bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of biliary stenting with clinical outcome in patients with advanced pancreatic cancer treated with chemotherapy.
Authors: Faloppi Luca , Maccaroni Elena , Giampieri Riccardo , Bianconi Maristella , Bittoni Alessandro , Del Prete Michela , Antognoli Stefania , Scartozzi Mario , Cascinu Stefano
Published: February 2017

349

Background: The head of the pancreas is a common location for primary pancreatic tumour and therefore obstructive jaundice is a common complication deriving from this location. Although very important in the palliative treatment of this setting of patients, endoscopic procedures are an important source of complications, frequently influencing the prognosis. Aim of our analysis was to assess the clinical outcome of pancreatic cancer patients with biliary stent.

Methods: We retrospectively analyzed a population of metastatic or locally advanced pancreatic cancer patients receiving at our Institution a first line chemotherapy between 2002 and 2010.

Results: 163 patients were eligible for our analysis, 29 (18%) carried a biliary stent before first line treatment. A statistically significant difference in time to progression (TTP) was found in patients with or without biliary stent (respectively 2.77 months vs 4.27 months p=0,03). Clinical characteristics were homogeneous between the two groups (age, sex, performance status, stage, objective response rate, chemotherapy performed, toxicity profile). Overall survival analysis was worse in patients with biliary stent (5.93 months vs 8.33 months). In the group of patients with biliary stent toxicity was worse in patients receiving a combination chemoterapy (GEMOX).

Conclusions: In our population placement of biliary stent seems to have a negative prognostic role in advanced pancreatic cancer patients. Our data also show that in patients with biliary stent the toxicity profile of chemotherapy may influence treatment adherence and clinical outcome. These observations seem to suggest that patients with obstructive jaundice even when successfully treated with plastic or metal stent may still represent a group of patients with a worse clinical outcome, not suitable for an intensive first-line approach such as FOLFIRINOX.
Helicobacter pylori and the risk of Barrett's esophagus: A meta-analysis.
Authors: Salami Augustine , Njei Basile M. , Ditah Ivo C.
Published: February 2017

35

Background: Helicobacter pylori infection (HPI) is well known to play a role in the carcinogenesis of gastric cancer, and has been associated with MALTomas, pancreatic and colon cancer. Barrett’s esophagus (BE) is associated with a 30 fold increase risk of esophageal adenocarcinoma. However, the association of BE with HPI is unclear. The purpose of this study is to summarise all available evidence on the direction and magnitude of the association between HPI and BE.

Methods: Two reviewers independently conducted a systematic search on the Cochrane library, MEDLINE and Pub Med databases from 1980 to Jan 2011. Identified articles comparing HPI in BE with controls were manually reviewed for additional references. H.pylori infection had to be confirmed by culture/serology or histology. Adjusted risk estimates were extracted and summarized using fixed-effects model. Inter-extractor discrepancies were resolved by referring to the original article. Publication bias was assessed using the Begg and Egger tests. Analysis was done using STATA version 11.

Results: 21 studies (16 case control and 5 cohort studies) were eligible for analysis. These studies involved 12,458 patients. The overall pooled risk ratio for the association between HPI and BE was 0.75 (95% CI- 0.59-0.94). By study design a similar trend was observed only among the case control studies, 0.54 (95% CI 0.33-0.88). Another subgroup analysis excluding the study by Veith (“outlier”) did not change direction of association. There was no evidence of publication bias or heterogeneity among included studies.

Conclusions: This study suggests that HPI is not associated with an increase risk of BE, and may actually confer decrease. These findings are consistent with previously published studies. Further data, preferably from prospective studies is needed to better elucidate the association between HPI and BE for more accurate determination.
Enhanced antitumor effect via combination of triptolide with 5-fluorouracil in pancreatic cancer cell lines.
Authors: Wang Wei
Published: February 2017

352

Background: Pancreatic cancer is one of the most aggressive types of cancer, and lack of effective treatment results in a very low 6-month survival rate. This study aims to explore the enhancement of therapeutic effect on human pancreatic cancer cell lines (AsPC-1, MiaPaCa-2 and PANC-1) via combination of triptolide (TPL),derived from the herb Tripterygium wilfordii, and 5-fluorouracil (5-FU).

Methods: Cell proliferation was measured by MTT, apoptotic cells were assessed by flow cytometry and western blot for cleaved caspase-8, 9, 3 and PARP. To explore the role of nuclear factor kappaB (NF-kB) activity in pancreatic cancer cell lines, AsPC-1/IkBaM and PANC-1/IkBaM cells (NF-kB activity of AsPC-1 and PANC-1 cells was silenced by IkB-a mutation) were treated with TPL plus 5-FU. NF-kB activity was determined by electrophoretic mobility shift assay.

Results: TPL demonstrated toxicity on three pancreatic cancer cell lines with the IC50 of 25-40 nM. The combination of TPL (IC30 concentration) and 5-FU enhanced the cytotoxicity significantly compared to not only 5-FU alone but also Gemcitabine (the first line drug for advanced pancreatic cancer) alone. Combination index (CI) indicated the effect of TPL plus 5-FU was highly synergistic. Furthermore, pancreatic cancer cells treated with TPL plus 5-FU exhibited increased apoptosis, as evidenced by stronger Annexin V/ PI staining, higher levels of pro-apoptotic proteins including cleaved caspases and activated PARP compared to cells treated with TPL or 5-FU or Gemcitabine alone. In the mechanism study, AsPC-1/IkBaM and PANC-1/IkBaM cells showed more resistance to enhanced apoptosis induced by TPL plus 5-FU compared to wild-type cells. It indicated the enhanced effect of TPL was related with NF-kB activity.

Conclusions: 1) TPL has a potent therapeutic effect on pancreatic cancer cell lines; 2) the combination of TPL with 5-FU enhances the therapeutic effect which is more powerful than Gemcitabine in vitro, low concentration of TPL showed high synergistic effect with 5-FU; 3) the inhibitory effect of TPL plus 5-FU on pancreatic cancer is mediated by the induction of apoptosis and TPL enhanced the apoptosis via inhibition of NF-kB activity.
Rapamycin in patients with advanced hepatocellular carcinoma progressing on prior antiangiogenic therapy.
Authors: Bouattour Mohamed , Wassermann Johanna , Dreyer Chantal , Vilgrain Valérie , Paradis Valerie , Raymond Eric , Faivre Sandrine J.
Published: February 2017

356

Background: PI3K/Akt/mTOR is a critical survival pathway in hepatocellular carcinoma (HCC) often correlated with poor prognosis. Rapamycin (sirolimus) and its analogue everolimus, are specific mTOR inhibitors that showed promising antitumor activity in preclinical models and clinical cases of HCC Aims: To evaluate the safety and efficacy of rapamycin in patients (pts) with advanced HCC after failure or intolerance to prior antiangiogenic therapy

Methods: In this retrospective cohort, we analyzed consecutive patients with progressive HCC after 1 to 3 lines of treatment including at least sorafenib. All pts received oral rapamycin at 20 to 30 mg once a week. Adverse events (AEs) were assessed using NCI-CTCAE v3.0, and tumor response was evaluated according to RECIST criteria.

Results: Nine patients (F/M: 1/8) with compensated liver cirrhosis (Child A, n = 6; Child B7, n = 2) or no cirrhosis (n=1) and histologically proven HCC were included in this study. Overall, therapy with rapamycin was well tolerated. Most common toxicities were asthenia (grade 1-2: 5 pts) anaemia (all grade: 5 pts; grade 3: 2 pts ) and thrombocytopenia (grade 1-2: 2 pts). Liver function deterioration was observed in 2 pts with advanced cirrhosis (Child B7). Radiological evaluation was available in 6 pts. No objective tumor response was observed however stable disease ≥ 3 months was observed in 4 cases. Moreover, 2 pts showed stable disease at 6 months. Prolonged stabilization under rapamycin was observed in pts who were previously controlled at least for 6 months with sorafenib. Rapamycin was discontinued due to disease progression in 7/8 pts, toxicity in 1/8 pts. One pt shows ongoing long-lasting disease stabilization (8 + months).

Conclusions: Rapamycin displayed an acceptable safety profile and may achieved disease stabilization in patients with heavily pretreated advanced HCC.
Laboratory values and their relationship with short- and long-term outcome following transthoracic esophagectomy in patients with esophageal cancer.
Authors: Bosch Dirk , Nijsten Maarten , Plukker John Theodorus
Published: February 2017

37

Background: Surgical resection in esophageal cancer patients remains the mainstay of therapy, but carries a considerable risk of post-operative complications. Deranged laboratory data in the early post-operative period could provide guidance in decision making for further treatment strategy. Therefore we related standard laboratory measurements on 90-day and 1-year mortality after esophagectomy.

Methods: Esophagectomy with curative intent was performed in 226 consecutive patients with cancer of the esophagus between January 2000 and December 2009. Prognostic analyses for albumin, lactate dehydrogenase (LDH), ALAT, ASAT, gGT, urea, creatinine, C-reactive protein (CRP), white blood cell count (WBC) and platelet count were performed with a Mann-Whitney U-test (p<0.05) and ROC curve (area under the curve (AUC) >0.7) for postoperative day (POD) 1, 2, 3, 4, 5, 10 and 15. Extreme laboratory values (cutoff points) were calculated (5th or 95th percentile) in the case of significant outcomes.

Results: Laboratory measurements between survivors and patients deceased within 90-days (n=16) were significantly different in the case of albumin on POD 1, 3, 5, 10 and 15 (5th percentile between 10-13.02, AUC: 0.761), CRP on POD 3, 4, 5, 10 and 15 (95th percentile between 228.8-324.7, AUC: 0.861) and LDH in the late postoperative period on POD 4, 10 and 15 (95th percentile between 387.1-512.2, AUC: 0.864). The other laboratory values showed no systematic differences. For one-year mortality (N=36), only albumin and CRP showed to have significant differences for non-survivors: albumin on POD 10 and 15 (5th percentile between13.2-13.75, AUC: < 0.7) and CRP on POD 3, 4 and 10 (95th percentile between 220.9-319.5, AUC: < 0.7).

Conclusions: Albumin and CRP are the strongest prognostic measurements in predicting 90-day and one-year mortality after esophagectomy.
The effect of total lymph nodes removed and the lymph node ratio on overall survival in resected pancreatic cancer.
Authors: Wai Christina , Devarajan Karthik , Hoffman John Parker
Published: February 2017

371

Background: Previous studies evaluating lymph node status in pancreatic cancer have demonstrated that the ratio of positive nodes to total numbers resected is an important prognostic factor for survival. In our study we sought to see if the total number of nodes removed and lymph node ratio (LNR) would influence overall survival.

Methods: A retrospective chart review of 210 patients from July 1998 to July 2011 who underwent resection of pancreatic adenocarcinoma was done. Patients were evaluated for demographic information, neoadjuvant therapy status, surgical margins, pathological stage, total number of lymph nodes retrieved and the number of positive lymph nodes. The LNR was calculated by taking the number of positive lymph nodes to the total number of lymph nodes retrieved. The endpoint evaluated was overall survival (OS).

Results: Of the 210 patients, 107 (51%) were male and 103 (49%) were female. The median age was 68. A total of 110 patients had 1 or more positive nodes. The median number of nodes evaluated for all patients was 15 (range 2-51) and the median number of positive lymph nodes was 1. In patients with positive lymph nodes, the median LNR was 0.15 or 15%. For the 210 patients, in univariate analysis, there was a statistically significant association between LNR and overall survival. When the LNR reached >11.2%, patient survival was worse (p=0.018). The total number of nodes removed was not significantly associated with OS for those with positive or negative nodes. However, with multivariable CART analysis, taking into account T stage and surgical margins, LNR had a significant impact on overall survival only for patients who had a R0 resection and T0-T2 disease. If there LNR was > 0, survival was better (p=0.043).

Conclusions: In certain GI malignancies, complete evaluation of local lymph nodes is important and changes the survival of patients. In T0-T2 stage pancreatic cancer patients resected with negative margins, outcome is worse if there are positive nodes in these patients. Therefore based on our data, the LNR may be useful for determining the prognosis of early T stage cancer patients.
Gemcitabine chemotherapy until symptomatic disease progression in advanced pancreatic cancer: A retrospective analysis.
Authors: Ma Yuk Ting , Hussain Syed A. , Johnson Philip James , Palmer Daniel H.
Published: February 2017

372

Background: Gemcitabine was established as the standard first-line therapy for patients with advanced pancreatic cancer in 1997 after a randomized phase III study showed a statistically significant improvement in clinical benefit response and a modest improvement in median survival time, compared to bolus 5FU chemotherapy. The natural history of advanced pancreatic cancer is characterised by the rapid and relentless progression of tumor-related symptoms, thus we have analysed the outcome of our patients with advanced pancreatic cancer who have been treated with gemcitabine until symptomatic disease progression, without the use of regular radiological assessment.

Methods: A retrospective analysis was conducted on all patients with advanced pancreatic cancer who were treated with first-line gemcitabine chemotherapy between January 2008 – December 2009.

Results: A total of 50 patients were identified (21 with locally advanced disease, 29 with metastatic disease). The overall median survival was 10.4 months (11.3 months for patients with locally advanced disease, 7.2 months for patients with metastatic disease).

Conclusions: Our single centre experience suggests that clinical decision-making based on symptomatic disease progression in advanced pancreatic cancer, results in survival outcomes that are comparable to published trial data.
Treatment of cholangiocarcinoma: Retrospective analysis of a single-center experience.
Authors: Gaudig Ina , Schwoerer Harald , Ramadori Giuliano
Published: February 2017

376

Background: Cholangiocarcinomas (CC) are relatively rare neoplasms, but they show a rising incidence worldwide. CC orginate from epithelial cells lining the intra- and extrahepatic biliary tract including the gallbladder.

Methods: We retrospectively evaluated 105 patients with CC treated in our centre between 2000 and 2010. This collective consisted of 45 women (42,9 %) and 60 men (57,1 %). The median age was 64 years (33 – 87 years). 23 % of the patients were adipose, 22 % were diabetic and 23 % suffered from neoplasms different from CC. Symptoms of patients at initial diagnosis of CC were: 47 % weight loss, 39 % upper abdominal pain, 36 % jaundice. Imaging diagnostics consisted of ultrasonography, endosonography, computertomography and eRCP. Tumormarkers as CA19-9 and CEA were elevated in 76 % and 48 % of patients with CC, respectively. Localization of CC: 46 % hilus (Klatskintumor), 23 % distal choledochal truct, 20 % intrahepatic, 11 % gallbladder.

Results: For 57 patients (54,3 %) primary curative surgery of the CC was considered. 13/57 showed at laparoscopy inoperability. 3/48 patients treated with palliative chemotherapy showed regression of CC, allowing surgery. Thus, 47/105 (45 %) underwent curative surgery of CC. Surgical results: 39/47 (83 %) R0-resection, 7/47 (15 %) R1-resection, 1/47 Rx-resection. Median recidive – free survival for patients with R0-resection was 14,4 months, for R1-resection 1,8 months. The mean survival time of CC patients undergone curative surgery was 22 months, that of patients with palliative chemotherapy 5 months. 1 – 3 and 5 year survival for curatively resected CC patients were 78 %, 39 % and 21 %, respectively. Palliative chemotherapeutic treatment caused 26 %, 2,5 % and 0 %, respectively. In the whole collective, median survival under chemotherapy (mainly gemcitabine) was 9 months, with best supportive care 2,5 months.

Conclusions: Resection of CC is treatment of choice in localized neoplasms. In advanced CC chemotherapy mainly based on gemcitabine was superior to best supportive care.
Patient-reported outcomes (PROs) comparison of 5-FU and capecitabine (cape) with concurrent radiotherapy (RT) for neoadjuvant treatment of rectal cancer: Results of NSABP R-04.
Authors: Yothers Greg , Ganz Patricia A. , Lopa Samia H. , Ko Clifford Y. , Wickerham D. Lawrence , Wolmark Norman
Published: February 2017

391

Background: Preliminary results of NSABP R-04 indicated that 5-FU and cape have similar pathologic complete response (pCR) outcomes and that the addition of oxaliplatin did not improve pCR. We present PROs comparing 5-FU and cape treatments on quality of life (QoL), convenience of care (CoC), and symptoms.

Methods: Clinical stage II or III rectal cancer patients were randomized to receive 5-FU (225mg/m2 5 days/wk) or cape (825 mg/m2 5 days/wk) along with RT (4,500cGy in 25 fractions over 5 wk + boost of 540-1080cGy in 3-6 daily fractions). About half of these patients were also randomized to receive oxaliplatin (50 mg/m2 /wk). QoL was assessed by the functional assessment of cancer therapy–colorectal (FACT-C) trial outcome index (TOI) and symptoms were assessed by the fluoropyrimidine specific symptom checklist (SCL) collected at baseline, after chemoradiation before surgery (post therapy), and at 1 year. CoC was assessed by the modified ECOG CoC scale post therapy. Primary hypotheses were to compare 5-FU and cape on the endpoints of change in TOI and SCL baseline to post therapy and CoC at post therapy. P-values, means, and confidence intervals (CI) are adjusted for clinical stage, sex, and intent for sphincter-saving surgery.

Results: 625 5-FU and 650 cape patients completed baseline and post therapy data forms. Patient characteristics were similar by treatment. Change in TOI was similar by treatment post therapy (p = .21). Change in SCL post therapy was greater for cape patients than for 5-FU patients (mean difference 1.02, 95% CI 0-2.04, p = .05). CoC was superior with cape compared to 5-FU post therapy (mean difference 3.07, 95% CI 1.31-6.01, p = .002). The change from baseline to post therapy for all FACT-C subscales was similar by treatment. Change in TOI, SCL, and all FACT-C subscales were similar by treatment at the 1-year assessment.

Conclusions: PROs indicate that patients treated with 5-FU and cape have similar QoL. Cape provides significantly greater convenience of care but slightly increased symptoms compared to 5-FU. NCI PHS grants U10CA37377, U10CA69974, U10CA12027, and U10CA69651, support from sanofi-aventis and Hoffmann La-Roche.
Effect of Oncotype DX colon cancer test results on treatment recommendations in patients with stage II colon cancer: Preliminary results.
Authors: Cartwright Thomas H. , Chao Calvin , Lopatin Margarita , Bentley Tanya GK , Broder Michael Samuel , Chang Eunice
Published: February 2017

398

Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has been clinically validated as an independent predictor of individual recurrence risk in stage II colon cancer patients following surgery. As a result, physicians have been ordering the Oncotype DX assay for stage II colon cancer patients since January 2010, yet no data exist on the assay’s impact on adjuvant treatment planning in practice. We performed a survey to characterize the impact of the assay on adjuvant treatment recommendations in stage II colon cancer.

Methods: U.S. medical oncologists (N=277) who ordered Oncotype DX for ≥3 patients with stage II colon cancer were contacted and asked to complete a web-based survey regarding the single most recent stage II colon cancer patient for whom the assay was ordered. The survey was developed through cognitive interviews with four medical oncologists, and the protocol was institutional review board approved.

Results: As a planned preliminary analysis, we analyzed surveys from 92 eligible physicians. Physicians were more often in community (85%) than academic or other practices, and had a median of 14.5 years (range, 2-40) of practice experience. The median patient age was 62 years (range, 34–81). 84% of patients had T3 disease. Patients had ≤8, 9-11 and ≥12 nodes examined 2%, 14% and 84% of the time and 36% had comorbidities. Of the 60 patients tested for MMR/MSI, 9 (15%) were MMR-D or MSI-high and 37 (62%) were MMR-P or MSI-low; 14 (23%) unknown. Median RS was 20 (range, 1-77). Before obtaining the RS, chemotherapy was planned in 38 (41%) patients, observation in 35 (38%), and there was no recommendation in 19 (21%). For the 73 patients with pre-assay recommendations, recommended treatment changed after obtaining the RS for 23 patients (32%), including changes from chemotherapy to observation and vice-versa.

Conclusions: These preliminary findings indicate that for stage II colon cancer patients, treatment recommendations were changed by RS results approximately one-third of the time. Final results will be reported to include accrual through December 2011.
Factors influencing the CEA positivity in patients with colon cancer including race.
Authors: Thota Ramya , Abu Hazeem Mahmoud , Kallam Avyakta , Silberstein Peter T. , Subbiah Shanmuga
Published: February 2017

409

Background: Carcinoembryonic antigen (CEA) is a widely used tumor marker for surveillance in colon cancer. However, its accuracy is still debatable as its levels vary based on several factors. Hence we attempted to identify various clinicopathological factors influencing the CEA levels in patients with colon cancer.

Methods: Retrospective analysis of 8910 colon cancer patients from 1995 to 2008 was done via the Veteran's Affairs Central Cancer Registry. Age at diagnosis, race, gender, stage, grade, CEA levels, depth of tumor invasion, nodal status, spread of tumor, smoking history, and family history data was studied. The influence of individual factors on CEA positivity was studied by using chi-square test for categorical variables and the unpaired t-test for continuous variables.

Results: Out of 8919 patients identified, 3643 were CEA positive and 5276 were CEA negative. CEA levels varied significantly by race, stage, grade, nodal status, smoking history, and tumor size. African Americans have higher CEA levels (22% vs. 15.5%; P<0.0001). CEA positivity increased with increase in stage (stage 1- 20.3% vs. 54.3%; stage 2 – 15.8% vs.22.5%; stage 3 – 10% vs. 12%; stage 4 – 54% vs. 11.4%; P<0.0001). Increasing in T stage showed a proportionate increase in CEA positivity (T1 – 6.4% vs. 18%; T2 – 13.4% vs. 24%; T3 – 64.2% vs. 52%; T4 – 16% vs.7%; P<0.0001). Majority of CEA positive patients are node positive (N0 – 49.4% vs. 70.4%; N1- 28% vs. 20%; N2 – 22.3% vs. 10%; P<0.0001). CEA positive tumors had larger size of tumor compared to CEA negative tumors (54.2 mm vs. 45.6 mm; P<0.0001). CEA positive patients had more poorly differentiated tumors (17.5 % vs. 14.2 %; P<0.0001). Current smokers showed higher CEA levels (54% vs. 41.4%; P<0.0001). Age, gender, location of tumor and family history showed no significant difference among CEA positive and negative tumors.

Conclusions: Significant clinicopathological differences noted in CEA positive and negative tumors. African Americans had high-CEA levels and these patients had larger tumor diameter, advanced T stage, more positive nodes, advanced stage and in current smokers. Moreover, a significant difference in histologic tumor grade was observed in CEA positive and negative patient groups.
Impact of tumor aneuploidy in pseudomyxoma peritonei.
Authors: Shetty Shreya Jagadish , Natarajan Bala , Loggie Brian W.
Published: February 2017

414

Background: DNA aneuploidy is an indicator of poor prognosis in epithelial cancers arising from the colon, rectum, kidney and breast. To our knowledge, there is no data on the occurrence of DNA aneuploidy in Pseudomyxoma peritonei (PMP). The aim of this study is to investigate the frequency of DNA aneuploidy and analyze its relation to clinicopathological characteristics of the patients.

Methods: One hundred and twenty patients with PMP were analyzed. Flow cytometry was used on paraffin embedded tissue samples and multiple tissue blocks and serial sections were analyzed for each tumor. The results of DNA analysis were correlated to clinicopathologic data. Chi- square test was used to analyze categorical variables and t-test was used for continuous variables. Kaplan-Meier analysis was used to study impact of aneuploidy on survival.

Results: Of 120 patients analyzed, 41.7% (70/120) patients had disseminated peritoneal adenomucinosis (DPAM), 32.5% (39/120) patients had either peritoneal mucinous carcinomatosis- intermediate type (PMCAI) or peritoneal mucinous carcinomatosis (PMCA) and 25.8% (31/120) had signet cell carcinoma (SCC). DNA aneuploidy was detected in 13% (16/120) of the PMP patients. The incidence of aneuploidy was 2% (1/50) in patients with DPAM, 25.6% (10/39) in patients with PMCAI or PMCA and 16% (5/31) in patients with SCC (p=0.004). Nearly 56% (67/120) of patients were males and 44% (53/120) were females. Gender did not impact the incidence of aneuploidy. Mean age of patients with aneuploid tumors and diploid- near diploid tumors was 56.8 (±13.5) years and 49.6 (± 11.8) years respectively (p=0.027). Median survival in patients with aneuploidy was 54 months compared to 100 months in patients with diploid/ near-diploid status (p=0.021).

Conclusions: Older age and high-grade PMP are associated with higher rates of aneuploidy. Aneuploidy was associated with worse survival in patients with PMP.
Early detection of colorectal cancer: A proteomic screening study for plasma biomarkers.
Authors: Thorsen Stine Buch , Lundberg Martin , Assarsson Erika , Gee Nick , Knowles Mick , Christensen Ib Jarle , Nielsen Hans J. , Ekstrom Bjorn , Andersson Claes , Gustafsson Mats , Brünner Nils , Stenvang Jan , Fredriksson Simon
Published: February 2017

415

Background: Colorectal cancer (CRC) is the third most frequent cancer disease in the US. As the 5 year survival is closely associated to stage of disease at the time of diagnosis, patients with localized tumor limited to the colon or rectum have more than 90% chance of 5 year survival, while tumors spreading to regional lymph nodes or to distant organs, have a 5 year survival rate of 69% and 12%, respectively. Since late diagnosis is equal to a poor prognosis for the patients, biomarker guided early detection could make a difference for these patients. One strategy is blood based assays, where we hypothesis that a tumor and its microenvironment will lead to a deposition of specific proteins in the blood. However, due to the complexity of plasma, it is not only a biological but also a technical challenge to detect the proteins specific for CRC. Consequently, we combined the technical evaluation of multiplex proximity probing assays (PPA) with the search for relevant biomarkers for CRC. Each of the protein assays were based on thorough literature studies on the biology of CRC.

Methods: Proteins were measured using multiplex PPA. Each assay was constructed from commercially available antibodies conjugated to two DNA oligonucleotides. When the antibodies from one assay bind the target protein simultaneously, it enables the DNA oligonucleotides to be either enzymatic ligated or extended to a PCR amplicon. This PCR amplicon reflects the identity of the proteins and can be quantified by real-time PCR. We evaluated the assays and searched for potential early markers using a collection of case-control plasma samples from a larger endoscopy study. In total we measure the levels of 150 different proteins in 296 human plasma samples from 74 CRC patients, 74 healthy individuals, 74 adenoma patients, and 74 patients with non-cancer diseases.

Results: We have a successrate of 80%, the sensitivity is for most assays below 5 pM, and we find no cross-reactivity in chicken plasma for any of the assays. We previous reported that CEA, TIMP-1, CA242, and IL8 were upregulated in CRC plasma. These proteins were also identified in our extended study and the data will be presented.

Conclusions: We find potential early markers, which we will validate in new sample material.
Bevacizumab in combination with FOLFIRI in metastatic colorectal cancer: A retrospective study of adverse events and their correlation with clinical outcome.
Authors: Lenehan John Gordon , MacKenzie Mary J. , Vincent Mark David , Welch Stephen
Published: February 2017

426

Background: Bevacizumab is a monoclonal antibody against the VEGF ligand that disrupts vascularization of solid tumors and is part of first-line therapy for metastatic colorectal cancer (mCRC) in Ontario. The current study is intended to assess the rate of adverse events in general practice and to explore the relationship of adverse events to clinical outcomes in patients (pts) receiving bevacizumab.

Methods: Patients with mCRC from one Ontario cancer centre who received FOLFIRI with bevacizumab (BEV-FOLFIRI) as first-line treatment were retrospectively reviewed. Data collected included demographics, adverse events, radiographic response, and survival times.

Results: 57 patients were included in the study with a median age of 61 years, all with ECOG ≤1, and received a median of 5.5 cycles of BEV-FOLFIRI. Median follow-up was 5.8 months. Progression-free survival (PFS) was 9.8 months (95% CI 8.2-11.0) and overall survival (OS) was 13.1 months (95% CI 12.0-15.0). The most common bevacizumab-related adverse event was proteinuria with 11 (19.3%) pts developing any grade. Other adverse events included venous thromboembolism (VTE) in 9 (15.8%) pts, hypertension (NCI-CTCAE v3) in 7 (12.3%) pts, and GI perforation in 2 (3.5%) pts. 15 (26.3%) pts had a favorable radiographic response with 40% of pts who developed significant hypertension considered responders, compared with only 25% of those without hypertension. When using NCI-CTCAE v4.03, 19 (33.3%) pts developed grade ≥2 hypertension and had significantly longer PFS (13.5 vs 8.9 months, p=0.005) and OS (16.3 vs 11.0 months, p=0.015). Finally, developing a VTE was associated with increased PFS (14.8 vs 9.6 months, p=0.012), whereas proteinuria was associated with a significantly reduced OS (6.6 vs 14.0 months, p=0.001).

Conclusions: Use of NCI-CTCAE v4.03 criteria for hypertension identifies more patients with significant hypertension. Patients with hypertension according to these criteria appear to have a better treatment response, suggesting hypertension may be a useful biomarker. Conversely, new or worse proteinuria related to therapy was associated with a poor treatment response.
Curative versus palliative therapy for patients with colorectal cancer presenting to the emergency department.
Authors: Barnett Andy Stuart , Chen Yiyi , Chen Zunqiu , Daya Mohamud , Thomas Charles R. , Herzig Daniel
Published: February 2017

433

Background: Colorectal cancer (CRC) is the second leading cause of cancer death in the United States for men and women combined, and can present emergently with symptoms such as abdominal pain, bleeding, and obstruction. Emergency presentation as the first indication of colorectal cancer is generally thought to be associated with advanced disease and poor outcome. The specific aim of this analysis was to describe characteristics of patients (pts) presenting to the Emergency Department (ED) at their index diagnosis, and to determine whether emergency presentation precludes treatment with curative intent.

Methods: We performed an IRB-approved retrospective cohort analysis. We queried the prospectively maintained institutional tumor registry to identify pts diagnosed with CRC from 2008-2010. EMRs were reviewed to identify which pts presented to the ED with acute symptoms of CRC as the initial sign of their illness. The primary outcome variable was treatment plan (curative vs. palliative). Secondary outcome variables included demographics, tumor type and location. Descriptive statistics were conducted for major variables. Χ2 and Fisher’s exact tests were used to detect the association between categorical variables. Two-sample t-test was used to identify the association between continuous and categorical variables.

Results: Between Jan 1 2008 and Dec 31 2010, 376 pts were identified with CRC. 214(57%) were male and 162(43%) were female, with mean age 60.6; SD: 13.3. 33 (8.8%) pts initially presented to the ED, of which 5 (15.5%) received palliation. Of 339 pts who initially presented elsewhere, 69 (20.5%) received palliation. Acute ED presentation with CRC symptoms did not preclude treatment with curative intent (p = 0.47). Pts who presented emergently were more likely to be female (64% vs male 41%; p=0.01), and older (65 vs. 60; p=0.02). There was no statistically significant relationship between age, gender, tumor location or type and treatment approach.

Conclusions: Pts with CRC may present to the ED with acute symptoms, which ultimately leads to the diagnosis. Emergent presentation of CRC does not preclude patients from receiving therapy with curative intent.
Correlation of postoperative CEA trends with survival and patterns of recurrence after hepatectomy for colorectal cancer metastases.
Authors: Shirley Lawrence Andrew , McNally Megan , Huntington Justin , Jones Natalie , Malhotra Lavina , Bloomston Mark , Schmidt Carl Richard
Published: February 2017

436

Background: Pre-operative carcinoembryonic antigen (CEA) level is associated with outcome after hepatectomy for colorectal cancer metastases. In this study we sought to determine the relationship between post-operative CEA and outcome after hepatectomy.

Methods: A single institution retrospective review of hospital records from 1993 to 2010 found 339 patients who underwent a liver resection for CRC metastases. Of these, 140 had CEA levels drawn pre-operatively, post-operatively, and at least once more in follow-up. A ΔCEA level was calculated by subtracting the initial post-operative CEA level from the highest CEA level drawn in follow-up. Outcomes were compared between patients with ΔCEA less than 5 and greater than 5.

Results: Of 140 patients, 61 had ΔCEA less than 5 and 79 had ΔCEA greater than 5. Patients with low ΔCEA had improved median overall survival (OS) (70.2 months) compared to those with high ΔCEA (38.7 months, P=0.0001). However, there was no significant difference in progression-free survival (PFS) (13.0 months vs. 12.3 months, P=0.982). 100 patients had recurrence after hepatectomy, 69 with high ΔCEA and 31 with low ΔCEA. Patients with low ΔCEA were more likely to have a single site of recurrence (77.4% vs. 53.6%, P<0.0001).

Conclusions: Although a rising CEA after hepatectomy for CRC metastases is associated with worse overall survival, there is no difference in progression-free survival between patients with rising CEA and those with stable-to-decreasing CEA. Patients with stable-to-decreasing CEA have patterns of recurrence more amenable to locoregional therapy. Post-operative CEA values are an important component of oncologic surveillance, and patterns of rise and fall may indicate patterns of recurrence.
Relationship of colorectal cancer incidence rate and age of diagnosis in eastern Kentucky.
Authors: Koura Adnan , Elsoueidi Raymond , Dignan Mark
Published: February 2017

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Background: Colorectal cancer is the third most commonly diagnosed cancer in US among men and women. Approximately 150,000 new cases of colorectal cancer are diagnosed each year and about 50,000 of them die. Nationally, it is documented that the highest percent of patients with colorectal cancer are diagnosed between the ages of 75-84. However, rates are higher in Eastern Kentucky and a larger proportion of cases appear to be diagnosed at a younger age.

Methods: Data on newly diagnosed cases of colorectal cancer were collected from the Appalachian Regional Healthcare Cancer Registry, a registry serving seven county regions in Eastern Kentucky, and compared to data from Surveillance Epidemiology and End Results (SEER).

Results: The age-adjusted incidence rate for SEER, 2004-2008, was 47.2 per 100,000 compared to 59.22 per 100,000 for Eastern Kentucky. The median age of diagnosis with colorectal cancer was 65 years in Eastern Kentucky, compared to age 70 in SEER and the proportion of patients diagnosed between age 35 and 64 was higher in Eastern Kentucky than in SEER: 6.96% vs. 3.90% for 35-44 and 25.35% vs. 19.60% for 45-64 (p < 0.05. For residents age 75-85+, the proportion in Eastern Kentucky was lower than SEER: 75 - 84 yrs 19.50% vs. 26.20% and 85+ yrs 5.85% vs. 12.20% (p < 0.05).

Conclusions: The results of this study reflect an increase incidence of colorectal cancer among the younger population in Eastern Kentucky compared to US national data. Also there was a decrease incidence of newly diagnosed cases among the elderly population. This could be attributed to many domestic risk factors including genetic, diet, obesity, smoking or other factors. Further studies to stratify above possible factors are warranted.
Association of colorectal cancer susceptibility variants with tumor subtypes in three large prospective cohorts.
Authors: Garcia-Albeniz Xabier , Nan Hongmei , Fuchs Charles S. , Giovannucci Edward L. , Ma Jing , Ogino Shuji , Kraft Peter , Chan Andrew T.
Published: February 2017

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Background: Genome-wide association studies (GWAS) have identified 17 colorectal cancer (CRC) susceptibility variants. However, their association with specific tumor subtypes has not been fully defined.

Methods: We genotyped (TaqMan OpenArray) 17 variants (rs6691170, rs6687758, rs10936599, rs11169552, rs7136702, rs6983267, rs16892766, rs10795668, rs3802842, rs4444235, rs4779584, rs9929218, rs4939827, rs10411210, rs961253 , rs7014346 and rs2151512 as proxy of rs4925386) in three independent prospective, CRC case-control studies nested within the Nurses’ Health Study, Health Professionals Follow-up Study, and Physicians Health Study cohorts (1227 cases, 2201 age- and race-matched controls). Genotyping success: 98.1%. All variants fitted HWE (P>0.05). We assessed the association of these variants with risk of CRC using logistic regression (LR) adjusted for age, race and study under an additive model. We used multinomial LR models to examine the association of variants to CRC according to T, N and M-stage, grade of differentiation, tumor site, and age at diagnosis. Heterogeneity in the associations were evaluated by a case-case only LR model.

Results: We observed associations with CRC for rs6983267 (OR 0.86, 95% CI, 0.77-0.95; p=0.0028 -T allele-), rs3802842 (OR 1.18; 95% CI, 1.05-1.31; p=0.0036 -C allele-), rs7014346 (OR 1.15, 95% CI, 1.04-1.28, p=0.0082 -A allele-), rs11169552 (OR 0.88, 95% CI 0.78-0.99 -T allele-) and rs4939827 (OR 0.90, 95%CI 0.82-1.00, p=0.0508 – C allele-). The association between rs4939827 (MAF 48.34%) and risk of CRC was significantly different according to T stage (p for heterogeneity < 0.0001). rs4939827 was associated with a lower risk of CRC with tumor stage T1 or T2 (OR, 0.72; 95% CI, 0.63-0.84, p<.0001) but not of cancers with tumor stage T3 or T4 (OR, 1.04; 95% CI, 0.92-1.19). This result is consistent within each cohort.

Conclusions: Among 17 CRC susceptibility variants, we observed that the minor allele of rs4939827 was associated with a lower risk of colorectal cancers with lower T stage but not higher T stage. These results suggest that rs4939827, which codes for an intronic region of SMAD7, may be mechanistically related to tumor invasiveness.
Impact of microRNA miR-345 in blood on survival and response in 144 patients with metastatic colorectal cancer treated with third-line cetuximab and irinotecan.
Authors: Schou Jakob Vasehus , Andersen Klaus Kaae , Jensen Benny Vittrup , Nielsen Dorte Lisbet , Høgdall Estrid V. , Johansen Julia S.
Published: February 2017

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Background: MicroRNAs (miR) are small non-coding RNAs regulating gene expression at a posttranscriptional level. A prognostic potential of miRs in cancer tissue, whole blood or serum/plasma has been proposed in a small subset of cancers. MiR-345 has been reported up-regulated in cancer tissue and involved in malignant transformation in cancer cells. The aim of the study was to describe the ability of miR-345 to predict OS and response in patients with metastatic colorectal cancer (mCRC) treated with 3. line cetuximab and irinotecan independent of their KRAS status.

Methods: A total of 144 patients with mCRC were included in a prospective phase II study of 3. line treatment with cetuximab and irinotecan. All patients had progressed on 5-FU, oxaliplatin and irinotecan prior to the protocol. MiRs were isolated from whole blood collected in PAXgene Blood RNA tubes (Qiagen), and miRNA profiling was performed using TaqMan MicroRNA Array v2.0 (Applied Biosystems). Cox proportional hazard model was applied to study the correlation between baseline miR-345 expression and OS. Logistic regression analysis was applied to study response (PR (n=25) vs. PD (n=38)) and clinical benefit (PR+SD > 9 months (n=32)) vs. no clinical benefit (PD+SD < 4 months (n=87)). Hazard ratios (HR) and odds ratios are per inter quartile range.

Results: High expression of miR-345 was associated with poor treatment response with an odds ratio of 1.43 (p= 0.002) for progressive disease as best overall response and 2.04 (p=0.01) for no clinical benefit. High expression of miR-345 was significantly associated with short OS (HR =5.01, 95% Confidence Interval (CI): 2.39-10.50) when adjusted for KRAS status and performance status. This finding was confirmed in the subgroup of patients with KRAS wild type (n=87) (HR=3.02, 95% CI: 1.00-9.07).

Conclusions: High expression of miR-345 in whole blood is correlated to lack of response and short OS in mCRC patients treated with cetuximab and irinotecan. This suggests that miR-345 may be a new predictive and prognostic biomarker for treatment with cetuximab and irinotecan.
Use of KRAS codon 13 mutations to predict response to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma.
Authors: Duldulao Marjun Philip , Lee Wendy , Chen Zhenbin , Li Wenyan , Nelson Rebecca A. , Kim Joseph , Garcia-Aguilar Julio
Published: February 2017

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Background: The predictive role of KRAS mutation in therapeutic management of metastatic colorectal cancer has been much investigated. However, the association between KRAS mutations and rectal cancer response to neoadjuvant chemoradiation therapy (CRT) remains unclear. Our objectives were to determine the incidence of KRAS mutations in patients with rectal cancer and identify potential correlations with response to CRT.

Methods: Patients with Stage II-III rectal cancer (n=148) from a multicenter prospective clinical trial were assessed. DNA was extracted from pretreatment tumor biopsies; and genotyping of KRAS was completed by PCR and direct sequencing. All patients underwent pre-operative CRT followed by surgery; and treatment response was evaluated by a pathologist. Surgical specimens without evidence of residual disease were deemed to have a pathologic complete response (pCR).

Results: Overall, 60 of 148 (40.5%) patients had KRAS mutation. Breakdown of the different KRAS mutations revealed that 40 (66.7%) mutations occurred in codon 12, 12 (20.0%) in codon 13, 5 (8.3%) in codon 61, and 3 (5.0%) in other locations. When examining the relationship between KRAS and CRT response, we observed that detection of any KRAS mutation was associated with a decreased rate of pCR compared to wild-type KRAS (13.3% vs. 33.0%, respectively; p=0.007). More specifically, patients with KRAS codon 13 mutations did not respond to CRT compared to non-codon 13 mutations (p=0.037). In contrast, the detection of codon 12 or codon 61 mutations was not associated with response to CRT ( Table ).

Conclusions: Patients with KRAS mutation have lower response rates to CRT compared to patients with wild-type KRAS. However, our results indicate that this association does not apply to all KRAS mutations, rather to KRAS codon 13 mutation alone. Thus, these data are the first to show that patients with KRAS codon 13 mutations may not derive pCR from neoadjuvant CRT.

[Table: see text]
Gene markers of progression of Barrett’s metaplasia to carcinoma.
Authors: Kemmner Wolfgang
Published: February 2017

46

Background: The incidence of esophageal adenocarcinoma (EAC) has increased strongly during the past 30 years and 5-year survival remained poor at approximately 20%. Barrett’s esophagus (BE) metaplasia is considered to be the key precursor lesion of EAC. The aim of this study was to generate and validate biomarkers to stratify patients with BE in terms of their risk for developing cancer.

Methods: We studied gene expression profiling of normal esophageal squamous epithelium (NE), BE, intraepithelial neoplasia (IEN) and esophageal adenocarcinoma (EAC). Laser capture microdissection (LMD) technique was applied to procure cells from defined regions. Microarray results were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in a second and independent cohort. Furthermore, immunohistochemistry was performed on a third independent cohort.

Results: The expression profile of BE was compared to EAC and NE resulting in a short list of 16 genes which were differentially expressed among all 3 groups. Hierarchical clustering of all samples based on the expression of these 16 candidate marker genes allowed a clear discrimination of NE, BE and EAC. Validation of the microarray results in an independent patient cohort by qRT-PCR confirmed that the genes CTHRC1, INHBA, PROCR and ADH7 expression correlate with the histological progression to EAC. Accordingly, immunohistochemistry showed that the presence of CTHRC1 and INHBA was high only in EAC.

Conclusions: Here, we focus on neoplastic progression and describe a set of genes representing potential biomarkers to predict oesophageal Barrett’s adenocarcinoma at its early stage. These biomarkers can be determined by quantitative expression analysis, which will complement conventional semi-quantitative immunohistochemical analysis in the future. This work was feasible only through intensive cross-discipline collaboration between clinical researchers, pathologists, and basic molecular researchers and is thought to be the starting point for a long-term multicenter study on the clinical validation of the putative markers described here.