tbuckley/cabot-search huggingface dataset:
PD1 and PD-L1 expression in glioblastoma.
Authors: Anna Sophie Berghoff, Barbara Kiesel, Georg Widhalm, Orsolya Rajky, Gerda Ricken, Adelheid Woehrer, Karin Dieckmann, Martin Filipits, Christoph Zielinski, Christine Marosi, Johannes A. Hainfellner, Matthias Preusser, Wolfgang Wick
Journal: Journal of Clinical Oncology (2014)

2011 Background: We aimed to investigate programmed cell death (PD)1 and PD-ligand (L)1 expression and relevance in glioblastoma. Methods: 135 specimens of 117 patients (median age 60); median KPS 90 (range 10-100) with glioblastoma were included. In 18 patients, resection specimens of the first local recurrence in addition to tumor tissue from the initial resection were available. Analyses of PD1, PD-L1, CD3 and CD8 expression were performed by immunohistochemistry and previously published semiquantitative evaluation criteria. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was analyzed using pyrosequencing and a cut-off at 8%. Results: We found sparse to moderate density of tumor-infiltrating lymphocytes (TILs) in a total of 100/135 (74.1%) cases (CD3+ 92/135, 68.1%; CD8+ 64/135, 47.4%). PD1 expression was found on scattered TILs, both in the perivascular compartment and within the tumor tissue, in 20/135 (14.8%) cases. PD-L1 expression was evident on tumor cells and macrophages/microglial cells throughout the tumor tissue with occasional focal accentuation in 116/135 (85.9%) specimens, with 44.5% showing PD-L1 staining of more than 50% of the viable tumor tissue. MGMT methylation was found in 37/99 (37.4%) analyzed samples. There was no significant correlation of expression of PD1 or PD-L1 with the density of TILs or MGMT methylation status (p>0.05), respectively. Younger age (p=0.009), high KPS (p=0.035) and MGMThypermethylation (p=0.008) showed a significant correlation with favorable overall survival, while TIL density or expression of PD1 (p=0.783) and PD-L1 (p=0.866) did not associate with patient outcome. Table 1 compares expression of PD1, PD-L1, CD3 and CD8 between matched specimens of the initial tumor and the first local recurrence. Conclusions: PD1 and/or PD-L1 are immunohistochemically detectable in a majority of glioblastoma samples. A clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma. N = 18 Initial tumor +, ↓ recurrence + Initial tumor - ↓ recurrence - Initial tumor + ↓ recurrence - Initial tumor - ↓ recurrence + PD-L1 12 (66.7%) 1 (5.6%) 4 (22.2%) 1 (5.6%) PD1 - 15 (83.3%) 3 (16.7%) - CD3 10 (55.6%) 3 (16.7%) 1 (5.6%) 4 (22.2%) CD8 10 (55.6%) 2 (11.1%) 4 (22.2%) 2 (11.1%)
Systems biology in personalized medicine in oncology: A case study in non-small cell lung cancer.
Authors: Fortunato Bianconi, Katia Perruccio, Vienna Ludovini, Elisa Baldelli, Guido Bellezza, Antonella Flacco, Mark Ragusa, Paolo Valigi, Lucio Crinò
Journal: Journal of Clinical Oncology (2012)

e21096 Background: Systems biology together with translational oncology is a new approach to discover sensitive pathways in specific cancers. In this study, we propose a computational modeling technique to investigate the possible effects various alterations, such as protein overexpression, gene amplification or mutations, may have on signaling, through of the EGFR and IGF1R pathways, in non-small cell lung cancer (NSCLC). Methods: EGFR and IGF1R pathways and the downstream MAPK and PIK3 networks have been reproduced through a mathematical model. One hundred-twenty five tumors from surgical NSCLC patients were evaluated for EGFR and IGF1R protein expression, by immunohistochemistry (IHC) and gene amplification, by fluorescence in situ hybridization (FISH). KRAS mutations (exons 2 and 3) were evaluated by direct sequencing Results: To correlate EGFR and IGF1R expression levels, and KRAS mutations to tumor cell proliferation, we focused on the ERK signaling pathway, which plays a central role in several steps of cancer development including proliferation and cancer cell migration. The mathematical model predicts a relationship between a simultaneous high expression level of both receptors and a modification on ERK time behavior, implying a stronger attitude for cell proliferation. Furthermore KRAS activating mutations predict high level of active ERK and high probability to have cell proliferation. Cell growth can be closely related to disease progression and act, in survival analysis, as DFS estimator. Patients with concomitant IGF1R/EGFR FISH/IHC positivity had a worse DFS ( p=0.005). KRAS mutations have a statistically significant shorter DFS (p&lt;0.001) as well Conclusions: We propose a Systems Biology approach, combined with Translational Oncology methodologies, to understand the interaction between EGFR, IGF1R and KRAS pathways in NSCLC. Computational model predictions confirm clinical evidences of survival analysis. Future work will validate our model with experiments on various NSCLC cell cultures and further investigate the response to drug administration. We thank AIRC and Fondazione Cassa di Risparmio for supporting the study.
Validation of an RNA cell cycle progression (CCP) score for predicting prostate cancer death in a conservatively managed needle biopsy cohort.
Authors: Jack M. Cuzick, Steven Stone, Gabrielle Fisher, Zi Hua Yang, Bernard North, Daniel Berney, Luis Beltran, David Greenberg, Henrik Møller, Julia E. Reid, Alexander Gutin, Jerry S. Lanchbury, Michael K. Brawer, Peter T. Scardino
Journal: Journal of Clinical Oncology (2014)

5059 Background: The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. To validate the predictive value of a cell cycle progression (CCP) score and a pre-specified linear combination of the CCP score with standard clinical variables (CAPRA) to form a combined clinical cell cycle risk (CCR) score for predicting prostate cancer death in a cohort of conservatively managed patients diagnosed by needle biopsy. Methods: A retrospective cohort study of 585 men diagnosed by needle biopsy in the UK from 1990-2003 using UK cancer registry data - supplemented by hospital records and histopathology review of diagnostic needle biopsies. The primary endpoint was prostate cancer death. Clinical variables consisted of centrally reviewed Gleason score, baseline PSA, age, clinical stage, and extent of disease. These were combined into a single predefined risk assessment (CAPRA) score. Results: In univariate analysis, the CCP score hazard ratio (HR) was 2.08 (95% CI (1.76, 2.46), P < 10-13) for a one unit change of the score and in a bivariate analysis including CAPRA, the CCP score HR was only marginally decreased (HR=1.76, 95% CI (1.44, 2.14)), and remained highly significant (P < 10-6). The predefined CCR score combining CCP and CAPRA was highly predictive (HR = 2.17; 95% CI (1.8, 2.6), χ ² = 89.0, P < 10-20) and captured all available prognostic information. The predictive value of the CCP score was maintained for 10 years, and there was no significant interaction with other prognostic factors. CAPRA identified 80 men (13.7%) in the low risk group (0-2) and they had a 10y prostate cancer mortality of 4.3%. CCR indicated 19 (3.2%) of these men had a higher risk, but identified a further 31 (5.3%) men with CAPRA > 2, but with a risk < 4.3% using the combined score. Conclusions: The CCP score provides substantially more significant pre-treatment prognostic information than available from clinical variables and is useful for determining which patients can be safely managed by a conservative policy avoiding radical treatment.
IFCT-1003 LADIE trial: Randomized phase II trial evaluating treatment with EGFR-TKI versus EGFR-TKI associated with anti-estrogen in women with non-squamous advanced stage NSCLC.
Authors: Julien Mazières, Fabrice Barlesi, Oliver Molinier, Isabelle Monnet, Clarisse Audigier-Valette, Benjamin Besse, Anne Claire Toffart, Patrick-Aldo Renault, Philippe Masson, Bertrand Mennecier, Severine Moreau Fraboulet, Sandrine Hiret, Virginie Westeel, Patrick Dumont, Alexis B. Cortot, Eric Pichon, Marie Paule Lebitasy, Franck Morin, Gerard Zalcman
Journal: Journal of Clinical Oncology (2015)

TPS8110 Background: The incidence of lung cancer is increasing dramatically in women and displays some specific epidemiological, radiological, clinical and pathological characteristics. Two main mechanisms emerged from recent findings in the field of lung carcinogenesis in women: the preferential involvement of the EGFR pathway and the potential impact of hormonal factors. The interaction of estrogen receptors with growth factor receptor signalling has also been shown. Preclinical data have shown that the combination of an EGFR-Tyrosine Kinase Inhibitor (TKI) with an anti-estrogen could overcome resistance to EGFR-TKI by postponing the reactivation of the PI3K-AKT pathway through the estrogen-mediated non-genomic pathway. Methods: We launched an open-label phase II randomized trial dedicated to women with advanced stage adenocarcinoma. Patients are treated by gefitinib (250 mg/d) vs. gefitinib + fulvestrant 500 mg MI / month (with a supplementary dose at day 15) in the EGFR mutated group (EGFR +) in first or second line setting and by erlotinib (150 mg/d, according to marketing authorization at trial initiation) vs. erlotinib + fulvestrant in the EGFR wild-type group (EGFR WT) in second or third line setting. Treatments are given until progression or unacceptable toxicity. Follow-up is performed in both arms every month to minimize the potential bias due to monthly fulvestrant injection. Primary objective is progression-free survival (PFS) at 3 and 9 months for EGFR WT and EGFR + patients, respectively. Secondary objectives are safety, overall survival and quality of life. Exploratory objective is biomarkers analysis. The main inclusion criteria are histologically-confirmed non-squamous NSCLC, available tumor tissue for EGFR mutation analysis, post-menopausal women, PS 0-2. The study has been approved by all ethical committees. First patients have been enrolled in May 2012. To date, 223 patients (89 EGFR+, 134 EGFR WT) have been enrolled and 394 (204 EGFR +, 190 EGFR WT) are expected. Clinical trial registry number NCT01556191. Clinical trial information: NCT01556191.
Multiplex testing in high risk <i>BRCA1/2</i>-negative families.
Authors: Irene Esteban, Sandra Bonache, Neus Gadea, Ana Tenes, Estela Carrasco, Judith Balmaña, Sara Gutierrez-Enríquez, Orland Díez
Journal: Journal of Clinical Oncology (2015)

e12557 Background: Familial breast cancer is a heterogeneous genetic condition. Susceptibility cancer gene panels that allow simultaneous analysis of multiple genes might broaden genetic diagnosis compared to sequential single testing. Methods: Two-hundred BRCA1/2-negative patients from high risk families were enrolled in a research study for massive parallel sequencing of 98 cancer susceptibility genes. We report preliminary results of the first 39 patients while the study is still ongoing. The inclusion criteria were (1) breast cancer (BC) under age 35, (2) presence of ovarian cancer under the age 50 in the family or (3) at least 3 breast or ovarian cancers under age 60 years in the family. DNA samples were processed using Agilent’s SureSelect Target Enrichment and sequenced on an Illumina MiSeq (2x150). The bioinformatic pipeline includes read alignment, variant calling by GATK and VarScan2, and annotation with ANNOVAR and ALAMUT. Results: Twelve truncating mutations were identified in PALB2 (2), ATM (2), BARD1, FANCA, FANCE, FANCI, FANCL, PTEN, SLX4 and XRCC2 in 10 patients (one patient with XRCC2 and SLX4, and one with ATM and FANCI). A missense deleterious variant in TP53 was identified in the patient with a FANCE mutation. In addition, 60 variants of uncertain significant in different genes were found in 32 patients (2/patient). So far, the panel was clinically beneficial for the 4 patients with deleterious variants in PALB2, PTEN, and TP53 (4/39 = 10%). Phenotypically, these families had one in situ BC with 1 first degree with BC, both under age 35 (TP53), young onset BC with family history of breast and ovarian cancer (PTEN), or an extensive family history of BC (2 PALB2). Conclusions: Multiplex genetic testing of a certain subset of high penetrant genes might be clinically useful for genetic diagnosis of familial breast and ovarian cancer patients. With an appropriate genetic counseling process, simultaneous multiplex testing might improve and accelerate genetic diagnosis and clinical management of so-far unidentified familial breast cancer cases.
Phase II multicenter trial of ipilimumab combined with fotemustine in patients with metastatic melanoma: The Italian Network for Tumor Biotherapy (NIBIT)-M1 trial.
Authors: Anna Maria Di Giacomo, Paolo Antonio Ascierto, Lorenzo Pilla, Ruggero Ridolfi, Mario Santinami, Alessandro Testori, Paola Queirolo, Ester Simeone, Massimo Guidoboni, Michele Del Vecchio, Pier Francesco Ferrucci, Antonella Marasco, Ester Fonsatti, Diego Annesi, Diana Giannarelli, Giorgio Parmiani, Michele Maio
Journal: Journal of Clinical Oncology (2012)

8513 Background: Ipilimumab (ipi), an antibody against cytotoxic T-lymphocyte-associated antigen-4, improves survival in patients (pts) with metastatic melanoma (MM); however, objective tumor responses are limited. NIBIT-M1 aims to investigate the efficacy and safety of ipi plus fotemustine (FTM), a cytotoxic alkylating drug, in pts with MM. Methods: Eligible pts, with or without brain metastases, received induction therapy with ipi 10 mg/kg every 3 weeks (Q3W) for four doses and FTM 100 mg/m2 weekly for 3 weeks. Ipi and FTM maintenance therapy was provided Q12W from Week 24 and Q3W from Week 9, respectively. The primary objective was the immune-related (ir) disease control rate (irDCR: pts with complete response [CR], partial response [PR] or stable disease [SD] as determined using the ir response criteria). Secondary objectives included ir objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS); overall survival (OS), and safety. Tumor assessments were performed Q8W from Week 12 to Week 36 and Q12W thereafter. Results: Among 86 pts with unresectable stage III (n=3) or stage IV (n=83) MM treated at 7 NIBIT centers, 42 were previously untreated, 44 had progressed following first-line treatment and 20 had asymptomatic brain metastases. As of December 2011, the irDCR was 46.5% (40/86; 95% CI, 35.7–57.6%); the irORR was 29.1% (95% CI, 19.8–39.8%; 5 CRs and 20 PRs) and with a median 8.3 months follow-up, median irPFS was 5.3 months (95% CI, 3.5–7.1). The 1-year OS rate was 51.8% (95% CI, 37.5–66.1%); median OS was not yet reached. Among all pts, 58.1% and 87% completed ipi or FTM induction, respectively. The most common grade 3/4 drug-related adverse events (AEs) (reported in 54.6% pts overall) were myelotoxicity (43.5%), increased ALT/AST (14.1/10.6%), gastrointestinal (4.7%) and skin-related (2.3%). AEs were generally manageable and reversible per protocol guidance. Conclusions: The study reached its primary objective with 46.5% of pts achieving disease control. The combination of ipi plus FTM is safe; the irDCR, 1-year OS rate and median irPFS warrant its further investigation in MM pts.
Device Thrombosis with Bioresorbable Scaffolds
Authors: Debabrata Mukherjee
Journal: New England Journal of Medicine (2017)

The development of coronary-artery stents was a major advance in interventional cardiology. However, conventional stents, which are metallic, cage-like structures, have some limitations — notably, they leave a permanent implant, which may prevent favorable arterial remodeling and preclude future surgical revascularization. Bioresorbable scaffolds were developed to overcome some of the disadvantages of metallic stents in that they gradually degrade in the body over time and leave no residual implant.1 The Absorb everolimus-eluting bioresorbable vascular scaffold (Abbott Vascular) was approved for use by the Food and Drug Administration (FDA) in July 2016.The largest trial of the Absorb bioresorbable scaffold was . . .
Inflammatory TNBC breast cancer: Demography and clinical outcome in a large cohort of TNBC patients.
Authors: Tithi Biswas, Jimmy T Efird, Paul R. Walker, Sarah Elizabeth James, Shreya Prasad, Timothy Zagar
Journal: Journal of Clinical Oncology (2014)

e12036 Background: Inflammatory breast cancer is a rare but aggressive form of breast cancer. Even with modern chemotherapy along with multimodality therapy, 5-year survival is poor in the range of 30-50%. Knowledge and information about inflammatory breast cancer with TNBC phenotype are limited. Here, we report the characteristics and outcome of TNBC inflammatory breast cancer cohorts from large TNBC dataset. Methods: Obtaining IRB approval we collected information on 476 women with TNBC diagnosis between 1996 and 2011. Data were gathered on age, race, grade, lymphovascular invasion (LVI), nodal involvement and treatment information. Overall Survival (OS) was computed from the date of diagnosis to the date of death or last follow-up (FU). For disease free survival (DFS), patients were scored if they failed either locally or distally. Statistical analysis was performed using SAS v9.3. Results: A total of 34 patients (7%) were diagnosed with inflammatory TNBC. The median age at diagnosis was 51 (35-77) years and 56% were white. The median FU was 2.9±2.8 years. 21% (n=7) presented with stage IV disease while 91% with axillary nodal involvement. 91% (n=29) had grade 3 disease and 29% (n=10) presented with LVI. All but 2 patients (94%, n=32) had neoadjuvant chemotherapy with 6% (n=2) achieving complete response and 74% (n=25) received Adriamycin-taxol containing regimen. 62% (n=21) underwent mastectomy, 71% (n=24) received either post-mastectomy or definitive radiation. The 2 and 5 year OS & DFS were 34%, 26% (vs 85%, 70%) & 27%, 23% (vs 77%, 65%), respectively for Inflammatory and non-inflammatory TNBC. Compared with non-inflammatory TNBC, the 2 and 5-year OS (p<0.0001) and DFS (p<0.0001) were significantly inferior. Conclusions: Inflammatory breast cancer with triple negative phenotype has particularly aggressive course with significantly inferior outcome compared with non-inflammatory TNBC. Newer strategies are required to improve the response rate and survival outcome.
Phase II study of the oral MEK inhibitor selumetinib (AZD6244) in advanced acute myeloid leukemia (AML).
Authors: Nitin Jain, Emily Curran, Neil M. Iyengar, Ernesto Diaz-Flores, Rangesh Kunnavakkam, Leslie Popplewell, Mark H. Kirschbaum, Harry Paul Erba, Margaret Green, Xavier Poire, Greg Koval, Kevin Shannon, Ehab L. Atallah, Philip Dy, Scott E. Smith, L. Austin Doyle, Richard A. Larson, Wendy Stock, Olatoyosi Odenike
Journal: Journal of Clinical Oncology (2012)

6582 Background: RAS-RAF-MEK-ERK pathway is activated in &gt;75% of AML patients (pts). Selumetinib (AZD6244) is an orally bioavailable small molecule inhibitor of the MEK kinase. We report here the results of a phase II multicenter trial using selumetinib in advanced AML pts. Methods: Pts ≥18 years (yrs) with relapsed/refractory AML or ≥60 yrs old with untreated AML who were not candidates for standard chemotherapy were eligible. Pts received selumetinib 100mg twice daily. Pts were screened for KRAS, NRAS and FLT3 mutations. Analysis for p-ERK (downstream of MEK) was performed by flow-cytometry. Results: 47 pts (27 men) were enrolled. Median age was 69 yrs (range, 26-83). 85% were ≥60 yrs. Disease stage included previously untreated AML (13 pts, all were ≥ 60 yrs; 11 had prior therapy for antecedent hematologic disease), primary refractory AML (14 pts), 1 st relapse (8 pts) and beyond first relapse (12 pts). Overall, 51% pts had secondary AML. Median number of prior therapies was 2 (range, 0-6). 51% had poor-risk cytogenetics. 10 pts had a FLT3 ITD, 3 pts had an NRAS mutation and one pt had a KRAS mutation. Selumetinib was well tolerated. Median number of cycles administered was 1 (range, 1-21). 49% received ≥2 cycles. Grade ≥3 adverse events possibly related to the drug included fatigue, dyspnea, and nausea occurring in 9%, 9% and 6% respectively. 1 pt has partial response, 3 pts had minor response (&gt;50% decrease in blood and/or marrow blasts lasting &gt;4 weeks), 2 pts had unconfirmed minor response (uMR: &gt;50% decline in marrow blasts without a follow up confirmatory biopsy), 4 pts had stable disease (median: 16.5 weeks, range: 9-85). No pt with FLT3 ITD or NRAS mutation responded. The sole pt with KRAS mutation had uMR with hematologic improvement in platelets. Analysis of p-ERK showed baseline activation in 15/21 (71%) pts, but no difference in baseline levels in the responders vs non-responders (p=0.27). Conclusions: Administration of selumetinib in advanced AML is associated with modest antileukemic activity, which is independent of baseline p-ERK levels. Given its favorable toxicity profile, combination with drugs that target relevant signaling pathways in AML should be considered. (Sponsored by NCI grant NO1-CM-62201)
Retrospective analysis of the impact of age on overall survival in patients with non-small cell lung cancer.
Authors: Dai Chu Nguyen Luu, Rizvan Mamet, Carrie C. Zornosa, Joyce C. Niland, Thomas A. D'Amico, Gregory Peter Kalemkerian, Marianna Koczywas, Katherine Pisters, Michael S. Rabin, Gregory Alan Otterson
Journal: Journal of Clinical Oncology (2012)

e18018 Background: Clinical trials have failed to demonstrate that age is a significant prognostic indicator among patients treated for non-small cell lung cancer (NSCLC). Clinical trials do not necessarily represent real-world experience, however. We sought to analyze the impact of age on survival in patients in the National Comprehensive Cancer Network (NCCN) NSCLC Outcomes Database. Methods: We performed a retrospective analysis of 6,834 NSCLC patients from the NCCN NSCLC Database representing 8 NCCN institutions. Of this population, 4,943 patients were eligible for our analysis. Exclusion criteria included the following: alive patients with &lt; 180 days of follow-up, patients with incomplete staging, and patients with a prior cancer diagnosis. The study population was separated into five age quintiles with equal number of patients in each group. Variables included institution, smoking status, gender, race, Charlson comorbidity score, ECOG performance status (PS), histology, stage, and receipt of resection, drug and radiation therapy. Multivariable Cox model was performed for the effect of age on survival after adjusting for the above variables. Model assumptions were evaluated via graphs and residual tests. Results: Across the five quintiles (&lt; 54, 54-60, 61-66, 67-72 and ≥ 73) there was a trend towards lower stage and higher Charlson score with increasing quintile. In addition, there was an increased proportion of patients with squamous cancer in the older age group. In the adjusted Cox model, there was a statistically significant longer survival in each of four younger quintiles compared to the reference group of ≥ 73 years of age (p=0.01). The adjusted hazard ratio of death for patients &lt; 54 was .82 (95% CI = .72 to .94), for patients 54-60 was .86 (95% CI = .76 to .97), for patients 61-66 was .84 (95% CI = .74 to .95), and for patients 67-72 was .84 (95% CI = .74 to .95). There were no statistically significant pairwise interactions among age, smoking status and stage. Conclusions: Even after adjusting for institution, comorbidity scores, smoking status, race, gender, ECOG PS, histology, stage and treatment, NSCLC patients who were ≥ 73 years of age had a worse survival when compared to younger age groups.