bluuebunny/crossref_metadata_2025_split huggingface dataset:
Removing barriers to clinical research in community hospitals—The Fox Chase Cancer Center Partners experience
Authors: O'Grady M. A. , Cohen S. J. , Keeley P. A. , Sein E. , Miller B. J. , Engstrom P. F. 
Published: March 2020

6614 Background: Although the majority of cancer patients are treated in community hospitals, resources to support community clinical trials are often limited. The Fox Chase Cancer Center Partners (FCCCP) initiative is a large academic and community based oncology program in the Delaware Valley. We hypothesized that a detailed clinical research assessment within the 18 main community cancer research programs of the FCCCP would result in improved clinical trial accrual. Methods: The FCCCP clinical team completed research assessments at 10 affiliated community hospitals during 2004–2006 to evaluate active trials, research nurses and data managers, and research barriers. Institutions were benchmarked for staffing, processes, outreach, and quality improvement. Results were presented to administration at each hospital and impact on research accrual recorded. Results: In 2004, 371 patients were treated on clinical trials at 18 FCCCP community research programs. The median number of data managers, research nurses, and open protocols per site was 0.7, 1.6 and 48 respectively. The most common perceived barriers to accrual by investigators and research staff were regulatory burden, time, and awareness. Recommendations included: improved tumor registry identification of clinical trial candidates, increased staffing, improved web-based outreach, and targeted research affiliations. With regulatory burden a significant research barrier, the following IRB streamlining processes were recommended: NCI Central IRB, for-profit IRBs, IRB reciprocity, and centralized health system IRBs. With implementation of recommendations, 10/18 IRBs have transferred to the NCI-Central IRB for phase III cooperative group studies. The median number of data managers and research nurses per site increased to 1.25 and 1.7 respectively. Although the median number of open trials per site remained at 48, accruals to clinical trials increased to 805, representing a 116% increase. Conclusions: Research assessments are feasible in a large academic-community hospital partnership program and result in best practice recommendations with increased clinical trial accrual. Larger scale implementation of research infrastructure in community oncology programs is warranted. No significant financial relationships to disclose.
Assessment of medication safety in the outpatient setting
Authors: Hoverman J. R. , Shuey K. M. , Richardson D. , Hansen K. , Dugger P. C. 
Published: March 2020

6631 Background: US Oncology provides the pharmacy and drug infusion support for over 700 medical oncologists and hematologists. As such medication safety is a principle concern for the delivery of quality care. As described earlier, a survey of affiliated practices indicated three areas of concern: 1) no uniform reporting mechanism, 2) no standard double check mechanism, and 3) variable inclusion of medication safety procedures and reporting into practice operations. This report describes the first three years experience and proposals for continuing improvement. Methods: An online reporting tool was made available to all practices. 337 practice sites and 35 practice groups were monitored. The first hour of chemotherapy (1HC) was used as the denominator for all occurrence calculations. All reporting was voluntary. Occurrences were rated as to severity, from 1 (error detected before any steps towards completion) to 7 (error resulting in death of the patient). The occurrences were categorized according to process, either in prescribing, calculation of doses, lab or allergy issues, or matching the mixed dose to the order or in administering a mixed dose. In each circumstance a near miss or failure to double check was determined. The total experience for the network was determined for 2004 and 2005 with projected data for 2006. Results: The 1HC numbers used as denominators are: 2004–534,542: 2005–534,606: 2006 –542,000. Occurrences with error rates were: 2004 –1,723 (0.32%), 2005 –2,467 (0.46%), 2006 –2,653 (0.49%). The percent practices participating were 70%, 83% and 75% for 2004, 2005 and 2006 respectively. When considering only reporting practices the occurrence rates were: 2004 –0.45%, 2005–0.55%, 2006–0.65%. The percent occurrences with temporary or permanent harm to the patient dropped from 19% in 2004 to 16% in 2006. A failure to double check was a contributing factor in 57% in 2004, 42% in 2006. Conclusions: An anonymous reporting mechanism resulted in an increase in occurrence reporting. An education program led to fewer failures to double check and a decrease in events causing harm to patients. Next steps include enhanced feedback to practices and the use of an EHR to improve processes. The malpractice environment in some areas inhibits reporting. No significant financial relationships to disclose.
Financial conflicts of interest amongst abstracts, speakers, and planning committee members at the American Society of Clinical Oncology Annual Meeting
Authors: Johnston K. L. , Go R. S. 
Published: March 2020

6635 Background: Financial conflicts of interest (COI) in medical research are an issue under scrutiny due to a potential risk for biased information. The objective of this study was to survey the extent of self-reported financial relationships with industry amongst abstracts, speakers, and planning committee members at the American Society of Clinical Oncology (ASCO) Annual Meeting. Methods: We used the 2005 and 2006 ASCO meeting program books to tally the total number of abstracts (all types), speakers for education (faculty) and abstract sessions (discussant), as well as planning committee (education and scientific) members (data available only for 2006). The number and nature of financial disclosures were noted. COI categories include: employment, consultant role, stock ownership, honoraria, research funding, expert testimony, or other remuneration. Results are presented as an average over 2 years whenever appropriate. Results: There were approximately 4,396 abstracts presented, 678 speakers, and 301 planners each year. COI were reported in 27%, 46.8%, and 67.4% amongst abstracts presented, speakers, and planners, respectively. Within reported COI, the most common were consultant or advisory role (24.6%), honoraria (21.7%), research funding (21.7%), employment (15.2%), and stock ownership (12.6%). Amongst abstracts with COI, 27.4%, 27.1%, and 45.5% reported 1, 2, or ≥ 3 COI, respectively. Amongst speakers and planners with COI, 35.9%, 38.1%, and 26% reported 1, 2, or ≥ 3 COI, respectively. Notably, COI disclosure was not provided by 14.8% of the speakers on time for the program book publication. Conclusions: Financial COI are prevalent amongst presentations and more so amongst speakers and planners at the ASCO annual meeting. A large proportion of speakers failed to provide disclosure on time. The overwhelming majority of the disclosures were COI other than research funding. While the actual impact of COI on the clinical and research practices of oncologists and researchers cannot be determined from our study, the potential for such influence is significant. No significant financial relationships to disclose.
Sustainable improvement in quality indicators in Ontario's surgical oncology program (SOP)
Authors: Stern H. , Fung-Kee-Fung M. , Urbach D. , Smith A. , Brouwers M. , Langer B. 
Published: March 2020

6638 Traditional approaches to quality improvement (QI) have in general utilized performance data against benchmarks, and pay for performance to drive quality. In 2002 the SOP of Ontario, Canada, population 12 million, combined such a QI strategy with philosophical, cultural change aimed on the development of a workforce capable of setting and implementing improvements through communities of practice (CoPs) and application of evidence. The objective was to facilitate implementation of a rigorously developed set of performance indicators, guidelines and standards of care. The most tangible examples of early success include the reduction in operative mortality of pancreatic cancer and the improvement in harvesting lymph nodes in colorectal cancer. A series of indicators, guidelines and standards for colorectal, prostate, thoracic, and hepatobiliary cancers, were developed in partnership with the program in evidence-based care utilizing a rigorous and transparent methodological framework. A value-based purchasing contract (volume-based funding dependent on submission of wait time data). Health service delivery research to identify gaps and evaluate success. CoPs approach to engaging surgeons in solving quality gaps, including opinion leaders, workshops, multidisciplinary teamwork and website tools. Significant improvements have been seen in colorectal and pancreatic caancer indicators. In pancreatic cancer they include a reduction in 30 day operative mortality, in Ontario from a mean of 10.2% in 1988–1996 to 4.5% in 2002–2004, a reduction in numbers of surgeons and hospitals performing pancreatic surgery, and an increase in volumes performed in high volume institutions. In colorectal cancer the compliance with the NCI guideline of 12 lymph nodes harvested increased from 27% in 1997–2000 to 69% in 2005. Oncologists have been engaged in solving system gaps through participation in guideline and standard development and implementation using the CoPs approach. Our experience supports the hypothesis that guidelines, standards and performance indicators, value- based purchasing, and CoPs social influence elements are essential components that can change practice and improve quality in a large jurisdiction cancer system. No significant financial relationships to disclose.
Post-radiation pulmonary epithelial regeneration from transplanted adult stem cells
Authors: Koratkar R. , Lakshmipathy U. , Jiang Y. , Kaur T. , Slater B. , Verfaillie C. M. , Jahagirdar B. N. 
Published: March 2020

7022 Background: Pneumonitis and pulmonary damage are common toxicities of chest radiation therapy (RT), which may be reduced by transplantation of stem cells that differentiate into pulmonary epithelium. Multipotent Adult Progenitor Cells (MAPC) are adult bone marrow (BM) derived cells, which after IV injection in NOD-SCID mice, differentiate into epithelial and hematopoietic tissues (Nature 418:41). Here we tested the ability of mouse (m) MAPC to regenerate epithelia after RT, in Fanconi Anemia C (FAC) mouse model, which inherently has DNA repair defects and is over sensitive to DNA-cross linking agents. Methods: One million, enhanced-green fluorescent protein (eGFP)- expressing, wild-type mMAPC were injected IV in FAC mice, 4–24 hours after 7.5 Gy (followed by mitomycin C {MMC} 0.1mg/kg/week X 4 in a subset) or 11 Gy RT. Non-eGFP expressing BM was co-transplanted after myeloablative (11 Gy) RT. BM, lungs, intestine and liver of the recipients were analyzed 3–10 months post-transplant for eGFP+ cells and epithelial (CK+) or hematopoietic (CD45+) differentiation using flowcytometry (BM) & immunohistochemistry. Control FAC mice were identically treated but without MAPC. Results: MAPC engraftment (>1% eGFP+ cells) was absent in all control mice. Following 7.5 Gy RT, autologous BM recovery occurred in all (N=10) mice and 1 mouse had 2.7% donor-derived hematopoietic (eGFP+/CD45+) cells after MMC. In both recipients of 11Gy RT, analyzed 9–10 months post-transplant, 5–7% of all CD45+ BM cells were donor MAPC-derived. No donor MAPC-derived epithelial cells were seen in the intestine or liver. However, lungs of most recipients had clusters of donor MAPC-derived epithelial cells, estimated to comprise 1–8% of all pulmonary epithelial cells, consistent with homing of MAPC in lungs following IV injection and their epithelial differentiation in the post-radiation, regenerative, pulmonary micro- environment. The highest degree of MAPC-derived pulmonary regeneration was seen following 11Gy RT that was persistent at 10 months post- transplant. Conclusions: Following radiation, IV injected mMAPC differentiate into hematopoietic and pulmonary epithelial cells that persist long-term. MAPC transplantation has the potential for reducing radiation-induced pulmonary toxicity. No significant financial relationships to disclose.
Efficacy of dasatinib in chronic phase chronic myelogenous leukemia patients after imatinib failure according to baseline BCR- ABL mutations
Authors: Hochhaus A. , Branford S. , Radich J. , Mueller M. C. , Shah N. , Erben P. , Ernst T. , Acevedo M. , Nicaise C. , Hughes T. 
Published: March 2020

7023 Background: Dasatinib is an oral, multi-targeted BCR-ABL and SRC kinase inhibitor with preclinical activity against 20/21 imatinib (Im) resistant BCR-ABL mutations. Clinical efficacy was demonstrated in phase I, II, and III studies in patients (pts) with chronic myelogenous leukemia (CML) in all phases of the disease and BCR-ABL positive acute lymphoblastic leukemia (ALL). We sought to establish a relationship between type of BCR-ABL mutations associated with Im resistance and efficacy of dasatinib in chronic phase (CP) CML pts. Methods: Between 10/03 and 03/06, dasatinib was commenced in 1,093 CP-CML pts recruited for three consecutive trials and administered for a median of 8.7 months (range <1–25.9). BCR-ABL mRNA was screened for mutations of amino acids 207–517 by D-HPLC and/or regular sequencing and data are available from 961 cases (88%). ABL polymorphisms K247R and E499E were excluded from analysis. Results: Prior to dasatinib, 75 different BCR-ABL mutations involving 56 amino acids were detected in 18/240 Im intolerant (7.5%) and 324/721 (45%) Im resistant pts. 267 pts showed one, 53 pts two, 16 pts three, and six pts four mutations. In Im resistant pts, response was not different between 370 pts with and 351 pts without baseline mutations: Complete hematologic response (CHR) was achieved in 89% vs 92%; major cytogenetic response (MCR) in 48% vs 52% being complete (CCR) in 38 vs 36%, respectively. Response dynamics were associated with preclinical activity of dasatinib: classifying mutations for IC50 values <2, 2–20 and >1,000nM (T315I), CHR was achieved in 93, 85 and 28%; MCR in 48, 42 and 0%; and CCR in 37, 35 and 0% of cases, respectively. During follow up, new mutations were detected in 30 cases, predominantly T315I (n=10), Y253H/F (n=4), and F317L (n=3). Conclusions: We conclude that dasatinib is capable of inducing hematologic and cytogenetic remissions in a significant proportion of Im resistant pts associated with BCR-ABL mutations, except T315I, but also in pts with BCR-ABL independent causes of resistance. Quality of response depends on the individual type of the mutation which is consistent with preclinical observations. No significant financial relationships to disclose.
Response dynamics to nilotinib depend on the type of BCR-ABL mutations in patients with chronic myelogenous leukemia (CML) after imatinib failure
Authors: Mueller M. C. , Branford S. , Radich J. , Kim D. W. , Martinelli G. , Saglio G. , Hughes T. , Shou Y. , Weitzman A. , Baccarani M. , Hochhaus A. 
Published: March 2020

7024 Background: Nilotinib (AMN107) is an oral, aminopyrimidine-derivative, selective inhibitor of the BCR-ABL tyrosine kinase with improved potency and specificity compared with imatinib. In preclinical models, activity of nilotinib was also demonstrated in 32/33 imatinib- resistant mutant cell lines. We sought to explore the efficacy of nilotinib in vivo according to the type of preexisting BCR-ABL mutations associated with imatinib resistance. Methods: We have investigated peripheral blood samples from 101 chronic phase (CP) and 41 accelerated phase (AP) CML patients (pts) who had been enrolled in a phase II study investigating the efficacy and safety of 400mg nilotinib bid after imatinib failure. Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. The analysis covered amino acids 207–517 of the BCR-ABL tyrosine kinase domain. Results: Prior to nilotinib, 24 different BCR-ABL mutations involving 20 amino acids were detected affecting 44% CP and 61% AP pts. After 6 mo of therapy, complete hematologic response was achieved in 59%, major cytogenetic response (MCR) in 25% being complete (CCR) in 16% of pts with mutations vs 81%, 51% and 33% of pts without mutations, respectively. Response dynamics were associated with preclinical activity of nilotinib: MCR was reached in 10/18 pts with mutations associated with preclinical IC50 to nilotinib of <100nM, 2/9 pts with IC50 of 100–1,000 nM, and 0/4 pts with mutation T315I demonstrating virtual resistance to imatinib and nilotinib. In AP pts, hematologic response was achieved in 56% and 31%, MCR in 24% vs 19%, and CCR in 24% vs 13% of pts with or without mutations, respectively. Conclusions: Nilotinib is efficacious in pts with BCR-ABL mutations, except T315I, as well as in patients with BCR-ABL-independent resistance. Time to response may depend on the individual type of the mutation and correlates with the IC50 to nilotinib. Thus, nilotinib may have an important therapeutic role in imatinib resistance as well as in frontline CML therapy to prevent emergence of resistant clones. [Table: see text]
Dasatinib 140 mg QD compared to 70 mg BID in advanced-phase CML or Ph(+) ALL resistant or intolerant to imatinib: One-year results of CA180–035
Authors: Pasquini R. , Ottmann O. G. , Goh Y. T. , Kim D. , Dorlhiac Llacer P. E. , DiPersio J. F. , Khoury H. J. , Van Tornout J. M. , Damokosh A. , Kantarjian H. M. 
Published: March 2020

7025 Background: Dasatinib, an oral multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases, has been shown to be safe and effective at 70 mg BID in advanced phase CML and Ph(+) ALL resistant or intolerant to imatinib. QD and BID schedules were equipotent in Phase I which led to this dose-optimization study. Methods: In this Phase-III, open-label, prospective study, patients with imatinib-resistant or intolerant advanced phase CML or Ph(+) ALL were randomized to dasatinib 140 mg QD or 70 mg BID. The primary objective compared the major hematologic response (HR) rate between the 2 regimens. Dose escalation was allowed for inadequate response and dose reduction for drug toxicity. Results: From June 2005 through March 2006, 611 patients (56% male) were randomized (median age 55 years). 42% of patients received imatinib at doses >600 mg/d and 37% were treated for >3 y. Response rates, with a median follow-up of 6.5 mo (range <1 to 17 mo), are summarized in the table below. Median durations of HR and progression-free survival were 10.2 and 7.9 mo for the 140-mg QD regimen vs 12.3 and 11.7 mo in the 70-mg BID arm. Drug-related toxicities in 140-mg QD (n=304) vs 70-mg BID (n=305) arms, respectively, listed as all grades (grade 3–4), were: pleural effusion 16% vs 23%, P=0.024 (5% vs 6%); peripheral edema 6% vs 13%, P=0.004 (<1%/1%); pericardial effusion <1% vs 4%, P=0.012 (0% vs 1%); neutropenia 85% vs 87% (65% vs 70%); thrombocytopenia 89% vs 92% (68% vs 70%). Dose reductions (24% vs 36%, P=0.002) and interruptions (47% vs 54%, P=0.105) were required less frequently for the 140-mg QD regimen, whereas dose escalations were more prevalent (33% vs 22%, P=0.005). Conclusions: Dasatinib 140 mg QD shows comparable hematologic and cytogenetic response and a trend for improved tolerability in relation to 70 mg BID. Further follow-up is ongoing to assess the long-term benefit of these two schedules in patients with ABP-CML or Ph(+) ALL; 1-year follow-up will be presented. [Table: see text] [Table: see text]
Phase I/II study of SPC2996, an RNA antagonist of Bcl-2, in patients with advanced chronic lymphocytic leukemia (CLL)
Authors: Tilly H. , Coiffier B. , Michallet A. S. , Radford J. A. , Geisler C. H. , Gadeberg O. , Dalseg A. , Steenken E. J. , Worsaae Dalby L. 
Published: March 2020

7036 Background: SPC2996 is a novel Bcl-2 mRNA antagonist, based on the high affinity RNA analogue, Locked Nucleic Acid (LNA), being developed by Santaris Pharma for the treatment of CLL. Bcl-2 expression is typically high in CLL cells and epidemiologic data suggest that over expression of Bcl-2 is associated with a less favourable outcome in this disease. Methods: The study was an international, multicenter, dose escalating phase I/II study. Included were patients with relapsed or refractory Chronic Lymphocytic Leukemia requiring therapy, with a screening blood sample showing circulating lymphocyte counts of > 5×109/L and expressing the phenotype CD5+CD20+CD23+. Number of patients: 3 at the first two dose levels and 6 at the following levels. The patients received 6 intravenous infusions over a 2 week period with a 6 months follow up period. Assessments included: physical examinations, ECG, CT-scan, flow cytometry, PK, mRNA Bcl-2, clinical chemistry and hematology. Results: A total of 25 patients have been treated with the last patient completing treatment on 29 September 2006. Final data will be presented at ASCO. Preliminary data show a patient population with mean age 63.6 years; 68 % male; median 6.5 years of disease; median 3 prior therapies. Dose escalation was stopped after group E (4 mg/kg/dose) due to 2 DLTs in this group. A decrease in lymphocyte count was observed in 6 out of 6 pts in group E, which started within 24 hrs of the first administration of the investigational drug. Four out of 6 pts showed a maximal reduction in lymphocyte count of = 50%. Lymph node data show a decrease in total lymph node SPD of = 50% in 1 out of 5 pt in group D (2 mg/kg) and 2 out of 4 pts in group E (4 mg/kg/dose). Conclusions: Treatment of CLL patients with SPC2996 gives promising results. In group E all patients responded with an immediate decrease in lymphocyte count after receiving the initial administration of 4 mg/kg. A new investigation has been started to explore other dosing regimens, giving a smaller number of higher doses. [Table: see text]
Increased frequency and suppressive function of CD4+ CD25high regulatory T-cells in acute myeloid leukemia patients
Authors: Boyiadzis M. , Szczepanski M. , Strauss L. , Czystowska M. , Welsh A. , Foon K. , Whiteside T. L. 
Published: March 2020

7054 Background: Regulatory CD4+CD25+ T cells (T reg) are critical regulators of immune tolerance. However, the functional role of T reg in human tumor immunity has been less well studied. The frequency of circulating Treg is increased in patients with solid malignancies. We evaluated the frequency, phenotype and suppressive function of T reg in patients with acute myeloid leukemia (AML). Methods: The frequency and phenotype of CD4+ CD25high T cells were investigated in the peripheral blood of fifteen newly diagnosed AML patients prior to any treatment and fifteen healthy donors by multiparameter flow cytometry. The suppressive function of Treg was evaluated using CFSE-labeled fresh autologous CD4+CD25- T cells activated with an anti-CD3 antibody. Results: The percentage of circulating CD4+ CD25high Treg was higher (p <0.001) in the AML patients (5.2 ± 1.3%, range 0.4 −7%) compared to healthy donors (1.1 ± 0.2%, range 0.8–1.5%). T reg expressing Foxp3, CTLA-4, CD45 RO, CCR4 and Fas receptor (CD95) were significantly elevated in the circulation of AML patients, but GITR expression on Treg was low. Suppression mediated by T reg co-incubated with proliferating autologous responders was also significantly higher (p<0.001) in AML than that mediated by control T reg (75 ± 6% vs 12%± 4%). Conclusions: These results indicate that T reg accumulate in the periphery of patients with AML and have vigorous suppressive functions. This high suppressive activity may impair the host anti-tumor responses and promote leukemogenesis. No significant financial relationships to disclose.