bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of primary tumor site on outcomes of treatment with etoposide and cisplatin in grade 3 gastroenteropancreatic neuroendocrine carcinoma.
Authors: Yoon Sang Eun , Kim Jung Hoon , Hur Joon Young , Lee Su Jin , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Lim Ho Yeong , Kang Won Ki , Kim Seung Tae
Published: January 2019

213

Background: Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a heterogeneous disease in terms of embryonic origin, aggressiveness, prognosis, and genomic profiling. Data regarding the efficacy of etoposide and cisplatin (EP) as a standard treatment of the primary tumor site in GEP-NEC are limited. Methods: We analyzed 64 patients with histopathologically confirmed metastatic GEP-NEC who received EP at Samsung Medical Center, Seoul, Korea, between January 2010 and January 2018. Based on primary tumor site, outcome of treatment with EP was evaluated. Results: Primary sites included 22 foregut-derived GEP-NECs (stomach, n = 6; duodenum, n = 4; pancreas, n = 12), 4 midgut-derived GEP-NECs, 5 hindgut-derived GEP-NECs of the rectum, 25 GEP-NECs originating from the hepatobiliary (HB) tract, and 12 GEP-NECs involving only intra-abdominal lymph nodes. No patient had a complete response (CR) and 17 had a partial response (PR), resulting in a 27.9% response rate (RR). When evaluating the efficacy of EP based on primary tumor site, the RR was most favorable in GEP-NECs involving only intra-abdominal lymph nodes, followed by GEP-NECs originating from foregut, midgut, HB, and hindgut. However, no statistically significant difference was observed for RR based on primary tumor site (p = 0.821). Similarly, no significant differences were found for progression-free survival (PFS) among patients with GEP-NECs arising from various primary tumor sites. Conclusions: Results from this study showed thatRR and PFS associated with EP treatment were not different based on the primary tumor site in patients with advanced or metastatic GEP-NEC.
Early detection of pancreatic ductal adenocarcinoma using abnormal urinary fragmentation ratio of a liver-originated protein.
Authors: Kan Motoyasu , Mitsunaga Shuichi , Ikeda Masafumi , Ohno Izumi , Tsubouchi Hironobu , Yanagi Shigehisa , Matsumoto Nobuhiro , Okumura Nobuaki , Takao Toshifumi , Nakazato Masamitsu
Published: January 2019

214

Background: Non PDAC tissue-originated proteins are cleaved by proteases derived from PDAC, which can result in abnormal cleavage patterns in the urine of PDAC patients. Urinary proteomic analysis for quantifying the ratios of the abnormal protein fragments to the non-fragmented protein levels in the urine may be useful to distinguish early PDAC from healthy controls. This proof-of-concept study was planned to determine the usefulness of measuring the protein fragments from non PDAC tissue-originated proteins in the urine using the multiple-reaction-monitoring technique (MRM) for discriminating resectable PDAC from healthy controls. Methods: Urinary proteins were digested with trypsin, and resultant peptides were measured by MRM analysis and the ratio of the level of each fragment to the non-fragmented protein level (fragmentation ratio) was calculated. Fragments for which the fragmentation ratios were higher in the PDAC group than those in the healthy group were defined as abnormal protein fragments. The diagnostic capability of each abnormal protein fragment for discriminating cases of PDAC from healthy controls was evaluated by receiver operating characteristic (ROC) curve analysis. Results: A total of 21 patients with resectable PDAC and 30 healthy control subjects were enrolled in this study. All the PDAC patients were treated by pancreatic resection. Urine samples for this study were collected prior to the surgery from the PDAC patients. The non PDAC tissue-originated protein was determined as a liver-originated protein. The fragmentation ratios for six fragments were found to be higher in the PDAC group as compared to those in the healthy control group, and these fragments were determined as abnormal protein fragments. ROC curve analysis was performed for each of the abnormal fragments to determine the areas under the curve (AUCs) for discriminating cases of PDAC from healthy controls. The best AUC was 0.81 (95% CI, 0.68-0.91). Conclusions: The urinary fragmentation ratios showed the ability to discriminate cases of resectable PDAC from a healthy control group; abnormal fragmentation ratios may be promising, noninvasively measurable biomarkers of early PDAC.
Clinical outcome of pancreatic cancer patients with indeterminate pulmonary nodules.
Authors: Kazarian Austin G , Mott Sarah L , Chan Carlos Hou Fai
Published: January 2019

220

Background: Indeterminate pulmonary nodules (IPNs) are often found on staging CT scans for pancreatic cancer and pose a treatment conundrum since resection is contraindicated in metastatic setting. Here we aim to determine the clinical outcome of pancreatic cancer patients with IPNs undergoing curative resection. Methods: Retrospective analysis of 1,182 pancreatic cancer patients in the institutional Oncology Registry between 2007 and 2017 was conducted. Survival probabilities were estimated using the Kaplan-Meier method. Time was calculated from diagnosis to death for overall survival (OS), and from operation to recurrence for recurrence-free survival (RFS). Cox regression models were used to assess the effects of demographic, clinicopathologic, and treatment variables on OS and RFS. Results: IPNs were found in 50 patients undergoing surgery (43 pancreatoduodenectomy, 7 distal pancreatectomy). Negative margins were obtained in 82% of patients. Six and 44 patients had stage 0/I and stage II disease, respectively. Twelve and 35 patients received neoadjuvant and adjuvant therapy, respectively. Over a median follow-up of 20 months from the time of diagnosis, 37 patients (74%) developed local recurrence or distant metastasis in liver (38%), lung (32%), peritoneum (8%), or other sites (8%). Median RFS was 14 months and median OS was 23 months. Tumor size (HR 1.56, CI 1.23-1.98, p < 0.01) and elevated pre-operative CA19-9 (HR 2.51, 1.22 – 5.15, p = 0.01) were associated with lower RFS. Tumor size (HR 1.43, CI 1.10-1.86, p < 0.01) and diabetes (HR 2.05, CI 1.02-4.11, p = 0.04) were associated with lower OS. Patients with lung only recurrence tended to have superior OS relative to other single sites (HR 2.05, CI 0.66-6.33, p = 0.21) or multiple sites (HR 2.30, 0.75-7.50, p = 0.15). Patients with lung only recurrence had a median survival after recurrence of 17.9 months compared to 6.5 months for other single sites or 4.3 months for multiple sites. Conclusions: Only a portion of IPNs develop into true lung metastasis and that isolated lung metastatic recurrence may confer a better survival over metastasis of other sites. Ongoing efforts will identify serum biomarkers to predict recurrence in the hopes of guiding future clinical practice.
Role of nonalcoholic steatohepatitis as a risk factor for intrahepatic cholangiocarcinoma and its role in patients’ prognosis: A case-control study.
Authors: De Lorenzo Stefania , Tovoli Francesco , Vasuri Francesco , Malvi Deborah , D'Errico Antonietta , Brandi Giovanni
Published: January 2019

224

Background: The prevalence of intrahepatic cholangiocarcinoma (ICC) is rising worldwide. The current epidemics of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) might be partly responsible for this trend. Methods: Case control study investigating the prevalence of histology-confirmed NASH in peritumoral liver of resected ICC patients and controls (pre-explant biopsies of liver donors). Controls were matched for age and sex in a 2:1 fashion. Correlates between NASH, tumor characteristics and overall survival (OS) were also explored in the ICC cohort. Results: Between 2006 and 2017, 84 ICCs were resected in our Institution. Sixty-two (74%) had no apparent risk factors for ICC. Amongst this group, the prevalence of NAFLD and NASH was 45.2% and 24.2%,respectively, compared to 44.3 and 8.9% in the 124 matched liver donors (p = 1.000 and p = 0.007, respectively). The 5-year OS rate was 20.0% in NASH and 57.4% in ICC without either NASH and other risk factors (p = 0.017). Main tumor size, sex and NASH (hazard ratio 2.618 , 95% confidence interval 1.140-6.013, p = 0.023) were independent predictors of the OS at the multivariate Cox regression. Conclusions: NASH (but not NAFLD) acts as a risk factor for ICC and may affect its long-term outcome. A collaborative multicenter approach could confirm and strengthen these data.
Incidence and trends of pancreatic cancer (PC) in Girona: A population-based study from the Girona Cancer Registry (1994-2015).
Authors: Garcia-Velasco Adelaida , Carmona Carmen , Bianca Antonia , Teixidor Helena , Valero Marc , Liñan Raquel , Carbajal Walter , Puigdemont Montserrat , Vilardell Loreto , Marcos Rafael
Published: January 2019

225

Background: PC is the third leading-cause of cancer death in Spain. In this study we aim to investigate PC’s incidence and trends during 1994-2015 in Girona. Methods: Data were extracted from the population-based Girona Cancer Registry. Incident PC cases were classified using the ICD-O-3 Third Edition. Age-adjusted incidence rates (ASRE) to the European standard population and world standard population (ASRW) were obtained. Trends were assessed using the estimated annual percentage of change (EAPC) of the ASRE13. Results: We identified 1590 PC incident cases, 45.8% females and 54.2%. Patients > 64 years old represented a 72.6% of cases. According to histology, epithelial tumors stand for a 44% of cases and neuroendocrine neoplasms represented only the 3% of all cases, being most of PC tumors’ histology non-specified. Cases detected only by death certificates (DCO) were 7.7% in males and 7.4% in females. For the whole study population, crude rate (CR) cancer incidence was 11.26 cases per 100,000 inhabitants/year (12.17 men; 10.34 women). Regarding the ASR, results show an ASRE13 of 12.99 (95% CI 12.36;13.65) and ASRW of 5.58 (95% CI 5.8;13.655.91). Age-specific rates reflected a drastic increase with age, having the population over 85 years the highest rate (74.5 cases per 100,000 inhabitants/year). We also found a significant increase in incidence of PC cases over the study period, with an EAPC of 1.41% per year, present in both men (EAPC = 1.30%) and women (EAPC = 1.37%). Conclusions: Incidence rates of PC in Girona are within the European average, and likewise they have been increasing for the last two decades. There is an increase of incidence in the elderly population reflected in age-specific rates, reason whereby we believe there are a high proportion of unspecific histologies. These results can be used as baseline for further research.
Validity of hepatic cone-unit resection for hepatocellular carcinoma.
Authors: Imura Satoru , Yamada Shinichiro , Saito Yu , Iwahashi Shuichi , Ikemoto Tetsuya , Morine Yuji , Shimada Mitsuo
Published: January 2019

228

Background: Anatomical liver resection (ALR) has been performed widely for hepatocellular carcinoma (HCC). However, there are difficult cases with typical ALR, due to tumor location or anatomical variation. The aim of this study is to review the cases of atypical ALR and to investigate the validity of small ALR for HCC. Methods: From 2007 to 2017, hepatic resection less than 2 segments was performed to 252 patients with HCC. (1) We reviewed cases with atypical ALR (eg. posterior segment + anterior dorsal area, S4 + S8 ventral area, etc.), and (2) Regarding the validity of cone-unite resection for single HCC, we compared the clinicopathological outcome with subsegmentectomy as a control. Results: (1) Atypical ALR was performed in 10% (17/169) of ALR less than 2 segments. There were 7 cases of extended anterior segmentectomy or extended S8 resection for patients having anterior or S8 portal branch that perfused to the right side of the right hepatic vein. Most of such atypical ALR tended to be indicated in right-side hepatectomy. (2) Liver function was well preserved in both groups, and it was better in subsegment group (ICGR15: 10.5 vs. 12.3%, ALB: 4.1 vs. 3.9g/dL). Regarding the tumor factor, the diameter was larger in the subsegment group than in the cone-unite group (2.8 vs. 2.1cm), and the proportion in which subsegmentectomy was performed in the case more than 3 cm was high (32 vs. 11%). There was no difference in OS and DFS between the two groups. Even when the tumor diameter was 3 cm or less, there was no difference in DFS between subsegment (n = 28) and cone-unite resection (n = 40). Conclusions: There are a number of cases that typical ALR is difficult, especially in the right-side hepatectomy. There was no difference in the prognosis depending on the range of resection, if HCC could be resected of subsegment or less. Therefore, depending on age and comorbidity, it is necessary to determine the type of hepatectomy without sticking to the subsegmentectomy.
Differences in presentation and management patterns in patients with hepatocellular carcinoma (HCC): Data from HCC registry in Asia.
Authors: Chow Pierce K. H. , Li Lequn , Li Jiangtao , Jia Fan , Wang Hee-Jee , Hasegawa Kiyoshi , Yang Jin-Mo , Tan Poh-Seng , Qin Shukui , Han Kwang-Hyub , Goh Brian , Han Ho Seong , Furuse Junji , Zhu Xu , Ling Joanna Zhi Jie , Gandhi Mihir
Published: January 2019

229

Background: HCC is the 6th most common cancer worldwide with > 70% of cases in Asia. There is limited real-world data on the diagnosis, treatment modalities, outcomes and treatment costs in HCC. Methods: The HCC Registry in Asia (AHCC08) is a multi-country longitudinal cohort study of HCC patients diagnosed between 2013 and 2019. Target sample size is 2500 from 9 geographies: China, Singapore, South Korea, Japan, Taiwan, Australia, New Zealand, Hong Kong, and Thailand. We present initial data on diagnosis, etiology, stage at presentation, and treatment modalities of HCC from China [CN] (5 centers), Singapore [SG] (3 centers), South Korea [SK] (4 centers), and Japan [JP] (2 centers). Results: 657 patients (436 CN; 102 SG; 85 SK; 34 JP) were evaluated in August 2018. Patients from China were diagnosed at a younger age, while patients from Japan were diagnosed at an older age (mean age 51 years CN; 67 years SG; 58 years SK; 68 years JP). The highest proportion of regular alcohol drinkers were from Japan (16% CN; 21% SG; 24% SK; 50% JP) and occasional drinkers from China (20% CN; 17% SG; 12% SK; 15% JP). 77% had Hepatitis B across the 5 geographies, with the highest incidence in China (93%), followed by South Korea (68%). 27% were diagnosed using AASLD/APASL imaging criteria, with the highest utilization in Singapore (66% AASLD; 80% APASL) and South Korea (64% AASLD; 20% APASL). Later-stage patients (according to Barcelona Clinic Liver Cancer staging guidelines) were more predominant in Japan (Stage C: 28% CN, 16% SG, 8% SK, 41% JP; Stage D: 0.5% CN, 0% SG, 1% SK, 3% JP). Relatively few radiofrequency ablations were carried out as the first-line therapy across the 5 geographies (2% CN; 5% SG; 2% SK; 0% JP). In China, liver resection was preferred in first-line HCC treatment (65% CN vs 28% SG, SK, and JP aggregated), followed by loco-regional (27% CN vs 7% SG, SK, and JP aggregated) and systemic therapy (2% CN vs 10% SG, SK, and JP aggregated). Conclusions: There is considerable variation in presentation and management patterns between the 5 geographies. These data will benefit policymakers, companies and clinicians in improving policies and developing treatment strategies for HCC. (ClinicalTrials.gov: NCT03233360).
Utilizing cultural and ethnic variables in a survey to identify individuals at high risk for gastric cancer.
Authors: Solsky Ian , Parides Michael , Schechter Clyde , Rapkin Bruce D. , In Haejin
Published: January 2019

23

Background: Absence of national US gastric cancer (GC) screening necessitates alternative methods like surveys to identify high-risk populations. Identification of high-risk persons may be enhanced by adding ethnic and cultural variables to more conventionally known risk factors for GC. Methods: Data from a prior case-control study of 40 GC cases and 100 controls were used. A "conventional" risk factor model (age, gender, family history of GC, body mass index, excessive salt intake, alcohol, smoking, blood type, H pylori) was compared to one incorporating ethnic and cultural variables (race, immigration, generation, cultural food at ages 15-18 years, acculturation and education) using model fit, sensitivity, specificity and expected positive predictive values (PPV). Stepwise regression was then used to create a model from this pool of variables. PPV was calculated using Bayes' Theorem applied to the baseline GC incidence in the US (7.2 per 100,000). Results: The "conventional" model required 14 questions and resulted in 25% sensitivity, 94% specificity, 28 per 100,000 PPV at the 70% probability cut-off, and AUC=0.871. The model incorporating ethnic and cultural variables required 38 questions and resulted in 48% sensitivity, 91% specificity, 38 per 100,000 PPV, and AUC =0.965. After eliminating items less predictive at p=0.2, age, gender, family history of GC, excessive salt intake, immigration, generation and race remained in the model. This model required 7 questions and resulted in 45% sensitivity, 96% specificity, 81 per 100,000 PPV and AUC=0.914. Conclusions: The model with the greatest ability to identify persons at risk of GC included ethnic and cultural variables. This model can be translated into a survey with few items that can serve as a highly scalable tool to identify high-risk individuals. Support: UG1CA189823 [Table: see text]
Immunotherapy response evaluation with MR elastography (MRE) in advanced HCC.
Authors: Qayyum Aliya , Avritscher Rony , Morani Ajaykumar , Sun Jia , Bhosale Priya , Hwang Ken-Pin , Stafford Jason , Abugabal Yehia I. , Ma Jingfei , Kaseb Ahmed Omar
Published: January 2019

230

Background: To determine changes in MRE HCC stiffness as predictor of immunotherapy response in patients with advanced HCC. Methods: This was a prospective, Institutional Review Board approved study of 15 patients with biopsy proven advanced HCC (not amenable to curative therapy), who were to be treated with Pembrolizumab. Eligible patients were > 18 years old with radiographic disease progression/intolerance to sorafenib. All patients had liver MRI with MR Elastography (MRE) and liver biopsy at baseline and at 9 weeks of therapy. HCC stiffness (kilopascals, kPa) was measured on liver MRE elastograms (stiffness maps). Change in HCC stiffness on MRE was compared with overall survival, time to disease progression, and total number of lymphocytes on targeted liver biopsy. Data cutoff date was September 1st 2018. Analysis was performed using descriptive statistics including Spearman correlation ( R), Cox regression, Wilcoxon rank sum test and Fisher’s exact test. Results: Of the initial 15 patients, 4 withdrew from therapy, 1 patient did not undergo MRE scan, and 1 patient had MRE failure. The final 9 patients included 6 men. Median age was 70 years (range, 54-78). Etiology of liver disease was HCV (n = 4) and NASH (n = 5). HCC was moderately differentiated in 8 of 9 patients and well-differentiated in 1 patient. Median overall survival and time to progression were 52 weeks (range, 16-112) and 18 weeks (range, 9-48), respectively. Average non-tumorous liver stiffness was 3.2 kPa (range, 2.1-4.3). No significant change in non-tumor liver stiffness was seen at 9 weeks (p = 0.12). Median baseline tumor stiffness was 4.5 kPa (range, 2.4-7.5). Increase in HCC stiffness at 9 weeks was seen in 5 patients, decrease in 3 patients and no change in 1. Change in HCC stiffness at 9 weeks correlated significantly with overall survival ( R = 0.83), and time to progression ( R = 0.96), (p < 0.05). Nine patients had liver biopsy at baseline and 7 had biopsy at 9 weeks. HCC T lymphocytes on biopsy (n/mm2) significantly correlated with HCC stiffness ( R = 0.79), (p < 0.01). Conclusions: Our pilot data suggests early change in tumor stiffness may help predict better immunotherapy response in patients with advanced HCC.
Epidemiology and characteristics of patients (pts) with hepatocellular carcinoma (HCC) and care in the United States.
Authors: Doleh Yunes , Wang Huifen , Sun Ping , Yu Binbing , Herr Iksha
Published: January 2019

231

Background: The incidence of liver and intrahepatic bile duct cancer, with HCC accounting for 72.7%, has doubled from 1992 to 2014 in the U.S. This study examined the latest epidemiology of HCC by analyzing 2 large U.S. databases. Methods: IBM MarketScan (IBM-MS) and Surveillance, Epidemiology, and End Results-National Program of Cancer Registries (SEER-NPCR) databases were analyzed separately. Pts (aged ≥ 18 years) with HCC as the primary cancer were identified from the IBM-MS database, who were covered by employer-provided commercial or Medicare Supplemental insurance. A new HCC diagnosis (Dx) was defined as the first HCC Dx using ICD-9/10 codes within the study period (Jan 2012-Sep 2017) and no other HCC Dx in the prior 12 months. Comorbidities, performance status, distribution of pts, and treatments received were described. In SEER-NPCR (Jan 2010-Dec 2014), a nationally representative patient sample was analyzed to describe the incidence and mortality of pts with HCC. Results: A total of 8,150 and 119,927 pts were identified in IBM-MS and SEER-NPCR, respectively. Pts were predominately male in both databases. The HCC incidence rates among the IBM-MS cohort were 5.9, 5.5, 4.9, and 4.7 per 100,000 person-years from 2013 to 2016, respectively. The downward trend in the HCC incidence rate post-2013 for this population coincided with the drop in HCC incidence rate from 2013 to 2014 in SEER-NPCR. Amongst the IBM-MS cohort, 6%, 36%, and 59% of pts had hepatitis B, hepatitis C, and cirrhosis at Dx, respectively. Most pts (88%) were considered having good performance status at Dx. Embolization and chemo/targeted therapies were the most common treatments received by pts irrespective of the disease stage (31% and 12%, respectively) and pts with de novo metastatic HCC (19% and 18%, respectively). About 44% of the HCC Dx occurred at hospital outpatient settings; 31% at inpatient settings and 23% at physician offices. Conclusions: This study identifies the recent epidemiologic changes in pts with HCC and characterizes their comorbidities in a commercially-insured and a U.S. representative population. These epidemiologic data may be important considerations for U.S. payers making coverage policies for pts with HCC.
Circulating tumor DNA may correlate with tumor size changes following therapy.
Authors: Chang John , Egert Daniel , Padniewski Jessica , Johnson Benjamin , Bay Curt , Dragovich Tomislav , Kundranda Madappa N. , Koo Phillip
Published: January 2019

233

Background: Pancreatic cancer has significant mortality at five years, even in resectable disease. Recent effort has been dedicated to identify a more specific tumor marker for screening and assessing tumor response, in part because 10% of the population does not produce CA19-9. Detection and quantification of circulating tumor DNA (ctDNA) in the bloodstream is a novel concept for screening and treatment response assessment. This study examined possible correlations between ctDNA levels and various aspects of pancreatic cancer in a total of 17 patients receiving treatment at Banner MD Anderson Cancer Center. Methods: Present study is approved by our local IRB. Research was conducted according HIPPA regulation. Subjects on the present study were obtained from the list of patients participating in our ctDNA trial. A total of 17 subjects were identified from the list. Their ctDNA index levels were obtained from the sponsor (Chronyx) at baseline and following each cycle of the treatment. For each CT scan and each ctDNA study, they are considered the same time if they are obtained within 4 weeks of each other. The sizes of the primary tumor and the largest metastatic lesion were on a transverse image at the largest extent of the lesion. Data was analyzed with Spearman's correlation. Results: Baseline ctDNA levels did not correlate with patient demographic data (N = 17; gender, p = 0.63; age, p = 0.82), baseline size of primary mass on CT scan (N = 16; p = 0.85), baseline vessel involvement on CT Scan (N = 17; p = 0.58), presence of metastasis on CT scan (N = 17; p = 0.78), size of largest metastasis on CT scan (N = 17; p = 0.85), presence of peripancreatic lymph nodes on CT scan (N = 17; p = 0.45), or overall survival (N = 8; p = 0.6). However, there is a trend toward correlating the change in ctDNA and change in size on CT scan following treatment (N = 7; p = 0.12). Conclusions: ctDNA at baseline appears to be secreted independent of the primary tumor size, location, or presence of metastasis. However, changes in ctDNA does seem to correlate with changes in tumor size following treatment. Although our data was not statistically significant, this may be related to the low sample size. With larger sample size, it is expected that changes in ctDNA may prove to correlate with changes in tumor size.
The spectrum of activating EGFR mutations from cell-free DNA (cfDNA) in large pancreatic cancer cohort.
Authors: Price Kristin Sedgwick , Kiedrowski Lesli Ann , De Zarraga Fernando I. , Cusnir Mike , Lanman Richard B. , Nagy Rebecca J
Published: January 2019

237

Background: Metastatic pancreatic cancer (mPC) is one of the deadliest cancers with a < 10% 5-year survival rate. Poor prognosis is well established with lack of response to or rapid progression on existing chemotherapy options. Targeted therapies, like EGFR-TKIs, have been shown to increase survival in other solid tumors like NSCLC with certain oncogenic drivers. Although treatment with the EGFR-TKI erlotinib, in combination with gemcitabine, is available for patients (pts) with mPC, the survival benefit is small in unselected patients. A better understanding of the spectrum of EGFR mutations in mPC may lead to improved therapy selection. Methods: We retrospectively reviewed genomic results from 2,938 consecutive mPC pt samples sent for ctDNA NGS analysis between 7/2014 - 9/2018 (Guardant Health, Inc.). All reported EGFR mutations were reviewed and activating mutations were determined based on literature review. Results: 19 EGFR activating mutations were identified in 16 unique pts (0.66% of total mPC pts with alterations detected). 3 mutations were identified in the extracellular domain and 16 mutations in the tyrosine kinase domain (3 in exon 18, 3 in exon 19, 6 in exon 20, 4 in exon 21). Alterations in exon 20 included 5 T790M mutations; two of these were reported at allelic frequencies suggestive of germline origin. Analysis of co-mutations revealed 7 pts with EGFR mutations that appeared subclonal relative to other potential drivers (4 KRAS, 2 ERBB2, 1 GNAS). The median number of alterations per sample was 4 (range 2-170) with the latter pt exhibiting a hypermutator phenotype. Multiple pts had more than one activating EGFR alteration including one who was found to have 4 EGFR sequence alterations (S768I, L861Q, T790M, p.Val769_Asp770insMet) plus EGFR amplification (plasma copy number 66.8). We will collect and report clinical details to characterize the treatment context for these pts. Conclusions: Activating EGFR mutations in mPC are rare but may present an opportunity for targeted therapy in this population. Further exploration is warranted to better understand the oncogenic activity of less common, subclonal, or co-occurring EGFR mutations and their sensitivity to EGFR-TKIs in mPC.
Impact of Ga-68 DOTATATE imaging on clinical management of neuroendocrine tumor patients: Post-FDA-approval analysis of first 200 clinical patients.
Authors: Chauhan Aman , Khouli Riham , Evers Mark , Oates Elizabeth , Anthony Lowell Brian
Published: January 2019

238

Background: Gallium 68 dotatate (Ga-68 DOTA) provides physiologic imaging and assists in the localization of disease in somatostatin (SSA) receptor positive neuroendocrine tumor (NET) patients. Questions regarding the value of Ga-68 DOTA imaging in the FDA post-approval era for NET patients include: usefulness in disease monitoring, correlation of Ga-68 DOTA avidity to Ki-67 index and its impact on clinical decision making. We present our experience with 200 Ga-DOTATATE scans performed at University of Kentucky. Methods: A retrospective review of the first 200 patients who had undergone Ga-68 DOTA imaging at the Markey Cancer Center from Dec 2016 to Dec 2017 was conducted. Results: 59.5% were females and the median age was 62 (30-84 years). Primary tumor sites included: small bowel 37.5%, pancreas 18.5%, bronchial 14%, colon 3.5%, rectum 2%, appendix 1.5%, adrenal 0.5%, prostate 0.5%, others 3% and unknown primary 19%. Ga-68 DOTA scan influenced clinical decisions in 39% (n = 78) patients. Ga-68 DOTA imaging identified primary tumors in 17 of 38 patients who were classified as NET of unknown primary based on CT imaging. Subgroup analysis of mean standardized uptake value (SUV) for hepatic metastatic lesions revealed 37.3 for G1 (n = 20) as compared to 32.3 for G2 (n = 37) and 17.46 for G3 (n = 4). Mean hepatic SUV of the lesion with the greatest radiolabel uptake in 96 patients was similar irrespective of exposure to SSA LAR; 31.3 versus 27.8 for SSA versus the no SSA cohorts. Conclusions: Ga-68 DOTA imaging impacted clinical decision making in 39% of NET patients (n = 200) and identified the primary site in 17 of 38 patients with unknown primary. Systemic exposure to long acting SSA does not seem to impact quality of Ga-68 DOTA scan.
High-income is a stronger predictor than race in understanding disparate survival outcomes in PDAC.
Authors: Alvarez Marcus A , Deneve Jeremiah Lee , Behrman Stephen W , Dickson Paxton Vandiver , Shibata David , Glazer Evan Scott
Published: January 2019

241

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) from low income and minority racial groups have a lower reported long-term survival rates. It is unknown whether this is related to access to care, variations in genetic polymorphisms, or income status. We hypothesized that income status predicts survival better than race in PDAC. Methods: The pancreatic cancer data set of the National Cancer Database (NCDB) was studied for years 2011-15. Income groups were divided into top quartile (high income) or bottom three quartiles (non-high income) while racial groups were classified as Caucasian or non-Caucasian. Kaplan-Meier survival analysis and Cox proportional hazard models (CoxHR) were utilized. Analysis was controlled for established risk factors such as stage, grade, lymphovascular invasion, resection, and margin status. Results: Of the 164,631 patients meeting criteria, the average age was 68 ± 12 years, 51% were male, and 84% were Caucasian (the remaining patients were predominantly African American, 11%). Of patients with stage I or II PDAC who underwent resection, Caucasian patients had worse survival (CoxHR = 1.21, P<0.001) while high-income patients had better survival (CoxHR= 0.86, P<0.001). To investigate only differences due to income or race, a survival model of highly selected, low risk patients (stage I or II lymph node negative well-differentiated tumors without lymphovascular invasion and in patients who underwent margin negative resection who received chemotherapy) found that high-income predicted survival similar to race (CoxHR =0.89, P<0.001 vs. CoxHR = 1.12, P=0.005, respectively). On multivariable analysis, high-income was more impactful on survival (CoxHR = 0.83, P<0.001) than Caucasian race (CoxHR = 1.16, P <0.001). High-income, non-Caucasian patients had a median survival of 64 months while all other groups had a median survival of 40 months (P=0.005). Conclusions: Caucasian PDAC patients have worse survival compared to non-Caucasian patients after selecting for patients with favorable tumor biology who received adequate therapy. The data suggests that high-income is slightly more important than race in understanding disparate outcomes in PDAC.
Aspirin and statin use and the risk of gallbladder cancer.
Authors: Prasai Kritika , Mady Mohamed , Yadav Siddhartha , Hassan Mohamed Abdelrahim Muddathir , Roberts Lewis R. , Mahipal Amit
Published: January 2019

243

Background: The risk factors for gallbladder cancer (GBC) are poorly understood and preventive therapeutic options have not been identified. The use of aspirin (ASA) and/or statin has been associated with reduced risk of several gastrointestinal cancers. In this study, we explore if the use of ASA or statin is associated with a reduced risk of GBC. Methods: We identified patients with GBC diagnosed between the years 2000 and 2016 at Mayo Clinic. We identified matched controls in 2:1 fashion for age, gender and country of residence from patients who underwent cholecystectomy at Mayo Clinic. We collected information on co-morbidities and use of statins or ASA by retrospective chart review. We compared baseline characteristics between cases and controls using Fisher’s exact test for categorical variables and Mann-Whitney U test for continuous variables. We used binomial logistic regression to calculate the odds ratio (OR) and 95% confidence intervals (CI) to estimate the association of ASA or statin use with GBC. The logistic regression model included history of cholelithiasis, diabetes, hypercholesterolemia (HCL), hypertension (HTN), hyperthyroidism, hypothyroidism, primary sclerosing cholangitis (PSC), inflammatory bowel disease (IBD), cirrhosis and statin or ASA use as covariates. Results: 633 cases and 1,266 controls were included in our final analysis. The median age at diagnosis of cases and controls was 67 years. The control group had a significantly (p < 0.05) higher proportion of patients with cholelithiasis, HCL, HTN, hypothyroidism and liver cirrhosis compared to the cases. The case group,contrarily, had a significantly higher proportion of patients with PSC and IBD. In univariate analysis, ASA (OR: 0.41; 95% CI: 0.33-0.52) or statin (OR: 0.48; 95% CI: 0.38-0.60) use was associated with a lower risk of GBC (p < 0.001). However, in multivariate analysis, ASA use was associated with a lower risk of GBC (OR: 0.52; 95% CI: 0.41-0.67, p < 0.001) whereas statin use was not (OR: 0.76; 95% CI: 0.56-1.03, p = 0.08). Conclusions: Our study demonstrates that aspirin use is associated with a reduced risk of GBC, whereas statin use is not. Further studies on GBC are needed to confirm these results and to elucidate mechanisms that explain the risk reduction with aspirin.
Epidemiological trends of small bowel tumors and changing incidence in Utah.
Authors: Thota Ramya , Herget Kim , Sause William T. , Curtin Karen , Sweeney Carol , Neklason Deborah Wood
Published: January 2019

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Background: The incidence and prevalence of small bowel tumors in particular adenocarcinomas are thought to be rising but updated epidemiological data is lacking. Therefore, in this study we explored the evolving epidemiology of small bowel tumors. Methods: This is a retrospective population based study using Utah Cancer Registry (UCR) and Surveillance Epidemiology, and End Results program (SEER) conducted between 1973-2015. The age adjusted incidence and prevalence was determined. The incidence and prevalence rates were compared to other SEER residents diagnosed with invasive small bowel tumors using ICD codes C17.0 – C17.9). Results: The small bowel tumors have steadily increased from 1990 to 2015. In the UCR, the highest incidence of and small bowel tumors was reported 1.7 per 100,000 in 2015. The prevalence of small bowel tumors in the state of Utah from 1973 – 2014 was 616 including 41 adenocarcinomas, 327 with carcinoid tumors and 248 with other histology’s. There was 1.67% increase in incidence of small bowel tumors in SEER while in Utah we noted 2.81 % annual increase of incidence from 1990 to 2015. Especially, for small bowel adenocarcinomas, Utah has an annual increase of 2.43% from 1990-2015, and SEER had a smaller increase of 0.71% per year over the same time frame. Conclusions: The incidence of small bowel adenocarcinomas between 1995 and 2015 show a steady increase in both UCR and SEER databases. Despite the rarity of these tumors rising incidence warrants increasing awareness and need for better treatments to improve the survival outcomes of these under-studied tumors.
Dissecting the spatial heterogeneity of single circulating tumor cells reveals immune evasion through MAX regulated CCL5 overexpression in hepatocellular carcinoma.
Authors: Sun Yun-Fan , Yang Xin-Rong , Jia Fan
Published: January 2019

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Background: The transcriptional heterogeneity and immune evasion mechanisms of CTCs during systemic circulation are not well defined. Methods: Blood was drawn from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) of 10 localized HCC patients. Single CTCs were isolated by negative enrichment and robotic micromanipulator, followed by single-cell RNA-sequencing (sc-RNAseq). After filtering, 113 CTCs with qualified data remained were subjected to further bioinformatics analysis. The scRNA-seq results were further validated in three independent cohorts of HCC patients. Results: Our scRNA-seq data revealed remarkable intra- and inter-vascular heterogeneity among CTCs from four vascular sites. We determined CTC transcriptional dynamics during transportation through consecutive vascular compartments and revealed their adaptation mechanisms under biomechanical stress during circulation. We further classified CTCs from different vascular sites into two subsets, namely dormant CTCs and activated CTCs. Dormant CTCs were associated with a non-cycling state and upregulation of EMT/angiogenic signatures and showed stronger prognostic ability for early recurrence than activated CTCs did. Furthermore, we discovered an immune escape mechanism by which CTCs recruited regulatory T cells (Tregs) via expression of CCL5, consequently promoting the formation of an immunosuppressive microenvironment favorable for their survival in the bloodstream and seeding in secondary organs. We proved that MAX, activated through the p38 pathway, was the key transcriptional factor regulating CCL5 overexpression, which was validated by ChIP, luciferase reporter gene and in vitro/vivo knockdown assays. And we further determined that Tregs-derived TGF-β1 can heighten MAX expression, thus amplifying the CCL5 expression. Conclusions: Collectively, our results reveal a previously unappreciated spatial heterogeneity of CTCs and a CTC immune-escape mechanism, which may aid in designing new anti-metastasis therapeutic strategies in HCC.
Soluble urokinase plasminogen activator receptor (suPAR) as a novel biomarker in patients undergoing resection of pancreatic adenocarcinoma.
Authors: Loosen Sven H , Binnebösel Marcel , Longerich Thomas , Roderburg Christoph , Trautwein Christian , Neumann Ulf Peter , Luedde Tom
Published: January 2019

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Background: Surgical resection represents the only potentially curative therapy for patients with pancreatic adenocarcinoma (PDAC), an aggressive malignancy with a very limited 5-year survival rate. However, even after successful R0 tumor resection, some patients are still facing an unfavourable prognosis underlining the need for better preoperative stratification algorithms. The soluble urokinase plasminogen activator receptor (suPAR) was recently described as a promising new biomarker for different clinical conditions including cancer. Here, we evaluated the potential role of circulating suPAR as a biomarker in patients undergoing resection of PDAC. Methods: Expression levels of uPAR, the membrane-bound source of circulating suPAR, were analysed in PDAC tissue samples using IHC. Serum levels of suPAR were measured by ELISA in an exploratory as well as a validation cohort comprising a total of 127 PDAC patients and 75 healthy controls. Results were correlated with clinical data. Results: Correlating with a high immunohistochemical expression of uPAR in PDAC tissue samples, serum levels of suPAR were significantly elevated in PDAC patients compared to healthy controls. Importantly, patients with high preoperative suPAR levels above a calculated cut-off value of 5.956 ng/ml showed a significantly reduced overall survival after tumor resection. The prognostic role of suPAR was further corroborated by uni- and multivariate Cox-regression analyses including parameters of systemic inflammation, liver and kidney function as well as clinico-pathological patients’ characteristics. Moreover, high baseline suPAR levels identified those patients particularly susceptible to acute kidney injury after surgery. Conclusions: Our data suggest that circulating suPAR represents a novel prognostic marker in PDAC patients undergoing tumor resection that might be a useful addition to existing preoperative stratification algorithms for identifying patients that particularly benefit from extended tumor resection.
Association of socioeconomic status with incidence and outcomes of gastric cancer in a Michigan cohort.
Authors: Karapetyan Lilit , Wang Ling , Gardiner Joseph , Laird-Fick Heather
Published: January 2019

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Background: The purpose of this study is to examine the association between socioeconomic factors and gastric cancer (GC) outcome in a cohort of patients in Michigan. Methods: We reviewed data for patients enrolled in the Michigan Cancer Surveillance Program, with diagnosis between 1990 and 2014 and follow up through 2016. Data extracted were age and stage at diagnosis, gender, race, zip code (as a proxy for family income), receipt of treatments, and survival status at last follow up. The poverty level (PL) was defined as average income by zip code < $24,600. Statistical comparisons were assessed by chi-square tests in contingency tables, by the log-rank test for survival, and Poisson regression for incidence rate comparisons. Results: We identified 10,828 GC patients (22.39% below PL, 64.64% between PL and 200% PL, 12.98% above 200% PL) with complete data for analysis. By race/ethnicity, 68.12% non-Hispanic blacks, 21.05% American Indian/Alaska Natives, 8.59% Asian/Pacific Islanders, 23.83% Hispanics, and 12.63% non-Hispanic whites lived in areas with average income below PL. The socioeconomic status by race among GC patients was significantly different (p < 0.0001). There was significant association of socioeconomic status and receipt of treatments. Patients living in areas below PL tended to have less information available about treatment received: unknown compared to no radiation (OR = 1.45, 95% CI 1.30-1.63), unknown compared to no chemotherapy (OR = 1.39, 95% CI 1.23-1.57), unknown compared to no surgery (OR = 1.49, 95% CI = 1.32-1.69). There was no significant relationship between stage at diagnosis and socioeconomic status (p = 0.153). The Poisson regression results showed that as average income increased in $10,000 increments in the area, incidence of gastric cancer is expected to decrease by 0.0642 (p < 0.0001). As income in the area increases by $10,000, risk of death is expected to decrease (HR 0.977, p = 0.0025). Conclusions: In Michigan, socioeconomic factors are associated with race, incidence of GC, receipt of treatments, and survival, but not stage at diagnosis.
Using novel real-time tracking to monitor postoperative recovery in a comprehensive cancer center.
Authors: Dong Sharlene , Barkley Rachel , Clark Clancy
Published: January 2019

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Background: Early mobilization is thought to be a key component of postoperative care following surgery. However, the benefit of early ambulation is not well studied. Normal and abnormal ambulatory patterns for postoperative cancer patients remains unknown. The aim of the current study is to characterize the postoperative movement patterns of the patients recovering from surgery at Comprehensive Cancer Center using an objective novel real-time location system (RTLS). Methods: In this retrospective cohort study, patient ambulatory movements were captured using RTLS. Clinical data was extracted from the medical record. A custom algorithm was created to measure postoperative ambulation and an ambulatory mobility event was defined as movement in and out of the patient’s room on the postoperative ward lasting from three to 60 minutes. Mobility data was analyzed to determine predictors of postoperative ambulation. Results: 358 postoperative patients (39.7% female, median age 62) were identified for inclusion in this study. 272 (76.0%) patients had a postoperative mobility event. Median number of walks 1.2 (IQR 0.7-2.2) per day was 6.7 (IQR) with median duration of 6.7 (IQR4.6-10.8) minutes. Time to first ambulatory event after surgery was 1.2 (IQR 0.9-2.0) days. Time to first ambulatory events varied by surgical service with Thoracic Surgery having the most patients ambulating on postoperative day zero (43.3%). In univariate analysis, young age, shorter operation length, and surgical service were predictors of early first ambulatory event (all p < 0.05). In multiple variable analysis, young age and surgical service were predictors of early first ambulatory event (all p < 0.05). Conclusions: The current study demonstrates the feasible application of RTLS to passively monitor the recovery of postoperative cancer patients In addition, this technology provides a novel opportunity to correlating patient movement with clinical outcomes, such as morbidity, mortality, and length of stay.
Clinical significance of monitoring KRAS in tissue and plasma of pancreatic cancer patients.
Authors: Watanabe Fumiaki , Suzuki Koichi , Endo Yuhei , Ishikawa Hideki , Kakizawa Nao , Noda Hiroshi , Rikiyama Toshiki
Published: January 2019

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Background: KRAS mutation is observed in 90% of pancreatic cancer patients. Therefore, investigating tumor DNA in plasma by KRAS monitoring may be even more valuable in pancreatic cancer patients. Methods: We collected the tissue and plasma of 78 pancreatic cancer patients (surgery group; 39, non-surgery group; 39). KRAS mutation in the tissue and mutated circulating tumor DNA (MctDNA) in plasma was detected by digital polymerase chain reaction in 78 patients. Identical KRAS mutation detected in tissue (ex. 12D, 12V) was monitored in plasma. Results: KRAS mutation in the tissue was detected in 65 of 73 patients. KRAS assessment in the tissue was not performed in 5 patients, because of tissues small amounts of tissue materials by biopsy. These 65 patients with KRAS mutation in tissue showed poorer prognosis (3 years OS; 23.4%) than 8 patients without mutation (3 years; 66.7%). MctDNA in plasma of surgery group was seen in 14 of 39 patients. Thirteen in 14 patients with MctDNA showed recurrence and 12 patients were dead. These 14 patients with MctDNA in plasma showed significantly poorer prognosis (2 years OS; 16.3%) than 25 patients without mutation (3 years; 71.6%) (p = 0.00). Univariate analysis revealed that poor differentiation and the detection of MctDNA were independent factors to predict poor survival in surgery group. The detection of MctDNA was confirmed to be an independent factor in multivariate analysis (Hazard ratio; 31.25). MctDNA in plasma of non-surgery group was seen in 28 of 39 patients. But, MctDNA in 6 patients was disappeared in clinical course. These 6 patients and 11 patients without MctDNA displayed better prognosis (2 years OS; 72.1%) than 22 patients with MctDNA (2 years OS; 12.1%) with significance (p = 0.0001). Univariate and multivariate analysis revealed that no treatment and the detection of MctDNA were independent factors to predict poor survival in non-surgery group. (Hazard ratio; 8.78, 4.76, respectively). Conclusions: KRAS monitoring in plasma reflects tumor dynamics. The appearance of MctDNA during KRAS monitoring provides important information for the treatment of pancreatic cancer patients.