tbuckley/cabot-search huggingface dataset:
Histologic determinants of long-term overall survival in patients (pts) with germ cell tumors (GCT).
Authors: Samuel Funt, Sujata Patil, Darren R. Feldman, Robert J. Motzer, Dean F. Bajorin, Joel Sheinfeld, Satish Tickoo, Victor E. Reuter, George J. Bosl
Journal: Journal of Clinical Oncology (2017)

4555 Background: GCT display totipotential differentiation ranging from pluripotent embryonal carcinoma to extraembryonic (choriocarcinoma, yolk sac) to somatic cell types (teratoma [T]). We hypothesized that long-term survival after platinum-based chemotherapy (PC) is dependent upon histology. Methods: Advanced GCT pts who received PC from 4/1975 to 5/1996 and had a pre-PC primary tumor specimen available were included. Each pre-PC cell type was reviewed and confirmed. Residual tumor size post-PC was recorded when available. Differences in cumulative incidence (CUI) of death due to disease (DOD) between histologic cell types and other baseline characteristics were evaluated using a competing risks approach and the Fine &amp; Gray test. Results: Pre-PC primary tumor specimens (96% testis, 3% mediastinum) were available from 231 pts. Median age was 29 years (y) and median followup 17 y (range 0.3-35 y). 41 pts had pure seminoma; of the remaining 190 with nonseminomatous GCT (NSGCT), 81 had an element of T (n=29 mature T, n=42 immature T, n=10 both). At PC start, 60% of pts were IGCCCG good risk, 26% intermediate, and 13% poor with no difference for NSGCT based on presence vs. absence of T (p=0.53). Of 72 deaths, 50 were DOD, 20 from other causes, and 2 from unknown causes. The 5, 10, and 15 y CUI of death from any cause was 20%, 23%, and 26%, respectively. CUI of DOD at 5, 10 and 15 y was 18%, 20%, 22%, respectively. CUI of DOD at 2, 5, 10 and 15 y by histologic group is provided in the Table. Presence of T was associated with greater CUI of DOD vs. NSGCT without T (p=0.04) and mature T with a greater CUI of DOD vs. immature T (p=0.03). NSGCT pts with T were also more likely to have residual retroperitoneal disease &gt;1cm after PC vs. those without T (50 vs. 4.2%; p=0.01). Conclusions: With long-term followup, the presence of an element of T, particularly mature T, in mixed NSGCT was associated with a higher risk of DOD than tumors without T, which have the same risk of DOD as pure seminoma. These data suggest that the presence of T in the primary tumor may be an important clinical predictor of long-term outcome in men with GCT. [Table: see text]
Interlaboratory-concordance of PD-L1 IHC for NSCLC.
Authors: Andreas H. Scheel, Gudrun Bänfer, Gustavo Bruno Baretton, Manfred Dietel, Rolf Diezko, Thomas Henkel, Lukas C. Heukamp, Bharat Jasani, Korinna Jöhrens, Thomas Kirchner, Iver Petersen, Simone Reu, Hans-Ulrich Schildhaus, Peter Schirmacher, Markus Tiemann, Arne Warth, Wilko Weichert, Juergen Wolf, Josef Rüschoff, Reinhard Buettner
Journal: Journal of Clinical Oncology (2017)

e20508 Background: Immunohistochemistry (IHC) of the PD-L1 protein has become a mandatory diagnostic test for NSCLC. We conducted a two-step round robin test to analyze interobserver- and interlaboratory-concordance of PD-L1 IHC and to compare four clinical trial assays (CTAs; 28-8, 22C3, SP264, SP142) and laboratory-developed tests (LDTs). Results of step-one showed that reproducible PD-L1 IHC scoring is feasible; here we present the data on interlaboratory concordance Methods: Interlaboratory-concordance was tested by a centrally prepared tissue-microarray containing 21 NSCLC specimens that was stained at ten sites using CTAs and LDTs. Assay-performance was assessed with a second tissue-microarray containing eleven cell-lines with defined PD-L1 expression. Slides were evaluated by central quality-control and image-analysis. Results: The four CTAs yielded reproducible IHC-stainings at all sites while the results of the LDTs were mixed: Six protocols showed appropriate IHC quality with staining patterns similar to 22C3 and 28-8 CTAs, five protocols yielded less DAB-deposits and reduced staining intensity. Interlaboratory-concordance of carcinoma cell scoring using the 6-step system was moderate (κ = 0.43-0.69) while the included cut-offs ≥1% and ≥50% showed substantial concordance for the CTAs (κ = 0.73-0.89) and moderate concordance for the LDTs (κ = 0.50). No significant differences in interlaboratory-concordance were found among the CTAs. However, differences in the resulting staining patterns were noticed: While 22C3 and 28-8 showed similar staining patterns, SP263 showed minor differences in some cases and SP142 showed distinct patterns. Conclusions: The data show that the PD-L1 CTAs can be reproducibly employed and scored at different sites. LDTs with staining patterns similar to the CTAs are possible yet have to be carefully calibrated to match the appropriate intensity-range. The choice of assay and the set-up of the IHC-protocol may strongly influence the resulting staining.
Abstract P095: Prospective Association of Physical Activity and Heart Failure Hospitalizations Among African-American Adults with Normal Ejection Fraction: The Jackson Heart Study
Authors: Patrick Koo, Annie Gjelsvik, Gaurav Choudhary, Wen-Chih Wu, Wei Wang, F. Dennis McCool, Charles B Eaton
Journal: Circulation (2016)

Introduction: Diastolic dysfunction (DD) with normal ejection fraction is prevalent in the African-American population due to a higher prevalence of associated risk factors. The potential benefit of moderate to vigorous physical activity (MVPA) to prevent heart failure admissions in African-American adults with normal ejection fraction is under-researched. The purpose of this study is to investigate the associations of DD and MVPA with heart failure hospitalizations (HFH). Hypothesis: We hypothesized that MVPA reduces the risk of HFH among African-American adults with normal ejection fraction. Methods: We performed a prospective analysis of 2,427 African-American adults who participated in the Jackson Heart Study and who had 2D echo and physical activity data and normal ejection fraction. MVPA per week is defined as the following: poor health [[Unable to Display Character: &amp;#8211;]] 0 minutes; intermediate health [[Unable to Display Character: &amp;#8211;]] 1-149 minutes; and ideal health [[Unable to Display Character: &amp;#8211;]] ≥ 150 minutes. DD is defined as using ratio of the early to late ventricular filling velocities, ratio of pulmonary venous systolic to diastolic velocities, and pulmonary venous atrial reversal velocity. We employed multiple variable logistic and cox proportional regression analyses adjusted for age, gender, BMI, smoking, hypertension, DM, COPD, CKD, and CHD to determine the associations of DD and MVPA with HFH. Results: Of the eligible population, 1,209 (50%) have DD. There were 171 HFH. DD is associated with HFH in the crude analysis (OR=2.24, 95% CI 1.40-3.57). The association was markedly attenuated after adjusting for age (OR=1.03, CI 0.63-1.71). Intermediate and ideal health MVPA in the crude analysis were associated with lower risk of HFH (HR=0.50, 95% CI 0.35-0.71 and HR=0.18, 95% CI 0.09-0.36, respectively), and full models revealed HR=0.71, 95% CI 0.49-1.04 and HR=0.31, 95% CI 0.16-0.63, respectively. There was no interaction between physical activity level and DD on HFH. Conclusion: In conclusion, ideal health MVPA is associated with reduced risk of HFH, whereas, intermediate health MVPA revealed a trend in risk reduction in African-American with normal ejection fraction.
Safety and efficacy of new techniques of radiotherapy in oligometastatic recurrence ovarian cancer (ROC) patients with BRCA 1/2 mutation. A monoistitutional experience.
Authors: Giuseppa Scandurra, Francesco Marletta, Sara Nicolini, Giuseppe Luigi Banna, Andrea Bendetto Di Stefano, Stefania Cali', Grazia Acquaviva, Giuseppe Corsaro, Maria Tamburo, Giuseppe Scibilia, Paolo Scollo
Journal: Journal of Clinical Oncology (2016)

e17094 Background: The role of radiotherapy in the ovarian cancer treatment has to be clarified. Fractioned Stereotactic Body Radiation Therapy (FSBRT), Intensity Modulate Radiotherapy (IMRT) and VMAT (Volumetric Modulated Arc Therapy) are improved of technologies that make irradiation abdominal well tolerated by patients (pts) with ROC selected by type of recurrence and biological characteristics. Methods: April 2013 to October 2015 fifteen radiation treatments to 11 pts affect by limphonodal ROC were performed at our istitution. Median age 48 year ( median 39-65 yrs) clinical FIGO stage IIIC 8 pts (72%) and 3, IV 3 pts ( 27%), histological subtype serus carcinoma G3-G4 11 pts (91%) and endometrioid adenocarcinoma G3 1 pts ( 9%). BRCA 1/2 mutation was present in 8 pts ( 72%), 1 pts refuse the test and 2 pts was wild tipe. All patients underwent surgery and 5 patients had secondary cytoreductive surgery after desease progression. All patients has chemotherapy based on carboplatin/paclitaxel regimen before radiation median 2 lines ( range 1-5 lines). Tumor recurrence was assessed by CA 125 biomarker and by abdominal TC scan and Abdominal Magnetic Resonance Imaging (MRI) and 18-FDG-PET WB at baseline and during the follow up. We performed 2 treatment on mediastinal nodes (FSBRT) and 9 treatment on abdominal nodes IMRT Volumetric Modulated Arc Therapy (VMAT) with simultaneously integrated PET\CT based boost (SIB) and 4 treatment FSBRT on abdominal nodes. No chemotherapy was admininistred after RT. Results: All pts had a Complete Response after RT assessend by 18-FDG- PET WB and TC scan. All pts treated with radiotherapy are alive. At a median follow up (FU) of 24 months (range 3-31 months) 7 pts (67%) have no evidence of disease. 4 pts receved new lines of chemotherapy post progression. The pts with BRCA1/2 mutation had the best response and a long FU without evidence of diasese. Treatment toxicity were Diarrea G2 3 pts (27%) Diarrea G1 in 2 pts (18%), Nausea G1 in 2 pts (18%). Conclusions: FSBRT, VMAT and IMRT are feasible and effective in nodes ROC, especially in patient with BRCA 1/2 mutation. More studies with more patients enrolled are required.
Biomarkers of brain injury and neurologic outcomes in children treated with chemotherapy for acute lymphoblastic leukemia (ALL).
Authors: Yin Ting Cheung, Raja B. Khan, Wei Liu, Tara M. Brinkman, Michelle N. Edelmann, Wilburn E. Reddick, Deqing Pei, Angela Panoskaltsis-Mortari, Deokumar Srivastava, Cheng Cheng, Leslie L. Robison, Melissa M. Hudson, Ching-Hon Pui, Kevin R. Krull
Journal: Journal of Clinical Oncology (2017)

10521 Background: Little is known about neurotoxic mechanisms associated with chemotherapy in children with ALL. Cerebrospinal fluid (CSF) biomarkers of brain injury may provide insight into this process. Methods: 235 patients (51% male; mean [SD] age diagnosed 6.8 [4.7] years) treated on a chemotherapy only protocol provided CSF samples following diagnosis and through consolidation. CSF was assayed for biomarkers of myelin degradation (myelin basic protein [MBP]), neuronal damage (nerve growth factor [NGF], total-Tau [T-Tau]) and astrogliosis (glial fibrillary acidic protein [GFAP]). Leukoencephalopathy was evaluated by brain MRI’s during therapy. At ≥5 years post-diagnosis, 138 (70%) of the 198 still eligible survivors (without relapse and unrelated neurologic injury) completed neurocognitive testing and brain diffusion tensor imaging of white matter integrity at age 13.6 [4.6] years. Log-binomial and general linear models were used to examine whether biomarker changes from baseline through consolidation were related to serum methotrexate exposure, acute leukoencephalopathy, and long-term brain outcomes. Results: NGF and T-Tau increased from baseline to consolidation ( P's &lt; 0.001), while MBP and GFAP were elevated at baseline and remained so through consolidation. The number of intrathecal injections (methotrexate, hydrocortisone, cytarabine) was positively correlated with NGF increase at consolidation ( P= 0.005). Increases in GFAP (RR 1.2; 95% CI [1.0 – 1.4]), MBP (RR 1.1 [1.0 – 1.1]) and T-Tau (RR 1.8 [1.1 – 2.8]) were related to higher risk for acute leukoencephalopathy, and higher diffusivity in frontal lobe white matter at ≥5 years post-diagnosis ( P’s &lt; 0.05). Increase in T-Tau at consolidation was associated with worse long-term sustained attention ( P= 0.03), and visual- ( P= 0.04) and visual-motor ( P= 0.02) processing speed. Conclusions: Glial injury, which is evident at diagnosis, may be related to leukemia and methotrexate exposure. Neuronal injury is associated with intrathecal chemotherapy and long-term neurocognitive and brain imaging outcomes. Monitoring CSF biomarkers may be useful in identifying individuals at risk for poor neurological outcomes.
Phase 1/2 precision medicine study of the next-generation BRAF inhibitor PLX8394.
Authors: Filip Janku, Ulka N. Vaishampayan, Vivek Khemka, Minny Bhatty, Eric Jeffrey Sherman, Jessica Tao, Jonathan R. Whisenant, David S. Hong, Nam Bui, Shivaani Kummar, Lynn G. Feun, Aparna Raj Parikh, Chao Zhang, Glenn Michelson, Eric Martin, Rafe Shellooe, Paul Severson, Michael Pelayo, David Alan Karlin, Sunil Sharma
Journal: Journal of Clinical Oncology (2018)

2583 Background: First-generation BRAF inhibitors (BRAFi) show high response rates and prolonged survival in some BRAFV600-mutant cancers; however, paradoxical activation of the RAF/MEK/ERK pathway promotes resistance and development of skin malignancies. PLX8394 is a next-generation, orally available small-molecule BRAFi that does not induce the RAF/MEK/ERK paradoxical activation and blocks signaling from both monomeric BRAFV600 and dimeric BRAFnon-V600 protein. Methods: This is a phase 1/2 study of PLX8394 and cobicistat (cstat,150mg), a CYP3A4 inhibitor used to enhance PLX8394 exposure, to determine the safety, tolerability in subjects with refractory solid tumors (phase 1) and RECIST response rate in BRAFV600 and dimer-dependent, RAS-independent BRAFnon-V600 mutant patients (phase 2). A hot-melt extrusion (HME) formulation of PLX8394 was used for this study. Results are reported as of January 8, 2018. Results: Phase 1: The RP2D was 900mg BID + cstat (Proc AACR-NCI-EORTC 2017, abst B176). A single DLT of reversible grade (G) 3 transaminitis occurred in a subject treated with PLX8394 900mg BID + cstat. Cstat co-administration resulted in a 2-3-fold increase in PLX8394 systemic exposure. Of 13 evaluable BRAFV600-mutated subjects, 3 (23%) achieved partial responses [colorectal cancer (42%), glioma (65%); both BRAFi naïve, and ovarian cancer (62%) previously treated with 3 lines of BRAF/MEKi]. Phase 2: Of 18 patients enrolled, 13 had BRAFV600 mutation [melanoma (n = 5), colorectal (n = 4), glioblastoma (n = 2), thyroid (n = 2)] and 5 BRAFnon-V600 mutation [pancreatic (n = 2), and prostate, thyroid, and colorectal (each n = 1)]. No prior MAPK pathway inhibitors were permitted for non-melanoma subjects. G≥3 AEs included G3 transaminitis and hyperbilirubinemia in one patient. Of 10 evaluable patients, 3 (30%, all with BRAFV600 mutations) had stable disease (+7%, -10%, -14%, respectively). Efficacy and exploratory biomarker analysis including transcriptome and ctDNA analysis is on-going. Conclusions: PLX8394 + cstat has been well tolerated and shows promising activity in refractory solid tumors with BRAF mutations. This work was sponsored by Plexxikon Inc. Clinical trial information: NCT02428712.
The Anatomical Location Shapes the Immune Infiltrate in Tumors of Same Etiology and Affects Survival
Authors: Saskia J. Santegoets, Vanessa J. van Ham, Ilina Ehsan, Pornpimol Charoentong, Chantal L. Duurland, Vincent van Unen, Thomas Höllt, Lilly-Ann van der Velden, Sylvia L. van Egmond, Kim E. Kortekaas, Peggy J. de Vos van Steenwijk, Mariëtte I.E. van Poelgeest, Marij J.P. Welters, Sjoerd H. van der Burg
Journal: Clinical Cancer Research (2018)

The tumor immune microenvironment determines clinical outcome. Whether the original tissue in which a primary tumor develops influences this microenvironment is not well understood.We applied high-dimensional single-cell mass cytometry [Cytometry by Time-Of-Flight (CyTOF)] analysis and functional studies to analyze immune cell populations in human papillomavirus (HPV)-induced primary tumors of the cervix (cervical carcinoma) and oropharynx (oropharyngeal squamous cell carcinoma, OPSCC).Despite the same etiology of these tumors, the composition and functionality of their lymphocytic infiltrate substantially differed. Cervical carcinoma displayed a 3-fold lower CD4:CD8 ratio and contained more activated CD8+CD103+CD161+ effector T cells and less CD4+CD161+ effector memory T cells than OPSCC. CD161+ effector cells produced the highest cytokine levels among tumor-specific T cells. Differences in CD4+ T-cell infiltration between cervical carcinoma and OPSCC were reflected in the detection rate of intratumoral HPV-specific CD4+ T cells and in their impact on OPSCC and cervical carcinoma survival. The peripheral blood mononuclear cell composition of these patients, however, was similar.The tissue of origin significantly affects the overall shape of the immune infiltrate in primary tumors.
Prospective clinical evaluation of blood-based tumor mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC): Interim B-F1RST results.
Authors: Vamsidhar Velcheti, Edward S. Kim, Tarek Mekhail, Christopher Dakhil, Philip J. Stella, Xiaowei Shen, Sylvia Hu, Sarah M. Paul, David S. Shames, Cindy Yun, See-Chun Phan, Mark A. Socinski
Journal: Journal of Clinical Oncology (2018)

12001 Background: TMB in both tissue and blood has shown promise in selecting for patients (pts) who clinically benefit from PD-L1/PD-1 inhibitors. In the randomized, 2L NSCLC Phase III OAK and Phase II POPLAR studies, high bTMB enriched for a PFS benefit in patients treated with atezo monotherapy. Here we report interim results from the single-arm, 1L NSCLC Phase II B-F1RST atezo monotherapy trial, which prospectively evaluated bTMB as a predictive biomarker for atezo using an NGS-based panel. Methods: Of 78 treated pts in the interim analysis population (IAP), 58 had adequate blood samples with sufficient detection of circulating tumor DNA (MSAF≥1%) and comprised the biomarker-evaluable population (BEP). A bTMB score of 16 (prevalence, 19% [11/58]) was prespecified to evaluate clinical efficacy in the BEP (bTMB high, ≥16; bTMB low, < 16). Statistical tests were 2-sided at a 0.1 level and 90% confidence interval. Results: Baseline characteristics were similar in the IAP and BEP. With a minimum follow-up of 6 mo, median PFS was 9.5 vs 2.8 mo for bTMB high vs low; HR, 0.49 (90% CI, 0.23, 1.04; P= 0.11). PFS HRs improved as bTMB scores increased (Table). In the BEP, the ORR was 12.1% (7/58) and disease control rate was 25.9% (15/58). In the bTMB high vs low groups, the ORR was 36.4% (4/11) vs 6.4% (3/47); odds ratio, 8.38 (90% CI, 2.02, 34.79; P= 0.02). Treatment-related serious AEs and treatment-related grade 3/4 AEs occurred in 14.1% and 16.7% of pts, respectively; 15.4% experienced AEs leading to discontinuation. Conclusions: PFS by various bTMB scores show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing 1L BFAST study (NCT03178552). The safety profile in B-F1RST is consistent with the known AE profile for atezo. Additional biomarker and clinical data will be reported. B-F1RST is ongoing and has completed enrollment at 153 patients. Clinical trial information: NCT02848651.PFS (mo) by bTMB cutoff scores (BEP, n = 58). bTMB Score bTMB High Median (n) bTMB Low Median (n) HR 90% CI 12 3.0 (22) 3.2 (36) 0.95 0.55, 1.63 14 3.4 (14) 3.2 (44) 0.73 0.39, 1.39 16 9.5 (11) 2.8 (47) 0.49 0.23, 1.04 20 9.5 (8) 2.7 (50) 0.23 0.08, 0.62
Patient’s perspective of living with and beyond the treatment of trastuzumab: Results from the PERSEPHONE early breast cancer trial.
Authors: Janet Dunn, Louise Hiller, Claire Balmer, Maggie Wilcox, Anne-Laure Vallier, Sophie Gasson, Claire Hulme, David Miles, Andrew M. Wardley, David A. Cameron, Helena Margaret Earl
Journal: Journal of Clinical Oncology (2018)

e22101 Background: PERSEPHONE is a randomised controlled non-inferiority trial comparing 6 months of trastuzumab to the standard 12 months in patients with HER2 positive early breast cancer. An important component of the trial was to collect information about the patients’ journey and their reported unmet needs. Collecting ‘quasi-qualitative’ data via open-ended questions at the end of a questionnaire is becoming increasingly common and championed as a way to add depth to assessments and complement quantitative survey data. Methods: Patients who received trastuzumab as part of the Persephone trial were requested to complete a questionnaire booklet prior to the commencement of trastuzumab, 3-monthly for a year following the start of trastuzumab (regardless of which arm of the trial they were randomised to), then every 6 months up to year 2. The booklet comprised of health resource usage information, general health questions, the EQ-5D and a free text page where patients were invited to record comments about the study or their treatment that they thought the trial team or future patients should know about. Within a mixed methods framework the exploration of the free text page was imported into NVIVO and explored using a thematic content analysis. Results: 4088 patients were randomised between 4th Oct’07 and 31st Jul’15. In total, 5542 experiences from the free text page were recorded from 2456 patients across the 6 different follow-up time-points. Patients offered information on all aspects of the study, including their views on the treatment, their care, the questionnaire they were asked to complete and research itself. The most often mentioned aspects of the study reported were the impact the treatments received had on participants personally - physically, psychologically or socially. By far the most frequently cited that participants wished to make known to others were aches and pains and fatigue; for many, these did appear to be particularly distressing and intractable. Conclusions: Patients experiences during and beyond trastuzumab treatment highlighted the long-term cumulative effects of their treatment and provides rich data to address unmet needs. Clinical trial information: 52968807.