tbuckley/cabot-search huggingface dataset:
Intracranial Aneurysms in Children with Sickle-Cell Anemia
Authors: Manoelle Kossorotoff, Valentine Brousse, David Grevent, Michel Zerah, Olivier Naggara, Francis Brunelle, Augustin Ozanne, Thomas Blauwblomme, Nathalie Boddaert, Mariane De Montalembert
Journal: Blood (2012)
How often do “breakthrough” interventions (BI) discovered in randomized controlled trials (RCTs) conducted during last 50 years inform the current practice?
Authors: A. Kumar, R. J. Wells, H. P. Soares, B. Djulbegovic
Journal: Journal of Clinical Oncology (2008)

6558 Background: The research conducted by the NCI cooperative groups (COG) is universally considered of vital importance for discovery of new treatments against cancer. A number of these discoveries can be considered BI. However, if these BI are to improve patients' outcomes, ultimately they should be recommended in practice guidelines, such as those by the NCCN, developed by 20 leading cancer institutions in the world. We sought to determine how often BI discovered by the COG are included in the 2008 NCCN guideline. Methods: We evaluated a consecutive series of all phase III RCTs started and completed between 1955–2000 (published by Dec 2006) by 8 NCI sponsored COGs. Data from 624 trials (781 comparisons) involving 216,451 patients were analyzed. We defined BI as those judged by the original researchers to be so beneficial that they should immediately become the new standard of care or had an effect size so large that they reduced the death rate by 50% or more (hazard ratio for death was 0.5 or less). We estimated how many of these interventions are recommended in the latest NCCN guidelines (for adult cancers as NCCN does not produce childhood cancer guidelines). One expert pediatric oncologist (RW) determined a proportion of the pediatric cancer BI currently used in practice. Results: Investigators judged that 15% (115/781) of trials resulted in discovery of BI. 2% of trials (12/614) identified experimental interventions that reduced death rate ≥ 50%. 23% of BIs were in pediatric oncology, while remaining (77%) discoveries were made in adult cancers. The trials that reported these discoveries were published from 1979–2004. 53% (48/89) of these treatments are still currently recommended in the NCCN guidelines. 58% (15/26) of pediatric discoveries are still influencing pediatric oncology care today. For adult cancers, most successful interventions were in the categories of definitive treatments that lead to prolongation of survival (27%), followed by adjuvant (23%) and curative therapies (14%). Advances in pediatric oncology have been mostly pronounced in treatment of acute leukemia. Conclusions: The investment that was made in conducting of RCTs during last several decades continues to impact patients outcomes today. No significant financial relationships to disclose.
The Glasgow whipple risk score to predict pancreas-specific complications after pancreaticoduodenectomy.
Authors: Lavanniya Kumar Palani Velu, Vishnuvardhan Chandrabalan, Ross Carter, Colin McKay, Donald McMillan, Nigel B Jamieson, Euan Dickson
Journal: Journal of Clinical Oncology (2015)

394 Background: Pancreas-specific complications (PSC), comprising postoperative pancreatic fistula, post-pancreatectomy haemorrhage, and intra-abdominal collections, are drivers of morbidity following pancreaticoduodenectomy (PD). Intra-operatively derived pancreatic gland texture is a major determinant of postoperative PSC. We have previously demonstrated that a postoperative day 0 (PoD 0 ) serum amylase ≥ 130 IU/L is an objective surrogate of pancreatic texture, and is associated with PSC. We sought to refine the PSC risk prediction model by including serial measurements of serum C-reactive protein (CRP). Methods: 230 consecutive patients undergoing PD between 2008 and 2014 were included in the study. Routine serum investigations, including amylase and CRP were performed from the pre-operative day. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP associated with clinically significant PSC. Results: 95 (41.3%) patients experienced a clinically significant PSC. ROC analysis identified post-operative day 2 (PoD 2 ) serum CRP of 180 mg/L as the optimal threshold (P=0.005) associated with clinically significant PSC, a prolonged stay in critical care (P =0.032), and a relaparotomy (P = 0.045). Patients with a PoD 0 serum amylase ≥ 130 IU/L who then developed a PoD 2 serum CRP ≥ 180 mg/L had a higher incidence of postoperative complications. Patients were categorised into high, intermediate and low risk groups based on PoD 0 serum amylase and PoD 2 serum CRP. Patients in the high risk group (PoD 0 serum amylase ≥ 130 IU/L and PoD 2 serum CRP ≥ 180 mg/l) had significantly higher incidence of PSC, a return to theatre, prolonged lengths stay (all P≤ 0.05) and a four-fold increase in perioperative mortality compared patients in the intermediate and low risk groups (7 deaths in the high risk group versus 2 and nil in the intermediate and low risk groups respectively). Conclusions: A high risk profile, defined as PoD 0 serum amylase ≥ 130 IU/L and PoD 2 serum CRP ≥ 180 mg/l, should raise the clinician’s awareness of the increased risk of clinically significant PSC and a complicated postoperative course following pancreaticoduodenectomy.
Lung toxicity among patients with cancer treated with a combination of docetaxel and gemcitabine: A meta-analysis of clinical studies.
Authors: D. Binder, R. Hübner, B. Temmesfeld-Wollbrück, T. Beinert, P. Schlattmann
Journal: Journal of Clinical Oncology (2011)

e19544 Background: The chemotherapy combination of docetaxel and gemcitabine was tested in several studies in patients with lung, breast and pancreatic cancer and other tumor entities. Some studies reported cases of severe or even fatal pulmonary toxicity that led to early termination of some studies. The authors hypothesized that a weekly administration or Asian ethnicity may be associated with an increased risk of lung injury. We created a meta-analysis model of published studies to identify explanatory factors for docetaxel-gemcitabine-dependent pulmonary toxicity. Methods: We searched MEDLINE/Pubmed, EMBASE and Cochrane Clinical Trials database for prospective full-text studies that used a schedule of docetaxel and gemcitabine. We performed a meta-analysis for proportions using the arcsine transformation and a meta-regression using a generalized linear mixed model based on a binomial distribution and a logit link. Results: We included 103 trials with 113 treatment arms comprising 5065 patients (major entities included non-small cell lung cancer, breast cancer, pancreatic cancer and urothelial cancer). We found that the sequence of the chemotherapy schedule had no influence on the incidence of severe pulmonary adverse events (F-test F=0.65, df=3,113, p=0.58) nor did the ethnicity of the participants, the study phase or treatment line. Conclusions: We could not demonstrate that a particular chemotherapy sequence or Asian ethnicity is associated with excess pulmonary toxicity with gemcitabine/docetaxel.
Evaluation of radiation oncology workflows to optimize efficiency and ensure sufficient time for quality assurance testing.
Authors: Sheri Weintraub, Deborah Schofield, Amanda Scott, Samuel Carnes, Desiree Vinson, Tushar Kumar, Patrick James Gagnon, Beth Herrick, Deborah Ventura, Lindsay Astle, Therese M. Mulvey, Urszula Andrade
Journal: Journal of Clinical Oncology (2014)

193 Background: Radiation treatment plan development involves many people throughout the various stages of the planning process. Delays at any point can result in compressed timeframes for final checks which can thereby threaten the quality and safety of the plan. We have used six sigma tools to establish goals, monitor delays, and to provide a framework for efficiency improvement. Methods: A team of physicians, physicists, dosimetrists, and therapists established time goals and broke the planning workflow into critical to quality elements. It was determined that contouring tasks shall be completed within 2 days of simulation and treatment plans shall be ready for final checks a minimum of 4 or 8 business hours prior to treatment (for 2-5 days or &gt; 5 days from simulation to treatment respectively). Emergent patients were excluded. Time measurements were calculated based on plan upload time and the patient’s scheduled start time. Delayed starts were accounted for to ensure that improved compliance was not at the expense of such delays. Six sigma methodology was used to perform a failure modes and effects analysis and to identify the most significant workflow challenges. Results: Baseline data involving 34 patients was collected. Only 73.5% of these patients complied with the established time goals. From the six sigma process, it was determined that physicians’ schedules were a major contributor to compliance failures. Enhancements were made in physician scheduling and communication with staff. Over the following 6 months, 129 additional patients were evaluated and 89.1% were in compliance with the set time goals. This was a statistically significant improvement (P-test, p=.052). Delayed patient starts made up 5.9% of the baseline data and 6.2% of the 129 additional patients. There was no significant change in these delays (Fisher’s exact test, p=1.000). Conclusions: Our findings validate the employment of six sigma practice in improving workflow. Continued efforts will be employed to ensure consistent quality improvement.
Correlation between recurrent chromosomal deletions status obtained on tissue cores and local invasive and systemic prostate cancer growth.
Authors: Meike Adam, Philipp Wenzel, Dominik Lanwehr, Pierre Tennstedt, Martina Kluth, Lia Burkhardt, Antje Krohn, Margit Fisch, Markus Graefen, Sarah Minner, Guido Sauter, Ronald Simon, Thorsten Schlomm
Journal: Journal of Clinical Oncology (2014)

24 Background: A variety of chromosomal deletions are known to occur frequently in prostate cancer, but the clinical significance of most of these deletions is unknown. To learn more about epidemiology, associations with other molecular features, and relevance for key clinical endpoints, several recurrent deletions were analyzed on a large-scale tissue microarray platform. Methods: A tissue microarray containing 11,156 prostate cancers was analyzed by fluorescence in situ hybridization (FISH) with dual-labeling probes including PTEN (10q23), TP53 (17p13.1), CHD1 (5q21), and MAP3K7 (6q15) together with their respective centromere probes. Patients were stratified into three major biological groups (organ confined, locally advanced, and systemic tumor growth) according to their multidimensional long-term follow up data. In addition, ERG fusion status and tumor cell proliferation (Ki67 labeling index) of all cancers were determined by immunohistochemistry. Results: Deletions were seen for PTEN in 17.9% of 6,122, TP53 in 14.7% of 7,604, CHD1 in 9.9% of 7,026, and for MAP3K7 in 18.7% of 3,528 interpretable cases. All deletions were strongly linked to a positive (PTEN, TP53) or negative ERG status (CHD1, MAP3K7, p&lt;0.0001 each) and early prostate-specific antigen recurrence. The combination of deletion information provided even better prognostic information, showing a dose dependent relationship between the number of deletions and the growth pattern (organ confined, local invasive, or systemic) of the tumor. Patients with no deletion had a 16.8% risk for local invasive and only 8.9% risk for systemic tumor growth, whereas the respective figures were 17.9% and 44.6% in patients with more than or equal to three deletions (p&lt;0.001). The chance of having an organ confined tumor was 68.0% for patients with no deletion and 23.1% for patients with more than or equal to three deletions (p&lt;0.001), respectively. Conclusions: Our data show, that these analyzed chromosomal deletions are tightly linked with ERG status in prostate cancer and that the deletion status obtained on small tissue cores correlates with key biological tumor features. Combinatorial analysis of genomic alterations in prostate biopsies might provide clinically relevant information.
A phase I trial of the monoclonal antibody FG-3019 to connective tissue growth factor (CTGF) in locally advanced or metastatic pancreatic cancer.
Authors: G. M. Heestand, J. M. Pipas, F. Valone, A. D. McMullen, P. Gadea, D. Williams, M. Zhong, T. Neff, G. A. Fisher, A. Koong
Journal: Journal of Clinical Oncology (2011)

269 Background: CTGF is highly expressed in pancreatic tumors and is thought to mediate local desmoplasia. FG-3019 is a fully human monoclonal antibody against CTGF. Studies using FG-3019 in murine xenograft models have shown reduced tumor growth and metastasis. Methods: This open-label, dose escalation study assessed the safety and pharmacokinetics of FG-3019 (3, 10, 15, and 25 mg/kg q14D). FG-3019 was initiated on D1 to assess single-agent toxicity. Standard gemcitabine and erlotinib were added on D15. Chemotherapy-naive patients with locally advanced or metastatic adenocarcinoma were eligible. Seventeen subjects (median age 66 yrs) were enrolled: n=4, 3, and 10 at 3, 10, and 15 mg/kg respectively. Enrollment is ongoing in the 25 mg/kg cohort. Seven subjects were female; four were stage 3, and 13 were stage 4. Results: No safety signals were detected with single-agent FG-3019. After beginning chemotherapy, four subjects experienced seven SAEs, which were deemed unrelated to FG-3019 including three deaths: sepsis, suicide, and disease progression. Nine subjects experienced grade 3 AEs, all of which were expected in patients with pancreatic cancer. There were no grade 4 hematologic abnormalities. AEs related to gemcitabine (hematologic, abnormal LFTs) and erlotinib (rash) occurred at a rate and severity consistent with the prescribing information (preliminary data). Steady-state Cmax (median 428, range 236-455 μg/mL), and T1/2 (median 6.6, range 6.3-6.7 days) at the 10 mg/kg dose level were comparable to PK data from subjects in non-oncological trials who received FG-3019 at the same dose level. One subject had a partial response by RECIST criteria for 9.7+ months. Another subject had a minor response for 7.7 months. Three of five subjects with PET scans at baseline and D15 experienced stable to reduced PET activity before starting chemotherapy. The median TTP across all cohorts was 3.7 months (95% CI 1.9-6.2), and the median OS was 9.4 months (95% CI 1.9-10.6). Conclusions: FG-3019 is well tolerated and dose escalation continues. Reduced PET activity after treatment with single-agent FG-3019 may indicate a biological effect of the agent. [Table: see text]
Trends in the design and interpretation of metastatic colorectal cancer phase III clinical trials.
Authors: Sunil Parimi, Soundouss Raissouni, Yongtao Lin, Jose Gerard Monzon, Patricia A. Tang, Vincent Channing Tam
Journal: Journal of Clinical Oncology (2015)

692 Background: Increasing use of subsequent lines of therapy and crossover in phase III randomized clinical trials (P3 RCTs) has shifted how we perceive the effectiveness of treatments for metastatic colorectal cancer (mCRC). This study aims to characterize the evolution of P3 RCTs in mCRC with respect to clinical trial design and result interpretation. Methods: Abstracts of P3 RCTs of systemic therapy for mCRC conducted between 1980 and 2014 were identified by searching PubMed, Medline, and ASCO abstracts. Data regarding trial design, agent(s) investigated, primary endpoint, secondary endpoint(s), primary endpoint significance and interpretation of the study results (conclusions) were extracted. Results: A total of 422 trials were identified by the search strategy, and 132 eligible trials were included. Over time the sample size of P3 RCTs in mCRC has been increasing and there has been a steady increase in trials studying targeted therapy (see table below for detailed results by decade). A trend towards a smaller percentage of P3 RCTs sponsored by co-operative groups has been observed in recent decades. The most common primary endpoint was overall survival (OS) which was used in 35% of the trials. A decreasing trend in the use of OS was observed since the 1990s. Other common primary endpoints include: progression-free survival (PFS) in 28% and response rate (RR) in 20% of the P3 RCTs. The primary endpoint was met in 45% of the trials. There was discordance between the primary endpoint significance and the authors’ conclusions in 14% of the trials. Conclusions: The design and interpretation of P3 RCTs for mCRC has changed over time from 1980 to present. The use of OS as the primary endpoint is decreasing, while the use of PFS is increasing. [Table: see text]
The I-ONE trial: Integrative oncology education for patient navigators—A randomized pilot trial of web-based distance learning with or without small group retreat.
Authors: Matthew P. Mumber, Karen Beard, Yuan Liu, Alice S. Kerber
Journal: Journal of Clinical Oncology (2016)

171 Background: One of the major barriers to implementation of an integrative oncology (IO) approach is appropriately trained providers. This trial investigated the effectiveness of a mixed method educational program versus web based learning only for oncology patient navigators relative to knowledge and application of IO modalities. Methods: Patient navigators were randomized 1:1 to Web based education only (WEB) vs. WEB plus residential retreat (WEB+R). The trial was conducted as a randomized, two-group, pre-test/post-test design with 4 repeated measures. The primary study outcomes were knowledge and attitudinal beliefs about the perceived efficacy of IO approaches, as well as clinical and personal practices related to IO. Results: 24 patient navigators from varied educational backgrounds and practice settings were randomized to WEB vs. WEB+R. Referrals to complementary therapies increased by 104% immediately after training (p = .013) and by 77.4% 30 days out. (p = .013). There was a statistically significant increase in attitudinal beliefs about the perceived efficacy of IO approaches as measured by the Integrative Medicine Attitude Questionnaire (IMAQ) from baseline to posttest (p = .013). There were no significantly different values between randomized groups in any of the areas surveyed, however internal group pre and post test comparisons had multiple statistically significant improvements in the WEB + R group while there were no such changes in the WEB group, suggesting a trend toward increased educational efficacy for WEB + R that was likely the major driver of entire group educational improvements. Conclusions: Both Web based and Web based plus small group retreat programs were found to be effective in increasing clinical application and attitudinal beliefs about IO in patient navigators. There was a trend toward improved educational efficacy with WEB +R likely related to shared group and personal experience. As IO approaches become part of standard of care, mixed method online plus small group retreat programs would be useful for widespread dissemination of medical knowledge and increased clinical application of IO approaches.
Impact of irinotecan and oxaliplatin on overall survival in patients with metastatic colorectal cancer (MCRC): A population- based study
Authors: H. J. Lim, C. Fitzgerald, S. Gill, B. Melosky, C. Speers, J. Barnett, H. Kennecke
Journal: Journal of Clinical Oncology (2007)

4077 Background: Over the past 10 years, chemotherapeutic options for MCRC has significantly expanded from 5-FU based therapy, to include irinotecan and oxaliplatin. The effect of the availability of these treatments on overall survival is evaluated among patients in 3 time cohorts referred to the British Columbia Cancer Agency (BCCA). Methods: Patients with newly diagnosed or relapsed metastatic colorectal cancer referred to the BCCA in 1995/96, 2000 and 2003/04 were included. In 1995/96, 5-FU was the only palliative chemotherapy agent available at BCCA and irinotecan and oxaliplatin were available in 2000 and 2003, respectively. A one year period was used for the irinotecan cohort to minimize overlap between groups. Overall survival estimates were generated using the Kaplan Meier method. Survival was calculated from time of diagnosis of distant metastatic disease to either death or last contact date. Results: Cohorts were generally similar, however, a significantly higher proportion of patients received chemotherapy in more recent eras ( Table 1 ). Only 25% of patients received both irinotecan and oxaliplatin in 2003/4 and only 10 % received biologic therapies. An improvement in median survival of 3.6 months was observed. The improvement in the treated subgroup was 4.2 months. Outcomes of patients untreated with chemotherapy were unchanged between cohorts. Conclusions: In this population based study, the proportion of patients with MCRC treated with chemotherapy significantly increased between 1995/6 and 2000/2003/4. Patients treated with chemotherapy experienced a 4.2 month increase in median survival in 2003/4 compared to 1995/6. Survival improvements were only significant in the time period when all three effective chemotherapies (5FU, irinotecan and oxaliplatin) were available. As bevacizumab was not available until 2006, its survival impact in this population is not yet known. [Table: see text] No significant financial relationships to disclose.
Association of neutrophil count with overall survival in localized prostate cancer.
Authors: Daniel Taussky, Houda Bahig, Guila Delouya, Paule Bodson-Clermont, Denis Soulieres
Journal: Journal of Clinical Oncology (2015)

121 Background: Systemic inflammation has been linked to worse outcome in metastatic prostate cancer. This study analyzes the influence of complete blood count (CBC) on outcome after curative radiotherapy for localized prostate cancer. Methods: We reviewed our institutional database of patients with localized prostate cancer treated with either definitive external beam radiotherapy (EBRT) or brachytherapy from September 2001- June 2014. Data on pre-treatment CBC such as hemoglobin (Hgb), mean corpuscular volume(MCV) and platelet count (PLT) were available in 1,021 pts, neutrophil/lymphocyte ratio (NLR) in 1,015 pts. Univariate and multivariate cox proportional hazards models were used to analyze the influence of complete blood count parameters on overall and recurrence free survival (PSA nadir + 2 ng/mL). A p&lt;0.05 was considered statistically significant. Results: Median follow-up was 44 months. 55 patients had biochemical recurrence and 68 patients died.On univariate analysis, increasing risk of biochemical recurrence was associated with a combination of all known risk factors as defined by the Cancer of the Prostate Risk Assessment (CAPRA) score, but not by age. When adjusting for age (p=0.009), CAPRA remained significant (p=0.0003) but no comorbidity or CBC. On univariate analysis for overall survival, CAPRA (p=0.0001) and neutrophil count (p=0.04, HR1.16, 1.01-1.34) as well as a cardiac history (p=0.009) were associated with increased risk of overall mortality. The first multivariate model was adjusted for age and included the CAPRA, comorbidity and CBC variables: age (p=0.006) and CAPRA (p=0.008) were prognostic, neutrophil count was borderline significant (p=0.056, HR 1.17, 0.99-1.37). In a second multivariate model without adjusting for age, neutrophil count was a significant prognostic factor for overall survival (p=0.032, HR 1.18, 1.01-1.38) as well as the CAPRA (p=0.005, HR 1.18, 1.05-1.33). Conclusions: In this testing cohort, neutrophil count was an independent risk factor for increased overall mortality in patients with localized prostate cancer. The influence of age on this prognostic factor will be further studied. A validation cohort is needed to corroborate these results.