bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethnicity and hepatocellular carcinoma risk factors in New Mexico: A retrospective analysis over a 12-year period.
Authors: Win Khine Zar , Osman Diaa , Du Ruofei , Patt Yehuda Z.
Published: March 2017

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Background: Common hepatocellular carcinoma (HCC) risk factors, such as hepatitis C virus (HCV) and hepatitis B virus infections, heavy exposure to alcohol and non-alcoholic steatohepatitis (NASH), vary in relation to gender, ethnicity, and geographic regions. New Mexico (NM) has the highest adjusted risk ratio of 1.27 for HCC when compared with other US geographic regions. The population of Hispanic Whites (HW), non-Hispanic Whites (NHW) and American Indians (AI) in NM provides a unique opportunity to study the prevalence of the known HCC risk factors among different ethnicities. Methods: We identified about 550 patients who were diagnosed and/or received treatment for HCC at the University of New Mexico (UNM) Hospital and the UNM Cancer Center from 2003 to 2015, using ICD 9/10 codes. Following approval by institutional review board, a retrospective chart review was conducted to correlate the known HCC risk factors and ethnicity of patients. This is a preliminary report of the findings in a randomly selected 226 of the 550 patients, and we expect to complete the analysis by the time of the GI ASCO symposium. A logistic regression with pairwise comparison was conducted to determine the distribution of the HCC risk factors among different ethnicities. Results: Among NHW, HCV is the most prevalent risk factor for HCC. AI have lower proportion of HCV infection, compared to NHW (35% vs 74%; P= 0.0008). However, DM and NASH were more frequently observed among AI than NHW, 54% vs 27% and 27% vs 9% ( P= 0.025 and 0.038) respectively. Table 1: Proportion of HCV, diabetes, NASH among AI, NHW and HW and pairwise comparison between ethnic groups. Conclusions: Among AI, the major risk factors for HCC seem diabetes mellitus and NASH. However, among NHW, chronic HCV infection is the most prevalent risk factor for HCC.[Table: see text]
Cholangiocarcinomas: A study of patient and disease characteristics and the potential use of tumor molecular profiling.
Authors: Prins Petra , Riskin Jeff , Charipova Karina , Dea Michelle , Furlong Ben , He Aiwu Ruth
Published: March 2017

270

Background: There are approximately 12,000 new cases of cholangiocarcinoma in the US annually and, as for most GI cancers, the incidence is rising each year. Unfortunately treatment options are limited and surgery is only a possible curative option if the disease is diagnosed at an early stage (5 yr. survival, 20-30 %). Molecular profiling may play a crucial role in the discovery of new (early) biomarkers and treatment options for cholangiocarcinoma. Methods: Clinical records 104 cholangiocarcinoma patients (pts) at the Lombardi Comprehensive Cancer Center were reviewed. Only pts that had received surgical therapy were eligible for study. Variables collected included pt demographics, initial disease stage, tumor differentiation, and clinical (pre-existing) conditions. Tumor recurrence and pt survival from time of surgery was evaluated. Molecular profiling data was analyzed when present. Results: In our cohort we identified 41 pts with cholangiocarcinoma who underwent surgery at LCCC. Clinical data was as follows: 20 males and 21 females. Average BMI at diagnosis was 25.8 kg/m2. Twelve pts had extrahepatic cancer, 20 intrahepatic, 5 gallbladder, 3 Hilar and 1 combined hepatocellular and bile duct cancer. Most tumors were stage T2 or T3 (61%), and were moderately (71%) to poorly differentiated (22%). Vascular or perineural invasion was identified in 46% of cases. Thirty-four percent and 37% had diabetes and hyperlipidemia, respectively. Tumor recurrence had occurred in 13 cases (32%), and median time to recurrence was 8.5 months (m). Median OS from surgery was 10.5 m (to date, 4 pts > 36 m). Molecular profiles were obtained in 5 cases. Most frequently observed genetic mutations were related to tumor suppression (PTEN, 4 cases) and DNA synthesis, repair, and regulation (TOP2A [3x], TOPO1 [2x], TP53 [2x]). Conclusions: Five-year survival rates for cholangiocarcinomas are low. To improve outcomes, improved early detection methods and better treatment options are urgently needed. Increasing the frequency of molecular profiling can result in new prognostic biomarkers as well as the potential for new treatment ideas.
Agreement validation between axial imaging modalities and endoscopic ultrasonography in staging resectability of pancreatic cancer.
Authors: Pham Nghia , Pappas Sam G. , Enchia Ebenezer , Gliniewicz Adam , Small William , Gupta Neil , Dudiak Christine M. , Mahmoud Faaiza , Ahuja Aakash , Aquisto Thomas , Gooneratne Nihal , Nanda Tejvir , Ozga Timothy , Martin Brendan , Thomas Tarita
Published: March 2017

273

Background: Vascular involvement is a key determinant of resectability and treatment sequencing in pancreatic cancer (PC). Current staging requires multidetector CT (MDCT) and endoscopic ultrasonography (EUS), but there are still occasions when vascular involvement cannot be fully assessed. Current NCCN guidelines recommend using magnetic resonance imaging (MRI) for clarifying these ambiguities. The primary aim of our study is to access the accuracy of CT, MRI, and EUS in staging resectabilty of PC. The secondary aim is to assess internal consistency in the evaluation of vascular involvement among different staging modalities. Methods: We retrospectively reviewed 40 medical records of patients who were treated at LUMC for PC from 2006 to present. We evaluated 8 MDCT scans and 8 MRI scans in addition to their EUS reports. Seven board certified radiologists analyzed the 16 imaging studies using a standardized template. Unweighted Kappa statistic and observed agreement analysis was calculated to assess inter-observer agreement on vessel involvement between the imaging studies compared to the EUS reports. We sought to examine degree of concordance for involvement of the superior mesenteric artery (SMA), superior mesenteric vein (SMV), and main portal vein (MPV) with the pancreatic tumor. Results: Low Kappa and observed agreement in respect to vascular involvement between MDCT and EUS was found for SMV (K = 0.33, 62.5%), SMA (K = -0.2, 62.5%), and MPV (K = 0.38, 75%), indicating low concordance. Low Kappa and observed agreement in respect to vascular involvement between MRI and EUS was found for SMV (K = 0.09, 37.5%), SMA (K = 0.14, 62.5%), and MPV (K = 0.47, 75%). Low Kappa and observed agreement in respect to vascular involvement between MRI and MDCT in comparison to EUS was found for SMV (K = 0.11, 50%), SMA (K = 0.20, 75%), and MPV (K = 0.14, 62.5%). Conclusions: Concordance was shown within each imaging modality when analyzed by radiologists. Due to high discordance across different staging modalities, however, MRI and CT scans complement each other in determining degree of vascular involvement. We believe both imaging modalities should be used in staging borderline resectable PC.
Opportunities for improving outcomes in pancreatic cancer patients: Characterizing the unresected “resectable” population.
Authors: Kish Jonathan , Feinberg Bruce A. , Maida Tracy , Biggs Craig , Mujumdar Urvi , Chopra Dhruv , Laney Jalyna R. , Kennedy Eugene
Published: March 2017

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Background: Resection is the only curative intent therapeutic option for pancreatic adenocarcinoma (PA). Recent studies suggest adjuvant chemo can significantly improve overall survival (OS). Patients who may be eligible for, but do not receive, a resection (“resectable”) may represent an opportunity to improve pancreatic cancer outcomes. This research sought to characterize this population using real-world data. Methods: Individuals with pancreatic cancer (ICD-9=157.x, excluding 157.4) diagnosed between 03/2012-06/2015 were selected from the Inovalon More2 claims database. Resection was defined as the presence of any of the following codes on any claim following diagnosis: CPT=48140, 48146, 48150, 48152-5. A diagnosis of metastatic disease was said to occur if any of the following ICD-9 CM codes were present on a claim: 196.0-196.3, 196.5-196.6, 197.0-197.8, and 198.0-198.8. Patients were deemed “resectable” if there was no claim for surgical resection and if their claim for metastatic disease was post-initiation of chemotherapy. Results: Of 7,159 patients identified with PA, 85.8% (n=6,145) were unresected, 40.8% (n=2,924) had received chemotherapy which included 54.4% (n=552) of resected patients and 38.6% (n=2,372) of non-resected patients. Of unresected patients receiving chemotherapy, 27.4% had no record of a metastatic diagnosis, 51.9% had a metastatic diagnosis prior to the start of chemotherapy (mean time metastatic diagnosis = 0.4 months) and 20.7% had a metastatic diagnosis after the initiation of chemotherapy (mean time metastatic diagnosis = 4.8 months). Overall, 18.5% (n=1139) of non-resected patients were classified as unresected “resectable”. Conclusions: The vast majority (85.8%) of pancreatic cancer patients did not undergo a surgical resection. We estimate as many as 18.5% of non-resected patients may be unresected “resectable” given 4.8 months between diagnosis, chemotherapy start and documentation of metastases. As surgical resection is the only curative intent therapeutic option, and prolongs survival even in those not cured, identifying patients who may be eligible for resection is critical to improving pancreatic cancer outcomes.
Impact of major vascular resection on short- and long-term outcomes in patients with intrahepatic cholangiocarcinoma.
Authors: Reames Bradley , Pawlik Timothy M. , Ejaz Aslam , Marques Hugo , Aldrighetti Luca , Maithel Shishir Kumar , Bauer Todd W. , Shen Feng , Poultsides George A. , Marsh J. Wallis , Popescu Irinel , Sandroussi Charbel , Clark T
Published: March 2017

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Background: Major vascular (IVC or portal vein) resection for Intrahepatic Cholangiocarcinoma (ICC) has traditionally been considered a relative contraindication to resection. We sought to define perioperative outcomes and survival of ICC patients undergoing liver surgery with major vascular resection using a multi-institutional database. Methods: 1,087 ICC patients who underwent liver resection between 1990-2016 were identified from 13 participating institutions. Multivariable logistic and cox regressions were used to determine the impact of major vascular resection on perioperative outcomes and long-term overall survival. Results: Of 1,087 patients who underwent resection, 128(11.8%) also underwent major vascular resection [21(16.4%)IVC resections, 98(76.6%)PV resections, 9(7.0%)combined resections]. One hundred eighty-seven(17.2%) patients received neoadjuvant therapy. Most patients underwent a major hepatectomy involving ≥ 3 liver segments(n = 664,61.1%). On final pathology, the majority of patients had T1(40.4%) or T2(35.5%) tumors; 194(17.8%) had lymph node metastasis. Patients undergoing major vascular resection had more advanced T3/T4 tumors [44(34.4%) vs. 137(14.3%) without resection;P < 0.001]. Of note, major vascular resection was not associated with the risk of any complication (OR .680,95%CI 0.32-1.45) or major complication (OR 0.69,95%CI 0.35-1.33); post-operative mortality was also comparable between groups (OR 1.06, 95%CI 0.32-3.48). In addition, median recurrence-free (14.0 months vs.14.7 months, HR.737,95%CI .49-1.10) and overall (33.4 months vs.40.2 months, HR .709,95%CI.36-1.40) survival were similar among patients who did and did not undergo major vascular resection, respectively(both P > 0.05). Conclusions: Among patients with ICC, major vascular resection was not associated with increased peri-operative morbidity or mortality at major centers. Long-term outcomes following resection of ICC requiring vascular resection were also comparable to outcomes following resection of tumors without vascular involvement. Concurrent major vascular resection should be considered in appropriately selected ICC patients.
The impact of extrahepatic disease among patients undergoing liver-directed therapy for neuroendocrine liver metastasis: A multi-institutional analysis.
Authors: Ejaz Aslam , Pawlik Timothy M. , Reames Bradley , Maithel Shishir Kumar , Poultsides George A. , Bauer Todd W. , Fields Ryan C. , Weiss Matthew J. , Marques Hugo , Aldrighetti Luca
Published: March 2017

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Background: Management of neuroendocrine liver metastasis (NELM) in the presence of synchronous extrahepatic disease (EHD) is controversial. We sought to examine the outcomes of patients undergoing liver-directed therapy for NELM in the presence of EHD using a large multicenter international cohort of patients. Methods: 612 patients who underwent liver-directed therapy were identified from 8 participating institutions. Postoperative outcomes, as well as overall (OS) and progression-free survival (PFS) were compared between patients with (N = 70, 11.4%) and without (N = 542, 88.6%) EHD. Results: Median age of the cohort was 57 years (IQR: 48, 65) with a slight majority of patients being male (N = 326, 53.3%). The majority of primary tumors were located in the pancreas (N = 254, 41.8%) followed by the small bowel (N = 188, 30.9%). At the time of liver-directed surgery, patients underwent surgery alone (N = 471, 77.0%), ablation alone (N = 15, 2.5%), or a combined approach (N = 126, 20.6%). Most patients underwent a non-anatomic wedge resection (N = 404, 66.0%). Patients with EHD had more aggressive high-grade tumors (EHD: 44.4% vs. no EHD: 16.1%; P < 0.001). EHD was most commonly located in the peritoneum (N = 29, 41.4%) and lung (N = 19, 27.1%). Among the 70 patients with EHD, 20.0% (N = 14) underwent concurrent resection for the EHD. After a median follow-up of 51 months, 174 (28.4%) patients died with a median OS of 140.4 months among the entire cohort. Patients with EHD had a shorter median OS versus patients who did not have EHD (EHD: 87 months vs. no EHD: not reached; P = 0.002). Similarly, PFS was shorter among patients with EHD compared with patients without EHD (EHD: 46.8 months vs. no EHD: 68.6 months; P = 0.005). In the cox regression model, the presence of EHD was independently associated with an increased risk of death (HR: 2.56, 95%CI 1.16-5.62; P = 0.02). Conclusions: Patients with NELM and EHD had more aggressive tumors, which conferred over a 2-fold increased risk of death compared with patients who did not have EHD. Surgical treatment of NELM among patients with EHD should be individualized.
Molecular biomarkers as predictors of patient survival in pancreatic adenocarcinoma (PDA): An analysis of the Know Your Tumor initiative (KYT).
Authors: Bender R Joseph , Halverson David , Mason Kimberly , Luo Linlin , Brody Jonathan Robert , Rahib Lola , Matrisian Lynn McCormick , Hendifar Andrew Eugene , Hoos William Arthur , Mikhail Sameh , Chung Vincent M. , Picozzi Vincent J. , Ramos Corinne , Heartwell Craig , Varieur Katelyn , Aberra Metasebia , Petricoin Emanuel , Madhavan Subha , Pishvaian Michael J.
Published: March 2017

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Background: Recent studies have expanded our knowledge of the genomic landscape of PDA. While critical and in some cases, potentially actionable alterations are being identified, limited outcomes data have thus far made it difficult to validate the relevance of these observations. Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera have facilitated commercial tumor molecular profiling for over 400 PDA pts since 2014 through KYT, and have developed a database of molecular and clinical information useful for data mining of biomarker-survival correlations. The survival significance of biomarkers was assessed using standard statistical methodology including Kaplan-Meier analysis and Cox proportional hazard models. Results: Linked molecular and outcomes data were available for 360 pts, of which 173 had treatment (tx) information available. Pathogenic mutations from targeted NGS, protein expression from IHC, and protein phosphorylation from RPPA were screened for correlations with overall survival (OS) and progression-free survival (PFS) independent of tx received. As shown in the table, mutations in 3 genes were associated with a better OS; while mutations in 8 genes were associated with poorer OS. Only two mutations were correlated with PFS in 1st or 2nd-line tx ( BRCA2 and KDM6A, worse PFS). Positive expression of 7 proteins, including TS, TOP1, and RRM1, were associated with reduced OS but were not correlated with PFS. High levels of phospho-ribosomal protein S6 were associated with both poor OS (HR=10.3, p=0.001) and poor PFS (HR=9.6, p=0.006). Conclusions: Multiple biomarkers had significant correlations with OS in PDA, while fewer were correlated with PFS. Growth of this registry database will further validate tx-specific predictive biomarkers for use in pts with multi-omic profiling data. [Table: see text]
Influence of cytotoxic tumor-infiltrating T lymphocytes on outcome in resectable pancreatic cancer: Results from the CONKO 001 trial.
Authors: Striefler Jana Kaethe , Sinn Marianne , Jöhrens Korinna , Pelzer Uwe , Blaeker Hendrik , Jühling Anja , Sinn Bruno Valentin , Oettle Helmut , Wislocka Lilianna , Bischoff Sven , Denkert Carsten , Riess Hanno , Lohneis Philipp
Published: March 2017

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Background: The role of T lymphocytes, frequently found in the tumor microenvironment, on development and behavior of several solid tumors is well recognized. Studies on breast cancer and colon carcinoma showed the prognostic and predictive impact of tumor infiltrating T lymphocytes (TILs) while there are no similar studies on pancreatic cancer (PC) until now. Methods: We evaluated the prognostic effect of CD8 and CD103 positive TILs in a cohort of PC patients in the CONKO-001 study treated with adjuvant Gemcitabine or observed only. In 165 formalin-fixed paraffin-embedded (FFPE) tissue samples suitable for tissue microarray construction, CD 8 und CD 103 positive TILs were identified by immunohistochemical staining and counted manually; a ratio of intraepithelial to total CD 103 positive TILs was calculated. Results: The mean number of CD8 positive TILs was 69, a high number ( > 42 TILs) of CD8 positive lymphocytes was significantly associated with longer disease-free (DFS) and overall survival (OS) in the overall study population (high vs low median DFS 12.8 vs 7.4 months; p = 0.007, median OS 26.7 vs 18.1 months; p = 0.018). Furthermore, a ratio of intraepithelial to total CD103 positive lymphocytes < 0.3 was associated with significantly improved DFS and OS in the overall study population (high vs low median DFS 6.5 vs 11.8 months; p = 0.031, median OS 16.6 vs 24.7 months; p = 0.009). Conclusions: Our results suggest that the presence of TILs is important for prognosis in resected PC. We showed for the first time a prognostic effect of CD 8 and CD 103 expressing lymphocytes in PC. Therefore, we suggest further analysis of lymphocyte populations in this dismal entity.
Impact of age on genomic alterations associated with pancreatic ductal adenocarcinoma (PDAC).
Authors: George Ben , Bailey Mark , Schrock Alexa Betzig , Thorpe Lauren , Gay Laurie M. , Ritch Paul S. , Thomas James P. , Erickson Beth , Tsai Susan , Christians Kathleen K. , Evans Douglas B. , Stephens Philip J. , Miller Vincent A. , Ross Jeffrey S. , Singhi Aatur D. , Ali Siraj Mahamed
Published: March 2017

282

Background: Large scale, retrospective, sequencing projects have identified well-defined subtypes of PDAC, but therapeutic paradigms remain unchanged. We hypothesized that genomic alterations associated with PDAC in young adults (YA, age < 50) are distinctly different from that of older adults (OA, age > 50) to identify an enrichment of targetable alterations. Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) PDAC clinical specimens and comprehensive genomic profiling (CGP) was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Results: CGP was performed on 1533 FFPE PDAC specimens, 566 (36.9%) were from the primary tumor, 967 (63.1%) from metastatic sites. Median age at diagnosis was 63 years (yrs), 180 (11.7%) were YA. KRAS mutations were identified in 78.7 of YA and 87.7% of OA. The differentially altered genes between the two groups were KRAS (p = 0.004), TP53 (p = 0.04), BRCA2 (p = 0.02), AKT2 (p = 0.03), MAP2K4 (P = 0.003) and DNMT3A (p = 0.0002). The median tumor mutational burden (TMB) for the entire study set was 2.7 (YA – 2.5, OA –2.7). BRAF kinase domain deletion was observed in 1 patient (OA). ALK fusions were present in 2 patients (1 YA & 1 OA) and these patients had durable responses to specific ALK inhibitors. Conclusions: The majority of the genomic alterations identified were not significantly different on the basis of age. However, identification of subpopulations, such as ALK kinase fusions and BRAF kinase domain deletions that can translate into sustained clinical benefit from matched targeted therapy is promising. This underscores the importance of CGP in PDAC to investigate other targetable genomic alterations.
Precision delivery of RAS-inhibiting siRNA to pancreatic cancer via peptide-based nanoparticles.
Authors: Strand Matthew S. , Pan Hua , Krasnick Bradley , Zhang Xiuli , Goedegebuure Peter S. , Fleming Timothy , DeNardo David G , Gillanders William E. , Hawkins William G. , Wickline Samuel A. , Fields Ryan C.
Published: March 2017

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Background: Greater than 95% of pancreatic adenocarcinomas (PDACs) are driven by KRAS activation; yet, despite decades of work, no RAS inhibitors have reached the clinic. Furthermore, the delivery of therapeutic agents of any kind to PDAC has been hindered by the extensive desmoplasia that accompanies these tumors. Herein, we show that serum-stable and pH-sensing nanoparticles (NPs) are taken up by PDAC cells, can deliver KRAS-specific siRNA into the cytoplasm and inhibit KRAS expression, thereby causing cell death. We go on to use a spontaneous model of pancreas cancer to show that this system can effectively deliver siRNA to stroma-rich tumors. Methods: The murine PDAC cell line KP1 was tested for NP uptake in vitro utilizing fluorescent siRNA NPs (fNPs) in combination with confocal microscopy and flow cytometry. KP1 cells were treated with KRAS-siRNA NP, and KRAS expression and cell viability were assessed with RT-PCR and CellTiter-Glo, respectively. Mice bearing subcutaneous KP1 tumors and KPPC mice with spontaneous PDAC were injected with fNP, and tumor fluorescence was assessed using an in vivo imaging system and fluorescence microscopy. Results: KP1 cells take up fNP in vitro, with > 99% of cells positive for fluorescent signal at 24 hours. Treatment with KRAS-siRNA NP of KP1 cells reduced KRAS expression by 69% (see Figure) and reduced cell viability by 45% compared to untreated and scramble-siRNA treated controls. Gemcitabine demonstrated an additive effect with anti-KRAS therapy. Tumors from KP1 cells grown in mice, and tumors from KPPC mice, were strongly fluorescent 24 hours after IV injection of fNP. Fluorescence microscopy showed successful delivery of fNP to tumors. Conclusions: Our NP system can precisely deliver siRNA to KP1 cells and spontaneous PDAC, overcoming the predominant stromal component in these tumors. KRAS-siRNA delivery downregulates KRAS expression, leading to cell death. This represents a novel treatment for PDAC. Furthermore, with its ability to deliver siRNA into the tumor microenvironment and suppress a known oncogene, this platform could be used to target other putative drivers of tumor progression across various cancer types.
Serum HER2 level during chemotherapy as a biomarker for advanced gastric cancer.
Authors: Saito Mayuko , Arimura Yoshiaki , Yamashita Kentaro , Suzuki Kazuya , Adachi Takeya , Kaneto Hiroyuki , Yawata Atsushi , Nakachi Kohei , Okuda Hiroyuki , Yoshimoto Mitsuru , Tanuma Tokuma , Hamamoto Yasuo , Nakase Hiroshi
Published: March 2017

29

Background: Recent studies showed that serum HER2 levels correlated with tissue HER2 status in gastric cancer. The aim of this prospective study (UMIN000006442, 000006445) was to investigate changes in serum HER2 levels and tissue HER2 status during chemotherapy for advanced gastric cancer (AGC). Methods: Chemotherapy (Capecitabine and cisplatin) with and without trastuzumab was administered to patients with HER2-positive and HER2-negative AGC, respectively. Serum HER2 level was measured using chemiluminescense immunoassay (CLIA) at 4 points: at the initial diagnosis, after two cycles of chemotherapy, at the initial evaluation of tumor response, and at the time of progression. If possible, second biopsy was performed at progression to compare tissue HER2 status before and after chemotherapy. Results: Thirty-three patients (14 HER2-positive and 19 HER2-negative) with a median age of 67 years (range 51-80) were recruited. The median baseline serum HER2 level of the HER2-positive group was significantly higher than that of the HER2-negative group (p = 0.038, 12.0 ng/ml (range 6.5-148.0) and 8.2 ng/ml (4.5-27.2), respectively). A Decrease in serum HER2 level was correlated with tumor response in the HER2-positive group while it was not in the HER2-negative group. Tissue samples at the time of progression were obtained in 6 out of 19 HER2-negative cases. Of these, serum HER2 level elevated at progression in 4 cases, and tissue HER2 status has turned to positive at tumor progression in one case. In the HER2-positive group, tissue samples at tumor progression were obtained in 2 cases, and both showed HER2-positive result, same as the initial diagnosis. Conclusions: Serum HER2 could be useful as a response indicator in HER2-positive AGC. Tissue HER2 status may change from negative to positive over time and serum HER2 has a possibility to predict it. Further studies are needed to confirm these findings. Clinical trial information: UMIN000006442,000006445.
Characteristics of long-term survivors in a randomized phase III trial (NAPOLI-1) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan (nal-IRI; MM-398) + 5-FU/LV.
Authors: Wang-Gillam Andrea , Li Chung-Pin , Bodoky Gyorgy , Dean Andrew , Lee Kyung-Hun , Cunningham David , Hubner Richard , Siveke Jens T. , Braiteh Fadi S. , Pipas J. Marc , Belanger Bruce , de Jong Floris , Mody Purvi D. , Chen Li-Tzong , Von Hoff Daniel D.
Published: March 2017

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Background: nal-IRI, a liposomal formulation of irinotecan, plus 5-FU/LV is approved in the United States and Taiwan for patients (pts) with mPDAC previously treated with gemcitabine-based therapy. Primary analysis of the NAPOLI-1 trial (NCT01494506) showed that nal-IRI+5-FU/LV significantly improved median overall survival vs 5-FU/LV (6.1 vs 4.2 months; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). Herein we report baseline characteristics of pts surviving ≥1 year (data cutoff, Nov 2015). Methods: This analysis includes 117 pts assigned to treatment with nal-IRI 70 mg/m2 (free base) + 5-FU/LV 2400/400 mg/m2 q2w, and 119 pts assigned to treatment with 5-FU/LV 2000/200 mg/m2weekly for weeks 1-4 q6w. Results: A total of 29 (25%) pts in the nal-IRI+5-FU/LV arm and 17 (14%) in the 5-FU/LV arm survived ≥1 year. These pts typically had better performance status, lower CA19-9 (U/mL) levels, and were less likely to have liver metastases at baseline, compared with the overall population (Table). For long-term survivors in the nal-IRI+5-FU/LV arm, a higher proportion of pts had neutrophil-to-lymphocyte ratio (NLR) >5, a marker of poor prognosis, suggesting that higher NLR may potentially be predictive of survival outcome with nal-IRI+5-FU/LV. Conclusions: More pts receiving nal-IRI+5-FU/LV versus 5-FU/LV were alive beyond 1 year. The most prominent prognostic markers of survival ≥1 year included lower CA19-9, KPS ≥90 and absence of liver metastases. These analyses may be limited by small sample sizes. Clinical trial information: NCT01494506. [Table: see text]
Phase IB trial of ADI-PEG 20 (A) plus nab-paclitaxel (nab-P) and gemcitabine (gem) in patients with advanced pancreatic cancer (PC).
Authors: Lowery Maeve Aine , Harding James J. , Yu Kenneth H. , Kelsen David Paul , Bomalaski John S. , Glassman Danielle C. , Covington Christina M. , Brenner Robin , Hollywood Ellen , Barba Adalberto , Johnston Amanda , Liu Kay Chia-Wei , Capanu Marinela , Abou-Alfa Ghassan K. , O'Reilly Eileen Mary
Published: March 2017

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Background: ADI-PEG 20 (A) is a pegylated form of arginine depleting enzyme, arginine deaminase. Normal cells synthesise arginine using the enzyme argininosuccinate synthetase (ASS). A selectively targets malignant cells which lack ASS. A has shown encouraging pre clinical activity as monotherapy in PC, and synergistic activity with gem and taxanes. Methods: Eligibility: Metastatic PC, up to one line of prior treatment (dose escalation cohort:ct) no prior treatment (expansion ct), ECOG 0-1.Treatment: gem 1,000 mg/m2, nab-P 125mg/m2 3 out of 4 weeks, A 18 mg IM weekly (ct 1), A 36mg weekly (ct 2 and expansion ct). Primary endpoint: determine MTD of A in combination with nab-P and gem. Statistical plan: Single arm, non-randomized, open-label, phase IB, standard 3 + 3 dose escalation with expansion ct of 9 patients at MTD. Secondary endpoints: progression-free survival (PFS), response rate, overall survival (OS), safety, tolerability, blood and archival tumor analyses for ASS expression and immunogenicity. Pts treated at MTD and on expansion cohort were eligible for primary and secondary endpoints. Results: Between 11/14 and 09/15, 18 pts enrolled. 4 pts (22%) had 1 prior line of therapy. Toxicity attributable to A was limited to grade 1 rash/erythema at injection site (n = 3). Cohort 2 was expanded to 6 pts due to DLT of elevated LFTs, no further DLTs observed. ≥ grade 3 toxicity attributable to gem and/or nab-P included elevation in AST/ALT, hematologic toxicity, fatigue, diarrhea, neutropenic fever, alopecia as expected. No A related grade 3-5 toxicities were observed. Response: 6 pts (40%) PR, including one previously treated pt, 8 pts (53%) stable disease (SD), 1 pt inevaluable. Two pts continue on study, median PFS 6.5 months (95% CI 5.3 – 15.2), median OS 11.3 months (95% CI 4.9- . ). Eight of 15 pts treated at MTD received 2nd-line chemotherapy at progression. Five of 11 archival tumors samples tested for ASS1 expression by IHC were deficient. Conclusions: A was well tolerated in combination with gem and nab-P. Activity was observed in treated and untreated pts, and in pts with ASS deficient and proficient tumors; synergy of A with cytotoxics may be independent of ASS status and future investigation in an unselected population is warranted. Clinical trial information: NCT02101580.
Profiling of small intestine neuroendocrine tumors to reveal characteristic miRNAs detectable in plasma.
Authors: Bowden Michaela , Zhou Chensheng Willa , Zhang Sui , Brais Lauren K. , Rossi Ashley , Naudin Laurent , Thiagalingam Arunthi , Sicinska Ewa , Kulke Matthew H.
Published: March 2017

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Background: Current blood-based biomarkers for neuroendocrine tumors are limited. We performed a multi-stage study to identify characteristic circulating miRNAs in patients with advanced small intestine neuroendocrine tumors, and to assess associations between miRNA levels and survival. Methods: Using a 742-miRNA panel, we identified candidate miRNAs similarly expressed in 19 small intestine neuroendocrine tumors and matched plasma samples. We refined our panel in an independent cohort of plasma samples from 40 patients with advanced small intestine NET and 40 controls, and validated this panel in a second cohort of 120 patients and 120 controls. Results: miRNA profiling of 19 tumors and matched plasma samples revealed 31 candidate miRNAs similarly expressed in both tissue and plasma. We evaluated expression of these 31 candidate miRNAs in 40 independent cases and 40 normal controls, and identified 4 miRNAs (miR-21-5p, miR-22-3p, miR-29b-3p, and miR-150-5p) that were differently expressed in cases and controls (p < 0.05). We validated these 4 miRNAs in a separate, larger panel of 120 cases and 120 controls. High circulating levels of miR-22-3p (p < 0.0001), high levels of miR 21-5p, and low levels of miR-150-5p (p = 0.027) were associated with the presence of advanced small intestine NET. While levels of 29b-3p were lower in cases than in controls in both the initial cohort and the validation cohort, the difference in the validation cohort did not reach statistical significance. We further found that high levels of circulating miR-21-5p, high levels of circulating miR-22-3p and low levels of circulating miR-150-5p were each independently associated with shorter overall survival. A combined analysis using all three markers was highly prognostic for survival (HR 0.47, 95% CI 0.27-0.82). Conclusions: Our study suggests that elevated circulating levels of miR-21-5p and miR-22-3p and low levels of miR-150-5p are characteristic in patients with advanced small intestine neuroendocrine tumors, and further suggests that levels of these miRNAs are associated with overall survival.
Overcoming erlotinib resistance with STAT3 inhibition in pancreatic cancer.
Authors: Salzberg Matthew Philip , Merchant Nipun B.
Published: March 2017

304

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a major therapeutic challenge. Cytotoxic chemotherapy remains the standard approach in PDAC, but results in minimal survival benefit for patients, highlighting a desperate need for novel treatment strategies. Epidermal growth factor receptor (EGFR) is overexpressed in 25-90% of PDACs and has been shown to be an adverse prognostic marker for survival, making it a rational target. To date, the combination of the EGFR tyrosine kinase inhibitor, erlotinib, with gemcitabine remains the only approved targeted therapy based on a significant, yet modest, improved overall survival when compared to gemcitabine alone in a phase III clinical trial. We have previously shown that constitutively activated signal transducer and activator of transcription 3 (STAT3) signaling is a biomarker of resistance to both gemcitabine and erlotinib. Therefore, we hypothesized that combined STAT3 and EGFR inhibition would overcome resistance to erlotinib and gemcitabine in PDAC. Methods: Human pancreatic cancer cell lines MiaPaca2 ( KRASG12C ; TP53mut ; EGFRwt) or BxPC-3 ( KRASwt ; TP53mut ; EGFRwt) were treated in a dose dependent manner with erlotinib in the presence or absence of gemcitabine. PDAC cells were additionally treated with EC50doses of a STAT3 inhibitor (AZD1480), erlotinib, and/or gemcitabine. Lysates were then collected and western blot analysis was performed to detect total and phosphorylated extracellular signal regulated kinase (ERK) or STAT3. Results: EGFR inhibition with erlotinib, with or without gemcitabine, results in decreased ERK activation, however, causes an increased activation of STAT3 signaling in both MiaPaca2 and BxPC-3 cells. Combined STAT3 and EGFR inhibition results in sustained attenuation of both phosphorylated ERK and STAT3 levels. Conclusions: Our study demonstrates that activated STAT3 signaling appears to be a mechanism of resistance to erlotinib and gemicitabine treatment in PDAC. Combining STAT3 inhibition with EGFR inhibition overcomes this resistance.
Analysis of prior malignancies in patients with cholangiocarcinoma.
Authors: Boucher Taryn Mary , Kemeny Nancy E. , Chou Joanne F. , Capanu Marinela , Lowery Maeve Aine , Cercek Andrea
Published: March 2017

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Background: Cholangiocarcinomas account for approximately 3% of gastrointestinal tumors. Our aim was to analyze types of prior malignancies in patients (pts) with cholangiocarcinoma, with a special interest in pts with prior breast cancer. Methods: An IRB waiver was obtained to retrospectively review female pts who presented with an initial diagnosis of cholangiocarcinoma to Memorial Sloan Kettering Cancer Center between January 2000 and August 2015. Results: Medical records of 804 female pts were reviewed. After excluding pts with limited records or without biopsy-proven cholangiocarcinoma, a total of 625 pts were analyzed. Of 625 pts with cholangiocarcinoma, 506 (81%) were intrahepatic (ICC), 85 (14%) hilar, 24 (4%) extrahepatic and 10 (2%) mixed ICC and hepatocellular carcinoma or rare variant. The median age at cholangiocarcinoma diagnosis was 63 years [range: 16-97 years] and 82.7% were white. Of the 625 pts, 105 (17%) had a history of another cancer: 44 (7.04%) breast, 9 (1.44%) colon, 9 (1.44%) melanoma and 5 (0.8%) ovarian. The remaining 38 pts with various prior cancers were grouped as Other. There was no association between the site of cholangiocarcinoma (intrahepatic versus extrahepatic) and type of prior cancer (p = 0.26). In pts with a prior cancer (n = 105), the median time from diagnosis of prior cancer to cholangiocarcinoma was 76 months [range: 2-624 months], which did not differ among types of prior malignancies (p = 0.25). The interval between diagnosis of breast cancer and cholangiocarcinoma was 82 months [range 4-526 months]. In pts with prior breast cancer, 21 (48%) received radiation and 25 (57%) received chemotherapy for their breast cancer. In 22 pts who had ER/PR testing, 16 were ER positive and 15 were PR positive. In 17 pts who had HER2 testing, 4 were HER2 positive. Conclusions: In 625 female pts with cholangiocarcinoma, 17% had a history of another cancer, with 44 (7%) having a history of breast cancer. The apparent increase in proportions of prior breast cancer compared to other cancers should be investigated further. An analysis of tumor mutations (MSK-IMPACT) and germline mutations in pts with cholangiocarcinoma and a history of breast cancer is underway to determine a potential association of molecular factors.
ATM as a biomarker for DNA damage repair deficiency in pancreatic ductal adenocarcinoma.
Authors: Golan Talia , Halparin Sharon , Stossel Chani , Raitses-Gurevich Maria , Atias Dikla , Buzhor Ella , Cohen Keren , Borshtein Roni , Schvimer Michael , Berger Raanan
Published: March 2017

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Background: Approximately 15% of PDAC tumors display DNA damage repair (DDR) deficiency. Germline BRCA (gBRCA) mutation serves as a robust biomarker for the DDR deficiency. A subset of patients displays a similar clinical phenotype but lack the gBRCA mutation. Identification of these BRCA-like subset of patients remains a challenge and an alternative approach may include DDR functional assays. Here we suggest loss of the ATM protein as one of the biomarkers for the identification of the DDR deficiency signature in PDAC. Methods: Patients were identified from the Sheba pancreatic cancer database based on strong family/personal history of BRCA- associated cancers or a durable response to platinum containing regimens ( ≥ 6 month) or harboring germline/somatic mutations in the DNA repair pathway (excluding gBRCA mutation). Archival FFPE blocks of primary tumors/metastatic lesions were used to explore ATM protein expression by IHC. Nuclear staining was regarded as positive. Tumor infiltrating lymphocytes served as an internal positive control. ATM loss was defined as less than10% neoplastic nuclear staining at any intensity in the presence of positive lymphocytes staining. Results: We identified 53 patients with DDR deficiency phenotype between 2014-2016 from the Sheba PDAC database (n = 250). Median age at diagnosis was 65 years (46-81) and the majority were female (62%). 47% were diagnosed at stage I/II and 53% stage IV. In the subgroup of patients with DDR deficiency phenotype, 55% displayed a family history of BRCA-associated cancers, 19% had a personal history of malignancy and23% had known mutation in DNA repair pathway. 23/53 identified subjects have been analyzed to date. We identified 52% loss of ATM in the analyzed group (n = 23). Conclusions: Loss of ATM in an unselected PDAC population is 12% (H. Kim et al, 2014). Our data demonstrate that 52% of the highly selected subgroup of PDAC patients (DDR deficiency phenotype) was found to have loss of ATM protein expression, suggesting it to be one of the biomarker for DDR signature. Identification of these patients, based on ATM protein expression profile may lead to personalized treatment options.
The efficacy of stratifying patients with laparoscopic gastrectomy at age, body mass index and preoperative serum C-reactive protein level for predicting an incidence ratio of postoperative complications.
Authors: Amada En , Takeuchi Hiroya , Nakamura Rieko , Suda Koichi , Wada Norihito , Kawakubo Hirofumi , Kitagawa Yuko
Published: March 2017

31

Background: Wide variety of Predictive factors (PF) of postoperative complications (PC) in patients with gastric cancer(GC) that have undergone laparoscopic gastrectomy(LG) has been reported. The aim of this study is to devise simple PF for PC for LG that can estimate risk of PC preoperatively. Methods: Two hundred and ninety-eight patients that have been underwent curative LG against GC during May 2012 to March 2016 were enrolled. Patients’ characteristics, preoperative (pre-) laboratory data, operative information and pathological factors were analyzed. Also PC with Clavien-Dindo classification Grade (CD)≥II (PC≥II), pancreatic fistula (PF), intraabdominal abscess (IA), pneumonia (PN) and anastomotic leakage (AL) with CD≥III were examined. Results: Patients with pStage I, II, III and IV was 83%, 11%, 5.6% and 0.4%, respectively. Patients with PC≥II, PF or IA, PN and AL was 17.4%, 5%, 1% and 2.3%, respectively. Patients with PC≥II were significantly elder (p=0.01) and had higher pre-serum-C-reactive protein level (CRP) (p=0.02). Also, patients with AL had significantly higher Body Mass Index (BMI) (p=0.04). We devised “ABC score” by Age, BMI and CRP. It is defined as a number of factors in age, BMI and CRP that are higher than cutoff value of 66 years’ old, 23 kg/m2 and 0.04 mg/dL, respectively. Patients with ABCs 0, 1, 2, and 3 were 26%, 33%, 34% and 7%, respectively. Patients with ABCs 3 had significant high risk of PC≥II and AL (HR 2.8, p=0.03 and HR 9.9, p=0.004, respectively). Also we found higher ABCs has higher risk of AL (HR1.2, p=0.07 for ABCs 2 and HR2.2, p=0.04 for ABCs 3). Conclusions: ABCs can be a PF for PC in patients with LG. Especially it may evaluate an incidence ratio of AL.
Phase I study of gemcitabine (G), dasatinib (D), and erlotinib (E) in advanced pancreatic carcinoma (PC).
Authors: Cardin Dana Backlund , Goff Laura Williams , Chan Emily , Whisenant Jennifer , Arlinghaus Lori R. , Yankeelov Thomas , Koyama Tatsuki , Berlin Jordan , Merchant Nipun B.
Published: March 2017

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Background: The combination of E with G remains the only approved targeted therapy for PC based on significant, yet modest, improved overall survival when compared to G alone in a phase III clinical trial. We have shown previously that adding the Src inhibitor D with E and G resulted in synergistic attenuation of tumor growth in vivo. The purpose of this study was to assess the safety of D given with E and G. Methods: This investigator-initiated study used 3+3 dose-escalation to determine the maximum tolerated dose in advanced PC patients (pts). Dose escalation started at 70 mg daily of D, 100 mg daily of E, and G on days 1, 8, and 15 (800 mg/m2) of a 28-day cycle. Diffusion-weighted MRI (DW-MRI) measurements (ADC) were collected prior to and at four weeks in a subset of pts (n=3). Results: Nineteen pts were enrolled. One pt experienced a DLT at the starting dose (L0); however, given the side effects observed in the first two pts, D was reduced to 50 mg (L-1). At L-1, one DLT was observed in 1/6 pts and the dose was re-escalated to L0. Zero DLTs were observed in the next four pts at L0 thus D was escalated to 100 mg (L1). Seven pts were treated at L1 as one pt was not evaluable for safety. In this cohort, 1/6 pts experienced a DLT. Although L1 was tolerable, dose escalation was stopped as it was felt L1was within the therapeutic window and escalation would enhance toxicity with minimal benefit. Most frequent toxicities (%) were anemia (89), elevated aspartate aminotransferase (79), fatigue (79), nausea (79), elevated alanine aminotransferase (74), lymphopenia (74), leukopenia (74), neutropenia (63), and thrombocytopenia (63), most Gr1/2. Zero responses were observed, but disease stabilization (SD) occurred in 9/13 (69%). Median duration of SD was 4 months, and median OS was 7.7 mos. At the time of data cutoff, two pts are still alive and in follow-up. Increase in ADC on MRI reflected a decrease in tumor cellularity suggesting therapeutic benefit; disease assessment at 8 weeks was SD. Conclusions: The most tolerable dose was determined to be 70 mg of D, 100 mg of E, and 800 mg/m2 of G. Clinical activity of this combination was observed as SD occurred in 69% of pts. DW-MRI could be a promising technique to assess clinical benefit early during the course of therapy. Clinical trial information: NCT01660971.
Monitoring tumor specific mutations in plasma during systemic treatment of biliary tract cancer.
Authors: Jensen Lars Henrik , Andersen Rikke Fredslund , Jakobsen Anders Kristian Moeller
Published: March 2017

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Background: We have previously reported a rate of 23% RAS/RAF mutations in plasma from patients with KRAS exon 2 and 3 wild-type, non-resectable biliary tract tumors. We wanted to explore the changes in circulating tumor specific DNA (ctDNA) during systemic chemotherapy in these patients. Methods: Patients with non-resectable biliary tract cancer treated within a phase II trial were included if they had KRAS exon 2 and 3 wild-type tumor tissue, had quantifiable levels of tumor specific DNA in plasma and progressive disease on imaging. They received gemcitabine, oxaliplatin and capecitabine with either bevacizumab or panitumumab. Treatment continued for up to six months until progression. Blood sampling and evaluation according to RECIST 1.1 were done every 12 weeks. Droplet Digital PCR was performed on DNA isolated from 4 ml plasma. A pre-amplification step was done and adequate positive and negative controls were included. The extended RAS and BRAF mutation analysis covered 20 mutations in KRAS exons 3/4, NRAS exon 2/3, PIK3CA and BRAF V600E. The percentage of tumor specific DNA relative to total DNA was reported. Results: The inclusion criteria were met by 13 patients, 10 women and three men. The typical pattern was seen in eight cases, where the percentage of tumor specific DNA dropped at least half during therapy and rose at least two-fold at progression. In three patients, a baseline sample was not available or there was not an initial drop, but the ctDNA rose at progression. One patient had an initial drop, but not a rise a progression based on imaging. The last patient progressed rapidly. Conclusions: This exploratory analysis pointed toward changes in percentage of tumor specific mutations in plasma as a marker of effect and progression. Dynamics of liquid biopsies is a promising tool in monitoring biliary tract cancer patients during systemic therapy. Clinical trial information: NCT01206049.