bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast cancer treatment and recurrence in octogenarians.
Authors: Harris Adam , McLaughlin Sarah A. , Adkisson Cameron , Bagaria Sanjay Prakash , Gibson Tammeza , Diehl Nancy N. , Pockaj Barbara A. 
Published: February 2017

94 Background: Octogenarian breast cancer (BrCa) patients accept less aggressive BrCa treatment due to decreased life expectancy, increased comorbidities, and high likelihood of death from other causes. Unfortunately little data exist stratifying octogenarian outcomes by disease risk. We sought to characterize treatment and recurrence patterns in patients >80yo. Methods: Retrospective review identified 432 women >80yo treated surgically for stage 0-3 BrCa between 11/99-8/11. We gathered clinicopathologic data and classified patients by disease risk as DCIS only, low risk (<2cm and ER positive and node negative), or high risk (>2cm or ER negative or node positive). We compared recurrence rates and estimated survival by Kaplan-Meier curves. Results: Among the 432 women, disease was found by mammogram in 86%, treated with BCT in 64%, and predominantly ER-positive (87%). We classified patients as having DCIS only (N=61), low risk (N=205), or high risk (N=166) disease. We identified the following deviations from standard treatment guidelines: 68% DCIS BCT and 38% high risk BCT patients did not have radiation therapy, 25% low risk BCT patients had surgery only, 51% low risk patients did not take adjuvant hormonal therapy, and 40% high risk patients had no adjuvant chemo/hormonal therapy. At 5 and 10 years the overall estimated survival was 63% and 31%, respectively. Overall, 19/432 (5%) patients developed recurrence (table 1). Patients needing mastectomy for high risk disease had significantly higher risk of recurrence than high or low risk BCT patients (p=0.02). Of the 19 recurrence patients, 7/19 (37%; 1 DCIS, 1 low risk, 5 high risk) occurred despite standard multimodality treatment, while12 (63%; 3 low risk, 9 high risk) had the initial tumor treated less aggressively due to patient choice (n=9) or medical co-morbidities (n=3). Conclusions: Significant deviations from treatment guidelines occur in women >80yo. Those with high risk disease should be counseled accordingly and encouraged to receive adjuvant treatment as two thirds of women >80yo will live at least 5 years. [Table: see text]
Outcome of rare types of breast cancer in Hispanic woman.
Authors: Campos Gomez Saul , Cruz Marlid , Perez Alvarez Sandra Ileana , Gamboa Dominguez Armando , Soriano Rodriguez Alejandra , Leon Rodriguez Eucario 
Published: February 2017

96 Background: Rarer histological types of breast cancer represent less than 5% of all cases. The identification might be of value in assessing prognosis and predicting response to therapy in a Hispanic population. Methods: A total of 1,400 consecutive woman diagnosed with any type of breast cancer between 1991 and 2010 were identified. Histological types were classified according to World Health Organization criteria and the Armed Forces. Ductal, lobular and mixed ductal/lobular carcinomas and women with missing data were excluded, leaving a total of 60 patients. Tumor grade, vascular invasion, hormonal receptor status, ki-67 labeling index, HER2 overexpression, tumor size and nodal status were recorded and analyzed by histologic type. Survival curves were calculated by histology. Results: A total of 60 patients were classified according histology in order of frequency as mucinous (36.7%), medullary (10%), papillary (8.3%), metaplastic (8.3%), tubulo-lobular (6.7%), tubular (5.0%), metaplastic with epidermoid differentiation (3.3%), signet cell adenocarcinoma (3.3%), apocrine (3.3%), neuroendocrine (3.3%), acinary (1.7%), histiocytoid (1.7%), leiomyosarcome (1.7%), phyllodes (1.7%), high grade sarcoma (1.7%), and mucinous papillary (1.7%). Women with leiomysarcome type had the youngest mean age at diagnosis (27y) followed by mucinous (32y), and high grade sarcoma was the oldest mean age (76yrs). Most of histologists (82%) presented as stage I and II at diagnosis. Only mucinous, medullary and metaplastic presented with advanced disease (4%). With respect to ER/PR status, 36% of mucinous cases and 60% of papillary cases were ER+/PR+, while 50% of medullary cases and 60% of metaplastic cases were ER−/PR−. Only 13% had overexpression of HER2. Compared with OS reported for ductal and lobular carcinoma, median survival was significantly longer 54 months (40.4–67.5) and DFS median 66.1 months (48-82 months). Conclusions: Rare breast carcinomas are a heterogeneous group with more favorable prognosis compared to ductal carcinoma. Though many of these histologic subtypes are quite rare, an accurate and reliable histopathology assessment is crucial in order to determinate treatment, principally to the need for systemic treatment.
A systematic approach to companion diagnostic development: A case study for omacetaxine (OM) for the treatment of chronic myelogenous leukemia (CML).
Authors: Preisig Carol L. 
Published: February 2017

100 Background: In the age of genomically informed medicine, therapeutic development carries with it the imperative to employ genomics in patient selection. Physicians expect genomics-based methods to identify treatments likely to be effective, and identify anomalies likely to cause adverse response for a given patient. Companion diagnostics should support such rule-in and rule-out decisions. We demonstrate a systematic approach to companion diagnostics that leverages new methods in translational bioinformatics and clinical economics. CML therapies have been at the forefront of genomically informed medicine. Early TKI inhibitors targeting the BCR-ABL fusion protein are highly effective. With time, however, they induce resistance-creating mutations in many patients. Omacetixine, a translation inhibitor, was expected to help this CML patient subpopulation which has few therapeutic alternatives. We use this well-characterized drug and publicly available data to demonstrate a prospective approach to companion diagnostics. Methods: We used translational bioinformatics, incorporating pathway, cell line, and patient data to identify biologically plausible biomarkers from which alternative companion diagnostic paths were constructed. These alternatives were analyzed using a modified version of the MIT Stratified Medicine Model to assess the clinical economics of each path. Results: From a systematic look at the biology of the disease, the unique mechanism of action of OM and the clinical need, we identified 3 alternative companion diagnostics for OM. Economic analyses quantified the trade-offs of targeting different subpopulations for the indication, clarifying the impact of biomarker selection based on clinical need or biology. Other analyses have shown that eNPV can be halved or doubled based on strategy choice. Conclusions: Combining applied translational bioinformatics and stratified medicine economics provides an effective approach to companion diagnostic selection. This approach can reduce drug-development cost and clinical risk while providing physicians with better genomics-based methods for clinical decision-making.
Uptake of BRAF and ALK mutation screening versus HER2 overexpression testing.
Authors: Steele Savanna D. , Combest Austin J. , Bonneterre Marie-Edith Anne , Adair Joseph Walt , Barefield Eric , Reitsma Dirk J. 
Published: February 2017

101 Background: Genetic mutation testing in cancer has become standard practice with the advent of targeted therapies such as vemurafenib, crizotinib, and trastuzumab and their associated companion diagnostics. We observed a rapid uptake in BRAF mutation screening in melanoma compared to ALK mutation in NSCLC and HER2 overexpression in breast cancer. Hypothesizing this discrepancy may be related to the overall impact the drugs had on standard of care within their respective indications, we evaluated the relationship between mutation screening frequency and hazard ratios (HRs) from pivotal clinical trials (Shaw Lancet Oncol 2011; Gerber Cancer Cell 2010; Slamon NEJM2001). As a historical control, we also assessed HER2 screening trends. Methods: BRAF, ALK, and HER2 screening data were collected via Ipsos’ Tandem Oncology Monitor, a commercial system in which oncologists in US (500) and EU (783) enter de-identified data on actual prescriptions and mutation screening orders by indication for cancer patients from their practice. Results: Our results show an increase in mutation testing from 42 to 83% for BRAF and from 13 to 34% for ALK from Q1 2011 to Q4 2011. HER2 testing has increased from 56%, Q1 2001, to 95%, Q4 2011. Correlation in uptake in testing vs. PFS/TTP HR endpoints in the US was -0.866. This implies a relationship between outcomes and the propensity for mutation testing. Conclusions: While it is likely that the potential for benefit drives mutation testing, clinicians may also be less likely to screen for an uncommon mutation (~5% of NSCLC patients), or may choose to test only those patients with known predisposing factors. Additionally, oncologists may go through a testing algorithm for NSCLC patients where mutations that are more common are screened first (i.e., EGFR – KRAS – ALK). BRAF testing reached nearly 90% in one year compared to nearly 10 years for HER2 and emphasizes the impact vemurafenib has had on standard of care. ALK mutation screening increased, but not to the same extent as BRAF. These results are encouraging, but also demonstrate that mutation testing in all patients is not yet a reality. [Table: see text]
New tissue aquisition tools for molecular biology.
Authors: Janssens Jaak 
Published: February 2017

102 Background: Histological and biomolecular examinations are a prerequisite to understand diseases, determine optimal individualized care, and identify targets for potential novel therapies. Despite this key role of tissue-based research the act of biopsy still remains troublesome. New direct and frontal biopsy technologies are emerging with the aim to alleviate the bottleneck of inappropriate minimal invasive interventions. Recent clinical trials evaluated the use of macrobiopsies in providing the necessary tissues for molecular biology. Methods: The new instruments for minimal-invasive procedures were evaluated in different single and multicenter clinical trials to generate data on providing enough high-quality tissue for biomolecular research in comparison to diagnostic surgery for various soft tissues and bone lesions throughout the body. In addition, patient comfort and costs data were taken up in the survey. Results: Direct and frontal type macrobiopsy systems give tissue samples between 150 mg and 300 mg of highly specified parts of the diseased area in a way very similar to open surgery. In addition, biopsy procedures are increasingly more patient friendly with appropriate comfort and safety. The new macrobiopsies are less expensive, making molecular biology at reach for every oncological patient, company, and health care provider. Conclusions: Direct and frontal macrobiopsies open new avenues for future bio-banking, pharmacogenomics, biomolecular research, and personalized medicine. It is anticipated that drug discovery and clinical implementation of targeted therapies will be highly facilitated, and that clinical research time for multicenter trials will be significantly shortened.
Decrease in CA-19-9 after neoadjuvant chemoradiation therapy to predict survival in locally advanced pancreatic cancer.
Authors: Singh Jaswinder , Jafri Syed Faisal , Pabla Maninder , Freilich Bradley L. , Cates Joe , Sheldon John M. , Shaeffer David , Connor Michael , Shah Raj , Cope Reed , Rath Niharika , Burt Michael , Mukherjee Srijita , Parikh Unnati , Feeback Jennifer Wanpen 
Published: February 2017

12 Background: Pancreatic adenocarcinoma is among the most lethal of human cancers. Data on overall survival rates of patients treated in the community hospital setting are limited. The purpose of this retrospective data collection study was to assess the CA19-9 change during the neo-adjuvant treatment of locally advanced pancreatic cancer patients and whether this test predicts the overall survival (OS). This study was conducted within a high volume community hospital setting. Methods: Eligibility included cytological or histological evidence of locally advanced, unresectable, and borderline resectable adenocarcinoma of the pancreas, not amenable for surgical resection. Resectability was determined with EUS and CT scan/MRI and was discussed in the multi-disciplinary conference. Patients diagnosed before July 2009 were treated with continuous 5-FU 200mg/m2 for 5 weeks with radiation of 1.8 Gy per daily fraction, for a total dose of 50.4 Gy over 5.5 weeks. Patients diagnosed after July 2009 received gemcitabine 400mg/m2 intravenously (over 60 minutes) beginning on the first day of radiation therapy (before radiation), then weekly thereafter during radiation. Results: Data were abstracted on 64 patients (40 deceased; 24 alive) diagnosed between 6/2005 and 4/2011. The median age was 68 years (range 41-87), and 52% were male. The majority of patients (97%) were diagnosed by endoscopic ultrasound (EUS) with biopsy. At diagnosis, 56 (88%) patients were locally advanced unresectable (without metastasis) or borderline resectable; 49 of these had neoadjuvant treatment, and 13 were later resected. Median OS for all 64 patients was 45.4 weeks (95% CI: 29.6-61.3), with no significant differences in OS by sex of patient (p = 0.210) or smoking history (p = 0.625). Twenty-two patients (34%) had >75% decreases in CA19-9 from baseline; median OS was 89.4 weeks in this group compared to 41.3 weeks in patients with changes in CA19-9 <75% (p = 0.025). Conclusions: This trial demonstrates improved overall survival in patients with locally advanced pancreatic cancer, who had significant decrease in CA19-9 (>75% decreases in CA19-9 from baseline) in response to neo-adjuvant chemotherapy and radiation.
Rapid detection of cancer-related cfc-DNA biomarkers directly from whole blood.
Authors: Heller Michael James , Sonnenberg Avery 
Published: February 2017

14 Background: We have developed a “Sample to Answer” dielectrophoretic (DEP) technology for detecting cancer and other disease-related cfc-DNA biomarkers directly from whole blood. Using AC/DC electric field microarray devices specifically designed for the isolation of cfc-DNA, exosomes and cellular nanoparticulates from blood samples, experiments were carried out by adding about 20ul of the patient blood sample to the DEP microarray device. Methods: The DEP field was applied at 10 kHz and 20 Vp-p for 15 minutes to nine microelectrodes. The microarray was then washed three times with 0.5x PBS with the DEP field on, and finally examined by epifluorescent microscopy. Results: For Chronic Lymphocytic Leukemia (CLL) cancer patient blood samples, results clearly show greenish white fluorescent circles around the nine DEP microelectrodes on the array. This is the SYBR Green fluorescent stained cfc-DNA from the CLL cancer patient blood sample now concentrated in the DEP high field regions. Normal blood samples show little or no fluorescence around the DEP high field microelectrodes. More than fifty CLL samples have been analyzed to date. Conclusions: DEP devices are now being used to collect cfc-DNA from other cancer patient whole blood, plasma and serum samples. Blood sample to PCR is now achieved in less than twenty minutes. Newer work has demonstrated that PCR can be carried out in-situ (in the same device). Thus, the new DEP technology and devices set the stage for “seamless sample to answer” diagnostic systems which will allow a variety of important cancer and other disease biomarkers to be rapidly isolated and analyzed directly from whole blood and other clinical samples.
Screening and Triage Test for Early Detection of Gastric Cancer (STEAD-GC): A noninvasive trial for early detection of gastric cancer.
Authors: Corvalan Alejandro , Maturana Maria Jose , Sanchez Marianela , Calvo Alfonso , Ferreccio Catterina 
Published: February 2017

17 Background: Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. Previously, we identified a potential biomarker for non-invasive detection of GC, the DNA methylation of the promoter region of Reprimo, a p53-dependent G2 arrest mediator candidate (Clin Cancer Res 2008;14:6264-9). Furthermore, we developed a quantitative assay (MethyLight) for a mass screening of GC (DDW2011-1029128). Here we reported the preliminary findings of our ongoing prospective trial STEAD-GC (Screening and Triage test for Early Detection of Gastric Cancer) which is being conducted in Chile, a country with a high mortality rate for GC. Methods: Twenty GC cases (tumor, non-tumor tissues and plasma samples) and 41 symptomatic chronic gastritis cases (29 tissues and 12 pairs of tissue and plasma samples) were evaluated for Reprimo levels by MethyLight after DNA extraction and bisulfite conversion. Results: Concentrations of DNA were similar in both groups (Avg 32.2 ng/ml [range: 8.9-70.8 ng/ml]). The average DNA levels of Reprimo were higher in GC [964,215 copies/ml, 539,593 copies/ml and 80,113 copies/ml in tumor, non-tumor and plasma, respectively] but lower in symptomatic chronic gastritis [137,721 copies/ml and 8,387 copies/ml, tissue and plasma, respectively]. Methods: Twenty GC cases (tumor, non-tumor tissues, and plasma samples) and 41 symptomatic chronic gastritis cases (29 tissues and 12 pairs of tissue and plasma samples) were evaluated for Reprimo levels by MethyLight after DNA extraction and bisulfite conversion. Conclusions: By using our previous cut-off of 15,125 copies/ml, our method correctly identified 10 out of 12 gastritis cases and 16 out of 20 GC cases (p value <0.001). Our data confirms our non-invasive method for early detection of GC may be suitable for a mass screening of GC.
CD98hc expression to predict prognosis in renal cell cancer.
Authors: Prager Gerald , Poettler Marina 
Published: February 2017

26 Background: CD98, a transmembrane protein, has a heteromeric structure, consisting of a heavy subunit (CD98hc) and a light subunit, extracellular linked together via disulfid bounds. A genetic knockout of CD98hc is embryonic lethal and overexpression of CD98hc in somatic cells led to malignant transformation. CD98hc is highly expressed in low differentiated papillary, clear cell and chromophobe RCC, but not in benign tumors. Notably, CD98hc expression directly correlated with grade of differentiation. Methods: To evaluate a potential functional role of CD98hc in renal cancer cell metastatic behavior, we generated a stable low CD98hc clear cell RCC cell line (Caki2) via lentiviral shRNA infection and compared tumor cell behavior with a high expressing mock transfected control. Results: We found that tumor cell behavior such as proliferation (52 ± 3% less 3[H] thymidin – incorporation in low CD98hc/Caki2 cells), cell survival upon anoikis (46% late and 45% early apoptosis in low CD98hc/Caki2 cells compared to high/CD98hc/Caki2 cells with 18% late apoptosis and 64% early apoptosis) and invasion/transmigration (520 ± 67 cells / field after 24h in low CD98hc/ Caki2 cells and 1257 ± 346 cells / field in high CD98hc/Caki2 cells analyzed in a modified boyden chamber) were considerably impaired whenever CD98hc expression was downregulated. To examine the mechanism by which CD98hc affected metastatic tumor cell behavior, we introduced two mutations in a reconstitution (silent mutation). A truncation mutant interfered with integrin interaction and a two point mutations (Cys109Ser and Cys330Ser) mutant affected amino acid transporter activity. Whenever integrin/CD98hc interaction was impaired tumor cell behavior including cell proliferation, cell survival, invasio/transmigration, and cell spreading as well as signal transduction pathways including FAK, c-src, MEK/ERK pathways were significantly compromised resembling the low CD98hc phenotype. Conclusions: For these data we conclude that metastatic tumor cell behavior such as cell survival, invasion and proliferation are dependent on CD98hc expression in renal cancer cells.
A pilot study on the anticancer effects of novel candidate agent COH-SR4 in lung cancer.
Authors: Berz David 
Published: February 2017

28 Background: Non-small cell lung cancer is the leading cause of cancer deaths in the US. The success of current treatment strategies is limited by frequent aberrations in multiple signaling pathways. This includes loss-of-function mutations in the tumor suppressor p53 and activating mutations in multiple growth factor receptors, which converge to activate PI3K/Akt pathway. This calls for the development of novel, more active treatments. We investigated the anti-cancer effects of a novel compound called 1, 3 bis (3, 5-dichlorophenyl) urea (COH-SR4) in lung cancer. Methods: The anticancer effects of COH-SR4 were tested in p53-null H358 lung cancer cells. The antiproliferative effects were investigated in vitro by MTT assay. The bio-availability and antitumor effects were determined in vivo following the administration of 4 mg/kg of COH-SR4 to mice and H358-nu/nu nude mice xenografts. Results: The treatment with COH-SR4 resulted in effective inhibition of the proliferative potential of H358 lung cancer cells [IC50: 23+2 µM], effectively inducing apoptosis. The 4 mg/kg COH-SR4 administration resulted in a free serum concentration of 1+ 0.3 µM. Regression of established H358-xenografts was achieved without any overt toxicity. The histopathology of resected tumor sections revealed an increase in pAMPK (T172) and a decrease in the nuclear proliferative marker Ki 67 and angiogenesis marker CD31. Western blot analyses of resected tumor lysates revealed a decrease in pAkt (S473) and anti-apoptotic protein Bcl2 along with an increase in pAMPK (T172), pro-apoptotic Bax and cleaved PARP levels. In addition, COH-SR4 lead to a decrease in the levels of the cell cycle regulators CDK4 and cyclin B1 as well as the mesenchymal marker vimentin, whilst increasing the epithelial marker E-cadherin. Conclusions: COH-SR4 represents a novel agent for the treatment of non small cell lung cancer. We demonstrated pronounced anti-proliferative and pro-apoptotic activity in vitro and in vivo as well as the capability to promote physiologic, epithelial differentiation. This implies not only therapeutic, but also preventive potential. Further studies are needed to establish the best possible clinical applications of COH-SR4 in lung cancer.