tbuckley/cabot-search huggingface dataset:
Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI+P) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mCPRC): Results for 2nd-line therapy.
Authors: Daniel Khalaf, Matti Annala, Daygen L. Finch, Conrad D. Oja, Joanna Vergidis, Muhammad Zulfiqar, Katherine Sunderland, Kevin Beja, Gillian Rae Vandekerkhove, Martin Gleave, Alexander William Wyatt, Kim N. Chi
Journal: Journal of Clinical Oncology (2018)

5015 Background: ABI+P and ENZ have similar efficacy for 1st-line treatment of mCRPC but cross-resistance confounds treatment with the alternate agent at progression. The optimal sequencing has not been prospectively investigated and predictive biomarkers are needed. Methods: A multi-centre trial of ABI+P followed by ENZ at PSA progression (arm A) vs ENZ followed by ABI+P (arm B). Primary endpoints were PSA decline > 50% (PSA50) on 2nd-line therapy and time to 2nd PSA progression (TT2P) (from start of 1st-line). Deep-targeted sequencing of serial samples of circulating tumour DNA (ctDNA) was performed. Results: 202 pts (101/ arm) were accrued with median follow-up 22.3 months (m). 65 pts from arm A and 71 from arm B crossed-over to 2nd-line treatment and 30 pts (15/arm) stopped treatment without cross-over. Baseline characteristics at time of 2nd-line therapy were balanced: median age 75 (range 50-93), PSA 14.5 (6.6-62.1), alkaline phosphatase > upper limit of normal (ULN) in 39% of pts and bone/liver metastasis (mets) in 89%/9%. ECOG PS was 0-1 in 89% vs 76% of pts for arm A vs arm B (p = 0.044) and LDH was > ULN in 25% vs 8% (p = 0.013). PSA50 for 2nd-line therapy for arm A vs arm B was 34% vs 4% (p˂0.001) and median time to PSA progression on 2nd-line therapy (TTPP) was 2.7 m vs 1.3 m (HR 0.38, 95% CI 0.26-0.56). For the intention-to-treat population, TT2P was 13.6 vs 11.9 m (HR 0.75, 95% CI 0.53-1.06). Median overall survival (OS) was not reached vs 24.3 m (HR 0.82, 95% CI 0.53-1.27). On multivariable analysis, factors associated with 2nd-line TTPP were: bone mets (HR 2.22, 95% CI 1.08-4.54), liver mets (HR 3.18, 95% CI 1.21-8.41) and treatment arm A vs B (HR 0.27, 95% CI 0.17-0.40). At progression, AR gene copy number increased in 14% of evaluable pts (7/49) and AR L702H/T878A(S) mutations were present in 8% of pts. ctDNA fraction ≥2% at baseline was associated with worse TT2P (HR 2.04, 95% CI 1.43 - 2.90) and OS (HR 4.07, 95% CI 2.40-6.91). Conclusions: The sequence of ABI+P followed by ENZ was associated with superior PSA50 and TTPP on 2nd-line therapy. AR alterations associated with ABI+P and ENZ resistance were detectable in ctDNA. Clinical trial information: NCT02125357.
P04.67 Assessments for prediction of bystander effect in HSV-tk/GCV gene therapy
Authors: H Kenmochi, T Yamasaki, M Horikawa, T Yamamoto, S Koizumi, T Sameshima, H Namba
Journal: Neuro-Oncology (2018)

Enzyme/prodrug gene therapy using stem cells as cellular vehicles is one of the feasible treatment strategies for malignant gliomas, because of the innate tumor tropism of stem cells. Although expectation for its clinical application is high, unrelenting efforts to seek therapeutic effectiveness are imperative. Despite needs for this, useful predictive methods for it have not been reported. Bystander effect which is characterized as a strong tumor killing in herpes simplex virus-thymidine kinase/ganciclovir system (HSV-tk/GCV system) is determined mainly by gap junctional activity. Here, we tried to establish predictive assessment methods for bystander effect measuring functional gap junction using high-content analysis. Two rat glioma cell lines, GS-9L and C6 were used. GS-9L was known to have a high endogenous expression of connexin43 (Cx43), a main component of gap junctions and C6, a lower expression. Using gap junctional permeable fluorescent dyes and high-content analysis, functional gap junction between the cells of the same cell line was assessed with “parachute assay” (calcein) and “scrape loading/dye transfer assay (SL/DT assay)” (lucifer yellow). Then, GS-9L and C6 cells were transduced with the HSV-tk gene (GS-9Ltk and C6tk cells) and the strength of in-vitro bystander effect between the same cell line (GS-9Ltk/GS-9L or C6tk/C6) were assessed by MTT assay at various tk/ tumor cell ratios (1:1 to 1:256) in the presence of 5µg/ml GCV for 7days. Western blotting and immunocytochemistry showed expression of Cx43 was high in GS-9L and low in C6. The parachute assay assessing first phase of homocellular contacts showed higher functional gap junction in GS-9L than that of C6. SL/DT assay assessing cellular contacts in stable culture condition also showed corresponding results. Bystander effect in in-vitro suicide gene therapy showed higher anti-tumor effect in combination of GS-9Ltk/GS-9L (tk/tumor cell ratio < 1:32) compared with that of C6tk/C6 (tk/tumor cell ratio < 1:4), which was consistent with parachute assay and SL/DT assay (p < **). In this research, assessments of functional gap junction using high-content analysis were consistent with in-vitro bystander effect. This result may allow these methods to be refined as predictive tools for bystander effect in stem-cell based gene therapy.
Genomic landscape of adult mixed phenotype acute leukemia (MPAL).
Authors: Kiyomi Morita, Feng Wang, Keyur Patel, Carlos E. Bueso-Ramos, Abdallah Abou Zahr, Curtis Gumbs, Jianhua Zhang, Xingzhi Song, Marisela Mendoza, Chang-jiun Wu, Steven Kornblau, Courtney Denton Dinardo, Farhad Ravandi, Guillermo Garcia-Manero, Elias Jabbour, Michael Andreeff, Hagop M. Kantarjian, Marina Konopleva, Andrew Futreal, Koichi Takahashi
Journal: Journal of Clinical Oncology (2017)

7023 Background: MPAL is a rare subgroup of acute leukemia characterized by both myeloid and lymphoid phenotypes. Genetic basis of MPAL is not well understood. Methods: We studied 31 patients (pts) with MPAL (median age 53) that met 2008 WHO criteria. Bone marrow samples were studied by targeted capture sequencing of 295 genes (median 393x), RNA sequencing, and Infinium methylation EPIC array (Illumina). Mutational landscape was compared to 194 AML, 71 B-ALL, and 6 T-ALL cases. Promoter methylation pattern was compared to the data from 194 AML (TCGA), 505 B-ALL and 101 T-ALL cases (Nordlund et al. Genome Biology. 2013). Results: Eighteen (58%) pts had myeloid-T and 13 (42%) had myeloid-B phenotype. Four pts had t(9;22), 1 had 11q23 rarrangement, and 8 had complex karyotype. MPAL had similar number of mutations with AML but had higher number of mutations than B-ALL or T-ALL. Both AML-type and ALL-type mutations were detected in MPAL, supporting the mixed phenotypic features. However, NPM1, CEBPA and GATA2 mutations were specific to AML and were not found in MPAL. Myeloid-T and myeloid-B showed distinct patterns of mutations, in which DNMT3A, IDH2, NOTCH1, IL7R, and FBXW7 mutations were enriched in myeloid-T whereas RUNX1 mutations were enriched in myeloid-B. Myeloid-T and myeloid-B also showed distinct patterns of promoter methylation. Overall, myeloid-T had more hypermethylated CpG loci than myeloid-B. Genes that have essential role in T-cell receptor (TCR) pathway ( CD3D, CD7, CD247, LCK, PRKCQ, CCR9, and TCL1A) were differentially methylated and differentially expressed between myeloid-T and myeloid-B. RNA sequencing revealed several known translocations such as, NSD1-NUP98, and KMT2A-MLLT4, in addition to the novel fusion proteins such as FOXP1-DNAJC15, RUNX1-NAP1L1, and BCL2-TM9SF3. Unbiased hierarchical clustering of MPAL, AML, B-ALL and T-ALL by promoter methylation revealed that myeloid-T had consistent similarity with T-ALL, while myeloid-B showed random similarity with either B-ALL or AML. Conclusions: MPAL is genetically heterogeneous and myeloid-T and myeloid-B shows distinct patterns of mutations, methylation and gene expressions. Therapy for MPAL may need to be tailored based on the genetic profiles.
Array-comparative genomic hybridization to predict resistance to VEGF-targeted therapies in patients with metastatic clear cell renal cell carcinoma.
Authors: Solene-Florence Kammerer-Jacquet, Frederic Dugay, Laurence Cluzeau, Angelique Brunot, Julien Dagher, Benoit Peyronnet, Romain Mathieu, Gregory Verhoest, Karim Bensalah, Brigitte Laguerre, Pierre Kerbrat, Frantz Dupuis, Jean-Christophe Bernard, Mokrane Yacoub, Alain Ravaud, Nathalie Rioux-Leclercq, Marc-Antoine Belaud-Rotureau
Journal: Journal of Clinical Oncology (2016)

e16074 Background: Clear cell renal cell carcinoma (ccRCC) are highly metastatic tumors. Anti-vascular growth epithelial factor (VEGF) therapies are currently used in first line treatment of metastatic ccRCC. However, 10 to 30% of patients are primary refractory to these treatments. Our objective is to compare molecular phenotypes of extreme responders to sunitinib first line therapy. Methods: For this purpose, we included 24 primary refractory patients and 21 long-term responders. Primary refractory patients were defined by progression as best response and long-term responders by at least 18 months of treatment without any progression. Progression was assessed according to revised response evaluation criteria in solid tumors (RECIST). We performed array-comparative genomic hybridization (CGH-array) on their 45 primary tumors and compared copy number alterations in the 2 groups of patients using Chi-squared and Mann-Whitney tests. Results: Primary refractory patients had more alterations than long-term responders (304 vs 155, p = 0.002) concerning both gains (135 vs 50, p = 0.011) and losses (169 vs 105, p = 0.049). Gains involving chromosomal loci located on 5p, 7p, 8q, Xq and loss on 9q were significantly associated with primary refractory patients (p < 0.05) whereas loss on 6q was significantly associated with long-term response (p = 0.021). Conclusions: Primary refractory patients had ccRCC with far more genetic alterations than long-term responders with identified gains and losses first described in this study. The impact of these alterations needs to be further investigated to propose them as potential predictive biomarkers.
Phase I, multi-center, open-label, dose-escalation study of pasireotide LAR (PAS) in patients with advanced neuroendocrine tumors (NET).
Authors: Jonathan R. Strosberg, Jennifer A. Chan, Alain C. Mita, Madan Kundu, Sue-zette Valera, Peter Unge, Christelle Darstein, Mike Hu, Edward M. Wolin, James C. Yao
Journal: Journal of Clinical Oncology (2016)

4095 Background: Pasireotide, a novel somatostatin analog, has been previously investigated but the maximum tolerated dose (MTD) has not been determined in pts with advanced NET. We report results of a planned interim analysis of a phase I dose-escalation (DE) study to determine the MTD, characterize safety, tolerability, PK, and efficacy trends in pts with advanced NET. Methods: Pts were enrolled in 2 phases: DE phase (to determine the MTD) at a starting dose of 80mg PAS i.m. followed by a dose expansion (DX) phase (evaluate safety and preliminary efficacy). Associations between PK parameters and clinical outcomes (probability of bradycardia, % tumor shrinkage, and glucagon levels) were evaluated using regression analysis. Bradycardia is defined as heart rate < 40 bpm. Results: As of July-2015, 29 pts (15, DE; 14, DX) were treated with 80 mg (13pts) and 120 mg (16pts) doses. No protocol defined dose-limiting toxicities were observed in the study; however in a post hoc analysis a higher incidence of bradycardia was seen with 120 mg (31.3%) vs 80 mg (0%). At data cut-off, 92.3% in 80 mg and 75% pts in 120 mg had discontinued treatment; primarily due to disease progression (44.8%) or adverse events (AEs; 27.6%). In the PK analysis, probability of bradycardia showed a moderate increase with increasing PAS concentration that was not statistically significant [Odds ratio for every 1.5x increase (95% CI): daytime, 1.672 (0.381-7.338); nighttime, 2.024 (0.494-8.292)]. No significant association was observed between PAS concentrations and glucagon levels. Two partial radiographic responses (PRs) were observed, both in the 120mg dose. PAS concentrations correlated with % tumor shrinkage although the association was not statistically significant (P= 0.08). The most common AEs in the 80 mg vs 120 mg were hyperglycemia (76.9% vs 81.3%), fatigue (53.8% vs 50%) and nausea (53.8% vs 31.3%). Conclusions: MTD was defined at 120 mg for PAS in pts with advanced NET. Although objective radiographic responses are rarely observed with SSA, 2 PRs were observed among 16 pts in the 120mg cohort. Bradycardia appears to be a dose-limiting effect, however the mechanism and clinical significance are uncertain. Clinical trial information: NCT01364415.
P01.055 Multiple extracranial metastases in a patient with oligodendroglioma - a case report
Authors: B Surboeck, M Ackerl, P Hitzenberger, J A Hainfellner, O Berger
Journal: Neuro-Oncology (2018)

Extracranial metastases (EM) in brain tumors are extremely rare. Oligodendroglioma is the least common brain tumor type to metastasize. Reported extracranial sites are bone, bone marrow, lymph nodes, liver, lung and scalp. Risk factors are prior neurosurgical resection and a prolonged survival of low grade glioma patients. No standard treatment exists, but temozolomide is the preferred treatment option. This work is a single case observation of a patient with oligodendroglioma and multiple EM. Histology was confirmed by an independent reference center. In 1997 a now 49-year-old male patient was diagnosed with oligoastrocytoma WHO II sinistral frontoparietal. In 2004 and 2009 local recurrence was detected. He received total resection and adjuvant chemotherapy (PCV). Histology showed an oligodendroglioma with anaplastic parts and a partial loss of 1p19q. 2012 again local recurrence was detected in MRI and the patient underwent gamma knife treatment. In August 2016 a calvaria lesion occurred, the histology revealed bone metastasis of oligodendroglioma. A PET-CT ten months later showed multiple thoracic and femoral bone metastases, while the lungs were tumor free. No specific treatment was obtained.In November 2017, the patient was admitted due to lymphadenopathia in both cervical regions. Biopsy showed infiltration by a population of cells consistent with metastatic glioma, showing positivity for Olig2, GFAP, S100 and SOX10 and 1p/19q co-deletion. KI-67 was 40%. The diagnosis was confirmed by an independent reference center. Currently the patient is receiving a 5/28 days temozolomide monotherapy regimen with 150mg/m2. A severe isolated normocytic and normochromic anaemia occurred propable on the basis of bone marrow involvement. EM of oligodendrogliomas are rare and infrequently reported. According to literature, most common sites include bone and bone marrow, as well as lymph-nodes and pulmonary metastasis. In our case the intracerebral lesion has been stable after the last treatment with gamma knife 2012. EM occurred 19 years after presentation of the primary tumor, this is above the range (months up to ten years) described in literature.The route of dissemination remains obscure. In some cases of neurosurgical excision material has been spread by seeding, which - due to the location in the skull - is unlikely in this case. The seeding into remote parts of the skull and lymph nodes, suggest a haematogenous/lymhogenous pattern.
TCT-792 Everolimus-eluting versus biolimus-eluting stent implantation in unselected patients with and without diabetes: a SORT OUT VIII substudy
Authors: Michael Maeng, Evald Christiansen, Christian Terkelsen, Steen Dalby Kristensen, Troels Thim, Svend Eggert Jensen, Bent Raungaard, Jens Aaroe, Anders Junker, Karsten Veien, Lisette Okkels Jensen
Journal: Journal of the American College of Cardiology (2018)
Stage at presentation to determine associations between histologic parameters of primary tumor and disease specific survival (DSS) in anorectal melanoma (AM).
Authors: Priyadharsini Nagarajan, Jin Piao, Jing Ning, Jonathan L. Curry, Carlos A. Torres-Cabala, Phyu P Aung, Wei-Lien Wang, Merrick I. Ross, Richard Eldon Royal, Jennifer Ann Wargo, Asif Rashid, Rashmi Samdani, Laura E Noordenbos, Alexander J. Lazar, Michael A. Davies, Victor Gerardo Prieto, Jeffrey E. Gershenwald, Michael T. Tetzlaff
Journal: Journal of Clinical Oncology (2018)

e21622 Background: AM is generally staged using criteria developed and validated for cutaneous melanoma despite limited evidence to support this. Thus, we analyzed a retrospective cohort of AM patients (pts) to identify primary tumor parameters that correlate with DSS. Methods: Primary tumor histologic features and other clinicopathologic factors, including tumor thickness (TT), level of rectal invasion (LEV), mitotic rate, ulceration (ULC), regression (REG), lymphovascular invasion (LVI), perineural invasion (PNI), satellitosis, margin status (MAR), and stage at presentation [disease localized to anorectum (L) without (LcN-) or with (LpN-) pathologic lymph node sampling, regional metastases (R) that were clinically occult (RpN+) or evident (RcN+) and distant metastases (D)] were collected from 160 AM pts treated at our institution. Univariate (UV) and multivariate (MV) Cox proportional hazards regression modeling determined associations with DSS. Results: The cohort (n = 160) included 67 L (27 LcN-, 40 LpN-), 55 R (18 RpN+, 37 RcN+) and 38 D pts. With median follow-up of 1.63 yrs, the median DSS was 1.75 yrs. Clinical stage significantly associated with DSS by MV analysis among all pts (p < 0.001). Various histopathologic parameters of the primary tumor independently associated with DSS in a stage-specific manner (Table). Conclusions: TT, LEV, REG and LVI independently associated with DSS in L or R pts, while only LEV correlated with DSS in D pts. The findings underscore the need for identification of AM-specific prognostic factors and the importance of integrating clinical stage when determining associations between primary tumor parameters and DSS in AM. p-value All pts L only LcN- LpN- R only RpN+ RcN+ L+R only D only UV Analysis of primary tumor parameters Age≥62y 0.01 TT < 0.001 0.001 0.02 0.03 0.004 0.03 < 0.001 LEV 0.03 ULC 0.05 REG 0.01 0.04 0.03 0.05 LVI < 0.001 0.02 0.006 0.02 0.02 < 0.001 PNI 0.04 0.01 0.03 0.01 MAR < 0.001 0.04 0.003 STAGE < 0.001 R 0.05 D < 0.001 MV Analysis of primary tumor parameters Age≥62y 0.02 TT 0.004 0.001 0.03 0.001 0.01 < 0.001 LEV 0.02 0.02 ULC 0.05 REG 0.001 0.004 0.005 LVI 0.003 0.006 0.02 0.008 0.03 STAGE < 0.001 D < 0.001
Value frameworks for cancer care: Do they account for potential durable survival with immunotherapies?
Authors: Daniel A. Goldstein, Racheli Magnezi, Moshe Leshno, Omer Ben-Aharon
Journal: Journal of Clinical Oncology (2017)

6601 Background: Modern immuno-oncologic agents may have the potential to provide durable survival for some patients. Simultaneously, there is growing concern regarding the cost of cancer care, and multiple frameworks have been developed to assess value. The points based framework created by the American Society of Clinical Oncology (ASCO) has a specific threshold, and more points are awarded if substantial durable survival is demonstrated. The objective of this study was to assess if modern immuno-oncologic agents reach defined efficacy thresholds in this framework. Methods: We reviewedall FDA approvals for immuno-oncologic agents since the first approval in 2011. We collected data regarding study endpoints, specifically the parameters defined in the updated ASCO value framework: improvement in proportion of patients alive with the test regimen, and survival rate with standard. We assessed whether bonus points would be rewarded as per the updated ASCO value framework for durable responses demonstrated on the tails of the Kaplan-Meier curves. These parameters were used as an input to check whether each drug reaches the required achievement defined in the framework. Results: 17 indications for four immunotherapy active ingredients were approved by FDA between 2011-2016: ipilimumab, pembrolizumab, nivolumab and atezolizumab. 59% of the approvals rely on survival endpoints such as overall, progression-free, or relapse-free survival. 41% are based on objective response rates. Only one drug (nivolumab indicated for melanoma first-line treatment) was found to fulfill the threshold defined for the survival rate of standard care (above 20%). Six drugs achieved the required level of improvement in proportion of patients alive in the test regimen compared to the standard (above 50%). As there was no overlap between these two groups of drugs, no drug was found to gain the durable survival bonus points defined by the ASCO framework. Conclusions: Durable survival and responses of modern immuno-oncology agents are currently not recognized to be significant by the ASCO value framework. This may be due to insufficient demonstration of efficacy of such agents, or may be due to an inappropriately calibrated value framework.
Liquid thermal biopsy as a new non-invasive method of diagnosis for lung cancer patients.
Authors: Alberto Rodrigo, Olga Abian, Adrián Velázquez-Campoy, Ana Callejo, Sonia Vega-Sánchez, Alexia Fernandez, Oscar Sánchez-Gracia, Patricia Iranzo, Mara Cruellas, Elisa Quilez, Dolores Isla
Journal: Journal of Clinical Oncology (2018)

e21207 Background: The Liquid Thermal Biopsy (LTB) is based on Differential Scanning Calorimetry (DSC) applied to serum or blood plasma samples. DSC has been developed as a new tool for the diagnosis and monitoring of different diseases. DSC is highly sensitive and it studies the unfolding transitions in proteins by thermal denaturation. Previous studies in our team developed tools that allow the multiparameter analysis of DSC profiles of the serum of patients with gastric cancer, finding important differences between Healthy Controls (HC) and cancer patients, also between stages of disease. Our main objective is to determine the LTB capacity to differentiate between HC and Lung Cancer Patients (LCP). Methods: 116 LCP (Average age 64'6±8'7, 83% men) stage distribution (II: 5'2%, III: 25'9%; IV: 69%), smoking status (63'8% smoking, 6'5% non smoking) histology distribution (37'1% Adenocarcinoma, 28'4% Squamous, 30'2% small cell) compared to 123 HC from a blood bank were included in our study. Blood samples from both groups were analyzed with a high sensitivity microcalorimeter VP-DSC (MicroCal-Malvern). The data were processed by Origin 7 software. The thermograms acquired were analyzed with a multiparametric method developed by our research group, procuring some indicators to interpret the results. After determining the Area Under the Curve (AUC) of the ROC curves, we obtained the Youden´s index to calculate the optimal value of sensitivity and specificity value for our LTB indicators. Results: 12 out of 28 parameters of our multiparametrical method showed statistical differences between HC and LCP. After developing ROC curves, AUC higher than 0'75 were observed in these 12 parameters, exceeding 0'86 in 3 of them. The Youden´s index was calculated for all of them, finding sensitivity and specificity values higher than 75-90% (for the best parameter both had more than 90%). Conclusions: LTB is a fast and non-invasive method that allows us to discriminate between HC and LCP with high sensibility and specificity. These results are our preliminary statistical analysis, which is very promising for future applications, such as screening programs for high risk patients. More results based on clinical and risk factors will be available soon