bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility study of preoperative chemotherapy for patients with advanced esophageal cancer with or without naso-gastric ED tube for enteral feeding.
Authors: Ogata Takashi , Osakabe Hiroaki , Nagasawa Shinsuke , Nakazono Masato , Hara Kentaro , Kumazu Yuta , Hayashi Tsutomu , Yamada Takanobu , Yoshikawa Takaki
Published: January 2019

184

Background: Advanced esophageal cancer patients sometimes have a difficulty to swallow food. On the other hand, standard treatment for resectable advanced esophageal cancer patients is surgery after 2 course preoperative chemotherapy of CDDP-5-FU (JCOG 9907). So we usually use naso-gastric ED tube for patients with difficulty of oral intake during preoperative chemotherapy to administrate adequate nutrition. But there is no report of the safety of this trial. Methods: The aim of this study is to clarify the safety of using ED tube during preoperative chemotherapy and compare the nutritional status between using ED tube or not. From Jan 2012 to June 2017, 122 patients were undergone esophagectomy with 2 course of preoperative chemotherapy, and 14 patients were treated with ED tube for nutrition(Group A) and 108 patients without ED tube(Group B). We evaluated the changes of nutritional status and postoperative complication as an indicator of safety. Results: Changes before and after preoperative chemotherapy(GroupA/B): average of body weight: 53.1→50.8/58.1→57.0, BMI: 20.0→19.2/22.0→21.6, TP: 6.7→6.9/7.3→6.9, alb: 3.5→3.8/4.3→4.2, pre-alb: 20.1→21.7/24.8→23.4, RBP: 2.77→3.33/3.15→3.23. Adverse events during chemotherapy: 1 case of Grade 3 hematologic toxicity and 1 case of Grade 2 non-hematologic toxicity were found at Group A(14.2%), and 11 cases of Grade 3 hematologic toxicity and 8 cases of Grade 2 non-hematologic toxicity were found at Group B(17.61%)(p = 0.758). Postoperative complications (clavien-dindo classification, Grade3 or more): 2 cases were observed at Group A(14.2%), and 21 cases were observed at Group B(19.4%)(p = 0.62). Conclusions: Preoperative chemotherapy with ED tube for nutrition was safe and effective to maintain the preoperative nutritional status.
Risk factors associated with outcomes following neoadjuvant chemoradiotherapy prior to esophagectomy in patients with adenocarcinoma of the esophagus.
Authors: Boussi Khalil , Thomas Tarita , Pappas Sam G. , Martin Brendan
Published: January 2019

186

Background: The study was conducted to evaluate risk factors associated with treatment outcomes following concurrent chemoradiotherapy (CRT) and esophagectomy in patients diagnosed with resectable esophageal cancer. Methods: IRB approval was obtained to evaluate patients with esophageal cancer treated at our center from 2002 to 2017 with neoadjuvant CRT followed by esophagectomy. Patient characteristics pre and post-surgery including age, number of positive lymph nodes, length of time between neoadjuvant therapy and surgery were evaluated. Univariable and multivariable frailty survival analysis were used to evaluate the association between risk factors and treatment outcomes. Results: 74 patients met inclusion criteria of CRT and esophagectomy. Controlling for the number of days between the end of radiotherapy and surgery, the hazard of death for patients who developed metastatic cancer following completion of therapy was 2.08 (95 CI: 1.04 – 4.13) times higher compared to patients who did not develop metastasis (p = .04). Adjusting for metastatic cancer, for every five additional days between the end of radiotherapy and surgery, patients’ hazard of death increased 5% (HR = 1.05, 95 CI: 1.02 – 1.07, p < .001). Controlling for metastatic cancer and the number of positive nodes, for every one-year increase in age, patients’ hazard of recurrence decreased 5% (HR = 0.95, 95 CI: 0.91 – 0.99, p = .04). Adjusting for age and the number of positive nodes, the hazard of recurrence for patients who developed metastatic cancer was 28.57 (95 CI: 6.58-123.97) times higher compared to patients without metastasis (p < .0001). Conclusions: Longer duration between completion of CRT and surgery as well as developing metastatic disease are associated with a significantly higher hazard of death. Additionally, developing metastatic cancer, increase in age, and additional positive lymph nodes are all associated with a significantly higher hazard of recurrence. Optimal timing between neoadjuvant therapy and surgery needs to be evaluated further, as increasing hazard of death following therapy suggests that there may be a role for adjuvant chemotherapy in these patients.
Exosomal miRNA signature of pancreatic cyst: Liquid biopsies as indicators of pancreatic cancer.
Authors: Joshi Virendra , Guanzon Dominic , Molina Cris , Nuzhat Zarin , Rice Gregory , Gallo Carlos saloman
Published: January 2019

225

Background: Pancreatic cysts are a group of lesions with malignant potential. Currently, there are no consistently reliable biomarkers or imaging modalities to accurately predict biologic behavior of these cysts. We tested the hypothesis that tumor-derived exosomes (better conserved than free miRNA) can be acquired endoscopically from pancreatic cyst fluid and may allow for improved distinction between benign, premalignant and malignant cysts. Methods: Exosomes were isolated and characterised by differential and buoyant centrifugation from pancreatic cyst fluid obtained from 30 patients with pseudocysts (PS), serous cystic (SC), mucinous cysts (MC), intraductal papillary mucinous neoplasms (IPMN), pancreatitis (PA), and pancreatic cancer (PC) , confirmed with imaging and histology. An Illumina TruSeq Small RNA kit was used to construct a small RNA library, and the libraries were sequenced using the Illumina NextSeq 500 platform. The resulting sequencing FASTQ files were analyzed using miRDeep2 to identify both known and novel miRNAs. Results: Four significant miRNAs which are shared between six of the analyses, specifically hsa-miR-199b-3p, hsa-miR-199a-2-3p, hsa-miR-199a-1-3p and hsa-let-7i-5p were identified. MiRNA hsa-miR-27a-3p was significant and shared between five of the analyses. A total of 15, 12 and 2 significant miRNAs were shared between four, three and two of the analyses, respectively. Importantly, there were a total of 10 significant miRNAs which were unique to each analysis, with the exception of IPMN vs Pseudocyst, and Pancreatic cancer vs Pancreatitis. Specifically these unique miRNAs for each analysis are: hsa-miR-92a-2-3p (Pancreatitis vs Pseudocyst); hsa-miR-92a-1-3p (Serous vs Pseudocyst); hsa-miR-30e-5p (Pancreatic cancer vs Serous), hsa-miR-30b-5p (IPMN vs Pancreatic cancer); and hsa-miR-23b-3p, hsa-miR-99b-5p, hsa-miR-222-3p, hsa-miR-31-5p, hsa-miR-151a-5p, hsa-miR-221-3p (Pancreatic cancer vs. Pseudocyst). Conclusions: Exosomal miRNAs in pancreatic fluid may be used as a biomarker to differentiate between various cyst types and pancreatic cancer. A larger cohort with miRNA quantification and is needed to further validate these findings .
Incidence trends of gastroenteropancreatic neuroendocrine tumors in the United States from 1975 to 2012.
Authors: Lee Mi Ri , Harris Cynthia , Baeg Kiwoon Joshua , Wisnivesky Juan P. , Kim Michelle Kang
Published: January 2019

231

Background: Although multiple studies document a rise in gastroenteropancreatic neuroendocrine tumor (GEP-NET) incidence over the past several decades, there are limited national data regarding recent trends. Using a population-based registry, we evaluated GEP-NET incidence trends in the US population from 1975-2012 by age and calendar year at diagnosis and year of birth. Methods: GEP-NET cases between 1975-2012 were identified from the most recent version of the Surveillance, Epidemiology, and End Results (SEER) registry based on histologic and site codes. We calculated overall annual incidence, age-adjusted incidence (number of cases per 100,000), annual percent change (APC), and average APC by 5 year age intervals. We also evaluated the incidence rates by age, period, and birth year cohorts. Results: We identified 22,744 patients with GEP-NETs. In adults age 25-39 years, GEP-NET incidence rates declined from the mid 1970s to early 1980s, then increased until 2012 (Table 1). In adults age 40 and older and between ages 15-24 years, incidence rates generally increased continuously from 1975 to 2012. Adults age 40-69 years demonstrated the most rapid increases in average APC, approximately 4-6% per year. Overall incidence rates were highest in adults age 70-84 years. Since the late 1880s, GEP-NET incidence has increased in consecutive birth cohorts. Conclusions: Our study demonstrates that more recent generations have had higher incidence rates than more distant generations. In addition, GEP-NETs are more common among older adults and the number of GEP NETs has increased in past decades. [Table: see text]
Correlative analysis of circulating tumor (ct) DNA and tumor mutational analysis (TMA) in patients with advanced pancreatobilliary malignancies (PBM).
Authors: Babiker Hani M. , Liu Alex John , Recio Boiles Alejandro , Saboda Kathylynn , Liau Joy , Scott Aaron James , Elquza Emad , Mahadevan Daruka
Published: January 2019

235

Background: Tumor archival tissue (TT) MA of PBM is challenging due to insufficient specimen acquired from fine needle aspirations. This is a barrier to analyzing specimens for targeted therapy (clinical trial enrollment). The correlation of cell free ctDNA and TMA has not been studied extensively. We hypothesize that somatic TMA correlates with ctDNA and will be a surrogate for enrollment to targeted trials. Methods: We retrospectively identified PBM patients evaluated in the Phase I Program and analyzed ctDNA and TT. ctDNA was extracted from plasma, genomic alterations were analyzed by parallel sequencing of amplified target genes (73 genes) using Illumina Hi Seq (Guardant360). Direct sequence analysis was performed on genomic DNA isolated from FFPE TT using the Illumina MiSeq platform, 592-whole gene targets (Caris MI/X). The primary objective was to correlate the mutation concordance rate (mCR, common mutations/all mutations) between ctDNA and TT. We utilized Stata 15 for descriptive analysis, Spearman correlation coefficient, and Wilcoxon Sign Rank test for statistical analysis. Results: Between 03/2016-08/2017, 28 patients (M:F 1:1) were identified, 89.2% had pancreatic adenocarcinoma, 54% were treatment naïve and age ranged from 52-83 years old. The mCR for ctDNA was 31% (21/67) and the mCR for TT was 38% (21/55). These mCRs were highly correlative with a Spearman’s Rho = 0.89, (p < 0.0001). The mCR in ctDNA was compared to mCR in TT using Wilcoxon Sign Rank Test and was found to not be statistically different (p = 0.69). Adequate TT for MA occurred in 64 % (18/28) of patients. Percentage of DNA alterations found was 89.3% (25/28) in ctDNA and 94.4% (17/18) in TT. Moreover, 61% (11/18) of patients had at least 1 shared mutation. Percentages of driver mutations identified were 92% (23/25) in ctDNA and 100% (17/17) in TT. The most common driver mutations in ctDNA were TP53, KRAS, SMAD4, and NF1. The most common driver mutations in TT were KRAS, TP53, CDKN2A, and SMAD4. Conclusions: There was a statistically significant correlation between mCR of ctDNA and TMs in PBM (p < 0.0001).
Effectiveness of colon cancer awareness month compared to pancreatic cancer awareness month at increasing internet search activity.
Authors: Nagpal Sajan Jiv Singh , Mukhija Dhruvika , Sharma Ayush , Khanna Sahil
Published: January 2019

240

Background: Colorectal and Pancreatic cancers have high mortality with about 50,000 patients dying from each annually. Cancer awareness months (CAMs) have been earmarked by cancer societies to change public attitudes towards prevention, screening and treatment of various cancers. Awareness campaigns lead by these societies have benefited significantly from readily available Internet access and growing social media. Internet search activity has been used as a surrogate tool to gauge public interest and awareness. We aimed to assess if cancer awareness months impact internet search activity for these cancers. Methods: Using Google Trends, a public web facility of Google Inc. based on Google Search, we compared the relative frequency of search of terms ‘Colon Cancer’ and ‘Pancreatic Cancer’ between 1st January 2004 and 31st December 2016 (n=156 months). The program assigns a reference value of 100 for the point of maximum popularity from among the search terms, and provides relative monthly scores for all terms, which we termed relative interest scores (RIS). Within each cancer, the median RIS was then compared for their respective awareness months (n=13; March for CRC and November for PC) to the to the remaining months (n=143). Results: The median (IQR) RIS for CRC was significantly higher for CRC during its CAM:54 (51-63) as compared to other months:47 (44-50); p=0.0001. However, there was no significant difference in the median RIS for PC during its CAM: 33 (27.5-35.5) as compared to other months: 31 (27-33); p=0.43. The point of maximum popularity during the study period (i.e. RIS 100), and other peaks in search volume for PC corresponded to significant news events associated with PC, and PC search volumes surpassed CRC in those months. Conclusions: Ongoing campaigns for CRC awareness appear to be effective in increasing internet search activity during its respective CAM. While differences could be due to established CRC screening guidelines, other reasons behind the success of CRC awareness campaigns should be adopted by PC as awareness campaigns for the two cancers are otherwise similar.
Racial disparities in the presentation of hepatocellular carcinoma in the population 65+ years in the United States.
Authors: Kaufman Michael Ross , Delgado David J. , Costa Stephanie , George Brandon , Mitchell Edith P.
Published: January 2019

249

Background: Insufficient evidence exists regarding the presentation and management of elderly patients with hepatocellular carcinoma (HCC). The purpose of this study was to describe racial differences in cancer staging of elderly (65+) patients with HCC diagnosed in the United States. Methods: A retrospective cohort study was conducted using the 1973-2014 Surveillance, Epidemiology and End Results Program (SEER) database of the National Cancer Institute. Patients with primary hepatocellular carcinoma, diagnosed between 2004 and 2014, and with complete information on race, gender, year of diagnosis, age, marital status, region and stage at diagnosis (Derived SEER Summary Stage 2000, and Derived American Joint Committee on Cancer (AJCC) Stage Group, 6th Edition) were included. Descriptive statistics were used to compare sociodemographic and clinical variables with race. Univariate and multivariate logistic regressions were preformed to describe the association of race with the diagnosis of late stage HCC (Regional/Distant vs Localized Stage for SEER Summary Stage, and Stage III/IV vs Stage I/II for AJCC Stage Group). Results: The sample consisted of 19,902 HCC patients: 69.7% White, 9.2% Black, 20.2% API, 1.0% AI; 69.1% male; 45.1% diagnosed in 2004-2009; 56.2% age 65-74, 35.6% 75-84, and 8.2% 85 and older; 58.3% married; 7.4% Midwest, 12.4% Northeast, 17.0% Southeast, 63.2% Pacific West; 44.9% Regional/Distant Stage (SEER Summary Stage) and 41.2% Stage III/IV (AJCC Stage Group). After controlling for confounding variables, Asian/Pacific Islanders had a decreased odds of presenting with late stage disease relative to whites in both the SEER Summary Stage (OR: 0.867, CI:0.805-0.934) and AJCC Stage Group (OR: 0.904, CI:0.838-0.975). Conclusions: Racial disparities exist at the presentation of HCC in the 65+ population. Asian/Pacific Islanders are less likely to be diagnosed with late stage HCC compared to whites. There is a need to study further these relationships in subpopulations.
Impact of hospital teaching status on stage I pancreatic cancer survival.
Authors: Chan Andy , Masuda Zachary K. , Walters Ryan W , Silberstein Peter T. , Aurit Sarah J
Published: January 2019

257

Background: Burke et al. (2017) revealed that academic hospitals had lower patient mortality rates for common conditions compared to community-based hospitals. We conducted a retrospective study to compare survival of Stage I pancreatic cancer patients in academic versus community-based hospitals throughout the US. Methods: We identified 6,276 patients with single primary Stage IA or IB adenocarcinoma of the pancreas from the NCDB diagnosed from 2004-2012. We only included those who had a partial pancreatectomy, Whipple procedure, or no surgical intervention. In this subset, treatment was classified as none, chemotherapy, radiation, or chemoradiation; we examined the number of days from diagnosis to treatment. Unadjusted survival stratified by facility type was estimated with the Kaplan-Meier method; multivariable Cox regression was used to adjust for patient and facility level characteristics. Results: The log-rank test indicated that survival for patients who received treatment from an academic facility was significantly longer than those treated at a community-based facility (p < 0.001). After adjusting for patient and facility characteristics, however, survival was no longer significantly associated with facility type (p = 0.52). Holding all else constant, patients who underwent a surgical intervention had a lower risk of death (HR = 0.44, 95% CI: 0.40 to 0.48). Chemoradiation had a lower risk than both radiation (HR = 0.75, 95% CI: 0.65 to 0.86) and chemotherapy (HR = 0.88, 95% CI: 0.82 to 0.95). Risk of death was increased for older males, those without private insurance, and patients with Stage IB adenocarcinoma. Conclusions: In the largest study examining the association between hospital teaching status and Stage I pancreatic cancer mortality, our data suggests that there is not a significantly lower mortality rate for patients at academic hospitals compared to patients at community-based hospitals. [Table: see text]
A phase 2 and biomarker study of sorafenib combined with FOLFOX in patients with advanced hepatocellular carcinoma (HCC).
Authors: Goyal Lipika , Zheng Hui , Abrams Thomas Adam , Miksad Rebecca A. , Bullock Andrea J. , Allen Jill N. , Yurgelun Matthew B. , Sheehan Susan , Lynch Patricia , Afflitto Anthony James , Dinicola Caroline , Maurer Jordan Robert , Reyes Stephanie , Knowles Michelle , Galway Aralee , Clark Jeffrey W. , Birnbaum Emilie , Khachatryan Anna , Duda Gabriel Dan , Zhu Andrew X.
Published: January 2019

270

Background: Sorafenib is the standard first line treatment for advanced HCC and showed a median time to progression (TTP) of 5.5 months and an overall response rate (ORR) of 2% in the phase III SHARP trial. FOLFOX has shown modest activity in HCC with a progression free survival (PFS) of 2.9 months and ORR of 8% in a phase III trial. In this single-arm, multicenter phase 2 and biomarker study, sorafenib plus FOLFOX was evaluated in the first line treatment of advanced HCC. Methods: Patients with histologically proven advanced HCC, Child Pugh A liver function, and no prior systemic therapies received sorafenib 400mg orally twice daily during a 2-week lead-in, followed by concurrent modified FOLFOX (5-FUCI 1200mg/m2/day for 46 hours and LV 400mg/m2 bolus, Oxaliplatin 85mg/m2) on day 1 and 15 of each 28-day cycle. The primary endpoint was TTP, calculated from date of study entry to date of radiological or clinical disease progression. Serial plasma anti-angiogenic and anti-inflammatory biomarkers were evaluated. Results: The study enrolled 40 patients with advanced HCC: median age, 65 years; male 85%; Child Pugh A5, 70%; BCLC stage C, 95%; HCC etiology, HCV 40%, HBV 13%, alcohol 13%. Grade 3/4 adverse events were notable for AST (23%), ALT (15%), bilirubin (10%), diarrhea (10%), anemia (10%), hypertension (5%), hand-foot syndrome (5%), and thrombocytopenia (5%). Dose reductions for sorafenib and FOLFOX were done in 73% and 65% of patients, respectively. The median TTP was 8.8 months (95%CI, 6.5-11.2). The ORR was 18%, and the stable disease rate was 55%. Among 36 patients with a baseline AFP ≥ 5 ng/mL, 10 (28%) had a ≥ 50% drop in AFP. Low baseline plasma levels of sVEGFR1, VEGF-C, and bFGF and high levels of s-cMET and IL-12 tended to associate with longer TTP (p < 0.10). Decreased s-cMET at day 15 and decreased s-cMET and IL-2 at day 43 were associated with longer TTP (p < 0.05). Conclusions: Sorafenib+FOLFOX demonstrated encouraging clinical efficacy with moderate toxicity in the first line treatment of advanced HCC. Initial biomarker evaluation suggested a correlation between TTP and baseline angiogenic markers as well as changes in IL-2 and s-cMET. Complete biomarker analysis will be presented at the meeting. Clinical trial information: NCT01775501.
Widespread somatic loss of heterozygosity as a possible marker of disease aggressiveness in metastatic well differentiated pancreatic neuroendocrine tumors.
Authors: Akala Omobolaji Oyekunle , Shah Ronak , Untch Brian R. , Kelly Virginia , Chou Joanne F. , Ladanyi Marc , Berger Michael F. , Klimstra David S. , Reidy Diane Lauren , Raj Nitya Prabhakar
Published: January 2019

275

Background: To assess the utility of molecular profiling to predict tumor biology, we performed next-generation sequencing (NGS) of metastatic well differentiated (WD) pancreatic neuroendocrine tumors (panNETs) in the routine practice setting. Our institutional NGS platform allows for evaluation of genetic alterations that contribute to tumorigenesis (sequence variants, copy number alterations, insertions/deletions, select rearrangements) as well as somatic loss of heterozygosity (LOH). Methods: NGS was performed using MSK-IMPACT, a matched tumor-normal sequencing platform that interrogates 468 cancer-related genes. LOH for all cases was determined by analysis of total, allele-specific, and integer DNA copy number genome-wide using the FACETS algorithm. Results: Since 2014, NGS has been performed in 96 tumor samples from 80 patients. The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). LOH was highly prevalent, identified in 51/96 samples (53%). A significant association (q-value < 0.05) was noted between LOH and the presence of altered MEN1, DAXX, PTEN, or TSC2. LOH was recurrently observed in chromosomes 1, 2, 3, 6, 8, 10, 11, 15, 16, 21, and 22. Since MEN1 alterations predict improved outcome, comparison was made between patients with LOH present/MEN1 wild type (WT) tumors (n = 16) and LOH absent/MEN1 altered tumors (n = 21); inferior overall survival (OS) was noted with LOH present/MEN1 WT status (p < 0.01). High grade pathology was observed in 6/16 (38%) LOH present/MEN1 WT tumors and in 1/21 (5%) LOH absent/MEN1 altered tumors (p < 0.0001). The mean Ki-67 index of LOH present/MEN1 WT tumors was 22% and that of LOH absent/MEN1 altered tumors was 9%. Conclusions: This is the first study to report widespread somatic LOH in metastatic WD panNETs. PanNETs appear to exhibit more LOH overall than virtually any tumor type studied. In this cohort, LOH was a prognostic marker of inferior OS and was associated with more aggressive pathologic features. LOH warrants further investigation as it may help better characterize these clinically heterogeneous tumors.
Mucosal injury of small intestine in patients with advanced gastric cancer who developed chemotherapy induced diarrhea (CID).
Authors: Sakumura Miho , Ando Takayuki , Hosokawa Ayumu , Mihara Hiroshi , Takagi Hiroaki , Yoshita Hiroki , Nanjo Sohachi , Ueda Akira , Fujinami Haruka , Kajiura Shinya , Ogawa Kohei , Sugiyama Toshiro
Published: January 2019

28

Background: Fluoropyrimidine is a key drug for patients with advanced or recurrent gastric cancer. It causes diarrhea, a common non-hematological toxicity. The consensus guideline suggests aggressive treatment including intravenous fluids and antibiotics, is necessary for patients with severe diarrhea accompanied by fever and sepsis. However, the frequency of complicating signs and the actual degree of damage of small intestinal mucosa have not been reported. We evaluated complicating signs and mucosal injury in patients with complicated CID. Methods: Between April 2007 and December 2016, 170 patients with advanced or recurrent gastric cancer who underwent S-1 or capecitabine based chemotherapy were retrospectively analyzed. Diarrhea was evaluated with CTCAE v4.0, and complicated CID was defined as CTC grade 3 or 4 diarrhea or grade 1 or 2 diarrhea with following signs: cramping, vomiting, decreased performance status, fever, sepsis, neutropenia, frank bleeding, and dehydration. To evaluate mucosal injury of small intestine, capsule endoscopy was performed in patients with complicated CID. Results: Among 170 patients, 15 patients (8.8%) showed complicated CID during chemotherapy (S-1 based chemotherapy, n = 13/148; capecitabine based chemotherapy, n = 2/22). Among the profile of complicated signs, cramping, fever, and vomiting were frequent, and observed in 11 (73%), 7 (47%), and 5 (33%) patients, respectively. Ten patients received capsule endoscopy after improvement of CID, and 6 (60%) patients had multiple erosions or ulcerations in small intestine. Conclusions: The incidence of complicated CID caused by fluoropyrimidine based chemotherapy was less frequent in patients with advanced or recurrent gastric cancer. However, most patients showed mucosal injury of small intestine in capsule endoscopy. Therefore, these findings strongly support the guideline that recommends aggressive therapeutic approach for patients with complicated CID.
Cell free circulating tumor DNA ERBB2 amplifications are targetable in patients with pancreatic ductal adenocarcinoma.
Authors: Barzi Afsaneh , Raymond Victoria , Wang-Gillam Andrea , Lanman Richard B.
Published: January 2019

282

Background: Molecularly targeted therapies have led to improved clinical benefit, however few targeted therapies exist in pancreatic ductal adenocarcinoma (PDAC). ERBB2 (HER2) amplifications (AMP) in PDAC have been described as potentially targetable, especially in KRAS wild type tumors. We describe the incidence of ERBB2 AMP in patients (pts) with PDAC who underwent cell-free circulating tumor DNA (cfDNA) testing with a CLIA/CAP/NYSDOH approved 73 gene assay. Methods: The Guardant Health Clinical Database was queried (March 2014-July 2017) for pts with a diagnosis of PDAC and an ERBB2 AMP identified on cfDNA (Guardant360). Copy number AMP ≥ 2.12 is reported. Pts with multiple cfDNA timepoints were included if an ERBB2 AMP was identified at any timepoint. Results: 30 pts met inclusion criteria (1.7% of pts with PDAC (1722)). Median age at test order was 63 years (range 24 to 92). 26 pts had one cfDNA timepoint, three pts had two, and one patient had three. In the pts with multiple timepoints, ERBB2 AMP was identified at one timepoint each for a total of 30 timepoints from 30 unique pts. In two pts, ERBB2 AMP was initially not detected (ND) and detected subsequently. In two pts, ERBB2 AMP was initially detected and subsequently ND. Median number of alterations per test was 6 (range 1 to 13). Median ERBB2 AMP was 2.47 copies (range 2.14 to 7.51). Concurrent KRAS single nucleotide variant was identified in 20 tests (66.7%); G12D(6), G12V(5), Q61H(1); G12D/ KRAS AMP(6), G12R/ KRAS AMP(2). Clinical follow-up was available for three pts, two of whom were treated with anti-HER2 therapy. One patient with a low ERBB2 AMP (2.20 copies) / KRAS wild type progressed on multiple lines of therapy. Following identification of cfDNA ERBB2 AMP, Traztuzumab was added to the FOLFOX regimen with clinical improvement and significant decline in CA19-9 (1,847 to 22 U/mL) over a four-month period. ERBB2 AMP decreased to undetected over the same period. For the past 8 months, patient has been on Trastuzumab alone with further decrease in CA19-9 (16 U/mL). Conclusions: cfDNA detects potentially targetable ERBB2 AMP in pts with PDAC, and targeted anti-HER2 therapy should be explored, even when these amplifications are detected at the lower range.
Is there association between characteristics of gastric tumor growth and activation of different growth factor systems?
Authors: Frantsiyants Elena , Goroshinskaya Irina A. , Surikova Ekaterina Igorevna , Bandovkina Valeria A. , Pogorelova Yulia A. , Nemashkalova Ludmila A. , Maslov Andrey A. , Medvedeva Dar'ja E. , Kaminskiy Gennadiy V. , Malinin Sergey A. , Tishchenko Irina , Chilhahyan Lusegen , Kit Oleg Ivanovich
Published: January 2019

29

Background: Signet-ring cell carcinoma of the stomach (SRCC) is significantly associated with poor prognosis and low treatment effectiveness, compared to adenocarcinoma of the stomach (AC). One of the causes of SRCC aggressive course can be its diffuse invasive growth pattern. The ability of tumor cells to synthesize and/or capture growth factors ensures the independent tumor development. VEGF, EGF, IGFI and EGFII facilitate neoangiogenesis and regulation of malignant processes in paracrine/autocrine mechanisms. The purpose of the study was to find the difference between local levels of VEGF, EGF, IGFI and IGFII in tumor and intact tissues in AC and SRCC. Methods: Levels of VEGF, EGF, EGFR, IGF-I and IGFII were determined by ELISA in tumor and intact gastric tissues of 15 AC patients and 10 SRCC patients (T2-3N0-2M0, G2-3), mean age 62.8±2.38 years. Results: Levels of IGF-I, IGF-II and VEGF in intact gastric tissues were similar in AC and SRCC. EGF and EGFR levels in AC were 2.9 and 1.5 higher than in SRCC. Levels of VEGF in AC tumor tissues, compared to intact gastric tissues, increased by 2.3 times, EGF and EGFR did not change, and IGFI and IGFII decreased by 2.1 and 1.8 times, respectively. Tumor tissues of SRCC patients showed the increased levels of EGF (by 2.9 times) and EGFR (by 1.8 times); VEGF and IGF were similar to the levels in intact tissues. SRCC was characterized by the activation of systems of EGF and IGF, but not VEGF. AC demonstrated the stimulation of VEGFA neoangiogenesis. Conclusions: The activation of systems of EGF and IGF in SRCC could be associated with some characteristics of the diffuse growth pattern and the tumor origin from neuroendocrine cells which facilitates the autocrine/paracrine regulation of the invasive growth. AC requires neoangiogenesis which is realized primarily by the VEGF system.
Genotyping of circulating tumor DNA in biliary tract cancer to reveal diagnostic and prognostic information.
Authors: Berger Andreas Wolfgang , Ettrich Thomas Jens , Schwerdel Daniel , Dolnik Anna , Beuter Florian , Blätte Tamara J. , Schmidt Stefan A. , Stanescu Nora , Steinacker Jochen , Marienfeld Ralf , Bullinger Lars , Seufferlein Thomas
Published: January 2019

291

Background: Biliary tract cancer (BTC) shows increasing incidence and is associated with a high mortality. Diagnosis is difficult due to the frequently occurring inaccessibility of the tumor for biopsy. Noninvasive approaches for (i) assessing and (ii) monitoring the tumor-specific molecular setup are desirable. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal. Methods: Blood and tumor tissue samples from patients with locally advanced or metastatic BTC prior to and during palliative treatment were collected. Tumor tissue and corresponding ctDNA samples underwent targeted genotyping of the 15 most frequently mutated genes in BTC. Findings were correlated with clinical and imaging data. Results: 24 therapy naive patients with histologically confirmed BTC were included for analyses. The overall mutational concordance (blood/tissue) was 74% and 92% for intrahepatic tumors. The mean variant allele frequency (VAF) in tumor tissue of therapy naïve patients was significantly higher compared to the respective ctDNA (p = 0.0291). In turn, the sequencing depth for ctDNA was significantly deeper (p = 0.0001), enabling us to detect also rare variants. Mean ctDNA VAF at baseline significantly correlated with tumor load (Spearman, r = 0.4073, p = 0.0433) and, exclusively for intrahepatic tumors, also with progression-free survival (Spearman, r = -0.5878, p = 0.0386). During 1st line palliative treatment, we detected a change in the mutational landscape in 36% of cases, Moreover, we had access to ctDNA samples of 5 pretreated patients. While ctDNA samples of therapy naïve patients (n = 23) showed a mean of 0.78 mutations per patient, ctDNA samples of pretreated patients (n = 5) exhibited a mean of 0.4 mutations (p = 0.5519). Conclusions: The molecular landscape of BTC is depicted in ctDNA which may enable to adapt diagnostic and therapeutic strategies to the specific molecular setup present at a certain time. In contrast, the use of targeted resequencing is likely to be insufficient for a comprehensive assessment of treatment induced BTC evolution. For this purpose, we suggest a more extensive analysis of ctDNA by broader sequencing applications and the incorporation of epigenetics.
Phase II study of olaparib for BRCAness phenotype in pancreatic cancer.
Authors: Golan Talia , Varadhachary Gauri R. , Sela Tal , Fogelman David R. , Halperin Naama , Shroff Rachna T. , Halparin Sharon , Xiao Lianchun , Aderka Dan , Maitra Anirban , Ackerstein Aliza , Wolff Robert A. , Shacham-Shmueli Einat , Javle Milind M.
Published: January 2019

297

Background: The subtype of pancreatic ductal adenocarcinoma cancer (PDAC) patients with DNA damage repair (DDR) deficiency from BRCA1/2 mutations has a favorable prognosis and is sensitive to platinum analogues and PARP inhibition. About 10-20% of PDAC patients have DDR deficiency without BRCA mutations (BRCA ness). The efficacy of olaparib in this population is unknown. Methods: Two parallel phases II trials (Israel and U.S.) are ongoing to determine the efficacy of olaparib in advanced PDAC with BRCA ness. Inclusion criteria: ≥ 1 prior systemic therapy for advanced PDAC, ECOG 0-1, germline BRCA 1/ 2 ( gBRCA) mutation negative, previously known DDR genetic aberrations (DDR-GA), family history of BRCA-associated cancers in ≥2 first-degree relatives (without DDR-GA), ATM loss by IHC (Israel only). Primary and secondary endpoints are objective response rate and PFS, respectively. With an type I error rate α of 0.1 and a β error rate of 0.2, and assuming P0 and P1 are 5% and 20%, respectively, study will enroll 24 patients at each site. Results: Thus far, 21 and 11 patients treated in Israel and U.S; respectively. DDR phenotype: Family history of BRCA cancer without DDR-GA (n = 14), DDR-GA (n = 12), ATM loss by IHC (n = 5). DDR-GAs were ATM (n = 6), PALB2 (n = 1), BRCA somatic (2), FANCB (1), PTEN (1) and CCNE1 (1). Efficacy data are in Table. Common toxicities were grade 1-2 anemia, fatigue and nausea. No responses were observed in platinum refractory cases. Conclusions: Olaparib was tolerated well in this study population. Olaparib showed encouraging initial antitumor activity in platinum-sensitive, gBRCA negative PDAC patients with DDR GA and in patients with family history of BRCA cancers (without identifiable DDR-GA). Clinical trial information: NCT02677038 ; NCT02511223. [Table: see text]
A translational effort to identify prognostic and predictive biomarkers in pancreatic cancer among RBM3-regulated genes.
Authors: Olsson Hau Sofie , Karnevi Emelie , Lundgren Sebastian , Li Bo , Lynch Seodhna , Elebro Jacob , Heby Margareta , Nodin Bjorn , Eberhard Jakob , Uhlen Mathias , Moran Bruce , Gallagher William M. , Jirstrom Karin
Published: January 2019

305

Background: Pancreatic cancer has a dismal prognosis and clinical protocols are still lacking predictive biomarkers. RNA-binding motif protein 3 (RBM3) has emerged as a promising biomarker in several solid cancers, including pancreatic cancer. High RBM3 expression in human tumors has been associated with good response to chemotherapy, as well as to confer increased chemosensitivity in vitro. The aim of this study was to identify RBM3-regulated genes in pancreatic cells in vitro, and further interrogate their potential utility as prognostic and predictive biomarkers in a translational setting. Methods: Next generation RNA-sequencing was applied to compare gene expression between MIAPaCa-2 cells with siRNA-downregulated RBM3 and control cells. Single genes with the strongest association to RBM3 were further selected by gene set enrichment analysis, and their prognostic value in pancreatic cancer was examined in The Cancer Genome Atlas (TCGA). The most promising biomarker candidates with well-validated antibodies were then analyzed by immunohistochemistry in tissue microarrays with tumors from a consecutive, retrospective cohort of 175 patients with periampullary and pancreatic adenocarcinoma. Results: MIAPaCa-2 cells with downregulated RBM3 displayed 21 differentially expressed genes (p < 0.01). One of the top downregulated genes was PDS cohesion associated factor A (PDS5A) encoding a protein involved in sister chromatid cohesion. PDS5A protein expression was reduced in siRBM3-treated MIAPaCa-2 cells compared to control cells. High PDS5A mRNA expression was significantly associated with a reduced survival in pancreatic cancer in the TCGA (n = 176, p = 0.026). High PDS5A protein expression in the separate cohort was significantly associated with a poor prognosis but predictive of improved response to adjuvant chemotherapy in KRAS-mutated, but not wild-type, pancreatobiliary-type tumors (p for interaction = 0.043). Conclusions: Here, we provide the first report of the expression of PDS5A in pancreatic and periampullary cancer, suggesting its potential utility as a prognostic and predictive biomarker. Further studies to unravel the underlying mechanisms are encouraged.
Bioengineered microRNA-1291 effects on pancreatic cancer cell proliferation and xenograft tumor growth.
Authors: Tu Mei-Juan , Duan Zhijian , Zhang Qianyu , Qiu Jing-Xin , Gonzalez Frank J , Kim Edward Jae-hoon , Yu Aiming
Published: January 2019

307

Background: MicroRNAs (miR) have proved to be vital regulators in the control of tumor progression. Our recent studies have revealed miR-1291 is downregulated in patient pancreatic cancer (PC) specimens and re-introduction of miR-1291 suppresses tumorigenesis of PC cells. We have developed a novel ncRNA bioengineering technology to produce a miR-1291 prodrug. In this study, we aimed to assess the effectiveness of this miR-1291 prodrug as a monotherapy, as well as in combination with chemotherapy, for treatment of PC. Methods: Sensitivity of PC cells to miR-1291 prodrug alone, gemcitabine plus nab-paclitaxel (Gem-nP) alone, and their combination was evaluated by CellTiter-Glo assay. Mature miR-1291 and ARID3B mRNA levels were determined by quantitative real-time PCR (q-PCR) assay. A luciferase reporter gene assay was used to validate interaction between miR-1291 and ARID3B 3’UTR. Target protein expression was examined by Western blot and immunofluorescence analyses. PANC-1 and PC patient-derived xenograft (PDX) mouse models were established and used to assess anti-tumor effects of miR-1291 monotherapy and combination therapy with Gem-nP. Results: Cytotoxicity assays showed that miR-1291 prodrug enhanced the sensitivity of PANC-1 and AsPC-1 cells to Gem-nP. Luciferase assays confirmed ARID3B as a target for miR-1291 as predicted by computational analysis. qPCR analysis demonstrated that miR-1291 prodrug was readily processed to mature miR-1291 and subsequently upregulated ARID3B mRNA levels. miR-1291 prodrug also elevated the protein levels of ARID3B. Co-administration of miR-1291 prodrug and Gem-nP increased caspase-3/7 and γH2AX levels in PC cells, compared to miR-1291 or Gem-nP treatment alone. In addition, systemic administration of in vivo-jet PEI formulated miR-1291 prodrug suppressed tumor growth in both a PANC-1 xenograft model and three PDX models, and largely enhanced the efficacy of Gem-nP. All treatments were well tolerated in mice in vivo. Conclusions: Our bioengineered miR-1291 prodrug has therapeutic potential as a monotherapy but also can act as a sensitizing agent to chemotherapy. This novel treatment approach should be further explored for PC.
Soluble urokinase plasminogen activator receptor (suPAR) as a novel serum biomarker for patients undergoing resection of colorectal liver metastases.
Authors: Loosen Sven H , Binneboesel Marcel , Klink Christian , Ulmer Tom Florian , Longerich Thomas , Trautwein Christian , Roderburg Christoph , Luedde Tom , Neumann Ulf Peter
Published: January 2019

309

Background: In colorectal cancer (CRC), the liver is the most common site of metastasis. Surgical resection represents the standard potentially curative therapy for patients with colorectal liver metastases (CRLM). However, 5-year survival rates after resection do not exceed 50%, and despite existing preoperative stratification algorithms it is still not fully understood which patients benefit most from surgery. The soluble urokinase plasminogen activator receptor (suPAR) has recently evolved as a promising biomarker for distinct clinical conditions. Here, we examined a potential role of circulating suPAR as a biomarker in patients undergoing resection of CRLM. Methods: Expression levels of uPAR, the membrane-bound source of circulating suPAR, were analysed in tissue samples of CRLM using RT-PCR and IHC. SuPAR serum levels were measured by ELISA in 104 patients undergoing surgical resection of CRLM as well as 50 healthy controls. Results were correlated with clinical data. Results: In line with an upregulation of uPAR in the CRLM tissue, serum levels of suPAR were significantly elevated in patients with CRLM compared to healthy controls. Patients with preoperative suPAR serum levels above our defined ideal cut-off value of 4.83 ng/ml showed a strikingly reduced overall survival after resection of CRLM, which could be confirmed for right- and left-sided primary CRC. Importantly, none of these patients reached long-term survival compared to patients with preoperative suPAR serum concentrations below the cut-off value. Moreover, multivariate Cox-regression analysis revealed preoperative suPAR serum levels as an independent prognostic factor in this setting. Additionally, elevated preoperative suPAR but not creatinine levels were a predictor of acute kidney injury after CRLM resection, correlating with a longer postoperative hospitalization. Conclusions: Serum levels of suPAR represent a promising novel biomarker in patients with resectable CRLM that might help to guide preoperative treatment decisions with regards to patients’ outcome and the identification of patients particularly susceptible to postoperative acute kidney injury.
Clinico-pathological analyses of the relationship between SMAD4, TP53, CDKN2A mutations and recurrence and prognosis in patients with pancreatic cancer: A single institutional study.
Authors: Fukahori Masaru , Naito Yoshiki , Ishikawa Hiroto , Ushijima Tomoyuki , Nagasu Sachiko , Miwa Keisuke , Sakaue Takahiko , Takahashi Kenjirou , Nakayama Masamichi , Yasumoto Makiko , Ishida Yusuke , Okabe Yoshinobu , Okuda Kouji , Torimura Takuji
Published: January 2019

319

Background: Gene mutations of SMAD4, TP53 and CDKN2A( p16) have been reported to be associated with poor prognosis and metastatic burden in advanced pancreatic cancer (PC). On the other hand, the association between these gene mutations and recurrence in PC is still unclear. The present study aimed to whether the 3 gene mutations were related to the recurrence and the prognosis in PC patients. Methods: Formalin-fixed paraffin-embedded tumor samples were gathered from patients with PC who underwent curative resection between January 2014 and December 2015. We retrospectively evaluated a relationship between the mutation status of SMAD4, TP53 and p16 and the recurrence and prognosis in patients with PC. Results: Totally, fifty-six samples of patients with PC (Stage I/ II/ III: 5/6/45 (UICC 7th)) were included in this analysis. Recurrence was seen in 32 patients (57.1%). Patients with PC both recurrence and advanced pathological stage showed poor prognosis. Each 3 gene mutation did not show a significant association with recurrence. TP53 and p16 single mutations did not show significant association with prognosis. However, the patients with PC who have SMAD4 mutation showed a significant poor prognosis (Overall survival: 18.6 vs. 34.5 months, p = 0.03). Multivariate analysis showed only recurrence was a significant prognostic factor (p = 0.01) Conclusions: The present study suggested that there was no association between SMAD4 and recurrence, whereas in case of recurrence, SMAD4 mutation may be associated with prognosis in PC patients.
Effect of a third-generation oncolytic herpes simplex virus on the growth of human hepatocellular carcinoma.
Authors: Nakatake Richi , Kaibori Masaki , Nakamura Yusuke , Matsushima Hideyuki , Okumura Tadayoshi , Inou Yasushi , Todo Tomoki , Kon Masanori
Published: January 2019

321

Background: Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 replicates efficiently and selectively in tumor cells, kills tumor cells without damaging the surrounding normal tissues, and induces host immune responses specific to tumor cells. Here we investigated the antitumor effects of T-01 on HCC. Methods: The cytopathic activities of T-01 were tested at different multiplicities of infection in 14 human and one murine hepatoma cell lines in vitro. In mouse various xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. Results: T-01 was cytotoxic to 13 cell lines (in vitro), including 10 human HCCs, two human hepatoblastomas, and one murine hepatoma. In mouse xenograft models of subcutaneous, orthotopic, and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the HCC cell lines HuH-7, KYN-2, and PLC/PRF/5 as well as those formed by the hepatoblastoma cell line HepG2 was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited and, in the contralateral tumors without T-01, T-01 also significantly reduced tumor growth compared with mock-infected tumors. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Conclusions: These results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC.