Background and Aims
Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly ...4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8+ T cells (CD8+ tumor‐infiltrating lymphocytes TILs) and its association with distinct T‐cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC).
Approach and Results
Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8+ TILs. 4‐1BB expression was almost exclusively detected on CD8+ T cells in the tumor—especially on programmed death 1 (PD‐1)high cells and not PD‐1int and PD‐1neg cells. Compared to PD‐1int and 4‐1BBnegPD‐1high CD8+ TILs, 4‐1BBposPD‐1high CD8+ TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1high CD8+ TILs, 4‐1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T‐cell activation.
Conclusion
4‐1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.
Background and Aim
This study aimed to investigate the relationship between hepatic steatosis (HS) evaluated by biopsy and visceral adiposity assessed by computed tomography in lean living liver ...donor candidates and to determine the risk factors for lean non‐alcoholic fatty liver disease (NAFLD).
Methods
This retrospective study included 250 lean (body mass index, < 23 kg/m2) potential living liver donors (mean age, 31.1 ± 8.6 years; 141 men) who had undergone liver biopsy and abdominal computed tomography between 2017 and 2018. Anthropometry, laboratory parameters, body composition, and the degree of HS were evaluated. Logistic regression was used to identify independent predictors of lean NAFLD.
Results
The visceral fat area (VFA) was significantly correlated with the degree of HS in men (r = 0.408; P < 0.001) and women (r = 0.360; P < 0.001). The subcutaneous fat area was significantly correlated with the degree of HS in men (r = 0.398; P < 0.001), but not in women. The skeletal muscle area did not correlate with the degree of HS in either men or women. In the multivariable logistic regression analysis, the VFA (odds ratio OR, 1.028; 95% confidence interval CI, 1.013–1.044; P < 0.001) and subcutaneous fat area (OR, 1.016; 95% CI, 1.004–1.028; P = 0.009) were independent risk factors for lean NAFLD in men, and the VFA (OR, 1.036; 95% CI, 1.013–1.059; P = 0.002) was an independent risk factor for lean NAFLD in women.
Conclusions
The severity of non‐alcoholic fatty liver was positively correlated with visceral fat accumulation in a lean Asian population. Visceral adiposity may be a risk factor for lean NAFLD in potential living liver donors.
Following curative liver resection (LR), resectable tumor recurrence in patients with preserved liver function leads to deciding between a repeat LR and a salvage liver transplantation (LT), if a ...donor’s liver is available. This retrospective study compared survival outcomes and recurrence pattern following salvage living donor LT (LDLT) and repeat LR in patients with recurrent hepatocellular carcinoma (HCC). We reviewed the medical records of patients who underwent repeat LR (n = 163) or LDLT (n = 84) for recurrent HCC following curative resections, between January 2005 and December 2017 at a single institution. A 1:1 propensity score matching led to 42 patients per group. Disease‐specific and recurrence‐free survival were significantly better in the salvage LDLT group than in the repeat LR group (p = .042; HR = 2.40; 95% CI, 0.69–6.00 and p < .001; HR = 4.23; 95% CI, 2.05–8.71, respectively). Despite significant differences in recurrence patterns between the two groups (p = .019), the patient death rates, after recurrence, were similar for both groups (p = .760). This study indicates that salvage LDLT is superior to repeat LR for treating patients with transplantable, intrahepatic HCC recurrence, even in patients with Child‐Pugh class A liver cirrhosis.
Salvage living donor liver transplantation is superior to repeat liver resection to treat patients with transplantable, recurrent intrahepatic hepatocellular carcinoma, even in patients with Child–Pugh class A liver cirrhosis.
•A broadband microwave-absorbing honeycomb core structure was fabricated.•Conductive particles and metal magnetic micropowders were not used in manufacture.•The fabricated structure significantly ...attenuated electromagnetic wave.•The findings have significant potential for use in stealth technology applications.
In this study, we designed and fabricated a broadband microwave-absorbing honeycomb core structure using a nickel-coated glass fabric, which can absorb the electromagnetic waves propagating along three orthogonal directions. The electromagnetic properties of the pristine glass fabric were modified via an electroless nickel plating. The elemental composition, phase identification, and magnetic characteristics of the nickel-coated glass fabric were examined via scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, and vibrating-sample magnetometry. Unlike the implement methods of conventional microwave-absorbing honeycomb core structure such as dip coating, spray coating, and foam-filling, the proposed structure was produced without incorporating conductive particles or metal magnetic micropowders within the polymer matrix. The fabricated structure exhibited an absorption of −10 dB from 5.8 to 18 GHz and it was in good agreement with simulation result. In addition, we performed tensile, compressive, and interlaminar shear tests to evaluate the mechanical performance of the structure. Given the desirable radar-absorption and mechanical characteristics of the structure, it has significant potential for use in stealth technology applications.
Background and Aims
Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to ...identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV‐infected iCCA (HBV‐iCCA) tumors.
Approach and Results
We profiled a cohort of 108 HBV‐iCCAs using whole‐genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV‐infected HCC (HBV‐HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV‐cHCC/CCA; n = 59), and conventional (n = 154) and fluke‐related iCCAs (n = 16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at nine different sites. The most common insertional hotspot (7 tumors) was in the TERT (telomerase reverse transcriptase) promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2 (FAT atypical cadherin 2), and were associated with enrichment of epithelial–mesenchymal transition–related genes. A distinctive intergenic insertion (chr9p21.3), between DMRTA1 (DMRT like family A1) and LINC01239 (long intergenic non‐protein coding RNA 1239), had oncogenic effects through activation of the mammalian target of rapamycin (mTOR)/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV‐iCCA was closer to that of nonviral conventional iCCA, than to HBV‐HCC and HBV‐cHCC/CCA.
Conclusions
Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.
T-cell exhaustion, or an impaired capacity to secrete cytokines and proliferate with overexpression of immune checkpoint receptors, occurs during chronic viral infections but has also been observed ...in tumors, including hepatocellular carcinomas (HCCs). We investigated features of exhaustion in CD8+ T cells isolated from HCC specimens.
We obtained HCC specimens, along with adjacent nontumor tissues and blood samples, from 90 patients who underwent surgical resection at Asan Medical Center (Seoul, Korea) from April 2016 through April 2018. Intrahepatic lymphocytes and tumor-infiltrating T cells were analyzed by flow cytometry. Tumor-infiltrating CD8+ T cells were sorted by flow cytometry into populations based on expression level of programmed cell death 1 (PDCD1 or PD1): PD1-high, PD1-intermediate, and PD1-negative. Sorted cells were analyzed by RNA sequencing. Proliferation and production of interferon gamma (IFNG) and tumor necrosis factor (TNF) by CD8+ T cells were measured in response to anti-CD3 and antibodies against immune checkpoint receptors including PD1, hepatitis A virus cellular receptor 2 (HAVCR2 or TIM3), lymphocyte activating 3 (LAG3), or isotype control. Tumor-associated antigen-specific CD8+ T cells were identified using HLA-A*0201 dextramers. PDL1 expression on tumor tissue was assessed by immunohistochemistry.
PD1-high, PD1-intermediate, and PD1-negative CD8+ T cells from HCCs had distinct gene expression profiles. PD1-high cells expressed higher levels of genes that regulate T-cell exhaustion than PD1-intermediate cells. PD1-high cells expressed TIM3 and LAG3, and low proportions of TCF1+, TBEThigh/eomesoderminlow, and CD127+. PD1-high cells produced the lowest amounts of IFNG and TNF upon anti-CD3 stimulation. Differences in the PD1 expression patterns of CD8+ T cells led to the identification of 2 subgroups of HCCs: HCCs with a discrete population of PD1-high cells were more aggressive than HCCs without a discrete population of PD1-high cells. HCCs with a discrete population of PD1-high cells had higher levels of predictive biomarkers of response to anti-PD1 therapy. Incubation of CD8+ T cells from HCCs with a discrete population of PD1-high cells with antibodies against PD1 and TIM3 or LAG3 further restored proliferation and production of IFNG and TNF in response to anti-CD3.
We found HCC specimens to contain CD8+ T cells that express different levels of PD1. HCCs with a discrete population of PD1-high CD8+ T cells express TIM3 and/or LAG3 and produce low levels of IFNG and TNF in response to anti-CD3. Incubation of these cells with antibodies against PD1 and TIM3 or LAG3 further restore proliferation and production of cytokines; HCCs with a discrete population of PD1-high CD8+ T cells might be more susceptible to combined immune checkpoint blockade–based therapies.
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Living donor liver transplantation (LDLT) is a significant advancement for the treatment of children with end‐stage liver disease given the shortage of deceased donors. The ultimate goal of pediatric ...LDLT is to achieve complete donor safety and zero recipient mortality. We conducted a retrospective, single‐center assessment of the outcomes as well as the clinical factors that may influence graft and patient survival after primary LDLTs performed between 1994 and 2020. A Cox proportional hazards model was used for multivariate analyses. The trends for independent prognostic factors were analyzed according to the following treatment eras: 1, 1994 to 2002; 2, 2003 to 2011; and 3, 2012 to 2020. Primary LDLTs were performed on 287 children during the study period. Biliary atresia (BA; 52%), acute liver failure (ALF; 26%), and monogenic liver disease (11%) were the leading indications. There were 45 graft losses (16%) and 27 patient deaths (7%) in this population during the study period. During era 1 (n = 81), the cumulative survival rates at 1 and 5 years after LDLT were 90.1% and 81.5% for patients and 86.4% and 77.8% for grafts, respectively. During era 2 (n = 113), the corresponding rates were 92.9% and 92% for patients and 89.4% and 86.7% for grafts, respectively. During era 3 (n = 93), the corresponding rates were 100% and 98.6% for patients and 98.9% and 95.4% for grafts, respectively. In the multivariate analyses, primary diagnosis ALF, bloodstream infection, posttransplant lymphoproliferative disease, and chronic rejection were found to be negative prognostic indicators for patient survival. Based on generalized care guidelines and center‐oriented experiences, comprehensive advances in appropriate donor selection, refinement of surgical techniques, and meticulous medical management may eventually realize a zero‐mortality rate in pediatric LDLT.
Health literacy is strongly associated with health inequality among persons with deafness, and hypertension (HTN) is the most prevalent chronic disease among persons with deafness in South Korea. ...Despite its importance, research regarding the health literacy levels of persons with deafness with HTN in South Korea is lacking. This study aimed to comprehensively assess the health literacy levels of persons with deafness with HTN in South Korea, including linguistic, functional, and internet health literacy. In this descriptive cross-sectional study, 95 persons with deafness with HTN were recruited through facilities associated with the deaf community. From August 2022 to February 2023, data were collected through face-to-face surveys attended by a sign language interpreter and online surveys. The data were analyzed using descriptive statistics and Spearman's correlation. Approximately 62.1% of the participants exhibited a linguistic health literacy level corresponding to less than that of middle school students, and the total percentage correct of functional health literacy was 17.9%. Each domain of internet health literacy was low. Significant correlations were found between some aspects of health literacy. The study's findings highlight the low health literacy levels across various facets among persons with deafness with HTN in South Korea. Based on these findings, several strategies are suggested for developing HTN self-management interventions for persons with deafness. This study contributes to the foundational understanding of health literacy among persons with deafness with HTN in South Korea and provides valuable insights and guidance for developing HTN self-management interventions.
Objectives
To investigate the value of preoperative gadoxetic acid–enhanced MRI for tumor staging and recurrence prediction of hepatocellular carcinoma (HCC) after primary liver transplantation (LT).
...Methods
This multicenter retrospective study included 122 recipients who underwent living donor LT (LDLT) for untreated HCC and pre-transplant gadoxetic acid–enhanced MRI from January 2009 to December 2013. Disease-free survival (DFS) was evaluated. Milan criteria, tumor grade, and microvascular invasion (MVI) were analyzed on the pathological examination of the explanted liver.
Results
The 1-, 3-, 5-, and 7-year DFS rates were 93.3%, 90.7%, 88.9%, and 86.1%, respectively. In the multivariable analysis, independent predictors of HCC recurrence were “beyond the Milan criteria” (hazard ratio HR, 3.54; 95% confidence interval CI, 1.13–11.12;
p
= 0.030) and peritumoral hypointensity on hepatobiliary phase (HBP) (HR, 18.30; 95% CI, 4.33–77.34;
p
< 0.001). Pre-transplant MRI yielded a 90.2% accuracy to categorize the Milan criteria when compared with the explanted liver. Peritumoral hypointensity on HBP was significantly associated with a worse tumor grade (
p
= 0.010) and MVI (
p
< 0.001). The 5-year DFS rate in patients with “beyond the Milan criteria” but the absence of peritumoral hypointensity on HBP was not different from that in patients “within the Milan criteria” (92.2% vs. 92.9%,
p
= 0.438).
Conclusions
Pre-transplant gadoxetic acid–enhanced MRI may assist in the HCC recurrence risk prediction.
Key Points
• Lesions beyond the Milan criteria and peritumoral hypointensity on hepatobiliary phase (HBP) were independent predictors of HCC recurrence.
• Peritumoral hypointensity on HBP significantly associated with a worse tumor grade and microvascular invasion.
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