions are suggested.

The crop-residue of fiber hemp cv. Futura 75: from a waste product to a source of botanical insecticides

Abstract

In the attempt to exploit the potential of the monoecious fiber hemp cv. Futura 75 in new fields besides textile, cosmetics and food industry, its crop-residue given by leaves and inflorescences was subjected to hydrodistillation to obtain the essential oils. These are niche products representing an ideal candidate for the development of natural insecticides for the control and management of mosquito vectors, houseflies and moth pests. After GC-MS analysis highlighting a safe and legal chemical profile (THC in the range 0.004–0.012% dw), the leaf and inflorescence essential oils were investigated for the insecticidal potential against three insect targets: the larvae of Culex quinquefasciatus and Spodoptera littoralis and the adults of Musca domestica. The essential oil from inflorescences, showing (E)-caryophyllene (21.4%), myrcene (11.3%), cannabidiol (CBD, 11.1%), α-pinene (7.8%), terpinolene (7.6%), and α-humulene (7.1%) as the main components, was more effective than leaf oil against these insects, with LD₅₀ values of 65.8 μg/larva on S. littoralis, 122.1 μg/adult on M. domestica, and LC₅₀ of 124.5 μl/l on C. quinquefasciatus larvae. The hemp essential oil moderately inhibited the acetylcholinesterase (AChE), which is a target enzyme in pesticide science. Overall, these results shed light on the future application of fiber hemp crop-residue for the development of effective, eco-friendly and sustainable insecticides.

Sustainable bioreduction of toxic levels of chromate in a denitrifying granular sludge reactor

Abstract

Biological removal of chromate [Cr(VI)] in the presence or absence of nitrate by granular sludge biofilms was investigated in batch experiments and in a sequencing batch reactor (SBR). Denitrifying granular sludge cultivated from activated sludge was able to directly reduce Cr(VI) in the presence of an electron donor. Bioreduction was dependent on the initial Cr(VI) and the granular sludge concentrations. Bioreduction of Cr(VI) was followed by Cr(III) precipitation or entrapment in the granular sludge which was corroborated with decrease in total soluble Cr and increase in inorganic content of biomass. Batch experiments revealed that Cr(VI) addition has no major influence on high-strength nitrate (3000 mg L⁻¹) denitrification, but nitrite denitrification was slowed-down. However, SBR experiment demonstrated successful denitrification as well as Cr(VI) removal due to enrichment of Cr(VI)-tolerant denitrifying bacteria. In fact, stable SBR performance in terms of complete and sustained removal of 0.05, 0.1, 0.2, 0.3, 0.5 and 0.75 mM Cr(VI) and denitrification of 3000 mg L⁻¹ was observed during 2 months of operation. Active biomass and electron donor-dependent Cr(VI) removal, detection of Cr(III) in the biomass and recovery of ~ 92% of the Cr from the granular sludge biofilms confirms bioreduction followed by precipitation or entrapment of Cr(III) as the principal chromate removal mechanism. Metagenomic bacterial community analysis showed enrichment of Halomonas sp. in denitrifying granular sludge performing either denitrification or simultaneous reduction of nitrate and chromate.

Issue Information

Traitement du lupus érythémateux par le bélimumab en pratique courante : étude rétrospective de 15 malades

Publication date: Available online 4 November 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): E. Garval, J.-L. Pennaforte, R. Jaussaud, A. Servettaz, P. Bernard, Z. Reguiai
IntroductionLe bélimumab (anticorps monoclonal anti-BLyS) a été récemment commercialisé dans le traitement du lupus érythémateux (LE) systémique. Le but de cette étude était d'en décrire l'efficacité, la tolérance, l'impact sur les paramètres sérologiques du LE et le rôle d'épargne des traitements de fond en pratique courante.Malades et méthodesCette étude rétrospective menée au CHU de Reims incluait tous les malades atteints de LE traités par bélimumab entre 2012 et 2016. L'efficacité du traitement était évaluée sur l'évolution clinique, la normalisation des concentrations d'anticorps anti-DNA et de complément, et l'épargne des autres traitements du LE.RésultatsUne réponse thérapeutique était obtenue chez 9 des 15 malades inclus (60 %), à type de rémission partielle pour 8 d'entre eux. La concentration médiane d'anti-DNA était de 50UI/mL (4 à 50) et celle de C3 sérique de 0,82g/L (0,36 à 1,23) à l'instauration du bélimumab, versus respectivement 25,5UI/mL (2 à 50) et 0,89g/L (0,34 à 1,22) à la date des dernières nouvelles (DDN), sans modification significative (respectivement p=0,12 et p=0,45). La posologie médiane de prednisone à l'instauration du bélimumab passait de 9,5mg/j (0 à 18) à 6mg/j (0 à 20) à la DDN. Huit malades (53 %) ont présenté des effets secondaires, toujours minimes.ConclusionLe bélimumab a eu chez 15 malades une efficacité modérée et une faible toxicité ; il a permis une épargne cortisonique modérée, en vue de limiter les effets secondaires de la corticothérapie au long cours.BackgroundBelimumab (an anti-BLyS monoclonal antibody) was recently approved for the treatment of systemic lupus erythematosus (SLE). The aim of the study was to describe efficacy and safety of the drug as well as its impact on serologic parameters and the role of long-term systemic sparing of treatment in clinical practice in LE.Patients and methodsWe conducted a retrospective study at Reims University Hospital between 2012 and 2016 including consecutive patients with LE treated with belimumab. Efficacy was evaluated in terms of clinical progression, and normalisation of laboratory factors (anti-DNA antibody and C3 serum levels) and sparing of associated long-term systemic therapies for LE.ResultsAmong the 15 patients included, a therapeutic response was obtained in 9 patients (60%), with partial remission in 8 of 9 cases. The median titre of anti-DNA antibody was 50IU/mL (range: 4–50) and the median C3 level was 0.82g/L (range: 0.36–1.23) before initiation of belimumab, vs. 25.5IU/mL (range: 2–50) and 0.89g/L (range: 0.34–1.22) at the last evaluation, respectively, without significant modification (P=0.12 and P=0.45). The median dose of prednisone at the time of the first belimumab infusion was reduced from 9.5mg/day (range: 0–18) to 6mg/day (range: 0–20) at the last clinical evaluation. Eight patients (53%) experienced adverse events, and these were very slight or moderate in all cases.ConclusionBelimumab appears to be an effective and well-tolerated treatment for moderately severe systemic LE, allowing sparing of maintenance corticosteroid therapy in order to decrease its frequent adverse events.

inside front cover (Editorial Board)

Publication date: December 2017
Source:Journal of Photochemistry and Photobiology B: Biology, Volume 177

Texture-specific bag of visual words model and spatial cone matching-based method for the retrieval of focal liver lesions using multiphase contrast-enhanced CT images

Abstract

Purpose

The bag of visual words (BoVW) model is a powerful tool for feature representation that can integrate various handcrafted features like intensity, texture, and spatial information. In this paper, we propose a novel BoVW-based method that incorporates texture and spatial information for the content-based image retrieval to assist radiologists in clinical diagnosis.

Methods

This paper presents a texture-specific BoVW method to represent focal liver lesions (FLLs). Pixels in the region of interest (ROI) are classified into nine texture categories using the rotation-invariant uniform local binary pattern method. The BoVW-based features are calculated for each texture category. In addition, a spatial cone matching (SCM)-based representation strategy is proposed to describe the spatial information of the visual words in the ROI. In a pilot study, eight radiologists with different clinical experience performed diagnoses for 20 cases with and without the top six retrieved results. A total of 132 multiphase computed tomography volumes including five pathological types were collected.

Results

The texture-specific BoVW was compared to other BoVW-based methods using the constructed dataset of FLLs. The results show that our proposed model outperforms the other three BoVW methods in discriminating different lesions. The SCM method, which adds spatial information to the orderless BoVW model, impacted the retrieval performance. In the pilot trial, the average diagnosis accuracy of the radiologists was improved from 66 to 80% using the retrieval system.

Conclusion

The preliminary results indicate that the texture-specific features and the SCM-based BoVW features can effectively characterize various liver lesions. The retrieval system has the potential to improve the diagnostic accuracy and the confidence of the radiologists.

Evaluation of the quality and quantity of compost and leachate from household waterless toilets in France

Abstract

One of the most undesired wastes is the human excreta due to the socio-environmental pressure. Otherwise, the nutriments contained in human excreta could be used as fertilizers to enrich the soil. Familial waterless litter composting toilets (FWLCT) are an alternative for locations where a centralized sewerage network cannot be provided or where there is a lack of standard urban infrastructure including roads, electricity, and water supply. The scientific researches on the composting techniques, the methods of control of the composting processors, and the rate of produced leachate are very limited. In this research, the composting systems included a feces and urine collection device. In each passage, the litter (carbonaceous material) is added to the excreta. Regularly, the buckets were emptied into a composting device located outside the house to which an additional portion of carbonaceous materials can be added. Monitoring was carried out on five rural and one urban familial composting areas in France for 1.5 years. The physiochemical and microbiological properties of the compost and leachate have been monitored and measured in compliance with the protocols. The results show that one of the main problems of this system of human excreta treatment is that the composting process does not achieve a significant rise in temperature and does not allow reaching the optimum temperatures (> 50 °C). Otherwise, from an agronomic point of view, the obtained compost is not rich enough in nutriments to be a good compost as soil fertilizer. But it can be used as a soil conditioner. The average leachate flux from the composters is 1.79 L/day. Because of the very short stay time in the piles, the leachate is contaminated by harmful bacteria and should be treated by another sanitation system.

Is there any association between urinary metabolites of polycyclic aromatic hydrocarbons and thyroid hormone levels in children and adolescents?

Abstract

Considering the possible effects of polycyclic aromatic hydrocarbons (PAHs) on thyroid function, the current study aims to investigate the association of PAH urinary metabolites with the level of thyroid hormones in a sample of Iranian children and adolescents. This cross-sectional study was conducted from September 2015 to July 2016 in Isfahan, Iran. Participants were 150 students, aged 6–18 years, who were selected by multistage cluster random sampling from schools of Isfahan province. Blood and urine samples of participants were obtained for measurement of thyroid hormone levels (measured by immunoradiometric assay) and PAH urinary metabolites, including 1-hydroxynaphthalene, 2-hydroxynaphthalene, 9-hydroxyphenanthrene, and 1-hydroxypyrene. The association of serum thyroid-stimulating hormone (TSH) and PAH urinary metabolites was determined by correlation and regression analyses. Multivariate regression analysis revealed significant association between serum TSH and PAH urinary metabolites; this association remained significant after adjustment for gender and age. The corresponding figures were r = 0.85 for 1-naphthol, r = 0.86 for 2-naphthol, r = 0.87 for 1-hydroxypyrene, and r = 0.42 for 9-phenantrol, respectively, all p values < 0.001. The mean levels of 1-hydroxypyrene and 9-phenanthrol were higher in boys than those in girls (p < 0.05). The findings of this study indicated significant positive association between urinary PAH biomarkers and the TSH level in children and adolescents. It can be suggested that long-term exposure to PAHs might result in thyroid function impairment. The clinical implication of the current findings should be confirmed by future longitudinal studies.

An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 1: new molecules, metabolism, fate, and transport

Abstract

With the exponential number of published data on neonicotinoids and fipronil during the last decade, an updated review of literature has been conducted in three parts. The present part focuses on gaps of knowledge that have been addressed after publication of the Worldwide Integrated Assessment (WIA) on systemic insecticides in 2015. More specifically, new data on the mode of action and metabolism of neonicotinoids and fipronil, and their toxicity to invertebrates and vertebrates, were obtained. We included the newly detected synergistic effects and/or interactions of these systemic insecticides with other insecticides, fungicides, herbicides, adjuvants, honeybee viruses, and parasites of honeybees. New studies have also investigated the contamination of all environmental compartments (air and dust, soil, water, sediments, and plants) as well as bees and apicultural products, food and beverages, and the exposure of invertebrates and vertebrates to such contaminants. Finally, we review new publications on remediation of neonicotinoids and fipronil, especially in water systems. Conclusions of the previous WIA in 2015 are reinforced; neonicotinoids and fipronil represent a major threat worldwide for biodiversity, ecosystems, and all the services the latter provide.

Modifications in the structure of the lichen Cladonia thallus in the aftermath of habitat contamination and implications for its heavy-metal accumulation capacity

Abstract

Phenotypic traits of lichens can be greatly modified by environmental factors. Granulose thalli on soil and podetia, densely covered with granules, referring to common and widespread lichen Cladonia cervicornis subsp. verticillata were found near zinc smelter. The granules are stratified, filled with fungal medulla and heavily encrusted with calcium oxalate weddellite crystals, not observed on regularly developed thalli of the species. Phylogenetic analysis revealed that deformed granulose forms belong to this taxon, showing that the phenotypic plasticity of the lichens of Cladonia can lead to the emergence of features that do not coincide with the taxonomic definition of the species. The heavy-metal accumulation capacity of both granulose and regular form of primary and secondary lichen thallus, in relation to the element content in corresponding substrate, was determined. Granulose-modified thalli accumulate greater amounts of heavy metals than regular ones, meaning that the bioaccumulation property of a given species may be greatly affected by morphological modifications. The granulose forms are also characterised by considerably higher ratios of Cd, Pb and As concentrations in lichen samples in relation to the corresponding substrates than regular ones. This means that collection of variously formed thalli should be avoided in biomonitoring sampling procedures. The results indicate that a substantial part of the element load, in particular zinc, in the examined lichen thalli collected near the smelter originates from atmospheric fallout.

Enhanced bioreduction of nitrobenzene by reduced graphene oxide materials: effects of surface modification and coexisting soluble electron shuttles

Abstract

Reduced graphene oxide (rGO) can enhance the bioreduction of nitrobenzene by Shewanella oneidensis MR-1. The effects of surface modification and coexisting soluble electron shuttles on rGO-enhanced bioreduction of nitrobenzene were investigated here. The results showed that rGO enhanced the secretion of extracellular polymeric substance and the bioreduction of nitrobenzene of several folds. No inhibition effect on nitrobenzene bioreduction was observed even when the concentration of rGO was as high as 200 mg/L. The surface modification of rGO might affect the electrical conductivity which was assumed as one of the main factors that contributed to the enhancement of nitrobenzene bioreduction by rGO materials. Moreover, the coexisting electron shuttles further enhanced the rGO-mediated nitrobenzene bioreduction. After the simultaneous addition of flavin mononucleotide (10 μM) and rGO (50 mg/L), the reduction rate increased 7.8 times to 424.98 ± 7.84 mg (nitrobenzene)/(g (dry cell)∙h), which was higher than those ever reported.

A case of dystrophic calcification in the masseter muscle

Abstract

Background

Dystrophic calcification can occur in any soft tissue with the absence of a systemic mineral imbalance and is often associated with trauma, infection, or inflammation. It is easily found in the site of the heart and skeletal muscles and rarely appears in the head and neck area.

Case report

We present a rare case of multiple calcified masses in the left masseter muscle of a 26-year-old female with a history of trauma in the area. In computed tomography, multiple radiopaque masses were observed inside the left masseter muscle and blood test results were normal. The calcified masses were diagnosed as dystrophic calcification and removed by surgery without any complications.

Conclusion

Different types of calcifications may occur in the cheek area, and they need to be distinguished from dystrophic calcification. Thorough clinical examination and history taking is required together with blood testing and radiographic examinations.