tbuckley/cabot-search huggingface dataset:
Association of gene expression with outcomes with everolimus as post-VEGF inhibitor therapy for renal cell carcinoma (RCC).
Authors: Eddy Shih-Hsin Yang, Amin Nassar, Mahsa Zarei, Opeyemi Jegede, Deborah L Della Manna, Sumanta K. Pal, Gurudatta Naik, Toni K. Choueiri, David J. Kwiatkowski, Guru Sonpavde
Journal: Journal of Clinical Oncology (2018)

e16554 Background: The use of everolimus (E) monotherapy to treat RCC has diminished due to the approvals of new agents. We hypothesized that gene expression associated with benefit may provide the rationale to employ E for select patients (pts). Methods: Formalin fixed paraffin embedded tumor tissue from a phase I/II trial that compared E alone or with BNC105P (B) following VEGF inhibitors was used. Since no significant differences in any outcomes were observed, both arms were combined. Of 154 pts enrolled, an adequate FFPE sample was available from 82 pts for RNA extraction and gene expression profiling using NanoString for cancer associated and kinase genes. The nSolver text files (.csv) and NanoString.rcc files were imported into Partek Genomic Suite 6.6 (PGS, Saint Louis, MO). 517 genes were evaluable and analyzed using penalized Cox regression for association with progression-free survival (PFS) controlling for clinical prognostic factors. The optimal model tuning parameter was determined using 10-fold cross-validation approach. The linear predictor of selected variables from the Cox regression was used to group patients based on PFS. The global performance of the model was assessed by C-statistic. Results: The median PFS (95% CI) was 4.9 (2.8, 6.2) months for 82 evaluable pts (E = 35, E+B = 47). Overexpression of 31 genes was significantly associated with PFS (p < 0.0001): the following were associated with low PFS: HSPA6 U2AF1 SPOP FGFR4 FZD8 EGFR FLNC HSP90B1 GADD45A DDIT3 PPP2CB COL1A2 FN1 SPP1 VEGFA S100A11 MMP7 ITGB8 and the following were associated with longer PFS: IGFBP3 COL1A1 RPS6 B2M FGFR3 RPS27A FLNA HSPB1 HES1 H3F3A PDGFRB NOTCH2 RUNX1T1. An optimal cutoff threshold of the linear predictor grouped pts into 3 cohorts with different (p < 0.0001) median PFS (95% CI): 2.2 (1.9, 2.4), 6.3 (4.1, 6.9), and 10.5 (8.1, 11.7) months (n = 32, 29 and 21, respectively). The estimated C-statistic (95% CI) was 76.3%. Clinical factors and trial arm were not associated with PFS. Conclusions: A 31-gene expression signature was associated with PFS of pts receiving E following VEGF inhibitors. With further validation, this signature may be useful to select pts for E to capitalize on its favorable therapeutic index.
Distinct immune signatures in chronic lymphocytic leukemia (CLL) and Richter’s syndrome (RS).
Authors: Yucai Wang, Sutapa Sinha, Haidong Dong, Charla Secreto, Timothy Call, Sameer Ashok Parikh, Jose Francisco Leis, Karen Rech, Andew L. Feldman, Saad Kenderian, Neil E. Kay, Stephen M. Ansell, Rong He, Wei Ding
Journal: Journal of Clinical Oncology (2018)

7524 Background: Immune checkpoint blockade with PD-1 inhibitor pembrolizumab was effective in RS but not CLL in a phase 2 study (NCT02332980). Analyzing the immune signatures including PD-L1 expression and T cell diversity is important for understanding the differential responses. Methods: 15 CLL and 14 RS patients in NCT02332980 were included. Expression of PD-L1 in lymph node (LN) was analyzed by immunohistochemistry staining. Peripheral blood (PB) and LN T cell diversity was analyzed using the ImmunoSEQ platform (Adaptive Biotechnology), which quantifies the clonailty of T cells by deep sequencing of the CDR3 region of T cell receptor (TCR). Data analysis (Student’s t-test and Mann-Whiney U test) was done by GraphPad Prism (v7). Results: PD-L1 expression was significantly lower in CLL (n = 6) vs RS (n = 12) patients (mean 5.5% vs 22.9%, P= 0.003). A control CLL cohort (n = 11, Mayo CLL tissue registry) also had lower PD-L1 expression (7.7%, P= 0.002 vs RS). RS Patients progressed on ibrutinib or chemotherapy had similar PD-L1 expression (25.3% vs 19.6%, P= 0.416). PB TCR clonality at trial baseline was significantly lower in RS (n = 13) vs CLL (n = 13) patients (median 0.098 vs 0.342, P= 0.026). Patients progressed on ibrutinib or chemotherapy had similar TCR clonality (CLL: 0.34 vs 0.24, P= 0.524; RS: 0.11 vs 0.09, P= 0.534). 5 RS patients achieved an objective response (1 CR, 2 PR, 1 CMR and 1 PMR), 4 of which were after progression on ibrutinib. For CLL patients, only 1 nodal reduction was seen. 4 RS patients had prior CLL samples available for TCR analysis. 2 patients had a notable decrease of TCR clonality (0.21-0.04 and 0.17-0.03) from CLL (PB) to RS state (LN), and achieved CR and PR, respectively. 2 other patients with stable clonality (0.04-0.05 and 0.03-0.08) had SD and PMR, respectively. PB TCR clonality did not change significantly with pembrolizumab (CLL [n = 11]: P= 0.775; RS [n = 11]: P= 0.830; paired t-test). Conclusions: RS patients had higher expression of PD-L1 and lower TCR clonality (more diverse T cells) compared with CLL patients. The distinct immune signatures may explain their differential responses to PD-1 blockade. The dynamic changes of TCR clonality during Richter’s transformation may predict a response to PD-1 blockade.
Randomized, open label, multicenter, phase II trial of transcatheter arterial chemoembolization (TACE) therapy in combination with sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.
Authors: Masatoshi Kudo, Kazuomi Ueshima, Takuji Torimura, Nobukazu Tanabe, Masafumi Ikeda, Hiroshi Aikata, Namiki Izumi, Takahiro Yamasaki, Shunsuke Nojiri, Keisuke Hino, Hidetaka Tsumura, Norio Isoda, Kohichiroh Yasui, Teiji Kuzuya, Takuji Okusaka, Junji Furuse, Norihiro Kokudo, Kiwamu Okita, Kenichi Yoshimura, Yasuaki Arai
Journal: Journal of Clinical Oncology (2018)

4017 Background: There is no proven evidence that combination therapy of TACE with sorafenib (TS group) prolong progression-free survival (PFS) and/or overall survival (OS) compared to TACE alone (T group) in patients with unresectable HCC. Methods: In this randomized, open label, multicenter, comparative trial (NCT01217034), patients with unresectable HCC, Child-Pugh score ≤7, ECOG performance status 0-1, no vascular invasion (VI), no extrahepatic spread (EHS), size≤10 cm and number≤10 and adequate organ function were randomized 1:1 (stratification by institution, Milan criteria in or out, and number of previous TACE 0 or 1-2) to T or TS. In TS group, sorafenib 400 mg once daily was pretreated for 2-3 weeks prior to TACE followed by 800mg once daily during on-demand conventional TACE sessions until the time to unTACEable progression (TTUP), which was defined as the time to the date of a state when TACE continuation is not possible due to untreatable tumor progression, deterioration to Child-Pugh C or appearance of VI/EHS. Co-primary endpoints are PFS and OS. Multiplicity is adjusted using a gatekeeping hierarchical testing. PFS event in this trial was defined as death or time to TTUP. Key secondary endpoints were time to progression and safety. PFS is expected to 40% extension from 18 months (control arm) to 25 months, target HR was 0.71, with a power of 0.80. Results: The trial was conducted in 33 institutions and a total of 156 patients were randomized to T (n = 76) or TS (n = 80). Median PFS in the T group and TS group was 13.5 and 25.2 months (HR = 0.59, 95%CI 0.41-0.87; p = 0.006), respectively. The number of OS events has not reached. Median TTP was 13.5 and 24.1 months in the T and TS groups (HR = 0.56, 95%CI 0.38-0.83; p = 0.004). Median TTUP was 20.6 and 26.7 months in the T and TS groups (HR = 0.57, 95%CI 0.35-0.92; p = 0.02), respectively. There was no unexpected toxicity. Conclusions: Sorafenib in combination with TACE significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with the known safety profile with previous TACE combination trials. Clinical trial information: NCT01217034.
Resistances to vismodegibs in a French case series of 207 patients with locally advanced basal cell carcinoma.
Authors: Nicole Basset-Seguin, Hayley Sharpe, Nicolas Poulalhon, Laurent Mortier, Philippe Saiag, Sandrine Monestier, Jeannie Hou, Martine Bagot, Bernard Guillot, Caroline Robert, Nicolas Meyer, Amir Khammari, Florent Grange, Caroline Dutriaux, Brigitte Dréno, Fred De Sauvage
Journal: Journal of Clinical Oncology (2016)

9562 Background: A Hh pathway inhibitor, vismodegib (VISMO) is approved for the treatment of locally advanced (la BCC) and metastatic BCC (mBCC). While most patients respond to drug treatment, in this work, we studied the frequency of primary resistance (RI), secondary resistance (RII) and stable disease (S) in patients treated with VISMO for laBCC. Methods: RI is tumor progression after at least 6 months of treatment, RII is tumor regrowth on treatment after a clear initial response and S is a tumor that has not progressed or responded after 6 months of treatment. The data from patients treated with VISMO were collected in 10 French centers. Demographics, Gorlin’s syndrome (GS), treatment history (previous radiotherapy RXT or chemotherapy CHT) and duration of treatment until tumor regrowth were collected. Results: 207 patients were analyzed. 10 cases of RI (4.8 %), 18 cases of RII (8.7 % ) and 19 cases of stable disease (9.2 % ) were observed. Among the RI cases, 3/10 patients had GS, 3/10 previously received RXT, and 2/10 were treated by CHT. Among the RII cases, 3/18 had GS, 1/18 was previously treated by RXT and 1/18 by CHT. The mean time to progression after initiation with VISMO was 13 months (range 6 -24 months). 3/19 S patients had GS, none were previously CHT-treated, but 6/19 had received RXT prior to VISMO treatment. The molecular exploration of the mechanisms of resistance in these tumors is in progress. We recently showed specific SMO mutations in RII patients, interfering with the ability of vismodegib to inhibit its signaling activity Conclusions: Resistance (RI, RII and S) to VISMO in BCC is low compared with other targeted therapies. The GS context and previous CHT do not seem to influence the incidence of resistance. Established RII mechanisms include mutations in SMO, while the underlying mechanisms of RI and S are still under investigation.
Retrospective cohort study comparing hydration protocols with or without mannitol in patients treated with cisplatin (HYDRA study).
Authors: Nathalie LeTarte, Emmie Lavallée, Anne-Marie Bégin, Marie-Lawrence Monfette, Étienne Boudrias-Dalle, Vanessa Samouelian, Denis Soulieres, Jean-Philippe Adam, Marie-Andrée Fournier
Journal: Journal of Clinical Oncology (2018)

10021 Background: Various hydration protocols have been used to mitigate acute kidney injury (AKI) induced by cisplatin. The use of mannitol remains controversial however recent studies suggested that mannitol has a protective effect against cisplatin-induced nephrotoxicity. Methods: This is a retrospective observational study including patients who received at least one dose of cisplatin between September 2010 and December 2016 at the Centre Hospitalier de l’Université de Montréal. After approval by our IRB, we compared the risk of all grade AKI between hydration protocols with or without mannitol (12.5 g if cisplatin < 75 mg/m2 or 25 g if cisplatin ≥ 75 mg/m2). Patients received a total of 3 or 4 L of fluids (D5/0.45 NS or NS) according to the cisplatin dose. AKI was evaluated by comparing baseline serum creatinine (SCr) to the highest SCr levels between each cycle. Results: Of 1932 patients identified, 1821 were included in this study of which 658 received mannitol whilst 1163 received hydration alone. The risk of all grade AKI was significantly lower in the mannitol group for patients with lymphoma, gynecologic, upper gastrointestinal and urinary tract malignancies. No difference was seen for head and neck, lung, germ cell and others cancer (see table I). In the subgroup of patients receiving cisplatin < 75 mg/m2, mannitol reduced all grade AKI for head and neck (HR 0.37 [95% CI 0.2 – 0.8]), lung (HR 0.56 [95% CI 0.3 – 0.98], upper GI (HR 0.15 [95% CI 0.1 – 0.5]) and urinary tract cancer (HR 0.14 [95% CI 0.1 – 0.5]). Conclusions: Hydration protocols containing mannitol were associated with a significantly lower risk of all grade AKI compared to hydration alone. Therebefore, mannitol should be added to hydration protocol with cisplatin especially those with doses < 75 mg/m2. All grade AKI for mannitol vs non-mannitol hydration. Malignancies Hazard Ratio [95% CI] p value Head and Neck (N = 543) 0.99 [0.7–1.5] p = 0.99 Lung (N = 456) 0.73 [0.5–1.1] p = 0.096 Gynecologic (N = 333) 0.50 [0.3–0.94] p = 0.033 Upper GI (N = 128) 0.32 [0.1–0.8] p = 0.009 Urinary tract (N = 80) 0.29 [0.1–0.7] p = 0.005 Lymphoma (N = 63) 0.33 [0.2–0.8] p = 0.008 Germ cell cancer (N = 69) 1.15 [0.3–4.4] p = 0.836 Other (N = 149) 1.29 [0.6–2.7] p = 0.508
Implementation of a Molecular Tumor Board at Dartmouth-Hitchcock Medical Center: the impact on treatment decisions over a two year period.
Authors: Erica Bernhardt, Mary D. Chamberlin, Laura J. Tafe, Ivan P Gorlov, Francine B Blumental de Abreu, Joel A Lefferts, Jason R Pettus, Jonathan D Marotti, Katarzyna J Bloch, Vincent Memoli, Arief A. Suriawinata, Jason D Peterson, Gregory J. Tsongalis, Todd W. Miller
Journal: Journal of Clinical Oncology (2016)

e23168 Background: Genetic profiling of tumors is quickly increasing as are trials targeting genetic alterations. Furthermore, genetic alterations are a relatively permanent part of a tumor profile, and can impact treatment decisions for years after profiling is performed. Follow up on the impact of genetic profiling and Molecular Tumor Board (MTB) recommendations during the first year of its existence, and new data for the second year, are presented. Methods: DNA from tumor specimens was sequenced in a Clinical Laboratory Improvement Amendments-certified laboratory to identify coding mutation in a 50-gene panel. Results were presented monthly to the MTB and collected into an IRB approved data set. Interpretation and recommendations for targetable alterations were collected as well as duration of response and outcomes. Results: During the first year, 32 cases were evaluated. In 56.3%, the MTB recommended treatment with a targeted agent based on interpretation of tumor-specific alterations. In the second year, 33 cases were evaluated and targeted therapy recommended for 66.7%. In year one, four patients (12.5%) were subsequently treated with a MTB-recommended targeted therapy: one in a clinical trial. In year two, six patients (18.2%) were treated with a MTB-recommended targeted therapy: four in a clinical trial. For those who did not receive targeted therapy, common barriers included rapidly progressive disease, lack of progression signaling need for therapy, and inability to travel for clinical trial. Conclusions: For the majority of cases, the MTB was able to provide recommendations based on targetable genetic alterations. As the MTB progressed into year two, available therapies and knowledge of targetable alterations increased. In turn, more patients were treated with targeted therapies. Increasing awareness of molecular profiling and therapies has improved acceptance of these treatments and expanded the number of patients receiving targeted therapy at our institution. Clinical trial enrollment continues to be a challenge emphasizing the need for a dedicated molecular trial research team to optimize screening at appropriate times in patients’ treatment history.
Germline mutation of the APC gene with classic form of familial adenomatous polyposis.
Authors: Irina Yu. Efimova, Oleg I. Kit, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Dmitry I. Vodolazhsky, Dmitry A. Kharagezov, Anton G. Milakin, Maksim N. Duritskiy, Vladimir E. Kolesnikov, Sergey Poluektov, Roman E. Tolmakh, Vyacheslav A. Sustretov
Journal: Journal of Clinical Oncology (2018)

e15694 Background: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder, caused by germline mutations of the adenomatous polyposis coli (APC) gene, with a frequency that range from 1 in 6,850 to 29,000 people. It is characterized by the detection in patient of hundreds to thousands adenomatous polyps that, if untreated, develop into colorectal cancer. Methods: For this study, we collected specimens of the venous blood of 13 patients (aged 22 to 42 years, median age 32.5) diagnosed with Familial Adenomatous Polyposis, classic form. The number of adenomatous polyps in their colon was significantly higher than 100. All patients were treated or clinically monitored at Rostov Research Institute of Oncology. To define the germline mutation in these patients, the APC was analyzed using DNA obtained from peripheral blood lymphocytes. PCR-amplified fragments of APC gene were purified and sequenced using an ABIPRISM 3500 unit (Life Technologies, United States). Results: Hereditary mutations in the APCgene were observed in 9 patients (69.2%) The most frequent mutations with incidence of 55.5% (5/9) were frameshift variants (all were deletions) and resulted in premature stop-codon formation (two - c.3927_3931delAAAGA, c.4666delA, c.1485delT and c.3495_3504delATATAATGAA). One of this mutation was identified as never-reported germline mutation (exon 15): an heterozygous ATATAATGAA deletion at position c.3495 resulting in a premature stop codon (p.Tyr1166ArgfsTer94) and in a truncated protein. The second mutations were nonsense mutations 33.3% (3/9): 847C > T(p.Arg283Term), c.2362A > T(p.Lys788Term), c.2365C > T(p.Gln789Term). Splicing site mutations were found in one patient (с.1744-2A > G). Hereditary mutations were found in six blood relatives of patients. Conclusions: Patients with clinical suspicion of an adenomatous polyposis syndrome should have genetic counseling and testing for germline mutation in APC gene. Find a mutation confirms the diagnosis of adenomatous polyposis and allows to determine the correct treatment for patient.
Racial disparities in colorectal cancer survival: A population-based cohort.
Authors: Muneer J Al-Husseini, Anas M Saad, Mohamed M Gad, Ahmad Rachid, Ahmed H. Salama, Talal Hilal
Journal: Journal of Clinical Oncology (2018)

e15643 Background: Colorectal cancer (CRC) has the second highest mortality rate in the United States with approx. 49,000 deaths per year. With the advances in CRC screening and incremental survival benefit from systemic therapy, the prognosis has improved over the last decade. However, access to medical care differs between patients of different races. We aimed to study racial disparities in CRC survival in the U.S. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to review CRC patients diagnosed between 1973 and 2014. We performed unadjusted Kaplan-Meier test and multivariable covariate-adjusted Cox models to calculate the overall and colorectal cancer-specific survival of patients according to their race. Results: We reviewed 547,108 with CRC and calculated their overall survival (OS) and colorectal cancer-specific survival according to different races. The median OS for blacks was 48 months (95% CI, 46.878-49.122), whites was 60 months (95% CI, 59.525-60.475), American Indians /Alaska Natives was 68 months (95% CI, 61.220-74.780),Asian or Pacific Islanders was 98 months (95% CI, 95.012-100.988). Cancer specific survival followed a similar trend with blacks having the worst survival, followed by whites and American Indians /Alaska Natives (with no significant difference between these two groups), and then Asian or Pacific Islanders having the best cancer specific survival. When adjusted for age, sex, marital status, stage, grade, and surgery, blacks had worse OS than whites (HR = 1.126, 95%CI [1.108-1.144], p < .001). American Indians /Alaska Natives had worse OS than whites (HR = 1.099, 95%CI [1.024-1.178], p = .008). Asian or Pacific Islanders still had better OS than whites (HR = .786, 95%CI [.771-.801], p < .001). Adjusted cancer-specific survival followed the same trend. Conclusions: Significant differences in CRC survival exists between races, with Asian or Pacific Islanders having the best survival outcomes and Blacks having the worst survival outcomes. Further research into the underlying factors of survival differences among races is necessary.
TCT-55 Clinical Predictors of Obstructive Coronary Artery Disease in Individuals with Suspected Coronary Artery Disease
Authors: Subhi Al'Aref, Alexander van Rosendael, Gabriel Maliakal, Gurpreet Singh, Xiaoyue Ma, Mohit Pandey, Jing Wang, Virginie Do, Timothy Suyong Kim, Manasa Gummalla, Stephan Achenbach, Mouaz AL-Mallah, Daniele Andreini, Jeroen Bax, Daniel Berman, Matthew Budoff, Filippo Cademartiri, Tracy Callister, Hyuk-Jae Chang, Kavitha Chinnaiyan, Benjamin Chow, Ricardo Cury, Augustin Delago, Gudrun Feuchtner, Martin Hadamitzky, Jörg Hausleiter, Philipp Kaufmann, Yong-Jin Kim, Jonathon Leipsic, Erica Maffei, Hugo Marques, Gianluca Pontone, Gilbert Raff, Ronen Rubinshtein, Leslee Shaw, Todd Villines, Heidi Gransar, Yao Lu, Erica Jones, Jessica Peña, Fay Lin, James Min
Journal: Journal of the American College of Cardiology (2018)
P01.168 International Inconsistency in management of recurrent glioblastoma creates challenges in developing new clinical trials
Authors: P M Brennan, I Phang, S Erridge
Journal: Neuro-Oncology (2018)

The optimal choice and timing of treatment for recurrent GBM is unclear. Understanding the effect of further treatment on survival and quality of life, compared with best supportive care, is a top 10 clinical priority for the UK neuro-oncology community. Prior to developing a clinical trial to address this uncertainty we surveyed the neuro-oncology community to understand current variations in practice. A google survey was designed to collect data. The Society of British Neurosurgeons, European Association of Neuro-oncology and a UK oncology network circulated the survey. 233, responses were received from clinical/medical oncologists, neurosurgeons, neurologists and radiologists. Responders were from UK (45), rest of Europe (123) and outwith Europe (65). 40% of responders reduced the frequency of radiological surveillance to 6 monthly in second year after diagnosis. There were variations in radiological definition of recurrence; 45.1% local recurrence of enhancing disease, 21.0% MR spectroscopy, 21.4% MR perfusion, the remainder used PET. Only 64% respondents presented every case of recurrence for multidisciplinary review. 45% of respondents did not consider a maximum age in deciding a therapeutic strategy. 43.0% had a minimum KPS of 70, 27.5% a minimum of 80. 53.4% did not consider MGMTmethylations status important.Only 50.3% of respondents thought repeat surgery should be undertaken only if more than 90% resection is anticipated. 50.0% of respondents had no minimum time to have elapsed since the first operation before consideration of re-operation. 40.2% will consider repeat surgery even if no further oncological treatment available. 41.0% will consider repeat temozolomide as second-line option after repeat surgery, 33.0% will consider PCV, 18.0% lomustine. 70% respondents would consider re-irradiation. The significant variation in management of recurrent disease reflects a lack of evidence-base treatment guidelines. This variation complicates design of clinical trials and consensus guidelines would help future trial design.
Risk of MGUS in relatives of multiple myeloma cases by clinical and tumor characteristics
Authors: Alyssa I. Clay-Gilmour, Shaji Kumar, S. Vincent Rajkumar, Abdul Rishi, Robert A. Kyle, Jerry A. Katzmann, David L. Murray, Aaron D. Norman, Alexandra J. Greenberg, Dirk R Larson, Megan M. O’Byrne, Susan L. Slager, Celine M. Vachon
Journal: Leukemia (2018)