bluuebunny/crossref_metadata_2025_split huggingface dataset:
Screening candidate targets by SAGE evaluation of rectal cancer transcriptome after chemoradiotherapy: Association of trefoil factor-family 3 (TFF3) expression with patients prognosis
Authors: Casado E. , Cejas P. , Sanchez J. , Blanco M. , Maurel J. , Castelo B. , Feliu J. , Miquel R. , De Castro J. , Sereno M. , Gonzalez Baron M. 
Published: August 2020

4107 Background: Treatment resistance and the lack of reliable prognostic factors are major obstacles in rectal cancer (RC) management. A blind screening of RC transcriptome changes after chemoradiotherapy (CRT) could pinpoint proteins potentially involved in CRT resistance. Evaluation of their relation with disease outcome could help to identify novel therapeutic and prognostic candidates. Methods and Results: In a first stage we screened dynamic changes of RC transcriptome after CRT using blind and directed strategies. On one side, we selected fresh RC samples, before and after CRT, from three uT3N0 patients with poor response, as assessed by Dworak´s TRG2 and minimal downstaging (ypT2–3N0). Serial Analysis of Gene Expression (microSAGE) was conducted, six libraries were generated, sequencing around 30.000 tags. MonteCarlo analysis of dynamic “intra-patient” changes, and “inter-patient” comparisons revealed a set of 25 genes with shared significant changes. On another side, a collection of 29 genes was selected from the literature, In a second stage we evaluated dynamic changes in the mixed set of 54 genes in a cohort of 125 stage II-III RC patients treated with preopCRT. Samples from 74 patients assured sufficient tumor quality and quantity before and after CRT. mRNA dynamic changes of gene expression were evaluated by TaqMan Low Density Arrays (TLDAs), and statistical analysis done by Wilcoxon test with bootstrap and regulated genes selected for discriminant and Cox proportional-hazards regression analysis. Induction of mRNA TFF3, screened in the blind phase SAGE and exhibiting important tumor promotion and progression functions, was associated with tumor relapse and shorter survival. Also, analysis of TFF3 immunohistochemical expression in surgical samples revealed that an on/off pattern of intraluminal gland expression (PAS independent) strongly predicted tumor relapse. Conclusions: Upregulation of TFF3 after CRT, and an easily determined IHC pattern, predicted RC relapse in preoperatively treated patients. Confirmatory prognostic studies in independent series should be conducted, and its potential therapeutic merits as a candidate target evaluated. No significant financial relationships to disclose.
Phase II study of preoperative panitumumab, 5-fluorouracil, and oxaliplatin with concurrent radiotherapy in locally advanced rectal cancer: Preliminary safety results (StarPan /STAR-02 Study)
Authors: Pinto C. , Di Fabio F. , Maiello E. , Di Tullio P. , Pini S. , Aschele C. , Garufi C. , Bochicchio A. , Pinotti G. , Latiano T. , Martoni A. 
Published: August 2020

4110 Background: The aim of this phase II study is to assess the activity of preoperative external radiotherapy combined with panitumumab, oxaliplatin and 5-fluorouracil in locally advanced rectal cancer patients (pts). Methods: Pts entering the study had histologically-proven rectal adenocarcinoma, either uT3N+ or T4 N-/+ stage, with location <12 cm from the anal margin. Panitumumab was administered at a dose of 6 mg/kg IV, 2 weeks before the start of chemoradiotherapy, and then in combination with chemoradiotherapy, every 2 weeks for 3 times. 5-fluorouracil and oxaliplatin were administered according to an established schedule of STAR-01 Study (oxaliplatin 60 mg/m2 IV weekly for six times, and 5- fluorouracil 225 mg/m2/day continuous infusion IV d 1–38). Radiotherapy was delivered up to a dose of 50.4 Gy in daily fractions of 1.8 Gy. Rectal surgery was performed 7–8 weeks after the end of neoadjuvant treatment. Eight courses of adjuvant chemotherapy with FOLFOX4 plus panitumumab at a dose of 6 mg/kg, every 2 weeks, were given after surgery. The primary endpoint of the study was the complete pathological response rate. Results: From February 2007 to December 2008, 35 out of the 55 planned pts were enrolled. Twenty nine pts completed neoadjuvant treatment and 20 underwent surgery (15 pts ongoing). The characteristics of 29 pts were: males 19 (65.5%) and females 10 (34.5%); median age 58 years (range 39–78); median Karnofsky PS 100 (range 70–100); stage: uT3N+ 22 (75.9%), uT4N- 3 (10.3%), uT4N+ 4 (13.8%). The most frequent grade 1–4 side-effects were acneiform rash (96.2%), diarrhea (51.7%) and fatigue (14.3%). Grade 3 diarrhea was registered in 35.7% pts, and grade 3–4 cutaneous toxicity in 51.8%. No grade 3–4 hematological toxicity was found. The median cumulative dose of delivered radiotherapy was 50.4 Gy. The planned dose of panitumumab, 5-fluourouracil and oxaliplatin was administered in 83%, 72% and 67% of pts, respectively. Conclusions: Despite the moderate increase of diarrhea, these early results demonstrate that panitumumab can be safety added to 5-fluorouracil/oxaliplatin-based chemoradiotherapy, without compromising the concurrent radiotherapy dose. No significant financial relationships to disclose.
A single-center study of the utility of squamous cell carcinoma antigen (SCCAg) levels in epidermoid carcinoma of the anal canal and margin (ECACM) treated with chemoradiation (CRT)
Authors: Swampillai A. , Williams M. , Osborne M. , Mawdsley S. , Hughes R. , Harrison M. , Glynne-Jones R. 
Published: August 2020

4117 Background: SCCAg is a tumour marker expressed by ECACM, measured by microparticle enzyme immunoassay; normal range 0–150ng/dl. Methods: This retrospective study examined the role of SCCAg in staging and prediction of recurrence in 195 patients (pts); 76 m:119 f with ECACM treated 1997–2007. All 195 were treated with CRT- (50.4Gy in 28 fractions of 1.8 Gy with 5-fluorouracil (5-FU) + mitomycin (MMC). Radiotherapy comprised the schedule of the UK Anal cancer Trial (ACT II). Variations included 5FU and cisplat, and capecitabine. 30 had neo-adjuvant chemotherapy followed by CRT and 3 pts had planned surgery followed by CRT. Median follow up was 36 months (range 1 - 168). Median age was 61 years (range 30 -91). In 149 pts with SCCAg samples taken prior to CRT, 107 had one or more samples taken at follow up at 3 - 6 monthly intervals. Clinical stage at diagnosis- Tx (6) T1 (28), T2 (80), T3 (65), T4 (16), N0 (126), N+ (66) Nx (3). Results: Mean baseline SCCAg by cT and cN stage were: T1 93 (ng/dl), T2 300, T3 607, T4 882, N0 376, N+ 529 (correlation coeff: T: 0.47, N: 0.33, both p< 0.001). 135 patients had baseline SCCAg with a documented response on completion of CRT. The mean baseline SCCAg for pts achieving CR was 408 and non CR was 513 (p = 0.13). Sensitivity of baseline SCCAg to predict relapse was 0.56 (specificity 0.4). Sensitivity of two consecutive elevated SCC levels during the follow up period in patients who achieved a CR to predict for relapse was 0.56 and specificity 0.83. The positive likelihood ratio was 3.3 (1.8 - 6.1) and the negative was 0.53 (0.3 - 0.9). Conclusions: There is a correlation between T and N stage and baseline SCC. In follow-up, a sustained rise in SCCAg increases the odds of relapse three-fold. We recommend SCCAg measurement in the first year after CRT. [Table: see text]
Impact of K-ras status on the effects of EGFR-targeted monoclonal antibody (MAb) therapy in advanced colorectal cancer (ACRC): A systematic review and meta-analysis of randomized controlled trials (RCTs)
Authors: Vale C. , Tierney J. F. , Meade A. , Fisher D. , Kaplan R. , Adams R. A. , Maughan T. S. , Parmar M. K. 
Published: August 2020

4122 Background: A recent systematic review, based largely on non-randomised, retrospective studies, suggested that K-ras mutations may identify patients who do not benefit from cetuximab and panitumumab. In support of this hypothesis, four RCTs have shown a lack of benefit or detriment of EGFR-targeted therapy in patients with K-ras mutations. In this systematic review, we aim to provide a comprehensive and unbiased synthesis of the effects of these MAbs, by K-ras status, in both chemotherapy (CT) responsive and CT-refractory ACRC patients. Methods: A systematic review and meta-analysis of all relevant RCTs is ongoing. Progression-free survival (PFS) is the primary outcome, with survival and response as secondary outcomes. We have conducted systematic searches of a number of trial sources. Data on trial and patient characteristics, and outcome have been extracted from trial reports or presentations, for all patients and for K-ras wild-type and mutant cohorts. Where possible, trial results were pooled in a stratified-by- trial meta-analysis. For unpublished RCTs, or those published with insufficient information, we are seeking further data. Results: Searches identified 15 eligible RCTs in CT-responsive patients, 12 using cetuximab and 3 panitumumab. Three of these trials included bevacizumab in both arms. PFS has only been reported for 6 RCTs, so further data are needed to ensure an unbiased analysis. Only two RCTs were identified in CT-refractory patients. Together, these showed an improvement in PFS with anti-EGFR MAb (HR=0.61, 95% CI 0.49–0.76, p<0.0001). Furthermore, there was a significant difference in the size of the effect by K-ras status (interaction p<0.0001), with an improvement in PFS for patients with wild type K-ras, (HR=0.43, 95% CI 0.35–0.52, p<0.0001), but not those with mutant K-ras (HR=0.99 95% CI 0.80–1.23, p=0.93). Conclusions: These preliminary results suggest that the benefits of anti-EGFR MAb therapy, at least in CT-refractory patients, are confined to those with wild type K-ras. Results for CT-responsive patients, and updated analyses for CT-refractory patients, will be presented. [Table: see text]
Oxaliplatin (OXP) plus protracted infusion 5-fluorouracil (PIFU) and external beam radiation (EBRT) prior to surgery (S) for potentially curable esophageal adenocarcinoma (EA): A Southwest Oncology Group (SWOG) phase II trial with molecular correlates (S0356)
Authors: Leichman L. , Goldman B. H. , Benedetti J. K. , Billingsley K. G. , Thomas C. R. , Iqbal S. , Lenz H. , Blanke C. , Gold P. J. , Corless C. L. 
Published: August 2020

4513 Background: Although neoadjuvant combined modality therapy (NACMTX) has become a standard of care in the United States, median overall survival (OS) for patients (PTS) with EA has changed little over the past 25 years. Progression free survival (PFS) and OS after NACMTX depend on extent of primary tumor response. New regimens to increase pathologic complete response (pCR) are needed. Based on phase I data, SWOG designed a phase II trial (S0356) to test OXP with PI5FU and EBRT for PTS with EA. Objectives included pCR rate ≥ 25%, acceptable toxicity (TOX), PFS, OS and exploration of molecular parameters relevant to pCR. Methods: Eligibility: clinical stage II/III EA, ≥ 18 years, Zubrod PS ≤ 2, standard hematologic/non-hematologic values, and tumor < 2 cm into the gastric cardia. OXP 85 mg/m2 was given day (d) 1, 15 and 29; PI5FU 180 mg/m2/d was given d 8-d43. EBRT 180 cGy/d started d 8 x 25 fractions, 5 d/week to total dose 4500 cGy. S was planned 2–4 weeks after NACMTX, with a second cycle of OXP/ PI5FU after S. Central pathology review of surgical specimens was mandated. The trial used a 2-stage design; the trial was halted at 45 PTS to review pCR rate; it reopened to full accrual. Results: 98 PTS enrolled between 9/15/04 and 8/18/08. 6 PTS were ineligible; 2 PTS did not receive therapy (TX). 90 PTS, 84 men (93%), median age 61.7 years, were analyzed. 4 deaths (4.5%) were due to protocol TX; 2 due to NACMTX, 2 to S. 43% and 18% of PTS had grade 3/4 toxicity, respectively: 39% GI, 22% flu-like/fatigue, 17% pulmonary, 16% hematologic, 14% mucositis and 3% neurologic. 77 PTS (86%) underwent S. 30 PTS (33%) had pCR. 9 PTS (10%) had in-situ cancer or T1N0M0. <50% received postoperative CTX. Conclusions: OXP, PI5FU and EBRT for PTS with EA has produced the highest pCR rate reported to date for a cooperative group trial. Significant but manageable non-hematologic TOX was observed. S mortality is acceptable. Future trials built on this platform should plan to complete all TX before S. Tumor molecular profiles (analyses in progress) may predict benefit from this treatment. Data on PFS and OS will follow. [Table: see text]
Disease-free survival as a surrogate endpoint for overall survival in an adjuvant trial of curatively resected stomach cancer using individual patient data meta-analysis
Authors: Burzykowski T. , Bang Y. ,   on behalf of the GASTRIC project
Published: August 2020

4517 Background: In investigations of the effectiveness of oncology drugs, overall survival (OS) is considered as the gold standard end point. However, the disadvantage of OS is that it requires an extended follow-up. A reasonable candidate for a surrogate for OS in the adjuvant setting is disease free survival (DFS). DFS is defined as recurrence of stomach cancer, all second cancers, or death from any cause. Recently, some evidence has been offered for the use of DFS as a surrogate for OS in, e.g., colorectal cancer. We evaluated 3 year DFS as a surrogate for 5 year OS in adjuvant trials of stomach cancer by using individual-patient data (IPD) meta- analysis validation criteria. Methods: The GASTRIC group initiated an IPD meta-analysis of all randomized clinical trials comparing chemotherapy versus surgery alone for patients with curatively resected stomach cancer. The validity of DFS at 3 years as a surrogate for OS at 5 years was investigated by using multiple analysis techniques, which included measures of correlation between the endpoints and between the treatment effects, and the percentage of agreement in the log-rank tests for the two endpoints at the trial level. Results: Among the 31 eligible trials, at most 25 collected the date of recurrence (5,014 pts). As of December 2008, IPD were available from 13 randomized controlled trials (3,161 patients). Seventy-seven percent of patients (1,280/1,652 pts) who recurred during the follow-up period, recurred within the first 3 years after study enrollment. At the trial level, 12 out of the 13 trials yielded the same conclusions for both endpoints at the 0.05 significance level. The R2 value between both endpoints was equal to 0.97 and Spearman's rank correlation was equal to 0.92. The R2 value between hazard ratios for OS and DFS was equal to 0.85 and Spearman's rank correlation was equal to 0.87. Conclusions: Our preliminary results, which are based on 63% of the targeted data, show that the 5-year OS and the 3-year DFS are highly correlated. Additionally, the hazard ratios for DFS and OS are also strongly associated. This suggests that 3-year DFS may be a good surrogate for a 5-year OS. The results based on the most recent update of the IPD will be presented during the conference. No significant financial relationships to disclose.
Activity of gemcitabine in direct patient-derived xenografts and clinical outcome: Validation of an in vivo model for drug development
Authors: Hidalgo M. , Garrido-Laguna I. , Uson M. , De Oliveira E. , Schulick R. , Hruban R. H. , Maitra A. , Jimeno A. , Rubio-Viqueira B. , Rajeshkumar N. V. 
Published: August 2020

4528 Background: Novel drugs are urgently needed for pancreatic ductal adenocarcinoma (PDA). Current preclinical models may not recapitulate the biology of human cancers. Direct xenografts have the potential to better represent the biology of human cancer. We have completed a clinical trial in which surgically resected PDAs were xenografted into nude mice thus generating an in vivo platform for drug development and biomarker identification. Methods: PDAs resected at Johns Hopkins Hospital are implanted into nude mice. From November 2005 to December 2008, 240 patients were consented, 236 operated, 102 were resectable PDAs thus fulfilling the inclusion criteria. 104 patients had other histologies and 34 were unresectable PDAs. Xenografted tumors were treated with gemcitabine and the activity in the xenograft correlated with patient clinical outcome. Results: Out of these 102 cases, 77 were xenografted, 53 were engrafted and reached the treatment phase. 35 out of the 53 originator patients were clinically treated with gemcitabine. The median overall survival of resected patients was 646 days (similar to 660 days from CONKO-001 trial). Patients whose carcinomas engrafted had a shorter median overall survival (319 vs. 728 days, p=0.002), probably reflecting a more aggressive tumor biology in the engrafted group. The response rate of gemcitabine in xenografts based on RECIST criteria was 8% (similar to response rate to gemcitabine in phase III trial by Moore et al.). In the adjuvant setting, the median disease free survival (DFS) was significantly longer in those patients predicted as sensitive by the xenograft model (568 vs. 286 days, p=0.037). In the metastatic setting, the median time to progression (TTP) was longer in those patients predicted as sensitive by the model (126 vs. 73 days) though this difference was not statistically significant. Overall the correlation between gemcitabine activity in this model and clinical outcome as measured by DFS was 0.71 in the subgroup of patients whose xenografts had a TGI lower than -10%. Conclusions: This preclinical model predicts gemcitabine outcome in the clinic in the adjuvant setting. Further studies to analyze the causes of shorter survival in patients whose PDA engrafted are warranted. No significant financial relationships to disclose.
Integrated development of s-trans, trans-farnesylthiosalicyclic acid (FTS, salirasib) in advanced pancreatic cancer
Authors: Laheru D. , Rudek M. , Taylor G. , Goldsweig H. , Rajeshkumar N. V. , Linden S. , Angenendt M. , Le D. , Donehower R. , Jimeno A. , Hidalgo M. 
Published: August 2020

4529 Background: The Ras signaling pathway stands as a strategic target in pancreatic cancer. S-trans,trans-farnesylthiosalicyclic acid (FTS) inhibits Ras dependent cell growth by dislodging all of the isoforms of Ras from membrane binding sites. Here we studied the activity of this agent in patients with advanced pancreatic cancer. Methods: Patients with treatment naïve advanced peri-ampullary cancer were treated with gemcitabine (Gem) administered at standard dose and schedule + FTS administered orally at doses of 200–800 mg bid 21 days of a 28 day cycle. Patients were treated until progression or protocol defined DLT. Plasma samples were collected when FTS was administered alone (C1D7 or C1D22) and in combination (C1D15 or C1D8) to characterize FTS pharmacokinetics. Plasma samples were collected when Gem was administered alone (C1D1) and in combination (C1D15 or C1D8) to characterize Gem pharmacokinetics. PBMCs and tissue biopsies pre treatment and during cycle 1 were collected to characterize the effect of Gem + FTS on levels of activated Ras protein. Treatment efficacy was assessed every other cycle. Results: Thirteen patients (8 male, 5 female, ages 40 to 80, ECOG 0–1) are enrolled to date. The most common adverse events were neutropenia, anemia, abdominal cramping, elevated liver function tests and diarrhea. At the time of this analysis, the progression free survival for these 13 patients is 4.7 months with median survival of >10.8 months and 1 year survival of 50%. Conclusions: 1. Salirasib in combination with gemcitabine appears to be safe with no PK interaction. 2. Salirasib in combination with gemcitabine at doses to 800 mg b.i.d. did not reach conventional MTD, although dose related diarrhea suggests better tolerance at doses up to 600 mg b.i.d. 3. Salirasib at doses of 400 to 800 mg b.i.d. in combination with gemcitabine demonstrated a PFS, MS and 1 year survival of 4.7 months, >10.8 months and 50% respectively. 4. Salirasib mechanism of Ras inhibition is confirmed by reduction of tumor Ras in pancreatic cancer patients. 5. Salirasib warrants evaluation in a controlled study with gemcitabine in pancreatic cancer; doses of 600 or 400 mg b.i.d. are recommended. No significant financial relationships to disclose.
Effect of gender and age on overall survival in patients with esophageal cancer
Authors: Chhibar R. S. , Yang D. , Zhang W. , Lurje G. , Pohl A. , Ning Y. , El-Khoueiry A. , Iqbal S. , Lenz H. J. 
Published: August 2020

4541 Background: The American Cancer Society estimated that during 2008 approximately 16,470 new esophageal cancer cases would be diagnosed in the United States. Previous studies indicate that the incidence of esophageal cancer is more in males than females; however the influence of sex in the progression of esophageal cancer is not clearly understood. In vitro and in vivo models showed that administration of estradiol significantly inhibited the growth of ER-positive and AR-positive KSE-1 tumors in both males and females in conjunction with an increase in the estradiol levels and a decrease in the DHT levels in the serum. Thus we tested the clinical significance of sex in the overall survival of esophageal cancer using SEER data. Methods: A total of 21,584 patients with localized and metastatic esophageal cancer from 1988–2004 were screened using the SEER registry. The patients were divided into age at diagnosis, sex and ethnicity. The analysis for overall survival was based on the Cox proportional hazards model adjusted for marital status, site of primary tumor, treatment, histology and tumor grade and stratified by year of diagnosis and SEER registry site. Pairwise interactions (age and sex, age and race, and sex and race) were also examined. Results: Females with localized esophageal cancer had significantly longer overall survival compared to males (p<0.001). In metastatic esophageal cancer, females seemed to have longer overall survival than males (p=0.054). Overall survival decreased with increasing age (p<0.001). African Americans with localized esophageal cancer have worse median overall survival compared to Caucasians (p<0.001). No significant difference was noted with respect to ethnicity in metastatic esophageal cancer (p=0.22). Also pairwise interactions did not have significant difference. Conclusions: This is the first and largest study showing gender as an independent prognostic factor in patients with localized and metastatic esophageal cancer. Females had a significant better overall survival than males in esophageal cancer suggesting that sex hormone pathways may have a potential impact on tumor progression. These data warrant further studies to explore the role of these pathways in the diagnosis and treatment of esophageal cancer. No significant financial relationships to disclose.