bluuebunny/crossref_metadata_2025_split huggingface dataset:
Next-generation sequencing (NGS) in pancreatic neuroendocrine tumors (panNETs): Defining differentiation and grade genetically.
Authors: Raj Nitya Prabhakar , Klimstra David , Shah Ronak , Osoba Muyinat , Alexander Derek , Reidy Diane Lauren 
Published: March 2017

291 Background: Advances in tumor sequencing technology have improved our understanding of the genetic basis of panNETs. Whole exome sequencing of well differentiated (WD) panNETs demonstrated changes in chromatin remodeling genes; in poorly differentiated (PD) neuroendocrine carcinomas, changes along the TP53/RB signaling pathways have been observed. We sought to validate these observations in clinical practice. Methods: This prospective study (NCT01775072) used the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) assay to do NGS on panNETs in the routine practice setting. MSK-IMPACT is an assay providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number changes, and select gene rearrangements. Results: Results are available in 89 tumor samples from 78 patients (mean patient age 53, 58% female); 31 tumors (35%) low grade, 35 tumors (39%) intermediate grade, and 23 tumors (26%) high grade; 5 patients (6%) with PD tumors and 73 patients (94%) with WD tumors. Changes in chromatin remodeling genes were observed only in WD tumors; DAXX alterations in 24 tumors (27%), ATRX alterations in 15 tumors (17%), and SETD2 alterations in 10 tumors (11%). RB1 alterations were identified in 3 tumors (3%); all of these tumors were PD/high grade. TP53 alterations were seen in 9 tumors (10%); 4/9 tumors (44%) PD/high grade, 3/9 tumors (33%) WD/intermediate grade, 2/9 tumors (22%) WD/low grade. All WD, TP53-altered tumors also had DAXX/ATRX changes. Conclusions: In line with prior work, using an institutional NGS assay, we demonstrated tumor differentiation and grade genetically. Changes in chromatin remodeling genes were exclusive to WD tumors. Only PD tumors had RB1 changes. While TP53 was altered in both WD and PD tumors, TP53-altered WD tumors also harbored changes in the chromatin remodeling genes.
Combined treatment with TLR7/8 agonists and carbon ion radiation induces local and abscopal immune responses in gastrointestinal tumor models.
Authors: Huber Peter E , Nicolay Nils H , Lopez Ramon 
Published: March 2017

292 Background: Radiotherapy is a mainstay of local tumor treatment for rectal and pancreatic carcinoma. Radiation has local and abscopal immunological effects, and may beneficially be combined with immune therapies. Photon radiotherapy can favorably be combined with a TLR7/8 agonist to induce strong immune responses in gastrointestinal tumors in mice. Here we investigated carbon ion particle radiation, which has superior physical radiation dose precision and a higher relative anti-tumor effect strength (relative biological effect, RBE, compared with photons), because it was unclear if carbon ions can also favorably be combined with immunotherapies such as TLR agonists. Methods: Therefore we investigated the effects of 3M-011, a TLR7/8 agonist (that was systemically given), and carbon ions in vivo in gastrointestinal tumors in mice in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro, cytotoxicity assays were applied to identify the immune cell populations involved in the therapy-induced immune reaction. The tumor specific T cell immune reaction was demonstrated by ELISPOT assays. Results: We found that the carbon ions and the TLR7/8 agonist 3M-011 induced strong immune responses in s.c. and orthotopic colorectal and pancreatic cancer models in mice. The TLR agonist dramatically enhanced the carbon ion effects in both local and distant antitumor activity. Depletion experiments showed that NK and CD8 T cells mediated the cytotoxic effects of the TLR agonist and in vivo depletion of CD11c+cells using a transgenic mouse carrying the diphteria toxin receptor showed that DCs are the necessary cell population inducing the detected antitumor immunity for monotherapies and combination treatment. Conclusions: Our findings suggest that TLR7/8 agonists are potent adjuvants not only to photon radiotherapy but also to particle radiation with carbon ions, and that the combination induced local and relevant systemic immune responses. In conclusion our preclinical proof of concept data supports the notion that TLR7/8 agonists may be favorably combined with particle radiation to treat GI tumors including pancreatic and rectal cancer.
Multivariate assessment of SPARC expression in resected pancreatic ductal adenocarcinoma to identify subgroups that are sensitive to adjuvant gemcitabine.
Authors: Kalloger Steve , Karasinska Joanna , Wong Hui-li , Renouf Daniel John , Schaeffer David F. 
Published: March 2017

297 Background: Secreted Protein, Acid, Cysteine-Rich (SPARC) has recently been postulated as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). The clinical trial findings investigating SPARC expression and nab-paclitaxel sensitivity have been discordant. This study aims to develop an integrated component based approach to the quantification of SPARC in PDAC to identify discrete predictive subgroups in a cohort of resected patients treated with an gemcitabine (GEM) or subjected to post-surgical observation. Methods: Immunohistochemical quantification of SPARC was performed on the epithelial and stromal compartments of resected PDAC on 219 patient samples on a tissue-microarray. The staining was assessed by the generation of H-Scores. The resultant scores were subjected to unsupervised hierarchical clustering. The maximum number of clusters was determined through an a priori decision that no cluster could be composed of less than 15% of the cohort. Univariable disease specific survival (DSS) analysis was performed with the Kaplan-Meier method to examine the cluster specific survival profiles with regard to gemcitabine sensitivity. Results: Mean age was 67 [38-88] with 56% being male. Most of the cohort had advanced disease with pT3 = 95% and pN1 = 72%. Lymphovascular and perinueural invasion were found in 58% and 93% of the cohort respectively. Clusters ranging in size from 35 to 76 cases were derived and represented the four-biomarker combinations of Low/Low, Low/High, High/High, and High/Low for the epithelial and stromal components respectively. None of the clinico-pathologic variables were significantly enriched in the clusters. Assessment of the predictive ability of the 4 clusters demonstrated that only one cluster (High/High) representing 76 (35%) patients in this cohort was sensitive to adjuvant GEM (p = 0.0067). Conclusions: This study shows that there is enhanced value in a combinatorial approach to the examination of SPARC in the stromal and epithelial components of PDAC where we have discovered that co-expression in both the epithelial and stromal components is significantly associated with sensitivity to adjuvant GEM.
Analysis of tissue and circulating tumor DNA by next-generation sequencing of hepatocellular carcinoma.
Authors: Ikeda Sadakatsu , Lim Jordan S , Kurzrock Razelle 
Published: March 2017

298 Background: Hepatocellular carcinoma (HCC) has limited treatment options. Molecular analysis of its mutational landscape may enable the discovery of new treatment option.However, biopsy is not routinely performed in HCC and involves risks. The utility of analyzing cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is not established. Methods: We performed 32 ctDNA NGS and 10 tissue NGS analyses in 26 patients with advanced HCC (January 2015 – October 2015). ctDNA analysis (54 to 70 genes) was performed using Guardant 360, which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations. The mutant allele fraction for detected alterations was calculated relative to wild type in ctDNA. Tissue NGS was performed using Foundation One or Molecular Health. The study ws conducted in accordance with UCSD Moores Cancer Center Institutional Review Board requirements. Results: Among 32 ctDNA NGS, at least one genomic alteration (excluding variants of uncertain significance (VUS)) was discerned in 27 samples (84.3%) (average = 2.1 alterations per patient [range, 0-5]) with a median mutant allele fraction of 0.92% (range, 0.06% - 40.57%). Ten patients had both ctDNA NGS and tissue NGS. The median time difference between the date of tissue and ctDNA NGS testing was 450 days (range, 29 – 876 days), possibly reflecting the challenge with doing a second tissue biopsy at the time of relapse. The most commonly mutated gene was TP53 (16 samples, 50.0%), followed by CTNNB1 (8 samples, 25.0%), ARID1A (6 samples, 18.6%), EGFR (4 samples, 12.5%) and MYC (4 samples, 12.5%). Amplification was observed in 11 genes, including CDK4, CDK6, CCNE1, EGFR, ERBB2, FGFR1, KRAS, and MYC. No fusions or indels were observed. At least one potentially actionable alteration was observed in 20 of the 26 patients (76.9%). In two patients treated on the basis of the ctDNA alterations alone, a response was seen. Conclusions: ctDNA profiling is feasible in advanced HCC, and may provide a tissue biopsy-free alternative in these difficult-to-biopsy patients. Further study of clinical validity and utility is ongoing.
Preclinical study of c-Met inhibitor as an adjuvant treatment for hepatocellular carcinoma with macroscopic portal vein invasion.
Authors: Kokudo Takashi , Inagaki Yoshinori , Hasegawa Kiyoshi , Shirata Chikara , Amikura Katsumi , Takahashi Amane , Kaneko Junichi , Akamatsu Nobuhisa , Arita Junichi , Sakamoto Yoshihiro , Sakamoto Hirohiko , Kokudo Norihiro 
Published: March 2017

301 Background: Patients with advanced hepatocellular carcinoma (HCC) demonstrating a macroscopic portal vein tumor thrombus (PVTT) have been reported to have an extremely poor prognosis. Palliative sorafenib is the only recommended treatment option. Methods: We statistically compared the patient characteristics and surgical outcomes in HCC patients with PVTT. Among 1,611 hepatic resections, 105 cases of PVTT were identified. Microarray analysis was performed in three patients to identify gene expression changes in PVTT compared with those in the principal tumor, and the changes were validated in 20 human HCC tissues with PVTT. The human HCC cell lines HuH-7 and SKHep-1 were used for this experimental study. A subcutaneously transplanted xenograft model was employed for the in vivo study. The c-Met inhibitor SU11274 was used in both in vitro and in vivoanalyses. Results: The median survival time in patients with PVTT was 2.01 years, while that in patients without PVTT was 6.43 years; the median time to recurrence was 0.31 and 1.61 years, respectively. Microarray analysis revealed 36 genes related to PVTT. Immunohistochemistry analysis revealed that compared with the principal tumor, E-cadherin (a key regulator of cancer metastatic potential) significantly decreased in PVTT in all 20 patients. The c-Met inhibitor elevated the E-cadherin expression level in HCC cells both in vitro and in vivo. This inhibitor induced sheet formation and attenuated the migration of HCC cells. Conclusions: Although liver resection provides acceptable overall survival for patients with PVTT, the recurrence rate remains high. The c-Met inhibitor exhibits an anti-metastatic effect in vitro and in vivo and may be useful as an adjuvant treatment for PVTT.
Genetic difference between multicentric carcinogenesis and intrahepatic metastasis of multiple hepatocellular carcinoma.
Authors: Midorikawa Yutaka , Yamamoto Shogo , Tatsuno Kenji , Ueda Hiroki , Tsuji Shingo , Nagae Genta , Takayama Tadatoshi , Aburatani Hiroyuki 
Published: March 2017

307 Background: Multiple hepatocellular carcinoma (HCC) is categorized into 2 types; multicentric carcinogeneis (MC) and intrahepatic metastasis (IM). Although discrimination of the types of multiple HCC is of clinical importance, it is difficult to determine it correctly even after histological diagnosis. Methods: In order to classify multiple HCC into MC and IM, we compared pairs of multiple HCC and matched non-tumoral liver samples from 22 patients who were clinically diagnosed MC and 8 patients with IM with regard to molecular aberrations using next generation sequencer. Results: Exome sequence showed that among the 22 patients with clinical MC, 7 patients were genetically determined as having IM (gIM) because of the concordance of mutations, while all the patients with clinical IM were as having MC (gMC). In 15 patients with gIM, 125 mutations (90.6%) per patient were common, which were consistent with the result of a pair of primary HCC, and only a few passenger mutations were different between IM specimens suggesting that IM pairs developed from the common ancestor. On the other hand, 138 somatic mutations per tumor, and no common somatic mutations were identified in the 15 patients with gMC. Clinically, vascular invasion was significantly frequent in gIM group ( P = 0.007). On the other hand, after a median follow-up of 2.56 years (range; 0.27−6.32 years), the median overall survivals were 3.7 years (95%CI, 1.26–6.14) and 3.37 years (2.02−6.32, P = 0.712) in the patients with IM and MC, respectively. The 3-year rates of overall survival were 71.7% and 65.1% in the two groups, respectively. Conclusions: Taken together, genetic comparison of mutations in a pair of HCCs makes it possible to classify MC and IM, which is available to make treatment plan for multiple HCC patients.
Subgroup analyses of a phase 1/2 study of lenvatinib (E7080), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: Ikeda Masafumi , Ikeda Kenji , Kudo Masatoshi , Osaki Yukio , Okusaka Takuji , Tamai Toshiyuki , Suzuki Takuya , Hisai Takashi , Miyagishi Hideaki , Okita Kiwamu , Kumada Hiromitsu 
Published: March 2017

309 Background: Lenvatinib is an oral tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT. A phase 1/2 trial in pts (n = 46) with advanced HCC and Child-Pugh score A treated with lenvatinib 12 mg once daily showed a median overall survival (OS) of 18.7 months, and a median time to progression (TTP) of 12.8 months by investigator review and 7.4 months by independent radiologic review (IRR). Objective response rate was 37.0% as assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Based on these results, a phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib is ongoing. Here, we report subgroup analyses of the phase 2 part of this study. Methods: Subgroups were retrospectively analyzed by Barcelona clinic liver cancer (BCLC) staging, disease etiology, prior therapy for advanced HCC (including sorafenib), and baseline Alpha-fetoprotein (AFP) levels. Efficacy endpoints including OS and TTP by IRR were assessed for each subgroup. TTP based on mRECIST and OS were assessed from the date of study registration to progressive disease and to death, respectively. Results: Median TTP and OS for each of the relevant subgroups of baseline characteristics are shown in the table. Conclusions: Pts with advanced HCC treated with lenvatinib showed similar TTP regardless of subgroup. Although the number of patients was limited, lenvatinib treatment shows promising efficacy even in patients with hepatitis B virus. Clinical trial information: NCT00946153. [Table: see text]
Clinical utilization of targetable molecular results in pancreatic cancer: Longer-term outcomes from the Individualized Molecular Pancreatic Cancer Therapy (IMPACT) trial.
Authors: Chantrill Lorraine A. , Nagrial Adnan , Johns Amber , McKay Skye , Gill Anthony J. , Pavlakis Nick , Grimison Peter S. , Asghari Gholamreza , Waddell Nicola , Chou Angela , Chin Venessa T. , Sebastian Lucille T , Verghis Jaclyn , Yip Sonia , Sjoquist Katrin Marie , Simes John , Biankin Andrew 
Published: March 2017

314 Background: The IMPaCT trial screened patients with advanced pancreas cancer for molecular targets and aimed to test molecularly guided therapy in a pilot randomized study, but closed in December 2015 having delivered personalized treatment to only 1 patient. A follow up analysis of the screened cohort provides insight into the clinical utilisation of targetable molecular results in pancreas cancer. Methods: IMPaCT screened for 3 genetic phenotypes matched to precision treatment: Her2 amplification (trastuzamab + gemcitabine), KRAS wildtype (erlotinib + gemcitabine) and DNA damage repair pathway defects (platinum-based). Previously recruited primary resected APGI participants known to be alive were also screened for these targets. The initial pilot protocol included randomisation, but after amendment in early 2015, became a single-arm study allowing one cycle of gemcitabine + nab-paclitaxel during screening. Results: A total of 101 potential patients were screened. This was enriched for patients with known targets where sequence data was available from primary pancreatectomy. 23 had one of the 3 molecular targets in this enriched population (4 Her2 amplified, 16 KRAS wt, 2 BRCA2, 1 ATM). The prospectively recruited de novo metastatic cohort (n = 63) had an actionable mutation detection rate of 14.3%. Of the 23 patients identified, 3 received personalised treatment off study, 1 on study, 3 are currently alive without recurrence, 1 is monitored for suspected recurrence, 2 developed second primary malignancies, 10 died or progressed prior to result and 3 decided not to use personalised treatment. The identification of a molecular target did not significantly affect overall survival. Conclusions: Although actionable molecular targets were detected, recruitment rates on the IMPaCT trial were low (1%). Follow up illustrates that these molecular results were incorporated into clinical care off trial or still have the potential to be utilised in another 6.9% of the cohort. Further follow up is planned for long term outcomes. Clinical trial information: ACTRN12612000777897.
Homologous recombination deficiency (HRD) in patients with pancreatic cancer (PC) and response to chemotherapy.
Authors: Shahda Safi , Timms Kirsten , Ibrahim Ashley , Reid Julia E. , Cramer Harvey M , Radovich Milan , Ibrahim Sulfikar , Allen Brian , O'Neil Bert H. 
Published: March 2017

317 Background: Mutations or copy number abnormalities of genes involved in homologous recombination occur in PC. DNA-based measures of HRD have been developed and may help identify tumors with better response to DNA damaging agents. This study aimed to describe the mutation and HRD status of PC and determine their association with treatment response and outcome. Methods: This was a retrospective analysis of tumor samples from patients treated at Indiana University for locally advanced or metastatic PC. Patients were included if they received gemcitabine/nab-paclitaxel or FOLFIRINOX and had adequate follow up to assess survival and response to therapy. Tumor analysis generated a 3-biomarker (LOH, TAI, LST) HRD score and mutation data for 45 genes. Results: Ninety-one samples met inclusion criteria, 78 (15 FFPE and 63 FNA) generated mutation data. HRD analysis was successful for 57; the primary cause of failure low tumor %. The final analysis set consisted of 78 samples with mutation status, including 57 with HRD scores (range= 5 -61 (median=18,)). Six BRCA1/ 2 mutations were detected, 5 had high HRD scores, with 4 in the top decile (p=0.011). Other DNA repair gene mutations ( ATM=3, ATR=1, BRIP1=1 and FANCI=1) were detected, but most retained one functional allele and were not associated with HRD score. There was no statistically significant correlation between HRD score and response to FOLFIRINOX (OR per interquartile range = 1.40, p=0.32 adjusted for treatment). HRD score was not associated with PFS or OS. For FOLFIRINOX, median survival times for low vs. high HRD (dichotomized at the median) were 5.3 vs. 9.4 months PFS (p=0.049) and OS 12.3 vs. 11.3 months (p=0.89). For gemcitabine/nab-paclitaxel, mPFS was 6.1 vs. 4.6 months (p=0.88), and mOS was 14.4 vs. 11.4 months (p=0.29). Conclusions: Mutations in DNA repair genes occur in PC, and HRD scores can be generated in the majority of cases. HRD score was not significantly associated with higher response rate or prolonged survival in relation to FOLFIRINOX in this small non-randomized retrospective cohort. Larger studies to examine the association of mutations in DNA repair genes and HRD may be needed to detect significant associations.
Preoperative vascular grading in patients undergoing surgery for pancreatic cancer: Does radiologic arterial or venous involvement predict margin status?
Authors: Reddy Sanjay S. , Karachristos Andreas , Ruth Karen , Hoffman John Parker 
Published: March 2017

319 Background: The use of neoadjuvant therapy has been widely used for borderline resectable pancreatic cancer (BLRPC). Controversy exists on the definition of BLRPC, and because of this, we examined the association of vascular involvement and margin status in patients who had initial resection. Methods: Records of 137 patients who had surgery for resectable or BLRPC were collected. Included were radiologist grading of venous/arterial involvement based on preoperative imaging. For patients with both staging recorded, we categorized vascular involvement as none, arterial only, venous only, or both. We examined the association of vascular involvement and margin status using Chi-square tests, and logistic regression. Results: Of 137 patients, all underwent surgery first. 85% had a Whipple without vascular resection, and 13% with. Of 134 patients with Ishikawa staging, there were 63% stage I, 17% stage II, 11% stage III, and 9% stage IV. Of 96 patients with arterial staging, there were 74% stage i, 16% stage ii, and 10% stage iii. Of 93 patients with both Ishikawa and arterial staging recorded, 61% had no vascular involvement, 7% arterial, 14% venous, and 17% had both. Ishikawa stage I-IV was associated with a positive SMA margin, and was seen in 14%, 44%, 53%, and 58%, respectively (p < 0.001). However, for arterial staging the association was weaker, and for arterial stages i-iii, a positive SMA margin was seen in 20%, 40%, and 40%, respectively (p = 0.06). Therefore, Ishikawa staging was more predicative of arterial involvement. Higher Ishikawa staging was associated with increased positive SMV margins; 5%, 26%, 33%, respectively (p < 0.001), while preoperative arterial staging was not predictive (p = 0.63). In logistic regression for any positive margin, only venous staging was significant in predicting a positive margin. Conclusions: The use of imaging in predicting positive margins is more accurate when using a venous grading system as opposed to an arterial one. With a more standard approach of designating degree of vein involvement, and better preoperative imaging, further studies will be needed to substantiate these findings.