Induced pluripotent stem cell-based assays recapture multiple properties of human astrocytes.

The majority of the population of glial cells in the central nervous system consists of astrocytes, and impairment of astrocytes causes various disorders. It is useful to assess the multiple astrocytic properties in order to understand their complex roles in the pathophysiology. Although we can differentiate human astrocytes from induced pluripotent stem cells (iPSCs), it remains unknown how we can analyse and reveal the multiple properties of astrocytes in complexed human disease conditions. For this purpose, we tested astrocytic differentiation protocols from feeder-free iPSCs based on the previous method with some modifications. Then, we set up extra- and intracellular assessments of iPSC-derived astrocytes by testing cytokine release, calcium influx, autophagy induction and migration. The results led us to analytic methods with conditions in which iPSC-derived astrocytes behave as in vivo. Finally, we applied these methods for modelling an astrocyte-related disease, Alexander disease. An analytic system using iPSC-derived astrocytes could be used to recapture complexities in human astrocyte diseases.

Alterations of ATG4A and LC3B in neurons derived from Alzheimer's disease patients.

We investigated the alterations in autophagy-related molecules in neurons differentiated from induced pluripotent stem cells obtained from patients with Alzheimer's disease (AD). Consistent with our previous microarray data, ATG4A protein was upregulated in the neurons derived from a familial AD patient with an APP-E693Δ mutation who showed accumulation of intracellular amyloid ß peptide (Aß). This upregulation was reversed by inhibiting Aß production, suggesting that the intracellular Aß may be responsible for the upregulation of ATG4A. The LC3B-II/LC3B-I ratio, an index of autophagosome formation, was lower in the neurons derived from the AD patient with APP-E693Δ as well as the neurons derived from other familial and sporadic AD patients. These findings indicate that dysregulation of autophagy-related molecules may accelerate the pathogenesis of AD.

Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study).

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Cytokine release syndrome following durvalumab and tremelimumab in advanced hepatocellular carcinoma: A case report with cytokine and damage-associated molecular pattern analysis.

Cytokine release syndrome (CRS) is a systemic inflammatory syndrome that causes fatal circulatory failure due to hypercytokinemia, and subsequent immune cell hyperactivation caused by therapeutic agents, pathogens, cancers, and autoimmune diseases. In recent years, CRS has emerged as a rare, but significant, immune-related adverse event linked to immune checkpoint inhibitor therapy. Furthermore, several previous studies suggested that damage-associated molecular patterns (DAMPs) could be involved in malignancy-related CRS. In this study, we present a case of severe CRS following combination therapy with durvalumab and tremelimumab for advanced hepatocellular carcinoma, which recurred during treatment, as well as an analysis of cytokine and DAMPs trends. A 35-year-old woman diagnosed with hepatocellular carcinoma underwent a partial hepatectomy. Due to cancer recurrence, she started a combination of durvalumab and tremelimumab. Then, 29 days post-administration, she developed fever and headache, initially suspected as sepsis. Despite antibiotics, her condition worsened, leading to disseminated intravascular coagulation and hemophagocytic syndrome. The clinical course and elevated serum interleukin-6 levels led to a CRS diagnosis. Steroid pulse therapy was administered, resulting in temporary improvement. However, she relapsed with increased interleukin-6, prompting tocilizumab treatment. Her condition improved, and she was discharged on day 22. Measurements of inflammatory cytokines interferon-γ, tumor necrosis factor-α, and DAMPs, along with interleukin-6, using preserved serum samples, confirmed marked elevation at CRS onset. CRS can occur after the administration of any immune checkpoint inhibitor, with the most likely trigger being the release of DAMPs associated with tumor collapse.

Paternal involvement in childcare and housework and mothers' spanking behavior: The Japanese longitudinal survey of newborns in the 21st century.

BACKGROUND: No previous study reported an association between paternal involvement in childcare and housework and maternal physical punishment. METHODS: Using data from the Japanese Longitudinal Survey of Newborns in the 21st century (N = 38,554), we analyzed responses about fathers' involvement in childcare and housework at 6 months and mothers' spanking of children at 3.5 years. Fathers' involvement in childcare and housework was scored and categorized into quartiles. Spanking frequency was asked in the "often", "sometimes", or "not at all" categories. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the mothers' often spanking children were computed for the fathers' involvement in childcare and housework. We also stratified the association by fathers' working hours (40-49, 50-59, or ≥ 60 hours/week). RESULTS: Among the 16,373 respondents, the proportion of mothers who often spanked their children was 4.8%. Compared with the lowest quartile, a higher frequency of paternal involvement in housework was associated with a lower risk of spanking children (p trend = 0.001). Adjustment for covariates attenuated the association, but significant association was observed in the 3rd quartile of paternal involvement in housework [OR (95% CI): 0.77 (0.62-0.96)]. When the fathers worked fewer than 50 hours a week, a significant negative association was observed between the fathers' frequency of childcare and the likeliness of the mothers' spanking their children (p trend = 0.02). CONCLUSIONS: The fathers' active involvement in childcare and housework could reduce the mothers' physical punishment for their children.

A de novo gene originating from the mitochondria controls floral transition in Arabidopsis thaliana.

De novo genes created in the plant mitochondrial genome have frequently been transferred into the nuclear genome via intergenomic gene transfer events. Therefore, plant mitochondria might be a source of de novo genes in the nuclear genome. However, the functions of de novo genes originating from mitochondria and the evolutionary fate remain unclear. Here, we revealed that an Arabidopsis thaliana specific small coding gene derived from the mitochondrial genome regulates floral transition. We previously identified 49 candidate de novo genes that induce abnormal morphological changes on overexpression. We focused on a candidate gene derived from the mitochondrial genome (sORF2146) that encodes 66 amino acids. Comparative genomic analyses indicated that the mitochondrial sORF2146 emerged in the Brassica lineage as a de novo gene. The nuclear sORF2146 emerged following an intergenomic gene transfer event in the A. thaliana after the divergence between Arabidopsis and Capsella. Although the nuclear and mitochondrial sORF2146 sequences are the same in A. thaliana, only the nuclear sORF2146 is transcribed. The nuclear sORF2146 product is localized in mitochondria, which may be associated with the pseudogenization of the mitochondrial sORF2146. To functionally characterize the nuclear sORF2146, we performed a transcriptomic analysis of transgenic plants overexpressing the nuclear sORF2146. Flowering transition-related genes were highly regulated in the transgenic plants. Subsequent phenotypic analyses demonstrated that the overexpression and knockdown of sORF2146 in transgenic plants resulted in delayed and early flowering, respectively. These findings suggest that a lineage-specific de novo gene derived from mitochondria has an important regulatory effect on floral transition.

A Transgenic Pig Model With Human Mutant SOD1 Exhibits the Early Pathology of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) causes progressive degeneration of the motor neurons. In this study, we delivered the genetic construct including the whole locus of human mutant superoxide dismutase 1 (SOD1) with the promoter region of human SOD1 into porcine zygotes using intracytoplasmic sperm injection-mediated gene transfer, and we thereby generated a pig model of human mutant SOD1-mediated familial ALS. The established ALS pig model exhibited an initial abnormality of motor neurons with accumulated misfolded SOD1. The ALS pig model, with a body size similar to that of human beings, will provide opportunities for cell and gene therapy platforms in preclinical translational research.

Clinical effects and emerging issues of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma from Japanese real-world practice.

BACKGROUND: Although the efficacy of atezolizumab has been demonstrated in randomized controlled trials, its long-term efficacy and association with adverse events in real-world practice are unknown. This study was designed to shed light on these issues. METHODS: In this multicenter retrospective study, data were collected from patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in seven institutions in Japan. The authors focused on the efficacy and adverse events related to vascular endothelial growth factor (VEGF) inhibition. RESULTS: A total of 123 patients were enrolled in this study. The median progression-free survival (PFS) for the first-line treatment group was 8.0 months (95% confidence interval [CI], 6.1-9.9), whereas the median PFS for the second- or later-line treatment group was 4.1 months (95% CI, 2.6-5.7), which was significantly worse than that of the first-line treatment group (p = .005). Twenty-seven patients had interrupted bevacizumab treatment. Proteinuria accounted for the largest proportion of bevacizumab treatment interruptions. The cumulative incidence rate of bevacizumab interruption due to anti-VEGF-related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus than in those without (p = .026). The landmark analysis showed that patients experienced bevacizumab interruption by 24 weeks from treatment initiation had poorer PFS than those who did not (p = .013). CONCLUSIONS: The PFS of atezolizumab plus bevacizumab as first-line treatment mostly replicates that of a global phase 3 trial. Interrupted bevacizumab treatment was more common in patients with hypertension and/or diabetes mellitus, which may be associated with worsening long-term PFS. PLAIN LANGUAGE SUMMARY: Atezolizumab plus bevacizumab has been the standard front line systemic therapy for advanced hepatocellular carcinoma. With the growing incidence of fatty liver due to metabolic syndrome as a background liver disease for hepatocellular carcinoma, the rate of comorbid hypertension and diabetes mellitus has been increasing accordingly. The present study demonstrated the cumulative incidence rate of bevacizumab interruption due to anti-VEGF-related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus. The landmark analysis clarified that interruption of bevacizumab might be a risk of impaired efficacy of atezolizumab plus bevacizumab over the long term in patients with advanced hepatocellular carcinoma.

Stratification of Stage II Colon Cancer Using Recurrence Prediction Value: A Multi-institutional International Retrospective Study.

OBJECTIVE: To create a recurrence prediction value (RPV) of high-risk factor and identify the patients with high risk of cancer recurrence. SUMMARY BACKGROUND DATA: There are several high-risk factors known to lead to poor outcomes. Weighting each high-risk factor based on their association with increased risk of cancer recurrence can provide a more precise understanding of risk of recurrence. METHODS: We performed a multi-institutional international retrospective analysis of patients with Stage II colon cancer patients who underwent surgery from 2010 to 2020. Patient data from a multi-institutional database were used as the Training data, and data from a completely separate international database from two countries were used as the Validation data. The primary endpoint was recurrence-free survival (RFS). RESULTS: A total of 739 patients were included from Training data. To validate the feasibility of RPV, 467 patients were included from Validation data. Training data patients were divided into RPV low (n = 564) and RPV high (n = 175). Multivariate analysis revealed that risk of recurrence was significantly higher in the RPV high than the RPV low (Hazard ratio (HR) 2.628; 95% confidence interval (CI) 1.887-3.660; P < 0.001). Validation data patients were divided into two groups (RPV low, n = 420) and RPV high (n = 47). Multivariate analysis revealed that risk of recurrence was significantly higher in the RPV high than the RPV low (HR 3.053; 95% CI 1.962-4.750; P < 0.001). CONCLUSIONS: RPV can identify Stage II colon cancer patients with high risk of cancer recurrence world-wide.

Miglustat, a glucosylceramide synthase inhibitor, mitigates liver fibrosis through TGF-ß/Smad pathway suppression in hepatic stellate cells.

Transforming growth factor (TGF)-ß/Smad pathway is implicated in the pathogenesis of liver fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen in response to chronic inflammation. It has been reported that ceramide regulates collagen production through TGF-ß/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-ß/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-ß and multiple miglustat concentrations to examine dose-dependent effects on the expression levels of ECM-related genes and Smad proteins. To evaluate the efficacy of miglustat for fibrosis mitigation, C57BL/6 mice were treated with carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis, followed by combined CCl4 plus miglustat for a further 2 weeks. To examine if miglustat can also prevent fibrosis, mice were treated with CCl4 for 2 weeks, followed by CCl4 plus miglustat for 2 weeks. Miglustat dose-dependently downregulated expression of α-smooth muscle actin and ECM components in TGF-ß-treated HHSteCs. Both phosphorylation and nuclear translocation of Smad2 and Smad3 were also suppressed by miglustat treatment. Sirius-Red staining and hydroxyproline assays of model mouse liver samples revealed that miglustat reduced fibrosis, an effect accompanied by decreased expression of ECM. Our findings suggest that miglustat can both prevent and reverse liver fibrosis by inhibiting TGF-ß/Smad pathway.

CDiP technology for reverse engineering of sporadic Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease that causes cognitive impairment for which neither treatable nor preventable approaches have been confirmed. Although genetic factors are considered to contribute to sporadic AD, for the majority of AD patients, the exact causes of AD aren't fully understood. For AD genetics, we developed cellular dissection of polygenicity (CDiP) technology to identify the smallest unit of AD, i.e., genetic factors at a cellular level. By CDiP, we found potential therapeutic targets, a rare variant for disease stratification, and polygenes to predict real-world AD by using the real-world data of AD cohort studies (Alzheimer's Disease Neuroimaging Initiative: ADNI and Japanese Alzheimer's Disease Neuroimaging Initiative: J-ADNI). In this review, we describe the components and results of CDiP in AD, induced pluripotent stem cell (iPSC) cohort, a cell genome-wide association study (cell GWAS), and machine learning. And finally, we discuss the future perspectives of CDiP technology for reverse engineering of sporadic AD toward AD eradication.

Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma.

PURPOSE: Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. METHODS: Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. RESULTS: A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3). CONCLUSION: Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.

Hyperprogressive disease during atezolizumab plus bevacizumab treatment in patients with advanced hepatocellular carcinoma from Japanese real-world practice.

BACKGROUND: Hyperprogressive disease (HPD) is a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy, in patients treated with immune checkpoint inhibitors (ICI). The aim of this study is to clarify the reality of HPD in patients with advanced hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atez/Bev) using tumor dynamics. METHODS: Medical records of consecutive patients with advanced HCC who were treated with Atez/Bev were retrospectively reviewed. HPD was defined as a more than two- or fourfold increase in tumor growth rate (TGR) or tumor growth kinetics rate (TGKR) before and after treatment. Overall survival (OS) and baseline characteristics with or without HPD were analyzed. RESULTS: A total of 85 patients were included in the analysis. When HPD was defined as a twofold of TGR or TGKR, 8 patients (8/85, 9.4%) had HPD and 11 had PD without HPD. A total of 5 patients (5/85, 5.9%) were diagnosed with HPD and 14 with PD without HPD when HPD was defined as a fourfold of TGR or TGKR. No significant difference was observed in the baseline characteristics between HPD and non-HPD. CONCLUSION: The prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than those treated with nivolumab monotherapy. The HPD mechanism in ICI combined with antibodies targeting vascular endothelial growth factor (VEGF) remains to be elucidated.

Thirty-two years' experience of treating fulminant hepatitis in a Japanese single center.

AIM: The prognosis of patients with acute liver failure has improved dramatically in the past three decades due to advances in medical critical care and use of liver transplantation (LT) in Western countries, where the etiology of acute liver failure is different from that in Japan. We analyzed patients with fulminant hepatitis (FH) and late-onset hepatic failure (LOHF) admitted to our unit over a 32-year period to clarify the nature of Japanese patients with FH and LOHF. METHODS: A total of 137 Japanese patients with FH and LOHF between 1986 and 2017 were analyzed for etiologies, disease types, treatment protocols, and outcome. RESULTS: Of 137 patients, 124 were FH (53 acute type and 71 subacute type) and 13 LOHF. The major etiology was due to viral infections in 48% of patients. A total of 23.4% of patients recovered without LT, 7.3% received LT, and 69.3% died without LT. The number of patients showed rise and fall without an evident decrease during the period. Patients with autoimmune hepatitis increased after the establishment of autoimmune hepatitis criteria in 1999 (p < 0.001), and that with indeterminate cause decreased (p < 0.01). The mean age was older in the last decade than in the first decade (p = 0.036). Spontaneous and overall survival rates were not different during the period. CONCLUSIONS: The prognosis of our patients with FH and LOHF has not improved, probably because of aging and the increasing proportion of etiologies with poor prognosis and difficult-to-treat patients without response to medications regardless of advancement of clinical management, including artificial liver support devices and LT.

Prognostic Impact of Main Lymph Node Metastasis in Patients with Colon Cancer.

BACKGROUND: Although extended lymph node dissection during colon cancer surgery is recommended in both Western and Eastern countries, the perception and clinical significance of main lymph node metastasis (MLNM) remains controversial. METHODS: In total, 1557 patients with colon cancer who underwent curative resection with D3 dissection were retrospectively analyzed. Clinicopathological factors associated with MLNM were analyzed. Kaplan-Meier survival analysis and log-rank tests were used to compare the prognosis between the MLNM and non-MLNM groups. RESULTS: Multivariate analysis showed that overall survival (OS) [hazard ratio, 2.117 (0.939-4.774), p = 0.071] and recurrence-free survival (RFS) [hazard ratio, 2.183 (1.182-4.031), p = 0.013] were affected by the MLNM status independent of the TNM stage. Survival analysis demonstrated that among patients with stage III disease, the OS and RFS rates were significantly different between patients with and without MLNM (OS: p = 0.0147, RFS: p = 0.0001). However, the OS and RFS rates were not significantly different between patients who had stage III disease with MLNM and patients who had stage IV disease (OS: p = 0.5901, RFS: p = 0.9610). CONCLUSIONS: MLNM is an independent prognostic factor for patients with colon cancer. The addition of the MLNM status to the current TNM classification may enhance the prognostic value of the TNM staging system and the clinical efficacy of adjuvant therapy in patients with colon cancer.

A diet-induced murine model for non-alcoholic fatty liver disease with obesity and insulin resistance that rapidly develops steatohepatitis and fibrosis.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Patients with NAFLD often suffer steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The presence of visceral obesity or type 2 diabetes mellitus (T2DM) is a major risk factor and potential therapeutic target for NAFLD. The establishment of animal models with these metabolic comorbidities and with the rapid progression of the disease is needed for developing treatments for NAFLD but remains to be archived. In the present study, KK-Ay mice, widely used as T2DM models, or C57BL6 mice were fed a high-fat, high-fructose, and high-cholesterol diet supplemented with cholic acid (NAFLD diet). The KK-Ay mice fed a NAFLD diet exhibited remarkable obesity and insulin resistance. A prominent accumulation of triglycerides and cholesterol in the liver was observed at 4 weeks. These mice developed steatohepatitis at 4 weeks and fibrosis at 12 weeks. In contrast, C57BL6 mice fed a NAFLD diet remained lean, although they still developed steatohepatitis and fibrosis. In summary, we established a diet-induced murine NAFLD model with the rapid development of steatohepatitis and fibrosis, bearing obesity and insulin resistance. This model could be useful as preclinical models for drug development of NAFLD.

Th1 - CD11c+ B Cell Axis Associated with Response to Plasmapheresis in Multiple Sclerosis.

OBJECTIVE: Although plasmapheresis is a treatment option for patients with autoimmune neurological diseases, treatment response varies greatly among patients. The main objective of this study was to find out if biological/immune traits correlate with a beneficial response. METHODS: We thoroughly analyzed immune phenotypes in paired blood samples from a cohort of 31 patients with multiple sclerosis before and after plasmapheresis, in parallel with clinical evaluation of treatment response. RESULTS: The frequency of IFN-γ+ Th1 cells was persistently higher in those who obtained benefit from plasmapheresis (responders) than nonresponders. The Th1 cell frequency before plasmapheresis provided a high predictive value for beneficial response, achieving area under the curve (AUC) of 0.902. Plasmapheresis treatment decreased inflammation-related gene expressions in Th1 cells. Meanwhile, IFNG expression in Th1 cells positively correlated with the frequency of CD11c+ B cells, of which a pathogenic role has been suggested in several autoimmune diseases. In line with this, in vitro experiments showed that CD11c+ B cells would increase in response to exogenous IFN-γ compared to IL-4, and secrete high amounts of IgG. B cell receptor analysis indicated that clonal expansion of CD11c+ B cells takes place in patients with multiple sclerosis. Interestingly, CD11c+ B cells, which showed unique gene expression profile, decreased after plasmapheresis treatment along with all the immunoglobulin subsets in the circulation. INTERPRETATION: Taken together, we postulate that Th1 cell - CD11c+ B cell axis is involved in treatment response to plasmapheresis, giving us clues to better understanding of complicated pathogenesis of autoimmune diseases, and getting closer to a personalized therapy. ANN NEUROL 2021;90:595-611.

Changes in therapeutic options for hepatocellular carcinoma in Asia.

The incidence rate of hepatocellular carcinoma (HCC) is expected to increase, with most cases occurring in Asia. In some parts of Asia, the occurrence of HCC developing from metabolic-related liver disease has markedly increased in recent years, whereas the occurrence of HCC developing from viral-hepatitis-related liver disease has decreased. Advancements in the treatment of HCC over the past few decades has been remarkable, with most treatment strategies to remove or control liver tumours (hepatic resection, local ablation, radiation therapy, transarterial chemoembolisation, hepatic arterial infusion chemotherapy) primarily developing in Asia. In addition, recent progress in systemic therapies has prolonged the prognosis of advanced HCC. Nowadays, six regimens of systemic therapies have become available in most countries, according to phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). In a global randomised phase III trial (IMbrave 150 trial), the most effective of the latest drug designs was newly emerged combination immunotherapy (atezolizumab plus bevacizumab), which has shown significantly prolonged overall survival compared with sorafenib, which was the first-line systemic therapy for more than a decade. Now, the treatment dynamics for HCC are undergoing a major transition as a result of two important changes: the replacement of viral-related HCC by metabolic-related HCC and the emergence of combination immune therapy.

Carbon-ion radiotherapy versus radiofrequency ablation as initial treatment for early-stage hepatocellular carcinoma.

AIM: Carbon-ion radiotherapy (C-ion RT) has shown potential as a curative treatment for patients with hepatocellular carcinoma (HCC). However, no reports have compared the effectiveness of C-ion RT and radiofrequency ablation (RFA). This study aimed to compare clinical outcomes between C-ion RT and RFA for patients with early-stage HCC. METHODS: Medical records of consecutive patients with HCC (single lesion ≤5 cm or two to three lesions ≤3 cm) who received either C-ion RT or RFA as initial treatment were retrospectively reviewed. Propensity score matching (PSM) was used to adjust for clinical factors between both groups. RESULTS: A total of 560 patients were included, among whom 69 and 491 received C-ion RT and RFA, respectively. After PSM (C-ion RT, 54 patients; RFA, 95 patients), both groups were well balanced. Carbon-ion radiotherapy had significantly lower cumulative intrasubsegmental recurrence rate after PSM compared to RFA (p = 0.004) (2-year, 12.6% vs. 31.7%; 5-year, 15.5% vs. 49.6%, respectively). However, no significant difference in cumulative local recurrence rate, stage progression-free survival, or overall survival (OS) was observed between both groups. In the RFA group, 6 of 491 patients (1.2%) showed grade 3 adverse events, whereas no grade 3 or higher adverse events were observed in the C-ion RT group. CONCLUSION: Carbon-ion radiotherapy provided a lower cumulative intrasubsegmental recurrence rate, but a comparable cumulative local recurrence rate, stage progression-free survival, and OS compared to RFA. Thus, C-ion RT appears to be one of the effective treatment options for early-stage HCC when RFA is deemed not indicated.

Surgical glove perforation during laparoscopic colorectal procedures.

BACKGROUND: It has been reported that in conventional open surgery, approximately 10% of surgical gloves are perforated during surgery without being noticed. To protect both the patient and medical staff from harm, double gloving or changing gloves routinely at certain intervals during surgery is recommended. However, whether these protective measures are also necessary for laparoscopic colorectal surgery is unknown because the actual perforation rate during laparoscopic procedures is unclear. METHODS: Seventy-seven laparoscopic colorectal surgeries were evaluated, and a total of 616 surgical gloves used in the surgeries were collected for analysis. The presence of glove perforation was tested by the standard water-leak test method (EN455-1). RESULTS: Seven perforations were detected (1.1%). The duration of the laparoscopic procedure was not a statistically significant risk factor for glove perforation (p = 0.41). Postoperative surgical site infections (SSIs) were observed in 12 cases (15.6%), but there was no significant correlation between the presence of glove perforation and SSI (p = 0.92). According to the bacterial cultivation results, the majority of causative agents of SSI were enterobacteria, which belong to the major gut flora. CONCLUSION: Although the perforation rate was considerably lower than that in open surgery, surgical glove perforation occurred during laparoscopic procedures. Double gloving in laparoscopic colorectal surgery is recommended not to prevent SSI but to protect medical workers from harmful infections after direct contact with the patient.