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Simple Summary: Systemic chemotherapies have revolutionized therapeutic paradigms for hepatocellular carcinoma (HCC) over the past decade. Various regimens have progressively become standard-of-care in clinical practice. However, there are no reports regarding the impact of multiple sequential therapies including immune-oncologic agents on their outcomes. This study investigated the change, over three time periods, in survival for patients with unresectable HCC, and the effects of sequential treatments on their outcomes. The results showed that the number of patients who received more than two lines steadily increased, and the overall survival significantly improved over time. Surprisingly, the 3-year survival rate increased from 12.1% in the early period to 44.4% for the most recent period. Using less than three lines, the non-objective response of the first line and extrahepatic metastasis were identified as the strongest drivers of a worse prognosis. Sequential treatment post-progression is valuable for prolonging survival. Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009–2013, n = 86; period 2: 2014–2018, n = 132; period 3: 2019–2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1–3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin–bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Therapeutic options for GEP-NETs are very limited, and at the same time, the incidence of these cancers is increasing. The evidence has shown that multiple neoplasms can be successfully treated with immune checkpoint inhibitors such as PD-1/PD-L1 inhibitors. Crucial to determining a patient's response to immunotherapy is access to the tumor microenvironment. Currently, there is no consistency regarding the future role of TME and immunotherapy in GEP-NETs. Thus, this review points to the solution in selecting a concrete patient group that, based on tumor features can benefit from immunotherapy. Neuroendocrine neoplasms (NENs) are a heterogenous and recurrent group of malignancies originating from neuroendocrine secretory cells diffused on all parts of the human body. Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) account for most NENs. Considering the abundance of possible origins, locations, and tumor specifications, there is still no consensus about optimal treatment options for these neoplasms. In light of the escalating immunotherapeutic approaches, it is crucial to define indications for such therapy in GEP-NETs. Bearing in mind the significance of pathophysiological mechanisms and tumor microenvironment (TME) impact on carcinogenesis, defining TME structure and correlation with the immune system in GEP-NETs appears essential. This paper aimed to assess the characterization of the tumor immune microenvironment for a better understanding of the possible therapeutic options in GEP-NETS. The authors performed a systematic review, extracting papers from the PubMed, Web of Science, and Scopus databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Among 3800 articles identified through database searching, 292 were assessed for eligibility. Ultimately, 28 articles were included in the qualitative synthesis. This paper sums up the research on the immune cell infiltrates, immune checkpoint expression, cytokine profile, neoangiogenesis, and microbiome in the TME of GEP-NETs. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide. During the early stages of the disease, HCC can be treated with surgery or radiofrequency procedures. Most HCC cases are discovered at later stages when these therapies cannot be used, and a treatment such as a liver transplant is needed. Recently, new options for the treatment of advanced HCC are available, called immune checkpoint inhibitors (ICIs). ICIs have been found to be safe and effective. However, there is concern that liver transplant patients may face graft rejection in both the pre- and post-transplant settings. Our review found that ICIs may be useful, especially in the pretransplantation setting. More data are needed to carefully select patients who will benefit from ICI treatment in both settings so that they can benefit from it while reducing harm. Hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths worldwide. As most patients present with advanced disease, curative therapy such as surgical resection and radiofrequency ablation are rarely utilized. With the advent of immunotherapy, historical treatment approaches such as liver transplantation are being challenged. In particular, the use of immune checkpoint inhibitors (ICIs) has emerged as a safe and useful option in the treatment of HCC. However, there is concern over adverse effects, such as graft rejection and graft loss. This updated review discusses the role of immunotherapy in the pre- and post-transplantation setting and provides insights into the potential of immunotherapy as an adjunct to liver transplantation. We deliberate on the use of ICI in the setting of the Milan criteria as well as the University of California San Francisco's expanded criteria for liver transplantation. Current data suggest that ICI has utility, especially in the pretransplantation setting. Nevertheless, larger, purposefully designed clinical trials are needed to clearly identify patients who will benefit most from ICI treatment in the transplant setting and determine parameters that will minimize the risk of graft rejection and maximize the benefits of this adjunct treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. High-risk patients should undergo semi-annual surveillance. Management of HCC is complex and requires multidisciplinary team evaluation and the consideration of patient's goals of care. Early HCC is best managed by curative-intent treatment with liver resection, transplantation, or ablation. Intermediate-stage disease may be treated with transarterial therapies. Advanced-stage disease should be treated with systemic therapy. There are many therapies and therapy combinations currently under investigation. Hepatocellular carcinoma (HCC) ranks fourth in cancer-related deaths worldwide. Semiannual surveillance of the disease for patients with cirrhosis or hepatitis B virus allows for early detection with more favorable outcomes. The current underuse of surveillance programs demonstrates the need for intervention at both the patient and provider level. Mail outreach along with navigation provision has proven to increase surveillance follow-up in patients, while provider-targeted electronic medical record reminders and compliance reports have increased provider awareness of HCC surveillance. Imaging is the primary mode of diagnosis in HCC with The Liver Imaging Reporting and Data System (LI-RADS) being a widely accepted comprehensive system that standardizes the reporting and data collection for HCC. The management of HCC is complex and requires multidisciplinary team evaluation of each patient based on their preference, the state of the disease, and the available medical and surgical interventions. Staging systems are useful in determining the appropriate intervention for HCC. Early-stage HCC is best managed by curative treatment modalities, such as liver resection, transplant, or ablation. For intermediate stages of the disease, transarterial local regional therapies can be applied. Advanced stages of the disease are treated with systemic therapies, for which there have been recent advances with new drug combinations. Previously sorafenib was the mainstay systemic treatment, but the recent introduction of atezolizumab plus bevacizumab proves to have a greater impact on overall survival. Although there is a current lack of improved outcomes in Phase III trials, neoadjuvant therapies are a potential avenue for HCC management in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is a highly lethal disease with an increasing incidence. Despite the advancements in diagnosis and recent therapeutic options, improving the prognosis of HCC patients remains challenging. One of the reasons of the unsatisfactory outcome of patients with HCC is the complex tumour microenvironment (TME), which is composed of immune and stromal cells, limiting effective treatments. Recent research has highlighted the importance of macrophages in the development and progression of HCC, opening new possibilities for therapy. This review focuses on the heterogeneity of tumour-associated macrophages (TAMs) in HCC, the mechanisms through which HCC tumour cells polarize macrophages, and the therapeutic targets that are currently being tested to explore novel therapies that can improve the prognosis and quality of life of HCC patients. Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer that comprises a complex tumour microenvironment (TME). Tumour-associated macrophages (TAMs) are one of the most abundant immune cells present in the TME, and play a key role both in the development and in the progression of HCC. Thus, TAM-based immunotherapy has been presented as a promising strategy to complement the currently available therapies for HCC treatment. Among the novel approaches focusing on TAMs, reprogramming their functional state has emerged as a promising option for targeting TAMs as an immunotherapy in combination with the currently available treatment options. Nevertheless, a further understanding of the immunobiology of TAMs is still required. This review synthesizes current insights into the heterogeneous nature of TAMs in HCC and describes the mechanisms behind their pro-tumoural polarization focusing the attention on their interaction with HCC cells. Furthermore, this review underscores the potential involvement of TAMs' reprogramming in HCC therapy and highlights the urgency of advancing our understanding of these cells within the dynamic landscape of HCC. [ABSTRACT FROM AUTHOR]

Hepatic sinusoidal obstruction syndrome (SOS) is a severe and life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a multi-center retrospective study to evaluate the utility of our ultrasonographic scoring system for the diagnosis of SOS (HokUS-10) in predicting SOS-related mortality (SOS-RM). We analyzed a total of 42 patients who developed SOS after HSCT. The cumulative incidences of SOS-RM, non-relapse mortality (NRM), and overall survival at day 180 after the diagnosis of SOS were 26.4%, 28.8% and 54.5%, respectively. The area under the receiver operating characteristic curve analysis showed that the optimal cut-off value of HokUS-10 total score to predict SOS-RM was 8 points after the treatment of SOS. In the individual HokUS-10 score, ascites and portal vein flow-related scores (PV mean velocity and PV flow direction) after the treatment of SOS were shown as significant risk factors for SOS-RM. Our study suggested that US findings after the treatment can predict the treatment outcomes for SOS. [ABSTRACT FROM AUTHOR]

Background: Analyses of tooth families and tooth-forming units in medaka with regard to tooth replacement cycles and the localization of odontogenic stem cell niches in the pharyngeal dentition clearly indicate that continuous tooth replacement is maintained. The secretory calcium-binding phosphoprotein (scpp) gene cluster is involved in the formation of mineralized tissues, such as dental and bone tissues, and the genes encoding multiple SCPPs are conserved in fish, amphibians, reptiles, and mammals. In the present study, we examined the expression patterns of several scpp genes in the pharyngeal teeth of medaka to elucidate their roles during tooth formation and replacement. Methods: Himedaka (Japanese medaka, Oryzias latipes) of both sexes (body length: 28 to 33 mm) were used in this study. Real-time quantitative reverse transcription-polymerase chain reaction (PCR) (qPCR) data were evaluated using one-way analysis of variance for multi-group comparisons, and the significance of differences was determined by Tukey's comparison test. The expression of scpp genes was examined using in situ hybridization (ISH) with a digoxigenin-labeled, single-stranded antisense probe. Results: qPCR results showed that several scpp genes were strongly expressed in pharyngeal tissues. ISH analysis revealed specific expression of scpp1, scpp5, and sparc in tooth germ, and scpp5 was continually expressed in the odontoblasts of teeth attached to pedicles, but not in the osteoblasts of pedicles. In addition, many scpp genes were expressed in inner dental epithelium (ide), but not in odontoblasts, and scpp2 consistently showed epithelial-specific expression in the functional teeth. Taken together, these data indicate that specific expression of scpp2 and scpp5 may play a critical role in pharyngeal tooth formation in medaka. Conclusion: We characterized changes in the expression patterns of scpp genes in medaka during the formation and replacement of pharyngeal teeth. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has gained attention in the last few years due to its increasing prevalence worldwide becoming a global epidemic. The increasing incidence of NAFLD and the concurrent increase in the number of hepatocellular carcinoma (HCC) cases at a global level is a matter of concern. HCC has several risk factors, of which NAFLD and its associated metabolic disturbances—type 2 diabetes mellitus, obesity, and dyslipidemia—are of great interest due to their accelerating rise in incidence worldwide. There is a high amount of data derived from basic and clinical studies that reveal the molecular pathways that drive NAFLD-associated HCC. Based on these findings, new prevention, surveillance, and treatment strategies are emerging. However, current data on treatment modalities in NAFLD-associated HCC are still scarce, though the results from non-NAFLD HCC studies are promising and could provide a basis for a future research agenda to address NAFLD/NASH patients. Clinicians should carefully assess all the clinical and radiological parameters and establish a prognosis based on the Barcelona Clinic Liver Cancer classification and discuss in a multidisciplinary team the treatment strategy. The specific factors associated with NAFLD-associated HCC which can have a negative impact on survival even in patients with early HCC, such as cardiovascular disease, type 2 diabetes, and obesity, should be taken into consideration. This review aims to discuss the latest recommendations regarding the diagnosis and treatment of NAFLD-associated HCC and the remaining challenges. [ABSTRACT FROM AUTHOR]

Background and aim: Baveno VII workshop recommends management of acute variceal bleeding (AVB) in cirrhotic patients with nonmalignant portal vein thrombosis (PVT) should be performed according to the guidelines for patients without PVT. Nevertheless, whether PVT affects the outcome of patients with cirrhosis and AVB remains unclear. The aim of this study was to assess the clinical impact of PVT on the outcomes in the pre-emptive TIPSS eligible patients with cirrhosis and AVB. Methods: From December 2010 to June 2016, 1219 consecutive cirrhotic patients admitted due to AVB with (n = 151; 12.4%) or without PVT (n = 1068; 87.6%), who received drug plus endoscopic treatment (a combination of vasoactive drugs, antibiotics, and endoscopic ligation for AVB, followed by beta-blockers plus variceal ligation for prevention of rebleeding) were retrospectively included. Fine and Gray competing risk regression models were taken to evaluate the impact of PVT on clinical outcomes after adjusting for potential confounders. Results: During follow-up, 211 patients (17.3%) died, 490 (40.2%) experienced further bleeding, and 78 (6.4%) experienced new or worsening ascites within 1 year. Compared with those without PVT, patients with PVT had a similar risk of mortality (PVT vs no-PVT: 19.9% vs 16.7% at 1 year; adjusted HR 0.88, 95%CI 0.51–1.52, p = 0.653), further bleeding (47.0% vs 39.2% at 1 year, adjusted HR 1.19, 95% CI 0.92–1.53, p = 183), and new or worsening ascites (7.9% vs 9.6%, adjusted HR 0.70, 95% CI 0.39–1.28, p = 0.253) after adjusting for confounders in multivariable models. These findings were consistent across different relevant subgroups and confirmed by propensity score matching analysis. Conclusions: Our study showed no evidence that the PVT was associated with an improved or worsened outcome among cirrhotic patients with AVB who received standard treatment. [ABSTRACT FROM AUTHOR]

Contrast-enhanced ultrasonography (CEUS) is a noninvasive imaging modality used to diagnose hepatocellular carcinoma (HCC) based on specific imaging features, without the need for pathologic confirmation. Two types of ultrasound contrast agents are commercially available: pure intravascular agents (such as SonoVue) and Kupffer agents (such as Sonazoid). Major guidelines recognize CEUS as a reliable imaging method for HCC diagnosis, although they differ depending on the contrast agents used. The Korean Liver Cancer Association--National Cancer Center guideline includes CEUS with either SonoVue or Sonazoid as a second-line diagnostic technique. However, Sonazoid-enhanced ultrasound is associated with several unresolved issues. This review provides a comparative overview of these contrast agents regarding pharmacokinetic features, examination protocols, diagnostic criteria for HCC, and potential applications in the HCC diagnostic algorithm. [ABSTRACT FROM AUTHOR]

Background and Aim: Progression of liver disease in cirrhosis is associated with an increased incidence of portal vein thrombosis (PVT) in cirrhosis. However, evidence suggests that spontaneous recanalization of PVT may occur even without anti‐thrombotic therapy. Thus, the present meta‐analysis was conducted to study the natural history of PVT in cirrhosis, facilitating decisions regarding anticoagulation. Methods: Three electronic databases were searched from 2000 to August 2022 for studies reporting the outcome of PVT in cirrhotics without anticoagulation. The pooled proportions with their 95% confidence intervals (CIs) were calculated using a random‐effect model. Results: A total of 26 studies (n = 1441) were included in the final analysis. Progression of PVT on follow‐up was seen in 22.2% (95% CI 16.1–28.4), while 77.7% (95% CI 71.6–83.9) remained non‐progressive (improved or stable). The most common outcome was a stable PVT with a pooled event rate of 44.6% (95% CI 34.4–54.7). The pooled rates of regression and complete recanalization of PVT in cirrhotics were 29.3% (95% CI 20.9–37.7) and 10.4% (95% CI 5.0–15.8), respectively. On follow‐up after improvement, pooled recurrence rate of PVT was 24.0% (95% CI 14.7–33.4). MELD score, and presence of ascites had a negative association, while a longer follow‐up duration had positive association with PVT regression. Conclusion: Approximately 25% of the cases of PVT in cirrhosis are progressive, 30% cases improve, and 45% remain stable. Future studies are needed to analyze the predictors of spontaneous regression. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies. [ABSTRACT FROM AUTHOR]

Purpose: To prospectively evaluate the potential of four-dimensional (4D) flow magnetic resonance imaging (MRI) in predicting treatment responses after transcatheter arterial chemoembolization (TACE) in cirrhotic patients with hepatocellular carcinoma (HCC). Methods: A total of 195 patients were classified into four groups (A–D): A, cirrhotic patients without HCC (n = 30); B, cirrhotic patients with HCC before TACE (n = 75); C, cirrhotic patients with HCC showing an incomplete response following TACE (n = 56); and D, cirrhotic patients with HCC achieving a complete response (CR) following TACE (n = 34). The patients were subjected to routine laboratory tests and 4D flow MRI using a 3-T MRI system to measure the quantitative parameters of blood flow in the portal vein (PV), splenic vein (SV), and superior mesenteric vein. The data collected by 4D flow MRI were compared among the groups using one-way analysis of variance. A multivariate analysis was performed to verify the association of clinical characteristics and 4D flow parameters with CR after TACE treatment. Results: The average through-plane velocity, peak velocity magnitude, average net flow, peak flow, and net forward volume in the PV and SV were significantly lower in groups B and C (P < 0.05) compared to those in group A. Moreover, average through-plane velocity and peak velocity magnitude in the PV in groups B and C were significantly lower than those in group D (P < 0.05). The multivariate analysis demonstrated that the average through-plane velocity and peak velocity magnitude in the PV were independently associated with CR in HCC patients after TACE (P < 0.05). Conclusion: The quantitative flow data obtained by 4D flow MRI may be useful for predicting CR after TACE in cirrhotic patients with HCC. [ABSTRACT FROM AUTHOR]

Background: Oxaliplatin-induced peripheral neurotoxicity (OIPN) limits the dose of chemotherapy and seriously affects the quality of life. Huangqi Guizhi Wuwu Decoction (HGWD) is a classical Traditional Chinese Medicine (TCM) formula for the prevention of OIPN. However, its specific pharmacological mechanism of action remains unknown. Our study found that HGWD can effectively alleviate chronic OIPN and regulate intestinal flora. Therefore, we explored the mechanism of action of HGWD in alleviating chronic OIPN from the perspective of intestinal flora. Methods: In this study, we established an OIPN model in C57BL/6 mice treated with different concentrations of HGWD. Mechanical pain and cold pain were assessed at certain time points, and samples of mice colon, dorsal root ganglion (DRG), serum, and feces were collected. Associated inflammation levels in the colon and DRG were detected using immunohistochemical techniques; the serum lipopolysaccharide (LPS) levels and associated inflammation were assessed using the appropriate kits; and 16S rRNA sequencing was used to examine the dynamic changes in gut microorganisms. Finally, established fecal microbiota transplantation (FMT) and antibiotic (ABX) pretreatment models were used to validate flora's role in HGWD for chronic OIPN by pain scoring and related pathological analysis. Results: HGWD treatment significantly alleviated pain sensitivity in chronic OIPN mice. Pathological results showed that HGWD treatment improved intestinal ZO-1 expression and reduced serum LPS levels and associated inflammatory factors in the colon, serum, and DRG. The 16S rRNA results showed that HGWD restored the composition of the intestinal flora in a time-dependent manner to alleviate OIPN. FMT and ABX experiments demonstrated that HGWD can alleviate chronic OIPN by regulating intestinal flora homeostasis. Conclusions: HGWD prevents chronic OIPN by dynamically regulating intestinal flora homeostasis, thereby ameliorating intestinal barrier damage and reducing serum LPS and relevant inflammatory factor levels in the colon, serum, and DRG. [ABSTRACT FROM AUTHOR]

The common snook (Centropomus undecimalis) is a protandric hermaphrodite fish that undergoes a sex change during its life cycle. In nature, common snook females develop directly from males shortly after spawning. However, the factors triggering this process remain unknown. This knowledge gap poses challenges for managing the species in captivity. To address this, we conducted a study on sex change induction in three-year-old males using estradiol and evaluated the potential effects of photoperiod manipulation on early maturation. Four treatment groups were employed: (1) fish with estradiol + natural photoperiod; (2) fish without estradiol + natural photoperiod; (3) fish without estradiol + controlled photoperiod; and (4) fish with estradiol + controlled photoperiod. The effectiveness of these treatments was assessed through histological procedures, which allowed for the examination of the fishes' gonads. Furthermore, the concentration of alkali labile phosphorus in fish plasma was measured and correlated with the histological results. Our findings revealed that administering 2 mg/kg estradiol implants resulted in a remarkable 100% female population within the estradiol-treated groups. No significant effect on fish maturation was observed due to the manipulated photoperiod conditions. This protocol offers improved management strategies for captive broodstock. Firstly, the concentration of estradiol used in this study proved sufficient to induce sex change in this hermaphroditic species, enabling the production of viable females at an early age and smaller size and facilitating easier broodstock manipulation. Secondly, the implementation of the alkali labile phosphorus technique allows for sex identification without the need to sacrifice the fish. In conclusion, our study provides valuable insights into sex change induction and photoperiod manipulation in common snook. The findings contribute to enhanced management practices for captive broodstock. However, further research is needed to explore the underlying mechanisms triggering sex change and to optimize protocols for long-term maintenance and successful reproduction in captivity. [ABSTRACT FROM AUTHOR]

The electronic medical records of patients who underwent EMR for nonampullary duodenal polyps of >= 10 mm with prophylactic defect closure attempted with TTS suturing between March 2021 and May 2022 were reviewed. Table 1 Baseline characteristics of the 36 patients who underwent attempted TTS suturing of EMR defects and details of the resected duodenal polyps. Results Baseline characteristics A total of 36 patients (61 % women; mean [SD] age, 65 [12] years) underwent EMR of duodenal polyps followed by attempted defect closure with TTS suturing. In the five patients who underwent surveillance endoscopy, the TTS suturing system remained completely intact in one patient (20 %), partially intact in three (60 %), and was not seen in the remaining case. [Extracted from the article]

Post-resective liver failure is a frequent complication of liver surgery and it is due to portal hyperperfusion of the remnant liver and to arterial vasoconstriction, as buffer response of the hepatic artery. In this context, splenectomy allows a reduction of portal flow and increases the survival chance in preclinical models. SerpinB3 is over-expressed in the liver in oxidative stress conditions, as a mechanism of cell defense to provide survival by apoptosis inhibition and cell proliferation. In this study, the expression of SerpinB3 was assessed as predictor of liver damage in in vivo models of major hepatic resection with or without splenectomy. Wistar male rats were divided into 4 groups: group A received 30% hepatic resection, group B > 60% resection, group C > 60% resection with splenectomy and group D sham-operated. Before and after surgery liver function tests, echo Doppler ultrasound and gene expression were assessed. Transaminase values and ammonium were significantly higher in groups that underwent major hepatic resection. Echo Doppler ultrasound showed the highest portal flow and resistance of the hepatic artery in the group with > 60% hepatectomy without splenectomy, while the association of splenectomy determined no increase in portal flow and hepatic artery resistance. Only the group of rats without splenectomy showed higher shear-stress conditions, reflected by higher levels of HO-1, Nox1 and of Serpinb3, the latter associated with an increase of IL-6. In conclusion, splenectomy controls inflammation and oxidative damage, preventing the expression of Serpinb3. Therefore, SerpinB3 can be considered as a marker of post-resective shear stress. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common solid tumor malignancies in the world and represents roughly 90% of all primary malignancies of the liver. The most common risk factors for HCC include hepatitis B virus, hepatitis C virus, alcohol, and increasingly, fatty liver. Most HCC is diagnosed at advanced stages, excluding the possibility of curative resection, which leaves systemic therapy as the only treatment option. However, given the extreme mutational diversity and heterogenous nature of HCC, efforts to develop new targeted systemic therapies were largely unsuccessful until recently. HCC pathogenesis is thought to be a multistage process driven by a wide array of nonmutually exclusive driver mutations accompanied by many passenger mutations, with the average tumor possessing approximately 40 genomic aberrations. Over the past two decades, several efforts to categorize HCC prognostically and therapeutically according to different molecular subclassifications with the intent to guide treatment and identify drug targets have emerged, though, no single consensus has been reached. Recent breakthroughs in drug development have greatly expanded treatment options, but the ideal of uniting each patient's unique HCC with a targeted systemic therapy remains elusive. [ABSTRACT FROM AUTHOR]

The treatment of advanced unresectable HCC (aHCC) remains a clinical challenge, with limited therapeutic options and poor prognosis. The results of IMbrave150 and HIMALAYA have changed the treatment paradigm for HCC and established immune checkpoint inhibition (ICI), either combined with anti-angiogenic therapy or dual ICI, as preferred first-line therapy for eligible patients with aHCC. Numerous other combination regimens involving ICI are under investigation with the aim of improving the tumour response and survival of patients with all stages of HCC. This review will explore the current evidence for ICI in patients with advanced HCC and discuss future directions, including the unmet clinical need for predictive biomarkers to facilitate patient selection, the effects of cirrhosis aetiology on response to ICI, and the safety of its use in patients with impaired liver function. [ABSTRACT FROM AUTHOR]

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2023 was held in Quebec City, Quebec 2–4 February 2023. The purpose of the conference was to develop consensus statements on emerging and evolving treatment paradigms. Participants included Canadian medical oncologists, radiation oncologists, pathologists and surgical oncologists from across Ontario, Quebec, and the Atlantic provinces. Consensus statements were developed following rapid review presentations and discussion of available literature. The recommendations proposed here represent the consensus opinions of physicians involved in the care of patients with gastrointestinal malignancies who participated in this meeting. [ABSTRACT FROM AUTHOR]

Contrast-enhanced ultrasound is a valuable tool to evaluate liver lesions in a pediatric patient cohort. Unusual progressive hepatic echogenicity (UPHE) is a self-limiting phenomenon noted in a cohort of children after administration of ultrasonographic contrast agents (UCAs). UPHE appears initially as heterogeneous branching similar to portal venous gas, culminating in a diffuse globular appearance. The etiology of UPHE is unclear and may be from underlying hepatic microvascular disease or altered gut permeability. This case series describes pediatric patients with UPHE following UCA bolus and discusses its potential mechanisms in children. [ABSTRACT FROM AUTHOR]

Methods for the synthesis of crinane alkaloids of isoquinoline series of Amaryllidaceae that possess various biological activities are reviewed. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of portal vein thrombosis (PVT) in cirrhosis is multifactorial, with altered hemodynamics being proposed as a possible contributor. The present systematic review was conducted to study the role of assessment of portal hemodynamics for the prediction of PVT in patients with cirrhosis. Methods: Three databases (Medline, Embase, and Scopus) were searched from inception to February 2023 for studies comparing portal venous system parameters in patients with cirrhosis developing PVT with those not. Results were presented as mean difference (MD) or odds ratio (OR) with their 95% confidence intervals (CIs). Results: A total of 31 studies (patients with cirrhosis: 19 studies, patients with cirrhosis undergoing splenectomy: 12 studies) were included. On pooling the data from multivariable analyses of the included studies, a larger portal vein diameter was a significant predictor of PVT in patients with cirrhosis without or with splenectomy with OR 1.74 (1.12–2.69) and OR 1.55 (1.26–1.92), respectively. On the other hand, a lower portal vein velocity (PVV) was a significant predictor of PVT in cirrhotics without or with splenectomy with OR 0.93 (0.91–0.96) and OR 0.71 (0.61–0.83), respectively. A PVV of <15 cm/s was the most commonly used cut‐off for the prediction of PVT. Patients developing PVT also had a significantly higher splenic length, thickness, and splenic vein velocity. Conclusion: The assessment of portal hemodynamic parameters at baseline evaluation in patients with cirrhosis may predict the development of PVT. Further studies are required to determine the optimal cut‐offs for various parameters. [ABSTRACT FROM AUTHOR]

Simple Summary: A number of agents, including immune checkpoint inhibitors, have become available for the treatment of hepatocellular carcinoma, but the objective response rate of these drugs is currently only 30% to 40%. Therefore, the identification of new predictive biomarkers and an increased knowledge of the mechanisms of response or resistance to systemic chemotherapies are required. In the systemic drug treatment of hepatocellular carcinoma, only the tyrosine kinase inhibitor (TKI) sorafenib was available for a period. This was followed by the development of regorafenib as a second-line treatment after sorafenib, and then lenvatinib, a new TKI, proved non-inferiority to sorafenib and became available as a first-line treatment. Subsequently, cabozantinib, another TKI, was introduced as a second-line treatment, along with ramucirumab, the only drug proven to be predictive of therapeutic efficacy when AFP levels are >400 ng/mL. It is an anti-VEGF receptor antibody. More recently, immune checkpoint inhibitors have become the mainstay of systemic therapy and can now be used as a first-line standard treatment for HCC. However, the objective response rate for these drugs is currently only 30% to 40%, and there is a high incidence of side effects. Additionally, there are no practical biomarkers to predict their therapeutic effects. Therefore, this review provides an overview of extensive research conducted on potential HCC biomarkers from blood, tissue, or imaging information that can be used in practice to predict the therapeutic efficacy of systemic therapy before its initiation. [ABSTRACT FROM AUTHOR]

Simple Summary: Skeletal muscle depletion is one of the established prognostic factors for hepatocellular carcinoma (HCC). This study clearly demonstrated that skeletal muscle mass continued to decrease significantly during lenvatinib (LEN) or sorafenib (SOR) treatment, which has recently played a major role in the treatment of unresectable HCC. Furthermore, the survival analysis using time-varying covariates in this study revealed that it was one of the independent prognostic factors together with tumor makers and liver functional reserve. These results can help improve the management of unresectable HCC because they suggest that it is essential to prevent skeletal muscle depletion, especially in using LEN/SOR to improve survival in HCC patients. This study aimed to assess the effects of lenvatinib (LEN) or sorafenib (SOR) treatment for hepatocellular carcinoma (HCC) on body composition and changes in body composition on survival. This study enrolled 77 HCC patients. Skeletal muscle index (SMI), subcutaneous and visceral adipose tissue indices (SATI and VATI), AFP, PIVKA-II, and ALBI scores were analyzed at the time of LEN/SOR introduction, three months after the introduction, at treatment discontinuation, and the last observational time. The differences between chronological changes in these values were analyzed using a paired t-test. The Cox proportional hazards model was used to analyze prognostic factors using time-varying covariates. The chronological changes in each factor were 45.5–43.6–40.6–39.8 (cm2/m2) for SMI, 41.7–41.6–36.3–33.7 (cm2/m2) for SATI, 41.9–41.1–37.1–34.8 (cm2/m2) for VATI, 2.379–26.42–33.61–36.32 (×103 ng/mL) for AFP, 9.404–13.39–61.34–25.70 (×103 mAU/mL) for PIVKA-II, and −2.56–−2.38–−1.99–−1.90 for the ALBI score. The presence of pre-treatment (p = 0.042), AFP (p = 0.002), PIVKA-II (p < 0.001), ALBI score (p < 0.001), and SMI (p = 0.001) were independent prognostic factors. Skeletal muscle mass decreases significantly during LEN/SOR treatment and is an independent prognostic factor for HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) continues to manifest a global burden with increasing incidence. Although many treatment modalities exist, the disease process is plagued with high recurrence and mortality. The comprehension of the mutation landscape of the disease in conjunction with the use of precision medicine will aid in individualized, targeted therapies for treatment. Through understanding the tumor microenvironment, management of the malignancy may be optimized. The purpose of our review is to emphasize the role and prospects of precision medicine in the treatment of HCC. Hepatocellular carcinoma (HCC) is the fourth most common malignancy worldwide and exhibits a universal burden as the incidence of the disease continues to rise. In addition to curative-intent therapies such as liver resection and transplantation, locoregional and systemic therapy options also exist. However, existing treatments carry a dismal prognosis, often plagued with high recurrence and mortality. For this reason, understanding the tumor microenvironment and mutational pathophysiology has become the center of investigation for disease control. The use of precision medicine and genetic analysis can supplement current treatment modalities to promote individualized management of HCC. In the search for personalized medicine, tools such as next-generation sequencing have been used to identify unique tumor mutations and improve targeted therapies. Furthermore, investigations are underway for specific HCC biomarkers to augment the diagnosis of malignancy, the prediction of whether the tumor environment is amenable to available therapies, the surveillance of treatment response, the monitoring for disease recurrence, and even the identification of novel therapeutic opportunities. Understanding the mutational landscape and biomarkers of the disease is imperative for tailored management of the malignancy. In this review, we summarize the molecular targets of HCC and discuss the current role of precision medicine in the treatment of HCC. [ABSTRACT FROM AUTHOR]

Histopathology is essential for the diagnosis and evaluation of disease activity of autoimmune hepatitis (AIH). We aimed to elucidate the characteristics of AIH from the localization of inflammation. We re-evaluated a nationwide survey that was performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017. A total of 303 patients were enrolled, and the clinical and treatment characteristics were compared between the patients with predominantly portal inflammation (230 patients) or lobular inflammation (73 patients). AIH patients with lobular inflammation had a higher probability of being diagnosed with acute hepatitis than those with portal inflammation. Liver enzyme levels were higher in patients with lobular inflammation, whereas immunoglobulin G levels were higher in patients with portal inflammation. The prevalence of an alanine aminotransferase level < 30 U/L after 6 months of treatment was significantly higher in patients with lobular inflammation than in those with portal inflammation (81.7% vs. 67.3%, P = 0.046). The localization of inflammation may be useful for evaluating the onset of AIH.

Background: Nivolumab and pembrolizumab have not been directly compared in clinical trials, and the aim of this study is to investigate the efficacy and safety of nivolumab versus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) in real-world practice. Methods: We retrospectively reviewed patients with HCC who received intravenous nivolumab or pembrolizumab alone as second-line and later therapy. The objective response was determined according to the Response Evaluation Criteria in Solid Tumors criteria version 1.1. Adverse events (AEs) were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The Kaplan–Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). Prognostic values were estimated using hazard ratios with 95% confidence intervals (CIs). Results: In total, 120 patients were enrolled, including 95 who received nivolumab and 25 who received pembrolizumab. All patients were staged as Barcelona Clinic Liver Cancer stage C, and 29 patients were classified as Child-Pugh classification B (7). The response rate of the pembrolizumab and nivolumab groups were 8.0% and 7.4%, respectively. There was no significant difference in the median PFS between the pembrolizumab and nivolumab groups (2.7 months versus 2.9 months). The median OS in the nivolumab group was longer than that in the pembrolizumab group (10.8 months versus 8.1 months); however, the difference was not statistically significant. The effects of pembrolizumab and nivolumab on the median PFS and OS were consistent across the subgroups based on baseline characteristics. The severity of all AEs was grades 1–2 without treatment interruption or dose adjustment; there was no statistically significant difference in the incidence of treatment-related AEs between these two groups. Additionally, the percentage of patients receiving subsequent therapy was consistent between the two groups. Conclusion: The efficacy and safety of pembrolizumab and nivolumab were comparable in the management of patients with pretreated HCC in real-world practice. [ABSTRACT FROM AUTHOR]

Background: Sorafenib resistance greatly reduces the efficacy of treatments in advanced hepatocellular carcinoma (HCC) patients, but the underlying mechanisms are not thoroughly understood. All-trans retinoic acid (ATRA), an anti-leukaemia agent, has attracted considerable attention due to its role in sensitizing cells to other anticancer treatments. We aimed to investigate the combined effect of ATRA and Sorafenib on HCC and the underlying mechanisms. Methods: CCK-8, cell sphere formation, trans-well migration, and wound-healing assays were used to analyse the biological behaviours of HCC cells in vitro. Western blotting and qRT-PCR analysis were conducted to measure the expression of p21 activated kinase 1 (PAK1) and phospho-p21 activated kinase 1 (pPAK1). Xenograft models were established to confirm the synergistic effects of ATRA and Sorafenib in vivo. TUNEL assays and immunohistochemistry were utilized to determine apoptosis, proliferation, PAK1 and pPAK1 levels in tumour tissues. Results: We observed that PAK1 was overexpressed in HCC, and its expression was negatively correlated with the survival of patients. PAK1 promoted the proliferation, self-renewal and epithelial-mesenchymal transition of HCC cells. Correlation analysis indicated that the IC50 of Sorafenib was positively correlated with the level of pPAK1 in HCC cell lines. ATRA inhibited the progression of HCC and sensitized HCC response to Sorafenib by downregulation of PAK1, as shown by the calculated coefficient of drug interaction and the data obtained from xenograft models. Conclusions: Our findings indicated that instead of treatment with Sorafenib alone, the combination of ATRA and Sorafenib provides a more effective treatment for HCC patients. 2_mPhFeBDQdvWNSurq11yx Video Abstract [ABSTRACT FROM AUTHOR]

Aims: Detection and characterization of idiosyncratic drug‐induced liver injury (DILI) currently rely on standard liver tests, which are suboptimal in terms of specificity, sensitivity and prognosis. Therefore, DILI diagnosis can be delayed, with important consequences for the patient. In this study, we aimed to evaluate the potential of osteopontin, cytokeratin‐18 (caspase‐cleaved: ccK18 and total: K18), α‐glutathione‐S‐transferase and microRNA‐122 as new DILI biomarkers. Methods: Serial blood samples were collected from 32 DILI and 34 non‐DILI acute liver injury (ALI) cases and a single sample from 43 population controls without liver injury (HLC) and analysed using enzyme‐linked immunosorbent assay (ELISA) or single‐molecule arrays. Results: All biomarkers differentiated DILI and ALI from HLC with an area under receiver operator characteristic curve (AUC) value of >0.75 but were less efficient in distinguishing DILI from ALI, with ccK18 (0.79) and K18 (0.76) demonstrating highest potential. However, the AUC improved considerably (0.98) for ccK18 when comparing DILI and a subgroup of autoimmune hepatitis cases. Cytokeratin‐18, microRNA‐122 and α‐glutathione‐S‐transferase correlated well with traditional transaminases, while osteopontin correlated most strongly with the international normalized ratio (INR). Conclusions: ccK18 appears promising in distinguishing DILI from autoimmune hepatitis but less so from other forms of acute liver injury. Osteopontin demonstrates prognostic potential with higher levels detected in more severe cases regardless of aetiology. [ABSTRACT FROM AUTHOR]

Intracranial aneurysms are reported to affect 2–5% of the population. Despite advances in the surgical management of this disease, diagnostic technologies have marginally improved and still rely on expensive or invasive imaging procedures. Currently, there is no blood-based test to detect cerebral aneurysm formation or quantify the risk of rupture. The aim of this review is to summarize current literature on the mechanism of aneurysm formation, specifically studies relating to inflammation, and provide a rationale and commentary on a hypothetical future blood-based test. Efforts should be focused on clinical-translational approaches to create an assay to screen for cerebral aneurysm presence and risk-stratify patients to allow for superior treatment timing and management. Cerebral Aneurysm Blood Test Considerations: There are multiple caveats to development of a putative blood test to detect cerebral aneurysm presence. [ABSTRACT FROM AUTHOR]

Background and Aims: Cavernous transformation of the portal vein can occur after portal vein thrombosis (PVT). In this study, we investigated clinical complications associated with cavernous transformation in the context of cirrhosis and PVT. Methods: In this retrospective cohort analysis, 204 patients with cirrhosis and PVT with or without cavernous transformation were identified using MUSC's Clinical Data Warehouse between January 1, 2013, through December 31, 2019. Complete demographic data, clinical history, and laboratory tests were abstracted from the electronic medical record. Results: Of 204 patients, 41 (20%) had cavernous transformation. MELD, Child–Pugh, and Charlson Comorbidity Index scores were similar among groups. There were no significant differences in the prevalence of esophageal varices (with or without bleeding), splenomegaly, or hepatic encephalopathy in patients with and without cavernous transformation, although ascites tended to be lower in patients with cavernous transformation (31/41 (76%) vs 142/163 (87%), p = 0.06). Patients with cavernous transformation were significantly less likely to have hepatocellular carcinoma (HCC) (13/41 (32%) vs 81/163 (50%), p < 0.05) and had significantly lower APRI (1.4 vs 2.0, p < 0.05) and Fib-4 (4.7 vs 6.5, p < 0.05). Patients with cavernous transformation had lower 5-year mortality (12/41 (29%) vs 81/163 (49%) died, p = 0.06). The 10-year mortality of patients with cavernous transformation without HCC was significantly lower than in those without cavernous transformation (8/28 (29%) vs 46/82 (56%), respectively, p < 0.05). Conclusions: Patients with cavernous transformation appeared to have better outcomes than those without cavernous transformation. [ABSTRACT FROM AUTHOR]

Background: The present descriptive study shares the overall experience of treating all these patients where different surgical process was adopted depending on the treatment required after carefully evaluating the risk factors and comorbidities. Methods: The present study was conducted at the Department of Thoracic Surgery, Choray Hospital, Vietnam between the period of 2010 to 2020. We have treated 95 patients altogether in this duration. Results: We were able to save most of the patients by applying thoracotomy and thoracic irrigation for most of the patients based on the observed indications that were identified immediately after the compulsory standard cervicotomy. The indication for thoracic interference was considered when the infection was deeply spread into the mediastinum and cannot get out through cervicotomy, although the most effective method of drainage was applied. Conclusion: Our statistical investigation of the patient data suggested the possible association and influence of comorbidity such as diabetes. Therefore, we recommend that in specific cases thoracotomy along with thoracic irrigation and repetitive surgical draining could be a better option to reduce the infection and the mortality rate. Trial registration: Retrospectively registered. [ABSTRACT FROM AUTHOR]

Contrast-enhanced ultrasound (CEUS) is a promising imaging modality in predicting the efficacy of neoadjuvant chemotherapy for pancreatic cancer, a tumor with high mortality. In this study, we proposed a deep-learning-based strategy for analyzing CEUS videos to predict the prognosis of pancreatic cancer neoadjuvant chemotherapy. Pre-trained convolutional neural network (CNN) models were used for binary classification of the chemotherapy as effective or ineffective, with CEUS videos collected before chemotherapy as the model input, and with the efficacy after chemotherapy as the reference standard. We proposed two deep learning models. The first CNN model used videos of ultrasound (US) and CEUS (US+CEUS), while the second CNN model only used videos of selected regions of interest (ROIs) within CEUS (CEUS-ROI). A total of 38 patients with strict restriction of clinical factors were enrolled, with 76 original CEUS videos collected. After data augmentation, 760 and 720 videos were included for the two CNN models, respectively. Seventy-six-fold and 72-fold cross-validations were performed to validate the classification performance of the two CNN models. The areas under the curve were 0.892 and 0.908 for the two models. The accuracy, recall, precision and F1 score were 0.829, 0.759, 0.786, and 0.772 for the first model. Those were 0.864, 0.930, 0.866, and 0.897 for the second model. A total of 38.2% and 40.3% of the original videos could be clearly distinguished by the deep learning models when the naked eye made an inaccurate classification. This study is the first to demonstrate the feasibility and potential of deep learning models based on pre-chemotherapy CEUS videos in predicting the efficacy of neoadjuvant chemotherapy for pancreas cancer. [ABSTRACT FROM AUTHOR]

The Owadów-Brzezinki palaeontological site is known for its very well-preserved fossils of Late Jurassic vertebrates, such as numerous fossil fish teeth and occasional dental bones. Some of these represent well-studied taxa, including the most common large predatory fish, with notable examples of caturoids (such as Strobilodus sp.) and pachycormids (Orthocormus teyleri). The current study presents the microstructure and histological features of the teeth of the selected specimens of the above taxa. They are determined through examinations of tooth cross-sections under thin microscopic observations and by the usage of scanning electron microscopy (SEM). The above inspections, combined with aspects of external tooth morphology, allowed us to determine the palaeoecology of the aforementioned taxa of large predatory fish. It is concluded that examined Caturoidea displayed a rather homogenous dentition belonging to the intermediate cut/slash guild, characterized by an internal orthodentin histology with prominent incremental Andresen growth lines of differing form, indicating living in a highly variable, unstable environment. The teeth of pachycormid specimen (O. teyleri) can be characterized as having denteon-based orthodentin histology, with a rapid rate of tooth eruption and a heterodont, elongated specialist dentition of the piercing guild. The observed structural differences in the teeth suggest a different niche distribution between the taxa studied. They help to explain how these predatory ray-finned fishes may have coexisted both in the local environment of the Owadów-Brzezinki and in the wider, more global context of Late Jurassic shallow marine environments. In addition, the tooth samples are characterised by pronounced surface bioerosion with traces of Mycellites ossifragus durophagous fungal activity, indicating an intense bioerosion caused by these microorganisms after the death of the fish. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and is often diagnosed at an unresectable advanced stage. Systemic chemotherapy as well as transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) are used to treat advanced HCC. TACE and HAIC have long been the standard of care for patients with unresectable HCC but are limited to the treatment of intrahepatic lesions. Systemic chemotherapy with doxorubicin or chemohormonal therapy with tamoxifen have also been considered, but neither has demonstrated survival benefits. In the treatment of unresectable advanced HCC, cisplatin is administered transhepatic arterially for local treatment. Subsequently, for cisplatin-refractory cases due to drug resistance, a shift to systemic therapy with a different mechanism of action is expected to produce new antitumor effects. Cisplatin is also used for the treatment of liver tumors other than HCC. This review summarizes the action and resistance mechanism of cisplatin and describes the treatment of the major hepatobiliary cancers for which cisplatin is used as an anticancer agent, with a focus on HCC. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitor (ICI)-based regimens are transforming the landscape of hepatocellular carcinoma (HCC) treatment. We describe the effect of combined ipilimumab and nivolumab in patients with advanced HCC after the failure of prior ICI-based combination treatments. Methods: The clinical course of patients with advanced HCC who received combined ipilimumab and nivolumab after prior ICI-based combination therapies was assessed. Progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) per RECIST v1.1 and mRECIST, overall survival (OS), and safety were analyzed. Results: Of 109 patients treated with atezolizumab and bevacizumab or other ICI-based combination treatments, ten patients received subsequent therapy with ipilimumab and nivolumab. The majority of patients had Barcelona Clinic Liver Cancer (BCLC) Stage C (80%) HCC and a preserved liver function as defined by Child–Pugh A (80%). At a median follow-up of 15.3 months, ORR for ipilimumab and nivolumab was 30% with a DCR of 40%. Median PFS was 2.9 months and the median OS was 7.4 months. Conclusion: This retrospective study demonstrates that combined ipilimumab and nivolumab can be effective and tolerable after prior ICI-based combination therapies and provides a rationale for the prospective clinical evaluation of this treatment sequencing. [ABSTRACT FROM AUTHOR]

Among ray‐finned fishes (Actinopterygii), the crushing, durophagous feeding strategy first evolved in the early Carboniferous period, with the †Eurynotiformes possessing dentitions with single layers of partially to fully fused blunt teeth. In the †'Platysomidae' (Permian), a new form of crushing dentition evolved (phyllodonty), in which multiple layers of superimposed crushing teeth developed intraosseously, within the jaw. The phyllodont durophagous dentition is also recovered from later‐occurring taxa originating mainly in the Mesozoic, such as the †Bobastraniiformes, the neopterygians †Pycnodontiformes and Ginglymodi, and in the teleost group †Phyllodonta. By comparison, †Kazanichthys viatkensis, an actinopterygian from the middle Permian of European Russia, is characterized by a third, putatively durophagous dentition, with anterior conical teeth and closely packed molariform teeth on the buccal dental plates (a potential similarity with eurynotiforms). Whereas the conical teeth are similar to those of basal actinopterygians, the molariform teeth superficially resemble teeth of some teleosts (Characiformes, Tetraodontiformes), but are unique among known fossil and living Actinopterygii in being crowned by anastomosing, sharp apical ridges. Teeth are ankylosed to the jaw and acrodont in implantation. There is neither evidence of plicidentine, nor cavities corresponding to intraosseous crypts. Most replacement teeth formed extraosseously, differing from the phyllodont dentition, but similar to several more phylogenetically basal actinopterygians. The dental system morphologically resembles recent Sparidae (Teleostei; Perciformes), possibly indicating a similar trophic adaptation. Based on these comparisons and patterns of wear, we propose that †K. viatkensis was a generalist durophagous feeder, with the ability to switch prey types with its unique and complex dentition. [ABSTRACT FROM AUTHOR]

The Notch pathway is an ancient, evolutionary conserved intercellular signaling mechanism that is involved in cell fate specification and proper embryonic development. The Jagged2 gene, which encodes a ligand for the Notch family of receptors, is expressed from the earliest stages of odontogenesis in epithelial cells that will later generate the enamel-producing ameloblasts. Homozygous Jagged2 mutant mice exhibit abnormal tooth morphology and impaired enamel deposition. Enamel composition and structure in mammals are tightly linked to the enamel organ that represents an evolutionary unit formed by distinct dental epithelial cell types. The physical cooperativity between Notch ligands and receptors suggests that Jagged2 deletion could alter the expression profile of Notch receptors, thus modifying the whole Notch signaling cascade in cells within the enamel organ. Indeed, both Notch1 and Notch2 expression are severely disturbed in the enamel organ of Jagged2 mutant teeth. It appears that the deregulation of the Notch signaling cascade reverts the evolutionary path generating dental structures more reminiscent of the enameloid of fishes rather than of mammalian enamel. Loss of interactions between Notch and Jagged proteins may initiate the suppression of complementary dental epithelial cell fates acquired during evolution. We propose that the increased number of Notch homologues in metazoa enabled incipient sister cell types to form and maintain distinctive cell fates within organs and tissues along evolution. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with unresectable hepatocellular carcinoma (HCC) who receive lenvatinib treatment often lose their appetite, which leads to poor outcomes, but the reason for appetite loss is unclear. FGF21 is a natural hormone-like factor that modulates appetite. We investigated the effect of lenvatinib on FGF21 levels in patients with HCC who were treated with lenvatinib and found that those with severe appetite loss showed increases in FGF21 levels before appetite loss occurred. This suggests that changes in FGF21 levels can be used to predict patients with a greater risk of marked appetite loss and provides insights into the mechanisms underlying lenvatinib-induced appetite loss in patients with HCC. Lenvatinib, used for unresectable hepatocellular carcinoma (HCC), causes appetite loss, but the underlying mechanisms, clinical impact, and predictive factors have been unclear. The endocrine factor FGF21 modulates appetite and is involved in cachexia. We evaluated the association between FGF21 level changes during lenvatinib treatment for unresectable HCC and appetite loss. Sixty-three eligible unresectable HCC patients who started lenvatinib treatment between 2018 and 2021 were included. We analyzed FGF21 levels at baseline; 1, 2, and 4 weeks after lenvatinib initiation, and before the onset of appetite loss. Grade ≥ 2 lenvatinib-induced appetite loss led to liver functional reserve deterioration at disease progression and a poor prognosis. Baseline characteristics and serum FGF21 levels were similar between patients with and without appetite loss. However, the serum FGF21 change rate increased significantly at 4 weeks post-lenvatinib initiation in patients with grade ≥ 2 appetite loss, as compared to those without appetite loss. Similar significant increases in the serum FGF21 level change rate were observed prior to grade ≥ 2 appetite loss onset. This suggests that changes in FGF21 levels can be used to predict patients with a greater risk of marked appetite loss and provides insights into the mechanisms underlying lenvatinib-induced appetite loss in patients with HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Although sarcopenia-related factors, including decreased skeletal muscle index (SMI), have been reported to affect therapeutic efficacy and the occurrence of adverse events in sorafenib or lenvatinib treatment for hepatocellular carcinoma (HCC), there is considerably less evidence regarding the relationship between SMI and prognosis in the HCC patients treated with atezolizumab plus bevacizumab (atezo/bev) therapy. Furthermore, there are no reports of muscle strength, including grip strength (GS), which is essential for an accurate diagnosis of sarcopenia. This is the first study to show the relationship between sarcopenia, diagnosed by decreased GS and SMI, and clinical outcomes in atezo/bev therapy, with novel evidence having a strong impact. The presence of sarcopenia is significantly associated with shorter overall survival with the occurrence of adverse events and decreased liver function. Monitoring of both GS and SMI is useful for assessing the general condition and predicting prognosis in HCC patients treated with atezo/bev therapy. Although there have been advances in the prevention and diagnosis of hepatocellular carcinoma (HCC) in recent years, many HCC patients are still diagnosed with advanced stage. Systemic therapy is indicated for unresectable HCC (uHCC) with major vascular invasion and/or extrahepatic metastases, and the atezolizumab plus bevacizumab (atezo/bev) combination is currently recommended as first-line treatment for uHCC. Recently, sarcopenia-related factors, including decreased skeletal muscle index (SMI), have been reportedly associated with prognosis in uHCC patients treated with sorafenib or lenvatinib. There are few reports on muscle strength assessments, including grip strength (GS), despite their importance in accurate sarcopenia diagnosis, and furthermore, there is no evidence regarding atezo/bev therapy. In this study, we investigated whether sarcopenia affects the clinical outcome of atezo/bev therapy. This study included 64 uHCC patients on atezo/bev therapy and assessed their GS and SMI, and SMI was measured using bioelectrical impedance analysis (BIA). We diagnosed sarcopenia based on GS and BIA-SMI and compared the clinical outcomes in the sarcopenia and non-sarcopenia groups. Of these patients, 28 had sarcopenia, and 36 had non-sarcopenia. Adverse events (AEs) frequently occurred, and the albumin-bilirubin score significantly decreased after atezo/bev therapy in the sarcopenia group than in the non-sarcopenia group. The median progression-free survival was 4.7 (0.4–26.4) and 10.6 (1.1–24.5) months in the sarcopenia and non-sarcopenia groups, respectively. The median overall survival (OS) was 12.6 (1.4–27.7) months in the sarcopenia group and was not reached in the non-sarcopenia group, indicating a significant difference in the Kaplan-Meier survival curves for both groups (p < 0.01). In multivariate analysis, sarcopenia was significantly associated with OS. In conclusion, sarcopenia was significantly associated with poor clinical outcomes based on the occurrence of AEs and decreased liver function in uHCC patients on atezo/bev therapy. GS and SMI are important parameters for accurately diagnosing sarcopenia. [ABSTRACT FROM AUTHOR]

Simple Summary: Embolization shuts down vessels and cuts off the supply of blood to liver tumors. Using small beads, drugs can be delivered locally. Thus far, the drugs loaded onto the beads have not been tailored to liver tumors because the physical properties of efficacious drugs precluded it. Our patented formulation enables targeted therapies to be loaded onto the beads. This study aims to examine the safety and feasibility of VX2 rabbit tumor model embolization using beads loaded with the targeted therapies. The study showed that embolization was possible. The targeted therapies eluted locally and did not escape into systemic circulation. Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, feasibility, and pharmacokinetics of sorafenib or regorafenib DEE-TACE in a VX2 model. DEE-TACE was performed in VX2 hepatic tumors in a selective manner until stasis using liposomal sorafenib- or regorafenib-loaded DEEs. The animals were euthanized at 1, 24, and 72 h timepoints post embolization. Blood samples were taken for pharmacokinetics at 5 and 20 min and at 1, 24, and 72 h. Measurements of sorafenib or regorafenib were performed in all tissue samples on explanted hepatic tissue using the same mass spectrometry method. Histopathological examinations were carried out on tumor tissues and non-embolized hepatic specimens. DEE-TACE was performed on 23 rabbits. The plasma concentrations of sorafenib and regorafenib were statistically significantly several folds lower than the embolized liver at all examined timepoints. This study demonstrates the feasibility of loading sorafenib or regorafenib onto commercially available DEEs for use in TACE. The drugs eluted locally without release into systemic circulation. [ABSTRACT FROM AUTHOR]

Choline availability regulates neural progenitor cell proliferation and differentiation in the developing cerebral cortex. Here, we investigated the molecular mechanism underlying this process and demonstrated that choline regulates the transcription factor SOX4 in neural progenitor cells. Specifically, we found that low choline intake during neurogenesis reduces SOX4 protein levels, causing the downregulation of EZH2, a histone methyltransferase. Importantly, we demonstrate that low choline is not involved in SOX4 protein degradation rate and established that protein reduction is caused by aberrant expression of a microRNA (miR-129-5p). To confirm the role of miR-129-5p, we conducted gain-of-function and loss-of-function assays in neural progenitor cells and demonstrated that directly altering miR-129-5p levels could affect SOX4 protein levels. We also observed that the reduction in SOX4 and EZH2 led to decreased global levels of H3K27me3 in the developing cortex, contributing to reduced proliferation and precocious differentiation. For the first time, to our knowledge, we demonstrate that a nutrient, choline, regulates a master transcription factor and its downstream targets, providing a novel insight into the role of choline in brain development. [ABSTRACT FROM AUTHOR]

Spontaneous portosystemic shunts (SPSS) are an often neglected cause of hepatic encephalopathy associated with cirrhosis. Nowadays, SPSS are considered as radiological biomarkers of clinically significant portal hypertension rather than the previous dogmatic perceived decompressive vessels. SPSS are not rare as they can be diagnosed in over 60% of the patients with cirrhosis by mere contrast-enhanced CT. Moreover, they are clinically relevant since they impact on all portal hypertensive related complications, in particular medically refractory HE, and represent an independent predictor of decompensation and mortality in cirrhosis, irrespective of the type of SPSS. Taken together, these elements warrant strategies to target these shunts directly which is currently is achieved via interventional radiology embolization. In this review, we discuss why it makes sense to tackle SPSS, how to do it and what it takes to do it right based on aggregated literature. [ABSTRACT FROM AUTHOR]

Meteoropathy is no longer considered a popular myth, but a new disease that significantly impacts daily life, particularly in individuals who experience mental illness, cardiovascular disorders, and respiratory conditions. However, there are very limited data on this condition. This study aimed to comprehensively review and analyze existing in vivo animal studies and human clinical trials investigating the effects of meteoropathy on health and its pharmacological treatment. A thorough literature search was conducted across databases such as PubMed and Scopus to gather relevant information. Our analysis primarily focused on the relationship between meteoropathy and mental health, including the influence on affective temperaments. Additionally, we explored various treatment approaches, emphasizing the combination of muscle exercises, pharmacological interventions, and naturopathy, which have shown promise in alleviating pain among individuals affected by meteoropathy. Future research in meteoropathy should shed light on synthesizing new pharmacological compounds. [ABSTRACT FROM AUTHOR]

Tumor growth depends on the vascular system, either through the expansion of blood vessels or novel adaptation by tumor cells. One of these novel pathways is vasculogenic mimicry (VM), which is defined as a tumor-provided vascular system apart from endothelial cell-lined vessels, and its origin is partly unknown. It involves highly aggressive tumor cells expressing endothelial cell markers that line the tumor irrigation. VM has been correlated with high tumor grade, cancer cell invasion, cancer cell metastasis, and reduced survival of cancer patients. In this review, we summarize the most relevant studies in the field of angiogenesis and cover the various aspects and functionality of aberrant angiogenesis by tumor cells. We also discuss the intracellular signaling mechanisms involved in the abnormal presence of VE-cadherin (CDH5) and its role in VM formation. Finally, we present the implications for the paradigm of tumor angiogenesis and how targeted therapy and individualized studies can be applied in scientific analysis and clinical settings. [ABSTRACT FROM AUTHOR]

STS-1 and STS-2 form a small family of proteins that are involved in the regulation of signal transduction by protein–tyrosine kinases. Both proteins are composed of a UBA domain, an esterase domain, an SH3 domain, and a PGM domain. They use their UBA and SH3 domains to modify or rearrange protein–protein interactions and their PGM domain to catalyze protein–tyrosine dephosphorylation. In this manuscript, we discuss the various proteins that have been found to interact with STS-1 or STS-2 and describe the experiments used to uncover their interactions. [ABSTRACT FROM AUTHOR]