bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer survivors and adverse work outcomes: associated factors and supportive interventions
Authors: de Boer Angela G E M , de Wind Astrid , Coenen Pieter , van Ommen Fenna , Greidanus Michiel A , Zegers Amber D , Duijts Saskia F A , Tamminga Sietske J
Published: November 2022

Introduction

The number of cancer survivors in a working age is rising. An awareness of factors associated with adverse work outcomes, and of supportive interventions, is needed.

Sources of data

A narrative review of research obtained via several databases, including Medline and PsycINFO, was conducted.

Areas of agreement

A range of factors is associated with adverse work outcomes such as prolonged sick leave, delayed return to work, disability pension and unemployment in cancer survivors. They include the cancer type and treatment, fatigue, cognitive functioning, work factors and elements of health care systems. Effective supportive interventions encompass physical and multicomponent interventions.

Areas of controversy

The role of behaviour determinants and legislative and insurance systems is unclear. It is furthermore uncertain what the optimal timing of delivering supportive interventions is.

Growing points

Further focus on vulnerable groups, including specific cancer types and those with lower income, lower educational level and in precarious employment, is needed.

Areas timely for developing research

Recent developments are tailored and timely interventions.
Management of Drug-Drug Interactions Between Long-Acting Cabotegravir and Rilpivirine and Comedications With Inducing Properties: A Modeling Study
Authors: Bettonte Sara , Berton Mattia , Stader Felix , Battegay Manuel , Marzolini Catia
Published: November 2022

Background

Long-acting (LA) intramuscular cabotegravir and rilpivirine are prone to drug-drug interactions (DDI). However, given the long dosing interval, the conduct of clinical DDIs studies with LA antiretrovirals is challenging. We performed virtual clinical DDI studies using physiologically based pharmacokinetic (PBPK) modeling to provide recommendations for the management of DDIs with strong or moderate inducers such as rifampicin or rifabutin.

Methods

Each DDI scenario included a cohort of virtual individuals (50% female) between 20 and 50 years of age with a body mass index of 18–30 kg/m2. Cabotegravir and rilpivirine were given alone and in combination with rifampicin or rifabutin. The predictive performance of the PBPK model to simulate cabotegravir and rilpivirine pharmacokinetics after oral and intramuscular administration and to reproduce DDIs with rifampicin and rifabutin was first verified against available observed clinical data. The verified model was subsequently used to simulate unstudied DDI scenarios.

Results

At steady state, the strong inducer rifampicin was predicted to decrease the area under the curve (AUC) of LA cabotegravir by 61% and rilpivirine by 38%. An increase in the dosing frequency did not overcome the DDI with rifampicin. The moderate inducer rifabutin was predicted to reduce the AUC of LA cabotegravir by 16% and rilpivirine by 18%. The DDI with rifabutin can be overcome by administering LA cabotegravir/rilpivirine monthly together with a daily oral rilpivirine dose of 25 mg.

Conclusions

LA cabotegravir/rilpivirine should be avoided with strong inducers but coadministration with moderate inducers is possible by adding oral rilpivirine daily dosing to the monthly injection.
Setting your clock: associations between timing of objective physical activity and cardiovascular disease risk in the general population
Authors: Albalak Gali , Stijntjes Marjon , van Bodegom David , Jukema J Wouter , Atsma Douwe E , van Heemst Diana , Noordam Raymond
Published: November 2022

Aims

Little is known about the impact of daily physical activity timing (here referred to as ‘chronoactivity’) on cardiovascular disease (CVD) risk. We aimed to examined the associations between chronoactivity and multiple CVD outcomes in the UK Biobank.

Methods and results

physical activity data were collected in the UK-Biobank through triaxial accelerometer over a 7-day measurement period. We used K-means clustering to create clusters of participants with similar chronoactivity irrespective of the mean daily intensity of the physical activity. Multivariable-adjusted Cox-proportional hazard models were used to estimate hazard ratios (HRs) comparing the different clusters adjusted for age and sex (model 1), and baseline cardiovascular risk factors (model 2). Additional stratified analyses were done by sex, mean activity level, and self-reported sleep chronotype. We included 86 657 individuals (58% female, mean age: 61.6 [SD: 7.8] years, mean BMI: 26.6 [4.5] kg/m2). Over a follow-up period of 6 years, 3707 incident CVD events were reported. Overall, participants with a tendency of late morning physical activity had a lower risk of incident coronary artery disease (HR: 0.84, 95%CI: 0.77, 0.92) and stroke (HR: 0.83, 95%CI: 0.70, 0.98) compared to participants with a midday pattern of physical activity. These effects were more pronounced in women (P-value for interaction = 0.001). We did not find evidence favouring effect modification by total activity level and sleep chronotype.

Conclusion

Irrespective of total physical activity, morning physical activity was associated with lower risks of incident cardiovascular diseases, highlighting the potential importance of chronoactivity in CVD prevention.
Is rare cancer care organized at national health system level? Multiple case study in six EU countries
Authors: Prades Joan , Trama Annalisa , Casali Paolo G , Emile Jean-Francois , Gaspar Nathalie , Janavicius Ramunas , Jančiauskienė Rasa , Karjalainen Sakari , Kopeckova Katerina , Pylkkänen Liisa , Svoboda Marek , Borras Josep M
Published: November 2022

Background

As a system of European Reference Networks (ERNs) emerges, the differences in quality of care for patients with rare cancers may increase at national level. We aimed to elucidate the processes and healthcare planning principles through which the reference centres (RCs) for rare cancers are embedded in national health systems.

Methods

We used a multiple case-study design based on the experiences of Czechia, Finland, France, Italy, Lithuania and Spain. Using sarcoma as an example of rare cancer, 52 semi-structured interviews were conducted during on-site visits, including a multidisciplinary group of professionals, Ministry of Health professionals, patient representatives and European policymakers.

Results

The comparative analysis showed substantial heterogeneity in the processes for formalizing RCs’ status and in their levels of integration in the different health systems, but two models (centre-based and the network-based) can be envisaged at national level. RCs for rare cancers were legally established only in France and Spain. Expert clinicians cooperate in a structured way, using network mechanisms, in France and Italy, and these countries, plus Finland and Lithuania, had a referral system to facilitate patients’ access from non-expert centres to RCs. Seven key healthcare planning principles in instituting RCs at the national level were identified.

Conclusions

The conditions governing patient access to treatment centres—whether RCs or not—are decided at the national level. It is advisable to progressively align the European and national levels so that the RCs that participate in the ERNs also play a significant role at the national level.
Differentiation of qualified tea beverages from spoiled ones by the LC-MS–based analysis of their polycarboxylic acids
Authors: Kang Yuting , Li Chenghua , Li Huiru , Li Jing , Jiang Kezhi
Published: November 2022

Polycarboxylic acids (PACs) are important metabolic products in almost all living bodies, yet current analytical methods for detection of PACs in tea beverages are still unsatisfactory due to the complex matrix and physicochemical properties of PACs. In this work, a rapid method was developed for the simultaneous determination of 7 PACs, including tartaric acid, α-ketoglutaric acid, malic acid, malonic acid, cis-aconitic acid, succinic acid, and fumaric acid, in beverages, based on selective removal of the matrix in combination with liquid chromatography–mass spectrometry (LC-MS) analysis. By stirring with activated carbon and the Na2CO3 solution, the matrix in beverages was selectively removed, and PACs were almost retained in the supernatant of diluted Na2CO3 solution. Under optimized parameters, the limit of quantitation for the PACs was in the range of 1–50 ng/mL, and the content of the PACs in 8 beverages was determined with the recovery range of 72.2%–122.5%. The contents of malic acid, malonic acid, and succinic acid in tea beverages were found to be greater than those in non-tea beverages. Moreover, the concentration of these PACs in beverages was found to be multiplied many times in their deterioration period, especially for fumaric acid and α-ketoglutaric acid. These results indicated that PACs can be selected as a criterion to differentiate qualified tea beverages from spoiled beverages.
Effects of a Saccharomyces cerevisiae fermentation product-supplemented diet on fecal characteristics, oxidative stress, and blood gene expression of adult dogs undergoing transport stress
Authors: Wilson Sofia M , Oba Patricia M , Applegate Catherine C , Koziol Samantha A , Panasevich Matthew R , Norton Sharon A , Swanson Kelly S
Published: November 2022

Previously, a Saccharomyces cerevisiae fermentation product (SCFP) was shown to positively alter fecal microbiota, fecal metabolites, oxidative stress, and circulating immune cell function of adult dogs. The objective of this study was to measure the effects of SCFP on fecal characteristics, serum oxidative stress biomarkers, and whole blood gene expression of dogs undergoing transport stress. Sixteen adult pointer dogs [8M, 8F; mean age = 6.7 ± 2.1 yr; mean body weight (BW) = 25.5 ± 3.9 kg] were used in a randomized crossover design study. All dogs were fed a control diet for 4 wk, then randomly assigned to a control or SCFP-supplemented diet (formulated to include approximately 0.13% of the active SCFP ingredient) and fed to maintain BW for 11 wk. A 6-wk washout preceded the second 11-wk experimental period with dogs receiving opposite treatments. After 11 wk, fresh fecal and blood samples were collected before and after transport in a van for 45 min. Change from baseline data (i.e., before and after transport) were analyzed using the Mixed Models procedure of SAS 9.4, with P < 0.05 being significant and P < 0.10 being trends. Change in serum malondialdehyde concentrations increased (P < 0.05) and serum 8-isoprostane concentrations tended to increase (P < 0.10) in dogs fed SCFP, but decreased (P < 0.05) in control dogs after transport. Other serum markers were unaffected by diet during transport stress. Fecal dry matter percentage tended to be affected (P < 0.10) by diet during transport stress, being reduced in control dogs, but stable in dogs fed SCFP. Other fecal characteristics were unaffected by diet during transport stress. Genes associated with activation of innate immunity were impacted by diet in response to transport stress, with blood cyclooxygenase-2 and malondialdehyde mRNA expression being increased (P < 0.05) in control dogs, but stable or decreased in dogs fed SCFP. Expression of other genes was unaffected by diet during transport stress. These data suggest that the benefits of feeding a SCFP during transport stress may be mediated through suppression of innate immune cell activation.
Geographical Variation of Cuticular Hydrocarbon Profiles of Adult Flies and Empty Puparia Amongst Three Populations of Calliphora vicina (Diptera: Calliphoridae)
Authors: Kula Canan , Amendt Jens , Drijfhout Falko P , Moore Hannah E
Published: November 2022

Blowflies (Diptera: Calliphoridae) are of great importance in forensic entomology and in determining the minimum post-mortem interval, as they may be the first group of insects to colonize decomposing remains. Reliable species identification is an essential prerequisite. Classically, morphological characters or DNA sequences are used for this purpose. However, depending on the species and the condition of the specimen, this can be difficult, e.g., in the case of empty fly puparia. Recent studies have shown that cuticular hydrocarbon (CHC) profiles are species-specific in necrophagous taxa and represent another promising tool for identification. However, the population-specific variability of these substances as a function of e.g., local climatic parameters has not yet been sufficiently investigated. The aim of this study was to determine the geographical variation of CHC profiles of the blowfly Calliphora vicina (Robineau-Desvoidy, 1830) depending on different countries of origin. Flies were reared in the United Kingdom, Germany, and Turkey in common garden experiments under ambient conditions. CHC profiles of the resulting adult flies and their empty puparia were analyzed using gas chromatography-mass spectrometry. Data were visualized by principal component analysis and clustered by population. The populations of the United Kingdom and Germany, both having similar climates and being geographically close to each other, showed greater similarities in CHC profiles. However, the CHC profile of the Turkish population, whose climate is significantly different from the other two populations, was very different. Our study confirms the high potential of CHC analysis in forensic entomology but highlights the need to investigate geographical variability in chemical profiles.
Hydroxyapatite-binding Silver/Titanium Dioxide as a Potential Control Compound Against Mosquito Vectors, Aedes aegypti (Diptera: Culicidae) and Anopheles dirus (Diptera: Culicidae)
Authors: Srisawat Raweewan , Sriwichai Patchara , Ruangsittichai Jiraporn , Rotejanaprasert Chawarat , Imaizumi Naoko , Yamaki Dai , Maekawa Maki , Eshita Yuki , Okazaki Narumi
Published: November 2022

Controlling mosquitoes is vital for counteracting the rising number of mosquito-borne illnesses. Vector control requires the implementation of various measures; however, current methods lack complete effectiveness, and new control agents or substances are urgently needed. Therefore, this study developed a nonwoven fabric sheet coated with hydroxyapatite-binding silver/titanium dioxide compound (hydroxyapatite-binding silver/titanium dioxide sheet [HATS])and evaluated its effectiveness on all stages of laboratory Aedes aegypti (Linnaeus); Diptera: Culicidae and Anopheles dirus (Peyton & Harrison); Diptera: Culicidae. We reared larvae with HATS and control sheets and assessed their mortality, emergence, and hatching rates. The submersion rates of engorged female mosquitoes in submerged HATS and control sheets were also compared. The HATS strongly affected mosquito development, resulting in high mortality rates (mean ± SE) of 99.66 ± 0.58% (L1–L2) and 91.11 ± 9.20% (L3–L4) for Ae. aegypti and 100% of both stages for An. dirus. In contrast, mosquitoes raised in the control sheet showed relatively high survival rates of 92.33 ± 3.21% (L1–L2) and 95.67 ± 0.58% (L3–L4) for Ae. aegypti and 86.07 ± 3.53% (L1–L2) and 92.01 ± 8.67% (L3–L4) for An. dirus. Submersion of engorged females was found in the HATS oviposition cup, leading to a decreased number of eggs and a low hatching rate compared to that of the control. Overall, HATS may be a useful new control method for Ae. aegypti and An. dirus.
A case of occipital spindle cell lipoma: a case report
Authors: Tamamine Shunya , Himejima Tomoki , Mitsui Toshihito , Masuoka Hiromu , Hihara Masakatsu , Kakudo Natsuko
Published: November 2022

Spindle cell lipoma (SCL) is a subtype of lipoma first defined by Enzinger; it accounts for ~1.5% of all fatty tumors. Most cases occur in the posterior neck and shoulders of middle-aged men and rarely in women or the occiput. A 41-year-old woman presented to us with complaints of a mass on her left occiput which had slowly grown in size over six years. We excised the tumor, and pathological findings confirmed the diagnosis of SCL. There was no recurrence one year after the surgery.
ANGI-06. CRISPRI SCREEN USING 3D BIOMIMETICS TO IDENTIFY NOVEL MARKERS OF GLIOBLASTOMA INVASION
Authors: Jain Saket , Akins Erin , Garcia Joseph , Kumar Sanjay , Aghi Manish
Published: November 2022

Despite the aggressive treatment regimen, patients with GBM have a very poor prognosis, with a median survival of less than 2 years. The main reason behind this poor survival is the infiltration of tumor cells into the surrounding normal tissue. These infiltrative cells escape both surgical resection and radiation therapy, leading to inevitable tumor recurrence. Current approaches have failed to recognize that infiltrating GBM cells extending beyond the tumor edge have evolved a unique adaptive cellular machinery due to local stressors in their microenvironment. Unfortunately, these cells at the invasive tumor front are often not the ones sampled in studies analyzing banked tumor tissue, Second, most studies of invasion have used two-dimensional (2D) culture systems coated with a thin layer of extracellular matrix proteins, which fail to capture the dimensionality, mechanics, and heterogeneity of GBM invasion. We addressed these limitations by using an advanced CRISPRi druggable genome screen to identify novel druggable markers of GBM invasion in a 3D engineered biomimetic model comprised of Hyaluronic Acid (HA) based matrix. To better understand druggable pathways underlying GBM invasion, we performed a large-scale CRISPRi screen with a sgRNA library that targets the druggable human genome (2,550 genes). In the primary screen, sgRNAs targeting 12 genes were enriched in the non-invasive fraction. Out of these 12 genes, 8 genes are associated with cellular metabolism or chromosome assembly. We then validated these 8 genes using small molecule inhibitors in our 3D-gel sphere cultures, from which we identified four druggable targets, SOD-1 and NDUFV2 associated with mitochondrial metabolism and AURKB and ACP1 related to centromere assembly and chromosome segregation. In follow-up to these novel findings linking mitochondrial metabolism and centromere assembly to GBM invasion, our next steps are to identify the mechanism linking these genes to GBM cell invasion followed by validation in vivo.
ANGI-07. THE DUAL ROLE CD97 PLAYS IN GLIOBLASTOMA INVASION AND PROLIFERATION
Authors: Slepak Tania , Eichberg Daniel , Guyot Manuela , Walters Winston , Komotar Ricardo , Ivan Michael
Published: November 2022

INTRODUCTION

Increased levels of adhesion G Protein-Coupled Receptor(GPCR) CD97 have been detected in multiple metastatic cancers. Glioblastoma(GBM), also overexpress this receptor, and its levels positively correlate with more aggressive GBM invasion. Here, using primary human GBM cells we investigated the effects of CD97 knockdown and overexpression in-vitro and in-vivo.

METHODS

CD97 consists of two distinct domains: the large extracellular fragment interacting with ECM and other cell surface receptors and the GPCR core that activates heterotrimeric G Proteins G12/13. To investigate the mechanism of action of CD97, we generated a CD97 knockdown (shCD97) and overexpression (CD97-WT) constructs. Additionally, we generated two functional mutants: a constitutively active mutant lacking the N-Terminus (dNTF) and dominant-negative mutant (H436A) that cannot activate G-Proteins downstream. Glioma Stem Cells(GSC) were transduced by control and CD97 lentiviral constructs and implanted into mouse brains. Once tumors formed the brains were harvested, sliced, and immunostained to evaluate invasion and proliferation. Comparing mutants to control, dunnett’s multiple comparisons test was used for statistical analysis.

RESULTS

Similar to CD97-WT, we found that both dNTF and H436A, increase tumor volume(p< 0.05). In contrast, the shCD97 mutant decreased tumor size(p< 0.05). Interestingly, only dNTF significantly increased tumor cell proliferation(p< 0.005), yet CD97-WT and H436A affected proliferation of non-tumor cells in the tumor bulk, indicating that this process requires the N-Terminus Fragment. In addition, over-expression of CD97-WT dramatically increases tumor invasion along myelinated fibers of corpus collosum, and tumor spread in the brain tissue(p< 0.05). Yet, the H436A mutant produced large, compact, and non-invasive tumors with sharp borders(p< 0.05) indicating that cell migration requires activation of G12/13. Surprisingly, immunostaining revealed that CD97 knockdown cells displayed invasive phenotype.

CONCLUSIONS

Our results demonstrate the dual role CD97 plays in GBM invasion and proliferation, alluding to the molecular mechanisms that can potentially be targeted in GBM treatment.
ANGI-09. BEVACIZUMAB IN ATYPICAL AND ANAPLASTIC MENINGIOMAS: THE BEMEN STUDY
Authors: Cerretti Giulia , Bosio Alberto , Maccari Marta , Padovan Marta , Caccese Mario , Zagonel Vittorina , Lombardi Giuseppe
Published: November 2022

BACKGROUND

the current standard to treat meningiomas can include surgical resection and radiotherapy. Despite the high rate of relapse no systemic treatment is indicated. Few data are available regarding the effectiveness of bevacizumab (BEV) in this setting. We performed a retrospective analysis investigating the efficacy and safety of BEV in meningioma patients relapsed after receiving surgery and radiotherapy. Gene mutations were also collected. Material and

METHODS

we analyzed pts treated with off-label BEV from Jul 2019 to Feb 2022. Inclusion criteria were diagnosis of grade 2-3 meningioma, previous treatment with surgery and radiotherapy, no indication to further surgery or reirradiation, absence of contraindications to the use of BEV. Data were estrapolated from clinical records.

RESULTS

Median follow up was 13 months (3-30 range). 26 pts were enrolled. Median age was 68 ys (29-84); male pts were 16 (61%);61% (16 pts) with atypical meningioma, 38.5% (10 pts) with anaplastic meningioma; 27% (7 pts) underwent 2 or more surgeries; 58% had 2 or more RT treatments; 96.1% (25 pts) received < 2 previous lines of systemic treatment. 61% of patients (16 pts) had NGS analyses available; 62% (10 pts) had NF2 mutations (1 pt had a confirmed diagnosis of neurofibromatosis type 2), 23% (6 pts) CDKN2A/2B deletion, 11% (3 pts) PTEN mutation. OS rate was 82% and 62% at 6 and 12 months respectively; 6 months PFS rate was 83%. The DCR was 71% and the ORR was 19%. Median PFS and OS weren't reached. 19% (5 pts) experienced CTCAE grade 1 or 2 toxicity, mainly hypertension.

CONCLUSION

BEV showed very promising activity in recurrent grade 2-3 meningioma. The treatment was well tolerated. BEV should be considered an optimal therapeutic option in this setting of meningioma patients. The NGS results might be useful in identifying targetable mutations in case of further recurrence.
ANGI-10. IMPLICATIONS OF EPITHELIAL MEMBRANE PROTEIN-2 (EMP2) IN THE PATHOGENESIS OF MENINGIOMAS
Authors: Mozaffari Khashayar , Aguirre Brian , Chandla Anubhav , Wadehra Madhuri , Yang Isaac
Published: November 2022

INTRODUCTION

VEGF-A is an important mediator of angiogenesis in meningiomas. However, targeting this protein with bevacizumab has offered only a modest improvement in survival, suggesting that there are other compensatory mechanisms involved, enabling vascularization despite ongoing treatment. Epithelial membrane protein 2 (EMP2), a cell surface protein, promotes angiogenic processes in gynecological cancers and brain tumors including gliomas and glioblastoma. However, little is known about its etiology and mechanism of action within meningiomas.

OBJECTIVE

We aimed to evaluate EMP2 expression in non-pathologic brain tissue, tumor specimens, and in meningioma cell lines. We also aimed to understand its mechanism within cells with regard to proliferation and invasion.

METHODS

Non-pathologic brain tissues from routine autopsies and tumor specimens from surgical resection were analyzed. Additionally, four meningioma cell lines were obtained (CH157, BEN-MEN1, SF1335 and IOMM-LEE) and changes in cellular proliferation and invasion were measured. Furthermore, EMP2 expression was modulated using lentiviral infection. A p-value < 0.05 was considered statistically significant.

RESULTS

EMP2 mRNA and protein expression were significantly higher in the meningioma specimens compared to non-pathologic meninges. Its expression also positively correlated with an angiomatous pattern and VEGF-A mRNA expression. In vitro, high EMP2 protein expression was noted in all cell lines, and quantification demonstrated highest expression in the malignant cell line, the IOMM-LEE. Viral vectors were subsequently utilized to create EMP2 overexpressing and knockdown IOMM-LEE models. Western analysis demonstrated a correlation between EMP2 overexpression and HIF1α, a key mediator of tumor growth and angiogenesis.

CONCLUSION

Our data from primary tumor samples and in vitro models implicate EMP2 in meningioma pathogenesis. This warrants further investigation by evaluating the effects of anti-EMP2 therapy on tumor growth and invasiveness in both in vitro andin vivo models.
ANGI-11. RAB27 IS REQUIRED FOR REGULATING INTACT VASCULATURE IN GLIOBLASTOMA
Authors: Adnani Lata , Meehan Brian , Rak Janusz
Published: November 2022

Rab27 is a GTPase involved in the biogenesis of extracellular vesicles (EVs) and cellular secretion pathway. Among two Rab27 isoforms (a and b) Rab27a has been identified in regulating angiogenesis during development and wound healing via VEGFR1. Here, we show that Rab27 plays a role in the development and stability of the brain vasculature including pathological angiogenesis in glioblastoma.. Thus, relative to wild-type C57bl/6 (WT) and double heterozygous Rab27a+/-;Rab27b+/- (dHET) mice, animals with Rab27a/b double knock-out (Rab27a/b-dKO) exhibit reduced microvascular density in brain cortices. Additionally, we also observed a reduction in permeability of Evans Blue in the Rab27 dKO cortices relative to controls. When neoangiogensis was induced following orthotopic inoculation of mouse glioma cells (GL261), a similar reduction and morphological anomalies were observed in the tumour vasculature relative to tumours established in control mice. Moreover, vascular permeability of tumours in Rab27a/b-dKO mice markedly exceeded that of similar tumours in wild type or heterozygous controls. Our results suggest Rab27a and Rab27b may play a critical role in ensuring stability of the vasculature under physiological conditions and in glioma.
BIOM-01. GENOMIC ALTERATIONS IN ALK FUSION-POSITIVE NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS WITH BRAIN METASTASES
Authors: Eichholz Jordan , Miao Emily , Lebow Emily , Walch Henry , Flynn Jessica , Zhang Zhigang , Hubbeling Harper , Beal Kathryn , Moss Nelson , Yu Kenny , Yang Jonathan , Meng Alicia , Kelly Daniel , Boerner Thomas , Gomez Daniel , Rimner Andreas , Schultz Nikolaus , Drilon Alexander , Imber Brandon , Pike Luke
Published: November 2022

PURPOSE

Brain metastases (BM) are common in patients with anaplastic lymphoma kinase fusion-positive NSCLC (ALK+ NSCLC). We characterized the genomics of patients with ALK+ NSCLC BM treated with alectinib with or without local therapy to identify correlations of co-mutations with CNS-specific outcomes.

METHODS

We retrospectively reviewed ALK+ NSCLC patients with BMs who received alectinib for the definitive treatment of BM from 1/2012 and 5/2021. Genomic characteristics of 27 specimens from 27 patients were assessed with MSK-IMPACT, a 505-gene next-generation sequencing (NGS)-based tumor sequencing assay with >700x coverage. Intracranial progression-free survival (iPFS) and overall survival (OS) from BM diagnosis were analyzed using standard statistical methods.

RESULTS

The median age at BM diagnosis was 57 years (range 25-83). Median iPFS was 1.94 years (95%CI: 1.58- not reached) and median OS was 6.08 years (95%CI: 1.7– not reached). All patients received alectinib for the treatment of brain metastases (78% as 1st-line TKI) and 22% received local therapy. The most frequently altered co- alterations were CDKN2A (48%), TP53 (22%), MAP2K4 (15%), SMARCA4 (11%), CREBBP (11%), and ATM (7%). CDKN2A alterations were more common in patients with intracranial progression (64% vs 31%). MAP2K4 alterations were enriched in metastatic samples (p = 0.028, q = 0.113). SMARCA4 co- alterations were associated with inferior OS (HR: 8.76, 95%CI = 1.74-44.2, p= 0.009) and trended toward association with iPFS but was insignificant (HR: 3.25, 95%CI = 0.83-12.4, p=0.089). We identified missense ALK alterations in CSF from a patient who acquired resistance to alectinib and had leptomeningeal progression (G1269A, I1171T, L1108P).

CONCLUSION

This study is the first analysis of CNS specific outcomes with detailed genomic annotation for ALK+ NSCLC patients who received definitive alectinib for BM. Further investigation into the role of CNS-penetrant TKIs and the genomic alterations predictive of CNS failure are needed.
BIOM-15. GLIOBLASTOMA CELLS SHOW ELEVATED CHITINASE 3-LIKE PROTEIN 1 GENE EXPRESSION IN RESPONSE TO HUMAN CEREBROSPINAL FLUID WITH INCREASED MIGRATION AND EPITHELIAL-MESENCHYMAL TRANSITION RELATED ACTIVITY
Authors: Whaley Lauren , Norton Emily , Corcino Victoria , Jones Vanessa , Chaichana Kaisorn , Quiñones-Hinojosa Alfredo , Guerrero-Cazares Hugo
Published: November 2022

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. GBM tumors proximal to the lateral ventricles have a worse prognosis with multifocality, recurrence, and lower overall survival. Studies suggest this increased aggressiveness is attributed to cerebrospinal fluid (CSF), as we have previously observed transcriptomic changes in GBM cells upon CSF exposure. GlioVis database reveals chitinase 3-like protein 1 (CHI3L1), a glycoprotein secreted by immune and cancer cells, is associated with poor prognosis and co-expressed with pro-inflammatory and tissue remodeling genes. We suggest exposure to CSF elevates CHI3L1 expression, consequently impacting malignancy-associated gene expression in patient-derived GBM lines. We first evaluated if patient CSF influences the expression of CHI3L1. GBM cells were treated with artificial CSF, non-cancer CSF, or cancer CSF for 72 hours. qPCR revealed significant increases in CHI3L1 (p< 0.0001), SPP1, and CD44 expression in cancer CSF groups compared to artificial CSF. CHI3L1 expression at the protein level is also increased by cancer CSF when profiled using Western Blot. Additionally, ELISA results indicated significantly higher levels of CHI3L1 in CSF samples obtained from patients with high-grade tumors compared to non-cancer samples. Next, we assessed if exogenous CHI3L1 stimulates GBM malignancy at the cellular level. An effective concentration of recombinant human CHI3L1 was determined through Alamar Blue assay, showing 500 ng/ml CHI3L1 increases viability in primary patient cell lines compared to non-treated media. Recombinant CHI3L1 also increases cell migration in Transwell assay. qPCR revealed Vimentin (p< 0.001) and Twist (p< 0.0001) expression significantly increases while E-cadherin (p< 0.001) significantly decreases in CHI3L1-treated groups, consistent with EMT and migratory activity. Ultimately, this study shows CHI3L1 is a CSF-induced factor in GBM and could be a therapeutic target as it enhances tumor malignancy by increasing proliferation, migration, and malignancy-promoting gene expression.
BIOM-24. TARGETED NEXT-GENERATION SEQUENCING (NGS) OF TEMPORALLY MATCHED CEREBROSPINAL FLUID (CSF) AND TUMOR TISSUE IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)
Authors: Abdalla Aseel , Till Jacob , Yee Stephanie , O'Rourke Donald , Brem Steven , Amankulor Nduka , Chen Isaac , Binder Zev A , Desai Arati , Phillips Richard , Hussain Jasmin , Kry Yolanda , Caldwell Michael , Beaubier Nike , Bagley Stephen , Carpenter Erica L
Published: November 2022

BACKGROUND

GBM genomic profiling relies on sequencing a limited tumor tissue sample, which is invasive and may underrepresent molecular heterogeneity. CSF, which can be obtained less invasively, is in intimate contact with tumor lesions and may better capture the full genomic profile of the tumor. However, datasets with contemporaneously collected CSF and tissue to support this claim have been lacking. To evaluate the performance of CSF NGS, we conducted a pilot study in patients with GBM undergoing a resection for suspected recurrence following first-line chemoradiotherapy.

METHODS

Paired CSF and tissue samples were sequenced using a hybrid capture-based NGS assay. Clinically meaningful variants were defined as those that are potentially targetable using off-label or clinical trial options, exhibit prognostic value, or may predict response or resistance to specific treatments.

RESULTS

Eighteen patients were enrolled, and 13 of 18 CSF samples (72.2%) were sequenced successfully. At least one variant was detected in all CSF samples analyzed. A median of 7 variants (range 1—67) was detected per sample across 54 genes. The median variant allele fraction was 0.6% (range 0.2—72.4%). Among 38 clinically meaningful genes, 102 variants were detected; 25 (24.5%) were detected in both tissue and CSF, while 60 (58.8%) were detectable solely in CSF. Hypermutation was detected by CSF in one patient. Of the 82 variants detected in this patient’s tumor, 15 (18.3%) were identified in both tissue and CSF, 15 (18.3%) were identified only in the tissue, and 52 (63.2%) were identified only in the CSF.

CONCLUSIONS

CSF NGS detects clinically meaningful variants at a substantial rate and frequently identifies mutations not detected by matched tissue NGS. These results suggest that CSF may be a suitable source material for tumor profiling, overcoming the limitations of tissue, and may also provide a more comprehensive tumor profile.
BIOM-31. TEMPOROSPATIAL PROTEIN PROFILING OF HUMAN GLIOBLASTOMAS REVEALS MOLECULAR MECHANISMS AND BIOMARKERS UNDERLYING RESPONSES TO IMMUNE CHECKPOINT INHIBITION
Authors: Young Jacob S , Lucas Calixto-Hope , Seo Kyounghee , Nguyen Minh , Chen William , Solomon David A , Berger Mitchel S , Phillips Joanna J , Aghi Manish , Raleigh David
Published: November 2022

Glioblastoma responses to immune checkpoint inhibition (ICI) are rare, and the molecular mechanisms underlying ICI responses are incompletely understood. Thus, serial glioblastoma samples are valuable resources for identifying biomarkers or therapeutic targets to increase the efficacy of ICI in patients with glioblastoma. We obtained paired glioblastoma samples from 7 patients who underwent sequential surgery, ICI, and eventual salvage surgery for recurrence. Patients were distinguished as ICI responders (n=3) or non-responders (n=4) based on (1) MRI evidence of tumor stability/reduction over 6+ months after ICI, or (2) pathologic evidence of predominant treatment effect at the time of salvage surgery after ICI. FFPE sections from each tumor (n=14) were stained using H&E or IHC/IF for macrophages/microglia (CD68) or T cells (CD3) and analyzed using light or fluorescence microscopy. Six regions-of-interest (ROIs) comprising viable tumor were selected neuropathologist from each sample (n=84 ROIs). ROIs were analyzed using quantitative spatial profiling of 72 proteins on the Nanostring Digital Profiler platform. Glioblastomas responding to ICI were enriched in T-cell proteins (CD3, CD4, CD8) and T-cell activation markers (CD25) at the time of salvage compared to initial surgery. Markers of MAPK signaling were suppressed in pre-ICI samples compared to post-ICI samples in responders. p-ERK was suppressed in post-ICI samples compared to pre-ICI samples in non-responders. Myeloid proteins (CD68, CD163, CD11c) were enriched in post-ICI samples compared to pre-ICI samples in non-responders. Principle components analysis revealed p-ERK and immune proteins (CD3, CD4, CD8, CD20, CD11c, CTLA4, CD68, CD45, CD56, and CD127) accounted for 62% of the variance among pre-ICI and post-ICI samples in responders. In conclusion, temporospatial protein profiling of human glioblastomas reveals molecular mechanisms and biomarkers underlying responses to immune checkpoint inhibition. These data establish a foundation for functional studies to reprogram the immunosuppressive glioblastoma microenvironment and sensitize tumors to immune checkpoint inhibition.
BIOM-32. DNA METHYLATION SUBCLASSES PREDICT THE BENEFIT FROM GROSS TOTAL TUMOR RESECTION IN IDH-WILDTYPE GLIOBLASTOMA PATIENTS
Authors: Drexler Richard , Schüller Ulrich , Eckhardt Alicia , Filipski Katharina , Hartung Tabea , Harter Patrick , Divé Iris , Forster Marie-therese , Czabanka Marcus , Jelgersma Claudius , Onken Julia , Vajkoczy Peter , Capper David , Siewert Christin , Sauvigny Thomas , Lamszus Katrin , Westphal Manfred , Dührsen Lasse , Ricklefs Franz
Published: November 2022

DNA methylation-based tumor classification allows an enhanced distinction into subgroups of glioblastoma. However, the clinical benefit of DNA methylation-based stratification of glioblastomas remains inconclusive. We performed a multicentric cohort study including 430 patients with newly diagnosed glioblastoma whose tumors were subjected to DNA methylation profiling. The primary outcome was overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the prognostic relevance of EOR and MGMTpromoter methylation status as well as surgical benefit for recurrent glioblastoma. After stratifying patients in accordance with their DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES), outcome analyses revealed no significant differences between these three methylation subclasses (p = 0.06). RTK I or RTK II tumors who underwent gross-total resection (GTR) or near GTR had a longer OS and PFS than partially resected patients (p < 0.01). In the MES subclass, no survival benefit for a maximized EOR was found (p = 0.33). In multivariate analysis, the therapy response-predictive value of MGMT promoter methylation was evident for RTK I (p < 0.01) and RTK II (p = 0.02) but failed to be an independent factor in the MES subclass (p= 0.06). For local recurrence, re-resection conveyed a progression-to-overall survival (POS) benefit (p < 0.01), which was evident in the RTK I (p = 0.03) and RTK II (p < 0.01) subclasses, but not in the MES subclass (p = 0.33).This study demonstrates a survival benefit from maximized EOR at surgery for newly diagnosed and recurrent glioblastomas of the RTK I and RTK II subclass but not the MES subclass. Hence, it needs to be carefully considered whether the MES subclass should be treated with maximal surgical resection, especially when located in eloquent areas and at time of recurrence.
BIOM-36. A STUDY OF CLINICAL AND MOLECULAR PROGNOSTIC FACTORS FOR RESPONSE TO REGORAFENIB IN RECURRENT GLIOBLASTOMA
Authors: Chiesa Silvia , Mangraviti Antonella , Martini Maurizio , Cenci Tonia , Mazzarella Ciro , Gaudino Simona , Bracci Serena , Martino Antonella , Della Pepa Giuseppe M , Offi Martina , Gessi Marco , Russo Rosellina , Martucci Matia , Bartoli Francesco Beghella , Bonaventura Rina Di , Larocca Luigi M , Lauretti Liverana , Olivi Alessandro , Pallini Roberto , Balducci Mario , D'Alessandris Quintino Giorgio
Published: November 2022

Introduction

Following the results from the REGOMA study, regorafenib has become the first chemotherapeutic option for recurrent glioblastoma, IDH-wildtype, in many countries. However, predictive factors for response to regorafenib are scarcely recognized. The objective of this study was to identify molecular predictive factors for response to regorafenib using a clinically available platform.

METHODS

We analyzed a prospective cohort of 30 patients harboring recurrent glioblastoma, IDH-wildtype, and treated with regorafenib. Next-generation sequencing (NGS) analysis was performed on DNA extracted from paraffin-embedded tissues using a rapid, cheap, and clinically validated platform. MGMT methylation was assessed using methylation-specific PCR, and EGFRvIII expression was assessed using RT-PCR.

RESULTS

In our series, six-month progression-free survival (PFS) was 30% and median overall survival (OS) was 7.5 months: these data are consistent with current literature. Among clinical variables, gross-total resection was endowed with a positive prognostic value for PFS (p=0.0296, log-rank test). NGS analysis revealed a mutation in the EGFR pathway (EGFR and/or PIK3CA) in 18% of cases; a mutation in the mitogen-activated protein-kinase (MAPK) pathway (RAS and/or RET) in 18% of cases; no mutations in the remaining cases. Patients carrying MAPK pathway mutation had a poor response to regorafenib treatment, with a significantly shorter PFS and a nonsignificantly shorter OS compared to EGFR-mutated patients (for PFS, 2.5 vs 4.5 months, p=0.0061; for OS, 7 vs 9 months, p=0.1076). By combining NGS analysis with RT-PCR for EGFRvIII, we identified 14 patients with EGFR pathway activation, who had a significantly longer PFS and OS after regorafenib treatment. Multivariate analysis confirmed that MAPK pathway mutations predicted a scarce response to regorafenib treatment.

Conclusions

Through an easy-to-use and cheap platform, we identified a mesenchymal, MAPK-altered signature in IDH-wildtype glioblastoma, predictive of scarce response to regorafenib at recurrence. We thus provide a molecular selection criterion to implement in the clinical practice.
BIOM-38. TETRASPANIN 12 AS A TUMOR SUPPRESSOR AND BIOMARKER PREDICTING GOOD PROGNOSIS OF MALIGNANT GLIOMA
Authors: Lee Yeo Song , Kim Chungyeul , Choi Hye Won , Lee Jungsul , Jung Hyena , Suh Sangil , Kim Hyungsin , Kang Shin-Hyuk , Kwon Taek-Hyun , Chong Kyuha
Published: November 2022

Tetraspanin 12 (TSPAN12), a member of the tetraspanin family that are increasingly known to be involved in various mechanisms of tumor progression, mediates various cellular signaling processes in cancer cells. With respect to the brain, previous studies have shown that TSPAN12 is related with the maturation of a membrane-associated metalloproteinase 10 and the production of amyloid β plaque, but there are no studies related to brain tumors to date. Therefore, we designed this study to investigate the role of TSPAN 12 on malignant glioma (MG) cells and patients. TSPAN12 silencing in MG cells significantly progressed cell proliferation, migration and invasion capacities, and extracellular matrix adhesion ability as well as stem cell properties, in vitro. Mechanistically, we identified that FAK and ERK signaling were involved in MG cells with TSPAN12 expression. Moreover, clinical analysis of MG patient tissues microarray showed that the expression level of TSPAN12 was negatively correlated with the prognosis in MG patients. Collectively, more studies are needed, but we suggest that TSPAN12 can be used as an alternative biomarker to predict the prognosis of MG patient and help develop MG treatment strategies.
BIOM-39. P-ERK ASSOCIATION WITH OVERALL SURVIVAL IN RECURRENT GBM PATIENTS TREATED WITH INTRACEREBRAL ADMINISTRATION OF PD-1 AND CTLA-4 BLOCKING ANTIBODIES
Authors: Arrieta Victor , Duerinck Johnny , Burdett Kirsten B , Geens Wietse , Schwarze Julia Katharina , Gould Andrew , Chen Li , McCord Matthew , Horbinski Craig , Zhang Hui , Stupp Roger , Neyns Bart , Sonabend Adam M
Published: November 2022

INTRODUCTION

Anti-PD-1 immunotherapy induces clinical responses in a subset of glioblastoma (GBM) patients. We previously reported that ERK1/2 phosphorylation (p-ERK) in pre-treatment tumor samples is predictive of overall survival (OS) following adjuvant anti-PD-1 therapy in two independent cohorts of recurrent GBM patients.

METHODS

Following the Remark criteria for biomarker validation, we investigated p-ERK as a predictive of OS in 24 evaluable tumor samples of recurrent GBM patients from a clinical trial. These patients underwent intracerebral administration of immune checkpoint inhibitors as part of a phase I clinical trial where intracerebral administration of ipilimumab (10 mg) or ipilimumab (5 mg) and nivolumab (10 mg) followed by postsurgical intravenous nivolumab (10 mg) was evaluated (NCT03233152; Duerinck J, et al. JITC, 2021). We quantified cell density of p-ERK+ cells in tumor regions. For exploratory purposes, patients were divided in 3 groups (n=8 per group) bases on p-ERK cell density.

RESULTS

We observed an incremental OS with high p-ERK GBM patients exhibiting a median OS of 81.6 weeks (95% CI 33.86-NA), intermediate p-ERK median OS of 43.1 weeks (95% CI 33.14-NA), and low p-ERK group with a median OS of 19.3 weeks (95% CI 16.14-NA). A Cox proportional hazards model adjusted for age and IDH mutant status showed a trend for p-ERK association with favorable OS (HR= 0.77, 95% CI 0.6-=1.01, P=0.056).

CONCLUSIONS

While the number of patients analyzed is relatively small, this study suggests the potential predictive power of p-ERK in an independent prospective GBM cohort treated with an alternative and unique administration approach of immune checkpoint blockade.
BIOM-44. MAGNETIC RESONANCE IMAGING MAPPING OF BRAIN TUMOR BURDEN TO EVALUATE RESPONSE TO PULSED LOW-DOSE-RATE RADIOTHERAPY FOLLOWING RESECTION OF GLIOBLASTOMA MULTIFORME: A 4-PATIENT CASE SERIES
Authors: Amidon Ryan , Prah Melissa , Straza Michael , Santos-Pinheiro Fernando , Bovi Joseph , Schultz Christopher , Schmainda Kathleen
Published: November 2022

BACKGROUND

Pulsed low-dose-rate radiotherapy (pLDR) is an accepted reirradiation technique for recurrent glioma, but its upfront use, concurrent with temozolomide (TMZ) following resection of high-grade glioma is currently under investigation. Evaluating the response to upfront radiation can be challenging and there is limited data on expected rates of pseudoprogression with pLDR. Standard magnetic resonance imaging (MRI) has limitations in differentiating pseudoprogression from tumor progression, sometimes necessitating surgery for pathologic confirmation. Advanced MRI can be used to create fractional tumor burden (FTB) maps that spatially distinguish active tumor from treatment-related effect (pseudoprogression), perhaps providing a more reliable imaging biomarker in the absence of additional surgery.

METHODS

We performed a retrospective chart review to report the responses of four patients with glioblastoma to upfront pLDR and TMZ following resection. Each patient received advanced surveillance MRI and redo surgery. Tumor pathology included IDH-wild type (n = 4) and O6-methylguanine-DNA methyltransferase (MGMT) methylated (n = 1) tumors.

RESULTS

The median age of patients was 57.5 years (range 55-60 years) and all were male. One patient experienced mortality and another was transitioned to hospice. In all four cases, there were concerns of tumor progression in postcontrast MRI. Pathologic diagnosis revealed either treatment effect (n = 2) or tumor (n = 2). FTB maps were predominantly indicative of lesion volumes being comprised of treatment effect (n = 3) and tumor (n = 1). From the three FTB maps in the former category, the median fraction of the enhancing tumor volume comprised of vascular tumor was 6.4% (range 1.8-6.8%).

CONCLUSION

This case series provides insight into response to upfront pLDR and TMZ following resection of glioblastoma and demonstrates the capacity for FTB mapping to spatially distinguish tumor progression from treatment effect in this patient population.