tbuckley/cabot-search huggingface dataset:
Evaluation of the effects of neoadjuvant pazopanib for renal cell carcinoma on intratumor genetic heterogeneity.
Authors: Jed Ferguson, Maxim McKibben, Joel S Parker, Eric Wallen, Christopher G. Wood, Thomas Powles, Kimryn Rathmell
Journal: Journal of Clinical Oncology (2015)

425 Background: The prevalence of intratumoral genetic heterogeneity in renal cell carcinoma (RCC) has recently been elucidated, and the clinical implications are currently under investigation. The effects of neoadjuvant pazopanib on intratumoral genetic heterogeneity in RCC are unknown. Methods: With IRB approval and informed consent, 5 patients with clinically localized clear cell RCC were treated with pazopanib chemotherapy for ≥8 weeks prior to radical nephrectomy. Prior to treatment, the tumors were sampled by percutaneous core biopsy for histologic and genetic analysis. Peripheral leukocytes were collected for wild-type genetic analysis. Following nephrectomy, tumors were sampled for histologic and genetic analysis. DNA was extracted from all samples and ultra-deep multiregion exome genetic sequencing was performed to identify genetic mutations. Mutant allele frequencies were calculated and compared between pre- and post-pazopanib samples. Hierarchical cluster analysis was performed to evaluate intra- and inter-tumoral heterogeneity, and the fraction of private mutations was tabulated to evaluate change in clonality after pazopanib treatment. Results: Patients age ranged from 52 to 75, and tumors ranged from T2 to T4 (all cN0M0). Percent change of tumor volume after treatment ranged from -10% to -33%. Hierarchical cluster analysis of genetic mutations revealed that all pre- and post-pazopanib sample pairs clustered more closely with each other than with the other tumors, suggesting that intertumoral heterogeneity overshadowed intratumoral heterogeneity. Important genetic mutations in RCC (such as VHL, PBRM1, and SETD2) were highly represented in our dataset, thus validating our approach. After pazopanib, total numbers of mutations as well as the fraction of private mutations decreased in all tumors, showing an increased clonality with pazopanib therapy. Conclusions: RCC is highly genetically heterogeneous. However, this heterogeneity decreases with neoadjuvant pazopanib. These data have implications for the accuracy of percutaneous biopsy to predict tumor biology, and begin to reveal insights into the biologic and genetic response of these tumors to pazopanib.
Concordance of Gleason score on biopsy and after prostatectomy: A SEER database analysis.
Authors: Andrew Thomas Wong, Manuj Agarwal, Elliot B. Navo, David Schwartz, David Schreiber
Journal: Journal of Clinical Oncology (2015)

50 Background: The Gleason score (GS) is a well-established prognostic factor and is used to guide clinical decision-making for patients with prostate cancer. Concordance between the clinical GS of the core biopsy and of the pathologic specimen after radical prostatectomy has ranged from 30% to 75% in prior single-institution studies. The objective of this study is to analyze biopsy concordance utilizing the population-based Surveillance, Epidemiology, and End Results (SEER) database. Methods: Patients diagnosed with localized prostate adenocarcinoma (cT1c-4 Nx-1 M0) who underwent prostatectomy from 2010-2011 were identified in the SEER database. Agreement between clinical and pathologic GS was analyzed using the kappa (k) statistic. Univariate and multivariate logistic regression was performed to identify factors which may impact concordance using SPSS v21. Results: A total of 34,195 patients were included in this analysis. Median age was 61 and median PSA was 5.9 ng/ml. The majority of patients had clinical GS of 6 or 7 (76.5 %) and PSA &lt; 10 ng/ml (77.4%). Overall concordance was 55.4% with k of 0.36, indicating fair agreement. Results are summarized in the Table. Of patients with clinical GS 6, concordance was 55.3%, with 43.1% upgraded to pathologic GS 7. Among patients with clinical GS 7, concordance was 66.9% for GS 3+4 and 42.9% for GS 4+3. Concordance was 24.8% among patients with clinical GS 8, with 57.4% downgrade rate. On multivariate analysis, Black race, increasing age, higher PSA and SEER registries California, Connecticut, Hawaii and Iowa predicted for decreased likelihood of concordance. Conclusions: This is, to our knowledge, the largest contemporary study of prostate biopsy concordance. We found a substantial rate of upgrade from GS 6 or 7 as well as significant downgrade from GS 8. Further investigation is needed to determine other potential factors to predict biopsy concordance. [Table: see text]
Immunohistochemical markers as prognostic indicators for efficacy of imatinib therapy in GIST
Authors: E. Stepanova, A. Meshcheryakov, O. Anurova, D. Shubina, M. Lichinitser
Journal: Journal of Clinical Oncology (2005)

9703 Background: 15 patients with metastatic gastrointestinal stromal tumors (GIST) took imatinib 400mg daily. C-kit expression was confirmed in all cases. The primary tumor was localized in stomach in 6 patients (pts), small bowel - 8 pts, large bowel - 1 patient. The primary tumor was removed in all patients. Before treatment metastatic sites were as follows: peritoneal metastases (mts) in 4 pts, liver - 3 pts, peritoneal and hepatic mts - 5 pts, two pts had additionally lung or bone mts. Partial response was achieved in 10 pts, stable disease - 5 pts. Median time to progression (TTP) was 11 (5–32) months. Methods: P53, Ki-67, Bcl-2, Bax, VEGFR, CD34, PDGFR, COX-2, nm-23 were evaluated immunohistochemically. Results: P53 was positive in 4 pts, Ki-67 - 5 pts, Bcl-2 - 12 pts, Bax - 2 pts, VEGFR - 6 pts, CD34 - 10 pts, PDGFR - 10 pts, COX-2 - 4 pts, nm-23 - 9 pts.Univariate analysis showed that PDGFR overexpression predicted for shorter TTP (p=0.02). There was also a trend to shorter TTP for Bcl-2, VEGFR, Ki-67. Conclusions: PDGFR overexpression corresponds to short TTP in GIST patients on imatinib therapy. Further investigations in bigger study groups should be done for Bcl-2, VEGFR, Ki-67. No significant financial relationships to disclose.
Association of mutations in chromatin modifiers with poor survival in clear cell renal cell carcinoma: Analysis of the Cancer Genome Atlas Project.
Authors: A. Ari Hakimi, Irina Ostrovnaya, Martin Henner Voss, Robert John Motzer, Paul Russo, Victor E. Reuter, James Hsieh
Journal: Journal of Clinical Oncology (2013)

360 Background: We have previously shown that mutations in the epigenetic modifiers PBRM1, BAP1, SETD2 and KDM5C are associated with adverse tumor characteristics and, in some cases, worse cancer specific survival in clear cell renal cell carcinoma (ccRCC). We analyzed publically available data from the Cancer Genome Atlas Project (TCGA), to assess the impact of mutations in these genes on cancer-specific survival. Methods: We analayzed the genomic and clinical data from the TCGA cohort of 424 patients with primary ccRCC. The Kaplan-Meier method was used to estimate the survival probabilities, and log-rank test was used to test the univariate association between mutation status and overall survival. Cancer specific survival (CSS) was analyzed using the competing risk method. Multivariate Cox proportional hazard regression and competing risk models were also fitted to adjust for the validated Mayo Clinic SSIGN prognostic score. Results: Mutations in these epigenetic modifiers are frequent (PBRM1, 33.7%; SETD2, 11.6%; BAP1, 9.7%, KDM5C, 5.7%). BAP1 (p=0.002, HR 2.21 [1.34-3.62]), SETD2 (p=0.036, HR 1.68 [1.03-2.72]) and KDM5C (p=0.016, HR 2.18 [1.16-4.11]) are associated with worse CSS by competing risk. When adjusting for the prognostic SSIGN score, only mutations in KDM5C remain significant (p&lt;0.0001 HR 4.03 [2.1-7.9]). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. Conclusions: BAP1, SETD2 and KDM5C mutations are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic and molecular interrogation of this novel class of tumor suppressors.
Edaravone-Encapsulated Agonistic Micelles Rescue Ischemic Brain Tissue by Tuning Blood-Brain Barrier Permeability
Authors: Qu Jin, Yu Cai, Sihan Li, Haoran Liu, Xingyu Zhou, Chunqiang Lu, Xihui Gao, Jun Qian, Jun Zhang, Shenghong Ju, Cong Li
Journal: Theranostics (2017)

Thrombolysis has been a standard treatment for ischemic stroke. However, only 2-7% patients benefit from it because the thrombolytic agent has to be injected within 4.5 h after the onset of symptoms to avoid the increasing risk of intracerebral hemorrhage. As the only clinically approved neuroprotective drug, edaravone (EDV) rescues ischemic brain tissues by eradicating over-produced reactive oxygen species (ROS) without the limitation of therapeutic time-window. However, EDV's short circulation half-life and inadequate cerebral uptake attenuate its therapeutic efficacy. Here we developed an EDV-encapsulated agonistic micelle (EDV-AM) to specifically deliver EDV into brain ischemia by actively tuning blood-brain barrier (BBB) permeability. The EDV-AM actively up-regulated endothelial monolayer permeability in vitro. HPLC studies showed that EDV-AM delivered more EDV into brain ischemia than free EDV after intravenous injection. Magnetic resonance imaging also demonstrated that EDV-AM more rapidly salvaged ischemic tissue than free EDV. Diffusion tensor imaging indicated the highest efficiency of EDV-AM in accelerating axonal remodeling in the ipsilesional white matter and improving functional behaviors of ischemic stroke models. The agonistic micelle holds promise to improve the therapeutic efficiency of ischemic stroke patients who miss the thrombolytic treatment.
Effects of denosumab on pain reduction in giant cell tumor of bone (GCTB): Interim phase II study results.
Authors: C. S. Cleeland, A. P. Staddon, S. Schuetze, A. Powell, A. Lopez Pousa, A. Cioffi, J. R. Kroep, S. Stacchiotti, K. Chung, C. Atchison, Y. Qian, Y. Zhao, I. A. Jacobs
Journal: Journal of Clinical Oncology (2011)

10037 Background: GCTB is a rare disease in which osteoclast-like giant cells and mononuclear cells express RANKL, a mediator of osteoclast activation. Symptoms include localized tenderness, swelling, and often severe, intractable pain. Denosumab is a fully human monoclonal antibody that binds RANKL to inhibit osteoclast-mediated bone destruction. In a previous phase 2 study, 86% of patients with GCTB responded to denosumab. This prespecified analysis of interim 12-month data from a second phase 2 study describes the effects of denosumab on pain in patients with GCTB. Methods: Adult and skeletally mature adolescent patients with GCTB (N=158) received subcutaneous denosumab 120 mg every 4 weeks with a loading dose of 120 mg SC on study days 8 and 15. The Brief Pain Inventory (BPI) Short Form (0-10) was administered before each dose. This analysis includes the 99 patients who received ≥1 dose of denosumab, were on study for ≥6 months, and completed ≥1 BPI assessment. Analyses included the proportion of patients with clinically meaningful reduction in worst pain (≥2‐point decrease in patients with baseline BPI score ≥2 points), proportion of patients with no/mild worst pain at baseline who reported moderate/severe worst pain (>4 points), and change from baseline in analgesic score (0 [no analgesics]–7 [strong opioids, >600mg oral morphine equivalent/day]). Results: Clinically meaningful reduction (≥2-point decrease) in worst pain was reported within 1 week of their first treatment for 32% (19/60) of patients. In addition, 66% (36/55) patients had clinically meaningful reduction in worst pain at week 9. Through week 61, 22% or fewer of patients who had no/mild pain at baseline reported moderate/severe pain (>4 points). Mean analgesic score change from baseline by visit remained constant over time and ranged from ‐0.2 to 0.1 (median 0.0, Q1 0.0, Q3 0.0). Conclusions: In this interim analysis, denosumab use in GCTB was associated with clinically meaningful reduction in worst pain in the majority of patients and the prevention of worsening pain. The reduction in worst pain and prevention of pain worsening were not accompanied by increased analgesic use.
Lymph node metastases in the prognosis of gastroenteropancreatic neuroendocrine tumors.
Authors: Jacob Andrew Martin, Juan P. Wisnivesky, Michelle Kang Kim
Journal: Journal of Clinical Oncology (2016)

224 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a diverse group of malignancies affecting over 65,000 patients in the United States. GEP-NETs are currently classified as lymph node positive (N1) or negative (N0). The prognostic utility of the extent of lymph node involvement remains unknown. In this study, we used a population-based registry to investigate the relationship between lymph node ratio (LNR) and survival in patients with GEP-NETs. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) data registry to identify patients with histologically confirmed, surgically resected NETs with lymph node involvement diagnosed between 1988 and 2011. Patients were divided into three groups based on the ratio of positive lymph nodes to total lymph nodes examined (LNR): ²0.20, &gt;0.2-0.5, and &gt;0.5. Kaplan-Meier, log-rank analysis, and Cox models were used to compare NET cancer-specific survival according to LNR category. Results: We identified 8,113 patients with GEP-NETs. Primary sites included small intestine (N=3,651), colon (N= 2,042), pancreas (N=1,070), appendix (N= 683), stomach (N=389), and rectum (N=278). Patients were 49% female, 76% white, and 12% black. Ten-year NET-specific survival rates were significantly different among patients in the three LNR groups and LN negative controls (p&lt;.0001). Survival was worse in patients with LNRs of &gt;0.2-0.5 (Hazard Ratio (HR) 1.338, p=.0002), and &gt;0.5 (HR 1.692, p&lt;.0001) compared to LN-negative controls. Higher LNR was correlated with worse survival. Conclusions: The degree of lymph node involvement is a prognostic factor across the most common primary sites of GEP-NETs. This information may be used clinically and in stratifying patients for clinical trials. Results across multiple sites may also be generalizable to GEP-NETs from rare primary locations that are difficult to study. [Table: see text]
Reducing wait time (WT) in the infusion center (IC).
Authors: Gail Foster, Lianne Lopez, Angela Aschian, Betty Chan, Martha Inofuentes, Zoraida Truax, Sally Golingay, Gwendoyn Lynch, Peggy Matsuura, Afsaneh Barzi
Journal: Journal of Clinical Oncology (2016)

249 Background: Lengthy WT is the primary source of dis-satisfaction with IC services. We created a patient (PT) flow diagram outlining each step beginning from PT check-in to discharge and plotted the impact of multiple disciplines on the WT. A team of nurses, pharmacists, physicians, and administrators, analyzed the flow and identified ways to improve efficiencies. Methods: First attempt was to improve communications between pharmacy and nursing, coordinating the preparation of medications with patient’s check-in time; use of a simple clipboard facilitated this task and improved the efficiency of the system. Next, the team worked on re-routing administration of non-intravenous medications to clinic nurses. Administration of all non-intravenous medications, not requiring prolonged monitoring, was shifted to clinic nurses. Hospital policies reviewed and in-services regarding specific medication, monitoring, and administration techniques were conducted prior to this transition. Our scheduling template was ignorant of the capacity and time frames available for each PT, therefore allowing more PT than available slots. With help from information technology, the scheduling template was redesigned to include constraints that would allow scheduling to the maximum of available slots. Our center does not have an emergency room. Therefore, on a daily basis an average of 5-7% of PT load is related to urgent treatments such as blood transfusion, hydration, antibiotic therapy, etc. To proactively anticipate this volume, a virtual bed was assigned to treat only urgent cases leaving one bed open at all times. A nursing staffing plan was also developed to staff these urgent cases. Lastly, physicians were trained to turn in the chemotherapy orders ahead of the scheduled time and to be prompt in responding to pharmacy and nursing staff for order clarification. Results: We selected time from check-in to IC to start of chemotherapy as our outcome measures. Prior to implementation of changes the average WT was 3 hours (H) &amp; 26 minutes (M). As a result of this project the WT was reduced to an average of 2 H &amp; 46 M in the 2 nd quarter and remained stable in the 3 rd quarter despite a 20% increase in the volumes. Conclusions: Delivery of timely PT care is possible through multidisciplinary efforts.
Fertility preservation treatment options: What do patients actually understand about their choices?
Authors: J. Mersereau, L. Kondapalli, U. Balthazar
Journal: Journal of Clinical Oncology (2011)

9109 Background: Young women with cancer are referred to discuss fertility preservation (FP), but due to time pressure and complexity of FP treatments, their comprehension of FP may be poor. We conducted a multi-center study to evaluate factors associated with knowledge about fertility preservation (FP) treatment following FP consultation. Methods: A survey instrument was developed to assess a patient's understanding of FP options after FP consultation. Information was collected about demographics, support systems, decisional conflict and perceived risks. A pilot group evaluated the survey and results were used to refine the content. The revised instrument was completed by consecutive new patients (ages 18-41) between 2008 and 2010, 3-12 months after initial FP consultation. Each correct answer was given one point to yield a knowledge score (KS) (maximum = 22). Results: Among 94 eligible subjects, 72 were successfully contacted and 51 completed the survey (71%). Median KS was 12 (range 4-19). Higher KS was noted in women who were college educated (12.4 vs. 9.2; p<0.01), Caucasian (12.3 vs. 10, p=0.03), had someone present at FP consultation (12.4 vs. 10.6, p=0.05), discussed FP options with someone (12.4 vs. 9.5, p<0.01), and used specific websites (eg FertileHope; 12.6 vs. 10.7, p=0.02). KS trended higher in subjects who discussed their FP options with their oncologist (p=0.06) and those who had contact with the FP provider following consultation (p=0.09). KS was not correlated with age, income, receiving FP treatment or decisional conflict. Conclusions: Post-consultation knowledge about FP options was poor, possibly due to stress and information complexity. Our data suggest that patients may have improved comprehension if they bring someone with them to the consultation, discuss options with someone after the visit, and reference specific FP websites. These actions may improve a patient's overall understanding about FP options.
DNA hypermethylation biomarkers to predict therapy response of antiangiogenic therapy in metastatic renal cell carcinoma patients.
Authors: Inga Peters, Natalia Dubrowinskaja, Mahmoud Abbas, Christoph Seidel, Michael Kogosov, Ralph Scherer, Kai Gebauer, Axel S. Merseburger, Markus A. Kuczyk, Viktor Gruenwald, Juergen Serth
Journal: Journal of Clinical Oncology (2014)

459 Background: Antiangiogenic therapy has demonstrated to increase progression-free (PFS) as well as overall survival (OS) in RCC patients. Clinical scoring systems like the Memorial Sloan Kettering Cancer Center (MSKCC) help to stratify patients for treatment options. However, identification of molecular phenotypes of RCC patients would improve stratification of specific targeted therapies. We investigated whether DNA hypermethylation based markers can predict the PFS following first-line therapy. Methods: We examined primary tumors from formalin-fixed paraffin embedded tissue specimens obtained from 18 patients receiving anti-VEGF based targeted therapy. Quantitative methylation-specific PCRs were carried out following bisulphite conversion of DNA for CpG island methylation analysis of the five candidate genes, CST6, GATA5, LAD1, hsa-miR124-3 and hsa-miR9.1 identified in advance as potential prognosticators for RCC. For Kaplan Meier survival analysis relative methylation values were uniformly dichotomized and logrank statistics calculated. The analyses of sensitivity and specificity were carried out using a cutoff of 6 months for PFS to categorize for therapy failure and response, as described in the literature. Results: Hypermethylation of CST6 and LAD1 shows a highly significant association with a shortened PFS following first-line therapy (p=0.009, p=0.004, logrank test). The median survival observed for the high and low methylation group was 2.0 and 11.4 months for CST6 and LAD1. Moreover, LAD1 methylation showed a specificity of 1.0 (0.65-1.0, 95%CI) and a sensitivity of 0.73 (0.43-0.90, 95%CI) for detection of therapy failure. For CST6 methylation analysis a specificity of 0.86 (0.49-0.97, 95%CI) and a sensitivity of 0.82 (0.52-0.95, 95%CI) was detected. Conclusions: The analysis of our discovery cohort revealed that CGI methylation of CST6 and LAD1 predicts a shortened PFS of patients after anti-VEGF therapy. Provided, these results can be confirmed in an independent larger evaluation cohort, detection of hypermethylated loci in primary RCC would allow, to our knowledge for the first time, a molecular-based clinical management of patients.