Results Of Biomarker Analyses Research Articles

Two-Year Outcomes and Biomarker Analysis of Locally Advanced Gastric and Gastroesophageal Junction Adenocarcinoma After Neoadjuvant Chemotherapy and Immunotherapy from the Phase II WuhanUHGI001 Trial.

This study reports the 2-year outcomes and biomarker analysis results of patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma who received neoadjuvant chemotherapy and immunotherapy in a phase II WuhanUHGI001 trial. Eligible patients with cT3/4aN+M0 locally advanced G/GEJ adenocarcinoma were screened, enrolled, and treated with 3 cycles of neoadjuvant tislelizumab and SOX followed by D2 gastrectomy and another 5 cycles of postoperative adjuvant SOX. The primary endpoint was major pathological response. Of the 49 included patients, 24 (49.0%) achieved major pathological response and 13 (26.5%) achieved pathological complete response. During a median follow-up of 26.8 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 69.4% and 81.2%, respectively. Grade 3-4 adverse events occurred in six patients (12.2%) during the neoadjuvant period, eight patients (17.0%) during the postoperative period, and seven patients (15.2%) during the adjuvant period. Biomarker analysis revealed that the pathological complete response showed no association with 2-year PFS and OS. Major pathological response showed a potentially strong association with improved 2-year PFS and OS rates. In addition, preoperative circulating tumor cells combined with pathological responses are helpful in prognosis assessment. In addition, our results showed that T downstaging, lymphocyte-to-monocyte ratio, and CD3+ T cells were independent factors that affect PFS. The signet ring cell component (SRCC), T downstaging, and neutrophil-to-lymphocyte ratio were independent factors affecting OS. Prognostic nomograms of PFS and OS constructed based on the multivariate Cox regression results demonstrated suitable calibration and discrimination ability. Neoadjuvant tislelizumab plus SOX exhibits promising efficacy and acceptable toxicity in patients with locally advanced G/GEJ adenocarcinoma. In addition, our study established a prognostic risk signature and nomograms based on clinicopathological characteristics, which can accurately predict patient outcomes and aid in personalized treatment planning.

Abstract 5184: Biomarker results from PEVENAZA, a randomized phase 2 study of venetoclax and azacitidine +/- pevonedistat in newly diagnosed AML patients unfit for intensive chemotherapy: Increased efficacy in a subset of patients with IDH1/2 mutations and other observations

Abstract Background: Many newly diagnosed patients with AML are ineligible for intensive chemotherapy due to pre-existing comorbidities and older age. VIALE-A, a phase-3 trial with venetoclax (ven) and azacitidine (aza) established this combination as a new standard of care (SOC) for this patient population. The addition of pevonedistat (pevo) to this combination was evaluated in the same patient population in the current trial (NCT04266795). Here we present results of biomarker analyses from baseline and on-treatment bone marrow samples. Methods: Molecular mutational analysis was performed using a next generation sequencing (NGS) panel on baseline bone marrow samples. Combining this data with cytogenetics allowed centralized assignment of risk category based on ELN2017 guidelines. Longitudinal bone marrow aspirate samples were also examined by multi-color flow cytometry for expression of select surface antigen expression and to identify AML leukemic stem cells (LSCs) from the blast population. Results: Eleven genes were selected for analyses based on prevalence and scientific interest, including DNMT3A, ASXL1, TET2, FLT3, and IDH1/2. In contrast to other genes and ELN risk categories, we observed a statistically significant increase (p-value 0.013) in CR+CRi rates for IDH1/2 mutant patients when treated with pevo + ven + aza (95%, n=21) compared to ven+aza control arm (62%, n=21). In addition, we evaluated the prevalence of CD33, CD123 and CLEC12a, targets of current AML developmental therapeutics, in both the blast and LSC populations at baseline. The median (n=120 pts) % blast cells expressing CD33, CD123, or CLEC12a were 89.8%, 63.2%, and 66.0%, respectively. The median (n=78 pts) % LSCs expressing CD33, CD123, or CLEC12a were 48.2%, 90.9%, and 32.0%, respectively. Importantly, we did not see any significant difference in median fluorescence intensity (MFI) or % expression in any of the three proteins after treatment with ven and aza (+/- pevo). Finally, no strong associations were observed between expression levels and either mutations or ELN risk categories. Conclusions: Analyses of biomarker samples as part of the PEVENAZA trial resulted in several insights for not only the pevonedistat program but also for other AML therapeutics in development. The observation that newly diagnosed patients with IDH1/2 mutations may benefit from the addition of pevo to ven+aza is certainly hypothesis-generating but would require further follow-up with higher patient numbers. In addition, baseline CD33, CD123, and CLEC12a expression levels were in line with published studies. Here we have also shown they remain similar after SOC treatment (ven+aza) supporting the development of agents that target these proteins in both first and second line settings for AML. Citation Format: Radha Ramesh, Xiang Fang, Shuli Li, Sharon Friedlander, Farhad Sedarati, Lionel Adès, Nicholas Short, Cristina Papayannidis, Tammie Yeh. Biomarker results from PEVENAZA, a randomized phase 2 study of venetoclax and azacitidine +/- pevonedistat in newly diagnosed AML patients unfit for intensive chemotherapy: Increased efficacy in a subset of patients with IDH1/2 mutations and other observations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5184.

Amelioration of walnut, peony seed and camellia seed oils against D-galactose-induced cognitive impairment in mice by regulating gut microbiota.

Diet adjustment will affect the health of gut microbiota, which in turn influences the development and function of the organism's brain through the gut-brain axis. Walnut oil (WO), peony seed oil (PSO) and camellia seed oil (CSO), as typical representatives of woody plant oils, have been shown to have the potential to improve cognitive impairment in mice, but the function mechanisms are not clear. In this study, we comparatively investigated the neuroprotective effects of these three oils on D-galactose (D-gal)-induced cognitive impairment in mice, and found that the ameliorative effect of WO was more prominent. During the behavioral experiments, supplementation with all three oils would improve spatial learning and memory functions in D-gal mice, with a significant reduction in the error times (p < 0.001) and a significant increase in step-down latency (p < 0.001); walnut oil supplementation also significantly increased the number of hidden platform traversals, the target quadrant spent times and percentage of distance (p < 0.05). The results of biomarker analysis showed that WO, in addition to significantly inhibiting D-gal-induced oxidative stress and neuroinflammation as did PSO, significantly increased the ACh content in the mouse brain (p < 0.05) and modulated neurotransmitter levels. The results of further microbiota diversity sequencing experiments also confirmed that dietary supplementation with all three oils affected the diversity and composition of the gut microbiota in mice. Among them, WO significantly restored the balance of the mouse gut microbiota by increasing the abundance of beneficial bacteria (Bacteroidetes, Actinobacteria, Firmicutes) and decreasing the abundance of harmful bacteria (Clostridium, Shigella, Serratia), which was consistent with the results of behavioral experiments and biomarker analyses. Based on the analysis of the fatty acid composition of the three oils and changes in the gut microbiota, it is hypothesized that there is a correlation between the fatty acid composition of the dietary supplement oils and neuroprotective effects. The superiority of WO over PSO and CSO in improving cognitive impairment is mainly attributed to its balanced composition of omega-6 and omega-3 fatty acids.

Abstract CT141: Combination of hormone therapy, GnRH agonist, and immunotherapy enhance immune activation in premenopausal ER+/HER2- metastatic breast cancer patients: Results of biomarker analysis from a pilot phase II study

Abstract Introduction: Immunotherapy has not been proved to be efficacious in ER+/HER2- metastatic breast cancer. Our team has reported an effective combination of exemestane, gonadotropin releasing hormone agonist, and pembrolizumab in premenopausal ER+/HER2- MBC. Here we report the updates of the final results and biomarker associates of the study. Methods: Premenopausal ER+/HER2- MBC patients who failed no more than 2 lines of hormone therapy without chemotherapy for MBC were enrolled in a tertiary medical center in Taiwan (NCT02990845). The primary endpoint was progression-free survival (PFS) rate at 8 months. The secondary endpoints included overall response rate, overall survival (OS), progression-free survival (PFS), and other biomarkers. Pre-treatment (N=12) and post-treatment (N=5) tumor tissue were collected for biomarker analysis, including tumor-infiltrating lymphocyte(TIL), PD-L1 expression by immunohistochemical staining, tumor mutational burden, RNAseq, and IO360 analysis. Results: A total of 15 patients were enrolled in the study with 14 evaluable patients. The progression-free survival rate at 8 months was 64.3%. The median PFS and OS were 10.34 months and 39.56 months respectively. The overall response was 35.7%. TIL, tumor mutational burden, or PD-L1 expression were not associated with the response to the treatment. In the NanoString IO-360 analysis, increased expression of genes in the immune related signature was noted in the post-treatment samples as compared to the pre-treatment samples. The expression levels of MHC class II and T cell-related genes were upregulated in the post-treatment samples. Most of the immune cell populations are increased after pembrolizumab/exemestane/leuprolide treatment. CD56 dim NK cells, Th1 cells, and NK cells are the top 3 populations that are increased after treatment. Using CIBERSORT algorithms to analyze RNAseq data from pretreatment samples, dendritic cells (p=0.039) and NK cells (p=0.082) were associated with the responders versus non-responders in the study. Conclusion: In this final analysis, pembrolizumab, exemestane, and leuprolide remain an effective treatment for premenopausal ER+/HER2- MBC. Pembrolizumab, exemestane, and leuprolide treatment is associated with immune system activation, turning the tumor microenvironment from cold to hot in luminal disease. Citation Format: I-Chun Chen, Ching-Hung Lin, Dwan-Ying Chang, Tom Wei-Wu Chen, Ming-Yang Wang, Wei-Li Ma, Yi-Ting Lin, Shu-Min Huang, Yen-Shen Lu. Combination of hormone therapy, GnRH agonist, and immunotherapy enhance immune activation in premenopausal ER+/HER2- metastatic breast cancer patients: Results of biomarker analysis from a pilot phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT141.

Geochemical analysis of oil and core samples derived from oil and gas fields in the South-Mangyshlak basin

This paper presents the results of biomarker analysis of 183 oil samples derived from 19 oil and gas fields and Rock-Eval pyrolysis performed on 93 core samples from 12 fields in the South Mangyshlak basin. According to the biomarkers, oils of studied fields were formed from shaly OM and can be divided into 3 groups: the first group includes Oymasha, Ashiagar, Atambay-Sartobe, Alatyube, Karagie North and Akkar North, which have OM of marine origin, while the second group includes oils from the Pridorozhnoye, Airantakyr, Burmasha and Bekturly fields, which have OM of lacustrine origin. The third group includes oils from rest fields, within each of which there are at least two sources: the oils of the lower pay zones have shaly OM of marine origin, and the OM of the oils of the upper horizons was formed in the lacustrine environment. Rock-Eval pyrolysis revealed that some fields can be considered synclinal. Keywords: chromatography; biomarkers; steranes; hopanes; Rock-Eval pyrolysis; South-Mangyshlak.

Biomarkers and Carbon Isotope of Monomer Hydrocarbon in Application for Oil-Source Correlation and Migration in the Moxizhuang-Yongjin Block, Junggar Basin, NW China.

Different opinions on the oil-source correlation and migration of the Moxizhuang-Yongjin block in the Junggar Basin, NW China, have seriously affected oil and gas exploration in this area. This research is based on the results of biomarker analysis and carbon isotope of monomer hydrocarbon on crude oil and source rock samples from different blocks. Two oil families (A1, A2, and B) are classified by cluster analysis on nine typical biomarker ratios. Typically, sub-family A1 oils are distributed in the Zhuang 102 well block of the Moxizhuang block, and their gammacerane index is the highest. The abundance of C24 tetracyclic terpanes is the lowest, the C27 regular steranes are dominant, and the organic matter is mainly input by lower aquatic organisms. Sub-family A2 oils are distributed in the Zheng 1-1 well block of the Moxizhuang block. The gammacerane index of oils is lower than the former, and the abundance of C24 tetracyclic terpanes is higher. In the dual input of lower aquatic organisms and terrestrial higher plants, the input of terrestrial higher plants accounted for a larger proportion. Family B oils are distributed in the Yong 2 well block of the Yongjin block, and their gammacerane index is the lowest. They have a high abundance of C24 tetracyclic terpanes, and C29 regular steranes are dominant, reflecting the characteristics of terrigenous organic matter contribution. Based on the biomarker compound composition, at least two oil charges are indicated: Sub-family A1 oils are likely sourced from the Wuerhe formation, sub-family A2 oils may be a mixture of Wuerhe formation and Badaowan formation, and family B oils are likely sourced from the Badaowan formation. The oil families with typical genetic affinities may indicate two major petroleum systems or multiple oil systems existing in the study area. In addition, the characteristics of hydrocarbon accumulation and migration are also discussed, the oil and gas in the West Sag of Well Pen 1 and Changji Sag are filled from deep to shallow in the vertical direction and migrated from south to north in the horizontal direction, at the same time, with the help of sand bodies and faults, and they migrated to the north and northeast. This work provides a scientific basis for oil and gas exploration in the hinterland of the Junggar Basin.

244 (PB024) - Phase I Biomarker Analysis Results of MORAb-202 (Farletuzumab Ecteribulin) Effects on Vascular Remodeling and Immune Modulation in Patients With Ovarian Cancer

Background: MORAb-202 is an antibody–drug conjugate consisting of the humanized anti-folate receptor-alpha (FRα) monoclonal antibody, farletuzumab, and the potent microtubule dynamics inhibitor, eribulin. It is highly stable in systemic circulation and releases eribulin in the targeted cells. While MORAb-202 is cytotoxic to FRα-expressing cancer cells, it also exerts cytotoxic bystander effects on adjacent tumor and stromal cells, as well as noncytotoxic bystander effects on the tumor microenvironment (TME) in preclinical models.

Organic Geochemistry and Oil-Source Correlation of Oil Seepages and Potential Source Rocks in Qiangtang Basin, China.

Different viewpoints on the oil-source correlation of the Angdarco paleo-reservoir in the Qiangtang Basin, northern Tibet, China, have seriously affected oil and gas exploration in this area. In this work, based on the results of biomarker analysis on six oil seepage samples and 11 potential source rock samples, the oil source of the oil seepages in the Angdarco area was examined by correlating the composition characteristics of n-alkanes, multiple factors of biomarkers, correlograms of biomarker parameters, and δ13C values of individual n-alkanes between oil seepages and potential source rocks. In addition, the sedimentary environment and thermal maturity characteristics of the potential source rocks were also discussed. The biomarkers indicated that the potential source rocks of the Lower Jurassic Quse Formation (J1q) presented characteristics of littoral sediments, deposited under suboxic conditions, while the potential source rocks of the Middle Jurassic Buqu Formation (J2b) were deposited in a marine sedimentary environment and presented characteristics of a low mature to mature stage. The potential source rocks of the Middle Jurassic Xiali Formation (J2x) were deposited in a low-salinity environment and presented characteristics of low-mature source rocks. Finally, the oil seepages of the Buqu Formation were deposited in a suboxic littoral environment and presented characteristics of a low mature to mature stage. It is concluded that the oil seepages in the Angdarco paleo-reservoir were mainly sourced from the Lower-Jurassic Quse oil shales. This work provides a scientific basis for the exploration of paleo-reservoirs in the southern Qiangtang Basin.

Abstract 3481: Pharmacokinetics of alofanib and biomarker analysis in patients with advanced gastric cancer: A phase 1b study

Abstract Alofanib is a potent, small molecule, allosteric inhibitor that binds to the non-active extracellular site of IIIc and IIIb FGFR2 isoforms. Phase 1b clinical study (RPT835GC1B) met its primary endpoints and recommended phase 2 dose was described early. Here, we present pharmacokinetics (PK) and results of biomarker analysis. Alofanib was administered daily intravenously for 5-days followed by a 2-day interval (rest). There were five dose levels using a 3 + 3 design. 21 patients have been enrolled in the study. Patients were Caucasian (100%), predominantly male (71%), 67% had 2 and more metastatic sites, including liver (43%) and bone (14.3%) metastases, 19% had ECOG PS 2, and were heavily pretreated (86% had previous 3 and more lines of therapy). The PK and biomarker analysis set included 18 patients. FGFR2 amplification was accessed by FISH with ZytoLight SPEC FGFR2/CEN 10 Dual Color Probe and FGFR2 expression was accessed by IHC with antibody 1G3 (Abcam (ab 5820). Table summarizes PK data. The geometric mean values of Cmax, AUC0-t, T1/2, Vd increased and CL, Kel decreased approximately dose-proportionally after single dosing, similar to previous preclinical studies. The decrease in the mean value of the Vd for a dose of 350 mg/m2 may be associated with a significant increase in AUC0-t. No correlations between PK values and objective response rate (n=2; 9.5%), progression-free (median 3.63 months (95% CI, 1.58 - 5.68) and overall (median 7.0 months (3.82 - 10.18) survival as well as in patients with liver metastases were found (all P&amp;gt;0.1). A positive FGFR2 IHC expression was observed in all tumor cells and a weak positive reaction in normal epithelium. FGFR2 amplification was confirmed by FISH in 1 (5.6%) patient.Alofanib PK in a gastric patient population is well characterized, supporting the use of a once-daily 350 mg/m2 dose. In further studies, the evaluation of FGFR2 amplification seems to be important. Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 50 mg/m2 100 mg/m2 165 mg/m2 250 mg/m2 350 mg/m2 Cmax, mcg/ml (CV%) 21.4 (32.3) 23.7 (18.4) 44.7 (15.5) 72.8 (64.3) 145.9 (42.7) AUC0-t, mcg*h/ml (CV%) 2.3 (31.9) 6.6 (14.2) 13.3 (49.9) 23.8 (8.7) 74.0 (57.5) Vd, ml/m2 (CV%) 4006.1 (28.3) 4907.5 (14.7) 5676.8 (26.6) 6686.7 (11) 3823.0 (63.8) CL, ml/h/m2 (SD) 19609.5 (7740) 14028.2 (1990) 11910.5 (8740) 10011.0 (827) 4183.0 (2420) Kel, 1/h (CV%) 4.9 (15.3) 2.9 (2.8) 2.1 (41.2) 1.5 (3.8) 1.1 (47.0) T1/2, h (SD) 0.1 (0.024) 0.2 (0.01) 0.3 (0.118) 0.5 (0.0171) 0.6 (0.293) Citation Format: Grigory Raskin, Vasily Kazey, Svetlana Gorbacheva, Aiyyna Nikiforova, Galina Statsenko, Elena Artamonova, Liubov Vladimirova, Natalia Besova, Anastasia Mochalova, Ivan Rykov, Vladimir Moiseyenko, Igor Utyashev, Sergei Iugai, Nadezhda Dragun, Dmitry Reznikov, Evgenia Gavrilova, Sergei Tjulandin, Ilya Tsimafeyeu. Pharmacokinetics of alofanib and biomarker analysis in patients with advanced gastric cancer: A phase 1b study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3481.

Geochemical studies of gases from oil and gas fields in the southern part of the caspian basin and their correlation with the results of oil geochemistry

This article presents the results and interpretation of the compositional and isotopic analysis of carbon in 14 gas samples derived from oil and gas fields and structures (Liman, East Makat, North Kotyrtas, Zholamanov, S. Nurzhanov and West Prorva) of the southern part of Pre-Caspian basin. According to the results of this study, all gases have a thermogenic source and their organic matters were deposited in the marine environment, which is also consistent with the results of biomarker analysis of oils from these studied fields. A sharp enrichment of propane with heavy carbon isotope in gas №55 of East Makat field suggests its biodegradation, which is also confirmed by the results of gas chromatographic analysis of oil from this well. A star diagram of gases was plotted based on normalized values of carbon isotopic composition of C1-C5, according to the results of which the studied samples can be divided into 5 genetically different groups. The identified groups based on results of this gas analysis are also consistent with the results of «fingerprinting» of oil from these fields. Keywords: gas composition; gas isotopic composition; Rayleigh fractionation; Bernard diagram; Clayton diagram; Laurent diagram; Chung diagram; enrichment in heavy isotope.

Discovery of metabolomic biomarkers for discriminating platinum-sensitive and platinum-resistant ovarian cancer by using GC-MS.

This study aims to determine ovarian cancer (OC) patients with platinum resistance for alternative treatment protocols by using metabolomic methodologies. Urine and serum samples of platinum-resistant and platinum-sensitive OC were analyzed using GC-MS. After data processing of GC-MS raw data, multivariate analyses were performed to interpret complex data for biologically meaningful information and to identify the biomarkers that cause differences between two groups. The biomarkers were verified after univariate, multivariate, and ROC analysis. Finally, metabolomic pathways related to group separations were specified. The results of biomarker analysis showed that 3,4-dihydroxyphenylacetic acid, 4-hydroxybutyric acid, L-threonine, D- mannose, and sorbitol metabolites were potential biomarkers in urine samples. In serum samples, L-arginine, linoleic acid, L-glutamine, and hypoxanthine were identified as important biomarkers. R2Y, Q2, AUC, sensitivity and specificity values of platinum-resistant and sensitive OC patients' urine and serum samples were 0.85, 0.545, 0.844, 91.30%, 81.08 and 0.570, 0.206, 0.743, 77.78%, 74.28%, respectively. In metabolic pathway analysis of urine samples, tyrosine metabolism and fructose and mannose metabolism were found to be statistically significant (p < 0.05) for the discrimination of the two groups. While 3,4-dihydroxyphenylacetic acid, L-tyrosine, and fumaric acid metabolites were effective in tyrosine metabolism. D-sorbitol and D-mannose metabolites were significantly important in fructose and mannose metabolism. However, seven metabolomic pathways were significant (p < 0.05) in serum samples. In terms of p-value, L-glutamine in the nitrogen metabolic pathway from the first three pathways; L-glutamine and pyroglutamic acid metabolites in D-glutamine and D-glutamate metabolism. In the arginine and proline metabolic pathway, L-arginine, L-proline, and L-ornithine metabolites differed significantly between the two groups.

Application of biomarkers and oil fingerprinting for genetic classification of oil families and prediction of oil migration pathways in Nuraly field

This paper presents the interpretation of the results of biomarker analysis and oil fingerprinting of all producing wells (36 samples) of Nuraly field for genetic typing and fluid communication assessment within the field, followed by predicting the hydrocarbon migration pathways. According to the biomarker study, it was revealed that the oils of central and western Nuraly have genetically different origins, and the petroleum accumulation in the southern part of West Nuraly was formed by the continuous secondary migration of HC from the northeastern and northwestern directions. Oils from central Nuraly field have higher thermal maturity and lower density than those of western Nuraly do. The thermal maturity of samples from Central Nuraly decreases from the northeastern part of Nuraly towards the southwestern part, which may also attest to hydrocarbon migration pathways. The presence of gas caps in the northeastern part of Central Nuraly may be due to their high thermal maturity.

Clinical activity of durvalumab and savolitinib in MET-driven, metastatic papillary renal cancer.

4511 Background: Savolitinib is a potent and selective MET inhibitor with activity in MET-driven papillary renal cancer (PRC). Durvalumab is a PD-L1 inhibitor which has been tested in combination with savolitinib in metastatic PRC with response rates of 29% (12/41). Here we describe the efficacy of this combination in MET-driven metastatic PRC. Methods: This single arm phase I/II trial explored durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in metastatic PRC, with a 4wk savolitinib run in. Biomarker analysis results were compared with responses to treatment as planned in the protocol. The analysis presented here focuses on those patients with MET DNA alterations (central analysis:chromosome 7 gain/MET or HGF amplification/MET kinase domain mutations). Confirmed response rate (RR) (RECIST v1.1), progression-free survival (PFS), tolerability (CTCAE v4.03) and overall survival (OS) were analysed. Results: 42 patients were enrolled in the metastatic papillary cohort, of which 41 patients received treatment. The median follow up was 26.8 months. The confirmed RR was 29% (12/41) and median PFS was 4.9 months (95% CI 2.5-10.0). 14/41 (34%) of these patients had MET-driven disease. 71% (10/14) of MET-driven patients had not previously received systemic therapy and 7% (1/14) were PD-L1 positive. IMDC good, intermediate, and poor risk disease occurred in 36% (5/14), 57% (8/14), and 7% (1/14) of MET-driven patients respectively. Confirmed RR in MET-driven patients was 57% (8/14) with duration of response at 9.4 months (95% CI 3.9-Not reached [NR]). Median PFS and OS in MET-driven patients were 10.5 months (95% CI 2.9-15.7) and 27.4 months (95% CI 7.3-NR) respectively. No new safety signals were seen. Conclusions: The combination of savolitinib and durvalumab has clinical activity in MET-driven PRC. A randomised phase III study is planned based upon these data. Clinical trial information: NCT02819596.

Results of biomarker analysis from phase II trial of nivolumab in refractory biliary tract cancer.

338 Background: Our previous phase II study demonstrated that nivolumab provides modest but durable clinical efficacy in patients (pts) with refractory biliary tract cancer (BTC), suggesting the significant clinical benefit of nivolumab in selected pts and identification of potential predictive biomarkers. Here, we report outcomes from the biomarker analysis. Methods: Pre-treatment tumor samples were obtained and assessed for immunohistochemistry (IHC) with PD-1 and PDL-1 antibodies, mRNA sequencing (RNAseq), and whole exome sequencing (WES). Clinical efficacy was correlated with the molecular analysis. Prior cisplatin exposure was reviewed to evaluate the impact of cisplatin on the tumor mutational burden (TMB) and clinical outcome. Results: Among 46 pts who had tumor response evaluation, 31 pts received cisplatin prior to nivolumab, and 15 were cisplatin-naive. Pre-treatment tumor samples were assessed for IHC (n = 42), RNAseq (n = 11), and WES (n = 11) based on tissue availability. There was no statistically significant correlation between prior cisplatin exposure and clinical outcome. Among 42 available tumor samples, 18 (43%) expressed PD-L1 positivity ( &gt; 1%), which was associated with a statistically significant prolonged progression free survival (PFS). Median PFS was 10.4 months for PD-L1 positive vs 2.4 months for PD-L1 negative (HR 0.23, 95% CI 0.10-0.51; P &lt; 0.001), while there was no statistically significant correlation between PD-1 expressing tumor infiltrating lymphocytes and clinical outcome. There was also no statistically significant difference in TMB of cisplatin-exposed (n = 8) vs. cisplatin-naïve tumor samples (n = 3) (9162, SD = 150 vs. 8898, SD = 806, p = 0.62). In comparing the group with prolonged disease control of at least 16 weeks (n = 4) to those with rapid disease progression (n = 7) who had mRNA sequencing performed, levels of AC005609.1, FAT3, TMEM151A, ADARB2, FAM153A were all significantly upregulated (p &lt; 0.01), while levels of CLCA1, MUC2, IGHV3-43, SWORA6, and CRISP3 were all significantly downregulated (p &lt; 0.01). Conclusions: Prior cisplatin exposure did not lead to statistically significant differences in clinical outcome or TMB in advanced BTC pts treated with nivolumab. However, PD-L1 expression &gt; 1% correlated with improved PFS, and variations in level of certain mRNA sequences were noted when comparing pts who had rapid disease progression vs. prolonged disease control with nivolumab. This suggests that BTC pts with positive PD-L1 expression and a particular mRNA profile may have a favorable response to nivolumab. Further studies are needed to confirm these findings. Clinical trial information: NCT02829918.

Effects of acute synovitis experimentally induced by amphotericin-b on the biomarkers of camel joint structures

The major objective of this study was to evaluate the effects of acute synovitis on the joint structures (bone, articular cartilage and synovial membrane) through the evaluation of biomarkers of bone, cartilage and synovial membrane in dromedary camels. Acute synovitis was experimentally induced by injecting amphotericin-B (20 mg in 4 ml sterilised distilled water) in the intercarpal joints of eight dromedary camels (treatment group) and other eight camels were used as a control group. Synovial fluid samples were collected prior to injection and 7, 14, 21 and 28 days post injection. Inflammatory biomarkers (Prostaglandin E2) and biomarkers of bone (bone alkaline phosphatase, osteocalcin and pyridinum cross-links) and cartilage (Chondroitin sulfate 846 epitope, C-terminal propeptide of type II procollagen, sulfated glycosaminoglycans and hyaluronan) were determined in the synovial fluid samples. The results showed significant elevations in the inflammatory, articular cartilage and bone biomarkers in the synovial fluid from the treatment group compared to the controls. Elevations of bone resorption and formation biomarkers were late in compare to cartilage biomarkers. This study proved that amphotericin B is an appropriate drug to induce synovitis in the camel joints when injected intra-articular. According to the results of biomarker analysis, it can be concluded that cartilage degradation proceeds bone degradation in camel joint with synovitis. Within articular cartilage tissue, proteoglycan synthesis proceeds type II collagen formation.

Metabolic Changes in Serum Metabolome of Beagle Dogs Fed Black Ginseng.

The effects of black ginseng, which has many kinds of biological activities, on dogs was investigated. Serum samples of beagle dogs, which were fed with black ginseng for 8 weeks, were measured using high-resolution magic angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectrometry. Acquired NMR data from the serum of dogs fed for 0, 4, and 8 weeks were analyzed by metabolic profiling and multivariate statistical analysis. In statistical analysis and biomarker analysis results of metabolite profiles, formate, glutamine, histidine, isoleucine, leucine, proline, and valine had variable importance in projection (VIP) scores above 1.0 and excellent area under the curve (AUC) values of receiver operating characteristic (ROC) curves above 0.9. In the result of multivariate statistical analysis, the score plot showed the discrimination between before and after feeding of black ginseng. These differences in metabolic profiles are considered to be due to the involvement of metabolic processes following black ginseng administration, such as enhancing immunity and energy metabolism. Through metabolomics analysis, we confirmed the biological efficacy of black ginseng in dogs and also confirmed that metabolomics can be applied to the pet health industry.

Petroleum source of oil seepages in the Kalpin area, NW Tarim Basin, China

Source rocks in Lower Cambrian (Є1) and Middle-Upper Ordovician (O2+3) have low S2 values, ranging from 0.01 to 0.34 and 0.01–5.95 mg HC/g Rock, respectively. The averages of TOC are 1.07% and 0.84% for Є1 and O2+3 source rocks, respectively. The equivalent vitrinite reflectance values (VREs) indicate that Є1 rocks are in a high-over mature stage for oil generation, and O2+3 rocks are sufficiently mature.Four oil seepages from the Yingshan Formation in the Qingsong quarry of the Aksu area and 34 core samples from Є1 and O2+3 rocks in the Kalpin area were analyzed for stable carbon isotopes. Moreover, 4 oil seepages and 16 core samples were analyzed by gas chromatography-mass spectrometry (GC-MS). Compared with O2+3 rocks, Є1 rocks are characterized by lower values of Gammacerane/C30 hopane (G/H), C28/(C27 + C28 + C29) 20R ααα sterane (C28%), C29/(C27 + C28 + C29) 20R ααα sterane (C29%), C26 20S/C28 20S triaromatic steroids (C26/C28), (C26 + C27)/C28 triaromatic steroids and (C26 20R + C27 20S)/C28 20R triaromatic steroids, and higher values of C21/C23 tricyclic terpane (C21/C23), C27/(C27 + C28 + C29) 20R ααα sterane (C27%), and C35 αβ (22R + 22S) homohopane/αβ C30-hopane (C35 H/H). The two sets of source rocks have a ‘‘V (C27>C28<C29)”-shaped regular sterane distribution pattern, and O2+3 rocks contain triaromatic steranes in abundances as high as those of Є1 rocks. C28C34 25-norhopanes (NHs) indicates that the degree of degradation of oil seepages falls at approximately PM 6, rendering many biomarker parameters ineffective for oil-source correlations, except for triaromatic steriods and carbon isotopic compositions. The values of C26/C28, (C26 + C27)/C28 triaromatic steroids and (C26 20R + C27 20S)/C28 20R triaromatic steroids using 0.50, 1.45 and 1.80 as threshold values, respectively, can differentiate Є1 and O2+3 rocks, and oil seepages show a natural affinity to the Є1 source rocks. The Є1 rocks have lighter δ13C of kerogen and heavier δ13C of group compositions than those of O2+3 rocks. The group compositions of oil seepages are depleted in 13C by approximately 0–1.5‰ compared with kerogens of Є1 extracts, further suggesting that the oil seepages are comparable to Є1 source rocks consistent with the results of biomarker analysis.

128P - Differential gene expression profiles in poor vs good responders to maintenance vinflunine in patients (p) with advanced urothelial carcinoma (aUC): Preliminary results of biomarker analyses from the MAJA trial (SOGUG 2011/02)

128P - Differential gene expression profiles in poor vs good responders to maintenance vinflunine in patients (p) with advanced urothelial carcinoma (aUC): Preliminary results of biomarker analyses from the MAJA trial (SOGUG 2011/02)

Theranos Experience Exposes Weaknesses in FDA Regulatory Discretion.

Theranos Experience Exposes Weaknesses in FDA Regulatory Discretion.

Adaptation of the human population to the environment: Current knowledge, clues from Czech cytogenetic and "omics" biomonitoring studies and possible mechanisms.

The human population is continually exposed to numerous harmful environmental stressors, causing negative health effects and/or deregulation of biomarker levels. However, studies reporting no or even positive impacts of some stressors on humans are also sometimes published. The main aim of this review is to provide a comprehensive overview of the last decade of Czech biomonitoring research, concerning the effect of various levels of air pollution (benzo[a]pyrene) and radiation (uranium, X-ray examination and natural radon background), on the differently exposed population groups. Because some results obtained from cytogenetic studies were opposite than hypothesized, we have searched for a meaningful interpretation in genomic/epigenetic studies. A detailed analysis of our data supported by the studies of others and current epigenetic knowledge, leads to a hypothesis of the versatile mechanism of adaptation to environmental stressors via DNA methylation settings which may even originate in prenatal development, and help to reduce the resulting DNA damage levels. This hypothesis is fully in agreement with unexpected data from our studies (e.g. lower levels of DNA damage in subjects from highly polluted regions than in controls or in subjects exposed repeatedly to a pollutant than in those without previous exposure), and is also supported by differences in DNA methylation patterns in groups from regions with various levels of pollution. In light of the adaptation hypothesis, the following points may be suggested for future research: (i) the chronic and acute exposure of study subjects should be distinguished; (ii) the exposure history should be mapped including place of residence during the life and prenatal development; (iii) changes of epigenetic markers should be monitored over time. In summary, investigation of human adaptation to the environment, one of the most important processes of survival, is a new challenge for future research in the field of human biomonitoring that may change our view on the results of biomarker analyses and potential negative health impacts of the environment.