tbuckley/cabot-search huggingface dataset:
Integrated comprehensive high-throughput kinomics profiling and whole exome sequencing of penile squamous cell cancer (PSCC).
Authors: Amitkumar N. Mehta, Christopher Willey, Michael Crowley, Joshua Anderson, Dongquan Chen, David Crossman, Andrea Necchi, Giuseppe di Lorenzo, Bernhard J. Eigl, Richard J. Lee, Lauren Christine Harshman, Tanya B. Dorff, Matt D. Galsky, Matthew I. Milowsky, Graeme Bolger, Mollie DeShazo, Gurudatta Naik, William E. Grizzle, Guru Sonpavde
Journal: Journal of Clinical Oncology (2014)

383 Background: Molecular drivers in penile squamous cell cancer (PSCC), an orphan malignancy, remain unclear. The Cancer Genome Atlas (TCGA) is not studying PSCC and the Catalogue of Somatic Mutations in Cancer (COSMIC) investigators have reported only targeted analyses of PSCC. We report the first integrated analyses of comprehensive kinomics and whole exome sequencing (seq) in tumors from patients (pts) with PSCC . Methods: We performed integrated functional kinomics profiling and comprehensive exome-seq of two frozen tissue samples from men with PSCC with a matched normal tissue procured from the Cooperative Human Tissue Network (CHTN). Kinomic profiling was performed using the PamStation 12 high-content phospho-peptide substrate microarray system (PamGene International). The protein tyrosine kinome and serine/threonine kinome PamChips were used to measure global kinase activity by detecting phosphorylation of various peptides through FITC-labeled antibodies. Upstream kinase prediction was performed using a scoring algorithm that incorporates the phosphonet database (www.phosphonet.ca). Exome capture was performed with the Agilent SureSelect v5 kit and whole exome-seq was done on the Illumina HiSeq2000 with paired end 100bp chemistry. Results: In the single patient, paired kinomics analysis comparing the tumor sample to adjacent normal tissue, the HER family (EGFR, ERBB2, 3 and 4), AXL, TYRO3 and SYK kinases were the most active. When combining the two tumors in an unpaired analysis against the normal sample, the HER (EGFR, ERBB2, 3 and 4), MER, FRK, and FAK, kinases showed increased activity. When comparing whole exome-seq of the two PSCC samples with normal, among the affected genes were CCDC181, ZNF717, MUC4, HGC6.3, NOTCH1, STK11, SIRPB1, SKA3, PDE6B, FAT1, CACNA2D1, USP17L11, MNT, and CEP89. We are evaluating 10 PSCC tumors and matched normal tissue by kinomics and whole exome-seq and will present these complete data and analysis at the conference. Conclusions: In our preliminary analysis of pts that underwent the first reported integrated kinomics and whole exome-seq performed in PSCC, we identified multiple potential therapeutic targets in tumors.
Phase II study of lovastatin to prevent rectal injury from radiation therapy for prostate cancer.
Authors: Mitchell Steven Anscher, Michael G. Chang, Drew Moghanaki, Mihaela Rosu, Ross Mikkelsen, Diane Holdford, Vicki Skinner, B Mayer Grob, Arun J. Sanyal, Nitai Mukhopadhyay
Journal: Journal of Clinical Oncology (2016)

120 Background: Late radiation induced rectal injury remains an issue. Large population based studies indicate an incidence of at least 15%. Statins have been shown to reduce the risk of late radiation injury in animal models. The purpose of this study was to prospectively test lovastatin as a potential protector against radiation induced rectal injury, particularly bleeding. Methods: Eligible patients included men with adenocarcinoma of the prostate who were to be treated with radiation therapy with curative intent. Patients receiving primary radiation therapy (external beam alone, brachytherapy alone, or a combination of both) or post-prostatectomy radiation were eligible, as long as the minimum dose to the rectum was 60 Gy. Patients began lovastatin 20-80 mg/d on day 1 of radiation. Lovastatin was continued for 1 year and patients were followed for an additional year. Patients were seen at 1, 2, 4, 6, 9, 12, 18, 21 and 24 months after treatment. At each follow-up, they were assessed for GI, GU and erectile complications using both patient reported (IIEF, EPIC) and physician reported (CTCAE v3) instruments. The primary endpoint of the study was the incidence of rectal bleeding at 24 months (Grade 2 or higher). Results: From April 2007 through May 2013, 73 patients were enrolled. 21 patients either withdrew or were removed from the study due to noncompliance with the lovastatin regimen or toxicity from the drug. Patients who withdrew or were removed were replaced, in order to achieve the target number of 53 evaluable patients with complete 2-year follow-up. A total of 50 patients are evaluable. All but 2/50 evaluable patients achieved the 24-month follow-up goal. At 24 months, there were a total of 4 patients with rectal bleeding attributable to radiation; 3 were grade 2 and 1 was grade 3 (4/48=8%). Conclusions: The incidence of rectal bleeding at 2 years in this population of patients receiving lovastatin during and after radiation therapy for prostate cancer was less than expected based on historical controls. These data suggest that statins may be useful to protect patients from radiation induced rectal injury. Clinical trial information: NCT00580970.
Randomized phase II trial of taxanes plus 5-fluorouracil for advanced gastric cancer
Authors: S. H. Park, S.-M. Bang, E. K. Cho, J. H. Lee, D. B. Shin, W. K. Lee, M. Chung
Journal: Journal of Clinical Oncology (2005)

4149 Background: Taxanes (paclitaxel or docetaxel) has been shown to be effective in patients with advanced gastric cancer. We compared the combination of paclitaxel and 5-FU with the combination of docetaxel and 5-FU as first-line chemotherapy for metastatic or recurrent gastric cancer. Methods: We randomly assigned 74 chemotherapy-naïve patients to receive paclitaxel 175 mg/m2 or docetaxel 75 mg/m2 on day 1, in combination with infusional 5-FU 500 mg/m2 daily for 5 days. Treatment was repeated every 3 weeks. Results: Of 36 patients in paclitaxel group and 38 in docetaxel group, 3 were ineligible or never received protocol therapy. After a median follow-up of 11 months, paclitaxel group showed, although statistically insignificant, better failure-free survival (4.8 months for paclitaxel group and 4.5 months for docetaxel group; P=0.71), overall survival (11.9 months v 9.2 months; P=0.06), and objective response rates (41.2% v 30.3%; P=0.07). Paclitaxel and 5-FU combination was associated with substantially less overall and grade 3/4 toxicities than docetaxel group (grade 3/4 toxicity in 26% v 39%; P=0.04). Of 298 cycles delivered, dose reduction was required less frequently in paclitaxel group (10/145 cycles v 33/153 cycles; P<0.01). Global quality of life was similar in both groups, but substantive differences in many symptom scores favored paclitaxel. Conclusions: Both paclitaxel and docetaxel in combination with 5-FU appear to have efficacy and manageable toxicity in patients with advanced gastric cancer. However, the combination of docetaxel and 5-FU suggests a trend towards better tolerability and efficacy. Further studies of this combination should be considered. No significant financial relationships to disclose.
The Benefit of Allogeneic Hematopoietic Cell Transplantation in Older Patients with Acute Myeloid Leukemia Is Restricted to Those in First Complete Remission At the Time of Transplantation.
Authors: Fotios V. Michelis, Hans A. Messner, Eshetu G Atenafu, Dennis Dong Hwan Kim, John Kuruvilla, Jeffrey H. Lipton, Jieun Uhm, David Loach, Vikas Gupta
Journal: Blood (2012)
Angiogenesis gene polymorphisms and clinical outcome of metastatic colorectal cancer treated with first-line bevacizumab and oxaliplatin-based chemotherapy.
Authors: A. Gerger, W. Zhang, D. Yang, P. O. Bohanes, Y. Ning, T. Winder, M. J. Labonte, P. M. Wilson, L. Benhaim, R. El-Khoueiry, G. Absenger, A. B. El-Khoueiry, S. Iqbal, H. Lenz
Journal: Journal of Clinical Oncology (2011)

3592 Background: The identification of patients who might benefit from bevacizumab (BV) treatment is essential in the management of metastatic colorectal cancer (mCRC). However, no validated biomarkers are available to predict the efficacy of BV. Angiogenesis is largely a host-mediated event and there is substantial germline genetic variability in the genes of angiogenesis pathways. We hypothesized that single nucleotide polymorphisms (SNPs) analyzed in a comprehensive panel of VEGF-dependent and -independent angiogenesis pathway genes predict BV efficacy in patients with mCRC. Methods: Whole blood samples were obtained from 130 patients (57 females and 73 males; median age 56 yrs (range 28–81 yrs)) with mCRC at the University of Southern California (105 pts) and the Medical University of Graz, Austria (25 pts). All study patients received first-line BV treatment combined with FOLFOX (66 pts) or XELOX (64 pts). The median follow-up was 25.4 months. 41 SNPs in 28 genes of VEGF-dependent (11 SNPs in 5 genes) and -independent (30 SNPs in 23 genes) angiogenesis pathways were determined by PCR-RFLP or direct DNA-sequencing. All candidate SNPs were evaluated for associations with progression-free survival (PFS) and response rate (RR). Results: The medium PFS was 11.2 months (95% CI, 8.1-14.9), whereas median overall survival has not been reached yet. In multivariate analysis after adjustment for site of metastasis and the chemotherapy backbone, the minor allele of CXCR1 rs2234671 (RR 32.4% vs 65%, p=0.004) and TNFβ rs909253 (RR 33.8% vs 62%, p=0.019) was significantly associated with lower RR. Furthermore, the minor allele of CXCR1 rs2234671 showed a trend for decreased PFS (7.8 vs 15.2 months; HR 1.60, p=0.05). In multiple comparison analysis including all SNPs, CXCR1 rs2234671 remained with a trend to lower RR (FDR adjusted p=0.061). Conclusions: Our results suggest that the IL-8 receptor CXCR1, a key player in VEGF-independent angiogenesis and possible stem cell marker, may lead to BV resistance and stem cell dependent chemoresistance. Larger prospective trials are warranted to confirm these findings.
Alpha Hemoglobin Stabilizing Protein (AHSP) Is a Susceptibility Gene to Drug /Infection-Induced Hemolytic Anemia.
Authors: Hitoshi Kanno, Naoyuki Kamatani, Takako Hamada, Kaori Furihata, Yukio Hattori, Shiro Miwa, Hisaichi Fujii
Journal: Blood (2005)
ACRIN 6691 monitoring and predicting breast cancer neoadjuvant chemotherapy response using diffuse optical spectroscopic imaging (DOSI).
Authors: B. J. Tromberg, J. A. Butler, D. A. Mankoff, S. J. Isakoff, N. M. Hylton, A. G. Yodh, D. Boas, K. Paulsen, B. W. Pogue, P. A. Kaufman, R. S. Mehta, P. M. Carpenter, A. Cerussi, Z. Zhang, D. M. Hartfeil, D. L'Heureux
Journal: Journal of Clinical Oncology (2011)

TPS249 Background: Imaging technologies monitoring and predicting breast cancer response to neoadjuvant chemotherapy (NAC) are of increasing interest. The utility of conventional imaging approaches varies and identifies the need for alternate functional imaging strategies. DOSI is a promising experimental technology that allows patients undergoing NAC to be followed with a “no significant risk” device meeting Food and Drug Administration criteria for exempt status. The current design is a mobile device which offers increased accessibility. DOSI is relatively simple to perform and interpret, as compared to mammography, magnetic resonance imaging, and positron emission tomography. Due to its size and portability, DOSI is a low barrier-to-access technology, creating new opportunities for patients to receive personalized treatment and for physicians to gain new insight into response mechanisms. Our long-term goal is to provide oncologists with a relatively simple, risk-free bedside tool that can be used to help inform medical decisions on chemotherapy regimen, duration, and timing of surgery, thereby maximizing therapeutic response and minimizing unnecessary toxicity. Methods: In this phase I/II multicenter study, women who have been diagnosed with breast cancer, have had confirmation by pre-treatment biopsy, and are scheduled to receive NAC followed by surgery are eligible for this trial. Approximately 60 patients receiving NAC will participate at five clinical sites. This protocol will evaluate a harmonized DOSI technology platform that has been standardized for NAC monitoring. The primary aim of this clinical trial is to determine whether the baseline to mid-therapy changes in the DOSI measurement of the quantitative tumor tissue optical index can predict final pathologic complete response in patients with breast cancer undergoing NAC. The secondary aims investigate the correlation between additional DOSI quantitative measurements of tumor biochemical composition obtained at other timepoints, the full range of pathologic response (i.e. complete, partial, and non-response), and any corresponding imaging measurements.
D-dimer levels and prediction of overall survival in cancer patients.
Authors: C. Ay, D. Dunkler, R. Vormittag, P. Quehenberger, R. Pirker, O. Wagner, C. Zielinski, I. Pabinger
Journal: Journal of Clinical Oncology (2010)

10587 Background: Procoagulant changes in the haemostatic system and activation of haemostasis are frequently observed in cancer patients, even in the absence of venous thromboembolism (VTE). Moreover, coagulation activation has been implicated in tumour progression, invasion, angiogenesis and metastatic spread. D-dimer is produced when cross-linked fibrin is degraded by plasmin and reflects the activation of coagulation and fibrinolysis. Recently, high D-dimer levels were reported to predict the occurrence of VTE in cancer patients. Our aim was to assess the prognostic value of D-dimer levels in cancer patients included in the ongoing prospective observational Vienna Cancer and Thrombosis Study (CATS), which was initiated in 2003 to identify predictive parameters for cancer-associated VTE. Methods: The CATS includes patients with newly diagnosed cancer or progression of disease after remission. Patients are followed over 2 years at regular intervals until occurrence of symptomatic VTE or death. D-dimer levels were measured with a D-Dimer latex agglutination assay. Kaplan-Meier and Cox regression analyses were applied for statistical calculation. Results: Data from 873 patients with solid tumours or haematological malignancies (394 female/479 male, median age [IQR]: 62 [53-68] yrs) were available for survival analyses. Main tumor entities were malignancies of the breast (n = 139), lung (n = 126), stomach (n = 36), lower gastrointestinal tract (n = 114), pancreas (n = 48), kidney (n = 24), prostate (n = 113), and brain (n = 109); 116 had hematologic malignancies; 48 had other tumors. Patients were followed for a median observation time of 731 days and 357 (40.1%) patients died during follow-up. The probabilities of overall survival for patients with D-Dimer levels at study inclusion in the first, second, third and fourth quartile were 88%, 82%, 66% and 53% after 1 year and 80%, 66%, 50% and 30% after 2 years, respectively (p < 0.001). The hazard ratio (HR) of D- dimer for mortality was 1.5 (95% CI: 1.4-1.6, p < 0.001) per double increase of D-dimer and remained similarly increased in multivariable analysis which included age, sex and metastatic spread. Conclusions: High levels of D-dimer independently predict mortality risk in cancer patients. No significant financial relationships to disclose.
Survivin expression in circulating tumor cells of patients with gastric cancer.
Authors: Masanori Terashima, Keiichi Hatakeyama, Yushi Yamakawa, Norihiko Sugisawa, Yuichiro Miki, Rie Makuuchi, Hironobu Goto, Masanori Tokunaga, Yutaka Tanizawa, Etsuro Bando, Taiichi Kawamura, Keiichi Oshima, Toru Mochizuki
Journal: Journal of Clinical Oncology (2014)

65 Background: Detection of circulating tumor cells (CTC) in peripheral blood is thought to be a promising method to evaluate the extent of minimal residual disease that may be useful for predicting recurrence and for monitoring treatment efficacy. However, unlike breast or lung cancer, little information is available in patients with gastric cancer. Among them, evaluation of survivin, a member of the inhibitor of apoptosis (IAP) family, mRNA expression in peripheral blood appears to be a promising procedure with relative good performance for predicting recurrence after curative resection. In order to evaluate the clinical significance of surviving expression in peripheral blood, we performed real-time RT-PCR analysis using whole blood obtained from patients with gastric cancer. Methods: A total of 95 patients with gastric cancer treated at our cancer center between Nov. 2009 and Aug. 2012 were enrolled in this study. Peripheral blood samples were collected using PAX gene and RNA was isolated using Boom method. After cDNA synthesis, quantitative real-time PCR targeting survivin gene was performed. The relative expression level of survivin mRNA was calculated with actin beta as an internal standard. Correlation between survivin expression and clinicopathologic factors was investigated. Results: Survivin mRNA expression level in peripheral blood ranged from 34.8 to 1889.6, and the median level was 370.3. Survivin mRNA level tended to be higher in patients with T4, N3b, CY1, and Stage IV. There was no significant correlation with histological type, lympho-vascular invasion, or macroscopic type. If we set a cut-off value at 540, survivin was positive in 27 patients (28%). Disease-free survival was significantly worse in survivin positive patients than in negative patients (p=0.0216). Conclusions: Survivin expression in CTC was higher in advanced stage and appears to be a good prognostic marker in patients with gastric cancer. Validation with large sample size should be performed to confirm the significance of survivin in CTC.
Progress in Exosome Isolation Techniques
Authors: Pin Li, Melisa Kaslan, Sze Han Lee, Justin Yao, Zhiqiang Gao
Journal: Theranostics (2017)

Exosomes are one type of membrane vesicles secreted into extracellular space by most types of cells. In addition to performing many biological functions particularly in cell-cell communication, cumulative evidence has suggested that several biological entities in exosomes like proteins and microRNAs are closely associated with the pathogenesis of most human malignancies and they may serve as invaluable biomarkers for disease diagnosis, prognosis, and therapy. This provides a commanding impetus and growing demands for simple, efficient, and affordable techniques to isolate exosomes. Capitalizing on the physicochemical and biochemical properties of exosomes, a number of techniques have been developed for the isolation of exosomes. This article summarizes the advances in exosome isolation techniques with an emphasis on their isolation mechanism, performance, challenges, and prospects. We hope that this article will provide an overview of exosome isolation techniques, opening up new perspectives towards the development more innovative strategies and devices for more time saving, cost effective, and efficient isolations of exosomes from a wide range of biological matrices.
Interim [<sup>18</sup>f] fluorodeoxyglucose positron emission tomography (PET) for early metabolic assessment of response to PEB chemotherapy for metastatic seminoma: Preliminary findings.
Authors: Patrizia Giannatempo, Alessandra Alessi, Daniele Raggi, Elena Farè, Silvia Tana, Nicola Nicolai, Gianluca Serafini, Barbara Padovano, Luigi Piva, Davide Biasoni, Tullio Torelli, Mario Catanzaro, Silvia Stagni, Massimo Maffezzini, Alessandro M. Gianni, Luigi Mariani, Flavio Crippa, Roberto Salvioni, Andrea Necchi
Journal: Journal of Clinical Oncology (2015)

381 Background: A risk-adapted strategy for metastatic seminoma may further refine the necessary burden of chemotherapy while sparing futile treatment. The objective of this study was to evaluate the association of the early metabolic response to cisplatin, etoposide, and bleomycin (PEB) and dimensional response. Methods: Patients (pts) with newly-diagnosed seminoma and who were candidate to PEB were staged at baseline by computed tomography (CT), PET and serum tumor markers (STM). Then, restaging with PET after 2 cycles of PEB (PET 2 ), and with CT after treatment (3-4 cycles [CT 3-4 ]) were provided. One (greatest) target lesion was chosen to evaluate metabolic/dimensional changes. Wilcoxon rank sum test was used to analyze the association between PET response and either the shrinkage of target lesion (primary endpoint) or baseline, or final dimensions. Results: In the time-frame 02/2009-11/2013, 37 pts have been enrolled. Two pts had CSIIA, 13 CSIIB, 13 CSIIC, and 9 CSIII. 3 had an intermediate prognosis because of liver (n=1) and bone (n=2) disease. The latter were recognized by PET while having a bone-negative CT scan. 4 had a retroperitoneal and 1 a mediastinal primary. All pts had a PET-positive target disease. After 2 cycles of PEB, 27 pts (72.9%) had a metabolic complete response (CR), 10 a partial response (PR). 12 pts had a CR at CT 3-4 . Median follow up was 18 months (IQR: 13-23). A significant association was found between PET2 response and baseline (p=0.003), final diameter (p&lt;0.001), and % of tumor shrinkage (p=0.014). Pts with PET2 CR had a median residual diameter of 1.2 cm (IQR: 1-1.9) while pts with PET2 PR 3.75 cm (IQR: 2.6-6.1, p=0.002). 6 Pts received RT after PEB. 2/10 pts with PET2 PR had a relapse (0/27 CR). Conclusions: A significant association was found between PET2 response and tumor shrinkage in pts with metastatic seminoma. PET2 CR pts could be predicted not to need additional re-imaging or treatment after PEB, and simplifying the follow up should be an endpoint. PET2 PR category includes pts yielding a difficult-to-treat disease. A detailed cost-efficacy analysis of the strategy will be required further.
Safety and Tolerability of Anti-Bacterial Prophylaxis during the Post-Engraftment Phase after Myeloablative Hematopoietic Stem Cell Transplantation.
Authors: Brandon Hayes-Lattin, Joseph Bubalo, Adam Dunn, Nan Subbiah, Bryon Allen, Suzanne Balleisen, Peter T. Curtin, Carol Jacoby, Jose F. Leis, Michael J. Mauro, Aleksandra Simic, Susan Schubach, Richard T. Maziarz
Journal: Blood (2004)
Drug-biomarker co-development in oncology – 20 years and counting
Authors: Julianne D. Twomey, Nina N. Brahme, Baolin Zhang
Journal: Drug Resistance Updates (2017)

Predictive biomarkers for oncology are necessary to accurately identify patients who will benefit from anticancer treatment. Recently approved oncology drugs target discrete molecular aberrations or pathways in tumor cells and consequently are active on a subset of patient population, yet clinical studies have shown that not all biomarker-positive patients respond. The advancement of predictive biomarkers needs to detect novel and evolving drug resistance mechanisms, not only to guide the selection of patient subsets for specific treatments, but to identify new therapeutic targets. Going beyond the "one marker, one drug" model to incorporate genomics, transcriptomics, and receptor status assessments during biomarker-drug co-development can aid in the successful application of molecular marker-based cancer therapy. This review provides the latest update of biomarker-based cancer therapeutics approved by the US Food and Drug Administration. We provide case studies of therapeutics selectively targeting HER2, EGFR, or PD-1/PD-L1 signaling pathways. We also discuss the challenges and promising future directions in the co-development of targeted cancer therapeutics and paired predictive biomarkers.