tbuckley/cabot-search huggingface dataset:
Should US doctors embrace electronic health records?
Authors: G Gellert, S Webster, J Gillean, E Melnick, H Kanzaria
Journal: BMJ (2017)

Moving to electronic healthcare infrastructure could help reduce an epidemic of iatrogenic harm, write <b>George A Gellert, S Luke Webster, and John A Gillean</b>. But hasty implementation has led to suboptimal systems that may jeopardize the clinician-patient relationship, say <b>Edward R Melnick and Hemal K Kanzaria</b>
Retrospective study to elucidate a K-ras phenotype in patients with colorectal cancer.
Authors: I. Garrido-Laguna, F. Janku, G. S. Falchook, A. Naing, S. Fu, J. Wheler, A. M. Tsimberidou, D. S. Hong, R. Kurzrock
Journal: Journal of Clinical Oncology (2011)

462 Background: Activating mutations of the K-ras oncogene in colorectal cancer (CRC) are associated with resistance to EGFR antibodies and poor prognosis. Clinical and pathological characteristics associated with K-ras mutations have not been systematically analyzed. Methods: Patients with CRC referred to the phase I program for targeted therapy were analyzed for K-ras mutations using PCR-based DNA sequencing. Patients with mutant K-ras were matched with wild-type (wt) K-ras controls. Multiple clinical and pathological characteristics were analyzed to determine, whether there is a phenotype associated with K-ras mutations. Results: A total of 107 patients with CRC were identified; 58 with K-ras mutations; and 49 with wt K-ras. Patients with K-ras mutations compared with wt K-Ras had more frequently lung metastases (80% vs. 57%, p = 0.013). There was a trend towards higher number of metastatic sites in K-ras mutant patients compared with wt K-ras (3.16 vs. 2.69; p = 0.07). There were no associations between K-ras mutations and gender, age at diagnosis, liver metastases, peritoneal metastases, and lymphatic involvement. The median time from diagnosis to development of metastatic disease was similar in K-ras mutant and K-ras wt patients (194 vs. 196 weeks, p = 0.43). The median survival from diagnosis was also similar in K-ras mutant and K-ras wt patients (254 vs. 223 weeks, p = 0.32). There was no difference in the median survival from diagnosis in patients with different types of K-ras mutations (codon 12, codon 13, and codon 61). Dukes staging was the only statistically significant prognostic factor on multivariate analysis (p &lt; 0.05). Conclusions: K-ras mutations in CRC in comparison with wt K-ras were associated with more frequent lung metastases. K-ras mutations did not impact survival. No significant financial relationships to disclose.
Metastatic esophagogastric adenocarcinomas (EGA): Treatment, prognosis, and pretherapeutic selection options.
Authors: Katja Ott, Susanne Blank, Dirk Jaeger, Wilko Weichert, Leila Sisic, Lars Grenacher, Markus W. Büchler, Florian Lordick
Journal: Journal of Clinical Oncology (2014)

142 Background: Nowadays an increasing number of patients (pts.) with metastatic disease (MD) are discussed in interdisciplinary tumor boards. Preliminary results of the FLOT-3 study suggest a benefit for pts. with limited MD after resection compared to pts. with chemotherapy (CTx) only. Own published data suggest that a subgroup of pts. may benefit from surgery (ESJO, 2013). Primary objective of this retrospective explorative study was the outcome of pts. with resected metastatic EGA and the evaluation of our preoperative prognosis score (PPS) in a larger patients`series. Methods: From 2001-2012 123/800 EGA were classified as cM1 either confirmed intraoperatively as pM1 or confirmed by imaging during follow-up. Response evaluation was performed clinically by endoscopy and CT-scan, histopathologically by the Becker regression score. The PPS for pts. treated with CTx contains grading, clinical response and presumed R-category. Analysis was performed retrospectively from a prospective database. Results: M1 sites (70 AEG, 53 gastric cancer): 27 liver, 43 distant lymph nodes, 16 peritoneum, 10 lung, 6 others, 21 multiple. 11 (9%) were only explored, the rest resected. 49/112 (40%) had multivisceral resections. 63/112 (56%) were completely resected (R0). 72 had preoperative CTx, 51 primary resection. 26 (21%) were classified as clinical responder, 16 (13%) as histopathological responder, 30 (42%) as subgroup with improved prognosis by the PPS. The median survival was 20.0 months (m.). Survival was significantly increased by resection, a complete resection and a preoperative CTx (primary resection: 11m., after CTx: 30 m.)(all p=0.001), but not by multivisceral resection, number or type of metastases or localization of the primary tumor. In pts. who had preoperative CTx, clinical response and the PPS (21 m. versus 66 m., p=0.005) significantly influenced survival. In R0 pts. preoperative CTx (p=0.03), clinical response and the PPS remained prognostic (both p=0.001). Conclusions: A primary resection without preoperative CTx is not appropriate for metastatic EGA. Subgroups of pts. with limited metastatic spread may be selected for surgery using the PPS. Prospective randomized studies are required.
Clinical significance of ABC transporter and DNA excision repair protein expressions in small-cell lung cancer (SCLC) patients
Authors: Y. Kim, G. Ishii, K. Goto, S. Ota, K. Kubota, H. Ohmatsu, S. Niho, K. Yoh, N. Saijo, Y. Nishiwaki, A. Ochiai
Journal: Journal of Clinical Oncology (2008)

8082 Background: Intrinsic or acquired drug resistance is considered to be a major factor limiting the effectiveness of chemotherapy, and both ATP-binding cassette (ABC) transporter and DNA excision repair proteins play a pivotal role in the mechanisms of drug resistance. The aim of this study was to investigate the expression of ABC transporter and DNA excision repair proteins, and to elucidate the clinical significance of their expression in patients with small-cell lung cancer (SCLC) using biopsy specimens. Methods: We investigated expression of the ABC transporter proteins, P-glycoprotein (Pgp), multidrug resistance associated-protein 1 (MRP1), MRP2, MRP3, and breast cancer resistance protein (BCRP), and the DNA excision repair proteins, excision repair cross-complementation group 1 (ERCC1) protein and breast cancer susceptibility gene 1 (BRCA1) protein, in tumor biopsy specimens obtained before chemotherapy from 130 SCLC patients who later received platinum-based combination chemotherapy, and investigated the relationship between their expression and both response and survival. Staining of all of the antibodies was considered positive if >10% of the tumor cells stained. Results: Expression rate of each protein was as follows: Pgp (33%), MRP1 (22%), MRP2 (19%), MRP3 (7%), BCRP (37%), ERCC1 (27%), and BRCA1 (83%). Although overall survival was not (p=0.1427), response (p=0.026) and progression-free survival (PFS; p=0.0103) were significantly associated with BCRP expression. No significant associations were observed between expression of other proteins and either response or survival. Response rate and median PFS were 87% and 5.6 months in BCRP-negative patients, 69% and 4.0 months in BCRP- positive patients, respectively. Conclusions: BCRP expression was significantly predictive of both response and progression-free survival (PFS) in SCLC patients receiving chemotherapy. These findings suggest that BCRP may play a crucial role in drug resistance mechanisms, and that it may serve as an ideal molecular target for the treatment of SCLC. No significant financial relationships to disclose.
RECORD-4 phase 2 trial of second-line everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC): Final OS analysis.
Authors: Thomas Cosgriff, Lin Yang, Anna Alyasova, Dingwei Ye, Andrey Karpenko, Hanzhong Li, Boris Alekseev, Li-ping Xie, Ruben Dario Kowalyszyn, Oleg Karyakin, Yeni Verónica Neron, LaTonya Collins, Thomas Brechenmacher, Chinjune Lin, Liza Morgan, Robert J. Motzer
Journal: Journal of Clinical Oncology (2016)

560 Background: The phase 2 RECORD-4 study assessed EVE in pts with mRCC who progressed after 1 prior anti-VEGF or cytokine (J Clin Oncol 2015;abstr 4518). At primary analysis, median progression-free survival (PFS, primary end point) in the overall population was 7.8 months (95% CI, 5.7-11.0). Here we present results of the final updated primary PFS and final overall survival (OS) analysis. Methods: RECORD-4 enrolled 134 pts with clear cell mRCC into 1 of 3 cohorts based on prior first-line therapy: sunitinib (cohort 1, n=58), other anti-VEGF (cohort 2, n=62: 23 sorafenib, 16 bevacizumab, 13 pazopanib, 10 other), or cytokines (cohort 3, n=14). Pts received EVE 10 mg/d until progression of disease (PD; RECIST, v1.0) or intolerance. Database lock for final analysis was June 26, 2015. Results: Demographics were balanced among cohorts; overall most pts were men (68%) and most had good/intermediate MSKCC prognosis (90%); median age was 59 yrs. Median duration of exposure was 5.8 mo. At the time of final analysis, study discontinuation was primarily due to disease progression (61%). In the overall population, median PFS (95% CI) was 7.4 (5.6-10.5) mo and median OS (95% CI) was 23.8 (17.0-not evaluable [NE]) mo (Table). Overall rate of grade 3 or 4 adverse events (AEs) was 56%. There were 13 on-treatment deaths; primary causes were disease progression, multi-organ failure, and respiratory failure (2.3% each). Conclusions: RECORD-4 final OS analysis supports EVE as a second-line option after sunitinib and other first-line therapies. EVE safety profile was consistent with previous experience. Clinical trial information: NCT01491672. [Table: see text]
Comparative outcomes for 3D conformal versus intensity modulated radiation therapy for esophageal cancer.
Authors: Jessica Freilich, Michael Chuong, Binglin Yue, William J. Fulp, Yazan Asad Abuodeh, Khaldoun Almhanna, Kenneth Meredith, Richard C. Karl, Sarah Hoffe, Ravi Shridhar
Journal: Journal of Clinical Oncology (2013)

76 Background: Emerging data suggests a benefit for using intensity modulated radiation therapy (IMRT) for the management of esophageal cancer. Methods: We retrospectively reviewed patients treated at our institution who received definitive or preoperative chemoradiation with either IMRT or 3D conformal radiation therapy (3DCRT) between October 2000 and January 2012. Kaplan Meier analysis and the Cox proportional hazard model were used to evaluate survival outcomes. Results: We evaluated a total of 232 patients (138 IMRT, 94 3DCRT) who received a median dose of 50.4 Gy (range, 44-64.8) to gross disease. Median follow up for all patients, IMRT patients alone, and 3DCRT patients alone was 18.5 (range, 2.5-124.2), 16.5 (range, 3-59), and 25.9 months (range, 2.5-124.2), respectively. We observed no significant difference based on radiation technique (3DCRT vs. IMRT) with respect to median overall survival (OS) (29 vs. 32 months; p=0.78) or median relapse free survival (RFS) (20 vs. 25 months; p=0.74). On multivariable analysis (MVA), not undergoing surgical resection resulted in worse OS (HR 2.255; p &lt;0.0001) and RFS (HR 1.893; p&lt;0.0001). Superior OS was associated on MVA with stage I/II disease (HR 0.523; p=0.010) and tumor length ≤5 cm (HR 0.567; p=0.006). Improved RFS on MVA was associated with stage I/II disease (HR 0.663; p=0.070), tumor length ≤5 cm (HR 0.611; p=0.011), adenocarcinoma histology (HR 0.532; p=0.055), and 3DCRT(HR 0.524; p=0.002). IMRT was also associated on univariate analysis with a significant decrease in acute weight loss (mean 6%+4.3% vs 9%+7.4%, p=0.0001) and on MVA with a decrease in objective grade ≥ 3 toxicity, defined as any hospitalization, feeding tube, or &gt;20% weight loss (OR 0.51; p=0.050). Conclusions: Our data suggest that while IMRT-based chemoradiation for esophageal cancer does not impact survival there was significantly less toxicity. In the IMRT group there was significant decrease in weight loss and grade ≥3 toxicity compared to 3DCRT.
Oral ibandronate preceded by an intravenous (i.v.) ibandronate loading dose in patients with breast cancer and bone metastases or multiple myeloma: phase III results
Authors: B. Bergström, M. Lichinitser, N. Andreeva, M. Budde, J.-J. Body
Journal: Journal of Clinical Oncology (2005)

8060 Background: Ibandronate is the only single nitrogen-containing bisphosphonate with i.v. and oral formulations. In phase III trials of patients with breast cancer and bone metastases both i.v. and oral ibandronate reduced metastatic bone pain and the risk of skeletal-related events. This 12-week trial determined the response of bone turnover markers to a single rapid infusion of i.v. ibandronate followed by daily oral ibandronate treatment. Safety data from 39 patients have been presented earlier.1 Here we discuss the bone turnover marker data of 34 patients. Methods: Patients with advanced multiple myeloma or breast cancer and ≥1 confirmed lytic or mixed bone lesion received a single 15-minute infusion of i.v. ibandronate 6mg followed by oral ibandronate 50mg once daily (n=34). Eligibility criteria included: ≥18 years of age; provided written informed consent; life expectancy ≥6 months, WHO Performance Status of 0, 1 or 2, and adequate renal function (serum creatinine ≤3.0 mg/dL). Cross-linked C-terminal telopeptide of type I collagen in serum (S-CTX), bone specific alkaline phosphatase (S-bALP), the amino-terminal procollagen propeptides of type I collagen (P1NP), and osteocalcin (OC) were measured. Results: Mean (CI) bone turnover marker percent changes are shown in the Table. Conclusions: The combination of an initial infusion of 6mg ibandronate followed by daily oral treatment results in a rapid decrease of S-CTX, a sensitive marker of bone resorption. Initial i.v. doses followed by oral maintenance treatment are undergoing further testing. 1. Früh M, et al. Ann Oncol 2004;15(Suppl. 3):iii49 (Abstract 187P). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche Roche
Nanoscale proteomic profiling to define diagnostic signatures and biomarkers of therapeutic activity in patients with RCC.
Authors: Alice C. Fan, John Leppert, Joanna E. Liliental, Liwen Xu, Alan E. Thong, Christine Yost, Alia Yaghi, James D. Brooks, Lauren Christine Harshman, Chiara Sabatti, Sandy Srinivas, Dean W. Felsher
Journal: Journal of Clinical Oncology (2013)

432 Background: Novel agents that inhibit kinases in the hypoxia and MTOR pathways can achieve response rates of 30-60% in renal cell carcinoma (RCC); however, protein biomarkers to diagnose RCC and guide treatment have not been identified. Methods: We developed the use of two high-throughput, nanoscale immunoassays to profile hypoxia and downstream signaling in clinical specimens from patients with RCC. These automated technologies minimize errors due to manual variability, and make 96 independent measurements per overnight experiment. We used size-based protein separation (Sally Instrument, Protein Simple) to quantify proteins using antibody-specific detection, normalized to loading control. Next, we used a nano-immunoassay with charge-based separation (NIA, Nanopro1000 Instrument, Protein Simple) to distinguish multiple charged modifications of individual proteins, and measure relative ratios of individual unphosphorylated and phosphorylated isoforms. Results: We first optimized assays for proteins in MAPK, PI3K and STAT pathways, and loading controls, to analyze frozen surgical specimens and ex-vivo fine needle aspirates (FNA’s) performed immediately following nephrectomy. We analyzed more than 200 FNA’s from solid tumors, comparing RCC with paired adjacent non-tumor tissue, and other epithelial malignancies. Basal MAPK signaling of tumors varied across 3 logs of expression. Unique to NIA, we analyzed percent phosphorylation and resolved differences in single phosphorylations. Subtle differences in basal MAPK signaling between tumor calls and adjacent non-tumor tissue can distinguish RCC from other malignancies. Lastly, we prospectively collected and analyzed blood peripheral mononuclear cells from 20 RCC patients before and during treatment with standard targeted therapies. Kinase inhibitors can preferentially inhibit or activate specific protein phospho-isoforms. Conclusions: Our studies demonstrate that rapid and quantitative nanoproteomic profiling in very small amounts of clinical specimen may accelerate translational studies for novel diagnostic and predictive biomarkers.
Identification of a retrovirus in human breast cancer
Authors: J. F. Holland, Y. Wang, S. Mellana, J. Jiang, B. Pogo
Journal: Journal of Clinical Oncology (2005)

548 Background: Breast cancer (BC) in mice is caused by mouse mammary tumor virus (MMTV). We have reported that 38% of BC in American women contain envelope gene sequences, 95% to 99% homologous to the env gene of MMTV implying the presence of a human mammary tumor virus (HMTV) (Cancer Res 55, 5173; 1995). Env positivity is high in regions with high incidence of BC (Western Europe, North Africa, the Americas, Australia) and low in low regions (Asia, Asia Minor) (Clin Cancer Res 10, 5647; 2004). Methods: Polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), and nucleotide sequencing were performed by standard Methods: Env positive breast cancer cells were co-cultured for five days through a micropore barrier with normal breast or peripheral blood mononuclear cells (PBMC). Results: A complete 9.9 kb proviral structure has been identified, 95% homologous to MMTV. Unique differences from MMTV are systematically found in the long terminal repeat (LTR) gene of the HMTV. Normal tissues of the same patient do not contain sequences, thereby excluding endogenous sequences and genetic inheritance as mechanisms of transmission. In six of twelve experiments viral sequences were transferred to allogeneic breast cells and in four of six to allogeneic PBMC as detected by specific monoclonal antibody staining and by PCR. Conclusions: HMTV is an infectious agent, horizontally acquired, that can be transmitted from BC cells in vitro. These data establish that a substantial proportion of human BC is associated with a viral agent, HMTV, closely similar to MMTV, which is known to cause mammary tumors in mice. The correlation of HMTV with human BC incidence is consistent with considerations of causality. No significant financial relationships to disclose.
Treatment costs of cancer trials in a single UK institution.
Authors: P. Corrie, J. Weaver, A. Chhabra, V. Kingshott, S. Bailey, E. Andersen, I. Ingman, R. Harris, G. Follows, T. Eisen
Journal: Journal of Clinical Oncology (2011)

e16532 Background: Since 2001, the UK Department of Health, partnered by key research funders and Pharma, has promoted the conduct of clinical trials in standard healthcare. The proportion of cancer patients entering trials has risen from 3.5% of incident cases in 2001 to 18.1% in 2009. The National Institute for Health Research (NIHR) structure attributes all costs involved as research, treatment or service support, with clear funding streams for each. Research is sponsored by commercial or academic institutions and, after review, may be adopted into the NIHR portfolio. For non-commercial research, treatment costs are the responsibility of the health service and its commissioners. Cancer drug trials are widely perceived to generate excess, undeclared costs to the NHS. We aimed to determine whether these claims could be substantiated. Methods: Addenbrooke’s is an acute general hospital which hosts one of the highest recruiting UK regional cancer research networks (37.2% patients entering trials in 2009/10). The case report forms of all Addenbrooke’s patients entered into cancer trials involving IMPs between 1 January and 31 December 2009 were reviewed. For each recruited patient, the cancer drug(s), exact dose(s) and number of cycles delivered were determined and (for licensed agents) costed, inclusive of relevant taxes. Results: 204 adult patients were entered into 43 trials (32 phase III, 9 phase II, 2 phase I). 31 trials were in the NIHR portfolio (23 academic, 8 commercially sponsored), 12 were commercial, non-portfolio trials. Patients received IMPs which were either unlicensed (13), licensed (2), or licensed drugs in an unlicensed indication (34). When compared with standard of care (SOC), drug cost savings were identified in 19 trials and excess treatment cost in 1 trial. The total value of drug provided free of charge was £517K ($827K), the excess treatment cost was £119 ($189). Compared to SOC, there was an overall drug cost saving of £242K ($385K). Savings were mainly attributable to pharmaceutical company support and trials addressing treatment duration. Conclusions: When public funding is being constrained, research may be restricted in an effort to save cost. This analysis supports the counter argument that clinical research generates cost-savings.
Convergence of Domain Architecture, Structure, and Ligand Affinity in Animal and Plant RNA-Binding Proteins
Authors: Raquel Dias, Austin Manny, Oralia Kolaczkowski, Bryan Kolaczkowski
Journal: Molecular Biology and Evolution (2017)

Reconstruction of ancestral protein sequences using phylogenetic methods is a powerful technique for directly examining the evolution of molecular function. Although ancestral sequence reconstruction (ASR) is itself very efficient, downstream functional, and structural studies necessary to characterize when and how changes in molecular function occurred are often costly and time-consuming, currently limiting ASR studies to examining a relatively small number of discrete functional shifts. As a result, we have very little direct information about how molecular function evolves across large protein families. Here we develop an approach combining ASR with structure and function prediction to efficiently examine the evolution of ligand affinity across a large family of double-stranded RNA binding proteins (DRBs) spanning animals and plants. We find that the characteristic domain architecture of DRBs—consisting of 2–3 tandem double-stranded RNA binding motifs (dsrms)—arose independently in early animal and plant lineages. The affinity with which individual dsrms bind double-stranded RNA appears to have increased and decreased often across both animal and plant phylogenies, primarily through convergent structural mechanisms involving RNA-contact residues within the β1–β2 loop and a small region of α2. These studies provide some of the first direct information about how protein function evolves across large gene families and suggest that changes in molecular function may occur often and unassociated with major phylogenetic events, such as gene or domain duplications.