bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline blood neutrophil-lymphocyte ratio to predict treatment response in gastric cancer.
Authors: Diaz Romero M
Published: February 2017

52

Background: Several studies have shown that the neutrophil to lymphocyte ratio (NLR) in peripheral blood is a prognostic factor of various cancers. Some biomarkers have been associated with response and prognosis in gastric cancer (GC)identify depends specimens on biopsies and limits their use in clinical practice.Pheripheral blood tests at the time of diagnosis can reflect evolution within the tumor. We evaluated whether the NLR would predict response in patients with GC with treatment neoadyuvant or palliative. Methods: We retrospectively analyzed 190 patients with GC (2011-2013) in National Cancer Institute Mexico. 73 patients were treated with chemotherapy neoadjuvant, 30 with chemoradiotherapy neoadjuvant and 117 patients palliative chemotherapy. NLR were calculated from complete blood counts in laboratory test at diagnosis, cutt of values for the NLR were > 2.5 and < 2.5 using median values reported in previous studies. Results: Characteristics of Patients: male 107, female 83, mean age 54 (20-81).The median number of cycles of chemotherapy before of assess response by tomography was 4. The response rate was partial 20.5%, stable disease 36.3% and progression 43.2%.The median NLR :2.9 (1.1-15.2).84 patients were detected with NLR < 2.5 and 106 patients with NLR greater 2.5. Low NLR group patients had a better disease control (partial response and stable disease) in 68 % vs. 47.1% than high NLR( p = 0.028). Progression of disease was reported in 32 %( n=27) with low NLR and 52.9 %( n=56) of group high NLR (P=0.002). Patients with neoadjuvant treatment 50 underwent surgery 30 with NLR ratio lesser 2.5 and 20 high.There are more advanced disease in patients greater 2.5 NLR than < 2.5 80 vs 56 (p=0.036). Response pathological complete after surgery in 2 patients with a lower value and 1 patient with 2.5. Overall survival in low NLR is longer than in group patients NLR >2.5, 11.3 vs. 9.1 months (p=0.49). Conclusions: These data give evidence that baseline NLR could be predictive marker of response and prognosis in patients with GC undergoing treatment. Limitations to our analysis are a small number of patients, short follow-up and will need to be stratified according to patient characteristics and treatment.
The effect of MRI or PET fusion in radiotherapy treatment planning on the pathological complete response rate in rectal adenocarcinoma.
Authors: Rana Zaker Hamid , Hong Robert , Han Joon , Chen Isaac , Nurhussien Mohammed , Nasr Nadim Munir
Published: February 2017

523

Background: A pathological complete response rate of 10% to 30% has been noted to occur following preoperative chemoradiation with CT-based treatment planning in patients with rectal cancer. Fusion of the treatment planning CT with other imaging modalities like MRI or PET may help identify tumor location and improve tumor coverage. This retrospective study sought to evaluate the effect of adding MRI or PET imaging to CT-based treatment planning and its impact on pathological complete response rates in patients with rectal cancer. Methods: A retrospective analysis was performed on 39 patients, who received neoadjuvant chemoradiation for rectal adenocarcinoma from February 2009 to September 2013. Patients were divided into two groups. The first group was treated using CT-only based treatment 3D-Conformal or IMRT planning (n=9) and the second was treated using either PET or MRI fusion with the simulation CT scan (n=30). Patients were treated to a total of 5,040 cGy in 28 fractions. Pathological complete response rates (ypT0N0M0) were assessed using postoperative pathologic reports following resection. Results: 39 patients with a median age of 62 received preoperative chemoradiation with an interval to surgery ranging from 34-162 days and a median of 70 days. Patients treated with PET or MRI fusion treatment planning showed a complete pathological response rate at the primary site of 60% and a complete lymph node pathological response rate of 70.83% compared to 22.22% at the primary site and 66.66% at lymph node sites in patients with CT-only treatment planning. In patients treated using MRI or PET fusion, middle rectal cancer showed the best complete pathological response rate at 80%, followed by lower rectal cancer at 41.66%, and upper rectal cancer at 37.5%. Conclusions: Although the sample size was small, utilization of MRI or PET fusion resulted in a higher pathological complete response rate when compared to CT-only based treatment planning, especially in middle rectal cancers. Further studies are needed to accurately identify those patients with a complete pathologic response which may ultimately alter their treatment course.
Measuring compliance to capecitabine in colon cancer: A comparison of administrative data and medical records.
Authors: Amlani Adam , Kumar Aalok , Cheung Winson Y.
Published: February 2017

531

Background: Studies of administrative data indicate that compliance with oral anti-neoplastic agents, including capecitabine, is suboptimal. Using a population-based cohort of colon cancer, our aim was to evaluate the proportion of patients deemed non-compliant that actually had a reasonable indication for not adhering to their prescribed oral systemic therapy. Methods: Consecutive patients diagnosed with stage III colon cancer from 2008 to 2010, referred to any 1 of 5 regional cancer centers in British Columbia, Canada, and who initiated at least 1 cycle of oral adjuvant capecitabine within 12 weeks of curative resection were reviewed. Administrative data from the provincial oncology pharmacy database were analyzed to assess for non-compliance, which was defined as any prescription refill delays of >/=1 week from the end date of the preceding cycle. Electronic medical records were abstracted to examine the factors, if any, which contributed to non-compliance. We compared administrative vs. medical record data to determine the level of concordance and the appropriateness of non-compliance. Results: We included 752 patients: median age was 70 years (IQR 35-87), 56% were men, and 86% had ECOG 0/1. Administrative data showed that 413 patients were non-compliant: 230 (56%) and 183 (44%) had 1 and >/=2 late refills, respectively. In this group, a total of 2095 cycles of capecitabine were delivered among which 688 (33%) treatment delays occurred. No differences in baseline characteristics were observed between individuals who were compliant and those who were not (all p>0.05). Of the 688 prescription delays that were ascertained from administrative data, medical records demonstrated that 30 (4%) were misclassified. From the remainder, the majority were attributable to valid reasons, including: 339 (49%) toxicities necessitating time off therapy; 170 (25%) physician discretion; 40 (6%) travel requiring adjustment to treatment schedule; and 6 (1%) patient refusal. Only 103 (15%) cases were considered as true non-compliance. Conclusions: Using administrative data alone to measure oral drug compliance without corroborating with medical records may overestimate the degree of non-adherence.
Changes in the inflammatory microenvironment in premalignant colonic adenomatous polyps: Evidence for immunosurveillance?
Authors: Mansouri David , Park James Hugh , Orange Clare , Crighton Emilia M. , Horgan Paul G. , Mcmillan Donald C.
Published: February 2017

535

Background: The majority of colorectal cancers develop through the adenoma-carcinoma sequence. Recently, the host inflammatory response has become recognized as a key determinant of outcome. In particular, a pronounced peri-tumoral local inflammatory infiltrate identifies those with a better outcome. The present study aimed to characterize the local inflammatory response in pre-malignant colorectal adenomatous polyps. Methods: Patients with adenomatous polyps removed at colonoscopy as part of a population FOBt screening program were identified from a prospectively maintained database. All polyps were greater than 1cm. Whole slide immunohistochemistry was performed to assess intraepithelial T-cell (CD3+), cytotoxic T-cell (CD8+) and macrophage (CD68+) infiltrate. Inter-observer agreement for assessment of inflammatory cell infiltrate was good or better for CD3+, CD8+ and CD68+staining (Kappa 0.66, 0.66, 0.79 respectively). Results: A total of 207 adenomatous polyps, 107 high-grade (HG), 100 low-grade (LG), from 134 patients were included. Median age was 65 years, 33 (25%) were female and 15 (11%) were taking regular aspirin. Comparing HG and LG polyps, there were more older and female patients in the HG group (p<0.05). There was no difference in location (p=0.222), macroscopic morphology (p=0.445) or aspirin (p=0.377) use between groups. Microscopically, HG polyps were more likely to contain a villous component than LG polyps (65% vs 50%, p<0.05). Overall, high levels of CD3+, CD8+ and CD68+ infiltrate were observed in 68%, 25% and 72% of polyps respectively. Both CD3+ (74% vs 61%, p<0.05) and CD8+ (37% vs 13%, p<0.001) infiltrate was higher in HG polyps compared to LG polyps. There was no association with polyp grade and CD68+infiltrate (74% vs 70%, p=0.540). Conclusions: An increase in local T-lymphocytic infiltrate, but not macrophage infiltrate was identified with progression from low-grade to high-grade dysplasia. This would suggest a specific response to early disease progression confirming increased immunosurveillance. Therefore, such early stage disease may amenable to immunomodulatory treatment.
Utility of invasive staging procedures in patients (pts) with localized esophageal cancer (EC).
Authors: Giever Thomas A. , Ranade Arjun , Thomas James P. , Ritch Paul S. , Haasler George , Gasparri Mario , Johnstone David , Gore Elizabeth , Johnstone Candice Aitken , Dua Kulwinder , Khan Abdul , Oh Young , George Ben
Published: February 2017

54

Background: Definitive treatment for localized EC involves surgery alone or tri-modality therapy (TMT-chemotherapy, radiation, and surgery). TMT is administered to pts with clinical T2 or higher and lymph node (LN) positive ECs. Standard staging includes Computerized Tomography (CT)/Positron Emission Tomography (PET) imaging and Endoscopic Ultrasound (EUS). We investigated whether performing an EUS altered treatment decision in localized EC pts where a combination of imaging and clinical symptoms suggested the need for TMT. Methods: We performed a retrospective review to identify pts with localized EC who had their staging work up and treatment at the Medical College of Wisconsin between 2003 and 2012. Relevant clinical information was collected through review of the electronic medical record. Results: We identified 65 pts; median age at diagnosis was 62 years, 49 (75%) were male, and 56 (86%) were Caucasian. Histology was adenocarcinoma in 48 (74%) pts with 21 (44%) having background Barrett’s esophagus. Common presenting symptoms included dysphagia (83%), weight loss (73%), and odynophagia (25%). Staging evaluation included CT, PET, and EUS in 100%, 98%, and 89% of pts respectively. EUS staging results are in the table below. Dysphagia was reported by 67% of T1, 80% of T2, 84% of T3, 50% of T4, and 100% of Tx pts; 70% of pts with dysphagia were node positive by EUS. PET positive primary tumors/LNs were found in 89%/29% of all pts and 89%/33% of pts with dysphagia. Of the pts with PET positive LNs, 68% had node positive disease on EUS. Eighteen (28%) pts had both dysphagia and PET positive LNs, none with T1-2N0 staging by EUS; 36 pts had dysphagia and PET negative LNs, 7 (19%) with T1-2N0 staging by EUS. Among those 7 pts, 4 underwent surgery (1 pt-pT3N1aMx; 3pts-pT1bN0Mx). Conclusions: Localized EC pts with both dysphagia and PET positive LNs are candidates for TMT even in the absence of EUS staging. The role of EUS in this population may be limited to investigating adjacent organ invasion or confirmation of LN involvement. With improving PET capabilities, the role of EUS in this pt population needs to be studied prospectively. [Table: see text]
Real-world treatment patterns and the uptake of biologics in elderly medicare patients with metastatic colon cancer.
Authors: Mullins C. Daniel , Bikov Kaloyan A. , Seal Brian S. , Hung Anna , Hanna Nader
Published: February 2017

540

Background: Metastatic colon cancer (mCC) patients may receive multiple lines of treatment (Tx1, Tx2, etc.) consisting of one or more cytotoxic (CYT: 5FU/LV, oxaliplatin [OX], irinotecan [IRI]) and biologic (BIO: bevacizumab [BEV], cetuximab [CET], panitumumab [PAN]) drugs. The National Comprehensive Cancer Network (NCCN) provides evidence-based Tx recommendations for each line. The objective of this study was to examine real-world clinical practice patterns between 2002 and 2010. In particular, we compared the most common regimens across Tx lines and how Tx patterns changed over time. We also documented the uptake and use of new BIOs. Methods: We used population-based SEER-Medicare data to determine Tx1, Tx2, and Tx3 regimens of 4,616 mCC patients (the median age at diagnosis was 78) diagnosed in 2003-2009 and followed through 2010. We will use an algorithm previously developed by us to identify regimens. Results: The most common CYT backbone in Tx1 was OX (51% of patients) followed by 5FU/LV (30%). In comparison, IRI was a preferred choice in Tx2 (65%) and Tx3 (31%). In 2003, the most common Tx1 regimens were 5FU/LV- (56%) and IRI-based (35%). 5FU/LV and IRI use decreased to 22% and 9% respectively in 2009, while OX use increased from 7% in 2003 to 63% in 2009. In 2004, the FDA approved BEV for Tx1. BEV’s share increased from 9% in 2004 to 53% in 2005. BEV was used in 9% of Tx2 regimens in 2004 and 46% in 2005. CET was approved in 2004. CET was used in less than 5% of Tx1 regimens in any year up to 2010. CET use in Tx2 increased from 19% to 27% between 2005 and 2007, and declined to 23% in 2010. The FDA approved PAN in September 2006 for treatment after failure of CYT-based regimens, i.e., primarily in Tx3 and beyond. Only 350 (8%) of patients received Tx3, and of these 59 (17%) received PAN without a CYT backbone. One in three Tx3 regimens consisted of biologics only (54% CET, 43% PAN). Conclusions: This study used SEER-Medicare registry data to examine and document real-world clinical practice patterns in treatment of elderly mCC patients between 2003 and 2010. We observed that as new biologic agents were introduced to the market, variations in the combinations and the number of treatment have significantly and rapidly changed.
Does post-treatment surveillance imaging improve outcomes in patients with locally advanced rectal cancer?
Authors: Wahl Michael , Haas-Kogan Daphne A. , Anwar Moshiur Mekhail , Venook Alan P.
Published: February 2017

548

Background: The optimal post-treatment surveillance strategy for pts with rectal cancer is undefined. Trials examining surveillance with serial CEA measurements and/or imaging for colorectal cancer have yielded conflicting results, and no prospective trials have been done specific to rectal cancer pts. In the absence of data, reputable guidelines advocate serial chest, abdomen and pelvic imaging, CEA and colonoscopy after definitive treatment of rectal cancer. The rationale is to identify recurrence before it is symptomatic: if local, to avoid morbidity and if distant, because of the possibility of curative therapy. However, frequent imaging raises concerns regarding radiation exposure, consequences from false-positive findings, and cost. Methods: We performed a retrospective cohort study of patients with stage II/III rectal cancer treated definitively with neoadjuvant chemoradiation followed by surgical resection over the past 10 years. CEA, imaging studies and colonoscopies were recorded for all pts with follow-up of at least 6 months, along with clinical endpoints of locoregional recurrence, development of distant metastases, nature of subsequent therapies, and survival. Results: 55 pts with complete follow-up data were identified (median follow-up, 3.2 years). Surveillance was performed with imaging, CEA and colonoscopy in 89%, 72% and 49% of pts, respectively. 6 local recurrences were identified (11%): two were diagnosed via surveillance imaging, 3 underwent surgery with curative intent, with one patient with no evidence of disease at last follow-up. In contrast, 13 pts (24%) developed distant metastases (6 liver, 5 lung, 2 diffuse metastases), of which 9 were detected on surveillance imaging, 7 underwent therapy with curative intent, and 6 had no evidence of disease at last follow-up. There were 8 false-positive imaging results, 2 of which resulted in unnecessary surgery. Conclusions: Our findings suggest that post-treatment surveillance imaging is useful for detecting oligometastatic disease amenable to curative therapy, but may be less so for locoregional recurrences. Prospective data is needed to further assess the utility of post-treatment imaging in this population.
Identifying patients at high risk for colorectal cancer: A pilot study of colonoscopy in patients with rectal bleeding in a low-income country.
Authors: Alatise Olusegun Isaac , Bello Ibrahim S. , Komolafe Akinwunmi O. , Adekanle Olusegun , Kingham T. Peter
Published: February 2017

560

Background: Colorectal cancer (crc) is one of the most common cancers worldwide. There is an increasing incidence in low and middle income countries (LMICs). Patient outcomes are poor due to a lack of screening programs. Timely and efficient referral leading to earlier diagnosis of crc is imperative to improve survival. This study was initiated to determine the value of colonoscopy in patients with rectal bleeding for diagnosing crc in Nigeria. Methods: This is a prospective study of patients older than 45 years that present with rectal bleeding at 5 primary health care facilities in Ile-Ife, Nigeria. Patients were enrolled when they were referred for colonoscopy at the Endoscopy unit of Obafemi Awolowo University Teaching Hospitals. Data obtained included the socioeconomic, clinical, anthropometric, colonoscopy and histopathological parameters. Results: In this interim analysis, 68 patients were recruited into the study. The median age was 58.5 years (range 45-89 years). Median duration of rectal bleeding was 6 months (0.25 -360 months). Fifty six (82.4%) patients had seen a doctor regarding their rectal bleeding prior to the current episode for which they were referred. Changes in bowel habits and weight loss were found in 29 (42.6%) and 30 (44.1%) patients respectively. Crc was found in 14 (21%) patients and polyps in 11 (16.2%) patients. Hemorrhoids were found in 68% of patients. Of the 14 patients with crc, 10 had stage II or III disease (71.4%). Weight loss occurred in 14 (100%) of patients with crc, compared to 16 (30%) of patients without crc (p<0.0001). Conclusions: Given the high specificity of rectal bleeding in predicting the possibility of occurrence of colorectal cancer and polyps, this symptom may be used to select patients needing screening in resource poor settings. [Table: see text]
Preoperative serum microRNA-203 as a novel prognostic and metastasis-predictive biomarker in patients with colorectal cancer.
Authors: Toiyama Yuji , Hur Keun , Okugawa Yoshinaga , Boland C. Richard , Goel Ajay
Published: February 2017

564

Background: Distant metastasis is the major causes of death in colorectal cancer (CRC) patients. Epithelial-mesenchymal transition (EMT) is a key process that converts polarized immotile epithelial cells into motile, invasive mesenchymal cells, enabling cancer cells to gain stem cell characteristics and an aggressive malignant phenotype such as metastasis. Mir-203 has been shown to directly suppress EMT activators such as ZEB2 and SNAI1/2. However, in spite of the key functional role of miR-203 in cancer metastasis, no previous studies have investigated the clinical significance of miR-203 in patients with CRC. Methods: To examine whether CRCs secret miR-203 in vitro and vivo,we first determined extracellular miR-203 levels in CRC cell culture media. Then, we quantified miR-203 levels in serum from mice with or without metastasis. Next, we investigated miR-203 expression in 58 pairs of primary CRC (pCRC) and corresponding matching liver metastasis (LM), as well as 186 serum and 154 matched tissue specimens from CRC patients. Results: HT-29 cells released miR-203 into culture media, which was dependent on cell number and duration of culture. In addition, high serum miR-203 levels were observed in mice with liver metastasis compared to control animals (p=0.0181). Mir-203 expression was significantly upregulated in LM compared to matching pCRC tissues (p=0.0002). Serum miR-203 was significantly upregulated in a tumor stage-dependent manner (p=0.0070), and high miR-203 expression was associated with poor survival in CRC patients (p<0.0001). In contrast to serum, no significant association between miR-203 expression in CRC tissues and clinicopathological findings was recognized. High serum miR-203 expression was an independent risk factor for poor prognosis (HR=2.1) as well as metastasis to lymph nodes (OR=2.5), liver (OR=6.2), peritoneum (OR=7.2), and distant organs (OR=4.4), respectively. Conclusions: High levels of serum miR-203, which may be derived from several metastatic sites, are associated with poor survival and metastasis, suggesting it is a promising non-invasive prognostic and metastasis-predictive biomarker in patients with CRC.
Genomic analysis and personalized cancer therapy for metastatic colorectal cancer.
Authors: Dang Rajan Paul , Ang Celina , Holcombe Randall F. , Sung Max W. , Cagan Ross L. , Schadt Eric , Posner Marshall R. , Donovan Michael J. , Winder Lewis A. , Kahn Adnan , Camille Nadia , Davis Claire R. , Smibert Peter , Misiukiewicz Krzysztof
Published: February 2017

568

Background: Standard approaches in cancer research identify new therapies based on observed benefit to average populations but without emphasis on individual patients whose responses can vary considerably. Also, targeted therapies rarely account for the genomic complexity of patient tumors; the result is poor efficacy and rapid resistance. We would identify drugs or drug cocktails that (1) target the details of an individual’s tumor and (2) account for its complexity. Models using the fruit fly Drosophila represent a potential new paradigm in cancer therapy. We have developed fly models that can include up to 10 of a patient’s tumor’s driver mutations; the result is an inexpensive drug-screening platform to identify drug cocktails through empirical screening. Methods: Patients with metastatic CRC who have progressed or become intolerant to fluoropyrimidines, oxaliplatin, irinotecan, avastin, and (if KRAS wild-type) EGFR inhibitor therapy. Mutations identified by deep DNA and RNA sequencing of individual tumors are screened for tumor drivers, which are then incorporated into the “personal” Drosophila model and tested against a library of FDA approved drugs. Fly mortality is used as a surrogate for toxicity; improvements in tumor mutation-linked eye and/or wing abnormalities serve to quantify efficacy. This allows rapid and parallel screening of up to 800 drugs and subsequent drug combinations. The most efficacious and least toxic combinations are presented to a multidisciplinary tumor board of experts, who will then select the best therapeutic option for the patient. Results: To demonstrate that the personalized Drosophila model approach is superior to the current standard, regorafenib, which performed best in CRC with a 10% response rate (RR) against placebo in a phase III trial. Using the 10% RR as a benchmark, we will apply a sequential Bayesian method for 50 MTC patients enrolled to receive personalized treatment to demonstrate that this approach has greater efficacy, or at minimum, substantially similar efficacy with reduced toxicity. Conclusions: To demonstrate that personalized cancer therapy is superior to the current standard and is an effective therapy worth exploring for other cancers too.
Genomic alterations to predict response to irinotecan-based chemotherapy in metastatic colorectal cancer.
Authors: De La Fouchardiere Christelle , Jiang Xiaojun , Pissaloux Daniel , Seigne Christelle , Wang Qing , Desseigne Françoise , Fondrevelle Marie-Eve , Cassier Philippe Alexandre , Attignon Valéry , Combaret Valérie , Pérol David , Tredan Olivier , Blay Jean-Yves
Published: February 2017

586

Background: No evidence exists concerning the superiority of oxaliplatin versus irinotecan-based chemotherapy for metastatic colorectal cancer. The choice is currently made by the clinicians according to awaited toxicity and association with targeted therapy. The correlation between response to chemotherapy (oxaliplatin and irinotecan containing regimens) and genomic alterations was investigated in metastatic colorectal cancer patients included in the ProfiLER protocol (NCT 02029001). Methods: From 03/2013 to 03/2014, 62 patients with metastatic colorectal cancer were included in the ProfiLER trial. Tumor samples were analyzed for mutations/insertions/deletions and copy number variations using target high-throughput sequencing (NGS) and comparative genomic hybridization array (CGH). Clinical data were collected retrospectively. We defined irinotecan and/or oxaliplatin responders as patients having CR, PR, SD as best response and non-responders as those having PD as best response. Results: 50/62 tumor samples fulfilled DNA quality requirements. CGH was feasible in 40 patients (64.5%). Among these 40 patients, 36 received oxaliplatin and irinotecan. None of the genomic alterations correlated to response to oxaliplatin. Conversely, analysis of the CGH and NGS data revealed different genomic alterations of tumors in patients receiving Irinotecan, allowing the separation between Irinotecan responders (IriR, n=27) and non-responders (IriNR, n=9) (Table). Conclusions: Specific genomic alterations of CRC cells seem to be associated with responses to systemic combination Irinotecan based-chemotherapy, including high GI, specific chromosomal gains, and tyrosine kinases mutations. A prospective validation of the CGH profile is planned and definitive results will be presented at the meeting. Clinical trial information: NCT 02029001. [Table: see text]
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.