tbuckley/cabot-search huggingface dataset:
P04.08 Is BCAT1 a new MR imaging-related biomarker for prognosis prediction in IDH1-wildtype glioblastoma patients?: Radiogenomics study
Authors: H. Cho, B. Hong, C. Park, S. Park, S. Choi
Journal: Neuro-Oncology (2017)

Purpose: To elucidate radiogenomics association beween magnetic resonance (MR) imaging signatures and expression level of branched-chain amino acid trasaminase1 (BCAT1) messenger RNA (mRNA) in the isocitrate dehydrogenase 1 (IDH1)-wildtype glioblastoma multiforme (GBM). Materials and Methods: Radiogenomic analysis was performed by using MR imaging in 69 patients with GBM in this retrospective study, which was approved by institutional review board in our institute. To evaluate the BCAT1 expression level, quantitative RT-PCR, immunohistochemistry and western blot were performed with GBM patient tissues. Eight MR imaging parameters were evaluated from DSC perfusion imaging (mean CBV, and 95% nCBV) and diffusion weighted imaging (mean ADC1000, and 5 % ADC1000), of which segmentation was based on both contrast-enhanced (CE) T1WI and FLAIR imaging. MR imaging was obtained at 3T scanner (Verio; Siemens Healthcare Sector) and post-processing was performed by using a dedicated commercialized software (Nordic ICE, NordicNeuroLab). The expression level of BCAT1 was compared, and correlated with quantitative MR imaging features by using t-test and Pearson correlation analysis, respectively. Progression-free survival (PFS) associated with interested BCAT1 mRNA and miRNA was performed by Kaplan-Meier survival analysis. Results: The expression level of BCAT1 RNA was significantly higher in IDH1-wildtype patients (n = 60) than in IDH1-mutant patients (n = 9) (P = 0.0021). Similar to this RNA expression results, immunohistochemistry and western blot showed that the BCAT1 protein expression was also higher in IDH1-wildtype patients than in IDH1-mutant patients. In MR imaging features, nCBV based on FLAIR (R2 = 0.08291, P = 0.0164) and 95 % nCBV based on CE T1WI (R2 = 0.07232, P = 0.0255) were significantly correlated with BCAT1 expression level in GBM patients. Moreover, median PFS in patients with BCAT1 expressing of ≤150 was longer than those with BCAT1 expressing of 150≤ (12 vs 43 months, P = 0.004). Conclusion: We found that high BCAT1 expression level was observed in IDH1-wildtype GBM, which was correlated with high CBV value. Thus, we believe that DSC-perfusion MR imaging could be helpful in predicting the prognosis related BCAT1 expression, which seems to be crucial in selecting future tailored treatment for IDH1-wildtype GBM patients.
P09.43 Novel geometrical imaging biomarkers predict survival and allow for patient selection for surgery in glioblastoma patients.
Authors: J. Pérez-Beteta, D. Molina, A. Martínez-González, E. Arregui, B. Asenjo, L. Iglesias, J. Martino, L. Pérez-Romasanta, E. Arana, V. M. Pérez-García
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma is the most frequent and lethal malignant brain tumor in adults. Preoperative magnetic resonance imaging is routinely used for diagnosis and treatment planning. One of the gold standards in imaging are the post-contrast T1-weighted magnetic resonance images (MRIs) that are used to define the macroscopic part of the tumor. A modern mathematical model has predicted a relation between tumor's growth speed, and so the patient outcome, with the width of contrast enhancing areas measured on the pre-surgery post-contrast 3D T1-weighted images. Other works have hypothesized the role of the tumor's surface as a driver for growth and infiltration in cancer. Materials and Methods: A retrospective study involving 7 hospitals was organized for the validation of the model predictions. Inclusion criteria where unifocal tumors and availability of 3D T1w MRIs and clinical data (age, survival, type of treatment, etc). 219 patients were included in the study. Tumors were manually segmented and thirty quantitative geometrical 3D variables computed including volumes (total tumor, contrast enhancing and necrotic), surfaces, volume ratios, 3D maximal diameter and several measures of the contrast enhancing 'rim'. A novel measure was defined accounting for how much the tumor surface as measured on the post-contrast T1w MRIs deviates from a sphere of the same volume. Kaplan-Meir and Cox regression methods were used to validate the relevance of the different features. Results: Patients with small contrast enhancing width (< 3.7 mm) showed a significant improvement in survival (p = 0.002, differences in median = 191 days, HR = 1.701). The tumor surface irregularity turned out to be a very powerful predictor of survival (p = 0.004, differences in median = 104 days, HR = 1.516). Both parameters were significant in multivariate analysis together with the age (p = 0.007 for surface irregularity and p = 0.009 for rim width). No other parameters including volumes, volume ratios, surfaces, maximal diameters, and other features were associated with survival neither in univariate nor in multivariate analyses. Conclusions: The width of the contrast enhancing rim and a novel surface irregularity parameter were predictors of survival in a large cohort of GBM patients. Since the study methodology was very robust (high resolution MRIs, tumor segmentation methodology) and the number of geometrically meaningful parameters large in comparison with previous studies this study may shed some light on the long debated topic of the role of geometrical measures on GBM patient's survival. FUNDING: James S. Mc. Donnell Foundation (USA) 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer [Collaborative award 220020450 and planning grant 220020420], MINECO/FEDER [MTM2015-71200-R], JCCM [PEII-2014-031-P].
Single nucleotide polymorphisms (SNPs) of the platinum pharmacogenetic and VEGF pathways: Association with survival of platinum-treated stage IV non-small cell lung cancer (NSCLC) patients.
Authors: Sinead Cuffe, Xiaoping Qiu, Abul Kalam Azad, Xin Qiu, Kevin Boyd, Qin Kuang, Sharon Marsh, Sevtap Savas, Marjan Emami, Nicole Perera, Prakruthi R. Palepu, Zhuo Chen, Devalben Patel, Dangxiao Cheng, Ronald Feld, Natasha B. Leighl, Frances A. Shepherd, Ming Sound Tsao, Wei Xu, Geoffrey Liu
Journal: Journal of Clinical Oncology (2012)

7586 Background: Two potentially important host pathways in lung cancer systemic therapy are: (i) the pharmacogenetic pathway of platinum agents (DNA repair, metabolism, and multidrug resistance genes); and (ii) the vascular endothelial growth factor (VEGF) pathway. We investigated the relationship between SNPs in these two pathways and clinical outcome in platinum-treated NSCLC patients. Methods: 188 platinum-treated Stage IV NSCLC patients underwent SNP genotyping for the platinum-related (48 SNPs in 7 genes) and VEGF (64 SNPs in 3 genes) pathways. SNPs were selected from the literature and through tagging. Association of SNPs and overall (OS) and progression free survival (PFS) were assessed using multivariate Cox proportional hazards models. Results: 72% were Caucasian; 73%, adenocarcinoma; 92%, ECOG PS 0-1; median age, 60 years; 54% received &gt; one line of systemic therapy; 10% received anti-VEGF therapy/placebo; Median OS, 1.3 yrs; median follow up, 2.2 yrs. The top significant SNPs in the platinum-related pathway were in ABCC2 (rs8187710 and rs2756109, r 2 =0.68). The G variants of the top SNP, ABCC2 rs8187710 (4554G&gt;A), were associated with worse OS (adjusted hazard ratio [aHR], 2.62; 95%CI: 1.5-4.5; p=0.0005) and PFS (aHR, 1.97; 95%CI: 1.2-3.4; p=0.01). Functionally, 4554G&gt;A impairs ATP-ase activity and is associated with higher cellular accumulation of ABCC2 substrates [PMID: 22027652]; furthermore, ABCC2 expression is associated with cisplatin resistance and clinical outcome in other cancers [PMID: 17145840]. Within the VEGF pathway, the top significant SNPs were in the same haplotype block of VEGFR1/FLT1 (rs1324057, rs7324547, r 2 =1.0): for rs1324057, the aHR for OS was 1.59 (95%CI 1.2-2.1); p=0.001; and the aHR for PFS, 1.48 (95%CI 1.1-1.9); p=0.004. VEGFR1/FLT1 rs7324547 has been associated with esophageal cancer risk [PMID: 21751195], but has not been assessed in lung cancer. Conclusions: SNPS of the VEGFR1 and ABCC2 genes are strongly associated with OS and PFS in this cohort of platinum-treated advanced NSCLC patients. Future studies should assess whether these are predictive or prognostic markers.
Effect of drug loading on the pharmacology, pharmacokinetics, and toxicity of an anti-CD30 antibody-drug conjugate
Authors: Kevin J. Hamblett, Damon L. Meyer, Dana F. Chace, Roger F. Zabinsky, Charles G. Cerveny, Michael M. Sun, Peter D. Senter, Joseph A. Francisco
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

624 

Antibodies that target tumor-associated antigens are currently used in the clinic to treat cancer, in some cases as front-line therapy. Even with these successes there is a need to improve the therapeutic activity of antibody-based therapies. We have recently shown that an antibody-drug conjugate (ADC) targeted to CD30 has potent and selective activity against CD30+ malignancies such as Hodgkin’s disease (HD) and anaplastic large cell lymphoma (ALCL) (Blood 102: 1458-1465, 2003). This ADC, cAC10-vcMMAE, consists of a chimeric anti-CD30 antibody, cAC10, conjugated with 8 molecules of the cytotoxic drug monomethyl auristatin E (MMAE). The drug moieties were attached via a Val-Cit peptide linker to the 8 cysteine residues that comprise the 4 inter-chain disulfide bonds of the cAC10 antibody. cAC10-vcMMAE first binds to CD30 expressed on the surface of CD30+ cells and, upon internalization, drug moieties are enzymatically released and inhibit tubulin polymerization. In the present work, we sought to optimize the therapeutic potential of cAC10-vcMMAE conjugates by assessing the impact of drug loading. ADCs with 2 and 4 drugs per mAb, cAC10-vcMMAE2 and cAC10-vcMMAE4, respectively, were constructed and compared to cAC10-vcMMAE8. Cytotoxicity of the ADCs against CD30+ cell lines in vitro was found to be dependent on drug loading; as drug loading increased ADC cytotoxicity was enhanced. Karpas-299, an ALCL line, and L540cy, a HD cell line, were implanted into SCID mice to compare the efficacy of the ADCs. Unlike the in vitro findings, decreasing drug loading did not necessarily reduce potency in vivo . Complete regressions were achieved with cAC10-vc-MMAE8 and cAC10-vcMMAE4 at the same dose of antibody even though the latter contained half the amount of cytotoxic drug. The difference between cAC10-vcMMAE2 and cAC10-vcMMAE4 was dependent on drug load in that twice the dose was required to achieve complete regressions with cAC10-vcMMAE2. The clearance of the cAC10-ADCs was directly related to the drug loading as cAC10-vcMMAE8 cleared faster than cAC10-vcMMAE4. Similarly, cAC10-vcMMAE2 cleared the slowest of any ADC tested, and was comparable in clearance with the naked cAC10 antibody. In contrast to the in vivo efficacy, there was evidence of a correlation between drug loading and the maximum tolerated dose (MTD). The MTDs of cAC10-vc-MMAE2 and cAC10-vc-MMAE4 in mice were at least four-fold and two-fold higher, respectively, than cAC10-vc-MMAE8. Our data indicates that decreasing the drug loading from eight to four drugs per antibody doubles the therapeutic window of the cAC10-vcMMAE. These results demonstrate that drug loading is a key design parameter in optimizing the therapeutic window of ADCs.
P01.31 Mammalian target of rapamycin complex 1 activation sensitizes human glioma cells to hypoxia-induced cell death
Authors: A. Thiepold, M. Foltyn, H. Urban, M. Voss, U. Hofmann, S. Dröse, P. N. Harter, M. Mittelbronn, J. P. Steinbach, M. W. Ronellenfitsch
Journal: Neuro-Oncology (2017)

Glioblastomas (GBs) are characterized by a fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from epidermal growth factor receptor (EGFR) via mammalian target of rapamycin complex 1 (mTORC1) is one of the most commonly altered signalling pathways in GBs. Therefore, EGFR and mTORC1 signalling are plausible targets for GB therapy and clinical trials with inhibitors are in progress. However, we have previously shown that EGFR and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting tumour cells from hypoxia-induced cell death. We hypothesized conversely that mTORC1 activation sensitizes glioma cells towards hypoxia-induced cell death. As a model for mTORC1 activation we used TSC2 gene suppression (TSC2sh). TSC2sh glioma cells showed increased sensitivity towards hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway (PPP). Mechanistically mTORC1 upregulates the first and rate limiting enzyme of the PPP, glucose 6-phosphate dehydrogenase (G6PD), in a post-transcriptional manner. Furthermore an increase in O2 consumption in TSC2sh cells was detected. This appears to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PGC-1-α and -β. In a translational approach, the finding that mTORC1 activation causes an increase in O2 consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify GB patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGF-A-targeting antibody bevacizumab.
P05.02 Chemotherapy-induced peripheral neuropathy in Egyptian patients: single institution retrospective analysis
Authors: A. Gaballah, K. Elhusseiny, A. Shafik, M. Ashraf
Journal: Neuro-Oncology (2017)

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect that may require treatment modification or cessation and worsen the patients’ quality of life. Typically, it is sensory and presents with “glove and stocking” distribution. It occurs in 30–40% of patients. The highest incidence reported with cisplatin, oxaliplatin, vincristine, paclitaxel, bortezomab and docetaxel. Its incidence and severity depends on treatment-related factors and patient-related factors. Till now, no specific treatment can be used to prevent the development of CIPN. The symptoms are self-limiting with recovery rate post-treatment of about 50%. Methods: This is a retrospective analysis that took place in the chemotherapy unit for patients received treatment between January 2014 and December 2015. We reviewed the patients and treatment-related factors. The incidence of neuropathy and grade were recorded using NCI-CTCAE v4.03. We selected 4 drugs for analysis; cisplatin, oxaliplatin, paclitaxel and docetaxel. Results: 250 patients were eligible. 53 patients received paclitaxel-containing regimens, 78 patients received docetaxel, 64 received cispaltin and 55 received oxalipaltin. The mean age was 50.11 years (SD ± 11.54). 21.6% of patients had DM, 4% had hepatic disease and 0.8% had renal impairment. The incidence of CIPN was 46.8%. Grade I represented 70.9%, 24.7% grade II, 4.4% was grade III. Incidence of CIPN was 74% in oxaliplatin group, 73.5% with paclitaxel, 35.9% with cisplatin and 17.9% with docetaxtel. After 6 months from cessation of chemotherapy 24% of patients recovered completely. Correlation with patients’ characteristics and CIPN was not significat with age (> or ≤ 60 years) (p = 0.781), while was significant in cisplatin subgroup (p = 0.043). Diabetes was significantly associated with CIPN (p = 0.007), but DM doesn’t increase CIPN grade (p = 0.648). In subgroup analysis, with cisplatin, median cumulative dose of 450 mg/m2 and patients received ≥ 6 cycles had higher incidence of CIPN (p value 0.006 and 0.010 respectively). Also, cumulative dose of 480 mg/m2 and ≥ 6 cycles increase the grade of CIPN (GII or more). In the oxaliplaitn group, none was significantly correlated with CIPN but with a trend in doses ≥ 95 mg/m2/cycle (p = 0.092). In the paclitaxel group, CIPN was significantly higher in patients received ≥ 4 cycles (p = 0.005) with a trend in patients received a cumulative dose ≥ 480 mg/m2 (p = 0.074). In the docetaxel group, none was correlated with CIPN but patients who received > 4 cycles or cumulative dose ≥ 360 mg/m2 had a higher incidence of grade II CIPN (p < 0.001 for both). Conclusion: CIPN is common problem affecting cancer patients’ quality of life and lead to interruption treatment. There are many factors that increase its incidence like presence of DM, type of chemotherapy, drug cumulative dose and total number of cycles. The recovery is spontaneous and may persist.
HAMSTRINGS TRAINING EFFECT ON HIP AND KNEE JOINT FUNCTION, MORPHOLOGY OF HAMSTRING MUSCLES, AND INJURY PREVENTION
Authors: Takashi Ono, Michio Tojima, Norikazu Hirose
Journal: British Journal of Sports Medicine (2017)

Background There is little information about the effect of hamstrings training on hip and knee joint function, morphology of each hamstring muscle, and the rate of injury incidence. Objective To clarify the effect of hamstrings training on H:Q strength ratio in hip and knee joint, the morphological adaptations of each hamstring muscle, and the rate of strain injury incidence. Design Prospective, randomized controlled trial. Setting Collegiate, elite division. Participants 23 healthy collegiate Lacrosse players were recruited voluntarily, and 20 (39 limbs) of them finished the study. Interventions Subjects were randomly divided into 3 groups; Single-leg Deadlift (DL) intervention, Nordic Hamstrings (NH) intervention, and control (CR). DL and NH groups joined the training program in twice a week for 6 months. Main Outcome Measurements Before (Pre) and 1, 3, and 6 months after training period, isokinetic strength testing was conducted to measure flexion and extension torques in hip and knee joint, and magnetic resonance imaging to determine the cross sectional area (CSA) of each hamstring muscle. Results After the training of 3 months, only in DL group, significant increase of hip extension torque (+25.2±9.4%) and H:Q ratios in the hip joint (1.28±0.43→1.61±0.48) were found, and significant increase of CSAs were found in biceps femoris long head (+12.0±3.7%) and semimembranosus (+25.5±4.1%) muscle (P&lt;0.05). No strain injury has reported in all groups. Conclusions Hip extension (Single-leg Deadlift) exercise training may be useful for preventing and rehabilitating from hamstring strain injury by stimulating hypertrophy in biceps femoris long head and semimembranosus muscle and promoting improvements in hip extensor strength and H:Q ratio in hip joint. These data may provide compelling evidence to warrant the further exploration of hip extension oriented exercises in hamstring strain injury prevention protocols.
Co-administration of liposomal l-OHP and PEGylated TS shRNA-lipoplex: A novel approach to enhance anti-tumor efficacy and reduce the immunogenic response to RNAi molecules
Authors: Eman Alaaeldin, Amr S. Abu Lila, Hidenori Ando, Masakazu Fukushima, Cheng-Long Huang, Hiromi Wada, Hatem A. Sarhan, Khaled A. Khaled, Tatsuhiro Ishida
Journal: Journal of Controlled Release (2017)
P04.11 Effect of hemisphere and tumor grade on default mode deactivation in glioma patients
Authors: J. M. Jansma, G. Rutten
Journal: Neuro-Oncology (2017)

Introduction: In healthy subjects, the brain not only activates a network of brain areas during performance of a cognitive task, but also deactivates specific regions. The latter is known as the default mode network (DMN). It is hypothesized in the literature that within the DMN, deactivation in the extended posterior cingulate cortex region (ePCC) is associated with external focus and alertness. In this study, we analyzed data from a database of patients with a low grade (LGG) or high grade glioma (HGG). All patients performed a language production task which was part of a clinical fMRI protocol. For language production tasks, deactivation in the DMN appears to be lateralized to the right hemisphere, in contrast to the activation which is generally lateralized to the left. We were interested whether hemispheric location and tumor grade would differentially affect the capacity to deactivate the ePCC. Methods. Our database (30 HGG patients with tumor in left hemisphere, average age 50,.5; 26 HGG, right, age 50,7; 37 LGG, left, age 37.6; 16 LGG right, age 36.5). All patients performed a verb generation fMRI protocol, prior to surgery. For each group, we calculated the average signal difference in the ePCC brain region, a-priori based on an anatomical atlas. Group means were compared using unpaired tests. Results: Results indicated that patients with a HGG in the right hemisphere showed significantly less deactivation in ePCC than patients with a HGG in the left hemisphere (t = 2.23, p = 0.03) or patients with a LGG in the left hemisphere (t = 2.00; p = 0.05), while the difference with patients with a LGG in the right hemisphere showed a trend (t = 1.80, p = = 0.08). In patients with a LGG, the hemisphere of the tumor did not have an effect on deactivation of the ePCC (t = 0.38; p = 0.70). Conclusion: Our study indicates that within the four groups of patients, those with a HGG in the right hemisphere showed the most impaired capacity to deactivate the ePCC during a cognitive task. It is known from healthy subjects that deactivation during a language production task tends to be right lateralized, and this may explain that this effect is less pronounced when the tumor is in the left hemisphere. The reduced capacity to inhibit ePCC in patients with a HGG may be associated with reduced alertness and capacity to focus.
Adenoma detection rate – is it all about adding water?
Authors: Peter Klare
Journal: Endoscopy (2017)

Detecting adenomatous polyps is the main task of screening colonoscopy. The discovery of the adenoma – carcinoma sequence some decades ago marked the basis for current endoscopic prevention strategies. Since the establishment of screening colonoscopy programs in many countries, both the incidence and the mortality derived from colorectal cancer have declined [1] [2]; the latter fact suggests effectiveness of this preventive approach.
Geoffrey Munro Gill
Authors: Margaret Gill, Pierre Fouin
Journal: BMJ (2017)

After house posts at the Aberdeen Royal Infirmary and Aberdeen City Hospital, Geoffrey Munro Gill (“Geoff”) joined the Royal Armey Medical Corps for his national service and was posted to Japan and Korea. On completing his service he did six months at Aberdeen Maternity Hospital before joining his father, James Gill, in general practice in Inverurie, Aberdeenshire. Never lacking involvement, he pioneered one of the first health centres in the …
Outcome of High Dose Melphalan with Autologous Hematopoietic Stem Cell Transplant In Myeloma Associated with AL Amyloidosis
Authors: Simrit Parmar, Mubeen Khan, Gabriela Rondon, Nina Shah, Qaiser Bashir, Shawndeep Tung, Jatin J Shah, Donna Weber, Robert Z. Orlowski, Sergio Giralt, Richard E. Champlin, Muzaffar H. Qazilbash
Journal: Blood (2010)
P2.03b-029 Analysis of Genomic Alterations and Heterogeneity in Pulmonary Adenoid Cystic Carcinoma by Next-Generation Sequencing
Authors: Min Li, Bingrong Zhao, Pengbo Deng, Liming Cao, Huaping Yang, Qihua Gu, Chengping Hu
Journal: Journal of Thoracic Oncology (2017)