bluuebunny/crossref_metadata_2025_split huggingface dataset:
The relationship between red cell distribution width (RDW), markers of systemic inflammation and survival in patients undergoing curative surgery for colorectal cancer.
Authors: Watt David G. , Park James Hugh , Horgan Paul G. , Mcmillan Donald C. 
Published: February 2017

589 Background: There is increasing evidence that red blood cell distribution width (RDW) has prognostic value in cardiovascular and autoimmune disease. It may reflect, in part, the systemic inflammatory response (SIR), a recently recognised prognostic factor in cancer. However, no studies have examined this hypothesis and prognostic value in cancer. The aim was to examine the relationship between pre-op RDW, markers of the SIR and survival in patients undergoing curative surgery for colorectal cancer (CRC). Methods: Data from consecutive patients (n=408) from a single institution (March 2008 to May 2013) were studied. The relationship between RDW (>14.5%) and markers of the SIR (modified Glasgow Prognostic Score (mGPS) and neutrophil-lymphocyte ratio (NLR)) and survival (cancer specific, CSS and overall, OS) were analysed using Spearman’s rank correlation and Cox regression analysis respectively. Results: The majority of patients were male (54%), had node negative disease (65%) and did not receive adjuvant therapy (70%). RDW was correlated with mGPS (rs =0.228, p <0.001) but not NLR (rs=0.069, p = 0.331). Median follow up was 31 months with 48 cancer and 29 non-cancer deaths. On univariate survival analysis pre-op mGPS and RDW but not NLR were associated with CSS (mGPS, HR 1.66, CI 1.22-2.27, p = 0.001; RDW, HR 2.24, CI 1.25-4.03, p = 0.007; NLR, HR 1.21, CI 0.57-2.56, p = 0.621) and OS (mGPS, HR 1.50, CI 1.16-1.93, p = 0.002; RDW, HR 2.78, CI 1.73-4.48, p <0.001; NLR, HR 0.96, CI 0.52-1.75, p = 0.890). On multivariate analysis, including TNM stage and other tumour factors, RDW was independently associated with OS (HR 2.19, CI 1.34-3.58, p = 0.002). Conclusions: RDW was significantly associated with markers of the SIR and was, independent of tumour factors, associated with survival in patients with CRC. These results point to the importance of the SIR on red blood cell formation and on outcome.
Genomic testing to enhance treatment choices and clinical trial accrual in metastatic colorectal cancer: Results of a prospective cohort study.
Authors: Sohal Davendra , Rini Brian I. , Pelley Robert James , Estfan Bassam N. , Shepard Dale Randall , Dreicer Robert , Bolwell Brian James , Khorana Alok A. 
Published: February 2017

593 Background: Tumor genome sequencing is being used widely in clinical settings but its value to individual patients has not been well-studied. A prospective cohort study of outpatient genomic testing to identify prevalence of actionable alterations and their impact on management decisions was conducted. Methods: Eligibility requirements included pathologic diagnosis of select solid tumor malignancies without a known curative option, age ≥18 years, and an ECOG PS of 0-2. Data for the colorectal cancer (CRC) subgroup are presented here. Tumor samples were sequenced for up to 315 candidate genes using FoundationOne (Cambridge, MA). Results were discussed at the Cleveland Clinic Genomics Tumor Board that made therapeutic recommendations to treating physicians. Results: From Aug 2013 to Aug 2014, samples from 45 patients with CRC were analyzed. Median age was 60 years; 23 (51%) were female; 38 (84%) were white. Median time from consent to result was 25 (range, 7-75) days. One (2%) sample had inadequate tissue. A median of 5 (range, 2-19) mutations were detected per sample; APC (89%), TP53 (73%) and KRAS (66%) were most common. A therapy targeting an actionable alteration was recommended in 22 (51%) patients; 88% of these recommendations were for clinical trials. To date, 6 (33%) of 18 patients who switched management after test results received genomics-driven therapies (Table). Previously unknown RAS (KRAS Q61H, NRAS) mutations were detected in an additional 3 patients, influencing EGFR antibody use decisions. The commonest reason for non-receipt of therapy based on the test result was non-availability of clinical trials. Conclusions: Routine tumor genome profiling in CRC patients is feasible and influenced treatment decisions in a third of patients. A genomics tumor board for the interpretation of rapidly evolving information, and improved access to clinical trials of targeted agents are critical to the success of precision oncology. [Table: see text]
Molecular selection for colorectal cancer (CRC) patients receiving cetuximab: Final results of a prospective study.
Authors: Scartozzi Mario , Giampieri Riccardo , Del Prete Michela , Mandolesi Alessandra , Faloppi Luca , Abouelkhair Khaled Mahmoud , Bianconi Maristella , Loretelli Cristian , Bittoni Alessandro , Ibrahim Ezzeldin M. , Scarpelli Marina , Montironi Rodolfo , Cascinu Stefano 
Published: February 2017

596 Background: Many markers for a “beyond-RAS” selection of CRC patients receiving cetuximab have been suggested, but none entered clinical practice mainly because prospective validation was lacking. Aim of our study was to evaluate if a molecular profile prospectively analysed was able to predict patients’ clinical outcome more accurately than RAS status alone. Methods: K-RAS (exons 2, 3, 4) wild-type CRC patients, candidates to second/third-line cetuximab with chemotherapy were prospectively allocated, after informed consent, into 2 groups on the basis of their molecular profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN >2.6, HER-3 Rajkumar score <8, IGF-1 immunostaining <2) and unfavourable (any of the previous markers altered or mutated). After the introduction of N-RAS status (exons 2, 3, 4) only RAS wild type patients were considered eligible for the study. Primary aim was response rate (RR). To detect a difference in terms of RR among patients with an unfavourable profile (estimated around 25%) and patients with a favourable profile (estimated around 60%) required sample size was 46 patients. Secondary endpoints were PFS and OS. Results: 46 patients were enrolled. 17 patients (37%) were allocated to the favourable and 29 patients (63%) to the unfavourable profile. Patients resulted comparable for clinical characteristics (age, sex, ECOG PS, previous treatments, number of metastatic sites). Patients with the unfavourable profile showed 2 BRAF mutations, 3 PIK3CA exon 20 mutations, 18 cases of EGFR GCN <2.6, 20 cases of HER-3 and 16 cases of IGF-1 overexpression respectively. RAS analysis of patients enrolled before the introduction of all RAS status (35 patients) revealed 1 N-RAS mutation (3%) in a patient already allocated to the unfavourable group for HER-3 overexpression. RR in the favourable and unfavourable group was 11/17 (65%) and 2/29 (7%) (p= 0.007) respectively. The favourable group also showed an improved median PFS (8 months vs. 3 months, p <0.0001) and OS (15 months vs. 6 months, p <0.0001). Conclusions: A beyond RAS selection may further improve clinical outcome. This approach may also allow an early switch to alternative treatment for unfavourable profile patients.
Comprehensive multiplatform biomarker analysis of 206 squamous cell anal cancers.
Authors: Boland Patrick McKay , Millis Sherri Z. , Arguello David , Gatalica Zoran , Reddy Sandeep K. , Meyer Joshua E. , Halfdanarson Thorvardur Ragnar 
Published: February 2017

603 Background: Anal squamous cell carcinoma (Anal SCC) is a rare, HPV-associated malignancy accounting for 2.4% of digestive system cancers. In most cases, these malignancies are detected in the early stages and successfully managed with chemoradiation therapy. Uncommonly, these cancers recur or present with metastases. In this setting, cisplatin and 5-fluorouracil represent the only endorsed regimen. Once beyond standard therapy, few therapeutic options exist for those patients with aggressive disease. The purpose of this study is to identify other novel, potential targets and therapeutic options for this disease, utilizing a multiplatform approach. Methods: 206 anal SCC specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH). 6 cases were documented as positive for HPV or HIV; status was not provided on the remaining 200. Results: Key results are shown in the table below, shown as percent change/total cases. Conclusions: Multiplatform tumor profiling identified a low incidence of gene mutations. Protein expression aberrations identified potential treatment options not routinely considered, such as topoisomerase inhibitors and taxanes. Mutations in PIK3CA, Akt1, and FBXW7 as well as PTEN loss indicate potential for targeting the PI3 kinase pathway. Additionally, immunomodulatory agents may be a therapeutic option, based on PD-1 expression levels. Targeting the ErbB-family receptors, namely with anti-EGFR agents or newer generation pan-HER - inhibitors, may represent another option, given EGFR and HER2 amplification as well as EGFR overexpression. It should be mentioned that differences in anal carcinomas whose etiology is of viral origin may present different treatment options based on the driver mutations. [Table: see text]
Comprehensive genomic profiling of cancer of the appendix to reveal new routes to targeted therapies.
Authors: Goldstein Daniel A. , Elvin Julia Andrea , Wang Kai , Shaib Walid Labib , Rossi Michael R. , Stephens Philip J. , Ross Jeffrey S. , El-Rayes Bassel F. 
Published: February 2017

608 Background: Cancers of the appendix are rare forms of malignancy that include two major mucin producing tumors, mucinous adenocarcinoma (MA) and goblet cell carcinoid (GCC). There is no clear standard of care for management of these malignancies. We queried whether comprehensive genomic profiling (CGP) of MA and GCC would reveal differences in the pattern of genomic alterations (GA) of these two subtypes of appendiceal cancer and serve as a guide for targeted therapies for this disease. Methods: DNA was extracted from 40 microns of FFPE sections from 20 clinically advanced appendiceal carcinomas (9 GCC and 11 MA). Comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation based libraries to a high mean coverage depth of >600X for 3,230 exons of 182 cancer-related genes, plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of GA including base substitutions, short insertions and deletions, copy number alterations and fusions/rearrangements. Clinically relevant GAs were defined as GAs linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Base substitutions in KRAS were seen in 73% of MA and 11% of GCCs. TP53 mutations were seen in 64% of MA and 22% of GCCs. MYC (36%), SMAD4 (27%), and APC (27%) mutations were found in MA but were absent in GCC. Other GA of low frequency, but clinically relevant in both subsets included ERBB2, GNAS, ARID1A, PIK3CA, NRAS, CTNNB1, BRCA1, BRAF, KDR, PTEN, MCL1, IDH1, FBXW7, and RICTOR. Conclusions: KRAS and TP53 mutations are common in appendiceal MA, but rare in appendiceal GCCs. This confirms the differences in biology and has implications regarding the use of targeted therapies such as anti-EGFR antibody treatments. The high frequency of clinically relevant genomic alterations uncovered in this study that can potentially serve as targets for therapies, either approved or in clinical trials, raises hope that CGP can lead to improvement in outcomes for patients with this aggressive form of malignancy.
Pre- and postoperative inflammatory response to predict survival in patients undergoing potentially curative resection for colorectal cancer.
Authors: Watt David G. , Ramanathan Michelle Leana , Park James Hugh , Horgan Paul G. , Mcmillan Donald C. 
Published: February 2017

609 Background: It is now recognized that the presence of a pre-op systemic inflammatory response (SIR) is associated with poor long term outcomes independent of tumour stage. However, although the post-op SIR has been associated with poorer short term outcomes, such as development of infective complications including anastomotic leak, and these complications have been implicated in poorer long term outcome, it is not clear whether the postoperative SIR is independently associated with long term outcome. Therefore, the aim of the present study was to determine whether post-op CRP concentrations were independently associated with long term outcome following potentially curative surgery for colorectal cancer. Methods: Data from consecutive patients (n=800) undergoing potentially curative resection of colorectal cancer from a single institution (March 1999 to May 2013) were studied. The relationship between post-op CRP on days 2, 3, and 4 (using standard thresholds for infective complications: day 2 CRP >190 mg/L, day 3 CRP >170 mg/L and day 4 CRP >145 mg/L) and cancer-specific survival (CSS) and overall survival (OS) was examined using Cox regression analysis. Results: The majority of patients were male (54%) and had node negative disease (61%). 26% received adjuvant therapy. Median follow up was 49 months with 169 cancer and 132 non-cancer deaths. On univariate survival analysis pre-op modified Glasgow Prognostic Score (mGPS) (HR 1.38, p=0.001), post-op day 2 CRP >190 mg/L (HR 1.47, p=0.012) and post-op day 3 CRP >170 mg/L (HR 1.46, p=0.018) were associated with CSS. On multivariate analysis both the mGPS (HR 1.20, p=0.080) and day 3 CRP >170 mg/L (HR 1.41, p=0.032) were independently associated with CSS and both the mGPS (HR 1.27, p=0.003) and day 3 CRP >170 mg/L (HR 1.32, p=0.027) were independently associated with OS. The post-op day 3 prognostic value was largely confined to the mGPS 0 group (HR 1.68, p=0.017 for CSS and HR 1.59, p=0.006 for OS). Conclusions: Both the pre- and post-op SIR were independently associated with long term survival following surgery for colorectal cancer. The SIR is a useful unifying concept, linking surgery and outcomes in patients with cancer.
The use of neoadjuvant chemotherapy plus molecular targeted-therapy in colorectal liver metastases: A systematic review and meta-analysis.
Authors: Sabanathan Dhanusha , Eslick Guy D , Shannon Jennifer Anne 
Published: February 2017

614 Background: Surgery remains the standard of care for patients with colorectal liver metastases (CLM) with a 5-year survival rate approaching 35%. Nordlinger et al. demonstrated perioperative chemotherapy confers a survival benefit in selected patients with CLM. The use of targeted molecular therapy in combination with neoadjuvant chemotherapy in CLM, however, remains controversial. We reviewed the literature of combination neoadjuvant chemotherapy and targeted molecular therapy on resectable and initially unresectable CLM. Methods: A literature search of databases (Medline and PubMed) was conducted to identify studies on neoadjuvant chemotherapy plus targeted molecular therapy in the management of resectable or initially unresectable CLM. We calculated pooled odds ratio (OR) and 95% confidence intervals (CI) using a random effects model for the relationship of combination neoadjuvant treatment on overall response rate and resectability rate. The analysis was stratified according to study design. Results: Ten studies were analysed, which included 828 patients that underwent systemic chemotherapy and molecular targeted therapy for CLM. Seven studies utilized cetuximab and three utilized bevacizumab. The use of combination neoadjuvant therapy was associated with an overall response rate of 73% (95% CI: 68-78%) and no heterogeneity was observed in the studies (I2=0.00, p=0.77). R0 resection rate after combination neoadjuvant therapy was 56% (95% CI: 25-82%), however, high levels of heterogeneity was observed (I2=94.02, p<0.001). Overall median PFS was 13.7 months. Conclusions: Current evidence suggests that neoadjuvant chemotherapy in combination with molecular targeted agents in the treatment of CLM confers high overall response rates. Combination treatment may also significantly increase resectability rates in initially unresectable CLM. However these results have not translated into significant survival benefits. The role of targeted molecular therapy, with a focus on the molecular mechanism of action in the adjuvant versus metastatic settings, requires further research.
Assessment of the tumor inflammatory cell infiltrate in preoperative colonoscopic biopsies of patients with primary operable colorectal cancer.
Authors: Park James Hugh , Mansouri David , Orange Clare , Horgan Paul G. , Mcmillan Donald C. , Roxburgh Campbell S.D. 
Published: February 2017

637 Background: The tumor inflammatory cell infiltrate is an important and potentially modifiable determinant of outcome in colorectal cancer (CRC). Although a weak inflammatory infiltrate is associated with poor prognosis independent of TNM stage, identifying such patients prior to surgery is problematic. The aim of the present study was to compare the tumor inflammatory cell infiltrate in matched preoperative colonoscopic tumor biopsies and resected tumor specimens from patients undergoing primary elective resection of CRC. Methods: Using an automated scoring system (nuclear h-score) CD3+ T-lymphocyte density was quantified in preoperative tumor biopsies of 76 patients undergoing elective resection of stage I-III CRC and compared to pathological characteristics and manual semi-quantitative (high vs. low) scoring of CD3+density within the invasive margin (IM) intraepithelial (IE) and cancer stroma (CS) compartments of resected tumor specimens. Results: The median h-score was 41 (range 14-85). Patients with a high tumor resection IM, IE and CS CD3+ density had a higher biopsy CD3+ density than patients with a low IM, IE and CS CD3+ density (median h-score: IM – 47 vs. 37, p=0.011; IE – 50 vs. 38, p=0.014, CS – 46 vs. 37, p=0.014). Patients with mismatch repair deficient tumors showed a trend towards a higher biopsy CD3+ density (57 vs. 40, p=0.169). No other pathological factors were associated with biopsy CD3+ density. When biopsy CD3+ density was categorised as high (h-score ≥41) or low (h-score<41), high biopsy CD3+ density was associated with CD3+ density within the IM, IE (both p≤0.05) and CS (p<0.01) and showed a trend towards greater 5-year survival (high – 80% (SE 7), low – 67% (SE 8), p=0.122). Conclusions: The results of the present study suggest that assessment of the inflammatory cell infiltrate in preoperative colonoscopic biopsies may provide reliable assessment of the inflammatory cell infiltrate within resected CRC tumors. Although requiring validation in an independent cohort, this has significant implications for the provision of neoadjuvant therapy, particularly targeting the inflammatory cell infiltrate, in patients with primary operable CRC.
Effects of IGF2BP2, KCNQ1, and GCKR polymorphisms on clinical outcome in metastatic gastric cancer treated with EOF regimen.
Authors: Liu Xin , Chen Zhiyu , Zhao Xiaoying , Huang Mingzhu , Wang Chenchen , Peng Wei , Yin Ji Liang , Li Jin , He Guang , Li Xin , Zhu Xiaodong 
Published: February 2017

64 Background: Genetic variants of T2D (type 2 diabetes mellitus)-related genes may increase the risk of gastric cancer (GC), but its role in predicting chemotherapy efficacy and GC outcome has not been investigated. The present study analyzed the polymorphisms of T2D-related genes and their impacts on the response to chemotherapy and survival of patients with metastatic gastric cancer (MGC). Methods: 108 consecutive patients with MGC treated with first-line chemotherapy of EOF regimen (epirubicin, oxaliplatin and 5Fu) were enrolled in the present retrospective study. The genomic DNA was extracted from blood samples, and eleven single nucleotide polymorphisms (SNPs) of five T2D-related genes (IGF2BP2, CDKAL1, FTO, KCNQ1 and GCKR) were determined using a polymerase chain reaction–restriction fragment length polymorphism assay. Results: Among the 11 SNPs, 3 SNPs (IGF2BP2 rs4402960, IGF2BP2 rs6769511 and KCNQ1 rs163182) were significantly associated with the disease control rate; 2 GCKR SNPs rs780093 and rs780094 were significantly associated with the PFS and OS. The genotype frequencies of rs4402960, rs6769511 and rs163182 showed significant differences between disease control (CR+PR+SD) and disease progressive (PD) patients (p = 0.031, p = 0.034 and P =0.020, respectively). After adjustment for clinical features in a multivariate Cox model, the GCKR SNPs rs780093 and rs780094 showed statistically significant impact on PFS (rs780093: HR,.477; 95% CI,.278-.820 and P =.007; rs780094: HR,.458; 95% CI,.266-.791 and P =.005) and OS (rs780093: HR,.471; 95% CI,.244-.910 and P =.025; rs780094: HR,.442; 95% CI,.228-.858 and P =.016). Conclusions: Our results firstly suggest that IGF2BP2 and KCNQ1 polymorphisms might be independent predictors of the response to chemotherapy and GCKR polymorphisms might be independent predictors of the PFS and OS in patients with MGC treated with first-line chemotherapy of EOF regimen in the Chinese Han population.
Safety, pharmacology, and preliminary clinical activity of MM-151: An oligocolnal anti-EGFR theraputic in patients with cetuximab-resistant CRC and other refractory solid tumors.
Authors: Lieu Christopher Hanyoung , Beeram Muralidhar , Harb Wael A. , Kearns Jeffrey D. , Sloss Callum Mortimer , Nering Rachel , Adjei Alex A. , Wolf Beni B. 
Published: February 2017

647 Background: MM-151 is an oligoclonal anti-EGFR antibody combination designed to provide enhanced targeting of the EGFR network. This work describes the first in human experience of MM-151 alone and in combination with irinotecan. Methods: A standard 3+3 design was used to assess safety and tolerability of MM-151 monotherapy (QW, Q2W, Q3W) and MM-151 (QW) in combination with irinotecan 180mg/m2 (Q2W). A monotherapy expansion cohort has begun in cetuximab-resistant CRC. Results: Results presented are based on preliminary data as of September 2, 2014, for MM-151 monotherapy (n=65; QW/Q2W) and MM-151 in combination with irinotecan (n=10). The most common tumor types were CRC (29 [39%]), NSCLC (9 [12%]), HNSCC (8 [11%]). The monotherapy RP2D has been defined as 10.5 mg/kg QW and dosing continues at 18 mg/kg Q2W. Most adverse events were CTCAE grades 1 and 2. The most common AEs were toxicities related to the EGFR-pathway, including rash (70%), hypomagnesemia (24%), fatigue, dry skin, and diarrhea (21%). IRR was initially observed at high frequencies; however, standardized pre-medication and a modified infusion schedule significantly decreased this frequency. At doses >9 mg/kg QW, trough total antibody levels at steady state were in the expected therapeutic range. Of the CRC patients enrolled, 3 experienced Partial Responses (PRs) per RECIST criteria and a total of 8 (31%) pts had SD for >4 months. Initial biomarker data suggests particular clinical activity in triple-wildtype, EGFR-ligand positive CRC patients. Combination therapy with irinotecan continues with MM-151 at 9 mg/kg QW and 3 PRs have been observed (CRC, HNSCC, melanoma). Initial safety data is consistent with known toxicities of MM-151 and irinotecan. Preliminary results from the monotherapy expansion cohort (10.5 mg/kg QW) in CTX-refractory CRC will also be presented. Conclusions: These results demonstrate that MM-151 monotherapy has an acceptable tolerability profile and objective clinical activity alone and in combination with irinotecan. Results also support further clinical evaluation in triple-wildtype, EGFR-ligand positive CRC and other EGFR dependent cancers. Clinical trial information: NCT01520389.