tbuckley/cabot-search huggingface dataset:
Prerandomization factors and utilization of neoadjuvant chemotherapy in a clinical trial of extended versus standard pelvic lymphadenectomy at the time of radical cystectomy for bladder cancer.
Authors: Seth P. Lerner, Hongli Li, Robert Scott Svatek, Theresa M. Koppie, Ajjai Shivaram Alva, Francisco G. La Rosa, Rick Bangs, Sumanta Kumar Pal, Siamak Daneshmand, Adam S. Kibel, Daniel J. Canter, Catherine M. Tangen, Ian Murchie Thompson
Journal: Journal of Clinical Oncology (2014)

295 Background: Despite level I evidence supporting the use of cisplatin-based NAC, this practice has not been widely adopted. We assessed contemporary utilization of NAC within the context of an ongoing prospective clinical trial (SWOG S-1011; NCT01224665) in order to identify clinical and/or demographic factors that are associated with receipt of NAC. Methods: S1011 tests the hypothesis that an extended pelvic lymphadenectomy (PLND) is associated with a 10-12% improvement in recurrence-free survival compared to a standard PLND among patients with clinical stage T2-4aN0-2M0 urothelial cell carcinoma of the bladder. Patients are registered prior to RC and are randomized intra-operatively to extended vs. standard PLND. Receipt of NAC, including type and duration are is a stratification factor and prospectively recorded at registration. We evaluated the association of pre-randomization factors, including age, gender, clinical stage, performance status, and institution with the receipt of NAC. Results: 243 patients have been registered as of 9/18/2013 and 229 randomized. Among randomized patients, 119 (52%) received NAC, including 97 (82%) treated with cisplatin-based NAC. The most common NAC regimens, Gem-Cis (gemcitabine-cisplatin) and MVAC (methotrexate, vinblastine, adriamycin, and cisplatin), were administered to 58 and 35 patients, respectively. 63% (40/64) of patients with cT3-4a disease received NAC vs. 48% (79/165) with cT2. There was no association of age, gender, race, ethnicity or PS with receipt of NAC. Among 8 institutions with at least 10 patients registered, the range of utilization of neoadjuvant chemotherapy received was 7% to 83%. Reason for not giving NAC is recorded at time of registration and a detailed analysis will be presented. Conclusions: Interim analysis of S1011, a prospective surgical trial, reveals the highest rate of integration of NAC with RC to date and reflects a considerable change in evidence based practice patterns. The institutional variation in utilization of NAC warrants further exploration of factors influencing delivery of care. Clinical trial information: NCT01224665.
Phase III results of a novel oral neurokinin-1 (NK-1) receptor antagonist, casopitant: Single oral and 3-day oral dosing regimens for chemotherapy-induced nausea and vomiting (CINV) in patients (pts) receiving moderately emetogenic chemotherapy (MEC)
Authors: S. M. Grunberg, Z. Aziz, A. Shaharyar, J. Herrstedt, F. Roila, S. VanBelle, R. R. Bandekar, M. E. Guckert, M. W. Russo, W. Arpornwirat
Journal: Journal of Clinical Oncology (2008)

9540 Background: In a phase II dose-ranging trial, casopitant, a novel NK-1 antagonist, plus ondansetron/dexamethasone (OND/DEX) demonstrated efficacy in reducing CINV in pts receiving MEC. This phase III trial evaluated three dosing regimens in pts receiving anthracycline and cyclophosphamide (AC)-based MEC. Methods: 1,933 pts with breast cancer (96%) were enrolled in a multinational, double-blind, active-controlled trial. All pts received DEX 8 mg IV D1 + OND 8 mg BID PO D1–3. Pts were randomized to receive no additional therapy (CTRL), a single oral dose (150 mg PO D1), or a 3-day oral or 3-day IV/oral dose (150 mg PO D1 or 90 mg IV D1 + 50 mg PO D2–3) of casopitant. Pts continued on therapy up to 4 cycles. Complete response (CR; no vomiting, retching, or rescue medications) in the first 120 hrs after each cycle of an AC-based MEC regimen was the primary endpoint. Here we report on pts receiving the oral dosing regimens of casopitant in addition to CTRL. Results: Both single oral dose and 3-day oral regimens of casopitant plus OND/DEX produced statistically significant improvement (at a 1.67% level of significance adjusted for 3 primary comparisons) in overall CR rates over 5 days. This clinical benefit appeared to be maintained through repeat cycles of MEC. Significant reductions in the number of pts experiencing emetic events in the overall and delayed phases were observed. Casopitant was generally well tolerated. AE frequency was similar across study arms. Common Aes were neutropenia, alopecia, fatigue, leukopenia, and constipation. Conclusions: Addition of a single oral dose or a 3-day oral regimen of casopitant to OND/DEX provided a clinically meaningful improvement in the proportion of patients achieving CR over 5 days. This benefit appeared to be maintained in initial and repeat cycles of MEC. The casopitant regimens were generally well tolerated over all cycles. Cycle of MEC Endpoints (0–120 hrs) CTRL n=479 (%) Casopitant 150 mg PO D1 n=479 (%) P-value 150 mg PO D1+50 mg PO D2–3 nCTRL n=479 (%)480 (%) P- value 1 Complete Response 284 (59) 351 (73) <0.0001 350 (73) <0.0001 Acute (0–24 hrs) 406 (85) 421 (88) 0.1586 427 (89) 0.0545 Delayed (24–120 hrs) 284 (59) 351 (73) <0.0001 350 (73) <0.0001 No vomiting 304 (63) 381 (80) <0.0001 387 (81) <0.0001 2 Complete Response 236/377 (63) 307/383 (80) NA 308/378 (81) NA 3 Complete Response 222/333 (67) 274/345 (79) NA 276/343 (80) NA 4 Complete Response 200/289 (69) 250/306 (82) NA 254/304 (84) NA Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Helsinn, Merck, Schering-Plough GlaxoSmithKline Helsinn, Merck GlaxoSmithKline
NOTCH2 inhibition on tumor growth and metastasis in bladder cancer.
Authors: Tetsutaro Hayashi, Kilian Gust, Wolfgang Jaeger, Shannon Awrey, Na Li, Manuel Altamirano-Dimas, Ralph Buttyan, Ladan Fazli, Akio Matsubara, Peter C. Black
Journal: Journal of Clinical Oncology (2014)

315 Background: Notch is a family of cell surface receptors that has been demonstrated in several malignancies to regulate differentiation, proliferation, and metastasis. We have investigated the role of Notch signaling in bladder cancer and report here effects of modulating Notch2 in preclinical models of bladder cancer. Methods: Notch2 staining was examined in cystectomy patients by immunohistochemistry (IHC). The high NOTCH2 expressing UM-UC3 and UM-UC13 bladder cancer cells were stably transduced with either Notch2 specific or control shRNA. The low Notch2 expressing RT4V6 and RT112 cells were transduced with NOTCH2 intracellular domain or empty vector. A Notch2 inactivating antibody, NRR2Mab, was provided by Genentech, Inc. (San Francisco, CA). The effects of NOTCH2 overexpression and inhibition were assessed for changes in proliferation under both adherent (AH) and anchorage independent conditions (AI), and invasive activities in vitro, as well as for expression of markers of epithelial to mesenchymal transition (EMT) and stem cell markers. In vivo effects were evaluated in an orthotopic bladder cancer xenograft model with bioluminescence imaging. Results: NOTCH2 overexpression in IHC correlated with higher grade and stage. Both NOTCH2 overexpressing cells showed spindle shaped morphology and increased cell growth in AH and AI and invasion compared to mock cells. This was associated with cell cycle progression and increased expression of EMT and stem cell markers. Stable NOTCH2 knockdown cells and cells treated with NRR2Mab demonstrated decreased growth in AI and invasion, and this was associated with decreased expression of EMT and stem cell markers. In vivo, RT4V6 NOTCH2 overexpression increased xenograft tumor growth and NOTCH2 overexpression increased ki67 positive cells and promoted EMT in IHC. Stable Notch2 knockdown inhibited xenograft tumor growth in UM-UC3 and UM-UC13. NRR2Mab treatment also inhibited UM-UC13 xenograft tumor growth and lymph node metastasis. Conclusions: NOTCH2 plays a crucial role in growth, self-renewal and invasion in bladder cancer. These results provide pre-clinical proof of principle that Notch2 inhibition may be a rational treatment for bladder cancer.
Comparison of the Feasibility of Adult Allogeneic Umbilical Cord Blood Transplantation between the Myeloablative Conditioning Regimen and the Non Myeloablative One.
Authors: Haruko Tashiro, Yasuji Kozai, Mitsuho Noguchi, Moritaka Goto, Kazuo Kawasugi, Hideki Kodo, Naoki Shirafuji
Journal: Blood (2004)
Impact of the Recurrence Score (RS) result and mismatch repair status (MMR) on agreement between oncologists (MDs) for stage II colon cancer (CC) recurrence risk (RR) assessment: A novel clinical utility endpoint for prognostic markers.
Authors: Robin Katie Kelley, Margarita Lopatin, Jimmy Hwang, Michael Crager, Adrienne A Brenner, Jane Kuczma, Ashley King, Calvin Chao, Mark Lee, Alan Paul Venook
Journal: Journal of Clinical Oncology (2013)

e14569 Background: Appropriate use of prognostic and predictive markers depends on quality of evidence for clinical utility in addition to clinical validity. In stage II CC, RR assessment is based traditionally on clinicopathologic factors (CP) with limited clinical validation and varies substantially across providers. We hypothesized that the validated Oncotype DX Colon Cancer RS and MMR tests may impact clinical decision-making by decreasing variation in RR assessment across MDs. We conducted a survey to compare the level of MD agreement on stage II CC RR assessment using CP alone vs CP+RS+MMR (CP+). Methods: A clinical trial database was randomly sampled for 100 cases of stage II CC stratified on T-stage, MMR and RS groups. Anonymous internet surveys asked each MD to assess 3-year RR for 10 cases with CP and 10 different cases with CP+. MDs were divided into panels of 5; all members of each panel reviewed the same cases. Agreement in RR among MDs was assessed using within-panel mean squared difference in RR assessments and analyzed using generalized linear models. Results: 30 community (C) and 20 university-based (U) MDs (Assoc of Northern California Oncologists or NCCN, respectively) completed evaluable surveys April-June 2012. For C vs U, median years in practice were 5 and 2; prior use of RS 13% vs 25%; and routine MMR use 21% vs 55%. The standard deviation of the differences (SDD) in RR assessments for CP alone was high overall (7%), and greater for U vs C MDs (8.2% vs 6.4%). CP+ produced higher agreement in RR assessments vs CP for both C (p&lt;.001) and U (p=0.04) MDs, with 23% and 20% proportional reduction in SDD. ForT3 MMR-proficient (P) patients (n=70), CP+ produced higher agreement in RR for both C (p&lt;0.001) and U (p=0.01) MDs with 37% and 29% reduction in SDD. Conclusions: Addition of RS+MMR to CP significantly increased MD agreement on RR assessment in stage II CC, including T3 MMR-P patients. Agreement was higher among C than U MDs. MD agreement on stage II CC RR assessment and Tx decision-making warrants consideration as a novel endpoint for clinical utility of RS, MMR, and other prognostic markers.
Long-Term Follow-up of HCV Infected Stem Cell Transplant Patients and Effects of Antiviral Therapy.
Authors: Per T. Ljungman, Anna Locasciulli, V. Gomez-Garcia de Soria, Albert N. Bekassy, Lorentz J. Brinch, Ildefonso Espigado, Augustin Ferrant, Ian M. Franklin, Joan O'Riordan, Montserrat Rovira, Peter J. Shaw, Hermann Einsele
Journal: Blood (2009)
Bevacizumab (Bmab) in combination with uracil-tegafur (UFT) and oral leucovorin (LV) in elderly patients (≥ 75 years old) with metastatic colorectal cancer (mCRC): A multicenter phase II trial (J-BLUE study).
Authors: Mitsuo Shimada, Tomohiro Nishina, Jun Higashijima, Toshikazu Moriwaki, Toshiki Masuishi, Yoshinori Sakai, Mitsuharu Ozeki, Yuji Negoro, Shunju Indou, Tadamichi Denda, Mikio Sato, Masamitsu Morimoto, Go Nakajima, Minoru Mizuta, Ikuo Takahashi, Yoshinori Hiroshima, Hiroyasu Ishida, Takashi Maeba, Ichinosuke Hyodo
Journal: Journal of Clinical Oncology (2014)

588 Background: Now fluoropyrimidine plus Bmab is considered a recommendable option to the majority of elderly mCRC patients who are deemed inappropriate for the standard doublet chemotherapy with biologics. Our previous phase II study of UFT/ LV in elderly mCRC patients (≥75 years old) had demonstrated acceptable safety and efficacy (overall response rate [ORR] 33%, progression-free survival [PFS] 5.3 months, overall survival [OS] 18 months). The aim of the present study was to investigate the efficacy and safety of Bmab in combination with UFT/LV for elderly mCRC patients. Methods: This study was designed as a single-arm, open-label, multicenter, cooperative group (SGOSG-TCTG) clinical trial (trial registration: UMIN000003515). Key eligibility criteria included age ≥75 years, ECOG performance status (PS) 0 or 1, first-line chemotherapy, measurable lesions, and preserved organ functions. Patients received UFT 300mg/m 2 /day and LV 75mg/body/day on days 1-21 followed by 7 days rest, and intravenous administration of Bmab 5mg/kg on days 1 and 15. Treatment repeated every 28 days. The primary endpoint was PFS, and secondary endpoints were ORR, OS, and safety. Results: A total of 55 patients were enrolled from 15 institutions between Aug 2008 and Mar 2012. Among them, 52 eligible patients were evaluated. Median age was 80 years (range: 75-87). ECOG PS 0 was 73%. Median PFS was 8.2 months (95% confidence interval [CI], 6.2-10.3, events in 86.5%). Confirmed ORR was 40.4% (95% CI, 27.0-54.9%). Median OS was 18.7 months (95% CI, 10.3-27.0, events in 48%). The most common grade ≥3 treatment-related adverse events were hypertension (11.5%), fatigue (7.7%), nausea (5.8%), and diarrhea (5.8%). The treatment-related death occurred in 2 (3.8%) patients. Main reasons for discontinuation of treatment were disease-progression (62.5%) and toxicity (27.1%). Conclusions: Bmab in combination with UFT/LV is tolerable and effective treatment option for elderly patients (≥75 years old) with mCRC. Further trial with Bmab plus UFT/LV targeting elderly mCRC patients would be warranted. Clinical trial information: 000003515.
Analysis of c-Met gene amplification in Japanese patients with advanced non-small cell lung cancer (NSCLC).
Authors: T. Sone, K. Kasahara, A. Sakai, H. Ikeda, K. Kurokawa, M. Fujimura
Journal: Journal of Clinical Oncology (2011)

e18021 Background: Several studies have reported that increased gene copy number (GCN) of c-Met is associated with poor prognosis and resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI). A recent phase II study of mostly Caucasian subjects showed that addition of a c-Met receptor TKI to EGFR-TKI prolonged progression-free survival in NSCLC. It is unclear whether c-Met gene status differs between Caucasians and Asians. Thus, c-Met GCN was evaluated in Japanese patients with advanced NSCLC to determine whether c-Met could be a therapeutic target in Asian patients. EGFR mutation and GCNs of EGFR and Her2 were also analyzed. Methods: Tumor samples suitable for gene amplification and mutation analysis were collected from 40 patients with institutional review board approval. Fluorescence in situ hybridization was used to assess c-Met, EGFR, and Her2 GCNs. DNA was extracted from tumor tissue after micro dissection. PCR and direct sequencing of exons 18, 19, and 21 of the EGFR gene were also performed. Results: Of the 40 patients, 10 (25%) were female, 12 (40.0%) were light or never-smokers, and 34 (85%) had adenocarcinoma. The median age was 63 (range 41-81) years, and 36 patients (90.0%) had a good PS (0-1). The median GCNs of c-Met, EGFR, and Her2 were 1.1 (range 0.3-1.7), 1.1 (range 0.9-7.0), and 1.2 (range 0.9-3.5). No patients had more than 4 c-Met copies. Overall survival was not significantly different between patients with more than 1.1 copies of c-Met and those with less than 1.0 copy of c-Met. GCNs of c-Met, EGFR, and Her2 were not associated with any patients’ characteristics. The c-Met GCN was significantly correlated with Her2 GCN (r=0.401), but not EGFR mutation status or EGFR gene amplification. Thirteen patients were treated with EGFR-TKI; the response rate was higher in patients with EGFR mutations (7/11 vs. 0/2). The mean c-Met GCN was not correlated with EGFR-TKI response (1.08 vs. 1.07). The mean EGFR and Her2 GCNs were higher in EGFR-TKI responders than non-responders (2.91 vs. 1.05, p=0.03; 1.46 vs. 1.12, p=0.053). Conclusions: The c-Met GCN of Japanese NSCLC patients was obviously smaller than in the previous study of Caucasians. There might be ethnic difference in c-Met gene amplification such as EGFR mutation.
Genomic profiling of esophagogastric (EG) tumors in clinical practice.
Authors: Jamie Cathleen Riches, Nikolaus Schultz, Geoffrey Yuyat Ku, Tooba Imtiaz, David Paul Kelsen, David H. Ilson, David B. Solit, Michael F. Berger, Marc Ladanyi, Maria E. Arcila, Efsevia Vakiani, Yelena Yuriy Janjigian
Journal: Journal of Clinical Oncology (2015)

57 Background: Esophagogastric (EG) cancer is a phenotypically heterogeneous disease. The Cancer Genome Atlas (TCGA) identified four distinct subsets: 1) Epstein Barr Virus (EBV) tumors with PIK3CA mutations, PD-L1/2 amplification (amp), 2) Tumors with Microsatellite instability (MSI-H), 3) chromosomally unstable (CIN) tumors with frequent amplifications, 4) chromosomally stable/diffuse type tumors with RHOA mutations. We explore the utility/feasibility of genomic profiling of EG tumors in routine clinical practice. Methods: Patients (pts) with metastatic EG adenocarcinoma undergoing treatment at MSKCC were consented for molecular testing under institutional protocol. Archival formalin fixed paraffin embedded (FFPE) samples were analyzed using an on-site 341 cancer-associated gene bait capture, next generation sequencing (NGS) assay. Results: Of 70 analyzed EG tumors, 66 (94%) harbored at least one genomic alteration, the most frequent being TP53 mutations (77%), HER2 amp (30%) and EGFR amp (10%). Alterations in PI3K/AKT/mTOR (9%) and G1-S1 cell cycle regulators (CDK12 (11%), CDKN2A (10%)) were also observed. A comparison with the TCGA results revealed an over-representation of the CIN subtype (65% vs 50% in TCGA). We found very few EBV or MSI tumors (3% each), with the remaining 29% being chromosomally stable. Data is reported in the clinical medical record and maintained in the MSKCC-internal cBioPortal for Cancer Genomics ( http://cbioportal.org ) (Gao, et al.). The portal is a web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data and when available, to link these data to therapeutic interventions and clinical outcomes. Conclusions: CIN tumors with frequent amplifications represent majority of metastatic EG cancer at our institution. Optimal development of target-specific therapy for EG tumors will require genomic characterization. Comprehensive molecular profiling is feasible in routine clinical practice and has created a roadmap for pt stratification and genome-guided trial development.
Two Distinct Co-Culture Systems, Designed to Mimic the Tumor Microenvironment, Induce Remarkably Similar Phenotypic Changes in Primary CLL Cells.
Authors: Andrea Gail Sherman Buggins, Laurence Pearce, Piers EM Patten, Liam Morgan, Paul Brennan, Chris Fegan, Stephen Devereux, Chris J Pepper
Journal: Blood (2009)
Surgeons’ preferences and practice patterns regarding intra-operative frozen section during partial nephrectomy.
Authors: Abhinav Sidana, James Donovan, Krishnanath Gaitonde
Journal: Journal of Clinical Oncology (2014)

436 Background: Intra−operative frozen section (FS) evaluation for tumor margin during partial nephrectomy (PN) is a matter of controversy in urologic oncology. We evaluate the preferences and practice patterns of urologists regarding intra−operative FS during PN. Methods: A 17 item questionnaire was designed to collect information on surgeons’ preferences and practice patterns regarding FS during PN. The survey was sent to the members of the Society of Urologic Oncology and the Endourological Society. Univariate and multivariate logistic regression analysis was done to identify the predictors determining the preferences. Results: 197 responses were received. 69% and 58% of respondents chose to obtain FS (always or sometimes) during Open Partial Nephrectomy (OPN) and Laparoscopic Partial Nephrectomy (LPN) respectively. There was a strong correlation between surgeons’ preferences during OPN and LPN. Younger surgeons are less likely to obtain FS during OPN (p&lt;0.05). For surgeons who did not routinely obtain FS, “confidence about complete resection” was the most common reason (79%), followed by “no change in management with positive margins” (35%). Majority (75%) believed the margins to be negative if surgical margin was free of tumor microscopically by one cell layer. Older surgeons considered negative margins to be free of tumor microscopically by &gt;= 5mm. Surgeons who performed more than 25 PNs annually were less likely to fulgurate the tumor bed after resection (p=0.025) while more likely to send an additional specimen from tumor bed for FS analysis (p=0.007). 54% and 42% of respondents would repeat FS for positive microscopic margins during OPN and LPN respectively. 95% of the respondents would not recommend additional treatment for positive margins on final pathology. Conclusions: Despite recent literature pointing to low clinical utility of intraoperative FS analysis, more than half of the surgeons still opt for intraoperative FS. Surgeon’s age and volume influence preferences and practice pattern in regards to FS analysis to some extent. Fellowship training, surgical approach and region of practice do not appear to dictate a surgeon’s preferences in regards to intra-operative FS during PN.
Full Dose Bendamustine (Treanda ®) Can Be Safely Combined with Rituximab, Etoposide and Carboplatin (TREC): Results of a Phase I Trial in Patients with Relapsed or Refractory Lymphoma
Authors: Lihua Elizabeth Budde, Shustov R Andrei, Gooley Ted, Tara L Chen, Edward N. Libby, Maria Corinna Palanca-Wessels, Mary Philip, Daniel B. Martin, Ryan D. Cassaday, Kiarash Kojouri, Oliver W. Press, Ajay K. Gopal
Journal: Blood (2012)