bluuebunny/crossref_metadata_2025_split huggingface dataset:
Budgetary impact of adding ziv-aflibercept to a United States health plan formulary as a post-oxaliplatin biologic option for patients with metastatic colorectal cancer (mCRC).
Authors: Huff Keith , Drea Edward , Hennessy Daniel , Thompson Stephen F. , Dhawan Ravinder 
Published: February 2017

765 Background: To assess the economic impact of the availability of ziv-aflibercept for patients with mCRC following disease progression after oxaliplatin, a user-adaptable budget impact model was developed for payers, based on use of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) chemotherapy alone or combined with a biologic agent, including ziv-aflibercept. Methods: A Markov-like model simulated transition from progression-free survival (PFS) to progressive disease (PD) and death. Over the model time frame of 1 year, each 90-day cycle adjusted for the probability of patients experiencing PFS, PD or death. Treatment options were FOLFIRI alone or combined with a biologic agent, ziv-aflibercept, bevacizumab, cetuximab or panitumumab. April 2013 United States utilization rates were used as baseline, with biologic agent drug costs as per July 2014 Medicare Part B Drug Average Sales Price. PFS and overall survival were calculated from clinical trial data of biologic agents combined with chemotherapy. Adverse event cost calculations used documented incidence rates and published cost sources. Other costs were for biomarker testing, drug administration/monitoring and death/terminal care. Results: The estimated number of patients receiving FOLFIRI alone or with a biologic agent for mCRC was 57 per million-member health plan. Using April 2013 utilization rates (including ziv-aflibercept at 3.4%), estimated treatment costs were $5.259M, a per-member-per-month (PMPM) cost of $0.0438. Changes in utilization rates of biologic agents, including, for example, ziv-aflibercept at 20.1%, would decrease costs by 2.1% ($108,176) to $5.151M annually, a PMPM decrease of $0.009. The model suggests cost savings primarily due to lower unit costs for ziv-aflibercept and lower death-related costs, rather than decreased adverse event management. Conclusions: The model estimates a PMPM cost saving with increased utilization of biologics, including ziv-aflibercept. Sensitivity analysis of utilization rate changes supports these findings. Including further user-defined scenarios allows plan-specific modeling of budgetary impact.
Unraveling the regulation of a putative cancer stem cell-like population in esophageal cancer.
Authors: Wang Da , Smit Justin , Chiu Roland , Plukker John Theodorus , Coppes Robert P. 
Published: February 2017

77 Background: Despite advances in the treatment of esophageal cancer (EC), most patients face poor outcome. Mounting evidence indicates that cancer stem cells (CSCs) might contribute to the poor prospects. Whereas most cancer cells are sensitive to chemo- and/or radiotherapy (CRT), CSCs are generally resistant and ultimately have the potential to generate a new tumor. Mechanisms regulating EC CSCs are poorly understood and need to be elucidated. Previously, we identified a putative CSC-like population (CD24-/CD44+) in EC cell lines and in esophageal adenocarcinoma (EAC). Here we show that the Hedgehog signaling pathway may regulate CSC-like populations in EC. Methods: To identify up-regulated CSC related genes, qPCR arrays were performed on CD24-/CD44+ OE21 esophageal squamous cell carcinoma (ESCC) and OE33 (EAC). CD24-/CD44+ was compared to CD24+/CD44+ and solid tumors generated from the same cell lines obtained from xenografts. Immunohistochemical (IHC) staining from tumor material of microscopical residual disease (mRD) patients after CRT was compared to surgery alone patients (S). Results: From a panel of 84 CSC related genes, Ptch1 was found to be up-regulated in the OE21 CD24-/CD44+ putative CSC-like population when compared to CD24+/CD44+ population and the solid tumor (2.5 and 3.7 fold, respectively). Furthermore, in OE33 this up-regulation was 1.4 and 1.7 fold. From 6 preselected candidate CRT response markers, CD44 and Sonic Hedgehog (SHH) expression was 55% (p<0.05) and 64% (P<0.005) enhanced in mRD compared to the S group in IHC material. Moreover, SHH expression showed a positive correlation coefficient of 0.551 (P<0.005) with CD44 and 0.512 (P<0.05) with Excision Repair Cross-Complementation group 1 (ERCC1, a nucleotide excision repair gene) in mRD tissue. Conclusions: These findings indicate that the Hedgehog pathway might be involved in regulating EC CSC-like properties. Although requiring further research, an exciting prospect would be the modulation of the Hedgehog pathway in combating CSC-like populations and the potential predictive value of SHH expression on treatment outcome.
Subjective and objective assessment of oxaliplatin-induced peripheral neuropathy.
Authors: Yamada Teppei , Yoshida Yoichiro , Aisu Naoya , Matsuoka Taisuke , Kojima Daibo , Tanimura Syu , Hoshino Seiichiro , Mogi Ai , Koganemaru Tomoko , Oda Mayumi , Fukuda Mahiru , Kiyomi Fumiaki , Noda Keita , Hirata Keiji , Tamura Kazuo , Yamashita Yuichi 
Published: February 2017

772 Background: Oxaliplatin-induced peripheral neuropathy (PN), for which no therapy has been firmly established, is a critical factor that makes the continuation of chemotherapy difficult. Numbness and pain are currently evaluated using subjective methods such as the visual analog scale (VAS). However, because the assessment of pain can greatly vary depending on the mood and physical state of the patient at the time of assessment, it is best to objectively evaluate pain. Therefore, a method for objective assessment is also required to evaluate drugs designed to ameliorate PN. Pain Vision PS-2100 (PV) is an analytical instrument that was designed to quantitatively and objectively assess sense perception and nociception in a patient. Although it is used in the field of anesthesiology, there have been no reports concerning its use for the assessment of oxaliplatin-induced PN. Methods: The present study examined the correlation of subjective and objective assessment results using VAS and PV, respectively, for cases of oxaliplatin-induced PN. Subjects comprised 58 patients with colorectal cancer who underwent chemotherapy at the Fukuoka University. Results: Both VAS and PV assessments of PN were performed 173 times in total, and partial correlation coefficient analysis adjusted by subject and gender. The VAS and PV mean values of PN were 20.5 (0–100) and 27.9 (0–416), respectively. The partial correlation coefficient was 0.258 (p=0.0053). Conclusions: Although both assessments evaluated the same events, no strong correlation was observed between the results and a weak correlation was observed between VAS and PV. These results suggest that because VAS and PV each measure different factors, both subjective and objective assessments of drugs designed to ameliorate oxaliplatin-induced PN are necessary.
“First chemotherapy” or “first local” approach for liver-only synchronic metastasis rectal cancer? A single institution experience.
Authors: Ghanem Ismael , Higuera Gomez Oliver , Mata Alberto , Reyes Jose , Rodriguez Nuria , Castell Jose , Custodio Ana B. , Martinez Virginia , Pastrian Laura Guerra , Feliu Jaime 
Published: February 2017

780 Background: Approximately 10% of patients (p) with rectal cancer have synchronic liver-only metastasis (RCSLM). Although local and systemic therapies are required for this setting, there is not a well defined sequence of treatments. We analyze both, the initial systemic and local approaches at a single institution. Methods: We retrospectively reviewed the medical records of RCSLM p between Jan 2006 and Dec 2013. The “first chemotherapy” (Ch) approach and the “first local” (Lo) approach (surgery or radiotherapy) were reviewed in terms of patient characteristics, tumour features and survival. Results: Forty-five p (26 men) with a median age of 65 years old (35-88) and ECOG 0-1 (91%) were analyzed. Most (84%) of the 32 p with known K-Ras status had wild-type. Twenty-five p (56%) had bilobar liver metastasis (LM) with a median number LM of 3 and a median size of 2.6 cm for the largest lesion. Thirty-four p (75%) were treated with curative intention and, liver and rectal resections (LRR) were performed for 24 p (53%). Bilobar LM (p=0.029), basal CEA>60 (p=0.014), non-LRR (p=0.001) and non-R0 resection of LM (p=0.004) were found to be predictor of poor overall survival (OS). Twenty-five p were treated with Ch and 9 p with Lo approach”. Table 1 shows the characteristics of both groups of p. After a median follow up of 28 months there were 12 events (35%) with a median OS of 55m vs. not reached (p=0.72) for Ch and Lo respectively. Conclusions: Bilobar LM, basal CEA>60, non-LRR and non-R0 resection of LM were predictors of poor OS. The Ch approach was chosen for patients with worse prognostic. However, there were no significant differences in OS between Ch and Lo approaches. Clinical trials are needed to evaluate the best therapy strategy at this setting. [Table: see text]
Weight loss at the first month of palliative chemotherapy to predict survival outcomes in patients with advanced gastric cancer.
Authors: Ock Chan-Young , Oh Do-Youn , Kim Tae-Yong , Lee Kyung-Hun , Han Sae-Won , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue 
Published: February 2017

83 Background: Weight loss during chemotherapy is a significant prognostic factor for poor survival in patients advanced gastric cancer (AGC). However, in most studies, weight loss was measured at the end of chemotherapy, limiting its clinical use. In this study, we evaluated whether weight loss during the first month of chemotherapy could predict survival outcomes in patients with AGC. Methods: We analyzed 719 patients with metastatic or recurrent AGC who were receiving palliative chemotherapy. We calculated initial body mass index (BMIi), percent weight loss after one month of chemotherapy (ΔW1m), percent weight loss after last administration of chemotherapy (ΔWend), and average weight loss per month during chemotherapy (ΔW/m). We correlated these data with overall survival (OS) by receiver operating characteristic (ROC) curves and Kaplan-Meier curves, and performed a subgroup analysis using Cox regression. Results: The probabilities of longer OS had stronger correlations with ΔW/m and ΔW1m than with ΔWend or BMIi. The optimal cutoff values of ΔW/m and ΔW1m for predicting shorter survival were 1% and 3%, respectively. A significant positive correlation between ΔW1m and ΔW/m (r2 = 0.591, p < 0.001) was observed. Patients with ΔW1m more than 3% significantly younger, had worse performance status, more diffuse-type Lauren classification, more HER2-negative pathology, a higher number of involved organs, and more peritoneal seeding at initial presentation. OS of patients with ΔW1m more than 3% were significantly shorter than patients with less weight loss (ΔW1m ≥3%: 9.7, <3%: 16.3 months, p < 0.001). Patients who recovered average weight loss per month after experiencing weight loss at the first month showed prolonged OS compared with patients who did not recovered (ΔW/m < 1%: 21.3, ≥1%: 7.8 months, p < 0.001). Subgroup analysis revealed ΔW1m accompanied poor survival irrespective of other clinical characteristics. Multivariate analysis showed weight loss at the first month of chemotherapy adversely affected OS (p= 0.038). Conclusions: Weight loss at the very first month of palliative chemotherapy could predict unfavorable survival outcomes in AGC.
Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal malignancies.
Authors: Zhang Tian , Boominathan Rengasamy , Foulk Brad , Connelly Mark Carle , Rao Chandra , Kemeny Gabor , Hurwitz Herbert , Garcia-Blanco Mariano A. , Armstrong Andrew J. 
Published: February 2017

84 Background: Multiple GI malignancies including gastric, pancreatic, and colorectal cancers harbor genetic alterations in the MET oncogene. MET amplification is associated with poor prognosis, and c-MET targeted therapies are in development. We aimed to capture and identify c-MET CTCs using a non-invasive, rapid test. Methods: We modified the CELLSEARCH platform by using nanomagnetic particles conjugated to antibodies against the extracellular domain of c-MET to capture c-MET-expressing CTCs. The method was validated by spiking MET-amplified gastric cancer cells, c-MET-overexpressing, nonamplified cancer cells, and MET-negative cancer cells into peripheral blood from healthy volunteers. Peripheral blood samples were obtained from patients (pts) with refractory metastatic gastric, pancreatic, and colorectal cancers, prepared in duplicate, and characterized by immunofluorescence staining for intracellular c-MET-PE, DAPI, and pan-CK-FITC. CD45 + cells were excluded. CTC enumeration with c-MET capture was compared to EpCAM capture. After CTC isolation, MET DNA FISH was performed. Results: The novel c-MET CTC assay was found to be 80% sensitive for MET-amplified cells, 40-80% sensitive for c-MET-overexpressed cells, and 100% specific for c-MET negative cells and in 10 healthy volunteers. In 7/7 pts with metastatic pancreatic and 8/8 pts with metastatic colorectal cancers, we did not capture c-MET CTCs. Of 3 gastric cancer pts tested thus far, one pt had a significant number of c-MET + CTCs, with 52 CTCs and 90 CTCs in each of the duplicate samples, compared to 20 CTCs with EpCAM capture. CTC FISH demonstrated polysomy 7 and METamplification. This pt had HER2 amplification in primary tumor tissue and had progressed on FOLFOX and trastuzumab at the time of enrollment. Conclusions: We have developed a sensitive and specific c-MET CTC assay. c-MET-expressing CTCs can be detected in gastric cancer but not controls or other GI cancers to date. While not detectable in many pts, high levels in one pt support the importance of MET amplification as a resistance mechanism to HER2 therapy, and suggest that this approach may be useful to identify and follow patients who may be candidates for c-MET directed therapies.
Dissecting the invasive potential of esophageal cancer by siRNA library screening.
Authors: Duggan Shane P , Phipps Sinead , Behan Fiona , Garry Catherine , Kelleher Dermot P 
Published: February 2017

86 Background: The low survival for esophageal cancer is in part attributed to its high invasive potential and distant metastasis. In cancer, abnormal cell migration is an essential component of metastasis, and it is reasonable to consider that the conversion between different forms of morphology permits tumor cells to metastasise. Discovering regulators of esophageal cancer morphogenesis may aid in the development of novel targeted therapies that limit metastatic potential. Methods: GOhTRT cells were seeded and treated with siRNA (Human Druggable Genome, Dharmacon) by reverse transfection. Cells were fixed, immunostained for DNA, tubulin and actin and imaged with automated microscope. Cell images were processed using the InCell Analyzer software and the R statistical software systems CellHTS2 and RNAither. The effect of RNAi knockdown on cell viability and cell motility were assessed using MTT cell proliferation assay and scratch wound assay. Results: 127 gene candidates greatly exhibited effects on F-actin and α-tubulin area staining. This list was refined to six high quality candidates (RRM2, ITGB8, GPS1, SPRY1, NOL1 and MYO9B). Silencing of GPS1, MYO9B and SPRY1 increased the rate of migration in a scratch wound assay, with 86.98% ± 3.097%, 75.78% ±5.454% and 72.97% ± 5.463% (p =0.0022) respectively. There was no significant difference in cell viability absorbance values for siGPS1 (0.9037 ± 0.06575; p =0.1905) and siSPRY1 (0.9088 ± 0.09849; p =0.2985), which suggests that the increased rate of wound closure previously seen is by virtue of migratory signalling as oppose to an increase in cell proliferation. Cell viability was decreased considerably in siRRM2 cells (0.2492 ± 0.02798; p <0.0001) and siMYO9B (0.4048 ± 0.04663; p<0.0001) in comparison to siNT cells (1.046 ± 0.07712). Conclusions: In summary, this screen successfully identified high confidence hits associated with cytoskeletal remodelling, some of which are already associated with metastasis in literature and database searches. Further mechanistic studies and gene pathway analysis of candidate genes will provide novel therapeutic targets which can be utilised to block the spread of cancer in patients.
The nucleoside diphosphate kinase-A as a migration suppressor in gastric lymphoma.
Authors: Kim Jae J. , Kim Jin Il 
Published: February 2017

87 Background: The nm23-H1 gene encodes the NDPK-A (nucleoside diphosphate kinase A) that contributes variably to the migration of cancer cell. To investigate the role of the NDPK-A in gastric lymphoma, we examined the expression of NDPK-A in two different cancer cell lines of the same gastric lymphoma patient. Methods: The primary cell line of gastric lymphoma, RF-1, was cultured from the primary gastric lymphoma site, and the other cell line RF-48 was metastasized to the peritoneum of the same patient after 6 months. We have generated stable gastric lymphoma transfectants, pIRES-NDPKA-GFP-neo, that constitutively over-express transfected and vector form of NDPK-A, in addition to a reporter, green fluorescent protein(GFP). The transfected gastric lymphoma cell migration assay was performed 24-well modified chemotaxis chambers with FluroBloc membrane. Results: In regard to the migration rate of the gastric lymphoma cell lines, RF-1 vector was 75.8±7.5%, RF-1 transfected was 54.4±12.3%, RF-48 vector was 84.7±15.4%, RF-48 transfected type was 62.3±9.2%, RF-48 migrated better than RF-1, and the vector type migrated better than the transfected type. NDPK-A was presented more in RF-1 than RF-48, and presented more in the transfected type than the vector type, and concerning the migration rate, RF-48 migrated better than RF-1, and the vector type migrated better than the transfected type. Conclusions: In regard to the migration rate of the gastric lymphoma cell lines, RF-1 vector was 75.8±7.5%, RF-1 transfected was 54.4±12.3%, RF-48 vector was 84.7±15.4%, RF-48 transfected type was 62.3±9.2%, RF-48 migrated better than RF-1, and the vector type migrated better than the transfected type. NDPK-A was presented more in RF-1 than RF-48, and presented more in the transfected type than the vector type, and concerning the migration rate, RF-48 migrated better than RF-1, and the vector type migrated better than the transfected type.
Determination of dihydropyrimidine dehydrogenase (DPYD) gene single-nucleotide polymorphism (SNP) in Mexican patients with locally advanced esophageal carcinoma.
Authors: Ruiz-Garcia Erika , Lopez-Yañez Alicia , Caderillo-Ruiz German , Deneken Connie Zuratzi , Diaz Consuelo , Herrera MaryTere , Moreno Jesus Zamora , López-Basave Horacio Noe , De La Garza Jaime G. , Meneses-Garcia Abelardo , Astudillo Horacio 
Published: February 2017

93 Background: Fluoropyrimidines as 5-fluorouracil (5-FU) and its prodrug capecitabine are chemotherapeutic drugs commonly used in the treatment of gastrointestinal cancer. Patients with deficiency of dihydropyrimidine dehydrogenase enzyme (DPD), which interfere with the pyrimidine metabolism, could be at risk toxicity (mild, severe or lethal) because 80-90% of the administered 5-FU is catabolized by DPD. Methods: Retrospectively, we analyzed the initial paraffin embedded tissue block of 72 Mexican patients with locally advanced esophageal cancer, DPD activity was evaluated through the detection of the seven most relevant DPYD SNPs (IVS14 + 1G>A; 85T>C/85T>T; 2657G>A; 2921A>T; 1679T>G; 2846A>T; and 496A>G). Results: We found that 20.83% (15/72) of our patients had three different polymorphisms: 9.72% (7/72) were positive for SNP 496A>G in heterozygous patients and 4.16% (3/72) in homozygous patients; 4.16% (3/72) were positive for SNP 2657G>A in heterozygous patients; 2.77% (2/72) were positive for SNPs 85T>C and 85T>T in heterozygous patients. The rest of patients 79.10% (57/72) were negative to these SNPs. Conclusions: This is the first study in Mexican population, determining DPYD SNPs. We found that frequency of SNP 85T>C and 85T>T is similar as Oriental race (2-3%), but contrast with Caucasians (0.19%). The SNP 2657G>A whose allelic frequency is unknown, in Mexicans is about 4%; meanwhile, for SNP 496A>G which Caucasian prevalence was reported 0.8%, in our Mexican sample was very high (14%). None of our patients even those with toxicity grade 3-4, were positive to the SNP associated to high toxicity (IVS14 + 1G>A). Because of this heterogeneity, know we are sequencing the complete gen.
FOrMAT: Feasibility of a molecular characterization approach to treatment of patients (pts) with advanced gastrointestinal (GI) tumors.
Authors: Moorcraft Sing Yu , Gonzalez de Castro David , Cunningham David , Walker Brian A , Hulkki Wilson Sanna , Diez Perez Javier , Peckitt Clare , Wotherspoon Andrew , Begum Ruwaida , Valeri Nicola , Gerlinger Marco , Braconi Chiara , Rao Sheela , Watkins David , Chau Ian , Starling Naureen 
Published: February 2017

TPS227 Background: The molecular characteristics of a pt’s tumour can determine their suitability for treatment with targeted drugs. Several molecular alterations are only seen in a small percentage of pts and so it is often necessary to screen many pts to identify those who may benefit from targeted therapies. Testing each pt for multiple biomarkers is also increasingly important. Targeted next generation sequencing (NGS) can rapidly interrogate tumours for actionable genetic aberrations and therefore facilitate a personalised treatment approach. FOrMAT aims to assess the feasibility of delivering validated NGS results (to accredited standards) in a clinically meaningful timeframe and how this could be adopted into routine clinical practice in the United Kingdom’s National Health Service. Methods: FOrMAT (ClinicalTrials.gov identifier NCT02112357) is a single-centre translational study in pts with locally advanced/metastatic GI tumours (including gastroesophageal, pancreatic, biliary tract and colorectal). Targeted capture sequencing is performed on archival or fresh biopsy samples to detect mutations, copy number variations and translocations in 45 genes which have prognostic, predictive or pharmacogenomic significance or are targets in current/upcoming clinical trials. Results are discussed by a Sequencing Tumour Board to establish if a pt is potentially suitable for a targeted therapy (e.g. within another clinical trial, as part of standard of care or via a compassionate access program). Changes to pts’ treatment are not mandated. The primary endpoint is the percentage of pts in whom a currently actionable molecular alteration was detected. Secondary endpoints include evaluation of the time required to obtain sequencing results. Blood samples will be collected at baseline and at the time of each tumour response assessment for analysis of molecular markers, including ctDNA and microRNA. Pts may also consent to optional biopsies for exploratory research into tumour heterogeneity and development of pt-derived organoids. The study aims to recruit 200 pts over 2 years. Recruitment started in February 2014 and to date 56 pts have been recruited. Clinical trial information: NCT02112357.