tbuckley/cabot-search huggingface dataset:
miR125 and miR200a as potential circulating miRNA biomarkers in metastatic urothelial carcinoma patients treated with docetaxel.
Authors: Stephanie A. Mullane, Chensheng Willa Zhou, William Martin-Doyle, Massimo Loda, Toni K. Choueiri, Joaquim Bellmunt, Michaela Bowden
Journal: Journal of Clinical Oncology (2015)

364 Background: Docetaxel is frequently used as second-line therapy in advanced bladder cancer. The response rate is 10-15% with a median PFS of 2.5 months and without data showing improvement of QoL, however, some selected patients derive significant benefit. Understanding the mechanisms underlying the sensitivity of docetaxel in bladder cancer will help to customize treatment in second line. Circulating miRNAs have been shown to be predict outcome in GU malignancies (for example, prostate cancer). Using circulating miRNA can identify patients who will respond to therapy non-invasively. The main aim of our study was identify circulating miRNAs predicting docetaxel response in urothelial carcinoma (UC). Methods: We obtained pre- and post-treatment plasma samples from patients included in the zactima phase II clinical trial assigned to the placebo + docetaxel arm. RNA from plasma was extracted and RT-PCR was performed on both the pre- and post-treatment samples looking at miRNAs known to be important in docetaxel response 1 (miR125, miR27a, miR34a, miR429, miR141, miR200a, miR200c, miR 146a, and miR9). Samples were normalized by the mean global miRNA levels. We divided patients based on progression free survival (PFS) as good responders (&gt;4 months PFS or 6 cycles) versus poor responders (&lt;2 months PFS or progression at first evaluation). Differences in miRNA levels were assessed using the student t test (p&lt;0.05). Results: miR125 and miR200a were shown to be significantly different between the poor and good responders (p=0.056 and p=0.028, respectfully) in the pre-docetaxel samples. Higher expression of both miRNAs correlated with a good response in our small patient cohort. Additional analysis comparing pre- and post-miRNA levels will be presented. Conclusions: miR125 and miR200a are potential extracellular biomarker to docetaxel treatment in metastatic UC.
Use of single nucleotide polymorphism (SNP) array karyotyping to detect clonal chromosomal abnormalities in myelodysplastic syndrome (MDS) and refractory anemia with ringed sideroblasts (RARS)
Authors: T. Ghazal, A. S. Haddad, L. P. Gondek, K. S. Theil, M. A. Sekeres, A. Lichtin, J. P. Maciejewski
Journal: Journal of Clinical Oncology (2008)

7090 Background: The current standard for identification of chromosomal abnormalities in MDS is metaphase cytogenetics (MC). However, this technique has low resolution and requires bone marrow sampling and cell growth in vitro. High density SNP arrays offer significantly higher resolution for identification of previously cryptic chromosomal (chr.) abnormalities. This study aims to elucidate the accuracy of SNP arrays compared to MC, and to measure concordance between testing on peripheral blood (PB) and bone marrow (BM) tissues. Methods: DNA was available for 38 pts (PB = 15, BM = 23) with ringed sideroblasts (RS) and was subjected to 250K SNP-A karyotyping. Pathologic lesions were defined upon exclusion of normal copy number polymorphisms identified in 81 controls, as well as the Database of Genomic Variants. Results: By MC, a defective karyotype was present in 17/38 pts (44%). When SNP-A was applied as a karyotyping tool (copy number and loss of heterozygosity (LOH) analysis), all aberrations found by MC were confirmed but new lesions were also detected so that an abnormal karyotype was established in 63% of patients (pts). Several previously cryptic lesions included losses of a portion of chr. 17 (N=3; 17q21.31, 17q21.33, 17q11.2) as well as gains (N=2; 17q12, 17q21.31). We have also detected segmental uniparental disomy (UPD) in chr 1 (N=3; 1p21.3–22.2, 1p, 1p35.1-pter). This type of lesion cannot be detected using MC and provides an additional mechanism leading to LOH. When both bone marrow and blood of 5 RARS pts were tested using SNP-A, blood analysis had 100% accuracy rate as compared to marrow. All defects seen in the marrow were also found in blood. Conclusions: Chromosomal defects are present in RARS patients and that arrays with higher resolution will detect more defects than MC. Our study also demonstrates testing of peripheral blood by SNP-A can complement marrow MC, especially in cases in which marrow is not available. Detection of clonal marker aberrations in blood of RARS patients suggests that mostly clonal dysplastic progenitor cells contribute to blood production rather than residual “normal” progenitors. No significant financial relationships to disclose.
A review of medical malpractice claims related to clinical genetic testing.
Authors: R. A. Lindor, G. E. Marchant
Journal: Journal of Clinical Oncology (2011)

6073 Background: The adoption of new genetic technologies into clinical practice has been much slower than many predicted. Though many factors underlie this delay, the current gap between public expectations and actual practice makes physicians extraordinarily vulnerable to medical malpractice lawsuits. Courts are beginning to take a lead role in setting the standards for genetic testing within the medical field. Because physicians’ responsibilities related to genetics are still in flux and rapidly evolving, the expectations placed on them are unclear and remain largely dependent on a case’s judge, jury, and jurisdiction. Methods: A search of a legal case database (Westlaw) for all federal and state cases involving liability relating to genetic testing was conducted. All cases involving malpractice claims against physicians or other health professionals for alleged negligence in recommending, conducting, or reporting genetic tests were included. The basis for litigation and outcomes of the cases were summarized. Results: Over 50 cases were identified in which health care providers—mainly physicians—were sued for their negligence in using and applying genetic testing methods. Of these, only three cases related to a hereditary cancer, though the causes of action recognized by the courts in other cases apply to hereditary cancers as well. Physicians were held liable for failing to: take an adequate family history, recommend the appropriate testing, refer to a geneticist or genetic counselor, interpret the test results correctly, interpret the test results in a timely manner, recommend the appropriate risk mitigation strategies, and failing to disclose their patients’ test results to at-risk family members. Conclusions: Though drug manufacturers, hospitals, and pharmacists have all been the subject of lawsuits related to genetic technologies, physicians appear to be the most vulnerable group. Courts are willing to require the use and understanding of genetic information even before the medical community itself is ready and able to do so. The number of lawsuits physicians will face in the future is likely to mushroom as the field of genetics continues to grow and public expectations continue to be fed by an optimistic media.
Pharmacogenetic investigation of lapatinib-associated diarrhea in metastatic breast cancer clinical trials.
Authors: L. P. Briley, M. Chiano, K. King, M. Casey, A. J. Preston, F. Sapunar, V. E. Mooser, L. R. Cardon, C. F. Spraggs
Journal: Journal of Clinical Oncology (2011)

552 Background: Diarrhea is common during lapatinib treatment. Most events are mild to moderate, self-limiting and managed proactively to prevent serious complications, however diarrhea may lead to non-compliance and possibly poor treatment outcomes. Pharmacogenetic associations with diarrhea caused by tyrosine kinase inhibitors have been reported for the functional variants CYP2C19*2 (lapatinib), ABCG2 Q141K (gefitinib) and EGFR −216G>T (erlotinib) in studies with few diarrhea cases (n<40). The present study evaluated these variants and explored additional genetic influences in a larger dataset in metastatic breast cancer (MBC) patients from lapatinib treatment (monotherapy or combination) clinical trials. Methods: In the primary dataset (8 trials), cases (n=285) were defined as patients who experienced NCI CTC AE grades ≥2 for diarrhea during lapatinib treatment. Controls (n=319) were patients who did not experience diarrhea and received lapatinib for at least 9days (median onset for diarrhea). Germline DNA was extracted from peripheral blood and genotypes were determined by standard methods. In addition to the four specified variants, genome wide association screen data (GWAS, 1M SNPs) including ∼500 tagging SNPs selected in 36 candidate genes for lapatinib metabolism or mechanism pathways were also investigated for diarrhea association using penalised logistic regression. Nominally significant associations were evaluated for confirmation in an independent dataset comprising 120 cases and 124 controls from a single MBC trial. Results: The reported variants in CYP2C19, ABCG2 and EGFR did not show significant association (p>0.05) with lapatinib associated diarrhea, despite >80% power to demonstrate similar effects. No GWAS SNPs achieved a genome-wide significance threshold (p=5×10−8), however 57 polymorphisms achieved p<10−4. None of these associations were confirmed in the second independent lapatinib dataset. Conclusions: Previously reported EGFR, ABCG2 and CYP2C19 variants were not found to be associated with lapatinib induced diarrhea. No robust associations were identified following candidate gene and genome-wide evaluation of common variants.
c.35 G &gt; A <i>KRAS</i>-mutant genotype and clinical outcome of patients with metastatic colorectal cancer.
Authors: Gemma Bruera, Katia Cannita, Edoardo Alesse, Corrado Ficorella, Enrico Ricevuto
Journal: Journal of Clinical Oncology (2014)

512 Background: KRAS genotype does not significantly affect prognosis of MCRC patients treated with bevacizumab-containing chemotherapy. Codon 12 mutations increase aggressiveness by differently modifying mutated KRAS and downstream signalling, thus conferring worse clinical behavior. Prognostic relevance of the prevalent c.35 G &gt; A KRAS mutation in MCRC patients fit and unfit for first-line bevacizumab added to triplet chemotherapy (FIr-B/FOx) was evaluated. Methods: KRAS codon 12/13 mutations were screened. Efficacy was evaluated and compared by log-rank. Results: Fifty-nine fit patients were treated with firstline FIr-B/FOx: wild-type, 31 (53%); mutant, 28 (47%). KRAS mutations: c.35 G &gt; A, 15 (25.4%); c.35 G &gt; T, 7 (11.8%); c.38 G &gt; A, 3 (5%); other, 3 (5%). Wild-type compared to mutant status did not significantly affect PFS (14 and 11 months) and OS (38 and 20 months). c.35 G &gt; A mutant showed: no significantly different PFS compared to wild-type; significantly worse OS (14 months) compared to wild-type and to other mutant (39 months). After progression, wild-type compared with mutant did not show significantly different PFS (10 months equivalently) nor OS (17 and 12 months); c.35 G &gt; A compared to wild-type and/or other mutant showed significantly worse PFS and OS. Among 39 unfit patients, treated with conventional regimens, wild-type compared to mutant significantly affected PFS (8 and 6 months), and not OS (13 and 8 months); c.35 G &gt; A mutation significantly affected worse PFS and OS compared to wild-type and/or other mutant. Conclusions: KRAS genotype does not significantly affect clinical outcome of MCRC patients treated with first line FIr-B/FOx, while mutant status may significantly affect worse PFS in patients unfit for intensive treatments. c.35 G &gt; A mutant status, compared to wild type and other mutant, may significantly affect worse clinical outcome in MCRC patients treated with first line intensive FIr-B/FOx and after progression, as well as in patients unfit for FIr-B/FOx, due to increased biological aggressiveness. It did not affect worse PFS only in patients treated with FIr-B/FOx, probably due to effectiveness of triplet chemotherapy plus VEGF inhibitor.
Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes
Authors: Qian Shi, Minghui Li, Delphine Mika, Qin Fu, Sungjin Kim, Jason Phan, Ao Shen, Gregoire Vandecasteele, Yang K. Xiang
Journal: Cardiovascular Research (2017)

Cardiac β-adrenergic receptor (βAR) signalling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between βARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists.Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of Gs-coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and Gq-coupled α1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β1AR and β2AR at putative protein kinase A (PKA) phosphorylation sites; but activation of Gi-coupled α2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β2AR phosphorylation effectively inhibit βAR agonist isoproterenol-induced PKA phosphorylation of phospholamban and contractile function in ventricular cardiomyocytes. Heterologous GPCR stimuli have minimal to small effect on isoproterenol-induced β2AR activation and G-protein coupling for cyclic adenosine monophosphate (cAMP) production. However, these GPCR stimuli significantly promote phosphorylation of phosphodiesterase 4D (PDE4D), and recruit PDE4D to the phosphorylated β2AR in a β-arrestin 2 dependent manner without promoting β2AR endocytosis. The increased binding between β2AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β2AR, inhibition of PDE4, or genetic ablation of PDE4D or β-arrestin 2 abolishes this heterologous inhibitory effect. Ablation of β-arrestin 2 or PDE4D gene also rescues β-adrenergic stimuli-induced myocyte contractile function.These data reveal essential roles of β-arrestin 2 and PDE4D in a common mechanism for heterologous desensitization of cardiac βARs under hormonal stimulation, which is associated with impaired cardiac function during the development of pathophysiological conditions.
15-year results for upfront TPDCV chemotherapy phase II trial for pediatric low-grade hypothalamic/chiasmatic gliomas
Authors: K. K. Mishra, A. Banerjee, S. Squire, K. Lamborn, W. Wara, M. D. Prados, D. A. Haas-Kogan
Journal: Journal of Clinical Oncology (2008)

10041 Background: As part of a single arm phase II protocol, a cohort of children with low-grade gliomas (LGG) was treated with TPDCV chemotherapy as primary treatment. This report focuses on the long-term outcomes of a subset of the patients with hypothalamic/chiasmatic (hyp/chiasm) LGGs. Preliminary data has been presented previously (Prados et al, JCO 32:235–241, 1997; ASTRO 49th Annual Meeting, 2007). Methods: Patients with no prior radiation or chemotherapy were enrolled on Protocol 8422 between 1984 and 1992. TPDCV regimen was given as six planned 42-day cycles to include 6-TG (hrs 0–66), dibromodulcitol (hr 60), procarbazine (hrs 60–78), CCNU (hr 72), and vincristine (day 14 & 28). No up-front radiation was given and salvage therapy was at the discretion of the treating physician. Results: 33 children with hyp/chiasm LGGs were enrolled, with a median age at diagnosis of 3.0 yrs (range 0.3- 16.2). Extent of resection at diagnosis included 0 GTRs, 12 (36%) STRs, 14 (42%) biopsy, and 7 (21%) with no surgery at dx. 20 (61%) had pathologic JPAs, 9 (27%) had grade II gliomas. Median f/u for surviving patients was 15.2 years (range 5.3–20.7). All patients had at least 5 years of follow-up and 20 of 23 surviving patients had at least 14 years of follow-up with regular interval scans. Median PFS was 3.1 years; median OS was not reached. Five-year PFS and OS were 30.3% and 90.9%, respectively. Fifteen-year PFS and OS were 23.4% and 71.2%, respectively. Of the 25 patients who progressed, 24 had their first progression event within 6 years of diagnosis. Thirteen were salvaged and currently NED (median f/u 15.5 years), two were AWD, and ten were dead at last f/u. Eighteen of 33 children were ≤ 3 yo at diagnosis; 17 of these 18 progressed and 13 underwent salvage RT. All 10 patients that died were ≤ 3 yo at diagnosis. Their median PFS was 1.9 years (range 0.6–5.7), and median OS was 6.6 years (range 2.1–15.4). Conclusions: Children with hypothalamic/chiasmatic LGGs treated with upfront TPDCV chemotherapy had 15-year OS of 71.2% and PFS of 23.4%. Most all progression events occurred within 6 years of diagnosis. Upfront chemotherapy delayed radiation in most cases until after age 3. Age was a significant prognostic factor for OS and PFS. All 10 children who have died were ≤ 3 yo at diagnosis. No significant financial relationships to disclose.
Interest of imaging mass spectrometry to determine the proteophenotype of non-small cell lung cancers (NSCLC).
Authors: R. Mengual
Journal: Journal of Clinical Oncology (2010)

e21105 Background: Imaging MALDI Mass Spectrometry (IMS) could get paramount to diagnose subtypes of NSCLC by comparative proteomic analysis of human tissues. We aimed to: i) differentiate healthy tissues from abnormal proteins of two NSCLC subtypes (adenocarcinoma and epidermoid cancers). ii) Build a strong and validated statistical model for each pathologist-diagnosed subtype. Methods: Profiling of tumor proteome by in situ IMS was performed with a Maldi Tof-Tof apparatus (ULTRAFLEX III Bruker-De). Tumoral and healthy tissues from a 50 patients were frozen or paraffin-embedded for pathology diagnosis. Imaging sets were analyzed by Principal Component Analysis (PCA) with a supervised or unsupervised hierarchical clustering. Specific models built with algorithms (genetic GA and quick classifier QC) and external classification generating a tumor percentage. Statistical models based on the pathologist diagnosis, were blindly validated afterwards on random samples. Results: Supervised and unsupervised characterized frozen healthy tissue from epidermoid cancer and adenocarcinoma tissues. Example of results from specific models: % spectrum “healthy” versus “adenocarcinoma” versus “epidermoid” 10-1-89 by GA and 3-1-96 by QC. The PCA discriminated biomarkers within each class, directly located on the corresponding imaging slide area. Deparaffined- trypsinated tissues differentiated healthy from tumoral tissue. Conclusions: IMS allowed to build reference models of proteophenotypes of NSCLC by focusing on limited area of tumoral tissue of a given sample image associated to specific statistical data analysis. cluster analysis allowed in all cases to specifically differentiate abnormal from normal tissue. The resulting “blinded” IMS models of the two NSCLC subtypes strictly overlapped, when applied prospectively, the pathologist-based subtype classification. Furthermore, CPA analysis yielded specific proteome features for each of these NSCLC subtypes. The deparaffined-trypsinated data not only improved our model, but opens new perspectives for IMS in the area of cancer as proteomic identification from the wealth of tissue banks paraffin-embedded. No significant financial relationships to disclose.
Do insulin-like growth factor associated proteins qualify as a tumor marker?
Authors: Christiane Matuschek, Matthias Peiper, Wilfried Budach, Peter Arne Gerber, Hans Bojar, Gerald Steinbach, Michael Rudoy, Wolfram Trudo Knoefel, Matthias Schauer
Journal: Journal of Clinical Oncology (2012)

18 Background: Insulin-like growth factor (IGF)-1, -2 and insulin-like growth factor binding proteins (IGFBP) are involved in the proliferation and differentiation of cells. It has never been evaluated if the IGF-system can serve as a tumor marker in neoplasms. Methods: In our prospective study, 163 patients with colorectal cancer (22), prostate cancer (21), glioblastoma (12), head and neck tumors (17), lymphomas (20), lung cancer (34), and other entities (37) were analysed for their IGF and IGFBP serum levels at the beginning and the end of radiotherapy and compared with 13 healthy people. Subgroups of patients with local tumor disease versus metastatic disease, primary and recurrent therapy and curative versus palliative therapy were compared. Results: The serum levels of IGF-2 were significantly elevated in patients with prostate and colorectal cancer. However, sensitivity and specificity were only 70%. IGFBP-2 serum levels were elevated in patients with head and neck tumors. Again, sensitivity and specificity were only 73%. A difference between local disease and metastatic disease could not be found. A difference between IGF serum levels before and after radiotherapy could not be detected. Conclusions: The IGF-system cannot serve as a new tumor marker. The detected differences are very small and sensitivity and specificity are too low. IGF measurement is not useful for the evaluation of the success of radiotherapy in malignancies.
<i>BCR/ABL</i> status of blood outgrowth endothelial cells from CML patients
Authors: J. Otten, A. Schultze, P. Schafhausen, S. Otterstetter, J. Dierlamm, C. Bokemeyer, T. H. Brummendorf, W. Fiedler, S. Loges
Journal: Journal of Clinical Oncology (2008)

7062 Background: As main actors in the generation of new blood vessels, endothelial progenitor cells have been intensely investigated during the past years. The detection of Philadelphia chromosome positive vascular endothelial cells in CML patients confirmed the existence of adult hemangioblasts with both hematopoietic and endothelial developmental potential (Lancet 2000;355:1688–91). To further investigate the origin of endothelial progenitor cells, we analyzed blood outgrowth endothelial cells from Philadelphia chromosome positive CML patients. Methods: OECs have been generated from the peripheral blood (PB) of Philadelphia chromosome positive CML patients (n=16) and healthy donors (n=300). The OEC clones have been analyzed for their proliferative potential, expression of endothelial markers by FACS analysis and presence of the BCR/ABL fusion gene by FISH and PCR. Results: A 10-fold higher frequency of OECs was found in PB of CML patients compared to healthy donors (7.2 and 0.7/108 MNCs, respectively, p<.0001). With an average of 26 total cell doublings, the CML OECs had an increased proliferative potential vs only 20 total cell doublings in healthy donors (p<.0001). Expression of endothelial markers by OECs, as analyzed by FACS, proved their endothelial nature. Remarkably, the FISH and PCR analysis of all 12 examined OEC clones from CML patients were negative for the BCR/ABL fusion gene though none of the analyzed patients was in more than minor cytogenetic remission and the mean frequency of Ph+ cells in PB or seperated CD34+ cells was 99% and 82% (n=14 and n=8, respectively). Conclusions: OECs are not clonally related to hematopoietic progenitor cells harbouring the BCR/ABL translocation. Hence, a putative common precursor of OECs and hematopoietic cells must represent a very early stem cell which is still BCR/ABL negative. A hierarchy of endothelial cells comparable to the hematopoietic system has been described because of different frequencies and proliferative potentials between OECs from umbilical cord and adult PB (Blood 2004;104:2752–60). We postulate that in contrast to OECs from healthy donors, the clones from CML patients represent a collective of more immature OECs probably being mobilized by pro-angiogenic cytokines such as VEGF, which are actively secreted by BCR/ABL+ cells. No significant financial relationships to disclose.