bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical trial screening of CDKN2A genomic alterations in patients with pancreatic cancer and hepatobiliary cancers requires greater precision than somatic sequencing alone.
Authors: Vaske Charles Joseph , Garner Chad , Seery Tara Elisabeth , Szeto Christopher , Reddy Sandeep K. 
Published: January 2019

287 Background: The TAPUR Study is a phase II multi‐basket study that evaluates the anti‐tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations known to be drug targets. Results in two cohorts of PC and GBC pts each with CDKN2A loss or mutation were reported at ASCO 2018. The conclusion was that monotherapy with palbocicilib is not associated with clinical activity in these patients. This may be a false conclusion if the genomic targets were absent in these patients. Methods: A total of 158 GI pts (P = 123, GB = 20, Bile Duct = 15) with deep whole exome sequencing (WES) of tumor and blood samples, and whole transcriptomic sequencing (RNA-Seq) (∼200x106 reads per tumor) were available for this analysis from a commercial database. Variant calling was performed through joint probabilistic analysis of tumor and normal DNA reads, with germline status of variants being determined by heterozygous or homozygous alternate allele fraction in the germline sample. Results: 26 somatic variants and 12 germline variants were detected, with one sample overlapping with a germline and a somatic variant (p.A148T and p.A76Rfs∗44). Counting all 11 discrete germline variants as false positives, a total 37 of 158 samples would be positive for CDKN2A mutant status, a rate of 23% (17%-31% CI). However, if the 8 common germline variants are excluded, the call rate is 29/158 = 18% (12%-25% CI). The false positive rate is 4/158 = 14% (4%-31% CI). By RNAseq, true somatic CDKN2A variants had significantly higher TPM counts than germline variants (T-test p = 0.0002). RB expression was not significantly different between the two groups. Conclusions: The failure of palbociclib to show benefit in CDKN2A mutated PC and GBC patients in the 20 patient cohort of the TAPUR study could possibly be explained by patient selection rather than solely drug failure. It is unlikely related to RB loss.
Single-cell analysis of immune-microenvironment and immune-tumor interaction in human gastric cancers.
Authors: Goh Michele , Lim Ze Ming , Koh Vivien , Lum Josephine , Zhang Xiaomeng , McGovern Naomi , Msallam Rasha , Larbi Anis , Poidinger Michael , Ginhoux Florent , Ng Matthew C.H. , Tan Patrick , Yong Wei Peng , So Jimmy Bok Yan , Chen Jinmiao 
Published: January 2019

29 Background: The incidence rates of gastric cancer in Asia are among the highest in the world. Gastric cancer is a heterogeneous disease. The Cancer Genome Atlas and Asian Cancer Research Group provide molecular classification of gastric cancers. Recently, immunotherapy was found to be effective in selected gastric cancer patients. Despite the molecular classification, a classification system based on immune microenvironment is in need to better stratify patients for ideal immunotherapy combinations. Methods: We have performed indexed-sorting single cell RNA-seq to analyze both CD45+ and CD45- cells from biopsy samples of 15 gastric cancer patients (5 Diffuse; 4 Intestinal; 5 Mixed; 1 unknown type). Using our ezsinglecell analytical pipeline, we have built a draft Asian Single-cell Immune Atlas (ASIA) of human gastric cancers. Results: We were able to probe fibroblast, epithelial cells and various subtypes of immune cells. Interestingly, we observed that fibroblast and mast cells were more enriched in diffuse type. In addition, we have profiled single immune cells in tumor and normal adjacent tissues to distinguish tissue-induced versus tumor-driven immune signatures. Comparing tumor and normal tissues, we found that tumor site has less natural killer (NK) and CD8 T cells; more B, myeloid and CD4 T cells. Moreover, CD8 T cells and NK cells showed distinct phenotypes in tumor compared to normal tissues. In particular, inhibitory receptor Tim-3 and CTLA-4 were up-regulated in the tumor. Most interestingly, T Cell Receptor (TCR) reconstruction revealed clonal expansion of CD8 T cells. Conclusions: Both immune (CD45+) and non-immune (CD45-) cell components of human gastric cancers are highly heterogeneous. Diffuse type showed differential tumor microenvironment compared to intestinal and mixed types. Tumor site presented an immune-suppressive phenotype compared to normal adjacent site. The clonal expansion of CD8 T cells suggested the role of adaptive immunity on recognizing tumor antigens. This discovery may determine the clinical applications of immunotherapy for gastric cancer in the future.
Transcript profiling of neuroendocrine tumors (NETs) to identify new targets and mechanism of progression.
Authors: Walzer Emily , Peri Suraj , Devarajan Karthik , Pei Jianming , Cai Kathy Q. , Gong Yulan , Cohen Steven J. , Astsaturov Igor A. , Engstrom Paul F. , Vijayvergia Namrata 
Published: January 2019

292 Background: Few studies have characterized the molecular drivers of NET growth and mechanisms differentiating poorly differentiated (PD) and well differentiated (WD) NETs. We explored the role of dysregulated transcriptome as the principal molecular mechanism of NETs with the goal to identify novel targets and biomarkers of differentiation. Methods: With IRB approval, de-identified, formalin fixed NET samples were used to extract total RNA for transcriptome analysis. All pathology specimens were centrally reviewed. Gene expression profiles of 774 genes were obtained using nCounter platform (PanCancer pathway panel, Nanostring TechnologiesTM). The resulting count data was voom normalized and differentially expressed genes between PD and WD NETs were identified using linear modeling methods available in R-Bioconductor LIMMA package. Candidate genes with potential therapeutic implications were validated in tissue microarrays by immunohistochemistry (IHC). Results: Analysis of gene count data between 16 PD and 23 WD NETs resulted in 154 differentially expressed genes on the 774 gene panel (FDR < 10% and 2 fold change (FC) up- or down-regulated), some of which may be potential drug targets (Figure 1). E.g. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for transcriptional repression, and CHK1, a G2/M cell cycle regulator, were upregulated in PD compared to WD NETs (2.7 and 3.1 FC, respectively) and serine/threonine-protein kinase PAK 3, involved in cytoskeleton reorganization, was upregulated in WD NETs (3.4 FC). IHC staining also suggested overexpression of EZH2 and its enzymatic substrate H3K27me in PD NETs (p < 0.001). PAK 3, another novel therapeutic candidate overexpressed in WD NETs (p < 0.001) was confirmed using IHC, validating the transcriptome analysis at protein level. Conclusions: These findings, combined with previously reported pathway analysis (Vijayvergia et.al 2017)], highlight biological differences between PD and WD NETs and serve as a platform for future research. They also support investigation of novel drugs that inhibit activity of EZH2 (e.g. EPZ6438) in PD NETs and PAK3 (e.g FRAX597) in WD NETs.
Association between overall survival and adverse events with lenvatinib treatment in patients with hepatocellular carcinoma (REFLECT).
Authors: Sung Max W. , Finn Richard S. , Qin Shukui , Han Kwang-Hyub , Ikeda Kenji , Cheng Ann-Lii , Kudo Masatoshi , Tateishi Ryosuke , Ikeda Masafumi , Breder Valery , Rau Kun-Ming , Ma Yuk Ting , Alsina Angel , Ryoo Baek-Yeol , Ren Zhenggang , Mody Kalgi , Dutcus Corina E. , Tamai Toshiyuki , Saito Kenichi , Piscaglia Fabio 
Published: January 2019

317 Background: In the phase 3 REFLECT study, lenvatinib (LEN) demonstrated a treatment effect on overall survival (OS) by statistical confirmation of non-inferiority to sorafenib (SOR) in patients (pts) with unresectable hepatocellular carcinoma (uHCC), who had not received prior treatment for advanced disease (Kudo M et al, Lancet 2018). Lenvatinib is approved in several major markets for the first line systemic treatment of uHCC. The most common adverse events (AEs) in pts treated with LEN were hypertension and diarrhea. In addition, LEN showed a different AE profile from that of SOR. Pts who received LEN experienced more instances of hypertension, proteinuria, dysphonia, and hypothyroidism than patients who received SOR. Recently, hypertension in LEN-treated pts with differentiated thyroid cancer was shown to be correlated with improved efficacy. Here we report the post hoc analysis exploring whether AEs associated with LEN were correlated with longer OS in REFLECT. Methods: 478 Pts were randomized to receive LEN (12 mg/d for actual body weight ≥ 60 kg or 8 mg/d for actual body weight < 60 kg). Subgroup analyses were conducted based on whether pts treated with LEN experienced any-grade AEs of interest (AEIs). OS was estimated by the Kaplan-Meier method. Results: The AEIs in pts treated with LEN were hypertension (42%), diarrhea (38%), proteinuria (24%), dysphonia (24%), and hypothyroidism (16%). OS was longer in pts who had several AEs of interest than in those who did not (table). Conclusions: In pts treated with LEN, the occurrence of hypertension, diarrhea, proteinuria, or hypothyroidism was generally associated with longer OS in pts with uHCC in this post hoc exploratory analysis. The potential confounding factors at baseline should be further investigated. Clinical trial information: NCT01761266. [Table: see text]
Surveillance for locally advanced esophageal and gastroesophageal junction (GEJ) cancers: Patterns of recurrence and methods of detection.
Authors: Matloubieh Jubin Eghbali , Licona-Freudensten Alexandra Pilar , Baran Andrea M , Lada Michal J , Jones Carolyn E , Peyre Christian G , Hezel Aram F , Noel Marcus Smith , Dunne Richard Francis , Tejani Mohamedtaki Abdulaziz 
Published: January 2019

32 Background: Trimodality treatment with neoadjuvant chemoradiation (CRT) followed by surgery is a standard treatment for esophageal/GEJ (E/GJ) cancers. Following esophagectomy, there is no strong consensus about optimal surveillance and routine imaging. At our institution, patients have surveillance CT scans every 4-6 months for the first 2 years post-surgery and every 6-12 months for the next 3 years. Methods: An IRB-approved chart review was performed identifying patients who underwent surgical resection for locally advanced E/GJ cancer between January 2011 and December 2015 at the University of Rochester. Study objectives were to describe timing of and methods used to detect recurrence as well as their impact on patient outcomes. Recurrence-free (RFS) and overall survival (OS) were graphed via the Kaplan-Meier method. Results: 138 patients underwent surgical resection for E/GJ cancer during the study period: 107 (77.5%) were male, median age was 64, and 116 patients (84.1%) had adenocarcinoma. 111 patients (80.4%) received neoadjuvant CRT. Median OS for entire cohort was 43.4 months. 65 patients (47.1%) relapsed with a median RFS of 19.8 months. Recurrence was detected by routine imaging in 34 patients (52.3%), imaging triggered by symptoms in 25 patients (38.5%), and symptoms alone in 6 patients (9.2%). Median OS post-relapse was 1.5 months when detected based on symptoms alone, 5.0 months when detected by imaging triggered by symptoms, and 13.5 months when detected by routine scans (Log-rank p = 0.046). There were no significant associations between baseline patient /tumor characteristics and subsequent method of recurrence detection. Conclusions: 47.1% of patients suffered relapse after trimodality therapy for E/GJ cancer, consistent with published literature. Almost half of these were detected based on symptoms despite routine imaging. Increased OS for patients with relapse detected by routine scans is likely related to lead time bias, but may be related to increased treatment intensity, or due to less aggressive tumors. Prospective randomized trials are needed to determine the true benefit of regular surveillance scans among esophageal cancer survivors.
Temozolomide in grade III neuroendocrine neoplasms (G3 NENs): A multicenter retrospective review.
Authors: Chan David , Bergsland Emily K. , Chan Jennifer A. , Gadgil Rujuta , Halfdanarson Thorvardur Ragnar , Hornbacker Kathleen , Kelly Virginia , Kunz Pamela L. , McGarrah Patrick Walsh , Raj Nitya Prabhakar , Reidy Diane Lauren , Thawer Alia , Whitman Julia , Wu Linda , Singh Simron 
Published: January 2019

321 Background: G3 NENs are aggressive, and optimal systemic treatment is unclear. Temozolomide (TEM)-based regimens have been used to treat grade 1-2 NETs, but their efficacy in G3 NENs (Ki-67 > 20%) remains undetermined. Aims: To assess the clinical efficacy of TEM-containing regimens in advanced grade III gastroenteropancreatic NENs (GEPNENs). Methods: A multicentre retrospective review (2008-2017) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports without formal RECIST criteria. Results: 118 patients in six centers were included (median age 55, 65% male, 15% functional, 75% pancreatic NEN). 57% were well-differentiated, 35% poorly-differentiated, and 18% unknown based on local pathology reports. The regimen used was CAPTEM in 93% and TEM in 7%. Best radiological responses were: complete response (1%), partial response (39%), stable disease (22%), progressive disease (31%), unknown (7%) not by RECIST. Median TTF was 150 days and median overall survival (OS) 18.0 months. Fifteen patients (14%) required dose reductions/discontinuation due to adverse events. TTF was shorter for patients on TEM alone (p = 0.02, Table 1). Well-differentiated NENs had better response rate (52% vs 26%, p = 0.02) and overall survival (30.1 vs 12.0 mo, p = 0.008) compared to poorly-differentiated NEN. Conclusions: This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NET centers. 40% of patients showed some degree of response, and treatment was generally well-tolerated. TEM-based regimens should be considered a viable treatment option in this setting. Prospective confirmatory trials (such as EA2142) may face difficulties in accrual due to disease rarity. [Table: see text]
A phase Ib study evaluating olaratumab in combination with nab-paclitaxel and gemcitabine in first-line treatment of metastatic pancreatic cancer.
Authors: Pelzer Uwe , Bendell Johanna C. , Womack Mark S. , Bahary Nathan , Macarulla Teresa , Borazanci Erkut Hasan , Levy Donna Elise , Mo Gary , Ramage Samuel Cowan , Garrido-Laguna Ignacio 
Published: January 2019

330 Background: Increased platelet-derived growth factor receptor alpha (PDGFRα) expression is linked to epithelial-mesenchymal transition in pancreatic cancer. Olaratumab (O) is a fully human monoclonal antibody against PDGFRα previously approved for the treatment of advanced soft tissue sarcoma. Here, we report the initial safety and antitumor activity data of O in combination with nab-paclitaxel + gemcitabine (nPG) in first-line metastatic pancreatic cancer patients (pts). Methods: In this 3+3 dose escalation study, pts with stage IV pancreatic cancer received intravenous 15 mg/kg (cohort 1) or 20 mg/kg (cohort 2) O + nPG (125 mg/m2/1000 mg/m2) on D1, 8, and 15 of a 28-day cycle. Following dose escalation, additional pts were enrolled in an expansion phase to confirm safety. Primary objective was to determine a dose of O that can be safely combined with nPG. Results: As of September 2018, 10 pts were treated in dose escalation (cohort 1: 3 pts; cohort 2: 7 pts) with no dose-limiting toxicities (DLTs) observed. Safety of 20 mg/kg O + nPG was confirmed in the expansion cohort; 1 of 12 pts (8.3%) experienced a DLT of grade 4 neutropenia. Most frequent adverse events (AEs) (≥ 25%) reported across all cohorts included fatigue (50%); neutropenia (50%); nausea (46%); thrombocytopenia (41%); and constipation (32%). Related grade ≥ 3 AEs reported in > 2 pts were neutropenia (N = 7; 32%), infusion-related reaction, and neuropathy (both N = 3; 14%). There were no deaths related to study drugs. Among pts evaluable for response, 2 of 15 pts had a partial response and 11 pts had stable disease as best response for an objective response rate of 13%. Notably, 2 of 3 pts in cohort 1 continue on treatment for more than 12 months as of the data cut-off. Updated data will be presented at the meeting. Conclusions: Both dose levels were tolerated. Safety profile was similar to nPG chemotherapy with most toxicity manageable through dose adjustments of nPG. Clinical trial information: NCT03086369.
Efficacy and safety of varlitinib, a reversible pan-HER tyrosine kinase inhibitor, in combination with platinum-based regimens in biliary tract cancers: A pooled analysis from three phase I studies.
Authors: Tan Aaron C. , Oh Do-Youn , Chao Yee , Hsieh Chih-Yi , Chang Wei-Ling , Isanto Fenny , Chen Ying-Chen , McHale Mark , Lindmark Bertil , Ng Matthew C.H. 
Published: January 2019

331 Background: Varlitinib is a nanomolar inhibitor of EGFR, HER2, and HER4 and has shown potent anti-tumor activity as monotherapy in preclinical BTC models. During Phase (Ph) 1 development, significant tumor shrinkage was observed in biliary tract cancer (BTC) patients (pts). Tissue microarray analysis has revealed that ~70% of BTC pts exhibit HER overexpression, suggesting varlitinib could be beneficial in BTC. Methods: Data from BTC pts were pooled from 3 Ph1 trials of varlitinib (dosed 200-500 mg BID) in combination with cisplatin and 5-FU/capecitabine (cape) (Study 002); oxaliplatin and 5-FU/cape (Study 002SG); cisplatin and gemcitabine (Study 007). The depth of tumor response, disease control rate (DCR), and treatment-related adverse events (TRAEs) were analysed. Results: As of 12 June 2018, 43 pts were recruited: 12 (27.9%); 10 (23.3%) and 21 (48.8%) from study 002; 002SG and 007 respectively. 002SG and 007 were still ongoing at data cut-off. 20 (46.5%) pts were male and the median age was 62 years (range 42-82). Most tumors were cholangiocarcinoma (74.4%), followed by gallbladder cancer (16.3%) and carcinoma of the Ampulla of Vater (9.3%). 14 (32.6%) pts had received ≥ 1 prior lines of treatment. Of the 37 pts evaluable for efficacy (those with measurable disease and received ≥ 1 dose of treatment), partial responses were observed in 10 (27.0%) pts and stable disease in 16 (43.2%) pts, with a DCR of 70.3%. The median depth of tumor response was -10.8% (range 49.5% to -87.1%). Of 43 pts, the most frequent (≥ 30%) TRAE (any grade) were fatigue (37%), decreased appetite (34%), and nausea (32%) and the most common Grade ≥ 3 TRAE were hyperbilirubinemia (12%), increased AST (9%), and neutropenia (9%). The median PFS data is not matured and will be provided if evaluable at the time of presentation. Conclusions: Varlitinib with platinum-based chemotherapy has a promising efficacy and safety profile in BTC. A Ph2/3 randomised study of varlitinib and cape in 2nd line BTC and a Ph1b/2 study of varlitinib with platinum-based chemotherapy in 1st line BTC are ongoing. Clinical trial information: NCT02648425, NCT02435927, and NCT02992340.
Progression-free survival (PFS) and subgroups analyses of lenvatinib in patients (pts) with G1/G2 advanced pancreatic (panNETs) and gastrointestinal (giNETs) neuroendocrine tumors (NETs): Updated results from the phase II TALENT trial (GETNE 1509).
Authors: Capdevila Jaume , Fazio Nicola , López-López Carlos , Teule Alexandre , Valle Juan W. , Tafuto Salvatore , Custodio Ana B. , Reed Nicholas , Raderer Markus , Grande Enrique , Garcia-Carbonero Rocio , Jiménez-Fonseca Paula , Alonso Vicente , Antonuzzo Lorenzo , Spallanzani Andrea , Berruti Alfredo , Sevilla Isabel , La Casta Munoa Adelaida , Hernando Jorge , Ibrahim Toni 
Published: January 2019

332 Background: Pts with advanced G1/G2 NETs have limited treatment options with overall response rates (ORR) with targeted agents (TA) < 10%. Benefit on PFS after TA therapy has not been demonstrated. The mechanism of action of lenvatinib (VEGFR1-3 & FGFR1-4 inhibitor) may increase efficacy and revert primary and acquired resistance to TA. We report the updated results on PFS, safety and subgroups. Methods: This prospective phase II study had two cohorts: G1/G2 panNETs and giNETs. All pts had baseline documented disease progression (PD) by RECIST. For panNETs, PD to TA was mandatory, regardless prior therapy with somatostatin analogs (SSAs) or chemotherapy (CHT), and for giNETs, PD on SSAs. Pts were treated with lenvatinib at 24 mg qd until PD or intolerable toxicity. The primary endpoint was ORR by central radiology review. PFS was calculated by investigator assessment. Biochemical responses were defined as reduction from baseline > 50%. With 55 pts per arm our study was powered to identify an ORR ≥ 25% (90% power, 5% α-error). Results: We recruited 111 pts (55 panNETs/56 giNETs). Prior therapies were CHT 32%, SSAs 87%, everolimus (E) 70% and sunitinib (S) 30% for panNETs. ORR was 29%, 40% for panNETs and 18.5% for giNETs. With a median follow-up of 17 months (m), PFS for panNETs was 15.8 m (95% CI 11.4-NR) and 15.4 m (95% CI 11.5-19.5) for giNETs. Dose reductions/interruptions were needed in 91.8% with a median dose of 20 mg qd. In the subgroups analyses, all pts obtained the same benefit in PFS and ORR, including grade and prior therapy with S (PFS: 16.4 m, ORR: 43.7%) or E (PFS: 15 m, ORR: 37.1%) (p = ns). A significant correlation of chromogranin A decrease and prolonged PFS in giNETs (17.6 m vs NR, p = 0.032) was observed. The most frequent G3-4 adverse events were hypertension (20.7%), asthenia (13.5%), diarrhea (7.2%) and abdominal pain (5.4%). Conclusions: Lenvatinib showed the highest reported ORR with a TA by central radiology assessment in panNETs and giNETs with promising PFS in a pretreated population. The benefit was observed across subgroups analyses, including pretreated pts with TA. Clinical trial information: NCT02678780.
Survival outcomes between surgery with adjuvant therapy compared to neoadjuvant therapy with surgery in stage I pancreatic adenocarcinoma: Results from a large national cancer database.
Authors: Datta Samit Kumar , Belini Geoffrey , Singh Maharaj , Papenfuss Wesley Allan , Sanchez Federico Augusto , Guda Nalini , Weese James L. , Chevinsky Aaron 
Published: January 2019

335 Background: There has been a paradigm shift in the treatment of stage 1 pancreatic adenocarcinoma (PAC) from surgery first followed by adjuvant therapy (AT) to Neoadjuvant therapy (NAT) first followed by surgery and this is reflected in the current NCCN guidelines as well. Data comparing these two modalities are limited. AIM: To compare long time survival between surgery vs Surgery + AT and NAT + Surgery in a large National Cancer Database. Methods: We identified patients with surgically resected AJCC clinical stage 1, 1A, and 1B PAC between 2004-2014. Patients were stratified into 3 groups to assess outcomes. Exclusion criteria: those with incomplete survival and sequence of therapy data. Hazard ratios (HR) were calculated for evaluation of survival, as well as for 30-Day and 90-Day Mortality between the 3 groups. Results were adjusted for age and Deyo-Charlson comorbidity index. Results: A total of 9684 pts with Clincal stage 1, 1A, 1B PAC between 2004-2014 were identified. Of these 2266 pts underwent surgery alone; 6222 had surgery followed by AT; and 1196 pts had neoadjuvant therapy followed by surgery. There was a HR of 0.995 (95% CI 0.935-1.058 p = 0.864) and 0.984 (95% CI 0.924-1.048, p = 0.617) for 30- and 90-Day mortality comparing upfront surgery to NAT, respectively. With AT as the reference group for survival, there was a HR of 1.362 (95% CI 1.286-1.443, p < 0.001) for surgery only and HR of 0.929 (95% CI 0.859-1.004, p = 0.064) for NAT. Conclusions: 1. Surgery alone had worse overall survival. 2. There was no significant difference in overall survival when comparing AT and NAT 3. A prospective randomized trial evaluating the differences in survival is needed.