bluuebunny/crossref_metadata_2025_split huggingface dataset:
A dendritic metagene that predicts prognosis and endocrine resistance in breast cancer.
Authors: Giampaolo Bianchini , Pusztai Lajos , Qi Yuan , Iwamoto Takayuki , Kelly Catherine M , Zambetti Milvia , Symmans William Fraser , Gianni Luca 
Published: March 2020

545 Background: High expression of dendritic-associated genes in estrogen receptor-positive (ER+), highly proliferative breast cancer is associated with good prognosis in untreated patients (pts) and poor response to neoadjuvant endocrine therapy (Dunbier SABCS 2010). We examined the prognostic and predictive value of a dendritic metagene (DM) signature in subgroups defined by proliferation and estrogen-related genes (Bianchini SABCS 2011). Methods: We evaluated Affymetrix HGU133A-based gene expression profiles from ER+ untreated (n=511) and adjuvant tamoxifen (TAM)-treated pts (n=606). Three previously defined scores were assessed: MKS for proliferation (Bianchini, Cancer Res 2010); estrogen-related score (ERS) adopted from Oncotype DX; and DM (Bianchini JCO 2010). Median cut-off points were used. Outcome was assessed according to distant relapse. Results: DM was significantly predictive for early (within 5 years) relapse. In TAM-treated pts with low-MKS tumors, DM was not significantly prognostic. The table shows hazard ratios (HRs) for low vs. high-DM by ERS in untreated and TAM-treated pts with high-MKS. In low-DM, the 5-yrs distant-event free survival was 92.3% and 60.6% (HR 6.58 (2.55-17.0); p<0.001) and in high-DM it was 80.7% and 79.8% (HR 1.06 (0.48-2.32); p=0.88), respectively in high and low-ERS respectively. The interaction between DM and ERS was significant only in TAM-treated tumors (p=0.003). In high-MKS/low-ERS tumors, DM retained significance over the 10-year period in multivariate analysis adjusting for clinical variables (HR= 2.27 (1.13-4.58); p=0.02). Conclusions: For high-MKS, untreated and TAM-treated tumors with low-ESR, high-DM is associated with a low risk of relapse, and for untreated tumors with high-ERS. These data suggest that high infiltration of tumor by dendritic cells may be a novel mechanism of endocrine resistance. DM could refine risk in poor prognosis ER+ tumors and rationalize immuno-modulating strategies. [Table: see text]
Randomized phase II trial of cisplatin and radiotherapy with or without erlotinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Authors: Martins Renato , Parvathaneni Upendra , Sharma Anand K. , Raez Luis E. , Papagikos Michael A. , Yunus Furhan , Bauman Julie E. , Eaton Keith D. , Liao Jay Justin , Mendez Eduardo , Futran Neal , Kurland Brenda F , Wang David X. , Xiaoyu Shawn , Wallace Sarah G. , Hayes David N. 
Published: March 2020

5503 Background: The combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced SCCHN. Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating EGFR as a target. Erlotinib, a small molecule inhibitor of EGFR, has activity in recurrent/metastatic disease. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy. Methods: Patients with locally advanced SCCHN were randomized to receive cisplatin 100mg/m2 on days 1,22 and 43 combined with 70Gy of radiotherapy (arm A) or the same chemoradiotherapy combined with erlotinib 150mg/day, starting one week prior to radiotherapy and continued to its completion (arm B). Randomizing 204 patients had 80% power to compare a 60% complete response rate (CRR) to a 40% null rate. Available tumors were tested for p16, ERCC1 and EGFR FISH. Results: Between June 2006 and October 2011, 204 patients were randomized. Results presented are based on intention to treat. There were more females on arm A however no other differences in patient characteristics, including p16 positivity. Patients on arm B had more rash and gastrointestinal adverse events, but treatment arms did not differ for rates of other grade III/IV toxicities or serious adverse events (SAEs). Arm A had a CRR of 61% and arm B had a CRR of 68% (p=0.3). With a median follow-up of 23 months, there were only 29 events in the overall survival analysis and 46 in the progression-free survival (PFS) analysis. The 2 and 3 year PFS were 71% and 63% for arm A and 78% and 73% for arm B (p=0.61). Conclusions: The addition of erlotinib did not increase the rate of SAEs but failed to significantly increase CRR. As seen in other recent trials, our results in both arms are superior to historical comparisons. Updated PFS data will be presented. Supported by a grant from the investigator-initiated trial program of Genentech/OSI.
Five years' results of the German ARO 04-01 trial of concurrent 72 Gy hyperfractionated accelerated radiation therapy (HART) plus once weekly cisplatinum/5-FU versus mitomycin C/5-FU in stage IV head and neck cancer.
Authors: Budach Volker , Cho Chie-Hee , Sedlmaier Benedikt , Wittlinger Michael , Iro Heinrich , Engenhart-Cabillic Rita , Hautmann Matthias , Strutz Juergen , Flentje Michael , Hueltenschmidt Beatrix , Moser Lutz , Bleif Martin , Budach Wilfried , Staar Susanne , Becker Gerd , Tribius Silke , Feyer Petra C. , Wernecke Klaus Dieter , Werner Jochen 
Published: March 2020

5512 Background: Are 6 cycles of once weekly DDP plus one cycle of 5-FU with concurrent HART superior to 2 cycles of MMC plus one cycle of 5-FU in terms of overall survival (OS) and metastases-free survival (MFS)? Methods: Eligibility: Stage IV SCC of oro(OP)- and hypopharynx(HP), KFS of ≥80% stratified for sites, N-status, grading, hemoglobin and center. The HART schedule was reported elsewhere (V.Budach, JCO 23;2005). HART was applied concurrently with DDP/5-FU at 30mg/m² days 1,8,15,22,29,36 or MMC/5-FU at 10mg/m2 day 1+36 and for both arms with 600mg/m² 5-FU days 1-5 as 120 hrs. c.i. TVD dose prescription was 72 Gy using 3D-conformal or IMRT-TP. 364 patients were analysed using an ITT principle for OS, MFS, progression-free survival (PFS) and loco-regional control (LRC). Hazard ratio (HR) calculations were adjusted for competing risk factors. Results: Median follow-up was 48 mos. for both arms. Mean age was 55.4 years, 83/17% were male/female and 100% stage IV patients (UICC 2002). 58.5%/41.5% of all patients suffered from OP- or HP cancer, respectively. The OS and MFS at 4 years for the DDP- versus MMC-arm was 42.1% vs. 38.8% (n.s.) and 67.3% vs. 56.6% (p=.05), respectively. The LRC and PFS for the DDP versus MMC-arm was 58.6% vs. 57.2% (n.s.) and 46.4% vs. 38.7% (n.s.). Seven items recorded for acute toxicity and 9 for late morbidity showed no significant differences between the treatment arms except for creatinine for the DDP-arm (p < 0.001) using nonparametric analyses of variances for repeated measurements. The overall compliance rates for RTX were 96%, DDP: 72%, 5-FU: 97%, MMC: 86%, respectively. Conclusions: This phase III trial first establishes level IB-evidence for a once weekly DDP chemoradiation regimen. For MFS at 4 yrs., DDP/5 FU-HART is superior to MMC/5 FU HART at equal levels of acute and late radiation sequelae for both treatment arms. No significant differences were seen yet for OS, PFS or LRC. Chemoradiation with weekly DDP/5-FU or MMC/5-FU shows excellent compliance rates and can easily compete with other concurrent chemo- or bio-radiation schedules including induction TPF followed by radiation.
Safety, molecular, and imaging responses to cetuximab administered in a window pre-operative study in squamous cell carcinoma of the head and neck (SCCHN).
Authors: Schmitz Sandra , Hamoir Marc , Reychler Herve , Magremanne Michele , Weynand Birgit , Lhommel Renaud , Hanin Francois-Xavier , Lonneux Max , Rommel Denis , Michoux Nicolas , Duprez Thierry , Machiels Jean-Pascal H. 
Published: March 2020

5519 Background: Only a minority of SCCHN pts benefits from anti-EGFR mAbs. Trials with pre- and post-therapy tumor biopsies are crucial to better characterize the molecular pathways involved in treatment response or resistance. Targeted agents (TA) are often investigated in unselected end-stage cancer pts, making difficult optimal translational research. One way to resolve this issue is to perform “window” studies where a TA is given during the incompressible period between the diagnosis and surgery. Methods: We conducted a phase I/II study: cetuximab (C) was given pre-operatively to treatment-naïve SCCHN pts selected for primary curative surgery. C (400mg/m2 first wk followed by 250mg/m2/wk) was given during 2 wks (day -15 until day -1, 3 infusions) before surgery (day 0). Tumour biopsies, FDG/PET, and CT were performed at diagnosis and surgery. In the phase I, we investigated the safety of preoperative C by progressively reducing the delay between the last dose of C and surgery (minimum delay : 24 hrs ; 3+3 phase 1 design). The aims of the phase II were (i) safety, (ii) C activity by FDG-PET (Po=0.10, P1=0.35, a=0.05 and b= 0.10). As controls, 5 additional pts were included without C treatment but with the same requirements regarding biopsies and imaging. Results: The phase 1 study (n=18) demonstrated that C infusion given 24 hrs before surgery was safe. Safety was confirmed in the phase II (n=20). 90 % had a FDG-PET partial response (PR) (EORTC guideline) in the C group and 0% in the controls. 52% had a ΔSUVmax decrease of >50%. 2 pts evaluable by CT/MRI had a PR (RECIST). Then, we compared the pre-and post treatment biopsies by immunochemistry. For the whole group, C did not reduce Ki67 (p=0.1) and did not seem to induce apoptosis (caspase). However, for pts with ΔSUVmax decrease > 25% or > 50%, Ki67 was decreased (p=0.04 and 0.006). C induced downregulation of pEGFR (p=0.0004) and pERK (p=0.007) but not pAKT/AKT (Histoscore). Conclusions: Pre-operative study with C is safe. Our findings suggest that the main downstream molecular pathway blocked by C in SCCHN is the RAS/RAF/ERK. Further analyses are ongoing to better characterize molecular response and escape mechanisms.
The influence of institutional head and neck cancer (HNC) clinical trial accrual on overall survival (OS): An analysis of RTOG 0129.
Authors: Wuthrick Evan John , Zhang Qiang , Machtay Mitchell , Ang K. Kian , Rosenthal David Ira , Nguyen-Tan Felix , Fortin Andre , Silverman Craig I. , Raben Adam , Kim Harold , Horwitz Eric M. , Read Nancy E , Harris Jonathan , Wu Qian , Gillison Maura L. ,   Radiation Therapy Oncology Group
Published: March 2020

5530 Background: NCCN recommends HNC patients (pts) be treated by providers with experience in HNC management. Whether treatment by experienced providers (measured by no. of pts treated) is associated with HNC survival outcome is unknown. Methods: Analysis included 471 pts in RTOG 0129 with stage III-IVa HNC with known tumor HPV and smoking status randomized to cisplatin concurrent with standard or accelerated fractionation radiotherapy (RT). Participating centers were stratified into pt accrual tertiles (ATs) to 21 RTOG HNC trials from 1997-2002. As a surrogate for experience, we investigated the independent effect of AT on OS and progression-free survival (PFS) in multivariable cox proportional hazards models. Results: Median follow up was 4.8 yrs (range 1.1 - 6.5). In Kaplan-Meier analysis, OS and PFS for pts at centers in the two lower AT (low accruing centers [LAC]) were similar and compared to the upper AT (high accruing centers [HAC]). Median accrual in LAC vs HAC was 11 vs 82 pts. Pts treated at LAC and HAC had similar age, HPV status, pack-years, N stage, comorbidities and study arm assignment (SAA), but pts at LAC had better performance status (PS)(Zubrod 0; 62% vs 52%; p=0.04), fewer T4 tumors (27% vs. 35%; p=0.05) and were more likely uninsured (12% vs 4%; p=0.009). Compared to HAC, LAC pts had significantly worse OS, (5 yr 51.0% vs 69.1%; p = 0.002), and PFS (5 yr 42.7% vs 61.8%; p = 0.001) and more locoregional failure (5 yr 36.4% vs 20.8%; p <0.001). Treatment at LAC was associated with ~90% increase in risk of death (OS HR 1.91, 95%CI 1.37-2.65) and progression (PFS HR 1.89, 95%CI 1.39-2.56) when compared to pts treated at HAC, after adjustment for age, PS, pack-years, T and N stage, SAA and HPV status. Acute and chronic toxicities, RT dose, fractions, and treatment duration did not differ for pts at LAC vs HAC. RT at LAC was more likely than HAC to differ from protocol (18% [16.8% acceptable variation {AV}, 1.2% unacceptable deviation {UD}] vs 6% [4.7% AV, 1.3% UD]; p<0.001). Conclusions: Pts with HNC treated at LAC in RTOG trials were associated with significantly worse survival outcomes compared to pts treated at HAC.
Prevalence, trends, and survival impact of human papillomavirus on oropharyngeal cancer in Indian population.
Authors: Bahl Ankur , Dar Lalit , Mohanti BK , Kumar Pankaj , Thakar Alok , Karthikeyan Venkat , Sharma Atul 
Published: March 2020

5540 Background: Among oropharyngeal squamous cell carcinoma (OSCC), the true prevalence of HPV remains variable and studies have estimated that up to 60% may be HPV positive. Patients with HPV positive tumor are usuallyyounger in age, less likely to have history of tobacco or alcohol consumption and associated with a better prognosis but this information for Indian patients is largely unknown. Methods: 105 newly diagnosed patients of OSCC were enrolled. HPV genotyping was done on the biopsy specimen by consensus polymerase chain reaction and reverse line-blot hybridization assay. HPV prevalence was studied according to gender, age, tobacco and alcohol use and high risk sexual behavior. Results: Overall HPV prevalence was 22.8%. HPV positive patients were younger by 8 years as compared to negative patients (P=0.003). No significant correlation between tobacco consumption, alcoholic habits, and HPV status was observed. The mean number of life time sexual partners in HPV positive patients was 1.66 while, it was 1.33 in HPV negative patients (P=0.049). Incidence of high risk sexual behaviors was more in HPV positive patients (P<0.001). There were no significant associations between the two groups with respect to tumor size, nodal stage and the overall stage of the tumor. 16% of the base of tongue cancers and 40% of tonsillar carcinoma were positive (P = 0.02). Among positive samples, HPV 16 was the commonest (79%) followed by HPV 18 (12%). 96% of patients received treatment. At 18.8 months there was no significant difference in OS, EFS between HPV positive and negative OSCC (P = 0.97 and P= 0.51 respectively). Conclusions: The current study reconfirms that HPV positive OSCC patients are younger with high risk sexual behavior. Impact of smoking and alcohol consumption on HPV status was not found in this study. HPV positive rates were significantly higher for tonsillar cancer. Contrary to literature, we did not find any differences in OS or EFS between two groups. Small numbers of patients in the study group, short follow up period and significant tobacco smoking in HPV group may be the one of the reason for this.
Phase II study of temsirolimus and erlotinib in patients (pts) with recurrent/metastatic (R/M), platinum-refractory head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Arias-Pulido Hugo , Lee Sang-Joon , Considine Michael , Fekrazad M Houman , Howard Jason , Bishop Justin A. , Olson Garth T , Jones Dennie V. , Fertig Elana J. , Chung Christine H. 
Published: March 2020

5549 Background: The Epidermal Growth Factor Receptor (EGFR) is a validated target in HNSCC. In R/M disease, primary or acquired resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. We hypothesized that concurrent mTOR blockade may improve efficacy of anti-EGFR therapy and conducted this phase II study. Methods: We evaluated the combination of erlotinib 150 mg po daily and temsirolimus 15 mg IV weekly in pts with platinum-refractory R/M HNSCC and ECOG PS 0-2. The exact, single-stage phase II design had 80% power (5% significance level) to detect improvement in progression-free survival (PFS) from 2.3 to 4.4 mos with 35 evaluable pts. Correlatives included determination of PIK3CA mutation (mut) status; p16, EGFR and PTEN expression; and immunomodulatory cytokine levels. Results: From Dec 2009 – Mar 2011, 12 pts enrolled. Six pts withdrew prior to first planned response assessment, due to toxicity (5) or death (1), prompting referral to the Data Safety and Monitoring Committee and early closure. Grade ≥ 3 toxicities included fatigue (5), diarrhea (2), GI infection/peritonitis (2), dyspnea (2), HN edema (2), and neutropenia (1). Among 8 progression-evaluable pt, median PFS was 1.9 mos. Median OS was 4.1 mos. 4/12 tumors were p16(+); 4/10 were EGFR(+); 11/11 showed no PTEN expression. PIK3CA mut was present in 1/11; the mut(+) pt withdrew after 3 wk for diarrhea/peritonitis with minor response. There were no associations between tumor p16, EGFR or PTEN status and oncologic outcomes. Five of 6 toxicity-related withdrawals occurred in p16(-) pts. Immunomodulatory cytokine levels in pre- and post-temsirolimus plasma did not significantly differ or associate with toxicity. Two pts with ≥ 4.4 mos PFS were p16(-) and PIK3CA mut(-). Conclusions: The combination of erlotinib and temsirolimus was poorly tolerated in this population, with toxicities predominant in p16(-) pts. Although the sample size was small, this R/M cohort demonstrated lack of PTEN expression and 9% PIK3CA mut, justifying further investigation of PI3K/Akt/mTOR pathway inhibitors in selected HNSCC pts.
Preoperative recombinant adenoviral human p53 gene combined with intensity-modulated radiation therapy in treatment of stage IV papillary thyroid carcinoma: A randomized clinical study.
Authors: Zhu Jingqiang 
Published: March 2020

5550 Background: Most of stage IV papillary thyroid carcinoma (PTC) is initially unresectable due to invading surrounding structures, and is also commonly resistant to standard radio- or chemo-therapy. P53 gene therapy could increase tumor radiosensitivity and inhibit tumor angiogenesis. This study is to evaluate the benefits of pre-operative recombinant adenoviral human p53 gene (rAd-p53) combined with intensity-modulated radiation therapy (IMRT) in treatment of stage IV PTC. Methods: Forty-six patients with historically-diagnosed stage IV PTC, satisfying the inclusion criteria, were randomly assigned into two groups: experimental group (EG) control group (CG). EG received intratumoral injection of 2-4×1012 rAd-p53 viral particles (VP) per 3 days for 10 times and IMRT once per day for 28 days at a total dose of 65 Gy. CG received the same IMRT therapy. Once month after the combined treatment, patients were assessed for resectability. A radical surgery was performed on the patients with a resectable tumor. All the patients received standard I131 therapy 1-1.5 months after surgery or after the last IMRT. Results: EG including 25 cases, 19 females and 6 males, had a radical surgery rate of 76% (19/25), one-year survival rate of 96%, and no local recurrence and distant metastases for patients having a surgery. The tumors in six patients of EG were still unresectable. But all these six patients had a local partial response. The tissue sample analyses showed increased fibrous tissues, apoptotic cells, and increased Bax and p21 protein and mRNA levels. CG including 21 cases, 15 females and 6 males, had a radical surgery rate of 47.6% (10/21), one-year survival rate of 81.0%, and distant metastatic rate of 20% (2/10) for patients having a surgery. The local partial response rate of unresectable patients in CG was 72.7% (8/11). There were no changes in Bax and p21 protein and mRNA levels. The main side effects of rAd-p53 were self-limited fever, occurring in 24 of EG patients. Conclusions: Pre-perative rAd-p53 combinedwith IMRT in treatment of the stage IV PTC increases radical surgical rate and response rate, and improves long-term efficacy.
Recombinant adenoviral human p53 gene combined with radio- and chemotherapy in treatment of advanced nasopharyngeal carcinoma: A randomized clinical study.
Authors: Lan Guiping , SI Yongfeng , Qin Yangda , Deng Zhuoxia , HE Chengcheng , Huang Bo , LU Jinlong 
Published: March 2020

5558 Background: Studies showed p53 gene therapy could enhance the anti-tumor effect of both chemo- and radiotherapy. The anti-tumor function of p53 gene is associated with up-regulated expression of p21 and Bax. Here, we investigate the beneficial role of recombinant adenoviral human p53 gene (rAd-p53) combined with chemoradiotherapy in treatment of advanced nasopharyngeal carcinoma (NPC), and p21 and Bax protein expression in pre- and post-treatment tumor tissues. Methods: Sixty-three patients with historically-diagnosed advanced NPC, with ECOG performance status less than 2, life expectancy greater than 3 months and adequate organ function tests, were randomly assigned into two groups: 32 in experimental group (EG) and 31 in control group (CG). EG received intratumoral injection of 1×1012 rAd-p53 viral particles (VP) per 3 days for 6-8 times, carboplatin 300 mg/m2 on day1 and continuous infusion of a total dose of 2000 mg/m2 of 5-Fu on day1-5 for 3 cycles, and radiotherapy at a dose of 2Gy/fraction for a total dose of 70-76 Gy/35-38f. CG received the same chemo- and radiotherapy. Pre- and post-treatment tissue samples were analyzed for Bax and p21 protein levels. Results: The median follow-up time was 28 months. EG achieved a complete response rate (CR) of 62.5% and overall response rate (RR) of 90.6%, both rates being statistically significantly higher than that of CG (CR=35.5%, RR=74.2%). One-year of overall survival (OS) was 100.0% for EG and 90.3% for CG, and one year of progress free survival (PFS) was 96.7% and 77.4% for EG and CG, respectively. Two-year OS was 95.7% and 86.4% for EG and CG, respectively, and two-year of PFS was 79.6% and 73.5% for EG and CG, respectively. After treatment, both Bax and p21 protein levels in EG increased significantly. In CG, both proteins levels also increased after treatment but not significantly. The main side effects of rAd-p53 were self-limited fever, occurring in all of EG patients. Conclusions: RAd-p53 as a component of the comprehensive therapy for advanced NPC contributes significant beneficial effects. Increased levels of Bax and p21proteins after treatment represent two mechanisms of p53 anti-tumor activities.