Development and Validation of a Novel Nomogram Integrated with Hypoxic and Lactate Metabolic Characteristics for Prognosis Prediction in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Accumulating evidence indicates that hypoxia and lactate metabolism play critical roles in tumor progression and therapeutic efficacy. This study aimed to construct a hypoxia- and lactate metabolism-related prognostic model (HLPM) to evaluate survival and treatment responses for HCC patients and develop a nomogram integrated with HLPM and clinical characteristics for prognosis prediction in HCC. Methods: Expression profile and clinical data of HCC were obtained from TCGA and ICGC databases. The univariate, LASSO and stepwise multivariate Cox analyses were used to identify the hypoxia- and lactate metabolism-related biomarkers, whose expression levels were then validated in 14 pairs tissue samples and single-cell RNA sequencing dataset. Kaplan-Meier survival curves were utilized to assess the prognostic values of biomarkers or models. Analyses of ImmuCellAI, TIDE and drug sensitivity were conducted to evaluate the therapeutic responses of patients. Furthermore, the nomogram integrated with hypoxic and lactate metabolic characteristics was established through univariate and multivariate Cox analyses. ROC curves, C-index, and calibration curves were depicted to evaluate the performance of the nomogram. Results: Five hypoxia- and lactate metabolism-related biomarkers (KIF20A, IRAK1, ADM, PPARGC1A and EPO) were used to construct HLPM. The expression of five prognostic biomarkers was validated in 14 pairs tissue samples and single-cell RNA sequencing dataset. Analyses of ImmuCellAI, TIDE and drug sensitivity implied that patients with low-risk score were more sensitive to immunotherapy and major chemotherapeutic agents. The nomogram that contained age, histological grade and risk score of HLPM was developed and exhibited a better capacity in prognosis prediction than HLPM only. Conclusion: A novel nomogram integrated with hypoxic and lactate metabolic characteristics was developed and validated for prognosis prediction in HCC, providing insight into personalized decision-making in clinical management.

A novel nomogram for prognosis stratification in salvage liver transplantation: a national-wide study with propensity score matching analysis in China.

Background: Salvage liver transplantation (SLT) has been reported to be an efficient treatment option for patients with recurrent hepatocellular carcinoma (HCC) after liver resection (LR). However, for recipients who underwent liver transplantation (LT) due to recurrent HCC after LR in China, the selection criteria are not well established. Methods: In this study, data from the China Liver Transplant Registry (CLTR) of 4,244 LT performed from January 2015 to December 2019 were examined, including 3,498 primary liver transplantation (PLT) and 746 SLT recipients. Propensity score matching (PSM) analysis was used to minimize between-group imbalances. The overall survival (OS) and disease-free survival (DFS) between PLT and SLT in recipients fulfilling the Milan or Hangzhou criteria were compared based on the multivariate analysis, nomograms were plotted to further classify the SLT group into low- and high-risk groups. Results: In this study, the 1-, 3- and 5-year OS and DFS of SLT recipients fulfilling Milan criteria (OS, P=0.01; DFS, P<0.001) or Hangzhou criteria (OS, P=0.03; DFS, P=0.003) were significantly reduced when compared to that of PLT group after PSM analysis. Independent risk factors, including preoperative transarterial chemoembolization (TACE), alpha fetoprotein (AFP) level, tumor maximum size and tumor total diameter were selected to draw a prognostic nomogram. The low-risk SLT recipients (1-year, 95.34%; 3-year, 84.26%; 5-year, 77.20%) showed a comparable OS with PLT recipients fulfilling Hangzhou criteria (P=0.107). Conclusions: An optimal nomogram model for prognosis stratification and clinical decision guidance of SLT was established. The low-risk SLT recipients based on the nomograms showed comparable survival with those fulfilling Hangzhou criteria in PLT group.

Protein induced by vitamin K absence or antagonist II: Experience to date and future directions.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with high mortality. The realization of precision medicine in HCC relies upon efficient biomarkers. Protein induced by vitamin K absence or antagonist II (PIVKA-II) is an immature prothrombin with insufficient coagulation activity, overexpressing in HCC cells. Previous evidence confirmed the role of PIVKA-II in screening and diagnosing HCC. However, the increased PIVKA-II was observed not only in HCC, but also in non-HCC individuals such as vitamin K deficiency. The joint detection of PIVKA-II and other biomarkers could significantly improve diagnostic accuracy in HCC. Furthermore, PIVKA-II serves as a valuable prognostic predictor, transplantation eligibility, resectability, tumor recurrence, therapeutic efficacy, and malignant tumor behaviors. Additionally, PIVKA-II represents a potential target for agent development to establish new therapeutic strategies. Besides HCC, PIVKA-II also serves as a biomarker of vitamin K status. In this review, we assess the role of PIVKA-II in diagnosis, prediction, and treatment. Over the past decades, substantial progress has been achieved in the application of PIVKA-II. Exploration and innovation are required for further advances in the field of PIVKA-II investigation.

Incorporation of protein induced by vitamin K absence or antagonist-II into transplant criteria expands beneficiaries of liver transplantation for hepatocellular carcinoma: a multicenter retrospective cohort study in China.

INTRODUCTION: In order to maximize the utilization of precious donor liver, precisely determining potential hepatocellular carcinoma (HCC) candidates who will benefit from liver transplantation (LT) is essential. As a crucial diagnostic biomarker for HCC, protein induced by vitamin K absence or antagonist-II (PIVKA-II) has become one of the key indicators for assessing tumor recurrence risk after LT. This study aims to investigate the role of PIVKA-II in recipient selection and prognostic stratification. METHODS: The clinicopathologic data of HCC patients undergoing LT from 2015 to 2020 in six Chinese transplant centers were collected. Univariate and multivariate analyses were performed to determine risk factors for disease free survival (DFS). Based on these risk factors, survival analysis was made by Kaplan-Meier method and their value in prognostic stratification was assessed. RESULTS: A total of 522 eligible HCC patients with pre-LT PIVKA-II records were finally included in this study. Tumor burden>8 cm, α-fetoprotein>400 ng/ml, histopathologic grade III and PIVKA-II>240 mAU/ml were identified as independent risk factors for DFS. DFS of patients with PIVKA-II≤240 mAU/ml ( N =288) were significantly higher than those with PIVKA-II>240 mAU/ml ( N =234) (1-year, 3-year, and 5-year DFS: 83.2, 77.3, and 75.9% vs. 75.1, 58.5, and 50.5%; P <0.001). Compared with Hangzhou criteria ( N =305), incorporating PIVKA-II into Hangzhou criteria (including tumor burden, α-fetoprotein, and histopathologic grade) increased the number of patients with eligibility for LT by 21.6% but achieved comparable DFS and overall survival. CONCLUSIONS: Incorporating PIVKA-II into existing LT criteria could increase the number of eligible HCC patients without compromising post-LT outcomes.

High resolution imaging and quantification of the nailfold microvasculature using optical coherence tomography angiography (OCTA) and capillaroscopy: a preliminary study in healthy subjects.

Background: A wide range of diseases, such as systemic sclerosis, can be diagnosed by imaging the nailfold microcirculation, which is conventionally performed using capillaroscopy. This study applied optical coherence tomography angiography (OCTA) as a novel high resolution imaging method for the qualitative and quantitative assessment of the nailfold microvasculature, and compared OCTA imaging with capillaroscopy. Methods: For qualitative assessment, high resolution OCTA imaging was used to achieve images that contained a wide field of view of the nailfold microvasculature through mosaic scanning. OCTA imaging was also used to observe the characteristic changes in the microvasculature under external compression of the upper arm. For quantitative evaluation, the capillary density and the capillary diameter of the nailfold microvasculature were assessed with both OCTA and capillaroscopy by repeated measurements over 2 days in 13 normal subjects. The results were analyzed using the intraclass correlation coefficient (ICC). Results: OCTA imaging showed the typical nailfold microvasculature pattern, part of which was not directly seen with the capillaroscopy. OCTA imaging revealed significant changes in the nailfold microvasculature when a large external pressure was applied via arm compression, but no significant changes were observed using capillaroscopy. The capillary density measured by OCTA and capillaroscopy was 6.8±1.5 and 7.0±1.2 loops/mm, respectively, which was not significantly different (P=0.51). However, the capillary diameter measured by OCTA was significantly larger than that measured using capillaroscopy (19.1±2.5 vs. 13.3±2.3 µm, P<0.001). The capillary diameter measurements using OCTA and capillaroscopy were highly reproducible (ICC =0.926 and 0.973, respectively). While the capillary diameter measured with OCTA was significantly larger, it was rather consistent with the diameter measured using capillaroscopy (ICC =0.705). Conclusions: This study demonstrated that OCTA is a potentially viable and reproducible tool for the imaging and quantification of the capillaries in the nailfold microvasculature. The results of this study provide a solid basis for future applications of OCTA in qualitative and quantitative assessment of nailfold microcirculation in vivo.

A new method for cartap detection with high sensitivity and selectivity based on the inner filter effect between GSH-Cu NCs and Au NPs.

Herein, a novel and sensitive fluorescence method for cartap determination is established on the basis of the inner filter effect (IFE) of gold nanoparticles (Au NPs) on the fluorescence of glutathione protected Cu NCs (GSH-Cu NCs). In the presence of Au NPs, the fluorescence of GSH-Cu NCs was strongly quenched by the IFE because the absorption spectra of Au NPs overlap well with the emission spectra of GSH-Cu NCs. Upon addition of cartap, cartap could induce the aggregation of Au NPs whose absorption spectrum does not overlap with the emission spectrum of GSH-Cu NCs. Then, with the increase in cartap concentration, the IFE-decreased fluorescence was gradually recovered, realizing the fluorescence sensing of cartap. Under optimal conditions, the proposed method has a good linear relationship with cartap concentration in the range of 7-100 nM, and the detection limit is 3.34 nM. In addition, satisfactory results were obtained for cartap analysis using tap water and cabbage as real samples, which demonstrated that the method as-developed would have great practical application prospects.

Effect of acupuncture at Neiguan point combined with amiodarone therapy on early recurrence after pulmonary vein electrical isolation in patients with persistent atrial fibrillation.

OBJECTIVE: Early atrial fibrillation (AF) recurrences are common and have been shown to predict AF recurrences late after AF ablation during follow-up. Neiguan point acupuncture has been recognized to be therapeutic in treating AF in clinical practice. METHODS AND RESULTS: Eighty-five patients were enrolled in succession due to persistent AF. All patients were randomized divided into control group and acupuncture group. In the control group (n = 45), amiodarone was orally taken from the first day after pulmonary vein isolation (PVI). In the acupuncture group (n = 40), patients were treated with Neiguan point acupuncture for 7 days and amiodarone was prescribed as same as the control group after PVI. The levels of inflammatory factors were analyzed before operation, 1 week after the operation and 3 months later. After 3 months, the acupuncture group had a lower rate of early recurrences than the control group (5/40 [12.5%] vs 15/45 [33.3%], P = 0.039). The inflammatory factors level in the two groups were significantly increased after ablation. However, compared with the control group, the levels of TNF-α, IL-6, CRP, TGF-ß1, MMP2 in the acupuncture group significantly lower (P < 0.05). In a multivariate analysis, acupuncture was an independent factor associated with a lower rate of early recurrences during the blanking period (odds ratio, 0.17; 95% confidence interval, 0.05-0.63; P = 0.008). CONCLUSION: Neiguan point acupuncture combined with amiodarone is superior to amiodarone alone in reducing early recurrences of patients with persistent AF after PVI. The efficacy of Neiguan acupuncture therapy on the early recurrence is associated with the decreased inflammation factors.

A pilot study of limb stimulation for the treatment of neonatal apnea.

This study explored the feasibility effect and safety of the limb stimulation (LS) for the treatment of neonatal apnea (NAP).The cases of 30 eligible premature infants with NAP were included in this retrospective study. These cases were equally divided into an intervention group (n = 15) and a control group (n = 15). The infants in both groups received caffeine treatment. Moreover, cases in the intervention group also received LS for a total 30 hours, while the subjects in the control group did not receive LS during this period. The primary outcome included apnea frequency (number of episodes per 24 hours), and apnea rate. The secondary outcomes consisted of desaturation (number of episodes per 24 hours), and heart rate (beats per minute). Additionally, adverse events were also documented during the treatment period.After treatment, LS did not show better outcomes in apnea frequency (P = .48), apnea rate (P = .33), desaturation (P = .55), and heart rate (P = .41). Furthermore, no significant differences of all adverse events were found between 2 groups.The results of this pilot study demonstrated that LS might be not efficacious for premature infants with NAP.