Artificial Intelligence Model for a Distinction between Early-Stage Gastric Cancer Invasive Depth T1a and T1b.

Background: Endoscopic submucosal dissection (ESD) is a widely accepted treatment for patients with mucosa (T1a) disease without lymph node metastasis. However, the inconsistency of inspection quality of tumor staging under the standard tool combining endoscopic ultrasound (EUS) with computed tomography (CT) scanning makes it restrictive. Methods: We conducted a study using data augmentation and artificial intelligence (AI) to address the early gastric cancer (EGC) staging problem. The proposed AI model simplifies early cancer treatment by eliminating the need for ultrasound or other staging methods. We developed an AI model utilizing data augmentation and the You-Only-Look-Once (YOLO) approach. We collected a white-light image dataset of 351 stage T1a and 542 T1b images to build, test, and validate the model. An external white-light images dataset that consists of 47 T1a and 9 T1b images was then collected to validate our AI model. The result of the external dataset validation indicated that our model also applies to other peer health institutes. Results: The results of k-fold cross-validation using the original dataset demonstrated that the proposed model had a sensitivity of 85.08% and an average specificity of 87.17%. Additionally, the k-fold cross-validation model had an average accuracy rate of 86.18%; the external data set demonstrated similar validation results with a sensitivity of 82.98%, a specificity of 77.78%, and an overall accuracy of 82.14%. Conclusions: Our findings suggest that the AI model can effectively replace EUS and CT in early GC staging, with an average validation accuracy rate of 86.18% for the original dataset from Linkou Cheng Gun Memorial Hospital and 82.14% for the external validation dataset from Kaohsiung Cheng Gun Memorial Hospital. Moreover, our AI model's accuracy rate outperformed the average EUS and CT rates in previous literature (around 70%).

Peripheral Blood Inflammatory Markers as A Reliable Predictor of Gastric Mucosal Metaplasia Change in the Middle-aged Population.

Purpose: The study aims to evaluate the efficacy of peripheral blood inflammatory markers as clinical predictors for gastric intestinal metaplasia (IM), a known precursor to gastric cancer. This research investigates the potential of these markers to serve as reliable indicators for detecting gastric IM. Methods: A retrospective cohort study was conducted on 59,143 individuals who underwent checkups at the Taoyuan Chang Gung Memorial Hospital Health Clinic Center from 2010 to 2014. Of these, 11,355 subjects who received gastroscopic biopsies were recruited. After omitting cases with incomplete blood data, the sample was narrowed to 10,380 participants. After exclusion and propensity score matching, subjects in the group with IM and control patients without IM were balanced and included in the study. These subjects were stratified by gender and age, and predictors such as the Systemic Inflammation Response Index (SIRI), Systemic Immune Inflammation Index (SII), and Monocyte-to-Lymphocyte Ratio (MLR) were evaluated. Multivariate logistic regression models were employed to analyze the presence or absence of IM accurately. Results: Out of the 10,380 subjects, 2,088 (20.1%) were diagnosed with IM, while 8,292 (79.9%) did not have IM. In our analysis, inflammation indices were found to have a limited impact on younger patients. For middle-aged and elderly individuals, SII showed statistical significance for predicting IM in males (p=0.0019), while SIRI and MLR were significant for females (SIRI p=0.0001, MLR p=0.0009). Additionally, the Area Under the Curve (AUC) value indicated that inflammation indices were more influential in females (55.1%) than males. Conclusions: The study results reveal that peripheral blood inflammatory markers could be useful in predicting gastric mucosal metaplasia changes, particularly in middle-aged and elderly populations. Although the markers' predictive power varies with gender, they represent a significant step forward in the non-invasive detection of gastric IM. This could aid in the early identification and management of precancerous conditions.

A colonial serrated polyp classification model using white-light ordinary endoscopy images with an artificial intelligence model and TensorFlow chart.

In this study, we implemented a combination of data augmentation and artificial intelligence (AI) model-Convolutional Neural Network (CNN)-to help physicians classify colonic polyps into traditional adenoma (TA), sessile serrated adenoma (SSA), and hyperplastic polyp (HP). We collected ordinary endoscopy images under both white and NBI lights. Under white light, we collected 257 images of HP, 423 images of SSA, and 60 images of TA. Under NBI light, were collected 238 images of HP, 284 images of SSA, and 71 images of TA. We implemented the CNN-based artificial intelligence model, Inception V4, to build a classification model for the types of colon polyps. Our final AI classification model with data augmentation process is constructed only with white light images. Our classification prediction accuracy of colon polyp type is 94%, and the discriminability of the model (area under the curve) was 98%. Thus, we can conclude that our model can help physicians distinguish between TA, SSA, and HPs and correctly identify precancerous lesions such as TA and SSA.

Dietary Exposure and Risk Assessment of Beta-Agonist Residues in Commercial Beef and Pork in Taiwan.

Beta-agonists (ß-agonists) in meat products in one's diet raise concerns about the possibility of foodborne illness. It may also lead to discomfort, such as headaches and occasional irregular heartbeats, which might be linked to a heightened concern for cardiovascular issues. Taiwan's high demand for meat and reliance on imported meat products from certain countries where ß-agonists are permitted has raised concerns. Recent import border checks and monitoring of meat products in the market have revealed the concentration of non-compliance with ß-agonist residue regulations, which is ten ppb. This study aims to analyze the concentration of ß-agonist residues in meat products sold in Taiwan and assess the current levels of exposure and dietary risk for consumers. The study analyzed 1415 samples of domestically produced and imported livestock products from supermarkets, traditional markets, and bulk stores in New Taipei City between 2019 and 2023. The samples were analyzed using the method for detecting 21 ß-agonists based on the Taiwan Food and Drug Administration's specifications. Estimated daily intake (EDI) of ß-agonists for different age groups and the target hazard quotient (THQ) were used to assess dietary exposure and risk. The results showed that all 1415 samples were compliant with regulations. Among them, 43 beef samples showed residues of ractopamine originating from the United States, with residue concentrations ranging from 1 to 10 µg/kg and an average residue concentration of 3.3 ± 1.9 µg/kg. Under average consumption, the highest EDI for the exposed population was observed in the 6-12 age group, with values of 0.1469 µg/kg/day, 0.0734 µg/kg/day, and 0.0242 µg/kg/day for the three residue concentrations (maximum detected residue, maximum allowable residue, and average detected residue, respectively). The THQs for ractopamine in imported beef samples were all less than 1, indicating no health hazards at the current intake levels of each age group and the residue concentrations in commercially available beef. Despite the findings, traders need to acknowledge regulatory variations between Taiwan and exporting countries when importing meat products. Traders should provide inspection reports to monitor ß-agonist residue levels in imports or explore sourcing beef from countries with ß-agonist bans.

Analyzing genomic variation in cultivated pumpkins and identification of candidate genes controlling seed traits.

Pumpkins are important vegetable crops widely grown worldwide, and seeds are considered a popular nutraceutical food and an excellent source of protein, oil, and vitamins. Seed size is one of the most important targets for commercial breeding in Cucurbita species; studies have shown that pumpkin seed size variation has a similar trend with fruit size, shape, and seed yield. However, few studies have been conducted to identify genetic loci controlling seed-related traits in cultivated pumpkins. This study analyzed the genomic characteristics of pumpkin breeding materials of 321 Cucurbita accessions collected worldwide, including Cucurbita moschata, Cucurbita maxima, and Cucurbita pepo, using extensive single nucleotide polymorphisms obtained from the genotyping-by-sequencing method, significant genetic variations were identified within and between Cucurbita species. Four major cultivar fruit types were further revealed in C. moschata species, and significant differentiation patterns were detected in several chromosomal regions. A total of 15 significant loci associated with pumpkin seed traits were mapped through a genome-wide association approach; 32 genes previously reported to be associated with seed size regulation in Arabidopsis and Oryza sativa were located in the intervals defined by linkage disequilibrium. Through this study, we gained a deep understanding of the genomic variation distribution across Cucurbita species. The available genetic resources and the associated genetic contents could be used in commercial pumpkin breeding and will facilitate molecular marker-assisted selection in pumpkin seed trait improvement.

Rapid detection of nicotine and benzoic acid in e-liquids with surface-enhanced Raman scattering and artificial intelligence-assisted spectrum interpretation.

Electronic cigarettes have rapidly gained acceptance recently. Nicotine-containing electronic cigarette liquids (e-liquids) are prohibited in some countries, but are permitted and simply available online in others. A rapid detection method is therefore required for on-site inspection or screening of a large amount of samples. Our previous study demonstrated a surface-enhanced Raman scattering (SERS)-based approach to identify nicotine-containing e-liquids; without any pre-treatment, e-liquid can be directly tested on our solid-phase SERS substrates, made of silver nanoparticle arrays embedded in anodic aluminium oxide nanochannels (Ag/AAO). However, this approach required manual determination of spectral signatures and negative samples should be validated in the second round detection. Here, after examining 406 commercial e-liquids, we refined this approach by developing artificial intelligence (AI)-assisted spectrum interpretations. We also found that nicotine and benzoic acid can be simultaneously detected in our platform. This increased test sensitivity because benzoic acid is usually used in nicotine salts. Around 64% of nicotine-positive samples in this study showed both signatures. Using either cutoffs of nicotine and benzoic acid peak intensities or a machine learning model based on the CatBoost algorithm, over 90% of tested samples can be correctly discriminated with only one round of SERS measurement. False negative and false positive rates were 2.5-4.4% and 4.4-8.9%, respectively, depending on the interpretation method and thresholds applied. The new approach takes only 1 microliter of sample and can be performed in 1-2 min, suitable for on-site inspection with portable Raman detectors. It could also be a complementary platform to reduce samples that need to be analyzed in the central labs and has the potential to identify other prohibited additives.

Surrogate and modified endpoints for immunotherapy in advanced hepatocellular carcinoma.

BACKGROUND AND AIMS: Immunotherapies have altered the treatment paradigm in HCC. Surrogate and modified endpoints are used to assess early success in clinical studies and guide clinical practice. We sought to determine whether surrogate endpoints and modifications to the conventional criteria for tumor response (RECIST), including modified RECIST (mRECIST) and immune-modified RECIST (imRECIST), are valid measures to predict overall survival (OS) in HCC treated with immunotherapies. APPROACH AND RESULTS: We performed an individual-level post hoc analysis of patients treated with atezolizumab and bevacizumab in the IMbrave150 trial (N = 279) and a cross-sectional analysis of a multicenter real-world patient cohort treated with immunotherapy (N = 328). Landmark analyses showed that objective response rates by RECIST were associated with greater OS including among Child-Pugh A and B patients and among patients treated with immunotherapies in the first- or second-line setting (IMbrave150: HR 0.24, 95% CI, 0.17-0.33; RW: HR 0.25, 95% CI, 0.15-0.43). Objective response rates by mRECIST or imRECIST were not associated with the greater predictive power of OS benefit (mRECIST: HR 0.30, 95% CI, 0.22-0.42; imRECIST: HR 0.36, 95% CI, 0.30-0.51). Progression-free survival determined by RECIST was only moderately correlated with OS, and this association was not improved using mRECIST or imRECIST. CONCLUSIONS: Our results clarify the utility of surrogate and modified endpoints in HCC treated with immunotherapies and support the use of RECIST objective response rates as an appropriate signal-finding measure for the evaluation of emerging treatments. Contrary to their intended purpose, mRECIST and imRECIST did not provide meaningful improvements in predicting OS benefits.

TLN1 contains a cancer-associated cassette exon that alters talin-1 mechanosensitivity.

Talin-1 is the core mechanosensitive adapter protein linking integrins to the cytoskeleton. The TLN1 gene is comprised of 57 exons that encode the 2,541 amino acid TLN1 protein. TLN1 was previously considered to be expressed as a single isoform. However, through differential pre-mRNA splicing analysis, we discovered a cancer-enriched, non-annotated 51-nucleotide exon in TLN1 between exons 17 and 18, which we refer to as exon 17b. TLN1 is comprised of an N-terminal FERM domain, linked to 13 force-dependent switch domains, R1-R13. Inclusion of exon 17b introduces an in-frame insertion of 17 amino acids immediately after Gln665 in the region between R1 and R2 which lowers the force required to open the R1-R2 switches potentially altering downstream mechanotransduction. Biochemical analysis of this isoform revealed enhanced vinculin binding, and cells expressing this variant show altered adhesion dynamics and motility. Finally, we showed that the TGF-ß/SMAD3 signaling pathway regulates this isoform switch. Future studies will need to consider the balance of these two TLN1 isoforms.

Anti-IL17A Halts the Onset of Diabetic Retinopathy in Type I and II Diabetic Mice.

There are ~463 million diabetics worldwide, and more than half have diabetic retinopathy. Yet, treatments are still lacking for non-proliferative diabetic retinopathy. We and others previously provided evidence that Interleukin-17A (IL-17A) plays a pivotal role in non-proliferative diabetic retinopathy. However, all murine studies used Type I diabetes models. Hence, it was the aim of this study to determine if IL-17A induces non-proliferative diabetic retinopathy in Type II diabetic mice, as identified for Type I diabetes. While examining the efficacy of anti-IL-17A as a potential therapeutic in a short-term Type I and a long-term Type II diabetes model; using different routes of administration of anti-IL-17A treatments. Retinal inflammation was significantly decreased (p < 0.05) after Type I-diabetic mice received 1 intravitreal injection, and Type II-diabetic mice received seven intraperitoneal injections of anti-IL-17A. Further, vascular tight junction protein Zonula Occludens-1 (ZO-1) was significantly decreased in both Type I and II diabetic mice, which was significantly increased when mice received anti-IL-17A injections (p < 0.05). Similarly, tight junction protein Occludin degradation was halted in Type II diabetic mice that received anti-IL-17A treatments. Finally, retinal capillary degeneration was halted 6 months after diabetes was confirmed in Type II-diabetic mice that received weekly intraperitoneal injections of anti-IL-17A. These findings provide evidence that IL-17A plays a pivotal role in non-proliferative diabetic retinopathy in Type II diabetic mice, and suggests that anti-IL-17A could be a good therapeutic candidate for non-proliferative diabetic retinopathy.

IL-17A Enhances Retinal Neovascularization.

Retinal neovascularization occurs in proliferative diabetic retinopathy, neovascular glaucoma, and age-related macular degeneration. This type of retinal pathology normally occurs in the later stages of these ocular diseases and is a prevalent cause of vision loss. Previously, we determined that Interleukin (IL)-17A plays a pivotal role in the onset and progression of non-proliferative diabetic retinopathy in diabetic mice. Unfortunately, none of our diabetic murine models progress to proliferative diabetic retinopathy. Hence, the role of IL-17A in vascular angiogenesis, neovascularization, and the onset of proliferative diabetic retinopathy was unclear. In the current study, we determined that diabetes-mediated IL-17A enhances vascular endothelial growth factor (VEGF) production in the retina, Muller glia, and retinal endothelial cells. Further, we determined that IL-17A can initiate retinal endothelial cell proliferation and can enhance VEGF-dependent vascular angiogenesis. Finally, by utilizing the oxygen induced retinopathy model, we determined that IL-17A enhances retinal neovascularization. Collectively, the results of this study provide evidence that IL-17A plays a pivotal role in vascular proliferation in the retina. Hence, IL-17A could be a potentially novel therapeutic target for retinal neovascularization, which can cause blindness in multiple ocular diseases.

Comparison of the effects of acupotomy and acupuncture on knee osteoarthritis: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Acupotomy and acupuncture are both treatments for knee osteoarthritis symptoms. However, acupotomy also has the additional anatomical effect of dissecting inflamed tissue. The problem this study aims to address is whether acupotomy is a better treatment than acupuncture in treating knee osteoarthritis. METHODS: We searched the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Airiti Library, and Wanfang Data databases from inception to March 2022 for randomized controlled clinical trials (RCTs) comparing the effects of acupotomy and acupuncture in patients with knee osteoarthritis. RESULTS: In total, we identified 43 RCTs in this meta-analysis. Compared to the acupuncture group, acupotomy had a higher cure rate (odds ratio (OR) 2.94, 95% confidence interval (CI) 2.36 to 3.65), indicating a better improvement in daily activity function. Acupotomy was also more effective in pain relief and knee score improvement. However, some RCTs indicated that adverse events in the acupotomy group were greater than in the acupuncture group (OR 1.23, 95% CI 0.42 to 3.60). CONCLUSION: Our findings indicated that acupotomy was a more effective treatment for knee osteoarthritis than acupuncture. However, most of the included RCTs had moderate risk of bias, meaning that more high-quality RCTs were needed.

Differential Surface Engineering Generates Core-Shell Porous Silicon Nanoparticles for Controlled and Targeted Delivery of an Anticancer Drug.

An approach to differentially modify the internal surface of porous silicon nanoparticles (pSiNPs) with hydrophobic dodecene and the external surface with antifouling poly-N-(2-hydroxypropyl) acrylamide (polyHPAm) as well as a cell-targeting peptide was developed. Specifically, to generate these core-shell pSiNPs, the interior surface of a porous silicon (pSi) film was hydrosilylated with 1-dodecene, followed by ultrasonication to create pSiNPs. The new external surfaces were modified by silanization with a polymerization initiator, and surface-initiated atom transfer radical polymerization was performed to introduce polyHPAm brushes. Afterward, a fraction of the polymer side chain hydroxyl groups was activated to conjugate cRGDfK─a peptide with a high affinity and selectivity for the ανß3 integrin receptor that is overexpressed in prostate and melanoma cancers. Finally, camptothecin, a hydrophobic anti-cancer drug, was successfully loaded into the pores. This drug delivery system showed excellent colloidal stability in a cell culture medium, and the in vitro drug release kinetics could be fine-tuned by the combination of internal and external surface modifications. In vitro studies by confocal microscopy and flow cytometry revealed improved cellular association attributed to cRGDfK. Furthermore, the cell viability results showed that the drug-loaded and peptide-functionalized nanoparticles had enhanced cytotoxicity toward a C4-2B prostate carcinoma cell line in both 2D cell culture and a 3D spheroid model.

Inhibition of CD40-TRAF6-dependent inflammatory activity halts the onset of diabetic retinopathy in streptozotocin-diabetic mice.

Diabetes initiates inflammation that can impair the retinal vasculature, and lead to diabetic retinopathy; one of the leading causes of blindness. Inflammatory pathways have been examined as potential therapeutic targets for diabetic retinopathy, but there is still a need for early-stage treatments. We hypothesized that the CD40-TNF Receptor Associated Factor 6 (TRAF6) axis plays a pivotal role in the onset of diabetic retinopathy, and that the CD40-TRAF6 axis would be a prime therapeutic target for early-stage non-proliferative diabetic retinopathy. The CD40-TRAF6 complex can initiate NFκB activation, inflammation, and tissue damage. Further, CD40 and TRAF6 are constitutively expressed on Muller glia, and upregulated in the diabetic retina. Yet the role of the CD40-TRAF6 complex in the onset of diabetic retinopathy is still unclear. In the current study, we examined the CD40-TRAF6 axis in diabetic retinopathy using a small molecule inhibitor (SMI-6877002) on streptozotocin-induced diabetic mice. When CD40-TRAF6-dependent inflammation was inhibited, retinal vascular leakage and capillary degeneration was ameliorated in diabetic mice. Collectively, these data suggest that the CD40-TRAF6 axis plays a pivotal role in the onset of diabetic retinopathy, and could be a novel therapeutic target for early diabetic retinopathy.

Levosimendan Administration May Provide More Benefit for Survival in Patients with Non-Ischemic Cardiomyopathy Experiencing Acute Decompensated Heart Failure.

BACKGROUND: Acute decompensated heart failure (ADHF) is a life-threatening condition with a high mortality rate. Levosimendan is an effective inotropic agent used to maintain cardiac output and a long-lasting effect. However, only few studies have compared the clinical outcomes, after levosimendan therapy, among etiologies of ADHF. METHODS: Between July 2014 and December 2019, 184 patients received levosimendan therapy for ADHF at our hospital. A total of 143 patients had ischemic cardiomyopathy (ICM), and 41 patients had non-ICM (NICM). Data on comorbidities, echocardiographic findings, laboratory findings, use of mechanical devices, consumption of other inotropic or vasopressor agents, frequency of HF hospitalization, cardiovascular (CV) mortality, and all-cause mortality were compared between the ICM and NICM groups. RESULTS: Patients with ICM were older with higher prevalence of diabetes mellitus when compared to patients with NICM. Patients with NICM had a poorer left ventricular ejection fraction (LVEF) and higher left ventricular end-systolic volume when compared to patients with ICM. At the 30 day follow-up period, a lower CV mortality (ICM vs. NICM: 20.9% vs. 5.1%; log-rank p = 0.033) and lower all-cause mortality (ICM vs. NICM: 28.7% vs. 9.8%; log-rank p = 0.018) was observed in the NICM patients. A significantly lower all-cause mortality was noted at 180 day (ICM vs. NICM: 39.2% vs. 22.0%; log-rank p = 0.043) and 1 year (ICM vs. NICM: 41.3% vs. 24.4%; log-rank p = 0.046) follow up in the NICM subgroup. NICM (hazard ratio (HR): 0.303, 95% confidence interval (CI): 0.108-0.845; p = 0.023) and ECMO use (HR: 2.550, 95% CI: 1.385-4.693; p = 0.003) were significant predictors of 30 day all-cause mortality. CONCLUSIONS: In our study on levosimendan use for ADHF patients, better clinical outcomes were noted in the NICM population when compared to the ICM population. In the patients with cardiogenic shock or ventilator use, significantly lower incidence of 30 day mortality presented in the NICM population when compared with the ICM population.

Early Levosimendan Administration Improved Weaning Success Rate in Extracorporeal Membrane Oxygenation in Patients With Cardiogenic Shock.

Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been increasingly used in patients with refractory cardiogenic shock (CS) or out-of-hospital cardiac arrest. It is difficult to perform VA-ECMO weaning, which may cause circulatory failure and death. Levosimendan is an effective inotropic agent used to maintain cardiac output, has a long-lasting effect, and may have the potential benefit for VA-ECMO weaning. The study aimed to explore the relationship between the early use of levosimendan and the rate of VA-ECMO weaning failure in patients on VA-ECMO support for circulatory failure. Methods: All patients who underwent VA-ECMO in our hospital for CS between January 2017 and December 2020 were recruited in this cohort study and divided into two groups: without and with levosimendan use. Levosimendan was used as an add-on to other inotropic agents as early as possible after VA-ECMO setting. The primary endpoint was VA-ECMO weaning success, which was defined as survival without events for 24 h after VA-ECMO withdrawl. The secondary outcomes were cardiovascular and all-cause mortality at the 30-day and 180-day follow-up periods post-VA-ECMO initialization. Results: A total of 159 patients were recruited for our study; 113 patients were enrolled in the without levosimendan-use group and 46 patients were enrolled in the levosimendan-use group. In levosimendan-use group, the patients received levosimendan infusion within 24 h after VA-ECMO initialization. Similar hemodynamic parameters were noted between the two groups. Poorer left ventricular ejection fraction and a higher prevalence of intra-aortic balloon pumping were observed in the levosimendan group. An improved weaning rate (without vs. with: 48.7 vs. 82.6%; p < 0.001), lower in-hospital mortality rate (without vs. with: 68.1 vs. 43.5%; p = 0.007), and 180-day cardiovascular mortality (without vs. with: 75.3 vs. 43.2%; p < 0.001) were also noted. Patients administered with levosimendan also presented a lower rate of 30-day (without vs. with: 75.3 vs. 41.3%; p = 0.034) and 180-day (without vs. with: 77.0 vs. 43.2%; p < 0.001) all-cause mortality. Conclusion: Early levosimendan administration may contribute to increasing the success rate of VA-ECMO weaning and may help to decrease CV and all-cause mortality.

Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are promising agents for unresectable hepatocellular carcinoma (uHCC), but lack effective biomarker to predict outcomes. The gut microbiome can modulate tumor response to immunotherapy, but its effect on HCC remains unclear. METHODS: From May 2018 to February 2020, patients receiving ICI treatment for uHCC were prospectively enrolled; their fecal samples were collected before treatment. The fecal microbiota and metabolites were analyzed from 20 patients with radiology-proven objective responses (OR) and 21 randomly selected patients with progressive disease (PD). After March 2020, 33 consecutive Child-Pugh-A patients were recruited as a validation cohort. Additionally, feces from 17 healthy volunteers were collected for comparison of background microbes. RESULTS: A significant dissimilarity was observed in fecal bacteria between patients with OR and patients with PD before immunotherapy. Prevotella 9 was enriched in patients with PD, whereas Lachnoclostridium, Lachnospiraceae, and Veillonella were predominant in patients with OR. Ursodeoxycholic acid and ursocholic acid were significantly enriched in the feces of patients with OR and strongly correlated with the abundance of Lachnoclostridium. The coexistence of Lachnoclostridium enrichment and Prevotella 9 depletion significantly predicted better overall survival (OS). In the validation cohort, better progression-free survival (PFS) and OS were noted in patients who had a preferable microbial signature in comparison with counter-group (PFS: 8.8 months vs 1.8 months; OS: not reached vs 6.5 months, both p<0.001). CONCLUSIONS: Fecal microbiota and bile acids were associated with outcomes of immunotherapy for uHCC. These findings highlight the potential role of gut microbiota and metabolites as biomarkers to predict outcomes of ICI-treated HCC.

Diabetes Aggravates Photoreceptor Pathologies in a Mouse Model for Ocular Vitamin A Deficiency.

Emerging evidence indicates that diabetes disturbs photoreceptor function and vitamin A homeostasis. However, the biochemical basis of this phenotype is not well established. Here, we compared the effects of streptozotocin-induced diabetes in wild-type (WT) mice and Stra6-/- mice, a mouse model for ocular vitamin A deficiency. After 8 weeks, diabetes increased serum retinyl esters in mice of both genotypes. The eyes of diabetic WT mice displayed increased superoxide levels but no changes in retinoid concentrations. Diabetic Stra6-/- mice showed increased ocular retinoid concentrations, but superoxide levels remained unchanged. After 30 weeks, significant alterations in liver and fat retinoid concentrations were observed in diabetic mice. Diabetic WT mice exhibited a decreased expression of visual cycle proteins and a thinning of the photoreceptor layer. Stra6-/- mice displayed significantly lower ocular retinoid concentration than WT mice. An altered retinal morphology and a reduced expression of photoreceptor marker genes paralleled these biochemical changes and were more pronounced in the diabetic animals. Taken together, we observed that diabetes altered vitamin A homeostasis in several organ systems and aggravated photoreceptor pathologies in the vitamin-deficient mouse eyes.

Patterns and outcomes of subsequent therapy after immune checkpoint inhibitor discontinuation in HCC.

The availability of immune checkpoint inhibitors (ICIs) for the management of advanced hepatocellular cancer (HCC) has changed the treatment paradigm. There are emerging questions regarding the efficacy of subsequent anticancer therapies. The primary aim of this retrospective, multicenter study was to examine the types of anticancer treatment received after ICIs and to assess the impact on post-ICI survival. We established an international consortium of 11 tertiary-care referral centers located in the USA (n = 249), Europe (n = 74), and Asia (n = 97), and described patterns of care following ICI therapy. The impact of subsequent therapy on overall survival (OS) was estimated using the Kaplan-Meier method and presented with a 95% confidence interval (CI). A total of 420 patients were treated with ICIs for advanced HCC after one line of systemic therapy (n = 371, 88.8%): 31 (8.8%) had died, 152 (36.2%) received best supportive care (BSC) following ICIs, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKIs, n = 132, 80.9%), in particular sorafenib (n = 49, 30.0%), were the most common post-ICI therapy followed by external beam radiotherapy (n = 28, 17.2%), further immunotherapy (n = 21, 12.9%), locoregional therapy (n = 23, 14.1%), chemotherapy (n = 9, 5.5%), and surgery (n = 6, 3.6%). Receipt of post-ICI therapy was associated with longer median OS compared with those who had received BSC (12.1 vs. 3.3 months; hazard ratio [HR]: 0.4 (95% CI: 2.7-5.0). No difference in OS was noted in those patients who received TKI before ICIs compared with those who received ICIs followed by TKI. Conclusion: Post-ICI therapy is associated with OS in excess of 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICIs.

Lenvatinib plus pembrolizumab for systemic therapy-naïve and -experienced unresectable hepatocellular carcinoma.

BACKGROUND: Lenvatinib combined with pembrolizumab showed a promising result in an early phase study for hepatocellular carcinoma (HCC). The efficacy and safety of lenvatinib plus pembrolizumab for patients with unresectable HCC (uHCC) beyond the first-line setting were unclear. METHODS: Seventy-one consecutive patients who received lenvatinib plus pembrolizumab for uHCC were prospectively enrolled. Effect of lenvatinib combinations on Albumin-Bilirubin (ALBI) score and factors associated with progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: Of the 71 cases, 58 (81.7%) were in BCLC C. There were 44 (62%) for the first-line systemic treatment, and 27 (38%) had experienced targeted therapy or nivolumab treatment. The objective response rate and disease control rate (DCR) were 34.1% and 84.1% for the first-line setting, and 18.5% and 70.4% for systemic therapy-experienced cases (Response Evaluation Criteria in Solid Tumors version 1.1, RECIST v1.1), respectively. The mean ALBI score was stable during the treatment course. After a median of 9.3 months of follow-up, the median PFS was 9.3 months versus 4.4 months, and the median OS was not estimable yet versus 12 months for Child-Pugh A versus B patients, respectively. Prior nivolumab failure was the only significant factor associated with poorer PFS (HR = 3.253, p = 0.004). Child-Pugh class B (HR = 2.646, p = 0.039) and prior nivolumab failure (HR = 3.340, p = 0.014) were independent factors for poorer OS in multivariate analysis. CONCLUSIONS: A high DCR was observed by lenvatinib/pembrolizumab combination without adverse effect on ALBI score for systemic therapy-naïve and -experienced uHCC. Suboptimal response to prior nivolumab-failed patients requires further exploration.