tbuckley/cabot-search huggingface dataset:
Response to epidermal growth factor vaccine in patients with metastatic non-small cell lung cancer (NSCLC) after progressing to first-line therapy.
Authors: Diego Venegas, Elia Neninger, Carlos Iberico, Claudia Oliva, Ashley E. Alarcon-Rozas, Claudia Patricia Lozada, Jose Galvez, Gisela Gonzalez
Journal: Journal of Clinical Oncology (2012)

2531 Background: A direct correlation between anti–epidermal growth factor (EGF)antibody titers and survival was demonstrated in vaccinated patients with novel NSCLC advanced in Phase II studies. We show the results of treatment with anti-EGF vaccine in a cohort of patients with metastatic NSCLC after progressing to first line therapy. We evaluated immunogenicity, safety, treatment response and effect on survival. Methods: 12 patients with metastatic NSCLC after progressing to first-line therapy received anti EGF-vaccine alone or in combination with chemotherapy. Results: From October 2009 until August 2011, 12 patients started treatment with anti EGF vaccine; mean age 56.5 (42-79 y); 66.7% male; ECOG 0 and 1: 41.7% and 58,3% respectively. Adenocarcinoma (50%), bronchioloalveolar (33.3%), adenosquamous (16.7%). Metastatic sites: lung (41.7%), pleura (25%), CNS (16.7%), Kidney (8.3%). In addition to chemotherapy previous used: radiotherapy (50%), surgery (41.7%), erlotinib (41.7%), bevacizumab (25%). The 50% patients received vaccine alone. The 83.3% of patients had titers 1/4000 sera dilutions or more (good responders). According to RECIST 1.1: CR: 8.3%, PR: 16.7%, SD: 41.7%, PD 25%. Median overall survival was 18.8 months (95% CI: 13.3- 24.4 m). Median progression-free survival was 7.3 months (95% CI: 6.4 -8.2 m). We found no statistically significant differences in OS and PFS when comparing vaccine alone or combined (p = 0.181 and p = 0.801). 75% of patients had adverse effect: more frequently were: 42.4% application site pain, 15.1% fever and 10.38% chills, none of them serious. Conclusions: Vaccination anti EGF in patients with metastatic NSCLC after progressing to first line, alone or in combination, was safe and provoked an increase in anti-EGF antibody titers, produced clinical benefit, improved overall survival and progression free survival.
Low expression of bax predicts poor prognosis in resected non-small cell lung cancer patients with nonsquamous histology
Authors: J. Choi, H. Lim, S. Kang, Y. Jung, H. Kim, Y. Oh, H. Choi, S. Hwang, K. Park, J. Han
Journal: Journal of Clinical Oncology (2006)

7215 Background: Both p53 and bax proteins are known to promote apoptosis, and decreased expression of bax and mutation of p53 have been associated with poor progosis in several malignancies. Methods: We investigated the expression of these proteins and their association with clinicopatholgic characteristics including disease-free survival (DFS) and overall survival (OS) in 209 non-small cell lung cancer (NSCLC) patients (pts) who underwent surgical resection (stage I: 97, II: 46, IIIA: 45, IIIB: 17, IV: 4) using immunohistochemistry. Ninety-one pts (44%) received adjuvant treatment (chemotherapy: 9, radiotherapy: 24, both: 58). Results: While 82 pts (39%) had overexpression of p53 (&gt;50% tumor cells positive), low expression of bax (no or weak staining in intensity) was observed in 159 pts (76%), which was significantly associated with male gender (p &lt; 0.0001), squamous cell carcinoma (p &lt; 0.0001), and overexpression of p53 (p = 0.028). With a median follow-up of 65 months (34–133 months) in survivors, 5-year DFS and OS of total pts were 38% and 46%, respectively, excluding 7 deaths from postoperative complications. Neither overexpression of p53 nor low expression of bax was associated with poor DFS (p = 0.728, p = 0.335) and OS (p = 0.927, p = 0.261). However, in pts with nonsquamous histology (111 pts), low expression of bax was significant independent predictor of poor DFS (p = 0.004) in addition to advanced stage (p &lt; 0.0001) and large primary tumor size (&gt;4 cm) (p = 0.005) in multivariate analysis. Furthermore, low expression of bax was associated with poor OS (p = 0.048) along with advanced stage (p = 0.01) and pneumonectomy (p = 0.003). Conclusions: Low expession of bax was significantly associated with poor prognosis in NSCLC pts with nonsquamous histology. No significant financial relationships to disclose.
Prognostic value of stem cell quantification in stage II colon cancer.
Authors: M. Angeles Vaz, Juan Carlos Martinez, Manuel Devesa, Javier Die Trill, Victor Abraira, Alejandro Riquelme, Alfredo Carrato
Journal: Journal of Clinical Oncology (2012)

e21104 Background: Cancer stem cells (CSCs) are a subset of tumor cells with capacity to self-renew and generate the diverse cells that comprise the tumor. They are considered cancer (Ca) initiating cells responsible for tumor recurrence and maintenance. These cells express pluripotency markers (CD133 and NANOG) and do not express markers of differentiation as cytokeratin 20 (CK20). The potential prognostic value of CSCs in colorectal cancer has been studied with conflicting results. However some of these series were based on heterogeneous situations, involving rectal and colon cancer (CC) and different tumor stages (I-IV). The aim of this study is to evaluate the prognostic value of CSCs in a highly homogeneous population of stage II CC. Methods: One hundred stage II CC patients (pts) treated by the same surgical team at Ramon y Cajal University Hospital between 1977 and 2005 were retrospectively analyzed. None of the pts received adjuvant chemotherapy. Inmunohistochemistry expression of CD133, NANOG and CK20 was scored on paraffin sections using four levels: &lt;10%,11-25%, 26-50% and &gt;50% positivity. Kaplan-Meier analysis and log rank test were used to compare survival. Results: Median age: 68 years (45-92). Median follow up: 5.8 years. Recurrent disease: 17 (17%). Expression of CD133 was shown in 60% of the tumors, in 95% for NANOG and 78% for CK20. No correlation was found among expression levels of CD133, NANOG or CK 20 and relapse-free survival (RFS) and overall survival (OS). However, a statistical significant correlation was found between established pathological prognostic factors and RFS and OS. Conclusions: Stem Cell quantification defined by CD133 and NANOG expression has no correlation with RFS or OS in this cohort of Stage II CC. However, a correlation with established prognostic pathological factors was found. Therefore, our results suggest that CSCs may not play a major role in early phases of CC.
Designing gene panels for tumor mutational burden estimation: the need to shift from ‘correlation’ to ‘accuracy’
Authors: Hao-Xiang Wu, Zi-Xian Wang, Qi Zhao, Feng Wang, Rui-Hua Xu
Journal: Journal for ImmunoTherapy of Cancer (2019)

Tumor mutational burden (TMB) assessment is at the forefront in precision medicine. The TMB could represent a biomarker for immune checkpoint inhibitors (ICIs) responses. Whole exome sequencing (WES) is the gold standard to derive the TMB; while targeted next-generation sequencing panels might be more feasible. However, mainstream panels use 'correlation' (R<sup>2</sup>) between panel- and WES-based TMB to validate TMB estimation, which could be vulnerable to be distorted by cases with relatively ultra-high TMB within each cancer type. The FDA-approved FoundationOne CDx (F1CDx) panel-based TMB estimation seemed reliable (R<sup>2</sup> ≥ 0.75) in 24 out of 33 cancer types from the Cancer Genome Atlas, but most of them were overestimated by correlation as only seven cancer types had satisfactory accuracy (the proportion of cases correctly identified as TMB-high or TMB-low using panel-based TMB) above 90%. After removing cases with relatively ultra-high TMB within each cancer type, the correlation (R<sup>2</sup>) in 16 of these 24 cancer types declined dramatically (Δ &gt; 0.25) while all of their accuracy remained generally constant, indicating that accuracy is more robust than correlation. Similar results were also observed in other four panels. Further incorporating accuracy in panel design revealed that the minimal number of genes needed to achieve ≥&nbsp;90% accuracy varied among cancer types and correlated negatively with their TMB levels (<i>p</i> = 0.001). In summary, currently available panels can accurately assess TMB only in several particular cancer types; and accuracy outperformed correlation in assessing the performance of panel-based TMB estimation. Accuracy and cancer type individualization should be incorporated in designing panels for TMB estimation.
High affinity CD3 RECRUIT TandAb for T cell-mediated lysis of CD19<sup>+</sup> tumor B cells.
Authors: Eugene Zhukovsky, Uwe Reusch, Carmen Burkhardt, Stefan Knackmuss, Ivica Fucek, Markus Eser, Fionnuala McAleese, Kristina Ellwanger, Melvyn Little
Journal: Journal of Clinical Oncology (2012)

8059 Background: CD19 is expressed from early B cell development to the differentiation into plasma cells and is an attractive target for B cell malignancies either lacking CD20 expression or refractory to anti-CD20 antibody therapies. T cells are potent tumor killing effector cells that are not recruited by native antibodies. The CD3 RECRUIT-TandAb AFM11, a human bispecific tetravalent antibody with two binding sites for both CD3 and CD19, is a novel therapeutic for the treatment of NHL that harnesses the cytotoxic nature of T cells. Methods: A bispecific anti-CD19/anti-CD3 tetravalent TandAb with humanized and affinity matured variable domains was constructed. The TandAb’s binding, T-cell mediated cytotoxic activity, and cytokine release were characterized in a panel of in vitro assays. In vivo efficacy was evaluated in a murine NOD/scid xenograft model reconstituted with human PBMC. Results: AFM11 mediates highly potent target tumor cell lysis in cytotoxicity assays: EC 50 values are low to sub-picomolar range in a panel of CD19 + cell lines and primary B-CLL tumor cells. The cytotoxic activity of tetravalent AFM11 is superior to that of alternative bivalent antibody formats possessing only a single binding site for both CD19 and CD3. High affinity binding of AFM11 to CD19, and more so to CD3 (low to sub-nanomolar Kd), is essential for efficacious T cell recruitment. The high affinity bivalent binding of AFM11 to CD3 does not trigger T cell activation in the absence of CD19 + target cells in functional in vitro assays. AFM11 activates T cells only in the presence of its targets and mediates lysis while sparing antigen-negative bystanders. AFM11 induces down-modulation of the CD3/TCR complex in the absence of target cells and at high concentrations. Also, AFM11-treated T cells can be re-engaged for target cell lysis. These features of AFM11-induced T cell activation may contribute additional safety with no compromise of efficacy. Finally, AFM11 demonstrates a robust dose-dependent inhibition of subcutaneous Raji tumors in mice. Conclusions: AFM11 is a novel highly efficacious drug candidate for the treatment of B cell malignancies with an advantageous safety profile.
[Abstract] Protein profiling to identify serum biomarkers for early detection of breast cancer in African American women
Authors: Padma P. Tadi-Uppala, William Blackledge, Larry Beeson, Pramila P. Thadi, Carlos A. Garberoglio, John Morgan, Gurunatha R. Uppala, Sharon S. Lum, Kumar Vs Kolli, David Kirchner, Alisha Preuss, Richard Mural, Michael Liebman, Susanna Montgomery
Journal: Cancer Research (2006)
Surgical resection based on ontogenetic cancer field theory for cervical cancer: mature results from a single-centre, prospective, observational, cohort study
Authors: Michael Höckel, Benjamin Wolf, Katja Schmidt, Meinhard Mende, Bahriye Aktas, Rainer Kimmig, Nadja Dornhöfer, Lars-Christian Horn
Journal: The Lancet Oncology (2019)
Identification of ABCA5 as a tissue and urine diagnostic marker for PIN
Authors: M. E. Stearns, Y. Hu, M. Wang, K. A. Veverka
Journal: Journal of Clinical Oncology (2007)

15508 Background: Bostwick and colleagues have suggested that prostatic intraepithelial neoplasia or PIN is the precursor of prostate cancer, and that a significant percentage of men with PIN develop prostate cancer (Sakr, 1994; Bostwick, 1995b; Arakawa, 1995; Qian, 1995; Qian, 1997). Currently there are no molecular diagnostic markers for PIN. Methods: Recently, we have developed ‘DNA-protein’ binding assays for the identification of novel transcriptional regulatory proteins associated with PIN glands. Electrophoretic mobility shift assays (EMSAs) with the 32P-labeled DNA probe was used for analysis of protein extracts from tissues and urine. Immunolabeling was carried out with rabbit antibodies specific for ABCA5. Results: Electrophoretic mobility assays (EMSAs) revealed that 1 DNA sequence (1 of 4,096 sequences screened) specifically bound a ∼160 Kda protein which was over-expressed in PIN and not found in BPH, SV or PCA glands (n=11). The gene encoding for the 160 Kda protein was cloned from a cDNA expression library by ‘in situ’ hybridization assays with the 32P-labeled DNA sequence. Sequencing revealed that the gene encoding for the 160 Kda protein was ABCA5, a member of the superfamily of ATP-binding cassette (ABC) transporters of multi-drug resistant genes. RT-PCR assays indicated the mRNA was over-expressed in PIN tissue, and was not present in BPH, or SV tissue. Rabbit polyclonal antibodies and immunolabeling showed that the antibodies specifically labeled the cell junctions of 3% glutaraldehyde fixed prostate cells. Immunohistochemistry indicated that ABCA5 was over expressed in foci of intermediate basal cells in normal glands, and in HGPIN. ABCA5 was faintly expressed in PCA glands. Enzyme linked immunoabsorbent assays (ELISAs) demonstrated in blinded studies that ABCA5 was a highly sensitive (&gt;98% sensitivity) urine diagnostic marker for HGPIN in biopsy positive patients (n=107) at a cut off” of 25 ng/ml. ABCA5 was present at very low levels (i.e. &lt;25 ng/ml) in the urine of patients diagnosed with BPH (n=79) or prostatitis or kidney and bladder cancer (&gt;86% specificity). Conclusions: The data suggest that the expression of ABCA5 is over-expressed by PIN and may be a highly sensitive and specific urine diagnostic marker for detection of early stage prostate cancer. No significant financial relationships to disclose.
The Goldilocks Window of Personalized Chemotherapy: Getting the Immune Response Just Right
Authors: Derek S. Park, Mark Robertson-Tessi, Kimberly A. Luddy, Philip K. Maini, Michael B. Bonsall, Robert A. Gatenby, Alexander R.A. Anderson
Journal: Cancer Research (2019)

Abstract The immune system is a robust and often untapped accomplice of many standard cancer therapies. A majority of tumors exist in a state of immune tolerance where the patient's immune system has become insensitive to the cancer cells. Because of its lymphodepleting effects, chemotherapy has the potential to break this tolerance. To investigate this, we created a mathematical modeling framework of tumor-immune dynamics. Our results suggest that optimal chemotherapy scheduling must balance two opposing objectives: maximizing tumor reduction while preserving patient immune function. Successful treatment requires therapy to operate in a “Goldilocks Window” where patient immune health is not overly compromised. By keeping therapy “just right,” we show that the synergistic effects of immune activation and chemotherapy can maximize tumor reduction and control. Significance: To maximize the synergy between chemotherapy and antitumor immune response, lymphodepleting therapy must be balanced in a “Goldilocks Window” of optimal dosing.
Epigenetic alterations are associated with tumor mutation burden in non-small cell lung cancer
Authors: Liangliang Cai, Hua Bai, Jianchun Duan, Zhijie Wang, Shugeng Gao, Di Wang, Shuhang Wang, Jun Jiang, Jiefei Han, Yanhua Tian, Xue Zhang, Hao Ye, Minghui Li, Bingding Huang, Jie He, Jie Wang
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> To profile genomic and epigenomic of a naïve Chinese non-small cell lung cancer (NSCLC) cohort and investigate the association between tumor mutation burden (TMB) and DNA methylation (DNAm) to explore potential alternative/complimentary biomarkers for NSCLC immunotherapies. <h3>Methods</h3> A total of 89 tumor tissues with matched normal tissues from Chinese NSCLC patients were collected and subjected to whole exome sequencing (WES). From comparison, each patient was evaluated for the TMB value and divided into high, medium and low TMB based on TMB tertile distribution and then relatively high and low TMB samples were selected and subjected to DNAm profiling. <h3>Results</h3> Patients in the low (<i>n</i> = 30), medium (<i>n</i> = 29), and high (<i>n</i> = 30) TMB tertiles had 1.1–2.5, 2.5–4.1, and 4.2–13.9 mutations/Mb, respectively. A statistical directly association between differential methylation probes (DMPs) and TMB level was observed in our cohort (<i>r</i> = 0.63, <i>P</i> value =0.0003) and this was confirmed by using TCGA NSCLC dataset (<i>r</i> = 0.43, <i>P</i> value =0.006). Relatively high TMB group (<i>n</i> = 16, 7.5–13.9 mutations/Mb) harbors more differential DMPs while less in relatively low TMB group (<i>n</i> = 13, 1.1–2.4 mutations/Mb). Eight hundred fifty-eight differential methylation regions (DMRs) were found in relatively high TMB group. In addition, 437 genes show DNAm aberrance status in high TMB patient group and 99 have been reported as its association with lung cancer. <h3>Conclusion</h3> To our knowledge, this is the first report for direct link between the methylome alterations and TMB in NSCLCs. High TMB NSCLCs had more DNAm aberrance and copy number variations (CNVs). In addition, the TMB distribution of Chinese NSCLCs population is lower than that of TCGA.
Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Melissa A. Lyle, Seethalakshmi R. Iyer, Margaret M. Redfield, Yogesh N.V. Reddy, G. Michael Felker, Thomas P. Cappola, Adrian F. Hernandez, Christopher G. Scott, John C. Burnett, Naveen L. Pereira
Journal: JACC Heart Failure (2019)
Regional differences in the use of trastuzumab in Sweden
Authors: U. Wilking, J. Bergh, N. Wilking, B. Jönsson
Journal: Journal of Clinical Oncology (2006)

16019 Background: The number of deaths due to metastatic breast cancer (MBC) in Sweden is around 1.500 patients/year. It is important that patients have access to new drugs that may delay disease progression and potentially improve survival. HER2 over expression (H+) is used to identify patients eligible for trastuzumab treatment (T). Between 15–30% of patients with MBC have H+ disease. Methods: This study uses sales data from the retail supplier in Sweden, as well as breast cancer mortality data from the National Board of Health and Welfare. Date of marketing approval for trastuzumab in Sweden is Oct 2000. The median treatment time used in this study, as reflected in the pivotal trials, has been set to 38 weeks. This study examines the variation of use in the six health care regions of Sweden (total population 9 millions). Results: The per capita use of T in patients with H+ MBC varies significantly across Sweden. In 2000 minor regional differences in usage were observed. These differences increased and in Q4 2004 usage (measured in sales) varied between 12.500 USD and 37000 USD per 100,000 inhabitants (regions with the lowest/highest sales). Only half (approx. 1100 patients) based on the estiamted prevalent 2200 patients (based on 25% H+ MBC patients) have received T. The first year after marketing authorization 9% of the prevalent population received T. Four years later 93% of the incident population received T. Conclusions: Access of T to patients with H+ MBC in Sweden varies significantly across the 6 Health Regions. Uptake has been slow and not all eligeble patients receive T, even 5 years after marketing authorization. [Table: see text]
Spatial chromatin architecture alteration by structural variations in human genomes at the population scale
Authors: Michal Sadowski, Agnieszka Kraft, Przemyslaw Szalaj, Michal Wlasnowolski, Zhonghui Tang, Yijun Ruan, Dariusz Plewczynski
Journal: Genome biology (2019)

The number of reported examples of chromatin architecture alterations involved in the regulation of gene transcription and in disease is increasing. However, no genome-wide testing has been performed to assess the abundance of these events and their importance relative to other factors affecting genome regulation. This is particularly interesting given that a vast majority of genetic variations identified in association studies are located outside coding sequences. This study attempts to address this lack by analyzing the impact on chromatin spatial organization of genetic variants identified in individuals from 26 human populations and in genome-wide association studies.We assess the tendency of structural variants to accumulate in spatially interacting genomic segments and design an algorithm to model chromatin conformational changes caused by structural variations. We show that differential gene transcription is closely linked to the variation in chromatin interaction networks mediated by RNA polymerase II. We also demonstrate that CTCF-mediated interactions are well conserved across populations, but enriched with disease-associated SNPs. Moreover, we find boundaries of topological domains as relatively frequent targets of duplications, which suggest that these duplications can be an important evolutionary mechanism of genome spatial organization.This study assesses the critical impact of genetic variants on the higher-order organization of chromatin folding and provides insight into the mechanisms regulating gene transcription at the population scale, of which local arrangement of chromatin loops seems to be the most significant. It provides the first insight into the variability of the human 3D genome at the population scale.
2008 oncology trends: Views from payors, specialty pharmacy, and oncology providers
Authors: D. G. Holcombe
Journal: Journal of Clinical Oncology (2009)

e20750 Background: Kikaku International Research was engaged by Genentech USA to conduct survey research among four key stakeholder groups involved in the financing, management and delivery of cancer care and drugs. Methods: Surveys were distributed and collected from January to June 2008. Survey questions addressed issues on volume of services, utilization of specialty pharmacy, management methodologies and degrees of involvement, volume and staffing levels in oncology practice, oncology physician staffing and retirement, payor evaluations, cost and impact of public and private payor reimbursement policies, Average Selling Price (ASP) and Medicare Modernization Act (MMA) issues and use of guidelines/pathways. Results: Managed Care Organizations: Ninety (90) managed care professionals responded. Key findings addressed: anticipated shifts in cancer spending from the medical benefit to the pharmaceutical benefit, adoption of ASP-based reimbursement and revaluation of professional fees. Specialty Pharmacy Providers: Forty-two (42) specialty pharmacy professionals responded. Key findings: total revenues and volume from cancer drugs and supportive care, distribution of drugs to patients and physician offices, Injectable drugs and oral drugs precription volume, patient education and disease management. Oncologists - Surveys were returned by 139 oncologists. Key findings: workloads and patient loads, income declines, drug margins declines, buy and bill volume. Oncology Practice Managers: Sixty (60) oncology practice managers responded to surveys about practice management, billing and reimbursement. Key findings: payer coverage and reimbursement policies, ASP rates, health plan contracts, negotiation of fee schedules. Conclusions: The conclusions of each section of the survey, when combined in aggregate, paint a picture of a very complex topic with wide variation in both approach and recommendations for how each segment addresses the specialty. Disconnects, challenges and opportunities observed in evaluating the responses include perspectives on ASP, Medical vs pharmaceutical benefit, contract negotiations, disease management, pharmaceutical management. [Table: see text]