bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of prognostic biomarkers for gastric cancer by gene expression analysis
Authors: Yamada Y. , Arao T. , Nishio K. , Koizumi F. , Saito D. , Gotoda T. , Shimoda T. , Taniguchi H. , Shirao K. , Saijo N. , Sasako M. 
Published: March 2020

4623 Background: Endoscopic biopsy before chemotherapy provides an excellent opportunity for studying biomarkers related to therapy-induced tumor responses or overall survival. This study was designed to identify prognostic biomarkers in patients with unresected gastric cancer. Methods: Samples were taken from histologically proved primary gastric cancers in 40 patients before chemotherapy. Microarray analysis was performed using Affymetrix HG-U133Plus2.0 GeneChips after RNA quality checks of the samples. Correlations between gene expression data and survival time were statistically evaluated with a univariate Cox proportional-hazards model. Identified genes were validated by real time RT-PCR analysis in same 40 test-set samples. Then, PCR-validated genes were evaluated for independent samples (validation set) to predict survival. Results: We obtained 185 candidate genes that were significantly associated with survival (p<0.005) on univariate testing in the 40 test-set sample. Real time RT-PCR analysis identified 5 genes that were reproducibly related to survival on the log-rank test (p<0.01). PCR analysis with each of these 5 genes discriminated short-term survivors with a sensitivity of 71% and a specificity of 46–77% in the test set. For the independent 19-sample validation set, single-gene PCR analysis had a sensitivity of 50–81% and a specificity of 38–62%. A multi-gene prediction panel will be evaluated. Conclusions: Gene expression profiling by microarray and real time RT-PCR is useful for predicting overall survival in gastric cancer. No significant financial relationships to disclose.
A novel multimodality treatment for resectable pancreatic cancer (PC)
Authors: Takamori H. , Kanemitsu K. , Chikamoto A. , Ishiko T. , Beppu T. , Hirota M. , Baba H. 
Published: March 2020

4630 Background: Patients with PC often suffer from tumor recurrence despite curative resection, thus indicating that systemic therapy added to local control might be required to further improve the survival. The aim of this phase II trial was to assess the feasibility and tolerance as well as overall survival of a novel multimodality therapy composed of pancreatic resection and intraoperative radiation therapy (IORT) combined with neoadjuvant (NAC) and adjuvant (AC) combination chemotherapy for patients with PC. Methods: Eligibility criteria included: no distant metastases / no tumor extension to the CA or the SMA by imaging, tumor size ≥ 1 cm, ECOG PS ≤ 2, age < 80, and normal organ function. For NAC, 5-FU was administered at a dose of 125 mg/m2 on days 1–5 every week as a continuous pancreatic and hepatic arterial infusion, and gemcitabine was infused intravenously at a dose of 800 mg/m2 for 30 min once weekly for 2 weeks. Pancreatic resection combined with IORT (30 Gy, 12 Mev of electron beam) was performed after a one-week rest following the completion of NAC. AC was performed in the same regimen as NAC after the recovery from surgery. We performed intension to treat analyses. Results: Between 2001 and 2006, 32 pts were enrolled: 32 received NAC, 28 received AC, and 28 received IORT. Of 32 pts given NAC, 13 had grade 3–4 hematological toxicity. All pts underwent surgery, including R0 resection in 26 pts, without delay by NAC- related toxicity. Of 28 pts given AC, 18 had grade 3–4 hematological, and 6 had non-hematological toxicity, although no chemotherapy-related death was observed. The median follow-up period was 20 months (rang 3.9 to 67.4). Overall survivals at 1, 3, and 5 years were 77.0 %, 60.2 %, and 48.1 %, respectively. Median survival was 38.5 months. Conclusions: This new multimodality treatment is feasible and tolerable, and may contribute to the survival benefit of patients with PC. No significant financial relationships to disclose.
Cyberknife stereotactic radiosurgery in patients with primary hepatocellular carcinoma
Authors: Kang K. , Choi B. , Jang H. , Bae S. , Ryu M. , Kang Y. , Jang J. , Choi G. , Choi I. 
Published: March 2020

4645 Background: Conventional radiotherapy has historically played a limited role in the primary treatment of hepatocellular carcinoma (HCC). This study evaluated the effect of Cyberknife stereotactic radiosurgery (SRS) with for both for small primary non-resectable HCC, and for advanced HCC with portal vein tumor thrombosis (PVTT). Methods: From March 2004 to March 2005, thirty one patients with HCC were treated Cyberknife SRS was used for 32 lesions in patients with SRS for primary HCC. There was performed in 22 patients (23 lesions) with targeting to the primary HCC was treated (Group A), and in 9 patients with targeting to the PVTT was treated (Group B). The total SRS doses treated were 30–39 Gy (median, 36 Gy) to the 70–85%, 3 fractions and the target volume was of 3.6–57.3 cc (median, 25.2 cc). Results: The median follow up was 10.5 months. A complete response (CR) was achieved in 10 lesions, a partial response (PR) in 13 lesions, stable disease was noted in 6 lesions, and disease progression in 3 lesions. The response rate (CR+PR) was 71.9% (group A: 82.6%, group B: 44.4%). The level of serum alpha-fetoprotein after the treatment was decreased significantly in 17 patients (54.8%) (group A: 54.5%, group B: 55.5%). Complications were observed in 15 patients, among them, greater than grade 3 complication was observed in two patients of group A (gastric ulcer bleeding (1), liver necrosis (1)). Conclusions: These results suggest that Cyberknife SRS could be considered as an effective and safe treatment for primary HCC. For PVTT, Cyberknife SRS as the only curative tool, and produced acceptable local control in this study. No significant financial relationships to disclose.
Comprehensive analysis of ERCC, XPD, and XRCC polymorphisms: Association with clinical outcomes in patients with advanced gastric cancer
Authors: Keam B. , Kim H. , Im S. , Ham H. , Han S. , Cho E. , Lee J. , Oh D. , Kim T. , Bang Y. 
Published: March 2020

4649 Background: Platinum-DNA adducts are repaired by nucleotide excision repair (NER) pathway, in which genes of the excision repair cross-complementation 1 (ERCC1), xeroderma pigmentosum group D (XPD) and X-ray repair cross-complementing group (XRCC) have an important role. The purpose of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of these genes and the clinical outcomes to combination chemotherapy of 5-FU and oxaliplatin in advanced gastric cancer (AGC). Methods: We searched SNPs of NER pathway genes from database of the International Hapmap Project. Tagging SNPs and halpotype blocks were founded by linakage disequilibrium and haplotype analysis. Whole blood samples were obtained from the patients before chemotherapy. DNA was extracted from the peripheral blood mononuclear cells and the genotyping was performed by SNaPshot methods. Seventy three metastatic or relapsed AGC patients received modified FOLFOX-6 as a first-line palliative chemotherapy and were analyzed. Results: By searching the database of the International Hapmap Project, we found 17 SNPs in ERCC, 69 SNPs in XPD, 78 SNPs in XRCC. We found that some SNPs played a role as a tagging SNP and belonged to haplotype block (5 tapping SNPs and one haplotype block in ERCC, 8 tapping SNPs and two haplotype blocks in XPD, 9 tapping SNPs and two haplotype block in XRCC). Tagging SNPs were analyzed and matched with clinical significance. Among the 22 tagging SNPs of NER pathway genes, only XPD-C156A SNP (rs238406) showed clinical correlation. AA genotype of XPD C156A showed higher response rate (CC: CA: AA= 29.2%: 43.3%: 63.2%, p=0.083) and toxicities (neutropenia of grade 3 or 4) (CC: CA: AA= 4.3%: 3.2%: 21.1%, p=0.060) than CC or CA genotypes. Conclusions: Our results suggest that some SNPs of ERCC, XPD and XRCC showed linkage disequilibrium and belonged to haplotype blocks. And XPD-C156A SNP showed clinical correlation in AGC patients treated with modified FOLFOX-6 regimen. These findings require independent prospective confirmation. [Table: see text]
Multicenter phase II study of combined neoadjuvant docetaxel and androgen ablation (ADT) prior to radical prostatectomy (RP) for patients (pts) with high risk localized prostate cancer (LCaP): Pathologic outcomes and 3-year follow-up analyses
Authors: Winquist E. , Chi K. N. , Chin J. , Goldenberg L. , Klotz L. , Berry S. , Saad F. , Perrotte P. , Ruether D. , Trachtenberg J. , Gleave M. E. 
Published: March 2020

5002 Background: Pts with high risk LCaP (cT3, Gleason score > 7 &/or PSA > 20) have an increased risk of relapse with a biochemical failure rate of >50% at 3 years after RP. Docetaxel is active in hormone refractory prostate cancer & potentially beneficial if combined with ADT for treatment naïve disease. The objectives of this trial were to assess the pathologic outcomes & feasibility of docetaxel + ADT in men with LCaP prior to RP. Methods: A phase II multi-center study of newly diagnosed previously untreated pts with clinically LCaP with high-risk features. All pts received ADT (buserelin acetate 6.3 mg q8 weeks x 3 and anti-androgen for 4 weeks) plus docetaxel (35 mg/m2 weekly for 6 out of 8 weeks for 3 cycles) prior to RP. Results: 72 men with a median age of 59 years (range 46–78) were enrolled at 6 sites. Baseline characteristics included: clinical stage T1C, T2 & T3 in 14%, 47% & 39%; and Gleason score <7, 7 & >7 in 10%, 30% & 60% of pts; respectively. Median baseline PSA was 10.8 μg/L (range 1.6–65.6) with PSA < 10 in 47%, 10–20 in 24% & >20 in 29% of pts. Eight pts did not complete protocol therapy because of toxicity (n=4), withdrawal of consent (n=1), or other reasons (n=3). 1 pt had myocardial infarction day 1 post-operatively & 1 pt had DVT 1.5 months after RP. No other major post-operative complications were reported. Of the 64 pts completing protocol therapy, 2 had a complete pathologic response and pathologic stage was T2 in 34 (53%) and T3 in 28 (44%) pts. Four pts had N1 disease & positive surgical margins were identified in 17 (27%). On multivariate Cox regression analysis only baseline Gleason score (=7 vs. >7) was associated with PSA recurrence-free survival (hazard ratio 4.58, 95% CI 1.32–15.93). At a median follow-up of 42.7 months (range 25.6–65.6), 19 (30%) pts have relapsed. Three pts have died at 32.0, 40.0 & 40.3 months, with all deaths attributed to prostate cancer. Conclusions: Combined ADT and docetaxel prior to RP was feasible and resulted in encouraging pathologic outcomes and PSA- recurrence free survival. These data further support the rationale for randomized trials determining the efficacy of chemo-hormonal therapy in pts with clinically LCaP. [Table: see text]
Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival of the TAX 327 study
Authors: Berthold D. R. , Pond G. , DeWit R. , Eisenberger M. , Tannock I. F. 
Published: March 2020

5005 Background: The TAX-327 study compared 3 weekly docetaxel (D3), weekly docetaxel (D1) or mitoxantrone (M), each with prednisone (P) for 1006 patients (pts) with metastatic hormone resistant prostate cancer (mHRPC). The original analysis, undertaken in August 2003 when 557 deaths had occurred, showed significantly better survival and response rates for pain, PSA and quality of life for D3 when compared with M (Tannock et al, NEJM 2004;351:1502–12). Here we present the updated survival analysis. Methods: Investigators were asked to provide date of death or last follow up for all patients alive in August 2003. Results: By December 2007 data on 276 additional deaths were obtained (total 833 deaths, see Table ). The survival benefit of D3 as compared with M has persisted with extended follow up while D1 continues to show no significant survival advantage. More patients (17.9% and 16.7%) survived =3 years in the D3 and D1 arms compared to M (13.7%). Similar trends in survival between treatment arms were seen for pts above and below 65 years of age, for those with and without pain at baseline, and for those with baseline PSA above and below median value of 115ng/ml. Conclusions: The present analysis confirms previous findings that survival is significantly longer with D3 than with M. Survival update is ongoing. [Table: see text] No significant financial relationships to disclose.
PSA density as a predictor of aggressive prostate cancer on repeat prostate biopsy
Authors: Rogosin S. , Collins L. , Mongoue-Tchokote S. , Blank B. H. , Beer T. M. , Mori M. , Garzotto M. 
Published: March 2020

5007 Background: Prostate biopsy procedures carry a high false-negative rate. However, since Gleason score is strongly associated with cancer-specific mortality; efforts to identify men who harbor high-grade prostate cancer will likely assist in patient selection for repeat biopsies. We sought to identify risk factors for the detection of aggressive prostate cancer (Gleason ≥ 7) on repeat biopsy. Methods: Clinical and pathologic variables collected from subjects undergoing a repeat biopsy included all prostate specific antigen (PSA) values, PSA density (PSAD), PSA doubling time (PSADT). PSADT was examined using PSAs up to the first biopsy, and also in an exploratory analysis using both pre- and post-biopsy PSAs. Predictors of aggressive prostate cancer were identified using recursive partitioning and a stepwise Cox regression model. Results: 511 patients with initial negative biopsies underwent 1,319 biopsy procedures. Median follow-up was 3.7 years. Aggressive cancer was diagnosed in 52 of 511 (10.18%) patients. Recursive partitioning analysis selected PSAD as the sole factor for distinguishing high- and low-risk groups. Based on K-M analysis, a PSAD <= 0.304 ng/ml/cc carried 2 and 5 year aggressive cancer detection rates of 4% (± 1.9%) and 9% (± 3.5%) respectively, whereas a PSAD > 0.304 ng/ml/cc carried cancer detection rates of 23% (± 11.9%) and 36% (±15.3%) at 2 and 5 years (p-value <.0001). Independent prognostic factors included (HR, 95% CI): PSA >= 9.7 (2.565, 1.404 - 4.688), PSAD 0.13 - < 0.19 ng/ml/cc (0.423, 0.179 - 0.999) and volume >= 43.3 cc (0.454, 0.247 - 0.833). PSADT became significant when all PSA data were analyzed: PSADT < 2 years (4.203, 1.894 - 9.325) and PSADT >= 5 years (0.17, 0.89- 0.326). Conclusions: In decision tree analysis, a high PSAD is predictive of aggressive prostate cancer on a repeat biopsy. In addition, high PSA, lower PSAD and prostate volume are predictive of aggressive prostate cancer. However in follow-up using all PSA values, a PSADT < 2 yrs. becomes the most significant predictor of aggressive cancer. Such data may help identify the most appropriate patients for a repeat biopsy and could reduce the rate of unnecessary biopsies and the inherent over-treatment of prostate cancer. No significant financial relationships to disclose.
Use of Von-Hippel Lindau (VHL) mutation status to predict objective response to vascular endothelial growth factor (VEGF) -targeted therapy in metastatic renal cell carcinoma (RCC)
Authors: Choueiri T. K. , Vaziri S. A. , Rini B. I. , Elson P. , Bhalla I. , Jaeger E. , Weinberg V. , Waldman F. M. , Zhou M. , Bukowski R. M. , Ganapathi R. 
Published: March 2020

5012 Background: The clinical response to VEGF-targeted therapy in metastatic RCC is robust, yet variability in outcome exists. VHL is often mutated in RCC, but the relation to therapeutic outcome is unclear. Identification of tumor molecular characteristics associated with outcome would aid in patient selection and interpretation of clinical trials. Materials and Methods: Patients with metastatic, clear-cell RCC with available baseline frozen or paraffin-embedded tumor samples who received VEGF-targeted monotherapy with sunitinb, sorafenib, axitinib or bevacizumab at Cleveland Clinic or University of California San Francisco, were included. Patient characteristics, VHL gene status (mutated or not mutated) and objective response rate (ORR) were documented. ORR was investigator-assessed per RECIST criteria. Fisher’s exact test and logistic regression models were used to assess ORR in univariate and multivariate analyses, respectively. Results: One-hundred twenty-three patients were evaluable. The ORR was 36.5% for the entire cohort. VHL mutation was found in 48% of patients and was seen across all three exons. Patients with VHL mutation had an ORR of 46% versus 28% for pts without a mutated VHL gene (p=0.06). In multivariate analysis, presence of a VHL mutation remained an independent prognostic factor associated with improved ORR (p=.02) when multiple clinical prognostic factors (ECOG PS, hemoglobin, corrected calcium, LDH, prior radiation, prior therapy and number of metastatic sites) were also considered. Conclusion: This is the first large study testing the impact of VHL mutation on response to VEGF-targeted agents in metastatic RCC. Although objective responses were more likely among patients with mutated VHL gene, lack of VHL mutation did not preclude a response. Additional tissue analysis and identification of biomarkers relevant to response to VEGF-targeted agents in metastatic RCC are warranted. [Table: see text]
Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: Survival and biomarker analysis
Authors: Bukowski R. M. , Eisen T. , Szczylik C. , Stadler W. M. , Simantov R. , Shan M. , Elting J. , Pena C. , Escudier B. 
Published: March 2020

5023 Background: Based on the significant PFS benefit of sorafenib (SOR) vs placebo (P) in a Phase III advanced RCC trial, P patients were unblinded and crossed over to SOR in May 2005. Final OS and biomarker data are reported. Methods: Final OS analysis was planned at ∼540 events (a=0.037 after adjusting for previous analyses). To minimize effect of crossover on OS, a secondary analysis was planned censoring P data on June 30, 2005 (a=0.037). Plasma VEGF and sVEGFR2 were measured by ELISA at baseline (BL), cycle (C) 1 day (D) 21, and C3D1. pERK was assayed by IHC. Results: 903 patients were randomized (SOR, 451; P, 452). The only OS analysis before crossover (May 2005) showed an estimated 39% OS improvement for SOR vs P (HR=0.72; p=0.018) (ECCO 2005); 216 P patients had crossed to SOR. OS analysis 6 months after crossover (Nov 2005) showed a 30% improvement in OS for SOR vs P (HR=0.77, p=0.015) (ASCO 2006). These OS differences did not reach prespecified O’Brien-Fleming statistical boundaries. Final OS (Sep 2006) at 561 deaths showed an improvement of 13.5% for SOR vs P and was not significant (median 17.8 vs 15.2 months; HR=0.88; p=0.146; a=0.037). Secondary analysis censoring P data (June 2005) showed a significant OS benefit for SOR vs P (HR=0.78, 95% CI: 0.62, 0.97; p=0.0287; a=0.037), suggesting crossover had confounded OS. Changes in VEGF (n=712) and sVEGFR2 (n=717) were observed after SOR treatment (AACR 2006); VEGF increased 32% (n=279) at C1D21 and 47% (n=203) at C3D1, and sVEGFR2 decreased 18% (n=282) and 24% (n=206). Using a COX proportional hazards model, BL VEGF was an independent prognostic factor (p=0.014); patients with high BL VEGF (>131 pg/ml) had poorer prognosis and a trend towards greater PFS benefit with SOR (SOR vs P, HR=0.48 vs 0.64 for high vs low VEGF, p=0.096). BL sVEGFR2, changes in VEGF or sVEGFR2 at C1D21, and pERK levels in limited diagnostic tumor biopsies were not predictive of SOR response. Conclusion: SOR demonstrated a PFS benefit in advanced RCC, although ITT final OS analysis showed a confounding effect of crossover. Significant OS benefit of SOR was seen in a planned secondary analysis adjusting for crossover. VEGF levels have prognostic importance, and SOR-associated changes in VEGF and sVEGFR2 are consistent with inhibition of VEGF signaling. No significant financial relationships to disclose.
Phase I/II trial of CCI-779 and bevacizumab in stage IV renal cell carcinoma: Phase I safety and activity results
Authors: Merchan J. R. , Liu G. , Fitch T. , Picus J. , Qin R. , Pitot H. C. , Maples W. , Erlichman C. 
Published: March 2020

5034 Background: The mammalian target of rapamicin (mTOR) and vascular endothelial growth factor (VEGF) pathways are critically involved in the pathogenesis and progression of clear cell renal cell carcinoma. Methods: The goal of the phase I portion of the trial was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combination of the mTOR inhibitor CCI-779 (C) and the anti-VEGF monoclonal antibody Bevacizumab (B). Patients with measurable stage IV clear cell RCC, performance status 0–2 and good organ function were eligible. Up to two prior treatment regimens were allowed. Treatment consisted of 25 mg IV weekly C and escalating IV doses of B (level 1= 5 mg/kg; level 2= 10 mg/kg) every other week. A cycle was defined as 4 weeks. Results: A total of 10 male and 2 female patients, median age 66 yrs (50–77) were enrolled to the phase I portion of the trial. PS: 0/1= 6/6; prior nephrectomy = 10; prior systemic therapy = 7 (prior cytokine therapy = 6); Number of metastatic sites: 1/2/≥3 = 2/2/8; one patient (out of 6) in dose level 1 experienced DLT which consisted of grade 3 hypertriglyceridemia. 1/6 patient in dose level 2 experienced DLT with grade 3 mucositis. Other grade 3 toxicities that were not DLTs included hypertension, proteinuria, hemorrhage, nausea/vomiting, dehydration, anorexia, pneumonitis, anemia, and hypophosphatemia. The best responses in the 12 evaluable patients included 7 PRs and 3 SDs. One patient had PD due to symptomatic deterioration and in one patient response information is not available at the time of this submission. Conclusions: Combination therapy with CCI-779 and Bevacizumab is safe and shows promising clinical antitumor activity. The recommended phase II dose is CCI-779 25 mg/week with bevacizumab 10 mg/kg every other week. The phase II study in stage IV renal cell cancer patients refractory to FDA approved receptor tyrosine kinase inhibitors is under way. The goals of the phase II portion are to determine the proportion of patients who have not had disease progression at 6 months, safety, response rates and correlative biomarker studies including determination of the tumor’s VHL-HIF-VEGF status, PTEN/AKT expression, plasma angiogenic activity and angiogenic cytokines. Supported by NCI N01-CM-62205 No significant financial relationships to disclose.