tbuckley/cabot-search huggingface dataset:
Validated biomarker signatures that predict pathologic response to preoperative chemoradiation therapy (CTRT) with high specificity and desirable sensitivity levels in patients with esophageal cancer (EC).
Authors: J. A. Ajani, X. Wang, Y. Hayashi, D. Maru, J. Welsh, W. L. Hofstetter, J. H. Lee, M. S. Bhutani, A. Suzuki, D. A. Berry, J. Izzo
Journal: Journal of Clinical Oncology (2011)

4027 Background: Currently biomarker(s) cannot predict response to CTRT in EC patients thus treatment choices remain empiric. We assessed NF-kB, Gli-1, and sonic hedgehog (immuno-histochemistry) in pre-treatment EC tissue, because the involved pathways mediate radiation and chemotherapy resistance. Methods: Discovery set (DS) included 60 EC patients. A multiple logistic regression model was fit by combining labeling index of each biomarker per patient to compute a linear Z score. The AUCs of the ROC curves were generated to assess sensitivity and specificity. Two methods of cross validation were implemented. Signatures were established for pathologic complete response (pathCR) and extreme resistance to CTRT (exCTRT-R). An independent validation set (VS) included 167 unique EC patients to test the signatures. Results: The AUCs for pathCR in DS = 0.953 (95% CI, 0.906-1.00), in VS=0.972 (0.950-0.993) and for exCTRT-R in DS = 0.881 (0.776-0.986), in VS = 0.957 (0.928-0.987). When specificity is 95% for pathCR or exCTRT-R, sensitivity is ≥45% in each cohort. The probability of pathCR or exCTRT-R for patients belonging to each quartile of the Z scores is tabulated as shown in the table. Conclusions: Our data suggest that the validated three-biomarker signatures for pathCR and exCTRT-R are highly predictive and may establish a path to personalized medicine for EC patients. Avoidance of unnecessary therapies including surgery to preserve the esophagus may be possible. On behalf of the Gastroesophageal Cancer Research Group at the University of Texas M. D. Anderson Cancer Center, Houston, TX. Supported by NCI (RO1CA138671, RO1CA150229, RO1CA111922, R21CA129906, and R21CA127672), UTMDACC (MRP and IPCT grants) and generous donors. Type of cohort Probability in 1st quartile (%) Probability in 2nd quartile (%) Probability in 3rd quartile (%) Probability in 4th quartile (%) PathCR in DS (n=60) 0/15 (0) 0/15 (0) 4/15 (27) 12/15 (80) PathCR in VS (n=167) 0/42 (0) 0/42 (0) 5/41 (12) 35/42 (83) exCTRT-R in DS (n=60) 1/15 (7) 0/15 (0) 6/15 (15) 11/15 (73) exCTRT in VS (n=167) 0/42 (0) 0/42 (0) 1/41 (2) 26/42 (62)
Heavy/Light Chain Specific Immunoglobulin Ratios at Presentation Are Prognostic for Progression Free Survival in the IFM 2005-01 Myeloma Trial.
Authors: Herve AvetLoiseau, Jean-Luc Harousseau, Philippe Moreau, Claire Mathiot, Thierry Facon, Michel Attal, Arthur Bradwell, Stephen Harding
Journal: Blood (2009)
Lenalidomide and low‐dose dexamethasone (Rd) versus bortezomib, melphalan, prednisone (VMP) in elderly newly diagnosed multiple myeloma patients: A comparison of two prospective trials
Authors: Massimo Gentile, Valeria Magarotto, Massimo Offidani, Pellegrino Musto, Sara Bringhen, Maria Teresa Petrucci, Francesca Gay, Alessandra Larocca, Giuseppina Uccello, Annamaria Petrungaro, Ernesto Vigna, Rosa Greco, Anna Grazia Recchia, Giovanni Tripepi, Roberto Ria, Francesco Di Raimondo, Antonio Palumbo, Fortunato Morabito
Journal: American Journal of Hematology (2016)

There are currently no direct head-to-head clinical trials evaluating bortezomib-melphalan-prednisone (VMP) versus lenalidomide and low-dose dexamethasone (Rd). VMP (257 cases) and Rd (222 cases) arms of two randomized phase III trials were employed to assess the treatment influence on outcome in untreated elderly MM patients. Progression free survival (PFS) and overall survival (OS) were the primary and secondary end-points, respectively, and were investigated according to treatments administered over a 60-months follow-up period. While VMP significantly reduced the disease progression rate between enrolment and 12 months of follow-up, no difference between the two schedules was found between 12 and 32 months. After 32 months, Rd-treated patients had a lower incidence of disease progression. A statistically significant higher OS rate was seen in the VMP arm, which was maintained after data adjustment for potential confounders. Both approaches showed acceptable toxicity profiles. The profound tumor reduction by VMP over Rd justifies the initial higher PFS rate in favor of the bortezomib schedule, while the Rd regimen overcomes this evident initial drawback in reducing the tumor burden by long-term drug administration, gaining a subsequent improved disease control. VMP is associated with a significant reduced risk of death. This study may help physicians make a more informed therapy choice.
<i>MYC</i> and human telomerase gene <i>(TERC)</i> gene copy number gain in resected in non-small cell lung cancer (NSCLC).
Authors: A. Flacco, V. Ludovini, F. R. Tofanetti, F. Bianconi, G. Bellezza, M. G. Mameli, G. Metro, C. Bennati, L. Cagini, N. Daddi, L. Pistola, A. Siggillino, E. Baldelli, A. Sidoni, F. Puma, M. Varella-Garcia, L. Crinò
Journal: Journal of Clinical Oncology (2011)

10580 Background: Long-term survival of resected NSCLC is disappointing and targets for a new generation of therapeutic agents are necessary. Abnormalities in MYC are well known in lung cancer and TERC maps in chromosomal region with frequent copy number gain (CNG) in NSCLC. This study investigates the incidence of MYC and TERC CNG and evaluates their correlation with clinicopathological parameters and outcome in resected NSCLC. Methods: 113 NSCLC patients subjected to curative pulmonary resection were tested for TERC and MYC CNG by fluorescence in situ hybridization (FISH) using commercial probes. Median age was 66 years (range 40–84); most patients were male (84%), former/current smokers (92%), had poorly differentiated histology (42%) and stage I disease (62%). The histological types included 51% squamous cell carcinoma (SCC), 30% adenocarcinoma, 8% BAC, and 11% of other subtypes. CNG was determined when ≥4 gene copies were displayed in ≥40% of tumor cells. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis. Results: Forty-one (36%) patients showed CNG for MYC and 41 (36%) for TERC. MYC and TERC gene amplification (GA) were found in 9 (8%) and 15 (13%) cases, respectively. MYC and TERC contemporary CNG was observed in 12 cases (11%): 2 (17%) cases with GA vs 10 (83%) high polysomy. TERC CNG was associated with SCC histology (80% vs 20% in non-SCC; p=0.001). In univariate analyses, both MYC CNG and GA were associated with shorter disease free survival (DFS, p=0.032 and P=0.022, respectively) and overall survival (OS; p<0.032 and P<0.000, respectively) while TERC CNG or GA showed no association. In multivariate analysis including stage and age, MYC CNG and GA remained significantly associated with worse DFS (p=0.022; p= 0.011 respectively) and OS (p=0.026; p<0.000), respectively). Conclusions: Our results indicate that MYC and TERC are frequently amplified in NSCLC. TERC CNG shows phenotypic properties strongly associated with SCC and is not a prognostic factor. CNG for MYC is a strong predictor of worse survival. We thank the Italian Association for Cancer Research AIRC (AF Fellowship).
Early Engraftment Kinetics of Leukocyte Subsets by Means of HLA-Specific Mabs After Double Umbilical Cord Blood Transplantation Show a Very Rapid Induction of Single Complete Donor Chimerism.
Authors: Judith AE Somers, Yvette van Hensbergen, Anneke Brand, Ellen Meijer, Eric Braakman, Machteld Oudshoorn, Kees Sintnicolaas, Arend Mulder, Jan J. Cornelissen
Journal: Blood (2009)
Individual Replacement Therapy (IRT) with a Pasteurized C1-Inhibitor Concentrate Compared to Prophylaxis with Danazol in Patients with Hereditary Angioedema (HAE) - a Prospective Study.
Authors: Wolfhart Kreuz, Inmarculada Martinez-Saguer, Emel Aygoeren-Puersuen, Eva Rusicke, Thomas Klingebiel
Journal: Blood (2004)
Independent Prognostic Impact of CD15 for Achievement of Complete Remission in Patients with Acute Myeloid Leukemia
Authors: Teresa Ceglie, Marta Chisini, Federico Vozella, Gioia Colafigli, Caterina Stefanizzi, Adriano Salaroli, Mariella D'Angiò, Marco Mancini, Daniela Diverio, Massimo Breccia, Francesca Mancini, Sara Raponi, Clara Minotti, Silvia Trisolini, Saveria Capria, Anna Maria Testi, Anna Guarini, Roberto Latagliata, Maria Stefania De Propris, Robin Foa
Journal: Blood (2014)
Abstract 724: Anti-tumor effect of Dasatinib in HER2 positive breast cancer with Trastuzumab resistance
Authors: Tatsuaki Takeda, Hirotaka Kanzaki, Shinichi Toyooka, Mototsugu Watanabe, Tomoaki Ohtsuka, Ken Suzawa, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo
Journal: Cancer Research (2015)

Abstract [Background] Overexpression of human epidermal growth factor receptor 2 (HER2) was observed in approximately 20%-25% of breast cancers and they are classified in HER2-positive breast cancer. Trastuzumab is a therapeutic drug for the first choice for HER2-positive breast cancer, showing good response. However, acquired resistance to trastuzumab is one of the critical clinical issues in breast cancer treatment, especially in the patients with recurrent breast cancer. Therefore it is necessary to develop the effective therapy to overcome resistance. In this study, we established a trastuzumab-resistant breast cancer cell line from a trastumab-sensitive cell line with HER2 amplification (BT-474), and demonstrated anti-tumor effect of dasatinib in the breast cancer cell with trastuzumab resistance. [Methods] Trastuzumab-resistant breast cancer cell line (BT-474-R) was established by treating BT-474 cells for long-term exposing with trastuzumab. We performed cell viability assay to analyze drug sensitivity. Then, we performed quantitative PCR and western blotting to investigate expression and activation of HER2 and related molecules. Cell viability assay and signal analysis were performed with or without trastuzumab and/or dasatinib treatment. [Results] Proto-oncogene tyrosine-protein kinase Src was up-regulated and activated in BT-474-R. Signaling molecules, such as Akt and MAPK, were also activated. Dasatinib, which is known as a Src inhibitor, suppressed the activation of signal molecules and cell survival of BT-474-R. Moreover, dasatinib treatment recovered sensitivity to trastumab in the BT-474-R with down-regulation of Src phosphorylation. [Conclusion] Src plays an important role in acquired resistance to trastumab in breast cancer. Our data also suggest that inhibition of Src may become the new strategy to overcome trastuzumab resistance. Citation Format: Tatsuaki Takeda, Hirotaka Kanzaki, Shinichi Toyooka, Mototsugu Watanabe, Tomoaki Ohtsuka, Ken Suzawa, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo. Anti-tumor effect of Dasatinib in HER2 positive breast cancer with Trastuzumab resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 724. doi:10.1158/1538-7445.AM2015-724
Cumulative Efficacy and Safety of 5-Year Deferasirox (Exjade®) Treatment in Pediatric Patients with Thalassemia Major: A Phase II Multicenter Prospective Trial
Authors: Antonio Piga, Kamila Kebaili, Renzo Galanello, Valentine Jehl, Corinne Rebischung, Henry Maseruka, Lisa Rojkjaer, Gian Luca Forni
Journal: Blood (2008)
Detailed analysis of survival and safety with sunitinib (SU) in a worldwide treatment-use trial of patients with advanced GIST
Authors: P. Reichardt, Y. Kang, W. Ruka, B. Seddon, A. Guerriero, A. Breazna, S. Lowry, G. D. Demetri
Journal: Journal of Clinical Oncology (2008)

10548 Background: SU is an oral multitargeted tyrosine kinase inhibitor of KIT, PDGFRs, VEGFRs, FLT3, CSF-1R and RET, approved multinationally for treatment of advanced imatinib (IM)-resistant/intolerant GIST. The objectives of this study are to grant access to SU to GIST pts who are otherwise unable to obtain SU, and to obtain broad safety and efficacy data from a large GIST population. Methods: This is an ongoing, open-label study assessing safety, antitumor response, TTP and OS in pts with advanced IM- resistant/intolerant GIST receiving SU 50 mg/d in 6-wk cycles (4 wk on treatment, 2 wk off). Results: As of Apr 2007, 1,097 pts had been enrolled and 1,091 had received at ≤1 SU dose. Median estimated TTP was 37 wk (95% CI 35–44) and OS was 73 wk (66–92) with 64% of pts alive in the overall population. In pts <59 yr (n=528; 68% alive), median OS was 92 wk (80-NC) vs. 64 wk (60–73) in pts ≥59 yr (n=562; 60% alive). OS estimates based on prior IM treatment history are presented in Table 1. The most common non- hematologic treatment-emergent grade 3/4 AEs were fatigue (10%), abdominal pain (10%) and hand-foot syndrome (9%). Grade 3/4 hematologic AEs included anemia (8%), neutropenia (8%) and thrombocytopenia (5%). Hypothyroidism (all grades) was reported in 7% of pts. The total incidence of hypertension was 23% (6% grade 3/4). The incidences of grade 3/4 cardiac-related events such as heart failure, congestive heart failure, myocardial infarction, pulmonary edema and reduced ejection fraction were low (0.5%, 0.3%, 0.3%, 0.3%, 0.1%, respectively). Incidences of grade 3/4 laboratory abnormalities associated with renal function included elevated creatinine levels (2%), hyponatremia (3%) and hypocalcemia (3%). Longer-term follow-up of all of these efficacy and safety measures will be presented. Conclusions: SU was effective and generally well tolerated in pts with advanced IM-resistant/intolerant GIST who are ineligible for other SU trials, with a safety profile consistent with that observed with SU in other GIST trials. OS by prior imatinib treatment history. Group n Alive n (%) Median OS (95% CI), wk Prior max. IM dose (mg) ≤400 339 231 (68) 93 (72–100) >400–600 203 121 (60) 68 (63–92) >600–800 522 333 (64) 73 (63-NC) >800 24 9 (38) 34 (17–68) Reason for stopping IM Intolerance 104 71 (68) 122 (92-122) PD ≤6 mo 146 82 (56) 60 (53–91) PD >6 mo 840 543 (65) 73 (68-93) NC = not yet calculable Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer, Inc. Infinity, Novartis, Pfizer, Inc. Pfizer, Inc. Novartis, Pfizer, Inc. Infinity, Novartis, Pfizer, Inc. Infinity, Novartis, Pfizer
Abstract 5447: Association of the hedgehog signal pathway to Gefitinib sensitivity in a 3D cancer cell lines screening
Authors: Gonzalo Castillo, Xiuyun Jiang
Journal: Cancer Research (2015)

Abstract Drug profiling of cancer cell lines is a useful tool for predictive biomarker discovery, traditional done in two-dimensional cultures, a growing body of evidence suggests that results cannot always be translated into xenografts or in the clinic due to the lack of complexity of the culture conditions. 3D cultures offer the ability to carry out the same type of studies with the added benefit of incorporating the 3-dimentional cellular interactions and physiological gradients normally seen in a tumor microenvironment. In this study we used Numira's 3D cell line screening platform on Gefitinib, a selective inhibitor of epidermal growth factor receptor (EGFR). We determined IC50 of Gefitinib in a panel of 60 cell lines grown as spheroids and used this information to investigate genes associated with sensitivity. Two mutated genes were associated with sensitivity to Gefitinb, as expected, the epidermal growth factor receptor (EGFR) was one of them, since mutations on EGFR are required for clinical efficacy. The second gene was smoothened (SMO), a G protein-coupled receptor of the hedgehog signaling pathway. It has been suggested that blockade of the hedgehog signaling pathway enhances anti-proliferative effects of EGFR inhibitors, we explored this potential synergy in a combination studies of Gefitinib and SMO inhibitors, Cyclopamine and GDC0449, the results are discussed. Citation Format: Gonzalo Castillo, Xiuyun Jiang. Association of the hedgehog signal pathway to Gefitinib sensitivity in a 3D cancer cell lines screening. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5447. doi:10.1158/1538-7445.AM2015-5447
DEBIRI and cetuximab (DEBIRITUX) as a secondline treatment for unresectable colorectal liver metastases (UCLM): results of a phase II trial exploring a new sequence
Authors: G. Fiorentini, C. Aliberti, D. Sarti, P. Coschiera, M. Tilli, L. Mulazzani, P. Giordani, F. Graziano, A. Marqués Gonzalez, R. García Marcos, F. Gómez Mugnoz, M. Cantore, S. Ricci, V. Catalano, A. Mambrini
Journal: Annals of Oncology (2015)
Abstract 163: Investigation of molecular mechanisms by which PCA3 modulates prostate cancer cell survival
Authors: Ana Emilia Goulart, Luciana B. Ferreira, Paula Priscilla de Freitas, Nadia Batoreu, MARTIN H. BONAMINO, Etel Rodrigues Pereira Gimba
Journal: Cancer Research (2015)

Abstract PCA3 is a prostate-specific non coding RNA (ncRNA), involved in the control of prostate cancer (PCa) cell survival, through modulating androgen receptor (AR) signaling. We aimed to investigate whether several cancer related genes, including those involved in epithelial-mesenchymal transition (EMT) and AR co-regulators could modulate LNCaP cell survival in response to PCA3 downregulation. We also aimed to promote PCA3 stable silencing through a lentiviral vector containing a PCA3 short hairpin RNA (shRNA) specific sequence. Small interfering RNA (siRNA) or lentivirus vector-based shRNA were used to downregulate PCA3 expression. Upon PCA3 downregulation, cells were analyzed by qRT-PCR to investigate mRNA expression. Flow cytometry was performed to analyze the percentage of LNCaP GFP + cells and trypan blue staining to analyze the number of viable cells after PCA3 stable silencing. Among 14 AR co-regulators genes investigated, 12 were upregulated in siPCA3-transfected cells in relation to controls. We also found that among 84 cancer-related genes tested, 16 were differentially expressed in LNCaP siPCA3-transfected cells when compared to transfected cells with a scramble sequence. Of these, 30% are genes coding for signal transduction molecules and transcription factors. Gene expression profile of EMT-related genes revealed that E-cadherin, Claudin-3, Cytokeratin-18, Snail, Twist and Slug are upregulated in LNCaP siPCA3-transfected cells compared to control, while Claudin-4, Cytokeratin-8 and Vimentin are downregulated. LNCaP cells transduced with lentiviral vectors carrying the GFP gene and shPCA3 stably dowregulated PCA3 expression, producing a reduction of 60% of LNCaP GFP+ cells compared to shScr transduced or non-transduced LNCaP cells. Our results suggest that the decrease in the number of LNCaP viable cells upon siPCA3 transfection is not modulated by the classical EMT program. Observed upregulation of most tested AR co-regulators upon PCA3 silencing indicates that this non-coding RNA could negatively modulate the transcription of these genes. Our data further suggest that that this ncRNA perform a regulatory role in gene expression, being able to modulate gene expression of several signaling pathways related to cancer. Finally, stable silencing of PCA3 expression using lentivirus vector shows potential as a PCa therapeutic approach by negatively modulating cell survival. Citation Format: Ana Emilia Goulart, Luciana B. Ferreira, Paula Priscilla de Freitas, Nadia Batoreu, MARTIN H. BONAMINO, Etel Rodrigues Pereira Gimba. Investigation of molecular mechanisms by which PCA3 modulates prostate cancer cell survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 163. doi:10.1158/1538-7445.AM2015-163
Abstract 1390: Combination of carbon ion beam and gemcitabine causes unrepairable DNA damage and death of radioresistant pancreatic cancer stem-like cells in vitro and in vivo
Authors: Sei Sai, Toshifumi Wakai, Guillaumes Vares, Shigeru Yamada, Takehiko Kamijo, Eun Ho Kim, Tadashi Kamada, Toshiyuki Shirai
Journal: Cancer Research (2015)

Abstract Purpose To elucidate whether carbon ion beam alone or in combination with gemcitabine has advantages over X-ray irradiation in targeting putative human pancreatic cancer stem cells (CSCs). Materials and Methods Human pancreatic CSCs sorted from PANC1 and PK45 cells were treated with carbon ion beam, X-ray alone or in combination with gemcitabine, and then colony, spheroid and tumor formation assays, RT Profiler PCR Array assay, immunofluorescence γH2AX foci assay as well as in vivo tumor control analysis were performed. Results The colony, spheroid formation as well as tumorigenicity assays confirmed that CD44+/ESA+ cells exactly have CSC properties compared to CD44-/ESA- cells. CSCs were more highly enriched after X-ray or gemcitabine compared to carbon ion beam alone, but extremely enhanced either X-ray or carbon ion beam in combination with gemcitabine. The number of colony and spheroid formed from CSCs after carbon ion beam was significantly reduced compared to that of X-ray, and it was extremely suppressed when combined with gemcitabine. The relative biological effectiveness (RBE) values for the carbon ion beam relative to X-ray at the D10 levels for CSCs were 2.13-2.78. RT Profiler PCR Array analysis showed that expressions of apoptosis-related genes (Bax, Cytochrome c), autophagy-related genes (LC3, p62), and senescence-related gene p21 were remarkably induced after carbon ion beam combined with gemcitabine compared to carbon ion beam alone or X-ray combined with gemcitabine. Immunofluorescence assay showed that not only the number but also the size of γH2AX foci in CSCs were lager 24 h after carbon ion beam combined with gemcitabine compared to carbon ion beam alone or X-ray combined with gemcitabine. Xenograft tumor control analysis showed that the tumors were not completely controlled even treated with 60 Gy of X-ray, but it was destroyed with 25 Gy of carbon ion beam combined with 50 mg/kg gemcitabine. Conclusions Carbon ion beam combined with gemcitabine has superior potential to kill pancreatic CSCs via unrepairable clustered DSB, and multiple cell death pathways at relatively lower doses compared to carbon ion alone or X-ray combined ith gemcitabine. Citation Format: Sei Sai, Toshifumi Wakai, Guillaumes Vares, Shigeru Yamada, Takehiko Kamijo, Eun Ho Kim, Tadashi Kamada, Toshiyuki Shirai. Combination of carbon ion beam and gemcitabine causes unrepairable DNA damage and death of radioresistant pancreatic cancer stem-like cells in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1390. doi:10.1158/1538-7445.AM2015-1390