bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of change in AFP > 15 ng/ml/month with stage at diagnosis and mortality in patients with hepatocellular carcinoma (HCC).
Authors: Ilagan-Ying Ysabel , Kaplan David Edward , Taddei Tamar H. , Njei Basile
Published: March 2017

255

Background: In a recent study, a change in AFP > 15 ng/ml/month was associated with poor post-transplant HCC survival. We hypothesized that change in AFP is associated with stage of HCC at diagnosis and mortality. Methods: Patients with potential HCC from 2008-2010 were identified by querying the Veterans Administration Corporate Data Warehouse. Diagnostic confirmation and tumor staging was obtained by manual chart abstraction. Dates of death were ascertained and censored from 12/31/2014. Logistic regression analysis was performed to determine the association between change in AFP and stage at diagnosis. Multivariable cox regression analysis adjusting for severity of liver disease was performed to determine the association between change in AFP and all-cause mortality. Results: Of 3,988 HCC cases, change in AFP > 15 ng/ml/month was associated with presentation at BCLC stage B (OR 2.26, CI 1.54-3.33, p < 0.001) and C (OR 3.39, CI 2.25-5.01, p < 0.001). There was no statistically significant association between AFP > 15 ng/ml/month with stage BCLC 0 or A (early HCC), or with BCLC stage D, likely reflecting a greater burden of liver disease severity over tumor burden in Stage D. Change in AFP > 15 ng/ml/month was associated with increased all-cause mortality (HR 1.49, CI 1.37-1.62, p < 0.001). Conclusions: In a large cohort of US Veterans with HCC, change in AFP > 15 ng/ml/month may be a useful prognostic marker for presentation with advanced stage cancer and all-cause mortality.
A novel t-stage classification system for adrenocortical carcinoma: Proposal from the U.S. Adrenocortical Carcinoma Study Group.
Authors: Poorman Caroline Elizabeth , Ethun Cecilia Grace , Postlewait Lauren McLendon , Tran Thuy , Pawlik Timothy M. , Wang Tracy S , Hatzaras Ioannis , Phay John E , Fields Ryan C , Weber Sharon M. , Sicklick Jason K. , Yopp Adam Charles , Prescott Jason David , Duh Quan-Yang , Solorzano Carmen C. , Votanopoulos Konstantinos Ioannis , Poultsides George A. , Maithel Shishir Kumar
Published: March 2017

266

Background: The 7th AJCC T-stage classification system for adrenocortical carcinoma (ACC), based on size and extra-adrenal invasion, does not adequately stratify patients by survival. Lymphovascular invasion (LVI) is a known poor prognostic factor. We propose a novel T-stage system that incorporates LVI to better risk-stratify patients undergoing resection for ACC. Methods: Patients undergoing curative-intent resections for ACC from 1993-2014 at 13 institutions comprising the US ACC Study Group were included. Primary outcome was disease-specific survival (DSS). Results: Of 265 patients with ACC, 149 had complete data for analysis. The current T-stage system failed to differentiate patients with T2 vs T3 disease ( p= 0.10). Presence of LVI was associated with worse DSS compared to no LVI (36 vs. 168mos; p= 0.001). After accounting for the individual components of the current T-stage system (size and extra-adrenal invasion), LVI persisted as a poor prognostic factor on multivariable analysis (HR 2.14, 95% CI 1.05-4.38, p= 0.04). LVI positivity further stratified patients with T2 and T3 disease, (T2: 37mos vs median not reached; T3: 36 vs 96mos; p =0.03), but did not influence survival in patients with T1 or T4 disease. By incorporating LVI, a new T-stage classification system was created: [T1: < 5cm, (-)local invasion, (+/-)LVI; T2: > 5cm, (-)local invasion, (-)LVI OR any size, (+)local invasion, (-)LVI; T3: > 5cm, (-)local invasion, (+)LVI OR any size, (+)local invasion, (+)LVI; T4: any size, (+)adjacent organ invasion, (+/-)LVI]. Each progressive new T-stage group was associated with worse median DSS (T1: 167mos; T2: 96mos; T3: 37mos; T4: 15mos; p< 0.001). Conclusions: The current AJCC T-stage system for ACC does not adequately stratify patients by survival, particularly for T2 and T3 disease. The proposed T-stage classification system, which incorporates lymphovascular invasion, better differentiates T2 and T3 disease and accurately stratifies patients by disease-specific survival. If externally validated, this novel T-stage classification should be considered for future AJCC staging systems.
Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: Results of GASTric cancer HER2 reassessment study 3 (GASTHER3).
Authors: Seo Seyoung , Ryu Min-Hee , Ahn Ji Yong , Park Yangsoon , Park Sook Ryun , Ryoo Baek-Yeol , Park Young Soo , Lee Gin Hyug , Jung Hwoon-Yong , Kang Yoon-Koo
Published: March 2017

27

Background: Although discordance of HER2 positivity between primary and metastatic lesions was well known, changes of HER2 positivity after chemotherapy have not been studied in gastric cancer (GC). Methods: A total of 48 HER2-positive advanced GC (AGC) patients who were treated with trastuzumab-containing 1stline chemotherapy and had paired biopsies at baseline and after progression were enrolled. Scores of HER2 immunohistochemistry (IHC) were reviewed and in situ hybridization (ISH) was conducted when tissues were available. Results: Thirty-nine patients were treated with capecitabine, cisplatin/oxaliplatin, and trastuzumab (XPT) while the other 9 received XPT plus pertuzumab/placebo. Objective response rate (ORR) was 76% (26 out of 34) and median progression free survival (PFS) and overall survival were 8.3 and 16.3 months, respectively. At baseline, HER2 was positive with IHC 2+ and ISH+ in 5 and with IHC 3+ in 43. Loss of HER2 positivity after progression was observed in 14 (28.6%); 10 with IHC 0 or 1+ and 4 with IHC 2+ but ISH- at 2nd biopsy. HER2 remained positive in the other 34; 4 with IHC2+ and ISH+, and 30 with IHC 3+ at 2nd biopsy. Applying H-score formula, mean scores decreased from 201 to 170 (Wilcoxon test; p=0.047). HER2 genetic heterogeneity (5% to <50% of tumor nuclei showing a HER2:CEP17 ratio ≥2) was noted only 1 out of 34 ISH-assessable patients (2.9%) at baseline while 7 out of 32 ISH-assessable patients (21.9%) had heterogeneity at 2nd biopsy. The mean ratio was changed from 6.5 (1.2-15.8) to 5.0 (0.4-15.2) (paired t-test, p=0.019) and all patients with genetic heterogeneity at 2ndbiopsy showed HER2 negative conversion. Among 13 who received 2ndline T-DM1, 3 showed HER2 negative conversion. Those 3 had no objective response at all and very short PFS (1.2, 1.3 and 3.4 months), whereas the others with stable HER2 status showed 44% of ORR and median PFS of 2.7 (0.4-36.8) months. Conclusions: A substantial portion of initially HER2-positive AGC patients showed HER2 negative conversion with increased HER2 heterogeneity after trastuzumab-containing chemotherapy. Loss of HER2 positivity could be a predicting factor for 2nd line anti-HER2 treatment.
Retrospective study of CT-guided radiofrequency ablation and laparoscopic radiofrequency ablation in the treatment of recurrent small hepatocellular carcinoma against the diaphragmatic dome.
Authors: Zheng Qin , Ding Huaiyin , Zhu Chuandong , Wang Lixue , Wan Yuan
Published: March 2017

272

Background: Radiofrequency ablation (RFA) have been used to treat hepatocellular carcinoma (HCC) in the subphrenic area. Very few studies focus on ablation of recurrent small HCC against the diaphragmatic dome. The therapeutic safety, efficacy, and hospital fee have never been compared between CT guided RFA and laparoscopic RFA (L-RFA) either. Methods: CT guided RFA and L-RFA were performed in totally 116 patients with 151 local recurrent HCC lesions abutting the diaphragm. We compared major and minor postoperative complications, hospital stay and fee, overall survival (OS), and local tumor progression (LTP) between two groups for evaluating respective therapeutic efficacy and safety. Moreover, in CT-guided percutaneous RFA group, depending on the locations of recurrent HCC nodules differentiated puncture paths and ablation methods were used, and intraoperative complications were recorded. Results: There is no significant difference in OS and LTP between CT- guided RFA and LRFA.In recorded postoperative complications, the morbidity in CT-guided RFA group is lower than that of L-RFA group. The average safety margin is 8 and 11 mm in CT-guided RFA and LRFA group, respectively. The shoulder and back pain is significantly high in L-RFA group probably due to pneumoperitoneum. Moreover, overall hospital stay and cost is also lower in CT-guided RFA group. Conclusions: Both CT-guided RFA and L-RFA are considered to be an effective approach for recurrent small HCC abutting diaphragm. Particularly, CT-guided RFA is an easy and economic with less complications if suitable puncture paths and ablation methods can be applied.
Effect of a mixed type Lauren's classification on agressiveness and lymph node metastasis in early gastric cancer.
Authors: Pyo Jeunghui , Lee Hyuk , Shin In Seub , Kim Tae Jun , Min Yang Won , Lee Jun Haeng , Kim Jae J. , Min Byung-Hoon
Published: March 2017

28

Background: The clinicopathological features of mixed type (MT) early gastric cancer (EGC) according to Lauren’s classification remain uninvestigated. This study aimed to clarify the clinicopathological features of MT EGC, particularly in relation to lymph node metastasis (LNM) and long-term survival. Methods: This study included 5,309 patients who underwent gastrectomy for EGC. The clinicopathological features, LNM, and long-term outcomes of patients with MT carcinomas were compared to those with intestinal type (IT) and diffuse type (DT) cancers. Furthermore, we evaluated the predictors of LNM in each Lauren classification subgroup. Results: Patients with MT carcinomas were more likely to have larger tumors, submucosal invasion, lymphovascular invasion (LVI), and LNM compared to those with IT or DT carcinomas. Multivariate logistic regression analysis revealed that Lauren’s classification was a significant predictor of LNM ( P < 0.001). The significant predictors of LNM in MT carcinomas were female sex, greater tumor size, presence of submucosal invasion, and LVI. However, the overall survival of patients with MT carcinoma was not significantly different from that of patients with IT or DT carcinomas ( P= 0.104). Conclusions: The presence of MT EGC carries a higher risk of LNM compared to IT or DT carcinomas. Therefore, MT carcinomas should be managed with gastrectomy that includes lymph node dissection instead of endoscopic resection.
Thromboembolic events (TE) among patients with metastatic pancreatic ductal adenocarcinoma (mPDA) after chemotherapy (Chemo).
Authors: Lyman Gary H. , Schabert Vernon F , Philip Philip Agop , Stokes Michael , Bhurke Sharvari , Kuderer Nicole M , Qadan Ammar , Khorana Alok A.
Published: March 2017

280

Background: Clinical trials suggest that patients with mPDA are at high risk of TE from both disease and treatment. TE rates and anticoagulant use among mPDA patients after first line chemo were investigated. Methods: Medicare beneficiaries enrolled in parts A, B, and D; diagnosed with mPDA; aged ≥ 65 years; and starting chemo between 1/1/2007 and 12/31/2012 were obtained from Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Eligible patients were enrolled from 12 months before chemo and followed until death, post-chemo disenrollment, or 12/31/2012. Arterial (ICD-9 410-411, 433-434), venous (ICD-9 415.1x, 453.4x, 453.8x, 453.9), and total TE were defined as ≥ 2 outpatient diagnoses ≥ 30 days apart, one inpatient diagnosis, or one outpatient diagnosis followed by outpatient anticoagulants within 90 days. Post-chemo TE incidence was calculated as the number of first events per 100 person-years (PY) for patients with and without TE 12 months before chemo. Time from chemo to first TE was estimated using the Kaplan-Meier (KM) method. Results: Among 1,308 eligible patients, mean age was 74 years [range 65-93]; 56% were female; 85% had no prior TE. Overall, 419 (32%) had a TE after chemo including 121 (9%) arterial and 363 (28%) venous TE. The table shows incidence, and time to TE for those with and without prior TE. Outpatient anticoagulants were prescribed for 276 (25%) patients with no prior TE and 110 (57%) patients with prior TE. Table. TE incidence and time to TE among mPDA patients after chemo Conclusions: mPDA patients face a substantial risk of TE after chemo, with nearly one-third of patients without prior TE and one-half of patients with prior TE experiencing events during treatment. These high rates of TE indicate the importance of conducting risk assessments for preventive measures early during a patients’ care.[Table: see text]
Adjuvant therapy in stage II pancreatic cancer: A National Cancer Database analysis.
Authors: Ahmed Aabra , Walters Ryan W , Malouff Timothy Dean , Krishnan Mridula , Jabbari Javaneh , Silberstein Peter T.
Published: March 2017

283

Background: Oldfield et al (2015) showed the conflicting evidence regarding the effect of adjuvant chemotherapy vs. chemoradiation in pancreatic cancer. Using patients identified by the National Cancer Database (NCDB), we are the largest study to compare survival in stage II pancreatic cancer patients who received adjuvant chemotherapy, chemoradiation, radiation, or no adjuvant therapy. Methods: We identified 65,091 patients with stage II pancreatic cancer who received surgery only or surgery in combination with chemotherapy, radiation, or chemoradiation. Between-therapy survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p < .05 indicated statistical significance. Results: Patient characteristics were similar between groups; although, patients receiving chemoradiation were younger, had fewer comorbidities, and were more likely to have private insurance compared to all other therapy groups. Statistically significant survival differences were indicated between all therapy groups (all adjusted p< 0.05), as patients receiving chemoradiation had the longest survival followed by patients receiving chemotherapy, patients receiving radiation therapy, and patients receiving no adjuvant therapy (median survival = 22.5, 19.6, 16.9, 14.8 months, respectively). When examining other variables, patients living in an area with a median income < $43,000 were 14% more likely to die compared to patients in an area with a median income ≥ $63,000 (p < 0.001) and those with no comorbidities were 19% less likely to die than patients with two or more comorbidities (p < 0.001). Conclusions: Our data suggests that adjuvant therapy improves median and 3-year survival compared to no adjuvant therapy. Of all adjuvant therapies examined, adjuvant chemoradiation was associated with the greatest increase in survival, followed by adjuvant chemotherapy. Table 1: Median survival and survival rates of stage II pancreatic cancer [Table: see text]
A phase I/II trial of MEK162 in combination with gemcitabine (G) and cisplatin (C) for patients (pts) with untreated advanced biliary cancer (ABC).
Authors: Lowery Maeve Aine , O'Reilly Eileen Mary , Harding James J. , Yu Kenneth H. , Cercek Andrea , Hollywood Ellen , Salehi Erica , Margona Ezra , Bradley Mikaela , Witter Trevor , Gerst Scott R. , Capanu Marinela , Saltz Leonard , Abou-Alfa Ghassan K.
Published: March 2017

290

Background: Activating mutations in the RAS/RAF/MEK/ERK signaling pathway are commonly found in ABC. MEK162 is an oral, selective small molecule inhibitor of MEK1/2; single agent activity of MEK162 in ABC has previously been observed. Preclinical data support anti-tumor synergy for MEK inhibition (MEKi) when combined with G & C, only when MEKi is held for 2 days prior to and on day of each G and C infusion. Methods: A Single arm, non-randomized, open-label, phase I/II,evaluated oral MEK162 twice daily with G and C IV infusions day 8 and 15 of a 21 day cycle. MEK162 was. Eligibility criteria were: untreated ABC, with advanced measurable disease, ECOG 0-1, adequate hematologic, renal, hepatic and cardiac function. The primary endpoints were to determine the MTD (phase 1); and 6 month PFS and response rate (RR) (phase II). Tumor tissue for targeted somatic mutational sequencing was evaluated. Results: Between 09/13 and 09/15, 12 pts were enrolled on phase 1, the MTDs were MEK162 45mg PO BID, in combination with G 800 mg/m2 and C 20mg/m2. 35 pts evaluable for primary endpoint of phase II (29 treated on phase II & 6 pts treated at MTD in phase 1): Male = 19, median age 63 years (range 48- 77). Cholangiocarcinoma (CC) = 24, and gallbladder adenocarcinoma (GB) = 11. Median overall survival was 21 months (95% CI 11- NA), median PFS 6 months (95% CI 4-14). Molecular profiling using MSK-IMPACT 410 gene panel was feasible in 29 pts; aberrations in the RAS-RAF-MEK-ERK pathway were notable in responding pts including mutations in PIK3CA, AKT2, PIK3CG, KRAS, BRAF and MAP3K1. Overall RR was 36%, GB 45%, CC 32%. Two pts had CR, two pts remain on study > 24 months, currently on MEK162 alone. Conclusions: The MTDs were MEK162 45mg PO BID, in combination with G 800 mg/m2 and C 20mg/m2.. Significant activity of the combination was noted in select pts with prolonged and complete response to treatment. Molecular profiling of BTC may facilitate selection of pts for further development of the combination. Clinical trial information: NCT01828034.
A phase IB study of CX-4945 in combination with gemcitabine plus cisplatin in the frontline systemic treatment of patients with advanced cholangiocarcinoma.
Authors: Borad Mitesh J. , Hubbard Joleen Marie , Oh Do-Youn , Rha Sun Young , Mody Kabir , Lim John K.C. , Richards Donald A.
Published: March 2017

294

Background: CX-4945 is a first-in-class casein kinase-2 (CK2) threonine kinase small molecule inhibitor. CK2 is pleiotropic and regulates key cellular processes such as proliferation and DNA damage repair, and has been shown to enhance efficacy of gemcitabine (G) and cisplatin (C) in cell line and xenograft CCA model systems. A Phase IB study of G+C with CX-4945 was conducted in advanced cholangiocarcinoma (CCA) patients. Methods: A multi-center “3+3” dose escalation study was conducted in advanced CCA patients. Eligible patients had ECOG PS 0-1 and adequate hematologic, hepatic, and renal function. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints included pharmacokinetic (PK) analyses, overall toxicity evaluation and preliminary assessment of efficacy. Routine clinical dosing for G (1000 mg/m2) and C (25 mg/m2), both on days 1 and 8 every 21 days, was used. Dose escalation cohort were CX-4945 given twice daily on days 0,1,2 and 7,8,9 at 200 mg (DL1), 400mg (DL2), 600 mg (DL3), 800 mg (DL4) and 1000 (DL5) mg. NCI CTCAE v4.03 was used for toxicity assessment and RECIST v1.1 for efficacy evaluation. Results: Nineteen patients were enrolled (DL1:n = 3; DL2:n = 4 DL3:n = 3; DL4:n = 4; DL5:n = 5). No dose limiting toxicities were encountered. MTD and RP2D were ascertained to be DL5. No grade 3 or 4 toxicities at prevalence > 10% were encountered and the overall toxicity profile of the combination was reflective of standard G+C toxicity profile. At data cut-off, preliminary efficacy evaluation demonstrated disease control rate (CR+PR+SD) of 64% (PR:32%, SD:32% and CR:0%), along with median progression-free survival (PFS) of 5 months (range 0-14 months). PK analyses showed no evidence of drug-drug interactions between G, C and CX-4945. Conclusions: RP2D for G+C with CX-4945 is DL5 (CX-4945 dosed on days 0,1,2 and 7,8,9 at 1000 mg PO bid with standard G and C dosing). Preliminary clinical efficacy and tolerability of the regimen support planned controlled, randomized Phase 2 evaluation. Clinical trial information: NCT02128282.
Evaluation of efficacy of oral administration of pro-drug of triptolide against pancreatic cancer.
Authors: Dudeja Vikas , Sharma Nikita , Modi Shrey , Merchant Nipun B. , Vickers Selwyn M. , Banerjee Sulagna , Saluja Ashok
Published: March 2017

296

Background: Pancreatic cancer is an aggressive disease. The current chemotherapy only marginally increases the survival of patients with PDAC. Hence there is an urgent need for novel therapies. We have shown that minnelide, a pro-drug of triptolide which is currently in phase I trials, when administered intra-peritoneally is very effective against pancreatic cancer in multiple animal models. In the current study we evaluated the efficacy of oral minnelide against pancreatic cancer, alone or in combination with standard therapy in PDAC. Methods: Xenograft, subcutaneous and orthotopic models were established using S2-VP10 and MIA PaCa-2 cell lines. Minnelide was used in doses ranging from 0.15-0.6 mg/kg/day either oral or i.p. and standard chemotherapy was gemcitabine 250 mg/kg/week + nab-paclitaxel 25 mg/kg/week. The tumor burden was compared between various treatment groups. Results: Minnelide i.p significantly decreased tumor mass in MIA PaCa-2 derived tumors and oral administration had equipotent effects. In the S2-VP10 model, combination of low doses of orally administered minnelide with gemcitabine + nab-paclitaxel was significantly more effective in decreasing the tumor burden leading to an increased survival of tumor bearing mice when compared with either therapy alone (p < 0.05). Combination therapy significantly reduced cancer-related morbidity by decreasing ascites and metastasis. Conclusions: Oral administration of minnelide is effective against pancreatic cancer at doses which have been shown to be safe in phase I clinical trial. Oral minnelide has great potential to emerge as novel therapy for pancreatic cancer.
RNA profiling of neuroendocrine tumors (NETs) to define new targets and mechanisms of progression.
Authors: Vijayvergia Namrata , Peri Suraj , Devarajan Karthik , Pei Jianming , Gong Yulan , Cohen Steven J. , Astsaturov Igor A. , Engstrom Paul F.
Published: March 2017

302

Background: NETs lack mutations in the “classical” signaling pathways but share mutations in regulators of gene expression (Jiao; 2011). We compared gene expression in PD & WD NETs to identify novel targets and biomarkers of differentiation. Methods: High quality RNA, extracted from paraffin blocks of deidentified NETs under an IRB-approved protocol, was profiled using a 770 gene panel (nCounter PanCancer pathway, Nanostring Technologies). The resulting data was used to identify the differentially expressed genes between PD and WD NETs using limma software (Ritchie; 2015). Gene Set Enrichment Analysis (Subramanian; 2005) identified differential pathway enrichment by calculating a Normalized Enrichment Score (NES). Results: Analysis of 16 PD and 23 WD NET samples identified 154 genes as extreme outliers ( > 2 fold up/downregulation between the subtypes). Compared to WD NETS, drug targets of interest overexpressed in PD NETs were histone lysine methyltransferase EZH2, and a cell cycle regulator CHEK1 (6.5x and 8.1x, respectively, p < 0.001). In contrast, serine/threonine protein kinase PAK 3 was upregulated in WD (10.6x, p < 0.001). These and other biomarkers will be further validated by immunolabeling of tissue sections. We also found differential enrichment of canonical pathways in PD versus WD NETs (table). Conclusions: Extreme outlier transcripts identified in PD & WD NETs support investigation of inhibitors of EZH2 (e.g. EPZ6438) and CHEK1 (e.g. LY2606368) in PD and PAK3(e.g. FRAX597) in WD NETs. Genes involved in cell cycle regulation and DNA repair in PD NETs and calcium / G protein coupled receptor signaling in WD NET account for biological differences between the 2 molecular subtypes and warrant future investigation as classifiers for NETs. Our findings provide mechanistic insights into the biology of NET and targets for therapy with direct clinical implications.[Table: see text]
Efficacy and safety of liposomal irinotecan (nal-IRI) + 5-fluorouracil and leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously received gemcitabine (gem)-based therapy: Post-hoc analysis of the NAPOLI-1 trial.
Authors: Chen Li-Tzong , Wang-Gillam Andrea , Yanshen Shan , Macarulla Teresa , Blanc Jean-Frédéric , Hubner Richard , Chiu Chang-Fang , Schwartsmann Gilberto , Siveke Jens T. , Pipas J. Marc , Belanger Bruce , de Jong Floris , Mamlouk Khalid , Von Hoff Daniel D.
Published: March 2017

303

Background: nal-IRI+5-FU/LV is approved in the United States and Taiwan for pts with mPDAC previously treated with gem-based therapy based on the NAPOLI-1 study which showed that nal-IRI+5-FU/LV improved overall survival (OS) vs 5-FU/LV (6.1 vs 4.2 mo; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). This post hoc analysis evaluated the efficacy and safety of nal-IRI+5-FU/LV in subgroups of pts defined by prior gem regimen including gem monotherapy and gem combinations (combo). Methods: This analysis (data cutoff, Nov 2015) focuses on the 236 pts assigned to nal-IRI+5-FU/LV q2w (n = 117) or 5-FU/LV qw for weeks 1-4 q6w cycle (n = 119). Pts previously received gem-based therapy in a neoadjuvant, adjuvant, locally advanced, or metastatic setting. Results: Of 117 pts in the nal-IRI+5-FU/LV arm, 53 (45%) previously received gem monotherapy and 64 (55%) previously received gem combo including erlotinib (n = 9) or nab-paclitaxel (n = 20). Of the 119 pts in the 5-FU/LV arm, 55 (46%) previously received gem monotherapy and 64 (54%) previously received gem combo including erlotinib (n = 17) or nab-paclitaxel (n = 11). Nal-IRI+5-FU/LV improved median OS, median PFS, and ORR vs 5-FU/LV, regardless of prior therapy (Table). Grade ≥3 treatment-emergent adverse events were not influenced by prior treatment. Clinical trial information: NCT01494506. Conclusions: These resultsshow consistent benefit of nal-IRI+5-FU/LV treatment across subgroups of pts who previously received gem therapy and support the ASCO guidelines recommending nal-IRI+5-FU/LV for this pt population. These analyses may be limited by the small sample size of treatment arms.[Table: see text]
A phase I study of ADH-1 with cisplatin (Cisp) and gemcitabine (Gem) in patients (Pts) with unresectable or metastatic pancreatic and biliary tract cancers.
Authors: Berim Lyudmyla Derby , Kos Beth M , Evande Ruby , Meza Jane L , Shostrom Valerie , Schwarz James K. , Grem Jean L.
Published: March 2017

306

Background: Pancreatic cancer cells in vitro undergo epithelial to mesenchymal transformation (EMT) by up-regulating mesenchymal markers, including N-cadherin. The EMT leads to increased motility & invasiveness with collagen exposure in a pancreatic cancer mouse model, which can be inhibited by N-cadherin knockdown. ADH-1 is a small, cyclic pentapeptide with inhibitory effects on stromal & endothelial cells expressing N-cadherin. Methods: Escalating doses of ADH-1 were given twice weekly for 3 wk (1,000, 2,000 & 4,000 mg) with Cisp 25 mg/m2 & Gem1000 mg/m2/100 min days 1 & 8 of a 3 wk cycle in pts with pancreaticobiliary cancers with ECOG PS 0-2 & adequate bone marrow, renal & hepatic function. Standard 3 + 3 dose escalation was used. Peripheral blood was collected for biomarkers prior to each dose of ADH-1 during cycle 1. Due to limited drug supply, ADH-1 was given for the 1st 3 cycles. Results: Between 05/2013 - 04/2015, 17 pts were enrolled, received at least 1 dose of therapy, and were evaluable for toxicity: m 13/F 4; median 60 yr (range 37-81); pancreas 9 /biliary 8. 3 pts had prior adjuvant therapy. The number pts with dose-limiting toxicity during cycle 1 of ADH-1 (mg) were 0/4 at 1,000; 1/7 at 2,000 (gr 4 ANC, platelet); 2/6 pts 4,000 mg (1 pt: gr 3 pulmonary embolus and gr 4 plt; 1: gr 4 cholangitis/sepsis/multiorgan failure). 5 of 8 pts who had ≥ 6 cycles were taken off study due to cumulative toxicities rather than PD. 14 pts had ≥ 3 cycles of therapy and were evaluable for response: SD in 9 subjects; PD in 5. The median number cycles was 5.5 (range 1-30). Median time to treatment failure (TTF) for all patients was 113 days (range 7-724). Median OS was 218 days (7-853+). Pts with biliary cancer had a longer TTF and OS vs pancreatic cancer (TTF 217 vs 93 days; OS 305 vs 180 days). 6 pts survived > 12 months (biliary 4, pancreas 2). Biomarker analysis (ICAM 1; E selectin; VEGF, Soluble VEGF-R 2 and 3, FGF basic) is ongoing. Conclusions: The phase II dose of ADH1 given with Cisp/Gem is 2,000 mg IV twice weekly. ADH-1 was relatively well tolerated. Most pts ultimately required dose delays or reductions due to cumulative toxicity with Cisp/Gem. Clinical trial information: NCT01825603.
Detection of circulating tumor cells (CTC) using a non-EpCAM-based, high-definition, single-cell assay in advanced hepatocellular carcinoma (HCC) for patients enrolled on phase I and II trials of sorafenib plus temsirolimus.
Authors: Kelley Robin Kate , Rodriguez Lee Mariam , Hwang Jimmy , Gordan John Dozier , Nimeiri Halla Sayed , Bocobo Andrea Grace , Kircher Sheetal Mehta , Kanakamedala Advaita , Mulcahy Mary Frances , Benson Al Bowen , Kuhn Peter , Venook Alan P.
Published: March 2017

311

Background: Noninvasive biomarkers are needed for diagnosis, prognosis, and molecular profiling of HCC due to scarcity of tumor tissue and heterogeneous tumor biology. CTC are detectable in metastatic HCC using methods which enrich for expression of the cell adhesion molecule, EpCAM. Because a subset of HCC does not express EpCAM, however, non-EpCAM enrichment methods are needed for CTC studies in HCC. Methods: This CTC cohort was derived from patients enrolled on multicenter phase 1 and 2 trials of the combination of sorafenib plus temsirolimus in advanced HCC (NCT01008917, NCT01687673) with approval and funding from the National Comprehensive Cancer Network (NCCN) Oncology Research Program. Eligibility required histologic diagnosis of incurable HCC with no prior systemic therapy. All patients in the cohort were treated at the recommended phase 2 dose of sorafenib 200 mg PO BID and temsirolimus 10 mg IV weekly. Whole blood samples were collected at baseline and on treatment. CTC were enumerated and analyzed cytomorphologically using a high-definition, single cell assay without EpCAM enrichment and blinded to clinical outcomes. Results: The CTC cohort was comprised of 36 patients (phase 1 n = 9, phase 2 n = 27). Characteristics: male 89%; white 64%, Asian/PI 28%, black 6%; HBsAg+ 31%, HCV+ 44%; Child Pugh A 92%, B7 8%; BCLC C 83%; tumor vascular invasion 47%; median AFP 74 ng/mL. Median OS from start of treatment was 392 days (95% CI: 214, 569). CTC ≥ 1/mL were detectable at baseline in 23/36 (64%) overall (95% CI: 47%, 80%), with similar findings in the phase 1 (56%) and phase 2 (67%) subsets. There was no significant relationship between baseline CTC values ≥ 1, 2, or 5/mL and overall survival (OS) on univariate analysis. Analyses of CTC relationship to clinical characteristics and time to progression, changes on treatment, and multivariable analysis for relationship to OS will be presented. Conclusions: CTC were detected in over 60% of patients in this advanced HCC clinical trial cohort using a non-EpCAM, high-definition single cell assay, suggesting future potential for noninvasive molecular profiling of HCC.
Germline mutations in seemingly sporadic pancreatic cancer.
Authors: Wong Cavin , Cuggia Adeline , Borgida Ayelet , Holter Spring , Hall Anita , Connor Ashton , Akbari Mohammad R , Gallinger Steven , Zogopoulos George
Published: March 2017

312

Background: Genetic predisposition underlies approximately 10% of pancreatic cancer (PC). Germline mutations in BRCA1, BRCA2, PALB2, ATM, TP53, MLH1, MSH2, MSH6, PMS2, PRSS1, APC, BMPR1A, STK11, CDKN2A, and SMAD4 are associated with PC susceptibility. Since young onset is not a hallmark of hereditary PC, we have hypothesized that seemingly sporadic cases may carry germline mutations in these genes. Methods: To investigate the prevalence of germline mutations in these 15 genes among sporadic PC cases, we analyzed lymphocyte DNA next generation sequencing data from 296 PC cases ascertained over 1 year from two PC referral centers in Toronto and Montreal. Results: We identified 21 mutations in 5 of the 15 genes (10 in BRCA2, 2 in BRCA1, 5 in ATM, 1 in p16, 3 in PRSS1) in 19 individuals. One individual carried two BRCA2 mutations that are usually observed together, and another individual carried both a PRSS1 and ATM mutation, however, in the absence of pancreatitis, PRSS1 mutations are not known to increase risk of PC. Incidences of 1.7% and 4.1% in ATM and BRCA-1 or -2 were observed. Approximately half of these mutations (4/9 for BRCA2, 1/2 for BRCA1, and 1/1 for p16) were known founder mutations in the French Canadian, Ashkenazi Jewish, Dutch or Asian populations. Since the role of ATMin PC predisposition remains under investigation, we obtained further evidence by testing for loss of the wild-type allele in cases with available tumor tissue. We observed loss of the wild-type allele in the 2 cases tested. Interestingly, the final pathology for the resected specimen from one of these two cases favored an ampullary cancer rather than a PC diagnosis. Conclusions: Since there are screening implications for the relatives of carriers and potentially treatment considerations for patients using therapies targeting DNA repair defects, these findings suggest a role for reflex testing of incident cases for at least population-specific recurrent mutations. Our findings also suggest that ATM germline mutations may give rise to ampullary cancer, underlie 1.4% of incident PC cases and imply broader testing considerations. For patients, testing may direct therapy choices if these tumors are targetable using agents that exploit DNA repair defects.
Tremelimumab: A monoclonal antibody against CTLA-4—In combination with radiofrequency ablation (RFA) in patients with biliary tract carcinoma (BTC).
Authors: Duffy Austin G. , Pratt Drew , Kleiner David E , Mabry Donna , Fioravanti Suzanne , Walker Melissa , Figg William Douglas , Steinberg Seth M. , Anderson Victoria , Krishnasamy Venkatesh , Wood Bradford J. , Greten Tim F.
Published: March 2017

316

Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Radiofrequency ablation (RFA) has been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment. Methods: Patients with refractory BTC were enrolled in a study of monthly Tremelimumab (10mg/kg, 6 doses) combined with RFA (to one lesion) performed on week 6. Tumor biopsies were performed at time of RFA with regular PBMC collection for intensive immunemontoring. Results: 17 pts enrolled. Characteristics: M:F 8:9; Median age 57(range 36-67); BTC subtype - intrahepatic/exrahepatic: 12/5. 13/17 had metastatic disease. All pts were chemorefractory with 12/17 having received at least 2 regimens. While on study, 6 pts had early PD within 6 weeks; 11 were able to undergo RFA. No DLT encountered. Most common toxicity was pruritus. There were no objective responses. Of evaluable pts N = 6 (55%) had stable disease as a best response. Conclusions: Tremelimumab in combination with subtotal RFA in patients with advanced BTC is safe and feasible. No objective responses have so far been seen in this predominantly primary intrahepatic BTC population. Full efficacy and immune monitoring data will be presented. Clinical trial information: NCT01853618.
Population pharmacokinetics (popPK) to evaluate the effect of intrinsic and extrinsic factors on regorafenib (REG) exposure in REG studies including patients with hepatocellular carcinoma (HCC).
Authors: Ploeger Bart , Cleton Adriaan , Keunecke Anne , Bruix Jordi , Meinhardt Gerold
Published: March 2017

320

Background: REG is approved for refractory metastatic colorectal cancer (CRC) and gastrointestinal stromal tumors (GIST). In the phase 3 RESORCE trial (N = 573), REG (160 mg QD, 3 weeks on/1 week off) significantly (P < 0.001) improved overall survival (OS) vs placebo in HCC patients who progressed on sorafenib (HR 0.63; 95% CI 0.50‒0.79). We evaluated REG PK in RESORCE using a popPK model and the influence of intrinsic and extrinsic factors (covariates) on REG PK. Methods: The average concentrations of REG and its pharmacologically active metabolites (M-2, M-5) were estimated based on sparse PK sampling in cycles 1–2. A covariate analysis was conducted using exposure and covariate data in 16 clinical REG trials in CRC, GIST, and HCC (1337 subjects) using a graphical and generalized additive modeling (GAM) approach. Results: eGFR, total plasma protein, hematocrit, total bilirubin, AST, ALP, and Asians vs non-Asians did not significantly (p > 0.05) influence exposure, whereas covariates significantly (p < 0.05) influencing exposure in 16 studies including RESORCE were: being a healthy volunteer vs a patient, sex, age, hemoglobin at baseline, plasma albumin at baseline, BMI, and body weight. The identified covariate effects were considered small compared with observed overall variability in exposure. Visual comparison of the exposure estimates in RESORCE showed these were comparable to those in phase 3 studies in CRC and GIST. Exposure in Asians was comparable to that in the rest of the world (ROW) and there was no apparent difference in exposure between Japanese, Chinese, and ROW and between patients with mild/moderate hepatic impairment vs normal hepatic function. Only small numerical differences in exposure across different age categories were observed, with a tendency towards higher exposure in patients ≥ 65 years of age. Conclusions: The RESORCE data confirm previous observations that the identified covariates that significantly (P < 0.05) correlated with exposure only describe a small fraction ( < 10%) of the overall variability in exposure and, thus, are not expected to have a clinically relevant impact on REG exposure. Clinical trial information: NCT01774344.
Expression of GRP78 protein in pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm.
Authors: Dhanarajan Asha R. , Hill Reginald , Pappas Sam G. , Abood Gerard J. , Gnerlich Jennifer Lynn , Ding Xianzhong
Published: March 2017

323

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to late detection, aggressive biology and resistance to chemotherapy. Markers for early detection of PDAC and mediators of chemoresistance are poorly understood. GRP78 is a major endoplasmic reticulum (ER) chaperone protein critical for protein quality control of the ER. Increased GRP78 expression promotes in vitro cancer cell survival, progression, and chemoresistance. This study aims to examine expression of GRP78 protein in PDAC and intraductal papillary mucinous neoplasm (IPMN) compared to normal pancreatic ducts using immunohistochemistry (IHC). Methods: The expression of GRP78 was assessed using IHC in 93 sections of formalin-fixed paraffin-embedded tissue: normal ducts (38), low grade IPMN (IPMN-LG, 26), high grade IPMN (IPMN-HG, 9), and PDAC (20). Immunostaining intensity of GRP78 protein was categorized as no or weak staining (0-1+) and strong staining (2-3+). Fisher’s exact test with two tails was performed using the GraphPad statistical software. Results: GRP78 expression was identified in the cytoplasm of normal pancreatic ducts, IPMN and PDAC with a fine granular pattern. All PDAC and IPMN-HG showed strong expression of GRP78 while the normal ductal cells showed only minimal expression of GRP78. 73% of IPMN-LG expresses GRP78 strongly. Statistical analysis revealed a significant difference in GRP78 expression level between normal ductal cells and all three pathological conditions including PDCA, IPMN-HG and IPMN-LG (all p < 0.0001). Conclusions: This study shows that the expression level of GRP78 is significantly increased in PDAC, IPMN-HG and IPMN-LG compared to normal ductal cells. There appears to be a progressive increase in GRP78 expression from IPMN-LG to IPMN-HG and invasive PDAC. Increased GRP78 expression may be a marker for those at risk of developing PDAC. Changes in GRP78 expression over time and its role in PDAC chemoresistance should be further assessed. [Table: see text]
Result of Arid1a deletion on intraductal papillary mucinous neoplasm formation.
Authors: Wang Sam C.
Published: March 2017

328

Background: ARID1A, a member of the SWI/SNF chromatin-remodeling complex, is mutated in up to 30% of pancreatic ductal adenocarcinoma (PDAC). Here, we studied the effect of Arid1a loss in pancreatic tumorigenesis in the setting of a constitutively activated Kras allele ( KrasG12D), which is the basis of a well-established mouse model of pancreas cancer. Methods: Arid1a was deleted during embryogenesis in acinar, duct, and islet cells in Ptf1a-Cre; Arid1af/f (CA) and KrasG12D; Ptf1a-Cre; Arid1a f/f (KCA) mice. Arid1a was inducibly deleted in adult mice specifically in duct or acinar cells with KrasG12D; Sox9-CreER; Arid1a f/f (KSERA), and KrasG12D; Ptf1a-CreER; Arid1a f/f (KPERA) mice, respectively. Tamoxifen was given at 4 weeks of age. Results: Genotyping of CA mice toes and pancreata showed Arid1a loss only in the latter confirming pancreas-specific recombination. Western blot confirmed decreased protein expression and immunohistochemistry (IHC) demonstrated Arid1a loss in most of the acini and half of the ducts. ~35% of CA mice developed benign appearing cysts by 4 months. KCA mice had macroscopic cysts by 3 weeks. The cyst fluid was thick and amylase rich. These cysts resembled intraductal papillary mucinous neoplasm (IPMN) as they had papillary features and stained for Alcian blue, confirming the presence of mucin. Muc protein staining pattern was consistent with pancreaticobiliary type IPMN. The stroma was negative for estrogen and progesterone receptors. KSERA mice developed large mucin producing ductal lesions by 12 weeks while only pancreatic intraepithelial neoplasias were seen in KPERA mice. Conclusions: Arid1a loss in the pancreas leads to pancreaticobiliary IPMN that appear to arise from the duct cells. Future directions include aging studies to determine if these cysts transform to frank PDAC, determining the status of ARID1A in human IPMN, and elucidating the mechanisms for cyst formation. Finally, this model may be useful as a platform to test therapeutic interventions to treat IPMN.
The effects of pioglitazone treatment on pancreatic cancer-related insulin resistance.
Authors: Stern Jennifer , Arriaga Yull Edwin , Gupta Arjun , Verma Udit , Karri Sirisha , Syed Samira K. , Khosama Leticia , Mansour John C. , Scherer Philipp , Beg Muhammad Shaalan
Published: March 2017

329

Background: Insulin resistance (IR) in pancreatic cancer (PC) patients is associated with cachexia and poor outcome. Pioglitazone (PIO) improves insulin sensitivity via activation of peroxisome proliferator-activated receptor (PPAR gamma). Effects of PIO on insulin sensitivity, glucose homeostasis, and circulating adipokine levels in PC have not been examined. Methods: Patients with metastatic PC were administered PIO 45mg/day orally for 8 weeks concurrent with chemotherapy. Patients with known DM at enrollment were identified Fasting plasma was collected at baseline, weeks 2, 4, 6, 8 of pioglitazone treatment and at 2 weeks-post treatment. The primary objective was to describe changes in indicators of IR, including glucoregulatory hormone levels, glucose tolerance, and inflammatory cytokines. Results: Fourteen patients (age 64y), with a mean BMI of 28 were enrolled. Mean adiponectin increased from baseline to week 8 of treatment (14.2± 3.3 and 46.9±11.4µg/ml, respectively, P ≤ 0.01), and returned to baseline levels at 2 weeks post-treatment (15.1±1.9 µg/ml). Markers of IR (serum glucose, insulin, glucagon, and response to an oral glucose bolus) did not correlate with tumor size, inflammatory cytokine levels, GM-CSF, or CA19-9. A dichotomous response to PIO treatment was observed between non-diabetic and T2DM patients. Fasting insulin increased 70.6±31.3% from baseline to treatment week 8 in patients with T2DM. In contrast, treatment of non-diabetic patients decreased fasting insulin by 40.2±6.3%, demonstrating a significant, P ≤ 0.01, difference in treatment response between PC patients with or without T2DM. Conclusions: We have demonstrated that PC patients respond to 8 weeks of PIO treatment with a significant rise in the insulin sensitizing adipokine, Adiponectin, with a complete wash-out after 2 weeks of cessation. PIO results in opposing fasting insulin responses in non-diabetic and DM patients suggests that diabetes status plays a significant role in the glucoregulatory effects of PIO treatment in PC patients. Clinical trial information: NCT01838317.
Preclinical antitumor activity of nanoliposomal irinotecan (Nal-IRI, MM-398) and utilization as a foundation of front-line pancreatic cancer regimens.
Authors: Gaddy Daniel F. , Lee Helen , Paz Nancy , Leonard Shannon C. , Kalra Ashish , Straubinger Ninfa L. , Straubinger Robert M , Gillard Bryan M. , Moser Michael T. , Foster Barbara A. , Drummond Daryl C. , Klinz Stephan G. , Hendriks Bart , Fitzgerald Jonathan B.
Published: March 2017

336

Background: Nanoliposomal irinotecan (nal-IRI, MM-398) recently gained approval in combination with 5-fluorouracil/leucovorin (5-FU/LV) in post-gemcitabine metastatic pancreatic ductal adenocarcinoma (PDAC) based on the extended survival and manageable safety profile observed in the Phase 3 NAPOLI-1 trial. Preclinically, we have previously demonstrated the anti-tumor activity of nal-IRI with 5-FU and oxaliplatin, standard of care agents in first-line PDAC, and are currently investigating this combination in patients with previously untreated metastatic PDAC in a Phase 2 clinical trial (NCT02551991). Herein, we further evaluate nal-IRI as a potential backbone of first-line metastatic PDAC by assessing the preclinical anti-tumor activity of nal-IRI relative to, and in combination with, gemcitabine and nanoparticle albumin-bound-paclitaxel (nab-P). Methods: Nal-IRI tumor metabolite (CPT-11 and SN-38) levels were measured in mice treated with nal-IRI in combination with gemcitabine or nab-P. Anti-tumor activity and tolerability of nal-IRI, 5-FU, gemcitabine and nab-P monotherapies and combinations were evaluated using pancreatic cancer cell line (ASPC-1 and CFPAC-1)-derived xenograft models, as well as a panel of five patient-derived xenograft models. Results: Administration of gemcitabine or nab-P prior to or simultaneously with nal-IRI resulted in unchanged or increased nal-IRI deposition, as measured by tumor CPT-11 and SN-38 levels at 24 hours post-injection. Moreover, in both cell line-derived and patient-derived xenograft models of PDAC, nal-IRI monotherapy demonstrated comparable or improved anti-tumor activity relative to gemcitabine or nab-P monotherapies. Further, nal-IRI consistently improved tumor growth inhibition and survival when used in combination with either 5-FU, gemcitabine and/or nab-P, relative to the combination of gemcitabine plus nab-P. All treatments were well-tolerated in these preclinical models. Conclusions: These findings illustrate the compatibility and therapeutic potential of nal-IRI as a foundation of first-line PDAC combination regimens, and warrant clinical evaluation.