Niraparib Population Pharmacokinetics and Exposure-Response Relationships in Patients With Newly Diagnosed Advanced Ovarian Cancer.

PURPOSE: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. METHODS: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. FINDINGS: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. IMPLICATIONS: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. CLINICALTRIALS: gov.

Genome of Laudakia sacra Provides New Insights into High-Altitude Adaptation of Ectotherms.

Anan's rock agama (Laudakia sacra) is a lizard species endemic to the harsh high-altitude environment of the Qinghai-Tibet Plateau, a region characterized by low oxygen tension and high ultraviolet (UV) radiation. To better understand the genetic mechanisms underlying highland adaptation of ectotherms, we assembled a 1.80-Gb L. sacra genome, which contained 284 contigs with an N50 of 20.19 Mb and a BUSCO score of 93.54%. Comparative genomic analysis indicated that mutations in certain genes, including HIF1A, TIE2, and NFAT family members and genes in the respiratory chain, may be common adaptations to hypoxia among high-altitude animals. Compared with lowland reptiles, MLIP showed a convergent mutation in L. sacra and the Tibetan hot-spring snake (Thermophis baileyi), which may affect their hypoxia adaptation. In L. sacra, several genes related to cardiovascular remodeling, erythropoiesis, oxidative phosphorylation, and DNA repair may also be tailored for adaptation to UV radiation and hypoxia. Of note, ERCC6 and MSH2, two genes associated with adaptation to UV radiation in T. baileyi, exhibited L. sacra-specific mutations that may affect peptide function. Thus, this study provides new insights into the potential mechanisms underpinning high-altitude adaptation in ectotherms and reveals certain genetic generalities for animals' survival on the plateau.

The technology of artificial pneumoperitoneum CT and its application in diagnosis of abdominal adhesion.

To retrospectively analyze the use of artificial pneumoperitoneum in CT scans, to explore its operation methods and technical points, and to lay the foundation for the widespread application of artificial pneumoperitoneum in CT. A total of 331 patients who underwent artificial pneumoperitoneum with CT angiography from January 1, 2013, to November 1, 2019, were recruited. All patients underwent standardized artificial pneumoperitoneum in the horizontal, left and right lateral, and prone positions during CT thin-layer scans of the abdomen and 3D reconstruction. Taking the surgical results as the gold standard, and using kappa test to verify the consistency of surgical results and imaging results. In all 331 patients, 43 patients had a normal peritoneal space, and 288 patients had an abnormal peritoneal space. And only 22 patients developed complications of subcutaneous emphysema, accounting for 6.6% of all 331 patients. In terms of the postoperative results, 28 were normal, and 303 were abnormal. The sensitivity, specificity and accuracy of CT diagnosis of abdominal adhesions using artificial pneumoperitoneum were 100%, 95.04%, and 95.46%, respectively. According to the Kappa consistency test, the imaging diagnosis from the CT scan with artificial pneumoperitoneum had a high consistency with the surgical results (kappa = 0.796, P < 0.05). The technique of artificial pneumoperitoneum CT is safe, reliable, highly practical, and proficient for obtaining good imaging results. It provides a good imaging basis for the diagnosis of intra-abdominal diseases, especially intra-abdominal adhesions.

Pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment.

PURPOSE: The purpose of this study is to characterize niraparib pharmacokinetics (PK) and safety in patients with normal hepatic function (NHF) versus moderate hepatic impairment (MHI). METHODS: Patients with advanced solid tumors were stratified by NHF or MHI (National Cancer Institute-Organ Dysfunction Working Group criteria [bilirubin > 1.5-3 × upper limit of normal and any aspartate aminotransferase elevation]). In the PK phase, all patients received one 300 mg dose of niraparib. In the extension phase, patients with MHI received niraparib 200 mg daily; patients with NHF received 200 or 300 mg based on weight (< 77 kg, ≥ 77 kg)/platelets (< 150,000/µL, ≥ 150,000/µL). PK parameters included maximum concentration (Cmax), area under the curve to last measured concentration (AUClast) and extrapolated to infinity (AUCinf). Safety was assessed in both phases. Exposure-response (E-R) modeling was used to predict MHI effects on exposure and safety of niraparib doses ≤ 200 mg or 300/200 mg or 200/100 mg weight/platelet regimens. RESULTS: In the PK phase (NHF, n = 9; MHI, n = 8), mean niraparib Cmax was 7% lower in patients with MHI versus NHF. Mean exposure (AUClast, AUCinf) was increased by 45% and 56%, respectively, in patients with MHI without impacting tolerability. In the extension phase (NHF, n = 8; MHI, n = 7), the overall safety profile was consistent with previous trials. In patients with MHI, E-R modeling predicted niraparib 200 mg reduced Grade ≥ 3 thrombocytopenia incidence, whereas a 200/100 mg regimen yielded exposures below efficacy-associated levels in 15% of patients. CONCLUSION: These findings support adjusting the 300 mg niraparib starting dose to 200 mg QD in patients with MHI. TRIAL REGISTRATION: NCT03359850; registered December 2, 2017.

Phase I Pharmacokinetic Study of Niraparib in Chinese Patients with Epithelial Ovarian Cancer.

LESSONS LEARNED: Pharmacokinetics characteristics of niraparib in Chinese patients were similar to those in white patients. Niraparib could be well tolerated by Chinese patients, and adverse events were manageable in this study. Population pharmacokinetics analysis indicated that baseline body weight had a modest impact on pharmacokinetics parameters of niraparib; however, it was not considered clinically important. BACKGROUND: This randomized, open-label, single-arm, phase I study was designed to investigate the pharmacokinetics (PK) and safety of niraparib in Chinese patients with epithelial ovarian cancer. METHODS: Eligible patients were randomized in a 1:1:1 ratio to receive 100, 200, or 300 mg of niraparib once daily. PK parameters were analyzed after single and multiple dose administrations. RESULTS: Thirty-six Chinese patients were enrolled in total. Niraparib was rapidly absorbed after administration, and median time-to-peak (Tmax ) was 3 hours. The long terminal elimination half-life (T1/2 ∼ 35 hours) supports once-daily dosing regimen. The exposure to niraparib showed linear and dose-proportional pharmacokinetics, whereas other PK parameters such as Tmax , T1/2 , and accumulation ratio were dose independent. Population PK analysis indicated that there was no effect of race on niraparib PK parameters, whereas baseline body weight had a modest impact on niraparib exposure. Grade 3/4 treatment-emergent adverse events (TEAEs; reported in ≥10% of patients) included platelet count decreased (a total of five patients who were all from the 300-mg group) and neutrophil count decreased. The TEAEs were manageable after dose modification. CONCLUSION: The PK profile of niraparib in Chinese patients is consistent with that in white patients. Niraparib is safe and well tolerated in Chinese patients with ovarian cancer.

Population Pharmacokinetics of Rolapitant in Patients With Chemotherapy-Induced Nausea and Vomiting.

Population pharmacokinetics of rolapitant and its active metabolite M19 were studied in 482 patients receiving this neurokinin-1 receptor antagonist in combination with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone for prevention of chemotherapy-induced nausea and vomiting (CINV). Patients received a single dose of rolapitant (range, 9-180 mg) before administration of moderately or highly emetogenic chemotherapy. Population pharmacokinetic analysis was performed via nonlinear mixed-effects modeling. Rolapitant pharmacokinetics was best characterized by a 2-compartment model. Population typical values were estimated to be 0.962 L/h for apparent oral clearance and 214 L for central compartment volume of distribution. The intercompartment clearance and peripheral compartment volume of distribution was estimated to be 2.79 L/h and 164 L, respectively. Metabolite M19 pharmacokinetics was described by a 1-compartment model with an apparent metabolite clearance of 1.83 L/h. Intersubject variability was moderate for pharmacokinetics parameters. Weight positively correlated with central compartment volume of distribution and peripheral compartment volume of distribution but not with apparent oral clearance. No other demographic, clinical, or pathophysiologic covariates, including liver and renal function, influenced rolapitant pharmacokinetics. A slight positive trend was observed between rolapitant exposure and efficacy (ie, complete response defined as no emesis and no use of rescue medication) in the delayed phase of CINV (>24-120 hours after chemotherapy). This further supports the 180-mg dose of rolapitant in CINV patients. In summary, this validated population pharmacokinetic model satisfactorily describes pharmacokinetics of rolapitant and M19 in patients with CINV. These results support the recommendation that no dose adjustment for patient variables investigated is necessary.

A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas.

BACKGROUND: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers. METHODS: In this sequential, open-label, phase 1 trial (NCT02048488), patients received doses of 30 mg, escalated to 480 mg every 24 hours (Q24h), followed by an expansion cohort of patients with ALK-positive cancers. The primary objective was to evaluate safety and tolerability. Secondary objectives included pharmacokinetics. RESULTS: TSR-011 320- and 480-mg Q24h doses exceeded the maximum tolerated dose. At the RP2D of 40 mg every 8 hours (Q8h), the most common grade 3-4 treatment-emergent adverse events occurred in 3.2-6.5% of patients. Of 14 ALK inhibitor-naive patients with ALK-positive NSCLC, 6 experienced partial responses and 8 had stable disease. CONCLUSIONS: At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued. CLINICAL TRIAL REGISTRATION NUMBER: NCT02048488.

Effect of niraparib on cardiac repolarization in patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer.

PURPOSE: Anticancer drugs may cause cardiovascular toxicities, including QT interval prolongation. Niraparib, a potent and selective once-daily oral poly (ADP-ribose) polymerase inhibitor, is approved as a maintenance therapy in platinum-sensitive recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC). Here, we present the effects of niraparib on cardiac repolarization, and the correlation between changes in baseline QT interval corrected by Fridericia's formula (ΔQTcF) and niraparib plasma concentrations. METHODS: Patients with EOC from the NOVA study (subset of n = 15), the food effect NOVA substudy (n = 17), and a QTc substudy (n = 26) underwent intensive electrocardiographic (ECG) monitoring that included triplicate ECG testing on Day 1 at baseline (predose) and at 1, 1.5, 2, 3, 4, 6, and 8 h postdose concurrent with time-matched blood sampling for determination of niraparib plasma concentrations. All patients received once-daily 300-mg niraparib until disease progression or toxicity. RESULTS: Across the 3 substudies, the upper limit of the two-sided 90% confidence interval (CI) of ΔQTcF was ≤ 10 ms at every postdose timepoint, with a maximum upper limit of 4.3 ms, which indicates no clinically meaningful effect on QTc prolongation. No statistically significant relationship between ΔQTcF and niraparib plasma concentration was observed (estimated slope: 0.0049; 95% CI: - 0.0020, 0.0117; P = 0.164). There were no clinically relevant changes in other ECG parameters that could be attributable to niraparib. CONCLUSION: Niraparib administration at the recommended daily dose of 300 mg for EOC is not associated with clinically relevant alteration of ECGs, including QTc prolongation.

A Phase 1 Assessment of the QT Interval in Healthy Adults Following Exposure to Rolapitant, a Cancer Supportive Care Antiemetic.

This 2-part study evaluated the QT/QTc prolongation potential and safety and pharmacokinetics of the antiemetic rolapitant, a neurokinin-1 receptor antagonist. Part 1 was a randomized, placebo-controlled single-dose-escalation study assessing the safety of a single high dose of rolapitant. Part 2 was a randomized, placebo- and positive-controlled, double-blind parallel-group study including 4 treatment arms: rolapitant at the highest safe dose established in part 1, placebo, moxifloxacin 400 mg (positive control), and rolapitant at the presumed therapeutic dose (180 mg). Among 184 adults, rolapitant was absorbed following oral administration under fasting conditions, with a median Tmax of 4 to 6 hours (range, 2-8 hours) and was safe at all doses up to 720 mg. No differences in mean change in QTcF were observed between placebo and rolapitant from baseline or at any point. At any point, the upper bound of the confidence interval for the mean difference between placebo and rolapitant was no greater than 4.4 milliseconds, and the mean difference between placebo and rolapitant was no greater than 1.7 milliseconds, suggesting an insignificant change in QTc with rolapitant. Rolapitant is safe and does not prolong the QT interval at doses up to 720 mg relative to placebo in healthy adults.

Effects of rolapitant administered orally on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects.

PURPOSE: Rolapitant is a neurokinin-1 receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed chemotherapy-induced nausea and vomiting. We evaluated the effects of rolapitant oral on the pharmacokinetics of probe substrates for cytochrome P450 (CYP) 2D6 (dextromethorphan), 2C9 (tolbutamide), 2C19 (omeprazole), 2B6 (efavirenz), and 2C8 (repaglinide) in healthy subjects. METHODS: This open-label, multipart, randomized, phase 1 study assessed cohorts of 20-26 healthy subjects administered dextromethorphan, tolbutamide plus omeprazole, efavirenz, or repaglinide with and without single, oral doses of rolapitant. Maximum plasma analyte concentrations (Cmax) and area under the plasma analyte concentration-time curves (AUC) were estimated using noncompartmental analysis, and geometric mean ratios (GMRs) and 90% confidence intervals for the ratios of test (rolapitant plus probe substrate) to reference (probe substrate alone) treatment were calculated. RESULTS: Rolapitant significantly increased the systemic exposure of dextromethorphan in terms of Cmax and AUC0-inf by 2.2- to 3.3-fold as observed in GMRs on days 7 and 14. Rolapitant did not affect systemic exposure of tolbutamide, and minor excursions outside of the 80-125% no effect limits were detected for omeprazole, efavirenz, and repaglinide. CONCLUSIONS: Inhibition of dextromethorphan by a single oral dose of rolapitant 180 mg is clinically significant and can last at least 7 days. No clinically significant interaction was observed between rolapitant and substrates of CYP2C9, CYP2C19, CYP2B6, or CYP2C8. CYP2D6 substrate drugs with a narrow therapeutic index may require monitoring for adverse reactions if given concomitantly with rolapitant.

Absorption, metabolism, and excretion of the antiemetic rolapitant, a selective neurokinin-1 receptor antagonist, in healthy male subjects.

Rolapitant is a neurokinin-1 receptor antagonist that is approved in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting (CINV) associated with initial and repeat courses of emetogenic cancer chemotherapy, including but not limited to highly emetogenic chemotherapy. Here, we assessed the absorption, metabolism, and excretion of 14C-labeled rolapitant in healthy male subjects. Rolapitant was administered as a single 180-mg oral dose containing approximately 100 µCi of total radioactivity, with plasma, urine, and fecal samples collected at defined intervals after dosing. Rolapitant had a large apparent volume of distribution, indicating that it is widely distributed into body tissues. Rolapitant was slowly metabolized and eliminated with a mean half-life of 186 h. Exposure to the major metabolite of rolapitant, C4-pyrrolidinyl hydroxylated rolapitant or M19, was approximately 50% of rolapitant exposure in plasma. Renal clearance was not a significant elimination route for rolapitant-related entities. Total radioactivity recovered in urine accounted for 14.2% of the dose, compared to 72.7% recovery in feces. Adverse events (AEs) were generally mild; there were no serious AEs, and no clinically significant changes in laboratory or electrocardiogram parameters were observed. The combination of rolapitant safety, its long half-life, extensive tissue distribution, and slow elimination via the hepatobiliary route (rather than renal excretion) suggest suitability that a single dose of rolapitant may provide protection against CINV beyond the first 24 h after chemotherapy administration.

Identification and functional characterization of long non-coding RNAs in human gastric cancer.

Abnormal regulation of long non-coding RNAs (lncRNAs) appears to be a primary feature of numerous types of human cancer. However, the association between the dysregulation of lncRNAs and functional alterations in gastric cancer (GC) remains unclear. In previous studies, we applied microarray and bioinformatics analyses to screen for key lncRNAs from the tumor tissues and matched adjacent non-tumor tissues of 10 patients with GC. There were seven key lncRNAs demonstrated to be significantly different between carcinoma tissues and adjacent non-tumor tissues. In the present study, the expression of these seven selected lncRNAs were validated in 82 patients with GC to further investigate the association between lncRNAs and GC clinical characterization. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results demonstrated that RP5-919F19, MCPH1 antisense RNA 1 (CTD-2541M15) and urothelial carcinoma-associated 1 (UCA1) exhibited consistent upregulation in cancer compared with adjacent non-tumor tissues, whereas AP000459, LOC101928316, tumor suppressor candidate 8 (LINC01071) and maternally expressed 3 (MEG3) showed consistent downregulation. The results from the microarray and RT-qPCR experiments achieved 100% agreement. A correlation analysis indicated that RP5-919F19, LOC101928316 and MEG3 were significantly associated with tumor differentiation degree, RP5-919F19, UCA1 and MEG3 were significantly associated with lymph node metastasis, and RP5-919F19, CTD-2541M15 and UCA1 were significantly associated with tumor-node-metastasis stage (P<0.05). In addition, it was identified that the differential expression of LINC01071 and LOC101928316 significantly correlated with the age and gender of the GC patients, respectively (P<0.05). The results suggest that the lncRNAs RP5-919F19, LOC101928316, CTD-2541M15, UCA1 and MEG3 are closely associated with the invasion and metastasis of GC, which reveals these indicators as potential specificity biomarkers for the diagnosis, prognosis and classification of GC. Thus, these lncRNAs merit further study as novel candidate biomarkers for the clinical diagnosis of GC and as potential targets for therapy.

The effect of food on the pharmacokinetics of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent ovarian cancer.

PURPOSE: Niraparib is a highly selective inhibitor of PARP-1 and PARP-2 approved in the United States for maintenance treatment of adult patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. In this open-label crossover study, we evaluated the effects of food on niraparib pharmacokinetics (PK) and safety. METHODS: Patients received a single 300-mg dose of niraparib either after a high-fat meal or under fasting conditions. After a 7-day PK assessment, all patients received a second 300-mg dose of niraparib under the opposite condition, followed by 7-day PK assessment. Blood samples for PK analyses were collected at baseline (on days 1 and 8) and up to 168 h post-dose. Bioequivalence between conditions was defined by the 90% confidence intervals (CIs) for area under the plasma concentration-time curve (AUC) from 0 to last measurable concentration (AUC0-last) and from 0 to infinity (AUC0-∞) being within the 80-125% range. RESULTS: The high-fat meal/fasting ratios of geometric least-squares means for AUC0-last and AUC0-∞ were 106.8 (90% CI 97.8-116.6) and 110.1 (90% CI 99.7-121.6), respectively, indicating bioequivalence between conditions. Mean half-life, maximum plasma concentration (Cmax), and time to Cmax after the high-fat meal were similar to, 27% smaller than, and 128% greater than after fasting, respectively. Adverse events were similar between conditions. CONCLUSIONS: A high-fat meal did not impact the PK profile of niraparib, indicating that niraparib can be taken with or without food. Niraparib was safe and well-tolerated.

Effects of Rolapitant Administered Intravenously or Orally on the Pharmacokinetics of Digoxin (P-glycoprotein Substrate) and Sulfasalazine (Breast Cancer Resistance Protein Substrate) in Healthy Volunteers.

Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. Four open-label phase 1 studies evaluated the safety and drug-drug interactions of a single dose of rolapitant given intravenously (166.5 mg) or orally (180 mg) with oral digoxin (0.5 mg) or sulfasalazine (500 mg), probe substrates for the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. Administration of intravenous rolapitant with the substrates did not result in clinically significant effects on digoxin and sulfasalazine pharmacokinetics. In contrast, peak concentration and area under the curve for last quantifiable plasma concentrations increased by 71% (geometric mean ratio [GMR], 1.71; 90% confidence interval [CI], 1.49-1.95) and 30% (GMR, 1.30; 90%CI, 1.19-1.42), respectively, when rolapitant was coadministered orally with digoxin compared with digoxin alone; they increased by 140% (GMR, 2.40; 90%CI, 2.02-2.86) and 127% (GMR, 2.27; 90%CI, 1.94-2.65), respectively, when rolapitant was given orally with sulfasalazine compared with sulfasalazine alone. Adverse events were mild to moderate in severity in the absence or presence of rolapitant. There were no abnormal clinical laboratory or electrocardiogram findings. Thus, whether administered orally or intravenously, rolapitant was safe and well tolerated. Patients taking oral rolapitant with P-gp and BCRP substrates with a narrow therapeutic index should be monitored for potential adverse events; although increased plasma concentrations of these substrates may raise the risk of toxicity, they are not contraindicated.

eEF1A1 Overexpression Enhances Tumor Progression and Indicates Poor Prognosis in Hepatocellular Carcinoma.

Liver is a major contributor of protein production physiologically. The aberrant state of protein synthesis leads to tumor progression. Eukaryotic elongation factor 1 alpha 1 (eEF1A1) is a major member of the eukaryotic elongation factor family that regulates protein synthesis. Although eEF1A1 plays an essential role in controlling the cell fate, its clinical significance in tumor development and progression has not been reported. Here, we aimed to uncover the expression and prognostic significance of eEF1A1 in hepatocellular carcinoma (HCC). Our data indicated that eEF1A1 expression was elevated in HCC cell lines and clinical samples at both the mRNA and protein levels. Immunohistochemistry revealed that eEF1A1 expression was upregulated in HCC samples compared with corresponding non-tumorous tissues. In 50 HCC cases with portal vein embolus, higher eEF1A1 immunoreactivity was detected in tumor metastases compared with the primary lesions. Kaplan-Meier analysis indicated that increased eEF1A1 expression was closely associated with unfavorable post-surgical overall and disease-free survival in 453 HCC patients. Moreover, multivariate analysis indicated eEF1A1 as an independent predictor for overall and disease-free survival. Collectively, our study suggests eEF1A1 as a novel prognostic biomarker and potential therapeutic target for HCC patients.

A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models.

Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both BRCA mutant (mut) and BRCA wildtype (wt) adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers who have demonstrated a complete or partial response to platinum-based chemotherapy. In patients without germline BRCA mutations (non-gBRCAmut), niraparib improved progression-free survival (PFS) by 5.4 months, whereas another PARP inhibitor (PARPi) olaparib supplied only 1.9 months of improvement in a similar patient population. Previous studies revealed higher cell membrane permeability and volume of distribution (VD) as unique features of niraparib in comparison to other PARPi including olaparib. Here, we explore the potential correlation of these pharmacokinetic properties to preclinical antitumor effects in BRCAwt tumors. Our results show that at steady state, tumor exposure to niraparib is 3.3 times greater than plasma exposure in tumor xenograft mouse models. In comparison, the tumor exposure to olaparib is less than observed in plasma. In addition, niraparib crosses the blood-brain barrier and shows good sustainability in the brain, whereas sustained brain exposure to olaparib is not observed in the same models. Consistent with its favorable tumor and brain distribution, niraparib achieves more potent tumor growth inhibition than olaparib in BRCAwt models and an intracranial tumor model at maximum tolerated doses (MTD). These findings demonstrate favorable pharmacokinetic profiles and potent antitumor effects of niraparib in BRCAwt tumors, consistent with its broader clinical effect in patients with both BRCAmut and BRCAwt tumors.

Cancer Incidence and Mortality Survey in Wuwei, Gansu Province, Northwestern China from 2003 to 2012: A Retrospective Population-based Study.

BACKGROUND: Population-based cancer registry collects the data on cancer incidence and mortality deaths from covered population to describe and survey the epidemics in certain areas. The aim of this study was to estimate the cancer incidence and mortality in Wuwei, Gansu province, Northwestern China from 2003 to 2012. The goal is to better understand cancer distribution and long-term development of cancer prevention and treatment in Wuwei. METHODS: Data were collected from the Wuwei Cancer Registry between 2003 and 2012. In this registry, data from 46 cancer report centers were included in this analysis. Incidence/mortality rates, age-specific incidence/mortality rates, age-standardized incidence/mortality rates, and cumulative incidence/mortality rates were calculated. Totally, 9,836,740 person-years (5,110,342 for males and 4,726,398 for females) had been monitored over this time period. The gender ratio of male/female was 1.08:1. The number of new cancer cases and related deaths was 24,705 and 17,287 from 2003 to 2012, respectively. RESULTS: The proportion of morphological verification was 74.43%. The incidence of cases identified through death certification only was 1.21%, and the mortality to incidence ratio was 0.70. The average crude incidence was 251.15/100,000 persons (310.61 and 186.87 for males and females per 100,000 persons, respectively). The age-standardized rates by Chinese standard population (ASR-China) and by world standard population (ASR-world) were 207.76 and 245.42 per 100,000 persons, respectively. The crude cancer mortality was 175.74/100,000 persons (228.34 and 118.86 for males and females per 100,000 persons). ASR for China and the world was 149.57 and 175.13/100,000 persons, respectively. The most common cancers and leading causes of cancer-related deaths in Wuwei were as follows: cancers of stomach, esophagus, liver, lung, colorectum, breast, cervix, lymphoma, blood (leukemia), brain, and central nervous system. In Wuwei, during 2003 and 2012, cancer incidence and mortality rates increased by 1.32% and 1.31%/year, respectively. During this time, colorectum cancer incidence and mortality rates increased by 2.69% and 7.54%/year, respectively, in Wuwei. The incidence and mortality of other gastric, esophageal, liver, and lung cancers also all increased. CONCLUSIONS: The results of this study report a more accurate cancer burden among the population of Wuwei, China. Active research of cancers etiology and effective prevention should be established to reduce the incidence and mortality associated with cancers.

Integrated analysis of long non-coding RNA competing interactions reveals the potential role in progression of human gastric cancer.

Abnormal expression of long non-coding RNAs (lncRNAs) have been shown to play an important role in tumor biology. The Cancer Genome Atlas (TCGA) platform is a large sample sequencing database of lncRNAs, and further analysis of the associations between these data and patients' clinical related information can provide new approaches to find the functions of lncRNA. In the present study, 361 RNA sequencing profiles of gastric cancer (GC) patients were selected from TCGA. Then, we constructed the lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network of GC. There were 25 GC specific lncRNAs (fold change >2, p<0.05) identified, 19 of them were included in ceRNA network. Subsequently, we selected these 19 key lncRNAs and analyzed the correlations with clinical features and overall survival, 14 of them were discriminatively expressed with tumor size, tumor grade, TNM stage and lymphatic metastasis (p<0.05). In addition, eight lncRNAs (RPLP0P2, FOXD2-AS1, H19, TINCR, SLC26A4-AS1, SMIM10L2A, SMIM10L2B and SNORD116-4) were found to be significantly associated with overall survival (log-rank p<0.05). Finally, two key lncRNAs HOTAIR and UCA1 were selected for validation of their expression levels in 82 newly diagnosed GC patients by qRT-PCR. Results showed that the fold changes between TCGA and qRT-PCR were 100% in agreement. In addition, we also found that HOTAIR was significantly correlated with tumor size and lymphatic metastasis (p<0.05), and UCA1 was significantly correlated with tumor size, TNM stage and lymphatic metastasis (p<0.05). The clinical relevance of the two lncRNAs and the bioinformatics analysis results were almost the same. Overall, our study showed the GC specific lncRNAs expression patterns and a ceRNA network in GC. Clinical features related to GC specific lncRNAs also suggested these lncRNAs are worthwhile for further study as novel candidate biomarkers for the clinical diagnosis of GC and potential indicators for prognosis.

High expression of zinc-binding protein-89 predicts decreased survival in esophageal squamous cell cancer.

BACKGROUND: Zinc-binding protein-89 (ZBP-89), a Krüppel-type four-zinc finger transcription factor, is associated with many cellular functions, including cell growth, differentiation, and apoptosis. It has been reported to be involved in several human cancers. However, ZBP-89 expression pattern and its clinical significance have not yet been investigated in esophageal squamous cell cancer. METHODS: In this study, immunostaining was performed to detect ZBP-89 expression in esophageal squamous cell cancer, and then the correlations between ZBP-89 expression and both clinicopathologic variables and overall survival were analyzed. RESULTS: Compared with adjacent normal tissues, ZBP-89 expression was significantly upregulated in esophageal squamous cell cancer tissues. Increased ZBP-89 expression was associated with N category (p = 0.009) and TNM stage (p = 0.023). Patients with high expression of ZBP-89 demonstrated shortened overall survival compared with those with low expression of ZBP-89 (mean overall survival, 56.961 months versus 76.029 months; p < 0.001). Multivariate Cox regression analysis indicated that ZBP-89 expression had a significant, independent predictive value for survival of esophageal squamous cell cancer (relative risk, 1.581; p = 0.024). CONCLUSIONS: Our data show that increased expression of ZBP-89 is associated with poor prognosis for esophageal squamous cell cancer patients and may act as a novel, useful, and independent prognostic indicator for esophageal squamous cell cancer. Further studies are warranted.