tbuckley/cabot-search huggingface dataset:
Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice
Authors: Julia K. Götzl, Alessio-Vittorio Colombo, Katrin Fellerer, Anika Reifschneider, Georg Werner, Sabina Tahirovic, Christian Haass, Anja Capell
Journal: Molecular Neurodegeneration (2018)

Heterozygous loss-of-function mutations in the progranulin gene (GRN) lead to frontotemporal lobar degeneration (FTLD) while the complete loss of progranulin (PGRN) function results in neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Thus the growth factor-like protein PGRN may play an important role in lysosomal degradation. In line with a potential lysosomal function, PGRN is partially localized and processed in lysosomes. In the central nervous system (CNS), PGRN is like other lysosomal proteins highly expressed in microglia, further supporting an important role in protein degradation. We have previously reported that cathepsin (Cat) D is elevated in GRN-associated FTLD patients and Grn knockout mice. However, the primary mechanism that causes impaired protein degradation and elevated CatD levels upon PGRN deficiency in NCL and FTLD remains unclear. mRNA expression analysis of selected lysosomal hydrolases, lysosomal membrane proteins and autophagy-related genes was performed by NanoString nCounter panel. Protein expression, maturation and in vitro activity of Cat D, B and L in mouse embryonic fibroblasts (MEF) and brains of Grn knockout mice were investigated. To selectively characterize microglial and non-microglial brain cells, an acutely isolated microglia fraction using MACS microbeads (Miltenyi Biotec) conjugated with CD11b antibody and a microglia-depleted fraction were analyzed for protein expression and maturation of selected cathepsins. We demonstrate that loss of PGRN results in enhanced expression, maturation and in vitro activity of Cat D, B and L in mouse embryonic fibroblasts and brain extracts of aged Grn knockout mice. Consistent with an overall enhanced expression and activity of lysosomal proteases in brain of Grn knockout mice, we observed an age-dependent transcriptional upregulation of certain lysosomal proteases. Thus, lysosomal dysfunction is not reflected by transcriptional downregulation of lysosomal proteases but rather by the upregulation of certain lysosomal proteases in an age-dependent manner. Surprisingly, cell specific analyses identified early lysosomal deficits in microglia before enhanced cathepsin levels could be detected in other brain cells, suggesting different functional consequences on lysosomal homeostasis in microglia and other brain cells upon lack of PGRN. The present study uncovers early and selective lysosomal dysfunctions in Grn knockout microglia/macrophages. Dysregulated lysosomal homeostasis in microglia might trigger compensatory lysosomal changes in other brain cells.
Predictors of radiologic progression free survival (rPFS) during abiraterone acetate (AA) treatment in a randomized phase II study of AA maintenance in combination with docetaxel (D) after disease progression to AA in metastatic castration resistant prostate cancer (mCRPC): ABIDO-SOGUG trial.
Authors: Daniel Castellano, María José Méndez-Vidal, Javier Puente, M Isabel Sáez, Albert Font Pous, Ignacio Duran, Carmen Santander, Alfredo Sanchez-Hernandez, Jose Angel Arranz Arija, Teresa Alonso, Begoña Mellado, Martin Lázaro Quintela, Aranzazu Gonzalez del Alba, Emilio Esteban, Pablo Maroto, Javier Cassinello, Miguel Ángel Climent
Journal: Journal of Clinical Oncology (2017)

e16536 Background: AA improves OS and rPFS in asymptomatic/minimally symptomatic mCRPC patients. D is currently one of the standard treatments after progression to AA. However, the value of maintaining AA along with D despite progression to AA has not been tested. ABIDO trial aims to evaluate efficacy and safety of AA + D maintenance after disease progression to first line AA in mCRPC. Clinicopathologic features associated with rPFS during first line AA are presented. Methods: ABIDO trial is a randomized, phase II, open-label study with two stages. In stage I pts receive AA (1000 mg + prednisone (P) 10 mg qd) until progressive disease. In the stage II pts will be randomized to receive three-weekly D 75 mg/m 2 plus P 10 mg/d with (arm A) or without (arm B) AA 1000 mg/d. Pts had no visceral metastases, ECOG PS 0-1, and adequate organ functions. Clinicopathological predictors for rPFS to first line AA were estimated using the Kaplan-Meier method and independent associations were evaluated using Cox regression models. Results: 143 pts were included. Analyzed variables were: median age was 70y, 60% of pts had ECOG 0, 84% bone metastases (18% &gt; 4), 42% BPI score 2-3, 53% Gleason &gt; = 8, 30% PSA &gt; 80 ng/mL, 38% node involvement and 11% had at least one lymph node &gt; = 3 cm; 53% of pts achieved 4 weeks PSA reduction &gt; 50%.Median rPFS was 18 months. Univariate analysis identified as significant variables: PSA, BPI, Gleason, node involvement, 4 weeks PSA reduction &gt; 50%, and total volume of lymph node metastasis. On multivariate analysis, BPI (0-1 vs 2-3) (hazard ratio [HR] 1.81; p = 0.039), Gleason ( &lt; 8 vs &gt; = 8) (HR 2.51; p = 0.005), node involvement (no nodes, nodes &lt; 3 cm and at least 1 node &gt; = 3 cm (HR 2.8; p = 0.001 and 3.57; p = 0.009) and PSA reduction &gt; 50% (HR 3.06; p &lt; 0.001) were independently associated with rPFS. Median rPFS was superior in pts with 3 or more good prognostic factors (14m vs not reached; p &lt; 0.001). Conclusions: BPI, Gleason, node involvement and 4-week PSA response were identified as independent prognostic factors for rPFS in first line AA treated patients. Clinical trial information: NCT02036060.
Uveal melanoma patients (pts) treated with abbv-075 (mivebresib), a pan-inhibitor of bromodomain and extraterminal (BET) proteins: Results from a phase 1 study.
Authors: Sapna Pradyuman Patel, Johannes E. Wolff, Rosa Margarita Mostorino, Xiaotian Chen, Mark D. McKee, Sarina Anne Piha-Paul
Journal: Journal of Clinical Oncology (2018)

e14585 Background: Uveal melanoma represents 3–5% of all melanomas, and approximately half of these pts will develop metastatic disease. Progression-free survival (PFS) with systemic therapy is 2.6–4 months. Despite this unmet need, very few drugs have been developed for this indication. ABBV-075 is a pan-BET inhibitor that has demonstrated promising activity in in vitro and preclinical animal models. M14-546 is the first-in-human phase 1 dose-escalation study to assess ABBV-075 safety and pharmacokinetics in pts with advanced cancer (NCT02391480). Herein we report the results of pts with uveal melanoma. Methods: Eligible pts were adults (≥18 years) with relapsed/refractory solid tumors. Dosing schedules were: a) daily; b) Monday, Wednesday, Friday; c) 4 days on, 3 days off. A classical 3+3 design was used. The dose-limiting toxicity period was 28 days. Endpoints included safety and preliminary efficacy. Results: As of December 2017, 10 pts with uveal melanoma received at least 1 dose of ABBV-075; follow-up data were available for 9 pts. Previous treatments included 1–8 lines of therapy, at least 1 of which was immunotherapy, for all pts. At the time of enrollment, median age was 54.5 years (range, 37–73); 9 pts had metastases. Median treatment duration was 8.07 weeks (range, 3.57–39.57). All pts experienced a treatment-emergent adverse event (TEAE). The most common TEAEs (≥50%) included thrombocytopenia (70%), nausea (50%), and dysgeusia (50%). Grade 3/4 TEAEs were reported in 6 pts (60%); thrombocytopenia (30%) was the most frequent. No pts died while on treatment. Efficacy was evaluated in pts who received ≥1 week of therapy; 4 pts achieved a best response of stable disease; 5 pts had progressive disease (PD) per RECIST v1.1. In 1 pt, the target lesion size was decreased by 17.5%, yet the disease was classified as PD, since a new lesion occurred. Median PFS was 2.0 months (95% confidence interval [CI]: 0.9–3.6), and overall survival was 7.4 months (95% CI: 1.8–11.0). Conclusions: These data reporting therapy with ABBV-075 in pts with uveal melanoma may serve to plan further studies of BET inhibition in this pt population with high unmet need. Clinical trial information: NCT02391480.
De-escalation in HPV-negative locally advanced head and neck squamous cell cancer (LA-HNSCC) in patients after induction chemotherapy: A retrospective case series.
Authors: Ryan J. Brisson, Sara Kochanny, Corey Christian Foster, Everett E. Vokes, Daniel J. Haraf, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2018)

e18090 Background: Concurrent chemoradiation (CRT) for LA-HNSCC is an effective treatment modality associated with significant acute and long-term toxicities. In pts with a favorable prognosis, namely HPV+ tumors, de-escalation approaches have been explored. One such approach is the use of induction chemotherapy (IC) to identify favorable tumor biology. We hypothesize that positive response to IC may also be relevant to HPV- pts. Here we report on two pts with P16+ IHC oropharynx (OP) cancers that were ultimately proven to be HPV negative by PCR and mutational profiling (false positive P16 IHC results), who experienced a deep response to IC and received de-escalated therapy. Methods: Two pts with OP primary tumors were treated consisting of 3 cycles of IC with carboplatin and paclitaxel followed by definitive radiotherapy with 50 Gy (RT50) to primary tumor and one echelon of nodal stations. HPV testing was done by P16 IHC and subsequently validated by HPV PCR, and mutational profiling. Results: Both pts (median age: 58.17 years) had HPV- (p16+/HPV PCR-) stage IVa OP cancer (T2N2b and T1N2b). Both experienced deep responses to IC with a mean reduction in tumor size of 69.9% per RECIST 1.1, and subsequently received response adapted therapy consisting of single modality radiation. Both patients underwent neck dissection post treatment, confirming a pathologic CR, and remain tumor free one year post-treatment. Acute toxicities included G2 mucositis; however, neither patient utilized percutaneous endoscopic gastrostomy tube or tracheostomy during treatment. In addition to the two pts in this analysis, our institution has had prior experience utilizing response to IC as a prognostic indicator for de-escalation of CRT in a mixed population of HPV+ and - pts (Villaflor et al. Annals 2015). Conclusions: Based on this retrospective review of 2 HPV- pts with LA-HNSCC, as well as our previous institutional experience treating HPV- pts with de-escalation protocols, the utilization of response to IC presents an intriguing prognostic indicator for the de-escalation of CRT that may also apply to HPV- pts.
Electric field release and measurement (EFIRM) method for robust and rapid quantification of micro-RNA cancer biomarkers.
Authors: Fang Wei, Andre Matthew Dewanto, Kostyantyn Krysan, Jason Hieu Tang, Brian Gardner, Michael Tu, Steven M. Dubinett, David T. Wong, David Chia
Journal: Journal of Clinical Oncology (2016)

e23163 Background: MicroRNA (miRNA) are short nucleic acids fragments ( < 40bp) that play an active role in the regulation of gene expression and metabolism. Studies of miRNA expression in cancer have shown its potential as a diagnostic marker for multiple forms of cancer. However, practical utilization of miRNA as a diagnostic tool has been limited by the complexity and difficulty of detecting and quantifying microRNA targets. For example, Quantitative Real-Time PCR (RT-qPCR) requires extraction and isolation of nucleic acid content from tissue and various amplification and sequence elongation protocols in order to make these markers detectable. In order to greatly simplify this process, we explore the usage of a method called Electric Field Induced Release and Measurement (EFIRM) to efficiently and simply capture these short sequences in tissue and biofluids. Methods: The EFIRM method works by using a surface immobilized capture probe sequence and pulsed electric fields to efficiently capture microRNA without amplification. In this study, we first designed and analytically validated the method for the miRNA 451a, miRNA 335-5p, miRNA 125b-5p, and miRNA 375 markers using synthetic oligonucleotides. Following this analytical validation, 15 blinded samples of total RNA extracts from organs provided by the National Institute of Standards and Technology (NIST) were tested and compared with RT-qPCR analysis of the same sample cohort. Results: A relative comparison between measurements made by RT-qPCR and EFIRM revealed comparable distributions of miRNA levels in 14 out of 15 NIST RNA samples provided, with strong correlation coefficients between the two methods correlating up to an R2 of 0.87. Conclusions: This data reinforces the potential of EFIRM as a simple, and efficient method to measure microRNA in biofluids.
Functional biomarkers of homologous repair (HR) deficiency to guide novel DNA damage response targeted therapy in clear cell renal cell carcinoma (ccRCC).
Authors: Patrick Glen Pilie, Christine B Peterson, Yang Peng, Lijun Zhou, Timothy Anthony Yap, Guang Peng, Eric Jonasch
Journal: Journal of Clinical Oncology (2018)

4576 Background: Treatment for advanced ccRCC has rapidly evolved; however, responses are not uniform and synthetic lethal treatments with associated predictive biomarkers are still lacking. We previously reported that HR deficiency (HRD) is an early event in ccRCC, and that an HRD signature predicts for loss of RAD51 protein expression and improved OS. HRD has been shown to predict response to DNA damage response (DDR) inhibitors (DDRi) across many tumor types. In this current study, we posited that HRD positive RCC is sensitive to DDRi, that a stage dependent increase in phosphoinositide-3-kinase (PI3K) activation drives resistance to DDRi, and this resistance can be overcome with PI3K pathway inhibitors. Methods: We performed reverse phase protein microarray (RPPA) on 12 patient-derived stage I ccRCC tumors and 12 normal kidney tissues. We analyzed differential protein expression in HRD versus HR intact (HRI) ccRCC samples from the Cancer Genome Atlas (TCGA). We assessed apoptotic activity and colony formation in HRD (ACHN) and HRI (786-O) RCC lines with and without CHK1 inhibitor (CHK1i) and/or mammalian target of rapamycin (mTOR) inhibitor (mTORi). Results: Early ccRCC had loss of protein expression of FOXO3a, p-ATM, p-CHK2, p53 (p < 0.05) compared to normal, reflecting early defective ATM signaling. In TCGA, 75% of stage I ccRCC had an HRD signature, which decreased to less than 50% in stage IV tumors. HRI tumors had significantly higher protein expression of RAPTOR, CMYC, and PI3K than HRD tumors. In a preclinical model, HRD ACHN was sensitive to CHK1 inhibitor, whereas HRI 786-O was resistant. Adding mTORi overcame resistance to CHK1 inhibition in 786-0. Conclusions: Early stage ccRCC has defective DDR protein signaling with loss of ATM pathway activation. Increased oncogenic signaling, including in the mTOR/PI3K/AKT pathway, may alter HR gene activity and sensitivity to DDRi. The addition of mTORi to DDRi overcomes resistance to DDRi in HRI ccRCC. This study provides rationale for future biomarker-driven clinical trials of DDR inhibitors in advanced ccRCC patient populations.
Promoting colorectal cancer (CRC) screening after multiplex genetic testing and genetic counseling.
Authors: Gregory Idos, Allison W. Kurian, Charite Ricker, Duveen Sturgeon, Julie Culver, Kerry Kingham, Rachel Koff, Nicolette M. Chun, Courtney Rowe-Teeter, John Kidd, Brent Evans, Krystal Brown, Meredith Mills, Cindy Ma, Christine Hong, Kevin McDonnell, Uri Ladabaum, James M. Ford, Stephen B. Gruber
Journal: Journal of Clinical Oncology (2018)

1582 Background: Cancer screening guidelines recommend that germline carriers with a pathogenic variant (PV) in a CRC susceptibility gene should undergo more frequent colonoscopy screening. We assessed the impact of genetic counseling and multiplex genetic panel testing (MGPT) on adherence to colonoscopy screening. Methods: In a prospective cohort study of 2000 patients undergoing MGPT, patients completed-self-adminstered questionnaires to document colon cancer screening within one year of testing. Patients were surveyed at 3, 6, and 12 months after genetic results disclosure. Multivariable logistic regression was used to analyze an association between MGPT result and colonoscopy after adjusting for study center, personal history of colorectal cancer and personal history of colorectal surgery. Results: 2000 patients completed MGPT and 1622 (81%) completed at least one follow-up survey. 242 (12%) tested positive for at least 1 PV in any one of 25 (or 28) genes. High risk CRC gene mutations were in PMS2 (n = 11), MLH1 (n = 10), MSH2 (n = 10), MSH6 (n = 8), EPCAM (n = 1), TP53 (n = 6), Biallelic MUTYH (n = 2), APC (N = 3). Moderate risk CRC mutations were in monoallelic MUTYH (n = 41), CHEK2 (n = 17), and APC I1307K (n = 16). Within 1 year of testing, patients with a PV were twice more likely (OR = 2.0, 95% CI [1.33, 2.92], p < 0.001) and patients with a VUS were as likely (OR = 1.2, 95% CI [0.86, 1.62], p = 0.312) to have a colonoscopy as compared to patients with a negative test result. Patients identified to carry a PV in a mismatch repair gene were 4x (OR = 3.6 95% CI [1.66-7.91], p = 0.001) or a PV in APC, Biallelic MUTYH, or TP53 were 10x (OR = 10.1, 95% CI [1.80-57.29], p = 0.009) more likely to undergo colonoscopy. Those with a mutation in a moderate risk gene were 3x (OR = 3.3, 95% CI [1.79-5.95], p < 0.001) more likely to undergo colonoscopy. Conclusions: MGPT and genetic counseling prompted patients with a PV in a high risk CRC gene to appropriate adoption and adherence to screening colonoscopy. In contrast, there was no difference in colonoscopy screening among those with a VUS or negative results. These findings demonstrate genetic testing and counseling can encourage appropriate CRC screening. Clinical trial information: NCT 02324062.
The role of dynamic susceptibility contrast perfusion- weighted MRI in the estimation of IDH mutation in gliomas.
Authors: Sotirios Bisdas, Eser Sanverdi, Carole Sudre, Diana Roettger, Sebastian Brandner, Vasileios Katsaros
Journal: Journal of Clinical Oncology (2018)

12063 Background: The presence of mutation in the encoding gene of isocitrate-dehydrogenase (IDH) has been defined as a molecular biomarker in the diagnosis and differentiation of gliomas. Dynamic Susceptibility Contrast Perfusion- Weighted Imaging (DSC - PWI) is a relatively recently established technique for gliomas staging and its diagnostic accuracy may benefit when using sophisticated image analysis algorithms. In this study, we aimed to investigate whether DSC - PWI, enhanced by texture analysis and machine learning, can stratify gliomas according to their IDH mutation status. Methods: 208 patients (F/ M : 84 / 119, median age : 47 [range 21-81 years]) from a multicenter setting, who have have been immunohistopathologically diagnosed with gliomas (IDH positive / negative: 98 / 105) were prospectively included in our study. The raw data from DSC - PWI was processed on a dedicated workstation, using a fully adaptive Bayesian method, to create leakage-corrected relative cerebral blood volume (rCBV) maps. Tumours were manually segmented and registered to rCBV maps. rCBV maps were used to generate distribution and rotational invariant Haralick texture features over the tumour mask. The predictive power of the extracted features in differentiating between IDH status was assessed in a 2-fold cross-validation setting of 1000 iterations using support vector machine and multinomial ordinal regression, respectively. Results: Overall sensitivity and specificity rates for the rCBV for IDH stratification were 68% and 81%, respectively. All except one of the ten classical histogram statistics and 12 texture features appeared significantly different across mutation status (p < 0.05) when using non parametric Wilcoxon test. In the case of the classification across grading, the same features led to a distance error (difference between the real and predicted grade) inferior or equal to 1 in 88.6 % of the cases and an exact prediction in 57.2% of cases. Conclusions: Preliminary results are promising in the differentiation of gliomas with DSC- PWI on the basis of IDH mutation status, especially regarding the high specificity rates obtained using features from rCBV data.
Outcomes of Delaying Parenteral Nutrition for 1 Week vs Initiation Within 24 Hours Among Undernourished Children in Pediatric Intensive Care
Authors: Esther van Puffelen, Jessie M. Hulst, Ilse Vanhorebeek, Karolijn Dulfer, Greet Van den Berghe, Sascha C. A. T. Verbruggen, Koen F. M. Joosten
Journal: JAMA Network Open (2018)

Undernourishment has been associated with poor outcomes of critical illness in children. The effects of withholding parenteral nutrition (PN) for 1 week in undernourished critically ill children are unknown.To assess the outcome effects of withholding PN for 1 week in undernourished critically ill children.This is a subanalysis of the randomized clinical trial Pediatric Early vs Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC; N = 1440), which focused on the subgroup of pediatric intensive care unit (PICU) patients identified as undernourished on admission. Children included in the PEPaNIC trial were enrolled between June 18, 2012, and July 27, 2015. Undernourishment was defined as weight-for-age z score less than -2 in children younger than 1 year, and body mass index-for-age z score less than -2 in children 1 year or older. Data analysis was conducted from August 3, 2017, to July 6, 2018.Patients were randomized to initiation of supplemental PN within 24 hours (early PN) or after 1 week (late PN) when enteral nutrition was insufficient.Primary end points were risk of new infections acquired in the PICU and time to live PICU discharge, assessed via multivariable logistic regression and Cox proportional hazard analyses, adjusted for risk factors.A total of 289 of 1440 children (20.1%), term newborn to age 17 years, were identified as undernourished, of whom 150 of 717 patients (20.9%) were in the late PN group and 139 of 723 patients (19.2%) were in the early PN group. On admission, characteristics were similar among the treatment groups. Mean (SD) weight z scores were -3.33 (1.18) in the late PN group and -3.21 (1.09) in the early PN group. Compared with well-nourished PICU patients, undernourishment on admission was associated with lower likelihood of an earlier live PICU discharge (adjusted hazard ratio, 0.86; 95% CI, 0.75-0.99; P = .03). Among undernourished PICU patients, late PN reduced the risk of new infections by 11.0% (adjusted odds ratio, 0.39; 95% CI, 0.19-0.78; P = .01), and shortened the duration of PICU stay by a median of 2 days (earlier live PICU discharge: adjusted hazard ratio, 1.37; 95% CI, 1.06-1.75; P = .01). The safety outcomes mortality, incidence of hypoglycemia during the first week, and incidence of weight deterioration during PICU stay were similar between the treatment groups.In undernourished critically ill children, withholding PN for 1 week was clinically superior to early PN.ClinicalTrials.gov Identifier: NCT01536275.