bluuebunny/crossref_metadata_2025 huggingface dataset:
Response rates in patients with relapsed/refractory acute myeloid leukemia with FLT3-ITD mutation using 5-azacitadine plus sorafenib.
Authors: Alattar Mona Lisa , Kantarjian Hagop , Levis Mark J. , Richie Mary Ann , Daver Naval Guastad , Garcia-Manero Guillermo , Faderl Stefan , Borthakur Gautam , Burger Jan Andreas , Kadia Tapan M. , Grunwald Michael Richard , Dellasala Sara , Cortes Jorge E. , Ravandi Farhad
Published: February 2017

24

Background: Outcome of patients with relapsed acute myeloid leukemia (AML) with FLT3-ITD mutation is poor. Elevated FLT3 ligand levels (FL) secondary to cytotoxic chemotherapy is a putative mechanism of resistance to the FLT3 kinase inhibitors. We hypothesized that FL levels will be lower when combining sorafenib with less intensive therapy such as 5-Azacytidine (5-Aza). This study was conducted to evaluate the efficacy and tolerability of the combination of sorafenib and 5-Aza in patients with refractory or relapsed AML with FLT3-ITD mutation. Methods: Patients were eligible if they had relapsed or refractory AML and were 18 years of age or older. They received 5-Aza 75 mg/m2 IV daily x 7 days and sorafenib 400 mg PO BID continuously; cycles were repeated in approximately one month intervals. Results: 38 patients with AML with a median age of 60 years (range, 24-87) were enrolled. 4 were inevaluable as they never received therapy or discontinued it before response assessment. FLT-3-ITD was detected in 30 (88%) patients. They had received a median of 2 prior treatments (range, 0-6); 13 (38%) had received ≥ 3 prior regimens and 8 had failed prior FLT3 kinase inhibitor. Response rate was 41%, including 6 (17%) with CRi, 4 (12) with CRp, 3 (9%) with CR, and 1(3%) PR. The median time to achieving CR/CRi was 2 cycles (Range, 1-6) and the median duration of CR/CRi was 3 months (Range, 1–12). Conclusions: Combination of 5-Aza and sorafenib is effective for patients with relapsed AML with FLT-3-ITD mutation.
Gene expression analysis of Notch signaling pathway receptors in colon cancer stem cells.
Authors: Papasotiriou Ioannis , Apostolou Panagiotis , Toloudi Maria , Chatziioannou Marina , Ioannou Eleni
Published: February 2017

29

Background: The Notch signaling pathway is not only involved in cell differentiation, but also in carcinogenesis. Four different receptors are included in this pathway (Notch-1, Notch-2, Notch-3, and Notch-4) and each is encoded by a different gene. Recent data suggest that the activation of Notch-1 induces epithelial to mesenchymal transition (EMT) consistent with cancer stem cell (CSC) phenotype. It raises therefore the question of whether there is an interaction between the receptors. The present study aims to find out the gene expression patterns of Notch receptors in Colon CSCs, under the suppression of Notch-1. Methods: The experiments were performed in Colon CSCs provided by CELPOGEN. The stemness of these cells was tested both in gene and protein level with qPCR and flow cytometry assays for the stemness markers Oct4-CD44. The gene suppressed with RNAi assays and the knockdown was evaluated with molecular biology methods. The gene expression analysis was performed after RT-qPCR assays, by using the comparative Ct method (ΔΔCt) for the calculation of relative quantitation. Results: The Colon CSCs expressed Oct4-CD44 both in gene and protein level, indicating the stemness status. The knockdown of Notch-1 up to 75%, led to a reduction of gene expression in Notch-2 and Notch-3 receptors, while no significant difference was observed in Notch-4. The Notch-2 expression was decreased up to 90% while that of Notch-3 was at the same level with Notch-1. Conclusions: This research study attempts to find out any possible correlation between the Notch receptors in Colon CSCS. The experimental data indicate that Notch-1 interacts with Notch-2 and Notch-3 by affecting heavily their gene expression. It is therefore necessary to study if the other receptors are capable for EMT and then to find out which factors are involved. Further studies to a greater range of samples need to be performed, in order to use these data at clinical level.
Effect of targeted therapy on circulating tumor cells in patients with metastatic breast cancer.
Authors: Giordano Antonio , Barnato Sara E. , Giuliano Mario , Alvarez Ricardo H. , Cristofanilli Massimo , Hortobagyi Gabriel N. , Valero Vicente , Reuben James M.
Published: February 2017

3

Background: Detection of ≥ 5 circulating tumor cells (CTCs) per 7.5 mL of blood before starting systemic treatment is a strong and independent predictor of worse progression-free survival (PFS) and overall survival (OS) in metastatic breast cancer (MBC) patients. It has been demonstrated that trastuzumab and bevacizumab can target CTCs in the peripheral blood of patients with breast cancer and modify the predictive value of the CTC count. We investigated time-related clinical trend of CTCs according to types of targeted therapy in MBC patients. Methods: Enumeration of CTCs was performed by the CellSearch technology as standard of care for 162 MBC patients receiving targeted therapy (trastuzumab, lapatinib, or bevacizumab) for MBC. The evaluation of CTCs was performed as follows: baseline CTC value defined as assay taken within 30 days before starting therapy, follow-up CTC value defined as the lowest CTC value after starting therapy. We analyzed the effect of treatments on CTC count by Wilcoxon matched pair test and estimated PFS and OS by Kaplan-Meier curves. Results: After a median follow-up of 26 months, 143 of 162 (88%) showed progression of disease and 96 (59%) had expired. Sixty-two (38%) patients have received treatment with trastuzumab, 31 (19%) patients with lapatinib, and 69 (43%) patients with bevacizumab. Among patients receiving anti-HER2 targeted treatments, trastuzumab and lapatinib, and those receiving bevacizumab, no differences in terms of median PFS and OS were observed between patients with CTCs greater or equal than 5 and less than 5. Analyzing separate anti-HER2 targeted treatments, we found trastuzumab decreased the number of CTCs at follow-up (P = 0.0003), whereas lapatinib did not (P = 0.14). However, bevacizumab also decreased the number of CTCs at follow-up (P < 0.0001). Conclusions: In MBC patients treated with targeted therapies, basal CTC count was not predictive of PFS and OS. Trastuzumab and bevacizumab significantly decreased the number of CTCs after starting treatment. Moreover, measuring CTCs during the follow-up of MBC patients may represent a predictive tool for targeted therapy failure.
Computed aided classification of circulating tumor cell and CK+ subclasses.
Authors: Gusyatin Oleg , Tims David , Milutinovic Aladin , Jiang Chunsheng
Published: February 2017

54

Background: Fluorescence microscopy imaging system (OnQView, On-Q-ity, Waltham, MA) in combination with advanced cell capture techniques (OnQChip, On-Q-ity, Waltham, MA) provides necessary sensitivity to detect circulating tumor cells (CTCs) in a blood sample. The detection process involves automatic identification of CTC candidates from the collected imagery followed by CTC subclass identification. Subclass identification process is manual and usually leads to increased sample processing time. Methods: We have developed a fully automated CTC detection and classification system allowing for substantial increase in throughput while maintaining high sensitivity and specificity. Detection is accomplished by a robust segmentation technique. A set of 25 image-based features is automatically computed for each detected candidate. Features include texture measurements, morphology measurements, multichannel intensity and contextual characteristics. All CTC subclasses as well as artifact classes are manually labeled and verified by trained imaging technologists.A hierarchy of Multi-Layer Perceptron Neural Network (MLPNN) classifiers is then trained and used to identify and reject artifacts and to identify CTC subclasses. Results: A total of 27 prostate cancer patients and 33 normal controls with two 3.75ml blood samples per patient were used to validate techniques. Probability of successful artifact rejection was achieved to be 0.78 and probabilities of subsequent successful CTC subclass identification ranged between 0.79 and 0.98 (intact CTCs = 95%; irregular CTCs = 98%; fragmented CTCs = 82%). Conclusions: A fully automated CTC detection and classification system was developed. Testing was conducted with 27 prostate cancer patients and 33 normal controls to yield an artifact rejection probability of 0.78 and CTC subclass identification probabilities of 0.79 to 0.98.
NGS-based targeted RNA sequencing for expression analysis of patients with triple-negative breast cancer using a modulized, 96-gene biomarker panel.
Authors: Lee Byung-In , Oades Kahuku , Vo Lien , Lee Jerry , Landers Mark , Wang Yipeng , Monforte Joseph
Published: February 2017

56

Background: Gene expression profiling has been shown to be effective in analyzing postoperative tumor samples in various cancers. However, in analyzing small specimens such as core biopsies, the limited amount of available material makes multi-gene analyses difficult or impossible. Microarray-based analyses also provide limited dynamic range. We describe the development of targeted RNA-sequencing methodology which combines the power of a universal RNA amplification with NGS for an ultra-deep expression analysis of multiple target genes, enabling <100 ng of sample input for multi-gene analysis in a single tube format. Methods: The gene expression patterns of triple-negative breast cancer FFPE samples were analyzed using a 96-gene breast cancer biomarker panel across three different platforms: Affymetrix Human Gene ST 1.0 microarrays, a pre-developed OncoScore qRT-PCR panel, and targeted RNA-seq. For targeted RNA-seq analysis, the 96-gene panel was amplified using a universal, single-tube “XP-PCR” amplification strategy followed by sequence analysis using the Ion-Torrent Personal Genome Machine. Results: Targeted RNA-seq provided the most sensitivity in terms of detection rates with <100 ng FFPE RNA input and provides unlimited dynamic range with increased sequencing depth. Expression ratio compression issues typically associated with a high number of pre-amplification cycles in standard multiplex-primed methods were not observed here. Low expressing genes, undetectable by qRT-PCR analysis from 1,000 ng input FFPE RNA, were detected and eligible for expression analysis with a significant number of sequencing reads. Alternative transcription/splicing analysis is also possible from sequence analysis of the target transcripts using targeted RNA-seq. Conclusions: By combining universally primed pre-amplification and NGS in multi-gene expression analysis, targeted RNA-seq provides the most sensitive gene expression analysis methodology.
Evaluating RASSF1 promoter methylation and the 16-gene signature as a prognostic marker in hepatoblastoma.
Authors: Eichenmuller Melanie , Kreuder Michaela , Regel Ivonne , Haberle Beate , Muller-Hocker Josef , von Schweinitz Dietrich , Kappler Roland
Published: February 2017

63

Background: Hepatoblastoma (HB) is the most common malignant liver tumor in childhood. Although combination of neoadjuvant chemotherapy and surgery has improved the outcome of standard-risk HB-patients up to 94% the outcome of high-risk HB-patients with metastatic tumors or invasion of large hepatic veins is still dismal and only 60% of these patients survive. Therefore, the identification of biomarkers that could help early detection of high-risk HB-patients and lead to risk-adapted therapies is of utmost importance. Methods: Genomic DNA of tumor and normal liver samples from 21 HB patients was extracted with standard procedures and bisulfite-treated using EpiTect Bisulfite Kit (Qiagen). Methylation status of the Ras association (RalGDS/AF-6) domain family member 1 (RASSF1) gene was analyzed by methylation-specific-PCR. cDNA of tumor and normal liver samples was used to determine the 16-gene expression signature according to Cairo et al. (2008, Cancer Cell) using real-time PCR. Association studies of molecular and clinical data were performed with GraphPad Prism Version 3.0 using two-tailed Chi square test. Results: We identified 9/21 HB cases hypermethylated in the RASSF1 promoter region. Interestingly, RASSF1 promoter methylation was significantly associated with metastases (p=0.0166) and occurrence of this epigenetic marker was associated with a reduced overall survival of patients (p=0.0008). Moreover, we discriminated HB tumors in C1 and C2 subclasses by using the 16-gene signature and correlation of these subtypes with the methylation status of RASSF1 showed a significant association (p=0.0037) for aggressive C2 tumors (8/11), but not C1 tumors (1/10). Conclusions: RASSF1 promoter hypermethylation is a strong prognostic marker for metastasis and worse outcome and correlates with an aggressive C2 HB-tumor profile. Since the detection of tumor-derived methylated DNA in the blood stream of cancer patients is nowadays practical, our data advise RASSF1 methylation assays to be used for risk assessment in HB-patients in the future.
A blood-based gene expression signature of early-stage non-small cell lung cancer.
Authors: Rotunno Melissa , Hu Nan , Su Hua , Wang Chaoyu , Bertazzi Pier Alberto , Caporaso Neil , Taylor Phil R. , Landi Maria Teresa
Published: February 2017

69

Background: Accurate blood-based biomarker for early cancer detection could be an easier and more convenient screening option than monitoring the target organ via tissue or imaging. We recently identified and validated eight genetic biomarkers of early-stage lung adenocarcinoma detectable in both peripheral whole blood (PWB) and lung tissue of smokers. Since biomarkers distinguishing benign disease versus lung malignancy across all cell types are needed in the diagnostic clinical setting, it is important to test the identified biomarkers in other lung cancer histologies, particularly in squamous cell carcinoma (SQCC), the second most common lung cancer histology after adenocarcinoma (AD). Methods: Using Real-Time Quantitative PCR (qRT-PCR), we measured mRNA levels for the eight candidate genes in PWB of 48 randomly sampled stage I SQCC cases, in addition to previously analyzed 82 AD cases and 130 age, sex, and smoking frequency matched healthy controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study. The qRT-PCR data were analyzed using the 2-ΔΔCtmethod to compare SQCC cases with controls. The area under the receiver operating characteristic curve (AUC) was computed to assess the predictive accuracy of the candidate biomarkers in SQCC separately, and in SQCC and AD together. Results: Expression of TGFBR3, RUNX3, TRGC2, TRGV9, TARP, and TSTA3 genes, significantly differentiated SQCC cases versus controls, while ACP1 and VCAN gene expression did not. The eight genes combined discriminated patients with lung cancer from healthy controls with similarly high accuracy in SQCC and overall (AUC = 0.80 ± 0.1). RUNX3 showed the highest single gene accuracy for SQCC (AUC = 0.78). Conclusions: We showed that the previously identified gene expression signature of early-stage lung AD also differentiated early stage SQCC from healthy controls and demonstrated its sensitivity and specificity as a potential diagnostic lung cancer biomarker. Since lung cancer is the most common cause of cancer mortality worldwide and current smokers are at very high risk, our smoking-specific findings, if confirmed and translated into screening approaches, have the potential to impact public health.
Detecting and classifying circulating tumor cell subclasses from On-Q-ity microfluidic chips using a customized imaging platform.
Authors: Jiang Chunsheng , Tims David , Milutinovic Aladin , Gusyatin Oleg , Merdek Keith D. , Sprott Kam M. , Dong Yi , Stocum Michael , Carney Walter P.
Published: February 2017

72

Background: Circulating tumor cells (CTCs) have clinical value in cancer diagnosis, prognosis, and treatment prediction. The On-Q-ity Microfluidic Chip (OnQchip) with a gradient design has the advantage of dual size and affinity capture resulting in increased efficiency. Accurately detecting and classifying these rare captured cells in patient blood however is difficult. We present an imaging platform for accurate and reproducible CTC detection, where identified cells and fragments are further classified into several subclasses that may have separate prognostic utilities. Methods: Whole blood from advanced stage cancer patients and non-diseased controls was processed within 36 hours of collection. Blood was run on OnQchips coated with anti-EpCAM antibody. Captured CTCs and cellular fragments were identified by on-chip immunofluorescence. Chips were imaged at 5X magnification on a rapid automated platform. Cytokeratin positive (CK+) events were identified and sorted via an advanced detection algorithm using a set of spatial and spectral features. Events were further validated and separated into subclasses by trained experts using 10X magnification. Results: Greater than 85% capture efficiency was repeatedly achieved in spiked blood with nearly 100% detection sensitivity and 3% false positive rate following automated sorting of CTC candidates. On a cohort of 27 prostate cancer patients and 33 normal subjects a median of 19 CK+events/7.5 ml blood were detected in cancer patients, compared to a median of only 6 in normals. ROC analysis yielded AUC values of 0.62 to 0.77 for separate subclasses of CTCs. An AUC of nearly 0.80 was achieved by combining two or more subclasses. Conclusions: Preliminary evaluation of this imaging platform shows efficient and reproducible CTC detection in spiked and patient samples. Enumeration using subclasses achieved high sensitivities and specificities in separating cancer patients from normals and therefore, makes this technology feasible for both research and clinical studies. Future clinical studies with large sample sizes will be performed to validate clinical significance of CTC subclasses.
Immunomodulatory effects of bevacizumab in metastatic malignant melanoma.
Authors: Mansfield Aaron Scott , Nevala Wendy Kay , Markovic Svetomir
Published: February 2017

82

Background: Metastatic malignant melanoma is a nearly uniformly fatal disease. Systemic therapy has notable but limited success. Novel therapeutic strategies are urgently needed. To that end, we’ve pursued combinatorial therapeutics using conventional chemotherapy added to an inhibitor of angiogenesis (bevacizumab) with some evidence of clinical benefit. Preliminary analysis of one of our trials suggested a previously unrecognized immunomodulatory effect of bevacizumab when added to chemotherapy in patients with metastatic melanoma, and this may have a potential impact on clinical outcome. Herein we evaluate the immunomodulatory effect of bevacizumab when added to chemotherapy in patients with metastatic melanoma. Methods: We measured levels of peripheral blood mononuclear cell phenotypes in addition to 42 cytokines, chemokines and growth factors in plasma of 55 patients who received albumin-bound paclitaxel and carboplatin (AC) and of 73 patients who received AC with bevacizumab (ACB) on clinical trials N057e and N0775 respectively. The relative percent change in PBMC cell counts and cytokine levels were determined from baseline at their restaging evaluation after two cycles of therapy. The Mann Whitney U test was used to compare responses between the groups. Results: There was a significant increase in CD197+type 1 macrophages in the group that received ACB (35.3%, -11.8-142.7%) compared to AC (-11.6%, -45.9-38.3%; p=0.004). There was a significant decrease in IL-6 in the group that received ACB (-42.4%, -87.7-0.0%) compared to AC (28.4%, -37.4-480%; p=0.0018). Conclusions: The addition of bevacizumab to chemotherapy for the treatment of metastatic melanoma modulates cellular immunity and a pro-inflammatory cytokine. Patients who received bevacizumab had a significant increase in CD197+ type 1 macrophages and a significant decrease in IL-6. Clinical significance of these findings is the subject of ongoing work.
Effect of pericytes on epithelial-to-mesenchymal transition in melanoma.
Authors: Trevino-Villarreal Jose Humberto , Sepulveda Rosalinda , Cotanche Douglas A. , Rogers Rick A.
Published: February 2017

84

Background: Melanoma-associated stroma cells play an important role in supporting cancer cell proliferation, invasion, and dissemination. Increased invasiveness has been observed in cancer cells undergoing epithelial-to-mesenchymal transition (EMT); however, it is unknown whether EMT is facilitated by stroma cells. We showed that pericytes constitute a predominant stroma subpopulation that promotes melanoma growth by interacting with cancer cells. This study investigates the mechanism by which pericytes facilitate melanoma development. Methods: GFP+ pericytes isolated from tumors and adipose tissue were co-cultured in vitro with B16 melanoma cells at a 3:1 ratio. After 4 days, proliferation of B16 cells and pericytes was assessed. Also, co-cultures were labeled for several markers and analyzed by flow cytometry (FC). Tumorigenicity was investigated by isolating B16 cells from co-cultures by FACS sorting and then injected into SCID mice to measure tumor growth. Results: B16 cells induced pericyte differentiation into FAP+ myofibroblasts. However, no change in the pericyte proliferation rate was observed. B16 cells co-cultured with pericytes, and later separated by FACS sorting, displayed faster proliferation rates in vitro, and induced increased tumor growth rates when injected into SCID mice, compared with naive B16 cells. Pericytes increased B16 cell proliferation rate and induced a change in cell morphology, from cobblestone to fibroblast-like colonies. Interaction between B16 cells and pericytes in co-culture increased pericyte production of TGF-β and increased the expression of the stem cell markers SSEA-1, OCT3/4 and CD271 in B16 cells. In addition, cadherin switching, demonstrated by loss of E-cadherin expression and an up-regulation of the mesenchymal markers N-cadherin and vimentin was observed in B16 cells. Conclusions: Pericyte production of TGF-β promotes B16 cell development of EMT, as shown by loss of E-cadherin expression and up-regulation of the mesenchymal markers N-cadherin and vimentin, resulting in an increase in melanoma cell tumorigenicity. These results suggest that therapies targeting stromal pericytes may be a promising approach for melanoma treatment.
Clinical and genomic analysis of metastatic disease progression in a background of biochemical recurrence.
Authors: Crisan Anamaria , Ghadessi Mercedeh , Buerki Christine , Vergara Ismael A. , Thompson Darby J. S. , Erho Nicholas , Sierocinski Thomas , Haddad Zaid , Zimmermann Benedikt , Sosu-Sedzorme Worlanyo , Harko Sebastian , Black Peter C. , Davicioni Elai , Jenkins Robert B.
Published: February 2017

90

Background: Biochemical recurrence (BCR) may be an indicator of metastatic prostate cancer; however, it isn't specific enough to differentiate patients who will experience rapid onset of metastases from those who do not. Such lack of specificity leads to overtreatment of men who will likely never experience metastatic disease in their lifetime. We hypothesize that genomic biomarkers, detectable in primary tumor tissue, may better identify rapidly progressing metastatic prostate cancer. Methods: FFPE prostatectomy specimens (n = 309) from the Mayo Clinic tumor registry were profiled using a high-density expression array. Patients were retrospectively classified into three outcome groups: NED (no evidence of disease recurrence); BCR-only (patients that experienced BCR but no metastatic progression); and MET (metastatic disease confirmed by positive CT or bone scans) and were matched on several criteria for analysis . Uni- and multi-variable analyses between outcome groups were used to analyze clinical and genomic variables (adjusting for adjuvant hormone therapy as a confounding factor). Results: Median follow-up was 16.8 years and MET patients were diagnosed a mean of 3.1 years following BCR. Univariable and multivariable analysis of clinical variables failed to show statistically significant differences between NED and BCR-only outcome groups. Differential expression analysis between NED and BCR-only groups showed no significant differences after false discovery correction. Conversely, 6,277 and 52,020 biomarkers were differentially expressed between MET and the BCR-only and NED groups, respectively. Conclusions: Considering the clinical and genomic results together, patients who experienced rapid metastatic disease were significantly different from both the NED and BCR-only groups. However, no significant differences were identified between the BCR-only and NED outcome groups. These results imply that BCR is not a good surrogate for men who are likely to experience rapid onset of metastatic disease and lethal prostate cancer.
Changes in VEGF-A-serum levels after DEBIRI-TACE in patients with liver metastases of chemorefractory colorectal cancer.
Authors: Pluntke Stefan , Dyrda Sven , Malik Amena , Wilke Hansjochen , Stahl Michael , Koch Jens-Albrecht
Published: February 2017

93

Background: TACE with irinotecan-loaded drug-eluting beads has shown activity in colorectal liver metastases. Among the factors potentially interfering with its effectiveness is a hypothetical neo-angiogenic reaction due to ischemia. Methods: Patients with predominant liver metastases from CRC which were refractory to chemotherapy and documented tumor progression during or shortly after the last chemotherapy, were prospectively treated with irinotecan-loaded drug-eluting beads with a size of 100-300 µm. Therapy was applied by a temporary catheter placed in the liver arteries. Usually each lobe of the liver was according to the recommended DEBIRI treatment algorithm. Each treatment of one liver lobe was performed with 1 vial of the 100-300 µm DC-Beads loaded with 100 mg irinotecan. Blood samples to measure the VEGF serum levels were taken before TACE and at days 7, 14, and 21 after first treatment. Results: Complete blood samples were taken from 15 patients from 2/11 to 2/12. 60% of patients had an increase of the VEGF-A-Level with a median of 107 %, 40% of patients had a decrease of the VEGF-A-Level with a median of – 39% respectively. The relative decrease of the VEGF-A-Levels depends on a prior liver resection (p=0.05), and a significant decrease was found in patients with a prior bevacizumab therapy (p=0.025). A trend to an increase in VEGF-A-Levels was detected in patients with a low count of liver metastases (p=0.087). Conclusions: These findings show different behavior of the VEGF-A-levels after DEBIRI-TACE, suggesting that the occlusion of blood vessels and subsequent ischemia induces neo-angiogenesis due to these growth factors in a subset of 60% of the patients treated with a DEBIRI-TACE. We found a trend for a lower count of liver metastases, prior liver resection and a prior bevacizumab-therapy, respectively influencing the VEGF-A-Level-changes. The trend toward a decrease in patients with a prior bevacizumab therapy may be due to a neoangiogenesis-pathway other than VEGF-mediated. These first results could implicate that antiangiogenic drugs might be effective as an additive therapy to chemoembolization in a subset of patients, e.g., those with no prior bevacizumab therapy.
Preliminary results of a biomarker discovery project for treatment-related brain injury (TRBI) in malignant glioma.
Authors: Yovino Susannah G. , Holdhoff Matthias , Savage William J. , Dulloor Pratima , Grossman Stuart A. , Everett Allen
Published: February 2017

94

Background: Patients with malignant glioma often develop increased enhancement in the tumor bed after chemoradiation (CRT). Current imaging techniques cannot distinguish if these changes are due to recurrent disease or treatment-related brain injury (TRBI). Serum biomarkers could help noninvasively make this distinction. Brain-specific proteins have been used as markers of the severity of other brain injuries including stroke, hypoxia, and traumatic brain injury. We hypothesized that similar changes could be observed following brain CRT and could provide preliminary data supporting biomarker development for TRBI. Methods: Patients receiving concurrent radiation and temozolomide (TMZ) for malignant glioma were eligible. The study was approved by the institutional review board. Informed consent was obtained from all patients. Serum is sampled before CRT, in the last week of CRT, and at 1 month, 6 mos, and 1 year after CRT. Neurologic exams, cognitive testing, and imaging are performed at the same intervals. Serum samples were tested for glial fibrillary acidic protein (GFAP), neurogranin, ICAM-5, B-syn-nuclein, and brain-derived neurotrophic factor (BDNF). Samples were measured in duplicate using an electrochemiluminescent immunoassay. Results: Data are available for the first 7 patients enrolled in this study. All of the tested markers except GFAP were measurable at baseline and all other time points. None of the markers were consistently elevated during the last week of CRT or at any other time point during follow-up. Three patients had resection of suspected recurrent disease. Two had recurrent tumor and 1 had no evidence of disease. No correlation was apparent with the findings at surgery and serum levels of GFAP, neurogranin, ICAM-5, B-synuclein, or BDNF. Conclusions: This study describes a mechanism for identifying a serum protein marker of TRBI. Preliminary results did not identify elevations in any of the selected markers immediately after CRT when signs of TRBI should be apparent or at other points in the clinical course. Testing of additional serum markers is needed to identify a biomarker of TRBI which would provide valuable information for managing high-grade glioma patients.
Development of open-access mock 510(k) regulatory documents on multiplex proteomic technologies.
Authors: Boja Emily , Hiltke Tara , Kinsinger Chris , Mesri Mehdi , Rivers Robert , Rodriguez Henry ,   Office of Cancer Clinical Proteomics Research
Published: February 2017

99

Background: Proteome-based biomarker science is progressing slowly for a variety of factors, including a lack of dialogue early in the discovery/development process with regulatory agencies such as the Food and Drug Administration (FDA). Although high-throughput multiplex proteomic-based technologies have the potential to accurately measure proteins of clinical significance in complex human matrices, regulatory approval for these analytical technologies have not been explored. Methods: To address this gap, investigators from the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) held a forward-thinking workshop, involving clinical laboratories, instrument manufacturers, researchers, and FDA representatives in order to streamline the regulatory approval of protein-based multiplex platforms. Results: Outcomes included a peer-reviewed workshop report published in special proteomics issue of Clinical Chemistry, and first-of-its-kind open access mock 510(k) regulatory documents (based on two most commonly applied quantitative proteomic technologies: multiplex mass spectrometry-based and multiplex affinity-based platforms) as public community resources (also published in Clinical Chemistry). Conclusions: These open-access documents provide a glimpse of the FDA’s perspective of novel approaches to in vitro diagnostics of multiplex protein assays and the process of premarket review. Therefore, these resources should enable others to focus on aspects of the process carefully monitored by the FDA, observe a format that is acceptable to the agency, and understand the iterative nature of review.
Attrition rates, reasons, and predictive factors in supportive/palliative oncology clinical trials at a comprehensive cancer center.
Authors: Glitza Isabella Claudia , Hui David , Bruera Eduardo , Chisholm Gary B.
Published: February 2017

108

Background: Attrition is common among supportive/palliative oncology clinical trials. Few studies have documented the reasons, and predictors for dropout. We aimed to determine the rate, reasons, and factors associated with attrition both before reaching the primary endpoint (PE) and the end of study (EOS). Methods: We conducted a review of all prospective interventional supportive/palliative oncology trials in our department between 1999 to 2011. Patient and study characteristics and attrition data were extracted. Results: 1,214 patients were included in 18 clinical trials. The median age was 60, performance status ≥3 41%, median fatigue 7/10, and median dyspnea 2/10. The attrition rate was 26% (95% confidence interval [CI] 23%-28%) for PE and 44% (95% confidence interval 41%-47%) for EOS. Common reasons for EOS dropout were patient preference (N=93, 17%), symptom burden (N=87, 16%), death (N=45, 8%), and hospital admission (N=43, 8%). At the patient level, EOS attrition was associated with Hispanic race (OR=1.88, 95% CI 1.27-2.78), higher baseline intensity of fatigue (odds ratio [OR]=1.09 per point, 95% CI 1.02-1.16), and dyspnea (OR=1.06, 95% CI 1.02-1.11) in multivariate analysis. At the study level, longer study duration (Spearman correlation 0.59, P=0.01) and outpatient studies (47% vs. 6%, P=0.05) were also associated with higher EOS dropouts. Higher dyspnea, fatigue, and longer study duration were associated with PE attrition. Conclusions: The attrition rate was high amongsupportive/palliative oncology clinical trials, and was associated with various patient characteristics and high baseline symptom burden. These findings have implications for future study designs including eligibility criteria and sample-size calculation.
Improving the quality of abstract reporting for economic analyses in oncology.
Authors: Ho Maria Yi , Chan Kelvin , Peacock Stuart , Cheung Winson Y.
Published: February 2017

109

Background: Increasing costs of cancer drugs underscore the importance of EA, which convey key information about the relative costs and benefits of new interventions. Although guidelines for abstracts exist for phase I, II, and III oncology trials, similar recommendations for EA are lacking. Our objectives were to 1) identify items considered to be essential for EA abstracts; 2) evaluate the quality of EA abstracts submitted to ASCO, ASH, and ISPOR meetings; and 3) propose guidelines for future reporting. Methods: Health economic experts were surveyed and asked to rate each of 24 possible EA elements on a 5-point Likert scale. A scoring system for abstract quality (0=poor and 100=excellent) was devised based on EA elements with an average expert rating ≥ 3.5. All EA abstracts from ASCO (‘97–‘09), ASH (‘04–‘09) and ISPOR (‘97–‘09) were reviewed and assigned a quality score. Results: Of 99 experts surveyed, 50 (51%) responded. Characteristics of respondents: average age = 53; male = 78%; US / Europe / Canada = 54% / 28% / 18%. A total of 216 abstracts were reviewed: ASCO 53%, ASH 14% and ISPOR 33%. Median quality score was 75 (range 48 to 93), but notable deficiencies were observed. For instance, the cost perspective of the EA was reported in only 61% of abstracts, while the time horizon was described in only 47%. An association was seen between year of presentation and overall quality of abstracts (p=0.001), with those from recent years demonstrating better quality scores. There were also disparities in quality scores among EA of different cancer sites (p=0.005). Conclusions: Quality of EA abstracts for oncology has improved over time, but there is room for improvement. Abstracts may be enhanced using guidelines derived from our survey of experts (see table). [Table: see text]
Opportunities for better management of cancer in patients receiving chemotherapy at Aurora Health Care (AHC), a large integrated health system in eastern Wisconsin.
Authors: Amin Paragkumar R. , Frick Jacob C. , Bjegovich-Weidman Marija , Mitchell Dorry , Tougas Jessica
Published: February 2017

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Background: Cancer patients, especially those on chemotherapy, have complex medical histories. They experience a variety of medical problems from their cancer and treatments. This quality improvement study is designed to collect information about chemotherapy related emergency department (ED) visits to estimate ED utilization rates, recognize patterns and evaluate other confounders. The goal is to assess and reduce ED use at AHC through improved care management. Methods: The one-year data analysis includes any patient who received chemotherapy in an outpatient care setting and had a visit to the ED within 60 days of treatment. Chemotherapy was defined by designated CPT codes combined with a primary cancer diagnosis. Every ED visit was matched to all available chemotherapy visits for each patient, retaining the chemotherapy visit nearest in chronology prior to the ED visit. Data Exclusions: (a) Patients who received chemotherapy outside AHC, and then accessed an AHC ED; (b) Patients who received inpatient chemotherapy. Results: There were 28,738 chemotherapy encounters for 4,264 unique patients system-wide. AHC EDs saw 1,669 visits for 1,048 unique patients within 60 days of chemotherapy (24.6%). The top three cancer diagnoses were 21% thoracic; 21% GI; and 16% lymph/hematopoietic. Of the 1,669 ED visits, 35% occurred within seven days and 77% within 30 days of treatment. Almost half (45.6%) of the ED visits occurred during normal office hours. No significant variation was noted by day of week. An initial focus was on the tertiary center which represented 318 (20%) of the 1,669 ED visits. The most common diagnoses for an ED visit were pain (17%) and deconditioning (17%), followed by infection (11%) and respiratory symptoms (11%). Conclusions: This study documents the ED utilization by AHC chemotherapy patients. Unexpectedly, ED use occurred frequently during normal office hours. Most visits were represented by a limited number of cancer diagnoses and presenting complaints. Intervention is planned to reduce ED use after chemotherapy at AHC through improved patient education and by shifting these visits to less expensive venues when possible.
Building success in quality improvement: An analysis of what barriers hinder and what catalysts promote the widespread adoption of quality improvement initiatives.
Authors: Sause William T. , Ruckdeschel John C. , Belnap Thomas W. , Jones Cory , Rowley Braden D.
Published: February 2017

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Background: Quality improvement initiatives and outcomes research activities at Intermountain Healthcare are regularly conducted across 9 clinical domains, including oncology. The purpose of this abstract is to define some of the projects initiated in the primary management of breast cancer and critically analyze the barriers and catalysts allowing for adoption of quality improvement processes. Methods: Between 2003 and 2010 we initiated approximately 15 projects designed to measure and improve quality of care delivery in the treatment of breast cancer. These projects included increasing the use of breast conservation for primary surgical management, reducing axillary dissections for patients with ductal carcinoma in situ and the adaptation of sentinel node biopsy rather than axillary dissection for primary breast cancer. Quality improvement projects involving diagnostic imaging included evaluation of the time from abnormal mammogram to biopsy and the utility of follow-up mammography following breast conservation. Results: Measured variability among practicing clinicians in many instances was substantially reduced or eliminated. Adoption of clinical improvements was most often rapid and noticeable across the entire health care system, however, in some instances quality processes were not completely adopted. The adoption of quality improvement initiatives occurred where obvious clinical benefit could be documented, technical expertise was enhanced and peer supervision existed. Adoption occurred less frequently when financial barriers to adoption existed, clinical benefit was less well defined and peer encouragement was less vigorous. Conclusions: Quality improvement processes across a large healthcare system can be instituted and adopted by a variety of facilities and practicing clinicians. Barriers and catalysts to adoption do exist and this presentation will attempt to document and outline opportunities for success using quality improvement in a large healthcare system.
A quality improvement program within the research setting to improve cancer clinical trial recruitment, accrual, and retention.
Authors: Michaels Margo , Blanchard Judith , Reims Kathleen , Little Kevin , Pokrashevsky Gina
Published: February 2017

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Background: Participation in and access to cancer treatment clinical trials (CCTs) is a key measure for delivery of quality cancer care. Yet adult trial participation in the U.S. remains under 3%, with even lower participation rates among minority groups and people over 65. There is little evidence for best practices in CCT accrual. If institutions are to be evaluated by the access they provide to CCTs, it is critical to identify practical, evidence-based approaches to maximize the efficiency of CCT recruitment, accrual, and retention efforts. The National Cancer Clinical Trials Pilot Breakthrough Collaborative (NCCTBC) is the first-ever national effort to identify such best practices in a real world setting. Methods: The purpose of this pilot was to test the feasibility of applying a proven quality improvement process to CCT accrual. More than 150 evidence-based changes to processes and procedures were identified. Five community oncology practices designed, tested, and implemented changes and reported monthly on 6 core measures to gauge improvement. Teams collaborated to share challenges and were provided coaching and technical assistance by national experts. Results: Teams have tested 35 changes over a 10-month period. Outcomes from the pilot are already showing promising results in identifying those changes that can have the most impact on improving accrual. For example: Improvements in race and ethnicity data capture are helping to address disparities in patient census. Improvements in processes for trial menu selection are leading to new ways of assessing patient populations and finding trials that match them. Documentation of pre-screening and offer rates is identifying system gaps and ways to increase these rates. Conclusions: Results affirm the feasibility of applying a quality improvement framework to address persistently low accrual rates and decrease health disparities among racial and ethnic minorities and the elderly. Based on lessons learned, we are making improvements to the NCCTBC infrastructure and processes and plan to recruit 10 new teams to test further changes.
Erlotinib patterns of use and out-of-pocket (OOP) expenses.
Authors: De Souza Jonas A. , Gleason Patrick P. , Starner Catherine I. , Qiu Yang P.
Published: February 2017

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Background: Erlotinib is an oral oncology drug FDA-approved for advanced pancreatic and non-small cell lung cancers. Data on its patterns of use, pharmacy dispensing, and patient’s OOP are scarce. Methods: Using integrated medical and pharmaceutical data from 4 Blue Cross Blue Shield plans, we retrospectively identified individuals who received erlotinib between 01/2011 and 06/2011. Their claims were further queried for neoplasm ICD9 codes. A new user was defined as having no erlotinib claims filed in the prior 180 days. All new users were followed for 180 days or until their death/disenrollment (censor date). Excess erlotinib tablets were calculated for individuals with a censor date. The cost of unused tablets was estimated considering the standard 30-day, as well as a hypothetical 15-day drug supply. A gap of 45 days without erlotinib, during the follow-up, was defined as non-persistent to erlotinib therapy. The OOP costs were recorded from their first erlotinib claim. Results: Among 3,357,936 members insured, 125 (40 per million) received erlotinib in the period; 102 members (81.6%) had a lung cancer diagnosis, 18 (14.4%) pancreatic cancer, and 5 (4%) had cancers where erlotinib use is not evidence-based; 31 (24.8%) had a total cumulative supply of less than 30 days suggesting one fill and then discontinuation; 60 patients (48%) were new users in the period, 47 with lung cancer and 12 with pancreatic cancer. Among new users, 27 (45%) died or disenrolled; 18 (30%) of these patients had 211 unused tablets, which amounted to $35,237 or $587 per new user. With a hypothetical 15-day drug supply, there would be 45 unused tablets, totaling $7,515 or $125 per new user. Among the 60 new users, individual OOP on their first claim was < $100 for 38 (63.3%) individuals and > $100 for 22 (36.7%). OOP greater than $100 was associated with a 45-day gap in erlotinib therapy over the 6-month period, p=0.047 (21.0% versus 45.5%). Conclusions: A fourth of patients received erlotinib for less than a month, indicating these patients were either at the end of their lives or had intolerable toxicities. In this cohort, higher OOP costs negatively impacted persistence to therapy. For new users, a care management program with a 15-day drug supply could potentially be a cost-saving approach.
Evaluation of inpatient cancer pain management at an academic medical center.
Authors: Mearis Michael , Shega Joseph , Knoebel Randall
Published: February 2017

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Background: The National Comprehensive Cancer Network (NCCN) guidelines on cancer pain management were developed to direct pain assessment and management. The purpose of this study was to assess whether adherence to guidelines was associated with improved outcomes. Methods: One-hundred and nine patients admitted to the inpatient hematology oncology service that received at least one dose of morphine, oxycodone, or hydromorphone were evaluated and allocated into groups based on adherence to the NCCN guidelines. Safety and achievement of analgesia (pain score ≤ 4) at 24-hours after opioid initiation were compared between the two groups. A multivariate analysis was performed to identify predictors of opioid regimens non-adherent to guidelines. Results: Sixty-four percent of patients were initiated on regimens adherent to the NCCN guidelines. 63% of patients initiated on regimens adherent to NCCN guidelines reached the endpoint of analgesia at 24 hours compared to 41% of those who were not (p = 0.028). Adverse events were infrequent (p > 0.5). Opioid tolerance was the variable most predictive of being initiated on regimens non-adherent to guideline recommendations (OR 3.1, 95% confidence interval 1.24-7.82). Conclusions: A significant number of patients presenting with cancer pain are initiated on regimens non-adherent to NCCN guidelines, leading to reduced attainment of adequate analgesia. Opioid tolerant patients are at an increased risk of inadequate analgesia, and should be identified and initiated on proper pain regimens taking home opioid usage into consideration.