tbuckley/cabot-search huggingface dataset:
OS09.1 Radiosensitivity gene signature and PD-L1 status predict clinical outcome of patients with lower grade glioma in the Cancer Genome Atlas (TCGA) Dataset
Authors: B. Jang, I. Kim
Journal: Neuro-Oncology (2017)

Background and Purpose: A radiosensitivity gene signature that included 31 genes was identified using microarray data from NCI-60 cancer cells; however, this signature has not been validated in independent datasets for lower grade glioma patients. We investigated the link between the radiosensitivity gene signature and programmed cell death ligand 1 (PD-L1) status and clinical outcome in order to identify a group of patients that would receive clinical benefit of radiotherapy (RT) combined with anti-PD1/PD-L1 therapy. Methods: We validated the identified gene signature related to radiosensitivity and analyzed the PD-L1 status of lower grade glioma in The Cancer Genome Atlas (TCGA) dataset using bioinformatic tools. To validate the gene signature, 516 samples were divided into two clusters using a consensus clustering algorithm based on expression profile of gene signature. According to their prognosis, two clusters were designated as their radiosensitive (RS) or radioresistant (RR). Patients were also stratified as PD-L1-high or PD-L1-low based on the median value of CD274 mRNA expression level as surrogates of PD-L1. The relationship between the RS/RR groups and PD-L1 status was also assessed and visualized with heat maps. The prognostic value was evaluated by Kaplan-Meier analysis and Cox proportional hazard models. Results: Patents assigned to the RS group had better 5-year overall survival (OS) rate than patients in the RR group by univariate analysis (63% vs. 52%, p=0.019) only when patients were treated with primary RT. The RR group was independently associated with the PD-L1-high group, and PD-L1 mRNA expression was significantly higher in the RR group (p<0.001) compared to that of the RS group. Among patients treated with elective primary or postoperative adjuvant RT, the RS group had better 5-year OS rate compared to the RR group in the PD-L1-high group (78% vs. 50%, p=0.031), and this difference was also significant by multivariate analysis (Hazard ratio=0.08, p=0.031). ESTIMATE immune score, representing the immunogenicity of tumors, is positively correlated with PD-L1 mRNA expression level (p=<0.001), and thus, we speculated that the PD-L1-high group had more immunogenic tumors, which could be more sensitive to radiation-induced immunologic cell death. Conclusion: We first evaluated the predictive value of the radiosensitivity gene signature following RT in for lower grade glioma patients in the TCGA and described a relationship with this radiosensitivity gene signature and PD-L1. The radiosensitivity gene signature and PD-L1 status were two important factors for prediction of the clinical outcome of RT in patients with lower grade glioma and may be used for selecting patients who will benefit from RT combined with anti-PD1/PD-L1 therapy.
P03.19 AQP4 in brain metastasis: its role and cross talk with the brain microenvironment.
Authors: B. Pollo, S. Scaranzin, S. Mazzetti, C. Calatozzolo, M. Farinotti, A. Marando, A. Silvani, F. Di Meco, M. Patanè
Journal: Neuro-Oncology (2017)

Aquaporins (AQPs) are a family of transmembrane channels, involved in transcellular and transepithelial fluids transport; AQP4 is enhanced in the brain, where is the main water channel, localized in the astrocytic endfoot processes. AQP4 is anchored to the blood-brain barrier (BBB) by the dystrophin-associated complex (DAPC) consisting of α-syntrophin and dystrophin. The AQP4 channel is co-expressed on the membrane with the inwardly rectifying K+ channel (Kir4.1) and the Na+/K+/Cl- cotransporter channel (NKCC1) to maintain extracellular homeostasis. In cancer AQPs promote cellular invasion and migration. Previously, in brain metastasis we observed AQP4 expression mostly in glial cells surrounding tumor, but also in metastatic cells (mainly on NSCLC). Therefore, in this study, our principal aim is to investigate the role of AQP4 pathway in tumor microenvironment, their cross talk with the extracellular matrix and its meaning in the metastatic process. So, we have performed a retrospective analysis about the expression of AQP4 and the molecules and channels associated to AQP4, on 87 brain metastases from different tumors: lung (n=36), breast (n=21), colon (n=7), kidney (n=11), melanoma (n=7), ovary (n=3), thyroid (n=1) and prostate (n=1). Dystrophin, α-syntrophin, Kir4.1 and NKCC1 were first evaluated by immunohistochemistry and then by molecular analysis. On 21 patients we analyzed both the primitive and metastatic tumor. We observed a great AQP4 expression at the metastasis-brain interface; high expression of α-syntrophin and NKCC1 was also observed, while Kir4.1 was lower. Western blot confirmed this expression of AQP4 both in tumor and in the surrounding tissue. qPCR showed a downregulation of AQP4 mRNA except for lung metastases. α-syntrophin showed a very high expression in metastatic cells compared to normal brain, but surprisingly mRNA levels were downregulated; dystrophin showed very low levels of expression both of protein and mRNA in tumor. NKCC1 and Kir4.1 channels were overexpressed compared to the brain. These results showed a deregulation of the whole pathway associated to AQP4 in the presence of the metastases. Besides, confocal images showed a polarization of AQP4 expression mostly in lung and breast metastases. The brain metastasis maintain the same profile of original tumor. Our preliminary studies in primitive neoplasms and their counterpart brain metastases suggest a cross talk from AQP4 pathway with adhesion molecules expression and extracellular matrix in response to the presence of tumor mass. In conclusion, our results confirmed a cross talk between AQP4 and the microenvironment during the metastatic process, having a role in to maintain homeostasis, trying to reduce the edema and to limit the spreading of tumor cells in the parenchyma. This study will provide an important step forward in the knowledge of microenvironment’s involvement in brain metastasis.
P09.13 F-18 FLT PET and MRI as outcome predictors in glioblastomas following chemoradiation therapy
Authors: H. Nandu, M. F. Kijewski, S. Dubey, A. P. Belanger, D. Reardon, P. Wen, S. Kesari, L. Horky, M. Park, R. Y. Huang
Journal: Neuro-Oncology (2017)

Purpose: To evaluate F-18 fluorothymidine (FLT) PET and MRI as pretreatment and post treatment biomarkers predicting progression free survival (PFS) and overall survival (OS) in patients with glioblastomas, and to discover predictors to improve stratification of patients for treatment. Materials & Methods: Twelve patients with newly-diagnosed glioblastomas who had had biopsy or subtotal resection were enrolled in a prospective clinical trial; they received baseline F-18 FLT PET and brain MRI as well as post- treatment PET and MRI at 4 weeks. Volumetric segmentation of tumor was performed on baseline FLAIR imaging and subsequently applied to T1+gadolinium contrast, T2, apparent diffusion coefficient (ADC), cerebral blood volume (CBV) images of baseline and post-treatment MRI, and to pre- and post-treatment FLT-PET images. The 10th, 25th, 75th, and 90th percentile values as well as mean signal intensity within each modality and time point were individually analyzed using the Kaplan-Meir approach to discover the best predictors of OS and PFS. Results: Several baseline MR parameters (mean and P90 ADC, P25 and P10 FLAIR) were significant predictors of OS (log-rank p = 0.041 ADC; p=0.016 FLAIR). Median survival was 10.07 months for low and 28.17 months for high ADC, and 17.8 months for low and 8.0 months for high FLAIR. Post-treatment ADC (P90 and P75) and normalized PET uptake (mean, P90, and P75) were significant predictors of OS (p=0.037 ADC; p=0.047 PET); median survival was 10.07 months for low and 28.17 months for high ADC, and 28.7 months for low and 10.8 months for high PET uptake. Conclusion: Volumetric analysis of baseline and post treatment diffusion MRI predicts progression and survival in patients with high-grade gliomas receiving chemoradiation therapy. Post treatment F-18 FLT PET also predicts survival.
SWOG S0120 Observational Trial for MGUS and Asymptomatic Multiple Myeloma (AMM): Imaging Predictors of Progression for Patients Treated At UAMS,
Authors: Christoph Heuck, Rachael Sexton, Madhav Dhodapkar, Qing Zhang, Saad Usmani, Bijay Nair, Frits van Rhee, Antje Hoering, John Crowley, John D Shaughnessy, Robert Z. Orlowski, Bart Barlogie
Journal: Blood (2011)
OS04.2 First in human study of the Cleveland Multiport Catheter and convection enhanced delivery of topotecan and gadolinium for recurrent GBM: Updated results
Authors: M. A. Vogelbaum, C. Brewer
Journal: Neuro-Oncology (2017)

Introduction: Most potential therapeutics fail to reach gliomas at clinically useful concentrations due to presence of the blood-brain and the blood-tumor barriers. Convection enhanced delivery (CED) was developed as a technique to bypass these barriers. The Cleveland Multiport Catheter (CMC) is a novel device that was designed to produce high volume, backflow resistant CED. The device consists of a central shaft, which is placed with use of conventional neurosurgical stereotactic techniques, that deploys 4 infusion microcatheters into target tissue. The device is designed to permit treatment within the operating room (OR) and/or in a nursing unit outside of the OR. Methods: A Sponsor-Investigator IND covering both the CMC and drug (topotecan HCL with gadolinium DTPA) was obtained from the FDA. Two pilot trials were opened to evaluate the use of the CMC in patients with recurrent high grade glioma. The first trial evaluated delivery in both enhancing tumor and tumor-infiltrated brain. The second trial evaluated delivery in tumor-infiltrated brain after resection of the enhancing tumor. We used MRI to evaluate the distribution of the infused gadolinium to evaluate drug delivery into enhancing tumor and non-enhancing, tumor infiltrated brain. Quantitative assessment of drug distribution was made by a blinded evaluator. Results: Ten patients have been treated with the CMC since December, 2014. All patients underwent successful stereotactic placement of two CMCs each and completed protocol-defined infusions ranging from 48 to 96 hours; 3 in the first pilot trial and 7 in the second trial. Intraoperative and peri-operative MR imaging has demonstrated tracer delivery from every CMC placed to date (20 catheters, 80 microcatheters) without obvious backflow along the CMC shaft. We found large differences in the volumes of distribution between catheters placed in enhancing versus nonenhancing, tumor infiltrated brain. After 3 patients were treated on the first protocol, we opened the second trial to treat tumor infiltrated brain only after resection of the enhancing mass. High volume CED distribution (range: 25 to 92 cc) was observed in the 7 patients who received 2 CMCs in tumor infiltrated brain. There were no hemorrhages related to catheter placement or removal. Infusion related safety data will be presented. Conclusions: Co-infusion of a tracer is an essential tool for understanding the delivery characteristics of a CED device. We have found that the CMC consistently provides high volume, backflow resistant CED in tumor infiltrated brain. Safety of CED appears to be primarily related to drug concentration and distribution.
Bioresorbable Fe–Mn and Fe–Mn–HA Materials for Orthopedic Implantation: Enhancing Degradation through Porosity Control
Authors: Michael Heiden, Eric Nauman, Lia Stanciu
Journal: Advanced Healthcare Materials (2017)

Resorbable, porous iron–manganese–hydroxyapatite biocomposites with suitable degradation rates for orthopedic applications are prepared using salt‐leaching for the first time. These transient biomaterials have the potential to replace inert, permanent implants that can suffer from long‐term complications, or have to be surgically removed, leaving an unfavorable void. Fe30Mn‐10HA materials are newly developed to address inadequate resorption rates of degradable materials proposed for orthopedic environments in the past. In this study, controllable porosities with 300 µm diameter pores are introduced into Fe30Mn alloys and Fe30Mn‐10HA composites, which enhance tissue ingrowth. For the composites, a Ca 2 Mn 7 O 14 phase generated within the Fe30Mn matrix during the sintering process greatly increases degradability. The combination of this second phase and added porosity is found to contribute to increased bone‐like apatite layer formation, mouse bone marrow mesenchymal stem cell attachment, and reduction of detrimental oxide layer flaking. Remarkably, after thirty days in vitro, there is a significant increase in degradation up to 0.82 ± 0.04 mm per year for 30 wt% porous Fe30Mn‐10HA biocomposites, compared to 0.02 ± 0.00 mm per year for traditional nonporous Fe30Mn, thereby increasing the viability of these materials for future clinical studies.
Reply
Authors: Tatehiro Kagawa, Yukihiko Adachi
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. Reply: We appreciate the interest shown by Dr. Kokudo and colleagues in our work1 and agree with their comments regarding the necessity of further research on the effects of SLCO1B3 gene variants on the indocyanine green (ICG) retention test. In our study, we have shown that ICG clearance is markedly delayed in individuals harboring a homozygous insertion of long interspersed element (L1) retrotransposon in intron 5 of the SLCO1B3 gene. These individuals are assumed to lack OATP1B3 function because hepatic OATP1B3 expression is undetectable. Furthermore, because they do not carry any pathogenic variants of the SLCO1B1 and NTCP (SLC10A1) genes, OATP1B3 is assumed to be the sole transporter involved in the hepatic uptake of ICG. Its transportation activity should therefore be taken into account when evaluating the ICG retention test, which is widely used to assess preoperative liver function. In this context, it is important to elucidate whether ICG clearance is impaired in individuals who carry a heterozygous L1 insertion in the SLCO1B3 gene. It should be noted that this insertion is not rare in the Japanese population, with an allele frequency of 0.054.2 A number of studies have documented the association of single‐nucleotide polymorphisms in introns of the SLCO1B3 gene with mild unconjugated hyperbilirubinemia3 and docetaxel‐induced leukopenia.4 The effects of these polymorphisms on OATP1B3 function should be explored further. In vitro studies have shown that drugs such as docetaxel and telmisartan are taken up into the liver mainly by OATP1B3.5 While we acknowledge that the results of in vitro studies do not always represent actual in vivo interactions, this does suggest that severe adverse reactions may occur when OATP1B3 function is markedly impaired. The relationship between transporters and substrates is often redundant. Therefore, uncovering simple combinations such as OATP1B3 versus ICG will provide further insight into the complicated hepatic transport system.
P04.01 [11C]-(R)PK11195 PET imaging and Dynamic MRI in Transforming Gliomas
Authors: E. Agushi, D. Coope, R. Hinz, A. Jackson, F. Roncaroli
Journal: Neuro-Oncology (2017)

Introduction: The diagnosis of transforming glioma can be challenging with conventional MRI. Stereotactic biopsies based on post-contrast MRI can miss the regions of early transformation, therefore leading to inaccurate tumour grade. Dynamic MRI together with positron emission tomography (PET) can provide additional physiological and biological information to identify regions of anaplastic transformation. The translocator protein (TSPO) is an 18 kDa mitochondrial molecule that can be imaged with PET using the radiotracer [11C]-(R)PK11195. We compared [11C]-(R)PK11195 PET to relative cerebral blood volume (rCBV), which is known to rise earlier than contrast enhancement during progression. Methods: Twenty-six patients (mean age 38 ± 11.5, M/F=16/10) with lesions suspicious of transforming glioma on clinical MRI were recruited. All patients underwent perfusion MRI and dynamic [11C]-(R)PK11195 PET scans. Parametric maps of rCBV and [11C]-(R)PK11195 binding potential (BP) were generated. Co-registered MR/PET images were used to guide biopsy/resection. The cohort consisted of 12 astrocytomas (5 grade III) and 14 oligodendroglioma (3 grade III) All but one were IDH1R132H mutant; all oligodendrogliomas showed 1p19q co-deletion; low-grade and anaplastic astrocytomas lost ATRX expression. Results: BP and rCBV differed between grade II and III tumours. Both AA and AO demonstrated higher mean and maximal BP of [11C]-(R)PK11195 (mean BP: 0.08 ± 0.18 vs. -0.07 ± 0.15, p=0.032; maximal BP: 1.59 ± 0.63 vs. 0.79 ± 0.28, p=0.001). Increased rCBV was found in oligodendrogliomas grade II and III compared to astrocytomas of similar grade (mean rCBV: 1.38 vs 0.97 and 1.44 vs. 1.09 respectively, p=0.01). Although, no significant increase of rCBV was found in AO and AA compared to lower grade oligodendrogliomas and astrocytomas (mean rCBV of whole tumour: 1.44 vs 1.38 and 1.09 vs.0.97 respectively, p=0.53). To further investigate correlations between rCBV and [11C]-(R)PK11195 BP, we defined a 10mm volume of interest (VOI) on highest uptake of radiotracer and compared with the mean rCBV of the same VOI. A significant correlation was found between BPmax and rCBV of the same 10mm VOI (pairwise correlation coefficient = 0.5984, p= 0.0042). High variance of [11C]-(R)PK11195 binding between grade III gliomas was observed; 5 out of 8 grade III gliomas (3 oligodedrogliomas) demonstrated high BP areas corresponding to or extending beyond areas of enhancement where present. Three grade III tumours with no contrast enhancement showed high [11C]-(R)PK11195 binding. Conclusions: [11C]-(R)PK11195 has the potential to detect transformation and provides information complimentary to perfusion metrics in early detection of progression.
Clinico-molecular study of synchronous head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC).
Authors: Somkiat Sunpaweravong, Patrapim Sunpaweravong, Tanadech Dechaphunkul, Tanjitti Pongrujikorn, Sacarin Bunbanjerdsuk, Natini Jinawath
Journal: Journal of Clinical Oncology (2015)

e17080 Background: The prognoses of HNSCC and ESCC are poor, especially when two primary tumors occur at the same time. In an earlier study, we found 12.4% of all HNSCC patients had a synchronous ESCC at the time of diagnosis. To confirm whether these second tumors were of metastatic origin or a separate second primary tumor (SPT), we employed genome-wide SNP array analysis to analyze the differential LOH pattern of each synchronous tumor pair. The clinical information of the patients with synchronous tumors was also summarized. Methods: Twenty-one synchronous HNSCC formalin-fixed paraffin-embedded (FFPE) tissue samples and their ESCC counterparts were subjected to DNA extraction, quality assessment, and subsequent SNP array experiments using Illumina HumanCytoSNP12 FFPE BeadChip, which contains 300,000 probes. Signal intensity and B-allele frequency data of each pair were analyzed to identify Copy Number Variation (CNV) and LOH using Nexus Copy Number software suite. Results: Comparing the LOH pattern of each primary HNSCC to its esophageal tumor counterpart, we found 20 out of 21 pairs had a low number of concordant LOHs (LOH at the same genomic location seen in both HNSCC and ESCC) and a high number of discordant LOHs (LOH identified solely in primary HNSCC, but not in second ESCC at the same genomic location). Only one of the cases fell into the undetermined category. We conclude that the second esophageal tumors in our patients were indeed individual SPTs. Synchronous HNSCC and ESCC are considered to be of worse prognostic value compared with non synchronous tumors. Conclusions: We propose here the use of a genome-wide SNP array as a tool to differentiate metastatic tumors from SPT. The SNP array offers genome-wide LOH information that earlier microsatellite analysis studies lack. The ability to accurately identify SPT should contribute to a better treatment plan and follow-up care of this group of patients. Clinical correlation using a larger study group may help clarify the clinical characteristics of SPT.
Epidemiological Study of Scarlet Fever in England and Wales Since 1900.
Journal: JAMA (1933)

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Botryoid nuclei resulting from cocaine abuse
Authors: Maurizio Fumi, Ylenia Pancione, Silvia Sale, Vincenzo Rocco, Barbara J. Bain
Journal: American Journal of Hematology (2017)

We were interested in the rapid disappearance of the abnormal leukocytes and sought to explain this by an in vitro experiment. A K2-EDTA-anticoagulated blood sample was incubated at 41.9°C for 1 h. A blood count and films were then performed and these were repeated over the next 8 h with storage at ambient temperature (Table 1). Reversion to normal cytology was demonstrated. This nuclear abnormality is thus reversible within certain limits. Botryoid nuclei are a feature of burns and of hyperthermia of diverse origins including heatstroke, brainstem hemorrhage or ischemia, encephalitis, malignant hyperthermia (genetically determined susceptibility to anesthesia-induced hyperthermia), and abuse of cocaine or methamphetamine.1-3 This observation can thus be a clue to drug abuse. In addition, the patient initially showed stress lymphocytosis with a subsequent rapid fall of the lymphocyte count to subnormal levels. Nothing to report.
Systematic Review and Meta-Analysis of the Association Between Transfusion Independence (TI) and Overall Survival (OS) in Patients (pts) with Myelodysplastic Syndromes (MDS)
Authors: Sue Harnan, Shijie Ren, Tim Gomersall, Emma Everson-Hock, Anthea Sutton, Sujith Dhanasiri, Austin Kulasekararaj
Journal: Blood (2014)