bluuebunny/crossref_metadata_2025 huggingface dataset:
Utility of comprehensive genomic profiling (CGP) to distinguish neoplasms pathologically diagnosed as PanNETs and PanNECs and identify potentially actionable genomic alterations (GA).
Authors: Singhi Aatur D. , Stephens Philip J. , Ross Jeffrey S. , Miller Vincent A. , Ali Siraj Mahamed , Schrock Alexa Betzig
Published: January 2019

274

Background: The majority of pancreatic neuroendocrine neoplasms are classified as pancreatic neuroendocrine tumors (PanNETs) or carcinomas (PanNECs). These are distinct entities with respect to clinical presentation, prognosis and treatment; however, locally advanced/metastatic cases may exhibit overlapping histopathologic features and, thus are challenging to differentiate and may result in inappropriate management. Recent sequencing studies have identified key differences between PanNETs and PanNECs. PanNECs often harbor recurrent GA in RB1, and members of the RAS/MAPK and TGF-β pathways. In contrast, PanNETs frequently exhibit GA in chromatin remodeling genes (e.g., MEN1, DAXX and ATRX). The purpose of this study was to evaluate the utility of CGP in the pathologic assessment of locally advanced/metastatic pancreatic neuroendocrine neoplasms. Methods: Hybrid-capture based CGP was performed for up to 315 cancer-related genes and intronic regions of up to 28 genes rearranged in cancer on 318 locally advanced/metastatic pancreatic neuroendocrine neoplasms. Results were correlated with submitting histopathologic diagnoses. Results: Among 50 pathologically-classified PanNETs, 41 (82%) and 9 (18%) cases harbored GA consistent with a PanNET and PanNEC, respectively. In comparison, among 268 pathologically-classified PanNECs, 209 (78%) and 59 (22%) cases had GA compatible with a PanNET and PanNEC, respectively. Commonly altered genes in CGP-classified PanNETs include: MEN1 (37%), DAXX (21%), CDKN2A/B (20%), ATRX (11%), TSC2 (10%), TP53 (8%), PTEN (8%), ARID1A (7%) and SETD2 (5%). Defects in the BRCA pathway were seen in 10% of PanNETs. Conversely, CGP-classified PanNECs had GA in TP53 (54%), RB1 (49%), KRAS (46%), CDKN2A/B (21%), GNAS (10%), PTEN (9%), SMAD4 (7%), MYC (7%) and ARID1A (6%). Conclusions: Pathologic discrimination between PanNETs and PanNECs can be difficult, but incorporating CGP improves the classification of these neoplasms. Further, the identification of recurrent GA in members of the BRCA family highlights a potential therapeutic target for locally advanced/metastatic PanNETs.
Mice with targeted KrasG12D and loss of p53 in the liver: A robust model for studying immunologic interventions for treating cholangiocarcinoma
Authors: Han Booyeon Julia , Figueroa Nathania , Belt Brian , O'Dell Michael , Hezel Aram F. , Linehan David
Published: January 2019

281

Background: Inflammation in the tumor microenvironment—chronically elevated cytokines, chemokines, and inflammatory cells—promotes tumorigenesis. Cholangiocarcinoma (CC) is the most common liver malignancy within the biliary tree with few treatment options and a poor 5-year survival. CC tumors are characterized with a dense tumor stroma and abundant inflammatory immune cell infiltrate, yet little is known about the immune dynamics underlying the disease. Here, we characterize immune signaling pathways in human CC and a spontaneous mouse model of the disease to identify potential targets susceptible to immune based therapies. Methods: Histology and immunohistochemistry (IHC) were performed on archived human specimens and tissue microarrays of 52 CC specimens constructed under an IRB approved protocol to identify the prognostic significance of cytokine and immune markers. Peripheral blood, bone marrow, and tissue from mice with targeted activation of KrasG12D and loss of p53 (Kras-p53-/-) in the liver that spontaneously developed CC tumors versus normal controls were collected and analyzed by histology, IHC, quantitative gene expression, and flow cytometry based studies. Results: High levels of inflammatory leukocytes in human CC were predominantly of monocytic and granulocytic origin including macrophages (TAM) and granulocytic-myeloid derived suppressor cells (G-MDSC) respectively. Malignant cells expressed high levels of CCL2 and TAM stained positive for its cognate receptor CCR2. In addition, CD8+ and CD4+ T cells expressing PD-1 were associated with PD-L1+ tumor cells. Kras-p53-/- mice developed CC tumors histologically similar to human disease: tumors had high levels of cytokines and induced myelopoiesis leading to significantly more monocytes and granulocytes in the bone marrow, blood, and spleen compared to normal liver controls. Tumors also expressed higher levels of CCL2 and PD-L1 with more CCR2+ TAMs and PD-1+ T cells compared to controls. Conclusions: Human CC utilizes immune signaling pathways and Kras-p53-/- mice recapitulate the immune dynamics of the disease representing a model to study immune based therapies for treating CC.
Relationship between mismatch repair status and long-term survival in patients with resected periampullary adenocarcinoma.
Authors: Heby Margareta , Lundgren Sebastian , Elebro Jacob , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin
Published: January 2019

289

Background: Periampullary adenocarcinomas, including pancreatic cancer, are a heterogenous group of tumors with poor prognosis. Emerging evidence indicates that tumor morphology, i.e. intestinal type (I-type) or pancreatobiliary type (PB-type), is a more relevant prognostic factor than anatomical tumor origin. The extent and clinical significance of deficient mismatch repair (dMMR) in periampullary adenocarcinoma is relatively unexplored. In this study, we examined the associations of MMR status with survival in patients with resected periampullary adenocarcinoma, with particular reference to tumor morphology and adjuvant treatment response. Methods: MMR status was assessed by immunohistochemistry on tissue microarrays with primary tumors from a retrospective consecutive cohort of 172 patients with periampullary adenocarcinoma treated with pancreaticoduodenectomy during 2001-2011 in Malmö and Lund University Hospitals, Sweden. Cox proportional hazards models were applied to calculate hazard ratios (HR) and 95% confidence intervals (CI) for death. Results: After a mean follow-up of 46.5 months (range 1.9-185.1), 35 patients (20.3%) were alive, 24 with I-type and 11 with PB-type tumors. Adjuvant chemotherapy was given in 77 (44.8%) cases, 18/63 (28.6%) I-type tumors and 59/109 (54.1%) PB-type tumors. MMR status could be evaluated in 170 cases, in which dMMR was denoted in 22 (12.9%) cases, 13/61(21.3%) in I-type and 9/109 (8.3%) in PB-type tumors. dMMR was associated with a significantly prolonged overall survival in the entire cohort (HR = 0.32, 95% CI 0.17-0.61), and in I-type tumors (HR = 0.27, 95% CI 0.09-0.79), however not independent of conventional prognostic factors. In PB-type tumors, dMMR was only prognostic in non-adjuvant treated cases (HR = 0.26, 95% CI 0.08-0.85), and there was a significant negative interaction between dMMR and adjuvant treatment (pinteraction= 0.008). Conclusions: dMMR signifies a prolonged survival in patients with periampullary adenocarcinoma, but may be a negative predictor of response to adjuvant chemotherapy in PB-type tumors. This finding may be highly relevant for clinical decision making and warrants further study.
Detection of copy number aberrations in cholangiocarcinoma using shallow whole genome sequencing of plasma DNA.
Authors: Farooq Maria , Egan Jan B. , McDonald Bradon , Markus Havell , Contente-Cuomo Tania , Fernandez-Zapico Martin , Vasmatzis George , Braggio Esteban , Borad Mitesh J. , Murtaza Muhammed
Published: January 2019

293

Background: Cholangiocarcinoma (CCA) is a deadly cancer with ~20% five year survival. Obtaining tissue to confirm diagnosis of CCA is often challenging. This also limits the use of tumor genotyping that could guide potential molecularly targeted treatment (such as FGFR inhibitors for a subset of cases). We investigated whether circulating tumor DNA (ctDNA) analysis in plasma is feasible for noninvasive tumor genotyping in patients with advanced CCA. Methods: We collected and processed plasma samples for ctDNA analysis from 17 patients with CCA at presentation and from 11 healthy volunteers. Following cell-free DNA extraction and quality assessment using digital PCR, we performed low-pass, shallow whole genome sequencing (sWGS). We analyzed sequencing data to identify copy number aberrations and quantify tumor fraction in plasma using recently published computational approaches. Results: Median total cfDNA concentration in patients with CCA was 7,003 genome equivalents (GEs)/mL plasma (range: 1,512- 107,707 GEs/mL) and significantly higher than healthy volunteers (two tailed t-test p < 0.04, median: 1,658 GEs/mL, range: 661-4,938 GEs/mL). We successfully sequenced all tumor libraries, generating a median of 173 million paired-end reads. ctDNA was detectable in 10/17 samples using sWGS. In these 10 samples, median tumor fraction in plasma DNA was 7.1% (range: 3.9%-44.6%). We found recurrent copy number aberrations expected in CCA including 1q gain in 80%, 7p gain in 50%, 1p loss in 70% and 3p loss in 50% of cases. Conclusions: ctDNA analysis for noninvasive tumor genotyping is feasible in patients with advanced cholangiocarcinoma. On-going work is focused on expanding these results using targeted and whole-exome sequencing.
Utility of next-generation sequencing in clinical decision making in hepatocellular carcinoma (HCC).
Authors: Thota Ramya , Lewis Mark Andrew , Raghunath Sharanya , Haslem Derrick S. , Nadauld Lincoln , Rhodes Terence Duane , Moulton Bryce , Abraham Tyler , Romero Robin , Fulde Gail , Christensen Bryce , Barker Tyler ,   Intermountain Precision Genomics Group
Published: January 2019

295

Background: HCC is a heterogeneous disease with diverse genomic alterations. The prior genomic studies have identified common alterations in TERT, P53, WNT pathways. However, most of these alterations are not targetable with current FDA approved targeted agents. In this study, we determine the clinical impact of targeted next generation sequencing in patients with advanced HCC. Methods: We retrospectively assessed all patients with gastrointestinal (GI) malignancies who have undergone next generation sequencing (NGS) between January 2013 and August 2017. The primary endpoint is to determine the frequency of clinically actionable mutations in HCC. Secondary endpoint is to identify number of patients eligible for current FDA approved targeted agents. Results: Of the 299 consecutive GI tumors sequenced, 29 cases were identified as HCC. Clinically actionable mutations were noted in 22 of 29 patients (pts) (76%). Most pts (52%) were found to harbor more than one potentially actionable genetic alterations (n = 15). The common pathways involved: P53 in 9 pts (22%), cell-cycle regulation in 7 pts (17.1%) and mitogen-activated protein kinase in 6 pts (14.6%). Other pathways involved were DNA repair in 4 pts (9.8%), WNT in 3 pts (7.3%), MYC in 3 pts (7.3%), NOTCH in 2 pts (4.9%), HNPCC in 2 pts (4.9%), APC in 2 pts (4.9%), phosphatidylinositol 3-kinase-AKT-mTOR in 1 patient (pt) (2.4%), BRINP in 1 pt (2.4%) and angiogenesis in 1 pt (2.4%). We noted 10 pts (34.5%) harbor alterations that could potentially be targeted with FDA approved treatments such as palbociclib (for CCND1/2 amplification), PARP inhibitors (for DNA repair defects), and immunotherapy (for MMR defects) on precision medicine clinical trials such as TAPUR or MATCH. Conclusions: Mutational profiling using a targeted NGS panel identified clinically actionable alterations in nearly 75% of advanced HCC patients. Almost one third of these patients were potential candidates for current FDA approved treatments. NGS and enrollment in clinical trials should be considered in all fit patients with HCC who had progression on current standard of care treatments.
Comprehensive genomic profiling of appendiceal adenocarcinoma.
Authors: Raghav Kanwal Pratap Singh , Loree Jonathan M. , Fournier Keith F. , Shaw Kenna Rael , Taggart Melissa W. , Foo Wai Chin , Matamoros Aurelio , Mehdizadeh Amir , Ahmed Shahab U. , Guerra Jennifer L. , Mansfield Paul F. , Royal Richard Eldon , Overman Michael J. , Eng Cathy
Published: January 2019

298

Background: Appendiceal adenocarcinomas (AAs) are orphan tumors. Little is known about their molecular profile limiting understanding of their biology and development of novel targeted therapies. The purpose of this study was to delineate the molecular landscape of AAs. Methods: We performed a retrospective review of AAs patients (pts) who were evaluated at MD Anderson Cancer Center between October 2012 and April 2017 and underwent next-generation sequencing (NGS) with internal or external assays (at least 45 genes) using either tumor tissue specimens or peripheral blood for circulating cell-free DNA (cfDNA). The primary outcome was to assess the prevalence of genomic alterations (GAs) in AAs. We then performed comparative exploratory analyses of GAs using TCGA colorectal cancer (CRC) sequencing. Results: A total of 78 patients were identified of which 57 (73%) and 18 (23%) underwent tissue based and ctDNA based sequencing, respectively (3 cases had both). At least 1 GA was found in 61 (78%) of AA specimens, with a mean (SD) of 2.8 (1.6) GAs per case. Of these 44 (72%) had ≥ 2 GAs and 31 (51%) had ≥ 3 GAs. The most frequent GAs were KRAS (38 [62%]), TP53 (22 [36%]), GNAS (17 [28%]), SMAD4 (11 [18%]), PIK3CA (10 [16%]), APC (9 [15%]), ATM (8 [13%]), BRAF (5 [8%]), KIT (5 [8%]), NRAS (3 [5%]) and MET (3 [5%]). GNAS mutations frequently co-occurred with KRAS mutations (42% v 5%, OR 14.3, P < 0.001). No GA was associated with grade, mucinous histology or overall survival (OS). Besides these mutations, we also found unusual cases with targetable mutations such as ALK, EGFR, MET, IDH1 and ERBB2. In our comparative analyses, mutations in KRAS (p = 0.009), TP53 (p = 0.020), GNAS (p < 0.001) and APC (p < 0.001) genes were significantly different from CRC whereas there was no difference in prevalence of PIK3CA, SMAD4 and ATM genes. Conclusions: To date, our analysis of one of the largest cohorts of AAs, demonstrate a majority of AAs harbor at least 1 GAs. Although treatment paradigms in AAs are extrapolated from CRC, the molecular profile of these tumors differs significantly. Molecular characterization of these rare tumors is a necessary first step towards discovery of opportunities for use of targeted therapies in these patients.
Kinetics and dosimetric predictors of acute radiation-induced lymphopenia in pancreatic cancer.
Authors: Ellsworth Susannah G. , Mereniuk Todd , Hobbs Robert F , Zhang Hong , Herman Joseph M. , Grossman Stuart A. , O'Neil Bert H. , Shahda Safi , Mohan Radhe , Kong Feng-Ming (Spring) , Jin Jianyue
Published: January 2019

300

Background: Radiation (RT) induced lymphopenia (RIL) is an adverse prognostic factor in pancreatic cancer (PC) and is likely due to the irradiation of lymphocytes in the RT field. The goal of this study was to identify dosimetric predictors for high rates of absolute lymphocyte count (ALC) loss during RT for PC. Methods: This was a retrospective study of 34 PC patients in an institutional database who had received concurrent 5-FU or gemcitabine-based chemoradiation (50-54 Gy) and had ≥ 3 ALCs measured during RT. Baseline ALC was normal (>1000 cells/uL) in 28/34 (82%) and grade 3-4 RIL occurred in 24/34 (71%). ALC was plotted against fraction # and a best-fit line for each patient was created to determine per-fraction loss in ALC (PFLAC). Linear regression was used to correlate PFLAC with dosimetric parameters including mean dose to gut, liver, kidney, spleen, and cisterna chyli, as well as estimated dose to immune cells (EDIC), which calculates dose to immune cells according to the % of body lymphocytes contained in each organ. Results: All patients exhibited exponential loss in ALC during RT. Mean PFLAC was 6.8% (range 1.7-13.4); fraction # was strongly correlated with ALC (mean R2 = 0.89). Patients with >/= grade 3 lymphopenia had a significantly higher PFLAC than those with grade 0 - 2 lymphopenia (mean daily loss 7.8% in Gr 3-4 vs. 4.8% in Gr 0-2, p = 0.001; independent sample T test). Field size was not correlated with PFLAC for high (> 1 Gy) or low (< 0.5 Gy) isodose volumes. Mean whole body (r = 0.59, p < 0.001), bowel (r = 0.39, p = 0.012), liver (r = 0.42, p = 0.007), and cisterna chyli (r = 0.583, p = 0.004) doses were moderately correlated with PFLAC; mean kidney (r = 0.22, p = 0.11) and spleen (r = 0.26, p = 0.06) doses were weakly correlated with PFLAC. EDIC was more strongly correlated with PFLAC than any individual organ mean dose (r = 0.69, p < 0.001). Conclusions: Patients undergoing RT for PC experience a predictable RIL characterized by an exponential loss of lymphocytes per day. PFLAC is a useful method of characterizing RIL and facilitates evaluation of dosimetric predictors of RIL. We identified dose to cisterna chyli as a significant contributor to RIL in PC; however, EDIC has a stronger correlation with RIL severity than any single organ dose.
Relationship between desmoplastic pattern and lymphocytes infiltration in pancreatic cancer.
Authors: Einama Takahiro , Ao Tadakazu , Kajiwara Yoshiki , Sueyama Takahiro , Shinto Eiji , Nishikawa Makoto , Noro Takuji , Hoshikawa Mayumi , Aosasa Suefumi , Hase Kazuo , Yaguchi Yoshihisa , Hiraki Shuichi , Tsujimoto Hironori , Ueno Hideki , Yamamoto Junji
Published: January 2019

317

Background: The proposed histologic desmoplastic reaction (DR) categorization and lymphocyte infiltration (LI) directly reflects tumor behavior in a modulating stromal environment and could provide valuable prognostic information for colorectal cancer patients, but the prognostic role of DR and LI has not been investigated in pancreatic cancer patients. Methods: A total of 87 pancreatic cancer patients who underwent potentially curative surgery for their tumors in our hospital (2008 to 2013) were included. DR was classified as mature, intermediate, or immature on the basis of the existence of keloid-like collagen and myxoid stroma-distinctive histologic products of extracellular matrix remodeling. LI was classified as Pattern I; circumferential lymphocytes zone without disruptions around tumor, Pattern II; lymphocytes zone with partial disruptions and thinning around tumor, Pattern III; focal lymphocytes foci around tumor at most invasive border without lymphocyte zone, and Pattern IV; no lymphocyte foci around tumor. Results: With regard to DR, 0, 23, and 64 patients were classified as mature, intermediate, and immature, respectively. Five-year overall survival rates (#%) were higher in immature group (p=0.0040) than those of intermediate group (#%). Multivariate analysis revealed that DR was an independent prognostic factor along with residual tumor (p=0.0300). With regard to LI, 0, 6, 70, and 11 patients were classified as Pattern I, Pattern II, Pattern III, and Pattern IV, respectively. There was no relationship between DR and LI. Conclusions: The DR categorization seemed to reflect tumor behavior and could provide valuable prognostic information for pancreatic cancer patients. We did not show any relationship between DR and LI in pancreatic cancer.
Effect of macrophages on pancreatic cancer.
Authors: Glazer Evan Scott , Reed Leighton F. , Freeburg Charlie J. , Husain S. Mazher , Deneve Jeremiah Lee , Dickson Paxton Vandiver , Shibata David
Published: January 2019

324

Background: Pancreatic Ductal Adenocarcinoma (PDAC) is expected to be the second leading cause of cancer related deaths by 2030. TGF-β is a well-studied PDAC mediator with a context dependent role as initially a tumor suppressor with potential to convert to a tumor promoter in later stages. Tumor associated macrophages and interleukins, such as the pro-inflammatory interleukin, IL23, are not well studied regarding PDAC. We hypothesized PDAC treated with TGF-β and macrophages would induce a more aggressive phenotype. Methods: We investigated aggressive behavior with a primary PDAC cell line in vivo and a metastatic PDAC cell line in vitro. A primary pancreatic cell line, Panc-1 cells, were pre-treated with PBS, IL23, macrophages (10:1 ratio of Panc-1 cells to macrophages), IL23 + macrophages, TGF-ß, TGF-ß + macrophages, or TGF-ß + macrophages + IL23. After treatment, cells were orthotopically implanted into the pancreas of NOD SCID gamma mice with 5 mice per group. Mice weights were recorded twice weekly for 4-weeks. Primary lesions and metastasis were investigated with ANOVA. AsPC-1 cells, a metastatic pancreatic cell line, were pre-treated with the same seven treatments. We investigated pSTAT3 expression and the streak closure in vitro. Results: Panc-1 cells treated with macrophages had the largest pancreatic tumor weight and diameter compared to PBS control, IL23 alone, and TGF-β alone (P < 0.001). When macrophages treatment included TGF-β, pancreatic tumor weights and diameters decreased as compared to macrophages alone and macrophages + IL23 (P < 0.001). Macrophage treatment induced higher liver weights and higher number of surface liver metastatic lesions suggesting higher metastatic disease burden (P < 0.03). AsPC-1 cells treated with combinations of macrophages and TGF-β increased pSTAT3 expression compared to PBS control. AsPC-1 cells treated with macrophages closed the gap in the scratch assay faster than PBS control 24 hours after treatment (P < 0.001). Conclusions: We demonstrated macrophages have a key role in converting primary pancreatic cancer into a more aggressive phenotype in vivo whereas they have less effect on metastatic pancreatic cancer in vitro.
Correlation of neutrophil lymphocyte ratio, platelet lymphocyte ratio and rate of change of CA 19.9 in predicting outcome for metastatic pancreatic cancer.
Authors: Dean Andrew Peter , Higgs Dom , Das Adarsh , Rogers-Seeley Madeline , Fennessy Sean , McGarvey Caoimhe
Published: January 2019

326

Background: CA19.9, NLR and PLR have all been proposed as prognostic in pancreatic cancer. We analysed correlation between NLR, PLR and rate of change of CA19.9. Methods: A total of 63 metastatic pancreatic cancer patients were identified from our database and evaluated retrospectively for blood count, NLR, PLR and serial CA19.9 levels during treatment. Daily Rate of Change of CA19.9 levels were calculated for the first 90 days (DRC90) of the patient’s treatment. Kaplan-Meir curves, univariate and multivariate Cox-regression analyses were calculated to assess the effects of these 3 markers on overall survival. Results: In a univariate analysis, PLR > 240, NLR > 5 and DRC90 > 0.4% were all significantly associated with deceased overall survival. The Cox proportional hazards model showed that NLR < 5 (HR 0.475, 95% CI 0.259 to 0.873, P = 0.017), PLR < 240 (HR 0.444, 95% CI 0.229 to 0.861, P = 0.016), and a DRC90 < 0.4% (HR 0.294, 95% CI 0.102 to 0.851, P = 0.024) were independent predictors of good prognosis (22.6 months vs. 9.6 months, 22.3 months vs 12.4 months and 23.9 months vs. 9.3 months respectively). In multivariate analysis, only a DRC90 < 0.4% was independently associated with a longer survival (HR 0.239, 95% CI 0.076 to 0.752, P = 0.014). The formula (F) {PLR + (NLRxNLR) + (DRC90 x 100)} was predictive for survival, as patients with F > 190 (HR 3.295, 95% CI 1.232 to 8.807, P = 0.017), having a significantly lower survival rate than patients with F < 190 (25.1 months vs. 10.6 months, log-rank P = 0.009). Conclusions: These findings indicate the prognostic utility of the rate of CA 19.9 decline - measured as a standardised daily percentage change in value over 90 days. Our data validates daily rate of change of CA 19.9 over 90 days as an independent variable that correlates with prognosis, independent of PLR and NLR. We also identified a novel formula - PLR + (NLRxNLR) + (DRC90 x 100) - as being predictive for survival. We would like to increase the sample size to further validate our initial findings and investigate possible relationships in combining these variables for better prognostication in metastatic pancreatic cancer.
Amplitude-modulated radiofrequency electromagnetic fields target hepatocellular carcinoma stem cells through activation of Cav 3.2 T-type calcium channels.
Authors: Jimenez Hugo , Wang Minghui , Zimmerman Jacquelyn W. , Pennison Michael J. , Sharma Sambad , Brezovich Ivan , Absher Devin , Myers Richard M , DeYoung Barry R. , Caudell David , Godwin Dwayne , Ghanekar Anand , Miller Lance D , Capstick Myles , Kuster Niels , D'Agostino Ralph , Barbault Alexandre , Watabe Kounosuke , Blackman Carl F , Pasche Boris
Published: January 2019

332

Background: Amplitude-modulated 27.12 MHz radiofrequency electromagnetic fields (AM RF EMF) delivered via a spoon-shaped antenna placed on the patient’s tongue result in shrinkage of the primary and metastatic tumors in patients with advanced hepatocellular carcinoma (HCC). (Costa FP, et al. Br J Cancer. 2011;105:640-648.) The mechanism by which AM RF EMF have direct antiproliferative effect and disruption of the mitotic spindle on cancer cells is largely unknown. (Zimmerman JW, et al. Br J Cancer. 2012;106:307-313.) Methods: We assessed the Specific Absorption Rate (SAR) level and distribution inside the human body. In vitro experiments with HCC cells were performed as previously described (Zimmerman). Immunodeficient mice were subcutaneously implanted with Huh-7 HCC cells or patient-derived xenografts (PDX). Mice were exposed to HCC-specific AM RF EMF using systems replicating human exposure levels and treatment duration. Tumor samples were examined for EMT and cell cycle markers. Results: Intrabuccal delivery results in whole-body absorption of AM RF EMF. Proliferation of hepatitis B positive and negative cell lines as well as HCC cancer stem cells (CSCs) are blocked by AM RF EMF through Cav 3.2 T-type voltage gated calcium channels (VGCC). Proliferation of HCC is inhibited in vivo and tumor shrinkage occurs by dedifferentiation of HCC cells into quiescent myofibroblasts while the growth of intestinal and blood marrow cells is unaltered. Conclusions: Whole-body SAR ranges from 0.2 to 1 mW/kg and is significantly below the international safety limits for human exposure. Intrabucally-administered AM RF EMF is a novel targeted therapy for systemic treatment of advanced HCC with minimal off target effects. Inhibition of HCC CSCs may explain the extremely long term survival (>5 years) of several patients with advanced HCC.
Deposition characteristics and resulting DNA damage patterns of liposomal irinotecan (nal-IRI) in pancreatic cancer xenografts.
Authors: Leonard Shannon C. , Paz Nancy , Klinz Stephan G , Gaddy Daniel , Lee Helen , Hendriks Bart S , Fitzgerald Jonathan B
Published: January 2019

335

Background: Liposomal irinotecan (nal-IRI, ONIVYDE) is approved in the US, EU and other countries in combination with 5-fluorouracil/leucovorin for treatment of patients with metastatic pancreatic cancer after disease progression following gemcitabine-based therapy. We report pharmacokinetic and extended pharmacodynamic effects of nal-IRI in pancreatic tumor models compared to non-liposomal irinotecan HCl. Methods: AsPC-1, BxPC-3 and CFPAC-1 tumors were grown in NOD-SCID mice. For efficacy animals were dosed q7d with 25-50 mg/kg irinotecan HCl or at 5x lower doses of nal-IRI. For PK-PD studies doses of 10-50 mg/kg of fluorescently-labeled nal-IRI were used; samples were collected up to 72 hr for irinotecan HCl and up to 168 hr for nal-IRI. Tumor samples were evaluated for liposome localization, macrophage and tumor markers, vessels, DNA damage and apoptosis. Results: nal-IRI yields sustained circulation and delivery of its payload to tumors compared to irinotecan HCl. This results in improved control of growth rates across a range of pancreatic tumor models even at 5x lower doses. DNA damage in BxPC-3 tumors has a comparable extent with both formulations, but is maximal at 6 hr after irinotecan HCl (50 mg/kg) and at 72 hr after nal-IRI (10 mg/kg). Liposomes deposit in tumors heterogeneously around functional vessels. Accumulation peaks at 6 - 24 hr with similar deposition patterns in cell- or patient-derived xenografts. Liposomes are predominantly taken up by macrophages and to a lesser extent by tumor or other stromal cells. DNA damage is mostly confined to tumor cells, a majority of which have not internalized liposomes. DNA damage and apoptosis are seen only minimally in non-tumor cells even when displaying high liposome uptake. Conclusions: nal-IRI improves tumoral deposition of its payload in pancreatic tumor models. Deposition is heterogeneous and restricted to perivascular areas. DNA damage predominantly in tumor cells outside of the liposomal deposition area suggests sufficient intratumoral levels of the SN-38 active metabolite, possibly after payload release by stromal macrophages and concomitant conversion. Effects of repeated dosing cycles should be explored.
A randomized phase II clinical trial of gemcitabine, oxaliplatin, erlotinib combination chemotherapy versus gemcitabine and erlotinib in previously untreated patients with locally advanced or metastatic pancreatic cancer.
Authors: Lim Sung Hee , Yun Jina , Lee Min-Young , Kim Han Jo , Kim Kyoung Ha , Kim Se Hyung , Lee Sang-Cheol , Bae Sang Byung , Kim Chan Kyu , Lee Namsu , Lee Kyu Taek , Park Sung Kyu , Hong Dae Sik , Choi Hyun Jong , Moon Jong Ho
Published: January 2019

344

Background: Erlotinib is the only targeted agent in combination with gemcitabine showing significantly improved outcomes in pancreatic cancer. Although combining platinum agent with gemcitabine has not provided clear survival benefit over gemcitabine alone, gemcitabine plus platinum resulted in improved response rate and progression-free survival (PFS). We tried to evaluate whether the addition of oxaliplatin to gemcitabine/erlotinib confers a clinical benefit to patients with locally advanced or metastatic pancreatic cancer. Methods: Chemotherapy-naïve patients with locally advanced or metastatic pancreatic cancer were randomly assigned to receive GEMOX-T (gemcitabine 1000mg/m2 IV and oxaliplatin 50mg/m2 IV on day 1, 8 plus erlotinib 100mg daily, every 3weeks) or GT (gemcitabine 1000mg/m2 IV on day 1, 8 plus erlotinib 100mg daily, every 3weeks). The primary endpoint was overall response and secondary endpoints included PFS, overall survival (OS) and toxicity. Results: Between May 2013 and April 2016, 65 patients were randomly assigned to treatment group (33 in GEMOX-T arm, 32 in GT arm). The median age of all patients was 61 years (range, 41-76) and about 80% of patients had metastatic disease. The overall response rate was 18.2 % in GEMOX-T arm and 6.2% in GT arm ( P = 0.051). The disease control rate was significantly superior in GEMOX-T arm compared to GT arm (72.7% vs. 43.8%, P = 0.019), with 1 patient in GEMOX-T group continuing the treatment with stable disease. After a median follow up of 19.7 months, there was significant difference in PFS: the median PFS were 3.9 months for GEMOX-T arm and 1.4 months for GT arm (Hazard ratio: 0.58, 95% CI 0.35-0.96, P = 0.037). However, it did not translate to improvement of OS (median OS; 6.2 m for GEMOX-T arm, 5.1 m for GT arm, P = 0.118). The most common grade ≥ 3 hematologic adverse events were neutropenia (16.9%) and anemia (13.8%). Conclusions: The addition of oxaliplatin to 1st line gemcitabine/erlotinib regimen demonstrated higher response rate and significantly improved PFS in patients with locally advanced or metastatic pancreatic cancer.
Independent imaging review (IIR) results in a phase 3 trial of lenvatinib (LEN) versus sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC).
Authors: Lencioni Riccardo , Kudo Masatoshi , Finn Richard S. , Qin Shukui , Han Kwang-Hyub , Ikeda Kenji , Cheng Ann-Lii , Piscaglia Fabio , Han Guohong , Ikeda Masafumi , Simon Krzysztof , Komov Dmitry , OuYang Xuenong , Evans T.R. Jeffry , Sung Max W. , Binder Terri A. , Damon Andrew , Kraljevic Silvija , Ren Min , Ryoo Baek-Yeol
Published: January 2019

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Background: LEN showed treatment effect on OS by statistical demonstration of noninferiority to SOR in a phase 3 study in pts with uHCC, with significant improvement ( P < 0.00001) in median PFS (7.4 vs 3.7 mos; HR: 0.66; 95% CI, 0.57−0.77), median TTP (8.9 vs 3.7 mos; HR: 0.63. 95% CI, 0.53−0.73), and ORR (24% vs 9%). Tumor assessments were by investigator review (IR) per modified RECIST (mRECIST). We present IIR results to assess concordance for IR vs IIR and mRECIST vs RECIST 1.1 by IIR. Methods: In this open-label study, pts with uHCC, ≥ 1 measurable target lesion, BCLC stage B or C, Child-Pugh class A, ECOG PS ≤ 1, and no prior systemic therapy were randomized 1:1 to LEN (body weight ≥60 kg: 12 mg/d; <60 kg: 8 mg/d) or SOR 400 mg twice daily. Primary endpoint was OS. Secondary efficacy endpoints were PFS, TTP, and ORR by mRECIST. IR tumor assessments were done every 8 wks. Post hoc exploratory blinded IIR studies were done using mRECIST and RECIST 1.1 (first timepoint at wk 8). Results: A total of 954 pts enrolled (LEN: 478; SOR: 476), of which 952 (99.8%) pts were IIR assessable (table). Adjudication rate (AR; percentage of cases adjudicated due to disagreement) for timepoint of PD was similar for mRECIST (47%) and RECIST 1.1 (45%); for responder (CR or PR)/nonresponder (SD, PD, or not evaluable [NE]), it was 32% for mRECIST and 17% for RECIST 1.1. PFS and TTP results were nearly the same per mRECIST by IIR as by IR and the same by IIR per mRECIST and RECIST 1.1. Very good concordance was seen between IIR and IR in best overall response (BOR) per mRECIST with the greatest discordance due to more pts being assessed as PR than SD for LEN. Conclusions: IIR supports IR results. ORR was higher in both arms by IIR vs IR but relative ORR was preserved in LEN vs SOR. Higher AR for IIR per mRECIST on response may be due to the greater number of responders or disease complexity. Median PFS and TTP were the same by IIR per mRECIST and RECIST 1.1, showing these data can be compared between methods. Clinical trial information: NCT01761266. [Table: see text]
The Canadian Cancer Trials Group PA.7 trial: Results from the safety run in of a randomized phase II study of gemcitabine (GEM) and nab-paclitaxel (Nab-P) versus GEM, nab-P, durvalumab (D), and tremelimumab (T) as first-line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Renouf Daniel John , Dhani Neesha C. , Kavan Petr , Jonker Derek J. , Wei Alice Chia-chi , Hsu Tina , Tang Patricia A. , Graham Barbara , Gallinaro Lisa , Hasan Tasnia , Li Weiwei , Hart Kate , Tu Dongsheng , O'Callaghan Christopher J.
Published: January 2019

349

Background: GEM and Nab-P is a standard first line therapy for mPDAC based on the MPACT Trial. D is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. T is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). PA.7 is designed to evaluate whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases treatment efficacy. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) is assessing the efficacy and safety of GEM and Nab-P vs. GEM, Nab-P, D, and T in patients (pts) with mPDAC (n = 190). Pts with untreated mPDAC and good performance status (ECOG PS 0-1) are eligible. A safety run in was planned for 10 pts receiving GEM, Nab-P, D and T. The study is then planned to randomize pts in a 2:1 ratio to receive GEM (1000mg/m2 D1, 8, 15); Nab-P (125mg/m2 D1, 8, 15); D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles vs. GEM and Nab-P alone. The primary endpoint is overall survival (OS); secondary endpoints include progression free survival (PFS), safety, overall response rate and quality of life. Results: 11 pts were enrolled in the safety run in (2 final pts enrolled on the same day). Median (Med) age = 59; 9 male/ 2 female; 2 ECOG 0/ 9 ECOG 1; no pts had prior adjuvant therapy. Med follow-up was 8.3 months at the time of data lock. Med number of treatment cycles was 6 (3-10). The most common Grade 3 or greater adverse events included fatigue (27%), anemia (36%), abnormal WBC (27%), hyponatremia (27%), hypoalbuminemia (45%), and abnormal lipase (45%). 1 pt (9.1%) experienced grade 3 colitis. 8/11 pts (73%) had a partial response, with the med duration of 7.4 months. Disease control rate was 100%. Med PFS was 7.9 months (95% C.I. 3.5-9.2 months). 6-month survival rate was 80% (95% C.I 40.9%-94.6%). Med OS has not been reached. Conclusions: The combination of GEM, Nab-P, D and T was well tolerated and promising efficacy signals were noted. The originally designed randomized phase II study is ongoing, and an international randomized phase III trial is planned. Clinical trial information: NCT02879318.
A phase II trial of gemcitabine (G), cisplatin (C), and nab-paclitaxel (N) in advanced biliary tract cancers (aBTCs): Updated survival analysis.
Authors: Shroff Rachna T. , Javle Milind M. , Xiao Lianchun , Kaseb Ahmed Omar , Varadhachary Gauri R. , Wolff Robert A. , Raghav Kanwal Pratap Singh , Iwasaki Michiko , Masci Peter , Ramanathan Ramesh K. , Ahn Daniel H. , Bekaii-Saab Tanios S. , Borad Mitesh J.
Published: January 2019

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Background: BTCs are often diagnosed at an advanced stage and have a poor prognosis. The standard therapy for aBTCs is the combination of GC. However, the median overall survival (mOS) is dismal at 11.7 months (mos) with a median progression free survival (mPFS) of 8 mos. Methods: A single arm, phase II study was conducted at MD Anderson and Mayo Clinic Arizona. Patients (pts) with aBTC were treated at initial dose level of G/C/N (in mg/m2) at 1000/25/125 (n = 30) which was reduced to lower doses due to grade 3/4 hematological (heme) toxicity (tox) - G/C/N: 800/25/100 (n = 30). Cycles were q21 days with restaging q3 cycles until progression. PFS was the primary endpoint (endpt). Using a Bayesian hypothesis test-based design, we assumed mPFS of 8 mos under the null hypothesis (H0), 10 mos under the alternative (H1). Secondary endpts included mOS, RECIST v1.1 response rate (RR), safety and CA19-9 response. Results: 60 pts were enrolled with 51 being response-evaluable having received more than 1 cycle of therapy (age: median 60 yrs [range 31-77], ECOG PS 0/1 (22/38), M/F (33/27), intrahepatic cholangiocarcinoma/extrahepatic/gallbladder (38/9/13). Median follow-up was 14 mos and median number of treatment (trmt) cycles = 5.24. Pts at initial dose level had significant grade 3/4 heme tox: neutropenia, febrile neutropenia, anemia, and thrombocytopenia leading to trmt discontinuation in 6/30 pts. After dose reduction to G/C/N (in mg/m2) at 800/25/100, trmt was better tolerated with only 3 pts experiencing grade 4 heme tox. Non-heme tox were grade 3 in 19 pts: nausea/vomiting, diarrhea, thromboembolic event/CVA, hypokalemia, constipation, cystitis, LFT elevations. The mPFS = 11.4 mos (95% CI: 6.1, 16.1) and mOS = 19.2 (95%CI: 13.6, NA), 1-year survival rate 67.6%. 51 pts evaluable for response: disease control rate (PR+CR+SD)-84.3% and RR-39%. 12 unresectable cases were operated post trmt with 1 pathologic CR. Conclusions: The combination of GCN was well tolerated at adjusted doses and demonstrates encouraging efficacy having met its mPFS endpt and an impressive mOS higher than historical control. These results merit evaluating GC +/-N in a randomized controlled study. Clinical trial information: NCT02392637.
Activity and safety of Nab-FOLFIRI and Nab-FOLFOX as first-line treatment for metastatic pancreatic cancer (phase II NabucCO study).
Authors: Giommoni Elisa , Maiello Evaristo , Vaccaro Vanja , Rondini Ermanno , Vivaldi Caterina , Tortora Giampaolo , Toppo Laura , Giordano Guido , Latiano Tiziana Pia , Antonuzzo Lorenzo , Lamperini Cinzia , Boni Luca , Di Costanzo Francesco
Published: January 2019

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Background: FOLFIRINOX is an approved regimen for metastatic pancreatic cancer (mPC). We performed a modification in FOLFIRINOX schedule, using nab-paclitaxel (nab-p) to obtain two regimens that could be as effective and less toxic than the original triplet. NabucCO study was a randomized phase II trial to assess activity and toxicity of nab-p instead of either oxaliplatin (Nab-FOLFIRI) or irinotecan (Nab-FOLFOX) in first line setting. Previous dose–finding NabucCO study defined that maximum tolerated dose of nab-p with FOLFIRI is 120 mg/m2, and with FOLFOX is 160 mg/m2. Methods: The study was a 1:1 parallel arm, open label, not comparative one to assess overall response rate (ORR) of Nab-FOLFIRI and Nab-FOLFOX as primary end-point. Patients (pts) with PS 0-1, untreated for mPC were randomized to receive leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2, irinotecan 180 mg/m2 plus nab-p 120 mg/m2 (arm A) or leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2 and oxaliplatin 85 mg/m2 iv plus nab-p 160 mg/m2 (arm B) every 2 weeks for up to 12 cycles. Secondary end points were clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS), and safety. Results: From November 2015 to January 2017, 84 pts were treated (42 for each arm). Median age was 60 years (29-65) in arm A and 64 years (47-64) in arm B. The ORR was 31 % for both schedules, with a CBR of 69% and 71%, respectively. At a median follow-up of 11.4 months for arm A and 14.5 months for arm B (censored on august, 31th 2017), 1-year survival is 41% and 50%, respectively. For Nab-FOLFIRI PFS and mOS were 6 months (90% CI: 4.9-8.0) and 13.2 months (90% CI: 8.3-14.8), while in Nab-FOLFOX were 5.6 months (90% CI:4.9-7.2) and 10.8 months (90% CI: 8.4-12.8). Grade ≥3 toxicities in arm A were neutropenia (19%) and febrile neutropenia (12%). In arm B, main grade ≥3 toxicities were neutropenia (29%), fatigue (14%), peripheral neuropathy (7%). No toxic death were registered. Conclusions: Nab-FOLFIRI and Nab–FOLFOX demonstrated a similar activity to FOLFIRINOX, with better safety profile in terms of neutropenia, fatigue and neuropathy. These results could justify a future phase III evaluation. Clinical trial information: NCT02109341.
Living with neuroendocrine tumors: Assessing quality of life (QoL) through a mobile application.
Authors: Adams Jared , Ray David , Willmon Renee , Kaleis Linda , Gautam Anand , Pulgar Sonia J. , Dasari A.
Published: January 2019

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Background: The study aim was to understand neuroendocrine tumor (NET) patients’ (pts) QoL through PROMIS-29, symptom tracking and patient journaling via the Carcinoid Health Storylines mobile application (app). Methods: This 12-week prospective, observational study was conducted among US NET pts recruited through the Carcinoid Cancer Foundation on either Lanreotide depot (L) or octreotide LAR (O) via surveys at baseline, week (w) 6, and w 12 with PROMIS-29 and symptom questionnaires at baseline, w 4 & w 8. Pts were asked to monitor symptoms, mood, bowel movement frequency, food, activity and sleep in their app 5x / week. Demographics and medical history were collected at baseline. Results: Of the 120 NET pts, 78% were female (mean age=57); 76% were gastroenteropancreatic NETs and 88% with metastases. L and O use was at 41% and 59% respectively. 82% completed ≥ 1 follow-up survey; the most common symptoms at baseline were fatigue (76.7%), diarrhea (62.5%), abdominal discomfort (64.1%) and trouble sleeping (57.5%). The baseline PROMIS-29 assessment revealed high proportions endorsing clinically significant depression (17.7%), anxiety (24.2%), fatigue (58.8%), dissatisfaction with social role (i.e. daily routine, 42.2%), difficulty with physical functioning (i.e. run errands, 16%) and insomnia (34.9%). Thus, 26.9% reported their QoL being poor and yet, a high percentage of patients were hopeful and reported their life as being meaningful (72.3%). Reported symptoms decreased significantly from initial to subsequent surveys (e.g. 59.3% to 33% for diarrhea; p=0.002). App tracking effectively captured day to day variations in reported symptoms and weekly averages correlated well with symptom surveys and PROMIS-29 scores. Seventy-seven pts journaled with 26 providing unsolicited injection experience (L =10; O =16). Conclusions: This study suggests that the use of apps for recording daily symptoms in NET pts, with decreased symptom reporting over time perhaps due to reduced recall bias from frequent tracking, or a potential therapeutic effect of journaling. Apps should be developed further to record the experiences and needs of NET pts.
Comparative effectiveness of nab-paclitaxel plus gemcitabine versus FOLFIRINOX in metastatic pancreatic cancer: A nationwide chart review in the United States.
Authors: Kim Sunnie S. , Signorovitch James , Yang Hongbo , Patterson-Lomba Oscar , Xiang Cheryl , Ung Brian , Parisi Monika , Marshall John
Published: January 2019

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Background: nab-Paclitaxel plus gemcitabine ( nab-P+G) and FOLFIRINOX (FFX) are among the most common first-line (1L) therapies for metastatic adenocarcinoma of the pancreas (mPC), yet there is no head-to-head trial comparing their efficacy and real-world data is limited. As new second-line (2L) therapies become available, it is important to understand the real-world effectiveness associated with different treatment sequences. Methods: This retrospective cohort study compared the efficacy and safety of 1L nab-P+G vs. FFX, overall and under specific treatment sequences. Medical records were reviewed by 215 physicians across the US who provided information for mPC patients who initiated 1L with nab-P+G or FFX between 04/01/2015-12/31/2015. The outcomes of interest were overall survival (OS) and tolerability. OS was evaluated using Kaplan-Meier curves, and compared between cohorts using Cox proportional hazards model adjusting for baseline characteristics. Results: Medical records were reviewed for 654 patients receiving nab-P+G (n = 337) or FFX (n = 317) as 1L therapy for mPC. Patients in the nab-P+G cohort were older, less likely to have ECOG ≤ 1 and had more comorbidities than patients in the FFX cohort. There was no statistically significant difference in OS (adjusted HR = 0.99, p = 0.96), with median OS (mOS) being 12.1 and 13.8 months for nab-P+G and FFX, respectively. Among the subgroup of patients with ECOG ≤ 1, mOS was 14.1 and 13.7 months, respectively (adjusted HR = 1.00, p = 0.99). Among patients with 1L nab-P+G and FFX, 36.1% and 41.3% received 2L therapy and experienced mOS of 16.3 and 16.6 months, respectively (HR = 1.04, p = 0.76). Among commonly observed adverse events (AEs) (≥ 5% of patients in both cohorts), the rates of diarrhea, fatigue, mucositis, nausea and vomiting were higher in the FFX than nab-P+G cohort (all p < 0.05). Conclusions: In a nationwide sample of mPC patients, real-world survival outcomes were similar between patients receiving 1L nab-P+G or FFX. both overall and among patients who went on to receive active 2L treatments. In addition, nab-P+G was associated with significantly lower rates of common AEs compared with FFX.