bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sidedness matters: Surrogate biomarkers prognosticate colorectal cancer upon anatomic location.
Authors: Ben-Aharon Irit , Goshen-Lago Tal , Geva Ravit , Beny Alexander , Dror Ygael , Steiner Mariana , Hubert Ayala , Idelevich Efraim , Purim Ofer , Mishaeli Moshe , Shulman Katerina , Man Sofia , Soussan-Gutman Lior , Liebermann Nicky , Brenner Baruch 
Published: March 2017

523 Background: Recent evidence indicate that the anatomic location of primary tumors across the colon correlate with survival in the metastatic setting, whereas left-sided tumors may exhibit superior survival compared with right-sided. The Oncotype DX, a 12-gene colon cancer assay, is a clinically validated predictor of recurrence risk in stage II colorectal cancer (CRC) patients. Previous studies had indicated that CDX2-negative colorectal tumors are often associated with several adverse prognostic variables. Recently, it has been shown that without adjuvant chemotherapy, CDX2-negative stage II CRC tumors were associated with a lower rate of disease-free survival than CDX2-positive stage II CRC tumors. We aimed to evaluate whether these validated two prognostic biomarkers may correlate with primary tumor location, and whether tumor location may reflect differential prognosis in stage II CRC. Methods: We retrospectively analyzed a cohort of patients with T3 mismatch repair proficient (MMR-P) stage II CRC for whom 12-gene assay was performed (between 1/2011-2/2016). Pathological report was reviewed for exact primary tumor location and CDX2 immunostaining. Recurrence score (RS) and CDX2 expression were correlated with primary tumor location. Results: The analysis included 1087 patients with MMR-P stage II CRC (median age 69 years (range 29-93)). Tumor distribution across the colon was as follows: 46% (n = 500) were right-sided (cecum, ascending colon, transverse colon) and 54% (n = 587) were left-sided (splenic flexure, descending colon, sigmoid colon and rectum). Recurrence score was higher in right-sided tumors compared with left-sided tumors (p = 0.01). The RS gradually decreased across the colon (cecum - highest score, sigmoid-lowest score, p = 0.04). Right-sided tumors exhibited more CDX2-negative tumors compared with left-sided tumors (p = 0.07). Conclusions: Our study indicate that right-sided colorectal tumors may display worse prognosis compared with left-sided tumors in MMR-P stage II CRC. Primary tumor location may serve as a prognostic factor that should be accounted for recurrence risk assessment and consideration of adjuvant treatment.
Impact of CEA alone or as part of a high intensity surveillance strategy in detecting curative colorectal cancer recurrence: A systematic review and meta-analysis.
Authors: Mercado Marck , Hart Rachel , Scheer Adena , Tricco Andrea , Hamid Jemila , Brezden-Masley Christine 
Published: March 2017

566 Background: Consensus is lacking regarding an effective surveillance strategy for the detection of colorectal cancer (CRC) recurrence at a curative stage. This study aims to evaluate the effect of carcinoembryonic antigen (CEA) measurement alone vs. CEA as part of an intensive surveillance strategy for the detection of curative CRC recurrence. Methods: A systematic review was performed using MEDLINE and EMBASE from January 2000 to April 2016 to identify randomized controlled trials (RCTs), cohort studies, quasi-experimental design studies, and case control studies including stage II/III CRC patients with curative resection and surveillance with repeated CEA measurements. Data screening, abstraction, and risk of bias assessment was independently performed by two reviewers. Risks of recurrence amenable to surgical resection, local and distant recurrence, disease-specific mortality and overall mortality were pooled using random effects meta-analysis. Results: Two RCTs and 9 cohort studies were included. A meta-analysis of 861 patients in RCTs demonstrated a non-significant reduction in the detection of curative recurrence using CEA measurement alone vs. intensive surveillance strategies with CEA (RR 0.76; 95% CI 0.41-1.41). There were no significant differences observed in the risk of locoregional or distant recurrence. Patients with CEA alone had a non-significant higher risk of disease specific and overall mortality ([RR 1.19; 95% CI 0.89-1.60], [RR 1.21; 95% CI 0.84-1.76], respectively). The heterogeneity of the cohort studies inhibited a quantitative meta-analysis. Among 2783 patients in 9 cohort studies using intensive surveillance strategies with CEA measurement, the rate of curative recurrence ranged from 21.3% to 56.8%. Conclusions: Limited data exists to guide the optimal surveillance strategy post-curative CRC resection. This study highlights the potential benefit of intensive surveillance strategies with CEA measurement as compared to CEA measurement alone in detecting curative CRC recurrence. However, further research to determine optimal CRC surveillance strategies is warranted.
Micrometastasis volume in stage II colorectal cancer: A prospective study by Clinical Study Group of Osaka University (CSGO).
Authors: Murata Kohei , Yamamoto Hirofumi , Fukunaga Mutsumi , Ohnishi Tadashi , Noura Shingo , Miyake Yasuhiro , Ikenaga Masakazu , Kato Takeshi , Takahashi Hidekazu , Haraguchi Naotsugu , Nishimura Junichi , Hata Taishi , Mizushima Tsunekazu , Ikeda Masataka , Ohue Masayuki , Hasegawa Junichi , Sekimoto Mitsugu , Nezu Riichiro , Doki Yuichiro , Mori Masaki ,   Clinical Study Group of Osaka University (CSGO), Colorectal Group
Published: March 2017

597 Background: We reported in a retrospective study that the presence of micrometastasis in lymph nodes (LNs), when assessed by CEA-specific RT-PCR, is a significant prognostic factor in stage II colorectal cancer (CRC). The aim of this study was to clarify the clinical value of micrometastasis in a prospective multicenter trial. Methods: From November 2001 to December 2005, a total of 419 CRC cases were preoperatively registered at a central data center. Of them, 315 node-negative stage II CRC were enrolled. After RNA quality check, 304 CRC cases were analyzed for CEA mRNA in LNs by both conventional RT-PCR (a band method) and quantitative RT-PCR. Long-term prognosis of the patients was determined by each method. Results: A positive band for CEA mRNA was detected in 73 (24.0%) of 304 patients. Post-operative adjuvant chemotherapy was applied in 31 CEA band-positive cases with an oral 5-FU derivative HCFU (1-hexylcarbamoyl-5-fluorouracil) for one year, while chemotherapy was not administered to CEA band-negative group. Multivariate Cox regression analyses revealed that a high micrometastasis volume (High-MMV, n = 95) was an independent poor prognostic factor for 5-year DFS ( P= 0.001) and 5-year OS ( P= 0.016). Conclusions: This prospective clinical trial demonstrates that micrometastasis volume is a useful marker in identifying patients who are at high or low risk for recurrence of stage II CRC.
Genetic variants of genes in CCL5/CCR5 pathway to predict regorafenib-induced hand-foot skin reaction in patients with refractory metastatic colorectal cancer: A report of ethnic difference.
Authors: Suenaga Mitsukuni , Schirripa Marta , Cao Shu , Zhang Wu , Yang Dongyun , Salvatore Lisa , Lonardi Sara , Moretto Roberto , Borelli Beatrice , Ning Yan , Okazaki Satoshi , Berger Martin D. , Miyamoto Yuji , Gopez Roel , Hanna Diana L. , Barzi Afsaneh , Wakatsuki Takeru , Yamaguchi Toshiharu , Loupakis Fotios , Lenz Heinz-Josef 
Published: March 2017

615 Background: CCL5/CCR5 pathway is involved in VEGF-A production and a recent study reported that serum CCL5 levels predict onset of hand-foot skin reaction (HFSR) due to regorafenib. We therefore tested whether genetic polymorphisms in the CCL5/CCR5 pathway predict onset of HFSR in patients with refractory metastatic colorectal cancer (mCRC) receiving regorafenib. Methods: Two independent cohorts treated with regorafenib were included in this study: a training cohort from Japan with 79 patients (median age 62 years, male 47%); and a testing cohort from Italy with 150 patients (median age 62 years, male 54%). Single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway ( CCL5, CCR5, PRCKD, CCL3, CCL4, KLF13, HIF1A) were selected for analyses using PCR-based direct sequencing. Adverse events were graded according to the CTCAE version 4.0. Comparisons of variants’ and adverse events’ distributions across two cohorts, and association between SNPs and adverse events were analyzed using contingency tables and Fisher’s exact test. Results: Grade 3 ≤ HFSR was more frequent in Japanese patients compared with Italian patients (32.9% vs. 16.0%, P= 0.004). The frequency of homozygous variant in CCL5 SNPs varied between Japanese and Italian patients (G/G variant in rs2280789, 21.5% vs. 1.3%, P< 0.001; T/T variant in rs3817655, 22.8% vs. 2.7%, P< 0.001). In the training cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3 ≤ HFSR compared to those with any A allele (53% vs. 27%, P= 0.078); and the T/T variant in rs3817655 was significantly associated with onset of grade 3 ≤ HFSR compare to any A allele (56% vs. 26%, P= 0.026). These findings were not confirmed in the testing cohort, and no significant differences for toxicities were observed in the other candidate SNPs. Conclusions: Germline CCL5 polymorphisms in the CCL5/CCR5 pathway may serve as predictor of onset of severe HFSR in refractory mCRC patients receiving regorafenib. The different percentage of homozygote of CCL5 SNPs confers the ethnic difference in developing severe HFSR between Italian and Japanese patients.
Poorly differentiated clusters as a prognostic marker at the invasive front of colon cancer.
Authors: Konishi Tsuyoshi , Shimada Yoshifumi , Lee Lik Hang , Cavalcanti Marcela Santos , Morris Martin , Hsu Meier , Gonen Mithat , Smith Jesse Joshua , Nash Garrett Michael , Temple Larissa K. F. , Guillem Jose G. , Paty Philip , Garcia-Aguilar Julio , Vakiani Efsevia , Shia Jinru , Weiser Martin R. 
Published: March 2017

621 Background: Histology at the invasive front of colon cancer can predict malignant potential. However, the optimal histological marker is yet to be established. This study compares the various invasive front histologic markers. Methods: A single-institution prospective database was queried for consecutive patients who underwent curative resection for Stage I-III colon adenocarcinoma from 2007-14. Histologic features were reviewed by a pathologist, including poorly differentiated clusters (PDC), tumor budding (BD), perineural invasion (PN), desmoplastic reaction (DR) and Crohn’s like reaction (CLR) at the invasive front, and WHO grade of the whole tumor. PDC was defined as cancer clusters of ≥ 5 cancer cells that lack a gland-like structure, and was graded into G1 ( < 5), G2 (5-9) and G3 ( ≥ 10) by the highest number of the clusters /HPF. Clinical outcome included recurrence free survival (RFS) and peak hazard function of recurrence and death identified using the kernel-smoothing method. Predictive accuracy was measured with concordance probability estimate (CPE) for proportional hazards regression. Inter-observer agreement was assessed by weighted kappa values on diagnoses rendered by 3 pathologists on 50 randomly selected cases. Results: The study cohort consisted of 851 patients with a median follow up of 36 months. PDC, BD, PN, DR and CLR at the invasive front were significantly associated with RFS. When analyzed by stage, PDC, BD and PN were associated with RFS both in Stage II and Stage III, while the others were prognostic only in Stage III. CPE was the highest in PDC (0.642), indicating the best predictive accuracy, while it was the lowest in WHO grade (0.526). Weighted kappa was also the highest for PDC, indicating the best inter-observer agreement (PDC: 0.824, WHO grade: 0.568). The smoothed graph of the hazard function showed that the risk of recurrence was not only the highest but peaked earlier for PDC G3 (between0 and 12 months) than PDC G2 (between12 and 24 months) and G1 (no evident peak). Conclusions: Of the commonly evaluated histologic markers at the invasive front, PDC grade is the most predictive and reproducible. Further confirmatory investigations are warranted to determine if PDC can replace WHO grade.
Screening of 129 FDA approved anti-cancer drugs in colorectal cancer cell lines resistant to oxaliplatin or irinotecan (SN38).
Authors: Stenvang Jan , Andreassen Christine Hjorth , Brünner Nils 
Published: March 2017

642 Background: In metastatic colorectal cancer (mCRC) only 3 cytotoxic drugs (oxaliplatin, irinotecan and fluorouracil (5-FU)) are approved and the first and second line response rates are about 50% and 10-15%, respectively. Thus, new treatment options are needed. Novel anti-cancer drug candidates are primarily tested in an environment of drug resistance and the majority of novel drug candidates fail during clinical development. Therefore, “repurposing” of drugs has emerged as a promising strategy to apply established drugs in novel indications. The aim of this project was to screen established anti-cancer drugs to identify candidates for testing in mCRC patients relapsing on standard therapy. Methods: We applied 3 parental (drug sensitive) CRC cell lines (HCT116, HT29 and LoVo) and for each cell line also an oxaliplatin and irinotecan (SN38) resistant cell line. We obtained 129 FDA approved anti-cancer drugs from the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI) ( https://dtp.cancer.gov/ ). The parental HT29 cell line and the drug resistant sublines HT29-SN38 and HT29-OXPT were exposed to 3 concentrations of each of the anti-cancer drugs. The effect on cell viability was analyzed by MTT assays. Nine of the drugs were analyzed for effect in the LoVo and HCT116 and the SN38- and oxaliplatin-resistant derived cell lines. Results: None of the drugs caused evident differential response between the resistant and sensitive cells or between the SN38 and oxaliplatin resistant cells. The screening confirmed the resistance as the cells displayed resistance to drugs in the same class as the one they were made resistant to. Of the drugs, 45 decreased cell viability in the HT29 parental and oxaliplatin- or SN-38 resistant cell lines. Nine drugs were tested in all nine CRC cell lines and eight decrease cell viability in the nine cell lines. These included drugs in different classes such as epigenetic drugs, antibiotics, mitotic inhibitors and targeted therapies. Conclusions: This study revealed several possible new “repurposing” drugs for CRC therapy, by showing that 45 FDA-approved anti-cancer drugs decrease cell viability in CRC cell lines with acquired drug resistance.
Randomized phase II study of panitumumab (Pmab) + irinotecan (CPT-11) versus cetuximab (Cmab) + CPT-11 in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) after fluoropyrimidine (FU), CPT-11, and oxaliplatin (L-OHP) failure: WJOG6510G.
Authors: Sugimoto Naotoshi , Sakai Daisuke , Tamura Takao , Hara Hiroki , Nishina Tomohiro , Esaki Taito , Okuda Hiroyuki , Denda Tadamichi , Tsuda Masahiro , Satoh Taroh , Makiyama Akitaka , Yamazaki Kentaro , Kuramochi Hidekazu , Hosokawa Ayumu , Tsuda Takashi , Taniguchi Hiroya , Kishimoto Junji , Boku Narikazu , Hyodo Ichinosuke , Muro Kei ,   West Japan Oncology Group (WJOG)
Published: March 2017

661 Background: Continuation of CPT-11 in combination with Cmab after CPT-11 failure has a survival benefit over Cmab alone. However, it is not clear whether CPT-11 with Pmab shows similar benefits. Methods: Pts with KRAS WT mCRC previously treated with FU-, L-OHP-, and CPT-11- based chemotherapies were randomized 1:1 to either Cmab + CPT-11(Cmab arm), or Pmab + CPT-11(Pmab arm). Primary objective was progression free survival (PFS), with an expected hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (80% CI) using cox proportional hazards model. Median PFS with both arms were assumed to be 6.0 months. Secondary objectives were overall survival (OS), response rate (RR), disease control rate (DCR), and safety. Results: From December 2011 to September 2014, 121 pts were enrolled from 31 sites in Japan. Because 1 patient declined before treatment, totally, 120 (Cmab arm: 59, Pmab arm 61) pts were eligible for efficacy analysis. Baseline characteristics were well balanced between the two arms. 116 pts (96.7 %) were previously treated with bevacizumab. Efficacy results are shown in the table. The common grade 3 or 4 adverse events in Cmab/Pmab arm were leukopenia 19.0/3.3%, neutropenia 27.6/8.3%, hypomagnesaemia 6.9/16.7%, and rash 5.2/13.3 %, respectively. Conclusions: Non-inferiority of Pmab to Cmab in combination with CPT-11 was suggested for patients with KRAS WT mCRC previously treated with FU-, L-OHP-, and CPT-11- based chemotherapies, associated with favorable PFS and OS. Clinical trial information: UMIN000006643. [Table: see text]
Total neoadjuvant therapy for locally advanced rectal cancer.
Authors: Cercek Andrea , Roxburgh Campbell SD , Strombom Paul , Smith Jesse Joshua , Temple Larissa K. F. , Nash Garrett Michael , Guillem Jose G. , Paty Philip , Garcia-Aguilar Julio , Yaeger Rona D. , Stadler Zsofia Kinga , Segal Neil Howard , Reidy Diane Lauren , Shia Jinru , Vakiani Efsevia , Wu Abraham Jing-Ching , Crane Christopher H , Gollub Marc Jeffrey , Saltz Leonard , Weiser Martin R. 
Published: March 2017

662 Background: Current therapy for locally advanced rectal cancer (LARC) consists of 6 months of perioperative therapy, either with pre-operative chemo-radiotherapy (CRT) and post operative adjuvant chemotherapy (PAC) or total neoadjuvant therapy (TNT) with induction chemotherapy (ICT) followed by CRT then surgery. The aim of our study was to report on the safety, efficacy and complete response rates comparing TNT to PAC in a larger series of LARC patients (pts) at Memorial Sloan Kettering Cancer Center (MSKCC). Methods: Pts treated at MSKCC (2009-15) were analyzed based on the intended treatment schedule (TNT or PAC). 730 LARC pts were treated with CRT, of these 320 received neoadjuvant CRT and 308 received TNT. Results: In the TNT group 205 pts (73%) underwent surgery within 26 weeks of completion of treatment, of which 38 (19%) had a pCR. Of the 78 pts who did not undergo surgery within 26 weeks, 68 (87%) had a complete clinical response (cCR). In the PAC group 293 pts (92%) underwent surgery within 26 weeks and 45 (15%) had a pCR. Of the 27 pts who did not undergo surgery within 26 weeks 22 (81%) had a cCR. The median follow up was 25 mo in the TNT group and 29 mo in the PAC group. There was no statistically significant difference in the distant metastasis free survival between the treatment regimens, despite a higher number of cT4 and cN + tumors in the TNT group. Fewer distant recurrences were seen in pts who had evidence of T downstaging (P < 0.001), N downstaging (P < 0.005), the presence of a cCR (P = 0.005) or a pCR (P < 0.005). Of the pts who received all treatment at MSKCC, comparison of dose of 5-FU and oxaliplatin between the preoperative (N = 249) and postoperative regimens (N = 101) was notable for a higher average dose received of both 5FU and oxaliplatin (p < 0.005 and p < 0.001) in the ICT group. Conclusions: These data add weight to the evidence already included in the NCCN guidelines that pre-operative chemotherapy as part of TNT is a viable treatment strategy with superior compliance and delivery of systemic therapy. Given the high complete response rate, TNT may be used as part of an organ preservation treatment strategy.
Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC).
Authors: Hochster Howard S. , Bendell Johanna C. , Cleary James M. , Foster Paul , Zhang Wei , He Xian , Hernandez Genevive , Iizuka Koho , Eckhardt S. Gail 
Published: March 2017

673 Background: Blockade of the PD-L1/PD-1 axis is a proven immunologic approach for treatment of many cancers; however, not all pts respond to monotherapy. Bev, an anti–VEGF-A antibody, has demonstrated clinical efficacy in mCRC and enhanced T-cell infiltration in tumors in preclinical studies. Thus, we postulated that combining atezo (anti-PD-L1) with bev would augment anti-tumor immune responses, resulting in improved and more durable clinical benefit. We report results from the first study of an anti-PD-L1 agent + VEGF-A blockade in MSI-high mCRC. Methods: A Ph Ib study (NCT01633970) investigated atezo + various chemotherapeutic/biologic regimens (eg, bev) in pts with advanced solid tumors, including mCRC. Pts received atezo 1200 mg q3w plus bev 15 mg/kg q3w (data cutoff, May 20, 2016). The primary objective was to evaluate the safety of atezo + bev. Secondary objectives included anti-tumor activity per RECIST v1.1. MSI status was tested locally. Results: Ten MSI-high mCRC pts were enrolled. Three pts had received 1 prior chemotherapy and 7 pts had received ≥ 2. Median age was 52.5 y. The minimum (range) of safety follow-up was 2.6 (2.6-20.3) mo. Median (range) treatment duration with atezo + bev was 10.1 (2-20) and 9.0 (2-19) mo, respectively. Efficacy results are shown below; the confirmed ORR per RECIST v1.1 was 30% (95% CI, 6.7%-65.3%). Median OS had not been reached with a median follow-up of 11.1 mo. Treatment-related all-grade AEs occurred in 80% of pts; 40% of pts had a related G3/4 AE. The most common related AE was proteinuria (40%; n = 3 G2 and n = 1 G3). No G5 events occurred. One AE led to discontinuation of atezo and 3 AEs led to discontinuation of bev. Biomarker data will be presented. Conclusions: Initial clinical activity was observed in heavily pretreated pts with MSI-high mCRC receiving atezo + bev; the disease control rate was 90%. This combination was well tolerated without unexpected toxicities. Further follow-up is ongoing. Clinical trial information: NCT01633970. [Table: see text]