bluuebunny/crossref_metadata_2025 huggingface dataset:
Automation of quantifying and mapping of stromal and malignant cells in pancreatic adenocarcinoma using deep learning.
Authors: Lee Sunyoung S. , Kim Jin Cheon , Dolan Jillian , Baird Andrew
Published: January 2019

266

Background: The characteristic histological feature of pancreatic adenocarcinoma (PAD) is extensive desmoplasia alongside leukocytes and cancer-associated fibroblasts. Desmoplasia is a known barrier to the absorption and penetration of therapeutic drugs. Stromal cells are key elements for a clinical response to chemotherapy and immunotherapy, but few models exist to analyze the spatial and architectural elements that compose the complex tumor microenvironment in PAD. Methods: We created a deep learning algorithm to analyze images and quantify cells and fibrotic tissue. Histopathology slides of PAD patients (pts) were then used to automate the recognition and mapping of adenocarcinoma cells, leukocytes, fibroblasts, and degree of desmoplasia, defined as the ratio of the area of fibrosis to that of the tumor gland. This information was correlated with mutational burden, defined as mutations (mts) per megabase (mb) of each pt. Results: The histopathology slides (H&E stain) of 126 pts were obtained from The Cancer Genome Atlas (TCGA) and analyzed with the deep learning model. Pt with the largest mutational burden (733 mts/mb, n = 1 pt) showed the largest number of leukocytes (585/mm2). Those with the smallest mutational burden (0 mts/mb, n = 16 pts) showed the fewest leukocytes (median, 14/mm2). Mutational burden was linearly proportional to the number of leukocytes (R2 of 0.7772). The pt with a mutational burden of 733 was excluded as an outlier. No statistically significant difference in the number of fibroblasts, degree of desmoplasia, or thickness of the first fibrotic layer (the smooth muscle actin-rich layer outside of the tumor gland), was found among pts of varying mutational burden. The median distance from a tumor gland to a leukocyte was inversely proportional to the number of leukocytes in a box of 1 mm2 with a tumor gland at the center. Conclusions: A deep learning model enabled automated quantification and mapping of desmoplasia, stromal and malignant cells, revealing the spatial and architectural relationship of these cells in PAD pts with varying mutational burdens. Further biomarker driven studies in the context of immunotherapy and anti-fibrosis are warranted.
Comprehensive genomic profiling (CGP) in KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC).
Authors: George Ben , Greenbowe Joel R. , Hendifar Andrew Eugene , Golan Talia , Javle Milind M. , Maitra Anirban , Bahary Nathan , Schrock Alexa Betzig , Stephens Philip J. , Miller Vincent A. , Ross Jeffrey S. , Yakirevich Evgeny , Ritch Paul S. , Thomas James P. , Ali Siraj Mahamed , Singhi Aatur D.
Published: January 2019

271

Background: Mutations in oncogenic KRAS have been widely accepted as the signature genomic alteration (GA) in sporadic PDAC, but therapeutic efforts aimed at targeting constitutively activated KRAS have been disappointing. We examined somatic GAs in KRAS WT PDAC utilizing a CGP platform to identify actionable targets. Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) PDAC clinical specimens and CGP was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 unique reads. Alterations in the RAS/ RAF/ MEK pathway genes ( KRAS, NRAS, HRAS, ARF, BRAF, EGFR, MAP2K2, MAP2K1, MAPK1) and DNA Damage Repair (DDR) pathway genes ( BRCA1/2, ATM, ATR, BRIP1, RAD50, RAD51, RAD52, PALB2, CHEK1, CHEK2) were examined. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. TMB was categorized based on mutations(m)/Mbp of DNA - high (H; > 20), Intermediate (I; 8-20) and low (L; < 8). Results: CGP was performed on 3426 PDAC specimens; 1815 (53%) were male, 390 (11.3%) were KRAS WT. GAs in the RAS/ RAF/ MEK pathway were identified in 90.6% of all cases, while 68 (17.4%) KRAS WT cases had one or more GAs in RAS/ RAF/ MEK pathway genes. DDR pathway GAs were identified in 1405 (41%) cases for a total of 2050 GAs, and 180 (46%) KRAS WT cases for a total of 285 GAs. DDR pathway alterations were common in KRAS WT PDAC compared to KRAS mutated PDAC (p = 0.028). Among the 842 (24.6%) cases with available TMB data, 5 (0.6%), 104 (12.3%) and 733 (87.1%) pts had H, I and L, TMB respectively. Among 88 (22.6%) KRAS WT cases with available TMB data, 2 (2.3%), 12 (13.6%) and 74 (84.1%) pts had H, I and L, TMB, respectively. MSI status was available in 2314 (67.5%) cases, 13 (0.6%) were MSI-high (MSI-H); among the KRAS WT cases, 222 (57%) had MSI status available, 3 (1.3%) were MSI-H. Conclusions: MSI-H status and high TMB are rare in PDAC, regardless of KRAS mutation status. GAs in the DDR pathway are relatively common in PDAC and may serve as predictive biomarkers for platinum chemotherapeutic agents and/or PARP inhibitors. Prospective validation of such predictive gene signatures will improve therapeutic efficacy and minimize toxicities.
Integrative whole exome, transcriptome, and clinical profiling of biliary tract cancers (BTCs).
Authors: Tran Nguyen H. , Vats Pankaj , Robinson Dan R. , Zalupski Mark , Hersberger Katherine E , Mendiratta-Lala Mishal , Kumar-Sinha Chandan , Wu Yi-Mi , Lonigro Robert J , Cao Xuhong , Chinnaiyan Arul , Sahai Vaibhav
Published: January 2019

279

Background: BTC is clinically and genomically heterogeneous and next generation sequencing may identify disease subsets with distinct prognostic and therapeutic implications. Methods: Patients (pts) with BTC underwent whole exome and transcriptome sequencing via the Michigan Oncology Sequencing (MI-ONCOSEQ) platform between 09/2011 and 07/2017. Results: 53 pts (47.2% female) with median age 60 (range 17-72) years had 38 intrahepatic, 6 perihilar, and 4 extrahepatic distal cholangiocarcinoma (CCA) while 3 had gallbladder and 2 mixed CCA/hepatocellular carcinoma. Forty-one pts (77.3%) had advanced BTC at diagnosis and 40 (75.5%) received platinum doublet as first line therapy. The most frequent somatic mutations were TP53 (35.8%), BAP1 (18.9%), KRAS (17.0%), IDH1 (15.1%), PBRM1 (13.2%), ARID1A (11.3%), and SMAD4 (11.3%). Median overall survival (OS) in 8 pts with IDH1 mutation was 16.8 months (none received IDH1 inhibitor). Putative pathogenic germline variants were noted in 6 (11.3%) pts of which 4 were biallelic (MSH2, BRCA1, BRCA2 and MUTYH) and 2 monoallelic (ATM and FH). Germline mutation in FH has not been reported in BTC. Biallelic DNA damage repair pathway mutations were noted in 14 (26.4%; 11 somatic, 3 germline) pts and their median OS was 16.8 months. Of these 9 pts with advanced BTC received 1st line platinum therapy and had a median PFS of 9.3 months (4 PR, 3 SD). Nine (17%) pts had FGFR2 fusion (6 partners); median OS not yet reached (6 alive; 5 received FGFR inhibitor). Potentially targetable molecular alterations (IDH1, MSH2, BRCA1/2, PALB2, ATM, FGFR2, ERBB2) were identified in 27 (50.9%) pts. Copy number profile shows frequent loss of chr1p, chr3p, chr4, chr6q, chr8p, chr9, and gain of chr1q, chr7, and chr8q. Immune profiling & pathway analysis of BTCs with clinical correlation is ongoing. Conclusions: Integrative sequencing of BTCs with clinical profiling will lead to more precise treatment of pts with BTCs.
The role of HNF4A in GATA4-deficiency phenotypes of hepatocellular carcinoma.
Authors: Tan Yu Bin , Shuen Timothy , Toh Han Chong
Published: January 2019

284

Background: Hepatocellular carcinoma (HCC) is the 2nd leading global cause of cancer death. Recently, we have discovered previously undescribed deletion and germline mutation of GATA4 and showed that GATA4 is a key differentiation driver and metabolic regulator in HCC. However, as GATA4 is mostly deleted in HCC, targeting GATA4-downstream molecules is ideal. In this study, proof-of-concept experiments were conducted to show that introduction of HNF4A, which is a GATA4-regulated downstream target, could partially rescue the impaired phenotypes in GATA4-deficient HCC cell line. Methods: Correlation analysis using gene expression microarray of human HCC samples was conducted to identify the genes that are positively correlated with GATA4. A transgenic mouse model with a liver-specific conditional GATA4 knockout was designed to identify liver morphology and gene expression changes which are correlated with the loss of Gata4 in the mouse liver. CRISPR-mediated knockout of GATA4 and lentiviral HNF4A overexpression was carried out in a GATA4-deficient HCC cell lines, PLC/PRF/5 and Hep3B, followed by proliferation, apoptosis, cell cycle and senescence functional assays. Results: Pearson correlation analysis from human HCC samples showed that expression of HNF4A is positively correlated with that of GATA4. Livers from conditional Gata4 knockout mice had lower Hnf4a gene expression when compared to age-matched control mice. Loss of function analysis by CRISPR-mediated GATA4 knockout further showed downregulation of HNF4A in GATA4-deficient PLC/PRF/5 cell line. Lentiviral HNF4A overexpression in PLC/PRF/5 and Hep3B demonstrated reduced proliferation and increased apoptosis while PLC/PRF/5 also showed cell cycle arrest at G2/M phase when compared to control. However, no senescence induction was detected in HNF4A-overexpressing cells. Conclusions: Transgenic mouse data, CRISPR-mediated knockout and analysis of HCC samples showed that HNF4A is a key GATA4-downstream target. HNF4A overexpression decreases proliferation, increases apoptosis and cell cycle arrest in GATA4-deficient HCC cell lines, thus representing a possible therapeutic target for HCC.
The role of soluble TGF-beta and its dynamics for predicting the prognosis in unresectable pancreatic cancer patients treated with chemotherapy.
Authors: Park Hyunkyung , Bang Ju-Hee , Nam Ah-Rong , Park Ji Eun , Kim Mei Hua , Bang Yung-Jue , Oh Do-Youn
Published: January 2019

288

Background: Transforming growth factor-beta (TGF-β) is a multifunctional regulatory factor. Here, we measured serum soluble TGF-β (sTGF-β) levels and evaluated its dynamics and prognostic capabilities during chemotherapy in unresectable pancreatic cancer patients. Methods: Sixty patients treated with FOLFIRINOX as the first-line palliative chemotherapy were prospectively enrolled. We prospectively collected blood samples at the time of diagnosis, first response assessment, and disease progression and measured serum sTGF-β using an enzyme-linked immunosorbent assay. Results: The patients’ median overall survival (OS) and progression free survival (PFS) were 10.3 (95% confidence interval [CI], 8.5–12.1) and 6.5 (95% CI, 4.9–8.1) months, respectively. Patients with low sTGF-β at diagnosis ( < 31.2ng/mL) had better OS and PFS than patients with high sTGF-β, respectively (OS, 13.7 vs. 9.2 months; hazard ratio [HR], 2.602; P =0.004; PFS, 9.0 vs. 5.8 months; HR, 2.010; P =0.034). At the time of disease progression, sTGF-β was increased compared with that of diagnosis (mean 26.4 vs. 23.9ng/mL). Especially, in patients with a partial response, sTGF-β was significantly increased at disease progression (mean 25.7 vs. 31.0ng/mL; P =0.049). Conclusions: Pre-treatment sTGF-β levels serve as a prognostic indicator in unresectable pancreatic cancer patients treated with FOLFIRINOX chemotherapy. Likewise, the dynamics of sTGF-β during chemotherapy have prognostic value.
Feasibility and clinical utility of EUS guided biopsy of pancreatic cancer for next-generation genomic sequencing.
Authors: Dreyer Stephan , Jamieson Nigel , Evers Lisa , Jones Marc , Martin Sancha , Duthie Fraser , Musgrove Liz , Cooke Susie , Bailey Peter , McKay Colin , Chang David Kuang-Fu , Biankin Andrew
Published: January 2019

296

Background: Next-generation sequencing technology has made genomic profiling guided therapy a reality for many cancer types. The aim of this study is to investigate the feasibility of genomic profiling using standard clinical endoscopic ultrasound (EUS) core biopsy samples of Pancreatic Cancer (PC) to allow personalised cancer care. Methods: 78 patients underwent additional research biopsy at the time of diagnostic EUS biopsy. En-face frozen section was performed to enable targeted macro-dissection prior to DNA extraction, quantification and targeted gene sequencing (Agilent Comprehensive Cancer Gene Panel). Matching formalin-fixed (FFPE) diagnostic EUS biopsies and fresh frozen surgical resection specimens also underwent genomic profiling for comparison. Whole genome (WGS) and RNA sequencing was performed in selected patients. Results: Targeted panel sequencing ( n = 61) revealed known PC genes ( KRAS, GNAS, TP53, CDKN2A, SMAD4) in 36 patients with histological evidence of PC. Potentially actionable somatic mutations (BRCA1, BRCA2, ATM, BRAF, JAK3) were found in 6 (17%) patients. WGS ( n = 5) of EUS samples confirmed mutations identified on panel sequencing and revealed relevant mutational signatures and structural variation patterns that can act as putative biomarkers of therapeutic responsiveness. RNA sequencing ( n = 54) segregated patients into key clinically relevant molecular PC subtypes based on transcriptome and reveals novel molecular insights into advanced, unresectable PC ( n = 38). Conclusions: We demonstrate here novel multi-omic analysis of pancreatic cancer using standard clinical EUS guided fine needle biopsies. Multi-omic analysis of EUS biopsies offers potential clinical utility to guide personalized therapy of PC in both the neoadjuvant and advanced settings.
Physical, emotional, and informational challenges of patients living with neuroendocrine tumors in the United States: Understanding their unmet needs.
Authors: Goldstein Grace , Majdi Abdelali , Bocher-Pianka Isabelle , Watts Rupert , Khan Mohid
Published: January 2019

299

Background: Surveys of neuroendocrine tumor (NET) burden on daily living rarely explore the impact that patient information sources can have on optimizing care. This subset of a large US survey focused on identifying the unmet needs, and available information sources and support that address the physical, emotional and informational challenges that patients with NETs experience. Methods: The Carcinoid Cancer Foundation is a US, non-profit organization that encourages and supports research and education on carcinoid and related NETs. A Carcinoid Cancer Foundation-approved survey was shared with patients with NETs via the Carcinoid Cancer Foundation website, e-newsletters and social media; some patients were emailed direct links to the online survey. Results: US, online surveys (N=428; 13 questions) were completed over 6 weeks in 2015. Patients had mostly small intestinal (40%), lung (13%) or pancreatic (11%) primary tumors; 66% of patients were diagnosed in the previous 5 years. Patients experienced multiple symptoms, most commonly diarrhea (47%), flushing (45%), changes in bowel/bladder habits (37%) and persistent pain (30%). Common emotions upon diagnosis were fear (58%), anxiety (53%), feeling overwhelmed (50%), confusion (39%) and sadness (34%). Greatest physical challenges were fatigue (66%), diarrhea (48%), pain/discomfort (40%) & sleep disturbance (35%). “Very useful” information sources were (1) NET/carcinoid disease awareness website, (2) carcinoid/NET support group, (3) Google, (4) discussion forums and (5) governmental/health-authority websites. Favored information formats included “patients-like-me” case studies (67%), email (59%), e-newsletters (56%), FAQs (50%), short interactive tutorials (32%) and “top tips” (31%). Information sought, but not found, included simple advice on diet, holistic treatment, complementary therapies, where to find the best treatment, pain management & prognosis. Conclusions: In the US, patients with NETs face negative emotions and multiple physical challenges that require psychological support/coping strategies, and they seek reliable, personally relevant, easily understood information, including that from interaction with other patients.
Impact of lung and heart dose on survival after radiotherapy for esophageal cancer.
Authors: Oh Patrick , Zhang Minsi , Brady Paul , Yorke Ellen , Won Elizabeth , Goodman Karyn A. , Wu Abraham Jing-Ching
Published: January 2019

3

Background: Chemoradiation is an essential tool in treatment of localized esophageal cancer. Recent data indicates that cardiac dose is an independent predictor of survival after chemoradiation for locally advanced lung cancer. However, the impact of normal tissue dose in esophageal cancer has not been well characterized. We investigated cardiac and pulmonary dose-volume histogram (DVH) metrics as potential predictors of overall survival (OS) after chemoradiation for esophageal cancer. Methods: We reviewed 453 consecutive patients with stage I-III esophageal cancer treated with definitive or preoperative chemoradiation (median dose 50.4 Gy in 28 fractions) between 2007 and 2015 at our center. Most (n = 442) received intensity-modulated radiation therapy. Radiation plans were reviewed and multiple DVH metrics for heart (max and mean dose, V5Gy, V10Gy, V20Gy, V30Gy, and V40Gy) and lung (mean dose, V5Gy, and V20Gy) were extracted for analysis. Other clinical covariates (surgery, performance status, stage, and histology) were recorded. Cox univariate (UVA) and multivariate (MVA) regression was used to analyze the association of these factors with overall survival. Results: Median follow-up for surviving patients was 28.4 months. On UVA, older age, lower performance status, Stage III disease, lack of surgery, heart V40Gy, lung V5Gy, lung V20Gy, and lung mean dose were significantly associated with decreased survival. On MVA, surgery (p = 0.008), stage III disease (p < 0.0002) and lung V20Gy (p = 0.0389) remained significant, while heart V40Gy did not (p = 0.211). Patients with lung V20Gy< 20% had a median survival of 44.0 months, compared to 24.0 months for patients with lung V20Gy≥20%. Conclusions: This comprehensive dosimetric analysis of heart and lung dose in a large cohort of esophageal cancer patients suggests that lung dose is a significant independent predictor of survival. Cardiac dose was not independently predictive after adjusting for lung dose and other clinical factors. This data suggests that esophageal cancer outcomes may be improved by minimizing lung dose, particularly the volume receiving 20Gy or more, and provides further rationale for pursuing new techniques to reduce lung dose, such as proton therapy.
A novel morphologic and metabolic feature fused treatment response evaluation pipeline for pancreatic adenocarcinoma patients.
Authors: Lao Yi , David John , Torosian Arman , Yang Wensha , Tuli Richard
Published: January 2019

311

Background: Adaptive radiation therapy for pancreatic adenocarcinoma (PA) relies on accurate treatment response assessment. Traditional RECIST criteria poorly characterize tumors with complex morphological features, while PET imaging inefficiently detects tumors with intrinsically low standardized uptake value (SUV). Here, we performed regional comparisons of 3D intact PA surfaces pre and post chemoradiotherapy (CRT) utilizing surface measurements containing both morphological and metabolic features to better assess response. Methods: Twenty-one locally advanced PA patients with pre- and 6-8 week post-CRT 18F FDG-PET/CT scans were evaluated. Boundaries of initial and post-CRT tumors were manually defined on respective CT images. On each of the tumors, 3D meshes were generated, followed by surface based registration to achieve vertex-wise correspondence. For each surface vertex, a multivariate vector was formed from two components: anatomic (deformation tensors resulted from surface registration), and metabolic (regional SUV obtained from radius to surface projections). To assess tumor response, paired mahabanobis distance (Mdist) between pre- and post-CRT tumor surfaces with previously formed multivariate vectors were calculated for each patient. Mdist was evaluated using Cox analysis correlated with overall survival (OS) and compared with measurements based on serum CA19-9, volume, SUVmax and SUVmean. Results: Among all the tested parameters, Mdist is the best predictor of OS, with a hazard ratio of 0.437 (p = 0.036). Post-CRT versus pre-CRT ratios based on volume and SUVmax both reached borderline significance (p = 0.0769 and 0.0799, respectively), while CA19-9 and SUVmean failed in predicting OS in our small cohort of patients. Conclusions: We introduced a PET/CT-based novel morphologic and metabolic pipeline for post-CRT response evaluation in locally advanced PA. The fused Mdist outperformed traditional morphologic, metabolic, and physiological measurements in OS prediction. The presented fused model may serve as a new biomarker to better characterize the heterogeneity of tumor response to CRT and a predictive marker for surgical resection.
Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors.
Authors: Walter Dirk , Harter Patrick , Battke Florian , Winkelmann Ria , Schneider Markus , Holzer Katharina , Koch Christine , Bojunga Jörg , Zeuzem Stefan , Hansmann Martin-Leo , Peveling-Oberhag Jan , Waidmann Oliver
Published: January 2019

312

Background: Data on intratumoral heterogeneity of small intestine neuroendocrine tumors (SI-NETs) and related liver metastasis is limited. Further investigation might have impact on development of targeted therapy regimens. The aim of the study was to characterize genetic heterogeneity of 5 patients suffering from SI-NETs. Methods: Formalin-fixed, paraffin-embedded tissues samples of primary and metastatic lesion as well as benign liver of five patients with synchronously metastasized, well or moderately differentiated SI-NETs were analyzed with whole exome sequencing. For one patient, chip based 850k whole DNA methylome analysis was performed of primary and metastatic tumor tissue as well as control tissue. Alterations that occurred only in one tumor site were defined as private, whereas mutations present in both metastasis and primary lesion were regarded as common. Results: 156 single nucleotide variants (SNVs) in 150 genes were identified and amount of mutations/per sample ranged from 9-34 (mean 22). The degree of common (0-94%) and private mutations/per sample was strongly varying (6-100%). In all patients, copy number variations (CNV) were found and the degree of intratumoral heterogeneity of CNVs corresponded to SNV analysis. DNA methylation analysis of a patient without common SNVs revealed are large overlap of common methylated CpG sites. Conclusions: SI-NET primary and metastatic lesions show a highly varying degree of intratumoral heterogeneity. Driver events might not be detectable with exome analysis.
A phase I study of veliparib (Vel) in combination with oxaliplatin (Ox) and capecitabine (Cap) in advanced solid tumors.
Authors: Turk Anita Ahmed , Deming Dustin A. , Lubner Sam Joseph , Mulkerin Daniel , LoConte Noelle K. , Tevaarwerk Amye , Wisinski Kari Braun , Eickhoff Jens C. , Liu Glenn
Published: January 2019

314

Background: Poly(ADP-ribose) polymerases (PARP) are activated by DNA strand breaks and important for DNA repair in response to platinum-based chemotherapy. PARP inhibition with Vel might enhance anti-tumor effects of Cap with Ox. This phase I study (NCI 8604) examines the tolerability, safety and preliminary efficacy of the combination of Vel with Cap and Ox. Methods: This is a phase I dose escalation protocol testing escalating doses of Vel with Cap and Ox every 28 days (Table 1). Pts were treated in cohorts of 3-6 pts until cycle 1 DLTs were defined. Key eligibility criteria included age ≥ 18 with histologically confirmed malignancy meeting at least one of the following: documented BRCA1/2 mutation and a BRCA related malignancy; a 20% probability of harboring a BRCA mutation; metastatic colorectal cancer; mucinous ovarian cancer; other GI malignancy in which Ox has demonstrated activity. Results: 17 pts (median age 52 [range 19-71]; 14 female, 3 male) were treated at 4 dose levels (DL) (Table 1). Pts had cholangiocarcinoma (6), breast (4), ovarian (4), neuroendocrine (1), pancreas (1), and colon (1) cancers. 7 pts (4 breast, 3 ovarian) are BRCA1+. Dose escalation was initiated at DL1. One DLT (mucositis) occurred at this dose level. At DL2, two DLTs (mucositis with neutropenic fever and thrombocytopenia) were noted. The protocol was amended for escalation to begin at DL1A. At DL2A, a grade 2 DLT of fatigue requiring dose delay occurred in one pt. Pts were on study for median 10 weeks (range 1 – 88). 24% of pts remained on study ≥ 6 months. Of the 14 pts with measurable disease, 5 had PR (2 ovarian, 2 breast, 1 colon) and 4 had SD (3 cholangiocarcinoma, 1 pancreas). Common AEs include nausea/vomiting (94%), diarrhea (47%), mucositis (41%), anemia (35%), neutropenia (24%), and thrombocytopenia (18%). Conclusions: Vel in combination with Cap and Ox is safe and well tolerated in pts with advanced solid malignancies. The recommended phase II dose is DL2A Vel 40mg BID (D 1-7, 15-21), Cap 1000mg/m2 BID (D 1-7, 15-21), and Ox 85mg/m2 (D 1 and 15). Clinical trial information: NCT01233505. [Table: see text]
Pilot evaluation of PD-1 inhibition in metastatic cancer patients with liver transplantations (LT): The Mayo Clinic experience.
Authors: DeLeon Thomas , Salomao Marcela , Aqel Bashar A. , Sonbol Mohamad B. , Bryce Alan Haruo , Borad Mitesh J.
Published: January 2019

328

Background: Patients with a history of solid organ transplants have been excluded from PD-1/PD-L1 inhibitor clinical trials due to concern for graft rejection. Only 2 case reports of PD-1 inhibitor use in patients with liver transplantation (LT) have been reported thus far. Here, we report our experience with using checkpoint inhibitors in metastatic cancer patients with LT. Methods: A single center pilot evaluation was conducted to evaluate the safety and efficacy of PD-1/PD-L1 inhibitors in patients with LT. PD-L1 staining on both the tumor and allograft were assessed if there was available tissue. The primary endpoint was evaluation of the risk for allograft rejection. Secondary endpoints included RECIST v1.1 and Immune-Related Response criteria (iRC) response rates, progression free survival (PFS) and overall survival (OS). Translational objectives included the relationship of PD-L1/PD-1 staining of tumor/allograft with response and rejection. Results: Six metastatic cancer patients with a history of LT received PD-1 inhibitor therapy (hepatocellular n=5, melanoma n=1). 3 patients were on mTOR inhibitor as immunosuppressive regimen and 3 on calcineurin inhibitor. Overall, allograft rejection was observed in 1/6 patients (on mTOR inhibitor). One patient achieved a CR (melanoma), 3 patients had PD and 2 patients discontinued therapy prior to restaging assessments. A single response (by both RECIST v1.1 and iRC) and rejection were reported in patients who received mTOR inhibitors (1 of 3). Three patients were tested for PD-L1 staining in the allograft tissue and all of them were negative (0% staining) with no graft rejections observed. Four patients had tumor PD-L1 evaluated (2 patients tested positive with 1 patient obtained a CR). The median OS, PFS and duration of therapy were 1.2, 1.8 and 1.2 months respectively. Conclusions: In this pilot evaluation of PD-1/PD-L1 inhibitors in LT patients both preliminary efficacy (1 of 4) and allograft rejection (1 of 6) was exhibited. Larger, prospective trials are needed to elucidate optimal patient and immunosuppressive regimen selection in these patients.
Clinical impact of tumour-infiltrating B-cells in periampullary adenocarcinoma in relation to adjuvant chemotherapy.
Authors: Lundgren Sebastian , Fristedt Richard , Elebro Jacob , Karnevi Emelie , Nodin Bjorn , Warfvinge Carl Fredrik , Micke Patrick , Eberhard Jakob , Tingstedt Bobby , Jirstrom Karin
Published: January 2019

330

Background: The prognostic significance of tumour-infiltrating lymphocytes of the B lineage in solid cancers has only recently begun to receive attention. Herein, we explored the relationship between B cell and plasma cell density and survival in patients with periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological type. Methods: Immunohistochemistry was applied to quantify the abundance of B cells (CD20+), and plasma cells (CD138+) in tissue microarrays with tumours from a retrospective consecutive cohort of 175 patients who had undergone pancreaticoduodenectomy for periampullary adenocarcinoma. Cox regression was applied to calculate univariable and multivariable hazard ratios (HR) for recurrence and death within five years up until March 2017. Multivariable HRs were adjusted for established clinical parameters. Results: High CD20+ cell density was an independent prognostic factor for a prolonged overall survival in both intestinal-type (HR 0.32; 95% CI 0.12-0.86) and pancreatobiliary-type (HR 0.38; 95% CI 0.23-0.66) tumours. CD138+ was an independent prognostic factor in pancreatobiliary-type tumours (HR 0.51; 95% CI 0.32-0.82) only. A significant positive interaction was seen between adjuvant chemotherapy and CD20+ cells in relation to OS for PB-type tumours (pinteraction= 0.027). Conclusions: These results demonstrate that dense infiltration into the tumour by cells of the B lymphocyte lineage confers an improved prognosis in periampullary adenocarcinoma including pancreatic cancer. The impact of B cells in the local anti-tumour response is gradually being unravelled, and their potential influence on adjuvant chemotherapy response in the more aggressive pancreatobiliary-type tumours may be clinically relevant and merits further study.
Effect of conventional liver irradiation on the pharmacokinetics of sorafenib through p-glycoprotein: Results of concurrent and sequential strategy.
Authors: Hsieh Chen-Hsi , Tsai Tung-Hu , Chen Yu-Jen , Wang Li-Ying
Published: January 2019

338

Background: Sorafenib is a multi-kinase inhibitor that demonstrated a significant improved survival of patients with hepatocellular carcinoma (HCC). The efficacy of radiotherapy (RT) concurrent or sequential with sorafenib in unresectable HCC patients has better effects than single agent. However, the mechanism for local RT on sorafenib in the plasma system remains unclear. Here, we evaluate the mechanism of liver irradiation on the pharmacokinetics (PK) of sorafenib using rats as an experimental model. Methods: Free-moving rat model was used in the current study. Image-guided RT with 2 Gy was delivered to the whole liver of Sprague-Dawley rats. The experimental animals were randomized to (A) the sorafenib-only (40 mg/kg, p.o.) group and (B) pre-treated with cyclosporin A [CsA, p-glycoprotein (p-gp) inhibitor, 20mg/kg, i.p. 30 min before RT] group. In each group, the experimental animals were randomized to sham RT (0 Gy with sorafnib), concurrent (after RT 1 hour) and sequential group (after RT 24 hour), respectively. The PK of sorafenib in the plasma system was calculated. Each group’s data was collected from six rats Results: For sorafenib-only group, compared to the sham-irradiated controls, the area under the concentration versus time curve (AUC) of sorafenib was increased by 132% in concurrent group [719 versus (vs.) 1669 min*ug/mL, p = 0.046]. On the contrary, the AUC of sorafenib was decreased by 59% in sequential group (719 vs. 297 min*ug/mL, p = 0.036). Compared to the sorafenib-only group, the AUC of sorafenib in the concurrent group pre-treated with CsA was decreased by 83% (1669 vs. 278 min*ug/mL, p = 0.011). Interestingly, the AUC of sorafenib in the sequential group pre-treated with CsA was increased by 275% (297 vs. 1113 min*ug/mL, p = 0.023). Conclusions: P-pg plays an important role for the PK of sorafenib that was modulated by whole liver irradiation in rodent model. The strategy for modulating the RT-PK phenomenon of sorafenib through p-gp is worth to investigate in the future.
The prognostic significance of exosomal markers (CD63 and CD9) expression using immunohistochemistry in patients with pancreatic ductal adenocarcinoma.
Authors: Khushman Moh'd M. , Bhardwaj Arun , Patel Girijesh K. , Laurini Javier , Roveda Kelly , Donnell Robert , Sherling Kelley , Case Brittany , Tan Marcus Chuan Beng , Thompson Lee W. , Nelson Cindy , Wyatt Mary , Patton Mary , Singh Seema , Wang Bin , Taylor William R. , Singh Ajay
Published: January 2019

342

Background: Exosomes are important mediators of intercellular communications and play pivotal roles in cancer progression, metastasis and chemoresistance. CD63 and CD9 are exosomal markers. In patients with pancreatic ductal adenocarcinoma (PDAC), positive correlation between CD9 expression and overall survival (OS) was reported. CD63 expression was conserved in all patients with no reported prognostic significance. This study explored the prognostic significance of CD63 and CD9 expression using immunohistochemistry (IHC) in patients with PDAC of mixed racial background. Methods: Between 2012 and 2016, 49 patients with PDAC had available tissues for CD63 and CD9 staining using IHC. Two pathologists independently scored CD63 and CD9 expression. Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean Quick-score (Intensity X Percentage of staining) was calculated. Results: Median age was 64 (range 42-85). 53% are males. 67% Caucasians, 27% African Americans (AA) and 6% are other ethnicities. 41% had stage IV while 59% had stage I-III. The mean CD63 and CD9 Q scores are higher in primary tumor from the pancreas compared to pancreatic tumor from metastatic sites (185 vs 102, p = 0.0002) and (48 vs 11, p = 0.0418) respectively. We fitted accelerated failure-time models to investigate the impacts of the covariates CD63 and CD9 on progression free survival (PFS) and OS. CD63 has significant impact on PFS (p = 0.0058) and OS (p = 0.0012). The higher the CD63 Q score, the longer the PFS and OS. CD9 doesn’t have significant impact on PFS (p = 0.8950) or OS (p = 0.7182). The mean CD63 and CD9 Q scores are slightly higher in AA compared to Caucasians (157 vs 149, p = 0.76) and (45 vs 29, p = 0.43) respectively. Conclusions: CD63 and CD9 expression is higher in primary tumor from the pancreas compared to pancreatic tumor from metastatic sites. There is correlation between CD63 expression (but not CD9 in this cohort) and PFS and OS. To our knowledge, this is the first study to show prognostic significance of CD63 expression in patients with PDAC using IHC. A trend of higher expression of CD63 and CD9 among AA compared to Caucasians was noticed.
Long-term outcomes of liver transplantation (LT) for the treatment of neuroendocrine liver metastases (NELM): The Mayo Clinic experience.
Authors: Sonbol Mohamad Bassam , Buras Matthew , Ahn Daniel H. , Borad Mitesh J. , Gores Gregory J. , Mathur Amit , Heimbach Julie , DeLeon Thomas , Taner C.Burcin , Halfdanarson Thorvardur Ragnar , Hobday Timothy J. , Ramanathan Ramesh K. , Mody Kabir , Stucky Chee-Chee H. , Truty Mark J. , Moss Adyr A , Bekaii-Saab Tanios S.
Published: January 2019

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Background: In this study, we sought to determine the prognostic factors impacting survival of patients with NELM who underwent LT at Mayo Clinic. Methods: We performed a three-site retrospective analysis of patients with unresectable NELM treated with LT from 1990 -2017. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, timing of diagnosis and transplant, extent of liver involvement, and tumor grade, were extracted. Extent of liver involvement was calculated using previously validated standardized volumetry with high defined as > 25% increase in the weight of the extracted liver at the time of the transplant as compared to the standard liver volume. Survival was calculated using the Kaplan–Meier method. Results: We identified 37 patients. Median age at LT was 47 (range 17.0-64.0), male: female (73% vs. 27%, respectively). Primary tumor site was in the pancreas in 51.3% and in the small bowels in 43.2%; 78.4% had NELM at presentation. While primary tumor resection was done at the time of LT in 5 (13.9%) cases, most patients (80.6%) had ˃6-months interval between primary tumor resection and LT surgery. Prior to LT, 25 (74.3%) patients received somatostatin analogues and 18 (61.3%) had liver-directed therapy. Median time from diagnosis to transplant was 33.6 months (0-246). High extent of liver involvement was identified in 12 patients (33.3%). Disease-Free Survival (DFS) at 3, 5, and 10 years was 56.8%, 43.1%, and 22.4% respectively. Overall-survival (OS) at 3, 5, and 10 years was 86.9%, 79.6%, and 52.6% respectively. High extent of liver involvement at the time of transplantation was associated with inferior DFS and OS and patients˃45 years-old at the time of transplantation had worse DFS. Patients whose disease met the OPTN (Organ Procurement and Transplantation Network) criteria for NELM transplantation had significantly better DFS and OS with median 10-year OS of 80.7 % vs. 17%. Conclusions: LT is a reasonable therapeutic option for selected patients with unresectable NELM with 10-year OS of 52.6%. High extent of liver involvement was associated with worse long-term outcomes while meeting OPTN criteria resulted in best outcomes.
Healthcare utilization and costs associated with GI cancers in the United States.
Authors: Deng Aileen , Basu Mallick Atrayee
Published: January 2019

361

Background: In 2009, adults had 4.7 million cancer-related hospitalizations. Adult hospital stays with cancer identified as the principal diagnosis cost $20.1 billion and accounted for 6% of adult inpatient hospital costs. GI cancer-related healthcare utilization has not been well-defined. The aim of this study was to evaluate the trends in the incidence and costs of GI cancer-related hospital admissions in the U.S. Methods: We reviewed the National Inpatient Sample Database (NIS) from 1997-2014. All patients with principle discharge diagnoses of esophageal, stomach, colon, rectum and anus, liver and intrahepatic bile duct and pancreas cancer were analyzed. Temporal trends in the number of hospital admissions, length of stay, hospitalization cost and mortality rates were obtained by HCUPnet. Results: GI cancer-related hospital admissions decreased from 230,537 in 1997 to 221,220 in 2014. Although the number of hospital admissions decreased for esophageal (12,157 to 11,885), stomach (23,528 to 21,800), colon (110,939 to 90,135), rectum and anus cancer (43,807 to 40,160), it has increased for liver and intrahepatic bile duct (11,243 to 21,775, p < 0.001) and pancreas cancer (28,862 to 35,465, p < 0.001). While the mean length of stay decreased from 9.6 days in 1997 to 7.6 days in 2014, the mean hospital charges per patient (adjusted for inflation) increased 127% from $34,747 in 1997 to $78,742 in 2014. The highest increase in mean hospital charges per patient were in liver and intrahepatic bile duct ($27,128 to $74,619 (175%), p < 0.001), rectum and anus ($32,566 to $80,789 (148%), p < 0.001) and pancreas cancer ($33,562 to $75,981 (126%), p < 0.001). Conclusions: GI cancer-related hospital admissions decreased from 1997 to 2014. Despite decrease in the mean length of hospital stay, the costs of hospitalizations have increased substantially, especially in liver and intrahepatic bile duct, rectum and anus and pancreas cancer. Our study suggests that shorter length of stay alone has not reduced costs of hospitalizations in GI cancers. There remains a growing need to understand healthcare costs and to develop effective value-based interventions in GI cancer-related hospital admissions.
Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer (BTC).
Authors: Xie Changqing , Fioravanti Suzanne , Walker Melissa , Mabry Donna , Kleiner David E , Wood Brad J. , Levy Elliot B , Krishnasamy Venkatesh P , Steinberg Seth M. , Duffy Austin G. , Greten Tim F.
Published: January 2019

365

Background: Treatment option for patients with advanced BTC is limited and prognosis is poor with a median survival of less than 1 year in the locally advanced or metastatic setting. It has been shown deregulation of the immune system plays an important role in the pathogenesis of BTC. This study aimed to investigate whether tremelimumab (Treme), anti-CTLA4, could be combined safely and feasibly with microwave ablation therapy to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Methods: Patients with refractory BTC were enrolled in a study of monthly Treme (10mg/kg, IV, 6 doses), followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal microwave ablation. Staging image was performed every 8 weeks. Adverse events (AEs) were collected and managed. Tumor samples and peripheral blood samples were collected to perform immune monitoring. Results: Twenty patients with refractory BTC were enrolled. Male: female ratio was 10:10 with median age 56.5 years (range 37-67). Six patients had extrahepatic cholangiocarcinoma (ECC), two patients had gallbladder cancer, whereas the remaining 12 patients had intrahepatic cholangiocarcinoma (ICC). No dose-limiting toxicities were encountered. The common AEs included lymphocytopenia, colitis, adrenal insufficiency, anemia, and elevated transaminases. The most common clinical toxicity was diarrhea. Sixteen patients were evaluable for response analysis, one (6%) patient achieved a confirmed partial response (lasting for 8 months), 6 (37.5%) achieved stable disease with the longest lasting for 9.2 months. Among all 20 patients, median progression free survival, time to progression, and overall survival were 3.4 months (95% CI 2.5-5.2 months), 3.3 months (95% CI: 2.5-4.6 months) and 6.0 months (95% CI 3.8-8.8 months) respectively in this small pilot cohort. T cell receptor (TCR) b screening showed Treme expanded TCR repertoire though non-significantly. RNA seq is ongoing and will be presented. Conclusions: Treme in combination with tumor ablation is a potential new treatment for patients with advanced BTC. TCR repertoire expansion induced by Treme may contribute to treatment benefit. Clinical trial information: NCT01853618.
Transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) with a novel radiopaque (RO) drug eluting bead (DEB).
Authors: Lencioni Riccardo , Fraud Tatiana , Doshi Mehul , Venkat Shree , Echenique Ana , Narayanan Govindarajan
Published: January 2019

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Background: Preclinical studies have suggested that RO beads may offer advantages over standard microspheres used for TACE of HCC. The ability to image bead distribution during the procedure is expected to improve the coverage of the tumor minimizing off-target delivery. We conducted a retrospective analysis of efficacy and safety of RO DEB-TACE in patients with HCC. Methods: Forty-eight patients (38 males and 10 females, median age 64 years) with nodular, noninvasive HCC unsuitable for curative treatments, Child-Pugh A (n = 29) or B (n = 19) liver functional status, and ECOG PS 0-1 received DEB-TACE with injection of 2-4 ml of 70-150-micron RO microspheres (LC Bead LUMI; BTG-Biocompatibles) loaded with 37.5 mg/ml doxorubicin. Thirty-seven of 48 patients (77%) had unilobar disease and 11 of 48 (23%) bilobar tumors. The baseline sum tumor diameter was 5.3±2.6 cm (range, 1.2-14.5 cm). The primary endpoint was tumor response by mRECIST. Secondary endpoints were time to progression (TTP), overall survival (OS), and safety. Results: The number of treatments was 1 in 28 patients (58%), 2 in 16 (33%), and 3 in 4 (8%). The mean doxorubicin dose per treatment was 43.9±34.4mg (range, 3.3-150 mg). Best response was CR, PR, SD, and PD in 32, 10, 4 and 2 patients, respectively, for an objective response rate (ORR) of 87.5%. Median TTP was 8.5 months (95% CI, 6.7-not reached). Median OS was not reached in Child class A patients; in class B patients it was 19.5 months (95% CI, 6.0-not reached). There was one treatment-emergent grade 5 AE unrelated to treatment. Grade 3/4 AEs included pain (n = 4), fatigue (n = 2), and fever (n = 1). Grade 3/4 laboratory abnormalities were thrombocytopenia (n = 9), leukopenia (n = 3), elevation of transaminases (n = 3) or bilirubin (n = 3), and anemia (n = 2). Conclusions: In this first clinical study, treatment with RO DEB-TACE resulted in a high ORR and was well tolerated. The encouraging efficacy signal requires confirmation with long-term survival data.
Subgroup analysis by baseline pain intensity (BPI) and analgesic use (BAU) in NAPOLI-1: A phase III study of liposomal irinotecan (nal IRI)±5-fluorouracil/ leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy.
Authors: Macarulla Teresa Mercade , Siveke Jens T. , Dean Andrew Peter , Hubner Richard , Blanc Jean-Frédéric , Cunningham David , Chen Li-Tzong , Mirakhur Beloo , Chen Jie , de Jong Floris A , Wang-Gillam Andrea
Published: January 2019

379

Background: We report an exploratory, post hoc subgroup analysis in pts with BPI and BAU data receiving nal-IRI+5-FU/LV, nal-IRI or 5-FU/LV in NAPOLI-1 (NCT01494506). In this pivotal trial, nal-IRI+5-FU/LV improved median OS (mOS) vs. 5-FU/LV (6.1 vs. 4.2 mo [HR=0.67; p=0.012]). Methods: BPI/BAU included an average of 3-7 days pt-recorded data before randomisation. Greater values indicated greater pain for BPI using a 100 mm visual analogue scale. BAU was converted to morphine equivalent mg/day. Results: Of 417 ITT pts, 295 had BPI and 299 had BAU data. Mean and median BPI were 28.6 and 25.0, respectively, and BAU were 33.3 and 8.1 mg/day, respectively. The percentage of pts with KPS ≥ 80 was higher in ≤ mean/≤ median (n=159/148) BPI groups vs. > mean/> median (n=136/147) BPI groups (96-97 vs. 83%) and in ≤mean/≤median (n=207/150) BAU groups vs. > mean/> median (n=92/149) BAU groups (95-97 vs. 82-85%). mOS and median PFS (mPFS) were higher for nal-IRI+5-FU/LV vs 5-FU/LV in all groups, with ≤ mean/≤ median BPI or BAU showing better outcomes vs. > mean/> median BPI or BAU (Table). Conclusions: BPI and BAU appear to have a prognostic effect on outcomes in mPDAC pts in the NAPOLI-1 study. No predictive effect was observed, with nal-IRI+5-FU/LV showing higher mOS vs. 5-FU/LV in all groups. Clinical trial information: NCT01494506. [Table: see text]