tbuckley/cabot-search huggingface dataset:
Effect of IMP3 on epithelial-to-mesenchymal transition and the function of colon cancer stem cells.
Authors: Ping Wei, Dawei Li, Ye Xu, Sanjun Cai, Xiang Du
Journal: Journal of Clinical Oncology (2015)

631 Background: EMT could promote the acquisition of stem-like properties in cancer cells and cancer stem cell (CSC) has EMT properties. However, the underlying mechanism of the interaction between EMT and CSC still remain unclear. We previously identified Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) plays a vital role in colon cancer carcinogenesis. Here, we aimed to identify the gene function between EMT and CSC in colon cancer. Methods: The expression of IMP3 was analyzed in human tumor tissues. Colonospheres were isolated from colon cancer cell lines and the biological features of IMP3 were investigated in the process of EMT and colonoshpere cells. Results: Increased IMP3 levels were significantly correlated with higher clinical stage, T classification, LNM, presence of distant metastasis. Patients with IMP3-positive localized tumors had lower 5-year disease-free survival (DFS) and overall survival (OS) than those with IMP3-negative tumors. Multivariate survival analysis showed that IMP3 was an independent prognostic marker for DFS and OS. Expanded colonospheres contained cells that expressed high levels of CD133 and had the ability to promote migration and activate the epithelial-mesenchymal transition. Down regulation of IMP3 in HCT116 cells inhibited the invasion, migration ability and epithelial-mesenchymal transition and the properties of colonospheres. Conclusions: These findings suggest that IMP3 plays an important role in colon cancer tumorigenesis and metastasis through transactivation of colon CSC with EMT property, which is helpful to identify critical marker and therapeutic target.
Micrometastases detection using <i>SNAI-1</i> and <i>SNAI-2</i> as biomarkers of dissemination in patients with breast cancer
Authors: J. J. Cruz, M. A. Nava Rodríguez, E. Del Barco, M. Sánchez-Martín, R. Salazar, C. Rodríguez, A. Gómez-Bernal, I. Sánchez-García
Journal: Journal of Clinical Oncology (2005)

9686 Background: Loss of expression of the E-cadherin cell-cell adhesion molecule is important in carcinoma development and progression. Two zinc-finger transcription factors, SNAI1 and SNAI2, repress endogenous E-cadherin expression suggesting SNAI1 and SNAI2 are potential in vivo molecular markers of disseminated carcinomas. Methods: In a series of 196 human breast carcinomas under different therapeutic regimens (107 -54%- with locoregional extension and 89 -45%- with metastasis either in bone and soft tissues or in solid organs), we have analyzed the expression of SNAI1 and SNAI2 in the peripheral blood by reverse trancriptase polymerase chain reaction (RT-PCR). We have also correlated these data with the clinical features of the tumors. Results: SNAI1 is present in the peripheral blood of both controls and tumor patients. However, SNAI2, which is not present in the peripheral blood of controls, was detected in 134 patients (68%). SNAI2 expression was positive in 76 (70%) patients without distant metastasis and in 58 (65%) patients with metastatic breast carcinomas, some of whom had received multiple cycles of quimiotherapy (48% of metastasis in bone and soft tissues and 52% of metastasis in solid organs). Conclusions: Considering that SNAI2 is involved in the induction of the invasive and migratory phenotype in mesenchymal cells, these results indicate that SNAI2 expression in peripheral blood could serve as a biomarker of early dissemination in breast carcinoma. Thus, we are now studying if SNAI2 expression could be used as a prognosis factor or to monitor treatment benefit and relapse. No significant financial relationships to disclose.
Everolimus plus octreotide LAR versus placebo plus octreotide LAR in patients with advanced neuroendocrine tumors (NET): Effect of prior somatostatin analog therapy on progression-free survival in the RADIANT-2 trial.
Authors: L. B. Anthony, M. Peeters, J. D. Hainsworth, E. Baudin, D. Hoersch, J. Klimovsky, K. Grouss, V. Jehl, M. E. Pavel, J. C. Yao
Journal: Journal of Clinical Oncology (2011)

4078 Background: Systemic treatment options for advanced NET continue to be limited. In the phase III RADIANT-2 study, everolimus, an oral mTOR inhibitor, plus octreotide LAR provided a clinically meaningful 5.1-month increase in median progression-free survival (PFS) vs placebo plus octreotide LAR (P+O) in pts with advanced, low- or intermediate-grade NET and a history of secretory symptoms associated with carcinoid syndrome (ESMO 2010 Abstract LBA8). We sought to determine the effect of previous treatment with a long-acting somatostatin analog (SSA) on PFS in this trial. Methods: Pts were randomized to everolimus 10 mg/d orally + octreotide LAR 30 mg intramuscularly q28d (E+O; n=216) or P+O (n=213). The primary endpoint was PFS per central review by RECIST (v1.0). SSA treatment before study entry study was permitted. Pts previously administered SSA in each treatment arm were identified. Results: Of 429 pts randomized to treatment, 339 (79%) had received SSA therapy before study entry, including 173 (80%) in the E+O group and 166 (78%) in the P+O group. More pts with prior SSA therapy vs those without had small intestine (85% vs 15%), lung (66% vs 34%), and colon (79% vs 21%) as the primary disease site. Elevated baseline chromogranin A (81% vs 19%) and 5-hydroxyindoleacetic acid (85% vs 15%) levels were also observed in pts with prior SSA therapy vs those without. Pts with prior SSA therapy vs those without had longer time (>6 months) since diagnosis (82% vs 18%). Everolimus improved median PFS vs placebo in pts with and without previous SSA treatment (Table). Conclusions: Treatment with everolimus plus octreotide LAR produces a clinically meaningful prolongation of median PFS benefit irrespective of previous SSA treatment in pts with advanced NET and a history of secretory symptoms associated with carcinoid syndrome. Group Everolimus median PFS (mo) Placebo median PFS (mo) HR (95% CI) P Prior SSA treatment 14.3 11.1 0.81 (0.6-1.09) 0.077 No prior SSA treatment 25.2 13.6 0.63 (0.35-1.11) 0.054
Phase I trial of yttrium 90 resin microspheres in the treatment of colon cancer liver metastases progressing despite hepatic arterial as well as systemic chemotherapy: Preliminary results.
Authors: Constantinos T Sofocleous, Nancy E. Kemeny, Neeta Pandit-Taskar, Kinh Gian Do, Lynn A Brody, Alessandra R Garcia, Marinela Capanu, Joanne F. Chou, Elena N Petre, Jorge A. Carrasquillo
Journal: Journal of Clinical Oncology (2012)

625 Background: Prospective evaluation of the safety of Selective Interval Radiation Therapy (SIRT) using yttrium 90 microspheres (Y90) in patients with colon cancer liver metastases (CLM) who failed hepatic arterial (pump) and systemic chemotherapy. Methods: This prospective single center study, assessed the safety, dose limiting toxicities (DLT) and the maximum tolerated dose (MTD) of Y90 in a selected, heavily pretreated population. Upon IRB and FDA approval individualized Y90 doses were calculated according to a volumetric method and the body surface area (BSA) method as instructed by the company. SIRT treatment was administered in three escalating dose levels (cohorts): the first cohort received 70%, the second 85%, and the third 100% of the calculated dose. All patients received chemotherapy as deemed by the patients' medical oncologist post SIRT treatment. DLT was defined as new, post treatment, grade 3 toxicities, and evaluated according to the NCI Common Toxicity Criteria (NCI-CTC) 3.0. Response to treatment was evaluated by imaging (using a combination of WHO, RECIST, modified RECIST and SUV changes) and CEA levels. Kaplan Meier methodology was employed to calculate Progression Free (PFS) and Overall (OS) Survival. Results: From September 2009-2011, 19 patients received Y90. Common complaints post treatments were: grade 1-2 fatigue and grade 1 fever, which are known side effects of SIRT. No DLTs were observed. Grade 3 hyperbilirubinemia was recorded for two patients and was attributed to progressive disease; one patient in the third cohort suffered grade 3 nausea and pain. Twelve patients (70.6%) responded (defined as stable disease or better) while five (29.4%) progressed-this was based on evaluations from initial post treatment imaging. Two patients’ imaging is pending. Median PFS and OS were 6 [95%CI: 3.2-9.7] and 16 [95%CI: 5.8-17.6] months respectively. Conclusions: It is safe to administer the entire dose of Y90 in patients with CLM who progressed despite prior pump and systemic chemotherapy. Oncologic outcomes are promising.
Correlates of decline in emotional well-being over time in breast cancer survivors.
Authors: N. K. Janz, C. R. Friese, S. J. Katz
Journal: Journal of Clinical Oncology (2011)

e19673 Background: Some women experience decline in emotional well-being (EWB) during breast cancer survivorship. We investigated whether receipt of emotional support, and perceived risk or worry about recurrence were associated with declines in EWB in a large diverse population-based sample. Methods: We surveyed 2,245 women newly diagnosed with breast cancer and reported to the Detroit and Los Angeles SEER registries from 6/05-2/06 and merged these data to SEER. Latina and African American (AA) women were oversampled. Women were surveyed again 4 years after diagnosis (expected n=1,520). We report on a preliminary sample of 707 women. Measures included change in EWB over time (decline, same, better [FACT-B]), receipt of emotional support (none, some, quite a bit/a lot) across 7 sources, perceived risk of recurrence (1-5 scale), worry about recurrence (mean of 3-items, 1-5 scale), and race/ethnicity (white, AA, and Latina- low vs. high acculturation). Results: Women reported getting quite a bit/a lot of emotional support from partners (76%), other family (70%) friends (58%) health care providers (53%), other women with breast cancer (50%) religious community (34%), and co-workers (31%). Latinas-low were more likely than other racial/ethnic groups to report no emotional support from health care providers, other women with breast cancer, and friends (ps <0.05). Women who reported no emotional support from providers (vs. quite a bit/a lot) perceived higher recurrence risk (13.1% vs. 5.3%, respectively, p<.01). Younger women and Latinas-low had higher perceived recurrence risk and worry about recurrence (ps < .01). Women with higher perceived risk were more likely to report EWB decline (24.4%) compared to women with low perceived risk (13.5%, p <.01). Women with EWB decline had higher mean worry scores (2.74) versus women who did not have EWB decline (2.40, p = .02). Conclusions: Declines in emotional well-being after breast cancer treatment are associated with perceived risk and worry about recurrence. Low acculturated Latinas are particularly vulnerable. Clinicians play a critical role in providing emotional support and should attend to women’s perceived risk and worry about recurrence, and the relationships to emotional well-being.
Radiosensitization by erlotinib and veliparib in esophageal squamous cell cancer.
Authors: Alexander Whitley, Tiffiny Cooper, Anusha Angajala, Hoa Trummell, Josh Jackson, James A. Bonner, Eddy Shih-Hsin Yang
Journal: Journal of Clinical Oncology (2014)

70 Background: Dysregulation of the HER/EGFR family is identified in esophageal cancers and confers resistance and inferior survival rates. In addition to their unique selectivity in killing DNA repair-deficient tumors, poly-ADP ribose polymerase inhibitors (PARPi) can enhance radiation-induced cytotoxicity. We and others have also previously demonstrated attenuation of DNA repair capacity in HER-inhibited cells to induce a contextual synthetic lethal interaction with PARPi. We thus hypothesized that erlotinib, a tyrosine kinase inhibitor directed against HER1/HER2, could induce a transient DNA repair deficit and subsequently increase DNA damage with the PARPi veliparib in esophageal cancer cells while increasing tumor radiation (RT) sensitivity. Methods: Esophageal SCC cell lines (KYSE-30, KYSE-410, and OE-21) were treated with combinations of vehicle, erlotinib, veliparib (a PARP1/2 inhibitor), and RT. DNA damage and repair and signaling proteins were assessed by immunofluorescence staining of cells for DNA damage and repair foci and/or western blot analysis. Cell viability and cytotoxicity were determined via cell proliferation assays and colony formation assays, respectively. Tumor growth delay was assessed in mice bearing esophageal tumor xenografts. Results: Consistent with our hypotheses, erlotinib increased γ-H2AX foci, a marker of DNA double strand breaks (DSBs), in all three esophageal SCC tumor cells. This coincided with reduced DSB-repair capacity as assessed via RAD51 foci and pDNA-PK. Triple combination with erlotinib, veliparib, and RT demonstrated enhanced cytotoxicity. A subsequent increase in Annexin positive cells was observed, indicative of activation of the apoptotic response. Importantly, the triple combination was most effective in suppressing the growth of esophageal tumor xenografts in vivo (2– to 5.5–fold lower tumor volume) relative to other treatment groups. Furthermore, we observed reductions in tumor volume from baseline with this triple combination in 3/6 mice. Conclusions: Thus, the combination of erlotinib, PARPi, and RT can be an innovative and effective treatment strategy to enhance the therapeutic ratio and improve outcomes in esophageal SCC cancer patients.
High-throughput mutation analysis in acute myeloid leukemia (AML).
Authors: J. Dunlap, C. L. Corless, W. H. Fleming, R. Braziel, N. Leeborg, K. Gatter, M. Loriaux, K. Kelemen, T. Kovacsovics, G. Fan
Journal: Journal of Clinical Oncology (2011)

6529 Background: Classification of AML increasingly depends on genetic analysis. Current guidelines recommend cytogenetics and screening for NPM1, FLT3-ITD, KIT and CEBPA mutations; however, the number of known mutations in AML is expanding rapidly. Here we report our experience using a multiplex mass spectroscopy-based panel for routine AML genotyping. Methods: 96 AML cases were screened for oncogene mutations using a panel covering 269 mutations across 31 genes. The analysis was performed by multiplex PCR for genes of interest followed by primer extension reactions for specific mutations. Products were quantitatively analyzed on a Sequenom MassARRAY system. Mutations were confirmed by conventional bi-directional sequencing. Cytogenetic analysis and routine molecular testing for NPM1, CEBPA, FLT3-ITD and KIT by standard PCR-based assays were also performed on a subset of cases. Results: The multiplex mass spectroscopy panel yielded a mutation frequency of 64% in cases with normal cytogenetics and 27% in those with abnormal cytogenetics. Recurrent mutations were identified in NPM1, NRAS, IDH1, KRAS, FLT3, and CBL. 5% of cases harbored multiple mutations. When combined with results of standard PCR-based tests, the mutation frequency in cases with normal cytogenetics reached 86% (Table). Conclusions: Our multiplex mass-spectroscopy-based approach identified recurring and sometimes overlapping mutations in NRAS, IDH1, KRAS, KIT, and CBL. A higher frequency and distinct distribution of mutations was identified in cases with normal cytogenetics compared to abnormal cytogenetics. Broad-based mutation profiling of AML will be helpful in defining important prognostic subgroups, and may contribute to the selection of patients for enrollment into trials with novel inhibitors. Cytogenetics Normal (n=36) % Abnormal (n=60) % CBL 5 0 NPM1 17 0 FLT3 ITD 6 10 CEBPA 3 2 NRAS 5 7 FLT3 PM 0 2 C-KIT 0 8 IDH1 0 3 KRAS 0 7 HRAS 0 2 PTPN11 0 2 FLT3PM+FLT3 ITD 0 2 NPM1+FLT3 ITD 22 2 NPM1+FLT3 TKD 5 0 NPM1+FLT3 PM 3 0 NPM1+ IDH1+ NRAS 3 0 CEBPA+FLT3 ITD 3 0 NPM1+IDH1 3 0 FLT3PM+NPM1+PTPN11 3 0 IDH1+FLT3 ITD 3 0 NPM1+CEBPA+FLT3 ITD 3 0 NPM1+FLT3 ITD+KRAS 3 0 C-KIT+ RAS 0 2
Use of the <i>XRCC1</i> single nucleotide polymorphism to predict pathologic complete response to neoadjuvant chemoradiation in stage II/III rectal cancer.
Authors: M. P. Duldulao, W. Li, J. Ho, Z. Chen, W. Lee, J. Kim, J. Garcia-Aguilar
Journal: Journal of Clinical Oncology (2011)

409 Background: The X-ray repair cross-complementing protein 1 (XRCC1) gene plays an important role in DNA damage repair; and the R194W and R399Q single nucleotide polymorphisms (SNPs) are associated with attenuated DNA repair activity. Our objective was to determine whether XRCC1 SNPs were associated with response to neoadjuvant chemoradiation therapy (CRT) in rectal cancer patients. Methods: We conducted a prospective multicenter phase II trial to investigate the effect of additional chemotherapy with a longer CRT-to-surgery interval on treatment response in patients with rectal cancer. Paired normal and rectal cancer tissues were prospectively collected from enrolled patients (n=110). DNA was extracted from normal rectal mucosa and analyzed for XRCC1 R194W and R399Q by polymerase chain reaction and sequencing. Each SNP was compared to response to CRT. Response to CRT was determined by a central pathologist. Results: Of the 110 patients, 25% (n=27) achieved a pathologic complete response (pCR). We examined the XRCC1 R194W SNP and observed that the allelic frequency of patients with the R/R genotype was 84% (n=92), the R/W genotype was 14% (n=16), the W/W genotype was 1% (n=2). By Fisher's Exact test, patients harboring either the R/W or W/W genotype, had a significantly higher rate of pCR compared to patients with the R/R genotype (44% vs. 21%, respectively; p=0.04). We then examined the R399Q SNP and observed that the allelic frequency of patients with the R/R genotype was 34% (n=37), the R/Q genotype was 49% (n=54), and the Q/Q genotype was 17% (n=19). In contrast, the detection of XRCC1 R399Q SNPs was not associated with pCR. Conclusions: We demonstrate that XRCC1 R194W SNP is associated with increased rate of pCR in our prospective multi-center trial. Although the detection of XRCC1 R399Q SNP is not associated with pCR, the detection of XRCC1 SNPs that predict treatment response may help identify patients who are unlikely to respond to CRT and therefore may potentially avoid treatment-associated morbidities. No significant financial relationships to disclose.
Functional Comparison and Longitudinal Assessment of Tri-Functional T-Cells Recognizing CMV pp65 and IE-1 Polypeptides in Hematopoietic Stem Cell and Solid Organ Transplant Recipients.
Authors: Don J. Diamond, Simon F. Lacey, Corinna La Rosa, Wendy Zhou, Ghislaine Gallez-Hawkins, Lia Thao, Jeff Longmate, Ajit Limaye, Ricardo Spielberger, Stephen J. Forman, John A. Zaia
Journal: Blood (2006)
Leveraging the strengths of an academic health system to improve community cancer care.
Authors: Kay M. Harse, Terri P. Wolf
Journal: Journal of Clinical Oncology (2013)

218 Background: To improve community cancer care quality, UC Davis Health System formed the UC Davis Cancer Care Network (CCN) to partner with select cancer centers in California to offer leading-edge care close to home. Hospital-based community cancer centers become affiliates of the UC Davis CCN through an evaluation process led by UC Davis. By synergizing the strengths of an academic health system and community-based oncology care, the network formalizes the commitment to collaboration with community providers. Methods: This quality model relies on a central university-based team interacting with affiliate sites to support them in their local missions. Affiliates progress through three phases of development of their cancer program. Each phase adds layers of quality to the organization. CCN staff members coordinate the phases: 1) Review and Develop Operations—site specific structures needed to be a comprehensive community cancer center; 2) Make Connections—within the network and the local community; 3) Become Self-Directed—identifying own needs and direction. The partnership attributes include: joint marketing, system synergies, certification assistance, coordinated service line development, dedicated personnel resources, on-site educational opportunities, and quality oversight. Results: Performance measurement includes: local market share, ACOS accreditation, adherence to national quality and patient satisfaction standards, assessment of community health needs and benefits, and enhancement of local capabilities (inpatient oncology unit, radiation, pathology, radiology, and surgical oncology services). Conclusions: This model demonstrates the benefit of partnering the strengths of an academic health system and community cancer programs to provide quality care.
Multi-drug resistance (MDR1/P-glycoprotein) gene expression in molecular breast cancer subtypes of African-American women
Authors: C. U. Ihemelandu, W. Frederick
Journal: Journal of Clinical Oncology (2008)

22038 Background: Molecular breast cancer subtypes respond differently to chemotherapy. Patients with the basal cell-like subtype despite initial chemosensitivity are associated with the worst distant-metastasis free survival. We sort to analyze the expression of the MDR1/P-glycoprotein gene among the molecular subtypes and its association with prognostic variables. Methods: A retrospective chart review for assessable immunohistochemical data for MDR1/P-glycoprotein, estrogen, progesterone and Her-2/neu on 232 patients diagnosed with breast cancer between 1998–2005. Subtypes analyzed were luminal A, luminal B, basal cell-like, and Her-2/neu. Results: Of the 232 patients 37 (15.9%) overexpressed while 195 (84.1%) underexpressed MDR1. As a function of the molecular subtypes no significant difference was noted in the expression of MDR1 (p=0.51). MDR1 overexpression was noted to be significantly associated with post-menopausal status (p=0.009), and low tumor grade (p=0.03). Patients with a low tumor grade were 3.1 times more likely to overexpress MDR1 (OR=3.1, 95% CI 1.0-11.5, p=0.03). MDR1 expression was not associated with lymph node metastasis, tumor size, or tumor stage. Treatment with chemotherapeutic drug was not associated with an increase in the proportion of tumors expressing MDR1 (OR=1.5, 95% CI 0.56-4.0, p=0.40). MDR1 expression showed no significant effect on overall survival (HR=1.4, 95% CI 0.51-4.00, p=0.49), or distant-metastasis free survival (HR=1.5, 95% CI 0.39-5.91, p=0.54). Conclusions: MDR1/P-glycoprotein expression does not differ among the molecular subtypes; however its expression is significantly associated with a low tumor grade and post-menopausal status, features associated with the luminal subtypes. No significant financial relationships to disclose.