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–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–Pugh class A and 71 patients were Child–Pugh class B. Objective response rate was lower in patients with Child–Pugh class B than A (2.8% vs. 15.9%; p = 0.010). Child–Pugh class B was an independent negative predictor for objective response. Median overall survival was shorter in Child–Pugh B patients (11.3 vs. 42.9 weeks; adjusted hazard ratio AHR, 2.10; p < 0.001). In Child–Pugh B patients, overall survival of patients with Child–Pugh score of 8 or 9 was worse than patients with Child–Pugh score of 7 (7.4 vs. 15.3 weeks; AHR, 1.93; p < 0.020). In conclusion, considering the unsatisfactory response in Child–Pugh B patients, nivolumab may not be used in unselected Child–Pugh B patients. Further studies are needed in this patient population.
Combined hepatocellular-cholangiocarcinoma (cHCC-CC) can present as a hypervascular or peripherally enhancing tumor in dynamic imaging. We evaluated the effect of transarterial chemoembolization ...(TACE) on prognosis according to post-operative recurrence imaging patterns.
We retrospectively analyzed 42 cHCC-CC and 59 hepatocellular carcinoma (HCC-control) patients at the Asan Medical Center. We classified recurrent cHCC-CC according to enhancement pattern (globally enhancing: GE cHCC-CC, peripherally enhancing: PE cHCC-CC) and evaluated tumor response, time-to-local progression (TTPlocal), and overall survival (OS).
The GE cHCC-CC group had a significantly higher best objective response rate (complete remission + partial response) than the PE cHCC-CC group (36% vs 0%, P = 0.005), and it was comparable to that of the HCC-control group (35.6%, P = 0.97). TTPlocal in the GE cHCC-CC group was significantly shorter than in the HCC-control group (6.6 vs 27.1 months, P < 0.001), and was not significantly different from that in the PE cHCC-CC group (5.3 months, P = 0.12). OS was 12.4 months, 52.8 months, and 67.5 months in the PE cHCC-CC, GE cHCC-CC, and HCC-control groups, respectively (Ps < 0.05). The adjusted hazard ratios (HRs) for TTPlocal and OS revealed an independent association with enhancement pattern of recurrent cHCC-CC (TTPlocal: HR 2.46; 95% CI 1.10-5.46; P = 0.03; OS: HR 5.97; 95% CI 2.38-14.96; P < 0.001).
The GE cHCC-CC group showed better response and prognosis after TACE than the PE cHCC-CC group, but poorer response and prognosis than the HCC-control group. Enhancement patterns at recurrence were crucially associated with tumor response and overall survival.
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.
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).
Patients treated with SBRT for single viable HCC after incomplete TACE between 2012 and 2017 at Asan Medical Center (Seoul, South Korea) were included. Incomplete TACE was defined as (1) evidence of viable HCC at the site of TACE on follow-up dynamic computed tomography (CT) or magnetic resonance imaging following one or more consecutive TACEs, (2) no definite tumor staining on superselective hepatic angiogram, or (3) no definite iodized oil uptake on post-embolization angiogram or CT. Doses of 10-15 Gy per fraction were given over 3-4 consecutive days. The primary outcome was local control rate at 3 years and secondary outcome included tumor response, overall survival rate, out-of-field intrahepatic recurrence-free survival, distant metastasis-free survival and treatment-related toxicities. Treatment-related adverse events were evaluated according to the common terminology criteria for adverse events, version 4.03.
A total of 302 patients were analyzed. 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.
SBRT could be considered a feasible salvage treatment option for HCC after incomplete TACE.
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 and >99% 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.
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.
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.
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 < .05). By association analysis, the prevalence of CC was associated with frailty by the CHS criteria (P < .001). The CHS frailty score was associated with the presence of CC by the univariate logistic regression analysis and the multivariate analysis adjusted for age, sex, and multimorbidity.
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.
Although they are less abundant in nature, methoxyflavonoids have distinct physicochemical and pharmacological properties compared to common nonmethylated flavonoids. Thus, enzymatic conversion and ...biotransformation using genetically engineered microorganisms of flavonoids have been attempted for the efficient production of methoxyflavonoids. Because of their regiospecificity, more than two flavonoid O-methyltransferases (FOMTs) and enzyme reactions are required to biosynthesize di(or poly)-methoxyflavonoids. For the one-step biotechnological production of bioactive di-O-methylflavonoids, we generated a multifunctional FOMT fusing a 3′-OMT (SlOMT3) and a 7-OMT (OsNOMT). The SlOMT3/OsNOMT fusion enzyme possessed both 3′- and 7-OMT activities to diverse flavonoid substrates, which were comparable to those of individual SlOMT3 and OsNOMT. The SlOMT3/OsNOMT enzyme also showed 3′- and 7-OMT activity for 7- or 3′-O-methylflavonoids, respectively, suggesting that the fusion enzyme can sequentially methylate flavonoids into di-O-methylflavonoids. The biotransformation of the flavonoids quercetin, luteolin, eriodictyol, and taxifolin using SlOMT3/OsNOMT-transformed Escherichia coli generated corresponding di-O-methylflavonoids, rhamnazin, velutin, 3′,7-di-O-methyleriodictyol, and 3′,7-di-O-methyltaxifolin, respectively. These results indicate that dimethoxyflavonoids may be efficiently produced from nonmethylated flavonoid precursors through a one-step biotransformation using the engineered E. coli harboring the SlOMT3/OsNOMT fusion gene.
Berberine (BBR) is one of the major alkaloids and has been reported to have a variety of pharmacologic effects, including inhibition of cell cycle progression. Here, we investigated the mechanisms of ...BBR protection of neuronal cells from cell death induced by the Parkinson’s disease-related neurotoxin 6-hydroxydopamine (6-OHDA). Pretreatment of SH-SY5Y cells with BBR significantly reduced 6-OHDAinduced generation of reactive oxygen species (ROS), caspase-3 activation, and subsequent cell death. BBR also upregulated heme oxygenase-1 (HO-1) expression, which conferred protection against 6-OHDA-induced dopaminergic neuron injury and besides, effect of BBR on HO-1 was reversed by siRNA-Nrf2. Furthermore, BBR induced PI3K/Akt and p38 activation, which are involved in the induction of Nrf2 expression and neuroprotection. These results suggest that BBR may be useful as a therapeutic agent for the treatment of dopaminergic neuronal diseases.
AIM To identify early predictive markers of poor outcomes in patients with acute liver injury from wild mushroom intoxication.METHODS This observational, retrospective record review involved adults ...aged ≥ 18 years admitted to emergency department with mushroom intoxication from January 2005 to December 2015. The diagnosis of mushroom intoxication was based on the following:(1) a positive history of recent wild mushroom intake(either raw or cooked);(2) the onset of gastrointestinal symptoms, such as watery diarrhea, vomiting, and/or abdominal pain, after ingestion; and(3) the exclusion of other possible causes of acute liver injury. Acute liver injury was defined by a > 5-fold elevation of liver enzymes or moderate coagulopathy (international normalized ratio(INR) > 2.0)Clinical and laboratory findings were compared in survivors and non-survivors.RESULTS Of 93 patients with mushroom intoxication, 23, 11 men(47.8%) and 12 women(52.2%), of median age 61 years, developed acute liver injury. The overall inhospital mortality rate was 43.5%(10/23). Among thelaboratory variables, mean serum alkaline phosphatase(73.38 ± 10.89 mg/dL vs 180.40 ± 65.39 mg/dL, P < 0.01), total bilirubin(2.312 ± 1.16 mg/dL vs 7.16 ± 2.94 mg/d L, P < 0.01) concentrations and indirect/direct bilirubin(2.45 ± 1.39 mg/dL vs 0.99 ± 0.45 mg/dL, P < 0.01) ratio as well as prothrombin time(1.88 ± 0.83 mg/dL vs 10.43 ± 4.81 mg/dL, P < 0.01), and activated partial thromboplastin time(a PTT; 32.48 ± 7.64 s vs 72.58 ± 41.29 s, P = 0.01), were significantly higher in non-survivors than in survivors. Logistic regression analysis showed that total bilirubin concentration(OR = 3.58, 95%CI: 1.25-10.22), indirect/direct bilirubin ratio(OR = 0.14, 95%CI: 0.02-0.94) and aP TT(OR = 1.30, 95%CI: 1.04-1.63) were significantly associated with mortality. All patients with total bilirubin > 5 mg/dL or aP TT > 50 s on day 3 died.CONCLUSION Monitoring of bilirubin concentrations and a PTT may help in predicting clinical outcomes in patients with acute liver injury from wild mushroom intoxication.
Abstract
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.
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