bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abcb1, ugt1a1 and oatp-c polymorphisms predict Irinotecan (CPT-11) toxicity
Authors: Rhodes K. E. , Zhang W. , Yang D. Y. , Gordon M. A. , Schultheis A. M. , Nagashima F. , Iqbal S. , Lenz H. 
Published: March 2020

3074 Background: Irinotecan (CPT-11), a topoisomerase I inhibitor, is approved for the use of both first- and second-line chemotherapy in metastatic colorectal cancer (CRC) patients. As of yet, only few reliable molecular markers have been identified for predicting CPT-11 toxicity. In this study, we tested specific gene polymorphisms that are known to be involved in the Irinotecan metabolic pathway: the ATP-binding cassette transporter subfamily (ABCB1, ABCG2 and ABCC2), carboxylesterase 1 (CES1), carboxylesterase 2 (CES2), uridine-diphosphoglucuronosyltransferase 1A1 (UGT1A1),hepatic organic anion transport protein (OATP-C) and cytochrome P450 (CYP3A4). Methods: We ran PCR-RFLP assays using genomic DNA from the blood of 54 advanced CRC patients treated with first-line 5FU/LV and CPT-11 at USC between 1999 and 2003. Results: Our cohort was comprised of 31 men (57%) and 23 women (43%) with a median age of 56 years (range: 34–77 years). Participants represented four ethnicities: 29 Caucasian (54%), 12 Asian (22%), 10 Hispanic (19%), and 3 African-American (6%). Three patients (6%) demonstrated complete response (CR), 20 patients (38%) showed partial response (PR), 24 patients (45%) continued with stable disease (SD), and six patients (11%) were found to have progressive disease (PD). One patient was invaluable for response data. Twenty-four patients (46%) experienced Grade 0–2 toxicity, while 29 (54%) experienced Grade 3–4 toxicity. One patient was inevaluable for toxicity data. The median progression-free survival was 10.9 months (95% CI, 7.6 to 12.1 months), and the median overall survival time was 27.9 months (95% CI, 21.3 to 56.6+ months) with median follow up of 30.0 months (range: 11.2 to 59.9 months). We found that the combination of at least one OATP-C 521 wild-type T allele, at least one ABCB1 1236 C allele and at least one UGT1A1*28 variant 7 repeat demonstrated a statistically significant association with Grade 3/4 toxicities (P=0.002, Fisher’s exact test). Conclusion: This is the first study to combine three independent gene polymorphisms within the same metabolic pathway in order to explain common CPT-11 grade 3–4 toxicity. [Table: see text]
Irinotecan pharmacogenetics: The influence of pharmacodynamic genes
Authors: Hoskins J. M. , Baiget M. , Marcuello E. , Altes A. , McLeod H. L. 
Published: March 2020

3075 Background: Pharmacogenetic determinants of the disposition of the topoisomerase I (TOP1) poison, irinotecan, appear to predict patient (pt) risk of developing severe toxicity, but do not explain all reported cases of toxicity or tumor response to irinotecan treatment. Proteins encoded by the TOP1, ADPRT, TDP1, CDC45L, NFKB1 and XRCC1 genes abate the cytotoxic action of camptothecins in vitro. Methods: Genetic variation in the drug target, TOP1, and downstream effectors may influence pt outcomes to irinotecan therapy. A retrospective haplotype-association study was undertaken to investigate the hypothesis. The association between common haplotypes of the 6 candidate genes and severe adverse events (Grade 3/4 diarrhea, neutropenia) and tumor response (objective response, overall survival) was examined in 107 advanced colorectal cancer pts treated with irinotecan-based regimens. Haplotype tags (htSNPs) were selected from haplotype cladograms of each gene. Patient DNA was typed for htSNPs using pyrosequencing and haplotype identities estimated using PHASE v.0.9. Results: Genotype frequencies were in Hardy-Weinberg equilibrium. TOP1 IVS4+61 was related to neutropenia incidence (GG<AG<AA, p<0.05) and TDP1 IVS12+79 to objective response (TT<TG<GG, p<0.05). TOP1 IVS4+61 AG+GG survived longer (24.9 months) than AA pts (7.8 months; p<0.005) and ADPRT +852 (A284A) CT+TT pts longer than CCs (p<0.05). More pts with the XRCC1 3/3 diplotype (83%) had an objective response to therapy than pts with other diplotypes (30%, p<0.05). There was a trend towards more ADPRT 2/2s (33%) experiencing severe neutropenia than pts with other diplotypes (13%, p=0.08). No genetic variant influenced diarrhea incidence. Conclusions: This is the first pharmacogenetic investigation of irinotecan pharmacodynamic factors. Our results suggest TOP1 and ADPRT variants may alter a patient’s risk of experiencing neutropenia and TOP1, TDP1, ADPRT and XRCC1 variants may influence tumor response to irinotecan-based therapies. [Table: see text]
A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a 3 week on 1 week off schedule in patients with advanced solid tumors
Authors: Lewis N. , Marshall J. , Amelsberg A. , Cohen R. B. , Stopfer P. , Hwang J. , Malik S. 
Published: March 2020

3091 Background: BIBW 2992 is a highly potent irreversible dual EGFR /HER2 receptor tyrosine kinase inhibitor. This is the first trial performed in the United States with this compound. Methods: Patients with refractory solid tumors (historically known to express EGFR and/or HER2) with normal end-organ function and PS 0–1 were enrolled into a phase I dose-escalation clinical trial. After completion of eligibility and informed consent, BIBW 2992 was administered orally, once daily, for 21 days followed by a 7-day rest. Three patients were accrued in each cohort using a traditional dose escalation 3+3 trial design. After reaching DLT, the MTD dose group was expanded to 18 patients. PK sampling and skin biopsies were performed at baseline and day 21. Tumor biopsies in appropriate patients were obtained pre- and post-treatment in the final cohort to analyze inhibition of the EGFR pathway. Results: Forty-three patients were enrolled. Dose levels ranged from 10 to 65 mg daily. Tumor types included colon (10), breast (8), pancreas and ovarian (4), thyroid and esophageal (3), prostate and NSCLC (2), gastric, cholangiocarcinoma, basal cell, parotid, NPC, HCC, and mesothelioma (1 ). An interim PK analysis showed that BIBW 2992 exposure and peak plasma concentrations increased with increasing dose on day 1 and at steady state. Steady state was reached at day 8. Adverse events were diarrhea, skin rash, pruritus, mucositis, nausea, and vomiting. Doses were escalated to 65 mg/day, with two DLTs noted (skin rash and mucositis). The 40-mg dose was chosen as the recommended phase II dose based on acceptable toxicity when administered chronically. No objective responses have been observed; however, 15 of 35 evaluable patients (43%) experienced stable disease and have been on treatment for > 3 mos. Four patients have continued in an extension study. Two of these patients are still active and one has been taking BIBW 2992 for approximately 1 year. Conclusion: BIBW 2992 is well tolerated at 40 mg per day using a 21-day, 7-day off-treatment schedule. The adverse events observed were typical of receptor tyrosine kinases, including skin rash, pruritis, mucositis and GI disturbance. [Table: see text]
Tumor response to pre-operative chemotherapy (CT) with FOLFOX-4 for resectable colorectal cancer liver metastases (LM). Interim results of EORTC Intergroup randomized phase III study 40983
Authors: Gruenberger T. , Sorbye H. , Debois M. , Bethe U. , Primrose J. , Rougier P. , Jaeck D. , Finch-Jones M. , Van Cutsem E. , Nordlinger B. 
Published: March 2020

3500 Background: After resection of LM, 5y survival is 30%, but cancer recurrence is frequent. The benefit of combining surgery and CT has not yet formally been proven. Methods: This study evaluates the value of pre- and postoperative CT in patients with potentially resectable liver metastases from colorectal cancer. Between September 2000 and July 2004, 364 patients were randomized between peri-operative FOLFOX4 (oxaliplatin 85mg/m2 and LV5FU2), 6 cycles before and 6 cycles after surgery (182 patients), and surgery alone (182 patients). The primary endpoint was progression free survival. The purpose of this analysis was to evaluate tumor response to pre-operative treatment and determine if CT induces a tumor size reduction. Results: Baseline characteristics were similar in both arms: median age: 62.5 yrs, prior adjuvant CT: 41.8%, 1 to 3 metastases: 92.3%, T3 or T4: 80.8%. In the CT arm, 97.7% of the patients were documented to have completed pre-operative CT (81.5% received 6 preoperative cycles). 28.9% of the patients who started pre-operative CT required a dose reduction. Of all patients entered in the trial, 88.3% and 94.9% underwent surgery in the CT and surgery arms, respectively. Resection was achieved in 95.6% of the patients operated (84.4% of all patients) in the CT arm, and 89.2% of the patients operated (84.7% of all patients) in the surgery arm. As previously reported, preoperative chemotherapy was safely administered. From imaging data (CT scan), median sum of largest diameters of lesions was 45 mm [Q1-Q3:28.0–70.0] (both arms) before treatment and decreased to 30 mm [Q1-Q3: 15.0–55.0] after CT (median relative difference of 29.7%). At pathological examination, median sum of largest diameters of lesions was 34.5 mm [Q1-Q3:20.0–53.0] in the CT arm and 45 mm [Q1-Q3: 29.0–69.0] in the surgery arm. Conclusions: CT scan measurements were consistent with those performed at pathological examination. Pre-operative CT with 6 cycles of FOLFOX4 resulted in a decrease in diameter of lesions. Since size of metastases at time of surgery is known to have an impact on survival, it is possible that preoperative chemotherapy will improve survival. Survival data should be available at the end of 2006. No significant financial relationships to disclose.
Tolerability of fluoropyrimidines appears to differ by region
Authors: Haller D. G. , Cassidy J. , Clarke S. , Cunningham D. , Van Cutsem E. , Hoff P. , Rothenberg M. , Saltz L. , Schmoll H. J. , Twelves C. 
Published: March 2020

3514 Background: Limited information is available regarding regional differences in tolerability for fluoropyrimidines. This is an initial assessment of the Roche phase III databases on patients treated for metastatic colorectal cancer (MCRC) and adjuvant colon cancer. Methods: Retrospective multivariate analyses (logistic regression) were performed using pooled data from two identical studies (n=1189) in MCRC comparing capecitabine (X) monotherapy with i.v. 5-FU/LV (Mayo regimen) [Hoff et al. and Van Cutsem et al. JCO 2001], and from an adjuvant study (n=1861) comparing XELOX (X+oxaliplatin) with either the Mayo or Roswell Park 5-FU/LV regimens [Schmoll et al. ASCO 2005]. Treatment-related safety parameters evaluated were: all grade 3/4 AEs, grade 3/4 GI events (diarrhea, nausea, vomiting, stomatitis), and grade 3/4 neutropenia events (febrile neutropenia, neutropenia reported as AE or lab value). Dependent variables for 1st-line MCRC data were: US vs. non-US; and for adjuvant colon cancer: US vs. non-US, US vs. Asia, and RoW (rest of the world) vs. Asia. Factors in the adjusted relative risk model were: age, gender, PS, BSA, BMI, baseline creatinine clearance and treatment (X vs. 5-FU/LV; XELOX vs. Mayo vs. RP). Results: Region was significantly associated with grade 3/4 AEs and grade 3/4 GI events in both settings ( table ). There were no relevant interactions between region and type of fluoropyrimidine treatment. Reporting of grade 3/4 neurosensory toxicity was similar in the US and outside US. Conclusions: Differences in the rates of grade 3/4 toxicity were significantly associated with the region of the world in which the patients were treated. Patients treated in the US experienced the highest rates of grade 3/4 toxicity (see table ). This difference was observed for both X and for 5-FU. The reasons for these differences remain to be elucidated. Acknowledgements: C. Allegra, J. Bertino, J-Y Douillard, B. Gustavsson, G. Milano, M. O’Connell, Y. Rustum, J. Tabernero, J. Fagerberg, F. Gilberg, and F. Sirzen. [Table: see text] [Table: see text]
Adjuvant therapy (AT) with raltitrexed (RAL) in colorectal cancer (CRC) patients (pts) intolerant of 5-fluorouracil (5FU)
Authors: Wilson K. S. , Barnett J. B. , Gill S. , Khoo K. E. , Fitzgerald C. A. 
Published: March 2020

3571 Background: Severe 5FU toxicity in AT of CRC may require discontinuation or change of therapy. RAL, a TS inhibitor, has different toxicity but similar efficacy in metastatic CRC. Excess mortality from RAL in the PETACC trial has limited its role in CRC AT. RAL AT (3 mg/m2 IV q3w) was offered at BCCA to pts with demonstrated intolerance to bolus (Mayo) 5FU. We sought to explore retrospectively the safety & efficacy of RAL AT in these pts. Methods: A search of BCCA Pharmacy & Clinical Records from Oct. 1999 to June 2004 identified CRC pts who received 5FU AT and RAL AT. Data was collected on pt and disease characteristics, therapy & follow-up (FU) status. Kaplan-Meier survival proportions were compared with historical experience. Results: Of 1,456 CRC pts who received 5FU AT, 44 pts (3%) received RAL following 5FU intolerance (42 pts GI/hem toxicity, 2 pts due to angina). Median age was 62.3 y (range 39.8 - 83.2); 31 female; 31 colon primary. Stage III: 39 pts (88.6%); N2: 14 (31.8%). Median # 5FU cycles given prior to RAL was 2 (1 - 4). 21 pts (48%) had only 1 cycle of 5FU before RAL. Grade ≥3 toxicities from 5FU occurred in 39 pts; 17 pts were hospitalised for 2 - 29d (median 8). Twelve of 44 pts also received RT. Median # RAL cycles: 5 (1–8); 77% received >3 cycles; 84% completed all planned RAL. Gr 1, 2, 3 RAL toxicity rates: 55%, 27%, 7% respectively. 1 pt was hospitalised (4 days, FN); no deaths. Median FU of living pts is 4.2 yr (range 1.4 - 6.5). Median survival for all pts is not yet reached. 3 Year Relapse free (RFS) and Overall Survival (OS) proportions were 72% (95% CI 58.5% - 85.5%) and 83.2% (95% CI 71.8% - 94.6%) resp. Stage III 3 Year RFS was 70.8% (95% CI 56.1% - 85.5%) and 3 Year OS was 83.6% (95% CI 71.4% - 95.8%). For N1 & N2 pts, 3 Year RFS was 83.8% (95% CI 69.3% - 98.3%) and 49% (95% CI 22.3% - 75.7%), and OS 91.4% (95% CI 80% - 100%) & 70.7% (95% CI 46.4% - 95%) resp. Conclusions: Severe 5FU intolerance was seen in 3% of pts. RAL AT can be given safely if further 5FU is contraindicated. Outcomes appear similar to historical experience with 5FU AT. [Table: see text] No significant financial relationships to disclose.
Phase II clinical study of combination therapy with irinotecan and S-1(IRIS) for inoperable recurrent advanced colorectal cancer: Hokkaido Gastrointestinal Cancer Study Group study HGCSG-0302)
Authors: Komatsu Y. , Yuki S. , Akita H. , Kudo M. , Tateyama M. , Saga T. , Megro T. , Suzuki G. , Sakata Y. , Asaka M. 
Published: March 2020

3589 Background: We planned to conduct a phase II clinical study of combination therapy with irinotecan and S-1, a new oral anticancer drug of the fluorinated pyrimidine type. We reported the interium reports of this study in colorectal cancer patients at GI cancer Symposium 2006. Methods: The antitumor effect was the primary endpoint, while the safety, progression-free survival time, and median survival time were the secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer aged 20–75 years. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15) as an intravenous infusion over 90 minutes, and oral S-1 (40 mg/m2) was administered after breakfast and dinner and then withdrawn for 2 weeks. Results: Forty patients were enrolled in the present study. There were 23 men and 17 women. The median age was 62 years (range: 34 to 74 years). Two patient showed grade 4 neutropenia, but the next course could be given safely after dose reduction. Three patients had grade 3 diarrhea, but therapy could be continued with addition of an antidiarrheal drug. No other serious adverse reactions occurred (either hematological or non-hematological), and all patients could receive therapy safely on an outpatient basis. Interim analysis suggested excellent results, with a response rate of 50%. To date, 231 cycles (median 8, range 1–19) have been administered. Median relative dose intensity was 97% for S-1 and 87% for irinotecan. 36 pts are evaluable for efficacy: RR was 47.2% (95% CI, 30.9–63.5%) and Disease Control Rate (PR + SD) was seen in 94.4% of pts. PFS of this regimen is 320 days. MST is not reached. Conclusions: IRIS therapy achieved a high response rate and could be given safely. These findings suggest that the therapy has potential as first-line treatment for inoperable advanced recurrent colorectal cancer. It seems that IRIS is a good treatment equal to FOLFIRI. In addition, this regimen could qualify as a candidate for future combination therapy with a molecular-targeting drug. The latest data will be reported at the meeting. No significant financial relationships to disclose.
Molecular staging with CM10 ProteinChip and SELDI-MS-TOF for colorectal cancer patients before surgery
Authors: Chen Y. , Xu W. , Zheng S. , Zhang S. 
Published: March 2020

3612 Background: The objectives of this are to detect the serum proteomic patterns by using SELDI-TOF-MS technology and CM10 ProteinChip in colorectal cancer (CRC) patients, and to evaluate the significance of the proteomic patterns in the tumor staging of colorectal cancer. Methods: SELDI-TOF-MS and CM10 ProteinChip were used to detect the serum proteomic patterns of 76 colorectal cancer patients which including 10 Stage I, 19 Stage II, 16 Stage III and 31 Stage IV patients. Models for various stages were developed and validated by using Support Vector Machine, Discriminant Analysis and time-series analysis methods. Results: The first model, formed by 6 protein peaks (M/Z: 2759.58, 2964.66, 2048.01, 4795.90, 4139.77 and 37761.60 Da), could be used to distinguish local CRC patients (StageIand Stage II) from regional CRC patients (Stage III) with an accuracy of 86.67% (39/45). The second model, formed by 3 protein peaks (M/Z: 6885.30, 2058.32 and 8567.75 Da), could be used to distinguish locoregional CRC patients (Stage I,Stage II and Stage III) from systematic CRC patients (Stage IV) with an accuracy of 75.00% (57/76). The third model could distinguish Stage I from Stage II with an accuracy of 86.21% (25/29). The fourth model could distinguish Stage I from Stage III with an accuracy of 84.62% (22/26). The fifth model could distinguish Stage II from Stage III with an accuracy of 85.71% (30/35). The sixth model could distinguish Stage II from Stage IV with an accuracy of 80.00% (40/50). The seventh model could distinguish Stage III from Stage IV with an accuracy of 78.72% (37/47). All four stages could be distinguished by using a two-dimensional scattered spots figure. Conclusion: We conclude that this method is promising in the staging of colorectal cancer patients before surgery. No significant financial relationships to disclose.
PGC-1 expression level in human colorectal cancer: A predictor of lymph node metastasis
Authors: Kwon H. , Shin S. , Roh M. S. , Choi H. J. , Kwak J. , Yang Y. S. , Park J. 
Published: March 2020

3616 Background: Previous study showed that the expression of peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ coactivator-1 (PGC-1) was correlated with clinical outcome in breast cancer. However, no published data are available about the biological and clinical significance of PGC-1 in colorectal cancer. Thus, our aim was to explore the expression of PPARγ and PGC-1 in colorectal cancer as well as their association with other clinicopathological features, and to evaluate the role of PPARγ and PGC-1 as a prognostic indicator of colorectal cancer. Methods: We have investigated the presence of PPARγ and PGC-1 in human colorectal cancer tissues and adjacent normal tissues from 108 primary colorectal cancer patients by immunohistochemistry. The correlation between their expression and clinicopathologic features was investigated. Three-year overall survival of patients with different expression of PPARγ and PGC-1 were analyzed by the Kaplan-Meier method. Results: No significant correlation was found between PPARγ expression and age at surgery, gender, histopathologic differentiation, depth of infiltration, relapse, and Dukes’ stage. No significant correlation was found between PGC-1 expression and age at surgery, the histopathologic differentiation, the depth of infiltration, and relapse. However, PGC-1 expression was closely related to Duke’s stage and nodal metastasis (p=0.024 and p=0.020, respectively). Survival analysis showed that the PGC-1-positive group has a reduced overall survival (p=0.0367). Conclusions: Based on our results, PGC-1 may be valuable marker of nodal metastasis and represent a biomarker of poor prognosis in colorectal cancer. No significant financial relationships to disclose.
P53 as a predictor of tumor burden in lymph nodes (LN) in colon cancer (Cca) patients (pts) undergoing sentinel lymph node (SLN) mapping (M)
Authors: Sehgal R. , Saha S. , Wiese D. , Parker R. , Huang W. , Arora M. , Doan K. , Ganatra R. , Yestrepsky B. , Yee C. , Patel M. 
Published: March 2020

3617 Background: p53 and LN status(S) are important prognostic markers in Cca. Our study was done to evaluate whether p53 S could predict tumor burden in LNs in Cca undergoing SLNM. Methods: Pts with Cca underwent SLNM to determine the LN S. A portion of tumor was used for detection of p53 S by IHC.p53 Histo Score (HS) was defined as (Intensity of stain in cells from 0–4 +1) × (% cells staining). HS of 180 was taken as cut off for significance based on previous studies on solid tumors. Metastatic foci in SLNs and nonSLNs were measured in greatest diameter by ocular micrometer. For overall tumor burden in SLNs and nonSLNs,all metastatic foci were added for each pt. Results: SLNM was successful in 100% of the 117 consecutive pts with Cca. Pts with distant metastasis (mets) (18) and skip mets (9) were excluded. Of the remaining 90 pts,39% were SLN positive (+ve) and 61% were SLN negative (-ve). HS of ≤ 180 was found in 66% and HS >180 was found in 34% of the pts. In 55 SLN -ve pts 76% had HS ≤ 180 while 24% had HS >180. In 35 SLN +ve pts, 49% had HS of ≤ 180 and 51% had HS >180. ( Table ) Of SLN +ve pts, size of metastatic tumor in LNs was available in 86% of pts. Average (av.) non SLN met size was 0.95 cms in pts with HS ≤ 180 and 3.4 cms in pts with HS > 180. Av. SLN met size was 0.63 cms in pts with HS ≤ 180 and 0.9 cms in pts with HS>180 ( Table ). No statistical significance was found among T stage of pts with HS >180 vs ≤ 180. Conclusion: Pts with p53 HS >180 showed significantly greater tumor burden in both SLNs and non SLNs as compared to pts with HS ≤ 180. Also probability of having SLN -ve disease is higher in pts with HS ≤ 180 as compared to pts with HS >180 in Cca. Thus,even in SLN -ve pts, high HS may indicate a worse prognosis. Hence,a high p53 HS might predict pts with Cca having higher tumor burden in LNs and thus identify an aggressive subgroup of pts. [Table: see text] No significant financial relationships to disclose.