tbuckley/cabot-search huggingface dataset:
Gene expression differences associated with silencing of E6 and E7 viral oncogenes in HPV16<sup>+</sup> oropharyngeal cancer cell lines
Authors: T. Rampias, C. Sasaki, B. A. Burtness, A. Psyrri
Journal: Journal of Clinical Oncology (2008)

6009 Background: Human papillomaviruses (HPV), especially type 16, play an aetiological role in a subset of head and neck squamous cell carcinomas (HNSCC). Notch signaling is an evolutionary conserved pathway controlling diverse aspects of development and tissue homeostasis. Deregulation of Notch signaling has been implicated in development of cancer. We sought to investigate whether E6 and E7 oncogene repression activates Notch signalling in HPV16 positive oropharyngeal cancer cell lines. Methods: In our analysis, we used the HPV16 positive oropharyngeal cancer cell lines 147T and 090 and the HPV negative cell line 040T as control. Short hairpin RNAs targeting HPV type 16 E6 and E7 genes were delivered by retrovirus infection to HPV16+ cells. E6 and E7 mRNA downregulation was confirmed by quantitative reverse transcription polymerase chain reaction and western blotting for p53 and Rb 48h after silencing. Total RNA of these cell lines were prepared before and 48h after silencing. Labeled cDNA probes were then prepared and microarrays were hybridized. Results: Repression of HPV E6 and E7 genes caused a significant upregulation of cellular p53 and pRb tumor suppressor proteins. Analysis of microarray data revealed upregulation of Notch1 (fold change = 1.517), Notch1/CBF-1 downstream transactivated gene HES1 (fold change = 4.267) and NF-κβ (fold change = 1.674). Decreased expression was found for Skp2 which is normally suppressed by Notch1 (fold change = 0.842). Notably, a significant activator of Notch pathway, deltex-1 was induced more than tenfold (fold change = 53.651). In addition a group of genes related to apoptosis was also upregulated tenfold or more (CD30L receptor, ubiquitin- conjugatying enzyme E2 J1), suggesting a possible association between Notch activation and apoptosis. NF-kappaB pathway was also activated by Notch, as NF-kappaB (fold change = 1.674) and CARMA1 (fold change = 36.040) were found to be induced. Conclusions: We provide evidence that repression of E6/E7 gene expression leads to activation of Notch and NF-kappa B pathways. Notch 1 is a p53-target gene. Therefore, restoration of p53 after E6 silencing results in activation of Notch pathway in HPV16+ HNSCC cell lines. No significant financial relationships to disclose.
Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macro-metastatic nodes: EADO trial.
Authors: J. J. Grob, T. Jouary, B. Dreno, R. Gutzmer, A. Hauschild, M. T. Leccia, M. Landthaler, J. Asselineau, C. Garbe, H. E. Pehamberger
Journal: Journal of Clinical Oncology (2010)

LBA8506 Background: Adjuvant therapy with low-dose adjuvant interferon alfa-2b (IFN) as well as with pegylated interferon alfa-2b (PEG-IFN) were both shown to be superior to observation in melanoma (M) patients (pts) without macro-metastatic nodes. However, the two strategies have never been assessed head to head. Weekly injection of PEG-IFN facilitates a longer duration of treatment which may be critical for benefit. We thus compared adjuvant therapy of flat low-dose PEG-IFN (36 months) versus low-dose IFN (18 months) in intermediate-risk M pts without macro-metastatic nodes. Methods: In this multicenter, open-label, prospective randomized phase III trial, pts with resected M ≥ 1.5 mm in thickness and without clinically detectable nodes were randomized either to IFN (3 MU subcutaneously [sc] 3 times a week for 18 months) or to PEG-IFN (100 mcg sc once weekly for 36 months). Sentinel node procedure (SNP) was not a standard in 2003 and thus was optional. Approach was consistent by center. Randomization was stratified for centers and SNP procedure. Primary endpoint was relapse-free survival (RFS), and secondary were distant metastasis-free survival (DMFS), overall survival (OS), and grade 3-4 severe adverse events (SAE). Sample size (890 pts) was calculated to detect a 10% difference (power &gt;80%, type I error of 5%, 2-sided) for RFS. Analysis describes 5-year probability of survival. Comparisons were done by intent-to-treat using Cox proportional models. Results: Of 898 pts enrolled, 896 (443 PEG vs 453 IFN) were eligible for evaluation after a median follow-up of 4.7 years. SLNB was performed in 68.2% of pts. Neither RFS (PEG-IFN 66.2% vs IFN 64.8%, p=0.43; HR, 0.91; 95% CI, 0.73 to 1.15) nor DMFS (71.3% vs 72.6%, p=0.86; HR, 1.02; 95% CI, 0.80 to 1.32) or OS (77.0% vs 78.4%, p=0.55; HR, 1.09; 95% CI, 0.82 to 1.45) showed statistical difference. There was an excess of SAE grade 3-4 in PEG-IFN arm (44.6% vs 26.6% in the first 18 months) which impacted on median duration of treatment (17.8 months in IFN arm; 19.2 in PEG-IFN arm, with only 28% completing 36 months treatment). Conclusions: Flat low-dose PEG-IFN did not show superiority over conventional low dose IFN. Attempts to increase benefit by prolonging treatment with PEG-IFN over 3 years were hampered by a high rate of treatment discontinuation possibly linked to SAEs with PEG-IFN. [Table: see text]
Interim results of a phase II trial of pemetrexed and oxaliplatin as 2nd/3rd line therapy in hormone refractory prostate cancer
Authors: T. B. Dorff, S. G. Groshen, D. Wei, C. Korn, A. Goldkorn, D. I. Quinn, J. Pinski
Journal: Journal of Clinical Oncology (2008)

5139 Background: There is no standard of care for treatment of men with metastatic, hormone-refractory prostate cancer (HRPC) after disease progression on docetaxel. Pemetrexed and oxaliplatin have both shown modest single-agent response rates in HRPC; this trial evaluates the response rate of these agents in combination. Methods: Men with HRPC whose disease had progressed despite docetaxel and had received no more than 2 prior chemotherapy regimens were eligible. A two-stage design (α=0.1, β=0.1) was used to distinguish between 14% and 30% clinical response rates as a primary endpoint (RECIST, or PSA if no measurable disease was present); a maximum of 47 patients are planned. After providing written informed consent, 20 men enrolled between July 2006 and September 2007. Pemetrexed was administered at 500 mg/m2 IV every 3 weeks and oxaliplatin 100 mg/m2 IV every 3 weeks. Folate and B12 supplementation were mandated, and a calcium + magnesium infusion was recommended before and after oxaliplatin administration. Results: Median age of study subjects was 68 (41–81). Median baseline PSA was 250 ng/mL (range 4.79 - 2290). All had metastatic disease with 1 (40%) or 2 (60%) prior chemotherapy regimens; 89% had bone involvement. Subjects received between 1 and 11 treatment cycles; 3 subjects continue on treatment. Responses are summarized in the table; five men (20%) had PSA decline >50%, and 2 (10%) had an objective PR by RECIST. Six men (30%) had stable PSA and 10 (50%) have stable disease by radiographic criteria. Toxicities are presented in the table; there were no grade 4 toxicities. Grade 3 events included fatigue (4 subjects), neurologic (3 subjects), and hematologic (4 subjects). One patient died while on study due to disease progression. Conclusions: This interim analysis documents the safety and preliminary efficacy of oxaliplatin and pemetrexed for 2nd and 3rd line treatment of HRPC. Accrual will continue to better characterize the clinical benefit and toxicity. Responses and Toxicities PSA Response PR (>50% reduction) SD Increase Inevaluable 5 (25%) 6 (30%) 4 (20%)* 5 (25%) RECIST response PR SD PD Inevaluable 2 (10%) 10 (50%)* 3 (15%) 5 (25%) *one unconfirmed Grade 1/2 Grade 3 TOXICITY Grade 1/2 Grade 3 Allergy/Immunology (Hypersensitivity) 2 1 Auditory Bleeding 9 3 0 0 Constitutional Dermatologic 11 3 4 0 Gastrointestinal Hematologic 14 15 0 3 Metabolic Neurologic 13 9 1 3 Pain Pulmonary 6 1 2 1 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis Lilly Oncology, sanofi-aventis Lilly Oncology, sanofi-aventis
Neoadjuvant chemoradiation for rectal cancer: A 5-year institutional experience at Sparrow Hospital
Authors: G. Srkalovic, R. A. Miranda, M. Maier, L. DiCarlo, U. Chamarthy, J. Herman
Journal: Journal of Clinical Oncology (2007)

14601 Continued efforts to improve local control and to maximize sphincter preservation in patients with rectal carcinoma led to consideration of preoperative chemoradiation. The purpose of this retrospective study is to examine clinical outcomes and find out which prognostic factors are related to survival in patients treated with neoadjuvant chemoradiation in Sparrow Hospital from 1998–2003. Forty two patients with biopsy proven rectal carcinoma without evidence of extra pelvic spread were treated in this fashion. Radiation therapy was administered for a total dose of 5.00 cGy. Chemotherapy used was 5-FU in 37 patients, and in combination with leucovorin in additional 5 patients. Surgical treatments performed were abdominoperineal resection (23 pts), low anterior resection in 13 pts., transanal excisions (2 pts), 2 patients had only exploratory laparotomy and for 2 patients records were not available. Cox proportional hazards regression techniques were used to estimate survival rates. Univariate and multivariate Cox proportional hazards analyses were used to evaluate relationship between risk factors and the survival. The SAS system (V9.1.3, Cary NC) was used for all analyses. Out of 42 patients analyzed 25 were males and 17 females. Mean age was 65 years (range 31 - 85). Median follow-up time was 57 months with a range from 7 to 98 months. After the surgery 4 patients had complete response, 12 were stage I, 10 stage II, 12 patients stage III, one patient had metastatic disease and for 2 patients records were inadequate. Analysis of disease free survival showed actuarial 5-year disease free survival to be 59%. Actuarial 5-year overall survival was 67%. Median overall survival was still not reached, while median disease-free survival is 78 months . Univariate and multivariate analyses showed that only postoperative stage was associated significantly with overall survival. Specifically, there was an increase in the risk of mortality of just over 3-fold for each increment in post-operative stage. In conclusion, in the community settings preoperative chemoradiation seem to provide good overall and disease free survival for patients with rectal cancer. Postoperative stage appears to be the most important prognostic factor for the survival. No significant financial relationships to disclose.
Abstract 17773: Cardiac Myocyte-specific Expression of LMNAD300N Activates MMP2 and Induces Severe Interstitial Fibrosis and Cardiac Systolic Dysfunction Leading to Premature Death in Mice
Authors: Ju-Yun Tsai, Un-Ho Jin, Raffaella Lombardi, Jin Xu, Grazyna Czernuszewicz, Ali J Marian
Journal: Circulation (2012)

Mutations in the LMNA, encoding lamin A/C, cause a wide range of diseases, collectively known as laminopathies. In the heart, LMNA mutations cause dilated cardiomyopathy (DCM), conduction defect and sudden death. We recently identified a p.D300N mutation in LMNA in a patient with restrictive cardiomyopathy, conduction defect, atrial fibrillation and premature death. To delineate the molecular mechanism(s) responsible for cardiac phenotype caused by the p.D300N mutation, we generated a Doxycycline (DOX)-inducible (Tet-off) bigenic mice and expressed LmnaD300N or a wild type (WT) Lmna (LmnaWT), under the transcriptional regulation of Myh6 promoter. Expression of LmnaD300N was associated with severe interstitial fibrosis (6-fold increase compared with LmnaWT, p
Vaccination with survivin and PSMA-derived peptides for controlling biochemical recurrence in prostate cancer: A pilot study
Authors: R. Valdagni, A. Marrari, P. Squarcina, S. Villa, P. Filipazzi, R. Salvioni, T. Rancati, M. Asioli, G. Parmiani, L. Rivoltini
Journal: Journal of Clinical Oncology (2009)

e16042 Background: A significant percentage of patients (pts) progress after first line treatment of prostate cancer (PCa). We present preliminary results of pilot study using a multiple peptide-based anti-tumor vaccine. Methods: A phase I-II trial of vaccination (vax) with HLA-A*0201-restricted peptides from PSMA and Survivin was carried out in 20 pts with b-failure after surgery or radiotherapy (mean pre-vax PSA: 1.83 ng/ml). Vax consisted of two peptides from PSMA (PSMA4–12 and PSMA711–719) and one from Survivin (SVV96–104/97M) given by 4 fortnightly (priming) and 4 monthly administrations (boosting). To selectively eliminate regulatory T cells (Treg) and possibly enhance immunization, peptides were preceded by low dose cyclophosphamide (CTX, 300 mg/mq, i.v.). Antigen (Ag) and tumor-specific T cell responses were extensively monitored in peripheral blood together with CD4+CD25+Foxp3+ Treg frequency. PSA trend was also registered. Results: Vax was well tolerated. Most pts (19/20) showed a significant increase of SVV96–104/97M-specific T cells (mean 14 in pre-vax vs 170 in post-vax PBMC), while response to PSMA was achieved in about half of the pts and only to PSMA711–719 peptide (mean 12 in pre-vax vs 86 in post-vax PBMC). Increments of HLA-A*0201/SVV96–104/97M or PSMA711–719 multimer+ CD8+ T cells were induced in 50 and 35% pts, respectively. Vax-induced Ag-specific T cells displayed however limited cross-reactivity with HLA-A*0201+ PCa cells. No effect of CTX on Treg frequency was observed. 6 pts had no biochemical response to vax and switched to hormonal therapy, while 14/20 exhibited a significant although transient PSA decrease during vax (11 in the priming phase and 3 in boosting). Conclusions: Peptide vax could rapidly enhance Ag-specific immune responses in most treated pts. However, the reduced ability of vax-induced Ag-specific CD8+ T cells to cross-recognize PCa cells, together with their low frequency in PBMC, could explain why PSA control was achieved only transiently and in strict dependence with vax administration. Anti- tumor vax represent a useful tool for controlling PCa biochemical recurrence in the absence of major side effects, but immunization protocols inducing efficient tumor cell killing still need to be identified. No significant financial relationships to disclose.
Abstract 19389: The Net Clinical Benefit of Left Atrial Appendage Closure in the Continued Access Protocol (CAP) Registry
Authors: Sandeep R Gangireddy, Jonathan L Halperin, Valentin Fuster, Vivek Y Reddy
Journal: Circulation (2012)

Introduction: PROTECT AF revealed LA appendage closure (LAAC) to be an effective alternative to warfarin in nonvalvular AF patients. The non-randomized CAP registry demonstrated that with increased operator experience, there were fewer procedure-related complications with LAAC. Our objective was to estimate the net clinical benefit (NCB) of percutaneous LAAC in the CAP registry. Methods: Post hoc analysis of outcomes in both the randomized PROTECT AF trial (n=707) and the non-randomized CAP registry (n=566). Based on the relative clinical impact, outcomes were weighted using death as the index parameter (ie, =1): ischemic stroke = 0.2, intracranial hemorrhage = 0.6, major bleeding = 0.1, tamponade =0.1. NCB was calculated as the sum of annualized rates of these outcomes after LAAC in the CAP registry minus rates on warfarin in the PROTECT AF control group. Results: The NCB of LAAC during 962 person-years of follow-up in the CAP registry was 3.87%/year (95% CI 1.90-6.11%/year), compared with 1.62%/year (95% CI -0.25-3.72%/year) in PROTECT-AF trial. Among patients with a history of ischemic stroke, NCB was greater in CAP (7.34%/year, CI 1.97-14.85%/year) than PROTECT AF (3.62%/year, CI -1.50-9.23%/year). In the registry, the NCB of LAAC increased from 1.64 %/year (95% CI -0.3-5.16%/year) in patients with CHADS2 scores=1 to 4.99%/year (95% CI 1.3-9.07%/year) in those with scores &gt;2. Conclusion: With increased operator experience, the net clinical benefit of LAA closure exceeds Warfarin therapy.
The association between autonomic dysfunction and survival in advanced cancer: A preliminary report
Authors: N. A. Fadul, F. Strasser, J. L. Palmer, S. Dalal, J. Allo, E. Bruera
Journal: Journal of Clinical Oncology (2009)

e20534 Background: Autonomic nervous system dysfunction (AD) is a common syndrome in patients with advanced cancer. It is associated with decreased survival in several patient populations including diabetes mellitus, heart failure and neurological diseases. Based on this available evidence, we hypothesized that autonomic dysfunction is associated with reduced survival in patients with advanced cancer. The objective of this preliminary study was to test the association between AD as measured by the standardized Ewing test and Heart Variability (HRV) measures and survival in patients with advanced cancer. Methods: We examined the relationship between survival and parameters of AD in male patients with advanced cancer who participated in a prospective study of autonomic dysfunction and hypogonadism. Eligibility criteria were defined based on the prospective study protocol. We collected demographic information, date of study entry and Ewing and HRV scores. Date of death was obtained from the online Social Security Death Index database. We defined survival as the interval between study entry and date of death. A survival analysis was used to test the association between survival (days) and Ewing test (0–5) and measures of heart rate variability (HRV), including time domain (SDNN) and frequency domain (Ultra low, Very low, Low, and High frequency) parameters.A spearman correlation test was also performed. Results: 47 male patients were included in this study. Median age was 59 (20–79) and 63% were caucasians. Autonomic dysfunction (AD), defined as Ewing score &gt;2, was present in 80% (38/47) of the patients. Median Ewing score was 3 (1–5), indicating moderate to severe AD. Spearman correlation for Ewing and SDNN HRV was 0.44 (p=0.002). There was a significant association between abnormal Ewing score and survival (p&lt;0.0001), and abnormal SDNN HRV and survival (p=0.056). Spearman correlation for Ewing score and survival and SDNN HRV and survival were r = -0.27620 (p=0.0602) and r =0.24198 (p= 0.1013) respectively. Conclusions: Autonomic dysfunction is associated with shorter survival in male patients with advanced cancer. Further longitudinal research in a larger cohort is justified based on these findings. No significant financial relationships to disclose.
A phase II study of external beam radiation therapy combined with permanent source brachytherapy for intermediate risk clinically localized adenocarcinoma of the prostate: Preliminary results of RTOG P-0019
Authors: W. R. Lee, M. Desilvio, C. F. Lawton, M. T. Gillin, G. C. Morton, S. Firat, M. Baikadi, M. R. Kuettel, K. M. Greven, H. M. Sandler
Journal: Journal of Clinical Oncology (2004)

4568 Background: External beam radiation therapy is commonly combined with permanent source brachytherapy in the treatment of prostate cancer. The primary objective of this study is to estimate the rate of acute- and late-grade 3–5 genitourinary and gastrointestinal toxicity following treatment with external beam radiation therapy and permanent source brachytherapy in a multi-institutional, cooperative group setting. Methods: Between January 2001 and November 2001, 138 patients from 20 institutions were entered on this study. Acute toxicity information is available in 131 patients, and 127 patients are analyzable for late toxicity. All patients were treated with external beam radiation therapy (45 Gy/25 fractions) followed 2–6 weeks later by an interstitial implant using I-125 to deliver an additional 108 Gy. The median followup is 20 months. Median pretreatment PSA = 7.5. Results: The most commonly reported acute toxicity is urinary frequency and dysuria. Acute Grade 3 toxicity was documented in 10/131 (7.6%) patients. No Grade 4–5 acute toxicity has been observed. Late Grade 3 toxicity has been observed in six men (5 urinary, 1 bowel). The 18-month month estimate of late Grade 3 GU/GI toxicity is 3.3% (95% CI 0.1–6.5). No late Grade 4–5 toxicity has been observed. In the sixty-one men that reported no impotence at baseline and received no androgen deprivation, the 18-month rate of Grade 2–3 impotence is 45.5% (95% CI 32.6–58.5%). Conclusions: The acute and late morbidity observed in this multi-institutional, cooperative group study is consistent with previous reports from single institutions with significant prostate brachytherapy experience. The combination of external beam radiation therapy and permanent source brachytherapy is worthy of further study and is currently under evaluation in RTOG 0232, a phase III trial that compares permanent source brachytherapy as monotherapy to the combination of external beam treatment followed by brachytherapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncura Oncura
Function preservation with multimodality treatment in locally advanced oral tongue cancer
Authors: R. Hussain, A. Jamshed, K. Rehman, H. Iqbal, R. Azhar, Z. Faruqui, Q. Ahmed
Journal: Journal of Clinical Oncology (2009)

e17051 Background: Total or near total glossectomy with postoperative radiation is a standard treatment option for locally advanced squamous cell carcinoma oral tongue (LASCCOT). However, the procedure is controversial due to dismal cure rates and major functional deficits that impact on speech, deglutition and quality of life. We evaluated function preservation and survival outcome in LASCCOT treated with induction chemotherapy, limited surgery, and postoperative radiation/chemoradiation. Methods: We retrospectively identified 15 patients with LASCCOT treated with induction chemotherapy, limited surgery and postoperative radiation/chemoradiation at our institution between 04/07 - 04–08. M67%:F33% median age 50 years. Pretreatment AJCC stage as assessed on MRI was T2N+ (tumour crossing midline) 13%, T3N0 20%, T3N+ 47%, and T4N+ 20%. Prior to surgery induction chemotherapy, consisting of cisplatin 75 mg/m 2 day 1 and gemcitabine 1 mg/m 2 day 1 and 8 every three weeks for 2 cycles was given. Four to six weeks following second cycle of chemotherapy local excision of residual primary tumor with ipsilateral modified neck dissection was performed. Postoperative radiation dose was 60Gy/30 fractions. Post therapy pathological stage was ypT0N0 20%, ypT1N0 20%, ypT1N+ 40%, ypT2N+ 13%, and ypT3N+ 7%. Patients with ypN+ disease received concomitant 3 weekly cisplatin 75 mg/m 2 with radiation. Results: Overall and disease free survival at 20 months was 60%. Twelve patients (80%) are alive and 3 patients (20%) have died of disease at 9, 14 and 14 months (locoregional failure 1 and distant metastasis 2 patients). In patients alive without disease assessment of deglutition and speech at the time of last follow up showed all patients on full oral diet with spontaneous intelligible speech. Conclusions: Multimodality treatment with induction chemotherapy, limited surgery and post operative radiation/chemoradiation may allow selected LASCCOT patients to avoid morbid surgery and preserve tongue function without compromising survival. This approach merits further investigation in clinical trials. No significant financial relationships to disclose.