tbuckley/cabot-search huggingface dataset:
P11.47 Generation, characterisation and drug screening of patient-derivedIDH1-mutated glioma cell lines
Authors: C Verheul, T V Kers, A Van Der Ploeg, M Van Der Kaaij, M Aghababazadeh, M De Wit, Y Hoogstrate, E Struys, C M F Dirven, S Leenstra, P J French, M L M Lamfers
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Despite considerable scientific efforts, endogenous in vitro isocitrate dehydrogenase (IDH)-mutated glioma models remain scarce. Availability of these models is key to understanding underlying molecular mechanisms and vital for the development of new therapeutic interventions. We established and characterized a set of seven cell lines derived from IDH1-mutated gliomas and utilized them to investigate IDH-mutant glioma drug-response in vitro. MATERIAL AND METHODS Fresh tumor material was collected directly from the operating room, mechanically and enzymatically dissociated and cultured under serum-free culture conditions. IDH mutation status was verified at several passages with Sanger sequencing, as well as with whole exome sequencing. D-2-hydroxyglutarate (D2-HG) levels were determined with mass-spectrometry. Genome-wide methylation profiling was performed using the Infinium MethylationEpic BeadChip array. Cell viability was measured using the ATP-based CellTiter-Glo assay. Cell proliferation was determined through cell counting. Drug screens were performed with an FDA-approved anti-cancer drug set from the NIH as well as two IDH-mutant specific inhibitors. RESULTS Over the last decade our lab processed over 800 glioma samples from all WHO grades and IDH mutational status. Optimisation of culture conditions led to the establishment of seven IDH1-mutant glioma cell lines. The IDH1-mutation was present during all tested passages in these cell lines. Whole exome sequencing showed a high concordance between tumor and cell lines with regard to driver gene mutations. Similarly, copy-number changes based on genome-wide methylation data also show a close resemblance between the parental tumor and resulting cell lines. The Heidelberg methylation profiler classified each cell line and its parental tumor as IDH mutant glioma. When exposed to an IDH1-mutant specific inhibitor, all cell lines showed a concentration-dependent decrease of D2-HG levels. The inhibitors showed little to no effect on viability up to 10uM during 8 days, however, long term treatment up to 4 weeks revealed a decrease in cell doubling time in 2 of 6 cultures. Drug screen results either alone or in combination with an IDH1-mutant specific inhibitor identified several interesting candidates that are currently followed up in additional experiments. CONCLUSION We established a unique set of patient-derived IDH1-mutant glioma cell lines that closely resemble their respective tumors and can be used to identify new therapeutic strategies.
Cardiac and Neuromuscular Features of Patients With<i>LMNA</i>-Related Cardiomyopathy
Authors: Giovanni Peretto, Chiara Di Resta, Jacopo Perversi, Cinzia Forleo, Lorenzo Maggi, Luisa Politano, Andrea Barison, Stefano C. Previtali, Nicola Carboni, Francesca Brun, Elena Pegoraro, Adele D'Amico, Carmelo Rodolico, Francesca Magri, Rosa C. Manzi, Alberto Palladino, Franco Isola, Lorenzo Gigli, Tiziana E. Mongini, Claudio Semplicini, Chiara Calore, Giulia Ricci, Giacomo P. Comi, Lucia Ruggiero, Enrico Bertini, Paolo Bonomo, Gerardo Nigro, Nicoletta Resta, Michele Emdin, Stefano Favale, Gabriele Siciliano, Lucio Santoro, Gianfranco Sinagra, Giuseppe Limongelli, Alessandro Ambrosi, Maurizio Ferrari, Pier G. Golzio, Paolo Della Bella, Sara Benedetti, Simone Sala
Journal: Annals of Internal Medicine (2019)

Mutations in the LMNA (lamin A/C) gene have been associated with neuromuscular and cardiac manifestations, but the clinical implications of these signs are not well understood.To learn more about the natural history of LMNA-related disease.Observational study.13 clinical centers in Italy from 2000 through 2018.164 carriers of an LMNA mutation.Detailed cardiologic and neurologic evaluation at study enrollment and for a median of 10 years of follow-up.The median age at enrollment was 38 years, and 51% of participants were female. Neuromuscular manifestations preceded cardiac signs by a median of 11 years, but by the end of follow-up, 90% of the patients had electrical heart disease followed by structural heart disease. Overall, 10 patients (6%) died, 14 (9%) received a heart transplant, and 32 (20%) had malignant ventricular arrhythmias. Fifteen patients had gait loss, and 6 had respiratory failure. Atrial fibrillation and second- and third-degree atrioventricular block were observed, respectively, in 56% and 51% of patients with combined cardiac and neuromuscular manifestations and 37% and 33% of those with heart disease only.Some of the data were collected retrospectively. Neuromuscular manifestations were more frequent in this analysis than in previous studies.Many patients with an LMNA mutation have neurologic symptoms by their 30s and develop progressive cardiac manifestations during the next decade. A substantial proportion of these patients will have life-threatening neurologic or cardiologic conditions.None.
A phase I study of an MVA vaccine targeting p53 in cancer.
Authors: Vincent M. Chung, Nicola Hardwick, Joshua D.I. Ellenhorn, Jonathan R. Espenschied, Dean Lim, Peiguo Chu, Dajun Qian, Joseph Kim, Joseph Chao, Marwan Fakih, Yun Yen, Don J. Diamond
Journal: Journal of Clinical Oncology (2013)

3089 Background: Despite chemotherapy, survival for most patients with metastatic gastrointestinal cancer is &lt;2 years. These dismal statistics reflect lack of effective therapy. We are conducting a first-in-human trial of modified vaccinia Ankara (MVA), an attenuated viral vaccine that targets wild-type (wt) p53. This approach applies to the majority of p53-involved tumors, since the bulk of the p53 sequence is identical, except for individual point mutations. Our phase I study evaluates the safety and tolerability of the vaccine. Methods: Patients with metastatic colon, gastric and pancreas cancer that failed standard treatment were eligible for vaccination if &gt;10% of the cells stained strongly positive for p53. A standard 3+3 design was employed and patients were accrued to either the 10 8 pfu or 5.6 x 10 8 pfu dose levels. A total of 3 injections were given, each spaced apart by 3 weeks and patients were evaluated for dose limiting toxicities. Results: Three patients were accrued to the 10 8 pfu dose level; 2 patients with colon cancer and 1 patient with pancreatic cancer. There were no dose limiting toxicities and the injection was well tolerated and only local irritation at the injection site was seen. The dose was escalated to 5.6 x 10 8 pfu; 3 patients were accrued, 1 with colon cancer and 2 with pancreatic cancer. There were no dose limiting toxicities observed in the 3 patients. Grade 2 toxicities that were at least possibly related to the vaccine include injection site reaction and fatigue seen in one patient each. One patient with pancreatic cancer had stable disease on CT after completion of the 3 injections. This dose level is being expanded to accrue an additional 6 patients to evaluate safety and immunogenicity using cytokine flow cytometry to characterize p53-specific CD4 + and CD8 + T cell response. Of the cell-surface markers employed, PD1 showed extraordinary strong expression prior to vaccine injection. All patients had a humoral response to the MVA backbone. Conclusions: Our MVA p53 vaccine is well tolerated with minimal grade 1-2 toxicities. The highest dose tested is 5.6 x 10 8 pfu and additional patients are being accrued to evaluate immunogenicity. Since many cancers have mutant p53, this is an attractive target and may potentially be used with many other cancers. Clinical trial information: NCT01191684.
TNF-α/IFN-γ profile of HBV-specific CD4 T cells is associated with liver damage and viral clearance in chronic HBV infection
Authors: Haoliang Wang, Heng Luo, Xing Wan, Xiaolan Fu, Qing Mao, Xiaomei Xiang, Yi Zhou, Weiwei He, Juan Zhang, Yanzhi Guo, Wenting Tan, Guohong Deng
Journal: Journal of Hepatology (2019)
Baseline covariates impacting overall survival (OS) in a phase III study of men with bone metastases from castration-resistant prostate cancer.
Authors: Karim Fizazi, Christophe Massard, Matthew Raymond Smith, Michael E. Rader, Janet Elizabeth Brown, Piotr Milecki, Neal D. Shore, Stephane Oudard, Lawrence Ivan Karsh, Michael Anthony Carducci, Ronaldo Damião, Huei Wang, Carsten Dietrich Goessl
Journal: Journal of Clinical Oncology (2012)

4642 Background: Prognostic models of OS in men with metastatic castrate-resistant prostate cancer (M+CRPC), have been limited. Here we present an analysis of baseline covariates associated with OS from an international phase 3 study that demonstrated superiority of denosumab over zoledronic acid for prevention of skeletal-related events (SRE) in this population (Fizazi et al., Lancet 2011;377:813-822). Methods: Patients had confirmed bone metastases (BM) from CRPC (a rising PSA despite castrate testosterone levels) and no prior bone anti-resorptive therapy. Proportional hazards modeling with various selection strategies was used to assess the prognostic significance of baseline covariates in multivariate analyses. Study-specified factors (previous SRE [Y vs N], PSA level [&lt;10 vs ≥10 ng /mL]) and additional variables (Cook et al., Clin Cancer Res 2006;12:3361-3367; Halabi et al., J Clin Oncol 2003;21:1232-1237; Halabi et al., J Clin Oncol 2008;26:2544-2549) were explored. As no difference in OS was observed between treatment arms, analyses were performed using the pooled overall patient population. Results: Analyses included all randomized subjects with available baseline covariate data (n=1745). At the primary analysis date (median study duration 12.2 months), OS was 51%. Various selection strategies produced consistent results. In multivariate analysis, bone-specific alkaline phosphatase (BAP) ≥146 μg/L (p&lt;0.0001) and corrected urinary N-telopeptide (uNTx) &gt;50 nmol/mmol (p=0.0008) were associated with shorter OS, as were prior SRE (p=0.0002), PSA ≥10 ng /mL (p&lt;0.0001), visceral metastases (p=0.0002), greater time from either diagnosis to first BM or first BM to randomization (p&lt;0.0001 for both), ECOG performance status 2 vs. 0/1 (p=0.017), BPI-SF pain score &gt;4 (p&lt;0.0001), age (p=0.008), alkaline phosphatase &gt;143 U/L (p&lt;0.0001), and hemoglobin ≤128 g/L (p&lt;0.0001). Conclusions: Besides known factors previously associated with OS in men with CRPC (Halabi et al., 2003), we show that bone-associated covariates (pain, prior SRE, BAP, and uNTx) are also important and independent prognostic factors for OS.
Absence of Contribution to a Differential Outcome of the Stringent Complete Response IMWG Category Respect to the Conventional CR in Multiple Myeloma. a Validation Analysis Based on the Pethema/GEM2012MENOS65 Phase III Clinical Trial
Authors: Ana Jiménez Ubieto, Joaquin Martinez Lopez, Laura Rosinol, Bruno Paiva, María Teresa Cedena, Noemi Puig, Maria Jose Calasanz, José Gonzalez Medina, Maria Luisa Martin-Ramos, Rafael Alonso Fernandez, Albert Oriol, Jesús Blanchard, Enrique M. Ocio, Javier De La Rubia, Rafael Rios, Jesús Martín, Miguel-Teodoro Hernández, Isabel Krsnik, Jose Maria Moraleda, Luis Palomera, Joan Bargay, Maria-Victoria Mateos, Jesús F San-Miguel, Joan Bladé, Juan-José Lahuerta
Journal: Blood (2018)
Safety and efficacy of axitinib in pretreated patients with metastatic renal cell carcinoma: A single center experience of the Medical University of Vienna, Austria.
Authors: Ursula Maria Vogl, Lothar Ponhold, Gottfried J Locker, Christoph Zielinski, Christoph Klingler, Gero Kramer, Manuela Schmidinger
Journal: Journal of Clinical Oncology (2013)

e15535 Background: Axitinib is a highly selective inhibitor of VEGFR-1, 2 and 3 and has recently been approved for second-line treatment of metastatic renal cell cancer (mRCC). We present data of 43 patients treated with axitinib in second-line and beyond. Methods: Medical records of all patients who were treated with axitinib between July 2009 and December 2012 were retrospectively reviewed. Axitinib was prescribed at a dose of 5 mg bid and escalated to 7 or 10 mg bid in the absence of hypertension and other dose-limiting toxicities. Objective response rate (ORR) was assessed by RECIST. Progression free survival (PFS) and overall survival (OS) were calculated from the first day of axitinib until progression and/or death, respectively. Results: Fourty-three patients with a median age of 65 years (range: 17-84) are currently evaluable for analysis. The majority of patients (58.1%) had an ECOG Performance status of 0 and were classified MSKC- intermediate risk (62.8%). All patients had undergone surgery for the primary tumor and 53.5% had three or more metastatic sites. Fifty-five percent of the patients received axitinib in third or fourth-line (14% and 41.9%, respectively). Prior therapies included sunitinib (86%), everolimus (35%) and pazopanib (35%) and 62.8% had progressed on sunitinib before axitinib was initiated. Objective remission and disease stabilization were observed in 14.3% and 40% of the entire population. The median PFS and OS were 6.8 months (95% CI: 5.5 – 8.0) and 17.2 months (95% CI: 10.8 – 23.6), respectively. Dose escalation to 7 or 10 mg bid was feasible in 40% of the patients. Fatigue (76.7%), hypertension (65.1%) and hypothyroidism (53.5%) were among the most commonly observed all grade toxicities. Conclusions: Axitinib showed considerable efficacy in both second-line and beyond second-line patients. Generous dose escalation based on a “treat to hypertension”-concept may have led to a longer PFS than previously reported from a purely VEGFR-TKI-refractory patient population.
Inhaled corticosteroids and pneumonia mortality in COPD patients
Authors: Pere Almagro, Pablo Martinez-Camblor, Joan B. Soriano
Journal: European Respiratory Journal (2019)

<b>Chronic use of ICS increases the risk of pneumonia in COPD patients, although this risk is not homogenous. This study confirms that the risk of pneumonia-related mortality in randomised clinical trials is not increased in patients treated with ICS.</b>http://bit.ly/2Zod6us
A European paediatric cancer mission: aspiration or reality?
Authors: Pamela R Kearns, Gilles Vassal, Ruth Ladenstein, Martin Schrappe, Andrea Biondi, Patricia Blanc, Angelika Eggert, Anita Kienesberger, Olga Kozhaeva, Rob Pieters, Kjeld Schmiegelow
Journal: The Lancet Oncology (2019)
OS1.1 Plasma PD-L1 levels over time differ between glioblastoma and lower-grade glioma patients
Authors: M Mair, A Ilhan-Mutlu, S Pajenda, G Widhalm, K Dieckmann, J A Hainfellner, C Marosi, L Wagner, M Preusser, A S Berghoff
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Immune modulating therapies are a promising treatment approach in patients with primary brain tumors, however their clinical efficacy is still under investigation as the systemic inflammatory responses are potentially challenged by the brain’s tight immune regulatory mechanisms. Here, we aimed to investigate soluble PD-L1 (sPD-L1) in the plasma of recurrent glioblastoma (GBM) and recurrent WHO grade II - III glioma (LGG) patients over their course of disease. MATERIAL AND METHODS 30 patients with recurrent GBM and 10 patients with recurrent LGG were treated with bevacizumab (400mg, q14 days) as a salvage therapy at the Medical University of Vienna. EDTA plasma samples were drawn prior to each treatment cycle. sPD-L1 was analyzed using a sandwich ELISA (Millipore ABF133 and clone 5H1). The lower limit of detection was 0.050 ng/ml as determined by serial dilutions of recombinant human PD-L1. RESULTS sPD-L1 values could be retrieved in a median of 6 timepoints per patient (range: 2 - 24). No significant difference in sPD-L1 concentrations between GBM and LGG patients was present at baseline (p &gt; 0.05). After 2 weeks of bevacizumab treatment, LGG patients presented with statistically significant lower sPD-L1 concentrations as compared to baseline (p = 0.036, Wilcoxon signed rank test), while no difference in sPD-L1 concentration was observed in GBM patients. Significantly higher sPD-L1 intra-patient variability was evident in LGG patients compared to GBM patients (p = 0.012, Mann-Whitney-U). In LGG patients, sPD-L1 correlated with leukocyte count (Spearman’s r = 0.397, p = 0.001) as well as with C-reactive protein level (Spearman’s r = -0.424, p = 0.001), while in GBM patients no correlation of sPD-L1 and systemic markers of inflammation was evident (-0.3 &lt; Spearman’s r &lt; 0.3). CONCLUSION sPD-L1 as a systemic marker of inflammation was lower in recurrent LGG patients compared to recurrent GBM patients after bevacizumab-based treatment, arguing that the glioma-immune system interactions differ between LGG and GBM. SUPPORT/DISCLOSURE This project was funded by the research budget of the Medical University of Vienna.
Total body irradiation (TBI) and risk of breast subsequent malignant neoplasm (SMN) after blood or marrow transplantation (BMT): A report from the BMT survivor study (BMTSS).
Authors: Andrew Michael McDonald, Yanjun Chen, Jessica Wu, Lindsey Hageman, Liton Francisco, Michelle Kung, Emily Ness, Kevin Battles, Wendy Landier, Donna E. Salzman, Daniel Jordan Weisdorf, Stephen J. Forman, Mukta Arora, Saro Armenian, Smita Bhatia
Journal: Journal of Clinical Oncology (2019)

11572 Background: The association between TBI and breast SMN in BMT recipients is not clearly defined. We address this limitation to develop evidence for screening guidelines for those at risk. Methods: Study participants were drawn from BMTSS – a multi-site retrospective cohort of patients who had received BMT between 1974 and 2014 and survived ≥2y post-BMT. Participants completed the BMTSS survey that included sociodemographics and health conditions. Breast SMN was confirmed by pathology report review. Clinical characteristics, pre-BMT and BMT exposures were abstracted from medical records. Using multivariable Cox proportional hazards models, freedom from breast SMN was measured from birth and TBI was treated as a time-varying covariate in analyses stratified by type of BMT (allogeneic; autologous). Results: 1546 female participants (allogeneic 808; autologous 738) received BMT at a mean age of 43.1±17.6y and were followed for 9.4±7.7y; primary diagnoses: HL/NHL (28%), AML/MDS (27%), PCD (19%), other (28%). TBI was used in 671 patients (allogeneic 57%; autologous 30%). Patients with pre-BMT chest radiation (n = 45) were excluded from the analysis. A total of 38 cases of breast SMN were identified (allogeneic 19; autologous 19). Allogeneic BMT: exposure to TBI (HR = 3.4; 95%CI 1.1-10.9, p = 0.04) and age at BMT &lt; 40y (HR = 4.0; 95%CI 1.3-12.8, p = 0.02) were associated with increased risk of breast SMN. Risk of breast SMN was higher and breast SMN developed earlier among those exposed to TBI before age 40y vs. those exposed after 40y (8.7% vs. 0% by attained age 50; 10.6% vs. 5.8% by attained age 60, p = 0.003). Autologous BMT: Age &lt; 40y was associated with a 4.8-fold higher risk (95%CI 1.1-20.1, p = 0.03) of breast SMN. TBI was associated with a 2-fold higher risk (p = 0.2). The cumulative incidence of breast SMN among those exposed to TBI at age &lt; 40y vs. age ≥40y was 5.1% vs. 2.4% by attained age 60 (p = 0.07). Conclusions: TBI is associated with breast SMN among allogeneic BMT recipients. The risk is especially high and occurs at a younger age, among those exposed at age &lt; 40y. These findings provide evidence for initiating screening at a young age after exposure to TBI.
Dermal sinus tracts
Authors: Mitchell T Foster, Christopher A Moxon, Elaine Weir, Ajay Sinha
Journal: BMJ (2019)

### What you need to know

A newborn boy was noted to have a high-lying pit above the natal cleft with surrounding hair (fig 1). The family were reassured by their primary care doctor, and no further investigation was performed.



Fig 1 
Photograph of patient’s lumbosacral region showing the small dermal sinus ostium in the sacral region with associated hair follicles. Given its low location, and the presence of only a small amount of hair, it is clear how this may have been mistaken for a benign coccygeal dimple. However, the associated cutaneous markers (hair follicles) and that the bottom of the lesion could not be clearly seen are the indicators that this is not an innocent lesion



At age 4 months, the boy presented with fever and vomiting to his local emergency department and was discharged with a diagnosis of suspected viral gastroenteritis. When he developed additional irritability, photophobia, and worsening pyrexia, lumbar puncture confirmed Escherichia coli meningitis, and the patient was started on intravenous antibiotics.

Clinical examination and magnetic resonance imaging (MRI) of the spine confirmed a lumbosacral dermal sinus tract with signs of associated infection of the cerebrospinal fluid (arachnoiditis around the cauda equina which had spread cranially, causing meningitis) (fig 2). After the infection had been treated with intravenous antibiotics, the …
Abstract #4672: Measurement of anti-cancer activity induced by anti-human CD24 monoclonal antibody for ovarian carcinoma cells
Authors: Kyoung Song, Sung Hyun Lee, Yoon-La Choi, Young Kee Shin
Journal: Cancer Research (2009)

CD24 is a glycosylphosphatidylinositol(GPI)-anchored membrane protein which consists of a small protein core comprising 27 amino acids and is extensively glycosylated. Almost half of the amino acid in CD24 are composed of Ser and Thr residues which can be potential sites for O-linked glycans. CD24, originally described as a B cell marker, started drawing considerable attention as anti-cancer target showing that CD24 overexpression in many carcinomas are significantly associated with a more aggressive course of the disease. In our previous studies, we found that expression of CD24 in ovarian cancer had association with tumor grade and stage. In this study, we tried to validate CD24 as anti-cancer target in ovarian cancer. From microarray result, ovarian cancer had the most relevant CD24 overexpression level difference from normal. To study CD24 targeting effect in ovarian cancer, we screened CD24 overexpression cell with various method like RT-PCR, QPCR, WB, FACS. And then ADCC and CDC effect, which were considered as major mechanism for mAb therapeutic effect , were measured with CD24 overexpression cell, OVCAR3 and SK-OV3 using commercial anti-CD24 mAb, SN3. Targeting of CD24 in those cell line showed dramatic cytotoxic effect more than 50% through natural immune system, ADCC and CDC . Another mechanism for anti-cancer effect ,which we have taken notice, is P-selectin binding to cancer cell via CD24 which could facilitate cancer metastasis. From this point of view, Anti-CD24 mAb could also play a metastasis-inhibiting role by preventing CD24 from binding to P-selectin. Practically, we confirmed that CD24 could interact to P-selectin from sandwich ELISA and FACS. Based on these results, we could have further study to confirm anti-metastatic effect in ovarian cancer metatastasis mouse model. Finally we conducted in vivo experiment with human ovarian cancer xenograft nude mouse. We observed mouse with treatment anti-CD24 antibody have a propensity to decrease the tumor growth rate compared with control group treating PBS. In conclusion, CD24 may have possibility as a validated target for monoclonal antibody therapy in Ovarian cancer  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4672.