bluuebunny/crossref_metadata_2025 huggingface dataset:
RARE-11. SELLAR GERMINOMA MASQUERADING FOR SIX YEARS AS AUTOIMMUNE HYPOPHYSITIS IN A 16-YEAR-OLD GIRL WITHOUT DIABETES INSIPIDUS
Authors: Hrachova Maya , Perez Rosenthal Mari , Xiao-Tang Kong
Published: November 2019

INTRODUCTION

Germinomas are rare malignant intracranial neoplasms which most commonly occur in young males in the pineal and suprasellar region. Less commonly, germinomas arise in the sellar region, where there is slight female predominance. Diagnostic challenges may arise, as autoimmune hypophysitis has similar clinical, imaging and histopathological features to germinoma. CASE REPORT: A 16-year-old girl (46, XX) presented with primary amenorrhea, failure of sexual development and growth delay. Stimulation tests confirmed panhypopituitarism except diabetes insipidus. Infectious and rheumatological workup was negative. She had normal levels of beta HCG, CEA and alpha-fetoprotein. MRI brain identified an enhancing hypothalamic pituitary stalk and pituitary mass. A biopsy was performed which showed a lymphocyte rich infiltration of the pituitary gland, suggesting autoimmune hypophysitis. She completed 4 cycles of low dose methotrexate weekly and remained on hormone replacement therapy for panhypopituitarism for three years until she developed daily headaches, blurry vision, and secondary amenorrhea. MR imaging showed increased nodularity at the pituitary infundibulum with involvement of the optic chiasm. This lesion progressed on mycophenolic acid, increased doses of hydrocortisone, high doses of prednisone and IV methylprednisolone. She was unable to tolerate azathioprine and rituximab after one year. Subsequently, she underwent partial resection of the suprasellar lesion with the pathology showing germinoma admixed with abundant lymphohistiocytic inflammation. A nongerminomatous component was not present histologically and CSF only showed an elevated beta HCG. Given that the tumor is localized to the central nervous system she is receiving treatment via SIOP CNS GCT 96 protocol.

DISCUSSION

Autoimmune hypophysitis and germinoma can share similar clinical, radiological and histopathological features. Our case demonstrates the need for careful histologic examination, close clinical and radiological follow up in patients with lymphocyte-rich suprasellar lesions if no response to immunosuppressant therapy is noted.
RARE-12. EARLY FOCAL RADIOTHERAPY AND TEMOZOLOMIDE FOLLOWING COMPLETE RESECTION APPEAR SUPERIOR TO INTENSIVE CHEMOTHERAPY IN CHILDREN WITH EMBRYONAL TUMORS WITH MULTILAYERED ROSETTES (ETMR)
Authors: Slavc Irene , Mayr Lisa , Gojo Johannes , Peyrl Andreas , Azizi Amedeo , Dieckmann Karin , Haberler Christine , Czech Thomas
Published: November 2019

BACKGROUND

Embryonal tumor with multilayered rosettes (ETMR) is an extremely rare entity characterized by LIN28A expression and alterations in the C19MC locus. ETMRs predominantly occur in young children and have a dismal prognosis. We report on our single institution experience in seven consecutive patients.

METHODS

Between 2006 and 2016, seven patients were diagnosed with ETMR. Diagnosis was established prospectively by characteristic histopathologic features, LIN28A immunostaining and amplification of the C19MC region in five patients and retrospectively confirmed in two additional patients originally diagnosed as central nervous system primitive neuroectodermal tumor. Tumor location was supratentorial in all patients. Median age at diagnosis was 25 months (range 5–38). Male to female ratio was 1:6.

RESULTS

All patients received gross total tumor resection and four patients were treated with intensive chemotherapy regimens including high-dose chemotherapy in three patients. Four patients recurred after a median of 6 months (range 2–11 months) and all except one patient who died after high-dose chemotherapy, succumbed to their disease after a median of 13 months (range 7–28 months). Consequently, the two most recent patients were treated with gross total tumor resection, primary focal radiotherapy and concomitant temozolomide followed by temozolomide for one year. Due to the high risk of leptomeningeal dissemination intraventricular chemotherapy was administered to all except one patient. Both patients who were treated with primary focal radiotherapy are in continuous complete remission 41 and 36 months after diagnosis.

CONCLUSION

Gross total resection followed by early focal radiotherapy, temozolomide, and intrathecal chemotherapy seem to be superior to intensive chemotherapy including high-dose chemotherapy.
RARE-22. CHALLENGES IN MANAGEMENT OF CNS INVOLVEMENT OF CUTANEOUS T-CELL LYMPHOMA
Authors: Chukwueke Ugonma , Kim Albert , Ng Samuel , Fisher David , Stuver Robert , Larocca Cecilia , Louissaint Abner , Weinstock David , Nayak Lakshmi , Meredith David
Published: November 2019

BACKGROUND

Cutaneous T-cell lymphoma (CTCL) is a group of T-cell lymphomas occurring primarily in the skin, without evidence of disease elsewhere. Central nervous system (CNS) involvement of CTCL is extremely rare, with a reported incidence of 5–9%. Due to its infrequency and radiographic appearance which mimics other CNS processes, CNS CTCL may be misdiagnosed. Here, we describe 8 cases of CNS CTCL at a single institution.

METHODS

The electronic medical records at our institution were queried for cases of CNS involvement by CTCL, between 2004–19. Clinical data, imaging and surgical pathology were reviewed.

RESULTS

Eight patients were diagnosed with CNS CTCL with median age of 68 and median time to development of CNS disease of 17 months. 1 patient had synchronous presentation of cutaneous and CNS disease identified at autopsy. Seven out of eight patients presented neurologically with behavioral and mental status changes and 1 patient had concurrent intraocular disease. Imaging showed bilateral non-enhancing T2/FLAIR signal changes in three patients; multifocal enhancement was noted in the others. Malignancy, inflammatory processes and infections including progressive multifocal leukoencephalopathy (PML) were often included in the radiographic differential diagnosis. Prior systemic therapies were variable, including palliative radiation, phototherapy, myeloablative chemotherapy followed by allogeneic stem cell transplant and oral methotrexate. 5 of 8 patients had active cutaneous disease at the time of CNS relapse. Six patients received initial treatment for CNS disease with high-dose methotrexate (HD-MTX). Comprehensive genomic analysis revealed recurrent alterations in genes associated with regulatory T-cell differentiation (SOCS1, NOTCH1), tumor suppressors (CDKN2A, PTEN, TP53); one case was hypermutated.

CONCLUSIONS

CNS involvement of CTCL is rare, occurring more than a year after initial cutaneous disease. Clinical and radiographic findings may be variable, necessitating high clinical suspicion. Most patients respond to HD-MTX. Further molecular analysis is ongoing.
RARE-28. HYPOTHALAMIC GERMINOMA AND NEUROSARCOIDOSIS: A TALE OF TWO PATHOLOGIES
Authors: Puri Sushant , Valy-Nagy Tibor , Sweiss Nadera , Maraka Stefania , Nicholas Martin
Published: November 2019

CASE 1: 30-year-old Caucasian male with a history of hereditary cavernomas, testicular germ cell tumor s/p orchiectomy 2017 presented next year with a chief complain of increasing lethargy. MRI Brain showed a new expansile, homogenously enhancing hypothalamic lesion causing obstructive dilatation of the lateral ventricles. MRI of neuraxis was not concerning for leptomeningeal spread. Initial differentials included suprasellar germinoma vs chiasmatic hypothalamic glioma vs metastatic lesion. Biopsies X2 showed gliosis and granulomatous inflammation. Despite radiation treatment for the hypothalamic mass clinical course continued to deteriorate. CSF results showed RBC - 1,200; WBC - 51 with 77% lymphocytes, 3% neutrophils, 20% monocytes. FDG-PET did not reveal evidence of metastatic disease. He was treated presumptively for neurosarcoidosis with high-dose corticosteroids and azathioprine and later transitioned to methotrexate and infliximab. Follow up MRI scans showed a reduction in the hypothalamic mass. CASE 2: A 23-year-old African American male treated for ADEM in 2010 presented to clinic with behavioral problems in 2017. Initial presentation included lethargy with imaging showing an incidental hypothalamic mass. Initial differentials included germinoma vs infundibular hypophysitis vs granulomatous process. He was treated with immunotherapy (corticosteroids and IVIG) with partial resolution of the growth. He was later diagnosed with suprasellar germinoma on biopsy subsequently treated with 2 cycles chemotherapy and proton beam radiotherapy in 2012. In 2017. to exclude tumor recurrence an LP showed elevated ACE however remainder of the clinical picture was not suggestive of neurosarcoidosis. DISCUSSION: Multiple case series have been described wherein hypothalamic germinoma mimics isolated neurosarcoidosis and vice-versa. Because of similar clinical picture and radiographic findings, the diagnosis is challenging. ACE is a nonspecific test for neurosarcoidosis, and it can be positive in the setting of germinoma as well. Hence specific molecular markers may be helpful in the diagnosis.
RARE-37. TREATMENT OF H3K27M MUTANT GLIOMAS WITH PANOBINOSTAT
Authors: Balakrishnan Samantha , Carabenciov Ivan , Ruff Michael , Uhm Joon , Kizilbash Sani
Published: November 2019

Panobinostat (PBST) is a histone deacetylase inhibitor with biologic rationale in the treatment of gliomas harboring H3 K27M mutation.

METHODS

We performed a retrospective medical record review of adult patients with H3 K27M mutant diffuse midline glioma treated with PBST at Mayo Clinic (Rochester, MN).

RESULTS

Four patients were identified with a mean age 40 years (range 22–62 years). Tumor location was: spinal cord (thoracic n=1, cervical n=1), brainstem (n=1), and thalamus (n=1).Two patients underwent biopsy alone while two underwent a partial resection. Three patients were treated with radiation (36–54 Gy) immediately prior to PBST monotherapy, and one patient was treated with PBST monotherapy without preceding radiation. All patients were otherwise chemotherapy naïve and did not receive any concurrent chemotherapy with PBST. PBST was dosed at either 10 mg (n=1) or 20mg (n=3) administered on days 1, 3, 5, 8, 10 and 12 of 21 day cycles. The mean duration of PBST therapy was 5 months (range 2–11 months). PBST was well tolerated overall. One patient experienced an objective response per RANO criteria. Two patients continue on therapy (5 cycles, 12 cycles) with stable disease. One patient rapidly progressed after 2 cycles of PBST therapy. In contrast with the patients who derived benefit from PBST, this patient was younger (22) and had multifocal disease with leptomeningeal involvement at treatment onset. The average progression free survival post PBST initiation was 8 months.

CONCLUSION

This single institution case series shows promise that PBST may have therapeutic benefit in adult patients with H3 K27M mutant diffuse midline glioma.
RARE-39. COMBINATION OF TUMOR TREATING FIELDS (TTFIELDS) WITH LOMUSTINE (CCNU) AND TEMOZOLOMIDE (TMZ) IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS - A BI-CENTRIC ANALYSIS
Authors: Lazaridis Lazaros , Schäfer Niklas , Schmidt Teresa , Weller Johannes , Tzaridis Theophilos-Dimitrios , Scheffler Björn , Pierscianek Daniela , Kleinschnitz Christoph , Stuschke Martin , Sure Ulrich , Herrlinger Ulrich , Kebir Sied , Glas Martin
Published: November 2019

BACKGROUND

TTFields combined with TMZ chemotherapy demonstrated significantly improved PFS, OS and long-term survival in newly diagnosed glioblastoma (ndGBM) patients in the EF-14 trial; independent of MGMT-promoter methylation-status, age, grade of resection, and performance status. Recently, improved efficacy of lomustine/TMZ compared to TMZ monotherapy in ndGBM patients with MGMT-promotor methylation was reported in the CeTeG trial. As TTFields demonstrated a favorable safety profile as well as a high potential for being combined with other modalities and the encouraging results for methylated MGMT-promoter GBM patients in the CeTeG trial, there is a strong rationale for combining these treatment regimens. Here, we present a case series of patients receiving a combination of TTFields and lomustine/TMZ.

METHODS

Patients with ndGBM and MGMT-promoter methylation underwent combined therapy of TTFields plus lomustine/TMZ after surgery and radiochemotherapy. MGMT-promoter status was measured by pyrosequencing. Safety, feasibility, and first efficacy results are reported at data cut-off (April 26, 2019).

RESULTS

Sixteen patients with MGMT-promoter methylated ndGBM (median, range: age 50, 27–70; KPS 90, 60–100) have been treated with a combination of TTFields plus lomustine/TMZ. The analysis included patients with complete resection (n=7), partial resection (n=8), as well as biopsy (n=1). CTCAE grade 3 hematotoxicity was observed in seven patients (44%) but was unlikely related to the addition of TTFields to lomustine/TMZ. Medical device site reactions (low-grade skin reactions) were detected in six patients (38%). At data cut-off, the analyzed patient population demonstrated a median PFS of 20 months; the median OS was not yet reached.

CONCLUSION

The results of this analysis indicate that the combination of TTFields/lomustine/TMZ is safe and feasible. Moreover, the observed survival outcomes point to preliminary beneficial effects of the triple combination. Additional follow-up and increased sample size are required and planned for further safety and efficacy assessment of this treatment regimen.
RARE-44. CLINICAL, PATHOLOGICAL AND IMMUNE MICROENVIRONMENT EVALUATION FOR TUMOR IMMUNITY IN GERMINOMA PATIENTS
Authors: Nishimoto Masaaki , Ohara Kentaro , Kamamoto Dai , Tamura Ryota , Miwa Tomoru , Yoshida Kazunari , Sasaki Hikaru
Published: November 2019

Pure germinomas are pathologically composed by large polygonal undifferentiated cells, accompanied by infiltrating small lymphocytes. Tumor immunity in intracranial germinomas have not been studied well and their role remains unclear. This study aimed to evaluate the clinical value of tumor immunity in intracranial germinomas. We investigated the expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and tumor-infiltrating lymphocytes (TILs) in 8 patients of intracranial germinomas by immunohistochemistry to analyze the association with their clinical courses and radiological features. We divided the patients into group with more than one year from onset to diagnosis as long-term onset group (LTOs), and the group with less than one year as short-term onset group (STOs). Three patients are in LTOs and five patients are in STOs. Median duration from onset to diagnosis in LTOs is 35 months (29–47), while median duration in STOs is 5.1 months (0.5–10). Mortality and recurrence were not observed in all patients. Radiological analysis showed that tumor locations in LTOs are relatively atypical and tumor size in LTOs is smaller than in STOs. TILs in LTOs are having higher expression than STOs. PD-L1 expression was observed in all 8 tumors. CD3, CD8 and PD-1 expressions were observed in all TILs. The ratio of PD-L1 positive-tumor cells was lower in LTOs than in STOs (p=0.012). CD8+ TIL density is higher in LTOs (p=0.003), whereas PD-1/CD8 ratio is lower in LTOs (p=0.047). Our data suggest that PD-1/PD-L1 pathway is associated with pathogenesis and tumor growth of germinomas, therefore immune checkpoint molecule inhibitors against PD-1/PD-L1 may be effective for refractory germinomas.
RARE-54. MEK INHIBITION FOR AGGRESSIVE GLIOMAS IN ADULTS WITH NEUROFIBROMATOSIS TYPE 1
Authors: Romo Carlos , Slobogean Bronwyn , Blair Lindsay , Blakeley Jaishri O
Published: November 2019

BACKGROUND

Neurofibromatosis type 1 (NF1) is caused by mutations of the tumor suppressor gene NF1 resulting in decreased levels of neurofibromin and dysregulation of the RAS pathway, including MEK/ERK upregulation. Central nervous system malignancies have an overall standardized incidence ratio of 37.5 in population studies, with higher rates of aggressive gliomas in adults with NF1. Further, the response to standard glioma therapies in this population is mixed in published series. MEK1/2 inhibitors have shown activity in both NF1 driven plexiform neurofibromas and low grade gliomas, however, data is lacking about their optimal dose or sequencing relative to standard glioma therapies for adults with NF1 associated aggressive gliomas. We present recent experiences with the MEK1/2 inhibitor trametinib in adults with NF1 and newly diagnosed aggressive gliomas.

METHODS

A retrospective chart review was conducted on all adult patients with NF1 and astrocytoma treated with trametinib at the Johns Hopkins Brain Cancer Program from 2016 to 2018.

RESULTS

Four patients met selection criteria. Median age at diagnosis was 37 years [25–43]. Histologic diagnoses were: pilocytic astrocytoma (1), diffuse astrocytomas (2), and anaplastic astrocytoma (1). All tumors were IDH1 wild-type. Three received trametinib as frontline therapy (2 mg daily), one as second line treatment. All achieved a partial radiographic response within 2 months from the start of trametinib. Median overall survival was 15 months [4–19]; three patients are alive at publication, with a median of 12 months from diagnosis. Median progression-free survival was 2.5 months [1–11].

CONCLUSIONS

Astrocytomas in adults with NF1, including histologically low-grade tumors, often have a more aggressive course than suggested by histology. These cases demonstrate clinical benefit from single agent MEK inhibition as well as possible synergistic effects with conventional therapies for gliomas in people with NF1, however, prospective investigation is needed.
STEM-02. GLIOBLASTOMA CANCER STEM CELLS UTILIZE ASYMMETRIC CELL DIVISION TO PROMOTE THERAPEUTIC RESISTANCE
Authors: Hitomi Masahiro , P Chumakova Anastasia , Silver Daniel , Knudsen Arnon , Kristensen Bjarne , Lathia Justin
Published: November 2019

Asymmetric cell division (ACD) enables the maintenance of a stem cell population while simultaneously generating differentiated progeny. Cancer stem cells (CSCs) undergo multiple modes of cell division during tumor expansion and in response to therapy, yet the functional consequences of these division modes has yet to be determined. Using a fluorescence-based system that reports the mitotic distribution of lipid rafts enriched in cell surface receptors, we found that ACD in glioblastoma CSCs generated a daughter cell with enhanced resistance to radiation and temozolomide. Single-cell analyses using our reporter system revealed that ACD also increased the co-inheritance of epidermal growth factor receptor (EGFR) and neurotrophin receptor (p75NTR), which was validated across four additional glioblastoma CSC models. Stimulation of both receptors maintained self-renewal under differentiation conditions, and stimulation with p75NTR ligands rescued the reduction in STAT3, AKT, and ERK induced by erlotinib-mediated EGFR inhibition. Finally, knockdown of p75NTR enhanced the therapeutic efficacy of EGFR inhibition in vivo. Taken together, our data indicate that co-inheritance of p75NTR and EGFR promotes resistance to EGFR inhibition through a redundant mechanism. Overall, these findings demonstrate that ACD produces progeny with enhanced growth factor receptors, which contributes to the generation of a more therapeutically resistant CSC population, and suggest that ACD needs to be considered in the development of next-generation targeting strategies.
STEM-10. BIDIRECTIONAL INTERACTION BETWEEN TUMOR-ASSOCIATED PLATELETS AND GLIOMA STEM CELLS IN GLIOBLASTOMA MULTIFORME
Authors: Raghavan Alankrita , Lee-Poturalski Christine , Willis John , Kerstetter-Fogle Amber , Harris Peggy , Rich Jeremy , Vogelbaum Michael , Jankowsky Eckhard , Sloan Andrew
Published: November 2019

Glioblastoma Multiforme (GBM) is the most common and lethal malignant primary adult brain tumor. Therapy resistance and tumor recurrence in GBM have been attributed to glioma stem cells (GSCs), which are found in hypoxic but perivascular niches. We hypothesized that the clinically documented and prognostically relevant increase in platelets in GBM promotes formation of functional hypoxic but perivascular niches that support GSCs due to formation of intravascular thromboses, a hallmark of GBM. Our preliminary in silico analysis from TCGA GBM samples indicates significant correlation of platelet and stemness signature expression (P < 0.001). High expression of platelet gene signatures also inversely correlates with overall survival in GBM patients (P < 0.02). Furthermore, we found significant co-localization of known platelet and stemness markers in primary GBM specimens, supporting our hypothesis and motivating further interrogation of GSC-platelet crosstalk. Our preliminary data suggest that GSCs exposed to either tumor or healthy platelets demonstrate increased self-renewal and stemness, as determined by a significant increase in OCT4, NANOG, and OLIG2 expression compared to unexposed GSCs. This increase in stemness and self-renewal markers was not seen in platelet-exposed differentiated glioma cell (DGC) counterparts. Conversely, platelets are stimulated by GSCs and GSC-conditioned media while DGCs elicit no stimulatory effects as measured by ATP release and aggregation assays. Our results implicate a functional role for platelet-GSC interactions in the maintenance of tumor cellular hierarchy that ultimately contributes to poor clinical outcomes in GBM. RNA-Seq of platelet-privileged GSCs is currently underway to elucidate the mechanism by which platelets impact GSC self-renewal. Successful characterization of potential crosstalk between platelets and GSCs may offer new clinical perspectives into GBM and inform development of a novel treatment paradigm to target these specific cell-to-cell interactions.
STEM-12. INCREASING INDUCED NEURAL STEM CELL PERSISTENCE IN THE TUMOR RESECTION CAVITY
Authors: Bomba Hunter , Sheets Kevin , Carey-Ewend Abigail , Goetz Morgan , Bago Juli , Khagi Simon , Hingtgen Shawn
Published: November 2019

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Afflicted patients have a median survival rate of only 15 months, and patient survival statistics have remained stagnant for over three decades. Current standard of care includes maximal safe tumor resection, chemotherapy, and radiation. Nevertheless, GBM is aggressive, making recurrence and deeper tumor infiltration inevitable. Neural stem cells transdifferentiated from a skin biopsy, i.e. induced neural stem cells (iNSCs), have the innate ability to home to tumors, and, when engineered with cytotoxic proteins, can actively kill cancer cells. However, direct injection of these cells into the hostile immune environment of the tumor resection cavity results in an accelerated clearance rate and therefore a shortened therapeutic window. To combat this clearance issue, we investigated the FDA-approved hemostatic matrix, Floseal, as a cell delivery platform to increase iNSC persistence. In vitro, SEM imaging showed homogeneous iNSC distribution throughout Floseal. Using our surgical resection model of GBM in mice, we delivered iNSCs into the post-surgical cavity in Floseal and by direct injection to model current clinical delivery strategies. Serial kinetic imaging showed that human iNSC persistence delivered into the cavity in Floseal persisted over 90 days, while cells directly injected into the brain parenchyma persist less than 20 days. When we investigated the impact on tumor kill, we found the increase in persistence increased survival of GBM-bearing mice more than 30 days compared to control cells. Light-sheet microscopy showed wild-type neural stem cells migrate into invasive GBM-8 tumors in the contralateral hemisphere, and we are now using this approach to validate the homing of iNSCs delivered via Floseal. Administration of iNSCs encapsulated in the biocompatible Floseal matrix offers a promising, clinically-translatable therapeutic strategy for GBM.
STEM-13. CANCER STEM CELL CYTOTOXICITY ASSAY-GUIDED TREATMENT IN RECURRENT GLIOBLASTOMA AND PROGRESSIVE ANAPLASTIC GLIOMA
Authors: Ranjan Tulika , Howard Candace , Yu Alexander , Xu Linda , Aziz Khaled , Jho David , Leonardo Jodi , Hameed Muhammad , Karlovits Stephen , Wegner Rodney , Fuhrer Russell , Lirette Seth , Denning Krista , Valluri Jagan , Paolo Claudio Pier
Published: November 2019

BACKGROUND

The presence of chemotherapy-resistant cancer stem cells (CSC) leading to tumor recurrence is postulated to be one of the major factors in the poor response to the current standard of care treatments in progressive high-grade gliomas. Unfortunately, in spite of several new drug discoveries for other tumor types, not many advances have been reported for this disease and therefore recurrent and progressive high-grade glioma survival remains dismal.

METHODS

We have used a CLIA and CAP accredited Cancer Stem Cell Cytotoxicity Assay(ChemoID) to guide most effective chemotherapy treatments from a panel of FDA approved drugs or their combinations for 12 recurrent glioblastoma (GBM) patients and 2 progressive anaplastic gliomas, all eligible to receive a stereotactic biopsy. Patients were evaluated by MRI scans and response was assessed according to RANO criteria.

RESULTS

The median age of our patient cohort was 49 years (21–63), with 11 males (79%) and 3 females (21%). We observed 6 complete responses (CR) 43%, 6 partial responses (PR) 43%, and 2 progressive diseases (PD) 14%. Of note, the two PD were observed in patients that could not be treated with assay recommended therapy due to their health status. Patients treated with ChemoID assay-directed therapy had a longer median overall survival (OS) of 13.3 months (5.4-NA) compared to the historical median OS of 9.0 months (8.0–10.8 months) previously reported (1). Notably, our recurrent and progressive high-grade glioma patient cohort treated with assay-guided therapy had a 57% probability to survive at 12 months, compared to the 27% historical probability of survival at 12 months observed in previous studies (1).

CONCLUSIONS

The data suggests that the ChemoID Cancer Stem Cell Cytotoxicity Assay has the potential to help guide individualized chemotherapy choices to improve recurrent and progressive high-grade glioma patient outcome. 1) Friedman, H.S. et. al. JCO2009 27:28, 4733–4740.
STEM-26. ALTERED LIPID METABOLISM MARKS GLIOBLASTOMA STEM AND NON-STEM CELLS IN SEPARATE TUMOR NICHES
Authors: Wallace Lisa , Gromovsky Anthony , Hale James , Knudsen Arnon , Prager Briana , Silver Daniel , Sloan Andrew , Kristensen Bjarne , Lathia Justin , Mark Brown J , Rich Jeremy , Hubert Christopher
Published: November 2019

Clinical glioblastoma is marked by a strikingly heterogeneous mix of cell types, cellular metabolisms, and cellular microenvironments spread in different spatial locations throughout a tumor. We have created 3-dimensional organoid models that partially mimic the transition zone between nutrient-rich cellular tumor regions and nutrient-poor psuedopallisading and perinecrotic tumor zones. We found a dramatic disparity in lipid droplet presence between these regions with high lipid accumulation in the hypoxic organoid cores of a wide spectrum of patient derived specimens. This is accompanied by regionally restricted upregulation of HILPDA gene expression in the cores of our models, in clinical GBM specimens but not lower grade brain tumors, and localized specifically to pseudopallisading regions of patient tumors. We further show that lipid droplet accumulation overall marks perinecrotic and pseudopallisading regions in clinical GBM, indicating broadly altered lipid metabolism between these distinct cell populations. High lipid droplet accumulation is largely restricted to the non-stem cell populations of GBM organoids and sorted xenograft tumors whereas the stem cells are lipid-poor, suggesting lipid levels may not be simply a product of the microenvironment but also may be a reflection of cell state. We performed global lipidomic analysis on prospectively sorted stem and non-stem cells of multiple patient-derived models and found that GBM stem cells have comparatively decreased levels of neutral lipids, indicating a significant metabolic shift compared to non-stem cells from the same patient. Conversely, GBM stem cells have significantly increased levels of rare specific lipid species, and also display altered phospholipid synthesis and species specific alterations in phospholipid classes. Our findings suggest avenues for therapy by targeting the altered lipid metabolic pathways of these disparate tumor cell populations.
Chlamydia trachomatis infection of the neovagina in transgender women
Authors: Radix Asa E , Harris Alexander B , Belkind Uri , Ting Jess , Goldstein Zil G
Published: November 2019

We report two cases of neovaginal Chlamydia trachomatis infection in transgender women who underwent penile-inversion vaginoplasty procedures with integrated peritoneum and urethral grafts. These tissue types may have facilitated C. trachomatis infection. Medical providers should implement neovaginal screening for bacterial STIs in transgender patients at risk for infection.
A Biopsychosocial Model of Chronic Pain for Older Adults
Authors: Miaskowski Christine , Blyth Fiona , Nicosia Francesca , Haan Mary , Keefe Frances , Smith Alexander , Ritchie Christine
Published: November 2019

Population

Comprehensive evaluation of chronic pain in older adults is multifaceted.

Objective and Methods

Research on chronic pain in older adults needs to be guided by sound conceptual models. The purpose of this paper is to describe an adaptation of the Biopsychosocial Model (BPS) of Chronic Pain for older adults. The extant literature was reviewed, and selected research findings that provide the empiric foundation for this adaptation of the BPS model of chronic pain are summarized. The paper concludes with a discussion of specific recommendations for how this adapted model can be used to guide future research.

Conclusions

This adaptation of the BPS model of chronic pain for older adults provides a comprehensive framework to guide future research in this vulnerable population.
Managing Colonial Diets: Wartime Nutritional Science on the Korean Population, 1937–1945
Authors: Ko Sunho
Published: November 2019

This article examines nutrition studies on Korean diets between 1937 and 1945 as a case study on the liaison between nutritional science and total war regimes in the twentieth century. Building on critical scholarship on nutritional science, this article argues that nutritional science—as a scientific governmental technology and racial discourse—served the wartime colonial regime in the Japanese empire aimed at managing the Korean population in the most scientific manner. As a governmental technology, nutritional science produced scientific frameworks and data that shaped state food policies for the efficient mobilisation of Korean diet and labor for war. As a racial discourse, nutritional science construed Korean diets as a scientifically defined nutrition problem. By construing the nutrition problem as an expression of colonial backwardness in need of governmental intervention, nutritional science justified wartime state policies like the school lunch programme as welfare measures to improve the colonial diet and body.
Droplet Digital PCR Technology for Detection of Ilyonectria liriodendri from Grapevine Environmental Samples
Authors: del Pilar Martínez-Diz María , Andrés-Sodupe Marcos , Berbegal Mónica , Bujanda Rebeca , Díaz-Losada Emilia , Gramaje David
Published: November 2019

Black-foot disease is one of the most important soilborne diseases affecting planting material in grapevine nurseries and young vineyards. Accurate, early, and specific detection and quantification of black-foot disease causing fungi are essential to alert growers and nurseries to the presence of the pathogens in soil, and to prevent the spread of these pathogens through grapevines using certified pathogen-free planting material and development of resistance. We comparatively assessed the accuracy, efficiency, and specificity of droplet digital PCR (ddPCR) and real-time PCR (qPCR) techniques for the detection and quantification of Ilyonectria liriodendri in bulk and rhizosphere soils, as well as grapevine endorhizosphere. Fungal abundance was not affected by soil-plant fractions. Both techniques showed a high degree of correlation across the samples assessed (R2 = 0.95) with ddPCR being more sensitive to lower target concentrations. Roots of asymptomatic vines were found to be a microbial niche that is inhabited by black-foot disease fungi.
Searches for cosmic magnetic monopoles: past, present and future
Authors: Patrizii Laura , Sahnoun Zouleikha , Togo Vincent
Published: November 2019

A paper titled ‘Quantised singularities in the electromagnetic field’ by P.A.M. Dirac appeared in 1931 in the
Proceedings of the Royal Society A
. The paper concerned ‘[ · 
s
] the reason for the existence of a smallest electric charge.’ Dirac showed that the quantization of the electric charge follows from the existence of at least one free magnetic charge, finding ‘a connection between the smallest electric charge and the smallest magnetic pole’, a connection called since then the ‘Dirac relation’. That seminal paper marked the opening of a new research field that has grown considerably since then. The search for magnetic monopoles in cosmic radiation encompasses many fields, from particle physics to astrophysics, from the extremely small to cosmology.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Physical implications of electroweak monopole
Authors: Cho Y. M.
Published: November 2019

The electroweak monopole in the standard model, the existence, characteristic features, cosmological production and physical implications are discussed. The discovery of the Higgs particle has been thought to be the ‘final’ test of the standard model. If the standard model is correct, however, it must have the electroweak monopole as the electroweak generalization of the Dirac monopole. This means that the detection of this monopole should become the final and topological test of the standard model. If detected, it becomes the first magnetically charged and stable topological elementary particle in the history of physics. Moreover, it has deep implications in physics. In cosmology, it could generate the primordial magnetic black holes which could explain the dark matter, become the seed of the large-scale structures of the universe, and be the source of the intergalactic magnetic field. Just as importantly, it could generate the hitherto unknown magnetic current which could have huge practical applications. Furthermore, the existence of the monopole requires us to reformulate the perturbative expansion in quantum field theory. This makes the detection of the electroweak monopole a most urgent issue. We discuss useful tips for the MoEDAL detector at LHC and similar experiments on how to detect the monopole successfully.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Reply To: Molecular Brightness analysis of GPCR oligomerization in the presence of spatial heterogeneity
Authors: Stoneman Michael R. , Biener Gabriel , Raicu Valerică
Published: November 2019

Annibale and Lohse have recently suggested a way1 in which the two-dimensional fluorescence intensity fluctuation (2D FIF) spectrometry2 may be further refined. Their main suggestion is to include a step in the analysis process where a case-by-case inspection of individual regions of interest of a membrane allows for selection of portions of the membrane which are “as homogenous as possible” and thereby exclude intensity spots potentially related to other sub-cellular structures. By incorporating that proposal into an objective and reproducible algorithm, here we show that 2D FIF has a built-in capability to automatically filter out such contributions, and that further removal of inhomogeneities does not alter the final results.
“Ghost ponds” – How to resurrect in-filled farmland ponds to assist aquatic biodiversity conservation in agricultural landscapes
Authors: Alderton Emily , Sayer Carl D. , Axmacher Jan C. , Patmore Ian R. , Burningham Helene , Brown Phill L. , Nobes Geoff
Published: November 2019

Growing recognition of the importance of ponds for landscape-scale biodiversity has led to considerable interest in their conservation, focusing on new pond creation, or existing pond restoration. However, there is a third approach; the re-excavation of ‘ghost ponds’ – former ponds deliberately filled-in due to agricultural intensification. Previous work has shown ghost ponds to retain viable sediment propagules of many aquatic plants for over a century, allowing for the rapid re-colonisation of resurrected pond sites. Here we detail the practicalities of the ghost pond resurrection approach, describing how to locate, identify, and excavate ghost ponds in agricultural land. We also report on colonisation by aquatic macrophytes and water beetles (Coleoptera) for three ghost pond resurrections in Norfolk, eastern England and make comparisons with neighbouring extant ponds restored to open-canopy conditions via major scrub and sediment removal at the same time. Ecologically important macrophyte taxa, including charophyte and Potamogeton species, successfully established in the ghost ponds and within one year they supported a comparable species diversity to the adjacent restored ponds. Our findings show that, where appropriate to land management goals, ghost pond resurrection could be a very valuable conservation approach within farmed landscapes.
B Cell Receptor-Responsive miR-141 and viral miR-BART9 promote Epstein-Barr Virus Reactivation Through FOXO3 Inhibition
Authors: Chen Yan , Fachko Devin , Ivanov Nikita S. , Skalsky Rebecca L.
Published: November 2019

Antigen recognition by the B cell receptor (BCR) is a physiological trigger for reactivation of Epstein-Barr virus (EBV) and can be recapitulated in vitro by cross-linking of surface immunoglobulins. Previously, we identified a subset of EBV microRNAs (miRNAs) that attenuate BCR signal transduction and subsequently, dampen lytic replication in B cells. The roles of host miRNAs in virus reactivation are not completely understood. To investigate this process, we profiled the small RNAs in latently infected and reactivated Burkitt’s lymphoma cells, and identified several miRNAs, such as miR-141, that are induced upon BCR cross-linking. Notably, EBV encodes a viral miRNA, miR-BART9, with sequence homology to miR-141. To better understand the functions of these two miRNAs, we examined their molecular targets and experimentally validated multiple candidates commonly regulated by both miRNAs. Targets included transcriptional regulators of the EBV immediate early promoters and B cell transcription factors, leading us to hypothesize that these miRNAs modulate kinetics of the latent to lytic switch in B cells. Through functional assays, we identified roles for miR-141 and EBV miR-BART9 and one specific target, FOXO3, in lytic reactivation. Our data support a model whereby EBV exploits BCR-responsive miR-141 and further mimics activity of this miRNA family via a viral miRNA to promote productive virus replication.

Importance

EBV is a human pathogen associated with several malignancies. A key aspect of lifelong virus persistence is the ability to switch between latent and lytic replication modes. Mechanisms governing latency and lytic reactivation are only partly understood, and how the EBV latent to lytic switch is post-transcriptionally regulated remains an outstanding question. This study sheds light on how miR-141 expression is regulated in Burkitt’s lymphoma cells, and identifies a role for FOXO3, a common target of both miR-141 and viral miR-BART9, in modulating EBV reactivation.
Asymmetric Hapln1a drives regionalised cardiac ECM expansion and promotes heart morphogenesis during zebrafish development
Authors: Derrick Christopher J , Sánchez-Posada Juliana , Hussein Farah , Tessadori Federico , Pollitt Eric JG , Savage Aaron M , Wilkinson Robert N , Chico Timothy J , van Eeden Fredericus J , Bakkers Jeroen , Noël Emily S
Published: November 2019

The mature vertebrate heart develops from a simple linear cardiac tube during early development through a series of highly asymmetric morphogenetic processes including cardiac looping and chamber ballooning. While the directionality of heart morphogenesis is partly controlled by embryonic laterality signals, previous studies have suggested that these extrinsic laterality cues interact with tissue-intrinsic signals in the heart to ensure robust asymmetric cardiac morphogenesis. Using livein vivoimaging of zebrafish embryos we describe a left-sided, chamber-specific expansion of the extracellular matrix (ECM) between the myocardium and endocardium at early stages of heart morphogenesis. We use Tomo-seq, a spatial transcriptomic approach, to identify transient and regionalised expression ofhyaluronan and proteoglycan link protein 1a(hapln1a),encoding an ECM cross-linking protein, in the heart tube prior to cardiac looping overlapping with regionalised ECM expansion. Loss- and gain-of-function experiments demonstrate that regionalised Hapln1a promotes heart morphogenesis through regional modulation of ECM thickness in the heart tube. Finally, we show that while induction of asymmetrichapln1aexpression is independent of embryonic left-right asymmetry, these laterality cues are required to orient thehapln1a-expressing cells asymmetrically along the left-right axis of the heart tube.

Together, we propose a model whereby laterality cues positionhapln1aexpression on the left of the heart tube, and this asymmetric Hapln1a deposition drives ECM asymmetry and subsequently promotes robust asymmetric cardiac morphogenesis.
Macroeconomic determinants of credit risks: evidence from high-income countries
Authors: Koju Laxmi , Koju Ram , Wang Shouyang
Published: November 2019

Purpose

The purpose of this paper is to empirically assess the significant indicators of macroeconomic environment that influence credit risk in high-income countries.

Design/methodology/approach

The study employs the system generalized method of moments estimator to avoid the dynamic panel bias and endogeneity issues. Different indices of economic growth are used in each model in order to find the most significant proxy of the economic cycle that influences problem loans. The analysis is carried out using a sample of 49 developed countries covering a 16-year period (2000–2015).

Findings

The overall empirical results highlight that the development of industrial sectors and exports are the main drivers of loan performance in high-income countries. The findings specifically recommend adopting an expansionary fiscal policy to boost per capita income and potential productivity for the safety of the banking system.

Practical implications

The findings have direct practical applicability for stabilizing the financial system. The study recommends the government to increase the productivity of export-oriented industries in order to boost employment and increase the payment obligations of individuals and business firms. More importantly, it highlights the essentiality of perfect economic policy to control default risks.

Originality/value

To the best of the authors’ knowledge, this is the first empirical study that compares the relative effect of three alternative proxies of the economic cycle on credit risk and identifies the most significant proxy. The current study also empirically shows that industrial development could be one of the crucial factors to improve financial health in developed countries.
Tracing the radical, the migrant, and the secular in the history of Australian schooling
Authors: Low Remy , Mayes Eve , Proctor Helen
Published: November 2019

Purpose

The purpose of this paper is to introduce a broad theoretical orientation for the themed section of History of Education Review, “Unstable concepts in the history of Australian schooling: radicalism, religion, migration”. Through the conceptual frame of “contrapuntal historiography”, it commends the practice of re-looking at taken-for-granted concepts and re-readings of the cultural archive of Australian schooling, with especial attention to silences, discontinuities and the movements of concepts.

Design/methodology/approach

Drawing on Edward Said’s approach of “contrapuntal reading”, this paper refers to the recent work of Bruce Pascoe as an exemplar of this practice in the field of Australian history. It then relates this approach to the study of the history of Australian schooling as demonstrated in the three papers that make up the themed section “Unstable concepts in the history of Australian schooling: radicalism, religion, migration”.

Findings

Following in the style of Said’s contrapuntal reading and the example of Pascoe’s work, this paper argues that there are inerasable traces of historical politics – that is, the records of constitutive exclusions and silences – which “haunt” taken-for-granted concepts like the migrant, the secular and the radical in the history of Australian schooling.

Originality/value

Taken alongside the three papers in the themed section, this paper urges the proliferation of different theoretical and disciplinary approaches in order to think anew about silences, discontinuities and movements of concepts as a counterpoint to dominant narrative lines in the history of Australian education.
Uncovering the factors impacting visitor’s satisfaction: evidence from a portfolio of events
Authors: Almeida António , Teixeira Sergio Jesus , Franco Mara
Published: November 2019

Purpose

The purpose of this paper is to get insights on a real-life portfolio of events from a demand-centred prospective, based on the identification of factors influencing the degree of attendee’s satisfaction, with the ultimate aim of identifying commonalities and prospective cross-leverage strategies among events.

Design/methodology/approach

Data from attendees to three major events taking place in Funchal, the capital city of Madeira, were analysed based on multivariate statistics and categorical regression owing to the overwhelming presence of categorical data in the database. The econometric analysis pursued in this paper is based on a sample of 1,830 tourists.

Findings

The research demonstrates that the impact of the socio-economic variables and travel arrangements on attendees’ satisfaction is rather irrelevant, irrespective of the event under analysis, with cross-cutting factors defining the overall quality of any event (mainly technical aspects such as aesthetical elements, organization and opening hours) determinant in predicting the overall degree of satisfaction. Another key finding relates to the existence of a number of commonalities among events, in terms of tourists’ profiles, market orientation, themes and resources laying ground to define ready-to-apply cross-leverage strategies.

Research limitations/implications

The analysis concentrated on three major events taking place in the capital city of a peripheral region. The content of the questionnaire co-developed with the destination management organization with order to get access to a large sample of respondents.

Practical implications

Lessons to be learnt in terms of managing a disparate collection of events developed over time in an ad hoc manner. A few examples of cross-leverage strategies are put forward.

Originality/value

The analysis and empirical content portrayed in this study contribute to the literature on event portfolio via description of real-life case examples of how to develop competencies based on post-event analysis in a proactive manner.