bluuebunny/crossref_metadata_2025_split huggingface dataset:
The distribution of chromosomal and microsatellite instability in colorectal cancers related to inflammatory bowel disease.
Authors: Brackmann Stephan , Pretorius Maria , Klepp Pasquale , Clausen Ole Petter Fraas , Andersen Solveig Norheim , Vatn Morten H , Lothe Ragnhild , Lind Guro E , Danielsen Haavard E 
Published: March 2020

3607 Background: Surveillance for colorectal cancer (CRC) in inflammatory bowel disease (IBD) has so far not been effective. Mucosal or fecal biomarkers may be useful in the selection of high risk patients. The yield may depend on the underlying carcinogenic pathway. In IBD associated CRC (IBD-CRC) the distribution of chromosomal instability (CIN) and microsatellite instability (MSI) is not well documented. Our objective was to determine the distribution of CIN and MSI and the association to clinico-histological factors in a cohort of patients with IBD-CRC. Methods: Ploidy was measured by high-resolution image cytometry and MSI by using two markers (BAT 25 and BAT26) in 62 patients with 72 CRC-IBD selected by matching the Norwegian Cancer Registry with IBD cohorts of three university hospitals in Oslo. The association between ploidy/MSI status and clinicohistological factors were analyzed by non-parametric tests. Results: Ploidy status was analyzed in 67 (93%), microsatellite stability in 68 (94%) tumors. Fourty-nine (73.1%) were non-diploid (43 aneuploid, 1 polyploid, 5 tetraploid), 13 (19.4 %) diploid, five (7.5%) indeterminate. Forty-three (63.2%) were microsatellite stable (MSS), four (5.8%) microsatellite instable (MSI). One tumor was MSI in BAT25 but MSS in BAT26. Twenty (29.5%) tumors showed no PCR-product in at least one of the markers. In 46 tumors, both ploidy and MSI status were available. All non-diploid tumours (36, 78.3%) were MSS and all MSI tumors (4, 8.7%) were diploid. Six (13%) tumors were diploid and MSS. Four patients were treated with 5-ASA prior to diagnosis of CRC. Three developed diploid, one aneuploid cancers. Of the untreated patients, 31 developed aneuploid, 7 diploid cancers (p=0.036). We did not find an association between age, gender, type of IBD, duration of IBD, localisation of CRC,TNM-stage and CIN or MSI. Conclusions: The majority of CRC-IBD in our cohort seem to present CIN and only a minority MSI. Some CRC-IBD patients present neither CIN nor MSI. Future studies should determine whether these display the CpG island methylator phenotype. Biomarkers for CRC-IBD should be derived from all three pathways.
SPIRITT (study 20060141): A randomized phase II study of FOLFIRI with either panitumumab (pmab) or bevacizumab (bev) as second-line treatment (tx) in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC).
Authors: Cohn Allen Lee , Hecht J. Randolph , Dakhil Shaker , Saleh Mansoor N. , Piperdi Bilal , Cline-Burkhardt Vivian Jean M. , Tian Ying , Go William Y. 
Published: March 2020

3616 Background: Pmab has demonstrated significant improvement in progression-free survival (PFS) in pts with WT KRAS mCRC as 2nd-line tx in a phase III trial comparing pmab + FOLFIRI vs FOLFIRI alone. Here, we describe the results of SPIRITT, a multicenter, randomized phase II study evaluating pmab + FOLFIRI and bev + FOLFIRI in pts with WT KRAS mCRC previously treated with a 1st-line bev + oxaliplatin (Ox)-based chemotherapy regimen. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg + FOLFIRI Q2W or to bev 5.0 or 10.0 mg/kg + FOLFIRI Q2W. Eligibility criteria included: WT KRAS mCRC, ECOG ≤ 1, no prior irinotecan or anti-EGFR tx, and tx failure of prior 1st-line bev + Ox-based therapy (≥ 4 cycles). The primary endpoint was PFS; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. No formal hypothesis was tested. Results: 182 pts with WT KRAS mCRC were randomized. All pts received tx. Efficacy results are shown (Table). Worst grade of 3/4 adverse events (AE) occurred in 78% of pts in the pmab + FOLFIRI arm and 65% in the bev + FOLFIRI arm. Grade 5 AEs occurred in 7% of pts in the pmab + FOLFIRI arm and 7% in the bev + FOLFIRI arm. Tx discontinuation due to any AE was 29% in the pmab + FOLFIRI arm and 25% in the bev + FOLFIRI arm. Conclusions: In this estimation study of pts with WT KRAS mCRC that previously received bev + Ox-based tx, the PFS hazard ratio (HR) was 1.01 (95% CI: 0.68 - 1.50). The OS HR was 1.06 (95% CI: 0.75 - 1.49). The observed ORR was higher in the pmab + FOLFIRI arm. 54% of bev + FOLFIRI pts received subsequent anti-EGFR tx. The safety profile for both arms was similar to previously reported studies. Tx discontinuation rates due to AEs were similar between the arms. Clinical trial information: NCT00418938. [Table: see text]
Overall survival (OS) analysis from PRIME: Randomized phase III study of panitumumab (pmab) with FOLFOX4 for first-line metastatic colorectal cancer (mCRC).
Authors: Douillard Jean-Yves , Siena Salvatore , Tabernero Josep , Burkes Ronald L. , Barugel Mario Edmundo , Humblet Yves , Bodoky Gyorgy , Cunningham David , Jassem Jacek , Rivera Fernando , Kocáková Ilona , Ruff Paul , Smakal Martin , Canon Jean-Luc , Rother Mark , Oliner Kelly S. , Tian Ying , Sidhu Roger 
Published: March 2020

3620 Background: The primary and final analyses of PRIME demonstrated that pmab + FOLFOX4 significantly improved progression-free survival (PFS) vs FOLFOX4 alone for first-line treatment of patients (pts) with wild-type (WT) KRAS exon 2 mCRC. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg every 2 weeks + FOLFOX4 or FOLFOX4 alone and had no prior chemotherapy for mCRC, ECOG performance status ≤ 2, and tumor tissue for biomarker testing. The primary endpoint was PFS by central assessment. Secondary endpoints included OS, objective response rate, and safety. KRAS exon 2 tumor status was determined by a blinded central lab prior to the primary analysis. This exploratory analysis of updated survival (>80% OS events) estimated the treatment effect of pmab + FOLFOX4 compared with FOLFOX4 alone on OS by KRAS exon 2 status. Previous analyses in pts with WT KRAS exon 2 tumor status reported OS with an event rate of 54% of pts in the primary analysis and 68% of pts in the final analysis. Results: 1183 pts were randomized and received treatment: 593 pts in the pmab + FOLFOX4 arm and 590 pts in the FOLFOX4 alone arm. The KRAS exon 2 ascertainment rate was 93%, consistent with the primary analysis. 535/656 pts (82%) with WT KRAS exon 2 mCRC had an OS event at the time of this analysis. Results are shown (Table). Conclusions: In this updated analysis, an improvement in OS was observed in pts with WT KRAS exon 2 mCRC treated with pmab + FOLFOX4 vs FOLFOX4 alone (p = 0.03). Median OS was reduced in pts with mutant (MT) KRAS mCRC (p = 0.16) and is consistent with previous analyses. Updated efficacy and safety results will be presented. KRAS testing is critical to select appropriate pts with mCRC for treatment with pmab. Clinical trial information: NCT00364013. [Table: see text]
Effect of EGFR inhibition on HER3/PI3K activation by feedback induction of ErbB heterodimers in cetuximab-sensitive colon cancer cells.
Authors: Jacobs Bart , Vecchione Loredana , Hoe Nicholas , De Schutter Jef , Biesmans Bart , Singh Sharat , Tejpar Sabine 
Published: March 2020

3626 Background: Although cetuximab treatment has been successful for the treatment of KRAS wild-type colorectal cancers, complete remissions are rarely seen in patients, leading ultimately to resistance. We hypothesized that in cetuximab-sensitive patients, the ErbB network is insufficiently targeted since network plasticity may occur. Methods: We have used EGFR-sensitive colorectal cancer cells and investigated ErbB network activity and adaptations by RTK arrays, western blot, and Collaborative Enzyme Enhance Reactive immunoassay (CEER). These were complemented by ErbB heterodimerization (HER2:3, HER1:2, HER1:3, HER3:PI3K) assays using CEER. Effects on cell survival were measured using colony formation assay. In addition to the EGFR sensitive cell line, 200 clinical colorectal cancer (CRC) samples were profiled utilizing CEER for RTKs, downstream signaling, and heterodimerization. Results: EGFR and downstream signaling proteins AKT, ERK, and RSK were potently inhibited by cetuximab or gefitinib at 24h of treatment in EGFR sensitive colorectal cancer cell line. At 24h of treatment, we observed approximately 2 folds increase in total HER2 and HER3 protein levels, 2.7 folds in phosphorylated HER3, and 5.4 folds in HER2:HER3 heterodimer formation. Concurrently, increased in ErbB heterodimer formation was accompanied by 5 folds increase in PI3K binding to HER3, resulting in enhanced HER3 signaling, with increase in AKT, ERK, and RSK. Co-treatment of these cells with cetuximab and HER2 inhibitor Trastuzumab or by treatment with lapatinib blocked the induction of HER2:HER3 heterodimer, HER3 phosphorylation, and PI3K binding to HER3. In 30% of the 200 clinical colorectal cancer samples profiled, we observed an increased in phosphorylated HER3, formation of HER2:HER3 and HER3:PI3K heterodimers along with HER1 activation (KRAS WT). Conclusions: Combination of HER2 inhibitor with an EGFR inhibitor could potentially increase the therapeutic index in cetuximab sensitive patients, and suppress activation of feedback mechanisms upon EGFR inhibition. Current findings suggest that CRC patients with similar profile would benefit from these combination therapies.
Guanylyl cyclase C (GCC) expression in lymph nodes (LNs) as a determinant of recurrence in stage II colon cancer (CC) patients (pts).
Authors: Sargent Daniel J. , Shi Qian , Gill Sharlene , Louvet Christophe , Everson Richard Bernard , Kellner Udo , Clancy Thomas E. , Pipas J. Marc , Resnick Murray B. , Meyers Michael O. , Huntsman David , Validire Pierre , Farooq Umar , Pavey Emily S , Haince Jean-Francois , Beaudry Guillaume , Fradet Yves 
Published: March 2020

3639 Background: The first phase of the multi-center prospectively specified retrospective study Validating Indicators To Associate Recurrence (VITAR), assessing the relationship between GCC gene expression in formalin fixed (FFPE) LNs and time to recurrence (TTR) in stage II CC pts not treated with adjuvant chemotherapy (Sargent, Annals Surg Onc 2011), showed promising initial results. Here we report a validation set of 463 new stage II CC pts. Methods: GCC mRNA was quantified by RT-qPCR using FFPE LNs from untreated T3N0 CC pts diagnosed from 1999-2008 with at least 12 LNs examined , blinded to clinical outcomes. Patients were classified by GCC LN ratio (LNR) (high risk: LNR > 0.1; low risk: LNR ≤ 0.1), with LNR defined as ratio of GCC positive to GCC informative LNs. Cox regression models tested the relationship between GCC and the primary endpoint of TTR, adjusted for age, tumor grade, number of LN examined pathologically, and lymphovascular invasion. Mismatch repair (MMR) status was also assessed. All primary analyses and cut-points were pre-specified. Results: 46pts (10%) recurred (rec), median follow-up was 65 months, median LNs examined was 20, and 42% (195/463) were classified high risk. Overall, TTR was not significantly associated with binary GCC LNR risk class (HR=1.47, p=.208) or DFS (HR= 1.39, p=.097). One site’s (n=97) tissue grossing method precluded appropriate LN assessment with existing GCC qualification methods. Excluding this site resulted in a TTR HR=1.91, p=0.051 (multivariate). In a post-hocanalysis excluding this site and using a 3-level GCC risk group of high (LNR > 0.20), intermediate (0.10 < LNR < 0.20) and low (LNR < 0.10), high risk group pts had a 5-yr rec risk of 22% versus 8% in low risk (HR 2.72, p=0.006). MMR status was not significantly associated with TTR (multivariate p=0.30). Conclusions: GCC status is a promising prognostic factor in appropriately staged stage II CC pts not treated with adjuvant therapy independent of traditional histopathology risk factors, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique. Outcome associations were strengthened when considering a 3-level GCC categorization.
A phase Ib study of gemcitabine plus PEGPH20 (pegylated recombinant human hyaluronidase) in patients with stage IV previously untreated pancreatic cancer.
Authors: Hingorani Sunil R. , Harris William Proctor , Beck J. Thaddeus , Berdov Boris A. , Wagner Stephanie Ann , Pshevlotsky Eduard M. , Tjulandin Sergei , Gladkov Oleg , Holcombe Randall F. , Jiang Ping , Maneval Daniel C. , Zhu Joy , Devoe Craig E. 
Published: March 2020

4010 Background: PEGPH20 is a PEGylated version of human recombinant hyaluronidase. In preclinical studies, PEGPH20 depleted pancreatic cancers of their high hyaluronan (HA) content. In a genetically-engineered murine model of PDA, PEGPH20 + gemcitabine (Gem) significantly prolonged survival compared to Gem alone. In Ph1 PEGPH20 monotherapy studies, the MTD was 3.0 μg/kg. The most common AEs were musculoskeletal events (MSEs). Methods: This was a dose-escalation study to find the recommended Phase 2 dose (RP2D) of PEGPH20 in combination with Gem in patients (pts) with Stage IV previously untreated pancreatic cancer. Pts received PEGPH20 at 1, 1.6, or 3 μg/kg IV twice a week for Wks 1-4, weekly for Wks 5-7, then 1 wk rest. Dose escalation was based on safety. Gem was given at 1000 mg/m2 IV once a week for Wks 1-7, then 1 wk rest. Thereafter, PEGPH20 + Gem were given once a week for 3 wks in 4-wk cycles. Dexamethasone was given pre and post PEGPH20 doses. Results: Of the 28 pts enrolled, the majority had a Karnofsky performance status of 80%, and 85%/19%/26% of pts had liver/lung/visceral metastases. The median age was 58 yrs. Four pts received PEGPH20 at 1 μg/kg, 4 at 1.6 μg/kg, and 20 at 3 μg/kg. The RP2D was 3 μg/kg. Treatment duration ranged from 1-274 days; 5 pts remain on study. Treatment was generally well tolerated. Ten pts had 1 Gem dose reduction, 2 pts had 1 PEGPH20 dose reduction (3 to 1.6 µg/kg), but no pt had a DLT. The most common PEGPH20-related AEs were MSEs (25% Gr1; 18% Gr2) and fatigue (21% Gr1; 11% Gr2). Objective response was assessed by an independent central radiologist using RECIST 1.1. Of the 21 pts evaluable for efficacy, 7 had partial response (PR) for an overall response rate (ORR) of 33%, and 9 had stable disease for ≥ 2 mo. Tumor biopsies from 12 pts were evaluable for HA staining. HA was high in 9 and low in 3. Of the 9 with high HA staining, 5 had PR (56% ORR); HA data were not available for the other 2 PR pts. PK results show dose-dependent exposure consistent with data from PEGPH20 monotherapy studies. Conclusions: PEGPH20 in combination with Gem is generally well tolerated in advanced pancreatic cancer and shows promising efficacy, especially in pts with high intratumoral HA content. Clinical trial information: NCT01453153.
Predictive value of phase II clinical trials in pancreatic cancer: Rethinking the road to progress.
Authors: Halperin Daniel M. , Lee J. Jack , Yao James C. 
Published: March 2020

4036 Background: Few new therapies for pancreatic adenocarcinoma (PC) have been approved by the Food and Drug Administration (FDA) or recommended by the National Comprehensive Cancer Network (NCCN), reflecting frequent failures in phase III trials. We hypothesize that the high failure rate in large trials is due to a low predictive value for “positive” phase II studies. Methods: Given a median time from initiation of clinical trials to FDA approval of 6.3 years, we conducted a systematic search of the clinicaltrials.gov database for phase II interventional trials of antineoplastic therapy in PC initiated from 1999-2004. We reviewed drug labels and NCCN guidelines for FDA approval and guideline recommendations. Results: We identified 70 phase II trials that met our inclusion criteria. Forty-five evaluated compounds without preexisting FDA approval, 23 evaluated drugs approved in other diseases, and 2 evaluated cellular therapies. With a median follow-up of 12.5 years, none of these drugs gained FDA approval in PC. Four trials, all combining chemotherapy with radiation, eventually resulted in NCCN recommendations. Forty-two of the trials have been published. Of 16 studies providing pre-specified type I error rates, these rates were ≥0.1 in 8 studies, 0.05 in 6 studies and <0.025 in 2 studies. Of 21 studies specifying type II error rates, 7 used >0.1, 10 used 0.1, and 4 used <0.1. Published studies reported a median enrollment of 47 subjects. Fourteen trials reported utilizing a randomized design. Conclusions: The low rate of phase II trials resulting in eventual regulatory approval of therapies for PC reflects the challenge of conquering a tough disease as well as deficiencies in the statistical designs. New strategies are necessary to quantify and improve odds of success in drug development. Statistical parameters of individual or coupled phase II trials should be tailored to achieve the desired predictive value prior to initiating pivotal phase III studies. Positive predictive value of a phase II study assuming a 1%, 2%, or 5% prior probability of success and 10% type II error rate. [Table: see text]
CA19-9 decrease at 8 weeks as a predictor of overall survival (OS) in a randomized phase III trial (MPACT) of weekly nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone in patients with metastatic pancreatic cancer (MPC).
Authors: Chiorean E. Gabriela , Von Hoff Daniel D. , Ervin Thomas J. , Arena Francis P. , Infante Jeffrey R. , Bathini Venu Gopal , Wood Tina Evans , Mainwaring Paul N. , Muldoon Robert T. , Clingan Philip R. , Kunzmann Volker , Ramanathan Ramesh K. , Tabernero Josep , Goldstein David , Ko Amy , Lu Brian 
Published: March 2020

4058^ Background: nab-P + G showed promising efficacy in a phase I/II study in MPC, and decreases in CA19-9 correlated with OS. In MPACT, patients (pts) who received nab-P + G vs G had improved median OS (8.5 vs 6.7 mo; HR 0.72; p = 0.000015), PFS (5.5 vs 3.7 mo; HR 0.69; p = 0.000024) and ORR (23% vs 7%; p = 1.1 × 10−10). Here we present a prespecified exploratory analysis of CA19-9 from the MPACT trial. Methods: 861 previously untreated pts with MPC were randomized 1:1 to receive nab-P 125 mg/m2 + G 1000 mg/m2 days 1, 8, and 15 every 4 weeks or G alone 1000 mg/m2 weekly for 7 weeks followed by a week of rest (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ≥ 2). CA19-9 was evaluated at baseline and then every 8 weeks. OS comparisons at different CA19-9 criteria were performed by stratified Cox proportional hazards model (P by stratified log-rank test using randomization criteria). Results: 750 pts had an evaluable CA19-9 at baseline. More pts in the nab-P + G arm vs the G arm demonstrated a best CA19-9 decrease from baseline of ≥ 20% and ≥ 90% (61% vs 44% and 31% vs 14%, respectively; Table). At the first postbaseline assessment (week 8), greater proportions of pts in the nab-P + G arm vs the G arm had CA19-9 decreases of ≥ 20% and ≥ 90% (Table). At that time point, for pts with a decrease of ≥ 20% in CA19-9, nab-P + G demonstrated a significantly longer OS vs G. The risk reduction for pts with a ≥ 90% decrease was greater than in pts with a ≥ 20% decrease. In pts with an 8-week CA19-9 decrease < 20%, median OS for nab-P + G vs G was 8.3 vs 8.0 mo (HR 0.92; p = 0.705). The relationship of CA19-9 kinetics with OS will also be examined. Conclusions: Higher proportions of pts in the nab-P + G arm had CA 19-9 responses of ≥ 20% and ≥ 90% vs the G arm. Pts who achieved a CA19-9 decrease at 8 weeks of ≥ 20% or ≥ 90% had significantly longer OS with nab-P + G than with G. Clinical trial information: NCT00844649. [Table: see text]
HPV status to predict outcome for anal cancer treated with radiochemotherapy.
Authors: Mai Sabine Kathrin , Reuschenbach Miriam , Ottstadt Martine , Welzel Grit , Trunk Marcus , Wentzensen Nicolas , Lohr Frank , von Knebel Doeberitz Magnus , Wenz Frederik K. 
Published: March 2020

4065 Background: Evaluation of the HPV infection- and transformation-status as a predictor of the response to definitive radio-chemotherapy for anal cancer. Methods: 80 patients (54 fm, 26 m) with histologically confirmed anal cancer and known HPV-Infection- (determined by PCR) and p16-expression-status (determined by immunohistochemistry) were analyzed. All pts. were treated with definitive radio-chemotherapy (RCT) with 5-FU/MMC, median age 60ys (35–86), median follow up 54mo (4–180). 41 pts. were HPV+ and p16+ (group 1), 10 pts. were HPV-/p16+ (group 2), 9 pts. were HPV+/p16- (group 3) and 17 pts. were HPV+/p16- (group 4). Endpoints were local control (LC) at 5ys and overall survival (OS) at 5ys. In addition to HPV/p16 status, the influence of T-stage and tumor localization (canal vs. margin) was analyzed. Results: More women than men were HPV+ (fm 77% vs. m 33%) while gender was evenly distributed among HPV-pts. (fm 48% vs. m 53%). Upon univariate analysis, gender, HPV+ and p16+ were significant predictors of both LC and OS (p<0.05) while T-Stage was predictive for LC (p<0.05). Upon multivariate analysis, gender and T-Stage significantly influenced LC (w85.2% vs. m54.9%, p=0.028; <T3 84.2% vs ≥ T3 48,1%, p=0,019). OS was significantly influenced by gender (w95% vs. m59.2%, p=0.005), while the influence of HPV/p16-status did not reach significance when all four groups were analyzed simultaneously in this moderately sized cohort. Upon direct univariate comparison of HPV+/p16+ und HPV-/p16-pts, both gender and combined HPV/p16-positivity had a significant influence on LC and OS. Upon multivariate analysis, combined HPV/p16-positivity resulted in better LC (HPV+/p16+: 85% vs. HPV-/p16-: 38.7%, p=0.003), while, as a consequence of moderate patient numbers, only gender significantly predicted OS (fm93.7% vs. m62.6%, p=0.015). Viral status, however, showed a trend for significance. Conclusions: The data from one of the largest monocentric series treated with a uniform treatment regimen suggest that HPV-status predicts response to RCT in pts. with anal cancer. Patients with tumors not associated with HPV whatsoever (HPV-/P16-) have both inferior LC and a clear trend for inferior OS and might require an intensified treatment regimen.