tbuckley/cabot-search huggingface dataset:
Use of protein-network modeling of prostate cancer gene signatures to investigate essential pathways in disease recurrence.
Authors: J. L. Chen, J. Li, W. M. Stadler, Y. A. Lussier
Journal: Journal of Clinical Oncology (2011)

46 Background: Numerous molecular pathways have been implicated in aggressive prostate cancer. However, it has been difficult to gain an overview of the dominant pathways involved. By analyzing multiple prostate cancer gene signatures of poor prognosis through a protein interaction network, we are able to in an unbiased manner prioritize shared key biological mechanisms. Methods: We evaluate prostate gene signatures through a previously published Single Protein Analysis of Network (SPAN) methodology to develop a prostate cancer network signature. We assess this signature using a Gene Ontology based information-theoretic metric as well as assess its prognostic ability in an independent clinical dataset. We then examine the interconnectivity of the network signature to develop a phenotype-pathway map that provides an executive summary of critical mechanisms involved in advanced prostate cancer. Results: Of the 13 prostate cancer signatures that were evaluated, nine gene signatures plus a previously unpublished gene signature met criteria for evaluation. SPAN analysis of these protein interactions resulted in a 42-gene network signature. This network signature had the highest information-theoretic score based on Gene Ontology annotation similarity. Further, the signature identified a statistically significant survival difference (p=0.009) in a cohort of men with prostate cancer in an independent dataset. Additional analysis of the signature generated a phenotype-pathway map that not only recapitulated the centrality of PIK3/NF-κB signaling, but also highlighted less well-established pathways such as the JAK2 kinase activation cascade. Conclusions: SPAN analysis provides a robust means of abstracting disparate prostate cancer gene expression signatures into clinically useful, prioritized pathways that may ultimately serve as attractive, therapeutic targets. No significant financial relationships to disclose.
Centralized revision of diagnostic pathologic slides for prostate cancer patients on active surveillance: Is it just time- and resource-consuming?
Authors: Maurizio Colecchia, MariaFrancesca Alvisi, Biagio Paolini, Nicola Nicolai, Sergio Villa, Roberto Salvioni, Cristina Marenghi, Tiziana Rancati, Riccardo Valdagni
Journal: Journal of Clinical Oncology (2012)

132 Background: Active Surveillance (AS) is offered to prostate cancer (PCa) patients (pts) with very low risk disease, with well defined diagnostic biopsy details. For this reason, in order to standardize diagnostic inclusion criteria, we requested pathologic review before AS enrollment. We here report on second opinion of PCa needle biopsies to determine how often the expert opinion of a uro-pathologist resulted in a different diagnosis, in the group of pts who were proposed for AS. Methods: AS institutional protocol (SAINT) started in Mar 05. Entry criteria: initial PSA≤10ng/ml, Tstage≤T2a, GPS≤3+3, positive biopsy cores≤20%, max core length containing cancer≤50%. In Nov 07 PRIAS started. PRIAS vs SAINT differs on: max 2 positive cores and PSA density&lt;0.2ng/ml/cc. A second opinion on biopsy was requested in 248 cases (Oct 05 - Jul 10), due to outside diagnosis. We analyzed differences between outside diagnosis and institutional expert opinion. We considered two classes of differences: minor differences (which did not prevent AS enrollment) and significant changes (which resulted in a change in prognosis and closed the possibility of AS enrollment). Results: 40/248 (16.1%) cases had minor differences (18 SAINT and 22 PRIAS). In SAINT pts, 12/18 (66.7%) biopsies were increased in the max core length containing cancer (but still≤50%) and 6/18 (33.3%) had a change in the number of positive cores (but still≤20% of total cores). In PRIAS pts 10/22 (45.5%) changes were related to upsizing (from 1 to 2 positive cores) and 5/12 to downsizing (from 2 to 1 positive core). 7/22 changes were related to differences in core length containing cancer (from below to above 50%). Significant differences were observed in 30/248 (12.1%). 20/30 were related to upgrading, 10/30 pts had an upsizing: 1 SAINT pt exceeded 20% of positive cores, 5 SAINT pts exceeded 50% of max tumor length of positive cores, while 4 PRIAS pts increased from 2 to 3 or 4 positive cores. Conclusions: Central pathology review reduces population heterogeneity in the specific setting of AS programs, significant reclassification of risk category involved 12% of pts. Current clinical consequences of central review cannot be determined.
An age-corrected matched-pair study of erectile function in patients treated with adaptive intensity modulated radiation therapy (IMRT) versus high-dose-rate brachytherapy (HDR) in prostate cancer.
Authors: Jillian Nicole Warner, Ovidiu Marina, Inga S. Grills, Chirag Shah, Michelle Wallace, Kimberly Marvin, Hong Ye, Gary S. Gustafson, Donald Brabbins, Larry Llyn Kestin, Michel Ghilezan, Alvaro Martinez
Journal: Journal of Clinical Oncology (2012)

225 Background: Increasing age is a likely contributor to erectile dysfunction (ED) after radiotherapy for prostate cancer. A matched-pair (MP) analysis, with age as a criterion, was used to investigate ED after IMRT and HDR monotherapy for prostate cancer. Methods: 430 patients with low (63%) or intermediate risk (37%) prostate cancer with full or partial erectile function were treated between 4/00 and 9/10 with IMRT (n=215) or brachytherapy (n=215). Patients with follow up (FU) &lt;1y were excluded. IMRT dose was 70.2–82.8 Gy (median 75.6) in 1.8 Gy/fx. HDR was given as 9.5 Gy x 4 (median), 13.5 Gy x 2 or 12 Gy x 2. MP, univariate, and multivariate analyses examined ED using CTCAEv4. Match criteria were age (±5y), Gleason (6,7), T stage (T1, T2), and PSA (&lt;4, 4–10, &gt;10). BF was by modified Phoenix criteria (nadir+5 for 2y, nadir+2 after). Results: Median FU was 3.4y (range 1–7.1) for IMRT and 3.1y (range 1–10.9) for HDR. There was no difference in PSA (4.8 vs. 4.6, p=0.4), T stage (88% vs. 88% T1, p=1.0) and Gleason score (63% vs. 63% 6, p=1.0) between IMRT and HDR. Despite age matching, IMRT patients were older (median 65 vs. 62 y, p=0.05). Pre-treatment potency grade 0, 1, and 2 were found in 70%, 14% and 15% of IMRT and 69%, 20% and 11% of HDR patients. 5y OS, CSS, and BF were 100%, 100% and 2.4% for IMRT, and 99% (p=0.35), 100% (p=1.0), and 10.6% (p=0.001) for HDR. On subset analysis of pre-treatment grade 0 patients, univariate analysis showed HDR (p&lt;0.001), increasing Gleason (p=0.05) and increasing FU time (p&lt;0.001) correlated with post-treatment ED, while age (p=0.32), PSA (p=0.46) and T stage (p=0.76) did not. On multivariate analysis, increasing FU time correlated with ED (p&lt;0.001), while treatment type (p=0.10) and Gleason (p=0.49) did not. Conclusions: Both IMRT and HDR yield comparable low (25%) rates of 1+ ED for patients with no ED at baseline. Increasing age does not appear to significantly impact ED for both IMRT and HDR. [Table: see text]
Melphalan Affects Genes Critical for Myeloma Survival, Homing, and Response to Cytokines and Chemokines
Authors: Shmuel Yaccoby, Joshua Epstein, Pingping Qu, Frits van Rhee, Maurizio Zangari, Christoph Heuck, Faith E Davies, Alan Mitchell, Antje Hoering, John Crowley, Bart Barlogie, Gareth J Morgan
Journal: Blood (2015)
Functional and oncologic outcomes of nephron-sparing surgery (NSS) for patients with renal cell carcinoma (RCC) greater than 4 cm in diameter.
Authors: C. Piper, S. Richter, B. Brehmer, D. J. Pfister, R. Epplen, A. Heidenreich
Journal: Journal of Clinical Oncology (2011)

347 Background: Organ preserving surgery represents the guideline recommended surgical treatment of choice for patients with small renal tumors ≤ 4cm in diameter. There are only few data in the literature with regard to the oncological and functional outcome of elective NSS in RCC larger than 4cm. Methods: We retrospectively reviewed the charts of all patients who underwent elective NSS for RCC at our institution during 2004-2009. We identified 288 patients of whom 196 (68.1%) patients and 92(31.9%) patients underwent NSS for a tumor &lt; 4cm (group 1) and a tumour ≥ 4cm (group 2), respectively. We analyzed tumor size, TNM-classification, OR time, surgical margins, complications, mortality, recurrences and metastases in both groups. Results: We identified significant differences between group 1 and 2 for the following variables: mean tumor size (2.9 vs. 8.6cm, p = 0.03), necessity for warm ischemia (15.1% vs. 51%, p = 0.001), mean ischemia time (3.5 vs. 10.2 min, p = 0.002), need for endoluminal stenting due to involvement of the renal pelvis (0.5% vs. 24.2%, p = 0.001). Significantly less pT2 (12.7% vs. 29.7%, p = 0.03) and pT3 tumors (8.7% vs. 12%, p = 0.05) were identified in group 1 when compared to group 2. There were no significant differences with regard to mean OR time (61 vs. 74 min), positive surgical margins (1/192 vs. 1/92), hospital stay, and perioperative complications. There were no significant differences with regard to stage specific overall survival, cancer-specific survival and progression-free survival. There was no significant survival difference between NSS and radical nephrectomy. Conclusions: NSS can be safely performed in RCC &gt; 4 cm without increasing the frequency of treatment-associated complications or decreasing cancer-specific survival. NSS should represent the treatment of choice in all patients with RCC of 4-7cm in diameter if technically feasible. No significant financial relationships to disclose.
Nitric oxide-releasing nanoparticle combination therapy to overcome drug resistance in platinum-resistant breast cancers.
Authors: M. L. Forrest, S. Cai, S. Duan, M. S. Cohen, Q. Yang
Journal: Journal of Clinical Oncology (2011)

278 Background: The most successful cancer chemotherapy regimens usually involve the administration of multiple cytotoxic agents simultaneously. Because different chemotherapies may have different mechanisms of action; it is difficult for cancer cells to become resistant to combination therapy. Recent investigations have discovered that nitric oxide (NO) may be involved in the reversal of cisplatin (CDDP) resistance in chemotherapy. Therefore, we sought to develop a combination regimen involving a NO-releasing prodrug (NO1) and cisplatin for the treatment of breast cancer. Methods: The prodrug NO1 was synthesized to be localized in tumor cells and to release nitric oxide over 10 hours. The antiproliferative activity of NO1 was determined in human breast cancer cell line, MDA-MB-468LN. To evaluate the effectiveness of the CDDP/NO combination regimen, platinum-resistant MDA-MB-468LN cells were treated with either cisplatin alone ([CDDP]=0.01, 0.02 or 0.03 mM) or the CDDP/NO combination ([CDDP]=0.01, 0.02 or 0.03 mM; [NO1]=0.02 mM). The cell viability was determined 48 hours post-treatment using a live/dead trypan blue exclusion assay. Results: The toxicity to breast cancer cells was higher than JS-K, a systemic NO agent currently in preclinical development. (NO1: IC 50 =26µM; JS-K: IC 50 =42 µM). In addition, NO1 had a long sustained release of nitric oxide, approximately one fold longer than JS-K (NO1: t1/2=6 h; JS-K: t1/2=3 h). The combination treatments resulted in 6.6-, 6.9- and 7.5-fold increase in cell death compared to cisplatin treatment alone at cisplatin concentrations of 0.01, 0.02 and 0.03 mM, respectively. A subsequent study in a murine xenograft of head and neck cancer found NO-1 conjugated to nanoparticles increased survival a mean of 10 weeks compared to controls (p&lt;0.0001). Conclusions: Nitric oxide prodrug NO-1 and nanoparticles of it have high anticancer activity in vivo and they can reverse platinum resistance in vitro. Ongoing studies are examining the safety and efficacy of CDDP/NO combination therapy in mouse xenografts of human breast cancer.
Deregulation of the PI3K/Akt Signal Transduction Pathway Is Associated with the Development of Chemotherapy Resistance and Can be Effectively Targeted to Improve Chemoresponsiveness in Burkitt Lymphoma Pre-Clinical Models
Authors: Sarah Frys, Natalie M Czuczman, Cory Mavis, Delphine C.M. Rolland, Megan S Lim, Aradhana Tiwari, Mitchell S. Cairo, Rodney R. Miles, Matthew J. Barth
Journal: Blood (2014)
Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML)
Authors: Amir T. Fathi, Harry P. Erba, Jeffrey E. Lancet, Eytan M. Stein, Farhad Ravandi, Stefan Faderl, Roland B. Walter, Anjali Advani, Daniel J. DeAngelo, Tibor J. Kovacsovics, Anand P Jillella, Dale L. Bixby, Moshe Y Levy, Megan M. O'Meara, Phoenix Ho, Anthony S. Stein
Journal: Blood (2016)
Cytogenetic Features and Prognosis In Argentinean Patients with Myelodysplastic Syndrome: a Multicenter Study
Authors: Carolina Belli, Raquel Bengió, Pedro Negri Aranguren, Francisco Sakamoto, María Gabriela Flores, Nora Watman, Elsa Nucifora, Jorge Arbelbide, María Virginia Prates, Irene B Larripa
Journal: Blood (2010)
Minimal Residual Disease (MRD) By Either Flow Cytometry or Cytogenetics Prior to an Allogeneic Hematopoietic Cell Transplant (allo-HCT) Predicts Poor Acute Myeloid Leukemia (AML) Outcomes
Authors: Lakshmikanth Katragadda, Maxim Norkin, Myron Chang, Yunfeng Dai, Jan S Moreb, W. Stratford May, Christopher R. Cogle, Helen Leather, Ying Li, Lamis K Eldjerou, John W Hiemenz, Randy A. Brown, John R. Wingard
Journal: Blood (2015)
Odontoma in a 255-Million-Year-Old Mammalian Forebear
Authors: Megan R. Whitney, Larry Mose, Christian A. Sidor
Journal: JAMA Oncology (2016)

This study describes cancer in a 255-million-year-old mammalian forebear and comments on the implications for establishing the phylogenetic and physiologic conditions under which such pathologic conditions first arose.
Relationship between OS and PFS in metastatic breast cancer (MBC): Review of FDA submission data.
Authors: P. Cortazar, J. J. Zhang, R. Sridhara, R. L. Justice, R. Pazdur
Journal: Journal of Clinical Oncology (2011)

1035 Background: An improvement in overall survival (OS) in a randomized controlled study is the gold standard endpoint for the regular approval of new treatments in MBC. Progression-free survival (PFS) has been used for approval of second and third-line indications or accelerated approval of first-line indications. We have further explored the relationship between OS and PFS in MBC. Methods: We reviewed 12 randomized clinical trials in 8,431 patients with MBC. The trials led to new drug approvals or were presented at an ODAC meeting. All of these trials had PFS as a primary or secondary endpoint. Due to important limitations (e.g., lack of endpoint definitions, inconsistent PFS definitions, or insufficient information on trial statistical design) with some published trials, we limited our evaluation and endpoints correlation to data reviewed by the FDA. The relationship between PFS and OS in MBC was investigated using a weighted linear regression model, where each trial was weighted by the sample size. The coefficient of determination (R2) was calculated to explain the variability of the treatment effect on PFS with respect to the treatment effect on OS, where treatment effects were derived as hazard ratios. Analyses were also performed within lines of therapy and for differences in median PFS and OS time. Results: A total of 16 PFS/OS comparison pairs, 10 in first line therapy and 6 in second/third line therapy. The medians (range) in the difference of median PFS and OS for first line are 2.3 (0.3, 5.6) months and 1.7 (−1.7, 5.4) months, respectively. For second/third line, the medians (range) in the difference of median PFS and OS are 1.9 (1.5, 2.8) months and 2.5 (−0.1, 3.3) months, respectively. Conclusions: Our evaluation is limited to 12 trials that were submitted to support approval in MBC. Although the number of comparison pairs was limited, the results (R=0.28) fail to demonstrate an association between PFS and OS. Less than 10% (R2=0.079) of the variation in OS is explained by the variation in PFS, suggesting that the relationship between PFS and OS is weak in MBC. The lack of association is especially apparent for second/third line therapy MBC.
Inhibition of Src and insulin/insulin-like growth factor-1 receptor (IR/IGF-1R) on tumors and bone turnover in prostate cancer (PCa) models in vivo compared with inhibition of either kinase alone.
Authors: Farshid Dayyani, Nila Parikh, Jian H. Song, John C. Araujo, Joan M. Carboni, Marco M. Gottardis, Geralyn C. Trudel, Christopher Logothetis, Gary E. Gallick
Journal: Journal of Clinical Oncology (2012)

61 Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases (SFK) and IR/IGF-1R, respectively. Based on a phase I/II clinical trial in which 9/19 pts treated with docetaxel + dasatinib were increased in serum IGF-1 levels after one cycle, the aim of this study was to establish potential antitumor cooperativity of inhibiting both IGF-1R and Src in experimental PCa models in vitro and in mice. Methods: Inhibition of Src and IGF-1R pathways was accomplished by pharmacologic agents (dasatinib against Src and BMS-754807 against IR/IGF-1R) as well as by shRNA, in PC3 and LNCaP cells. In vivo studies were done after orthotopic and intratibial injection of PC3 cells in nude mice. Results: SFK inhibition decreased proliferation and migration of PCa cells whereas IGF-1R blockade induced apoptosis. All anti-tumor effects were enhanced by dual blockade. IGF-1 induced phosphorylation of Akt1 and 2. Only Akt 1 phosphorylation was decreased by dasatinib; whereas Akt 1 and 2 phosphorylation were completely abrogated by the combination. Dasatinib and BMS-754807 inhibited orthotopic in vivo tumor growth of PC3 cells more potently than either inhibitor alone. Similarly, intratibial tumor growth and bone destruction was significantly reduced with the drug combination, accompanied by a decrease in serum bone turnover markers alkaline phosphatase and N-telopeptide. Conclusions: Dual inhibition of Src and IGF-1R has greater anti-tumor effect in PCa cells compared to inhibiting either alone. In the presence of IGF-1, dasatinib and BMS-754807 are necessary to inhibit IGF-1-induced phosphorylation of Akt1 and 2 in tumor cells in culture. In intratibial models, decreased bone turnover markers in serum support the concept of targeting both the epithelial and bone microenvironment. The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking complementary processes of tumor growth and progression.
Physicians’ perspectives on treatment options and outcomes in metastatic triple-negative breast cancer.
Authors: D. Yee, L. Chen, A. Goren, R. Lorenzo
Journal: Journal of Clinical Oncology (2011)

e11542 Background: Triple-negative breast cancer (TNBC) is a clinically aggressive type of BC associated with poorer overall prognoses than ER+, PR+, or HER2+ BCs, without specific targeted treatments. Data have been limited on the treatment experience from the physician’s perspective.Objective: This study was aimed at evaluating physician perceptions of, and experience with, metastatic TNBC (mTNBC) and its treatment in the United States.Methods: Physicians on a US oncology panel (AllGlobal, a Kantar Health Company) were invited and self-selected to participate in an Internet-based survey. Questionnaires were developed to examine a range of assessments pertaining to experience, challenges, and goals with current treatments and physicians’ perceptions of patients’ experience with mTNBC. Results: A total of 161 oncologists (89% office-based, 11% hospital-based) participated. Compared with treatment goals for non-TNBC, physicians targeted symptom relief to a greater extent (1st-line: 32.0% vs 31.1%; 2nd-line: 38.7% vs 36.8%; P<0.05) and prolonged overall survival (OS) to a lesser extent (53.5% vs 55.7%; 41.7% vs 43.1%; P<0.05) as treatment goals for TNBC. Relapsed mTNBC was ranked as the most challenging BC, followed by de novo mTNBC and non-TNBCs. “Aggressive disease and bad prognosis” and “treatment options are more limited” were cited as the top 2 contributing factors. On average, only about 1/3 of 1st-line and 1/5 of 2nd-line treatments were rated as satisfactory. Combination therapies were more frequently rated as highly toxic and very expensive versus monotherapies. According to physicians, patients with mTNBC versus non-TNBC feel more hopeless and depressed when learning of diagnoses, are significantly less likely to expect/experience a full recovery or cure, an extension of OS or progression-free survival, symptom relief, or tolerable side effects (all P<0.05), or expect to have treatment meet or exceed their expectations (P<0.001).Conclusions: These survey results indicate that physicians are dissatisfied with current treatments for mTNBC and perceive that patients with TNBC are worse off than patients with other BCs. The study underscores a strong unmet need for targeted TNBC treatments.
Eight Cycles of BEACOPP Escalated Compared with 4 Cycles of BEACOPP Escalated Followed by 4 Cycles of BEACOPP Baseline with Our without Radiotherapy in Patients in Advanced Stage Hodgkin Lymphoma (HL): Final Analysis of the Randomised HD12 Trial of the German Hodgkin Study Group (GHSG).
Authors: Volker Diehl, Heinz Haverkamp, Rolf Peter Mueller, Hans Theodor Eich, Hans Konrad Mueller-Hermelink, Thomas Cerny, Jana Markova, Anthony Ho, Lothar Kanz, Richard Greil, Wolfgang Hiddemann, Andreas Engert
Journal: Blood (2008)
Survival, health care utilization, and cost of metastatic triple-negative breast cancer in a U.S.-managed care setting.
Authors: O. Baser, W. Wei, H. J. Henk, L. Xie
Journal: Journal of Clinical Oncology (2011)

e11576 Background: Triple-negative breast cancer (TNBC) is a high-grade cancer with a poor prognosis characterized by a lack of ER and PR expression and no HER2 overexpression. Differences in survival and economic burden between metastatic TNBC (mTNBC) and metastatic non-TNBC (mNon-TNBC) are not well understood. Objective:To measure and compare survival, healthcare utilization, and costs between mTNBC and mNon-TNBC. Methods: This retrospective study used the Impact Intelligence Oncology Management system linked with 1999-2009 managed care healthcare claims and social security administration mortality data. Patients were followed from metastatic diagnosis until death, disenrollment, or end of the observation period. Staging, ER, PR, and HER2 status were obtained at initial diagnosis; recurrence was identified from medical claims. Risk-adjusted overall survival rate, healthcare utilization, and costs during the follow-up period were compared. Results: A total of 579 patients (290 de novo stage IV, 289 recurrent) were identified and 23% had TNBC (47 de novo stage IV, 87 recurrent). Patients with mTNBC vs mNon-TNBC were younger (56 vs 59 years, P<0.03), more likely to be 18-44 years old (20.2% vs 11.7%, P=0.01), be recurrent (64.9% vs 45.4%, P<0.0001), and have a higher mortality rate (67.2% vs 50.8%, P=0.0008). mTNBC had significantly higher mortality risk than mNon-TNBC (HR=1.69, P<0.001). In terms of adjusted annual healthcare utilization and cost, mTNBC patients had more all-cause and cancer-related number of hospitalizations (2.06 vs 1.34, P=0.003; 0.88 vs 0.56, P=0.011), all-cause hospitalization days (31.39 vs 16.92, P=0.012), all-cause total costs ($131,272 vs $109,865, P=0.042), all-cause and cancer-related inpatient costs ($32,233 vs $13,834, P<0.0001; $16,790 vs $8,395, P=0.021), and cancer-related emergency room costs ($208 vs $58, P=0.049). Patients with mTNBC also had higher all-cause total ($127,505 vs $106,120, P=0.037) and inpatient ($31,865 vs $13,534, P<0.001) costs to payers. Conclusions: This real-world study demonstrates that mTNBC is associated with significantly poorer survival and higher healthcare utilization and costs compared with mNon-TNBC.