bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiation therapy sequencing for resected pancreatic adenocarcinoma in the National Cancer Data Base: A multi-institutional comparative analysis.
Authors: Colbert Lauren E , Hall William A , Nickleach Dana , Liu Yuan , Switchenko Jeffrey M , Gillespie Theresa Wicklin , Lipscomb Joseph , Kooby David A. , Kauh John S. , Landry Jerome C.
Published: February 2017

305

Background: Pancreatic adenocarcinoma (PAC) remains a devastating malignancy and the role for preoperative radiation therapy (prRT) remains uncertain. This analysis used the National Cancer Data Base (NCDB) to report outcomes for the largest known retrospective cohort of patients treated with prRT for resectable PAC to date. Methods: NCDB data were obtained for all patients who underwent resection and RT for PAC from 1998-2002. Patients with metastatic (M1) disease, combined prRT and poRT, missing OS or missing RT variables were excluded. The difference in patients’ characteristics was assessed by a Chi-square test and ANOVA. The Kaplan-Meier method was used to estimate overall survival (OS); survival differences were assessed using a log-rank test. A Cox proportional hazards model was used for unadjusted and multivariable (MV) survival analysis. Two MV logistic regression models also were used to assess for differences in margin status and lymph node (LN) status across treatment groups. Results: 5,414 analyzable patients were identified. 5.1% (277/5,414) received prRT and 94.9% (5,137/5,414) received poRT. All patients underwent resection and prRT or poRT +/- chemotherapy; 92.9% chemo. 793 patients were AJCC 5th edition stage I, 1,002 stage II, 2,990 were stage III, and 522 were stage IVa; 107 patients were M0 with unknown overall stage. There was no significant difference in OS between the two groups on unadjusted Kaplan-Meier analysis. In covariate-adjusted analysis, there was no significant difference in OS in the prRT (HR, 1.20 [95% CI .98-1.48]; p = 0.08) compared with poRT; prRT was associated with lower rates of LN positivity (OR, 0.45 [95% CI 0.31-0.65]; p < 0.001) and higher rates of negative margins (OR 1.71 [95% CI 1.17-2.52]; p = 0.006). Conclusions: In the largest published series of prRT patients to date, prRT was associated with negative margins and LN negativity at resection. There was no significant difference in OS between the groups. Limitations of this study include its retrospective nature, a small prRT cohort and lack of comorbidity data. These data may be useful in generating future prospective studies of prRT for PAC.
The efficacy and safety of the capecitabine/temozolomide (CAPTEM) regimen in the treatment of well-differentiated neuroendocrine tumors with liver metastasis after failure of previous therapy: Columbia University Medical Center experience.
Authors: Oberstein Paul Eliezer , Gulati Anthony Paul , Krantz Benjamin A , Moss Rebecca Anne , Schreibman Stephen M. , Tsushima Dawn , Mowatt Kelley B , Allendorf John , Schrope Beth , Lee James A , Sherman William H. , Chabot John A , Fine Robert
Published: February 2017

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Background: We have observed efficacy and tolerability of the CAPTEM regimen in pNET. We conducted a retrospective review of patients with liver metastasis from any NET, including carcinoid, who were treated with this regimen at our institution between 2002-2008. Methods: We identified patients with neuroendocrine tumors who demonstrated progressive liver metastasis while on treatment with long-acting octreotide (up to 60mg/month) and were then treated with CAPTEM as per our institutional protocol. Patients received capecitabine for 14 days at 1000mg PO bid with temozolomide at 150 or 200mg/m2 in bid dosing on days 10-14 of each 28 day cycle. All patients had contrast enhanced CT or MRI, response was assessed by a radiologist utilizing RECIST 1.0 criteria. Results: We identified 18 patients (50% female, median age- 55), 9 had pNET (2 functional, 7 non-functional), 2 had MEN1, 4 had carcinoid (1 functional), 2 with gastrinoma and 1 with glucagonoma. All patients had Ki-67 <10%, 11 patients (61%) had received previous chemotherapy (median of 2 regimens), and 50% had previous chemoembolization. Performance status at time of enrollment was 0-2 (5 patients, 28% with PS-2.)The response rate in the population was 61% (11/18) with 1 CR and 10 PR by RECIST 1.0 criteria. Stable disease was seen in 4 (22%) patients and clinical benefit (CR+PR+SD) in 83%. Response was noted in carcinoid patients (2 of 4, with 1 CR and 1 PR in this group) and in MEN1 patients (1 of 2 with PR). Median PFS was 14.0 months (range 4.2-18 months). Treatment was well tolerated; the most common grade 1/2 toxicities were lymphopenia (50%) and neutropenia (44%), 1 patient had hand-foot syndrome. Grade 3 thrombocytopenia was observed in 2 patients (11%), there was no other grade 3 or 4 toxicities. Conclusions: The CAPTEM regimen is well tolerated and is associated with a significant response in patients with liver metastasis from NET including the difficult to treat cases of carcinoid and MEN1. A prospective Phase II trial of this regimen is ongoing.
Use of total parenteral nutrition (TPN) in terminally ill gastrointestinal (GI) cancer patients (pts) compared to other malignancies (OM): A single-institution experience.
Authors: Cass-Garcia Margaret , Hodul Pamela Joy , Almhanna Khaldoun
Published: February 2017

309

Background: TPN is increasingly used in terminally ill cancer patients. The purpose of this study is to determine the validity of TPN in terminally ill GI cancer patients compared to OM. Methods: Cancer pts with limited life expectancy were given TPN between 2007 and 2012. Patients had advanced stage cancer with inoperable non-functional GI tract or failure to thrive. The primary outcome was survival from time of initiating TPN. Results: 89 pts were started on TPN (57 with GI cancer and 32 with OM). The majority of OM were GYN cancer. The mean age was 56 in the GI group vs. 58 in the OM. 47% of all patients underwent treatment while on TPN. The median duration of TPN was 38 days (39 days in the GI group vs. 52 days in the OM group). The median time from TPN to death was 70 days (55 days in the GI group vs. 77 days in the MO group). 14 patients had restored bowel function. 3 patients are living and only one is on TPN. 26 pts required palliative gastrostomy tube. TPN complication was high with 68% of pts requiring readmission, many were admitted several times. Conclusions: Terminal cancer patients receiving TPN had a median survival of 70 days; survival was shorter in the GI cancer group. Quality of life did not improve in the majority of patients; nor did it influence ultimate outcome. These data, thus, raise the question of the validity of the use of TPN in terminally ill pts.
A phase II trial of y-90 radioembolization in patients with progressive hepatic metastases from neuroendocrine carcinoma at an NCI-designated comprehensive cancer center.
Authors: Sahai Vaibhav , Nimeiri Halla Sayed , Mulcahy Mary Frances , Salem Riad , Benson Al Bowen
Published: February 2017

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Background: Patients with neuroendocrine carcinoma mostly present with symptomatic metastatic disease due to mass effect or release of biologically active polypeptides or amines and have a 5-year survival rate of 22%. The objective of this study was to assess the efficacy of hepatic artery radioembolization with Yttrium (Y)-90 microspheres in patients with unresectable progressive hepatic metastasis from neuroendocrine tumors. Methods: We conducted a prospective, single institutional, one-arm phase II study at an NCI-designated comprehensive cancer center. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included objective overall response rate (ORR), 1-year overall survival (OS) rate and safety and toxicity profile. Results: A total of 22 patients were enrolled between July 2007 and September 2009 with ECOG performance status 0-1, 45% males and median age of 62.5 (28-88) years. Histology included small bowel carcinoid (n=12), pancreatic neuroendocrine (n=7) and neuroendocrine tumors of unknown primary (n=3). Patients received a median of 2 (1-2) treatments with lobar approach in 95% and segmental approach in 5%. The primary endpoint of 6-month PFS rate in patients with one, two or three hepatic lesions was 82%, 82% and 72% respectively. ORR (partial and complete response) as per RECIST v1.0 was 48% in patients with one lesion, 29% with two lesions and 29% with 3 lesions. Median PFS was 9.4 (8.0-14.8) months. One-year OS rate was 86% and at 2-year was 78%. No procedure related complications were reported and grade 3 toxicities included hyperbilirubinemia (n=1) and elevated alkaline phosphatase (n=1). Conclusions: Y-90 radioembolization is a promising treatment option for patients with unresectable progressive hepatic metastases from neuroendocrine carcinoma with acceptable toxicity. Limited prospective data is available and there is a strong unmet need for randomized clinical trials with radioembolization.
A phase II trial of second-line axitinib following prior antiangiogenic therapy in advanced hepatocellular carcinoma (HCC).
Authors: McNamara Mairead Geraldine , Horgan Anne M , Aspinall Alex , Chen Eric Xueyu , Burak Kelly , Dhani Neesha C. , Petronis Jennifer , Sinaei Mehrdad , Kim Tae Kyoung , Rogalla Patrik , Bathe Oliver F. , Knox Jennifer J.
Published: February 2017

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Background: Second-line options in treatment of HCC are limited. Axitinib is a multi-targeted tyrosine kinase inhibitor (TKI) of VEGFRs 1, 2, and 3, PDGFR and c-KIT that warrants exploration in HCC. Methods: This is an open-label, single-arm, two-stage phase II trial of axitinib in advanced HCC. Eligible patients (pts) are Child-Pugh A/B7, with measurable progressive disease after TKIs/antiangiogenic drugs. Axitinib starts at 5 mg bid orally, titrated to 10 mg bid as tolerated. Treatment continues to progression (PD) or intolerable toxicity. Primary endpoint is response defined by reduction in size by RECIST 1.1 on CT scan at 16 wks, secondary endpoints to compare response by RECIST 1.1 to Choi criteria and modified RECIST, explore dynamic imaging models, feasibility, safety, PFS and overall survival. Results: We present results of 15 (of 29) pts enrolled from 01/11 - 09/12. Median age; 62y (range 18-78) with ECOG PS 0 (5 pts), 1 (10 pts) with prior therapy of Temsirolimus/Bevacizumab (2 pts), sorafenib (13 pts). A planned safety/futility interim analysis was passed. Most common axitinib-related AEs were hypertension (HTN) (60%), hand-foot skin reaction (HFSR) (60%), diarrhea (60%), fatigue (50%). Most common axitinib-related grade 3 (G3) AEs were HTN (20%) and diarrhea (20%). There were no G3 HFSR. There was 1 G4 hyperbilirubinaemia. 60% of pts had dose interruptions due to AEs; most common reasons included fatigue (20%), HTN (10%), and HFSR (10%). 20% required dose reductions, 14% of pts tolerated dose escalation above 5 mg bid. As of 09/12, 8 pts remain on study, 7 pts discontinued (4pts: PD, 3pts: AEs). Med duration of treatment; 4.0 mo (range 6 d - 15.5 mo). Out of 9 evaluable for response, there was 1 confirmed PR per RECIST 1.1; 3 other pts had tumor reduction; 10%, 22%, 23%, 2 PR by Choi criteria and none by modified RECIST. Early on-treatment perfusion changes were noted on functional imaging. Of the 9 pts with evaluable AFP response, 3 (33%) had >50% decrease from baseline. 11 pts are still alive, 4 pts are deceased secondary to PD. Conclusions: Axitinib is tolerated and has shown preliminary efficacy in this VEGF pretreated HCC pt population.This is early analysis and updated data will be presented. Clinical trial information: NCT01334112.
TH-302 plus gemcitabine (G+T) versus gemcitabine (G) in patients with previously untreated advanced pancreatic cancer (PAC).
Authors: Ryan David P. , Reddy Shantan G. , Bahary Nathan , Uronis Hope Elizabeth , Sigal Darren , Cohn Allen Lee , Schelman William R. , Stephenson Joe , Eng Clarence , Borad Mitesh J.
Published: February 2017

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Background: TH-302 is a hypoxia-targeted drug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G+T to standard dose G as first-line therapy of PAC. Methods: An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1,000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G+T arm. The primary efficacy endpoint was a comparison of PFS between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Overall survival (OS) was a secondary endpoint. Results: 214 pts were treated; 163 (76%) Stage IV and 51 (24%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 38% ECOG 0/62% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G+T240; 55% G+T340. Median PFS was 3.6 mo in G vs 5.6 mo in G+T240 (p=0.06) and 6.0 mo in G+T340 (p=0.01). Median OS was 6.9 mo in G vs 8.7 in G+T240 (p=0.83) vs 9.2 mo in G+T340 (p=0.80). 6-mo OS was 57% in G vs 69% in G+T240 (p=0.12) and 73% in G+340 (p=0.04); 12-mo OS was 26% in G vs 37% in G+T240 (p=0.18) and 38% in G+340 (p=0.13). RECIST best response was 10% in G vs 17% in G+T240 and 26% in G+T340. 14 and 12 pts in G crossed over to T240 and T340, respectively. Median post crossover PFS was 1.8 mo in T240 vs 2.9 mo in T340 (p=0.13). Median post crossover OS was 2.6 mo in T240 vs 13.4 mo in T340 (p=0.01). AEs leading to discontinuation were: 16% G, 17% G+T240 and 12% G+T340. Rash (47% in G+T340) and stomatitis (42% in G+T340) were greater in combination, 3 pts Grd 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G+T240 and 63% G+T340 and Grd 3/4 neutropenia were 31% G, 56% G+T240 and 60% G+T340. Conclusions: The combination of G plus TH-302 improved the PFS of G. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. A phase 3 study of TH-302 (340 mg/m2) in combination with G is planned with OS as the primary efficacy endpoint. Clinical trial information: NCT01144455.
Neuroendocrine tumors (NET) of the gastrointestinal tract: Patterns of management and experience at Winship Cancer Institute of Emory University.
Authors: Zafar Syed Farhan , Patil Dattatraya Hari , Kauh John S. , Adsay Volkan , Brutcher Edith , Maithel Shishir K. , Wang Zhibo , Chen Zhengjia , El-Rayes Bassel F.
Published: February 2017

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Background: NET are a group of diverse malignancies observed commonly in the gastrointestinal tract. Pancreatic neuroendocrine tumors (PanNET) have been reported to have worse outcomes as compared to neuroendocrine tumors of the gastrointestinal tract (GNET). Our objective was to compare the clinical characteristics, patterns of treatment and survival in PanNET and GNET. Methods: After IRB approval, we identified 379 patients (pts) from 1996-2011 in the Winship registry. A chart review was done. Patients were categorized in mutually exclusive groups of PanNET and GNET. Results: Demographic information and basic characteristics are listed in the table. Treatment modalities for PanNET included surgery (91%), chemotherapy (14%), biologics (sunitinib or everolimus)(6%) and somatostatin analogues (11%). Liver directed therapies were employed in 30 pts with PanNET. Most common modality was radiofrequency ablation (23 pts) followed by Yttrium-90 embolization (5 pts) and chemoembolization (2 pt).Treatment for GNET included surgery (78%), chemotherapy (11%) and somatostatin analogues (17%). Median survival for GNET (all stage) was 11.6 years and PanNET (all stage) was 10.5 years (p=0.063). Using multivariate analysis, only age at diagnosis (p<0.001 for age cohort of <55 yrs) and clinical stage (p=0.002, for local disease) were found to be significant factors. Conclusions: Pts with NET have good prognosis. In our series, both PanNET and GNET, had comparable survival outcomes even in advanced stage. [Table: see text]
Antitumor activity of nanoparticle albumin-bound paclitaxel in experimental gastric cancer.
Authors: Zhang Changhua , Ostapoff Katherine T , Awasthi Niranjan , Schwarz Margaret A. , Schwarz Roderich
Published: February 2017

33

Background: Gastric cancer is the second most common cause of cancer related death worldwide and lacks highly effective adjuvant or definitive systemic treatment for advanced disease. Nab-paclitaxel is a novel microtubule-targeting cytotoxic agent and not tested in gastric cancer as of yet. Methods: Human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied for treatment effects on cell proliferation, mitotic arrests and apoptosis in vitro and vivo. Tumor growth and survival studies were performed in murine xenografts. Results: Nab-paclitaxel inhibited cell proliferation with an IC50 of 2.01 nM in SNU16, 23.3 nM in AGS and 48.69 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 μM to 1.51μM) and epirubicin (0.12 μM to 0.25 μM). Nab-paclitaxel treatment caused increased expression of the mitotic-spindle associated phospho-stathmin, nuclear fragmentation or karyopyknosis, and apoptotic events as confirmed through increased expression of cleaved-PARP and caspase-3. After a two-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the local tumor growth inhibition rate was 77, 17.2 and 21.4 percent, respectively (p=0.002). Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues. There was an increase in median animal survival after nab-paclitaxel treatment (86 days) compared to controls (24 days, p=0.0004) or to oxaliplatin therapy (37.5 days, p=0.0005). Conclusions: The strong antitumor activity of nab-paclitaxel in experimental gastric cancer supports such microtubule-targeting therapy for clinical application. Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of nab-paclitaxel use in gastric cancer based on this putative biomarker.
FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): Results of the phase III randomized TRIBE trial.
Authors: Loupakis Fotios , Cremolini Chiara , Masi Gianluca , Lonardi Sara , Zagonel Vittorina , Trenta Patrizia , Tomasello Gianluca , Ronzoni Monica , Ciuffreda Libero , Zaniboni Alberto , Tonini Giuseppe , Buonadonna Angela , Valsuani Chiara , Chiara Silvana , Carlomagno Chiara , Boni Corrado , Marcucci Lorenzo , Boni Luca , Falcone Alfredo
Published: February 2017

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Background: First-line FOLFOXIRI demonstrated superior activity and efficacy compared to FOLFIRI. Moreover, the outcome is improved by the addition of bev to first-line doublets. A phase II study of FOLFOXIRI/bev showed promising activity and manageable toxicities. The present trial compared FOLFOXIRI/bev to FOLFIRI/bev as first-line treatment in unresectable mCRC. Methods: Eligibility criteria included: measurable and unresectable mCRC, age 18-75 years, no prior chemotherapy for advanced disease. Patients (pts) were randomized to either FOLFIRI/bev (bev 5 mg/kg, irinotecan 180 mg/sqm, l-LV 200 mg/sqm, 5FU bolus 400 mg/sqm, 5FU infusion 2400 mg/sqm over 48h q2w, arm A) or FOLFOXIRI/bev (bev 5 mg/kg, irinotecan 165 mg/sqm, oxaliplatin 85 mg/sqm, l-LV 200 mg/sqm, 5FU infusion 3200 mg/sqm over 48h q2w, arm B). Treatment was planned for a maximum of 12 cycles followed by maintenance with bev and 5FU until progression. Primary endpoint was progression-free survival (PFS). Results: Between July 2008 and May 2011, 508 pts were randomized among 35 italian centers. Pts characteristics were (arm A/arm B): median age 60/61 yrs, ECOG PS 1-2 11%/10%, synchronous metastases 81%/79% multiple sites of disease 74%/70%. At a median follow-up of 20.9 months 391 pts have progressed. The study met its primary endpoint: FOLFOXIRI/bev significantly increased PFS (median 9.5 vs 11.9 months, HR 0.72 [95%CI:0.59-0.87], p=0.001). Response rate was also significantly increased (53% vs 64%, p=0.015). Main per patient toxicities were (arm A/arm B): grade 3-4 diarrhea 10%/18%, grade 3-4 vomiting 3%/4%, grade 3-4 stomatitis 4%/8%, grade 3-4 peripheral neurotoxicity 0%/5%, grade 3-4 neutropenia 20%/49%, febrile neutropenia 6%/8%, hypertension 2%/4%, thromboembolic events 7%/7%, bleeding 1%/1%. Deaths within 60 days were 3% and 4%. Conclusions: FOLFOXIRI/bev significantly increases PFS and response rate compared to FOLFIRI/bev. Chemotherapy- and bev-related toxicities occur with the expected incidence. Clinical trial information: NCT00719797.
Use of adjuvant chemotherapy (AC) and outcomes in stage II colon cancer (CC) with versus without poor prognostic features.
Authors: Kumar Aalok , Kennecke Hagen F. , Lim Howard John , Renouf Daniel John , Woods Ryan , Speers Caroline , Cheung Winson Y.
Published: February 2017

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Background: AC is frequently considered in patients (pts) with "high risk" stage II CC, defined by the presence of >/=1 poor prognostic features such as obstruction or perforation, T4 stage, <12 lymph nodes removed, positive resection margins, and lymphovascular or perineural invasion. Survival benefits associated with AC use in high risk pts remain largely unproven. Our aims were to examine patterns of AC use in stage II CC and to explore the impact of AC on survival in high vs. low risk pts. Methods: All pts with stage II CC in British Columbia from 1999 to 2008 and evaluated at 1 of 5 regional cancer centers were reviewed. Kaplan-Meier and Cox regression methods were used to correlate high vs. low risk status and receipt of AC with relapse-free (RFS), disease-specific (DSS), and overall survival (OS). Results: We identified 1,697 pts: 1,236 (73%) high risk and 461 (27%) low risk among whom 363 (29%) and 61 (13%) received AC, respectively. Individuals with high risk disease who received AC were younger (median 62 vs. 72 yrs, p<0.01) and had better performance status (ECOG 0/1 47% vs. 34%, p=0.02). For high risk pts, AC was associated with improved 5-year OS (Table). Adjusting for confounders, an OS advantage from AC persisted for high risk pts (HR 0.67, 95CI 0.52-0.86, p=0.002), with no significant RFS or DSS benefits. Subgroup analyses revealed individuals with T4 lesions had significantly improved RFS (HR 0.63, 95CI 0.42-0.95, p=0.03), DSS (HR 0.59, 95CI 0.37-0.93, p=0.03), and OS (HR 0.50, 95CI 0.33-0.77, p=0.002). For low risk pts, AC was associated with worse RFS (HR 2.27, 95CI 1.03-4.97, p=0.04) and DSS (HR 2.97, 95CI 1.10-8.02, p=0.03). Conclusions: In this population-based cohort study, AC was associated with an OS advantage in high risk pts, likely due to pt selection. RFS and DSS benefits were mainly seen in T4 lesions, suggesting a limited role for AC in pts deemed high risk. A possible trend towards harm was seen in the low risk group receiving AC. Better risk stratification schemes including those that incorporate molecular testing are warranted. [Table: see text]
Founder mutation versus full sequencing of MYH for increasing clinical sensitivity.
Authors: Ceulemans Sophia , Arnell Christopher , Burbidge Lynn Anne , Abbott Brian , Kaldate Rajesh R. , Landon Michelle
Published: February 2017

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Background: MYH-associated polyposis is an autosomal recessive syndrome caused by biallelic mutations in the base excision repair gene MYH. Initial reports indicated that a majority of European biallelic individuals carried two founder mutations, Y165C and G382D. A common MYH analysis strategy involves evaluation of the two founder mutations (FMs) with subsequent full sequencing only if one of the FMs is identified. This study aimed to determine the sensitivity of full MYH sequencing over the strategy described above in a cohort of individuals that has undergone genetic testing by a commercial laboratory. Methods: A retrospective analysis was performed on 1,522 individuals who had clinical MYH testing ordered either independently or in conjunction with APC gene analysis. All patients underwent MYH analysis for Y165C and G382D. Subsequent full gene sequencing was performed for all patients, except for those biallellic for the two FMs. Demographic, personal, and family cancer histories were collected on the test request form. Results: 86 biallelic individuals were identified, with 47 carrying two FMs, 18 carrying one FM and one mutation identified on sequencing, and 21 carrying biallelic mutations identified only on full sequencing. 21/86 (24.4%) biallelic MYH mutation carriers would have been missed by FM analysis only. The mutation spectrum is distributed among different ethnicities (Table). The majority of individuals met clinical criteria for a polyposis syndrome, with 21 individuals reporting more than 99 adenomas (24.4%) and 50 individuals reporting 20-99 adenomas (58.1%). Conclusions: Analysis of only the two MYH FMs would miss 24% of biallelic individuals in our cohort. Due to the ethnicity distribution of mutations, it is difficult to predict who would be missed by this strategy. Consideration of MYH full sequencing is warranted to achieve highest clinical sensitivity. [Table: see text]
Predicting risk of chemotherapy-induced side effects in patients with colon cancer with single-nucleotide polymorphism (SNP) Bayesian networks (BNs).
Authors: Sonis Stephen T. , Schwartzberg Lee Steven , Walker Mark S. , Weidner Susan M , Alterovitz Gil
Published: February 2017

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Background: Patients receiving standard chemotherapy for colon cancer are at significant, but unequal, risk for development of treatment-induced side effects. Currently, there is no accurate way to identify these risks for individual patients. This study adopted a novel approach to creating a risk prediction model for chemotherapy-induced side effects through the development of clusters of SNPs defined by BNs. It was designed to assess the feasibility of identifying SNP-BNs that could accurately predict the risk for 6 common, and often debilitating, side effects: chemotherapy-induced nausea/vomiting (CINV), diarrhea, oral mucositis (OM), cognitive dysfunction (CD), peripheral neuropathy (PN), and fatigue. Methods: Patients (n=57) with colon cancer who received at least 3 cycles of FOLFOX6 +/- bevacizumab (along with standard supportive care strategies) were enrolled. Saliva samples were collected, DNA was isolated, and SNPs were analyzed on Illumina Omni microarrays (2.5 x 106 SNPs). Side effects under consideration were observed using Patient Care Monitor, a validated patient-reported symptom assessment instrument. BNs were developed for each of the 6 side effects and cross-validated using robust statistical analyses. Results: The percentage of patients who experienced moderate-to-severe side effects was notable despite supportive care measures. These included the following: CINV (32%), diarrhea (16%), OM (26%), CD (21%), PN (26%), and fatigue (56%). SNP-BNs were defined for each of the 6 side effects and were found to predict risk with a high degree of accuracy (>90%) and receiver operating characteristic (ROC) curves (>0.920). Conclusions: This study calls attention to the fact that treatment-related side effects persist in patients receiving FOLFOX6 +/- bevacizumab for colon cancer. SNP-BNs were identified that could accurately predict 6 of the most common treatment-related side effects. This genomic-based tool has the potential to offer clinicians accurate and actionable information for individualizing a patient’s cancer care plan.
Marker detection in rectal cancer chemoradiation response using an exhaustive combinatorics approach.
Authors: Smith David D. , Avila Karin , Chen Zhenbin , Li Wenyan , Garcia-Aguilar Julio
Published: February 2017

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Background: Our objective was to detect a set of markers that predicted tumor response to chemoradiationtherapy (CRT) in a prospective phase II protocol. Our hypothesis was that certain combinations of markers had a synergistic effect on those patients with a complete response (pCR) versus other responses. Methods: 132 rectal cancer patients’ tumors were evaluated for mutations and polymorphisms in 23 genes. The factors were selected prospectively as having the potential to influence CRT outcome. Our selected risk factors were transformed to yes/no values from predetermined cutoffs. We performed a massive computational combinatorics search for those combinations of factors associated with tumor response (3 million possible combinations). Our best sets of candidates were those with the largest association with tumor response to CRT (CR vs other) by Fisher’s Exacttests after adjusting for False Discovery Rate. Results: 33 of 132 (25%) patients achieved a pCR and 99 (75%) patients had non-pCR. Our results showed that sets of markers may work alone or synergistically. For example, some markers may not be associated with CRT response by themselves, but are highly correlated to outcome in the presence of other markers. Interactions such as we modeled here are often not considered by informatics software due to computational complexity. Conclusions: A combinatorics approach is computationally expensive but is able to detect marker combinations that are more complex (i.e., nonlinear) than those commonly used in popular informatics software. Our methods are readily extensible to any marker detection scenario, given sufficient computational resources. [Table: see text]
Phosphorylated AMP-activated protein kinase and MAPK3/1 expression associated with prognosis for patients with gastric cancer.
Authors: Kim Jong Gwang , Chae Yee Soo , Kang Byung Woog , Lee Yoo Jin , Kim Min Chan , Kim Ki Han , KIm Su-Jin
Published: February 2017

36

Background: Phosphorylated AMP-activated protein kinase (pAMPK) has central roles in cellular metabolic sensing and energy balance homeostasis, and interact with various pathways [e.g., TP53, MTOR, NUAK2 (sucrose nonfermenting-lkie kinase), MAPK3/1(ERK), and PDK (pyruvate dehydrogenase kinase)]. The present study analyzed the expression of pAMPK, NUAK2, MAPK3/1, and PDK-1 and their impact on the survival of patients with resected gastric cancer. Methods: Six hundred and twenty-one patients with surgically resected gastric adenocarcinoma with curative intent were enrolled in the present study. Immunohistochemical staining for pAMPK, NUAK2, MAPK3/1, and PDK-1 was performed using tissue microarrays of operative specimens of gastric cancer. The expressions were divided into two or three groups according to the intensity score [pAMPK: negative (0), weak to intermediate positive (2), strong positive (3); NUAK2: negative (0), positive (2); MAPK3/1: negative (0), focal positive (2), diffuse positive (3); PDK-1: negative (0), positive (2)]. Results: Positive pAMPK, NUAK2, MAPK3/1, and PDK-1 expression was observed in 379 (61.0%), 257 (41.4%), 327 (52.7%), and 67 (10.8%) cases, respectively. Multivariate survival analysis showed that the survival for the patients with negative expression of pAMPK was worse than for the patients with the weak to strong positive expression [disease free survival (DFS): hazard ratio (HR)=1.361, P=0.029), and the negative expression of MAPK3/1 was also associated with a worse survival compared to the positive expression (DFS: HR=1.401, p=0.029). Conclusions: pAMPK and MAPK3/1 expressions were found to be an independent prognostic marker for patients with gastric cancer. Accordingly, the analysis of pAMPK and MAPK3/1 expression can help identify patient subgroups at high risk of a poor disease outcome.
Colorectal cancer inherited susceptibility: The first replication study in the Brazilian population.
Authors: Gomy Israel , Santos Erika Maria Monteiro , Spilborghs Graziela Machado Gruner Turco , Viola Sandra Regina de Araujo da Silva , Aguiar Samuel , Carraro Dirce Maria , Rogatto Silvia Regina , Carvajal-Carmona Luis , Rossi Benedito Mauro
Published: February 2017

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Background: Inherited susceptibility to colorectal cancer (CRC) is known since twin studies have revealed 35% of heritability. Genome-wide association studies (GWAS) have uncovered less than a half of this proportion through genotyping tagSNPs of individuals with European ancestry. To date only 20 common SNPs have achieved genome-wide significance and replication studies from non-European populations are scarce. Here we show preliminary data of the first study of CRC inherited susceptibility in the Brazilian population and aimed to replicate European studies. Methods: We genotyped 1,395 individuals (675 cases and 720 controls) for 10 tagSNPs (rs6983267, rs4939827, rs4779584, rs16892766, rs10795668, rs4444235, rs9929218, rs10411210, rs961253, rs3802842) using TaqMan SNP Genotyping Assays and SDS2.3 software (Applied Biosystems). We exclude from the analysis SNPs with significant deviation from Hardy-Weinberg equilibrium. Results: Significant association was found between six out of ten SNPs and CRC risk for most genetic models. One SNP (rs10411210) was associated with a low risk of CRC. Conclusions: Despite we did not analyze population stratification, this study partially replicate European GWAS in an admixed population. Therefore, it is worth to explore other ethnic backgrounds that would ultimately help to uncover the missing heritability of CRC and narrow the boundaries of the genetic architecture of CRC susceptibility. [Table: see text]
Presenting characteristics of insured and uninsured patients with anorectal malignancy referred for radiotherapy at an urban safety net hospital.
Authors: Nichols Romaine Charles , Morris Christopher G. , Zaiden Robert Anthony , Awad Ziad , Colaco Rovel , Hoppe Bradford S. , Mendenhall William M. , Mendenhall Nancy Price
Published: February 2017

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Background: This retrospective study compares: presenting characteristics; time intervals between symptom emergence, tissue diagnosis and initiation of therapy; and survival, for insured (IP) and uninsured patients (UP) with anal (22) or rectal (39) malignancy referred for radiotherapy at University of Florida Shands Hospital in Jacksonville. Methods: From 5/2002 to 8/2012, 63 newly diagnosed patients were evaluated. 2 patients were excluded due to mental illness. Records were reviewed to capture: 1.) Patient demographics; 2.) Stage at diagnosis; 3.) Weight loss at diagnosis; 4.) Patient reported date of symptom onset; 5.) Date of tissue confirmation of malignancy; 6.) Date of first therapeutic intervention (i.e. surgery, chemotherapy or radiotherapy); 7.) Insurance status at each of the above time points; and 8.) Survival data. Results: At the time of symptom emergence, 32 patients were uninsured and 29 were insured. Median age of UP was 52 years vs. 64 years for IP (P=0.0005). UP experienced median intervals of 258.5 days between symptom emergence and tissue confirmation of malignancy vs. 58 days for IP (P=0.0013). UP experienced median intervals of 314.5 days between symptom emergence and treatment initiation vs. 120 days for IP (P=0.0024). UP presented with T4 primary tumors in 41% of cases vs. 7% for IP (P=0.0027). UP presented with a median weight loss of 10 lbs vs. 0 lbs for IP (P=0.0158). UP presented with lymph node metastasis in 66% of cases vs. 45% for IP (P=0.1264). With a median follow up of 22 months for UP and 32 months for IP, 2 year actuarial overall survival was 87% for UP and 74% for IP (P=0.5503). Conclusions: UP presented at a younger age than IP (P=0.0005) and demonstrated:1.) Longer intervals between symptom emergence and tissue confirmation of malignancy (P=0.0013); 2.) Longer intervals between symptom emergence and treatment initiation (P=0.0024); 3.) Greater likelihood of presenting with a T4 tumor (P=0.0027); 4.) Greater weight loss at presentation (P=0.0158); 5.) A trend toward a greater likelihood of presenting with lymph node metastasis (P=0.1264); 6.) No difference in actuarial 2 year survival from date of diagnosis compared to IP. (P=0.54).
Population-based trends in positron emission tomography (PET) utilization after resection for colon cancer.
Authors: Bailey Christina Edwards , Hu Chung-Yuan , You Y. Nancy , Rodriguez-Bigas Miguel A. , Kaur Harmeet , Ernst Randy , Skibber John Michael , Chang George J.
Published: February 2017

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Background: While most colon cancer staging and treatment guidelines do not routinely include PET imaging, its use has been increasing. The primary aim of this study is to evaluate the trends in PET utilization during the first 2 years after diagnosis of colon cancer. Methods: A retrospective cohort study of patients ≥ 65 years old with colon cancer who underwent surgical resection in the Surveillance, Epidemiology, and End Results-linked Medicare database (2001-2007, Medicare Part A/B only) and had at least 2 years of follow-up was performed. PET utilization was assessed using the test for trends and multivariate logistic regression for patient, tumor and treatment response characteristics. Results: Of 28,762 patients who underwent primary resection of colon cancer, 3,897 (13.6%) had at least one PET scan within 2 years after surgery. The utilization rate steadily increased from 7.5% in 2001 to 18.7% in 2007 (p = 0.01). A total of 7,175 PET scans were performed on 3,897 patients, among which 2,348 (60.2%) had 1 PET scan, 834 (21.4%) had 2 PET scans and 715 (18.4%) had >2 PET scans. The majority of PET scans were performed within 2 months after surgery (n=1314) and a 2ndpeak was observed at 9 months. Additional factors significantly associated with increased PET scan use included SEER region, stage, and grade (Table). Conclusions: The utilization of PET scans after colon cancer resection has steadily increased since 2001 with the majority of PET scans being performed within 2 months after surgery and its use was subject to geographic variation. Further study is needed to examine the impact of this pattern on long-term oncologic outcomes. [Table: see text]
Association of radiologically defined hepatosteatosis and colorectal cancer liver metastases.
Authors: Parasca Adrian D. , O'Brien Timothy E.
Published: February 2017

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Background: Non alcoholic fatty liver disease (NAFLD) is common, with a prevalence estimated at 15-35%. NAFLD was found to be an independent risk factor for colorectal cancer (CRC). The relationship between CRC and metastasis to a fatty liver has not been well established. We performed a retrospective chart review to address the association of radiologic hepatosteatosis and liver metastases in patients with CRC. Methods: Medical records of 291 patients diagnosed with colorectal adenocarcinoma between 2006-2010 at MetroHealth Medical Center were reviewed. Patients with CRC and no abdominal imaging within 3 months of diagnosis were excluded. Demographic and tumor related data were collected. Presence of hepatic steatosis was defined by radiographic reports (CT, MRI, or US). Results: 6/38 (18.8%) patients with hepatosteatosis had liver metastases, compared to 60/253 (23.7%) with no steatosis. The difference did not reach statistical difference (p=0.40). Hepatosteatosis was noted in 27/280 (9.6%) contrasted CTs, 4/42 (9.5%) MRIs and 12/54 (22.2%) U/S. 66 (22.7%) patients had liver metastases. Patients with ≤3 metastases were less frequent in the non-fatty 22/59 (37.3%) vs fatty liver group 3/6 (50%), but this was not statistically significant (p=0.67). Fatty liver patients were more likely to have a stage ≤ II compared to non-fatty liver patients (OR 2.40, p=0.018). Patients with hepatosteatosis had a higher mean BMI (32.8 vs 27.6, p<0.001). BMI was an independent predictor of steatosis. Alcohol consumption was not associated with BMI or steatosis. There was no statistically significant difference between racial groups and gender with respect to steatosis and liver metastases. Conclusions: This retrospective study suggests that liver metastases in CRC patients are less common in those with fatty livers compared to those with non-fatty livers. CRC patients with hepatosteatosis were also more likely to have earlier stage disease. Larger studies are needed to confirm these findings.
Mucinous neoplasms of the appendix: A single-center experience.
Authors: Guo Sharon , Barry Maura Meredith , Hajdu Cristina , Cohen Deirdre Jill
Published: February 2017

368

Background: Appendiceal neoplasms are poorly understood and represent less than 0.5% of all gastrointestinal cancers. We describe the presentation, pathologic characteristics, and treatment interventions that may have affected patient (pt) outcome. Methods: This is a retrospective review of pts with appendiceal neoplasms treated at NYU Medical Center and/or NYU Cancer Center between 2002-2011. Pt demographics and medical history were collected, including pathology reports, operative findings, imaging studies, treatment and outcomes. Results: 41 consecutive pts with varying stages of appendiceal cancer were identified (70.7% female, median age 57). Most common presentations included: 15 (36.6%) gynecologic complaints, 12 (29.2%) acute appendicitis, and 11 (26.8%) abdominal symptoms. Histologic subtypes were 27 (65.9%) mucinous cystadenomas and 14 (34.1%) adenocarcinomas of which 12 (29.3%) were mucinous adenocarcinoma and 2 (4.9%) were signet cell mucinous adenocarcinoma. Distribution of stages was: 27 (65.9%) stage 0, 2 (4.9%) stage I, 2 (4.9%) stage IIA/B, 6 (14.6%) stage IVA, and 4 (9.8%) stage IVB. All pts underwent one or more of the following procedures: appendectomy (n=39), colectomy (n=9), bilateral salpingo-oophorectomy (n=4), other (n=1). 9 of 10 stage IV pts underwent debulking, of those 2 had suboptimal debulking. 1 stage II pt and 4 stage IV pts (all mucinous adenocarcinoma subtype) received hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin-C (all female, median age 39). In contrast, 6 stage IV pts (2 signet cell adenocarcinoma, 4 mucinous adenocarcinoma subtypes) did not receive HIPEC (67% female, median age 80). 1 pt received systemic 5FU based chemotherapy in addition to HIPEC (female, age 39). Median overall survival (mOS) for all pts ≥ stage II is 32 months. mOS in pts ≥ stage II who did not receive HIPEC is 8 mo whereas mOS in pts ≥ stage II who received HIPEC has not been reached. Conclusions: Appendiceal cancer is frequently detected as an incidental finding for gynecologic and abdominal complaints or presents as acute appendicitis. Surgery is the mainstay of treatment for this disease. Additional therapy including HIPEC may be of benefit in select advanced stage patients.
Racial disparities and the outcome of metastatic (met) colorectal cancer (CRC).
Authors: Barzi Afsaneh , Shabihkhani Maryam , Yu Steven , Yang Dongyun , Ji Lingyun , Lenz Heinz-Josef
Published: February 2017

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Background: Over the past decade survival of patients (pts) with CRC has improved. Although, the mortality rate for CRC is lower in Hispanics (H) than Whites (W), the decrease in mortality has been smaller among H during this period. H are the largest and minority in U.S. and therefore it is important to explain the discordant improvement in their outcome from CRC. We conducted a retrospective review of our CRC pts to determine whether treatment (TX) related factors would explain the observed difference in the outcome. Methods: Data for pts treated with at least one cycle of chemotherapy (CT) in the first line setting for met CRC at Los Angeles County Hospital and Norris Cancer Center between 2004 and 2011 were collected. Pts, disease, and TX related factors were reviewed and included for analysis. H were compared to non-Hispanics (NH) including Asians (A), Blacks (B), and W as a group and to W. Descriptive statistics were used to describe the population and where appropriate chi-square, Wilcoxon, and log-rank tests were used for comparison between the groups. Results: A total of 190 pts, 53% H, 24% A, 10% B, and 13% W were included for analysis. The median age of the population was 55 (21-82) years. 72 % of pts had de-novo met disease. 47% of patients had left, 24% right sided, and 29% rectal cancer. One-third of the patients received bevacizumab in the first line setting. Median time (MT) from first symptom to presentation was 85 days (d); 87 d in H and 74 d in NH (P=0.57). MT from diagnosis to TX was 70 d; 72 d H and 69 d NH (P=0.79). The median time from first TX to progression (TTP) was 8.9 (95% CI: 9.9-12.9) months (m) in H, 11.5 m in NH (P=0.058), and 12.6 m in W (P=0.079). Median BMI was 25.6; 26.5 in H, 24.1 in NH (P=0.001). There was no significance statistical difference between site of the disease, type and number of cycles of CT among the groups. Conclusions: Despite similar access to care in H and NH in our cohort, TTP is shorter for H than NH and W. Although the P is nonsignificant in this small sample, the trend is intriguing. The results need to be confirmed in larger cohorts and prospective studies. Given that the TX for met CRC is mostly unchanged since 2004, the results suggest an inherent biological difference between H and NH with obesity playing a significant role in the outcome.
Stratification of patients with colorectal cancer of UICC stage II using prognostic mutations signatures obtained by deep amplicon sequencing of cancer genes.
Authors: Rosenthal Andre , Ridwelski Karsten , Marusch Frank , Pross Matthias , Mantke Rene , Manger Thomas , Pertschy Jörg , Buthut Thomas , Gellert Klaus , Gruetzmann Robert , Engelhardt Holger , Nartschik Peter , Koll Rainer , Kretschmar Karin , Kretschmar Karl-Heinz , Drescher Bernd , Stecker Katrin , Raspe Ricado , Klaßen Susanne , Adams Hans-Peter
Published: February 2017

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Background: Assignment of patients (pts) with UICC-stage II colorectal cancer (CRC) to adjuvant therapy remains controversial. The clinical utility of histo-pathological parameters (pT4, L+, V+) as well as tumor RNA expression signatures like Oncotype Dx Colon Cancer Assay, ColoPrint, or Predictor C is low given their positive predictive value (PPV) of 0.13, 0.22, 0.19, and 0.33, respectively, when adjusted to an incidence of 10% for occurrence of metastatic disease (mets) within 3 years after diagnosis. Methods: We applied deep amplicon sequencing of 48 well-known cancer genes to DNA samples of primary tumors from 173 pts with UICC-stage II CRC using the Illumina MiSeq technology. Patients were selected from a prospective, multicenter clinical diagnostic study named MSKK. More than 6,500 patients with CRC have been recruited into this study conducted by 39 hospitals in Germany. 79 of the 173 pts had progression of disease events within 3 years after R0 resection including 40 pts with mets, 12 pts with local recurrences, and 27 pts with secondary malignancies. 94 pts remained progression-free. Results: Deep sequencing revealed a total of 2,221 sequence variations (SV) including missense, stop, InDel, noncoding, nonsense SV. 401 SV were in COSMIC, 750 SV in normal tissue. The remaining 1471 SV served as basis for development of SV-signatures (SVS) for prediction of progression events in a classical double-nested bootstrap approach in order to generate second order unbiased estimates of performance of SVS, namely sensitivity(S+), specificity (S-), PPV, and negative predictive value (NPV). The best SVS for prediction of metastases contained SV in less than 15 genes and has a S+ of 0.41, S- of 0.93, PPV of 0.40, and NPV of 0.93 (incidence of metastasis: 10%). The best SVS for prediction any progression event has a S+ of 0.33, S- of 0.93, PPV of 0.54, and NPV of 0.84 (incidence for any progression = 20.5%). Conclusions: This deep sequencing based prognostic tissue test with a PPV of 40% and a NPV of 93% represents a milestone over prognostic tests based on RNA expression. The increased PPV leads to more patients being treated correctly with adjuvant therapy.