scholarly journals TAMI-13. IMPORTANCE OF CD38 INHIBITION IN PRE-RECURRENT GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii215-ii216
Author(s):  
Renee Hirte ◽  
Ian E Olson ◽  
Masum Rahman ◽  
Moustafa Mansour ◽  
Amanda Munoz Casabella ◽  
...  
Keyword(s):  
Glioma Cell ◽  
Large Scale ◽  
Progression Free Survival ◽  
Standards Of Care ◽  
Screening Methods ◽  
Human Glioma ◽  
Glioma Tissue ◽  
Free Survival ◽  
Nad Synthesis ◽  
Large Scale Screening

Abstract Glioblastoma multiforme (GBM) is the most aggressive CNS neoplasm with a mere 15 month progression-free survival following current standards-of-care. Furthermore, conventional therapies have been effective, in part, by inducing a senescent-like phenotype in at least a proportion of glioma, as well as within the tumor-adjacent, healthy brain cells. Through an N-glyco-capture large-scale screening method, we were able to identify 25 genes exclusively overexpressed on glioma cell surfaces. Of those 25 targets, CD38 was an attractive target due to pre-existing FDA approved therapeutics. Recent studies have shown, however, that senescent cells, such as those induced via chemo- and radiotherapies, secrete a pro-inflammatory array of cytokines, known collectively as senescence associated secretory phenotype (SASP), that are capable of increasing CD38 expression in monocytes. CD38 functions as an ectoenzyme to convert extracellular NAD+ to nicotinamide (required for glioma cell salvage pathway NAD+ synthesis) and ADPR/cADPR (a cellular proliferation signal). To examine the effects of radiation on human glioma tissue, we performed reverse cyclase assays (RCA) on paired primary and recurrent human glioma tissue samples and found an increase in CD38 activity in post-irradiated tissues (recurrent glioma) compared to pre-irradiated (primary glioma). Through proliferation assays, we also found an increase in glioma cell growth following treatment with cADPR compared to untreated. Our results demonstrate that CD38 activity is tumorgenic, and furthermore that conventional chemo- and radiotherapies increase this CD38 activity. This indicates that treating CD38 with previously FDA approved therapeutics may provide hope for increasing progression free survival in our GBM patient population, and moreover emphasize the importance of leveraging novel large scale screening methods for identifying additional opportunities for treatment.

scholarly journals Evidence-Based Minireview: Should all newly diagnosed MM patients receive CD38 antibody–based treatment?

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 259-263
Author(s):  
Charlotte L. B. M. Korst ◽  
Niels W. C. J. van de Donk
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
Standards Of Care ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Free Survival ◽  
Depth Of Response ◽  
Cytogenetic Aberrations ◽  
Number Of Patients ◽  
Pretreated Patients

Abstract CD38 antibodies were first evaluated in extensively pretreated patients with multiple myeloma (MM). Currently, there are 3 CD38 antibody–based regimens approved for the treatment of both transplant-eligible (daratumumab plus bortezomib-thalidomide-dexamethasone [D-VTd]) and transplant-ineligible (daratumumab plus lenalidomide-dexamethasone [D-Rd] or daratumumab plus bortezomib-melphalan-prednisone [D-VMP]) patients with newly diagnosed MM (NDMM). The phase 3 studies that evaluated these regimens uniformly showed that the addition of daratumumab to backbone regimens improved the depth of response, which translated into improved progression-free survival and also overall survival in 2 of the studies. Importantly, elderly patients age 75 years or older benefit from these regimens, indicating that these regimens have an acceptable safety profile. Although the number of patients with high-risk cytogenetics was relatively small, these patients also experienced benefit from the addition of daratumumab to standard-of-care regimens, but poor risk conferred by the cytogenetic aberrations is not completely abrogated. Altogether, daratumumab-based regimens have high anti-MM activity and a favorable toxicity profile and therefore represent new standards of care for patients with NDMM.

scholarly journals Efficacy and safety of bevacizumab in the treatment of adult gliomas: a systematic review and meta-analysis

BMJ Open ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. e048975
Author(s):  
Huan Wang ◽  
Jianxin Guo ◽  
Tianze Wang ◽  
Kai Wang ◽  
Zhuojun Wu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Large Scale ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Secondary Outcome ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Significant Difference ◽  
Clinical Centre

ObjectiveTo assess the efficacy and safety of bevacizumab (BEV) in patients with glioma.DesignSystematic review and meta-analysis.ParticipantsAdults aged 18 years and above, whose histology was confirmed to be malignant glioma.Primary and secondary outcome measuresThe main indicators included progression-free survival (PFS) rate and overall survival (OS) rate, and the secondary indicators were adverse reactions.ResultsA total of 11 clinical centre trials were included in this study for meta-analysis, including 2392 patients. The results of the meta-analysis showed that the median PFS rate of the BEV group was significantly higher than that of the non-BEV group (p<0.00001). When comparing PFS between two groups, we found that the PFS in the BEV group was higher than that in the non-BEV group at 6 months (OR 3.31, 95% CI 2.74 to 4.00, p<0.00001), 12 months (OR 2.05, 95% CI 1.70 to 2.49, p<0.00001) and 18 months (OR 1.31, 95% CI 1.02 to 1.69, p=0.03). But at 24 months (OR 0.83, 95% CI 0.50 to 1.37, p=0.47), there was no significant difference between the two groups. At 30 months (OR 0.62, 95% CI 0.39 to 0.97, p=0.04), the PFS of the BEV group was lower than that of the non-BEV group. Moreover, The results showed that BEV had no significant effect on improving OS, but the adverse reaction in BEV group was significantly higher than that in non-BEV group.ConclusionThe evidence suggests that BEV can significantly prolong the PFS of patients with glioma within 18 months and shorten the PFS of patients after 30 months. This limitation may be related to the subgroup of patients, the change of recurrence mode, the optimal dose of drug, the increase of hypoxia, the enhancement of invasiveness and so on. Therefore, it is necessary to carry out more samples and higher quality large-scale research in the future.

scholarly journals Oral ixazomib, lenalidomide, and dexamethasone for newly diagnosed transplant-ineligible multiple myeloma patients

Blood ◽  
2021 ◽  
Author(s):  
Thierry Facon ◽  
Christopher P Venner ◽  
Nizar J Bahlis ◽  
Fritz Offner ◽  
Darrell White ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Standards Of Care ◽  
Newly Diagnosed ◽  
Double Blind ◽  
Free Survival ◽  
Feasible Option ◽  
Grade 3 ◽  
Continuous Dosing

Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued; treatment continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS (mPFS) was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P &lt; .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P &lt; .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, mPFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov (#NCT01850524).

scholarly journals Case Report: Detection of Double ROS1 Translocations, SDC4-ROS1 and ROS1-GK, in a Lung Adenocarcinoma Patient and Response to Crizotinib

2021 ◽  
Vol 8 ◽  
Author(s):  
Long Xu ◽  
Xiaoxia Chen ◽  
Hong Huo ◽  
Yongye Liu ◽  
Xiaodan Yang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Large Scale ◽  
Molecular Subtype ◽  
Brain Lesion ◽  
Progression Free Survival ◽  
Free Survival ◽  
Highly Sensitive ◽  
Duration Of Response ◽  
Lung Adenocarcinoma Patient ◽  
Nsclc Patients

ROS1 rearrangement, identified in ~2% of non-small cell lung cancer (NSCLC), has defined a distinctive molecular subtype. Patients with ROS1 fusion have been shown to be highly sensitive to treatment with crizotinib. However, the efficacy of crizotinib in NSCLC patients with double ROS1 fusions remains to be elucidated. Here, we report a 40-year-old male diagnosed with stage IIIA lung adenocarcinoma. Two ROS1 fusions [SDC4-ROS1 (EX2:EX32) and ROS1-GK (EX31:EX13)] were detected simultaneously in tumor tissue of this patient by next-generation sequencing. Crizotinib was administered, and the patient showed a partial response in lung lesions. Nevertheless, a brain lesion was found at 8 months after treatment. The slightly short duration of response may be related to the presence of ROS1-GK rearrangement. This case proved that patients with SDC4-ROS1 and ROS1-GK fusions may be sensitive to crizotinib, but short progression-free survival of this case showed that the presence of ROS1-GK rearrangement may affect the efficacy of crizotinib. A large-scale investigation on the efficacy of ROS1 inhibitors in patients with complex ROS1 fusions should be conducted in the future.

scholarly journals Effects of Fibrin Clot Inhibitors and Statins on the Intravesical Bacille Calmette–Guérin Therapy for Bladder Cancer: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiyong Cai ◽  
Jiao Hu ◽  
Belaydi Othmane ◽  
Huihuang Li ◽  
Dongxu Qiu ◽  
...  
Keyword(s):  
Large Scale ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Fibrin Clot ◽  
Pooled Analysis ◽  
Case Control Studies ◽  
Cancer Specific Survival ◽  
Free Survival ◽  
Bcg Therapy ◽  
Intravesical Bcg

ObjectiveTo assess the effect of fibrin clot inhibitors (aspirin, clopidogrel, and warfarin) and statins on intravesical BCG therapy.MethodA systematic literature search was carried out through PubMed, Embase, and the Cochrane Central Search Library in March 2020. Accumulative analyses of odds ratios (ORs), hazard ratio (HR), and corresponding 95% confidence intervals (CIs) were performed. All analyses were performed by using Review Manager software version 5.3 and Stata 15.1.ResultsFour cohort studies and nine case–control studies containing 3,451 patients were included. The pooled analysis indicated that statins (HR = 1.00; 95%CI, 0.82 to 1.22; p = 1.00) and fibrin clot inhibitors (HR = 1.01; 95%CI, 0.64 to 1.59; p = 0.98) did not affect the efficacy of BCG on recurrence-free survival. The cumulative analysis showed that statins (HR = 0.79; 95%CI, 0.41 to 1.49; p = 0.46) and fibrin clot inhibitors (HR = 1.62; 95%CI, 0.90 to 2.91; p = 0.11) did not affect the efficacy of BCG on progression-free survival. There were no differences on cancer-specific survival (HR = 1.68; 95%CI, 0.64 to 4.40; p = 0.29) and overall survival (HR = 1.13; 95%CI, 0.73 to 1.78; p = 0.58) after taking statins.ConclusionThe present study shows that the application of fibrin clot inhibitors and statins do not influence the efficacy of BCG on oncological prognosis. Consequently, we do not need to stop using them or change to other drugs during intravesical BCG treatment. However, large-scale multi-center prospective research is still needed to confirm the above conclusions.

scholarly journals Role of MicroRNA-124 as a Prognostic Factor in Multiple Neoplasms: A Meta-Analysis

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Zijian Zhou ◽  
Jiancheng Lv ◽  
Jingzi Wang ◽  
Hao Yu ◽  
Hongcheng Lu ◽  
...  
Keyword(s):  
Large Scale ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
Protective Role ◽  
Cochrane Library ◽  
Free Survival ◽  
Multiple Neoplasms ◽  
Microrna 124

Objective. MicroRNA-124 (miR-124) was revealed to be an attractive prognostic tumour biomarker in recent studies. However, the results remain inconclusive. Hence, this meta-analysis was carried out to clarify the precise predictive value of miR-124. Materials and Methods. Relevant studies were searched in PubMed, EMBASE, Web of Science, and the Cochrane Library up to October 2018. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were extracted from the selected studies. Results. A total of 29 articles investigating the correlation between miR-124 expression and prognosis were initially identified. The pooled HR for overall survival (OS) of high miR-124 expression in multiple cancers was 0.55 (95%CI=0.50–0.61). Disease-free survival (DFS)/progression-free survival (HR=0.48, 95%CI=0.38–0.61) revealed a protective role of increased miR-124 expression. Epigenetic hypermethylation of miR-124 mediated the silencing of its expression, which is correlated significantly with unfavourable survival (OS: HR=2.06, 95%CI=1.68–2.53; DFS/recurrence-free survival: HR=2.77, 95%CI=1.85–4.16). Conclusions. Taken together, our results suggest that miR-124 plays an antioncogenic role in various tumors, such as lung cancer and colorectal cancer. If methylation of miR-124 could be prevented, progression and metastasis would be improved; thus, miR-124 may be a promising biomarker and novel therapeutic target. Further large-scale studies are needed to confirm this possible effect.

The 2-deoxyglucose uptake method as a first screen for neurotoxic compounds

1984 ◽  
Vol 62 (8) ◽  
pp. 998-1009 ◽  
Author(s):  
P. Muller ◽  
Lise Martin
Keyword(s):  
Large Scale ◽  
Alternative Methods ◽  
Screening Methods ◽  
Indirect Measure ◽  
Dg Method ◽  
New Compounds ◽  
The Brain ◽  
Efficient Screening ◽  
Uptake Method ◽  
Large Scale Screening

Our primary goal is to develop a screening procedure to detect and partially characterize neurotoxic compounds. There is a great need for a new approach to screening for neurotoxicants because our industrialized world abounds with untested and potentially neurotoxic compounds. A large number of new compounds are introduced each year. Although a number of testing approaches to the screening for neurotoxicants have been proposed in the recent years, a consensus on the most adequate approach is yet to emerge. The existing methods share a number of shortcomings. Thus, most methods only detect a fraction of the tested neurotoxicants. Other methods lack the necessary resolution to detect the neurotoxic damage reproducibly and reliably. Furthermore, many screening approaches are too time consuming and costly to be used for the large-scale screening of neurotoxicants. It is, therefore, imperative to develop reliable and efficient screening methods applicable in regulatory toxicology. In this report, we describe two versions of the same method that we feel may be very beneficial for the large-scale screening of neurotoxicants. The 2-deoxyglucose (2-DG) uptake method provides an indirect measure of neuronal activity in different areas of the brain. The ability of the method to detect most, if not all, neuroactive substances is reviewed in this report. In the context of this report, a neuroactive substance is defined as a substance acting directly on the central or peripheral nervous system neurons and (or) glia. The 2-DG method equals the sensitivity of the most sensitive alternative methods which were selectively designed to detect the effects of specific groups of compounds. The generality and sensitivity of the 2-DG method are of major importance. Thus, if a tested compound does not affect the uptake of 2-DG into the brain, it is not likely to be neuroactive. Since neurotoxic compounds are a subset of neuroactive compounds, a compound that is not neuroactive is also not neurotoxic. Thus, a single test may, in some instances, determine if a tested compound is nontoxic. In addition, it appears that each compound or, at least, each family of compounds produces a characteristic profile ("pattern") of the sites of altered 2-DG uptake. This pattern can be exploited to characterize the tested compound and help us decide whether it is neurotoxic or neuroactive. Preliminary results from our laboratory indicate classical neurotoxic agents such as acrylamide, triethyltin, and 2,5-hexanedione induce a generalized depression of the 2-DG uptake throughout the brain. As a result, it may be difficult to differentiate these compounds on the basis of their respective 2-DG pattern. On the other hand, most of the therapeutics tested to date have distinct 2-DG uptake patterns which may help to distinguish therapeutics from classicial neurotoxicants. Additional experimental work is required to clarify this matter. The method has not been extensively used in the field of toxicology, mainly because the existing original 2-DG method is too complex and expensive for the large-scale screening for neurotoxicants. In this report, we review the efforts made to simplify this method as a general neurotoxicology screen. Our initial experience with this method in testing for neurotoxic compounds is also reviewed.

Large-Scale High Resolution Integration of Copy Number and Gene Expression in DLBCL Reveals Focal and Frequent Deletions in Chromatin Modifying Genes with Outcome Correlation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 295-295
Author(s):  
Fong Chun Chan ◽  
Susana Ben-Neriah ◽  
Raymond Lim ◽  
Sandy Hu ◽  
Sanja Rogic ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Resolution ◽  
Clinical Outcome ◽  
Copy Number ◽  
Large Scale ◽  
Progression Free Survival ◽  
Rna Seq ◽  
Free Survival ◽  
Modifying Genes ◽  
Genomic Aberrations

Abstract Abstract 295 Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma (NHL), accounting for approximately 30–40% of all new lymphoma cases. While standard therapy using rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has significantly increased the survival of DLBCL patients, approximately one third of DLBCL patients still remain unresponsive to or relapse after standard treatment. Further investigation into the genomic architecture of DLBCL will contribute to elucidating the causes of the poor outcomes in this subgroup of patients. While the copy number and the gene expression profiles of DLBCL specimens have been well described as separate analyses, a large-scale high resolution integration of both orthologous measurements has yet to be reported. The integration of these two data types in a clinically well-annotated cohort of DLBCL is crucial as it can potentially distinguish driver from passenger genomic aberrations and reveal associations with clinical outcome. Methods and Patients: Affymetrix SNP 6.0 microarrays were used to ascertain the copy number profiles in 151 pretreatment biopsies of DLBCL that were representative of the population of DLBCL patients treated at the British Columbia Cancer Agency. Clinical outcome data were available for all 151 patients with 142 patients receiving R-CHOP or R-CHOP-like treatment. Matching RNA-seq libraries were used to quantitate the gene expression levels in 91 samples. The SNP 6.0 pre-processing method cRMAv2 was used to generate raw probe intensities that were then normalized to 1258 HapMap3 SNP 6.0 arrays. Copy number state calls were predicted using HMM-Dosage. RNA-seq data were aligned using the split-read aware aligner GSNAP and gene expression values were generated using the metric reads per kilobase of transcript per million mapped reads. DriverNet analyses were utilized to predict functionally relevant driver genes and outcome correlations in R-CHOP treated patients were performed using Cox regression and the log-rank test. Results: The copy number landscape derived from the SNP 6.0 microarrays revealed previously reported large scale chromosomal deletions in chromosome 6p and amplifications in chromosomes 3, 7 and 18. By integrating the gene expression with copy number data, we found that gene copy number was correlated with its own gene expression (classified as being cis-correlated) in 23.5% of genes. In addition, we investigated copy number aberrations which were highly correlated with gene expression across the genome (classified as trans-correlated). This analysis revealed aberration hotspots in genomic locations 3q26-q28 (TBL1XR1, BCL6, TP63), 17p12 (NCOR1, MAP2K4), 18q11.1-q11.2 (RBBP8) and 22q11.21 (BID, IL17RA) suggesting that these hotspots regulate important pathways that may contribute to the pathogenesis of DLBCL. We identified previously reported focal amplifications (e.g. REL) and deletions (e.g. B2M, CDKN2A). Moreover, we identified novel focal deletions, including homozygous deletions, in chromatin modifying genes: LCOR (7.9%), RCOR1 (9.9%), and NCOR1 (17.9%), all of which were cis-correlated and were validated using fluorescence in situ hybridization. DriverNet analyses identified RCOR1 deletions as one of the main driver alterations. RCOR1 deletions were also found to be associated with progression-free survival (5-year progression-free survival: deleted 40% vs. non-deleted 75%, p=0.0188). Discussion: Our systematic integration of SNP 6.0 and RNA-seq data confirmed findings of previous studies and also revealed novel genomic aberration hotspots and highly focal and frequent deletions in chromatin modifying genes. Results derived from our large-scale high resolution data set indicate the feasibility and efficacy of integrative genomic analyses in revealing novel and pathogenetically relevant genomic aberrations in lymphoid cancers. The discovery of the association of RCOR1 deletions with progression-free survival suggests that RCOR1 deletions could be used as a prognostic marker and might indicate a molecular phenotype that can be targeted by novel therapeutic agents in DLBCL. Disclosures: No relevant conflicts of interest to declare.

Second-Line Intraperitoneal Chemotherapy for Recurrent Epithelial Ovarian, Tubal and Peritoneal Cancer: A Propensity Score-Matching Study

Chemotherapy ◽  
2016 ◽  
Vol 61 (5) ◽  
pp. 240-248 ◽  
Author(s):  
Chien-Hsing Lu ◽  
Yen-Hou Chang ◽  
Wai-Hou Lee ◽  
Yi Chang ◽  
Chia-Wen Peng ◽  
...  
Keyword(s):  
Propensity Score ◽  
Propensity Score Matching ◽  
Large Scale ◽  
Progression Free Survival ◽  
Second Line ◽  
Free Survival ◽  
Peritoneal Cancer ◽  
Platinum Sensitive ◽  
Resistant Disease ◽  
Platinum Refractory

Background: The superiority of frontline intraperitoneal (IP) over intravenous (IV) chemotherapy is well established in the treatment of epithelial ovarian cancer. However, the role of IP chemotherapy in the second-line setting has rarely been investigated. Methods: Consecutive patients diagnosed with recurrent epithelial, tubal and peritoneal cancers between January 2000 and December 2012 were recruited using a propensity score-matching technique to adjust relevant risk factors. Results: In total, 310 patients were included in the final analysis (94 for platinum-refractory/resistant disease and 216 for platinum-sensitive disease). IP chemotherapy demonstrated significantly longer median progression-free survival than IV chemotherapy (4.9 vs. 2.4 months, p < 0.001, for platinum-refractory/resistant disease, and 9.8 vs. 6.9 months, p < 0.001, for platinum-sensitive disease). Conclusions: Second-line IP chemotherapy confers longer progression-free survival than IV chemotherapy. Large-scale clinical trials should be conducted to validate the true efficacy.

scholarly journals RRM1 Expression as a Prognostic Biomarker for Unresectable or Recurrent Biliary Tract Cancer Treated with Gemcitabine plus Cisplatin

2021 ◽  
Vol 10 (20) ◽  
pp. 4652
Author(s):  
Jung Won Chun ◽  
Boyoung Lee ◽  
Weon Seo Park ◽  
Nayoung Han ◽  
Eun Kyung Hong ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Large Scale ◽  
Cytidine Deaminase ◽  
Progression Free Survival ◽  
Chemotherapy Response ◽  
Nucleoside Transporter ◽  
Free Survival ◽  
Equilibrative Nucleoside Transporter ◽  
Tract Cancer

The combination of gemcitabine plus cisplatin (GP) is regarded as a first-line treatment for patients with unresectable or recurrent biliary tract cancer (BTC). Several proteins including human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (DCK), cytidine deaminase (CDA), and ribonucleotide reductase subunit 1 (RRM1) are known to be involved in gemcitabine uptake and metabolism. This study was aimed to identify the predictive and prognostic values of these biomarkers in patients who treated with GP for advanced BTC. Tumor samples were obtained from 34 patients with unresectable or recurrent BTC who were treated with GP between August 2015 and February 2018. Intratumoral expression of hENT1, DCK, CDA and RRM1 was determined by immunohistochemistry and analyzed for association with chemotherapy response, progression-free survival (PFS) and overall survival (OS). Median OS was significantly longer in the RRM1-negative group than in the RRM1-positive (9.9 months vs. 5.9 months, p = 0.037). Multivariate adjustment analyses also demonstrated RRM1 expression as an independent prognostic factor for OS in patients treated with GP chemotherapy. Increased intratumoral expression of RRM1 on immunohistochemical staining may be a biomarker predicting poor survival in patients with GP chemotherapy for advanced BTC. Large-scale well-predefined prospective research is needed to validate the utility of biomarkers in clinical practice.

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