Fabrication of polymeric sorafenib coated chitosan and fucoidan nanoparticles: Investigation of anticancer activity and apoptosis in colorectal cancer cells.

The most prevalent form of colon cancer also ranks high among cancer-related deaths globally. Traditional chemotherapy drugs do not provide sufficient therapeutic efficacy, and advanced colon cancer demonstrates considerable resistance to chemotherapy. As an oral kinase inhibitor, sorafenib (SOR) suppresses the growth of tumour cells, the formation of new blood vessels, and the death of cancer cells. Unfortunately, sorafenib's limited bioavailability, rapid metabolism, and poor solubility have severely limited its clinical use. We developed nanoparticles targeting P-selectin and SOR, with fucoidan (FU) as a ligand. The SOR-CS-FU-NPs were developed by coating polylactide-co-glycolide nanoparticles with chitosan and FU through electrostatic interaction. The SOR-CS-FU-NPs exhibited an average particle diameter of 209.98 ± 1.25 nm and a polydisperse index (PDI) of 0.229 ± 0.022. The SOR-CS-FU nanoparticles exhibited a continuous release pattern for up to 120 h. The SOR-CS-FU nanoparticles exhibited cytotoxicity 8 times greater than free SOR in HCT116 colorectal cancer cells. The cellular absorption of Rhodamine-CS-FU-NPs was three times more than that of free Rhodamine and 19 times greater than that of Rhodamine-CS-NPs. Enhanced reactive oxygen species (ROS) generation and mitochondrial membrane potential damage were also shown in SOR-CS-FU-NPs. An investigation of cell death found that SOR-CS-FU-NPs had an apoptosis index that was 7.5 times greater than free SOR. After that, the SOR-CS-FU-NPs demonstrated a more significant inhibition of cell migration, leading to a wound closure of about 5 %. No toxicity was shown in the non-cancer VERO cell line when exposed to the developed NPs. Taken together, these results provide strong evidence that biocompatible SOR-CS-FU-NPs fabricated effective carriers for the targeted delivery of dasatinib to colorectal cancer.

A Novel Combinatorial Regimen Using Sorafenib and Uttroside B, A US FDA-designated 'Orphan Drug', for the Treatment of Hepatocellular Carcinoma.

INTRODUCTION: Sorafenib (Sor) is the first-line treatment option in clinics for treating advanced unresectable hepatocellular carcinoma (HCC). However, acquired chemoresistance and adverse side effects associated with Sor monotherapy limit its clinical benefits. We have previously reported the exceptional anti-HCC potential of uttroside B (Utt-B), a furostanol saponin isolated in our lab from Solanum nigrum Linn. leaves. The current study has evaluated the supremacy of a combinatorial regimen of Sor and Utt-B over Sor monotherapy. METHODS: MTT assay was used for In vitro cytotoxicity studies. A clonogenic assay was conducted to assess the anti-proliferative effect of the combination. Annexin V/PI staining, confocal microscopy, FACS cell cycle analysis, and Western blotting experiments were performed to validate the pro-apoptotic potential of the combination in HepG2 and Huh7 cell lines. Pharmacological safety evaluation was performed in Swiss albino mice. RESULTS: Our results indicate that Utt-B augments Sor-induced cytotoxicity in HepG2 and Huh7 cells. The combination inhibits the proliferation of liver cancer cells by inducing apoptosis through activation of the caspases 7 and 3, leading to PARP cleavage. Furthermore, the combination does not induce any acute toxicity in vivo, even at a dose five times that of the effective therapeutic dose. CONCLUSION: Our results highlight the potential of Utt-B as an effective chemosensitizer, which can augment the efficacy of Sor against HCC and circumvent Sor-induced toxic side effects. Moreover, this is the first and only report to date on the chemosensitizing potential of Utt-B and the only report that demonstrates the therapeutic efficacy and pharmacological safety of a novel combinatorial regimen involving Utt-B and Sor for combating HCC.

Circulating microRNAs as biomarkers for stratifying different phases of liver cancer progression and response to therapy.

Hepatocellular carcinoma (HCC) is the most common liver cancer and is among the leading causes of cancer-related death worldwide. There is no reliable biomarker for the early diagnosis of HCC. Circulating microRNAs (miRNAs) have attracted attention as potential biomarkers of disease. By small-RNA next-generation sequencing, the analysis of serum miRNAs led to the identification of molecular signatures able to discriminate advanced HCC from early HCC (n = 246); advanced HCC from CIRRHOSIS (n = 299); advanced HCC from HEALTHY (n = 320); HEALTHY from early HCC (n = 343); and HEALTHY from CIRRHOSIS (n = 414). Cirrhotic patients and early HCC patients exhibited similar serum miRNA profiles, yet a small number of miRNAs (n = 57) were able to distinguish these two classes of patients. A second objective of the study was to identify serum miRNAs capable of predicting the response to therapy in patients with advanced HCC. All patients were treated with sorafenib as first-line therapy: 24 were nonresponsive and 24 responsive. Analysis of circulating miRNAs revealed a 54 miRNAs signature able to separate the two subgroups. This study suggested that circulating miRNAs could be useful biomarkers for monitoring patients with liver diseases ranging from cirrhosis to advanced HCC and possibly predicting susceptibility to first-line treatment based on sorafenib.

Hemoglobin nanoclusters-mediated regulation of KPNA4 in hypoxic tumor microenvironment enhances photodynamic therapy in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant tumor known for its hypoxic environment, which contributes to resistance against the anticancer drug Sorafenib (SF). Addressing SF resistance in HCC requires innovative strategies to improve tumor oxygenation and effectively deliver therapeutics. RESULTS: In our study, we explored the role of KPNA4 in mediating hypoxia-induced SF resistance in HCC. We developed hemoglobin nanoclusters (Hb-NCs) capable of carrying oxygen, loaded with indocyanine green (ICG) and SF, named HPRG@SF. In vitro, HPRG@SF targeted HCC cells, alleviated hypoxia, suppressed KPNA4 expression, and enhanced the cytotoxicity of PDT against hypoxic, SF-resistant HCC cells. In vivo experiments supported these findings, showing that HPRG@SF effectively improved the oxygenation within the tumor microenvironment and countered SF resistance through combined photodynamic therapy (PDT). CONCLUSION: The combination of Hb-NCs with ICG and SF, forming HPRG@SF, presents a potent strategy to overcome drug resistance in hepatocellular carcinoma by improving hypoxia and employing PDT. This approach not only targets the hypoxic conditions that underlie resistance but also provides a synergistic anticancer effect, highlighting its potential for clinical applications in treating resistant HCC.

Anti-proliferation evaluation of new derivatives of indole-6-carboxylate ester as receptor tyrosine kinase inhibitors.

Aim: The main goal was to create two new groups of indole derivatives, hydrazine-1-carbothioamide (4a and 4b) and oxadiazole (5, and 6a-e) that target EGFR (4a, 4b, 5) or VEGFR-2 (6a-e). Materials & methods: The new derivatives were characterized using various spectroscopic techniques. Docking studies were used to investigate the binding patterns to EGFR/VEGFR-2, and the anti-proliferative properties were tested in vitro. Results: Compounds 4a (targeting EGFR) and 6c (targeting VEGFR-2) were the most effective cytotoxic agents, arresting cancer cells in the G2/M phase and inducing the extrinsic apoptosis pathway. Conclusion: The results of this study show that compounds 4a and 6c are promising cytotoxic compounds that inhibit the tyrosine kinase activity of EGFR and VEGFR-2, respectively.

[Box: see text].

Additional Hepatic Arterial Infusion Chemotherapy to Sorafenib Was Cost-Effective for Hepatocellular Carcinoma with Major Portal Vein Tumor Thrombosis.

Purpose: The combination of sorafenib and hepatic arterial infusion chemotherapy (SoHAIC) has shown to enhance overall survival rates in patients with advanced hepatocellular carcinoma and major portal vein tumor thrombosis (HCC-Vp3-4) compared to sorafenib alone. Our objective was to evaluate the cost-effectiveness of SoHAIC versus sorafenib for the treatment of HCC-Vp3-4, taking into account the viewpoint of Chinese healthcare payers. Methods: This pharmacoeconomic study employed a Markov model to assess the cost-effectiveness of treating HCC-Vp3-4 with SoHAIC in comparison to sorafenib. The patient characteristics were drawn from individuals from the trial conducted between June 2017 and November 2019, with cost and health value data sourced from published literature. The primary outcome measure in this research was the incremental cost-effectiveness ratio (ICER), which indicates the additional cost per quality-adjusted life year (QALY). The willingness-to-pay (WTP) threshold per QALY was set at $30,492.00. Furthermore, 1-way sensitivity and probabilistic sensitivity analyses were carried out to validate the consistency of the results. Results: In the baseline scenario, sorafenib resulted in 0.42 QALY at a cost of $10,507.89, while SoHAIC generated 1.66 QALY at a cost of $32,971.56. When comparing SoHAIC to sorafenib, the ICER was $18,237.20 per QALY, which was below the WTP threshold per QALY. Furthermore, the 1-way sensitivity analysis demonstrated that the ICER remained within the WTP threshold despite fluctuations in variables. In the probabilistic sensitivity analysis, SoHAIC had a 98.8% probability of being cost-effective at the WTP threshold, considering a wide range of parameters. Conclusion: In this cost-effectiveness evaluation, SoHAIC demonstrated cost-effectiveness over sorafenib for HCC with major portal vein tumor thrombosis, as observed from the perspective of a Chinese payer.

A potent formula against triple-negative breast cancer-sorafenib-carbon nanotubes-folic acid: Targeting, apoptosis triggering, and bioavailability enhancing.

Triple-negative breast cancer (TNBC) has short survival rates. This study aimed to prepare a novel formula of sorafenib, carbon nanotubes (CNTs), and folic acid to be tested as a drug delivery system targeting versus TNBC compared with free sorafenib and to evaluate the formula stability, in vitro pharmacodynamic, and in vivo pharmacokinetic properties. The formula preparation was done by the synthesis of polyethylene glycol bis amine linker, CNT PEGylation, folic acid attachment, and sorafenib loading. The prepared formula has been characterized using X-ray diffraction, Flourier-transform infrared, 1HNMR, UV, high resolution-transmission electron microscope, field emission scanning electron microscopy, and Zeta potential. In vitro studies included drug release determination, MTT assay, flow cytometry to determine the apoptotic stage with percent, cell cycle analysis, and apoptotic marker assays for caspase-3, 8, 9, cytochrome c, and BCL-2. The in vivo study was performed to determine bioavailability and half-life in rats. The in vitro MTT antiproliferative assay revealed that the formula was threefold more cytotoxic toward TNBC cells than free sorafenib, and the flow cytometry showed a significant increase in apoptosis and necrosis. The formula has a greater inhibitory effect on BCL-2 and a lessening effect on cytochrome c and caspases 3, 8, and 9 than free sorafenib. In vivo experiments proved that our novel formula was superior to free sorafenib by increasing bioavailability by eight times and prolonging the half-life by three times. These results confirmed the successful preparation of the desired formula with better pharmacodynamic and pharmacokinetic properties. These promising results may show a novel therapeutic strategy for TNBC patients.

Endoplasmic Reticulum Membrane Protein Complex Regulates Cancer Stem Cells and is Associated with Sorafenib Resistance in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential. Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC's clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle. Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells' sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1's role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation. Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy.

Substituted indole derivatives as UNC-51-like kinase 1 inhibitors: Design, synthesis and anti-hepatocellular carcinoma activity.

The five-year survival rate for patients with hepatocellular carcinoma (HCC) is only 20 %, highlighting the urgent need to identify new therapeutic targets and develop potential therapeutic options to improve patient prognosis. One promising approach is inhibiting autophagy as a strategy for HCC treatment. In this study, we established a virtual docking conformation of the autophagy promoter ULK1 binding XST-14 derivatives. Based on this conformation, we designed and synthesized four series of derivatives. By evaluating their affinity and anti-HCC effects, we confirmed that these compounds exert anti-HCC activity by inhibiting ULK1. The structure-activity relationship was summarized, with derivative A4 showing 10 times higher activity than XST-14 and superior efficacy to sorafenib against HCC. A4 has excellent effect on reducing tumor growth and enhancing sorafenib activity in HepG2 and HCCLM3 cells. Moreover, we verified the therapeutic effect of A4 in sorafenib-resistant HCC cells both in vivo and in vitro. These results suggest that inhibiting ULK1 to regulate autophagy may become a new treatment method for HCC and that A4 will be used as a lead drug for HCC in further research. Overall, A4 shows good drug safety and efficacy, offering hope for prolonging the survival of HCC patients.

Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth.

Thioredoxin Reductase (TrxR) functions to recycle thioredoxin (Trx) during hydroperoxide metabolism mediated by peroxiredoxins and is currently being targeted using the FDA-approved anti-rheumatic drug, auranofin (AF), to selectively sensitize cancer cells to therapy. AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the H727 atypical lung carcinoid cell line. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, an FDA-approved multi-kinase inhibitor that depleted intracellular glutathione (GSH). The pharmacokinetic, pharmacodynamic, and safety profile of AF was examined in nude mice with DMS273 xenografts administered AF intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1-5 d. Plasma levels of AF were 10-20 µM (determined by mass spectrometry of gold), and the optimal inhibition of TrxR activity was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. This AF treatment extended for 14 d, inhibited TrxR (>75%), and resulted in a significant prolongation of median overall survival from 19 to 23 d (p = .04, N = 30 controls, 28 AF). In this experiment, there were no observed changes in animal bodyweight, complete blood counts (CBCs), bone marrow toxicity, blood urea nitrogen, or creatinine. These results support the hypothesis that AF effectively inhibits TrxR both in vitro and in vivo in SCLC, sensitizes NETs and SCLC to sorafenib, and could be repurposed as an adjuvant therapy with targeted agents that induce disruptions in thiol metabolism.

Kombo knife combined with sorafenib in liver cancer treatment: Efficacy and safety under immune function influence.

BACKGROUND: In the quest to manage hepatocellular carcinoma (HCC), the focus has shifted to a more holistic approach encompassing both data analytics and innovative treatments. Analyzing rich data resources, such as the cancer genome atlas (TCGA), and examining progressive therapies can potentially reshape the trajectory of HCC treatment. AIM: To elucidate the immunological genes and the underlying mechanism of the combined Kombo knife and sorafenib regimen for HCC by analyzing data from TCGA and machine learning data. METHODS: Immune attributes were evaluated via TCGA's postablation HCC RNA sequencing data. Using weighted gene coexpression network analysis and machine learning, we identified genes with high prognostic value. The therapeutic landscape and safety metrics of the integrated treatment were critically evaluated across cellular and animal models. RESULTS: Immune genes-specifically, peptidylprolyl isomerase A and solute carrier family 29 member 3-emerged as significant prognostic markers. Enhanced therapeutic outcomes, such as prolonged progression-free survival and an elevated overall response rate, characterize the combined approach, with peripheral blood mononuclear cells displaying potent effects on HCC dynamics. CONCLUSION: The combination of Kombo knife with sorafenib is an innovative HCC treatment modality anchored in immune-centric strategies.

Challenges in treating radioiodine-refractory thyroid cancer: a global perspective with a focus on developing nations in Latin America.

PURPOSE: This article aims to comprehensively analyze the unique challenges in managing patients with metastatic Differentiated Thyroid Cancer (DTC) that develop radioiodine-refractory disease, especially in developing countries in Latin America. We discuss key contentious aspects of their treatment, such as the optimal timing for initiating systemic therapy, the choice of first-line medications, the appropriate timing for requesting molecular interrogation, and the challenges associated with accessing these drugs and molecular panels. METHODS: To illustrate these challenges and enhance understanding, we present five real clinical cases from the authors' experiences. RESULTS: Patients with Differentiated Thyroid Cancer (DTC) generally have an excellent prognosis, with an overall 10-year survival rate exceeding 97%. However, approximately 5% of DTC patients, especially those with distant metastases, may develop radioiodine-refractory disease, reducing survival rates. Access to medications remains difficult and time-consuming, particularly for patients within the public healthcare system. Urgent discussions on drug pricing involving all stakeholders are imperative. To break free from complacency, stakeholders must prioritize patient well-being by advocating for evidence-based drug pricing, increased participation in clinical trials, and streamlined regulatory processes. CONCLUSION: Beyond the recognized need for prospective randomized clinical trials to determine the optimal first-line drug and the timing of molecular testing, this type of manuscript plays a pivotal role in stimulating discussions and disseminating comprehensive knowledge about the challenges associated with treating and monitoring patients with radioiodine-refractory thyroid carcinoma, especially in developing countries.

Enhanced anticancer activity of silver doped zinc oxide magnetic nanocarrier loaded with sorafenib for hepatocellular carcinoma treatment.

Drug delivery is the process or method of delivering a pharmacological product to have therapeutic effects on humans or animals. The use of nanoparticles to deliver medications to cells is driving the present surge in interest in improving human health. Green nanodrug delivery methods are based on chemical processes that are acceptable for the environment or that use natural biomaterials such as plant extracts and microorganisms. In this study, zinc oxide-superparamagnetic iron oxide-silver nanocomposite was synthesized via green synthesis method using Fusarium oxysporum fungi mycelia then loaded with sorafenib drug. The synthesized nanocomposites were characterized by UV-visibile spectroscopy, FTIR, TEM and SEM techniques. Sorafenib is a cancer treatment and is also known by its brand name, Nexavar. Sorafenib is the only systemic medication available in the world to treat hepatocellular carcinoma. Sorafenib, like many other chemotherapeutics, has side effects that restrict its effectiveness, including toxicity, nausea, mucositis, hypertension, alopecia, and hand-foot skin reaction. In our study, 40 male albino rats were given a single dose of diethyl nitrosamine (DEN) 60 mg/kg b.wt., followed by carbon tetrachloride 2 ml/kg b.wt. twice a week for one month. The aim of our study is using the zinc oxide-superparamagnetic iron oxide-silver nanocomposite that was synthesized by Fusarium oxysporum fungi mycelia as nanocarrier for enhancement the sorafenib anticancer effect.

Research progress of sorafenib drug delivery system in the treatment of hepatocellular carcinoma: An update.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors in the contemporary era, representing a significant global health concern. Early HCC patients have mild symptoms or are asymptomatic, which promotes the onset and progression of the disease. Moreover, advanced HCC is insensitive to chemotherapy, making traditional clinical treatment unable to block cancer development. Sorafenib (SFB) is a first-line targeted drug for advanced HCC patients with anti-angiogenesis and anti-tumor cell proliferation effects. However, the efficacy of SFB is constrained by its off-target distribution, rapid metabolism, and multi-drug resistance. In recent years, nanoparticles based on a variety of materials have been demonstrated to enhance the targeting and therapeutic efficacy of SFB against HCC. Concurrently, the advent of joint drug delivery systems has furnished crucial empirical evidence for reversing SFB resistance. This review will summarize the application of nanotechnology in the field of HCC treatment over the past five years. It will focus on the research progress of SFB delivery systems combined with multiple therapeutic modalities in HCC treatment.

SOD1 inhibition enhances sorafenib efficacy in HBV-related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS-mediated cell death.

Hepatitis B Virus (HBV) infection significantly elevates the risk of hepatocellular carcinoma (HCC), with the HBV X protein (HBx) playing a crucial role in cancer progression. Sorafenib, the primary therapy for advanced HCC, shows limited effectiveness in HBV-infected patients due to HBx-related resistance. Numerous studies have explored combination therapies to overcome this resistance. Sodium diethyldithiocarbamate (DDC), known for its anticancer effects and its inhibition of superoxide dismutase 1 (SOD1), is hypothesized to counteract sorafenib (SF) resistance in HBV-positive HCCs. Our research demonstrates that combining DDC with SF significantly reduces HBx and SOD1 expressions in HBV-positive HCC cells and human tissues. This combination therapy disrupts the PI3K/Akt/mTOR signalling pathway and promotes apoptosis by increasing reactive oxygen species (ROS) levels. These cellular changes lead to reduced tumour viability and enhanced sensitivity to SF, as evidenced by the synergistic suppression of tumour growth in xenograft models. Additionally, DDC-mediated suppression of SOD1 further enhances SF sensitivity in HBV-positive HCC cells and xenografted animals, thereby inhibiting cancer progression more effectively. These findings suggest that the DDC-SF combination could serve as a promising strategy for overcoming SF resistance in HBV-related HCC, potentially optimizing therapy outcomes.

[Sodium butyrate and sorafenib synergistically inhibit hepatocellular carcinoma cells possibly by inducing ferroptosis through inhibiting YAP].

OBJECTIVE: To investigate whether sodium butyrate (NaB) and sorafenib synergistically induces ferroptosis to suppress proliferation of hepatocellular carcinoma cells and the possible underlying mechanisms. METHODS: CCK8 assay and colony formation assay were used to assess the effects of NaB and sorafenib, alone or in combination, on proliferation of HepG2 cells, and ferroptosis of the treated cells was detected with GSH assay and C11-BODIPY 581/591 fluorescent probe. TCGA database was used to analyze differential YAP gene expression between liver cancer and normal tissues. The effects of NaB and sorafenib on YAP and p-YAP expressions in HepG2 cells were invesitigated using Western blotting. RESULTS: NaB (2 mmol/L) significantly reduced the IC50 of sorafenib in HepG2 cells, and combination index analysis confirmed the synergy between sorafenib and NaB. The ferroptosis inhibitor Fer-1 and the YAP activator (XMU) obviously reversed the growthinhibitory effects of the combined treatment with NaB and sorafenib in HepG2 cells. The combined treatment with NaB and sorafenib, as compared with the two agents used alone, significantly inhibited colony formation of HepG2 cells, further enhanced cellular shrinkage and dispersion, and decreased intracellular GSH and lipid ROS levels, and these effects were reversed by Fer-1 and XMU. TCGA analysis revealed a higher YAP mRNA expression in liver cancer tissues than in normal liver tissues. NaB combined with sorafenib produced significantly stronger effects than the individual agents for downregulating YAP protein expression and upregulating YAP phosphorylation level in HepG2 cells. CONCLUSION: NaB combined with sorafenib synergistically inhibit hepatocellular carcinoma cell proliferation possibly by inducing ferroptosis via inhibiting YAP expression.

Case report: Precision guided reactive cancer management: molecular complete response in heavily pretreated metastatic CRC by dual immunotherapy and sorafenib.

Background: Metastatic colon adenocarcinoma presents significant challenges in treatment, particularly when resistant to standard therapies. Precision oncology, guided by multidisciplinary tumor boards (MTBs), offers a promising way for individualized therapeutic approaches. Integration of comprehensive genomic profiling (CGP) and minimal residual disease (MRD) testing strengthens treatment decision-making, yet challenges persist in identifying and overcoming resistance mechanisms. FLT3 amplification can be one of those resistance/escape mechanisms that needs to be targeted. Case presentation: This case report presents a 58-year-old male diagnosed with metastatic colon adenocarcinoma with liver metastasis, resistant to conventional treatments. Utilizing CGP and MRD testing, our multidisciplinary MTB identified a complex mutational profile, including APC, DAXX, TP53 mutations, and CDK8 and FLT3 amplifications. With a tumor mutational burden of 10 muts/mb and TPS, CPS scores of 0, immunotherapy was considered, employing dual immune checkpoint inhibitors alongside mebendazole and Lenvatinib targeting the WNT and VEGF/angiogenesis pathways. MRD testing revealed early treatment failure. Re-evaluation identified high copied FLT3 amplification (62 copies) as a resistance mechanism, prompting modification to incorporate sorafenib and dual immunotherapy with mebendazole. Subsequent MRD assessments and radiological scans demonstrated a remarkable therapeutic response, with sustained efficacy and absence of detectable residual disease. Conclusion: This case highlights the successful application of precision oncology principles, facilitated by dynamic MTB-guided treatment strategies. Integration of MRD testing provided early detection of treatment inefficacy, allowing for timely intervention and adaptation of the treatment plan. Additionally, the case highlights the educational value of rare molecular alterations, emphasizing continual learning and refinement of treatment approaches in precision oncology.

Ropivacaine synergizes with sorafenib to induce apoptosis of hepatocellular carcinoma cells via the IL-6/STAT3 pathway.

The development of resistance in hepatocellular carcinoma (HCC) cells limits the effectiveness of sorafenib, but combination therapy with other drugs may have a positive effect. However, the effect of ropivacaine combined with sorafenib on the treatment of HCC cells and its potential regulatory mechanisms remain unclear. The proliferation and apoptosis of HCC cells treated with ropivacaine, sorafenib, and ropivacaine plus sorafenib were analyzed by cell-counting kit 8 and flow cytometry. The protein levels were measured by Western blot. The antitumor effect of ropivacaine, sorafenib, and their combination was verified by a tumor xenograft model. Ropivacaine and sorafenib markedly impeded the viability of HCC cells in a concentration-dependent manner. Compared with ropivacaine or sorafenib treatment alone, ropivacaine and sorafenib combination treatment impeded HCC cell proliferation, facilitated apoptosis, enhanced cleaved caspase-3, cleaved caspase-9, and cyclin D1 protein expression, while it reduced IL-6 and p-STAT3 expression and inhibited tumor growth in vivo. Importantly, the activation of the IL-6/STAT3 pathway could reverse the repressive or stimulative effects of ropivacaine and sorafenib on the proliferation and apoptosis in HCC cells. In summary, ropivacaine synergistically induces sorafenib-stimulated apoptosis of HCC cells via the IL-6/STAT3 pathway. Ropivacaine is a potential drug for the treatment of HCC when combined with sorafenib.

Internist's tumour into thyroid: A case report.

Renal cell carcinoma (RCC) is well known for its unpredictable and diverse behaviour, with tendency to cause synchronous or metachronous metastasis to unusual site, which is why it is called the "internist's tumour."Although thyroid gland is an infrequent site for metastasis of different primary malignancies, metastatic RCC is one of the most common secondary thyroid malignancies. Diagnosis relies on a high index of suspicion in patients with prior RCC, combined with cross-sectional imaging and biopsy. A case of secondary thyroid neoplasm from RCC after 13 years of radical nephrectomy is described with clinicopathological features and literature review.

Sorafenib maintenance in FLT3-ITD mutated AML after allogeneic HCT: a real-world, single-center experience.

Despite allogeneic hematopoietic stem cell transplant (allo-HCT) and the development of novel FLT3 inhibitors in both induction (midostaurin) and in the relapsed/refractory setting (gilteritinib), FLT3-ITD mutated leukemia (FLT3-ITD+ AML) still represents a challenge for modern hematology. Sorafenib is, to this date, the only inhibitor that demonstrated efficacy in improving both progression-free and overall survival as post-HCT maintenance therapy, even if its use in this setting has not been approved so far by regulatory agencies. The aim of our study was to evaluate the feasibility, safety, and efficacy of sorafenib maintenance in preventing early relapse in FLT3-ITD+ AML after HCT in a single-center experience. We analyzed 26 consecutive patients who received post-HCT 2-year maintenance with sorafenib at our center between 2017 and 2023. The median time from HCT to sorafenib start was 130 days, and the median dosage was 200 mg per day. Two (8%) and three (12%) patients discontinued maintenance due to toxicity and disease relapse, respectively. Eight (31%) patients terminated the 2-year maintenance and stopped sorafenib, while 13 patients are still under treatment. Overall, 21/26 patients (81%) are alive and in stable complete remission as outlined by a 2-year disease-free survival of 83.61%. No major long-term toxicity was reported at the last follow-up. Our real-world experience supports the use of sorafenib as a feasible and effective therapeutic option in post-HCT maintenance for FLT3-ITD+ AML.