Alpha-1 antitrypsin deficiency associated with increased risks of skin cancer, leukemia, and hepatic cancer: A nationwide cohort study.

BACKGROUND: α1-Antitrypsin deficiency is characterized by elevated elastase activity and excessive elastin degradation, which may impact cancer development and progression. We tested the hypothesis that individuals with α1-antitrypsin deficiency have increased susceptibility to cancer in the Danish population. METHODS: In a nationwide nested study, we identified 2702 individuals with α1-antitrypsin deficiency and 26,750 control subjects without α1-antitrypsin deficiency matched on age, sex, and municipality. We recorded admissions due to cancer as outcomes during a median follow-up of 62 years. RESULTS: Individuals with α1-antitrypsin deficiency versus control subjects had an increased hazard of skin cancer (2.18, 95%CI: 1.81-2.63), leukemia (1.76, 1.12-2.79), liver cancer (3.91, 2.23-6.85), and cancer overall (1.25, 1.13-1.38). Corresponding hazard ratios when the entire Danish population was used as control group were 3.02 (2.55-3.58), 1.83 (1.19-2.81), 4.46 (2.74-7.28), and 1.45 (1.31-1.59). When the analysis was stratified according to comorbidities, the hazard for skin cancer was higher in those with chronic obstructive pulmonary disease (COPD) (3.59, 2.60-4.95) and skin disease (2.93, 2.19-3.92) but remained elevated in those without any of these diseases. Hazards for skin cancer in individuals with α1-antitrypsin deficiency were similar when stratified by liver cirrhosis and ischemic heart disease (ps for interaction: ≥0.76). Hazards for liver cancer in individuals with α1-antitrypsin deficiency versus control subjects were similar when stratified according to liver cirrhosis, COPD, skin disease, and ischemic heart disease (ps for interaction: ≥0.13). CONCLUSION: Individuals with α1-antitrypsin deficiency have increased risks of skin cancer, leukemia, and liver cancer in the Danish population.

Characteristics, diagnosis, treatment and prognosis of double primary hepatic cancer: experience based on a series of 12 cases.

Double Primary Hepatic Cancer (DPHC) which refers to synchronous hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) coexisting in the same liver, has rarely been reported. Here we discussed the clinical characteristics, diagnosis, treatment, and prognosis of DPHC based on an analysis of 12 DPHC cases. Meanwhile, data of 60 HCC cases and 60 ICC cases were collected at a ratio of 5:1 and with matched age and gender to DPHC in the same period. A total of 4,626 cases of primary liver cancer were screened, and the proportion of DPHC was approximately 0.26%. Hepatitis B Virus prevalence in the DPHC group (83.3%) was higher than that in the ICC group (38.3%). Lymph node metastasis was more common in the DPHC group (16.7%) compared to the HCC group (1.7%). The median disease-free survival (DFS) and overall survival (OS) for DPHC were 6.0±2.6 months and 15.0±1.7 months, respectively. Pathological diagnosis indicated a significant effect of preoperative adjuvant transarterial chemoembolization (TACE) on HCC, but limited efficacy on ICC. Both alpha fetoprotein and carbohydrate antigen 19-9 levels were elevated in the DPHC group. In conclusion, the preferred treatment for DPHC is radical resection and regional lymphadenectomy. Preoperative TACE is effective for DPHC with large HCC components. The prognosis for DPHC is marked by high recurrence and high mortality.

Electrochemotherapy and Calcium Electroporation on Hepatocellular Carcinoma Cells: An In-Vitro Investigation.

PURPOSE: Electrochemotherapy, clinically established for treating (sub)cutaneous tumors, has been standardized in the framework of the European Standard Operating Procedure on Electrochemotherapy (ESOPE). Due to common side effects of chemotherapeutic drugs, recent advances focus on non-cytotoxic agents, like calcium, to induce cell death (calcium electroporation). Therefore, this study aims to determine the efficacy of electrochemotherapy with bleomycin or cisplatin, or calcium electroporation on human hepatocellular carcinoma cells (HepG2) in vitro using the ESOPE protocol. METHODS: HepG2 cell viability was measured with a MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay after electrochemotherapy with the chemotherapeutic drugs bleomycin or cisplatin (0-20 µM), or after calcium electroporation (0-20 mM), to determine its efficacy on HepG2 cells in vitro using the ESOPE protocol (8 rectangular pulses, 1000 V/cm, 100 µs) compared to non-electroporated drug treatment. RESULTS: Cell viability was significantly lower in electroporated samples, compared to their non-electroporated controls (27-75% difference). Electrochemotherapy with bleomycin and calcium electroporation, reached (almost) complete cell death (- 1 ± 3% and 2.5 ± 2%), in the lowest concentration of 2.5 µM and 2.5 mM, respectively. Electrochemotherapy with 2.5 µM cisplatin, significantly decreased cell viability to only 68% (± 7%). CONCLUSION: Electrochemotherapy with bleomycin or cisplatin, or calcium electroporation were more effective in reducing the HepG2 cell viability in vitro using the ESOPE protocol compared to the non-electroporated drug treatments alone. When comparing electrochemotherapy, HepG2 cells are more sensitive to bleomycin than cisplatin, in similar concentrations. Calcium electroporation has the same effectiveness as electrochemotherapy with bleomycin, but calcium potentially has a better safety profile and several treatment advantages.

Hepatocellular carcinoma as a complication of chronic Budd-Chiari syndrome (BCS) in a child.

Hepatocellular carcinoma (HCC) is an extremely rare long-term complication of Budd-Chiari syndrome (BCS) which may occur due to long-term venous congestion causing fibrosis, cirrhosis and subsequent hepatocellular dysplasia or anaplasia. This complication is even rarer in paediatric BCS and warrants early diagnosis for a favourable prognosis. Benign regenerative nodules seen with BCS are difficult to differentiate from malignant nodular lesion of HCC, thereby making serial imaging less sensitive for early diagnosis of HCC in BCS. Surveillance guidelines like adults do not exist in monitoring chronic paediatric BCS due to rarity of this complication. Six monthly serum alpha-fetoprotein monitoring in addition to radiological surveillance improves the sensitivity of early detection of HCC transformation in BCS and should be the way ahead in paediatric BCS as well. We describe a paediatric patient who presented with advanced HCC after 25-month follow-up for BCS.

Massive fabrication of functional hepatic cancer spheroids by micropatterned GelMA hydrogel chip for drug screening.

Since hepatic cancer incidence and mortality continue to grow worldwide, it is necessary to develop the biomimetic tumor models for drug development and tumor therapeutics. Cellular spheroids as an excellent simple 3D model can bridge the gap between 2D cell culture and live tissue. In this study, we proposed a biological methacrylated gelatin (GelMA) hydrogel-based microplatform for the massive generation of hepatocellular spheroids and downstream investigation of drug resistance. Micropatterned GelMA hydrogel microwell chip (GHM-chip) with tunable array was easily achieved in standard 24-culture well plates through the micro-molding fabrication strategy. The fabricated GHM-chip induced multicellular self-assembly behavior within the defined topography and further formed spheroidal structure. By regulating cell seeding density and designing microwell size, uniform hepatic cancer spheroids with tunable diameters were obtained in a simplicity, stability and controllable manner. In addition, the screening chemotherapy study of anti-cancer drug was completed through non-destructive recovery of spheroids from the GHM-chip. Beyond that, the recovered functional spheroids have potential application value in various biomedical fields such as tumor biology, pharmacology, and tissue microengineering. Finally, the proposed GHM-chip incorporated into standard cell culture plates with easy to manufacture and operate properties, may be an efficient culture microplatform for cancer research applications.

A quartet of cancer stem cell niches in hepatocellular carcinoma.

Hepatocellular Carcinoma (HCC), the most prevalent type of primary liver cancer, is known for its aggressive behavior and poor prognosis. The Cancer Stem Cell theory, which postulates the presence of a small population of self-renewing cells called Cancer Stem Cells (CSCs), provides insights into various clinical and molecular features of HCC such as tumor heterogeneity, metabolic adaptability, therapy resistance, and recurrence. These CSCs are nurtured in the tumor microenvironment (TME), where a mix of internal and external factors creates a tumor-supportive niche that is continuously evolving both spatially and temporally, thus enhancing the tumor's complexity. This review details the origins of hepatic CSCs (HCSCs) and the factors influencing their stem-like qualities. It highlights the reciprocal crosstalk between HCSCs and the TME (hypoxic, vascular, invasive, and immune niches), exploring the signaling pathways involved and how these interactions control the malignant traits of CSCs. Additionally, it discusses potential therapeutic approaches targeting the HCSC niche and their possible uses in clinical practice.

Clinical outcomes of MAFLD versus NAFLD: A meta-analysis of observational studies.

IMPORTANCE: The recent change in terminology from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) highlights the link between hepatic steatosis and metabolic dysfunction, taking out the stigmata of alcohol. OBJECTIVE: We compared the effects of NAFLD and MAFLD definitions on the risk of overall and cardiovascular (CV) mortality, liver-related events (LRE), nonfatal CV events (CVE), chronic kidney disease (CKD), and extra-hepatic cancers (EHC). DATA SOURCES AND STUDY SELECTION: We systematically searched four large electronic databases for cohort studies (published through August 2023) that simultaneously used NAFLD and MAFLD definitions for examining the risk of mortality and adverse CV, renal, or oncological outcomes associated with both definitions. In total, 21 eligible cohort studies were identified. Meta-analysis was performed using random-effects modelling. RESULTS: Compared with those with NAFLD, individuals with MAFLD had significantly higher rates of overall mortality (random-effect OR 1.12, 95% CI 1.04-1.21, p = .004) and CV mortality (random-effect OR 1.15, 95% CI 1.04-1.26, p = .004), and a marginal trend towards higher rates of developing CKD (random-effect OR 1.06, 95% CI 1.00-1.12, p = .058) and EHC events (random-effect OR 1.11, 95% CI 1.00-1.23, p = .052). We found no significant differences in the risk LREs and nonfatal CVE between MAFLD and NAFLD. Meta-regression analyses identified male sex and metabolic comorbidities as the strongest risk factors related to the risk of adverse clinical outcomes in MAFLD compared to NAFLD. CONCLUSIONS AND RELEVANCE: Individuals with MAFLD have higher rates of overall and CV mortality and higher rates of developing CKD and EHC events than those with NAFLD, possibly due to the dysmetabolic risk profile related to MAFLD.

Causal relationships between immune cells, inflammatory factors, serum metabolites, and hepatic cancer: A two-sample Mendelian randomization study.

Background: Observational studies and clinical trials suggest associations between immune cells, inflammatory factors, serum metabolites, and hepatic cancer. However, the causal relationships between these factors and hepatic cancer remain to be established. Objective: To explore the causal relationships between immune cells, inflammatory factors, serum metabolites, and hepatic cancer. Methods: This study employed comprehensive two-sample Mendelian randomization (MR) utilizing publicly available genetic data (GWAS) to analyze causal relationships between 731 immune cell traits, 91 inflammatory factors, 1400 serum metabolites, and hepatic cancer. The primary analysis used inverse variance-weighted (IVW) MR, with additional sensitivity tests to assess the validity of causal relationships. Results: After correction for heterogeneity and horizontal pleiotropy, in exploring the causal relationships between immune cell groups and hepatic cancer, we found that Terminally Differentiated CD4-CD8- T cell %T cell was negatively associated with hepatic cancer, serving as a protective factor, while Effector Memory CD4-CD8- T cell %CD4-CD8- T cell was positively associated with hepatic cancer, acting as a risk factor. In investigating the causal relationships between inflammatory factors and hepatic cancer, C-C motif chemokine 19 levels were positively associated with hepatic cancer, representing a risk factor, while Interleukin-10 levels were negatively associated with hepatic cancer, acting as a protective factor. Regarding the causal relationships between serum metabolites and hepatic cancer, (N(1) + N(8))-acetylspermidine levels were negatively associated with hepatic cancer, serving as a protective factor, while 1-(1-enyl-palmitoyl)-GPC (p-16:0) levels were positively associated with hepatic cancer, acting as a risk factor. Conclusion: Our MR analysis indicates causal relationships between immune cells, inflammatory factors, serum metabolites, and hepatic cancer. However, further validation is needed to assess the potential of these immune cells, inflammatory factors, and serum metabolites as preventive or therapeutic targets for hepatic cancer.

Ruthenium complex containing 1,3-thiazolidine-2-thione inhibits hepatic cancer stem cells by suppressing Akt/mTOR signalling and leading to apoptotic and autophagic cell death.

Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF6, to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs.

Solitary liver metastasis from adenoid cystic carcinoma of the submandibular gland.

Adenoid cystic carcinoma (ACC) is a rare tumour of the salivary glands characterised by distant metastases, mainly to lungs and bone. Isolated metastasis to the liver is unusual. We present the case of a woman with an ACC of the submandibular gland (pT1N0) who underwent radical submandibular gland excision and selective neck dissection. Preoperative imaging identified a liver lesion with features suggestive of a haemangioma. Two-year postoperatively, a surveillance CT neck/trunk showed an increase in size of the left liver lobe lesion. Subsequent MR liver and US-guided biopsy confirmed the lesion to be metastatic ACC. The patient underwent a successful left lateral liver sectionectomy. She remains disease-free 2.5 years after her liver resection. A literature search revealed only four other similar cases. This report highlights that even early-stage ACCs of the salivary gland may present with synchronous solitary liver metastasis which can be effectively treated with curative surgery.

In-vitro cytotoxic and anti-inflammatory potential of Asparagus densiflorus meyeri and its phytochemical investigation.

Genus Asparagus is well known for its pharmacological activities and ethnopharmacological applications.  In folk medicine, it is used in the management of several diseases such as diabetes, inflammations, and rheumatism. This work aimed to investigate the potential of Asparagus densiflorus meyeri root & aerial parts extracts as cytotoxic and anti-inflammatory and the investigation of their chemical profile. GC analysis & Folin-Ciocalteu and gravimetric methods were used respectively to estimate the lipoidal, phenolic, and saponin contents. MTT assay was conducted using two cell lines (MCF-7 & HepG2) to investigate the cytotoxic and anti-inflammatory activity using TNF-α stimulated MCF-7 cells through monitoring the level of nitric oxide release and NF-κB gene expression. Preliminary phytochemical investigation indicated that both extracted parts are equally rich in saponins, flavonoids, carbohydrates and/or glycosides, and sterols and/or triterpenes. Palmitic acid and ß sitosterol represented the major saturated fatty acids and sterol, respectively. A significant cytotoxic activity against MCF-7 cells was recorded for DCM extract (IC50 26.13 µg/ml). All tested extracts showed a significant decrease in NO release and NF-κB gene expression thus it possesses a potential anti-inflammatory activity. A. densiflorus meyeri is considered a good candidate as a food supplement for protection from malignancy.

Meta-analysis of transarterial chemoembolization combined with cryoablation vs transarterial chemoembolization alone for ≥ 5 cm hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) ranks sixth globally in cancer incidence and third in mortality rates. Unfortunately, over 70% of HCC patients forego the opportunity for curative surgery or liver transplantation due to inadequate physical examinations, poor physical condition, and limited organ availability upon diagnosis. Clinical guidelines endorse transarterial chemoembolization (TACE) as the frontline treatment for intermediate to advanced-stage HCC. Cryoablation (CRA) is an emerging local ablative therapy increasingly used in HCC management. Recent studies suggest that combining CRA with TACE offers complementary and synergistic effects, potentially improving long-term survival rates. However, the superiority of combined TACE + CRA therapy over TACE alone for HCC lesions equal to or exceeding 5 cm requires further investigation. AIM: To compare the efficacy and safety of TACE combined with CRA vs TACE alone in the treatment of HCC with a diameter of ≥ 5 cm. METHODS: PubMed, EMBASE, Cochrane Library, CNKI, Wanfang, and VIP databases were searched to retrieve all relevant studies on TACE and CRA up to July 2022. Meta-analysis was performed using RevMan 5.3 software. RESULTS: After screening according to the inclusion and exclusion criteria, 6 articles were included, including 2 randomized controlled trials and 4 nonrandomized controlled trials, with a total of 575 patients included in the meta-analysis. The results showed that the objective response rate [odds ratio (OR) = 2.56, 95% confidence interval (CI):1.66-3.96, P < 0.0001), disease control rate (OR = 3.03, 95%CI: 1.88-4.89, P < 0.00001), 1-year survival rate (OR = 3.79, 95%CI: 2.50-5.76, P < 0.00001), 2-year survival rate (OR = 2.34, 95%CI: 1.43-3.85, P = 0.0008), and 3-year survival rate (OR = 3.34, 95%CI: 1.61-6.94, P = 0.001) were all superior to those of the control group; the postoperative decrease in alpha-fetoprotein value (OR = 295.53, 95%CI: 250.22-340.85, P < 0.0001), the postoperative increase in CD4 value (OR = 10.59, 95%CI: 8.78-12.40, P < 0.00001), and the postoperative decrease in CD8 value (OR = 6.47, 95%CI: 4.44-8.50, P < 0.00001) were also significantly higher than those in the TACE-alone treatment group. CONCLUSION: Compared with TACE-alone treatment, TACE + CRA combined treatment not only improves the immune function of HCC patients with a diameter of ≥ 5 cm, but also enhances the therapeutic efficacy and long-term survival rate, without increasing the risk of complications. Therefore, TACE + CRA combined treatment may be a more recommended treatment for patients with HCC with a diameter of ≥ 5 cm.

Red Sea Sponge Callyspongia siphonella Extract Induced Growth Inhibition and Apoptosis in Breast MCF-7 and Hepatic HepG-2 Cancer Cell Lines in 2D and 3D Cell Cultures.

Introduction: The increasing incidence of cancer diseases necessitates the urgent exploration of new bioactive compounds. One of the trends in drug discovery is marine sponges which is gaining significant support due to the abundant production of natural pharmaceutical compounds obtained from marine ecosystems. This study evaluates the anticancer properties of an organic extract from the Red Sea sponge Callyspongia siphonella (C. siphonella) on HepG-2 and MCF-7 cancer cell lines. Methods: C. siphonella was collected, freeze-dried, and extracted using a methanol-dichloromethane mixture. The extract was analyzed via Liquid Chromatography-Mass Spectrometry. Cytotoxic effects were assessed through cell viability assays, apoptosis detection, cell cycle analysis, mitochondrial membrane potential assays, scratch-wound healing assays, and 3D cell culture assays. Results: Fifteen compounds were identified in the C. siphonella extract. The extract showed moderate cytotoxicity against MCF-7 and HepG-2 cells, with IC50 values of 35.6 ± 6.9 µg/mL and 64.4 ± 8 µg/mL, respectively, after 48 hours of treatment. It induced cell cycle arrest at the G2/M phase in MCF-7 cells and the S phase in HepG-2 cells. Apoptosis increased significantly in both cell lines, accompanied by reduced mitochondrial membrane potential. The extract inhibited cell migration, with notable reductions after 24 and 48 hours. In 3D cell cultures, the extract had IC50 values of 5.1 ± 2 µg/mL for MCF-7 and 166.4 ± 27 µg/mL for HepG-2 after 7 days of treatment, showing greater potency in MCF-7 spheres compared to HepG-2 spheres. Discussion and Conclusion: The anticancer activity is attributed to the bioactive compounds. The C. siphonella extract's ability to induce apoptosis, disrupt mitochondrial membrane potential, and arrest the cell cycle highlights its potential as a novel anticancer agent. Additional research is required to investigate the underlying mechanism by which this extract functions as a highly effective anticancer agent.

Association between Metabolic-Dysfunction-Associated Steatotic Liver Disease and Hepatic Cancer: Current Concepts and Future Challenges.

Background: This study systematically reviewed the association between metabolic-dysfunction-associated steatotic liver disease (MASLD) and the development of hepatic cancer. Previous research has highlighted MASLD as a predisposing condition. Aim: To collect recent global data on the relationship between MASLD and hepatic cancer. Methods: A systematic review was conducted, which included an analysis of studies on the relationship between MASLD and the incidence of hepatic cancers, focusing on the role of fibrosis and MASLD severity as predictors of cancer risk. Following standard methodological frameworks for the assessment of longitudinal studies, the review gathered information on fibrosis scores, hepatocellular carcinoma (HCC) incidence, and other types of hepatic neoplasms. Results: A total of 522 studies were initially identified, of which 6 studies were appropriate for the review. They collectively revealed that the stage of fibrosis in MASLD is a significant independent predictor of mortality and liver-related events, with higher fibrosis stages correlating with greater risk. Longitudinal data showed that increases in FIB-4 scores were linked to a higher risk of developing HCC and cirrhosis. MASLD was also associated with an increased risk of non-hepatic cancers such as colorectal cancer in males and breast cancer in females. The severity of MASLD was found to be a modifiable risk factor for biliary tract cancer (BTC), with the risk further amplified by diabetes. Moreover, lifestyle factors and comorbidities, such as smoking and diabetes, were identified as modifiers of cancer risk in MASLD patients. Conclusions: The systematic review identified the association between MASLD and an elevated risk of hepatic cancer, establishing a clear link between the severity of liver fibrosis and the incidence of HCC and other hepatic neoplasms. This supports the need for screening for hepatic cancer in patients with MASLD, particularly in the presence of advanced fibrosis or other risk-modifying factors.

Previously undiagnosed genetic disease in adult patient with hepatic masses and reported history of congenital hyperinsulinism.

Glycogen storage disease type 1A (GSD1A), also known as Von Gierke's disease, is a rare autosomal recessive disorder affecting glycogen metabolism in the liver. It most commonly presents in infancy with hypoglycaemia and failure to thrive, but cases have been reported as undiagnosed until adulthood. A woman in her early 20s with diabetes mellitus presented with right upper quadrant pain and was found to have several haemorrhagic hepatic adenomas. This patient had insulin-dependent diabetes since a pancreatectomy at age 9 months due to continued episodes of hypoglycaemia and suspected insulinoma. During the hospital stay, the hepatic adenomas were embolised, but significant lactic acidosis and hypoglycaemia continued. Further workup revealed a chronic lactic acid level, during several hospital stays, of above 5 mmol/L. After cytology of hepatic tissue ruled out hepatocellular carcinoma, the patient was discharged and recommended to follow-up for genetic testing, which confirmed the diagnosis of GSD1A.

Efficacy of dual checkpoint inhibitors in a patient with a mixed hepatocellular cholangiocarcinoma.

A woman in her 60s was diagnosed with a metastatic, unresectable rare histological type of liver cancer; combined hepatocellular cholangiocarcinoma. She had palliative chemotherapy, initially with gemcitabine and cisplatin, and then with oxaliplatin, L-folinic acid and fluorouracil. Both treatment strategies demonstrated disease progression, and somatic mutation profiling revealed no actionable mutations. The patient was started on immuno-oncology (IO) with nivolumab and ipilimumab, followed by maintenance nivolumab. She has achieved a sustained ongoing partial response since the start of this therapy for at least 12 months. The outcome in this patient is in keeping with the growing evidence of the role that IO agents have in metastatic biliary tract cancer and also serves to highlight their importance in mixed histology liver tumours.

Novel insights into rosacea's role in cancer risk: A Mendelian randomization approach.

BACKGROUND: Chronic inflammation has been shown to promote cancer progression. Rosacea is indeed a long-term inflammatory skin condition and had been reported to link with increased risk for several types of malignancies, but evidence for causality is lacking. OBJECTIVES: To systematically estimate the causal relationship between rosacea and several types of cancer, including cutaneous malignant melanoma (CMM), cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), actinic keratosis (AK), thyroid cancer, breast cancer, glioma and hepatic cancer, as well as explore the potential underlying pathogenesis. METHODS: We conducted a bidirectional two-sample Mendelian randomization study to probe the potential causal relationships between rosacea and several types of cancer. Instrumental variables were established using genome-wide significant single nucleotide polymorphisms associated with rosacea and cancers. The assessment of causality was carried out through multiple methods, and the robustness of the results was evaluated via sensitivity analyses. RESULTS: There was no significant indication of causal effects of rosacea on CMM (pivw = 0.71), cSCC (pivw = 0.45), BCC (pivw = 0.90), AK (pivw = 0.73), thyroid cancer (pivw = 0.59), glioma (pivw = 0.15), and hepatic cancer (pivw = 0.07), but the genetic risk of rosacea was associated with an increased susceptibility to human epidermal growth factor receptor (HER)-negative malignant neoplasm of breast (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.18; pivw = 0.01). TANK (TRAF family member associated nuclear factor kappa B (NFKB) activator) was identified as a common protective gene for both rosacea (OR, 0.90; 95% CI, 0.82-0.99; pivw = 0.048) and HER-negative malignant neoplasm of the breast (OR, 0.86; 95% CI, 0.75-0.98; pivw = 0.032), which was primarily enriched in the negative regulation of NF-κB signal transduction and may contribute to the genetic links between rosacea and this subtype of breast cancer. CONCLUSIONS: Our findings provide suggestive evidence for causal links between rosacea and HER-negative malignant neoplasm of the breast risk.

Probiotic-derived silver nanoparticles target mTOR/MMP-9/BCL-2/dependent AMPK activation for hepatic cancer treatment.

Recent advances in nanotechnology have offered novel ways to combat cancer. By utilizing the reducing capabilities of Lactobacillus acidophilus, silver nanoparticles (AgNPs) are synthesized. The anti-cancer properties of AgNPs have been demonstrated in previous studies against several cancer cell lines; it has been hypothesized that these compounds might inhibit AMPK/mTOR signalling and BCL-2 expression. Consequently, the current research used both in vitro and in silico approaches to study whether Lactobacillus acidophilus AgNPs could inhibit cell proliferation autophagy and promote apoptosis in HepG2 cells. The isolated strain was identified as Lactobacillus acidophilus strain RBIM based on 16 s rRNA gene analysis. Based on our research findings, it has been observed that this particular strain can generate increased quantities of AgNPs when subjected to optimal growing conditions. The presence of silanols, carboxylates, phosphonates, and siloxanes on the surface of AgNPs was confirmed using FTIR analysis. AgNPs were configured using UV-visible spectroscopy at 425 nm. In contrast, it was observed that apoptotic cells exhibited orange-coloured bodies due to cellular shrinkage and blebbing initiated by AgNP treatment, compared to non-apoptotic cells. It is worth mentioning that AgNPs exhibited remarkable selectivity in inducing cell death, specifically in HepG2 cells, unlike normal WI-38 cells. The half-maximum inhibitory concentration (IC50) values for HepG2 and WI-38 cells were 4.217 µg/ml and 154.1 µg/ml, respectively. AgNPs induce an upregulation in the synthesis of inflammation-associated cytokines, including (TNF-α and IL-33), within HepG2 cells. AgNPs co-treatment led to higher glutathione levels and activating pro-autophagic genes such as AMPK.Additionally, it resulted in the suppression of mTOR, MMP-9, BCL-2, and α-SMA gene expression. The docking experiments suggest that the binding of AgNPs to the active site of the AMPK enzyme leads to inhibiting its activity. The inhibition of AMPK ultimately results in the suppression of the mechanistic mTOR and triggers apoptosis in HepG2 cells. In conclusion, the results of our study indicate that the utilization of AgNPs may represent a viable strategy for the eradication of liver cancerous cells through the activation of apoptosis and the enhancement of immune system reactions.

Appraisal of folate functionalized bosutinib cubosomes against hepatic cancer cells: In-vitro, In-silico, and in-vivo pharmacokinetic study.

Targeted therapies enhance the efficacy of tumour screening and management while lowering side effects. Multiple tumours, including liver cancer, exhibit elevated levels of folate receptor expression. This research attempted to develop surface-functionalised bosutinib cubosomes against hepatocellular carcinoma. The novelty of this work is the anti-hepatic action of bosutinib (BST) and folic acid-modified bosutinib cubosomes (BSTMF) established through proto-oncogene tyrosine-protein kinase (SrC)/ focal adhesion kinase(FAK), reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and cell cytotoxicity. Later, the in-vivo pharmacokinetics of BSTMF were determined for the first time. The strong affinity of folic acid (FA) for folate receptors allows BSTMF to enter cells via FA receptor-mediated endocytosis. The particle size of the prepared BSTMF was 188.5 ± 2.25 nm, and its zeta potential was -20.19 ± 2.01 mV, an encapsulation efficiency of 90.31 ± 3.15 %, and a drug release rate of 76.70 ± 2.10 % for 48 h. The surface architecture of BSTMF was identified using transmission electron microscopy (TEM) and Atomic force microscopy (AFM). Cell-line studies demonstrated that BSTMF substantially lowered the viability of Hep G2 cells compared to BST and bosutinib-loaded cubosomes (BSTF). BSTMF demonstrated an elevated BST concentration in tumour tissue than in other organs and also displayed superior pharmacokinetics, implying that they hold potential against hepatic cancers. This is the first study to show that BSTMF may be effective against liver cancer by targeting folate receptors and triggering SrC/FAK-dependent apoptotic pathways. Multiple parameters demonstrated that BSTMF enhanced anticancer targeting, therapeutic efficacy, and safety in NDEA-induced hepatocellular carcinoma.

Primary hepatic Castleman disease.

Castleman disease (CD) is a rare, benign lymphoproliferative disorder with characteristic histopathological features, but variable aetiology, presentation, treatment and prognosis. It is broadly classified based on its location and histopathological features, with unicentric hyaline vascular disease presenting most commonly. We present a case of primary, unicentric hepatic CD that was incidentally found on imaging and managed with laparoscopic resection.