BEZ235 in combination with everolimus for advanced solid malignancies: Preliminary results of a phase Ib dose-escalation study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13518-e13518 ◽  
Author(s):  
Mohamad Adham Salkeni ◽  
Olivier Rixe ◽  
Nagla Abdel Karim ◽  
Sue Ogara ◽  
Monica Feiler ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dose Escalation ◽  
Mtor Inhibitor ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear ◽  
Phase Ib ◽  
Solid Malignancies

e13518 Background: The mammalian target of rapamycin (mTOR) is a critical signaling pathway in many tumors including cancers of the breast and colon, glioblastoma multiforme, and hepatocellular carcinoma (HCC). Preclinical studies demonstrated the combination of BEZ235, a competitive dual phosphatidylinositide 3-kinase (PI3K)/mTOR inhibitor, and the mTOR inhibitor, everolimus led to greater regression of a carcinogen-induced HCC than treatment with higher doses of either drug alone. Based on this, we initiated a study of BEZ235 combined with everolimus in patients with advanced solid tumors. Methods: A single institution phase Ib dose-escalation study. Patients with advanced solid malignancies, no available standard of care treatment option, and ECOG performance status 0-2 were eligible. Prior treatment with PI3K inhibitors was not allowed. Sequential cohorts of 3-6 patients were treated. The starting dose was everolimus 2.5 mg and BEZ235 200 mg daily in an oral sachet formulation. Cohort 2 received everolimus 2.5 mg and BEZ235 400 mg daily. Pharmacokinetic and pharmacodynamic studies were performed during the first cycle. The phosphorylation of specific downstream effectors of the mTOR pathway was assessed in peripheral blood mononuclear cells (PBMC). Results: Eleven patients, median age 58 (36-73 years) were treated. Tumors included non-small cell lung cancer, colon cancer, and glioblastoma, hepatocellular carcinoma, pancreatic cancer, esophageal cancer, adenoid cystic carcinoma of the larynx, and appendiceal carcinoma. Four patients were treated on cohort 1. None experienced dose-limiting toxicity. Seven patients were treated on the second dose cohort. One patient withdrew necessitating replacement and another developed grade 3 stomatitis from herpes virus requiring cohort expansion. The most common adverse events were thrombocytopenia, lymphopenia, transaminitis, diarrhea, nausea and fatigue. No tumor responses were noted. PBMC showed a decrease in 4E-BP1S65 phosphorylation on day 28 in 2 of 3 patients in cohort 1. Conclusions: The combination of BEZ235 and everolimus was well tolerated at these doses. The trial remains open to accrual. Clinical trial information: NCT01508104.

Phase I study of the novel pro-drug MIV-818 in patients with hepatocellular carcinoma, intra-hepatic cholangiocarcinoma or liver metastases.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 309-309
Author(s):  
T.R. Jeffry Evans ◽  
Eric Van Cutsem ◽  
Hans Prenen ◽  
Mark R. Middleton ◽  
Debashis Sarker ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Liver Metastases ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Phase Ib ◽  
Starting Dose ◽  
Liver Biopsies

309 Background: MIV-818 is an orally administered troxacitabine (TRX)-based nucleotide prodrug. It is highly metabolized by human hepatocytes, directing high levels of the chain-terminating nucleotide tri-phosphate to the liver, while minimizing exposure to other organs. The tri-phosphate is incorporated into DNA during replication, which leads to DNA double strand breaks, DNA damage responses, and cytotoxicity. Methods: Patients (pts), ≥18 years, ECOG performance status < 1, adequate organ function, with treatment-refractory hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA) or liver metastases (LM) from solid tumors were enrolled. In phase Ia, MIV-818 monotherapy was administered in an intra-patient dose-escalation design with doses of 3-70mg for 3-5 days in cycles of 21 days. Phase Ib is an inter-patient dose escalation in a 3+3 cohort design and is currently ongoing. Treatment is given until disease progression or unacceptable toxicity. The primary objective is to assess safety and tolerability and, for phase Ia, also to establish the starting dose for phase Ib. Key secondary objective was to evaluate the overall response rate based on RECIST v1.1. The pharmacokinetics of MIV-818 and its metabolites were evaluated, and on-treatment liver biopsies were collected to assess the pharmacokinetics and the pharmacodynamic effects of MIV-818. Results: Nine patients (7M; 2F), ECOG performance status 0 (n=3) or 1 (n=6), median age = 57 years (range: 50-84) with HCC (2 pts), iCCA (1) or LM (6) from solid tumors (mainly GI tract), previously treated with median 2 (1-5) lines of therapy, were included in phase Ia. Patients were dosed up to 60 mg 5 days/week. The most common treatment related AEs were those in the hematological system: neutropenia grade (gr) 1-4, neutropenic sepsis gr 4; thrombocytopenia gr 1-2, anemia gr 1-2. Elevated bilirubin gr 1-3 and liver enzymes gr 3 were also reported. Most of the AEs were reversible. Five pts discontinued due to AE and 4 pts discontinued due to progressive disease outside the liver after 2-4 cycles. Starting dose of phase Ib was determined to be 40mg 5 days/week. Tumor biopsies showed evidence of selective DNA damage in tumor tissue, including in hypoxic regions, with minimal or no impact of MIV-818 observed in healthy liver tissue. Conclusions: MIV-818 had an acceptable safety and tolerability profile. Biomarker data of liver biopsies demonstrated a selective effect of MIV-818 on cancer cells. Updated safety and efficacy data from phase Ib will be presented at the meeting. (NCT03781934). Clinical trial information: 2018-000995-14.

A phase I-II and pharmacodynamic (PD) study of the combination of the proteasome inhibitor bortezomib (B) and paclitaxel (P) in patients with taxane-sensitive solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13029-13029
Author(s):  
E. Gallerani ◽  
S. Cresta ◽  
D. Tosi ◽  
C. Sessa ◽  
G. Capri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Anticancer Agents ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Peripheral Blood Mononuclear

13029 Background: Proteasome inhibition blocks the chemotherapy-induced activation of NF-кB increasing chemosensitivity to anticancer agents due to increased apoptosis. NF-кB is frequently aberrantly activated in primary human carcinomas and over-expressed in aggressive breast cancer lines1 supporting the rationale for combining B with P. We designed a phase I-II and PD trial to determine the recommended dose (RD) of the B&P combination, to screen for antitumor activity in patients with potentially taxane-sensitive tumors, to search for drug-induced changes and to identify potential surrogate markers of drug activity and toxicity in peripheral blood mononuclear cells (PBMC). Methods: Eligibility included ECOG performance status < 2, neurotoxicity < 2 and adequate organ functions. Treatment was given Q21 days: B on days 1,4, 8 and 11 and P on days 1 and 8. PBMC for gene expression profiling have been collected on day 1 and 4 before and after therapy. RECIST for response was applied. Results: Twenty-nine patients (20 female, median age 60 yrs) were accrued and 25 are evaluable (breast cancer: 13, ovarian cancer: 7, prostate cancer 1, other 4) ; 16 pts were treated in 4 escalation levels and the RD defined respectively at 1.3 mg/m2/dose & 100 mg/m2/dose for B&P. Neurotoxicity was the main toxicity (G1 36%, G2 20% and 1 case G3) requiring treatment discontinuation in 2 pts at cy 6 & 7. Other toxicities (all grades) were nausea and vomiting (68%), diarrhea (56%, G3 12%), alopecia (52%), asthenia (36%, G2 4%), and myalgia (32%, G2 8%). Antitumor activity consisted of 3 PR in pts with ovarian cancer lasting respectively 14, 8+ and 16 wks; 2 PRs in pts with breast cancer (12+ wks,14+ wks) and 1 PR in a pt with prostate cancer. Conclusions: Thus far the regimen has acceptable toxicity with evidence of antitumor activity. The trial will continue until accrual of four additional patients as planned. Footnotes 1 Adams J Current Opin Oncol 2002, 14:628–634. [Table: see text]

Role of gemcitabine along with dendritic cell therapy in advanced-stage pancreatic cancers: Phase I/II trial results in 26 patients from India.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13071-e13071
Author(s):  
Jamal Anono Khan
Keyword(s):  
Dendritic Cell ◽  
Phase I ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Age Groups ◽  
Blood Chemistry ◽  
Advanced Stage ◽  
Ecog Performance Status ◽  
Peripheral Blood Mononuclear ◽  
End Point

e13071^ Background: Pancreatic cancer is the leading cause of cancer deaths worldwide with a very poor survival rate. No adequate therapy allows the patient to have a longer life of even 1 year. Methods: Dendritic cell(DC) based immunotherapy along with gemcitabine chemotherapy is planned to do phase I/II trial in 26 patients of advanced stage adenocarcinoma of pancreas. Inclusion criteria was defined as unresectable disease, ECOG performance status of not more than 2, Blood chemistry and hematocrit within normal range and of all age groups. Peripheral blood mononuclear cells are cultured in GM-CSF/IL-4 in RPMI. At 6th day of culture, the immature dendritic cells are exposed to antigens previously isolated from fresh excised tissue and further matured for 2 days. The cells along with medium are harvested and 1 million mature DC are infused IV by mixing them in 100 ml of dextrose normal saline with ondasnetron 4mg injection. Gemcitabine was given on day 1 and on day 8th and DC on day 15th. The cycle is repeated every month for 3 months followed by DC therapy alone at every 23 days interval till patient survives. The primary end point was overall survival and the secondary end point was improvement in quality quotient. Results: 6 patients survived for 24 months, 10 for 12 months and 3 for 6 months, with radiological improvement in only 4 patients with 25% reduction of disease. The quality quotient of 14 patients improved by second dose of dc therapy with improved appetite and decreased pain in abdomen including cheerfulness in 13 patients. Conclusions: Gemcitabine and DC immunotherapy is a good option for advanced stage pancreas cancer patients.

Phase I/II study of GM-CSF gene-transduced allogeneic prostate cancer cellular immunotherapy (GVAX IT) in advanced prostate cancer patients made lymphopenic by chemotherapy and infused with autologous peripheral blood mononuclear cells (MC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14635-14635 ◽  
Author(s):  
B. D. Curti ◽  
I. Assman ◽  
T. Moudgil ◽  
T. Ratzow ◽  
D. Haley ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Study Groups ◽  
Phase Iii ◽  
Cellular Immunotherapy ◽  
Ecog Performance Status ◽  
Peripheral Blood Mononuclear ◽  
Pre Treatment

14635 Background: GVAX IT has been tested in phase I/ II and is currently being tested in phase III clinical trials of patients (pts) with androgen-independent prostate carcinoma (AIPC). Immunological and PSA responses have been described in men receiving GVAX IT. Preclinical studies have shown that antitumor immune responses induced by GVAX IT could be augmented further by making animals lymphopenic and reconstituting with lymphocytes prior to vaccination. A clinical trial was designed to study the effects of lymphopenic reconstitution in pts with AIPC. Methods: All pts had MC collection by leukapheresis pre-treatment. Study groups were as follows: Arm A - GVAX IT given every two weeks for 6 months; Arm B - Cyclophosphamide (350 mg/m2 IV on days 1–3), MC infusion on day 6, GVAX IT on day 7, then every 2 weeks for 6 months; Arm C - Cyclophosphamide (350 mg/m2 IV on days 1–3) and fludarabine (20 mg/m2 IV on days 1–3), MC infusion on day 6, GVAX IT on day 7, then every 2 weeks for 6 months. Results: Seven pts have been treated thus far and completed at least 2 GVAX IT treatments. Pts had ECOG performance status ≤ 1, castrate testosterone levels, ≤ 1 prior chemotherapy regimen and measurable or evaluable metastatic AIPC. Lymphopenia was induced in all pts enrolled in Arms B and C, with recovery of total granulocytes and lymphocytes within 4 weeks following treatment. Monitoring of humoral and cellular immunological responses is underway and shall be presented. Conclusions: GVAX IT and lymphopenic reconstitution is feasible in men with AIPC. Analysis of clinical and immune response is ongoing. Supported by DAMD grant PC020094 and generous support of Mr. Tom Denhart, the Chiles Foundation and the Murdock Trust. [Table: see text]

scholarly journals Phase Ib Study of the Histone Deacetylase 6 Inhibitor Citarinostat in Combination With Paclitaxel in Patients With Advanced Solid Tumors

2022 ◽  
Vol 11 ◽  
Author(s):  
Michael S. Gordon ◽  
Geoffrey I. Shapiro ◽  
John Sarantopoulos ◽  
Dejan Juric ◽  
Brian Lu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Mononuclear Cells ◽  
Pharmacokinetic Parameters ◽  
Advanced Solid Tumors ◽  
Histone Deacetylase 6 ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear ◽  
Once Daily ◽  
Phase Ib

BackgroundCitarinostat (CC-96241; previously ACY-241), an oral inhibitor of histone deacetylases (HDACs) with selectivity for HDAC6, has demonstrated synergistic anticancer activity with paclitaxel in multiple solid tumor models. Combination therapy using citarinostat with paclitaxel was evaluated in this phase Ib 3 + 3 dose-escalation study in patients with advanced solid tumors.MethodsPatients with previously treated advanced solid tumors received citarinostat 180, 360, or 480 mg once daily on days 1 to 21 plus paclitaxel 80 mg/m2 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was determination of the maximum tolerated dose (MTD). Secondary endpoints included safety, antitumor activity, pharmacokinetics, and pharmacodynamics.ResultsTwenty patients were enrolled and received study treatment; 15 had received prior taxane therapy. No dose-limiting toxicities were reported at any dose; therefore, the MTD was not identified. Citarinostat 360 vs 480 mg was associated with reduced incidence and severity of neutropenia. Three patients experienced a confirmed partial response and 13 achieved stable disease. Pharmacokinetic parameters were linear up to citarinostat 360 mg, the dose at which the highest levels of histone and tubulin acetylation were observed in peripheral blood mononuclear cells.ConclusionsThe combination of citarinostat plus paclitaxel showed an acceptable safety profile, with no unexpected or dose-limiting toxicities and potential evidence of antitumor activity in patients with heavily pretreated advanced solid tumors. Citarinostat 360 mg once daily is considered the recommended phase II dose for use in combination with paclitaxel 80 mg/m2 every 3 of 4 weeks. This trial is registered on ClinicalTrials.gov (NCT02551185).

A phase I/II study of docetaxel in combination with doxorubicin HCI liposome injection in advanced androgen-independent prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14588-14588
Author(s):  
M. E. Martin ◽  
L. A. Ferguson ◽  
D. A. Williams ◽  
D. A. Laber
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Performance Status ◽  
Objective Response ◽  
Active Agent ◽  
Patient Characteristics ◽  
Ecog Performance Status ◽  
Dose Escalation Study ◽  
Number Of Cycles

14588 Background: There is no cure for men with AIPC. Recently two landmark studies demonstrated an improvement in survival for men with AIPC treated with docetaxel based chemotherapy. Doxorubicin is a very active agent against AIPC. Doxil is liposome-encapsulated doxorubicin with less toxicity. Methods: Objectives are to evaluate the efficacy and safety of DoxTax. A phase I dose escalation study was performed. Three cohorts according to the following dose escalation schedule were formed. In the absence of DLT, level 3 was the recommended dose for the phase II study. Response was assessed by size of measurable and non-measurable lesions (RECIST JNCI.2000), and PSA levels (JCO.1999). Toxicity was graded by the NCI CTCAE. Results: Eleven subjects with AIPC were enrolled and evaluated for toxicity and response. Total number of cycles administered: 59, median of 5.5 cycles/patient. Patient characteristics: Median age 67 years (53–81); prior hormonal manipulations 2 (1–2); prior chemotherapy 1 (0–2); ECOG performance status 1 (1–2); and median PSA 78 ng/ml (8.73–783). Objective response: Out of 11 subjects, four men (36%) achieved a reduction in PSA of > 50%, while one (9%) achieved a >80% PSA reduction, for an overall PSA response of 45%. Seven patients had measurable lesions. Using RECIST criteria, five of seven subjects maintained (SD). Palliative response: Nine subjects (82%) improved their ECOG performance status. Additionally, 8 men (73%) had decreased level of pain. Toxicity: No dose limiting toxicity occurred. One patient had grade 3 generalized weakness related to disease progression. Grade 1–2 adverse events were not related to the dose and included: 64% fatigue, 45% anemia, 18% neutropenia, alopecia, anorexia, vomiting, 9% each for nausea, thrombocytopenia, weakness, hand/foot, and neuropathy. Conclusions: DoxTax is a well-tolerated, easy to administer and effective therapy for patients with metastatic AIPC. Accrual to the phase II trial is ongoing. [Table: see text] [Table: see text]

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654 administered daily for 28 days to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3586-3586
Author(s):  
Ignacio Garrido-Laguna ◽  
Patrick Michael Dillon ◽  
Stephen Patrick Anthony ◽  
Margit Janat-Amsbury ◽  
Nissa Ashenbramer ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear

3586 Background: TP-3654 is an oral, second generation, potent PIM-1 kinase inhibitor with activity against PIM 2, 3 and favorable selectivity against other kinases. These cytoplasmic serine/threonine kinases are highly expressed in many cancers and their oncogenic potential has been largely attributed to supressing apoptosis downstream of stimuli including inflammatory cytokines and other immune effectors. TP-3654 has efficacy in various hematologic and solid tumor models inducing stromal Pim-1 also has been shown to mediate various aspects of the tumor microenvironment. Thus, Pim kinases are attractive targets for the treatment of many human malignanices. Methods: A first in human, multicenter, phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-3654 in patients with advanced solid tumors. Results: Ten patients were enrolled between 30Apr and 31Dec2019 receiving 480, 720, and 1080 mg respectively. Grade 3 AEs were scrotum wound infection, altered mental status, anemia, fall, and lower extremity edema, none were related to study drug and all were manageable with supportive care. There were no Grade 4 or 5 AEs and no DLTs. Median duration of SD was 5.5 months (6/10) and with prolonged SD > 16wks (4/10). One CRC patient with 4 lines of prior therapy had a 22% reduction in tumor volume (SD > 5+ mos). TP-3654 plasma PK values (Cmax, AUC) continuously increased through all 3 cohorts. Average Cmax (ng/mL) and AUC0-24 (ng*hours/mL) were 195, 1965 (480mg); 357, 3310 (720mg); 735, 6922 (1080mg), respectively. PK values increased linearly with higher doses without reaching saturation. Peripheral Blood Mononuclear Cells were isolated from subjects prior and up to 24hours after treatment. Western Blot from protein lysates revealed a decrease in phosphorylation of BAD and p70s6K proteins, both regulated by PIM-1 kinase. Conclusions: These findings suggest that TP-3654 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, and resistant solid tumors warranting further clinical development in selected indications.

A phase Ib dose-escalation study of eribulin mesylate in combination with capecitabine in patients with advanced/metastatic cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2552-2552 ◽  
Author(s):  
Muhammad Yaser Nasim ◽  
Ruth Plummer ◽  
T.R. Jeffry Evans ◽  
Rosemary Morrison ◽  
David Alan Anthoney ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dose Escalation ◽  
Metastatic Cancer ◽  
Performance Status ◽  
Metastatic Breast ◽  
Dose Intensity ◽  
Open Label ◽  
Eribulin Mesylate ◽  
Dose Escalation Study ◽  
Phase Ib

2552 Background: Eribulin mesylate is a microtubule dynamics inhibitor approved by FDA for patients (pts) with metastatic breast cancer after treatment with at least two prior chemotherapeutic regimens. This Phase Ib, open-label dose-escalation study determined the maximum tolerated dose (MTD) of eribulin in combination with capecitabine. Methods: Pts with advanced solid malignancies refractory to standard therapies, adequate organ function and ECOG performance status ≤2 received eribulin mesylate (2–5-min IV) by Schedule 1 (1.2, 1.6 or 2.0 mg/m2 on Day 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m2 on Days 1 and 8), in combination with twice-daily oral capecitabine 1000 mg/m2 Days 1-14 every 21 days. The MTD was defined as the highest dose in each schedule where ≤1/6 pts experienced dose-limiting toxicity (DLT). Safety and pharmacokinetics (PK) were assessed. Results: Of the 34 pts recruited, 19 (53% male; median age 62 years; 42% ECOG 0, 58% ECOG 1) and 15 (33% male; median age 61 years; 33% ECOG 0, 60% ECOG 1, 7% ECOG 2) were enrolled in Schedules 1 and 2, respectively. Most common tumor types were large intestine (20.6%), lung/bronchus (17.7%) and breast (14.7%). DLTs are shown in the table; there were no unexpected toxicities with the combination. The MTD for eribulin mesylate was 1.6 and 1.4 mg/m2 for Schedules 1 and 2, respectively, in combination with capecitabine 1000 mg/m2 twice-daily. Eribulin PK were dose proportional and independent of schedule or capecitabine co-administration. Combination with eribulin had no effect on the disposition of capecitabine and its metabolites. Although sample size was small, preliminary signs of efficacy were observed. Conclusions: The combination of eribulin and capecitabine was well tolerated with no unexpected safety findings. Schedule 2 MTD (1.4 mg/m2 Days 1 and 8) delivered a higher dose intensity of eribulin than Schedule 1 and was selected for evaluation in an ongoing Phase II breast cancer study. [Table: see text]

scholarly journals Identification of BHLHE40 expression in peripheral blood mononuclear cells as a novel biomarker for diagnosis and prognosis of hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pattapon Kunadirek ◽  
Chaiyaboot Ariyachet ◽  
Supachaya Sriphoosanaphan ◽  
Nutcha Pinjaroen ◽  
Pongserath Sirichindakul ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Early Stage ◽  
High Sensitivity ◽  
Peripheral Blood Mononuclear ◽  
Diagnosis And Prognosis ◽  
Transcription Profiles ◽  
Blood Mononuclear Cells

AbstractNovel and sensitive biomarkers is highly required for early detection and predicting prognosis of hepatocellular carcinoma (HCC). Here, we investigated transcription profiles from peripheral blood mononuclear cells (PBMCs) of 8 patients with HCC and PBMCs from co-culture model with HCC using RNA-Sequencing. These transcription profiles were cross compared with published microarray datasets of PBMCs in HCC to identify differentially expressed genes (DEGs). A total of commonly identified of 24 DEGs among these data were proposed as cancer-induced genes in PBMCs, including 18 upregulated and 6 downregulated DEGs. The KEGG pathway showed that these enriched genes were mainly associated with immune responses. Five up-regulated candidate genes including BHLHE40, AREG, SOCS1, CCL5, and DDIT4 were selected and further validated in PBMCs of 100 patients with HBV-related HCC, 100 patients with chronic HBV infection and 100 healthy controls. Based on ROC analysis, BHLHE40 and DDIT4 displayed better diagnostic performance than alpha-fetoprotein (AFP) in discriminating HCC from controls. Additionally, BHLHE40 and DDIT4 had high sensitivity for detecting AFP-negative and early-stage HCC. BHLHE40 was also emerged as an independent prognostic factor of overall survival of HCC. Together, our study indicated that BHLHE40 in PBMCs could be a promising diagnostic and prognostic biomarker for HBV-related HCC.

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