bluuebunny/crossref_metadata_2025_split huggingface dataset:
Economic evaluations of sunitinib versus interferon-alfa (IFN-α) in first-line metastatic renal cell carcinoma (mRCC)
Authors: Remák E. , Mullins C. D. , Akobundu E. , Charbonneau C. , Woodruff K. 
Published: March 2020

6607 Background: A randomized phase III trial of sunitinib vs. IFN-a as first-line therapy for patients with mRCC is ongoing. An interim analysis of this study demonstrated superiority for the primary endpoint, progression-free survival (PFS), in the sunitinib arm vs. the IFN-a arm (median PFS = 11 months [95% CI: 10–12] vs. 4 months [95% CI: 4–6]; P<0.000001). Because of the clinical significance of these results, the objective of this study was to demonstrate the economic value of sunitinib vs. IFN-a in this setting from a US third-party payer perspective. Methods: Two Markov models with a 5- and 10-year time horizon were developed to evaluate the cost- effectiveness of sunitinib vs. IFN-a. The models projected survival and costs in 6-week cycles based on extrapolation of the trial survival data. Model 1 looked at first-line treatment followed by palliative care only, while Model 2 incorporated second-line treatment. Effectiveness was measured in terms of progression-free months (PFM) in Model 1, and life-years (LY) gained and quality adjusted life-years (QALY) gained in Model 2. Resource utilization included drugs, tests, scans, monitoring, physician visits, hospitalizations and treatment of adverse events. Costs and survival benefits were discounted annually at 3% and 5% in Model 1 and 2, respectively. All costs were adjusted to 2006 US dollars. Scenario and probabilistic sensitivity analyses were conducted. Results: Projected PFS and overall survival were longer for sunitinib than for IFN-a. The incremental cost-effectiveness ratios of sunitinib vs. IFN-a over 5- and 10-years were $7,769 and $7,782/PFM, respectively, in Model 1. Model 2 results at 10 years were $67,215/LY and $52,593/QALY gained. The key drivers of the model results were survival and sunitinib drug costs. Both models were robust in the tested scenarios. Conclusions: Both analyses found that sunitinib is a cost-effective alternative to IFN-a as first-line treatment in mRCC, with cost-effectiveness ratios within the established threshold that society is willing to pay for health benefits (i.e. $50,000–100,000/LY or QALY). No significant financial relationships to disclose.
Quality of reports related to survival events in randomized clinical trials: A review of recent cancer trials published in eight major journals
Authors: Mathoulin-Pelissier S. , Gourgou-Bourgade S. , Bonnetain F. , Kramar A. 
Published: March 2020

6611 Background: About ten years ago, Altman pointed the low quality of survival analyses published in cancer journals. Despite the development of Consort statement, the lack of quality standards remained in the reports of randomized clinical trials (RCT).The aim of this study was to evaluate quality of definitions and reports of survival endpoints in recent cancer RCTs. Methods: A computerized search in Medline databases identified 274 cancer RCTs published from January 2004 to December 2004 in 4 general medical journals (BMJ, JAMA, Lancet, NEJM) and 4 clinical oncology journals (BJC, Cancer, JCO, JNCI). Eligible papers were these that reported primary analyses of RCT with survival endpoints. Three methodologists have reviewed and scored 1/3 of papers according to 7 key points: prevalence of adequate definition of survival end-points (time to origin, survival events, censures) and relevant information about their analyses (Kaplan-meier method, confidence interval, number of events, patients at risk). Reliability of scoring was checked among a random subsample of 30 papers with an independent biostatistician (kappa coefficient). Results: Following eligibility screening, 149 papers were not included. Among the 125 selected papers, 104 trials were of phase III (83%) and 98 publications (78%) were obtained from the 4 oncology journals. Among these RCTs, a total of 268 survivals endpoints were recorded and overall survival (OS) was the most frequent outcome (118 terms, 44%). Survival terms were adequately defined in 116 endpoints (43%) and OS was most frequent adequately defined (49%). Accurate information about analysis was found in 51 endpoints (19%). The less adequate information was patient's number at risk (55%). Finally, according to the 7 key methodological points, optimal quality of report was found in 19 of the endpoints (7 %) i.e.6 articles (kappa value: 0.65). Conclusions: Majority of published papers failed to provide an adequate definition and analysis reports of survival endpoints. Finally survival definitions add another source of variability actually not controlled. Readers should critically pay attention to the reported definitions since the lack of these elements may lead to misinterpretation of the RCT results. No significant financial relationships to disclose.
Prospective assessment of chemotherapy-induced neurotoxicity in breast cancer (HOR 02) and questionnaire survey of physicians’ perspectives
Authors: Kuroi K. , Shimozuma K. , Ohashi Y. , Takeuchi A. , Aranishi T. , Morita S. , Ohsumi S. , Makino H. , Watanabe T. , Hausheer F. H. 
Published: March 2020

6619 Background: Physician-based instruments (e.g., NCI-CTC) are widely used to assess chemotherapy-induced peripheral neuropathy (CIPN). However, current evidence suggests that physician-based assessments under-report the incidence and severity of CIPN. To overcome this limitation, a patient-based questionnaire, patient neurotoxicity questionnaire (PNQ) was developed, and a phase III randomized adjuvant trial of breast cancer (N-SAS BC 02; AC followed by PAC/DOC vs. PAC/DOC alone) has demonstrated that PNQ is reliable and sensitive and responsive instrument to assess CIPN (Shimozuma et al., SABCS 2004; #6037). We prospectively evaluated the reliability and sensitivity of PNQ in advanced or metastatic breast cancer treated by weekly administration of paclitaxel. Moreover, a questionnaire survey was conducted on physician perspectives regarding the assessment of CPIN in Japan. Methods: CIPN and QOL were prospectively assessed in thirty-five patients with advanced or metastatic breast cancer who received weekly paclitaxel (80–100 mg/m2/w). PNQ and FACT-Ntx subscale were compared to NCI-CTC. Assessments were conducted at baseline, 8 wk, 16 wk after starting treatments. A questionnaire was sent to physician who participated in N-SAS BC 02 to clarify their perspectives regarding the CPIN. Results: Average response rate of the instruments was 89%. Sensory PNQ scores correlated with sensory FACT-Ntx scores (r=0.51), and NCI-CTC scores (r=0.58). NCI-CTC scores mainly distributed between 0 and 1, while PNQ scores widely distributed. Follow-up study revealed that sensory CIPN assessed by PNQ appeared to be sensitive as compared to NCI-CTC. In clinician survey, 47 out of 61 physicians (77%) responded, and majority of them considered neurosensory symptoms as diagnostic hallmark for CIPN. However, for the justification for treatment delay, dose modification, or treatment cessation, most laid weight on functional impairment in patients with CIPN. Most (80%) rated PNQ is helpful in management of patients at risk for CIPN. Conclusions: This study confirmed that physicians tended to underestimate CIPN, and PNQ was a more reliable and valid instrument to assess CIPN with high acceptability in physicians. [Table: see text]
Conflicts of interest among articles published in the Journal of Clinical Oncology
Authors: George B. , Simhan S. , Lee J. A. , Mathiason M. A. , Go R. S. 
Published: March 2020

6633 Background: The integrity of scientific and clinical research is dependent on the avoidance of conflicts of interest (COI). Hence, the American Society of Clinical Oncology (ASCO) has implemented a COI policy pertaining to articles published in the Journal of Clinical Oncology (JCO). In this study, we examined the prevalence and nature of COI among scientific articles published in JCO. Methods: We reviewed original articles, review articles and ASCO special articles published in JCO from August 2005 to January 2006. COI was categorized into employment/leadership position, consultancy, stock ownership, honoraria, research funding, expert testimonials and other remuneration. Results: Out of a total of 514 articles reviewed, original articles, review articles and ASCO special articles comprised 88.3%, 11.1% and 0.06% respectively. Overall 34.8% of the articles reported at least 1 COI. Among articles with COI, 21.8%, 27.4% and 50.8% reported 1, 2 and 3 or more COI, respectively. Consultancy (64.8%) was the most common COI, followed by honoraria (64.2%), research funds (58.7%), employment/leadership (40.2%), stock ownership (39.7%), testimonials (11.2%) and other remuneration (10.1%). COI was reported in 58.3% of clinical trials compared to 24.6% in other articles (P = 0.001). Out of the total of 4,944 authors, 14.0% reported a COI. Among authors with COI, 47.9%, 38.2% and 13.9% reported 1, 2 and 3 or more COI, respectively. The prevalence of COI among articles originating from North America, Europe and Asia/Australia were 38.2%, 31.8% and 13.8%, respectively (P = 0.020). Conclusions: COI were widely prevalent in articles published in JCO. Clinical trials had a higher prevalence of COI compared to other scientific articles. The prevalence of COI was equally high in articles originating from North America and Europe, but much lower in articles from Asia/Australia. The majority of reported COI were unrelated to research funds. No significant financial relationships to disclose.
Hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL): 25-year experience at the University of Minnesota
Authors: Tomblyn M. B. , DeFor T. E. , MacMillan M. , Higgins P. D. , Dusenbery K. E. , Weisdorf D. J. 
Published: March 2020

7001 Background: HCT is frequently used for management of ALL. Methods: We reviewed the records of 623 consecutive patients (63% male, median age 13 years) treated with myeloablative TBI-containing conditioning and either autologous or allogeneic transplantation between 1980 and 2005 at the University of Minnesota. Donor types were autologous (34%), related (45%), unrelated (16%) or cord (11%). Disease status at transplant was CR1 (24%), CR2 (50%), CR3 (18%) and relapse (8%). Univariate and multivariate analyses were performed for clinical endpoints including overall survival (OS), progression free survival (PFS), relapse, treatment-related mortality (TRM), and Grades II-IV acute and chronic graft versus host disease (GVHD). Results: Median follow-up among survivors was 8.3 years (1.0–22.9). The estimated incidence of acute GVHD was 42% and chronic GVHD was 16%. At 5 years, OS, PFS, and relapse were estimated at 29%, 26%, and 43% respectively. 5-year OS for each group: autologous (17%, 12–22%), related (35%, 29–41%), matched unrelated (42%, 29–55%), mismatched unrelated (21%, 11–33%), and cord blood (46%, 33–59%). TRM at 2 years was 28%. Multivariate analysis for OS, PFS, relapse and TRM for donor type is shown ( Table ). Acute GVHD was more frequent with unrelated donors (p<0.01) but similar for related donors and cords. Presence of acute GVHD led to improved PFS (RR 0.6, 0.4–0.7, p<0.01) and decreased relapse (RR 0.5, 0.3–0.8, p<0.01) at 1 year. 5-year OS improved significantly from 1980–1984 (28%, 20–37%) to 2000–2005 (45%, 33–56%), p < 0.01. Conclusions: Allogeneic HCT results in a durable PFS, although TRM is increased with unrelated mismatched donors. As expected, autologous HCT results in increased relapse rates. Despite significant mismatch, umbilical cord HCT led to similar OS, PFS, relapse, TRM and chronic GVHD compared to related donor HCT. Development of acute GVHD decreases relapse, resulting in improved PFS. No significant financial relationships to disclose. [Table: see text]
Long-term survival of patients with AML in remission after reduced intensity allogeneic hematopoietic stem cell transplantation (RISCT)
Authors: Popat U. R. , de Lima M. , Anderlini P. , Andersson B. , Couriel D. , Hosing C. , Kebriaei P. , Qazilbash M. , Alousi A. , Champlin R. , Giralt S. 
Published: March 2020

7002 Background: RISCT was developed to harness graft versus leukemia effect to treat older patients (pts) and pts with comorbidities. Limited data are available on long term outcome of pts with high risk AML treated in complete remission (CR), a group most likely to benefit from this approach. Methods: Thirty six consecutive pts with AML in CR, treated between 1999 and 2006 with Fludarabine 120–125 mg/m2 and Melphalan 100–140 mg/m2 are included. Pts were not eligible for myeloablative transplantation because of age or comorbidity. Tacrolimus and Methotrexate were used as GVHD prophylaxis. Additionally pts receiving stem cells from an unrelated donor received rabbit antithymocyte globulin. Results: There were 24 males and 12 females with a median age of 57 (range 21–71). Eighteen(50%) pts had secondary AML. Thirty(83%) pts were in first CR and 6(17%) in second CR. Cytogenetic risk groups were as follows: 2 good risk (in CR2), 22 intermediate risk(61%), and 10(28%) poor risk. Source of stem cells was peripheral blood in 18 pts (50%) and bone marrow in 18 pts (50%). Donors were siblings in 21(58%) pts and unrelated in 15 (42%)pts. Hematopoietic cell transplant specific comorbidity score of 3 or higher was present in 26 pts (72%). All pts engrafted achieving full donor chimerism by day 30 with median time to neutrophil engraftment of 12.5 days (8–19 days). Cumulative incidence of grade 2–4 acute graft versus host disease (GVHD), grade 3–4 GVHD and chronic GVHD was 25% (95% CI; 14%–44%), 11% (95% CI; 4%–28%), and 63% (95% CI; 47%–84%) respectively. Cumulative incidence of nonrelapse mortality was 19% (95% CI; 8%–41%). With a median follow up of 852 days, 3 year overall and disease free survival is 75% (SE 9%) and 63% (SE 10%) respectively. Comorbidity scores didnot impact outcome. Conclusions: Reduced intensity allogeneic transplantation with Fludarabine and Melphalan conditioning produces durable long term remission in pts with high risk AML in complete remission. These results in older pts and/or pts with comorbidities are comparable to published results in younger pts receiving myeloablative transplantation. Comorbidity scores by themselves should not be used to exclude patients from receiving transplant. No significant financial relationships to disclose.
MicroRNA (miR) expression signatures in molecular subsets of cytogenetically normal (CN) acute myeloid leukemia (AML): A Cancer and Leukemia Group B (CALGB) study
Authors: Radmacher M. D. , Marcucci G. , Paschka P. , Vukosavljevic T. , Whitman S. P. , Ruppert A. S. , Mrózek K. , Kolitz J. E. , Larson R. A. , Bloomfield C. D. 
Published: March 2020

7010 Background: Aberrantly expressed miRs contribute to malignant transformation by hybridizing to specific mRNA targets and suppressing their translation into proteins. In CN AML, the largest cytogenetic AML subset, several molecular markers are associated with favorable [e.g., NPM1 mutation (mutNPM1)] or unfavorable [e.g., FLT3 internal tandem duplication (ITD) or high ERG expression (↑ERG)] outcome. We explored if differentially expressed miRs are associated with the aforementioned markers. If so, this might indicate a role for miRs in leukemogenesis and prognosis in CN AML. Methods: Diagnostic samples from 100 adults <60 years, treated on CALGB 19808 (Blood 2005; 106:122a), were analyzed on miR microarrays. Among 305 miR probes, we identified differentially expressed miRs (P<0.005) when comparing patients (pts) with or without mutNPM1, FLT3 ITD or ↑ERG. Results: Nine miRs were differentially expressed in FLT3 ITD compared with FLT3 wild-type pts. miR 155, previously reported in aggressive cancers, was upregulated in FLT3 ITD pts. Strong signatures were associated with mutNPM1 (42 miR probes) and ↑ERG groups (54 miR probes). Consistent with their better prognosis, pts with mutNPM1 had upregulated miRs 10 and 196 targeting HOX genes, miRs 15 and 16 targeting BCL2 and let-7 targeting RAS. Consistent with a more aggressive phenotype, ↑ERG pts had downregulation of let-7 and miR 15 and 16 but also miRs 30, 103, and 24 which target, respectively, CDK6, FBXW11 and MAPK14, all involved in cell cycle regulation and proliferation. Four miRs were associated with event free survival (EFS); all were also associated with ↑ERG. High expression of miRs 124, 129, and 194 was significantly associated with worse EFS and ↑ERG. Low expression of miR 181 was associated with worse EFS and ↑ERG. Notably, downregulation of mir 181 has also been reported in pts with aggressive B-cell chronic lymphocytic leukemia. Conclusions: We report the first miR expression signatures within molecular subsets of CN AML. Further study is warranted to elucidate mechanisms by which miRs contribute to leukemogenesis and impact prognosis, and to determine whether miRs can be therapeutically targeted. No significant financial relationships to disclose.
Outcome prediction in adult core binding factor (CBF) acute myeloid leukemia (AML) with gene expression profiling: A Cancer and Leukemia Group B (CALGB) study
Authors: Paschka P. , Radmacher M. D. , Marcucci G. , Ruppert A. S. , Vukosavljevic T. , Whitman S. P. , Mrózek K. , Liu C. , Larson R. A. , Bloomfield C. D. 
Published: March 2020

7011 Background: In CBF AML with t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) [abbreviated inv(16)], KIT mutations (mutKIT) and, in inv(16), trisomy 22 predict outcome and may guide the development of novel risk-adapted therapies. However, prognosis of patients (pts) lacking the aforementioned markers is less clear. Therefore, we profiled gene expression in t(8;21) (n=22) or sole inv(16) (n=25) pts who lacked mutKIT to identify signatures predictive of outcome. All pts were treated on CALGB trials incorporating consolidation therapy with multiple courses of higher dose cytarabine. Methods: Gene expression profiling was performed using Affymetrix U133 plus 2.0 arrays on diagnostic samples. As differences in gene expression distinguished all t(8;21) pts from all inv(16) pts, indicating two different biological entities, we pursued outcome prediction separately for each cytogenetic group. Gene expression-based outcome predictors for event-free survival (EFS) were constructed using a cross-validated prediction algorithm. Results: Among t(8;21) pts, EFS for predicted good (n=13) and poor (n=9) outcome groups differed strikingly (P=0.005; estimated 3-year EFS rates: 69% v 11%). Prediction was correct for 77% of pts. Among sole inv(16) pts, EFS for predicted good (n=18) and poor (n=7) outcome groups also differed (P=0.08; 3-year EFS rates: 78% v 29%). Prediction was correct for 76% of pts. FLT3 mutations appeared not to account for differences in EFS between the predicted groups; only the predicted outcome groups were associated with EFS (all baseline clinical characteristics at P>0.10). Pts with predicted poor outcome had higher expression of genes with leukemogenic potential such as WT1 [t(8;21) and inv(16)], CCNA1 [t(8;21)] and the oncogene MYCN [inv(16)]. Conclusions: Gene expression profiling improves outcome prediction in CBF AML pts lacking the known prognostic markers. Future studies should explore the clinical usefulness of targeting products of over- expressed genes, such as WT1 encoding a potential target for immunotherapy in AML. No significant financial relationships to disclose.
High BAALC expression associates with other molecular prognostic markers, poor outcome and a distinct gene expression signature in cytogenetically normal acute myeloid leukemia (CN AML): A Cancer and Leukemia Group B (CALGB) study
Authors: Langer C. , Ruppert A. S. , Radmacher M. D. , Whitman S. P. , Paschka P. , Baldus C. D. , Mrózek K. , Kolitz J. E. , Marcucci G. , Bloomfield C. D. 
Published: March 2020

7013 Background: High BAALC expression predicts poor outcome in CN AML patients (pts). Yet, little is known about BAALC's function or its relation to other prognostic markers. We evaluated BAALC expression in the context of molecular markers and clinical outcome in 172 de novo CN AML adults, aged <60 years (y) treated on similar CALGB protocols (9621 and 19808). Methods: BAALC expression was measured by quantitative real-time RT-PCR in pretreatment blood samples. Pts were grouped as high (n=86) or low BAALC (n=86) expressers using the median expression value, by protocol, as a cutoff. Gene expression profiling (Affymetrix U133 plus 2.0 GeneChip) was performed on high (n=26) and low (n=24) pts. Results: BAALC expression was associated with several molecular markers ( Table ). Complete remission (CR) rate was lower in high BAALC pts (79% v 90%), for whom achieving CR was almost 4 times less likely than for low BAALC pts (P=.02; odds ratio=0.27), after adjusting for age (P=.004), ERG expression (P=.05) and white blood cell count (WBC; P=.04). With a median follow-up of 4.3 y, high BAALC pts had shorter overall survival (OS) (P=.002; 3-y OS: 42% v 59%). In a multivariable model, high BAALC provided further adverse prognostic information (P=.06; hazard ratio=1.66) independent of FLT3 ITD (P<.001), WBC (P=.007) and NPM1 (P=.02). A gene expression signature was identified consisting of 312 probe sets differentially expressed (P<.001) between BAALC groups. High BAALC was associated with overexpression of, among other genes, PROM1, CD34 and KIT indicating a less differentiated phenotype in these pts. Conclusions: Although associated with other prognostic markers, high BAALC expression independently predicts outcome and is associated with a distinct gene expression profile, potentially identifying new therapeutic targets in this pt subset. No significant financial relationships to disclose. [Table: see text]