Non-small cell lung cancer (NSCLC) with driver mutations, notably epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase, shows reduced sensitivity to immune checkpoint inhibitors. A subgroup analysis of the IMpower150 data on patients resistant to EGFR tyrosine kinase inhibitors (EGFR-TKI) before enrollment demonstrated prolonged progression-free survival (PFS) with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) over bevacizumab, carboplatin, and paclitaxel. However, due to the exploratory nature and small sample size, the efficacy of ABCP post-EGFR-TKI failure is still debated. We evaluated ABCP therapy against other platinum-based regimens without immune checkpoint inhibitors in terms of effectiveness and toxicity.

Data from patients with advanced or recurrent NSCLC harboring EGFR-sensitizing mutations treated with platinum-based chemotherapy or ABCP at five Japanese hospitals were retrospectively analyzed. Propensity score matching compared efficacy outcomes, including overall response rate (ORR), PFS, and OS.

Of 183 EGFR mutation carriers, 33 underwent ABCP therapy, while 150 received platinum-based chemotherapy. Following propensity score matching, 32 and 74 patients were analyzed. In the ABCP group, median PFS and OS were 6.8 and 16.7 months compared to 5.8 and 25.7 months with platinum-based chemotherapy, showing no significant differences in PFS (p = 0.46) and OS (p = 0.85). In liver metastases, ABCP yielded a median PFS of 9.9 versus 6.1 months and an ORR of 62.5 % versus 35.7 % relative to platinum-based chemotherapy, without statistical significance (PFS p = 0.16; ORR p = 0.70).

Compared with platinum-based chemotherapy, ABCP did not improve effectiveness in patients with EGFR-mutated NSCLC after EGFR-TKI failure.

Small cell lung cancer (SCLC) is difficult to treat due to its aggressiveness, early metastasis, and rapid development of resistance to chemotherapeutic agents. Here, we show that treatment with a dopamine D2 receptor (D2R) agonist reduces tumour angiogenesis in multiple in vivo xenograft models of human SCLC, thereby reducing SCLC progression. An FDA-approved D2R agonist, cabergoline, also sensitized chemotherapy-resistant SCLC tumours to cisplatin and etoposide in patient-derived xenograft models of acquired chemoresistance in mice. Ex vivo, D2R agonist treatment decreased tumour angiogenesis through increased apoptosis of tumour-associated endothelial cells, creating a less favourable tumour microenvironment that limited cancer cell proliferation. In paired SCLC patient-derived specimens, D2R was expressed by tumour-associated endothelial cells obtained before treatment, but D2R was downregulated in SCLC tumours that had acquired chemoresistance. D2R agonist treatment of chemotherapy-resistant specimens restored expression of D2R. Activation of dopamine signalling is thus a new strategy for inhibiting angiogenesis in SCLC and potentially for combatting chemotherapy-refractory SCLC progression.

Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.

Since the advent of immunotherapy in clinical practice, it has profoundly transformed the paradigm of cancer treatment and has been rapidly adopted in clinical settings. Concurrently, the combination of immunotherapy with anti-angiogenic therapy has shown great promise in clinical research. The inevitable joint application brings about a greater number of adverse reactions. These adverse reactions are often perplexing, with the uncertainty of whether they stem from immunotherapy, anti-angiogenic therapy, or both. This is a case report of adverse reactions occurring when immune drugs and anti-vascular drugs are used together. This case is analyzed to provide a warning for adverse reactions in the clinical application of anti-angiogenic therapy combined with immunotherapy.

A 52-year-old cervical cancer patient with metastases had abdominal pain and fever post-treatment with bevacizumab, pembrolizumab, and chemotherapy, suggesting intestinal perforation.

After 2 chemotherapy cycles with bevacizumab and pembrolizumab, the patient had fever up to 39°C and abdominal pain. Exam showed tenderness, rigidity, and weak bowel sounds. Blood tests revealed leukocytosis and neutrophilia. Imaging indicated pneumoperitoneum and possible intestinal obstruction.

Emergency laparotomy revealed a small intestine perforation with strictures, leading to resection and ileostomy due to edema.

The postoperative recovery was good. We consider intestinal perforation caused by bevacizumab. Therefore, the patient was subsequently discontinued from bevacizumab and continued to receive paclitaxel, cisplatin and pembrolizumab. At present, the patient has finished chemotherapy and is receiving pembrolizumab maintenance therapy with no significant gastrointestinal adverse reactions.

Anti-angiogenic drugs and immunotherapy drugs each have their own side effects, and the occurrence of adverse reactions becomes more complex when used in combination. In the clinical process of combined medication, more attention should be paid to adverse reactions, early identification of severe adverse reactions, and active management.

Head and neck tumors represent a prevalent category of oral and maxillofacial malignancies, posing significant therapeutic and prognostic challenges due to their complex anatomical structure, tumor heterogeneity, and resistance to conventional therapies. Recent studies have highlighted the strong association between tumor progression and neoangiogenesis, with the angiopoietin (ANG) family playing a central role in this process. Comprising ANG1, ANG2, ANG3, and ANG4, these factors regulate multiple signaling pathways that promote cellular growth, differentiation, and proliferation, thereby driving angiogenesis and accelerating tumor growth and metastasis. Therefore, a comprehensive investigation of the ANG family's role in head and neck tumors may offer critical insights into tumorigenesis mechanisms and unveil novel therapeutic targets. Such research has the potential to improve treatment outcomes and enhance the quality of life for patients.

The tumor microenvironment (TME) is a highly complex and continuous evolving ecosystem, consisting of a diverse array of cellular and non-cellular components. Among these, benign non-immune cells, including cancer-associated fibroblasts (CAFs), adipocytes, endothelial cells (ECs), pericytes (PCs), Schwann cells (SCs) and others, are crucial factors for tumor development. Benign non-immune cells within the TME interact with both tumor cells and immune cells. These interactions contribute to tumor progression through both direct contact and indirect communication. Numerous studies have highlighted the role that benign non-immune cells exert on tumor progression and potential tumor-promoting mechanisms via multiple signaling pathways and factors. However, these benign non-immune cells may play different roles across cancer types. Therefore, it is important to understand the potential roles of benign non-immune cells within the TME based on tumor heterogeneity. A deep understanding allows us to develop novel cancer therapies by targeting these cells. In this review, we will introduce several types of benign non-immune cells that exert on different cancer types according to tumor heterogeneity and their roles in the TME.

Chemotherapy serves as the primary treatment for cancers, facing challenges due to the emergence of drug resistance. Combination therapy has been developed to combat cancer drug resistance, yet it still suffers from lack of specific targeting of cancer cells and poor accumulation at the tumor site. Consequently, targeted administration of chemotherapy medications has been employed in cancer treatment. Doxorubicin (DOX) is one of the most frequently used chemotherapeutics, functioning by inhibiting topoisomerase activity. Enhancing the anti-cancer effects of DOX and overcoming drug resistance can be accomplished via delivery by nanoparticles. This review will focus on the development of peptide-DOX conjugates, the functionalization of nanoparticles with peptides, the co-delivery of DOX and peptides, as well as the theranostic use of peptide-modified nanoparticles in cancer treatment. The peptide-DOX conjugates have been designed to enhance the targeted delivery to cancer cells by interacting with receptors that are overexpressed on tumor surfaces. Moreover, nanoparticles can be modified with peptides to improve their uptake in tumor cells via endocytosis. Nanoparticles have the ability to co-deliver DOX along with therapeutic peptides for enhanced cancer treatment. Finally, nanoparticles modified with peptides can offer theranostic capabilities by facilitating both imaging and the delivery of DOX (chemotherapy).

Reconstructing the tumor immune microenvironment is an effective strategy to enhance therapeutic efficacy limited by immunosuppression in non-small-cell lung cancer (NSCLC). In this study, it is found that selenium (Se) depletion and immune dysfunction are present in patients with advanced NSCLC compared with healthy volunteers. Surprisingly, Se deficiency resulted in decreased immunity and accelerated rapid tumor growth in the mice model, which further reveals that the correlation between micronutrient Se and lung cancer progression. This pioneering work achieves 500-L scale production of Se nanoparticles (SeNPs) at GMP level and utilizes it to reveal how and why the trace element Se can enhance clinical immune-mediated treatment efficacy against NSCLC. The results found that translational SeNPs can promote the proliferation of NK cells and enhance its cytotoxicity against cancer cells by activating mTOR signaling pathway driven by GPXs to regulate the secretion of cytokines to achieve an antitumor response. Moreover, a clinical study of an Investigator-initiated Trial shows that translational SeNPs supplementation in combination with bevacizumab/cisplatin/pemetrexed exhibits enhanced therapeutic efficacy with an objective response rate of 83.3% and a disease control rate of 100%, through potentiating selenoprotein-driven antitumor immunity. Taken together, this study, for the first time, highlights the translational SeNPs-enhanced therapeutic efficacy against clinical advanced NSCLC.

Several debilitating eye diseases that lead to vision loss are driven by ocular neovascularization, which entails abnormal blood vessel growth in the eye. Neovascularization is often induced by the upregulation of vascular endothelial growth factor (VEGF) ligands, which activate angiogenesis through engagement of VEGF receptor (VEGFR) proteins on endothelial cells. Therapeutic interventions that block ocular neovascularization by targeting VEGF ligands, particularly VEGF-A, have revolutionized eye disease treatment. However, a significant population of patients are either non-responders or develop resistance, which can be driven by the upregulation of other VEGF family ligands such as VEGF-C. Here, we engineered two bispecific receptor decoy fusion proteins that incorporate domains of VEGFR-1 and VEGFR-2 for more effective and comprehensive inhibition of VEGF ligands. We demonstrated that our engineered proteins bind all VEGF ligands and can sequester two ligands simultaneously. We further showed that these molecules block VEGF activity to potently inhibit proliferation, migration, and survival of human endothelial cells. Moreover, these receptor decoy proteins significantly reduced ocular neovascularization in two mouse models at doses wherein the current standard-of-care anti-VEGF therapy is ineffective. Collectively, our engineered receptor decoy proteins present a new architecture for VEGF pathway inhibition, offering a promising treatment paradigm for ocular diseases.

To assess the efficacy and safety of lenvatinib/bevacizumab combined with programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors and gemcitabine/oxaliplatin (GEMOX) as first-line treatments in patients with advanced biliary tract cancer (BTC). Patients with advanced BTC who received lenvatinib/bevacizumab combined with PD-1/PD-L1 inhibitors plus gemcitabine/oxaliplatin (GEMOX) chemotherapy were retrospectively screened. The primary endpoints were overall survival (OS) and progression-free survival (PFS), whereas the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors for survival were analyzed. A total of 172 individuals were enrolled and categorized into four groups: Group A received GEMOX plus PD-1 antibody (sintilimab or camrelizumab) and lenvatinib; group B received GEMOX and PD-1 antibody (sintilimab or camrelizumab) and bevacizumab; group C received GEMOX and PD-1 antibody (sintilimab or camrelizumab); and group D received GEMOX alone. The median OS was 13.63 months (95% confidence interval [CI]: 12.37-14.89), 12.41 months (95% CI: 10.67-12.32), 11.23 months (95% CI: 9.39-13.07), and 8.86 months (95% CI: 7.28-10.44) in groups A, B, C, and D, respectively (P = 0.312). In groups A, B, C, and D, the median PFS was 12.42 months, 11.05 months, 8.89 months, and 6.02 months. A statistically significant difference was observed (t = 2, 95% CI: 11.31-13.53, P < 0.01). The ORR was 45.00% (17/40) in group A, 34.78% (16/46) in group B, 16.67% (5/30) in group C, and 17.86% (10/56) in group D. The DCR was 87.50% (35/40), 78.26% (36/46), 76.67% (23/30), and 58.93% (33/56) in groups A, B, C, and D, respectively. In addition, regression analysis showed that patients' metastasis site, whether the neutrophil-lymphocyte ratio was < 2.3, and whether chemotherapy was administered through hepatic artery embolization and was independent prognostic factors influencing median OS and PFS. Almost all patients included in the study experienced treatment-related adverse events (TRAEs) of varying degrees of severity, with grade 1-2 adverse events predominating. Lenvatinib/bevacizumab combined with programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors and gemcitabine/oxaliplatin (GEMOX) represent an effective and tolerable regimen for advanced BTC in a multicenter retrospective real-world study.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, necessitating the continuous evolution of therapeutic approaches. Despite advancements in early detection and localized treatments, metastatic colorectal cancer (mCRC) poses significant challenges due to low survival rates and resistance to conventional therapies. This review highlights the current landscape of CRC treatment, focusing on chemotherapy and targeted therapies. Chemotherapeutic agents, including 5-fluorouracil, irinotecan, and oxaliplatin, have significantly improved survival but face limitations such as systemic toxicity and resistance. Targeted therapies, leveraging mechanisms like VEGF, EGFR, and Hedgehog pathway inhibition, offer promising alternatives, minimizing damage to healthy tissues while enhancing therapeutic precision. Furthermore, future directions in CRC treatment include exploring innovative targets such as Wnt/β-catenin, Notch, and TGF-β pathways, alongside IGF/IGF1R inhibition. These emerging strategies aim to address drug resistance and improve patient outcomes. This review emphasizes the importance of integrating molecular insights into drug development, advocating for a more personalized approach to combat CRC's complexity and heterogeneity.

We performed a comprehensive systematic review and network meta-analysis (NMA) to assess the efficacy of pharmacological agents for the treatment of proliferative vitreoretinopathy (PVR) following retinal detachment (RD) surgery. A systematic search was performed across PubMed, Scopus, Web of Science, and Embase. Randomized and non-randomized controlled trials and comparative observational studies evaluating the effect of pharmacological agents in a clinical setting were included. The primary outcome was retinal reattachment rate, and secondary outcomes were PVR recurrence, reoperation, intraocular pressure (IOP), epiretinal membrane (ERM), and macular edema. A total of 23 studies with 1749 eyes were included. Twelve different drugs or drug combinations were assessed. The NMA was performed for retinal reattachment, PVR recurrence, and reoperation rate outcomes. Among the pharmacological agents analyzed, adjunctive therapy with 13-cis-retinoic acid (13-cis-RA) demonstrated a statistically significant improvement in retinal reattachment rates (RR=1.36, 95 % CI: 1-1.84) and a reduction in reoperation rates (RR=0.23, 95 % CI: 0.07-0.69) compared to the control group, while none of the other drugs had statistically significant results. Additionally, adjunctive therapy did not yield significant improvements in IOP, ERM, or macular edema, except for a reduction in macular edema associated with dexamethasone in one study. This systematic review and NMA indicate that most pharmacological agents could not significantly improve retinal reattachment, reduce PVR recurrence, or lower reoperation rates following RD surgery. 13-cis-RA was the only drug that showed a significant impact on lowering retinal detachment and reoperation rates. Further high-quality clinical trials are warranted to confirm these findings.

IntroductionThis study aims to evaluate the effect of bevacizumab treatment on the incidence of hypertension in patients with ovarian cancer.MethodsA comprehensive search of PubMed, Scopus, Embase, Cochrane, Web of Science, and Google Scholar databases was conducted until August 2024. We included only randomized clinical trials that compared ovarian cancer patients treated with Bevacizumab to those treated with other therapies. The primary outcome was the relative risk (RR) of developing hypertension, stratified by grade. Statistical analyses were performed using a random-effects model to account for heterogeneity between studies. Subgroup analyses were conducted based on hypertension severity (grade ≥2 and grade ≥3) and disease stage. Sensitivity analyses and publication bias assessments were also performed.ResultsA total of 11 randomized trials were included, comprising 5212 patients. The meta-analysis revealed that patients receiving Bevacizumab had a significantly higher risk of hypertension compared to controls (RR = 2.91, 95% CI: 1.65-5.16, P = 0.0002). Subgroup analysis showed that the risk of grade ≥2 hypertension was 1.68 times higher (95% CI: 0.92-3.07), and grade ≥3 hypertension was 5.10 times higher (95% CI: 2.46-10.55) in the Bevacizumab group. Sensitivity analysis confirmed the robustness of these findings, and no significant publication bias was detected.ConclusionBevacizumab treatment in ovarian cancer significantly increases the risk of hypertension, particularly severe hypertension (grade ≥3). These findings underscore the need for vigilant blood pressure monitoring and management in patients receiving Bevacizumab to mitigate cardiovascular complications and optimize treatment outcomes.

In clinical use, bevacizumab has improved the overall survival (OS) and progression-free survival (PFS) of malignant solid tumors, and the safe use of bevacizumab has gradually become the mainstream direction of clinical, nursing and pharmaceutical research. Bevacizumab is a humanized anti-VEGF drug. By binding to VEGF, it loses the opportunity to activate VEGFR and then plays an anti-angiogenic role. In addition, more and more studies have emphasized the efficacy and safety of bevacizumab in the treatment of brain metastases from solid tumors. Bevacizumab has its advantages in terms of crossing the blood-brain barrier, increasing radiosensitivity, and reducing radiation-induced brain edema. However, VEGF can maintain the normal function of vascular endothelial cells. Blocking the VEGF pathway can lead to endothelial dysfunction, and the anti-VEGF mechanism of bevacizumab will inevitably lead to a series of thrombotic events and bleeding events. This study reported six cases of cerebrovascular accidents, including ischemic stroke and cerebral hemorrhage, after bevacizumab use. At the same time, this study reviewed the related studies of cardiovascular and cerebrovascular accidents caused by bevacizumab, and analyzed the management of such bevacizumab-related adverse events. We put forward our own views on the early identification and long-term management of adverse events, as well as the subsequent reuse of bevacizumab, hoping to provide more basis for the management of clinical bevacizumab application.

The most common types of renal carcinoma is kidney renal clear cell carcinoma (KIRC). ESM1 is a secreted protein, which involved in, lipids and glucose metabolism, but their role in angiogenesis is contradictory in different disease, especially in KIRC. Bioinformatic analysis confirmed the ESM1 expression and prognosis in KIRC. IHC staining revealed protein expression of ESM1 in KIRC samples. The role of ESM1 in KIRC proliferation and migration were tested by MTT, EdU, transwell analysis. The role of its paracrine function in KIRC angiogenesis was tested by functional experiments. The downstream molecular mechanism of ESM1 were further elucidated by WB and functional experiments. ESM1 was significantly increased in KIRC with prognostic significance. ESM1 knockdown inhibited the invasiveness capability and viability of KIRC cell. The paracrine of ESM1 enhanced HUVECs proliferation and migration to format tube in KIRC cell conditional medium. ESM1 knockdown induced the inactivation of Akt/mTOR and Ras pathway to attenuate proliferation, migration, invasion and angiogenesis in KIRC. ESM1 was a key role in the tumor microenvironment (TME) of KIRC, which promoted the proliferation, migration, invasion, and angiogenesis by activating Akt/mTOR and Ras pathway. It is a potential therapeutic target for KIRC patients.

The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.

Systemic therapy for hepatocellular carcinoma has evolved from sorafenib to now include immune checkpoint blockade, either atezolizumab/bevacizumab or durvalumab/tremelimumab, and soon to include camrelizumab/rivoceranib and nivolumab/ipilimumab. Second-line therapy remains predominantly either a multikinase inhibitor or ramucirumab. Areas of development include testing immune checkpoint-based regimens in the adjuvant setting after surgery, ablation, or transarterial embolization. Also of interest are studies for patients with Child-Pugh B liver function and adding new checkpoint molecules to the current standard platforms.

Nidogen 1 (NID1) is a highly conserved structural component of the extracellular matrix (ECM), which interacts with different basement membrane (BM) proteins to form a stabilized meshwork. The promoting ability of NID1 in cancer development and metastasis has been demonstrated in multiple cancer types, including ovarian cancer, breast cancer, and hepatocellular carcinoma (HCC). This suggests that NID1 holds great potential as a therapeutic target for cancer treatment. However, currently, there is a lack of commercially available neutralizing antibody for clinical testing and treatment.

To address this, we utilized hybridoma technology to develop a monoclonal neutralizing antibody which targets the critical G2 region of NID1. The therapeutic effect of this NID1 neutralizing antibody against a wide range of human cancer cells was evaluated.

The results showed that NID1 neutralizing antibody effectively attenuated the growth, motility and metastasis of HCC, lung cancer, breast cancer and nasopharyngeal carcinoma cells in vitro. The proof-of-concept of targeting NID1 using neutralizing antibody was further demonstrated in various animal models. Mechanistically, our findings indicate that treatment with NID1 neutralizing antibody leads to the deregulation of hypoxia-inducible factor-1 (HIF-1α) pathway in cancer cells.

Taken together, this study offers promising prospects for a new pan-cancer monoclonal antibody-based strategy by targeting the tumor-associated membrane protein NID1.

We analyse mathematical models of blood flow in two simple vascular networks in order to identify structural features that lead to the formation of multiple equilibria. Our models are based on existing rules for blood rheology and haematocrit splitting. By performing bifurcation analysis on these simple network flow models, we identify a link between the changing flow direction in key vessels and the existence of multiple equilibria. We refer to these key vessels as redundant vessels, and relate the maximum number of equilibria with the number of redundant vessels. We vary geometric parameters of the two networks, such as vessel length ratios and vessel diameters, to demonstrate that equilibria are uniquely defined by the flow in the redundant vessels. Equilibria typically emerge in sets of three, each having a different flow characteristic in one of the network's redundant vessels. For one of the three equilibria, the flow within the relevant redundant vessel will be smaller in magnitude than the other two and the redundant vessel will contain few Red Blood Cells (RBCs), if any. For the other two equilibria, the redundant vessel contains RBCs and significant flow in the two available directions. These structural features of networks provide a useful geometric property when studying the equilibria of blood flow in microvascular networks.

New cases and deaths of gastrointestinal cancers are predicted to increase significantly by 2040. This study aims to explore cross-country inequalities and trends in global burdens of colon and rectum cancer (CRC), esophageal cancer (EC) and gastric cancer (GC).

Data from the Global Burden of Diseases Study 2019 were analyzed to examine trends in disability-adjusted life-years (DALYs) for three gastrointestinal cancers with estimated annual percentage change (EAPC) and Joinpoint analysis. Inequality in their DALYs rates was assessed with the slope index of inequality and the concentration index, based on the Socio-Demographic Index (SDI).

From 1990 to 2019, the age standardized DALYs rate of CRC decreased in these countries from high and high-middle SDI regions, with the EAPC values of - 1.018% and - 0.161%, respectively, but increased among low, low-middle and middle SDI regions (EAPC = 1.035%, 0.926% and 0.406%, respectively). The age standardized DALYs rates of EC and GC decreased in all SDI regions. Moreover, the slope index changed from 358.42 (95% confidence interval 343.28 to 370.49) to 245.13 (217.47 to 271.24) for CRC, from - 63.88 (- 87.48 to - 48.28) to - 1.36 (- 32.44 to 25.87) for EC, and from 126.37 (101.97 to 146.47) to 58.04 (20.54 to 96.12) for GC. The concentration index for CRC moved from 29.56 (28.99 to 29.84) to 23.90 (23.19 to 24.26), from - 9.47 (- 10.30 to - 9.24) to - 14.64 (- 15.35 to - 14.24) for EC, and from 8.44 (7.85 to 8.72) to - 6.42 (- 7.65 to - 6.12) for GC.

This study suggests strong heterogeneity in global DALYs for gastrointestinal cancers across different SDI regions. Higher SDI regions faced a greater burden of CRC, while the burdens of EC and GC were more prevalent in lower SDI regions.

Vascular endothelial growth factor (VEGF), also known as VEGF-A, has been linked to various diseases, such as wet age-related macular degeneration (wAMD) and cancer. Even though there are VEGF inhibitors that are currently commercially available in clinical applications, severe adverse effects have been associated with these treatments. There is still a need to develop novel VEGF-based therapeutics against these VEGF-related diseases. Here, we established a series of VEGF-based computational docking analyses and cell models, such as a wound healing assay in HaCaT cells and an evaluation of NF-κB performance in macrophages, to screen a large library of flavonoid-type phytochemicals. Three flavonoids, namely, farrerol, ononin and (-)-epicatechin, were shown to express binding affinities to VEGF protein and inhibit VEGF-mediated biological activities. The investigation evidently suggested that the three flavonoids above could be considered potential anti-VEGF agents for the following drug development against VEGF-mediated diseases.

Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study.

This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs).

Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.09-1.26, p = 1.33 × 10- 5). Additionally, the inhibition of FGFR1, FLT1, and MAP2K2 exhibited suggestive association with corresponding cardiovascular disease outcomes. Nevertheless, only VEGFA expression and stroke shared a causal variant (93.6%), whereas FGFR1, MAP2K2, and FLT1 did not share causal variants with corresponding cardiovascular diseases in the colocalization analysis.

This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy.

Ovarian cancer is a leading cause of mortality among women with gynecological malignancies, largely due to its asymptomatic nature in early stages and frequent late diagnosis. Targeted therapies, such as angiogenesis inhibitors and poly(ADP-ribose) polymerase inhibitors (PARPi), have emerged as promising treatments by disrupting tumor vasculature and impairing DNA repair mechanisms, particularly in patients with BRCA mutations. The objective of the present study was to comprehensively evaluate the combined use of different angiogenesis inhibitors and PARPi in ovarian cancer treatment by meta-analysis. This included assessing their impact on objective response rate (ORR) and progression-free survival (PFS), understanding the role of BRCA mutation status, and comparing the effects of various angiogenesis inhibitors when used in combination with PARPi. The PubMed, Embase and Cochrane databases were searched from inception to February 2024. Only studies on the combined treatment of ovarian cancer with angiogenesis inhibitors and PARPi were included. Duplicate studies, studies with incomplete data, animal studies, literature reviews and systematic studies were excluded. The results underscored a noteworthy improvement in the ORR and median PFS (mPFS) among patients receiving combination therapy compared with those on monotherapy. Specifically, the pooled ORR for combination therapy was significantly higher than that of monotherapy, indicating a substantial benefit in terms of tumor response. Furthermore, combination therapy was found to significantly prolong PFS, offering patients a longer duration without disease progression. Subgroup analyses of patients treated with angiogenesis inhibitors combined with PARPi provided deeper insights, revealing that patients with BRCA mutations exhibited an ORR of 90% compared with 61% in those without BRCA mutations. Additionally, when different angiogenesis inhibitors were compared, patients treated with anti-VEGF agents combined with PARPi showed a longer mPFS (15.53 months) than those treated with TKIs combined with PARPi (7.49 months). In conclusion, the present study demonstrates that combinations of angiogenesis inhibitors and PARPi show great potential for improving treatment outcomes in ovarian cancer, particularly in patients with BRCA mutations. The observed differences in efficacy between various angiogenesis inhibitors highlight the importance of personalized treatment approaches. Further research is warranted to explore the long-term benefits of these combination strategies and refine them to obtain optimal patient outcomes.

Clinical outcomes for the treatment of peritoneal carcinomatosis (PC) have remained suboptimal. Microsphere-based intraperitoneal chemotherapy has shown considerable potential in preclinical studies. However, due to the complications associated with peritoneal adhesions, there has been a lack of comprehensive reviews focusing on the progress of microsphere applications in the treatment of PC.

We provide an overview of the current clinical treatment strategies for PC and analyze the potential advantages of microspheres in this context. Regarding the issue of peritoneal adhesions induced by microspheres, we investigate the underlying mechanisms and propose possible solutions. Furthermore, we outline the future directions for the development of microsphere-based therapies in the treatment of PC.

Microspheres formulated with highly biocompatible materials to the peritoneum, such as sodium alginate, gelatin, or genipin, or with an optimal particle size (4 ~ 30 μm) and lower molecular weights (10 ~ 57 kDa), can prevent peritoneal adhesions and improve drug distribution. To further enhance the antitumor efficacy, enhancing the tumor penetration capability and specificity of microspheres, optimizing intraperitoneal distribution, and addressing tumor resistance have demonstrated significant potential in preclinical studies, offering new therapeutic prospects for the treatment of PC.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) remains a significant hurdle for patients with EGFR-mutated non-small cell lung cancer (NSCLC), particularly those lacking the EGFRT790M. IMpower 150 study demonstrated promising efficacy for a combination of immune-chemotherapy and bevacizumab in patients with EGFR-mutated NSCLC.

This open-label, single-arm, phase II trial evaluated the efficacy and immune cell profile of the modified regimen combining atezolizumab, bevacizumab (7.5 mg/kg) and chemotherapy in patients with EGFR-mutated NSCLC following TKI failure. The primary endpoint was objective response rate (ORR). The re-biopsy tissue specimens and serial peripheral blood samples were collected to analyse the immune cell profile and tumour microenvironments.

22 EGFR-mutant NSCLC patients participated in this study. The ORR was 42.9%, with a disease control rate (DCR) of 100%. Median progression-free survival (PFS) was 6.3 months. Patients with programmed death-ligand 1 (PD-L1) expression ≥1% exhibited significantly higher ORR (75 vs. 23.1%; p = .032) and longer PFS (14.0 vs. 6.1 months; p = .022) compared with those with PD-L1 expression < 1%. Grade ≥ 3 adverse events occurred in 40.9% of patients. Higher peritumour nature killer (NK) cell infiltration and lower peripheral helper T cell counts before treatment were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ myelod-derived suppressor cells (MDSCs) increased, while regulatory T cells decreased.

This modified combination regimen may be a promising therapeutic option for EGFR-mutant NSCLC patients with TKI resistance, especially those with PD-L1-positive tumours. Furthermore, immune cell profiling may aid in identifying patients who may benefit from this approach.

The combination regimen yielded promising efficacy in NSCLC patients after EGFR-TKI resistance, particularly those with PD-L1-positive tumours. Higher peritumour NK cell and lower peripheral helper T cell were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ MDSC increased, but Treg cells decreased.

Bevacizumab-based chemotherapy is a recommended first-line treatment for metastatic colorectal cancer (mCRC). Robust biomarkers with clinical practice applicability have not been identified for patients with this treatment. We aimed to evaluate the prognostic yield of serum mid-infrared spectroscopy (MIRS) on patients receiving first-line bevacizumab-based chemotherapy for mCRC.

We conducted an ancillary analysis from a multicentre prospective study (NCT00489697). All baseline serums were screened by attenuated total reflection method. Principal component analysis and unsupervised k-mean partitioning methods were performed blinded to all patients' data. Endpoints were progression-free survival (PFS) and overall survival (OS).

From the 108 included patients, MIRS discriminated two prognostic groups. First group patients had significantly lower body mass index (p = 0.026) and albumin levels (p < 0.001), and higher levels of angiogenic markers, lactate dehydrogenase and carcinoembryonic antigen (p < 0.001). In univariate analysis, their OS and PFS were shorter with respective medians: 17.6 vs 27.9 months (p = 0.02) and 8.7 vs 11.3 months (p = 0.03). In multivariate analysis, PFS was significantly shorter (HR = 1.74, p = 0.025) with a similar trend for OS (HR = 1.69, p = 0.061).

By metabolomic fingerprinting, MIRS proves to be a promising prognostic tool for patients receiving first-line bevacizumab-based chemotherapy for mCRC.

Endothelial cells (ECs) and pericytes (PCs) are crucial components of the vascular system, with ECs lining the inner layer of blood vessels and PCs surrounding capillaries to regulate blood flow and angiogenesis. Intercellular communication between ECs and PCs is vital for the formation, stability, and function of blood vessels. Various signaling pathways, such as the vascular endothelial growth factor/vascular endothelial growth factor receptor pathway and the platelet-derived growth factor-B/platelet-derived growth factor receptor-β pathway, play roles in communication between ECs and PCs. Dysfunctional communication between these cells is associated with various diseases, including vascular diseases, central nervous system disorders, and certain types of cancers.

This review aimed to explore the diverse roles of ECs and PCs in the formation and reshaping of blood vessels. This review focused on the essential signaling pathways that facilitate communication between these cells and investigated how disruptions in these pathways may contribute to disease. Additionally, the review explored potential therapeutic targets, future research directions, and innovative approaches, such as investigating the impact of EC-PCs in novel systemic diseases, addressing resistance to antiangiogenic drugs, and developing novel antiangiogenic medications to enhance therapeutic efficacy.

Disordered EC-PC intercellular signaling plays a role in abnormal blood vessel formation, thus contributing to the progression of various diseases and the development of resistance to antiangiogenic drugs. Therefore, studies on EC-PC intercellular interactions have high clinical relevance.

Radiation therapy is widely recognized as an efficacious modality for treating neoplasms located within the craniofacial region. Nevertheless, this approach is not devoid of risks, predominantly concerning potential harm to the neural structures. Adverse effects may encompass focal cerebral necrosis, cognitive function compromise, cerebrovascular pathology, spinal cord injury, and detriment to the neural fibers constituting the brachial plexus. With increasing survival rates among oncology patients, evaluating post-treatment quality of life has become crucial in assessing the benefits of radiation therapy. Consequently, it is imperative to investigate therapeutic strategies to mitigate cerebral complications from radiation exposure. Current management of radiation-induced cerebral damage involves corticosteroids and bevacizumab, with preclinical research on antioxidants and thalidomide. Despite these efforts, an optimal treatment remains elusive. Recent studies suggest the gut microbiota's involvement in neurologic pathologies. This review aims to discuss the causes and existing treatments for radiation-induced cerebral injury and explore gut microbiota modulation as a potential therapeutic strategy.

Vascular endothelial growth factor (VEGF) is a critical angiogenesis biomarker associated with various pathological conditions, including cancer. This study leverages pre-biotinylated FcγRI interactions with IgG1-type monoclonal antibodies to develop a sensitive VEGF detection method. Utilizing surface plasmon resonance (SPR) technology, we characterized the binding dynamics of immobilized biotinylated FcγRI to an IgG1-type antibody, Bevacizumab (AVT), through kinetic studies and investigated suitable conditions for sensor surface regeneration. Subsequently, we characterized the binding of FcγRI-captured AVT to VEGF, calculating kinetic constants and binding affinity. A calibration curve was established to analyze the VEGF quantification capacity and accuracy of the biosensor, computing the limits of blank, detection, and quantification at a 95% confidence interval. Additionally, the specificity of the biosensor for VEGF over other protein analytes was assessed. This innovative biomimetic approach enabled FcγRI-mediated site-specific AVT capture, establishing a stable and reusable platform for detecting and accurately quantifying VEGF. The results indicate the effectiveness of the plasmonic sensor platform for VEGF detection, making it suitable for research applications and, potentially, clinical diagnostics. Utilizing FcγRI-IgG1 antibody binding, this study highlights the industrial and clinical value of advanced biosensing technologies, offering insights to enhance therapeutic monitoring and improve outcomes in anti-VEGF therapies.

Breast cancer is a challenging global health problem among women. This study investigates the intricate breast tumour microenvironment (TME) dynamics utilizing data from mammary-specific polyomavirus middle T antigen overexpression mouse models (MMTV-PyMT). It incorporates endothelial cells (ECs), oxygen and vascular endothelial growth factors (VEGF) to examine the interplay of angiogenesis, hypoxia, VEGF and immune cells in cancer progression. We introduce an approach to impute immune cell fractions within the TME using single-cell RNA-sequencing (scRNA-seq) data from MMTV-PyMT mice. We quantify our analysis by estimating cell counts using cell size data and laboratory findings from existing literature. We perform parameter estimation via a Hybrid Genetic Algorithm (HGA). Our simulations reveal various TME behaviours, emphasizing the critical role of adipocytes, angiogenesis, hypoxia and oxygen transport in driving immune responses and cancer progression. Global sensitivity analyses highlight potential therapeutic intervention points, such as VEGFs' role in EC growth and oxygen transportation and severe hypoxia's effect on cancer and the total number of cells. The VEGF-mediated production rate of ECs shows an essential time-dependent impact, highlighting the importance of early intervention in slowing cancer progression. These findings align with clinical observations demonstrating the VEGF inhibitors' efficacy and suggest a timely intervention for better outcomes.

Angiogenesis is a key player in drug resistance to targeted therapies for breast cancer. The average expression of angiogenesis-related cytokines is widely associated with the treatments of target therapies for a population of cells or spheroids, overlooking the distinct responses for individuals. In this work, a highly integrated microfluidic platform is developed for the generation of monodisperse multicellular tumor spheroids (MTSs), drug treatments, and the measurement of cytokines for individual MTSs in a single chip. The platform allows the correlation evaluation between cytokine secretion and drug treatment at the level of individual spheroids. For validation, quantities of six representative proangiogenic cytokines are tested against treatments with four model drugs at varying times and concentrations. By applying a linear regression model, significant correlations are established between cytokine secretion and the treated drug concentration for individual spheroids. The proposed platform provides a high-throughput method for the investigation of the molecular mechanism of the cytokine response to targeted therapies and paves the way for future drug screening using predictive regression models at the single-spheroid level.

Growth factors signal through engagement and activation of their respective cell surface receptors to choreograph an array of cellular functions, including proliferation, growth, repair, migration, differentiation, and survival. Because of their vital role in determining cell fate and maintaining homeostasis, dysregulation of growth factor pathways leads to the development and/or progression of disease, particularly in the context of cancer. Exciting advances in protein engineering technologies have enabled innovative strategies to redesign naturally occurring growth factor ligands and receptors as targeted therapeutics. We review growth factor protein engineering efforts, including affinity modulation, molecular fusion, the design of decoy receptors, dual specificity constructs, and vaccines. Collectively, these approaches are catapulting next-generation drugs to treat cancer and a host of other conditions.

Natural compounds demonstrate unique therapeutic advantages for cancer treatment, primarily through direct tumor suppression or interference with the tumor microenvironment (TME). Glycyrrhizic acid (GL), a bioactive ingredient derived from the medicinal herb Glycyrrhiza uralensis Fisch., and its sapogenin glycyrrhetinic acid (GA), have been recognized for their ability to inhibit angiogenesis and remodel the TME. Consequently, the combination of GL with other therapeutic agents offers superior therapeutic benefits. Given GL's amphiphilic structure, self-assembly capability, and liver cancer targeting capacity, various GL-based nanoscale drug delivery systems have been developed. These GL-based nanosystems exhibit angiogenesis suppression and TME regulation properties, synergistically enhancing anti-cancer effects. This review summarizes recent advances in GL-based nanosystems, including polymer-drug micelles, drug-drug assembly nanoparticles (NPs), liposomes, and nanogels, for cancer treatment and tumor postoperative care, providing new insights into the anti-cancer potential of natural compounds. Additionally, the review discusses existing challenges and future perspectives for translating GL-based nanosystems from bench to bedside.

Clear cell renal cell carcinoma (ccRCC) represents the most prevalent form of renal cell carcinoma. The management of early-stage ccRCC has a better prognosis, while patients with metastatic ccRCC have a lower five-year survival rate. Angiogenesis serves as the fundamental process underlying tumor metastasis. Therefore, it is crucial to discover new targets for angiogenesis to improve patient survival rates.

The Cancer Genome Atlas database, International Cancer Genome Consortium database, Clinical Proteomic Tumor Analysis Consortium database, and a gene set of the vascular endothelial growth factor (VEGF) signaling pathway were utilized to identify differentially expressed genes. Western blot (WB), quantitative real-time polymerase chain reaction, and immunohistochemistry were employed to validate the downregulation of phospholipase C gamma 2 (PLCG2) in ccRCC tissues and cells. Cell Counting Kit-8 (CCK-8) assays, transwell assays, tube formation assays, and oil-red staining were performed to elucidate the biological functions of PLCG2 in tumor cells. Gene set enrichment analysis was applied to explore the downstream pathway. Subcutaneous tumor models and live small animal fluorescent imaging assay were utilized for in vivo investigation of the roles played by PLCG2.

Our study has identified a novel biomarker, PLCG2, for ccRCC. PLCG2 is a central gene in regulating angiogenesis in ccRCC, as validated by bioinformatics analysis. The findings revealed a diminished expression of PLCG2 in both ccRCC tissues and cells. Further experiments in vivo and in vitro have demonstrated the significant roles of PLCG2 in tumor proliferation, invasion, migration, and lipid accumulation. Results of tube formation assays and WB support the role of PLCG2 in regulating VEGFA expression and angiogenesis.

Our results show that PLCG2 functions as a potential biomarker and an independent prognostic indicator for ccRCC. PLCG2 may modulate angiogenesis by influencing the expression of VEGFA. Therefore, targeting PLCG2 could potentially lead to drug discovery and improved cancer treatment strategies.

According to the widely accepted "three Es" model, the host immune system eliminates malignant cell precursors and contains microscopic neoplasms in a dynamic equilibrium, preventing cancer outgrowth until neoplastic cells acquire genetic or epigenetic alterations that enable immune escape. This immunoevasive phenotype originates from various mechanisms that can be classified under a novel "three Cs" conceptual framework: (1) camouflage, which hides cancer cells from immune recognition, (2) coercion, which directly or indirectly interferes with immune effector cells, and (3) cytoprotection, which shields malignant cells from immune cytotoxicity. Blocking the ability of neoplastic cells to evade the host immune system is crucial for increasing the efficacy of modern immunotherapy and conventional therapeutic strategies that ultimately activate anticancer immunosurveillance. Here, we review key hallmarks of cancer immune evasion under the "three Cs" framework and discuss promising strategies targeting such immunoevasive mechanisms.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Histology separates two main subtypes: embryonal RMS (eRMS; 60%-70%) and alveolar RMS (aRMS; 20%-30%). The aggressive aRMS carry one of two characteristic chromosomal translocations that result in the expression of a PAX3::FOXO1 or PAX7::FOXO1 fusion transcription factor; therefore, aRMS are now classified as fusion-positive (FP) RMS. Embryonal RMS have a better prognosis and are clinically indistinguishable from fusion-negative (FN) RMS. Next to histology and molecular characteristics, RMS risk groupings are now available defining low risk tumors with excellent outcomes and advanced stage disease with poor prognosis, with an overall survival of about only 20% despite intensified multimodal treatment. Therefore, development of novel effective targeted strategies to increase survival and to decrease long-term side effects is urgently needed. Recently, immunotherapies and nanomedicine have been emerging for potent and effective tumor treatments with minimal side effects, raising hopes for effective and safe cures for RMS patients. This review aims to describe the most relevant preclinical and clinical studies in immunotherapy and targeted nanomedicine performed so far in RMS and to provide an insight in future developments.

Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, is widely used as a first-line treatment for metastatic colorectal cancer (mCRC), with hypertension being a common adverse effect. However, there is limited data on the predisposing factors contributing to bevacizumab-induced blood pressure (BP) elevation. This study aims to identify clinical risk factors associated with bevacizumab-related hypertension in patients with mCRC.

This retrospective study included 178 patients treated between January and June 2020. Demographic data and medical histories were extracted from hospital electronic medical records.

Among the 178 patients, 54 (30.3%) developed bevacizumab-related hypertension, with a median onset time of 48 days. Univariate and multivariate analyses identified pre-existing hypertension [odds ratio (OR), 3.30; 95% confidence interval (CI), 1.56-6.99] and age ≥60 years (OR, 2.04; 95% CI, 1.00-4.17) as independent risk factors for bevacizumab-related hypertension. The area under the receiver operating characteristic (ROC) curve was 0.66 (95% CI, 0.57-0.75, P < 0.001). The median overall survival (OS) for the cohort was 30.53 months (95% CI, 22.23-38.84). No significant differences in OS were observed between patients with and without bevacizumab-related hypertension (31.13 vs. 27.87 months, P = 0.86).

Pre-existing hypertension and age ≥60 years are significant clinical risk factors for bevacizumab-related hypertension in mCRC patients. Bevacizumab-related hypertension did not affect overall survival. Clinicians should closely monitor BP within the first 2 months of bevacizumab treatment in high-risk patients.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.