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Background The incidence of hepatocellular carcinoma (HCC) has been increasing among the elderly populations. Trans-arterial chemoembolization (TACE), a widely used first-line non-curative therapy for HCCs is an issue in geriatrics. We investigated the prognosis of elderly HCC patients treated with TACE and determined the factors that affect the overall survival. Methods We included 266 patients who were older than 65 years and had received TACE as initial treatment for HCC. We analyzed the skeletal muscle index (SMI) and visceral-to-subcutaneous fat ratio (VSR) around the third lumbar vertebrae using computed tomography scans. Muscle depletion with visceral adiposity (MDVA) was defined by falling below the median SMI and above the median VSR value sex-specifically. We evaluated the overall survival in association with MDVA and other clinical factors. Results The mean age was 69.9 ± 4.5 years, and 70.3% of the patients were men. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, 29, 136, and 101 patients were classified as BCLC 0, A, and B stages, respectively, and 79 (29.7%) had MDVA. During the median follow-up of 4.1 years, patients with MDVA had a shorter life expectancy than those without MDVA (P = 0.007) even though MDVA group had a higher objective response rate after the first TACE (82.3% vs. 75.9%, P = 0.035). Multivariate analysis revealed that MDVA (Hazard ratio [HR] 1.515) age (HR 1.057), liver function (HR 1.078), tumor size (HR 1.083), serum albumin level (HR 0.523), platelet count (HR 0.996), tumor stage (stage A, HR 1.711; stage B, HR 2.003), and treatment response after the first TACE treatment (HR 0.680) were associated with overall survival. Conclusions MDVA is a critical prognostic factor for predicting survival in the elderly patients with HCC who have undergone TACE.

Successful pregnancy inevitably depends on the implantation of a competent embryo into a receptive endometrium. Although many substances have been suggested to improve the rate of embryo implantation targeting enhancement of endometrial receptivity, currently there rarely are effective evidence-based treatments to prevent or cure this condition. Here we strongly suggest minimally-invasive intra-uterine administration of embryo-secreted chemokine CXCL12 as an effective therapeutic intervention. Chemokine CXCL12 derived from pre- and peri-implanting embryos significantly enhances the rates of embryo attachment and promoted endothelial vessel formation and sprouting in vitro. Consistently, intra-uterine CXCL12 administration in C57BL/6 mice improved endometrial receptivity showing increased integrin β3 and its ligand osteopontin, and induced endometrial angiogenesis displaying increased numbers of vessel formation near the lining of endometrial epithelial layer with higher CD31 and CD34 expression. Furthermore, intra-uterine CXCL12 application dramatically promoted the rates of embryo implantation with no morphologically retarded embryos. Thus, our present study provides a novel evidence that improved uterine endometrial receptivity and enhanced angiogenesis induced by embryo-derived chemokine CXCL12 may aid to develop a minimally-invasive therapeutic strategy for clinical treatment or supplement for the patients with repeated implantation failure with less risk.

BACKGROUND & AIMS The optimal systemic chemotherapy for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) has not yet been defined. The definition and classification of cHCC-CCA has changed recently in the 5th edition of WHO classification. We reviewed the pathological findings with the new classification and analysed the efficacy of systemic chemotherapy in patients with unresectable/metastatic cHCC-CCA. METHODS Among 254 patients with histologically confirmed cHCC-CCA from 1999 to 2015 in Asan Medical Center, Seoul, Korea, 99 patients who received systemic chemotherapy for unresectable/metastatic disease were included. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were retrospectively evaluated. RESULTS Sorafenib (n = 62) and cytotoxic chemotherapy (n = 37) were administered as first-line chemotherapies; the ORR was 14.1%, and the median PFS and OS were 3.8 and 10.6 months, respectively, with a median follow-up duration of 39.6 months. The efficacy outcomes were not significantly different between patients who received sorafenib and those who received cytotoxic chemotherapy (ORR, 9.7% vs 21.6%, P = .14; median PFS, 4.2 vs 2.9 months, P = .52; median OS, 10.7 vs 10.6 months, P = .34). In multivariate analysis, large intrahepatic tumour burden (≥30% of liver volume), elevated serum bilirubin and non-platinum containing first-line chemotherapy remained as significant prognostic factors for poorer OS. CONCLUSIONS The efficacy outcomes according to first-line treatment were not significantly different between sorafenib and cytotoxic chemotherapy, and pathological findings were not found to help for determining appropriate therapeutic agent or assessing the prognosis. To overcome the poor treatment outcomes, further studies are needed to find proper treatment targets, biomarkers and the best treatment strategies.

Introduction: Atezolizumab-bevacizumab is the new standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, the optimal sequence of therapy after disease progression on atezolizumab-bevacizumab is unclear. Methods: This multinational, multicenter, and retrospective study assessed clinical outcomes of patients with advanced HCC who received subsequent systemic therapy after progression on atezolizumab-bevacizumab between July 2016 and April 2019. Results: Among 71 patients treated with atezolizumab-bevacizumab, a total of 49 patients who received subsequent systemic therapy were included in this analysis; the median age was 60 years (range, 37–80) and 73.5% were male. All patients were classified as Child-Pugh A and Barcelona-Clinic Liver Cancer stage C. Multikinase inhibitors (MKIs), including sorafenib (n = 29), lenvatinib (n = 19), and cabozantinib (n = 1), were used as second-line therapy for all patients. The objective response rate and disease control rate were 6.1 and 63.3%, respectively, in all patients. With a median follow-up duration of 11.0 months, median progression-free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI] 1.8–4.9) and 14.7 months (95% CI 8.1–21.2) in all patients. Median PFS with lenvatinib was significantly longer than that with sorafenib (6.1 vs. 2.5 months; p = 0.004), although there was no significant difference in median OS (16.6 vs. 11.2 months; p = 0.347). Treatment-related adverse events (TRAEs) of any grade and grade 3 occurred in 42 (85.7) and 8 (16.3%) of patients. Common TRAEs included hand-foot syndrome (n = 26, 53.1%), fatigue (n = 14, 28.6%), hypertension (n = 14, 28.6%), and diarrhea (n = 12, 24.5%). Conclusion: Second-line treatment with MKIs, mostly sorafenib and lenvatinib, showed comparable efficacy and manageable toxicities in patients with advanced HCC after disease progression on atezolizumab-bevacizumab.

There is a significant discrepancy between the actual choice for initial treatment option for hepatocellular carcinoma (HCC) and recommendations from the currently used BCLC staging system. We develop a machine learning-based clinical decision support system (CDSS) for recommending initial treatment option in HCC and predicting overall survival (OS). From hospital records of 1,021 consecutive patients with HCC treated at a single centre in Korea between January 2010 and October 2010, we collected information on 61 pretreatment variables, initial treatment, and survival status. Twenty pretreatment key variables were finally selected. We developed the CDSS from the derivation set (N = 813) using random forest method and validated it in the validation set (N = 208). Among the 1,021 patients (mean age: 56.9 years), 81.8% were male and 77.0% had positive hepatitis B BCLC stages 0, A, B, C, and D were observed in 13.4%, 26.0%, 18.0%, 36.6%, and 6.3% of patients, respectively. The six multi-step classifier model was developed for treatment decision in a hierarchical manner, and showed good performance with 81.0% of accuracy for radiofrequency ablation (RFA) or resection versus not, 88.4% for RFA versus resection, and 76.8% for TACE or not. We also developed seven survival prediction models for each treatment option. Our newly developed HCC-CDSS model showed good performance in terms of treatment recommendation and OS prediction and may be used as a guidance in deciding the initial treatment option for HCC.

Background/Aims: Stereotactic body radiation therapy (SBRT) is used as an alternative ablative treatment in patients with hepatocellular carcinoma (HCC) not suitable for curative treatments. The purpose of this prospective study was to evaluate the long-term efficacy of SBRT for small (≤5 cm) HCCs.Methods: A phase II, single-arm clinical trial on SBRT for small HCCs was conducted at an academic tertiary care center. The planned SBRT dose was 45 Gy with a fraction size of 15-Gy over 3 consecutive days. The primary endpoint was 2-year local control rate. Radiologic responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) and the modified RECIST criteria.Results: Between 2013 and 2016, 50 patients (53 lesions) were enrolled, with a median follow-up period of 47.8 months (range, 2.9–70.6). Patients’ age ranged from 41 to 74 years, and 80% were male. Median tumor size was 1.3 cm (range, 0.7–3.1). The 2- and 5-year local control rates were 100% and 97.1%, respectively. The 5-year overall survival rate was 77.6%. Six months after SBRT, radiologic responses were evident in 44 lesions (83%) according to the RECIST criteria and 49 (92.4%) according to the modified RECIST criteria. None of the patients showed grade ≥3 adverse events.Conclusions: SBRT showed excellent results as an ablative treatment for patients with small HCCs while showing minimal toxicities. SBRT can be a good alternative for both curative and salvage intents in patients with HCCs that are unsuitable for curative treatments.

Regorafenib and nivolumab are drugs approved for second‐line treatment of patients with hepatocellular carcinoma (HCC) after sorafenib failure. However, the effectiveness of regorafenib and nivolumab following sorafenib has not been directly compared. This study retrospectively evaluated 373 patients with HCC who were treated with regorafenib (n = 223) or nivolumab (n = 150) after sorafenib failure between July 2017 and February 2019. Progression‐free survival (PFS; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69‐1.06; P = 0.150), time to progression (TTP; HR, 0.95; 95% CI, 0.77‐1.19; P = 0.680), and overall survival (OS; HR, 0.83; 95% CI, 0.64‐1.07; P = 0.154) did not differ significantly between groups of patients treated with regorafenib and nivolumab, findings consistently observed by multivariable‐adjusted, propensity score‐matched, and inverse probability treatment weighting (IPTW) analyses. However, the objective response rate was significantly higher in the nivolumab than in the regorafenib group (13.3% vs. 4.0%; P = 0.002). When the effectiveness of regorafenib and nivolumab was compared in nonprogressors to treatment, defined as patients who achieved complete response, partial response, or stable disease after first response evaluation, PFS (HR, 0.50; 95% CI, 0.33‐0.75; P = 0.001), TTP (HR, 0.48; 95% CI, 0.31‐0.73; P, In this retrospective comparative study, the effectiveness of regorafenib and nivolumab following sorafenib in HCC was investigated. The oncological outcomes were not different between the regorafenib and nivolumab groups. However, nivolumab showed better outcomes than regorafenib when progressors to each were excluded.

Disability studies (DS) is an interdisciplinary field grounded in a minority studies philosophy that approaches disability as a socially constructed phenomenon. The first special issue of the American Journal of Occupational Therapy on DS was published in 2005. The present issue serves as a follow-up to highlight opportunities for and examples of DS integration into occupational therapy education, research, and practice. Studies in this special issue reflect a DS approach to research that prioritizes lived experiences, critical approaches, and participatory methodologies. Reported interventions focus on changing societal barriers rather than remediating individual impairments and acknowledge instrumental activities of daily living often neglected by traditional research. Studies on educational practices in occupational therapy have found persistent issues around negative attitudes toward disability and many opportunities to better infuse disabilities studies into curricula. Revisiting DS as it applies to occupational therapy has shown that many of the issues and considerations raised in 2005 remain in the field today. Recommendations across articles in this special issue highlight that advocacy and working for broader social change are essential for occupational therapy practitioners, given ongoing occupational injustices for people with disabilities. Infusing DS ideas into occupational therapy can promote greater alignment with priorities of disability communities and spur professional change to dismantle oppressive structures and ideologies.

Little is known about how quality of life (QOL) can assist clinical decision-making for patients with hepatocellular carcinoma (HCC). This study aimed to investigate the reliability and validity of QOL as well as its prognostic value and utility.A prospective cohort of 300 HCC patients at various stages was recruited from 2015 to 2017 in Korea. The subjects answered the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) and QLQ-HCC18 and the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. Prognostic nomograms including the QOL scales were developed. The prediction performance of the Barcelona Clinic Liver Cancer (BCLC) and the American Joint Committee on Cancer (AJCC) staging systems when they were incorporated with QOL was investigated.The EORTC QLQ-C30 and QLQ-HCC18 subscales showed higher reliability than FACT-Hep subscales. With regard to the validity, both questionnaires discriminated the patients by stages, treatment modalities, and performance status effectively. Multivariable analysis revealed that EORTC role functioning and EORTC appetite loss subscales were statistically associated with overall survival and disease progression. The developed nomograms accurately estimated the 1-year overall survival and disease progression-free rates. Incorporating the EORTC role functioning subscale or Hepatobiliary Cancer Subscale of FACT-Hep with the BCLC and AJCC systems improved the prognostic classification. Incorporating QOL into the AJCC system showed better predictive accuracy than incorporating performance status into it did.The findings suggest that QOL data can serve as a reliable predictive factor and assist prognostic calculation for HCC patients.

BACKGROUND & AIMS As surrogate markers for autoimmune hepatitis (AIH), serum alanine aminotransferase (ALT) and immunoglobulin G (IgG) are convenient to measure under immunosuppression. However, the long-term prognosis of patients who achieve complete biochemical remission (CBR) in comparison with patients who achieve only biochemical remission (BR) is uncertain. METHODS A total of 291 patients (89.7% female) diagnosed with AIH were retrospectively reviewed. CBR was defined as normal ALT and IgG levels with immunosuppression, while BR was defined as normal ALT levels. CBR was further divided into early CBR (

Although targeted deep sequencing of cell-free DNA (cfDNA) was recently used to investigate tumor somatic mutations in particular subtypes of non-Hodgkin lymphomas (NHLs), the immense genetic heterogeneity across subtypes poses a hurdle to design a universal gene panel applicable for diverse subtypes of NHLs. We designed a panel targeting 66 genes associated with NHLs and performed targeted deep sequencing to analyze plasma cfDNA from patients with various subtypes of NHLs. Genetic profiling in plasma cfDNA using the method resulted in 88.0% sensitivity and99% specificity in detecting mutations present at a frequency greater than 20% in the tumor biopsies. Furthermore, the level of ctDNA significantly decreased and increased depending on designated clinical responses to therapy and disease progression. These results demonstrated that ctDNA sensitively indicated the presence of cancer and reliably correlated with tumor burden, suggesting potential utility of the method for patients with various subtypes of NHLs.

Importance: In 2005, the American Journal of Occupational Therapy published a special issue focused on disability studies. Contributing authors challenged readers to reflect on their practices and recommended ways to change the field, yet literature on the current state of the integration of disability studies into occupational therapy is scarce. Objective: To engage the original authors of the 2005 special issue in an examination of perspectives on how disability studies perspectives have contributed to changes within occupational therapy and what work remains. Design: The research team conducted semistructured interviews with 11 authors who published an article in the special issue. Interview transcripts were analyzed using thematic analysis. Triangulation of coders, multiple phases of data analysis, and member checking were used to establish trustworthiness. Results: Five themes emerged from the data: (1) exposure to disability and disability studies, (2) impact of the special issue on occupational therapy, (3) changes observed in occupational therapy beyond the special issue, (4) challenges integrating disability studies into occupational therapy, and (5) disability studies–informed recommendations for occupational therapy. Conclusions and Relevance: Although the original contributing authors acknowledged the transformative impact of disability studies on their own practice and scholarship, the results suggest that disability studies remains outside mainstream occupational therapy scholarship. Exploring the connections and divergence between disability studies and fields such as occupational science could improve understanding of how disability studies concepts are defined and used in theory and practice. What This Article Adds: Since the publication of the original special issue in 2005, the field of disability studies has continued to influence occupational therapy, although more often in individual than in systemic ways. Work is needed to embrace a disability studies–informed critical and intersectional foundation for the profession and explore the ways in which occupational therapy can better partner with populations through a disability studies lens.

BACKGROUND AND AIMS Programmed death 1 (PD-1) inhibitors have improved survival outcomes and produced durable responses in advanced hepatocellular carcinoma (HCC) for some patients. Here, we evaluated the relationship between the baseline and kinetics of the neutrophil-lymphocyte ratio (NLR) and clinical outcomes in nivolumab-treated HCC patients. METHODS All consecutive HCC patients treated with nivolumab between July 2017 and June 2020 were screened for the eligibility. The NLRs were calculated before and at 2, 4 and 6 weeks after treatment. Survival outcomes were compared based on the baseline and kinetics of NLR. We additionally analysed the association of the baseline and dynamic changes in the NLR with hyperprogression (HPD). RESULTS Among the 194 included cases, most patients were male (82.0%) and had a Child-Pugh Class A disease (70.6%). Patients with a baseline NLR ≥ 3 (hazard ratio [HR] 2.46; 95% CI 1.63-3.71) had a poorer overall survival than patients with baseline NLR

Background & Aims Hepatitis B virus (HBV) reactivation is a well-known complication in patients with chronic hepatitis B treated with cytotoxic chemotherapy. However, the risk of HBV reactivation through use of immune checkpoint inhibitors (ICIs) is not well understood. Therefore, we aimed to evaluate the risk of HBV reactivation and hepatic adverse events in patients with cancer receiving ICIs according to cancer type and virologic serology. Methods This historical cohort study included 3465 patients with cancer treated with ICIs between January 2015 and September 2020. The primary outcome was the occurrence of HBV reactivation, and the secondary outcome was presence of hepatic adverse events during ICI treatment. Results The mean patient age was 62.2 years, and 68.8% of patients were men. Of the 3465 eligible patients, 511 (14.7%) showed hepatitis B surface antigen (HBsAg) positivity. The incidence rates of HBV reactivation of the total patients, HBsAg-positive patients, and HBsAg-negative patients were 0.14% (5/3465), 1.0% (5/511), and 0.0% (0/2954), respectively. Among HBsAg-positive patients, HBV reactivation occurred at a rate of 0.5% (2/409) and 2.9% (3/102) in patients with and without hepatocellular carcinoma, respectively. The HBV reactivation rates were 0.4% (2/464) and 6.4% (3/47) in patients with and without antiviral prophylaxis, respectively. Grade 3–4 hepatitis occurred in 23 (4.5%) HBsAg-positive, and 218 (7.4%) HBsAg-negative patients. No HBV-related fatality occurred. Only 2 patients (0.4%) experienced HBsAg seroclearance after ICI treatment among HBsAg-positive patients. Conclusions In general, HBV reactivation was rarely observed in patients with antiviral prophylaxis while undergoing ICI treatment. However, HBV reactivation may occur in HBsAg-positive patients without antiviral prophylaxis or noncompliant with antiviral prophylaxis.

Background: To evaluate the clinical outcomes of patients who received stereotactic body radiation therapy (SBRT) for single viable hepatocellular carcinoma (HCC) at the site of incomplete transarterial chemoembolization (TACE).Methods: Incomplete TACE was defined as (1) evidence of viable HCC at the site of TACE on follow-up images following one or more consecutive TACEs, (2) no definite tumor staining on celiac angiogram, or (3) no definite iodized oil uptake on post-embolization angiogram or computed tomography. A total of 302 patients were treated between 2012 and 2017 at Asan Medical Center (Seoul, South Korea). Doses of 10–15 Gy per fraction were given over 3–4 consecutive days. Treatment-related adverse events were evaluated according to the common terminology criteria for adverse events, version 4.03.Results: The median follow-up duration was 32.9 months (interquartile range [IQR], 23.6–41.7) and the median tumor size was 2.0 cm (range, 0.7–6.9). The local control (LC) and overall survival rates at 3 years were 91.2% and 72.7%, respectively. 95.4% of the tumors reached complete response (CR) during the entire follow-up period (anyCR). The median interval from SBRT to anyCR was 3.4 months (IQR, 1.9–4.7), and 39.9% and 83.3% of the lesions reached CR at 3- and 6-months after SBRT, respectively. Radiation-induced liver disease was observed in 8 (2.6%) patients. No patients experienced gastroduodenal bleeding within the radiation field.Conclusion: SBRT should be considered a feasible salvage treatment option for HCC after incomplete TACE.

Background Oral health is essential for daily living and plays a pivotal role in overall health conditions and well-being. This study evaluated the impact of self-reported oral health on geriatric conditions, institutionalization, and mortality. Methods This study analyzed the population of the Aging Study of Pyeongchang Rural Area that had undergone geriatric assessments between 2016 and 2017. The oral health status of the participants was determined using three items from the General Oral Health Assessment Index, and the participants were classified into three groups according to the total sum of the scores as good (3), fair (4–7), or poor (8–15). The outcomes were the incidence of geriatric syndromes at 2 years and the composite outcome of mortality and institutionalization. Results Among the 1189 participants, 44.1 % were women, and the mean age of the study population was 75.0 years. Good, fair, and poor oral health were observed in 597 (50.2 %), 406 (34.1 %), and 186 (15.6 %) individuals, respectively. Worsening oral health status was associated with the incidences of various geriatric syndromes at follow-up, and these associations were attenuated after adjusting for baseline demographic and geriatric parameters. Similarly, the significant association between baseline oral health status and the incidence of the composite outcome was attenuated after adjusting for demographic and geriatric parameters. Conclusions Oral health affected the geriatric health conditions in this prospective, longitudinal cohort of community-dwelling older adults. The correlations and interactions of oral health status with other functional parameters may deserve consideration as a geriatric domain.

Background. Endometrial angiogenesis plays crucial roles in determining the endometrial receptivity. Defects in endometrial receptivity often cause repeated implantation failure, which is one of the major unmet needs for infertility and contributes a major barrier to the assisted reproductive technology. Despite the numerous extensive research work, there are currently no effective evidence-based treatments to prevent or cure this condition.Method. As a non-invasive treatment strategy, Botulinum toxin A (BoTA) was administered into one side of mouse uterine horns and saline was infused into the other side of horns for the control. Impact of BoTA was assessed in the endometrium at 3 or 8 days after infusion.Results. We demonstrated that BoTA administration enhances the capacity of endothelial cell tube formation and sprouting. The intrauterine BoTA administration significantly induced endometrial angiogenesis displaying increased numbers of vessel formation and expression levels of related-marker genes. Moreover, BoTA intrauterine application promoted the endometrial receptivity and the rates of embryo implantation were improved with BoTA treatment with no morphologically retarded embryos. Conclusion. Intrauterine BoTA treatment has a beneficial effect on vascular reconstruction of functional endometrium prior to embryo implantation by increasing endometrial blood flow near the uterine cavity suggesting BoTA treatment as a potential therapeutic strategy for patients who are suffering from repeated implantation failure with the problems with endometrial receptivity.

Background Despite constipation being a common clinical condition in older adults, the clinical relevance of constipation related to frailty is less studied. Hence, we aimed to investigate the association between chronic constipation (CC) and frailty in older adults. Methods This is a cross-sectional analysis of a population-based, prospective cohort study of 1278 community-dwelling older adults in South Korea. We used the Rome criteria to identify patients with irritable bowel syndrome with predominant constipation (IBS-C) and functional constipation (FC). We investigated whether participants consistent with the criteria for IBS-C and FC had CC. Frailty was assessed using the Cardiovascular Health Study (CHS) frailty phenotype. Results In the study population with a mean age of 75.3 ± 6.3 years, 136 (10.7%) had CC. The participants with CC were older, had higher medication burdens, and had worse physical performances compared to those without CC (All P P Conclusions Frailty was associated with CC in community-dwelling older people, suggesting that constipation should be considered as an important geriatric syndrome in clinical practice concerning frail older adults.

This study aims to suggest a simple migratory cell monitoring method in the Transwell system by utilizing retroreflective Janus microparticles (RJPs) as an optical probe. The RJP could be internalized on cells without compromising the cell viability and can be registered as bright spots within the cell body by inducing retroreflection from nonspectroscopic light sources. Conventional optical probes (e.g., fluorophores, chromogens, and nanoparticles) have been extensively studied and applied across diverse platforms (e.g., Boyden chamber, wound closing, and microfluidic chips) for understanding in vitro kinetic cell behavior. However, the complexities of running such platforms and setting up analytical instruments are limiting. In this regard, we aimed to demonstrate a modified Transwell migration assay by introducing the retroreflection principle to the cell quantification procedures that ensure a simplified optical setup, assure easy signal acquisition, and are compatible with conventional platforms. To demonstrate retroreflection as a signaling principle, a half-metal-coated silica particle that can induce interior retroreflection was synthesized. Because the RJPs can concentrate incident light and reflect it back to the light source, retroreflection was distinctively recognizable and enabled sensitive visualization. To verify the applicability of the developed migration assay, cell quantification during the incremental progress of macrophage migration, and cell quantification under gradients of chemoattractant monocyte protein-1, was accomplished by obtaining phagocytosed RJP-mediated retroreflection signals. Considering that conventional assays are designed as endpoint measurements, we anticipate the proposed retroreflection-based cell quantification technique to be a promising solution, bypassing current limitations.

Nivolumab has shown durable response and safety in patients with hepatocellular carcinoma (HCC) in previous trials. However, real-world data of nivolumab in HCC patients, especially those with Child&ndash, Pugh class B, are limited. To investigate the effectiveness and safety of nivolumab in a real-world cohort of patients with advanced HCC, we retrospectively evaluated 203 patients with HCC who were treated with nivolumab between July 2017 and February 2019. Of 203 patients, 132 patients were classified as Child&ndash, Pugh class A and 71 patients were Child&ndash, Pugh class B. Objective response rate was lower in patients with Child&ndash, Pugh class B than A (2.8% vs. 15.9%, p = 0.010). Child&ndash, Pugh class B was an independent negative predictor for objective response. Median overall survival was shorter in Child&ndash, Pugh B patients (11.3 vs. 42.9 weeks, adjusted hazard ratio [AHR], 2.10, p &lt, 0.001). In Child&ndash, Pugh B patients, overall survival of patients with Child&ndash, Pugh score of 8 or 9 was worse than patients with Child&ndash, Pugh score of 7 (7.4 vs. 15.3 weeks, AHR, 1.93, 0.020). In conclusion, considering the unsatisfactory response in Child&ndash, Pugh B patients, nivolumab may not be used in unselected Child&ndash, Pugh B patients. Further studies are needed in this patient population.

Pattern-recognition receptors including Toll-like receptors (TLRs) recognize invading pathogens and trigger an immune response in mammals. Here we show that mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as a negative regulator of lipopolysaccharide (LPS)-induced activation of the TLR4-NF-κB signaling pathway associated with inflammation. Myeloid-specific genetic ablation of MST1/STK4 increased the susceptibility of mice to LPS-induced septic shock. Ablation of MST1/STK4 also enhanced NF-κB activation triggered by LPS in bone marrow-derived macrophages (BMDMs), leading to increased production of proinflammatory cytokines by these cells. Furthermore, MST1/STK4 inhibited TRAF6 autoubiquitination as well as TRAF6-mediated downstream signaling induced by LPS. In addition, we found that TRAF6 mediates the LPS-induced activation of MST1/STK4 by catalyzing its ubiquitination, resulting in negative feedback regulation by MST1/STK4 of the LPS-induced pathway leading to cytokine production in macrophages. Together, our findings suggest that MST1/STK4 functions as a negative modulator of the LPS-induced NF-κB signaling pathway during macrophage activation.

The influence of direct-acting antivirals (DAAs) on chronic hepatitis C (CHC)-related hepatocellular carcinoma (HCC) remains controversial. We investigated the effect of eradicating CHC using DAAs on treatment outcomes in patients with CHC-related HCC treated with transarterial chemoembolization (TACE). This nationwide, multi-center, retrospective study recruited patients with CHC-related HCC treated with TACE as the first-line anti-cancer treatment, and who achieved a sustained virological response (SVR) using DAAs (DAA group) between 2006 and 2017. Patients achieving an SVR following interferon-based treatment (IFN group) and those without treatment (control group) were also recruited for comparison. A total of 425 patients were eligible for the study. Of these, 356 (83.8%), 26 (6.1%), and 43 (10.1%) were allocated to the control, IFN, and DAA groups, respectively. A multivariate analysis showed that liver cirrhosis, segmental portal vein thrombosis, and larger maximal tumor size independently predicted an increased risk of progression (all p

Background: Only few surgeons have tried to perform laparoscopic combined resection for T4b gastric cancer. The purpose of this study was to investigate the feasibility of laparoscopic combined resection through a comparison of the clinical outcomes between cT4a and cT4b cases. Methods: We reviewed the medical charts of patients who underwent laparoscopic gastrectomy for clinically T4 gastric cancer from May 2014 and July 2018. During this period, 62 patients with serosa-positive gastric cancer underwent laparoscopic curative surgery. The patients were divided into the following groups: patients who underwent gastrectomy and combined resection for the invaded organs (combined resection group) and those who did not undergo combined organ surgery (gastrectomy only group). Clinical outcomes were compared between the gastrectomy only and combined resection groups. Results: Of 62 patients included in this study, 43 and 19 patients were included in the gastrectomy only and combined resection groups, respectively. The operation time was significantly longer in the combined resection group (364.6 ± 102.5 vs. 247.7 ± 66.1 min; p < 0.001). The incidence of grade ≥ III complications was comparable between the groups (26.3% vs. 11.6%; p = 0.147). The time from the first operation to the initiation of adjuvant chemotherapy showed no statistically significant difference between the groups (48.1 ± 45.4 days vs. 31.6 ± 9.2; p = 0.134). Conclusions: Focusing on the high quality of image and new devices of laparoscopic surgery, it is necessary to re-evaluate the oncologic outcomes of combined resection for T4b gastric cancer.

Background & aim In clinical practice, transarterial chemoembolization (TACE) has been widely used for the treatment of hepatocellular carcinoma (HCC) beyond as well as within guideline recommendations. Here we aimed to verify whether two consecutive non-responses could be an optimal criterion for creating a rule to stop TACE being performed on these patients. Methods This study evaluated 200 patients with HCC beyond the Milan criteria, initially treated with TACE. TACE response was determined using the mRECIST criteria via dynamic CT or MRI. Median follow-up duration was 23.9 months. Results Within the 200 patients analyzed, 183 (91.5%) were male, with a total median age of 59.8 years. The mean size of the largest tumor was 6.8 cm, with 80 (40.0%) patients with ≥4 tumors. After the first TACE procedure, complete response, partial response, stable disease, or progressive disease were observed in 48 (24.0%), 87 (43.5%), 59 (29.5%) and 6 (3.0%) of patients, respectively. 45 (22.5%) patients showed no objective response (OR) following two consecutive TACE sessions. Of these, 28 received a subsequent TACE, with a 10.7% OR rate. Patients without OR showed poorer survival when compared to patients who achieved OR after repeated TACE. Multivariable analysis showed that size of the largest tumor >5cm and high alpha-fetoprotein of >200 ng/mL were significant factors associated with failure of OR to two consecutive TACE sessions. Conclusion Patients showing no OR to two consecutive TACE sessions will present a poor OR to subsequent TACE procedures. Early transition to systemic therapy may be advocated in such cases.

Background & aimHepatic resection is a treatment option for patients with hepatocellular carcinoma (HCC). However, factors associated with candidacy for resection and predictive of liver-related morbidity after resection for HCC remain unclear. This study aimed to assess candidacy for liver resection in patients with HCC and to design a model predictive of liver-related morbidity after resection.MethodsA retrospective analysis of 1,565 patients who underwent liver resection for HCC between January 2016 and December 2017 was performed. The primary outcome was liver-related morbidity, including post-hepatectomy biochemical dysfunction (PHBD), ascites, hepatic encephalopathy, rescue liver transplantation, and death from any cause within 90 days. PHBD was defined as international normalized ratio (INR) > 1.5 or hyperbilirubinemia (> 2.9 mg/dL) on postoperative day ≥ 5.ResultsThe 1,565 patients included 1,258 (80.4%) males and 307 (19.6%) females with a mean age of 58.3 years. Of these patients, 646 (41.3%) and 919 (58.7%) patients underwent major and minor liver resection, respectively. Liver-related morbidity was observed in 133 (8.5%) patients, including 77 and 56 patients who underwent major and minor resection, respectively. A total of 83 (5.3%) patients developed PHBD. Multivariate analysis identified cut-off values of the platelet count, serum albumin concentration, and ICG R15 value for predicting liver-related morbidity after resection. A model predicting postoperative liver-related morbidity was developed, which included seven factors: male sex, age ≥ 55 years, ICG R15 value ≥ 15%, major resection, platelet count < 150,000/mm3, serum albumin concentration < 3.5 g/dL, and INR > 1.1.ConclusionHepatic resection for HCC was safe with 90-day liver-related morbidity and mortality rates of 8.5% and 0.8%, respectively. The developed point-based scoring system with seven factors could allow the prediction of the risk of liver-related morbidity after resection for HCC.

Hepatocellular carcinoma (HCC), a representative example of a malignancy with a poor prognosis, is characterized by high mortality because it is typically in an advanced stage at diagnosis and leaves very little hepatic functional reserve. Despite advances in medical and surgical techniques, there is no omnipotent tool that can diagnose HCC early and then cure it medically or surgically. Several recent studies have shown that a variety of pathways are involved in the development, growth, and even metastasis of HCC. Among a variety of cytokines or molecules, some investigators have suggested that arrest-defective 1 (ARD1), an acetyltransferase, plays a key role in the development of malignancies. Although ARD1 is thought to be centrally involved in the cell cycle, cell migration, apoptosis, differentiation, and proliferation, the role of ARD1 and its potential mechanistic involvement in HCC remain unclear. Here, we review the present literature on ARD1. First, we provide an overview of the essential structure, functions, and molecular mechanisms or pathways of ARD1 in HCC. Next, we discuss potential clinical implications and perspectives. We hope that, by providing new insights into ARD1, this review will help to guide the next steps in the development of markers for the early detection and prognosis of HCC., Liver cancer: The search for an early-stage indicator A protein that is highly expressed in cancer with extensive blood vessel development may provide a potential biomarker for early-stage liver cancer. Liver cancer is often not diagnosed until it is advanced and is also hard to be cured despite of advances in treatment, meaning patients often die from the disease. No tools for early detection or prognosis prediction exist, and scientists are keen to find useful biomarker molecules. Young-Hwa Chung at the University of Ulsan College of Medicine, Asan Medical Center, Seoul, and co-workers in South Korea reviewed recent research into one possible cancer-related protein, arrest-defective 1 (ARD1), known to be highly expressed in certain cancers and possibly associated with poor prognosis. While ARD1 appears to regulate pathways critical to cancer progression and promote cancer cell invasiveness, further in-depth investigations are needed to clarify its specific role in liver cancer.

Liver fibrosis can be reversed by removing its causative injuries; however, the molecular mechanisms mediating the resolution of liver fibrogenesis are poorly understood. We investigate the role of a scaffold protein, A-Kinase Anchoring Protein 12 (AKAP12), during liver fibrosis onset, and resolution. Biliary fibrogenesis and fibrosis resolution was induced in wild-type (WT) or AKAP12-deficient C57BL/6 mice through different feeding regimens with 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing chow. AKAP12 expression in portal fibroblasts (PFs) and liver sinusoidal endothelial cells (LSECs) gradually decreased as fibrosis progressed but was restored after cessation of the fibrotic challenge. Histological analysis of human liver specimens with varying degrees of fibrosis of different etiologies revealed that AKAP12 expression diminishes in hepatic fibrosis from its early stages onward. AKAP12 KO mice displayed reduced fibrosis resolution in a DDC-induced biliary fibrosis model, which was accompanied by impaired normalization of myofibroblasts and capillarized sinusoids. RNA sequencing of the liver transcriptome revealed that genes related to ECM accumulation and vascular remodeling were mostly elevated in AKAP12 KO samples. Gene ontology (GO) and bioinformatic pathway analyses identified that the differentially expressed genes were significantly enriched in GO categories and pathways, such as the adenosine 3′,5′-cyclic monophosphate (cAMP) pathway. Knockdown of the AKAP12 gene in cultured primary PFs revealed that AKAP12 inhibited PF activation in association with the adenosine 3′,5′-cyclic monophosphate (cAMP) pathway. Moreover, AKAP12 knockdown in LSECs led to enhanced angiogenesis, endothelin-1 expression and alterations in laminin composition. Collectively, this study demonstrates that AKAP12-mediated regulation of PFs and LSECs has a central role in resolving hepatic fibrosis., Liver fibrosis: Reversing the damage A scaffolding protein that modulates cell signaling pathways contributes to reverse liver scarring. Liver fibrosis is caused by a build-up of scar tissue that interferes with liver function. However, the damage is reversed when the cause of injury is removed. Kyu-Won Kim at Seoul National University, South Korea, and colleagues examined the levels of A-Kinase Anchoring Protein 12 (AKAP12), a scaffolding protein that regulates the subcellular location of signaling proteins, in mouse and human livers. Levels of AKAP12 were reduced in fibrotic livers but restored when fibrosis was reversed. Mice lacking AKAP12 were unable to effectively repair the damage caused by fibrosis. Genetic analyses suggest that AKAP12 stimulates signaling through the adenosine 3′,5′-cyclic monophosphate (cAMP) pathway, which can inhibit fibrosis. These findings highlight a key role for AKAP12 in accelerating liver recovery.

SAM domain and HD domain containing protein 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase (dNTPase) that inhibits retroviruses by depleting intracellular deoxynucleotide triphosphates (dNTPs) in non-cycling myeloid cells. Although SAMHD1 is expressed ubiquitously throughout the human body, the molecular mechanisms regulating its enzymatic activity and function in non-immune cells are relatively unexplored. Here, we demonstrate that the dNTPase activity of SAMHD1 is regulated by acetylation, which promotes cell cycle progression in cancer cells. SAMHD1 is acetylated at residue lysine 405 (K405) in vitro and in vivo by an acetylatransferase, arrest defective protein 1 (ARD1). Acetylated SAMHD1 wildtype proteins have enhanced dNTPase activity in vitro, whereas non-acetylated arginine substituted mutants (K405R) do not. K405R mutant expressing cancer cells have reduced G1/S transition and slower proliferation compared to wildtype. SAMHD1 acetylation levels are strongest during the G1 phase, indicating a role during G1 phase. Collectively, these findings suggest that SAMHD1 acetylation enhances its dNTPase activity and promotes cancer cell proliferation. Therefore, SAMHD1 acetylation may be a potent therapeutic target for cancer treatment.

Background/Aims Little is known about the treatment or outcomes of hepatocellular carcinoma (HCC) complicated with bile duct invasion. Methods A total of 247 consecutive HCC patients with bile duct invasion at initial diagnosis were retrospectively included. Results The majority of patients had Barcelona Clinic Liver Cancer (BCLC) stage C HCC (66.8%). Portal vein tumor thrombosis was present in 166 (67.2%) patients. Median survival was 4.1 months. Various modalities of treatment were initially employed including surgical resection (10.9%), repeated transarterial chemoembolization (TACE) (42.5%), and conservative management (42.9%). Among the patients with obstructive jaundice (n=88), successful biliary drainage was associated with better overall survival rate. Among the patients with BCLC stage C, overall survival differed depending on the initial treatment for HCC; surgical resection, TACE, systemic chemotherapy, and conservative management showed overall survival rates of 11.5, 6.0 ,2.4, and 1.6 months, respectively. After adjusting for confounders, surgical resection and repeated TACE were significant prognostic factors for HCC patients with bile duct invasion (hazard ratios 0.47 and 0.39, Ps

Endoscopic variceal ligation is the preferred endoscopic treatment method for esophageal variceal bleeding. The incidence of complications such as chest pain, bleeding, stricture formation, and aspiration pneumonia is low. We report a case wherein a malfunctioning multiple-band ligator could have potentially caused damage to the esophageal varices and massive bleeding. The equipment was safely removed using scissors and forceps. To the best of our knowledge, this is the first published report detailing the management of a case of esophageal variceal bleeding.

We report a case with hepatitis C virus genotype 1 b liver cirrhosis who received liver transplantation because of acute-on-chronic liver failure during daclatasvir (DSV) and asunaprevir (ASV) combination therapy. To our knowledge, this is the first case received liver transplantation during DSV + ASV therapy. Therefore, clinicians should pay particular attention to the possibility of acute liver failure during DSV and ASV combination therapy.

Background Hepatic resection has been the main treatment option for patients with hepatocellular carcinoma (HCC). Several previous studies attempted to establish reliable criteria to predict mortality or post-hepatectomy liver failure (PHLF) after liver resection Methods A total of 1,481 consecutive patients underwent hepatic resection between January 2016 and December 2017. Laboratory tests were assessed before, and 1,2,3,5,7, and 10 days after surgery. Post-hepatectomy hepatic dysfunction was defined as an increase in the total bilirubin ≥2.9 mg/dL (50 μmol/L) or an increase INR on or after postoperative day 5, compared with the values of the previous day. PHLF includes post-hepatectomy hepatic dysfunction, ICU stay, development of ascites requiring diuretics or drainage procedure, and mortality from any cause. Patients were randomly divided into train set (n=1,111) and validation set (n=370). Results Of 1,565 patients with available data, the mean age was 58.3 years and male comprised 80.6% of patients. 403 (32.1%) patients underwent major hepatic resection and 481(38.3%) revealed cirrhosis at pathologic specimens. The mortality at 30 and 90 days were 0.3% and 0.9%, respectively. PHLF developed in 117(9.3%) patients: posthepatectomy hepatic dysfunction in 62 (4.9%) patients, ICU stay in 18(1.4%) patients, ascites in 42(3.3%) patients, and death 11 (0.9%) patients. In multivariable logistic regression, age over 70 years (adjusted odds ratio [AOR]: 2.89, 95% confidence interval [95% CI]: 1.65–4.97), cirrhosis (AOR:2.60, 95% CI:1.67–4.08), albumin less than 3.5 (AOR:2.17, 95% CI:1.56–3.01), major hepatic resection compared with minor resection (AOR:2.26, 95% CI:1.41–3.62), and high indocyanine green (ICG) index at 15 minutes over 20% (AOR:2.53, 95% CI:1.21–5.46) were significantly associated with a high risk of PHLF. Integer values were assigned to each factor to develop a model that predicted PHLF, which presented an area under the curve of 0.780. Conclusions Cirrhosis, age over 70 years, major resection, lower albumin and high ICG level were associated independently with PHLF. A composite integer-based risk scoring model could accurately predict PHLF in patients undergoing hepatic resection for HCC

Objective Autoimmune hepatitis (AIH) is a chronic progressive liver disease characterized by circulating autoantibodies and hyperglobulinemia. This study was conducted to identify the features of AIH accompanied by systemic lupus erythematosus (SLE-AIH) that differ from those of primary AIH (P-AIH), and to evaluate factors that affect the outcome for SLE-AIH patients. Methods From May 1995 to April 2014, clinical data (including liver pathology) from 164 patients with P-AIH and 23 patients with SLE-AIH were collected from an electronic database at a tertiary referral center. AIH was diagnosed according to the diagnostic scoring system for AIH (revised in 1999). SLE patients fulfilled at least 4 of the 1997 revised American College of Rheumatology criteria. Progression was defined as occurrence of cirrhosis, hepatocellular carcinoma, liver transplantation, or death from hepatic failure. Results The age at the time of AIH diagnosis was lower and initial levels of serum IgG were higher in SLE-AIH than in P-AIH patients. Progression was more common in P-AIH, and hepatocellular carcinoma, liver transplantation, or death occurred only in P-AIH patients. Among 23 patients with SLE-AIH, 8 with cirrhosis had higher levels of serum IgG than 15 patients without cirrhosis (mean ± SD 4,077.4 ± 1,641.0 mg/dl and 2,560.7 ± 932.2 mg/dl, respectively; P = 0.017). Moreover, a serum IgG level more than 2-fold the upper normal limit was associated with a high risk of cirrhosis in SLE-AIH (odds ratio 11.00 [95% confidence interval 1.420–85.201]; P = 0.026). Conclusion Initially high levels of serum IgG are a poor prognostic factor for SLE-AIH. Additionally, the long-term outcome for SLE-AIH might be better than for P-AIH.

Although antiviral prophylaxis is essential in hepatitis B patients in the context of cancer chemotherapy, there is little evidence-based consensus regarding the appropriate prevention strategy depending on the underlying type of cancer and viral status. This retrospective study included a comprehensive cohort of 302 hepatitis B surface antigen-positive patients with various cancers undergoing chemotherapy and antiviral prophylaxis. The rates of hepatitis B virus (HBV) reactivation during antiviral therapy (>1 log10 IU/mL increase or positive conversion of serum HBV DNA) and relapse when off antivirals ([re]appearance of HBV DNA >2,000 IU/ml with related alanine aminotransferase elevation) were evaluated, together with the associated risk factors, in a competing risks analysis where cancer death was considered as the competing event. During antiviral prophylaxis, HBV was reactivated in six patients (1.9%), who had leukemia (n = 4) or lymphoma (n = 2) and were treated with lamivudine (n = 4) or entecavir (n = 2). The incidence rate of HBV relapse in 127 off-prophylaxis patients was 21.3% during a median post-antiviral period of 11.7 months. Lymphoma, pre-prophylactic HBV DNA ≥2,000 IU/ml, and age ≥50 years were independent predictors of off-treatment HBV relapse (adjusted hazard ratios 5.25, 3.07, and 0.34, respectively; Ps

Background & aims We investigated potential aetiologies, clinical characteristics and prognosis of non-B non-C (NBNC) hepatocellular carcinoma (HCC) patients in hepatitis B virus (HBV) endemic area, according to potential causes such as previous HBV exposure, chronic alcohol intake and metabolic syndrome. Patients and methods Among 4690 HCC patients treated at Asan Medical Center between 2007 and 2009, 523 were newly diagnosed with NBNC HCC, and their medical records and survival data were analyzed retrospectively. Results Among 321 NBNC HCC patients whose hepatitis B core antibody (anti-HBc) test results were available, 81.0%, 37.1% and 15.5% had anti-HBc positivity, chronic alcohol intake and metabolic syndrome respectively. One-hundred and fifty-two patients (47.4%) had previous exposure to HBV without chronic alcohol intake or metabolic syndrome. Hepatitis B surface antibody (anti-HBs) was positive in 48.0% of the 523 NBNC HCC patients, which was much lower than that in general Korean population, and 52.3% of anti-HBc-positive NBNC HCC patients were negative for anti-HBs. Anti-HBc-negative alcoholic patients presented with more advanced cirrhosis with Child-Pugh class B/C liver function than anti-HBc-positive patients (P = 0.002). In multivariate analysis, baseline liver function, alpha-foetoprotein levels and tumour stage were significant prognostic factors and aetiology did not affect patient survival. Conclusions Prior HBV infection could be a potential aetiology in over 40% of NBNC HCC patients in HBV endemic area. Positivity for anti-HBc and negativity for anti-HBs may be a serologic surrogate marker for occult HBV infection in these area. The prognosis of NBNC HCC was determined by tumour stage and underlying liver function.

There is a heavy emphasis in rehabilitation on restoration of function post-stroke at the expense of addressing how to manage the impact of stroke and the environment long term. Management of chronic health conditions is often and effectively addressed using self-management education; however, self-management is mostly focused on managing symptoms and health behaviors, not additional participation and community reintegration issues experienced following stroke. This study evaluated the Improving Participation after Stroke Self-Management Program (IPASS) to improve self-efficacy and participation in everyday life activities for individuals living with the long-term consequences of stroke.A multisite, single-blind, exploratory randomized clinical study was conducted with participants with mild-to-moderate chronic stroke (n = 185). Participants were randomized either to receive the IPASS intervention immediately or to a wait list control group. The assessment was completed pre- and post-intervention and at 6-9 months post-intervention follow-up. The primary outcome assessments included measures of self-efficacy to manage chronic health conditions and to participate in everyday life activities.The results show that there was significant short-term increase in health-related self-efficacy both within-group and between-groups in managing chronic conditions which were retained at follow-up; the average effect size was 0.46, indicating moderate effect overall. Further, a significant short-term increase was found in participation self-efficacy, with an overall moderate effect size of 0.55.These results provide early support for the use of IPASS to help improve self-efficacy to manage health behaviors and to improve participation post-stroke. Further investigation is warranted to confirm these findings with an active control group and a more sensitive outcome measure to capture participation changes.