Association Between HLA-DRB1 Alleles and Graves' Disease in Asian Populations: A Meta-Analysis.

Graves' disease (GD) is an autoimmune disease that primarily affects the thyroid gland. It is the most common cause of hyperthyroidism. Genetic studies have shown that human leukocyte antigen (HLA) plays an important role in the development of GD. In this article, we performed a meta-analysis determined to evaluate the relationship between HLA-DRB1 alleles and GD. This meta-analysis included 9 studies (3582 cases in the case group and 23070 cases in the control group) and 27 alleles was performed. The combined results showed that, compared with the control group, GD patients have a significant increase in the frequency of DRB1*1403 (OR=2.50, 95% CI=1.78-3.51, pc<0.0001) and have a significant decrease in frequencies of DRB1* 0101 (OR=0.45, 95% CI=0.34-0.59, pc<0.0001) and DRB1*0701 (OR=0.44, 95% CI=0.35-0.55, pc<0.0001). The meta-analysis indicated that, in Asian populations, DRB1*1403 is a risk allele for GD, and DRB1*0101 and DRB1*0701 are protective against the occurrence of GD. We surprisingly discovered that the susceptibility alleles for GD in Asian populations are completely different from Caucasians and the protective alleles for GD in Asians are quite similar to those of Caucasians. The results of our study may provide new opportunities for gene-targeted therapy for GD in Asian populations.

Lamprey VDAC2: Suppressing hydrogen peroxide-induced 293T cell apoptosis by downregulating BAK expression.

The voltage-dependent anion channel 2 (VDAC2) is the abundant protein in the outer mitochondrial membrane. Opening VDAC2 pores leads to the induction of mitochondrial energy and material transport, facilitating interaction with various mitochondrial proteins implicated in essential processes such as cell apoptosis and proliferation. To investigate the VDAC2 in lower vertebrates, we identified Lr-VDAC2, a homologue of VDAC2 found in lamprey (Lethenteron reissneri), sharing a sequence identity of greater than 50 % with its counterparts. Phylogenetic analysis revealed that the position of Lr-VDAC2 aligns with the lamprey phylogeny, indicating its evolutionary relationship within the species. The Lr-VDAC2 protein was primarily located in the mitochondria of lamprey cells. The expression of the Lr-VDAC2 protein was elevated in high energy-demanding tissues, such as the gills, muscles, and myocardial tissue in normal lampreys. Lr-VDAC2 suppressed H2O2 (hydrogen peroxide)-induced 293 T cell apoptosis by reducing the expression levels of Caspase 3, Caspase 9, and Cyt C (cytochrome c). Further research into the mechanism indicated that the Lr-VDAC2 protein inhibited the pro-apoptotic activity of BAK (Bcl-2 antagonist/killer) protein by downregulating its expression at the protein translational level, thus exerting an anti-apoptotic function similar to the role of VDAC2 in humans.

Correlation of pathological examination with indocyanine green (ICG) intensity gradients: a prospective study in patients with liver tumor.

BACKGROUND: Intraoperative indocyanine green (ICG) fluorescence imaging has been shown to be a new and innovative way to illustrate the optimal resection margin in hepatectomy for hepatocellular carcinoma. This study investigated its accuracy in resection margin determination by looking into the correlation of ICG intensity gradients with pathological examination results of resected specimens. METHODS: This was a prospective, single-center, non-randomized controlled study. Patients who had liver tumors indicating liver resection were recruited. The hypothesis was that the use of intraoperative near-infrared/ICG fluorescence imaging would be a promising guiding tool for removing hepatocellular carcinoma with a better resection margin. Patients were given ICG (0.25 mg/kg) 1 day before operation. Resected specimens were inspected under a fluorescent imaging system. Biopsies were taken from tumors and normal tissue. Color signals obtained from ICG fluorescence imaging were compared with biopsies for analysis. RESULTS: Twenty-two patients were recruited for study. The median size of their tumors was 2.25 cm. One patient had resection margin involvement. Under ICG fluorescence, the tumors typically lighted up as yellow color, wrapped by a zone of green color. Tumors of 17 patients (77.3%) displayed yellow color and were confirmed malignancy, while tumors of 12 patients (54.5%) displayed green color and were confirmed malignancy. Receiver operating characteristic curve was used to measure the sensitivity and specificity of the green color to look for a clear resection margin. The area under the curve was 85.3% (p = 0.019, 95% confidence interval 0.696-1.000), with a sensitivity of 0.706 and specificity of 1.000. CONCLUSION: The use of ICG fluorescence can be helpful in determining resection margins. Resection of tumor should include complete resection of the green zone shown in the fluorescence image.

Effects of intracellular Ca2+ on developmental potential and ultrastructure of cryopreserved-warmed oocyte in mouse.

Maintaining appropriate intracellular calcium of oocytes is necessary to prevent ultrastructure and organelle damage caused by freezing and cryoprotectants. The present study aimed to investigate whether cryoprotectant-induced changes in the calcium concentrations of oocytes can be regulated to reduce damage to developmental potential and ultrastructure. A total of 33 mice and 1381 oocytes were used to explore the effects of intracellular calcium on the development and ultrastructures of oocytes subjected to 2-aminoethoxydiphenyl borate (2-APB) inhibition or thapsigargin (TG) stimulation. Results suggested that high levels intracellular calcium interfered with TG compromised oocyte survival (84.4 % vs. 93.4 %, p < 0.01) and blastocyst formation in fresh and cryopreservation oocytes (78.1 % vs. 86.4 %, and 60.5 % vs. 72.5 %, p < 0.05) compared with that of 2-APB pretreated oocytes in which Ca2+ was stabilized even though no differences in fertilization and cleavage was detected (p > 0.05). Examination by transmission electron microscopy indicated that the microvilli decreased and shortened, cortical granules considerably decreased in the cortex area, mitochondrial vesicles and vacuoles increased, and the proportion of vacuole mitochondria increased after oocytes were exposed to cryoprotectants. The cryopreservation-warming process deteriorated the negative effects on organelles of survival oocytes. By contrast, a low level of intracellular calcium mediated with 2-APB was supposed to contribute to the protection of organelles. These findings suggested oocyte injuries induced by cryoprotectants and low temperatures can be alleviated. More studies are necessary to confirm the relationship among Ca2+ concentration of the cytoplasm, ultrastructural injuries, and disrupted developmental potential in oocytes subjected to cryopreservation and warming.

Stage-by-stage analysis of the effect of blood transfusion on survival after curative hepatectomy for hepatocellular carcinoma-a retrospective study.

OBJECTIVE: This study is to examine the impact of perioperative (intraoperative/postoperative) blood transfusion on the outcomes of curative hepatectomy for hepatocellular carcinoma. Hepatectomy is a well-established curative treatment for hepatocellular carcinoma, and blood transfusion cannot always be avoided in treating the disease. METHODS: A retrospective study of patients having curative hepatectomy for hepatocellular carcinoma from January 2010 to December 2019 at a single center was conducted. The patients were stratified by their disease stage. Patients with and without perioperative blood transfusion were matched by propensity-score matching and compared for each disease stage. Univariate and multivariate analyses were performed to identify prognostic factors for overall survival for each stage. RESULTS: A total of 846 patients were studied. Among them, 125 received perioperative blood transfusion and 720 did not. Patients with blood transfusion had worse disease-free and overall survival. After stratification and matching, the ratios of transfusion to non-transfusion were 33:165 (stage 1), 28:140 (stage 2), and 45:90 (stage 3). Perioperative blood transfusion was associated with a higher incidence of postoperative complications in all three disease stages (p = 0.004/0.006/0.017), and hence longer hospitalization (p < 0.001 in all stages), but had no significant impact on hospital mortality (p = 0.119/0.118/0.723), 90-day mortality (p = 0.259/0.118/0.723), disease-free survival (p = 0.128/0.826/0.511), or overall survival (p = 0.869/0.122/0.122) in any disease stage. Prognostic factors for overall survival included tumor size, tumor number, alpha-fetoprotein level, and postoperative complication of grade ≥ 3A. CONCLUSION: Perioperative blood transfusion was associated with a higher incidence of complications but had no significant impact on survival after curative hepatectomy for hepatocellular carcinoma.

Evolutionary analysis of SLC10 family members and insights into function and expression regulation of lamprey NTCP.

The Na ( +)-taurocholate cotransporting polypeptide (NTCP) is a member of the solute carrier family 10 (SLC10), which consists of 7 members (SLC10a1-SLC10a7). NTCP is a transporter localized to the basolateral membrane of hepatocytes and is primarily responsible for the absorption of bile acids. Although mammalian NTCP has been extensively studied, little is known about the lamprey NTCP (L-NTCP). Here we show that L-NTCP follows the biological evolutionary history of vertebrates, with conserved domain, motif, and similar tertiary structure to higher vertebrates. L-NTCP is localized to the cell surface of lamprey primary hepatocytes by immunofluorescence analysis. HepG2 cells overexpressing L-NTCP also showed the distribution of L-NTCP on the cell surface. The expression profile of L-NTCP showed that the expression of NTCP is highest in lamprey liver tissue. L-NTCP also has the ability to transport bile acids, consistent with its higher vertebrate orthologs. Finally, using a farnesoid X receptor (FXR) antagonist, RT-qPCR and flow cytometry results showed that L-NTCP is negatively regulated by the nuclear receptor FXR. This study is important for understanding the adaptive mechanisms of bile acid metabolism after lamprey biliary atresia based on understanding the origin, evolution, expression profile, biological function, and expression regulation of L-NTCP.

Magnetic resonance imaging-based classification of the myodural bridge complex and its influencing factors.

Cerebrospinal fluid (CSF) circulation is considered the third circulation of the human body. Recently, some scholars have proposed the myodural bridge (MDB) as a novel power source for CSF flow. Moreover, the suboccipital muscles can exert a driving force on the CSF via the MDB. This hypothesis is directly supported by head rotation and nodding movements, which can affect CSF circulation. The MDB has been validated as a normal structure in humans and mammals. In addition, the fusion of MDB fibers of different origins that act in concert with each other forms the MDB complex (MDBC). The MDBC may be associated with several CSF disorder-related neurological disorders in clinical practice. Therefore, the morphology of the MDBC and its influencing factors must be determined. In this study, T2-weighted imaging sagittal images of the cervical region were analyzed retrospectively in 1085 patients, and magnetic resonance imaging (MRI) typing of the MDBC was performed according to the imaging features of the MDBC in the posterior atlanto-occipital interspace (PAOiS) and posterior atlanto-axial interspace (PAAiS). The effects of age and age-related degenerative changes in the cervical spine on MRI staging of the MDBC were also determined. The results revealed four MRI types of the MDBC: type A (no MDBC hyposignal shadow connected to the dura mater in either the PAOiS or PAAiS), type B (MDBC hyposignal shadow connected to the dura mater in the PAOiS only), type C (MDBC hyposignal shadow connected to the dura mater in the PAAiS only), and type D (MDBC hyposignal shadow connected to the dura mater in both the PAOiS and PAAiS). The influencing factors for the MDBC typing were age (group), degree of intervertebral space stenosis, dorsal osteophytosis, and degenerative changes in the cervical spine (P < 0.05). With increasing age (10-year interval), the incidence of type B MDBC markedly decreased, whereas that of type A MDBC increased considerably. With the deepening of the degree of intervertebral space stenosis, the incidence of type C MDBC increased significantly, whereas that of type A MDBC decreased. In the presence of dorsal osteophytosis, the incidence of type C and D MDBCs significantly decreased, whereas that of type A increased. In the presence of protrusion of the intervertebral disc, the incidence of type B, C, and D MDBCs increased markedly, whereas that of type A MDBC decreased considerably, with cervical degenerative changes combined with spinal canal stenosis. Moreover, the incidence of both type C and D MDBCs increased, whereas that of type A MDBC decreased. Based on the MRI signal characteristics of the dural side of the MDBC, four types of the MDBC were identified. MDBC typing varies dynamically according to population distribution, depending on age and cervical degeneration (degree of intervertebral space stenosis, vertebral dorsal osteophytosis formation, simple protrusion of intervertebral disc, and cervical degeneration changes combined with spinal canal stenosis, except for the degree of protrusion of the intervertebral disc and the degree of spinal canal stenosis); however, it is not influenced by sex.

Advanced glycation end-products and its soluble receptor are not independent predictors of incident dysglycaemia or metabolic syndrome in women with polycystic ovary syndrome: a prospective observational study.

BACKGROUND: To evaluate the association of serum advanced glycation end-products (AGEs) and its soluble receptor of AGE (sRAGE) levels with dysglycaemia and metabolic syndrome in women with polycystic ovary syndrome (PCOS). METHODS: This was an analysis of a cohort of women with PCOS who were prospectively recruited for a longitudinal observational study on their endocrine and metabolic profile between January 2010 and December 2013. The association of serum AGEs and sRAGE levels with dysglycaemia and metabolic syndrome at the second-year visit (the index visit) and the sixth-year visit (the outcome visit) were determined. Comparisons of continuous variables between groups were made using the Mann-Whitney U-test. Spearman test was used for correlation analysis. Multivariate binary logistic regression analysis was employed to identify the factors independently associated with the outcome events. RESULTS: A total of 329 women were analysed at the index visit. Significantly lower serum levels of sRAGE (both p < 0.001), but no significant difference in AGEs, were observed in those with dysglycaemia or metabolic syndrome. At the outcome visit, those with incident metabolic syndrome had a significantly lower initial serum sRAGE levels (p = 0.008). The association of serum sRAGE with dysglycaemia and metabolic syndrome at the index visit was no longer significant in multivariate logistic regression after controlling for body mass index, free androgen index and homeostatic model assessment for insulin resistance (HOMA-IR). sRAGE was also not significantly associated with incident metabolic syndrome at the outcome visit on multivariate logistic regression. CONCLUSIONS: Serum sRAGE levels are significantly lower in women with PCOS who have dysglycaemia or metabolic syndrome, and in those developing incident metabolic syndrome in four years. However, it does not have a significant independent association with these outcome measures after adjusting for body mass index, free androgen index and HOMA-IR.

Implementation of digital home monitoring and management of respiratory disease.

PURPOSE OF REVIEW: Digital respiratory monitoring interventions (e.g. smart inhalers and digital spirometers) can improve clinical outcomes and/or organizational efficiency, and the focus is shifting to sustainable implementation as an approach to delivering respiratory care. This review considers key aspects of the technology infrastructure, discusses the regulatory, financial and policy context that influence implementation, and highlights the over-arching societal themes of equity, trust and communication. RECENT FINDINGS: Technological requirements include developing interoperable and connected systems; establishing stable, wide internet coverage; addressing data accuracy and monitoring adherence; realising the potential of artificial intelligence; and avoiding clinician data overload. Policy challenges include concerns about quality assurance and increasingly complex regulatory systems. Financial barriers include lack of clarity over cost-effectiveness, budget impact and reimbursement. Societal concerns focus on the potential to increase inequities because of poor e-health literacy, deprivation or lack of available infrastructure, the need to understand the implications for patient/professional interactions of shifting care to remote delivery and ensuring confidentiality of personal data. SUMMARY: Understanding and addressing the implementation challenges posed by gaps in policy, regulatory, financial, and technical infrastructure is essential to support delivery of equitable respiratory care that is acceptable to patients and professionals.

Stanniocalcin 1 is a serum biomarker and potential therapeutic target for HBV-associated liver fibrosis.

Stanniocalcin 1 (STC1), a secreted protein, is upregulated in human cancers including hepatocellular carcinoma (HCC). While most HCCs develop from chronic liver disease, which involves progressive parenchymal injury and fibrosis, the role of STC1 in this preneoplastic stage remains poorly understood. In this study we investigated the clinical relevance and functional significance of secreted STC1 in liver fibrosis. To this end, the STC1 level was determined in the serum samples of chronic hepatitis B patients and correlated with the degree of liver fibrosis. Diagnostic performance of STC1 was analysed by area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive predictive value, and negative predictive value. The results were compared with other well-characterised serum biomarkers for liver fibrosis: Aspartate transaminase to Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4). The functional role of STC1 was interrogated by in vitro experiments using cell line models. Expression of fibrogenic markers was quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Our results showed that the serum STC1 level in chronic hepatitis B patients was positively correlated with the degree of liver fibrosis and showed a stepwise increase in accordance with the severity of fibrosis. The AUROCs for detecting significant fibrosis (>9.0 kPa) and cirrhosis (>12.0 kPa) was 0.911 and 0.880, respectively. STC1 demonstrated a superior specificity and positive predictive value when compared to APRI and FIB-4. Consistent with this, STC1 was elevated in the liver tissues and sera of CCl4 -treated mice showing marked liver fibrosis. In vitro, STC1 was secreted by the human hepatic stellate cell line LX2. Human recombinant STC1 (rhSTC1) induced expression of fibrogenic markers in LX2 cells. The profibrogenic phenotype conferred by rhSTC1 or TGF-ß1 in LX2 cells could be attenuated using anti-STC1 antibody. Taken together, STC1 is a specific serum biomarker for HBV-associated liver fibrosis. STC1 functionally promotes liver fibrogenesis and is a potential actionable target. © 2022 The Pathological Society of Great Britain and Ireland.

A dyadic advance care planning intervention for people with early-stage dementia and their family caregivers in a community care setting: a feasibility trial.

BACKGROUND: Advance care planning (ACP) is highly relevant for people with early-stage dementia to communicate their care preferences for serious illness conditions with their family caregivers before they become mentally incapacitated. METHODS: A multi-centre, quasi-experimental study was conducted to test the feasibility and acceptability of a theory-guided, dyadic ACP intervention ('Have a Say' programme) among participants with early-stage dementia-family caregiver dyads. The feasibility of the trial design, intervention procedures, subject recruitment and retention, and study instruments were assessed. Study outcomes were measured at baseline (T0), immediately after the intervention (T1), and at 1 month (T2) and 3 months post-intervention (T3). Acceptability of the intervention was determined by the satisfaction score, completion rate and qualitative interviews as process evaluation with a purposive sample of participants and ACP facilitators. Generalised estimating equations were performed to examine differential changes between groups over time, with covariates adjusted. RESULTS: Subject recruitment from five elderly community centres yielded a recruitment rate of 60% and resulted in 36 client-caregiver dyads. The intervention was acceptable to the dyads, with a mean satisfaction score of 4.4 out of 5 and completion rate of 94.4%. The attrition rates at T1, T2, and T3 were 8.3%, 13.9%, and 19.4%, respectively. The intervention group reported a significantly greater improvement in the readiness for ACP at T1, self-efficacy for ACP at T3, and dyadic concordance on end-of-life care preferences at all time points than the control group, but not on depressive symptoms. Family caregivers in the intervention group reported a significantly higher caregiving burden at T2 than the control group. The qualitative findings revealed that triadic involvement of and trusting relationships among the dyads and ACP facilitators, and documentation of clients' views are the programme strengths, while the structured format and discussion about medical issues posed implementation challenges. CONCLUSIONS: This ACP intervention and trial design were feasible and acceptable to the dyads. Several refinements were identified, including adding a nurse-led group-based session for information giving, allowing flexibility in arrangement, and adding measure of ACP engagement of family caregivers. A rigorous trial to test the effects of the ACP intervention is warranted. TRIAL REGISTRATION: Retrospectively registered on 14/08/2020 at clinicaltrials.gov (Identifier: NCT04513106).

A Highly Efficient Workflow for Detecting and Identifying Sequence Variants in Therapeutic Proteins with a High Resolution LC-MS/MS Method.

Large molecule protein therapeutics have steadily grown and now represent a significant portion of the overall pharmaceutical market. These complex therapies are commonly manufactured using cell culture technology. Sequence variants (SVs) are undesired minor variants that may arise from the cell culture biomanufacturing process that can potentially affect the safety and efficacy of a protein therapeutic. SVs have unintended amino acid substitutions and can come from genetic mutations or translation errors. These SVs can either be detected using genetic screening methods or by mass spectrometry (MS). Recent advances in Next-generation Sequencing (NGS) technology have made genetic testing cheaper, faster, and more convenient compared to time-consuming low-resolution tandem MS and Mascot Error Tolerant Search (ETS)-based workflows which often require ~6 to 8 weeks data turnaround time. However, NGS still cannot detect non-genetic derived SVs while MS analysis can do both. Here, we report a highly efficient Sequence Variant Analysis (SVA) workflow using high-resolution MS and tandem mass spectrometry combined with improved software to greatly reduce the time and resource cost associated with MS SVA workflows. Method development was performed to optimize the high-resolution tandem MS and software score cutoff for both SV identification and quantitation. We discovered that a feature of the Fusion Lumos caused significant relative under-quantitation of low-level peptides and turned it off. A comparison of common Orbitrap platforms showed that similar quantitation values were obtained on a spiked-in sample. With this new workflow, the amount of false positive SVs was decreased by up to 93%, and SVA turnaround time by LC-MS/MS was shortened to 2 weeks, comparable to NGS analysis speed and making LC-MS/MS the top choice for SVA workflow.

COVID-19 Vaccine Allergy Safety Track (VAS-Track) pathway: real-world outcomes on vaccination rates and antibody protection.

BACKGROUND: Misdiagnosed vaccine-related "allergies" lead to unnecessary vaccine deferrals and incomplete vaccinations, leaving patients unprotected against COVID-19. To overcome limitations and queues for Allergist assessment, the "VAS-Track" pathway was developed to evaluate patients via a multi-disciplinary triage model including nurses, non-specialists, and Allergists. OBJECTIVE: We assessed the effectiveness and safety of VAS-Track and evaluate its real-world impact in terms of vaccination rates and COVID-19 protection. METHODS: Patients referred to VAS-Track between September 2021 and March 2022 were recruited. Subgroup analysis was performed with prospective pre- and post-clinic antibody levels. RESULTS: Nurse-assisted screening identified 10,412 (76%) referrals as inappropriate. 369 patients were assessed by VAS-Track. Overall, 100% of patients were recommended to complete vaccination and 332 (90%) completed their primary series. No patients reported any significant allergic reactions following subsequent vaccination. Vaccination completion rates between patients seen by non-specialists and additional Allergist review were similar (90% vs. 89%, p = 0.617). Vaccination rates were higher among patients with prior history of immediate-type reactions (odds ratio: 2.43, p = 0.025). Subgroup analysis revealed that only 20% (56/284) of patients had seropositive COVID-19 neutralizing antibody levels (≥ 15 AU/mL) prior to VAS-Track, which increased to 92% after vaccine completion (pre-clinic antibody level 6.0 ± 13.5 AU/mL vs. post-clinic antibody level 778.8 ± 337.4 AU/mL, p > 0.001). CONCLUSIONS: A multi-disciplinary allergy team was able to streamline our COVID-19 VAS services, enabling almost all patients to complete their primary series, significantly boosting antibody levels and real-world COVID-19 protection. We propose similar multidisciplinary models to be further utilized, especially in the settings with limited allergy services.

Rotablation for Octogenarians in a Modern Cathlab: Short- and Intermediate-Term Results.

Background: There are limited reports on the treatment of complex calcified lesions using rotational atherectomy (RA) in octogenarians, particularly in high-risk patients. Objective: To evaluate procedural and clinical outcomes of RA in octogenarians. Methods: Consecutive RA patients from 2010 to 2018 were selected from our catheterization laboratory database, stratified into two groups (≥ or < 80 years old), and analyzed. Results: A total of 411 patients (269 males and 142 females) with a mean age of 73.8 ± 11.3 years were enrolled, of whom 153 were ≥ 80 years old and 258 were < 80 years old. Most of the patients displayed high-risk features. The baseline Syntax scores were high in both groups, and most lesions were heavily calcified (96.1% vs. 97.3%, p = 0.969, respectively). The use of hemodynamic support intra-aortic balloon pump was more frequent in the octogenarians (21.6% vs. 11.6%, p = 0.007), but the RA completion rate was similarly high (95.9% vs. 99.1%, p = 0.842). There was no difference in acute complications. The total/cardiovascular (CV) death rate within one year was higher in the octogenarians, along with higher major adverse cardiovascular event (MACE)/CV MACE rates in the first month. Cox regression analysis showed that age ≥ 80 years, acute coronary syndrome, ischemic cardiomyopathy/shock, multi-vessel disease and serum creatinine were all predictors of MACE, and that these factors plus peripheral artery disease were predictors of all-cause mortality in these patients. Conclusions: RA is feasible with a very high success rate in high-risk octogenarians with complex anatomies, and with equal safety and no increase in complications. The higher rates of all-cause death and MACE were attributed to an older age and other traditional risk factors.

Verifying the Benefits of Radical Treatment in Posttransplant Hepatocellular Carcinoma Oligo-recurrence: A Propensity Score Analysis.

This study verified whether radical treatment for hepatocellular carcinoma (HCC) oligo-recurrence after liver transplantation conveys survival benefits. A retrospective study of 144 patients with posttransplant HCC recurrence was performed. Propensity score matching was performed to adjust for baseline covariates between patients who received radical and palliative treatments. The primary endpoint was postrecurrence survival. A total of 50 patients (35%) received radical treatment for recurrence, and 76 (53%) and 18 (13%) patients received palliative and supportive treatments, respectively. Compared with the radical group, patients who received palliative treatment had more early recurrences (time from transplant 17 versus 11 months; P = 0.01) and more extensive disease in terms of tumor numbers (1 versus 4; P < 0.001), size of largest tumor (1.8 versus 2.5 cm; P = 0.046), numbers of involved organs (interquartile range [IQR], 1-1 versus 1-2; P = 0.02), and alpha-fetoprotein (AFP) level (7 versus 40 ng/mL; P = 0.01). Multivariate Cox regression analysis revealed that early recurrence (time from transplant hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.01-1.03; P = 0.001), larger recurrent tumor (HR, 1.12; 95% CI, 1.03-1.23; P = 0.01), liver recurrence (HR, 1.84; 95% CI, 1.17-2.90; P = 0.01), and log10 AFP level at recurrence (HR, 1.27; 95% CI, 1.07-1.52; P = 0.01) predicted poor survival. Mammalian target of rapamycin inhibitor (HR, 0.331; 95% CI, 0.213-0.548; P < 0.001) and radical treatment (HR, 0.342; 95% CI, 0.213-0.548; P < 0.001) were associated with improved survival. After 2-to-1 propensity score matching for covariates, the 50 patients who received curative treatment survived significantly longer than the 25 matched patients who received palliative treatment (median survival time, 30.9 ± 2.4 versus 19.5 ± 3.0 months; P = 0.01). Radical treatment conveys survival benefits to HCC oligo-recurrence after liver transplantation.

Hepatitis B Virus-Telomerase Reverse Transcriptase Promoter Integration Harnesses Host ELF4, Resulting in Telomerase Reverse Transcriptase Gene Transcription in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) integrations are common in hepatocellular carcinoma (HCC). In particular, alterations of the telomerase reverse transcriptase (TERT) gene by HBV integrations are frequent; however, the molecular mechanism and functional consequence underlying TERT HBV integration are unclear. APPROACH AND RESULTS: We adopted a targeted sequencing strategy to survey HBV integrations in human HBV-associated HCCs (n = 95). HBV integration at the TERT promoter was frequent (35.8%, n = 34/95) in HCC tumors and was associated with increased TERT mRNA expression and more aggressive tumor behavior. To investigate the functional importance of various integrated HBV components, we employed different luciferase reporter constructs and found that HBV enhancer I (EnhI) was the key viral component leading to TERT activation on integration at the TERT promoter. In addition, the orientation of the HBV integration at the TERT promoter further modulated the degree of TERT transcription activation in HCC cell lines and patients' HCCs. Furthermore, we performed array-based small interfering RNA library functional screening to interrogate the potential major transcription factors that physically interacted with HBV and investigated the cis-activation of host TERT gene transcription on viral integration. We identified a molecular mechanism of TERT activation through the E74 like ETS transcription factor 4 (ELF4), which normally could drive HBV gene transcription. ELF4 bound to the chimeric HBV EnhI at the TERT promoter, resulting in telomerase activation. Stable knockdown of ELF4 significantly reduced the TERT expression and sphere-forming ability in HCC cells. CONCLUSIONS: Our results reveal a cis-activating mechanism harnessing host ELF4 and HBV integrated at the TERT promoter and uncover how TERT HBV-integrated HCCs may achieve TERT activation in hepatocarcinogenesis.

Analysis of Survival Benefits of Living Versus Deceased Donor Liver Transplant in High Model for End-Stage Liver Disease and Hepatorenal Syndrome.

BACKGROUND AND AIMS: Previous recommendations suggested living donor liver transplantation (LDLT) should not be considered for patients with Model for End-Stage Liver Disease (MELD) > 25 and hepatorenal syndrome (HRS). APPROACH AND RESULTS: Patients who were listed with MELD > 25 from 2008 to 2017 were analyzed with intention-to-treat (ITT) basis retrospectively. Patients who had a potential live donor were analyzed as ITT-LDLT, whereas those who had none belonged to ITT-deceased donor liver transplantation (DDLT) group. ITT-overall survival (OS) was analyzed from the time of listing. Three hundred twenty-five patients were listed (ITT-LDLT n = 212, ITT-DDLT n = 113). The risk of delist/death was lower in the ITT-LDLT group (43.4% vs. 19.8%, P < 0.001), whereas the transplant rate was higher in the ITT-LDLT group (78.3% vs. 52.2%, P < 0.001). The 5-year ITT-OS was superior in the ITT-LDLT group (72.6% vs. 49.5%, P < 0.001) for patients with MELD > 25 and patients with both MELD > 25 and HRS (56% vs. 33.8%, P < 0.001). Waitlist mortality was the highest early after listing, and the distinct alteration of slope at survival curve showed that the benefits of ITT-LDLT occurred within the first month after listing. Perioperative outcomes and 5-year patient survival were comparable for patients with MELD > 25 (88% vs. 85.4%, P = 0.279) and patients with both MELD > 25 and HRS (77% vs. 76.4%, P = 0.701) after LDLT and DDLT, respectively. The LDLT group has a higher rate of renal recovery by 1 month (77.4% vs. 59.1%, P = 0.003) and 3 months (86.1% vs, 74.5%, P = 0.029), whereas the long-term estimated glomerular filtration rate (eGFR) was similar between the 2 groups. ITT-LDLT reduced the hazard of mortality (hazard ratio = 0.387-0.552) across all MELD strata. CONCLUSIONS: The ITT-LDLT reduced waitlist mortality and allowed an earlier access to transplant. LDLT in patients with high MELD/HRS was feasible, and they had similar perioperative outcomes and better renal recovery, whereas the long-term survival and eGFR were comparable with DDLT. LDLT should be considered for patients with high MELD/HRS, and the application of LDLT should not be restricted with a MELD cutoff.

Prospective Study of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma on Waitlist for Liver Transplant.

BACKGROUND AND AIMS: There are no prospective data on stereotactic body radiation therapy (SBRT) as a bridge to liver transplantation for HCC. This study aimed to evaluate the efficacy and safety of SBRT as bridging therapy, with comparison with transarterial chemoembolization (TACE) and high-intensity focused ultrasound (HIFU). APPROACH AND RESULTS: Patients were prospectively enrolled for SBRT under a standardized protocol from July 2015 and compared with a retrospective cohort of patients who underwent TACE or HIFU from 2010. The primary endpoint was tumor control rate at 1 year after bridging therapy. Secondary endpoints included cumulative incidence of dropout, toxicity, and posttransplant survival. During the study period, 150 patients were evaluated (SBRT, n = 40; TACE, n = 59; HIFU, n = 51). The tumor control rate at 1 year was significantly higher after SBRT compared with TACE and HIFU (92.3%, 43.5%, and 33.3%, respectively; P = 0.02). With competing risk analysis, the cumulative incidence of dropout at 1 and 3 years after listing was lower after SBRT (15.1% and 23.3%) compared with TACE (28.9% and 45.8%; P = 0.034) and HIFU (33.3% and 45.1%; P = 0.032). Time-to-progression at 1 and 3 years was also superior after SBRT (10.8%, 18.5% in SBRT, 45%, 54.9% in TACE, and 47.6%, 62.8% in HIFU; P < 0.001). The periprocedural toxicity was similar, without any difference in perioperative complications and patient and recurrence-free survival rates after transplant. Pathological complete response was more frequent after SBRT compared with TACE and HIFU (48.1% vs. 25% vs. 17.9%, respectively; P = 0.037). In multivariable analysis, tumor size <3 cm, listing alpha-fetoprotein <200 ng/mL, Child A, and SBRT significantly reduced the risk of dropout. CONCLUSIONS: SBRT was safe, with a significantly higher tumor control rate, reduced the risk of waitlist dropout, and should be used as an alternative to conventional bridging therapies.

Impact of Three-Dimensional (3D) Visualization on Laparoscopic Hepatectomy for Hepatocellular Carcinoma.

BACKGROUND: The impact of three-dimensional (3D) visualization on laparoscopic hepatectomy for hepatocellular carcinoma is largely unknown. METHODS: A retrospective review with propensity-score matched analysis of 3D and two-dimensional (2D) laparoscopic hepatectomy performed in a tertiary hepatobiliary surgery center. RESULTS: Since the availability of 3D laparoscopy, the proportion of laparoscopic major hepatectomies has significantly expanded (1.7% vs. 24.0%, p < 0.0001) and the percentage of difficult resections among patients who underwent laparoscopic hepatectomy has also increased (12.6% vs. 40.0%, p = 0.0001). A total of 305 patients (92 in the 3D group and 213 in the 2D group) underwent laparoscopic hepatectomy between 2002 and 2019. The 3D group had better liver function, larger tumors at more difficult locations, more major resections, and more difficult surgeries. After propensity score matching, 144 patients were analyzed (72 in both the 3D and 2D groups). Patients were comparable in terms of liver status, tumor status, and complexity of liver surgery. Operative time (218 vs. 218 mins, p = 0.50) and blood loss (0.2 vs. 0.2L, p = 0.49) were comparable between the two groups, however overall complications were higher in the 2D group (1.4 vs. 11.1%, p = 0.03). Patients who underwent 3D laparoscopic major hepatectomy had a shorter hospital stay than their comparable counterparts operated through an open approach (7 vs. 6 days, p = 0.003). CONCLUSIONS: 3D visualization enhanced the feasibility of laparoscopic major hepatectomy and difficult laparoscopic liver resection. 3D resection was potentially associated with fewer operative morbidities and the 3D laparoscopic approach did not jeopardize the outcome of major hepatectomy.

Rotablation in Patients with Advanced Renal Insufficiency through End-Stage Renal Disease: Short- and Intermediate-Term Results.

Objective: Patients with advanced renal insufficiency are at high risk of coronary artery disease (CAD) and complex lesions. Treating complex calcified lesion with rotational atherectomy (RA) in these patients might be associated with higher risks and poorer outcomes. This study was set to evaluate features and outcomes of RA in these patients. Method: Consecutive patients who received coronary RA from April 2010 to April 2018 were queried from the Cath Lab database. The procedural details, angiography, and clinical information were reviewed in detail. Results: A total of 411 patients were enrolled and divided into Group A (baseline serum creatinine <5 mg/dl, n = 338) and Group B (baseline serum creatinine ≥ 5 mg/dl through ESRD, n = 73). Most patients had high-risk features (65.7% of acute coronary syndrome (ACS), 14.1% of ischemic cardiomyopathy, and 5.1% of cardiogenic shock). Group B patients were significantly younger (66.8 ± 11.4 vs. 75.2 ± 10.7 years, p < 0.001) and had more RCA and LCX but less LAD treated with RA. No difference was found in lesion location, vessel tortuosity, bifurcation lesions, chronic total occlusion, total lesion length, or total lesion numbers between the two groups. Less patients in Group B obtained completion of RA (95.9% vs 99.1%, p=0.037). There was no difference in the incidence of procedural complication or acute contrast-induced nephropathy. Group B patients had more deaths and MACE while in the hospital. The MACE and CV MACE were also higher in Group B patients at 180 days and one year, mostly due to TLR and TVR. Multivariate regression analysis showed that ACS, age, peripheral artery disease (PAD), advanced renal insufficiency, ischemic cardiomyopathy/shock, and high residual SYNTAX score were independent risk factors for in-hospital MACE, whereas ACS, advanced renal insufficiency, ischemic cardiomyopathy/shock, triple-vessel disease, and PAD independently predicted MACE at 6 months. Conclusions: Rotablation is feasible, safe, and could be carried out with very high success rate in very-high-risk patients with advanced renal dysfunction through ESRD without an increase in procedural complication.