bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subtle Structural Differences Trigger Inhibitory Activity of Propafenone Analogues at the Two Polyspecific ABC Transporters: P‐Glycoprotein (P‐gp) and Breast Cancer Resistance Protein (BCRP)
Authors: Schwarz Theresa , Montanari Floriane , Cseke Anna , Wlcek Katrin , Visvader Lene , Palme Sarah , Chiba Peter , Kuchler Karl , Urban Ernst , Ecker Gerhard F. 
Published: March 2016

AbstractThe transmembrane ABC transporters P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) are widely recognized for their role in cancer multidrug resistance and absorption and distribution of compounds. Furthermore, they are linked to drug–drug interactions and toxicity. Nevertheless, due to their polyspecificity, a molecular understanding of the ligand‐transporter interaction, which allows designing of both selective and dual inhibitors, is still in its infancy. This study comprises a combined approach of synthesis, in silico prediction, and in vitro testing to identify molecular features triggering transporter selectivity. Synthesis and testing of a series of 15 propafenone analogues with varied rigidity and basicity of substituents provide first trends for selective and dual inhibitors. Results indicate that both the flexibility of the substituent at the nitrogen atom, as well as the basicity of the nitrogen atom, trigger transporter selectivity. Furthermore, inhibitory activity of compounds at P‐gp seems to be much more influenced by logP than those at BCRP. Exploiting these differences further should thus allow designing specific inhibitors for these two polyspecific ABC‐transporters.
Recent Development of Benzimidazole‐Containing Antibacterial Agents
Authors: Song Di , Ma Shutao 
Published: March 2016

AbstractClinically significant antibiotic resistance is one of the greatest challenges of the twenty‐first century. However, new antibacterial agents are currently being developed at a much slower pace than our growing need for such drugs. Given their diverse biological activities and clinical applications, many bioactive heterocyclic compounds containing a benzimidazole nucleus have been the focus of interest for many researchers. The benzimidazole nucleus is a structural isostere of naturally occurring nucleotides. This advantage allows benzimidazoles to readily interact with the various biopolymers found in living systems. In view of this situation, much attention has been given to the exploration of benzimidazole‐based antibacterial agents, leading to the discovery of many new chemical entities with intriguing profiles. In this minireview we summarize novel benzimidazole derivatives active against various bacterial strains. In particular, we outline the relationship between the structures of variously modified benzimidazoles and their antibacterial activity.
Bevacizumab combined with docetaxel, oxaliplatin, and capecitabine, followed by maintenance with capecitabine and bevacizumab, as first‐line treatment of patients with advanced HER2‐negative gastric cancer: A multicenter phase 2 study
Authors: Meulendijks Didier , de Groot Jan Willem B. , Los Maartje , Boers James E. , Beerepoot Laurens V. , Polee Marco B. , Beeker Aart , Portielje Johanna E.A. , Goey Swan H. , de Jong Robert S. , Vanhoutvin Steven A.L.W. , Kuiper Maria , Sikorska Karolina , Pluim Dick , Beijnen Jos H. , Schellens Jan H.M. , Grootscholten Cecile , Tesselaar Margot E.T. , Cats Annemieke 
Published: March 2016

BACKGROUNDThe current study was a multicenter, single‐arm, phase 2 study performed to investigate the feasibility and efficacy of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine (B‐DOC) in patients with advanced human epidermal growth factor receptor 2 (HER2)‐negative, previously untreated, gastric or gastroesophageal adenocarcinoma.METHODSTumor HER2 status was determined centrally. Patients received 6 cycles of bevacizumab at a dose of 7.5 mg/kg, docetaxel at a dose of 50 mg/m2, and oxaliplatin at a dose of 100 mg/m2 (all on day 1) combined with capecitabine at a dose of 850 mg/m2 twice daily (days 1‐14) every 3 weeks followed by maintenance with capecitabine and bevacizumab in patients with disease control. The primary objective was to demonstrate a progression‐free survival (PFS) of >6.5 months, according to the 95% confidence interval (95% CI). Secondary endpoints included safety, objective response rate, overall survival (OS), analyses of circulating tumor cells (CTCs), and pharmacogenetic analyses.RESULTSSixty eligible patients were enrolled. The median PFS was 8.3 months (95% CI, 7.2‐10.9 months). The objective response rate was 70% (95% CI, 55%‐83%) and the disease control rate was 96% (95% CI, 85%‐99%). The median OS was 12.0 months (95% CI, 10.2‐16.1 months). According to CTC‐AE v4.0, the most common treatment‐related grade ≥3 adverse events were neutropenia (20%), leukocytopenia (18%), diarrhea (15%), and nausea/vomiting (15%). The presence of CTCs at baseline was strongly predictive of PFS (hazard ratio [HR], 3.8; P =.007) and OS (HR, 3.4; P =.014). The methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype was strongly associated with PFS (HR, 4.7 for TT vs CC or CT; P =.0007) and OS (HR, 5.9; P =.0001).CONCLUSIONSThe B‐DOC regimen plus maintenance was feasible and active. CTCs were found to be prognostic in patients treated with B‐DOC. Docetaxel‐based triplet chemotherapy as a backbone for targeted therapies is feasible and deserves further study. Cancer 2016;122:1434–1443. © 2016 American Cancer Society.
Web‐based collaborative care intervention to manage cancer‐related symptoms in the palliative care setting
Authors: Steel Jennifer L. , Geller David A. , Kim Kevin H. , Butterfield Lisa H. , Spring Michael , Grady Jonathan , Sun Weiing , Marsh Wallis , Antoni Michael , Dew Mary Amanda , Helgeson Vicki , Schulz Richard , Tsung Allan 
Published: March 2016

BACKGROUNDThe aim of this study was to examine the efficacy of a collaborative care intervention in reducing depression, pain, and fatigue and improve quality of life.METHODSA total of 261 patients with advanced cancer and 179 family caregivers were randomized to a web‐based collaborative care intervention or enhanced usual care. The intervention included the following: 1) a web site with written and audiovisual self‐management strategies, a bulletin board, and other resources; 2) visits with a care coordinator during a physician's appointment every 2 months; and 3) telephone follow‐up every 2 weeks. Primary patient outcomes included measures of depression, pain, fatigue, and health‐related quality of life. Secondary outcomes included Interleukin (IL)‐1α, IL‐1β, IL‐6, and IL‐8 levels, Natural Killer (NK) cell numbers, and caregiver stress and depression.RESULTSAt the baseline, 51% of the patients reported 1 or more symptoms in the clinical range. For patients who presented with clinical levels of symptoms and were randomized to the intervention, reductions in depression (Cohen's d = 0.71), pain (Cohen's d = 0.62), and fatigue (Cohen's d = 0.26) and improvements in quality of life (Cohen's d = 0.99) were observed when compared to those in the enhanced usual car arm at 6 months. Reductions in IL‐6 (φ = 0.18), IL‐1β (φ = 0.35), IL‐1α (φ = 0.19), and IL‐8 (φ = 0.15) and increases in NK cell numbers (φ = 0.23) were observed in comparison with enhanced usual care arm at 6 months. Reductions in caregiver stress (Cohen's d = 0.75) and depression (Cohen's d = 0.37) were observed at 6 months for caregivers whose loved ones were randomized to the intervention arm.CONCLUSIONSThe integration of screening and symptom management into cancer care is recommended. Cancer 2016;122:1270–82. © 2016 American Cancer Society.
Number of positive nodes is superior to the lymph node ratio and American Joint Committee on Cancer N staging for the prognosis of surgically treated head and neck squamous cell carcinomas
Authors: Roberts Thomas J. , Colevas A. Dimitrios , Hara Wendy , Holsinger F. Christopher , Oakley‐Girvan Ingrid , Divi Vasu 
Published: March 2016

BACKGROUNDRecent changes in head and neck cancer epidemiology have created a need for improved lymph node prognostics. This article compares the prognostic value of the number of positive nodes (pN) with the value of the lymph node ratio (LNR) and American Joint Committee on Cancer (AJCC) N staging in surgical patients.METHODSThe Surveillance, Epidemiology, and End Results database was used to identify cases of head and neck squamous cell carcinomas from 2004 to 2012. The sample was grouped by the AJCC N stage, LNR, and pN and was analyzed with Kaplan‐Meier and multivariate Cox proportional hazards models. The sample was also analyzed by the site of the primary tumor.RESULTSThis study identified 12,437 patients. Kaplan‐Meier survival curves showed superior prognostic ability for LNR and pN staging in comparison with AJCC staging. Patients with a pN value > 5 had the worst overall survival (5‐year survival rate, 16%). Patients with oropharyngeal tumors had better outcomes for all groupings, and a pN value > 5 for oropharyngeal cancers was associated with decreased survival. Multivariate regressions demonstrated larger hazard ratios (HRs) and a lower Akaike information criterion for the pN model versus the AJCC stage and LNR models. The HRs were 1.78 (95% confidence interval, 1.62‐1.95) for a pN value of 1, 2.53 (95% confidence interval, 2.32‐2.75) for a pN value of 2 to 5, and 4.64 (95% confidence interval, 4.18‐5.14) for a pN value > 5.CONCLUSIONSThe pN models demonstrated superior prognostic value in comparison with the LNR and AJCC N staging. Future modifications of the nodal staging system should be based on the pN with a separate system for oropharyngeal cancers. Future trials should consider examining adjuvant treatment escalation in patients with >5 lymph nodes. Cancer 2016;122:1388–1397. © 2016 American Cancer Society.
Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients
Authors: Song Young Shin , Lim Jung Ah , Choi Hoonsung , Won Jae‐Kyung , Moon Jae Hoon , Cho Sun Wook , Lee Kyu Eun , Park Young Joo , Yi Ka Hee , Park Do Joon , Seo Jeong‐Sun 
Published: March 2016

BACKGROUNDRecent reports suggest that mutations in the promoter of the gene encoding telomerase reverse transcriptase (TERT) affect thyroid cancer outcomes.METHODSIn all, 551 patients with differentiated thyroid cancer (DTC) enrolled in this study. The median follow‐up duration was 4.8 years (interquartile range, 3.4‐10.6 years).RESULTSTERT promoter mutations were detected in 25 DTCs (4.5%): 2.8% in neither BRAF‐mutated nor RAS‐mutated tumors, 4.8% in BRAF‐mutated tumors, and 11.3% in RAS‐mutated tumors. Moreover, they were frequently observed in American Thyroid Association (ATA) high‐risk and TNM stage III/IV groups (9.1% and 12.9%, respectively). The coexistence of BRAF or RAS with TERT promoter mutations increased aggressive clinicopathologic features, recurrence (hazard ratio [HR] for BRAF, 4.64; 95% confidence interval [CI], 1.42‐15.18; HR for RAS, 5.36; 95% CI, 1.20‐24.02), and mortality (HR for BRAF, 15.13; 95% CI, 1.55‐148.23; HR for RAS, 14.75; 95% CI, 1.30‐167.00), even after adjustments for the age at diagnosis and sex, although the significance was lost after additional adjustments for pathologic characteristics. Furthermore, TERT promoter mutations significantly increased the risk of both recurrence and mortality in the ATA high‐risk (HR for recurrence, 5.79; 95% CI, 2.07‐16.18; HR for mortality, 16.16; 95% CI, 2.10‐124.15) and TNM stage III/IV groups (HR for recurrence, 3.60; 95% CI, 1.19‐10.85; HR for mortality, 9.06; 95% CI, 2.09‐39.26).CONCLUSIONSThe coexistence of BRAF or RAS mutations enhanced the prognostic effects of TERT promoter mutations. Furthermore, TERT promoter mutations strengthened the predictions of mortality and recurrence by the ATA and TNM staging systems, particularly for high‐risk patients with DTC. Cancer 2016;122:1370–1379. © 2016 American Cancer Society.
Increase in primary surgical treatment of T1 and T2 oropharyngeal squamous cell carcinoma and rates of adverse pathologic features: National Cancer Data Base
Authors: Cracchiolo Jennifer R. , Baxi Shrujal S. , Morris Luc G. , Ganly Ian , Patel Snehal G. , Cohen Marc A. , Roman Benjamin R. 
Published: March 2016

BACKGROUNDThere has been increasing interest in the primary surgical treatment of patients with early T classification (T1‐T2) oropharyngeal squamous cell carcinoma (OPSCC), with the stated goal of de‐escalating or avoiding adjuvant treatment. Herein, the authors sought to determine the degree to which this interest has translated into changes in practice patterns, and the rates of adverse postoperative pathologic features.METHODSPatients with T1 to T2 OPSCC in the National Cancer Data Base who were treated from 2004 through 2013 were categorized as receiving primary surgical or primary radiation‐based treatment. Trends in treatment selection and factors related to the selection of primary surgery were examined. The rates of adverse pathologic features including positive surgical margins, extracapsular spread (ECS), and advanced T and N classifications after surgery were analyzed.RESULTSOf 8768 patients with T1 to T2 OPSCC, 68% underwent primary surgical treatment, increasing from 56% in 2004 to 82% in 2013 (P<.0001). The highest versus lowest volume hospitals treated 78% versus 59% of patients with primary surgery (odds ratio, 2.23; 95% confidence interval, 1.55‐3.22 [P<.0001]). Higher lymph node classification was found to be predictive of lower rates of primary surgery, but the majority of patients with clinical N2/N3 disease underwent primary surgery. Among patients treated with surgery, positive surgical margins were present in 24% and ECS in 25% of patients. The rate of positive surgical margins decreased over time (P<.0001) and was observed less often at high‐volume centers (P<.0001). Among candidates for single‐modality therapy (those with clinical T1‐T2/N0‐N1 disease), 33% had positive surgical margins and/or ECS and 47% had at least 1 adverse feature (T3‐T4 disease, N2‐N3 disease, positive surgical margins, and/or ECS).CONCLUSIONSPrimary surgical treatment among patients with early T classification OPSCC has become more widespread. Cancer 2016;122:1523–32. © 2016 American Cancer Society.
Disease‐related costs of care and survival among Medicare‐enrolled patients with myelodysplastic syndromes
Authors: Zeidan Amer M. , Wang Rong , Davidoff Amy J. , Ma Shuangge , Zhao Yinjun , Gore Steven D. , Gross Cary P. , Ma Xiaomei 
Published: March 2016

BACKGROUNDAlthough newer treatments for myelodysplastic syndromes (MDS), particularly hypomethylating agents (HMAs), are expensive, it is unclear whether MDS‐related costs of care are associated with overall survival. This study evaluated the relation between MDS‐related costs and survival among Medicare beneficiaries with MDS.METHODSEligible patients were identified from the Surveillance, Epidemiology, and End Results–Medicare database with codes for MDS from International Classification of Diseases for Oncology, 3rd edition. The patients were diagnosed between January 1, 2005 and December 31, 2011, were 66 years old or older, and were followed through death or the end of study (December 31, 2012). Medicare payments were used to estimate costs. Cumulative costs in a propensity score–matched group of cancer‐free Medicare beneficiaries were subtracted from costs in the MDS cohort in each registry to estimate MDS‐related costs. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from multivariate Cox proportional hazards models adjusted for patient and disease characteristics.RESULTSThere were 8580 eligible patients, and 1,267 (14.7%) received HMAs. The overall 2‐year survival rate was 48.7%, and the 2‐year registry‐specific MDS‐related cost per patient ranged from $40,793 to $78,156 across 16 registries. The 2‐year MDS‐related cost was not associated with survival in the overall study population (first tertile, reference; second tertile, HR, 0.96; 95% CI, 0.89‐1.04; P = .29; third tertile, HR, 0.98; 95% CI, 0.91‐1.06; P = .64) or in subgroups of patients who did or did not receive HMAs.CONCLUSIONSMedicare expenditures for elderly patients with MDS varied across registries but were not associated with survival. A lack of an association between costs and outcomes warrants additional research because it may help to identify potential areas for cost‐saving interventions without compromising patient outcomes. Cancer 2016;122:1598–607. © 2016 American Cancer Society.
Patient preferences regarding incidental genomic findings discovered during tumor profiling
Authors: Yushak Melinda L. , Han Gang , Bouberhan Sara , Epstein Lianne , DiGiovanna Michael P. , Mougalian Sarah S. , Sanft Tara B. , Abu‐Khalaf Maysa M. , Chung Gina G. , Stein Stacey M. , Goldberg Sarah B. , Pusztai Lajos , Hofstatter Erin W. 
Published: March 2016

BACKGROUNDDuring the process of tumor profiling, there is the potential to detect germline variants. To the authors' knowledge, there currently is no accepted standard of care for how to deal with these incidental findings. The goal of the current study was to assess disclosure preferences among patients with cancer regarding incidental genomic variants that may be discovered during tumor profiling.METHODSA 45‐item questionnaire was administered to 413 patients in ambulatory oncology clinics. The survey captured demographic and disease variables and personal and family history, and presented case scenarios for different types of incidental germline variants that could theoretically be detected during genomic analysis of a patient's tumor.RESULTSThe possibility of discovering non‐cancer‐related, germline variants did not deter patients from tumor profiling: 77% wanted to be informed concerning variants that could increase their risk of a serious but preventable illness, 56% wanted to know about variants that cause a serious but unpreventable illness, and 49% wanted to know about variants of uncertain significance. The majority of patients (75%) indicated they would share hereditary information regarding predisposition to preventable diseases with family and 62% would share information concerning unpreventable diseases. The most frequent concerns about incidental findings were ability to obtain health (48%) or life (41%) insurance. Only 21% of patients were concerned about privacy of information.CONCLUSIONSPatients with cancer appear to prefer to receive information regarding incidental germline variants, but there is substantial variability with regard to what information patients wish to learn. The authors recommend that personal preferences for the disclosure of different types of incidental findings be clarified before a tumor profiling test is ordered. Cancer 2016;122:1588–97. © 2016 American Cancer Society.
National trends and determinants of proton therapy use for prostate cancer: A National Cancer Data Base study
Authors: Mahal Brandon A. , Chen Yu‐Wei , Efstathiou Jason A. , Muralidhar Vinayak , Hoffman Karen E. , Yu James B. , Feng Felix Y. , Beard Clair J. , Martin Neil E. , Orio Peter F. , Nguyen Paul L. 
Published: March 2016

BACKGROUNDIn the current study, the authors sought to both characterize the national trends in proton therapy use for prostate cancer and determine the factors associated with receipt of this limited resource, using what to the best of their knowledge is the largest nationwide cancer registry.METHODSThe National Cancer Data Base was used to identify 187,730 patients diagnosed with nonmetastatic prostate cancer from 2004 through 2012 who received external beam radiotherapy as their initial form of definitive therapy. Multivariable logistic regression analysis adjusted for sociodemographic and clinical factors was used to identify independent determinants of proton therapy use.RESULTSThe rate of proton therapy use increased significantly from 2.3% in 2004 to 5.2% in 2011 and 4.8% in 2012 (P value for trend <.0001). Proton therapy for prostate cancer was much more likely to be delivered at an academic compared with nonacademic center and to patients who were white, younger, healthier, from metropolitan areas, from zip codes with higher median household incomes, and who did not have an advanced stage of or high‐grade disease (all P<.0001). Compared with white patients, those who were black and Hispanic were found to be significantly less likely to receive proton therapy even after robust multivariable adjustments (adjusted odds ratio, 0.20 [95% confidence interval, 0.18‐0.22; P<.0001] and adjusted odds ratio, 0.57 [95% confidence interval, 0.48‐0.66; P<.0001], respectively).CONCLUSIONSThe use of proton therapy to treat patients with prostate cancer more than doubled from 2004 to 2012, with striking racial disparities in its use noted despite robust multivariable adjustments. Long‐term follow‐up is needed to determine whether the increased use of proton therapy for prostate cancer is justified, and ongoing efforts should be made to ensure equal access to resource‐limited oncologic therapies. Cancer 2016;122:1505–12. © 2016 American Cancer Society.
Time consumed by microscopic and nonmicroscopic tasks in image‐assisted gynecologic screening: Implications for workload assessment
Authors: Renshaw Andrew A. , Underwood Dawn , Aramoni Ghada , Cash Beverly , Croyle Maureen , Deeds Dave , Dolar Sandra , Gmitro Stephen , Ray Nancy , Sabo Debbie , Shorie Julie A. , Springer Bridgette , Weber Moffsinger Dana , Elsheikh Tarik M. 
Published: March 2016

BACKGROUNDGynecologic screening cytology is a complex task that includes microscopic activities and nonmicroscopic activities. The authors sought to determine the amount and percentage of time that cytotechnologists spend on those activities using the ThinPrep imaging system.METHODSIn arm 1, a total of 550 consecutive unselected slides were reviewed by 11 cytotechnologists, and the time used for individual subtasks of the screening process was recorded. In arm 2, a total of 20 unselected slides were each screened by 10 different cytotechnologists (200 slides in total) and total screening times and full manual review (FMR) times were recorded.RESULTSIn arm 1, cases with and without FMR required an average of 5.6 minutes and 3.0 minutes, respectively, to screen. Overall, review of fields of view (FOVs) took 95 seconds. FMR took an average of 2.6 minutes. The average screening times for FOV‐only cases was significantly longer than the US Food and Drug Administration/Centers for Medicare and Medicaid Services (FDA/CMS) workload limit of 2.4 minutes (P = .005). However, in arm 2, the time needed to screen a case increased by an average of 1 minute compared with arm 1, including 1.1 minute for FOV‐only cases and >2 minutes for FMR plus FOV cases. Approximately 100% of cases screened as FOV only exceeded the FDA/CMS workload limit of 2.4 minutes.CONCLUSIONSThe FDA/CMS workload limits for FOV‐only cases appears to significantly underestimate the time needed to screen those cases, but seems to be appropriate for the majority of FMR plus FOV cases. Approximately 60% and 30% of the time designated to screening slides was spent on nonmicroscopic activities for FOV‐only cases and FMR cases, respectively. Cancer Cytopathol 2016;124:501–7. © 2016 American Cancer Society.