PIVKA-II Levels Research Articles

Efficacy and safety of donafenib as adjuvant therapy for patients with hepatocellular carcinoma undergoing curative resection: A retrospective, multicenter cohort study.

e16234 Background: A growing incidence of hepatocellular carcinoma and its high risk of recurrence after curative-intent treatment underscore the need for effective adjuvant treatment options. This study aimed to assess the efficacy of adjuvant donafenib in patients with hepatocellular carcinoma (HCC) following radical resection. Methods: This multicenter, real-world study retrospectively gathered clinical data of 82 patients who had undergone radical resection of HCC and received adjuvant therapy with donafenib. The primary endpoint was recurrence-free survival (RFS). The secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analysis was performed to evaluate RFS and OS, while the Cox proportional-hazards model was used to estimate risk factors for tumor recurrence and death. Results: A total of 82 patients with HCC who received donafenib following surgical resection were included in the study, of which were classified as high risk for tumor recurrence (with multiple or large tumor, microvascular invasion, poor tumor differentiation). The median duration of donafenib adjuvant therapy was 10.6 months (range: 0.2–26.1 months). All patients completed follow-up as required, with a median follow-up time of 19.4 months (range: 2.8–57.6 months). During the follow-up period, a totally postoperative recurrence rate was 15.9% (13/82). 1-year recurrence rate and 2-year recurrence rate were 7.3% (6/82) and 12.2% (10/82), and 1-year survival rate and 2-year survival rate were 95.1% (78/82) and 93.9% (77/82). Kaplan-Meier analysis demonstrated that patients with higher preoperative AFP level (AFP > 400ng/mL), higher preoperative PIVKA-II level (PIVKA-II > 40mAU/mL), or poor tumor differentiation (Edmondson stage III-IV) exhibited higher rate of tumor recurrence after operation (all p value < 0.05). Multivariate analysis indicated that preoperative AFP level was an independent risk factor for tumor recurrence in patients with donafenib treatment. Treatment-related adverse events (TRAEs) occurred in 67.1% (55/82) of patients, of which the most frequent were hand-foot syndrome (25.6%, 21/82), diarrhea (20.7%, 17/82), and fatigue (17.1%, 14/82). Only 8.5% (7/82) of patients had a grade ≥3 TRAEs, with the most common being hand-foot syndrome (2.4%, 2/82) and hypertension (2.4%, 2/82). No treatment-related deaths were reported. Conclusions: This study represents the largest multicenter investigation of adjuvant therapy with donafenib to date, and the findings indicate that donafenib has the potential to be an effective treatment option for preventing postoperative recurrence in HCC. Furthermore, the preoperative AFP ≤400ng/mL can serve as an effective biomarker for postoperative administration of donafenib in HCC patients.

Evaluation of the risk of developing hepatocellular carcinoma in chronic Hepatitis C patients receiving antiviral treatment.

Chronic HC leads to the development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The treatment of chronic HC with DAAs reduces mortality from LC and HCC.The study aimed to investigate the serological markers specific to HCC (PIVKA-II and AFP) in patients with chronic HC before and after DAA treatment. The study involved 35 HCV patients (mean age: 56.23 ± 1.45) divided into two groups. Group 1 included 15 HCV + HCC patients and Group 2 included 20 HCV non-HCC patients. At the end of treatment all the patients were HCV RNA negative. Three months after the end of antiviral treatment, HCV RNA was undetectable in all patients, while a complete biochemical and virological response was observed in 66.7% of HCV + HCC patients and 85.0% of HCV non-HCC patients. PIVKA-II levels before the initiation of antiviral treatment were high in all patients. At the end of the treatment, in the HCV non-HCC group, normalization of PIVKA-II levels was observed only in 20.0% cases, and in 60.0% of cases 3 months after the treatment. Meanwhile, in patients with HCC and chronic HCV, PIVKA-II levels were within the normal range 3 months after treatment in only 13.3% of patients. It is necessary to monitor HCV patients with cirrhosis (F4) and severe fibrosis (F3) without HCC, who have high PIVKA-II and AFP levels and/or ALT activity despite obtaining sustained virologic response 3 months after treatment with DAAs.

#1943 The association of uncarboxylated, non-phosphorylated Matrix Gla protein with arterial stiffness in hemodialysis and peritoneal dialysis patients

Abstract Background and Aims Vitamin K deficiency has been identified as a marker of vascular calcification AND STIFNESS and an independent cardiovascular risk factor in hemodialysis (HD) and peritoneal dialysis (PD) patients, as the most powerful inhibitor of vascular calcification, Matrix Gla Protein requires vitamin K to become activated. However, until to date, it has not yet been clarified whether hepatic or extrahepatic markers of vitamin K status reflect the arterial status of dialysis patients. In this study we aimed to investigate the association of vitamin K deficiency with arterial stiffness in End-Stage Kidney Disease (ESKD) patients. Method In 42 ESKD patients undergoing either HD or PD, we measured plasma levels of the inactive vitamin-K dependent Matrix Gla Protein (dp-ucMGP) and serum levels of prothrombin (PIVKA-II) as markers of extrahepatic and hepatic insufficiency of vitamin K (CARIM Institute, Maastricht, Netherlands). In these patients we determined arterial stiffness parameters (pulse wave velocity-PWV) by the Mobil-O-Graph device (IEM, Stolberg, Germany). Results Serum PIVKA-II was associated with T2D duration (r = −0.38, p = 0.013), phosphorus levels (r = −0.41, p = 0.009) serum albumin (r = −0.33, p = 0.036) Spearman's rho test, and the type of transporter in PD patients (p = 0.039), Kruskal-Wallis test. Plasma dp-ucMGP was associated with PWV (r = 0.51, p = 0.001), peripheral (r = −0.37, p = 0.016) and central diastolic blood pressure (BP) (r = −0.34, p = 0.026) and age (r = 0.41, p = 0.007), Spearman's rho. Patients with T2DM, history of acute myocardial infarction and those receiving warfarin had significantly increased levels of circulating dp-ucMGP (p = 0.036, p = 0.039 and p < 0.0001, respectively, Kruskal-Wallis). Warfarin was associated with a 2.5-fold and a 23-fold increase in dp-ucMGP and PIVKA-II levels, respectively. Stepwise multiple regression analysis showed that PWV (p = 0.001, B = 494, 95% CI: 242-746) was an independent predictor of dp-ucMGP, independent of age, T2T2, history of myocardial infraction and diastolic BP. Conclusion Elevated plasma dp-ucMGP levels (suggesting extrahepatic vitamin K deficiency) were associated with increased arterial stiffness in dialysis patients.

Association between serum levels of GDF-15, suPAR, PIVKA-II, sdLDL and clinical outcomes in hospitalized COVID-19 patients.

To quantify the circulating levels of novel serum biomarkers including GDF-15, PIVKA-II, sdLDL, suPAR, and of CRP in hospitalized COVID-19 patients compared with healthy subjects, and to evaluate their association(s) with outcomes in COVID-19. We considered patients with confirmed COVID-19, hospitalized in an Internal Medicine ward. The clinical characteristics were collected, including the number and type of comorbidities. Serum levels of GDF-15, PIVKA-II, suPAR, sdLDL, as well as CRPwere measured. As outcomes, we considered Intensive Care Unit (ICU) transfer or death, as well as the length of stay (days) and in-hospital complications. Data were statistically analyzed, as appropriate, and a p value < 0.05 was considered significant. Ninety-three patients and 20 healthy controls were enrolled. COVID-19 patients vs. controls showed higher median levels of GDF-15 (p < 0.0001), PIVKA-II (p < 0.0001) and sdLDL (p = 0.0002), whereas no difference was observed for suPAR. In COVID-19 patients, the most frequent comorbidities were arterial hypertension (62.4%) and cardiovascular disease (30.1%). GDF-15 levels positively correlated with age (r = 0.433, p < 0.0001), and this correlation was confirmed for suPAR (r = 0.308, p = 0.003) and CRP (Rho = 0.40 p < 0.0001), but not for PIVKA-II and sdLDL. Higher GDF-15 levels were associated with a higher number of comorbidities (p = 0.021). The median length of stay was 22 (15; 30) days. During hospitalization, 15 patients (16%) were ICU transferred, and 6 (6.45%) died. GDF-15 serum levels correlated with the length of stay (rho = 0.27 p = 0.010), and were associated with ICU transfer or death (p = 0.003), as well as PIVKA-II (p = 0.038) and CRP (p < 0.001). Moreover, higher GDF-15 and PIVKA-II serum levels were associated with infectious complications (p = 0.008 and p = 0.017, respectively). In this cohort of hospitalized COVID-19 patients, novel inflammatory biomarkers, including GDF-15, suPAR and PIVKA II were associated with some patient's clinical characteristics, complications, and poor outcomes.

Vitamin K prophylaxis in neonates: comparing two different oral regimens.

This prospective study compared PIVKA-II and PT-INR levels in infants who received two vitamin K (VK) prophylactic regimens. A single institution administered 119 healthy newborns 2 mg of VK syrup. Infants were assigned to a 3-time regimen (n = 56) with VK at birth, five days (5D), and 1-month-old (1 M), or a 13-time regimen (n = 63) with VK at birth, 5D, and then weekly for 11 weeks. The 13-time regimen significantly lowered PIVKA-II and reduced PT-INR at 1 M in both breastfed (PIVKA-II: 18-16 mAU/mL, p = 0.02; PT-INR: 1.37-1.13, p < 0.01) and formula-fed infants (PIVKA-II: 18-15 mAU/mL, p = 0.01; PT-INR: 1.54-1.24, p < 0.01), compared to baseline measurements taken at 5D. The 3-time regimen did not significantly alter PIVKA-II levels and only improved PT-INR (2.00-1.50, p < 0.01) in formula-fed infants. The 13-time VK regimen significantly enhanced coagulation profiles more effectively than the 3-time regimen.

Diagnostic accuracy of serum protein induced by vitamin K absence (PIVKA-II), serum a-fetoprotein and their combination for hepatocellular carcinoma among Caucasian cirrhotic patients with diagnostic or non-diagnostic serum a-fetoprotein levels.

The aim of our study was to evaluate the accuracy of serum biomarkers (AFP/PIVKA-II) and their combination in HCC diagnosis among Caucasian cirrhotic patients. Serum AFP/PIVKA-II levels were evaluated in 218 cirrhotics (163 males, 118 CTP-A, 66 ALBI-I, 111 with varices, 63 with diabetes) with (n = 90) or without (n = 128) HCC. Patients with HCC were categorized to BCLC Stage 0/A (n = 12), B (n = 21), C (n = 48), and D (n = 9). The two groups were comparable for all baseline parameters except for age, platelets, and diabetes presence. Median levels of AFP (239.1 vs. 4.0 ng/mL) and PIVKA-II (4082.7 vs. 45.8 mAU/mL) were both significantly higher in HCC group compared to controls (p < 0.001). AUROC and cutoff value for HCC diagnosis were 88%/12.35 ng/mL (AFP) and 84.4%/677.13 mAU/mL (PIVKA-II), whereas their combination showed better diagnostic accuracy (AUROC = 90.2%). The diagnostic accuracy of each biomarker separately was moderate or good in BCLC-0/A/B and was excellent only for BCLC-C patients (AFP: AUROC = 94.3%, cutoff = 12.35 ng/mL and PIVKA-II: 91.3%, 253.51 mAU/mL) whereas their combination presented quite acceptable results in BCLC-B (AUROC = 92.4%) and BCLC-C (AUROC = 95.7%). Excluding HCC patients with high AFP (above 400 ng/mL), the diagnostic accuracy of each biomarker separately and their combination was moderate/good in all groups, except for their combination in BCLC-C (AUROC = 90.5%). Each biomarker separately showed acceptable accuracy for detecting HCC in cirrhotic patients and excellent for those in BCLC-C stage. The combination of the biomarkers presented excellent results in BCLC-B/C patients. The diagnostic accuracy of PIVKA-II and the combination of the two biomarkers in patients expressing low/non-diagnostic AFP levels was good in BCLC-B and excellent in BCLC-C patients.

The Role of PIVKA-II as a Predictor of Early Hepatocellular Carcinoma Recurrence-Free Survival after Liver Transplantation in a Low Alpha-Fetoprotein Population.

AFP and the RETREAT score are currently used to predict HCC recurrence after LT. However, superior discriminating models are needed for low AFP populations. The aim of this study is to investigate the predictive value of PIVKA-II on recurrence-free survival after LT in a low AFP population and microvascular invasion on explant. A retrospective cohort study including all consecutive patients transplanted for HCC between 1989 and 2019 in the Erasmus MC University Medical Center in Rotterdam, the Netherlands, was used. AFP and PIVKA-II levels were determined in serum samples collected at the time of transplantation. Data on tumor load and microvascular invasion were retrieved from patients' records. The study cohort consisted of 121 patients, with HCC recurrence in 15 patients (12.4%). The median AFP was 7.7 ng/mL (4.4-20.2), and the median PIVKA-II was 72.0 mAU/mL (41.0-213.5). Patients with low AFP (≤8 ng/mL) and PIVKA-II (≤90 mAU/mL) had a 5-year recurrence-free survival of 100% compared to 85.7% in patients with low AFP and high PIVKA-II (p = 0.026). Regardless of the AFP level, patients within the Milan criteria (based on explant pathology) with a low PIVKA-II level had a 5-year recurrence-free survival of 100% compared to patients with a high PIVKA-II level of 81.1% (p = 0.002). In patients with microvascular invasion, the AUC for PIVKA-II was slightly better than the AUC for AFP (0.775 vs. 0.687). The dual model of PIVKA-II ≤ 90 mAU/mL with either AFP ≤ 8 ng/mL or with patients within the Milan criteria identifies patient groups which can be exempted from HCC surveillance after LT in a low AFP population. PIVKA-II may be a better predictor for explant microvascular invasion than AFP and could play a role in future models identifying LT candidates with the highest risk for HCC recurrence.

Predictive value of PIVKA-II and AFP for the non-objective response of HBV-associated hepatocellular carcinoma after transarterial chemoembolization: a prospective study.

To determine the predictive value of serum abnormal prothrombin (PIVKA-II) and alpha-fetoprotein (AFP) for the non-objective response of HBV-associated hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE). This prospective study included HBV-associated HCC patients who underwent TACE at the Fourth People's Hospital of Qinghai Province between December 2021 and July 2022. According to contrast-enhanced ultrasound and upper abdomen contrast-enhanced MRI, the patients were divided into the objective response group and the non-objective response group 3 months after TACE. There were 54 patients, of whom 31 experienced non-objective responses. The PIVKA-II levels in the objective response group were significantly lower than in the non-objective response group at 1 month [352.00 (142.16-722.54) vs. 528.58(241.32-1681.23) mAU/ml, P = 0.005] and 3 months [28.96 (20.01-42.49) vs. 2082.55 (52.63-10 057.30) mAU/ml, P = 0.016] after TACE. The Spearman rank correlation analysis showed no significant correlation between PIVKA-II and AFP (r = 0.315, P > 0.05). The areas under the curve (AUCs) of AFP and PIVKA-II before TACE were 0.632 and 0.529. One month after TACE, the AUC of PIVKA-II combined with AFP (AUC = 0.787) was higher than for PIVKA-II (AUC = 0.658) and AFP (AUC = 0.749). PIVKA-II does not outperform AFP in predicting non-objective response after TACE in HCC patients. The combination of PIVKA-II and AFP might improve the diagnosis of HCC non-objective response after TACE.

Favorable Impact of Serum TERT C228T for Prognosis after Surgical Resection for Liver Cancer

Introduction: Personalized medicine and molecular therapies with the diagnosis of somatic genetic alterations are expected to be developed for liver cancer. Nevertheless, it is unknown whether a mutation in the telomere reverse transcriptase promoter (TERT C228T) in serum cfDNA might be useful for making prognostic predictions after surgical resection for primary liver cancer. Methods: This cohort study retrospectively investigated 111 patients who had undergone surgical resection of liver cancer for the first time. We investigated the differences between clinicopathological features and prognosis according to classification of three tumor markers, including AFP, PIVKAII, and TERT C228T. Results: Multivariate analysis identified etiology (fatty liver disease vs. HBV odds ratio [OR] 6.853) and fibrosis stage (2–4, OR: 0.137) as determinants of TERT C228T-positive liver cancer with normal levels of AFP and PIVKAII (TERT single positive liver cancer). TERT single positive (Yes, OR: 0.301), fibrosis (FIB)-4 index (≥3.25, OR: 2.038), Child-Pugh classification (B, OR: 4.975), and number of tumors (≥2, OR: 4.098) were identified as determinants of the recurrence of liver cancer. TERT single positive (Yes, OR: 3.311), FIB-4 index (≥3.25, OR: 0.433), and number of tumors (≥2, OR: 0.262) were identified as determinants of disease-free survival. Conclusions: Our results highlight the impact of classification of prognostic tumor markers. TERT single positive is one predictor of favorable prognosis after surgical resection for liver cancer.

#5184 THE RELATIONSHIP OF BONE MINERAL DENSITY AND VITAMIN K IN RENAL TRANSPLANT PATIENTS

Abstract Background and Aims Kidney transplantation is the best treatment for end-stage renal disease (ESRD). Osteoporosis is a common health problem in kidney transplant recipients. It is known that the risk of bone fracture increases by 30% in the first 3 years after transplantation in kidney transplant recipients. Vitamin K is a cofactor involved in the activation of osteocalcin. This protein plays a role in bone mineralization. Currently, vitamin K cannot be measured directly from blood samples, and markers such as proteins induced in the absence of vitamin K (PIVKA-II) and undecarboxylated osteocalcin (ucOC) are used for indirect measurement of vitamin K. In our study, we aimed to investigate the relationship between vitamin K and osteoporosis by measuring serum PIVKA-II, ucOC and BMD in kidney transplant recipients. Method It was a cross-sectional observational study. Patients were selected from kidney transplant patients over 18 years old. A control group was formed from dialysis patients over the age of 18. For vitamin K levels, PIVKA-II and ucOC levels were measured in serum samples taken from patients. The relationship between vitamin K markers, bone mineral densitometry and the risk of major osteoporotic fracture calculated by FRAX in kidney transplant patients was evaluated. Results 68 kidney transplant patients and 20 dialysis patients followed in our clinic were included in this study. As results, it was observed the increased risk of osteoporosis in postmenopausal women patients related with decreased serum vitamin K level (r = −0.520, p = 0.047). Of the transplant group, PIVKA-II and Lumbar I-IV BMD values were statistically significant (p = 0.034, r = -0.258). PIVKA-II was found to be a risk factor for low BMD by multiple linear regression analysis in the transplant group (beta coefficient = −0.195, p = 0.037). Conclusion In our study, it has been proven that as the vitamin K level decreases in kidney transplant patients, the vertebral bone mineral density decreases while the risk of osteoporosis increases. This result shows that vitamin K replacement may have positive effects on bone metabolism.

#6246 PIVKA II IS A BIOMARKER FOR PREDICTING CORONARY CALCIFICATION IN HEMODIALYSIS PATIENTS WITH DIABETES

Abstract Background and Aims Vascular calcification (VC) is a commonly occurring and serious complication in end-stage renal disease (ESRD) patients that increases mortality. Vitamin K deficiency is well known to cause the occurrence of VC through the inactivation of Vitamin K dependent proteins (VKDP). Therefore, a marker that can easily predict the risk of VC due to vitamin K deficiency is needed in clinical practice. In this study, we aim to investigate whether the easily measurable vitamin K absence II (PIVKA-II) can serve as a surrogate marker for predicting coronary artery calcification (CAC) in ESRD patients receiving hemodialysis and what factors influence the prediction of CAC. Method This study is an observational study conducted on end-stage renal disease patients receiving hemodialysis treatment. Patients with liver cirrhosis, HCC, or a history of coronary artery disease with stent placement were excluded, as well as patients with active infectious diseases. CAC score was measured by Non-enhanced computed tomography, and before starting hemodialysis, blood samples were collected to measure PIVKA-II, osteocalcin (OC), and bone-specific alkaline phosphatase (BAP) among other bone markers. PIVKA-II was measured two times with 3 months interval, and the average value was calculated. Additionally, ankle-brachial index (ABI) and DEXA bone densitometry were also performed. Results In this study, 69 dialysis patients participated. Among them, 34 patients had diabetes mellitus (DM). The study compared two groups based on the presence of DM. The results showed that patients with DM had higher Body Mass Index (BMI) (p = 0.01) and a higher frequency of vascular diseases such as coronary artery disease or cerebrovascular disease (p = 0.004). The DM group also had higher LDL cholesterol levels (p = 0.03), but there was no significant difference between the two groups in terms of PIVKA-II, BAP, and Osteocalcin levels (Table 1). When analyzing the factors that had a correlation with the CAC score in all 69 patients, LDL cholesterol (r = -0.37, p = 0.002) and CRP (r = 0.28, p = 0.03) were found to have a significant correlation, but PIVKA-II (p = 0.065, Figure 1A), BAP (p = 0.57), and OC (p = 0.45) did not. In the DM group, there was a statistically significant correlation between CAC score and PIVKA-II (r = 0.283, p = 0.001), but there was no correlation between CAC score (Figure 1B) and CaxP, LDL cholesterol, CRP, BAP, and OC (p = 0.7, p = 0.4, p = 0.3, p = 0.7 and p = 0.4 respectively). Conclusion The results suggest that in patients with diabetes who undergo dialysis, PIVKA-II can be clinically useful as a surrogate marker for predicting CAC associated with vitamin K deficiency. This is because diabetic patients may have more pronounced VKDP inactivation and VC due to vitamin K deficiency, but additional research is needed to fully understand this relationship.

Diagnostic and Prognostic Nomograms for Hepatocellular Carcinoma Based on PIVKA-II and Serum Biomarkers

Background: The aim of the present study was to develop an improved diagnostic and prognostic model for HBV-associated HCC by combining AFP with PIVKA-II and other potential serum/plasma protein biomarkers. Methods: A total of 578 patients, including 352 patients with HBV-related HCC, 102 patients with HBV-associated liver cirrhosis (LC), 124 patients with chronic HBV, and 127 healthy subjects (HS), were enrolled in the study. The serum levels of AFP, PIVKA-II, and other laboratory parameters were collected. Univariate and multivariate logistic regression and Cox regression analyses were performed to identify independent diagnostic and prognostic factors, respectively. The diagnostic efficacy of the nomogram was evaluated using receiver operator curve (ROC) analysis and the prognostic performance was measured by Harrell’s concordance index (C-index). Results: AFP and PIVKA-II levels were significantly increased in HBV-related HCC, compared with those in HBV-associated LC and chronic HBV participants (p &lt; 0.05 and p &lt; 0.001, respectively). The diagnostic nomogram, which included age, gender, AFP, PIVKA-II, prothrombin time (PT), and total protein (TP), discriminated patients with HBV-HCC from those with HBV-LC or chronic HBV with an AUC of 0.970. In addition, based on the univariate and multivariate Cox regression analysis, PIVKA-II, γ-glutamyl transpeptidase, and albumin were found to be significantly associated with the prognosis of HBV-related HCC and were incorporated into a nomogram. The C-index of the nomogram for predicting 3-year survival in the training and validation groups was 0.75 and 0.78, respectively. The calibration curves for the probability of 3-year OS showed good agreement between the nomogram prediction and the actual observation in the training and the validation groups. Furthermore, the nomogram had a higher C-index (0.74) than that of the Child−Pugh grade (0.62), the albumin−bilirubin (ALBI) score (0.64), and Barcelona Clinic Liver Cancer (0.56) in all follow-up cases. Conclusion: Our study suggests that the nomograms based on AFP, PIVKA-II, and potential serum protein biomarkers showed a better performance in the diagnosis and prognosis of HCC, which may help to guide therapeutic strategies and assess the prognosis of HCC.

Association between Posttreatment Serum Platelet-to-Lymphocyte Ratio and Distant Metastases in Patients with Hepatocellular Carcinoma Receiving Curative Radiation Therapy.

We sought to investigate whether serum immune and inflammatory parameters can help to predict distant metastasis (DM) in patients with unresectable hepatocellular carcinoma (HCC) undergoing curative radiation therapy (RT). A total of 76 RT courses were analyzed. The following variables were included in the analysis: systemic inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), absolute lymphocyte count, lymphocyte-to-monocyte ratio, albumin, albumin-to-alkaline phosphatase ratio, RT-related parameters, and levels of total protein, hemoglobin, α-fetoprotein, and PIVKA-II. Distant control (DC) and overall survival (OS) rates were calculated and compared. The mean age was 61.4 years, and most patients were men (n = 62, 81.6%). The median RT fraction number and fractional doses were 12 (range, 4-30) and 5 (range, 2-12) Gy, respectively. With a median follow-up of 12 (range, 3.1-56.7) months, the 1-year DC and OS rates were 64.4% and 55.2%, respectively. The development of DM significantly deteriorated OS (p = 0.013). In the multivariate analysis, significant independent prognostic indicators for DC and OS rates were the highest posttreatment PLR (≤235.7 vs. >235.7, p = 0.006) and the lowest posttreatment PNI (≤25.4 vs. >25.4, p < 0.001), respectively. Posttreatment serum PLR might be helpfully used as a predictive biomarker of DM in unresectable HCC patients undergoing RT. Future research is necessary to confirm our findings.

The neutrophil-to-lymphocyte ratio at the start of the second course during atezolizumab plus bevacizumab therapy predicts therapeutic efficacy in patients with advanced hepatocellular carcinoma: A multicenter analysis.

Atezolizumab plus bevacizumab (Atez/Bev) therapy is expected to have good therapeutic efficacy for patients with advanced hepatocellular carcinoma (HCC). However, the clinical indicators that predict therapeutic efficacy have not been established. We retrospectively investigated whether the neutrophil-to-lymphocyte ratio (NLR) during Atez/Bev therapy could predict therapeutic efficacy. In total, 110 patients with HCC were enrolled; they were treated with Atez/Bev therapy and evaluated for their initial response by dynamic CT or MRI at least once between October 2020 and July 2022. Of the 110 patients with HCC at the initial evaluation, two (2%) showed a complete response (CR), 22 (20%) partial response (PR), 62 (56%) stable disease (SD), and 24 (21%) progressive disease (PD). The NLR at the start of the second course (NLR-2c) increased from CR+PR to SD to PD. There was no significant association between the baseline NLR and the initial therapeutic response. Patients with CR+PR had lower NLR-2c values than those with SD+PD (p<0.001) and the optimal cut-off value of NLR-2c was 1.97. Patients with NLR-2c <1.97 had better overall survival and progression-free survival (PFS) than those with NLR-2c ≥1.97 (p=0.005 for overall survival; p<0.001 for PFS). A multivariate analysis showed that female sex, higher PIVKA-II levels at baseline, and higher values of NLR-2c were significantly associated with poorer PFS. The NLR-2c value predicts the initial therapeutic response and prognosis of patients with HCC treated with Atez/Bev therapy.

Levels of PIVKA-II and alpha-fetoprotein in unresectable hepatocellular carcinoma compared to healthy controls and predictive values of both markers with radiological responses after loco-regional interventions.

The significance of the current study was to determine normative levels of PIVKA-II and AFP in patients with unresectable HCC and healthy participants. The second goal was to assess the roles of PIVKA-II and AFP in predicting radiological response after loco-regional therapy. This prospective cohort study enrolled consecutive samples of HCC patients and healthy controls. Venous blood samples were obtained at baseline and after interventions to determine serum levels of PIVKA-II and AFP using the chemiluminescent microparticle immunoassay method. Radiologic responses were determined based on the WHO criteria. Fifty-four HCC patients (mean age 58.9 years, 49 males) and 40 healthy controls (mean age 33.5 years, 26 males) were recruited. The median serum levels of PIVKA-II and AFP in HCC vs. healthy controls were 988.4 vs. 24.2 mAU/ml and 13.6 vs. 1.7 ng/ml, respectively (both p<0.001). With ROC curve analysis, the area under the curve (AUC) for PIVKA-II was 0.95 95% CI [0.90-0.99], and for AFP it was 0.98, 95% CI [0.95-1.0]). The cut-off value for PIVKA-II was 41.4 mAU/ml, and AFP was 4.8 ng/ml. PIVKA-II levels correlated significantly with radiological responses (r=0.64, p=0.02) but not AFP (r=0.09, p=0.2). PIVKA-II and AFP levels are distinctive between unresectable HCC and healthy controls. However, PIVKA-II, not AFP, can predict the radiological response after loco-regional therapy.

Clinical value of serum AFP and PIVKA‐II for diagnosis, treatment and prognosis of hepatocellular carcinoma

The accuracy of alpha-fetoprotein (AFP) as a diagnostic marker for hepatocellular carcinoma (HCC) is insufficient, and the application of abnormal prothrombin (PIVKA-II) in HCC is still controversial. Serum AFP and PIVKA-II levels were analyzed in 145 cases of HCC, 57 of benign liver disease, 55 of cholangiocarcinoma and gallbladder carcinoma, 112 of other gastrointestinal tumors with liver metastasis, and 101 healthy controls. Receiver operating characteristic curve and area under the curve were used to evaluate the diagnostic value of AFP and PIVKA-II for HCC. The changes in serum AFP and PIVKA-II levels before and after treatment in 47 HCC patients who underwent surgery and 77 who received interventional treatment were used to evaluate treatment efficacy and prognosis in HCC. The concentrations of AFP and PIVKA-II in the HCC group were significantly higher than those in other groups (p < 0.01). The diagnostic value of PIVKA-II in HCC was better than that of AFP, and combined detection improved the diagnostic sensitivity and specificity. The levels of AFP and PIVKA-II after liver cancer surgery were significantly lower than those before surgery. Elevated levels of PIVKA-II before surgery predicted disease progression, and patients who remained positive for PIVKA-II after surgery had worse prognosis than those who became negative after surgery. Combined detection of AFP and PIVKA-II is superior to both tests alone. We found that higher serum level of PIVKA-II indicates more severe HCC, with worse prognosis, while the level of AFP had no correlation with the prognosis.

Changes in ALBI Score and PIVKA-II within Three Months after Commencing Atezolizumab Plus Bevacizumab Treatment Affect Overall Survival in Patients with Unresectable Hepatocellular Carcinoma.

In this study, we aimed to evaluate the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) treatment for unresectable hepatocellular carcinoma (HCC) and to analyze the factors affecting overall survival (OS). A total of 69 patients who received Atez/Bev at our institutions for unresectable HCC were enrolled in this study. OS and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Changes in clinical indicators within 3 months were defined as delta (∆) values, and the Cox proportional hazards model was used to identify which ∆ values affected OS. The median OS, PFS, objective response rate, and disease control rate were 12.5 months, 5.4 months, 23.8%, and 71.4%, respectively. During the observational period, 62 patients (92.5%) experienced AEs (hypertension (33.3%) and general fatigue), and 27 patients (47.4%) experienced grade ≥ 3 AEs (hypertension (10.1%) and anemia (7.2%)). There was a significant deterioration in the albumin-bilirubin (ALBI) score (-2.22 to -1.97; p &lt; 0.001), and a reduction in PIVKA-II levels (32,458 to 11,584 mAU/mL; p = 0.040) within 3 months after commencing Atez/Bev. Both the worsening ∆ ALBI score (p = 0.005) and increasing ∆ PIVKA-II (p = 0.049) were significantly associated with the OS of patients.

Simple Predictive Markers and Clinicopathological Features of Primary Liver Cancer following HCV Clearance with Direct-Acting Antivirals

Introduction: Simple predictive markers enabling even nonspecialized medical doctors and clinicopathological features of primary liver cancer (PLC) following HCV clearance with direct-acting antivirals (DAAs) are unclear. Methods: The subjects of this retrospective study were 2,476 patients following HCV clearance with DAAs. All patients were confirmed to be PLC-free before and during DAAs. Results: PLC was diagnosed in 73 patients during the follow-up, with an incidence rate per 1 000 person-years of 5.9. The annual rate of PLC during the first 6 years was 0.6%. Multivariate analysis identified gender, GGT, and FIB-4 index as the significant determinants of PLC. According to a combination of these risk factors, the cumulative PLC incidence rates were significantly different among the five subgroups based on the number of PLC risk scores. In 73 patients with PLC, the rates of abnormal AFP, PIVKAII, and serum TERT C228T positive were 37.0, 32.4, and 22.2%. PIVKAII levels in BCLC stage A and B were significantly higher than those in stage 0. In 41 patients, who underwent surgical resection for PLC, maximum tumor diameters of abnormal PIVKAII were significantly larger than those of normal PIVKAII. PLC of abnormal PIVKAII significantly indicated presence of vp more than that of normal PIVKAII, and did not contain well-differentiated HCC. Conclusions: Combination of simple markers, enabling even nonspecialized medical doctors, is useful for the evaluation of PLC risk following HCV clearance with DAAs. However, imaging studies are regularly recommended for the early detection of PLC.

The levels of endothelin, renin, copeptin, testosterone, estradiol, osteocalcin and PIVKA-II in adolescents aged 17 years with newly diagnosed hypertension

Background. The purpose of the work is to study the blood content of biologically active substances — peptides and hormones that can affect blood pressure and the development of hypertension, depending on the gender and disease course in adolescents aged 17 years by comparing them with healthy individuals. Materials and methods. There were examined 87 adolescents (37 boys and 50 girls) who were divided into 4 main groups with stable and labile hypertension and 2 control groups with normotension. All patients underwent daily blood pressure monitoring and a comprehensive clinical examination, which ruled out symptomatic hypertension. The serum concentrations of biologically active substances were determined, namely endothelin, renin, copeptin, testosterone, estradiol, osteocalcin and protein induced by vitamin K absence (PIVKA-II), by enzyme immunoassay. Results. It was found that the most important feature that distinguishes hypertensive adolescents from normotensive peers was renin, which serum concentrations were almost 1.5 times higher in boys with labile hypertension and twofold — with stable hypertension. Girls with stable hypertension had the same patterns, with a twofold increase in renin level. Regardless of hypertension course, female adolescents had higher endothelin levels. In addition, girls with stable hypertension had high serum content of PIVKA-II. Conclusions. The elevated serum renin level in boys and girls at late stages of puberty as an indicator of renal dysfunction can be considered an essential cause of hypertension development. Determining the importance of renal dysfunction with increased levels of vasopressor hormones directs therapeutic efforts in the treatment of adolescents with hypertension precisely to the correction of this link in the pathogenesis of juvenile hypertension.

Clinical significance of PIVKA-II levels after liver transplantation for hepatocellular carcinoma

Felipe ALCONCHEL*, Francisco VILLALBA, Luis SÁENZ, María Isabel SÁNCHEZ, David FERRERAS, Pedro CASCALES, Ricardo ROBLES, Francisco SÁNCHEZ-BUENO, Pablo RAMÍREZ. Ann Hepatobiliary Pancreat Surg 2022;26:S226. https://doi.org/10.14701/ahbps.2022S1.LV-PP-9-3