tbuckley/cabot-search huggingface dataset:
Quantitative gene expression underlying <sup>18</sup>f-fluorodeoxyglucose uptake in colon cancer.
Authors: Bodil E. Engelmann, Tina Binderup, Andreas Kjær, Annika Loft, Thomas A. Gerds, Anne Kiil Berthelsen, Kim Brinch, Jan E. Latocha, Carsten Sloth, Liselotte Højgaard
Journal: Journal of Clinical Oncology (2015)

653 Background: Positron emission tomography (PET) with the glucose analogue 18 F-fluorodeoxyglucose (FDG) is widely used in oncologic imaging. This study examines the molecular mechanism underlying the detection of colon cancer (CC) by FDG-PET. Methods: Pre-operative PET/CT scans and tissue samples from primary CC and surrounding normal mucosa were obtained from 42 patients. FDG uptake was quantified using maximal standardized uptake value (SUV max ). The expression of ki67, glucose transporter 1 (GLUT-1), hexokinase 1 (HK1), hexokinase 2 (HK2), vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF1α) and carbonic anhydrase IX (CaIX) mRNA was examined by quantitative real time reverse transcriptase-polymerase chain reaction. Results: All primary tumours showed increased uptake of FDG. The mean SUV max was 15.0 (range 5.3 – 37.8). No correlation was found between tumour size and SUV max . Mean gene expression levels of GLUT1, HK2, ki67, HIF1α, VEGF and CaIX, but not HK1, were significantly higher in primary tumours than in surrounding normal colonic mucosa. Linear regressions pairing tumour SUV max with gene expression levels showed significant correlations between SUV max and HK2, ki67 and CaIX, respectively. Conclusions: These results confirm FDG PET/CT as a functional imaging method in CC, and that FDG accumulation reflects molecular events related to glycolysis, cell proliferation, hypoxia, but not angiogenesis.
Use of operability classifications to predict outcome of patients with anatomically resectable pancreatic adenocarcinoma treated with neoadjuvant therapy.
Authors: Ching-Wei David Tzeng, Jason B. Fleming, Jeffrey Edwin Lee, Lianchun Xiao, Peter W. T. Pisters, Jean-Nicolas Vauthey, Eddie K. Abdalla, Robert A. Wolff, Gauri R. Varadhachary, David R. Fogelman, Christopher H. Crane, Aparna Balachandran, Matthew H.G. Katz
Journal: Journal of Clinical Oncology (2012)

293 Background: We previously introduced a novel classification system for assessing “operability” in patients with localized pancreatic adenocarcinoma (PDAC) that integrates cancer biology, patient physiology, and tumor anatomy. We sought to analyze resection rates, reasons for no resection, and outcomes after neoadjuvant therapy (NT) of patients with both resectable anatomy and either “operable” or “borderline” biology/physiology. Methods: We evaluated consecutive patients (2002-2007) with radiographically resectable cancers treated with NT prior to potential resection. Borderline resectable anatomy (BR-A) was excluded. We compared clinical factors and outcomes of 217 patients classified by established criteria as “potentially resectable-operable” (PR-OP, no evidence of extrapancreatic disease, performance status [PS] ≤1); “borderline resectable-B” (BR-B, findings suspicious for extrapancreatic disease); or “borderline resectable-C” (BR-C, severe but reversible comorbidities or marginal PS ≥2). Results: 138 PR-OP, 41 BR-B, and 38 BR-C patients began NT. 62.7% of all patients underwent subsequent pancreatectomy. Resection rates after NT for PR-OP, BR-B, and BR-C were 74.6%, 46.3%, and 36.8%, respectively (p&lt;0.001). Metastases were detected during NT in 23.0% of all patients and were the most common contraindication to resection in PR-OP (15.2%) and BR-B (46.3%) patients. PS rarely precluded surgery except in BR-C patients (31.6%). Factors independently predicting not utilizing surgery after NT were older age, poor PS, new pain medications, and complications on NT (p&lt;0.05). Median OS of all patients was 20.9 (95% CI, 17.1-27.1) mo. Resected and unresected BR-B and BR-C patients had OS similar to that of PR-OP patients (resected medians 33.0, 39.8, 36.0 mo, respectively; unresected medians, 10.1, 12.6, 12.9 mo; p&lt;0.001). Conclusions: Our operability classification system describes discrete clinical subgroups among PDAC patients with similar, resectable tumor anatomy but vastly heterogeneous physiology and cancer biology. It can be used with NT to predict outcomes, individualize treatment, and optimize survival rates.
TRC105 for the treatment of hepatocellular carcinoma: Preclinical data and preliminary results from two clinical trials evaluating monotherapy and combination with sorafenib.
Authors: Austin G. Duffy, Chi Ma, Susanna Varkey Ulahannan, Suzanne Fioravanti, Aradhana Venkatesan, Ismail B. Turkbey, Peter L. Choyke, Jane B. Trepel, Liang Cao, Kathryn Compton, William Douglas Figg, Tim F. Greten
Journal: Journal of Clinical Oncology (2014)

211 Background: Endoglin (CD105), is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including in HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that acts by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Preclinical: Murine BNL HCC cells were grown subcutaneously in wildtype Balb/c mice and treated with antibody to murine CD105, (clone MJ7/18; 10-200ug) ± sorafenib (10 mg/kg daily p.o.) or sorafenib alone. Clinical: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks plus sorafenib 400mg bid; or (if sorafenib-refractory) a phase II study of TRC105 at 10 or 15mg/kg q 2wks. Correlative biomarkers: DCE-MRI; FDG-PET; color Doppler ultrasonography; circulating endothelial and endothelial progenitor cells, plasma levels of angiogenic factors; soluble CD105 and tumor IHC for CD105. Results: Preclinical studies: CD105 expression was increased in BNL HCC tumors of mice treated with sorafenib. Anti-CD105 + sorafenib was more effective than sorafenib alone. Clinical trials (N=16): M:F 13:3; Median age = 55 (range 24-67); Phase I with sorafenib (N=8): 1 DLT (increased AST) occurred at 10mg/kg. The most frequent toxicity has been epistaxis. One patient with coronary stenosis developed a fatal MI and one patient with thrombocytopenia developed G3 cerebral tumor hemorrhage. Phase II (N=8): No grade 3/4 treatment-related toxicities . Most frequent toxicities headache (G2; N=3) and epistaxis (G1; N=4). No patient was progression free at 4 months. Median time on study: Phase I- 4 months; Phase II - 2 months. Preliminary evidence of biologic response seen on DCE-MRI in 1pt (of 3 evaluable) with a reduction in Ktrans and kep and 3pts (of 3 evaluable) with reduction in intra-tumoral color flow on Doppler. Conclusions: TRC105 is well tolerated both as single agent and combined with sorafenib. Evidence of biological activity was observed. Full preclinical, clinical and correlative data will be presented. Clinical trial information: NCT01306058, NCT01375569.
Survival benefit of second-line chemotherapy in advanced pancreatic adenocarcinoma: A systematic review of the literature.
Authors: Adnan Nagrial, Venessa T. Chin, Katrin Sjoquist, Lorraine A. Chantrill, Desmond Yip
Journal: Journal of Clinical Oncology (2014)

296 Background: There is currently no standard of care for the second-line treatment of advanced pancreatic cancer. Very few randomised studies have been performed in this setting. The aim of this analysis was to compare the different therapeutic approaches in this setting, and the rate of second line treatment delivery and its influence on reported overall survival. Methods: We carried out a systematic analysis of studies in advanced pancreatic cancer. 1 st and 2 nd line chemotherapy trials were identified from MEDLINE, EMBASE &amp; CENTRAL using the COCHRANE sensitive search strategy. Objective response rates (ORR) and survival (PFS &amp; OS) were extracted and compared amongst groups using the Mann-Whitney U test. For 1 st line studies, the percentage of patients who received 2 nd line chemotherapy was also extracted and plotted against reported median overall survival (OS) and post-progression survival (PPS), defined as arithmetic difference between median OS and progression-free survival. Linear regression was used to explore the relationship between overall survival and second-line chemotherapy. Results: 20 first line clinical trials with 42 treatment arms met the inclusion criteria treating an aggregate total of 5,768 patients. Overall survival was positively correlated with use of second-line chemotherapy (r=0.65; p=0.012). 61 second-line studies were identified treating an aggregate total of 2,562 patients in 66 treatment arms. Combination treatment was associated with an improved response rate (p=0.045) and PFS (p=0.024) when compared to single agent therapy. Conclusions: In this exploratory analysis, these data suggest that there is a small benefit of second-line chemotherapy in pancreatic cancer. In first-line chemotherapy studies, the use of subsequent treatment correlates with improved overall survival. In second line studies, combination chemotherapy is associated with higher response rates and survival.
Impact of preoperative systemic chemotherapy on liver histology and outcome of hepatic resection for colorectal cancer liver metastases (CRLM)
Authors: R. Adam, M. Sebagh, M. Plasse, V. Karam, S. Giachetti, D. Azoulay, M. Bouchahda, C. Jasmin, D. Castaing, F. Lévi
Journal: Journal of Clinical Oncology (2005)

3529 Background: Preoperative chemotherapy for CRLM can produce histologic changes in non tumoral liver. Methods: A retrospective analysis was performed in data from 92 patients (pts) who had liver resection for CRLM without (17 pts) and with chemotherapy (75 pts). 5-FU-leucovorin was given to all patients of C+, alone (FUFOL, 23 pts) or combined with oxaliplatin (FOLFOX, mostly chronomodulated, 52 pts). The same pathologist blindly reviewed histological specimens of the non-tumoral liver parenchyma. Histological and clinical data from both groups, as well as within the C+ group were compared. Results: Vascular changes were more frequent in the C+ than in the C- group (52 vs 18%, p< 0.01) in relation with increased sinusoidal dilatation (23 vs 6%) and peliosis (25 vs 6%) while the incidence of regenerative nodular hyperplasia was similar. There was also a trend towards a higher incidence of fibrosis and centrolobular necrosis (CLN) in the C+ group. FOLFOX-treated patients had less steatosis and fibrosis, equal sinusoidal changes but more CLN (35 vs 4%, p= 0.07) than FUFOL patients. While demographic and operative data were similar between groups, C+ received more blood transfusions than C- group (2.0±2.6 vs 0.3±0.8 units, p12 courses of any chemotherapy (p=0.01). Conclusion: Systemic chemotherapy can produce hepatic vascular changes and increase the risk of operative bleeding. FOLFOX-treated patients had less steatosis and fibrosis, similar sinusoidal alterations but more CLN than FUFOL-treated patients. None of these changes seemed to exert a clinically relevant impact on the outcome of patients following liver resection for CRLM. No significant financial relationships to disclose.
APACT: Phase III randomized trial of adjuvant treatment with <i>nab</i>-paclitaxel (<i>nab</i>-P) plus gemcitabine (Gem) versus Gem alone in patients (pts) with resected pancreatic cancer (PC).
Authors: Margaret A. Tempero, Dana Backlund Cardin, David Goldstein, Eileen Mary O'Reilly, Philip Agop Philip, Hanno Riess, Teresa Macarulla, Lotus Yung, Mingyu Li, Brian D. Lu, Andrew Biankin
Journal: Journal of Clinical Oncology (2016)

TPS473 Background: Gem therapy improves outcomes in pts with resected PC. However, disease recurrence is common, prompting a need for improved regimens. nab-P + Gem was superior to Gem alone in MPACT, a phase III trial of pts with metastatic PC (mPC) for all endpoints, including overall survival (OS; median, 8.7 vs 6.6 months; hazard ratio [HR] 0.72; P &lt; 0.001). Toxicities were manageable and consistent with prior studies. The APACT trial will compare adjuvant nab-P + Gem vs Gem alone in pts with resected PC. Methods: Pts (≈ 800) with confirmed PC (R0 or R1 resection); stage T1 - 3, N0 - 1, M0; Eastern Cooperative Oncology Group performance status ≤ 1; adequate organ function; and CA19-9 &lt; 100 U/mL within 14 days of randomization are eligible. Pts with mixed-origin tumors; present or previous mPC; any other malignancy within 5 years of randomization; HIV or hepatitis B or C infection; or prior neoadjuvant treatment or radiotherapy for PC are ineligible. Randomization should occur once pts adequately recover from surgery but ≤ 12 weeks after surgery. Pts will receive 6 cycles of either nab-P 125 mg/m 2 plus Gem 1000 mg/m 2 or Gem 1000 mg/m 2 on days 1, 8, and 15 of a 28-day cycle. Stratification factors are resection (R0 vs R1) and nodal (LN+ vs LN−) status and geographic region (North America vs Europe vs Australia vs Asia Pacific). Pts with &gt; 2 dose reductions will be discontinued. The primary endpoint is independently assessed disease-free survival (DFS). Secondary endpoints are OS and safety. Quality of life and correlation of tumor heterogeneity with clinical outcome are exploratory outcomes. At least 489 DFS events from 800 pts will allow 90% power to detect an HR for DFS of 0.74 at a 2-sided significance level of 0.05. Interim analyses, 1 for safety (after 100 pts are treated for ≥ 2 cycles) and 2 for efficacy (the first for futility and the second for futility and superiority), will be performed. As of July 2015, &gt; 400 pts were enrolled, and 80% of all activated study sites (n = 141) randomized ≥ 1 pt. Of the 674 screened pts, ≈ 25% were ineligible, mainly due to postsurgical disease recurrence identified at screening. Pt enrollment is ongoing. ClinicalTrials.gov: NCT01964430. Clinical trial information: NCT01964430.
Molecular and genomic characterization of invasive circulating tumor cells (iCTCs) from men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Terence W. Friedlander, Gayatri Premasekharan, Vy Ngo, Shaun Doty, Anna Harris, Michael Winter, Elizabeth Gilbert, Charles Craik, Pamela Paris
Journal: Journal of Clinical Oncology (2014)

120 Background: Identification, enumeration, and genomic analysis of circulating tumor cells (CTCs) may allow for a better understanding of the mechanisms of resistance to therapies in metastatic castration-resistant prostate cancer (mCRPC). The Vitatex VitaAssay platform captures invasive CTCs (iCTCs) in a cell surface marker-independent fashion based on their ability to invade a fluorescently-labeled cell-adhesion matrix (CAM), allowing for the analysis of multiple CTC subpopulations. Here we sought to estimate epithelial, mesenchymal, and stem-like iCTC subpopulation diversity in men with CRPC starting abiraterone acetate therapy, to compare the genomic profiles of iCTCs to matched metastatic biopsies, and to explore the potential for 2D and 3D CTC culture. Methods: iCTCs were isolated from men with mCRPC using the CAM platform, and paired metastatic biopsies were performed. iCTCs were defined as CAM+/CD45-/CD14-/DAPI+, mesenchymal iCTCs as vimentin+/CAM+/CD45-/CD14-/DAPI+, and stem-like iCTCs as CD44+/CAM+/CD45-/CD14-/DAPI+. iCTCs were enumerated and purified using FACS. Agilent array comparative genomic hybridization (aCGH) of iCTCs and paired biopsies was performed, and to explore the potential for ex-vivo cell expansion and spheroid formation, iCTCs were cultured separately in CAM and in matrigel for up to 10 days. Results: iCTCs were isolated using the CAM platform from 29 men, of whom seven have undergone paired metastatic biopsy. The median pre-FACS purity was 1.06% (range 0.11%-10.16%). Post-FACS purity was increased to greater than 90%, and a median of 60 (range 2 to 1,314) iCTCs/7.5ml were detected by FACS. Both vimentin+ and CD44+ iCTCs are detectable, and compromise between 10 to 50% of total iCTCs. iCTC aCGH profiles resemble paired soft tissue biopsy, in vitro iCTCs culture is feasible, and iCTC spheroids were observed. Conclusions: Multiple CRPC iCTC subpopulations are identifiable from men starting abiraterone therapy, and cell sorting techniques increase iCTC purity. iCTCs resemble metastatic CRPC tissue and can be expanded in culture. Further enumeration, genomic profiling, and clinical correlation of paired iCTCs taken from men with abiraterone-resistant CRPC is underway, and may shed light on mechanisms of abiraterone resistance.
Low Level of Serum Haptoglobin in Patients with Acquired Bone Marrow Failure (BMF) Syndromes.
Authors: Kazuhiko Ikeda, Naoto Takahashi, Junichi Kameoka, Katsushi Tajima, Kazunori Murai, Yoshiko Tamai, Hideyoshi Noji, Yoji Ishida, Ken-Ichi Sawada, Tsutomu Shichishima
Journal: Blood (2007)
Use of a gene expression signature related to epithelial-to-mesenchymal transition (EMT) to predict for overall survival (OS) in cohorts of lung and head and neck cancer (HNSCC) patients.
Authors: J. S. Yordy, L. Shen, L. Diao, J. Wang, K. Coombes, U. Giri, Y. Xie, J. D. Minna, L. Girard, J. Weinstein, J. Heymach, K. K. Ang, M. D. Story, R. Meyn
Journal: Journal of Clinical Oncology (2011)

7010 Background: Improved predictions for survival and response to therapy will help to refine clinical care and potentially improve outcomes for patients with cancers of the upper aerodigestive tract. Methods: Gene expression analysis using three mesenchymal (M) and three epithelial (E) non-small cell lung cancer (NSCLC) cell lines identified 574 differentially expressed probes based on a false discovery rate (FDR) of 30%, which were then used to categorize a panel of 50 cell lines on the Illumina gene expression platform into 30 E-like and 20 M-like cell lines. 46 of these cell lines were analyzed with Affymetrix arrays, corresponding to 27 E-like and 19 M-like cell lines, and the top 4054 differentially expressed probes based on a FDR of 20% were filtered to retain probes with at least 2-fold average difference in expression. Overlap with the Director’s Consortium (DC) of mostly early stage lung adenocarcinoma patients treated with surgery and adjuvant therapy as appropriate resulted in 991 probes, which were then ranked using a survival-based Cox regression model with patients combined from the UM and HLM cohorts in the DC. The top 112 probes based on a FDR of 25% were then used in a supervised PCA analysis and two-evenly divided groups of patients were compared using Kaplan-Meier survival analysis. The 112 probe signature was independently tested in the DC MSK cohort and a cohort of surgical-pathologic high-risk HNSCC patients treated with surgery and post-operative radiotherapy. Results: Gene expression related to EMT is able to identify two highly different E-like and M-like groups of cell lines. This cell-line derived and clinically refined EMT-related gene expression signature predicted for OS in an independent cohort in the DC (p = 0.0016) as well as in HNSCC patients (p = 0.003). Conclusions: A gene expression signature related to EMT predicts for OS in lung cancer and HNSCC patients. Further prospective validation will be needed to verify these results. In addition, this signature distinguishes between unique biological phenotypes and therefore may also be significant in predicting response to specific therapeutic interventions.
Assessing the impact of a targeted electronic medical record intervention on growth factor usage in cancer patients.
Authors: Jordan Bernens, Kara Hartman, Brendan F. Curley, Sijin Wen, Jame Abraham, Michael David Newton
Journal: Journal of Clinical Oncology (2014)

262 Background: Patients receiving chemotherapy are at risk for febrile neutropenia following treatment. The American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) recommend screening patients for risk of febrile neutropenia and risk stratification based on likelihood of febrile neutropenia events. Prophylactic growth factors (G-CSF) should be in patients receiving high-risk regimens or intermediate-risk regimens with individual risk factors. The impact of electronic medical record system (EMR) implementation on compliance with G-CSF support guidelines has not been studied. Methods: At West Virginia University/Mary Babb Randolph Cancer Center we conducted an IRB approved retrospective chart review of cancer patients receiving chemotherapy from January 1, 2007 to August 1, 2008 (pre-EMR) and January 1, 2011 to December 31, 2011 (post-EMR). We reviewed the chemotherapy regimens and patient risk factors for developing febrile neutropenia, and determined if the G-CSF usage was consistent with guideline recommendations. Results: Compliance with prophylactic G-CSF guidelines was 75.6% in the post-EMR arm, compared to 67.5% in the pre-EMR arm (p=0.041, ch-square). The post EMR data of 1,042 new chemotherapy initiations showed: (see Table). The appropriateness of usage in high and low risk patients were the most compliant, as G-CSF orders were built into chemotherapy plans of high risk regimens and omitted from low risk regimens. Conclusions: Appropriate prophylactic G-CSF usage can be improved when orders are integrated into standard chemotherapy order sets in an EMR. An area of further improvement would include automatic identification of individual risk factors by the EMR. [Table: see text]
A multicenter phase II study of istiratumab (MM-141) plus nab-paclitaxel (A) and gemcitabine (G) in metastatic pancreatic cancer (MPC).
Authors: Andrew H. Ko, James Murray, Kerry E Horgan, Julia Dauer, Michael Curley, Jason Baum, Chrystal Ursula Louis, Alexey Lugovskoy
Journal: Journal of Clinical Oncology (2016)

TPS481 Background: Despite recent advances in the treatment of MPC, overall prognosis for patients remains poor. This may be attributed in part to the ability of pancreatic tumors to co-opt growth factor signaling pathways to counteract the activity of chemotherapy. We previously demonstrated that IGF-1 and heregulin, the ligands for IGF-1R and ErbB3, respectively, can decrease the cytotoxic activity of A/G (JCO 33 2015 s3 a289). Additionally, co-expression of IGF-1R and ErbB3 is known to be associated with poor survival prognosis in MPC patients (JCO 33 2015 s3 a295). Istiratumab, a fully human bispecific antibody directed at IGF-1R and ErbB3, produced significant tumor regression, including durable complete responses, when combined with A/G in preclinical models of pancreatic cancer, and has been shown to be safe and tolerable in a Phase 1 study (JCO 33 2015 s3 a384). On these bases, the current Phase 2 study was developed to evaluate istiratumab plus A/G in pts with MPC. Methods: Eligible patients have biopsy-confirmed MPC, ECOG PS 0-1, no prior therapy for advanced disease, and elevated serum levels of free IGF-1 (estimated to be ~40% of all screened patients). The study design includes two parts: Part 1 (n = 12) is an open-label assessment of the safety, tolerability, and pharmacokinetics (PK) of a fixed dose of istiratumab (2.8 grams IV q 2 weeks) in combination with A/G; in Part 2 (n = 146), pts are randomized 1:1 to receive A/G plus either istiratumab or placebo. The primary objective of Part 2 is to compare progression free survival (PFS) between the two treatment arms in two distinct cohorts: a) patients with high free serum IGF-1 levels (i.e., the entire study cohort), and b) patients with both high free serum IGF-1 levels and positive expression of heregulin in tumor tissue. Additional objectives include safety, overall survival, PK and immunogenicity analyses of istiratumab, and correlative analyses of pre-defined biomarkers and their potential correlation with study outcomes. The study is designed with 80% power to detect a hazard ratio of 0.63 in favor of the experimental arm (8 vs 5 months) at a one-sided significance level of 0.05. The study has been open to enrollment as of September 2015. Clinical trial information: NCT02399137.