bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of pre-diagnosis statin use on survival among patients with pancreatic cancer.
Authors: Huang Brian Z , Chang Jonathan I , Wu Bechien U
Published: February 2017

427

Background: Recent studies have suggested associations between statin use and enhanced survival among patients with pancreatic ductal adenocarcinoma (PDAC). We aimed to explore the impact of pre-diagnosis statin treatment on survival across different agents and exposure levels. Methods: We conducted a retrospective cohort study on 2,142 pancreatic cancer patients diagnosed from 2006-2014 in an integrated healthcare system. Patients were identified from an internal cancer registry and followed until censored at death, date of last contact, or end of study. We used electronic pharmacy records to abstract information on the type, length and dosage of all statin exposures in the year prior to diagnosis. The overall influence of statins as well as the individual effects of simvastatin, lovastatin, atorvastatin, pravastatin and rosuvastatin were assessed using Cox proportional hazards regression. All analyses were adjusted for age, race, stage, receipt of surgery, receipt of chemotherapy and Charlson comorbidity index. We further adjusted for cholesterol control to determine whether statins acted through a lipid-mediated pathway. Results: Overall statin use was associated with a 13% decrease in the risk of mortality (HR 0.87, CI 0.79-0.97). Specifically, those who had used statins for 9-12 months (HR 0.85, CI 0.75-0.95), received higher doses (40+ mg/day) (HR 0.86, CI 0.76-0.98) or were active users at diagnosis (HR 0.86, CI 0.78-0.96) all had better survival compared to non-statin users. When assessing the individual statins, we found similar improvements in survival only among simvastatin users. Further stratified analyses revealed that simvastatin decreased the risk of death by 26% in stage IV patients (HR 0.74, CI 0.64-0.85), but had no effect for stage I-III patients (pinteraction= 0.03). Cholesterol control did not impact any of the associations between statin use and survival. Conclusions: We found that pre-diagnosis statin use, specifically simvastatin, was associated with improved survival in pancreatic cancer patients.
The role of mTOR inhibitors in targeting a putative cancer stem cell-like population in esophageal cancer.
Authors: Wang Da , Chiu Roland , Plukker John Theodorus , Coppes Robert P.
Published: February 2017

43

Background: Despite modern advances in the treatment of esophageal cancer (EC), using neoadjuvant chemoradiotherapy (CRT) and esophagectomy, most patients face poor outcome. Growing evidence indicates that cancer stem cells (CSCs) might contribute to the poor prospects. CSCs are usually resistant to CRT and ultimately can generate a new tumor. The mammalian target of rapamycin (mTOR) pathway is associated with cancer stemness. However, its role in EC CSC-like populations needs to be elucidated. Here, we investigate the role of mTOR pathway on the stemness of a putative CSC-like population. Methods: Previously, we identified a putative CSC-like population (CD44+/CD24-) in EC cell lines and in tumor biopsy from EC patients. qPCR was used to measure the expression of mTOR in CD44+/CD24- CSC-like population of OE21 squamous cell carcinoma and OE33 adenocarcinoma cell lines compared to controls, that consisted of solid tumors generated from the same cell lines obtained from xenografts. mTOR inhibitors rapamycin and torin-1 were used to see their effect on CD44+/CD24- expression and sphere formation. Results: mTOR expression was 2-fold up-regulated in the OE33 CD44+/CD24- CSC-like population compared to control. Furthermore, in OE21 this up-regulation was 1.9-fold. Surprisingly, inhibiting the mTOR pathway with rapamycin enhanced OE33 CD44+/CD24- expression compared to its control (p = 0.01). In pilot experiments this effect was dose dependent and cells treated with rapamycin formed more spheres than control. Rapamycin did not alter the expression of CD44+/CD24- in OE21. Inhibiting the mTOR pathway with Torin-1 enhanced OE21 CD44+/CD24- expression by 1.2-fold compared to control (N = 2). In another pilot experiment Torin-1 treated cells were able to form more spheres compared to control. Torin-1 did not have an effect on the expression of CD44+/CD24- in OE33. Conclusions: These findings indicate that inhibiting the mTOR pathway may enhance CSC-like properties in EC. Additional research needs to be done to further support this hypothesis and elucidate the mechanism in this process. Furthermore, the effect of mTOR pathway inducers in EC needs to be explored.
Comparative effectiveness and resource utilization of nab-paclitaxel plus gemcitabine (nab-P+G) versus FOLFIRINOX (FFX) in first-line treatment of advanced pancreatic adenocarcinoma (PDAC) in a U.S. community oncology setting.
Authors: Braiteh Fadi S. , Patel Manish , Parisi Monika , Ni Quanhong , Park Si yeon , Faria Claudio
Published: February 2017

433

Background: Both nab-P+G and FFX demonstrated superior overall survival (OS) over gemcitabine monotherapy for the treatment of PDAC; but there is no real-world effectiveness and utilization study of nab-P+G vs. FFX. The objective of this study is to compare real-world treatment patterns of patients receiving nab-P+G vs. FFX as first-line treatment for advanced PDAC. Methods: A retrospective cohort study was performed using fully de-identified data from a nationally representative electronic medical record platform of 1,300 community oncology physicians. Patients diagnosed with PDAC between September 2013 and October 2014 who received either nab-P+G or FFX as 1st line therapy were included in the analysis. We calculated median time to treatment discontinuation (TTD) and database persistence (DP), a proxy for OS, using the Kaplan Meier method, and assessed supportive care usage with Poisson regression. Results: 202 (out of 851) patients met eligibility criteria (nab-P+G, n = 122; FFX, n = 80). Patients on nab-P+G were older than patients on FFX (mean age 67.0 v 61.4; p < 0.01), but other baseline characteristics were comparable. TTD (3.4 v 3.8 mos) and DP (8.6 v 8.6 mos) were not statistically different for nab-P+G and FFX, respectively. The rate of AE-related discontinuation was similar in patients on nab-P+G and FFX (18% v 21%); however patients on nab-P+G utilized less doses of granulocyte-colony stimulating factor (GCSF) agents (2.0 v 4.4; p < 0.01), but needed more doses of erythropoietin-stimulating agents (ESA) (0.9 v 0.1; p < 0.01) and steroids (7.9 v 5.8; p < 0.01) per 100 days. Conclusions: TTD and DP for patients with advanced PDAC did not differ significantly between nab-P+G and FFX, although supportive care medications differed. Patients treated with nab-P+G required fewer doses of GCSF and more doses of ESA and steroids, though AEs leading to discontinuation was not statistically different. Management of chemotherapy related toxicities may incur substantial burden on the U.S. healthcare system, especially if an alternative therapy exists with similar clinical outcomes.
Pilot trial of CRLX101 in patients (pts) with advanced, chemotherapy-refractory gastroesophageal cancer (GEC).
Authors: Chao Joseph , Lin James , Frankel Paul Henry , Clark Andrew J. , Wiley Devin T. , Garmey Edward Graeme , Fakih Marwan , Lim Dean , Chung Vincent M. , Luevanos Eloise , Eliasof Scott , Davis Mark E. , Yen Yun
Published: February 2017

44

Background: Camptothecin (CPT) derivatives such as irinotecan have activity in 2nd-line therapy in advanced GEC with reported response rates of 0-15%. CRLX101 is an investigational nanoparticle-drug conjugate (NDC) with a CPT payload. Preclinical evidence indicates preferential uptake in tumors, and animal GEC xenograft models demonstrate superiority of CRLX101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) to assess preferential uptake of CRLX101 in tumor vs. adjacent normal tissue in endoscopically accessible tumors in patients with chemotherapy-refractory GEC. Data demonstrating preferential tumor uptake of CRLX101 has been presented separately and here we report on the clinical outcomes of patients enrolled. Methods: All pts initiated CRLX101 dosed intravenously at RP2D (15 mg/m2) on days 1 and 15 of a 28-day cycle until disease progression or intolerant toxicity. While detection of preferential CRLX101 tumor uptake was the primary endpoint, with 10 pts enrolled a secondary analysis could be performed with the study having 90% power to detect ≥ 1 responder if the true response rate is ≥ 21%. Responses were assessed using RECIST 1.1. Results: Between Dec. 2012 and Dec. 2014, 10 patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) GEC and adenocarcinoma histology were enrolled and evaluable for response and toxicity. The median time-to-progression was 1.9 mo (range 0.6-8.7 mo). Best response was seen in 1 pt with stable disease (SD) for 8 cycles. Only ≥ grade 3 toxicities related to CRLX101 occurred in a single patient with grade 3 anemia and chest pain who was able to resume therapy without any further toxicity after CRLX101 was reduced to 12 mg/m2. Conclusions: CRLX101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with CRLX101 in advanced GEC should focus on combination strategies. Its favorable toxicity profile and evidence of preferential tumor uptake support further clinical research of combining CRLX101 with other targeted therapies such as anti-angiogenesis (ramucirumab) and/or immune checkpoint inhibitors. Clinical trial information: NCT01612546 Clinical trial information: NCT01612546.
Variations in the perioperative management of pancreatoduodenectomy between academic and community institutions: An IHPBA/AHPBA web-based survey.
Authors: Anantha Sandeep , Macedo Fransisco Igor , Race Alice J , Singh Awinderpreet , Mittal Vijay K , Parikh Janak A , Jacobs Michael J
Published: February 2017

448

Background: Pancreatoduodenectomy is the surgical treatment for pancreatic head and periampullary malignancy and is performed by surgeons practicing in all kinds of hospital settings, academic, community and hybrid. The perioperative management is varied amongst surgeons owing to diverse training experience. We aim to evaluate these variations by comparing the hospital settings. Methods: A pilot 25-item survey questionnaire was electronically distributed using Survey Monkey to IHPBA and AHPBA members between May and August 2015 regarding practice patterns and perioperative care of pancreatoduodenectomy. Results: We received 285 responses with participants from academic (56.1%), community (12.6%) or hybrid institutions (31.2%). Most participants performed 10-25 cases annually in each group (46.9%, 50%, 51.7%, respectively). Surgeons from academic institutions routinely culture bile intraoperatively more often than in community institutions (46.3% vs. 22.2%, p<0.01). However, surgeons from community programs tend to continue prophylactic antibiotics beyond 24 hours (30.6% vs. 44.4%, p<0.01) and are more likely to use antibiotic abdominal irrigation (2.5% vs. 11.1%, p<0.01) as compared to those from academic institution. Routine postoperative culture and measurement of amylase rich drain fluid, types of drains (self-suction or gravity), length of postoperative antibiotic regimen, type of skin closure and wound care were statistically similar Conclusions: Our survey included a wide range of members from academic, community and hybrid centers. Practice patterns vary significantly among surgeons practicing in academic, community or hybrid institutions and are not standardized. Further studies are warranted to elucidate the impact of these variations on surgical outcomes of patients undergoing pancreatoduodenectomy.
Characterizing tumor responses from RAINBOW, a randomized phase III trial of ramucirumab (RAM) plus paclitaxel (PAC) vs placebo (PBO) plus PAC in patients (pts) with previously treated advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Bodoky Gyorgy , Gil-Delgado Marian , Cascinu Stefano , Lipatov Oleg N. , Cunningham David , Van Cutsem Eric , Muro Kei , Chandrawansa Kumari , Liepa Astra M. , Carlesi Roberto , Ohtsu Atsushi , Wilke Hansjochen
Published: February 2017

45

Background: In RAINBOW, OS and PFS were improved for pts with previously treated gastric/GEJ adenocarcinoma in the RAM + PAC arm. Objective response rate was also significantly improved: 28% (92/330) RAM + PAC vs 16% (54/335) PBO + PAC (P =.0001). Timing and duration of responses and quality of life (QoL) are described. Methods: Patients were randomized 1:1 to RAM 8 mg/kg or PBO on days 1 and 15 + PAC 80 mg/m2 on days 1, 8, and 15 (28-day cycle). Radiographic assessment of disease per RECIST v1.1 and assessment of QoL with the EORTC QLQ-C30 were done at baseline and 6-wk intervals following the first dose of study therapy. Time to response (TTR) was the time from randomization to first tumor response (complete or partial). Duration of response (DoR) was the time from first tumor response to disease progression. A swimmer plot of DoR, survival, and status at study end was developed. Time-to-event curves were generated using the Kaplan-Meier method. Hazard ratio (HR) for DoR was generated from a stratified Cox model. QoL scores were classified as improved or worsened if change from baseline was ≥ 10 points (100-point scale), otherwise considered stable. Results: Median TTR was 6.7 wks (range 4.3-33.3) for RAM + PAC pts and 6.6 wks (5.1-37.1) for PBO + PAC pts. A detailed swimmer plot confirms a majority of RAM + PAC pts (58% [53/92]) and PBO + PAC pts (61% [33/54]) responded by the first 6-wk assessment. Of these responders, 11% (6/53) and 6% (2/33) were still responding at 12 mos. Median DoR was 4.4 mos (95% CI 4.1, 5.5) in the RAM + PAC arm and 2.8 mos (95% CI 2.1, 4.2) in the PBO + PAC arm (HR = 0.66, 95% CI 0.45, 0.97; P =.0332). At 6 wks, rates of improved/stable QoL scores among responders were similar between treatment arms and higher among the responders (73% RAM + PAC vs 74% PBO + PAC) than in the intent-to-treat population (53% vs 50%). Conclusions: Patients with advanced gastric/GEJ cancer not only showed an improved response rate with RAM + PAC, but responses were also more durable. For the majority of pts, response occurred within the first 6 wks of therapy and was associated with QoL benefit. Clinical trial information: NCT01170663.
Predictors and survival for pathologic tumor response grade (TRG) in borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) treated with induction chemotherapy and neoadjuvant stereotactic body radiotherapy (SBRT).
Authors: Mellon Eric Albert , Hoffe Sarah E. , Frakes Jessica M. , Strom Tobin Joel Crill , Springett Gregory M. , Shridhar Ravi , Centeno Barbara , Malafa Mokenge Peter , Hodul Pamela Joy
Published: February 2017

453

Background: Neoadjuvant therapy response correlates with survival in several gastrointestinal malignancies. Thus, we intensified our neoadjuvant approach to pancreas adenocarcinoma in part to induce greater response. Here we analyzed whether pre- and post- therapy CA19-9 or SUVmax correlated with College of American Pathology TRG at pancreatectomy and whether TRG associated with survival. Methods: After IRB approval, we identified BRPC and LAPC patients treated in our standardized pathway who underwent surgical resection with reported TRG (n = 81, median follow-up 30.8 months). Patients had baseline CA19-9, CT, endoscopic ultrasound, and FDG PET/CT then underwent multi-agent chemotherapy (79% with planned 3 cycles of GTX) followed by 5 fraction SBRT. They then underwent restaging CT, PET/CT, and CA19-9 prior to resection. Overall (OS) and progression free survival (PFS) were estimated and compared by Kaplan-Meier and log-rank methods. Univariate ordinal logistic regression correlated TRG with baseline, re-staging, and change in CA19-9 (16% with missing values or CA19-9 < 5 excluded) and SUVmax (14% with missing values or no hypermetabolism excluded). Results: Decrease in CA19-9 before and after neoadjuvant therapy correlated with improved TRG (p = 0.02) as did re-staging SUVmax (p < 0.01), though not decrease in SUVmax (p = 0.08). The TRG groupings had similar OS and PFS except the TRG 0 (complete response) group. Compared to TRG 1-3 patients (median OS 38.4 months, median PFS 17.8 months), the 6 patients with TRG 0 had no deaths (p = 0.05) and only 1 failure (p = 0.03). A group of 10 TRG 1 patients with only isolated tumor cells remaining had similar outcomes to the other TRG 1-3 patients. Conclusions: Pre-operative PET-CT and CA19-9 response correlate with neoadjuvant therapy response by TRG. Patients with complete pathologic response have superior outcomes. This provides rationale for further intensification of neoadjuvant therapy in BRPC and LAPC. Further work seeks to identify techniques to better select which BRPC and LAPC patients should undergo tumor resection.
Conditional probability of survival in gallbladder carcinoma as a prognostic tool for long term survivors.
Authors: Rajeev Rahul , Berger Nicholas Gerard , Hammad Abdulrahman Y , Miura John Thomas , Johnston Fabian McCartney , Gamblin T. Clark , Turaga Kiran
Published: February 2017

455

Background: Gallbladder carcinoma (GBC) often presents in an advanced stage and despite radical resection and nodal harvest, prognosis remains poor. Conventional survival statistics do not account for time elapsed from diagnosis and may not carry relevant prognostic information for long term survivors. This study sought to estimate the conditional probability of survival (CS) in patients of GBC. Methods: Patients with GBC were identified from the Surveillance, Epidemiology and End Results (SEER) database (1988-2012). Overall probability of survival (OS) was estimated using Kaplan-Meier method. Cumulative incidence method was employed to calculate CS. Results: Of 15,046 GBC patients identified, Stage IV disease was the most common presentation (n = 5625). Surgical intervention was reported in 9,720(65%) patients with cholecystectomies (n = 8254) outnumbering radical resections (n = 1116). 3-year OS for all stages was 18% and conditional probability of surviving additional 3 years (CS3) at 1, 2 and 3 years from diagnosis was 42%, 57% and 66% respectively. Stage III and IV disease had 3-year OS rates of 19% and 3% respectively while CS3 increased progressively with each year survived(33% and 17% at 1 year, 51% and 34% at 2 years, 60% and 56% at 3 years). Conclusions: Conditional probability of survival is favorable in patients surviving one year from diagnosis and shows an increasing trend with time. Improvements in survival are more substantial in patients with adverse initial prognosis. Conditional survival provides valuable information on prognosis to patients after curative surgery and can be the basis of follow-up guidelines.
Effect of transarterial chemoembolization prior to selective internal radiation therapy on yttrium-90 microsphere delivery in hepatocellular carcinoma patients.
Authors: Lin Mu-Han , Saboury Babak , Mohammadi Homan , Moeslein Fred M , Chuong Michael David
Published: February 2017

458

Background: Transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT) are commonly used for treatment of liver tumors. The use of TACE, which is macroembolic, prior to SIRT may cause hemodynamic changes in tumor vasculature that impair yttrium-90 (90Y) microsphere delivery to the targeted lesions. This work aims to quantify dosimetric tumor coverage using positron emission tomography (PET) dosimetry after SIRT alone compared to TACE followed by SIRT. Methods: A total of 40 consecutive hepatocellular carcinoma (HCC) SIRT patients who had a post-SIRT PET scan were evaluated. Yttrium-90 PET scan was performed within 2 hours after completion of SIRT. 3D dose distribution of each patient was then reconstructed from the PET images. To quantify the quality of SIRT microsphere delivery, we evaluated the selectivity index (SI) defined as the ratio of the average dose inside the treated lesion(s) and the average dose of the normal liver. The SI values of patients were compared based on whether TACE was previously used. Results: Thirty patients had complete data for analysis. The average dose for a total of 125 targeted lesions was 106 Gy (range 0 Gy – 495 Gy). The average SI of the entire patient group was 3.0, indicating that the targeted lesion dose was three times higher than normal liver dose. The average SI was 1.7 for the 13 patients who had prior TACE and 3.8 for the 17 patients who did not have prior TACE (p = 0.01). Nearly 80% of the patients with prior TACE demonstrated poor 90Ymicrosphere delivery (SI < 2) while none demonstrated excellent microsphere delivery (SI > 4). On the other hand, the incidence of SI < 2 and SI > 4 among patients with no prior TACE was 24% and 40%, respectively. Conclusions: 3D dose evaluation using post-SIRT PET suggests that 90Y microsphere delivery to liver tumors is impaired among patients who received prior TACE compared to those who receive SIRT alone. These data warrant evaluation of clinical outcomes in SIRT patients based on prior use of TACE and may provide a rationale for the use of SIRT prior to TACE.
Phase Ib trial of gemcitabine with yttrium-90 in patients with hepatic tumors of pancreatobiliary origin.
Authors: Kim Hyun S , Camacho Juan C. , El-Rayes Bassel F.
Published: February 2017

460

Background: The rationale for combining Gemcitabine (G) with Yttrium-90 (Y90) is based on G being a potent radio sensitizer and activity of Y90 against liver tumors of pancreatobiliary histology. Therefore, a safety and efficacy trial of adding G to Y90 is required. Methods: Eligibility: Chemo-naïve patients with histologic diagnosis of unresectable PC or CC with liver predominant disease. Design: Open label phase I design with 3+3 G dose escalation. Induction G on Day 1 followed by Y90 on Day 2 and subsequent pre-assigned dose levels of G until week 12. Primary objective: To determine the maximal tolerated dose of G that can be used in combination with Y90. Secondary objectives: To characterize the toxicity, evaluate hepatic progression free survival (HPFS); determine tumor response rate using RECIST and PERCIST criteria; determine the progression free survival (PFS) and overall survival (OS). Correlative Imaging: 18-FDG PET/CT with contrast at baseline and 12 weeks. Results: 14 patients were recruited and 8 met the inclusion criteria. Seven out of eight patients tolerated the dose escalation regime of G (dose level 1-400 and dose level 2-600mg/m2). All the patients developed grade 1 toxicities (Hepatobiliary 25%, Bone marrow 25%, Fatigue 100%). Three patients (37.5 %) had grade 2 hepatobiliary toxicity and one patient (12.5 %) had grade 3 hepatobiliary toxicity, which required short-term hospitalization. No radiation pneumonitis, gastrointestinal ulceration, or procedure-related mortality occurred. Six patients (75%) developed grade 1 toxicity (fatigue). All of the patients had SD in the liver by RECIST; the objective response rate was 62.5% by PERCIST (CR12.5%, PR50%, SD25% PD12.5%). Overall objective response rate was 0% by RECIST (SD62.5%, PD37.5%); and 50% for PERCIST (CR12.5%, PR37.5%, SD12.5%, PD37.5%). The median OS from diagnosis was 13.8 months (95% CI, 9.65 to 26.29 months) and from Y90 therapy 10.9 months (95% CI, 6.47 to 22.39 months). PFS was 6.92 months (95%CI, 4.37-16.5 months) and HPFS of 8.72 months (95%CI, 4.48-19.36 months). Conclusions: In patients with hepatic tumors of pancreatobiliary origin, Gemcitabine at 600mg/m2 with Y90 therapy appears to be a viable and safe therapy. Clinical trial information: NCT01434459.
Peripheral trafficking of bone marrow-derived stem cells in patients with different types of gastric neoplasms: Significance of complement and interleukins.
Authors: Blogowski Wojciech , Zuba-Surma Ewa , Budkowska Marta , Salata Daria , Tarnowski Maciej , Dolegowska Barbara , Starzynska Teresa
Published: February 2017

49

Background: Increasing evidence suggests that gastric malignancy may be a stem cell disorder. Methods: Using FACS analysis supported by ImageStream technique verification, various populations of bone marrow-derived stem cells (BMSCs), such as Lin-CD45-CD133+CXCR4+ very small embryonic/epiblast-like stem cells (VSELs), CD45-STRO-1+CD105+ mesenchymal stem cells (MSCs), Lin-CD45+CD133+ hematopoietic stem/progenitor cells (HSPCs), and CD34 +/ KDR +/ CD31 +/ CD45- endothelial progenitor cells (EPCs) were enumerated and sorted from peripheral blood samples of patients with gastric cancer (n = 23) and other gastric tumors (GISTs, NENs, lymphomas; n = 15) and control patients (n = 15). RT-qPCR analysis for the expression of cancerous, embryonic, and tissue trans-differentiation markers (Oct-4, Nanog, TFF-1, TFF-2, Lgr-5, BMI-1) in circulating VSELs was employed. The plasma levels of stromal-derived factor-1 (SDF-1), complement-derived anaphylatoxins/molecules (C3a, C5a, C5b-9/MAC), and interleukins (IL-6, IL-8, IL-17 and IL-23) were measured. Results: Significantly lower numbers of circulating HSPCs, and intensified peripheral trafficking of both VSELs and MSCs was observed in patients with gastric cancer, but not in those with other types of gastric tumors. In gastric cancer patients, the circulating VSELs presented higher gene expression of Oct-4, Nanog, Lgr-5, BMI-1, and TFF-1/2. The abnormal balance in the peripheral trafficking of BMSCs in patients with gastric cancer was not associated with the clinical stage of the disease or with the systemic levels of stromal-derived factor-1 (SDF-1), but correlated with the levels of C5b-9/MAC, IL-6, IL-8 and IL-23. Conclusions: Abnormal peripheral trafficking of BMSCs occurs in patients with gastric cancer, but not in those with other types of gastric neoplasms. Selected interleukins and complement cascade-derived molecules, but not SDF-1, seem to be significant players associated with this phenomenon (POIG.01.01.02-00-109/09 and IP2014003273).
ACCORD12/0405-Prodige 2 phase III trial neoadjuvant treatment in rectal cancer: Results after 5 years of follow-up.
Authors: Francois Eric , Gourgou-Bourgade Sophie , Azria David , Conroy Thierry , Bouche Olivier , Doyen Jerome , Seitz Jean-François , Mineur Laurent , Etienne Pierre-Luc , Gerard Jean-Pierre
Published: February 2017

490

Background: The ACCORD 12 randomized trial was aiming at improving ypCR by increasing the radiation dose and adding oxaliplatin (OX) to a standard RT 45 Gy with concurrent capecitabine. On short term benefit of OX was not demonstrated (Gérard JP et al. J Clin Oncol. 2010;28:1638-44) at 3 years no significant difference in clinical outcome was achieved (Gérard JP et al. J Clin Oncol. 2012;30:4558-65. François E et al. Radiother Oncol. 2014;110:144-9). This is an update of results at 5 years. Methods: Between 11/2005 and 07/2008, 598 patients were randomized. Inclusion criteria: adenocarcinoma of rectum accessible to digital examination, T3 Nx M0 (or T2 distal anterior rectum). Randomization was between two neoadjuvant treatments chemo radiotherapy: Cap45 (45 Gy + capecitabine) and Capox50 (50 Gy + cape. and oxaliplatin). Main end point was sterilization of the operative specimen. Bowel function for patients treated with anterior resection was analyzed with a global score (1 very poor to 7 excellent). A total of 253 patients received adjuvant chemotherapy usually with FOLFOX: 133 in Cap45, 120 in Capox50. Results: In the ITT population, with a median follow-up of 60 months, updated carcinologic results were calculated using the Kaplan-Meier method. Out of 299 pts randomized in CAP45 and 299 pts in CAPOX50 results were respectively the following 1) 5y-cumulative incidence of Loc. Recurrence : 8.8% vs 7.8% (p = 0.78 HR = 0.92 [0.51-1.66]) 2) 5y-cumulative incidence of dist metastasis : 29.3% vs 27.1% (p = 0.48 HR = 0.89 [0.62-1.54]) 3) 5y-disease free survival rate : 60.4% vs 64.7% (p = 0.25 HR = 0.86 [0.66-1.11]) 4) 5y-overall survival rate : 76.4% vs 81.9% (p = 0.06 HR = 0.71 [0.50-1.01]) 5) bowel function median score : 5.2 [1-7] vs 4.9 [1-7]. Conclusions: At 5 years there was no significant difference in terms of local recurrence or distant metastases rates between both regimens. The new finding is a trend for improved overall survival in the Capox 50 groups may be related to subsequent salvage secondary treatments. At time of meeting the prognostic factors will be available in details and these results put in perspective with other phase III trial testing the role of oxaliplatin in Europe and the US. Clinical trial information: NCT00227747.
A novel 2-gene blood test for colorectal cancer recurrence.
Authors: Pedersen Susanne Kartin , Symonds Erin L , Mansfield Scott , Byrne Susan , Bambacas Libby , Hollington Paul , Murray David , Baker Rohan , LaPointe Lawrence Charles , Young Graeme P
Published: February 2017

495

Background: Annual computed tomography (CT) scans and periodic carcinoembryonic antigen (CEA) testing are monitoring methods for colorectal cancer (CRC) recurrence. We have previously described a 2-gene blood test for CRC (methylated BCAT1 and IKZF1) that may indicate tumour DNA shedding into the blood. The aim was to compare the 2-gene and CEA blood tests at detecting recurrence in CRC surveillance patients. Methods: Methylated BCAT1/IKZF1and CEA (positive ≥5ng/mL) were measured in patients previously diagnosed with CRC (excluding those undergoing active treatment). McNemar’s test was used for statistical analyses, using clinical findings including CT to diagnose recurrence. Results: At study midpoint, 340 patients were enrolled (64% men, average 64yr at diagnosis), including 59 patients with blood testing done pre- and post-resection, and 105 with CT surveillance scans (median 18 months after primary diagnosis). Following resection (median 2.3 months), 91% of patients who were 2-gene positive prior to treatment showed either no detectable methylated BCAT1/IKZF1(26/35) or significantly reduced levels in blood (6/35). Residual disease was found in two patients (2/3) who remained gene positive post treatment. Recurrence was identified in 30/105 (29%) patients with surveillance CT scans. Of these, 67% and 27% were 2-gene and CEA positive, respectively, with 8 (27%) cases positive by both tests (Table 1, p<0.001). In 13 cases with local recurrence, 54% were 2-gene positive, with only 1 (8%) positive by both tests (p=0.03). In 17 cases with distant recurrence, respective 76% and 41% were 2-gene and CEA positive (p=0.03). In patients with no evident disease, 20% were positive for one test but not the other (2-gene test, 16%; CEA, 4%; p = 0.04). Conclusions: Following resection, most patients had either reduced or no methylated BCAT1/IKZF1 in blood, indicating a correlation with the presence of cancer. Two-gene positivity correlated with local (54%) and distant (76%) recurrence with 2.5-fold more recurrence cases detected than with CEA. The 2-gene test may be better than CEA for recurrence monitoring. [Table: see text]
Patterns of recurrence by microsatellite instability in colorectal cancer.
Authors: Kim Chang-gon , Ahn Joong Bae , Jung Minkyu , Beom Seung Hoon , Kim Joo Hoon , Heo Su Jin , Kim Ji Hyung , Shin Sang Joon
Published: February 2017

501

Background: Although colorectal cancer (CRC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CRC, patterns of recurrence has not been precisely investigated. We aim to explore patterns of recurrence and prognosis of CRC with MSI-H (high-frequency MSI) in comparison to MSI-L (low-frequency of MSI)/MSS. Methods: Patients with stage I-III colorectal cancer who received complete surgical resection were included using retrospective cohort of Yonsei Cancer Center. Patients were categorized to MSI status (MSI-H vs. MSS-L/MSS). Patterns of recurrence, disease free survival (DFS) and overall survival (time from diagnosis to death as OS1 and time from recurrence to death as OS2) between two groups were compared. Results: A total of 2944 patients were evaluated. Of all, 263 patients (8.9%) has MSI-H tumor. Patients with MSI-L/MSS tumor experienced more systemic recurrence events than patients with MSI-H tumor (13.1% vs. 4.6%). In patients who experienced recurrence, MSI-H tumor has tendency toward young age, proximal location and poorly differentiated histology. MSI-H tumor is more likely to recur as peritoneal metastasis (33.3% vs. 8.0%, p-value 0.002) and lymph node metastasis (25.0% vs. 7.7%, p-value 0.033). In contrast, MSI-L/MSS tumor is more likely to recur as lung metastasis (37.1% vs. 0.0%, p-value 0,008). There was no difference in DFS [hazard ratio (HR) = 0.753, p-value 0.241] and OS1 [HR = 1.486, p-value 0.203]. However, OS2 was marginally inferior in MSI-H tumor [HR = 1.779, p-value 0.064]. Conclusions: Patterns of recurrence in MSI-H CRC is different from that of MSI-L/MSS and modification of surveillance strategy in MSI-H CRC should be considered. In addition, prognosis of recurred MSI-H CRC is not superior than MSI-L/MSS and prognostic value of MSI in this circumstance should be evaluated using larger sample size.
Perioperative chemotherapy using FOLFOX with panitumumab for locally advanced rectal cancer: Phase II trial.
Authors: Ota Mitsuyoshi , Watanabe Jun , Ishibe Atsushi , Suwa Hirokazu , Momiyama Masashi , Ichikawa Yasushi , Kunisaki Chikara , Endo Itaru
Published: February 2017

502

Background: Neoadjuvant chemotherapy for locally advanced rectal cancer is required to achieve tumor reduction when skipping routine use of preoperative radiation therapy. It is known that EGFR inhibitor has impact on early tumor shrinkage in metastatic colorectal cancer. We evaluated the effect of preoperative infusional fluorouracil, leucovolin, and oxaliplatin (FOLFOX) with panitumumab. Methods: Forty-three patients with clinical stage III rectal cancer without invasion to other organs were enrolled in this multicenter phase II trial. All patients had KRAS wild tumors confirmed by biopsy. Patients received six cycles of FOLFOX with panitumumab. Reduction rate of primary tumor was measured by T2 weighted sagittal image of magnetic resonance imaging. Excluding patients whose disease progressed after the six cycles, total mesorectal excision was performed two weeks after neoadjuvant chemotherapy. After surgery, adjuvant chemotherapy with six cycles of FOLFOX without panitumumab was planned before diverting stoma closure. The primary outcome was the response rate of the primary lesion. Results: Between January 2012 and December 2014, 42 out of 43 patients completed preoperative chemotherapy; one patient did not complete the regimen due to grade III neutropenia. There was no progressive disease in the 42 patients and response rate was 69.8% in this series. Average reduction rate of the primary lesion was 47.6%. All of the 43 participants had R0 resections without mortality or severe complications. Pathological complete response rate to chemotherapy was 7.0% (3 of 43). Thirty-eight out of 43 patients started adjuvant chemotherapy and 32 patients completed the regimen. Grade 3 or worse peripheral neuropathy was not seen during neoadjuvant chemotherapy and seen in 2.6% (1 of 38) during adjuvant chemotherapy. Conclusions: Periopative chemotherapy using FOLFOX with panitumumab seemed to have two advantages; one is tumor reduction which enables skipping neoadjuvant radiation therapy, the other is safely administering a larger dose of chemotherapy than adjuvant only in locally advanced rectal cancer. Additional impact of EGFR inhibitor should be followed in long term results. Clinical trial information: UMIN000006039.
Prevalence of metabolic syndrome in older (50 years and older) vs younger (less than 50 years) patients with colorectal cancer diagnosed in a safety net hospital system.
Authors: Sharma Ashish , Chan Johanna , Trang Tony , Suarez Milena Gould
Published: February 2017

512

Background: Colorectal cancer (CRC) incidence has declined overall with screening, though incidence in patients younger than 50 years has increased. Younger patients present with more aggressive and advanced stage CRC. Potential mechanisms are sporadic, genetics, and environmental (alcohol, smoking, metabolic syndrome). Metabolic syndrome (MetS) is an established risk factor for CRC. We examined the prevalence of MetS in younger patients ( < 50 yrs) compared with older patients ( ≥ 50 yrs) with CRC in a safety net hospital population. Methods: IRB-approved retrospective chart review of all patients diagnosed with CRC in the Harris County Hospital District cancer registry from Jan 2008 to Dec 2013. Data was collected for patient characteristics and metabolic syndrome to compare 2 patient groups: < 50 yr (younger) and ≥ 50 yr (older). MetS was defined using 2005 AHA/NHLBI criteria as ≥ 3 of the following components: abdominal obesity (waist circumference > 102 cm in men, > 88 cm in women), serum triglycerides (TG) ( > 150 mg/dL), serum HDL ( < 40 mg/dL in men and < 50 mg/dL in women), BP > 130/85 mmHg, fasting glucose/diabetes ( ≥ 100 mg/dL). Per WHO criteria, BMI > 30 was used as surrogate for waist circumference. Descriptive statistics were performed using t-test for continuous variables and Chi-square / Fisher’s exact test for categorical variables. Results: 625 cases of CRC diagnosed showed median age of 56.5 years and 54.7% female patients. The majority (77.76%) of cases occurred in the older group. Overall, 208/625 patients (33.28%) had MetS. Average BMI overall was 27.33. Prevalence of MetS was 38.27% vs 23% (older vs younger; p = 0.0001). In older compared with younger patients, average BMI 26.13 vs 25.05 (p = 0.02), obesity 25.92% vs 35.87% (p = 0.05), BP > 130/85 mmHg 56.3% vs 31.6% (p = 0.001), low HDL 41.7% vs 31.9% (p = 0.02), TG > 150 34.7 % vs 22.3 % (p = 0.02) and diabetes 36.2% vs 11.5% (p = 0.001). Conclusions: Overall prevalence of MetS in our patient cohort was similar to that of general population (which approximates 34%). Prevalence of MetS was higher in older patients with CRC than in younger patients, though this may reflect the natural history of MetS.
Efficacy of panitumumab (pmab) vs. cetuximab (cmab) in patients (pts) with wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) treated with prior bevacizumab (bev): Results from ASPECCT.
Authors: Peeters Marc , Kim Tae Won , Li Jin , Cascinu Stefano , Ruff Paul , Suresh Attili Venkatasatya , Thomas Anne , Tjulandin Sergei , Guan Xuesong , Hoang Tien , Hei Yong Jiang , Price Timothy Jay
Published: February 2017

519

Background: The phase 3 ASPECCT trial of pts with chemorefractory WT KRAS exon 2 mCRC demonstrated that pmab was noninferior to cmab for overall survival (OS). A previous subgroup analysis of hazard ratios (HRs) suggested that pts who had received prior bev (any line, at any point before study start) in the pmab arm may have had better outcomes vs pts in the cmab arm (Price, 2014). Methods: Pts were randomized 1:1 to receive pmab or cmab. The subset of pts who had received prior bev were analyzed based on the final analysis of ASPECCT. Results: 999 pts were randomized and treated: 499 pmab and 500 cmab. The prior bev subset included 126 pts in the pmab arm (25%) and 132 pts in the cmab arm (26%). Pts in the pmab arm had longer median OS and progression-free survival (PFS) and higher objective response rates (ORR) compared with pts in the cmab arm. Results are shown (table). After adjustment for baseline covariates including ECOG performance status, number of metastatic sites, and baseline LDH, OS HR was 0.65 (95%CI=0.49-0.85) with pmab vs cmab in pts who had received prior bev. Pts in the pmab and cmab arms who did not receive prior bev had similar OS, PFS, and ORR. Post-progression antitumor therapy was similar between the pmab (47%) and cmab arms (52%) in pts who received prior bev. Conclusions: In ASPECCT, pts with WT KRASexon 2 mCRC who received prior bev-containing regimens may have derived greater benefit with pmab versus cmab monotherapy. Clinical trial information: NCT01001377. [Table: see text]
Assessing distress in patients with gastrointestinal tumors during radiotherapy.
Authors: Hollant Laeticia , Single Megan Paige , Gaines Katherine , Smart Bridget , Habboush Jacob , Kaleem Tasneem , Tzou Katherine S. , Ko Stephen , Biers Heather , Day Atiya , Miller Robert Clell
Published: February 2017

524

Background: Psychosocial distress during radiotherapy (RT) for gastrointestinal tumors is poorly characterized. Since 2012, patients receiving RT in our clinic have been prospectively screened for causes of distress. The results of our screening were reviewed in order to elucidate concerns of GI cancer patients and to delineate patterns within patient reported distress (PRD). Methods: Patients treated with RT at our institution receive a 30 question PRD survey that also includes a linear analog measure of overall distress at the start and during RT. The PRD survey asks patients to rate forms of distress on a scale of 1 to 5 (5 being the most distressed). The survey also asks patients to rate overall distress according to the National Comprehensive Cancer Network (NCCN) Distress Thermometer on a scale 0 to 10. The reported results were retrospectively reviewed in patients receiving definitive RT for GI cancers from 04/02/2012 to 08/05/2015. Results: PRD surveys were completed by 113 patients, 55 (48.7%) male and 58 (51.3%) female. Median age was 65 years (range 28 to 93). The most common tumor histology was adenocarcinoma, 67 (59.3%). 105 patients (93.0%) received chemotherapy and 66 (58.4%) underwent surgery. Overall, NCCN distress thermometer results ranged from 0 to 10, with a median of 4.3. The mean distress scores for the top five complaints ranged from 1.27 to 2.63. Top distresses were “How will I feel during treatment” (2.63), “Fatigue” (2.45), “Pain that affects daily functioning” (2.35), “Out of pocket medical costs” (2.31), and “Sleep difficulties” (2.31). The least concerning complaints were “Housing during treatment” (1.27), “A loved one relying on me for their physical care” (1.30), “Spirituality” (1.33),“Family communication about my illness”(1.37), and “Transportation” (1.38). Conclusions: Patients’ major concerns were aligned with daily quality of life, such as fatigue, pain and insomnia. Highest reported distress was linked with the process of RT and side effects associated with treatment. Medical expenses were also perceived as a burden. Medical providers should identify psychosocial stressors during RT in order to effectively communicate and provide resources to improve quality of life.
How often does the patient repeat screening colonoscopy? A study for personalized recommendation of screening colonoscopy interval.
Authors: Kim Eun Sun , Chun Hoon Jai , Jeen Yoon Tae , Keum Bora , Choi Hyuk Soon
Published: February 2017

527

Background: Colorectal cancer (CRC) is the third most common cancer and the second most frequent cause of cancer death of female and fourth most of male in South Korea. Most CRCs develop through the adenoma–carcinoma sequence, which allows for screening and prevention of CRCs by screening colonoscopic examination and polypectomy. However, there have been limited data on personalized optimal time interval of next surveillance colonoscopic examination. The aim of our study is to recommend personalized interval by analysis of various clinical factors obtained by health care examination. Methods: We enrolled the patients who underwent two times more voluntary, complete screening colonoscopy at health care unit of Korea University Medical Center Anam Hospital from July 1, 2004 to July 31, 2010. The clustering analysis using the partitioning around medoids algorithm and Hierarchial cluster were conducted including the 32 clinical, geographic and laboratory data. For each cluster, we then performed survival analysis that provides the probability of having polyps according to the number of days until next colonoscopy. Results: Totally 8,332 patients underwent screening colonoscopy, among them 625 patients performed repeat colonoscopy exam. 625 patients divided four clusters by clustering analysis. Adenoma detection at first screening colonoscopy was the most potent risk factor of develop of adenoma at next screening. Male gender, triglyceride (>134 mg/dL), and age (>56 years old) were significant factor for decision of the personalized interval of next screening colonoscopy. For example, male patient, who had adenoma at fist screening, the predicted risk of adenoma is 50% after 25 months. Conclusions: Our study can provide personalized time interval of next screening colonoscopy according to patients’ individual clinical data. Further study are necessary for validation our results.
Rate of implementation of universal testing for Lynch Syndrome in a county hospital system.
Authors: Sharma Ashish , Chan Johanna , Trang Tony , Suarez Milena Gould
Published: February 2017

533

Background: Lynch Syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). Universal testing is recommended as a cost effective strategy for screening for LS in all patients with CRC diagnosed < 70 years of age. This has shown to be beneficial in clinical decision making and cancer surveillance of both the patient and at risk relatives. According to a study in 2012, 71% of NCI institutions were performing universal testing versus 15%-36% of programs in the community. The aim of our study was to determine the outcomes of Universal Testing for LS in CRC in a County Hospital System. Methods: IRB-approved retrospective chart review of all patients diagnosed with colorectal cancer from cancer registry at Harris County Hospital District from March 2010 to Dec 2013. Patients between 18-70 yr were included. We collected data on patient characteristics, universal testing [immunohistochemistry (IHC) at our institution], and LS diagnosis (confirmed with germline testing for mismatch repair gene) in our patient cohort diagnosed with CRC. Descriptive statistics were performed using t-test for continuous variables. Results: Overall, 430 patients had CRC diagnosis in our study period, and 54 years was median age of diagnosis. IHC was performed in 359/430 (83.4%) CRC cases. IHC was positive in overall 26/430 (6%) cases of CRC. LS was confirmed in 9/430 (2%) CRC cases. IHC was more often positive with CRC diagnosed in patients younger than 50 years than in patients 50 years or older (7.91% vs 3.09%; p = 0.04). Conclusions: Universal testing for screening of LS amongst patients with CRC can result in significant rates of detection. In this study we have shown that this is possible in a largely safety-net setting.