bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose escalation and pharmacodynamic study of intravenous adminstration of Reolysin, a live replication competent RNA virus in patients with advanced solid tumors
Authors: Ghalib M. H. , Desai K. K. , Gollamudi R. , Chaudhary I. , Einstein M. , Coffey M. , Mettinger K. , Mani S. , Goel S. 
Published: August 2020

3583 Background: Reolysin is reovirus serotype 3 - Dearing strain, a double-stranded replication- competent RNA non-enveloped icosahedral virus. It induces cytopathic and anti-cancer effects in cells with an activating mutation in the ras proto-oncogene. Methods: This was a single center dose escalation trial of Reolysin administered intravenously every four weeks in doses ranging from 1X108 to 3X1010 tissue culture infective dose (TCID)50. Serum for neutralizing antibody, and serum, stool, saliva, and urine for viral shedding were collected. Tumor samples were analyzed for activating mutations in the ras and braf oncogenes. Results: Eighteen patients received 27 doses of Reolysin in 6 dose cohorts accomplishing a 300 fold dose escalation without a protocol-defined dose limiting toxicity. Drug related grade 2 toxicities included fatigue and fever (1 patient each). All patients developed neutralizing antibody during the course of the study. Viral shedding was observed in 6 patients [urine (5), serum (4), saliva (3), and stool (2)]. One patient with anthracycline and taxane refractory breast cancer experienced a partial response (PR) and her tumor had a mutation in the ras oncogene. Biopsy from a chest wall mass showed evidence of necrosis and viral replication by electron microscopy. The overall clinical benefit rate was 45% and appeared higher in patients with viral shedding (67%) than those without (33%). Conclusions: Reolysin administered as a one hour infusion on a monthly schedule is safe and well-tolerated even in multiple doses. Reolysin has anti-tumor activity as a single agent warranting further evaluation, including in combination with chemotherapy. Viral shedding may suggest intrapatient replication yielding a benefit and should be studied carefully in future studies. [Table: see text]
Results of a completed phase I clinical trial of CYT-6091: A pegylated colloidal gold-TNF nanomedicine
Authors: Libutti S. K. , Paciotti G. F. , Myer L. , Haynes R. , Gannon W. , Walker M. , Seidel G. , Byrnes A. , Yuldasheva N. , Tamarkin L. 
Published: August 2020

3586 Background: CYT-6091 is the first tumor-targeted nanomedicine formulation designed to safely deliver an API that itself is not approved for systemic administration due to unacceptable toxicity. CYT-6091, consisting of tumor necrosis factor-α (TNF) covalently linked to pegylated colloidal gold nanoparticles, has been safely administered in preclinical models, demonstrating an increased T1/2 compared to native TNF, a documented trafficking of nanoparticles to tumor, and no hypotension, the known DLT for TNF. Methods: CYT-6091 was tested in a phase I open label trial in solid tumor, advanced stage patients. Patients (n = 3/dose), admitted to the NIH Clinical Center ICU, received two IV injections of CYT-6091 on day 0 and 14. Dosing started at 50 μg/m2 of TNF, up to 600 μg/m2. Vital signs were monitored and blood samples were drawn over 48 h. The primary endpoint of the study was to determine the MTD for CYT-6091. Secondary endpoints included PK, disease response (staged 45 days post treatment by RECIST), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue. Results: Twenty-nine patients were treated. Even at the lowest dose (50 μg/m2), patients exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the 29 patients treated with doses of 50–600 μg/m2 showed a DLT hypotensive response, and in fact, no DLT was seen. T1/2 estimates for TNF, administered as CYT-6091, are 120, 131, 127, 146, 112, 113, 266, 371, and 160 minutes for 50, 100, 150, 200, 250, 300, 400, 500, 600 μg/m2, respectively (published T1/2 for native TNF is ∼27 minutes). In the 28 patients eligible for response assessment, there was 1 PR (100 μg/m2 dose, 7 months duration) and 3 SD (2, 2, and 3 months duration). Electron micrographs show gold nanoparticles in tumor biopsies. Conclusions: CYT-6091 is well tolerated at doses up to 600 μg/m2 of TNF, levels 3-times greater than the published MTD for native TNF. CYT-6091 targets tumors in humans. Efficacy studies in combination with chemotherapy are planned. [Table: see text]
A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study
Authors: Kerr D. , Gray R. , Quirke P. , Watson D. , Yothers G. , Lavery I. C. , Lee M. , O’Connell M. J. , Shak S. , Wolmark N. ,   Genomic Health and QUASAR Colon Teams
Published: August 2020

4000 Background: New clinical tools are needed to improve risk assessment and treatment decisions in stage II colon cancer. Four development studies [Surgery (Sx) alone: NSABP C-01/C-02 (n=270) and CCF study (n=765); Sx+5FU/LV: NSABP C-04 (n=308) and C-06 (n=508)] were performed to select the genes for prediction of recurrence and 5FU/LV benefit. To determine clinical utility of the prespecified assay, we performed a large, independent, prospectively designed, clinical validation study in stage II colon cancer pts from the QUASAR trial. Methods: Gene expression was quantitated by RT-PCR from 30 μm manually microdissected fixed paraffin-embedded primary colon cancer tissue. Recurrence-free interval (RFI), disease-free survival (DFS), and overall survival (OS) were analyzed using Cox regression. Results: Combined analysis of the four development studies (total n=1,851; 761 candidate genes) identified 48 genes significantly associated with recurrence risk and 66 genes predictive of 5FU/LV benefit. Multivariate analysis, in the context of stage, grade, nodes examined, and MSI status, yielded 18 genes (7 prognostic genes, 6 predictive genes, 5 reference genes) and separate prognostic recurrence score (RS) and predictive treatment score (TS) algorithms. In the QUASAR validation study, tumor blocks were collected for 68% of pts; 1,490 pts with blocks had stage II colon cancer and RT-PCR was successful in 1,436 eligible pts (711 Sx, 725 Sx+5FU/LV). Median FU=6.6 yrs. In the primary analysis of RFI in pts following Sx, the RS predicted recurrence risk (HR/25 units=1.58, 95% CI 1.15–2.15; p=0.004). The RS also predicted DFS (p=0.01) and OS (p=0.04). Recurrence risk increased monotonically with increasing RS. In multivariate analyses, RS retained prognostic significance (p=0.008) independent of mismatch repair (MMR), T stage, nodes examined, grade, and lymphovascular invasion. MMR deficiency (HR=0.31, 95% CI 0.15–0.63; p<0.001) and T4 stage (HR=1.94, 95% CI 1.35–2.79; p=0.005), together ∼25% of pts, also were independently prognostic. 5FU/LV benefit was significant (p<0.001). However, TS was not validated as a predictor of 5FU/LV benefit (interaction p=0.19). Conclusions: The colon cancer recurrence score is a validated, independent predictor of individualized recurrence risk for stage II colon cancer patients following surgery. [Table: see text]
Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial)
Authors: Tejpar S. , Bosman F. , Delorenzi M. , Fiocca R. , Yan P. , Klingbiel D. , Dietrich D. , Van Cutsem E. , Labianca R. , Roth A. 
Published: August 2020

4001 Background: Patients with high MSI (MSI H) tumors are increasingly being recognized as a prognostic and predictive subgroup in colon cancer (COC). We investigated the incidence of MSI-H in stage II (n=395) and stage III (n=859) COC, its association with histopathological variables and its prognostic and predictive impact. Methods: The study accrued 3278 patients with Stage II and Stage III COC to receive post-operative 5-FU -LV with or without irinotecan (IRI). Paraffin tissue blocks of 1327/1405 available patients were successfully analyzed for MSI status using the NCI extended panel of 10 markers. MSI-H was defined as instability in ≥3 markers. Relapse Free Survival (RFS) and Overall Survival (OS, median follow up 68 months) were assessed. Results: MSI H was present in 22% (85) of Stage II and 12% (103)of Stage III colon cancer . MSI H status was significantly associated with age <60, higher T stage, higher grade, lower N stage and right sided tumor location. The table presents univariate RFS and OS hazard rates (with 95% confidence intervals) for prognostic and predictive impact per stage and arm, estimated by a survival regression analysis using Cox proportional hazards model and of selected P values by Wald tests. Conclusions: Microsatellite instability is a strong prognostic factor for RFS and OS when considering Stage II and Stage III COC. Subgroup analysis suggests a stronger effect in Stage II than in Stage III, but is limited by sample size and multiple testing. Taken together with differences in incidence between the stages, this may suggest stage specific biological effects of MSI. In contrast to previous reports (a) in Stage II the prognostic effect of MSI remained significant even in pts treated with 5FU (w/o IRI),(b) There is no evidence for an effect of the addition of IRI. [Table: see text] [Table: see text]
Stage-specific prognostic value of molecular markers in colon cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60–00 trial
Authors: Roth A. D. , Tejpar S. , Yan P. , Fiocca R. , Dietrich D. , Delorenzi M. , Labianca R. , Cunningham D. , Van Cutsem E. , Bosman F. 
Published: August 2020

4002 Background: We compared the incidence of molecular markers in stage II (SII) and III (SIII) colon cancer and tested their prognostic value per stage, using PETACC 3, an adjuvant trial with 3,278 patients. We included expression of P53, SMAD4, thymidylate synthetase (TS) and hTERT, mutations of KRAS and BRAF, microsatellite instability (MSI) and 18qLOH. Methods: 1,564 formalin fixed paraffin embedded tissue blocks were prospectively collected and DNA from normal and tumor tissue was extracted after macrodissection. High P53, TS and hTERT expression and SMAD4 loss were assessed by immunohistochemistry. MSI was studied with 10 markers. KRAS exon 2 and BRAF exon 15 mutations were analyzed by allele specific real time PCR. 18qLOH was studied by pyrosequencing 7 SNPs. Prognostic value of the markers was analysed per stage by Cox regression for Relapse Free Survival (RFS). Results: marker frequencies and stage specific p-values in prognostic models in 420 SII and 984 SIII patients are listed in the table . Significant differences in frequency per stage were found for all markers except KRAS and BRAF. An interaction test for differences between marker prognostic value for SII and SIII was significant for MSI (p=0.04) and 18qLOH (p=0.04) in SII. Multivariate analysis including markers, T stage, N stage (for SIII), Tu grade, age <60, sex, treatment arm, and Tu site found T stage (p=0.0001) and MSI (p=0.02) as independently significant clinical predictors in SII; N stage (p<0.0001), T stage (p<0.0001), SMAD4 (p<0.0001) and P53 (p=0.01) in SIII. Conclusions: Molecular markers in colon cancer have a stage specific prognostic value. The possibility that the stages represent different diseases, rather than sequential steps in the evolution of a single disease, needs to be considered. [Table: see text] [Table: see text]
The German quality assurance system for the molecular-pathological detection of KRAS-mutations in colorectal cancer
Authors: Jung A. , Baretton G. , Dietel M. , Gabbert H. , Kreipe H. , Schlake W. , Tannapfel A. , von Knebel Döberitz M. , Kirchner T. 
Published: August 2020

4018 Background: In the beginning of 2008 the EMEA (European Medicines Agency) approved with panitumumab for the first time an EGFR (epidermal growth factor receptor) targeting therapy for patients with metastatic colorectal cancer overexpressing the EGFR and showing wildtypic sequences in the KRAS gene as a predictive biomarker. Thus, the need for assuring the quality of laboratories emerged. The German Society for Pathology in cooperation with the Federation of the German Pathologist supported by an unrestricted financial grant of Amgen Germany arranged a quality assurance system (QAS). In this context two round- robin tests were carried out which results are presented here. Methods: Collection of results from two round -robin tests and their statistical analysis applying binary classification tests. Results: Test sets of 4 histological sections from ten different cases of colorectal tumors with known mutational status of the KRAS gene were prepared for the round-robin tests. The method for the mutation detection was unrestricted. A total of 74 participants from universities (44 - 59.5 %) or other institutions (30 - 40.5 %) attended the tests. 11 participants (14.8 %) failed the test (6 universities: 13.6 %, 5 institutions: 16.6 %). For the analysis didesoxy-sequencing (DDS: 55 - 66.2 %), ARMS®-PCR (8 - 10.4 %), melting-point analysis (MPA: 7 - 9.1 %), pyrosequencing (PS: 6 - 7.8 %), hybridization (HYB: 4 - 5.2 %), or SSCP (1 - 1.3 %) were used, in which some participants (3) used more than one method. It turned out that all methods employed for the testing gave similar results when comparing the rate of correct or wrong hits or the rate of false positive detection: DDS (0.92, 0.07, 0.02), ARMS®-PCR (0.91, 0.08, 0.05), MPA (0.94, 0.06, 0.04), PS (0.95, 0.05, 0.03) or HYB (0.90, 0.10, 0.08). Conclusions: The quality of the molecular-pathological detection of KRAS mutations as precondition for an EGFR targeted therapy should be tested since about 15 % of laboratories did not meet a sufficient grade. For the mutation detection no method seemed superior. [Table: see text]
Evaluation of the effect of intravenous calcium and magnesium (CaMg) on chronic and acute neurotoxicity associated with oxaliplatin: Results from a placebo-controlled phase III trial
Authors: Grothey A. , Nikcevich D. A. , Sloan J. A. , Kugler J. W. , Silberstein P. T. , Dentchev T. , Wender D. B. , Windschilt H. E. , Zhao X. , Loprinzi C. L. 
Published: August 2020

4025 Background: Cumulative sNT is the dose-limiting toxicity of oxaliplatin which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant setting. We recently demonstrated the protective effect of CaMg against oxaliplatin-induced sNT as assessed by NCI-CTC (Nikcevich ASCO 2008). It is unclear, though, if CaMg reduced acute and/or chronic, cumulative sNT. Methods: 104 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to IV CaMg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo (PL) in a double-blinded manner. NCI-CTC, an oxaliplatin-specific sNT scale and patient-reported outcome (PRO) questionnaires were used to differentially assess the effect of CaMg on acute (effect on sNT on days 1–4 after oxaliplatin) and chronic sNT (area between curves over whole course of therapy). Results: A total of 102 pts (50 CaMg, 52 PL; 96 mFOLFOX6, 6 FOLFOX4) were available for analysis. Apart from a strong reduction in muscle cramps with CaMg (p=0.002), no difference was found between CaMg and PL in PRO with regard to items reflecting acute sNT (e.g. sensitivity to cold, swallowing of cold liquids, throat discomfort) on days 1–4 after oxaliplatin of any treatment cycle. In contrast, CaMg was able to significantly reduce cumulative sNT in form of numbness in fingers (p=0.02), impaired ability to button shirts (p=0.05), tingling in fingers (p=0.06), and muscle cramps over the course of therapy (p=0.01). Conclusions: In our phase III, placebo-controlled trial, CaMg was able to significantly reduce chronic, cumulative sNT related to oxaliplatin as evaluated by specific PRO questionnaires. No effect was noted on phenomena associated with acute sNT. CaMg can be recommended as neuroprotectant against oxaliplatin-related chronic sNT, oxaliplatin's dose-limiting toxicity. [Table: see text]
Treatment intensification by induction chemotherapy (ICT) and radiation dose escalation in locally advanced squamous cell anal canal carcinoma (LAAC): Definitive analysis of the intergroup ACCORD 03 trial
Authors: Conroy T. , Ducreux M. , Lemanski C. , Francois E. , Giovannini M. , Cvitkovic F. , Mirabel X. , Bouché O. , Montoto-Grillot C. , Peiffert D. 
Published: August 2020

4033 Background: Concomitant radiochemotherapy (CRT) is the standard treatment of LAAC. The addition of an ICT (2 cycles of 5 FU-Cisplatin) and of a higher dose of irradiation boost (HDRT) to CRT were evaluated in a factorial 2X2 arms trial (A= ICT; B=ICT+HDRT; C= Reference arm = Pelvic RT 45 Gy/25 fractions with 2 cycles of 5FU-Cisplatin and a boost of 15 Gy; D= HDRT). The aim of the study was to detect a increase from 70 to 85% of colostomy-free survival (CFS) at 3 years. Methods: 307 pts with T2 > 4 cm or T3-T4 Nx or any T, N1–3 M0 LAAC were included. Mean age was 59 y and sex-ratio was 1/6. The 4 arms were well balanced concerning the sex-ratio, age, stage, T size and differentiation. Results: 306/307 pts were eligible. Toxicities were similar in the 4 arms (toxic deaths: A=4, B=2, C=2, D=1). The compliance was: 99% for ICT, 100% for pelvic RT-CT, and 96% for the boost. The tumour complete response (+ partial response) at 2 months were: A=78% (+18%), B=86% (+13%), C=74% (+21%), D=74 % (+22%) (NS). The median follow-up was 43 months. Overall failure rates were 28% (A=28%, B=21%, C=30%, D= 30%). The actuarial results at 3 years were: CFS was 83%: A= 83%, B= 85%, C= 86%, D= 80% with no significant difference of ICT nor HDRT (A+B=84% vs C+D=83% for ICT; A+C= 84% vs B+D=83% for HDRT). Local control was 88%: A= 80%, B= 96%, C= 90 %, D= 87%: (NS). Event-free survival was 71% : A= 70%, B= 78%, C= 67%, D= 68%: (NS). Overall survival was 78% at 3 y (73% at 5 y) with no difference between arms. Specific survival was 84 % : A= 79%, B= 88,5%, C= 89%, D= 79%: (NS) Conclusions: Neither ICT nor HDRT improved the CFS at 3 years, nor the secondary end points. No significant financial relationships to disclose.
Generation and validation of a primary-tumor-derived four-gene prognostic signature for recurrence (R) of stages I/II colorectal cancer (CRC) following potentially curative resection
Authors: Lenehan P. F. , Fry D. W. , Heyman E. R. , Eliason J. F. , Worzel W. P. 
Published: August 2020

4035 Background: Current guidance for postoperative clinical management of stages I/II CRC patients (pts) is suboptimal. We hypothesized that a molecular prognostic test using primary CRC tissue would better predict the chances of tumor R within 3 years (y) than NCCN Clinical Practice Guidelines. Methods: Archival formalin-fixed paraffin-embedded (FFPE) primary adenocarcinoma tissues obtained at initial resection with curative intent were retrieved for 145 stage I/II (pT1–4 pN0 M0) CRC pts from multiple international sites; none had neoadjuvant or adjuvant therapy. Pts had tumor R by 36 months (mo) or confirmed non-recurrence (NR) for ≥36 mo after surgery. Pts were stratified by R/NR status and then randomized to a Training Set (TSet) (n=73; 34R, 39NR) or Validation Set (VSet) (n=72; 33R, 39NR). Tumor gene expression was quantified by DASL assay (Illumina, San Diego) using a custom 512-gene panel. Genetic programming (GP), a machine-learning technique, defined 15 TSet genes as key for differentiating pts with R versus NR. Results: Successive GP analyses of TSet data evolved a prognostic signature that mathematically combined 4 of the 15 key genes identified. This selected dichotomous rule correctly classified 28/33 R and 35/39 NR VSet pts (85% sensitivity, 90% specificity). ‘High risk’ pts had a significantly higher probability of R by 36 mo than ‘low risk’ pts: 88% PPV, 88% NPV; relative risk (RR) 7.0 (95% CI: 3.1, 16.1; p<0.0001). RR by stage (I/II) = 7.00/7.28 and tumor site (colon/rectum) = 8.75/4.50. Kaplan-Meier recurrence-free survival: hazard ratio 11.8 (95% CI: 4.5, 31.1; p<0.0001). NCCN Guidelines (V.2.2008) correctly classified 24/33 R and 15/39 NR VSet pts: 73% sensitivity, 38% specificity, 50% PPV, 63% NPV; RR 1.33 (95% CI: 0.74, 2.40; p=0.32). Conclusions: A GP derived 4-gene prognostic test using FFPE tumor tissue can differentiate early stage CRC pts at high versus low risk for R within 3y better than current NCCN Guidelines. [Table: see text] [Table: see text]
Identification of subtypes in colorectal cancer and their prognostic values
Authors: Kennedy R. D. , Proutski V. , Tanney A. , Winter A. , Black J. M. , Kerr P. , Johnston P. G. , Harkin D. P. 
Published: August 2020

4041 Background: The discovery and widespread acceptance of molecular subtypes in breast cancer has changed the way that this disease is viewed. Similarly, we have focussed on stage II colorectal cancer where 20–25% of patients are at risk of recurrent disease following surgery. There are currently several types of colorectal cancer recognised by histopathological methods, however, little has been published regarding disease classification at a molecular level. Methods: We have taken an unbiased approach to the molecular classification of colorectal cancer. Using a colorectal cancer disease specific microarray platform we have performed expression profiling and bioinformatic analysis of 500 formalin fixed and paraffin embedded (FFPE) stage II colorectal cancer samples, in order to identify and characterise molecular subtypes. Results: We have identified molecular subtypes for colorectal cancer. One of these subtypes is enriched with tumours with microsatellite instability (MSI) that are predominantly proximal, mucinous and poorly differentiated. It is notable that while MSI is generally accepted to be associated with a good prognosis, we have found both good and poor prognosis patients within this subtype. A second subtype contains tumors with a low CpG island methylator phenotype. Another subtype is defined by an expression pattern consistent with activation of tumor suppressors. The remaining subtypes are newly identified. Conclusions: We have identified molecular subtypes in colorectal cancer. We will present how knowledge about these subtypes may affect patient management and may be used to guide the development of novel therapeutic strategies. [Table: see text]