tbuckley/cabot-search huggingface dataset:
Determining viability of circulating tumor cells (CTCs) as a predictive biomarker for response in patients (pts) with metastatic castrate resistant prostate cancer (mCRPC) treated with Radium 223 (Ra).
Authors: Cristina Suárez, Daniel Castellano, Jose Angel Arranz Arija, Maria Jose Mendez-Vidal, Jose Jimenez, Aranzazu Gonzalez del Alba, M Isabel Sáez, Claudia Aura, Begona Mellado, Jose Luis Perez-Gracia, Josep Puig, Rafael Morales, Joan Carles
Journal: Journal of Clinical Oncology (2015)

e16051 Background: Ra improves survival in bone symptomatic mCRPC pts. Response assessment to Ra is difficult because of low PSA responses and pts are monitored through alkaline phosphatase (ALP) and clinically. CTCs count is a well-known predictive and prognostic biomarker in mCRPC. The aim of the study was to assess CTCs as a predictive biomarker for response to Ra therapy. Methods: Blood samples were collected from 46 pts with mCRPC treated with Ra at 8 hospitals in Spain between February and October 2014. Samples were obtained at baseline, at cycle 3 and at progression and were centrally analyzed using the CellSearch System. Statistic analysis was done with SAS v9.3 program. CTCs outcome at cycle 3 was defined as: response: decrease > 50% in relation to baseline or ≤ 5 CTCs; progression: increase > 50% or > 5 CTCs; and stabilization: absence of either response or progression. Results: We collected samples at baseline, cycle 3 and progression from 42, 32 and 18 pts respectively (see table). Pts characteristics were (medians): age: 76 years (range: 52-90); ECOG PS: 1 (range 0-2); ALP: 160 U/L (range: 35-1189); PSA: 169 ng/dL (range: 0.2-1623); LDH: 253 U/L (range: 141-1455); hemoglobin: 120 g/dL (range: 87-152). Twenty-one pts (50%) had > 5 CTC at baseline and 28 had sequential samples at baseline and at cycle 3. Thirteen of 15 pts (87%) with ≤ 5 CTCs at baseline remained on treatment after cycle 3, versus 7 of 13 pts (54%) with > 5 CTCs (p = 0.09). We observed CTCs response in 8 pts (29%), stabilization in 12 (42%) and progression in 8 (29%). Patients with ≤ 5 CTCs at cycle 3 had a higher probability to remain on treatment: 14 of 16 pts (88%) with ≤ 5 CTCs at cycle 3 remained on treatment after cycle 3 versus 6 of 12 pts (50%) with > 5 CTCs (p = 0.04). Conclusions: CTCs at cycle 3 may be helpful to monitor response to Ra, patients with ≤ 5 CTCs at entry can receive greater than 3 cycles. All these findings warrants validation in confirmatory studies. Baseline (n=46) Cycle 3 (n=46) Progression (n=46) N. of CTCs Total no-missing n 42 32 18 Not detected (0) n (%) 10 ( 23.8%) 9 ( 28.1%) 3 ( 16.7%) CTC <= 5 n (%) 11 ( 26.2%) 9 ( 28.1%) 9 ( 50.0%) CTC > 5 n (%) 21 ( 50.0%) 14 ( 43.8%) 6 ( 33.3%) Missing n 4 14 28
Referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: A nationwide study based on 240,134 consultations and 134,652 genetic tests.
Authors: Pascal Pujol, Dominique Stoppa-Lyonnet, Thierry Frébourg, Julien Blin, Marie Christine Picot, Christine Lasset, Catherine Bonaiti, Pascaline Berthet, Sophie Grandjouan, Florent Soubrier, Bruno Buecher, Rosine Guimbaud, Rosette Lidereau, Philippe Jonveaux, Sylviane Olschwang, Claude Houdoyer, Brigitte Bressac, Virginie Galibert, Frederique Nowak, Catherine Nogues
Journal: Journal of Clinical Oncology (2013)

1528 Background: Patients referral to dedicated consultations for cancer predisposition syndrome has become a standard in clinical practice. Based on nationwide data from the French national cancer institute (NCI), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with a BRCA1/2 or MMR mutation. Methods: All French cancer genetics centres completed annually a survey collecting standardized parameters for the NCI from 2003 to 2011. We report on the analysis of a total of 240,134 consultations and 134,652 genetic tests that enabled to identify 32,494 mutation carriers. Results: From 2003 to 2011, 141,639 (59 %) and 55,698 (23.2 %) patients were referred for a breast or a colorectal cancer predisposition syndrome, respectively. During this period, we found a dramatic and steadily increase in genetic tests performed for the BRCA1/2 genes (from 2095 to 7393 tests/year, P&lt;0.0001) but not for the MMR genes (from 1144 to 1635/year, P=NS). The percentage of deleterious mutations identified in the probands tested was 13.8 % and 20.9 % in BRCA1/2 and Lynch syndromes, respectively. In families with a BRCA1/2 or a MMR identified mutation, there was an average number of 3.03 relatives performing target tested. Conclusions: This nationwide study shows a lack of referral and genetic testing in Lynch syndrome as compared to BRCA1/2 syndrome. Only a third of relatives for a proband identified with a BRCA1/2 or MMR gene mutations performed a genetic targeted test. Enhanced information about validated benefit of genetic testing should be given to clinicians and patients particularly for Lynch syndrome and for relatives of a proband carrying an identified BRCA1/2 or MMR genes mutation.
LMS-02: A phase II single-arm multicenter study of doxorubicin in combination with trabectedin as a first-line treatment of advanced uterine leiomyosarcoma (u-LMS) and soft tissue LMS (ST-LMS): First results in patients with u-LMS.
Authors: Patricia Pautier, Anne Floquet, Didier Cupissol, Benjamin Lacas, Emmanuelle Bompas, Christine Chevreau, Frédéric Selle, Beatrice E. Weber, Cecile Guillemet, Nicolas Penel, Florence Duffaud
Journal: Journal of Clinical Oncology (2013)

10505 Background: U-LMS and ST-LMS are rare tumours with poor prognosis when metastatic or locally advanced, presenting moderate chemosensitivity mainly to doxorubicine (doxo), ifosfamide (ifo), cisplatin, gemcitabine (gem) and trabectidine (trab). Response rates (RR) in combination therapies (1 st line) does not exceed 50% for U-LMS and 35% for ST-LMS. The most active ones are doxo combinations (most of the time with ifo or dacarbazine) and gem + docetaxel (in particular in U-LMS) with a mean response durations of 3 to 6 months. Trab was demonstrated a definite activity on pre-treated LMS (RR of approximately 20% in LMS overall [U-LMS in particular]). In view of these encouraging results on LMS, a study combining trab with doxo as first line therapy for LMS is of interest. Methods: Patients (pts) received every 3 weeks, 6 cycles of doxo 60 mg/m 2 followed by trab 1.1 mg/m 2 3-h at day 1, and pegfilgrastim 6 mg on Day 2. Study primary objective: to determine the disease control rate (DCR) (ORR+SD). Secondary objectives: PFS 12 wks, RR by RECIST and duration, OS and toxicities. Patients were stratified into U-LMS (n=45) and ST-LMS (n=62) group. Herein, we report the first results in pts with U-LMS; mature data will be shown in ASCO Meeting. Results: 45 pts with U-LMS have been enrolled until November 2012. Median age is 58 years, 38 where of with data collected for at least 1 cycle, 85% had metastatic disease (mostly lung 30/33, liver and bone), and 26 pts have received 6 cycles. For 33 pts with at least 1 disease assessment (every 2 cycles), the ORR was 55% (18 PR) and 13 SD (39%) had SD disease for a DCR of 94% at that time. Presently, the median PFS at 12 weeks is 94,3% [95%IC:86-100]. Main grade 3-4 toxicities in 187 cycles were neutropenia (51%), febrile neutropenia (7%), thrombopenia (14%), anemia (7%), fatigue (5%), vomiting (6%) and transiet transaminase increase (22%). Conclusions: The combination of trab plus doxo seems to be an effective first-line treatment for pts with U-LMS, with meaningful clinical benefits and an acceptable and manageable safety profile. Clinical trial information: 2009-012430-70.
Predictive and pharmacodynamic biomarkers of kinase inhibitors in renal cell carcinoma circulating tumor cells using the versa platform.
Authors: Joshua Michael Lang, Toni K. Choueiri, Stephanie Margaret Thiede, Jacob T Tokar, Lindsay Nicole Strotman, Benjamin Pun Casavant, Jamie M Sperger, Rana R. McKay, Edwin Jason Abel, Scott Michael Berry, David J. Beebe
Journal: Journal of Clinical Oncology (2014)

e15600 Background: Clinical outcomes in metastatic clear cell renal carcinoma (ccRCC) have improved with novel therapeutic advances targeting the Vascular Endothelial Growth Factor (VEGF) and mammalian Target of Rapamycin (mTOR) pathways. However, more than half of patients treated with these agents do not receive meaningful clinical benefit. Furthermore, no biomarkers exist to identify or target intrinsic or acquired resistance to these therapies. Methods: Using the recently developed VERSA CTC platform, we report a novel type of circulating tumor cell (CTC) in patients with ccRCC using carbonic anhydrase IX (CAIX). We then applied a novel quantitative immunocytochemistry analysis to analyze phospho-protein activity in CAIX+ CTCs. Results: In a multi-center biomarker clinical trial, we identified a range of CAIX+ CTCs in patients with metastatic ccRCC, ranging from 1-146 CTCs per 7.5mL of blood. A subset of patient samples also included clumps of exfoliated CAIX+ cells in peripheral circulation. We then performed intracellular analysis VEGFR2 phosphorylation in CAIX+ CTCs as a predictive biomarker for therapeutic response and resistance in patients treated VEGF targeting agents. We identified altered phosphorylation patterns using in vitro lines and CAIX CTCs that correlated with response to VEGF targeting therapies including sunitinib. We then performed intracellular analysis of 4EBP1 phosphorylation in CAIX+ CTCs as a predictive biomarker of mTOR activity. We identified altered phosphorylation patterns as a predictive biomarker for agents in this therapeutic class. These assays can also act as pharmacodynamic biomarkers to determine if administered agents alter the activity of their respective targets following dosing in individual patients. Finally, we extracted nucleic acids from CAIX+ CTCs from a subset of these patients for transcriptomic analyses to interrogate intrinsic and acquired mechanisms of resistance. Conclusions: These studies indicate that a comprehensive, real-time analysis of the phospho-proteins in CAIX+ CTCs can be serially assessed by the VERSA platform for early signs of tumor resistance to targeted therapies in patients with ccRCC.
Chronomodulated hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil (5-FU), and oxaliplatin (l-OHP) plus intravenous (iv) cetuximab (Cet) (Chrono-Optiliv) in patients with unresectable liver metastases from wt KRAS colorectal cancer (LM-CRC) after treatment failure (European Phase II trial NCT 00852228).
Authors: Mohamed Bouchahda, Abdoulaye Karaboué, Marie-Christine Etienne-Grimaldi, Etienne Chatelut, Pasquale F. Innominato, Gilles Paintaud, Luana Ricca, Eric Vibert, Yves Ajavon, Sameh Awad, Denis Castaing, C. N. J. Focan, Gerard Milano, Jean Francois Morere, Rene Adam, Francis Levi
Journal: Journal of Clinical Oncology (2013)

3606 Background: Hepatic artery triplet chronotherapy is an effective salvage therapy for pretreated LM-CRC (Bouchahda et al. Cancer 2009). The combination of iv Cet with chrono or conventional triplet HAI allowed complete macroscopic resection (R0-R1) of previously unresectable LM-CRC in 28% of the pts, and median progression-free (PFS) and overall survival (OS) of 8.7 and 25.7 months respectively, despite prior chemotherapy (Lévi et al. ASCO-GI 2013). Purpose: To relate tolerability and efficacy of Chrono-Optiliv to pharmacokinetics (PK). Methods: 18/64 registered patients received iv Cet (500 mg/m²) and chrono HAI of Irinotecan (180 mg/m²), 5-FU (2800 mg/m²), and l-OHP (85 mg/m²) q2 weeks. Liver surgery was performed according to q6wks reviews. The systemic exposure to the 4 drugs was determined on 1 st course in 11 pts, through 16 samples over 56h. Results: 8F, 10M, aged 33-72 years had good PS (0/1: 83%/17%), a median of 7 LM-CRC (2-50) in 6 segments (1-8) with median largest diameter of 47 mm (15-130). LM-CRC were bilateral in 13 pts (72%); 10 pts (56%) got Chrono-Optiliv as 3 rd -4th line. Main grade 3-4 toxicities were neutropenia (56%), abdominal pain (44%), diarrhea and fatigue (22%). The rate of objective responses was 50% [26.9-73.1], and that of R0-R1 33.3% [11.5 -55.1], resulting in median PFS and OS (months) of 12.6 [8.8 -16.1] and 21.9 [7.4-36.4] respectively. Plasma PK revealed the expected Cet levels and a relevant systemic exposure to the HAI drugs, with median trapezoidal AUC’s of 12.4 µg*mn/mL (2.6-38.5) for SN-38, 142 µg*mn/mL (96- 434) for 5-FU and 100 µg*mn/mL (37-189) for free l-OHP. A significant correlation was found between free l-OHP AUC and abdominal pain (p=0.016) and between SN38 AUC and both neutropenia (p=0.018) and response (p=0.028). Conclusions: The significant systemic exposure to the HAI drugs together with iv Cet could explain efficacy and lack of early progression on Chrono-Optiliv. The results call for upfront testing of optimized Chrono-Optiliv. Clinical trial information: NCT 00852228.
A gene expression signature of MEK pathway activation to predict survival in triple-negative breast cancer.
Authors: Justin M. Balko, Melinda Sanders, Maria Gabriela Kuba, Joseph A. Pinto, Franco F. Doimi, Henry Leonidas Gomez, Carlos L. Arteaga
Journal: Journal of Clinical Oncology (2012)

1024 Background: Tumor cell proliferation measured by Ki67 in the surgically removed tumor after neoadjuvant chemotherapy (NAC) has been shown to predict patient outcome in breast cancer. It is unclear from these studies if breast cancer subtype may account in part for the predictive ability of Ki67. Thus, we tested whether Ki67 score in the surgically-resected residual tumor (RT) after NAC predicted outcome in a cohort of triple negative breast cancer (TNBC). Gene expression profiling was performed to identify molecular subtype and test the association with gene modules indicative of signaling pathway activation. Methods: Ki67 was scored in the RT of 89 patients with stage II-III TNBC (ER/PR/HER2 negative by IHC at diagnosis) that had been treated with NAC. Expression levels for 450 genes were quantified by Nanostring. Ki67, node and menopause status, age, therapy type (± taxanes), molecular subtype, and gene expression scores were tested for association to RFS and OS using univariate and multivariate CoxPH models. Results: Ki67 score in the post-NAC RT demonstrated a wide range (1.5-77.7%; median: 36.2%). Twenty seven % of RTs were 3+ HER2 by IHC. Molecular subtype in the RT was as follows: 64% Basal-like; 20% HER2-enriched; 6% LumA; 6% LumB; 4% Normal-like. In univariate analyses to respectively predict RFS and OS, node status (p=0.005 and p=0.02), number of nodes (p=0.003 and p&lt;0.001), and the score of a gene expression module of MEK pathway activation (p=0.04 and p=0.01,) were significant. Basal-like subtype approached significance for RFS (p=0.1) and OS (p=0.05). In multivariate analyses, node status (p=0.002 for RFS and p&lt;0.001 for OS) and MEK pathway activation score (p=0.04 and p=0.01) were significant predictors. Conclusions: Ki67 in the RT after NAC was not predictive of outcome in a cohort of TNBC. However, a gene expression signature of activated MEK was negatively associated with outcome. These data are consistent with the reported preclinical activity of MEK inhibitors against basal-like breast cancer cells and a possible role of this signaling pathway in chemotherapy resistance. They also support deep sequencing studies to identify genetic alterations in the RAS/MEK/MAPK pathway in TNBC.
Lymphoid and myeloid biomarkers for clinical outcome of combined immunotherapy with granulocyte-macrophage colony-stimulating factor-tranduced allogeneic prostate cancer cells (GVAX) and ipilimumab in castration-resistant prostate cancer patients.
Authors: Alfons JM van den Eertwegh, Tanja de Gruijl, Saskia Santegoets, Anita Stam, Mary E von Blomberg, Kristen Hege, Natalie Sacks, Karin Jooss, Israel Lowy, Winald R. Gerritsen
Journal: Journal of Clinical Oncology (2012)

2562 Background: In a phase-I dose escalation trial in patients with castration-resistant prostate cancer we showed that GVAX and ipilimumab had an acceptable safety profile. Moreover, we observed tumor responses and prolonged survival as compared to the Halabi predicted overall survival (OS). However, ipilimumab can also lead to severe immune-related adverse events. To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity. Methods: Patients had castration-resistant prostate cancer and were chemotherapy-naïve. They received bi-weekly GVAX for a 24 week period combined with monthly intravenous administrations of ipilimumab. Each cohort of 3 patients received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/kg. In an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg ipilimumab. Flowcytometric monitoring of lymphoid and myeloid subsets in blood were performed. Results: We observed a significantly prolonged OS for patients with high pre-treatment frequencies of CD4+CTLA-4+, CD4+PD-1+, or differentiated CD8+ T cells, or low pre-treatment frequencies of differentiated CD4+ T cells or CD4+CD25 hi FoxP3+ regulatory T cells. In contrast, increased frequencies of granulocytic Myeloid-Derived Suppressor Cells (MDSC) and high pre-treatment frequencies of monocytic CD14+HLA-DR lo/- MDSC were associated with reduced OS. Treatment-induced CD4+ T cell differentiation and CD4+ and CD8+ T cell activation was associated with clinical benefit. Moreover, treatment-induced activation of CD1c+ conventional Dendritic Cells (cDC) and 6-sulfo LacNAc+ inflammatory DC were associated with significantly prolonged OS. Conclusions: Together these data provide an immune profile to predict clinical outcome. Importantly, cluster analysis revealed pre-treatment, CRPC-associated expression of CTLA-4+ by CD4+ T cells to be a dominant predictor for OS after GVAX/ipilimumab. This potentially biomarker for patient selection should be validated in patients treated with ipilimumab.
Moving From Static to Dynamic Models of the Onset of Mental Disorder
Authors: Barnaby Nelson, Patrick D. McGorry, Marieke Wichers, Johanna T. W. Wigman, Jessica A. Hartmann
Journal: JAMA Psychiatry (2017)

<h3>Importance</h3> In recent years, there has been increased focus on subthreshold stages of mental disorders, with attempts to model and predict which individuals will progress to full-threshold disorder. Given this research attention and the clinical significance of the issue, this article analyzes the assumptions of the theoretical models in the field. <h3>Observations</h3> Psychiatric research into predicting the onset of mental disorder has shown an overreliance on one-off sampling of cross-sectional data (ie, a snapshot of clinical state and other risk markers) and may benefit from taking dynamic changes into account in predictive modeling. Cross-disciplinary approaches to complex system structures and changes, such as dynamical systems theory, network theory, instability mechanisms, chaos theory, and catastrophe theory, offer potent models that can be applied to the emergence (or decline) of psychopathology, including psychosis prediction, as well as to transdiagnostic emergence of symptoms. <h3>Conclusions and Relevance</h3> Psychiatric research may benefit from approaching psychopathology as a system rather than as a category, identifying dynamics of system change (eg, abrupt vs gradual psychosis onset), and determining the factors to which these systems are most sensitive (eg, interpersonal dynamics and neurochemical change) and the individual variability in system architecture and change. These goals can be advanced by testing hypotheses that emerge from cross-disciplinary models of complex systems. Future studies require repeated longitudinal assessment of relevant variables through either (or a combination of) micro-level (momentary and day-to-day) and macro-level (month and year) assessments. Ecological momentary assessment is a data collection technique appropriate for micro-level assessment. Relevant statistical approaches are joint modeling and time series analysis, including metric-based and model-based methods that draw on the mathematical principles of dynamical systems. This next generation of prediction studies may more accurately model the dynamic nature of psychopathology and system change as well as have treatment implications, such as introducing a means of identifying critical periods of risk for mental state deterioration.
Genome-wide association study for identification of candidate SNPs associated with carboplatin and paclitaxel clearance in ovarian cancer patients.
Authors: Bo Gao, Yi Lu, Annemieke J.M. Nieuweboer, Hongmei Xu, Jonathan Beesley, Inge M. Ghobadi Moghaddam-Helmantel, Anne-Joy M. de Graan, Peter de Bruijn, Howard Gurney, Sharon Johnatty, Philip James Beale, Ron H.J. Mathijssen, Paul R. Harnett, Rosemary L Balleine, Georgia Chenevix-Trench, Stuart MacGregor, Anna deFazio
Journal: Journal of Clinical Oncology (2014)

5563 Background: Epithelial ovarian cancer (EOC) is generally treated by cytoreductive surgery and carboplatin/paclitaxel chemotherapy. Five-year survival is ~20% for patients with advanced disease. There is wide inter-individual variation in chemotherapy pharmacokinetics (PK), response and toxicity. Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help optimize treatment. Methods: Carboplatin and paclitaxel concentrations were collected during cycle one (N=61) and three (N=7) of chemotherapy on 61 prospectively recruited Australian women with EOC. Paclitaxel concentrations were also obtained on 38 Dutch patients for meta-analysis. A genome wide association study (GWAS) was performed in all patients using Illumina OmniExpress arrays (719,665 SNPs). PK parameters were obtained using nonlinear mixed-effect modelling (NONMEM). Covariates associated with carboplatin and paclitaxel PK parameters were identified and for each SNP, both unadjusted and adjusted analysis were performed to test associations with carboplatin clearance (CL) and time of paclitaxel concentration > 0.05 µmol/L (Tc>0.05). Results: There was a 5- and 4-fold inter-individual variation in carboplatin and paclitaxel CL respectively, with little intra-individual variation. Carboplatin CL correlated with relative thrombocytopenia (p = 0.018) , whereas paclitaxel Tc>0.05 predicted relative neutropenia (p = 0.002). In the GWAS, SNPs in ABCC2 were associated with carboplatin CL (p = 10-6), and a novel SNP in chromosome 1 (rs17130142) was associated with paclitaxel Tc>0.05 with genome wide significance (p = 2.0 × 10-9). Conclusions: Our GWAS approach identified SNPs associated with carboplatin and paclitaxel PK parameters. In the case of carboplatin, SNPs were identified in the ABCC2 gene, which encodes a known carboplatin transporter, indicating biological plausibility. These findings support a GWAS approach as an effective strategy for identification of novel pharmacogenomic markers. Validation of these candidates in further studies may provide novel biomarkers for EOC treatment optimisation.
Direct‐acting antivirals for hepatitis C virus induce a rapid clinical and biochemical remission of porphyria cutanea tarda
Authors: A. Combalia, J. To‐Figueras, M. Laguno, M. Martínez‐Rebollar, P. Aguilera
Journal: British Journal of Dermatology (2017)

Sporadic porphyria cutanea tarda (PCT) is strongly associated with HCV infection in our population 1,2,3,4. . Therapeutic options for PCT include phlebotomies and low-dose 4-aminoquinolines, which show high rates of disease remission. However, some PCT patients may present frequent relapses attributable to resistance/intolerability/poor adherence to conventional treatments and/or persistence of risk factors. In 2014 we reported the first case of a patient with active PCT and HCV-HIV co-infection cured with direct antiviral agents (DAAs) 5. Herein, we present a larger cohort of patients, demonstrating the rapid and persistent remission of PCT with DAAs regimes administered for HVC infection.

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