tbuckley/cabot-search huggingface dataset:
Independent validation of a genomic classifier in an at-risk population of men conservatively managed after radical prostatectomy.
Authors: Eric A. Klein, Jianbo Li, Andrew J. Stephenson, Kasra Yousefi, Michael W. Kattan, Cristina Magi-Galluzzi
Journal: Journal of Clinical Oncology (2014)

16 Background: Patients with locally advanced prostate cancer after radical prostatectomy (RP) are at risk for clinical progression and by current guidelines are candidates for adjuvant radiation. While clinical trials comparing adjuvant radiation to observation demonstrated benefits for many of these patients about 50% men on the control observation arm did not progress. This study evaluated whether a validated genomic classifier ([GC], Decipher) for predicting metastasis can be used to identify high-risk patients that may be spared unnecessary secondary therapy. The objective was to validate GC predictions in an at risk population conservatively managed after RP. Methods: A case-cohort design was used to sample patients with either preop PSA&gt;20 ng/mL, pT3, positive surgical margin or Gleason score 8 or more disease, treated at Cleveland Clinic with RP from 1987 to 2008. Patients with lymph node metastasis or neo-adjuvant or adjuvant treatment were excluded. Cases were defined as local recurrence and/or regional/distant metastasis confirmed by biopsy or positive CT/bone scan. Random sampling of the cohort, including all cases, yielded 220 patients. Tissue was available for 196 and GC scores were generated for 184 patients. AUC for survival data, weighted Cox regression analysis and cumulative incidence adjusting for competing risk were used to assess GC performance for predicting distant metastasis (DM) in comparison to the 2005 Stephenson nomogram. Results: GC had an AUC of 0.89 (95% CI 0.62-0.97) for predicting DM at 5 years post-RP. A combined GC-Stephenson model yielded an AUC of 0.81 (95% CI 0.62-0.96). GC was the predominant predictor in multivariable Cox analysis with an HR of 1.55 (95% CI 1.25-1.90) for a 10% increase in score. Patients with high (21.7%) and low GC scores (58.7%) had a 3.97 fold higher and 3.88 fold lower incidence of DM at 5 years than the intermediate group (19.6%), respectively. Conclusions: We present results of a second, blinded independent validation study of GC performance in a conservatively managed RP cohort. In an at risk population use of GC may further allow identification of men that may be safely spared adjuvant radiation therapy.
The impact of antiviral therapy on the outcome of hepatitis B viral (HBV)-related hepatocellular carcinoma (HCC) detected in surveillance prorgram.
Authors: V. W. Wong, F. Mo, G. S. Liem, T. Mok, A. T. Chan, H. L. Chan, W. Yeo, S. L. Chan
Journal: Journal of Clinical Oncology (2010)

4028 Background: The role of antiviral therapy (AT) on the outcome of established HBV-related HCC is unclear. Based on two independent prospective cohorts on surveillance of HCC (Mok et al. J Clin Oncol 23:8041-7,05 and Chan et al. Hepatology 31:763- 8,00), we aimed to evaluate the impact of AT on the outcome of HCC. Methods: All HCC cases in the two cohorts were identified. The baseline demographics, tumor features/stage, laboratory parameters at the time of HCC diagnosis, together with virologic factors (HBV genotype and DNA) and anticancer therapy were reviewed. The use and duration of AT was documented retrospectively. Univariate and multivariate analyses were conducted. Overall survival was the primary endpoint. Results: 148 HCC were confirmed amongst 1,429 HBV carriers in the surveillance programs over 10 yrs median follow-up. Median age=58; 116M:32F. Most had early-stage HCC (TNM stage I/II=59.5%). 52 pts received AT during surveillance while 45 (86.5%) continued AT after the diagnosis of HCC. There were no differences in the baseline characteristics, tumor stage, and number of tumors between pts with or without AT. Pts with AT had significantly longer median OS (5.34 vs. 1.44 years; p=0.0003). Exploratory analyses found that pts on AT had higher albumin, better Child-Pugh stage, lower ALT, and were more likely to undergo surgery (46.2% vs. 25.0%; p=0.009) than pts without AT (Table). Longer duration of AT was associated with better OS (>12 ms vs. ≤12 ms; HR=0.28, 95%C.I.=0.12-0.63; p=0.0023). In multivariate analysis, use of AT>12ms remained to be a significant prognostic factor (HR=0.35, 95% C.I.=0.19-0.66) after adjustment of tumor stage, liver function and ECOG. Conclusions: AT is associated with a higher chance of curative surgery and longer survival for HCC detected in surveillance program. Use of AT>12 months is an independent prognostic factor. AT Without AT P Alb 38 (19-48) 33 (12-47) 0.009 ALT 43 (19-154) 68 (21-728) 0.0022 ALP 87.5 (53-300) 112 (49-440) 0.0035 Surgery 24 (46.2) 24 (25.0) 0.009 Child A, B, C 41 (78.9), 6 (11.5), 5 (9.6) 56 (59.6), 31 (32.9), 7 (7.5) 0.02 TNM I/II, III, IV 32 (61.8), 23 (23.0), 8 (15.4) 56 (58.3), 27 (28.1), 13 (13.5) 0.53 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb and Pharmasset, Novartis, Roche, Schering-Plough Bristol-Myers Squibb, Novartis, Roche
A longitudinal study of processing speed among children treated for medulloblastoma (MB), supratentorial primitive neuroectodermal tumor (SPNET), or atypical teratoid rhabdoid tumor (ATRT)
Authors: S. Palmer, D. Wallace, M. Bonner, R. Raggl, L. Chapieski, L. Janzen, S. Knight, R. Boyle, C. Armstrong, A. Gajjar
Journal: Journal of Clinical Oncology (2009)

10028 Background: Indicating a strong relationship to intelligence, processing speed parallels with the rate of knowledge acquisition. To further our understanding of the etiology of deficits in intellectual ability that continues to plague this group of children, the current study prospectively examined longitudinal changes in an underlying cognitive ability, processing speed. Methods: The study included 174 patients (median age at diagnosis = 9.0) enrolled on a multi-site protocol (SJMB03) for MB, SPNET or ATRT. Patients were treated with post-surgical risk-adapted craniospinal irradiation (CSI) followed by 4 cycles of high-dose chemotherapy (cyclophosphamide, cisplatin, vincristine) with stem cell support. High risk (HR, n = 55) patients received 36 - 39.6 Gy CSI and 3D conformal boost to the primary site to 55.8 –59.4 Gy. Average-risk (AR, n=119) patients received 23.4 Gy CSI, 3D conformal boost to the primary site to 55.8 Gy. Those who had posterior fossa syndrome were excluded (n = 26) resulting in 148 patients who completed 459 neuropsychological evaluations using the Woodcock Johnson Tests of Cognitive Abilities-III over a period of 0.03 –4.94 years postdiagnosis. Results: Multivariate modeling revealed a statistically significant decline in processing speed for those &lt; 7 years of age at time of diagnosis (-3.83 points per year, p = 0.003). Those who were &gt; 7 years at diagnosis did not experience a significant change (.86, NS). HR patients experienced greater declines (-.82) than those who were AR (-0.29), but neither slope was statistically significant. Interaction models revealed declines for those in the &lt;7/AR group (-4.17, p = 0.003), and &lt;7/HR group (-3.38, NS). Those &gt;7/AR and &gt;7/HR did not experience significant change (1.06 and 0.32, respectively). Conclusions: Young age at diagnosis is a prominent risk factor for processing speed impairment among survivors of pediatric embryonal tumors. Processing speed may also be among the first deficits to appear following treatment. This study represents the largest comparison of processing speed ability among patients treated for pediatric embryonal tumors with conventional or reduced dose CSI and adjuvant chemotherapy. No significant financial relationships to disclose.
High-dose Ifosfamide (HDIFX) as a 14-day continuous infusion (ci) in advanced adult soft tissue sarcoma (STS): A single- institution retrospective case series analysis
Authors: P. Coco, E. Fumagalli, R. Bertulli, P. Dileo, F. Grosso, S. Stacchiotti, C. Piovesan, R. Sanfilippo, M. Accolla, P. G. Casali
Journal: Journal of Clinical Oncology (2007)

10067 Background: High-dose IFX (≥12 g/sqm) is active even in STS patients pretreated with standard-dose IFX, though with substantial toxicity. Prolonged continuous infusion, through a portable pump, may be an alternative way of administration. A Phase II study thereof is ongoing in Italy, but some pts have been treated off the study, either prior to its start or for practical reasons. Such consecutive pts seen at a single institution have been retrospectively reviewed. Methods: Between July 2001 and September 2006, 45 adult patients (M:F = 25:20; mean age 47 yrs; PS 0–1) with progressing advanced/metastatic STS, all previously treated with anthracyclines and standard-dose IFX, were given ciHDIFX, at the dose of 14 g/sqm as a 14-day continuous infusion every 4 weeks, using two portable infusional devices, with equidose Mesna, lasting 7 days each. Diagnosis was leyomiosarcoma in 12 patients, synovial sarcoma in 9, liposarcoma in 5, and other histological types in 19. Disease was advanced inoperable in 6 pts, and metastatic in 39. The total number of cycles was 176 (median number per pt: 4). Results: A PR was seen in 5 pts (synovial sarcoma, 2; leyomiosarcoma, 1, liposarcoma, 1; chondrosarcoma, 1), and SD in 22 (&gt;6 mos in 12), for a clinical benefit rate = 37%. PFS at 6 months was 35%. Median PFS was 11 mos in pts with PR and 6 in those with SD. Median PFS was 8 months in 9 patients undergoing complete tumor resection. Most common side effects were nausea (G1–2 in 14 pts) and asthenia (G1–2 in 15 pts). G2 anemia was seen in 8 pts, G2 neutropenia in 6. One pt with a single kidney had a reversible G2 hypercreatininemia. No grade 3–4 toxicity were recorded. Conclusions: In this series, ciHDIFX was associated with a PR and 6-mos PFS rate in the range of active second-line agents in advanced STS. This regimen was exceedingly well tolerated. No significant financial relationships to disclose.
Phase II study of sunitinib in patients with non-small cell lung cancer (NSCLC) and irradiated brain metastases: Final efficacy and safety results.
Authors: S. Novello, C. Camps, F. Grossi, J. Mazieres, L. E. Abrey, J. Vernejoux, A. D. Thall, T. Usari, R. C. Chao, G. Scagliotti
Journal: Journal of Clinical Oncology (2010)

7581 Background: Brain metastases (BrMs) occur in ≥ 25% of patients (pts) with NSCLC. Sunitinib (SU) is an oral, multitargeted inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R, and RET that has single-agent antitumor activity in refractory NSCLC. Final data are presented from this phase II study that assessed the efficacy and safety of SU in NSCLC pts with previously irradiated BrMs. Methods: Pts with NSCLC ≥ 18 years of age who had received whole brain radiation therapy for BrMs and ≤ 2 prior systemic therapies received SU at a starting dose of 37.5 mg with continuous daily dosing (CDD) in 4-week cycles. The primary endpoint was PFS. Antitumor efficacy was based on overall (RECIST) and intracranial (WHO criteria) tumor assessments. Intracranial disease was assessed by MRI. Safety was assessed by monitoring AEs and focused on neurologic status. Results: Sixty-four pts received SU for a median of 2 cycles (range: 1–13). Pts (male/female: 61%/39%; median age 61 yrs, range: 35–77) had a good performance status (ECOG 0/1, n = 63; ECOG 2, n = 1), and most had adenocarcinoma (n = 40, 63%) or squamous cell carcinoma (n = 12, 19%). Most received prior systemic therapy (n = 53, 83%). Stable disease was reported in 16 (27%) of 60 pts via RECIST and in 6 (26%) of 23 pts with measurable BrMs via WHO; one pt (4%) had an intracranial PR. Median PFS was 9.4 weeks (95% CI: 7.5, 13.4). Median OS was 26.0 weeks (95% CI: 13.4, 38.1). Dose reductions to 25 mg occurred in 25% pts. Most frequent grade (G) 3/4 AEs were dyspnea (n = 6, 9%) and fatigue (n = 5, 8%). Serious neurologic AEs occurred in 6 pts (9%): epilepsy (n = 2) and convulsion, cerebral ischemia, intentional self injury and tremor (all n = 1). Six pts had peripheral neuropathy (G1/2 n = 4; G3 n = 2) and one pt had G4 mental impairment. ICH was not reported. G3/4 hematologic abnormalities included lymphopenia (n = 12) and neutropenia (n = 8). Conclusions: This phase II study reveals that treatment with SU on a CDD schedule is manageable in NSCLC pts with BrMs. No cases of ICH were reported. Preliminary efficacy assessments of the complete data set indicate that the primary endpoint (PFS > 10 weeks) was not met in these heavily pretreated pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer
Covalent coupling of a novel TLR7 agonist to antigen elicits an effective immune response in a murine melanoma tumor model
Authors: G. A. Daniels, M. Chan, C. C. Wu, R. Tawatao, D. Messmer, B. Eftimie, H. Cottam, D. Carson
Journal: Journal of Clinical Oncology (2007)

3019 Background: Toll-like receptor (TLR) signaling triggers innate immune stimulation capable of generating an adaptive immune response under appropriate conditions. TLR agonists have shown efficacy in preclinical and clinical cancer therapies. However, one limitation to this approach has been the use of TLR agonists delivered at distances away from the target (ie-subcutaneous injections for general immune stimulation) or the inability to effectively couple antigen with adjuvant. Methods: We have synthesized a novel TLR7 agonist capable of covalent coupling to primary amines under physiologic conditions. In vitro activity of adjuvant alone or antigen-adjuvant complexes were tested for innate immune activation by utilizing bone marrow-derived murine or peripheral blood mononuclear cell-derived dendritic cells (DC) with respect to DC maturation and cytokine secretion (IL12, IL6, TGFbeta and IFNgamma). Immunocompetent syngeneic C57/b6 mice were prophylactically vaccinated with intradermal with either antigen, antigen mixed with adjuvant or antigen- adjuvant coupled complexes and challenged with B16 melanoma tumor cells expressing the cOVA transgene. Results: The effective concentration (EC50) for each compound generally followed a bell shaped distribution with higher doses being inhibitory. Maximal stimulation occurred between 10 and 1000nM. Coupled adjuvant molecules retained activity with generally lower EC50 values. Coupling 1V199 to chicken ovalbumin nearly doubled median survival from 22 to 35 days following subcutaneous tumor challenge compared with chicken ovalbumin alone. Conclusions: Covalent linkage of a TLR7 agonist to antigen stimulates DC cytokine production and protects mice from tumor challenge. Use of a soluble TLR7 agonist which retains its immune stimulating properties following coupling to antigen under physiologic conditions may be useful in the development of an in situ vaccine in solid tumor therapy. No significant financial relationships to disclose.
The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04.
Authors: M. S. Roh, G. A. Yothers, M. J. O'Connell, R. W. Beart, H. C. Pitot, A. F. Shields, D. S. Parda, S. Sharif, C. J. Allegra, N. J. Petrelli, J. C. Landry, D. P. Ryan, A. Arora, T. L. Evans, G. S. Soori, L. Chu, R. V. Landes, M. Mohiuddin, S. Lopa, N. Wolmark
Journal: Journal of Clinical Oncology (2011)

3503 Background: The optimal chemotherapy regimen to be given concurrently with preop radiation therapy (RT) in patients with resectable adenocarcinoma of the rectum is unknown. NSABP R-04 compared the efficacy of 4 chemotherapy regimens administered concomitantly with preop RT. Methods: Patients with clinical stage II or III rectal cancer undergoing preop RT (4,500cGy in 25 fractions over 5 wk + boost of 540cGy-1080cGy in 3-6 daily fractions) were randomly assigned to one of the following chemotherapy regimens: continuous IV infusion (CVI) 5-FU (225mg/m2 5 days/wk), with or without IV oxaliplatin (OX) (50mg/m2 /wk x 5); oral capecitabine (CAPE) (825 mg/m2 BID 5 days/wk), with or without OX (50mg/m2/wk x 5). Prior to random assignment the surgeon indicated if the patient was eligible for sphincter-saving surgery (SSS) based on clinical staging. The endpoints were complete pathologic response (pCR), SSS, and surgical downstaging (SD, conversion to SSS). Results: From July 2004 to August 2010, 1,608 patients were randomly assigned. No significant differences in the rates of pCR, SSS, or SD were identified between the 5-FU and CAPE regimens or between the regimens, with and without OX (Table). Patients treated with OX experienced significantly more grade 3/4 diarrhea. Conclusions: Administration of capecitabine with preop RT achieved similar rates of pCR, SSS, and SD compared to CVI 5-FU. The addition of oxaliplatin did not improve preliminary outcomes but added significant toxicity. The definitive analysis of local tumor control will be performed in fall 2013. Funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U10-CA-25224 with support from sanofi-aventis US Inc. and Hoffmann La-Roche. Endpoint 5-FU (± OX) CAPE (± OX) P value pCR 135/719 = 18.8% 157/707 = 22.2% 0.12 SSS 445/727 = 61.2% 445/710 = 62.7% 0.59 SD 39/188 = 20.7% 43/187 = 23.0% 0.62 Grade 3/4 diarrhea 70/625 = 11.2% 68/628 = 10.8% 0.86 Endpoint (FU or CAPE) No OX (FU or CAPE) + OX P value pCR 111/580 = 19.1% 121/578 = 20.9% 0.46 SSS 370/582 = 63.6% 353/584 = 60.4% 0.28 SD 35/152 = 23.0% 29/151 = 19.2% 0.48 Grade 3/4 diarrhea 41/622 = 6.6% 97/631 = 15.4% < 0.0001
Detection of hepatitis C virus RNA in hemodialysis patients.
Authors: M Kuhns, M de Medina, A McNamara, L J Jeffers, K R Reddy, M Silva, C Ortiz-Interian, M Jimenez, E R Schiff, G Perez
Journal: Journal of the American Society of Nephrology (1994)

The clinical significance of the high prevalence of antibodies to hepatitis C virus (HCV) in dialysis patients remains undefined. In order to assess the relationship between seropositivity and potential infectivity, 63 patients undergoing maintenance hemodialysis were evaluated between April and May 1990. The mean duration of maintenance hemodialysis was 45 mo (range, 13 to 144). Eighty-two percent (52 of 63) had received blood transfusions, and 16% (10 of 63) had a history of iv drug abuse. Serum samples were analyzed by HCV-cDNA polymerase chain reaction; antibodies to HCV structural (core) and nonstructural regions NS3 and NS4 were determined by enzyme immunoassay. Specimens repeatedly reactive for anti-HCV and HCV-RNA-positive samples were tested by HCV MATRIX dot immunoblot assay and HBV-DNA PCR. Twenty-five percent (16 of 63) were anti-HCV-positive. Of the 16 anti-HCV-positive patients, HCV-RNA was detected in 5 (31%) with the NS3 primers and in 12 (75%) with 5'-noncoding primers. Among the anti-HCV-negative patients, HCV-RNA was detected in 2 (4.3%) of 47 patients. Eleven of the 18 patients with HCV infection (anti-HCV and/or HCV-RNA-positive) had evidence of additional present or past viral infections (human immunodeficiency virus and/or hepatitis B virus). In summary, HCV-RNA is present in at least 75% of anti-HCV-positive patients, suggesting that they may be infectious. The detection of HCV-RNA in anti-HCV-negative patients may indicate early or chronic HCV infection not detected by current antibody assays or the inability of these patients to mount or sustain a significant antibody response.
Correlation of FGF2 tumor expression with tumor response, PFS, and changes in plasma pharmacodynamic (PD) markers following treatment with brivanib alaninate, an oral dual inhibitor of VEGFR and FGFR tyrosine kinases
Authors: S. Platero, O. Mokliatchouk, G. C. Jayson, D. J. Jonker, L. S. Rosen, S. Luroe, J. Kelsey, D. Feltquate, L. Velasquez, S. Galbraith
Journal: Journal of Clinical Oncology (2008)

3506 Background: Many tumors express the FGFR ligand FGF2, and increased levels of FGF are correlated with poor prognosis in pts with RCC, HCC, NSCLC, esophageal, and pancreatic cancer. Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Brivanib inhibits FGF-stimulated and FGF-dependent cell lines. Methods: An open-label Phase I dose- escalation study of brivanib was conducted in pts with cancer who failed prior therapy (ASCO #3559, 2007). Tumor response (modified WHO) was evaluated q 8 weeks. Immunohistochemistry was used to assess expression of FGF2 in archival tumor tissue. Pts were scored positive if ≥10% of tumor cells had weak staining and negative if <10% of tumor cells had positive staining. Plasma samples were collected pretreatment (x2) and on select days during treatment. Plasma PD markers collagen IV (COL IV) and sVEGFR2 were measured using ELISA. Results: 43 evaluable pts with available archival tumor tissue were analyzed for correlations between FGF2 status (+ or -) and treatment dose with tumor response, PFS, and changes in PD plasma markers. 19 pts were FGF2- and 24 pts were FGF2+. Low (<600 mg) and high (≥600 mg) doses of brivanib were given to 17 and 26 pts, respectively. All groups of pts except high-dose FGF2+ pts had an increased average change in mean tumor size. Median PFS was longer in FGF2+ pts than FGF2- pts (Table). A greater decline from baseline in COL IV was measured in FGF2+ pts than FGF2- pts. Differences in tumor responses, PR, and SD ≥8 wks for FGF2+ and FGF2- pts are shown in the table. Conclusions: Whereas FGF overexpression is typically correlated with poor prognosis, FGF2+ tumor expression is associated with a trend for improved tumor response, PFS, and changes in plasma PD markers following treatment with brivanib compared with pts whose tumors do not express FGF2. Mean change in tumor size (%) (∼8 wks) Median PFS (days) COL IV change from baseline (%) (Day 26) (n = 42) sVEGFR2 change from baseline (%) (Day 26) (n = 39) PR SD ≥8 wks PD Low (<600 mg) (n = 17) High (≥600 mg) (n = 26) Low (<600 mg) (n = 17) High (≥600 mg) (n = 26) FGF2- (n = 19) 71 24 54 56 -16 -15 0 5 14 FGF2+ (n = 24) 28 0.9 71 107 -30 -23 2 13 9 P value 0.03* 0.075† 0.029* 0.138* * Wilcoxon rank-sum test (combined low and high dose assessing FGF2- vs FGF2+). † Log-rank test (combined low and high dose assessing FGF2- vs FGF2+). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb