bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic variability in DNA repair and clinical outcome in stage III non-small cell lung cancer (NSCLC) treated with concurrent platinum-based chemoradiation
Authors: Al Omari A. , Murry D. J. , Smith B. J. , Clamon G. , Bhatia S. , Vaena D. 
Published: August 2020

e14621 Background: Concurrent platinum-based chemoradiation (CRT) is the standard of care for stage III NSCLC. CRT is associated with multiple toxicities and substantial interpatient variability in clinical outcomes, with a 20% cure rate. We evaluated the relationship of genetic polymorphisms in platinum metabolic and DNA repair pathways with clinical outcomes in patients treated for stage III NSCLC. Methods: This pilot study was IRB approved and all patients provided written informed consent. Patients with stage III NSCLC who completed CRT were eligible for enrollment. Genomic DNA was extracted from peripheral blood. Genotyping using Pyrosequencing™ was performed for 5 single nucleotide polymorphisms (SNPs): the detoxification enzyme GSTP1 I105V, and the DNA repair genes ERCC1 N118N, ERCC2 K751Q, ERCC2 R156R and XRCC1 R399Q. Pre-treatment variables, progression-free survival (PFS) and toxicity data were obtained from retrospective review of medical records. Results: 23 pts have been enrolled to date. Median age was 58 yrs (49–81). 5 pts received cisplatin and 18 carboplatin. Median radiation dose was 6480 cGy (5000–7020) and median V20 was 27%. 10 pts had grade 3/4 acute CRT toxicities and 7 pts required treatment breaks. Median duration of follow-up was 21 months (4–100). 14 pts recurred and median PFS was 12 months (4–100). 15 pts remain alive. Controlling for age, V20 and radiation dose and using multivariate cox proportional hazards regression, the ERCC2 K751Q and R156R genotypes were independent predictors of PFS (HRs= 0.404 & 2.184, p-values= 0.0172 & 0.0152, respectively, subjects with at least 1 variant allele being reference group). Using multiple logistic regression, the ERCC2 R156R variant showed a trend towards improved response (OR=2.98, p-value= 0.09). Overall survival data is limited by the majority of pts still being alive. Conclusions: Clinical and treatment variables were typical of a stage III NSCLC population. This pilot pharmacogenomic study indicates that outcomes were independently affected by genetic polymorphisms. Our findings, if validated prospectively, could have significant impact on optimizing treatment selection for stage III NSCLC pts, without need for additional tumor tissue. No significant financial relationships to disclose.
In vivo activity of R1530 (R) alone and in combination with bevacizumab (B) and peginterferon alfa-2a (P) in a renal cell carcinoma (RCC) xenograft model
Authors: Higgins B. , Packman K. , Zhang Y. , Char H. , Simcox M. , Kolinsky K. 
Published: August 2020

e14629 Background: R1530 is a multikinase inhibitor currently in clinical phase I testing. Its inhibitory profile includes several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. These properties translate into a potent cytotoxicity in a wide range of cancer cell lines in vitro and tumor growth inhibition in human tumor xenografts. Preclinical studies were conducted to evaluate the effects of R alone and in combination with B and P in the Caki-1 RCC xenograft model. Methods: We initially evaluated the antitumor activity of optimal dose (OD) and 1/2 OD R alone and with OD B. This was followed up with testing of OD & 1/2 OD P ± OD B, along with triplets of 1/2 OD P + OD B + 1/2 OD R and OD P + OD B + 1/2 OD R. A final study compared 1/2 OD R to OD R triplets to attempt to increase tumor growth inhibition (TGI) and increase life span (ILS). Results: No doublets or triplets tested showed antagonism or enhanced toxicity. Antitumor activity and survival results are listed below (Table). Conclusions: 1/2 OD R + OD B or OD R + OD B doublets gave better TGI and ILS than monotherapy. Comparing these two doublets, TGI is better in the high dose combination but ILS is equivalent. All TGI and ILS are better in doublet P + B combinations over respective single agent arms except for TGI (but not ILS) for 1/2 OD P vs its correlative doublet with B. The OD P + B doublet gave better TGI and ILS than 1/2 OD P + B doublet. TGI and ILS do not differ between triplets containing OD R + 1/2 OD or OD P or for triplets containing the OD P + 1/2 OD or OD R. Therefore, either agent can be alternatively dose reduced without a loss of tumor response or detriment to survival in this preclinical model of RCC. [Table: see text] [Table: see text]
Evaluation of thymoquinone (TQ) as an antiproliferative, proapoptotic, and immunomodulatory agent in a non-small cell lung cancer cell (NSCLC) line
Authors: Jafri S. H. , Glass J. , Shi R. , Kleiner H. 
Published: August 2020

e14644 Background: NSCLC is the most common cause of cancer death worldwide. We performed in vitro testing of Thymoquinone (TQ), a derivative of black caraway seed against NSCLC cell line NCI-H460 Methods: Cells were grown in RPMI and were plated at a density of 5,000 cells per well in a 96 well plate and cell growth determined in the presence of 80 and 100μM of TQ dissolved in DMSO with appropriate solvent only as control. Cell proliferation was determined at 24, 48 and 72 hrs intervals using 3-(4,5-dimethyltiazol 2-yl)-2,5-diphenyltetraolium bromide (MTT) assay. Factorial analyses of variance (ANOVA) were used to determine the effect of TQ and control with the time. Student-Newman-Keuls test was used to determine statistical significance with P value <0.05 considered significant. Apoptosis was detected using Annexin V-FITC Aptosis Detection Kit analyzing the effects of TQ at 24 hrs after treatment by flow cytometry. The immunomodulatory effects of TQ were tested using RayBio Human Cytokine Antibody Array C series 200. NCI-H460 cells (50,000 cells per well in duplicate 6 well plates) were grown in serum free RPMI media. 24 hrs after treatment with TQ or DMSO media was collected and analyzed for expression of various cytokines. Results: The MTT assay showed that TQ at 80 and 100 μM significantly inhibited cell growth as compared to control and at 24 hrs for example, 100 μM TQ inhibited cell growth by 78%. Apoptosis occurred rapidly after treatment with TQ with 73.5% of cells being positive for expression of Annexin-V as detected by flow cytometry after 24 hrs of exposure to TQ as compared to 2.6% of controls. The cytokine array revealed that TQ significantly decreased expression of ENA-78(Epithelial neutrophil activating peptide), and GRO (Growth related oncogene).ENA-78 is correlated with vascularity and tumor growth in NSCLC tumor, whereas GRO is associated with neoangiogenesis. Conclusions: TQ is shown to be a powerful anti-proliferative, pro-apoptotic and anti- angiogenic agent in a NSCLC cell line. No significant financial relationships to disclose.
Cure rate in early colorectal cancer estimated from disease-free survival curves from phase III comparative clinical trials: Necessity of long follow-up
Authors: Barrajon E. , Lopez A. , Esquerdo G. , Cervera J. M. 
Published: August 2020

e15006 Background: The traditional end point for adjuvant clinical trials is overall survival (OS). Short-term disease-free survival (DFS) has been accepted as a surrogate of 5-year OS in colorectal cancer trials. Nevertheless, recent adjuvant trials have not shown a consistent improvement in OS despite a significant improvement in DFS. Two reasons may explain this effect: 1) a delay in relapse produced by treatment, not affecting the cure rate, or 2) more effective treatments in relapsing patients which delay death, hiding a real difference in cure rates. The aim of this project is to study the relationship between DFS and OS in trials of early colorectal cancer. Methods: Phase III comparative trials in colorectal cancer were searched in databases and cancer meetings. Trials were split to build and validate the model. United States 2000 population life table data were obtained from Berkeley Mortality Database. Survival curves were modelled according to a cured fraction following a Weibull distribution and a relapsing fraction following a binomial distribution. DFS was modelled as time to a single event and OS was modelled as time to two events. Cured fraction was estimated and odds ratio (OR) with 95% confidence interval was calculated for experimental arms. Time to achieve a plateau in DFS was estimated as the curve point with a risk of relapse below 1%. Regression analysis between DFS and OS was performed for different intervals of follow up. Results: Thirty six study arms reporting DFS were analyzed to build the model. The model is consistent with an annual event rate of 0.33. DFS curves with this event rate predict a mean cure rate of 0.58 (range: 0.11–0.73). Estimated time to achieve a plateau in DFS is 9.3 years (range: 8.3–11.2 years). Significance of OR is coherent with hazard ratio reported in the studies. Trials finished after 1999 show more OS related to DFS. Regression analysis between DFS and OS show changing parameters at different intervals of follow up and some non-linearities. Trial validation, and analysis with trials reporting relapse free survival will be presented. Conclusions: Follow up of up to 10 years in colon adjuvant trials appears to be appropriate to reliably detect benefit in OS instead of a delay effect on relapse. No significant financial relationships to disclose.
Presurgical comparative imaging evaluation in patients with colorectal cancer liver metastasis (PROMETEO Study)
Authors: Rojas Llimpe F. , Di Fabio F. , Ercolani G. , Giampalma E. , Serra C. , Castellucci P. , Pini S. , Mutri V. , Golfieri R. , Pinto C. , Martoni A. 
Published: August 2020

e15010 Background: The aim of the study was to define the specific diagnostic accuracy of different imaging techniques in patients (pts) with resectable colorectal cancer liver metastasis (CLMs). Methods: Consecutive pts with, potentially resectable CLMs afferent to the Multidisciplinary Liver Team of Bologna Sant’Orsola Malpighi Hospital performed, in the 3 weeks prior to liver surgery, computed tomography scan (CT), magnetic resonance diffusion-weighted (MR-DW), and liver contrast-enhanced ultrasonography (CEUS1). Liver contrast-enhanced ultrasonography was also performed intra-operatively (CEUS2). All the imaging exams were performed according to the standard operative procedures. Results: From December 2007 to December 2008, twenty-nine out of 50 pts enrolled in the PROMETEO study underwent liver resection. The pt characteristics were: 18 (62%) males, 11 (38%) females; 18 (62%) synchronous metastasis, 11 (38%) metachronous metastasis; 15 (51.7%) neoadjuvant chemotherapy; 7 (24.1%) previous liver surgery; 3 (10.3%) previous loco-regional treatment. Ninety-three liver lesions were resected; the median number lesions per patient was 2 (range 1- 10). All lesions were studied with CT and CEUS1, 90 (96.8%) with CEUS2, 83 (89.2%) with PET and 85 (91.4%) with MR-DW. Five lesions at pathological examination were non-metastasis (1 hamartoma, 1 steatosis, 1 giant-cell reaction, 2 necrosis). Only 3 lesions were not detected by all imaging techniques (in one pt. previously treated with chemotherapy and radiofrequency). Conclusions: These results show that CT, CEUS1 and MR-DW have a good accuracy in the detection of liver metastasis in patients who are candidates for resection. CEUS2 presents the best pathological predictive value. [Table: see text] No significant financial relationships to disclose.
Addition of bevacizumab or sunitinib to biweekly cetuximab and irinotecan as salvage therapy in patients with metastatic colorectal cancer after failure to CetIri
Authors: Pfeiffer P. , Joergensen T. L. , Jensen B. V. , Qvortrup C. , Skougaard K. , Bjerregaard J. K. , Hansen T. P. , Høgdal E. , Nielsen D. 
Published: August 2020

e15011 Background: The combination of cetuximab and irinotecan (CetIri) given biweekly has shown remarkable efficacy in patients with chemo-resistent metastatic colorectal cancer (mCRC). At the time of PD to CetIri many patients are still in an excellent performance status and they are often requesting further therapy. Preclinical and clinical studies have shown an additive effect of inhibiting both the EGFR and the VEGF pathways. The Danish National Board of Health (DNBH) launched a national programme for experimental cancer therapy in 2004. According to this programme, non-proven therapy may be offered after approval by an expert panel appointed by DNBH that subsequently finances the cost of treatment. Inspired by BOND-2, we have offered dual-modulated therapy with a combination of biweekly CetIri with either bevacizumab 5 mg/kg (CIB) or sunitinib 25 mg/day continuously (CIS). Methods: Observational study designed to evaluate the toxicity and safety of CIB or CIS. From January 2007 to April 2008, 51 patients received either CIB (n=24) or CIS (n=27) at two oncologic departments. Therapy was approved by DNBH in each case. All patients had mCRC resistant to 5-FU, oxaliplatin, irinotecan and CetIri. CIB or CIS was offered independently of KRAS status and EGFR expression. Results: Results were updated December 1st 2008. Median duration of therapy was 30 weeks/10 weeks, response rate was 8%/0%, median PFS was 8.7/3.2 months and median OS was 12.1/8.7 months, respectively for CIB/CIS. Toxicity was comparable except for patients receiving CIS where fatigue and diarrhea were more common. Conclusions: Modulation of the VEGF pathway in combination with biweekly CetIri is a promising and tolerable treatment option for patients with mCRC refractory to CetIri. Some patients had extraordinary long PFS and OS. We are currently performing translation research into predictive markers. [Table: see text]
POCHER (preoperative chemotherapy for hepatic resection) with cetuximab (Cmab) plus CPT-11/5-fluorouracil (5-FU)/leucovorin(FA)/oxaliplatin (L-OHP) (CPT-11-FFL) in unresectable colorectal liver metastases (CLM)
Authors: Garufi C. , Torsello A. , Tumolo S. , Mottolese M. , Campanella C. , Zeuli M. , Lo Re G. , Sperduti I. , Pizzi G. , Ettorre G. M. 
Published: August 2020

e15020 Background: We have previously shown preliminary data with Cmab+ all active drugs, CPT-FFL, with primary end- point CLM resectability (Garufi C. et al ASCO GI 2008). Here we report definitive clinical results. Methods: Unresectability criteria: size>5 cm (a), multinodular (b), ilar location (c), extrahepatic disease (d), >3 stable mets after chemotherapy before surgery (e). Aim of the study was to have at least 30% liver resection rate (power of 80% for p0=10% and p1=25%). Pts received weekly Cmab 400 then 250 mg/m2/wk plus CPT-11, 130 mg/m2/d1, 6 h infusion, (peak at 13:00) and a 12-h, days 2–5, infusion of L-OHP 20 mg/m2/day (peak at 16:00), FA 150 mg/m2/day plus 5-FU 600 mg/m2/d (peak at 4:00), q 2 wks; after the first 17 pts 5-FU and L-OHP were reduced to 550 and 15 mg/m2 respectively. Results: Since 07/20/2006 we enrolled 43 pts, irrespective of EGFR, K-ras and gene copy number (gcn): M/F 27/16, median age 60,7 y (33–76), median PS 0. Primary tumor: colon/rectum 34/9, primary tumor resected 39 pts (79%), synchronous metastases: 35 pts (81%), liver <25%/25%: 9/34 ((21/79%); median CEA/CA19–9: 55 ng/ml (1–6,600)/91.8 U/L (2.66440); unresectability: (a): 9 (21%), (b):14 (33%), (c) 1, (d): 4 (9%), (e): 15 (35%). We had 34 partial responses (79%, CI 79.1–87.0), 5 SD (11.6%) and 4 patients not evaluable becouse of toxicity. Complete Resection of CLM was obtained in 27 pts (63%) with 4 pts still to be resected. Median number (n.) of courses (c) was 10 (2–18), median n. of c before surgery (s) was 5 (3–10) and after s was 6 (1–6); median time from last c to s was 2 wks (2–4), from s to recovery chemo was 10 wks (2–16). Median follow-up was12 months, median PFS 13 months (7–19), median OS not reached with 2-y survival of 61%, 8 pts alive without recurrence (19%), 11 deaths (25%).Major limiting toxicity was diarrhea, with no difference after dose reduction: Grade 0–1: 6% of pts, G2 6%, G3 76%, G4 12%; neutropenia G3 6% with no febrile neutropenia. Conclusions: This is the first phase II study with CPT-FFL + Cmab in pts with unresectable CLM. Complete resection was obtained in 63% of pts with diarrhea being limiting toxicity. Analysis of EGFR status, K-ras and gcn will be further presented. No significant financial relationships to disclose.
A phase Ib/2, dose-escalating, safety, and efficacy study of imprime PGG, cetuximab and irinotecan in patients with advanced colorectal cancer (CRC)
Authors: Tamayo M. E. , Cornelio G. H. , Bautista J. B. , Flores M. L. , Kurman M. R. , Paul M. M. , Gargano M. A. , Patchen M. L. 
Published: August 2020

e15062 Background: Imprime PGG (Imprime PGG Injection) is a ß-glucan polymer being developed for treatment of cancer in combination with complement-activating monoclonal antibodies. This trial evaluates the safety and efficacy of Imprime PGG in combination with cetuximab and irinotecan in CRC patients (pts). Methods: Pts with recurrent/progressive CRC (Karnofsky > 70%) previously treated with 5-FU (alone or combined with other therapies) were treated with Imprime PGG (weekly), cetuximab (weekly; loading dose 400 mg/m2, then 250 mg/m2), and irinotecan (wks 1–4 of each 6-wk cycle; 125 mg/m2). In a 3 + 3 design, Imprime PGG dosing started at 2 mg/kg and escalated to 4 and 6 mg/kg after safety review. Safety (primary endpoint) was assessed by adverse events (AEs) and efficacy (secondary endpoint) by RECIST. Results: Imprime PGG was dosed in 3 pts at 2 mg/kg, 6 pts at 4 mg/kg and 1 pt at 6 mg/kg. Median age was 56. One pt remains on therapy at wk 49; other pts exited due to progressive disease (5 pts), irinotecan intolerance (2 pts), investigator discretion (1 pt), and withdrawn consent (1 pt). Median duration of treatment was 17.5 wks. No protocol-defined dose-limiting toxicities were observed. AEs experienced by > 50% of pts included diarrhea (90%), hypokalemia, neutropenia (80%), weight loss (70%), anemia, anorexia, leucopenia (60%), alopecia, dry skin, hypomagnesemia, increased amylase, vomiting (50%). Grade 4 SAEs included increased amylase, increased lipase, and neutropenia. Partial response (PR) occurred in 3 pts (30%) and stable disease (SD) in 7 pts (70%), yielding a disease control rate (PR + SD) of 100%. The median time to progression was 22.3 wks. Conclusions: Imprime PGG combined with cetuximab and irinotecan in CRC pts was safe and efficacy warrants further investigation. [Table: see text]
Updated phase II study results of capecitabine (X) + irinotecan (I) + bevacizumab (A) as first-line therapy for metastatic colorectal cancer (MCRC)
Authors: Beslija S. , Banjin M. , Jungic S. , Obralic N. , Kecman-Malcic G. , Rakita I. , Salkic B. , Pasic A. , Tinjic L. , Smoljanovic V. 
Published: August 2020

e15064 Background: The oral fluoropyrimidine X has improved efficacy, safety, and convenience vs. 5-FU/LV in MCRC [Van Cutsem et al. Br J Cancer 2004] and early-stage colon cancer [Twelves et al. NEJM 2005]. A recent study showed that I + X q2w is active and well tolerated [Garcia-Alfonso et al. ESMO 2006]. The humanized monoclonal antibody A targets VEGF and limits tumor angiogenesis. The addition of A to 5-FU/LV/I (IFL regimen) improves survival significantly in patients (pts) with MCRC [Hurwitz et al. NEJM 2004]. Replacing 5-FU/LV with X in this combination is a logical step forward. Here we report data from an open-label phase II trial of XIA in MCRC. Methods: Pts with untreated, histologically confirmed MCRC received I 175mg/m2 i.v. d1, X 1,000 mg/m2 orally bid d2–8, and A 5 mg/m2 d1. Treatment was repeated q2w x 12 cycles in the absence of progressive disease (PD) or unacceptable toxicity. Pts without PD after 12 cycles of XIA continued on the same dose of A + X 1,500 mg/m2 bid d2–8, q2w. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall response rate (ORR, RECIST), overall survival (OS), safety, and quality of life. Results: 57 pts have been enrolled. Baseline characteristics: M/F 44%/56%; median age 52 years (range 30–70); disease stage at initial diagnosis II/III/IV 16%/9%/75%; no. of metastatic sites 1/>1 47%/53%; most common metastatic site liver. Pts received a median 12 cycles (range 1–12) of XIA. All 57 pts are evaluable for safety and 56 for efficacy. ORR is 46% (3 CR, 13 PR); 5 pts (22%) have stable disease and 35 have PD. Median PFS and OS are 14.9 months (range 1.7–39.2) and 18.3 months (range 2.9–39.2), respectively. Grade 3 adverse events occurring in more than 1 pt are diarrhea (9%), hypertension (9%), hand-foot syndrome (7%), ileus (4%), and hypertriglyceridemia (4%); there is one report of grade 4 leucopenia. Conclusions: The XIA combination appears to be highly active and well tolerated as first-line treatment for MCRC; further studies of XIA are warranted. [Table: see text]
Incidence and significance of K-RAS mutation in first line treatment of colorectal cancer (cc): Experience of a single institution (Hospital Universitario Central de Asturias (HUCA))
Authors: Vieitez J. , Jiménez Fonseca P. , Fernandez de Sanmamed M. , Pitiot A. S. , Crespo G. , Berros J. , Muriel C. , Izquierdo M. , Pardo P. , Lacave A. 
Published: August 2020

e15081 Background: Although the significance of K-RAS mutation and cetuximab/panitumumab has been established in first line (ASCO 08 abstract 2# and 4000#) and in previously treated patients (pts) (NEJM 2008; 359: 1757. JCO 2008; 26: 374. JCO 2008; 26: 1626), data of the significance of this mutation in relation to bevacizumab is scarcer (JNCI 2005; 97: 981). Methods: Sample tissue of alive patients diagnosed of stage IV colorectal cancer were analyzed for the presence of K-RAS mutation by PCR amplification and direct sequencing. Data regarding presence of K-RAS mutation were retrospectively analyzed in relation to clinical data. Results: From IV to XII 08 122 paraffin embedded samples were analyzed. The percentage of mutant cases were 41% (95% CI 32–51%). The most frequent mutant type was Gly12Asp (37%) followed by Gly12Val (25%) and Gly13Asp (19%). We have clinical data of 94 pts. 62 were men and 32 female. 25 pts had received previous complementary treatment; in 80 pts primary tumor was previously resected (85%); median number of affected organs was 1 (1–4); in first line 76 pts received bevacizumab and 18 did not received any biological agent. Response Rate (RR) between mutant and no mutant pts was 48% (95% CI 37–59%) vs 47.8% (95% CI 32–63%) (p=0.92). Median follow up was 15.4 months. Progression free survival was 15 months for mutant and native K-RAS. There were no differences in response or PFS in any subgroup studied. Multivariable Cox analysis did not find any significant difference between sex (p=0.78), primary resected organ (p=0.28), liver metastases (p=0.37), LDH value at diagnosis (p=0.0.43), employ of biological agents in first line (p=0.37) or mutation in K-RAS gene (p=0.68). Conclusions: The percentage of K-RAS mutants is coherent with the results of the literature; mutations Gly12Asp, Gly12Val, and Gly13Asp represents the majority of the cases (81%); no significant relation was found between responses or DFS and mutations in the gene. No significant financial relationships to disclose.