bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology, prevalence and national trends of combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) in hospitalized US patients between 2002-2014.
Authors: Elkafrawy Ahmed , Othman Hasan F. , Asif Samia , Al-Sayyed Leen , Shrestha Anuj
Published: May 2019

e15616

Background: cHCC-CCA represents a rare type of primary liver cancer that was first identified in 1949. The aim of this study is to evaluate epidemiology, clinical outcomes and national trends of cHCC-CCA in hospitalized US patients using the Nationwide Inpatient Sample database (NIS). Methods: NIS database was inquired to identify patients with HCC between 2002 and 2014 using ICD9-CM codes. Patients with HCC were classified into two groups, one group with cholangiocarcinoma (CCA) and the other group without CCA. SPSS version 25 was used for statistical analysis. Results: We identified 525,699 patients with HCC between 2002-2014. Of them, 2,158 patients (0.4%) had CCA. In the cHCC-CCA group, 87.8% of the patients were above 50 years old, 58.1% were male, 63.7% were Caucasian, and 10% were African American. Mortality in patients hospitalized with cHCC-CCA was 8.5% compared to 11.1% in patients with HCC (OR 0.74, 95% CI 0.64-0.86, P < 0.0001). Mortality in cHCC-CCA patients decreased from 19.1% in 2002 to 7.9% in 2014. The median length of stay (LOS) in patients with cHCC-CCA was 6 days compared to 4 days in patients with HCC (P < 0.0001). Median LOS for patients with cHCC-CCA was unchanged between 2002 and 2014. The median hospitalization cost of charge in cHCC-CCA patients was 41,012 USD compared to 28,371 USD in HCC patients. In the cHCC-CCA group, it increased from 17,243 USD in 2002 to 37,234 USD in 2014. Only 0.9% of patients with cHCC-CCA underwent liver transplantation compared to 3.5% of HCC patients (OR 0.26, 95% CI (0.17-0.41), P < 0.0001). Conclusions: Prevalence of cHCC-CCA was 0.4% of patients with HCC during the study period. cHCC-CCA was unexpectedly associated with less mortality; possibly because of limitations in comparison due to the smaller number of patients compared to HCC alone. cHCC-CCA was also associated with lower rates of liver transplantation but more prolonged LOS and higher hospitalization cost of charge compared to HCC patients. In the same period, mortality decreased in cHCC-CCA patients and cost of charge increased while prevalence and LOS were unchanged. Further studies are needed to evaluate and understand cHCC-CCA as a separate entity.
Outcomes of treatment of carcinoma gall bladder undergoing curative intent surgery.
Authors: Chaturvedi Arun , Kumar Vijay , Gupta Sameer , Akhtar Naseem , Saini Shiv Rajan , Prakash Puneet
Published: May 2019

e15621

Background: Gall bladder carcinoma (GBC) is the most common malignancy of the biliary tract. North India reports one of the highest incidences of GBC in the world. Majority of patients present with advanced disease where surgery is not possible. We report the results of patients undergoing curative intent surgery at a tertiary care University hospital in North India. Methods: Data of 270 patients undergoing curative intent surgery for GBC at the Department of Surgical Oncology, King George’s Medical University, Lucknow (India) between January 2014 and December 2018 was retrospectively studied. We have analysed the collected data using descriptive and survival statistics. Results: During the period of study 270 patients were operated for GBC. Mean age of patients was 50.2 years and majority (75.2%) were females. On surgical exploration 82 (30.4%) had unresectable disease and only a biopsy or palliative procedure was done. Simple cholecystectomy was done where frozen section showed benign calculus cholecystitis in 26 (9.6%) patients. Radical cholecystectomy was performed in 162 (60%) patients. Final histopathology revealed Xanthogranulomatous cholecystitis in 28 (17.3%) of these 162 patients. Adjacent organ resection was done in 29 of the 134 (24.1%) patients undergoing radical cholecystectomy for pathologically proven GBC. Colon and CBD were the most common adjacent organs resected. Completion radical cholecystectomy was done in 22 patients with incidental GBC. Adjuvant chemotherapy as per our institutional protocol was given to 68 (50.7%) patients having Stage 3 or more disease. After a mean follow-up of 19 months the median disease free interval (DFI) is 38 months and the median overall survival (OS) has not been reached. Patients undergoing adjacent organ resection had an inferior median OS of 20 months compared to those without it where the median has not been reached (Log Rank P = 0.006). Conclusions: Nearly a third of GBC patients planned for curative intent surgery are found to have unresectable disease on exploration. This proportion needs to be brought down. Radical cholecystectomy in properly selected GBC patients without adjacent organ involvement gives satisfactory survival outcomes.
Health-related quality-of-life in patients with cholangiocarcinoma: Results of a systematic literature review.
Authors: Cho Yohan , Chadwick Claire , Barrett Scott , Bibeau Kristen , El-Hadi Wissam , Hopkinson Devan
Published: May 2019

e15623

Background: Cholangiocarcinoma (CCA) is a rare biliary tract cancer (BTC) with a historically poor prognosis and limited treatment options. Both quality and quantity of life can be important factors when deciding treatment, thus assessment of health-related quality-of-life (HRQoL) is needed to justify the use of novel therapies. HRQoL questionnaires are a standardized way to understand the patients’ perspective and treatment experience. The objective of this review was to examine the published literature specific to HRQoL in CCA. Methods: A systematic literature search was conducted using EMBASE and MEDLINE from Jan 2008 to June 2018 to identify abstracts with published HRQoL data in CCA patients. This review also included global conference proceedings (2015-2018) and HTA websites. Articles were considered relevant if they reported HRQoL data in patients with CCA, bile duct carcinoma, and/or hepatobiliary system cancer. Results: Of the 2,933 studies initially identified, 7 ongoing or completed studies met the scoping criteria to be included in the review. No articles in this literature review reported data from clinical trials. Multiple HRQoL measures were utilized; however within the studies, EORTC QLQ-BIL21 was the only HRQoL measure developed and validated specifically for BTC (CCA, gallbladder, or ampulla vater) identified in this review. 3/7 studies included information on CCA subtypes (intrahepatic, extrahepatic) with 2/3 studies reporting HRQoL by subtype. Patient symptoms were reported in 4/7 studies, including gastrointestinal distress, abdominal pain, fatigue, fever, itching, difficulty sleeping, anxiety, jaundice and weight loss. Conclusions: Within this literature review, few studies have been published with HRQoL data in CCA patients. Data from the existing published literature is generally from a heterogeneous patient population, and not consistently specified for CCA stage or subtype. To better understand HRQoL in CCA patients, more data needs to be generated that include clinical trials for novel therapies.
Molecular pathway activation-based analysis for personalized prescription of tyrosine kinase inhibitors for advanced solid tumor patients.
Authors: Poddubskaya Elena , Baranova Madina , Allina Daria , Sekacheva Marina , Makovskaia Lyudmila , Albert Eugene , Suntsova Maria , Aleshin Alexey
Published: May 2019

e15636

Background: Tyrosine-kinases (TKs) play key roles in cancer by acting as major components of various signaling pathways. Tyrosine kinase inhibitors (TKIs) act by inhibiting TKs, thereby modulating downstream signaling. Here we report a molecular pathway analysis-based approach to personalize prescription of TKIs for advanced and recurrent solid tumors, exemplified by successful cases of off-label prescriptions of TKIs to unresectable metastatic cholangiocarcinoma (MCC) and to recurrent ovarian granulosa cell tumor (GCT) patients. Methods: To isolate RNA, we used patient’s tumor histologically verified formalin fixed, paraffin embedded (FFPE) tissue blocks containing > 75% tumor cells. Gene expression levels were established using CustomArray platform. Tumor expression was compared with the corresponding normal tissues and a second-opinion platform Oncobox (Omicsway, USA) was applied for finding abnormally activated molecular pathways and for the corresponding ranking of target drugs. Results: For a 26-year-old woman with progressive ovarian GCT despite multiple previous lines of therapy who underwent salvage therapy selection, the following target drugs could be potentially most effective for treatment according to the Oncobox test: Regorafenib, Sorafenib, Sunitinib, Pazopanib, Axitinib, Imatinib. In Oct 2015, patient was administered Sorafenib, but it was not well tolerated, and this therapy was terminated after 2 months. However, ultrasound examination indicated an associated decrease in the size of neoplasms. Therapy regimen was switched to Imatinib, which was well tolerated and resulted in a disease stabilization. As for Feb 2019, Imatinib administration is continued and patient is physically active with Karnofsky scale index 90%. Another patient with MCC was prescribed with subsequent TKI monotherapies for Sorafenib and Pazopanib that occupied, respectively, 2nd and 4th positions of the Oncobox drug rating. It resulted in a two-year stabilization. Conclusions: Our results evidence that sequential personalized prescription of different TKIs based of gene expression tests may be a perspective avenue of further clinical investigations.
Myopenia as a significant prognostic factor in BCLC-B intermediate-stage hepatocellular carcinoma treated with sorafenib.
Authors: Okada Mao , Nakanishi Hiroyuki , Kurosaki Masayuki , Kirino Sakura , Osawa Leona , Watakabe Keiya , Wang Wan , Shimizu Takao , Takaura Kenta , Takada Hitomi , Kaneko Shun , Tamaki Nobuharu , Yasui Yutaka , Tsuchiya Kaoru , Itakura Jun , Takahashi Yuka , Izumi Namiki
Published: May 2019

e15639

Background: Tyrosine kinase inhibitors (TKI) are important treatment options for unresectable hepatocellular carcinoma (HCC). The survival benefit of sorafernib was demonstrated not only in advanced stage but also for BCLC-B intermediate stage who are refractory to transcatheter arterial chemoembolization by OPTIMIS study. Skeletal muscle mass depletion (Myopenia) is a poor prognostic factor in HCC treated by resection or loco-reginal ablation, but its effect on survival in TKI treated patients, especially in those within BCLC-B stage remains unclear. The aim of the present study is to elucidate the impact of myopenia on survival among HCC treated with sorafenib, especially in BCLC-B stage. Methods: In 213 patients who started treatment with sorafenib between 2009 and 2016, myopenia at baseline was determined by using skeletal muscle index calculated from CT images of the third lumber vertebra level. The impact of myopenia on survival was analyzed in whole patients, after stratification by BCLC stage, and after matching for backgrounds within BCLC-B patients. Results: The median survival in whole, BCLC-C, and –B was 13.7, 8.7 and 15.2 months, respectively. Myopenia was not a significant prognostic factor in whole patients and in BCLC-C stage. However, among BCLC-B patients (n = 104), survival was significantly better in patients with no myopenia (p = 0.05). Among them, 85 patients who continued sorafenib for more than 8 weeks were extracted and those with or without myopenia were matched for backgrounds by propensity score. Backgrounds including etiology, Child-Pugh score, BMI, AFP and PIVKA-Ⅱwas not different between myopenia (n = 30) and no myopenia group (n = 30) after matching. The overall survival at 6-, 12-, and 24-months was 96%, 74%, and 62% in no myopenia group which was significantly better compared to 89%, 64%, and 28% in myopenia group (p = 0.019). The hazard ratio was 2.12 (95% CI 1.11-4.03). Conclusions: Absence of myopenia predicts favorable outcome in sorafenib treated HCC patients within BCLC-B intermediate stage.
High spatiotemporal heterogeneity, clonal selection and neoantigen evolution in acquired sorafenib-resistant patient-derived xenograft models of hepatocellular carcinoma.
Authors: Yang Xin-Rong , Hu Bo , Zhou Jian , Fan Jia
Published: May 2019

e15641

Background: Patient-derived xenograft (PDX) models have been regarded as valuable preclinical models for oncology drug development and exploring underlying mechanism of drug resistance. As the standard treatment option for advanced hepatocellular carcinoma (HCC), the survival benefit of sorafenib is modest. Even among those who initially responded well to sorafenib treatment, most patients ultimately develop progressive disease owing to acquired drug resistance. Understanding how selective pressure from sorafenib directs the evolution of HCC and shapes its clonal architecture is a central biological question with important clinical implications to combat acquired drug resistance. Methods: Three sorafenib-resistant PDX models were generated by continuous sorafenib treament for more than six months. Whole exome sequencing (WES) and RNA sequencing were performed. The subclone of mutation, fusion genes, and the evolving landscape of tumor neoantigens were further explored. Finally, the antitumor efficacy of recombinant mouse PD-1 antibody was evaluated in sorafenib resistance syngeneic tumors model by immune-competent C57BL/6J mice with Hepa 1-6. Results: High spatiotemporal heterogeneity was observed in engraftment among pre- and post- sorafenib resistance in established acquired-resistance PDX models. Clonal selection on engraftment was observed in established acquired-resistance PDX models. There are many high expressed genes, which showed subclone expansion with the emergence of sorafenib resistance. There is vary difference of neoantigens between pre- and post-resistance engraftment as well as sampling points in same tissues. It was presented that a high burden of clonal neoantigens in sorafenib resistant tissues (P < 0.05), while there has no difference in tumor mutation burden. Moreover, the intra-tumor heterogeneity upon the neoantigen landscape was much bigger than that upon tumor mutation burden. We found that fusion subclone sizes were increased significantly after sorafenib resistance (P < 0.05). Finally, the antitumor efficacy of recombinant mouse PD-1 antibody was confirmed in sorafenib resistance syngeneic tumors mice model (P < 0.001). Conclusions: High spatiotemporal heterogeneity, clonal selection and neoantigen evolution was observed in acquired sorafenib-resistant PDX model of HCC. Immunotherapy such as immune checkpoint inhibitors might be a promising strategy for HCC patients with acquired sorafenib resistance. .
Hepatocellular carcinoma with tumor thrombus in portal vein branch: Transarterial chemoembolization combined with Iodine125 brachytherapy versus transarterial chemoembolization combined with sorafenib.
Authors: Huang Jingjun , Huang Wensou , Cai Mingyue , Guo Yongjian , Zhou Jingwen , Zhu Kangshun
Published: May 2019

e15646

Background: Patients with hepatocellular carcinoma (HCC) accompanied with portal vein tumor thrombus (PVTT) have a poor prognosis. Although transarterial chemoembolization (TACE) plus sorafenib (TACE-S) could lead to an improved survival than TACE alone in HCC patients with first- or second-branch PVTT (branch PVTT), the survival was very limited. We compared the safety and efficacy of TACE plus Iodine125 brachytherapy (TACE-I) with TACE-S in patients with unresectable HCC and branch PVTT. Methods: The medical records of consecutive patients with HCC and branch PVTT who underwent TACE-I (TACE-I group) or TACE-S (TACE-S group) from January 2015 to December 2017 were retrospectively evaluated. Iodine125 seeds were implanted into the PVTT under CT guidance 3-5 days after the initial TACE. The matched peripheral dose of Iodine125 brachytherapy was set to be 120-140 Gy. Sorafenib was administered 400 mg twice daily. Outcomes of patients who underwent TACE-I, including adverse events, treatment responses, time to progression (TTP), and overall survival (OS), were compared with those of patients who underwent TACE-S. Results: One hundred and twenty patients were included in the analysis; 62 patients underwent TACE-I and 58 underwent TACE-S. The overall incidence of adverse events was significantly lower in TACE-I group than in TACE-S group (58.1% vs. 93.1%, P < .001), and incidence of grade 3 or higher adverse events also was significantly lower in TACE-I group than in TACE-S group (3.2% vs. 27.6%, P < .001). PVTT OR rates at 12 weeks (58.1% vs. 13.8%, P < .001) and at 24 weeks after the treatment (68.9 % vs. 10.9%, P < .001) in TACE-I group were higher than those in TACE-S group. TACE-I led to significantly longer TTP (median, 11.2 months vs. 6.2 months, P < .001) and OS (median, 20.9 months vs. 14.0 months, P < .001) than TACE-S. In uni- and multivariable analyses, TACE-I treatment, PVTT extent, tumor size ≥10 cm, PVTT OR at 12 weeks, and intrahepatic tumor OR at 12 weeks were independent prognostic factors for OS. Conclusions: TACE-I had less side effects and may improve OS than TACE-S for HCC patients with branch PVTT.
Effect of cholangitis on pre-operative evaluation of regional lymphadenopathy by CT in pancreato-biliary malignancies.
Authors: Chandra Abhijit , Gupta Vivek , Kumar Saket , Joshi Pradeep , Gupta Vishal , Gorla Pavan Kumar , Agarwal Akshay Anand
Published: May 2019

e15651

Background: Regional lymph nodes metastasis is a poor prognostic factor in pancreato-biliary malignancies. CT findings like lymph node size > 10mm, irregular shape, heterogenous enhancement, conglomeration and infiltration can suggest metastatic involvement. Cholangitis can induce reactive changes in regional lymph nodes. This study aimed to find if episodes of cholangitis interfere with the pre-operative CT evaluation of regional lymphadenopathy in pancreato-biliary malignancies. Methods: Regional lymph nodes metastasis is a poor prognostic factor in pancreato-biliary malignancies. CT findings like lymph node size > 10mm, irregular shape, heterogenous enhancement, conglomeration and infiltration can suggest metastatic involvement. Cholangitis can induce reactive changes in regional lymph nodes. This study aimed to find if episodes of cholangitis interfere with the pre-operative CT evaluation of regional lymphadenopathy in pancreato-biliary malignancies. Results: A total of 41 patients of gallbladder cancer and 20 patients of periampullary cancer were included. A total of 206 lymph node stations were sampled. In gallbladder cancer group, CT finding of lymph node size > 10mm, ill-defined borders and conglomeration; while intra-operative findings were node size > 10mm, hard consistency and necrosis on cut-section significantly predicted metastatic lymphadenopathy on univariate analysis. In multivariate analysis, size > 10mm measured intra-operatively was the only significant predictor of metastatic lymphadenopathy.21.9% patients (9/41) had history of cholangitis pre-operatively. In this subgroup, none of the CT characteristic or intra-operative nodal feature significantly predicted malignant involvement. In periampullary cancer, nodal necrosis on intra-operative cut-section was a significant predictor of malignant involvement in univariate, but not in multivariate analysis. Subgroup analysis of patients with history of cholangitis (10/20) did not reveal any significant pre-operative or intra-operative lymph nodal feature predicting malignant involvement. Conclusions: In patients with gallbladder or periampullary cancer with history of cholangitis, the typical CT characteristics or the intra-operative characteristics of regional lymph nodes cannot be relied on to predict metastatic lymph node involvement. Thus, cholangitis affects the clinical staging of these malignancies.
Expression and heterodimerization of Type A and B Cholecystokinin Receptors in Gallbladder cancer.
Authors: Chandra Abhijit , Nigam Jaya , Goel Madhumati , Parmar Devendra , Satyam Leena Khare
Published: May 2019

e15655

Background: Gallbladder cancer is the most common malignancy of the biliary tract and endemic in Northern India. The prognosis of gallbladder cancer remains dismal despite any treatment because of late presentation and aggressive tumor biology. Cholecystokinin (CCK) is present in abundance in gallbladder tissue and mediates function through two structurally related receptors, the type A (CCKAR) and B (CCKBR) receptors. Previously, heterodimerization of CCKAR and CCKBR receptor has been demonstrated in vitro, and was shown to bind natural agonists normally but exhibited agonist stimulated cellular signaling, promoting cell growth. In this study we examined the expression level of CCKAR and CCKBR in resected gallbladder tissue samples and also attempted to determine the dimerization status of CCKAR and CCKBR receptors in gallbladder cancer comparing them to cholelithiasis and normal gallbladder tissue. Methods: Tissue samples from resected normal gallbladder (n = 10), cholelithiasis (n = 25) and gallbladder cancer (n = 25)) were evaluated for the expression of CCKAR and CCKBR by immunohistochemistry. Determination of CCKAR and CCKBR expression was also done by western blot in representative samples from each of these tissue types while their dimerization status was evaluated by immunoprecipitation. Results: By Immunohistochemistry technique, positive CCKAR expression was observed in 80% gallbladder cancer, 84% cholelithiasis, 90% normal gallbladder, P = 0.76. However significantly higher expression of CCKBR was noted in gallbladder cancer (60%) as compared to cholelithiasis (25%) and normal gallbladder (20%), P = 0.013. We also observed progressively increasing level of expression of CCKAR and CCKBR in gallbladder cancer as compared to cholelithiasis and normal gallbladder by western blot. In addition, we also observed a higher level of heterodimer formation in gallbladder cancer compared to cholelithiasis and normal gallbladder using immunoprecipitation technique. Conclusions: Our results provide the first evidence of increasing trend of heterodimerization of CCKAR and CCKBR in gallbladder cancer which has potential clinical and therapeutic significance.
Characterization of tumor mutation burden, PD-L1 and hepatitis B virus in Chinese hepatocellular carcinoma patients.
Authors: Xu Junjie , Liang Xiao , Liu Lingxiang , Mou Haibo , Wan Zhe , Jiang Shi , Yang Zhe , Zeng Daobing , Chen Xiaoqian , Shi Junping , Yao Ming , Chen Zhonghai , Wang Kai
Published: May 2019

e15666

Background: Hepatocellular carcinoma (HCC) has a high mortality rate and is the fourth most common cancer in China. Immunotherapy of immune checkpoint inhibitors (ICI) is a promising novel treatment strategy, but the response rate is generally low and it is not clear which patients will benefit from ICI immunotherapy. Methods: Deep sequencing targeting 450 cancer genes was done on FFPE and matched blood samples from 601 Chinese HCC patients (pts). Genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations (CNV), gene rearrangements and fusions were analyzed. Tumor mutation burden (TMB) was measured by an algorithm developed in-house, PD-L1 expression was done by immunohistochemistry staining and Hepatitis B Virus (HBV) by target capture. Results: Patients, median age 55 years old, had TMB values in a range of 0.7 to 69.6 Muts/Mb. The 1st Quartile, median and 3rd Quartile TMB values were 3.8, 5.4 and 7.8 Muts/Mb, respectively. Comparing 155 pts with TMB-H (≥3rd Quartile) to 181 TMB-L (≤1st Quartile) pts, the mutant frequencies of TERT (49% vs 38%, p= 0.044), CTNNB1 (32% vs 11%, p< 0.001), LRP1B (14% vs 5%, p= 0.004) and ARID1A (12% vs 5%, p= 0.014) were higher. The mutant frequency of TP53 was lower (57% vs 68%, p= 0.035). TMB-L had younger pts (median age 50y vs 60y, p< 0.001) and CNV (382 vs 232, p< 0.001). PD-L1 expression was detected seen in 222 pts, including 152 pts of Dako 28-8 Ab and 70 pts of Dako 22C3 Ab with no preference. The PD-L1 positive rate (TPS ≥1%) was 7% and 34% in 28-8 group and 22-C3 group, respectively. Eleven pts were both TMB-H and PD-L1 positive. HBV probe signal was detected in 285 pts, 262 of which were positive (≥10 reads). TMB, PD-L1 expression and HBV were not found to be significantly correlated. Conclusions: In our study, 37% of Chinese HCC pts with PD-L1 positive or TMB-H may benefit from immunotherapy. TMB-H HCC pts were older, had more common TERT, CTNNB1, LRP1B and ARID1A mutations, and fewer TP53 mutations and CNV. In our current cohort, TMB and PD-L1, TMB and HBV, and PD-L1 expression and HBV were not correlated significantly.
Imaging biomarker phenotyping system (iBiopsy) to accelerate hepatocellular carcinoma (HCC) drug development.
Authors: Liu Yan , Ramos Corinne , Baudot Pierre , Brag Johan , Lucidarme Olivier
Published: May 2019

e15671

Background: Current drug therapies in HCC remain limited because of substantial genomic, cellular and molecular heterogeneity of the liver tumor microenvironment (TME). This heterogeneity has implications for tumor development, immune response and cellular invasion and is compounded by multiple molecular pathways related to the various HCC etiologies. In this context, it is challenging to find biomarkers that are predictive of therapeutic response or outcome. A systems biology approach leveraging the iBiopsy phenotyping platform to automatically detect HCC and TME subtypes using non-invasive medical imaging could help identify specific disease pathways and accelerate HCC drug development. Methods: In this retrospective study, 50 patients with primary HCC were used to extract voxel level image signatures from the segmented livers on CT scans. The automatic classification of liver signatures was obtained by Log Linear Local density peak clustering computed using Wasserstein’s optimal transport distance between Gray Level Co-occurrence matrices of local luminance tiles of the Liver. Through this hypothesis-free clustering, phenotypes representative of tumor and tumor environment were identified and further correlated with clinical data. Results: Nine classes of statistically significantly distant clusters were identified on the 50 patients. Preliminary correlation analysis on individual patient showed that up to 3 clusters were specific to the tumor and characterized phenotype heterogeneity within the tumor. Notably, specific clusters at the tumor front-line and surrounding adjacent non-tumoral tissue were also identified. Conclusions: Preliminary results show that a multiplicity of phenotypes representative of a complex heterogeneous lesion and tissue microenvironment that might have prognostic and predictive value can be identified. This support the use of a non-invasive phenotypic approach for the subtyping of HCC that can be used for the identification of a multiplicity of important biological pathways that can be specifically targeted to treat HCC.
HIV associated hepatocellular cancer (HCC) in an inner-city minority population.
Authors: Mukthinuthalapati V V Pavan Kedar , Putta Aakash , Farooq Muhammad Zain , Batra Kunnal , Rubinstein Paul G. , Gupta Shweta
Published: May 2019

e15680

Background: The Highly Active Anti-Retroviral Therapy (HAART) era has seen a rise in the incidence of non-AIDs defining cancers. This study was undertaken to study the characteristics associated with HIV+ HCC in an inner-city minority population. Methods: Patients with diagnosis of HCC since January 2011 until December 2018 were identified from our hospital’s electronic medical database using ICD-9/ICD-10 codes. Charts were retrospectively screened to confirm diagnosis of HCC and identify HIV+ patients. HIV+ HCC were compared to HIV- cohort from 2011 to 2016. Statistical analysis was done using the chi-square and t-test. Results: A total of 14 HIV+ HCCs were identified and compared to 239 HIV- HCC (Table 1). All HIV+ HCC were men (100%) with 86% African Americans (AA) (p < 0.05). HIV+ HCC were more likely to be HCV+, HBV+ and less likely to have history of alcoholism. Seventy-nine percent HIV+ HCC were Child-Pugh A at diagnosis compared to 35% in HIV- HCC. The median years between diagnosis of HIV and HCC was 18. All 14 HIV+ HCC (100%) were on HAART at the time of HCC diagnosis with viral load (available for 12) undetectable in 10 (83%) and < 100 copies/mL in 2 (17%). The average CD4 count at HCC diagnosis was 258 cells/µL with 10 (71%) having CD4 counts > 200 cells/µL. HCC was multifocal in 71% HIV+ compared to 49% of HIV- patients. AFP levels were < 20 ng/mL for 50% of the HIV+ HCC patients. There were 43% BCLC B and no BCLC D patients in HIV+ HCC compared to 17% and 24% in HIV- (p < 0.05 for both). 67% HIV+ BCLC Stage C patients died within 20 weeks of HCC diagnosis. Conclusions: HIV+ HCC is predominantly AA, exclusively male disease in our inner-city population. Compared to other studies showing HIV+ HCC to be younger than the HIV- patients, our HIV+ patients were similar in age to the HIV- cohort. HIV+ HCC is more multifocal with early mortality despite early BCLC stage.. Studies are needed to investigate if frequent HCC screening may be needed in HIV+ patients with HCV/HBV co-infection.[Table: see text]
Trends from NSQIP 2015 to 2017 in neoadjuvant therapy use before pancreatic adenocarcinoma resection.
Authors: Gologorsky Rebecca C , Ely Sora , Dominguez Dana , Huyser Michelle , Chang CK
Published: May 2019

e15685

Background: Morbidity and mortality associated with surgical resection of pancreatic adenocarcinoma remains high, and prognosis is poor even after R0 resection. Preoperative chemoradiation, previously only indicated to downstage borderline-resectable disease, has been increasingly used even in cases that appear resectable at time of diagnosis. Response to therapy can be prognostic and guide clinical decision-making. We investigated significant trends over time in neoadjuvant treatment of patients within the National Surgical Quality Improvement Project (NSQIP) database treated surgically for pancreatic adenocarcinoma. Methods: We queried NSQIP data for patients who underwent pancreaticoduodenectomy or subtotal pancreatectomy for pancreatic adenocarcinoma in 2015-2017. We examined differences by year in neoadjuvant treatment use with Chi-square test. Results: There were 8626 patients included. Use of neoadjuvant treatment (chemotherapy or chemoradiotherapy) increased over the study period, and complication by pancreatic fistula and delayed gastric emptying decreased qualitatively over the same time (12% to 9%; 14% to 12%). This increase in use of neoadjuvant chemotherapy was significant among patients with T1, T2, and T3 tumors (Table 1). However, despite NCCN/ASCO guidelines recommending neoadjuvant for all patients with T4 tumors, only about a quarter of these patients received it, and this proportion did not change over time. Conclusions: Preoperative chemotherapy is particularly important in ≥T3 disease because of low rates (50%) of adjuvant therapy, likely secondary to postoperative morbidity. The NSQIP data reflects the trend toward increasing neoadjuvant therapy in lower-T stage disease, but not among patients with T4 disease. This may be because NSQIP data largely reflects community hospital populations, and this practice was first adopted by academic institutions. Based on our findings, it is important that medical oncology be involved early in the multidisciplinary care of patients with pancreatic adenocarcinoma.[Table: see text]
The effect of race on adherence to NCCN Guidelines for patients with biliary tract cancers (BTC) after surgery.
Authors: Alahmadi Asrar , Cioffi Gino , Opneja Aman , Patil Nirav , Bajor David Lawrence , Saltzman Joel N. , Barnholtz-Sloan Jill , Lee Richard T.
Published: May 2019

e15686

Background: BTC has a limited prognosis even for localized cancers (15-30% 5-year survival) emphasizing the importance of multidisciplinary management. NCCN guidelines recommend adjuvant chemotherapy (CT) +/- radiotherapy (RT) for high risk disease. We analyzed adherence to NCCN guidelines among patients following surgery for BTC and the influence of race. Methods: Subjects were identified from the National Cancer Database (NCDB) for BTC patients who underwent surgery and found to have metastatic lymph nodes (LN+) or positive surgical margins (M+) from 2004 to 2015. We defined adherence to NCCN guidelines as receiving surgery+ CT +/- RT and non-adherence to the guidelines as surgery +/- RT. Descriptive studies and multivariate logistic regression analysis was performed. Results: A total of 3,792 patients were identified with approximately half being female (55.4%) and between the ages of 50-69 (52.8%). Most were White (76.3%) followed by Black (10.6%), Hispanic (8.5%), and Asian (5.3%). The BTC included extrahepatic cholangiocarcinoma (CCA) (48.6%), gallbladder cancer (43.5%), and intrahepatic CCA (7.9%). Most patients had an R0 resection (71.9%) but also had LN+ disease (88.0%). There were no significant differences between racial groups in disease presentation (histological grade, tumor stage) and surgical outcomes (LN+, M+, hospital readmission, and 90 day post-surgery mortality). Hispanic patients as compared to White patients were less likely to be insured (85.7% vs 96.3%, p < 0.001) and less likely to be treated at an academic facility (42.1% vs 52.1%, p = 0.008). Overall 29.7% of patient did not adhere to NCCN guidelines with Hispanics having the highest proportion of non-adherence as compared to Whites, (36.1% vs 28.7%, p = 0.029). On multivariate analysis, Hispanic race (HR = 1.51, 95% CI: 1.15-1.99) remained significant for receiving treatment non-adherent to NCCN guidelines. Conclusions: This study indicates that Hispanics are significantly more likely to receive non-adherent care in comparison to White patients in accordance with NCCN guidelines. More research is needed to confirm and understand the observed disparities and guide targeted interventions.
Evaluation of Ki67 and other predictors of survival in metastatic neuroendocrine tumor (NET) to the liver treated with Y90 radioembolization.
Authors: Cronan Julie , White Bernadette , Ermentrout Robert Mitchell , Bercu Zachary Louis , Shaib Walid Labib , Newsome Janice , Kokabi Nima
Published: May 2019

e15687

Background: Ki67 index is a predictor of survival in patients with metastatic neuroendocrine tumor (NET). The purpose of this study is to evaluate Ki67 index and other potential predictors of overall survival (OS) in patients with NET metastases to the liver treated with Y90 radioembolization. Methods: In an institutional review board-approved retrospective study, consecutive patients with NET metastases to the liver who were treated with Y90 radioembolization from 2013-2018 at a single institution were evaluated. Patients with documented Ki67 index were stratified according to 2017 World Health Organization (WHO) grading based on Ki67 index (G1: < 3%, G2: 3-20%, G3: > 20%). Age, gender, and objective tumor response on post Y90 imaging were also evaluated as potential predictors of survival after Y90. Objective tumor response was evaluated at 1 and/or 3 months post Y90 with multiphase MRI utilizing Response Evaluation Criteria for Solid Tumors (RECIST). Overall survival (OS) from time of Y90 was analyzed using Kaplan-Meier estimation. Predictors of survival were evaluated using log-rank test with p < 0.05 as the statistically significant level. SPSS software v. 25 (IBM Corporation, Armonk, NY) was used for all statistical analysis. Results: A total of 77 patients were identified; 36 (47%) had a documented Ki67 index from either their primary tumor, liver metastasis, or both. Primary tumor site included pancreatic (n = 10), small bowel (n = 7), pulmonary (n = 5), gastric (n = 3), large bowel (n = 3), and renal (n = 1). A primary site was not identified in several patients (n = 7).G1 tumors comprised 31% (n = 11) of patients, while G2 and G3 tumors made up 50% (n = 18) and 19% (n = 7) of the cohort, respectively. Median overall survival (OS) of the entire cohort was 51.1 months. Median OS in patients was 63.0 months in G1 tumors, 51.1 months in G2 tumors, and 3.1 months in G3 tumors (p < 0.001). Objective response on initial MRI follow-up after Y90 radioembolization also predicted prolonged OS (51.2 months versus 17.9 months, p < 0.001). Age at time of diagnosis and gender were not predictors of survival after Y90 radioembolization. Conclusions: WHO grading based on KI67 index and objective tumor response appear to be predictors of prolonged survival in patients with metastatic NET to the liver treated with Y90 radioembolization.
Monitoring of neuroendocrine tumors in elderly patients in the Brittany region.
Authors: Metges Jean-Philippe , Deniel Lagadec Delphine , Pracht Marc , Lievre Astrid , Robinet Gilles , Estivin Sandrine , Corre Romain
Published: May 2019

e15690

Background: NeuroEndocrine Tumors (NETs) remain a poorly known entity, especially in older patients. The therapeutic management is multidisciplinary combining surgery, interventional radiology, chemotherapy, cancer supportive care and also geriatrics oncology. The aim of this study performed by the OncoGeriatry Coordination Unit (UCOG) of Brittany, in collaboration with the National Reference Network for the management of NET (RENATEN), was to analyze the current management of NETs in older patients (more than 75 years old) and to develop recommandations to optimize the management of elderly patients with NENs. RENATEN’s guidelines mean systematic discussion of the cases in Regional Multidiscplinary Tumor Board (MTB) dedicated to NETs (RENATEN MTB). Methods: This study is a retrospective observational study including patients aged 75 years and over, with a NET that has been diagnosed in an pathological laboratory or whose file has been discussed in a MTB (usual MTB or RENATEN MTB) between 2014 and 2017 in the Brittany area. Results: 51 patients with a median age of 79 years [75-92] have been included up until now, among whom 77% had digestive NET, 12% urological, 8% dermatological (Merkel tumor), 4% pulmonary, 2% gynecological and 2% NETs of unknown origin. Tumor grade was 1, 2, 3 and unkown in 20%, 14%, 37% and 29% respectively. Overall, 33% of the tumors were well differentiated and 63% were metastatic (synchronous metastases :78%). Only 20% of patients benefited from a geriatric oncology consultation to help the clinician in the therapeutic decision. File of 53% of patients has been discussed one time in a specialized RENATEN MTB and 57% in another MTB. No proof of discussion in MTB was found in 12%. The treatment proposed in the RENATEN MTB was effective in 85% of patients (2 patients died immediately after RENATEN MTB, 2 patients did not wish to be treated). Only 14% of patients received initial surgery, 10% radiotherapy and 41% chemotherapy. The overall survival of this cohort is 11.3 months [0.3 -89] (for grade 3, 7.9 months [0.8-21.7]). Conclusions: The rate of multidisciplinary meeting presentation has to be improved, as well as the geriatric oncology management. A cohort of more than 100 patients will be presented at the meeting and treatment response and survival data based on age class, tumor grade, histological subtypes and therapeutic strategy will be shown.
A retrospective series of centralized reviewed GEP MANECs receiving a first-line adenocarcinoma-oriented chemotherapy.
Authors: Spada Francesca , Milione Massimo , Maisonneuve Patrick , Prinzi Natalie , Smiroldo Valeria , Bolzacchini Elena , Carnaghi Carlo , La Rosa Stefano , Capella Carlo , Sessa Fausto , Fazio Nicola
Published: May 2019

e15695

Background: Mixed adeno-neuroendocrine carcinomas (MANECs) are very rare malignancies. Due to their biological and clinical heterogeneity, there is not a universally shared clinical approach. Methods: We retrospectively analyzed clinical records of 22 patients from 4 Italian referral centers with advanced MANEC of the gastro-entero-pancreatic (GEP) tract who received a first line chemotherapy and were part of a previously published series of 160 patients (M. Milione et al, Endocrine Related Cancer 2018). Surgical specimens were centrally reviewed by a team of 7 expert pathologists. Clinical and biological data were correlated with outcomes. Results: All patients developed distant metastases (32% synchronous, 68% metachronous). Primary sites were colorectal in 13 patients, esophago-gastro-duodenal in 6, and pancreato-biliary in 3. Ki-67 index in the NEC component was ≥55% in 77% of the patients. Three patients (2 colorectal) received neo-adjuvant chemotherapy, 4 adjuvant (2 colorectal), and 2 peri-operative (one colorectal, one pancreas). The most common regimen was adenocarcinoma-oriented (59% fluoropyrimidines /oxaliplatin). Overall, 14% of patients had a partial response (PR) and 18% stable disease (SD). The median OS in the whole cohort was 0.9 years (95% CI 0.3-1.4). It was longer in patients with Ki-67 < 55% in the NEC component (median 2.5 years; 95% CI 0.5-2.5) than in those with Ki-67 ≥ 55% (median 0.9 years; 95% CI 0.3-1.0) (Wilcoxon P =0.10), regardless of the type of therapy. Mutations in either KRAS (codons 12 and 13) or TP53 (exons 5-8) genes performed by NGS were observed in 9 (8 colorectal, one pancreas) out of 19 patients. Only one of them, (colon primary site), experienced SD. Conclusions: This analysis suggested that an adenocarcinoma-oriented regimen could be active as first line chemotherapy in patients with advanced GEP-MANECs especially with Ki-67 index < 55% in the NEC component. Since its descriptive design and various clinical management, this study cannot either suggest a specific therapy or a real impact of chemotherapy on prognosis. However, it produced solid hypotheses for future prospective-interventional studies in selected populations.
Characterization of a novel entity of high-grade well-differentiated colorectal neuroendocrine tumors.
Authors: Punekar Salman Rafi , Masri-Lavine Lena , Hajdu Cristina , Newman Elliot , Becker Daniel Jacob
Published: May 2019

e15696

Background: Small studies suggest that a new pathologic entity of high-grade (by Ki-67 or mitotic index) well-differentiated (by histologic features) neuroendocrine tumors (NETs) exist throughout the GI tract, but the prognosis and characteristics of affected patients are unknown. We sought to further characterize the prognosis and demographics of patients with high-grade (HG) well-differentiated (WD) colorectal NET. Materials and Methods: We used the Surveillance Epidemiology and End Results (SEER) database to study patients with NETs of the colon and rectum diagnosed from 2000 to 2015. We identified patient demographics, clinical and tumor characteristics, and studied associations with tumor grade. We compared overall survival (OS) between patients with low-grade (LG)(grade 1-2) well-differentiated (ICD-0-3 = carcinoid), high-grade (grade 3-4) well-differentiated, and high-grade poorly-differentiated NETs (ICD-0-3 = small cell neuroendocrine). We used logistic regression to detect associations with grade and Cox proportional hazards models to examine predictors of survival. Results: We identified 5,894 cases with colorectal carcinoid tumor (5780 [98.1%] LG and 114 [1.9%] HG); the cohort was 68% white, 48% male, and had a median age of 54. Patients diagnosed with HG carcinoid tumors were more likely to be of older age (OR 2.23; 95% CI 1.19-4.19 for age 60-69 vs < 50) and unmarried (OR 1.56; 95% CI 1.02-2.38), and less likely to be diagnosed after 2010 (OR 0.09; 95% CI 0.06-0.15). OS for patients with HG carcinoids (median 36 m; 95% CI 13-92) fell in between OS for those with HG small cell NETs (median 7 m; 95% CI 6-8), and LG carcinoid tumor (median not reached, > 120 m). Among patients with carcinoid tumors, black patients (HR 1.31; 95% CI 1.03-1.67, older patients (HR 3.60; 95% CI 2.50-5.19 for age 60-69 vs < 50), unmarried patients (HR 1.52; 95% CI 1.24-1.87), and those with HG features (HR 3.85; 95% CI 2.88-5.15) had worse survival. Conclusions: We defined a subset of high-grade well-differentiated NETs, more commonly diagnosed in older, unmarried patients, with a prognosis between that of high grade small cell NETs and low grade carcinoid tumors. Our analysis adds the first national registry study to the literature in support of a new classification of non-pancreatic high-grade well differentiated NETs.
Comprehensive characterization of pseudomyxoma peritonei.
Authors: Malouf Gabriel G. , Dohan Anthony , Yao Hui , Mouawad Roger , Carapito Raphael , Bahram Seiamak , KHAYAT INSTITUT CANCEROLOGIE Meyer , Kurtz Jean-Emannuel , Su Xiaoping , Pocard Marc
Published: May 2019

e15701

Background: Pseudomyxoma peritonei (PMP) is a rare malignant tumor characterized by the infiltration of the peritoneum by mucus-secreting tumor cells. The genetic landscape of these tumors and correlation with clinico-pathological tumor features is unclear to date. Methods: We performed whole-exome sequencing (WES) on 8 PMPs and matched normal. We then validated our finding using ultra-deep sequencing of hotspot mutations (~82.270 x) in 45 clinically annotated samples. In addition, bulk RNAseq was performed on 10 samples and MCP-counter was used to infer absolute abundance of eight immune and two stromal cell populations. Results: Overall, 323 somatic mutations were identified through WES with most frequent mutations involving GNAS (R186H) (50%), KRAS (G12D) (50%), AHNAK2 (25%) and ATXN1 (25%). Furthermore, ultra-deep sequencing uncovered KRAS, GNAS and IDH1/2 hotspots mutations in 16 (35.5%), 11 (24.4%) and 2 (4.4%) PMPs, respectively. Strikingly, KRAS mutations were enriched in females (79% vs 39%, p = 0.03) while GNAS in males (67% vs 28%, p = 0.04). No other significant associations were identified between mutations and other clinico-pathological features. Using MCP-counter, fibroblasts, endothelial cells and moncoytic cells were the most frequent inferred cells. Unsupervised clustering using expression of most variable cells identified two PMP clusters, namely C1 (n = 4) and C2 (n = 6). C2 cluster displayed higher T cells as compared to C1 (p < 0.0001), consistent with increased cytotoxic lymphocytes (p = 0.04). Notably, C2 was enriched for tumors with higher grade as compared to C1 (80% vs 0%; p = 0.04). Conclusions: Our study represents the largest study to data exploring genetic and immune alterations in PMPs. We uncovered puzzling associations between genetic landscape of PMPs and patients gender, which deserve further validation in an independent cohort. The association of high-grade tumors with increased tumor infiltrating lymphocytes suggests the existence of an immunogenic microenvironment; PD-1/PD-L1 blockade might represent a therapeutic option for these patients.