Antiangiogenic medications for cancer treatment have generally failed in showing substantial benefits in terms of prolonging life on their own; their effects are noticeable only when combined with chemotherapy. Moreover, treatments based on prolonged antiangiogenics administration have demonstrated to be ineffective in stopping tumor progression. In this scenario, nanotherapeutics can address certain issues linked to existing antiangiogenic treatments. More specifically, they can provide the ability to target the tumor's blood vessels to enhance drug accumulation and manage release, ultimately decreasing undesired side effects. Additionally, they enable the administration of multiple angiogenesis inhibitors at the same time as chemotherapy. Key reports in this field include the design of polymeric nanoparticles, inorganic nanoparticles, vesicles, and hydrogels for loading antiangiogenic substances like endostatin and interleukin-12. Furthermore, nanoformulations have been proposed to efficiently control relevant pro-angiogenic pathways such as VEGF, Tie2/Angiopoietin-1, HIF-1α/HIF-2α, and TGF-β, providing powerful approaches to block tumor growth and metastasis. In this article, we outline a selection of nanoformulations for antiangiogenic treatments for cancer that have been developed in the past ten years.

Colorectal cancer remains one of the most commonly diagnosed cancers globally, with a significant impact on public health. Targeted therapies have revolutionized the treatment landscape for colorectal cancer by offering increased specificity and reduced systemic toxicity compared to conventional chemotherapy. This study provides a comprehensive bibliometric analysis of global research on targeted therapy for colorectal cancer, focusing on publications from 2015 to 2024. A total of 3213 publications were retrieved from the Web of Science Core Collection and analyzed using bibliometric tools to construct knowledge maps and visualize research trends. The regression analysis shows a strong upward trend in publications from 2015 to 2024 (P < 0.001, R2 = 0.889). China leads in publication output, with the University of Texas MD Anderson Cancer Center contributing the highest number of studies. Tabernero and Kopetz are the core authors in the field. Research in this domain has primarily concentrated on the development and clinical assessment of drugs targeting the EGFR, RAS, VEGF, and BRAF signaling pathways, as well as investigating the pathogenesis, drug resistance, and metastatic mechanisms of colorectal cancer. Current advancements emphasize Artificial Intelligence-driven multi-omics integration, the creation of novel therapeutics targeting established molecular pathways, and the execution of global clinical trials to validate personalized treatment strategies.

Adding monoclonal antibodies to chemotherapy drastically changed the landscape of advanced colorectal cancer. The prediction of benefit from anti-EGFR therapies is mainly based on the absence of mutations in RAS and BRAF genes, the primary tumor sidedness and microsatellite MSS/MSI status. Molecular hyperselection may optimize the outcome of patients receiving anti-EGFR while detecting additional resistance alterations, both in chemo-naïve and in chemo-refractory settings.

Our review focuses on negative molecular hyperselection, both on tissue samples and ctDNA, and the impact of this further patient selection on response rate and survival outcomes. We searched electronic database, selecting relevant English-language publications from 2017 to 2024.

Negative hyperselection beyond RAS and BRAF in advanced colorectal cancer appears to be a powerful tool for predicting outcomes to anti-EGFR therapy and spare patients from unnecessary treatment. This improvement appears in both naïve and pre-treated patients. However, data come mainly from retrospective studies. Therefore, to validate and integrate these findings in the clinical practice, prospective studies should be conducted. It will be interesting to elucidate the role of ctDNA in this setting and the choice of molecular techniques, considering costs and accessibility, to guarantee its implementation in the clinic.

In the era of immunotherapy, the lymphatic system has garnered significant attention from researchers. Increasing evidence highlights the complex regulation of lymphatic vessels (LVs) within the tumor microenvironment, unveiling a paradox in tumor progression: while LVs enhance immune surveillance, they simultaneously foster immune suppression. This review summarizes the regulatory factors of lymphangiogenesis, discusses the intricate effects of LVs on immunotherapy, and emphasizes the potential connection between lymphangiogenesis and tertiary lymphoid structure. Additionally, current therapeutic strategies targeting lymphangiogenesis are critically evaluated, with a forward-looking perspective on future research directions and regulatory approaches to achieve precise targeting and optimize immunotherapy paradigms.

Appropriate assessment of disease burden in patients with peritoneal surface malignancy (PSM) is critical for treatment decision-making, and conventional cross-sectional imaging (computed tomography and/or MRI) often underestimates burden of disease. Advances in imaging for PSM include novel functional imaging modalities that target cells unique to the tumor microenvironment. Novel alternative methods of diagnosis and disease monitoring are also potentially applicable to management of PSM. These include forms of "liquid biopsy" targeting circulating tumor DNA. Novel regional therapies include both new therapeutic agents (immune-based and nanoparticle-based), as well as new methods of delivery such as pressurized intraperitoneal aerosolized chemotherapy.

Lenvatinib is an orally available multi-tyrosine kinase inhibitor that mainly targets vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling. These inhibitory activities of lenvatinib exhibit antitumor efficacy, mainly due to their repressive effects on angiogenesis. In addition, a recent non-clinical evaluation using mouse tumor models revealed that lenvatinib causes immunomodulatory effects, including activation of effector T-cells and regulation of tumor-associated macrophages (TAMs). Combined treatment with lenvatinib and anti-programmed cell death-1 antibody (anti-PD-1) resulted in enhanced antitumor activity relative to monotreatment with anti-PD-1 or lenvatinib. This review summarizes the antitumor mechanisms of lenvatinib and of lenvatinib plus anti-PD-1 combination therapy.

Exosomes, as mediators of intercellular communication, can be released from different types of cells and regulate the function of the target cell by transferring cargo, such as proteins, DNA, and RNA. Recent investigations have revealed a preponderance of long noncoding RNAs (lncRNAs), a subclass of noncoding RNAs, within exosomes, where they exhibit notable stability and are implicated in the development and progression of neoplastic processes, such as tumor angiogenesis. Angiogenesis, as a hallmark of cancer, provides diffusible nutrients and oxygen to the distant cells and guarantees tumorigenesis and metastasis. Exosomal lncRNAs, including MALAT1, OIP5-AS1, PART1, SNHG family, FAM225A, ATB, RAMP2-AS1, UCA1, TRPM2-AS, FGD5-AS1, and LINC0016, could modulate tumor angiogenesis by activating signaling cascades and mediators within the target cells, such as microRNAs (miRNAs). Regulation of tumor angiogenesis through modulation of exosomal lncRNAs could be a reliable strategy for cancer therapy. In this review, we discuss the characteristics and biogenesis of exosomes and lncRNAs and how exosomal lncRNAs are involved in various processes of tumorigenesis. Our primary focus is on exosomal lncRNAs, their impact on tumor angiogenesis, and their potential as novel diagnostic markers and therapeutic targets for various cancers.

A sustained blood supply is critical for tumor growth, as it delivers the nutrients and oxygen required for development. Targeting of blood vessel formation via immunotherapies is an area of great importance. Knowing that certain embryonic genes, such as carcinoembryonic antigens (CEA) and oncofetal fibronectin, become reexpressed in malignant transformation, we hypothesized that a similar phenomenon holds true for tumor endothelial cells (TECs) as well. An approach for identification of highly selective tumor endothelial markers was conducted to develop targeted antiangiogenic immunotherapies. We first queried the transcriptome that is present during embryo development. We then performed a systematic search for genes selectively expressed in the mouse embryo at days E11 and E18, as compared to the transcriptome of the adult mouse. Subsequently, we queried for expression of these embryonic genes in sorted murine TECs. This approach identified among others the tumor endothelial antigens fibrillin-2 (Fbn2), elastin microfibril interface-located protein 2 (Emilin2) as well as the tumor endothelial antigens lysyl oxidase (Lox) and serine/cysteine protease inhibitor, clade E, member 1 (Serpine1; Pai-1). For these selected genes, functional involvement in angiogenesis was confirmed in in vitro bioassays. We subsequently used iBoost conjugate vaccine technology to develop vaccines against the selected targets. For all four targets, vaccination readily induced target-specific antibody responses in mice, resulting in inhibition of tumor growth. Access to highly specific tumor endothelial markers provides opportunities for direct targeting of the tumor vasculature with high specificity, without affecting healthy vasculature.

The combination of anti-epidermal growth factor receptor (EGFR) therapy and chemotherapy is currently a preferred first-line treatment for patients with unresectable, RAS and BRAF wild-type, left-sided metastatic colorectal cancer (mCRC). Several studies have also demonstrated the benefit of anti-EGFR therapy in subsequent line settings for this patient population. However, direct evidence comparing the effectiveness of frontline vs subsequent anti-EGFR therapy remains limited, leaving a crucial gap in guiding optimal treatment strategies.

To compare overall survival (OS) between frontline and subsequent anti-EGFR treatment in patients with unresectable, RAS and BRAF wild-type, left-sided mCRC.

We retrospectively reviewed the medical records of mCRC patients treated at The King Chulalongkorn Memorial Hospital and Songklanagarind Hospital, Thailand, between January 2013 and April 2023. Patients were classified into two groups based on the sequence of their anti-EGFR treatment. The primary endpoint was OS.

Among 222 patients with a median follow-up of 29 months, no significant difference in OS was observed between the frontline and subsequent-line groups (HR 1.03, 95%CI: 0.73-1.46, P = 0.878). The median OS was 35.53 months (95%CI: 26.59-44.47) for the frontline group and 31.60 months (95%CI: 27.83-35.37) for the subsequent-line group. In the subsequent-line group, 71 patients (32.4%) who ultimately never received anti-EGFR therapy had a significantly worse median OS of 19.70 months (95%CI: 12.87-26.53).

Frontline and subsequent-line anti-EGFR treatments provide comparable OS in unresectable, RAS/BRAF wild-type, left-sided mCRC patients, but early exposure is vital for those unlikely to receive subsequent therapy.

Bevacizumab (BV) is an effective therapeutic antibody utilized in various cancers. Serum BV concentration can be a factor that potentially affects its therapeutic efficacy. Although proteinuria could affect BV pharmacokinetics, its influence was not evaluated in the previous population pharmacokinetic (PopPK) studies. Because BV can cause proteinuria as an adverse event, the present study aimed to develop a PopPK model in patients with proteinuria and to evaluate the influence of proteinuria on BV pharmacokinetics.

This prospective cohort study enrolled 70 Japanese cancer patients newly starting BV, and 368 concentration samples from these patients were analyzed. Serum BV concentrations were measured at several time points including at the onset of proteinuria. PopPK analysis was conducted using a non-linear mixed-effects modeling program. A two-compartment model was used to estimate total body clearance (CL).

Serum BV concentrations divided by the dose per body weight and dosing interval tended to be lower in patients with higher urinary protein to creatinine ratio (UPCR). The covariate analysis showed that increasing BV CL was associated with decreasing serum albumin concentration and increasing body weight and UPCR. The simulated median trough concentrations of BV in patients with Common Terminology Criteria for Adverse Events grades 1, 2, and 3 proteinuria were decreased by 12.0%, 20.6%, and 31.5%, respectively, compared to those in patients with grade 0.

We successfully established a PopPK model incorporating UPCR to predict serum BV concentrations in patients with proteinuria. Our study provides additional insights to better understand BV pharmacokinetics.

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 a significant global health challenge, demanding continuous advancements in treatment strategies. This review explores the complexities of targeting colorectal cancer stem cells (CSCs) and the mechanisms contributing to resistance to 5-fluorouracil (5-FU). The efficacy of 5-FU is enhanced by combination therapies such as FOLFOXIRI and targeted treatments like bevacizumab, cetuximab, and panitumumab, particularly in KRAS wild-type tumors, despite associated toxicity. Biomarkers like thymidylate synthase (TYMS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are crucial for predicting 5-FU efficacy and resistance. Targeting CRC-CSCs remains challenging due to their inherent resistance to conventional therapies, marker variability, and the protective influence of the tumor microenvironment which promotes stemness and survival. Personalized treatment strategies are increasingly essential to address CRC's genetic and phenotypic diversity. Advances in immunotherapy, including immune checkpoint inhibitors and cancer vaccines, along with nanomedicine-based therapies, offer promising targeted drug delivery systems that enhance specificity, reduce toxicity, and provide novel approaches for overcoming resistance mechanisms. Integrating these innovative strategies with traditional therapies may enhance the effectiveness of CRC therapy by addressing the underlying causes of 5-FU resistance in CSCs.

Colorectal cancer (CRC) poses a substantial global health challenge, ranking as the third most commonly diagnosed and second most fatal cancer worldwide. With an increasing incidence, particularly in older populations, CRC demands innovative therapeutic approaches to address the limitations of existing treatments. One critical target in CRC is the KRAS gene, which is frequently mutated and implicated in various cancer-related processes. This narrative review explores the promising role of Sotorasib plus Panitumumab combination therapy in CRC treatment. Combining Sotorasib with Panitumumab, an EGFR antagonist, offers a synergistic approach to comprehensively block KRAS and EGFR pathways, potentially overcoming resistance mechanisms observed in monotherapies. The review discusses the evolution of CRC treatment from traditional chemotherapy to the advent of targeted therapies like Bevacizumab and Cetuximab. It highlights the limitations of existing therapies, including resistance and toxicities, emphasising the urgency for innovative approaches. The CodeBreak clinical trials, specifically CodeBreak 101 and CodeBreak 300, provide a focal point for evaluating the efficacy of Sotorasib plus Panitumumab in patients with refractory KRAS G12C-mutated mCRC. Preliminary results demonstrate significant improvements in progression-free survival (PFS) and objective response rates, suggesting a paradigm shift in CRC treatment. The preliminary findings from the CodeBreak 300 trial signify a transformative impact of Sotorasib plus Panitumumab in refractory KRAS G12C-mutated mCRC. With a notable increase in PFS and objective response rates and a well-tolerated safety profile, this combination therapy emerges as a potential new standard of care. The results present an optimistic outlook for patients resistant to conventional therapies.

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.

Intravitreal injections have revolutionized the treatment of various sight-threatening diseases of the posterior segment of the eye. Initially explored for treatment of bacterial endophthalmitis, intravitreal injections rapidly expanded to combat retinal vascular disease in particular. Especially anti-vascular endothelial growth factor agents have emerged as a cornerstone of intravitreal therapy, targeting neovascular age-related macular degeneration and diabetic macular edema as important examples. Advances continue, with novel therapies such as complement inhibitors now available as treatment for geographic atrophy secondary to non-neovascular age-related macular degeneration, offering hope for a previously untreatable condition. Pioneering approaches such as the port delivery system and intravitreal gene therapy aim to improve treatment efficacy while minimizing patient burden. Despite notable successes, challenges for intravitreal therapies persist, including ocular and systemic complications and high treatment burden. Future research endeavors aim to address these challenges and enhance treatment outcomes. This comprehensive review critically evaluates the efficacy, safety, and cost-effectiveness of intravitreal injections, delving into emerging trends and future directions.

Colorectal cancer (CRC) is ranked as the second leading cause of cancer-related deaths globally, necessitating urgent advancements in therapeutic approaches. The emergence of groundbreaking therapies, including chimeric antigen receptor-T (CAR-T) cell therapies, oncolytic viruses, and immune checkpoint inhibitors, marks a transformative era in oncology. These innovative modalities, tailored to individual genetic and molecular profiles, hold the promise of significantly enhancing patient outcomes. This comprehensive review explores the latest clinical trials and advancements, encompassing targeted molecular therapies, immunomodulatory agents, and cell-based therapies. By evaluating the strengths, limitations, and potential synergies of these approaches, this research aims to reshape the treatment landscape and improve clinical outcomes for CRC patients, offering new found hope for those who have exhausted conventional options. The culmination of this work is anticipated to pave the way for transformative clinical trials, ushering in a new era of personalized and effective CRC therapy.

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.

This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of KRAS-mutant metastatic colorectal cancer (mCRC).

This multicenter, open-label, single-arm study enrolled patients with KRAS-mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m2 once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS-mutant CRC.

Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, P < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, P < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis.

Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with KRAS-mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).

MiRNAs are small RNA strands that are managed following transcription and are of substantial importance in blood vessel formation. It is essential to oversee the growth, differentiation, death, movement and construction of tubes by angiogenesis-affiliated cells. If miRNAs are not correctly regulated in regard to angiogenesis, it can deteriorate the health and lead to various illnesses, which include cancer, cardiovascular disorder, critical limb ischemia, Crohn's disease, ocular diseases, diabetic microvascular complications, and more. Consequently, it is vital to understand the crucial part that miRNAs play in the development of blood vessels, so we can develop reliable treatment plans for vascular diseases. This write-up will assess the critical role of miR-21/exosomal miR-21 in managing angiogenesis associated with bone growth, wound recovery, and other pathological conditions like tumor growth, ocular illnesses, diabetes, and other diseases connected to formation of blood vessels. Previous investigations have demonstrated that miR-21 is present at higher amounts in certain cancerous cells, and it influences a multitude of genes that moderate the increased creation of blood vessels. Furthermore, studies demonstrated that exosomal miR-21 has the capacity to interact with endothelial cells to foster tumor angiogenesis. For that reason, this review explains the critical importance of miR-21/exosomal miR-21 in managing both healthy and diseased states of angiogenesis.

Peritoneal carcinomatosis is a common yet deadly manifestation of gastrointestinal cancers, with few effective treatments. To identify targetable determinants of peritoneal metastasis, we focused on appendiceal adenocarcinoma (AC), a gastrointestinal cancer that metastasizes almost exclusively to the peritoneum. Current treatments are extrapolated from colorectal cancer (CRC), yet AC has distinct genomic alterations, mucinous morphology and peritoneum restricted metastatic pattern. Further, no stable preclinical models of AC exist, limiting drug discovery and representing an unmet clinical need. We establish a first-in-class stable biobank of 16 long-term cultured AC patient-derived organoids (PDOs), including 3 matched, simultaneously resected primary AC-peritoneal carcinomatosis (AC-PC) pairs. By enriching for cancer cells, AC PDOs enable accurate genomic characterization relative to paucicellular AC tissue. We establish an organoid orthotopic intraperitoneal xenograft model that recapitulates diffuse peritoneal carcinomatosis and show that PC-organoids retain increased metastatic capacity, decreased growth factor dependency and sensitivity to standard of care chemotherapy relative to matched primary AC organoids. Single cell profiling of AC-PC pairs reveals dedifferentiation from mucinous differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. Through hypothesis-driven drug testing, we identify KRAS MULTI -ON inhibitor RMC-7977 and Wnt-targeting tyrosine kinase inhibitor WNTinib as novel, clinically actionable strategies to target AC-PC more effectively.

Colorectal cancer (CRC) is one of the most common malignancies worldwide, with high morbidity and mortality rates. Conventional treatments, including surgery, radiotherapy, and chemotherapy, have limited effects on advanced and metastatic CRC (mCRC). Fruquintinib, a novel and highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor, has shown significant efficacy and tolerance in treating mCRC. The FRESCO and FRESCO-2 trials demonstrated that fruquintinib significantly prolongs progression-free survival and the overall survival of refractory mCRC patients, establishing it as the standard third-line treatment strategy for mCRC. In addition, the combination of fruquintinib with other anticancer drugs and immune checkpoint inhibitors demonstrated potential for enhanced efficacy, which warrants further exploration. In this review, we aimed to systematically summarize the current knowledge about the pharmacological mechanisms, pharmacokinetic characteristics, adverse events, and corresponding treatment options of fruquintinib and provide an update on the clinical trials related to fruquintinib in CRC by conducting a comprehensive literature search of PubMed and consulting the relevant clinical trials via ClinicalTrials.gov and the ChiCTR website, aiming to offer new insights into the role of fruquintinib in the comprehensive treatment of CRC.

Colorectal cancer (CRC) is the third most common cancer in the world, with an average 5-year overall survival (OS) rate of approximately 60% [...].

The use of targeted drugs and immunotherapy has significantly impacted the treatment of Colorectal Cancer. However, horizontal comparison among various regimens is extremely rare. Therefore, we evaluated the survival efficacy of multiple treatment regimens of targeted therapy and/or immunotherapy with or without chemotherapy in patients with Colorectal Cancer.

A systematic search was conducted in PubMed, EMBASE, and Cochrane databases, covering the period from the establishment of the databases to October 29, 2024. To obtain articles that met the inclusion and exclusion criteria and contained the required data for conducting a network meta-analysis (NMA). The NMA evaluated overall survival (OS) and progression-free survival (PFS).

A total of 90 studies were identified, comprising a sample size of 33,167 subjects. In terms of PFS, compared with simple chemotherapy strategies, most of the other single or combined strategies are significantly effective, among which targeted therapy strategies have more advantages. Encorafenib + Binimetinib + Cetuximab (ENC-BIN-CET) shows significant benefits in all comparisons except when compared with Chemotherapy + Cetuximab + Dalotuzumab (Chemo-CET-DAL), Encorafenib + Cetuximab (ENC-CET), and Panitumumab + Sotorasib (PAN-SOT). The ENC-CET and PAN-SOT targeted strategies also show significant benefits. Pembrolizumab (PEM) monotherapy has advantages over all others except when it is not superior to some targeted strategies. Chemotherapy + Bevacizumab + Atezolizumab is only inferior to some strategies. In terms of OS, the combinations of Chemotherapy + Bevacizumab, ENC-CET, Chemotherapy + Panitumumab, and ENC-BIN-CET are superior to simple chemotherapy regimens. ENC-BIN-CET shows OS benefits in all comparisons except some. ENC-CET significantly improves OS in most cases, and PEM also significantly improves OS in some regimens. In the probability ranking of OS and PFS, ENC-BIN-CET has the best effect, followed by ENC-CET.

In conclusion, pembrolizumab is still effective in prolonging survival. Dual- and triple-drug targeted strategies are the best in terms of OS and PFS, and the combination of targeted immunotherapy and chemotherapy also works. However, not all combinations are beneficial. As targeted drugs play an active role, specific drugs for colorectal cancer regimens should be carefully selected.

It is becoming increasingly evident that diabetic vascular complications seriously threaten human health. The most prevalent microvascular complications include kidney disease, retinal disease, cardiovascular diseases and amputation. Conventional treatments can only relieve the progression of the diseases, and is no longer appropriate for the long-term management of diabetic patients. Exploring a novel therapeutic regimens and improvements in management of Diabetic Complications is required. Alternative splicing has been found to play a crucial role in the occurrence and treatment of diseases, including the destruction and generation of blood vessels in diabetes. Alternative splicing is an important factor in the high complexity of multicellular eukaryotic transcriptome, and angiogenesis, which is an important process controlled by alternative splicing mechanism. This review mainly introduces the current understanding of alternative splicing and the role that alternative splicing plays in the diabetic complications, with a special focus on vascular system. In this study, we summarized alternative splicing in relation to diabetes complications and the pathogenesis of diabetic vasculopathy. It discussed potential treatment strategies for correcting aberrant splicing and suggested novel approaches for addressing diabetes complications.

Cancer is the second most common cause of death worldwide. Bowel emergencies in patients with cancer are becoming increasingly more prevalent due to advances in cancer therapy and longer overall patient survival. When these patients present acutely, they are often frail and may have pre-existing co-morbidities. This article discusses the imaging features of bowel emergencies commonly encountered in oncological patients in clinical practice. These include chemotherapy related colitis, neutropenia enterocolitis and typhlitis, toxic megacolon, bowel perforation, malignant bowel obstruction and gastrointestinal haemorrhage. The radiologist plays a key role in identifying these oncological emergencies and guiding further management.

The management of patients with diffuse liver metastases remains a significant clinical challenge. In many cancer patients, metastatic disease may be isolated to the liver or the liver may be the dominant site of progressive metastatic cancer. In this setting, progression of disease in the liver generally is the most significant cause of morbidity and mortality.

Gastric-type endocervical adenocarcinoma (GEA) is a rare malignant tumor that is not associated with high-risk HPV infection, known for its high invasiveness and resistance to current treatments. This study assessed the effectiveness of anti-angiogenic regimens in real-world GEA patients.

Patients with GEA were enrolled between February 2012 and March 2023, and their clinicopathological characteristics were collected from their medical records. The patients were categorized into groups based on whether they received anti-angiogenic treatments or not. Survival analysis was conducted using the Kaplan-Meier method.

A total of 43 GEA patients were enrolled in this study, with 23 cases who received anti-angiogenic drugs (nine received them as the primary treatment, 12 as first-line therapy after recurrence/metastasis, and two as second-line therapy) as the observation group. The other 20 patients who received similar treatments without the anti-angiogenic regimens serve as the control group. Compared to the control group, the addition of anti-angiogenic drugs as the primary treatment mildly extended progression-free survival (PFS) while not being statistically significant (16 months vs 11 months, p = 0.744). The negative results were also observed in 12 patients who started anti-angiogenic therapy as first-line therapy after recurrence/metastasis (8.5 months vs 9 months, p = 0.518). As for the overall survival (OS), no benefits were detected in either patients who started the anti-angiogenic therapy as primary or subsequent treatments (p = 0.499 and 0.450, respectively).

We firstly evaluated the efficacy of anti-angiogenic drugs in treating patients with GEA. Although with a small sample size, our preliminary results clearly proposed that the anti-angiogenic therapy failed in suppressing tumors and should not be a preferred choice for GEA. As a much rarer tumor without standard treatments, we herein warned of a pitfall for gynecologic oncologists when facing this malignancy.

Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.

BRAF mutations occur in 5-10% of metastatic colorectal cancer (mCRC) cases, but their implications for prognosis and optimal treatment remain unclear.

This multicenter, prospective observational study analyzed 377 RAS wild-type cases from 511 patients across 32 centers, using PCR-based methods.

BRAF mutations were identified in 21% (79/377) of cases, predominantly V600E (89.9%) with a minority of non-V600E (10.1%). Microsatellite instability (MSI) testing revealed MSI-high in 11.3%, exclusively among V600E cases. V600E mutations were linked to right-sided tumors, poor differentiation, and elevated CA19-9 levels. Median survival was significantly lower in V600E cases compared to BRAF wild-type (12.4 vs. 37.5 months, HR 3.25, p < 0.001) and marginally lower non-V600E cases (12.4 vs. 34.7 months, HR 0.61, p = 0.057). Chemotherapy regimens (doublet vs. triplet) and targeted treatments (bevacizumab vs. anti-EGFR) showed no significant survival differences in V600E patients. Similarly, RAS/BRAF wild-type patients had comparable survival with bevacizumab versus anti-EGFR, even for left-sided tumors.

These findings highlight distinct clinical and prognostic profiles for BRAF V600E and non-V600E mutations, while treatment choice appears to have limited impact on survival in these subgroups or RAS/BRAF wild-type cases.

Colorectal cancer, being 1 of the most significant malignant tumors globally, poses a substantial risk to human health. Unfortunately, its 5-year survival rate stands at a mere 65%. There remains an urgent need for the development of novel treatments to combat this detrimental malignancy effectively. The Shenmai Injection (SMI) is a Chinese medicine that has been proven to have significant clinical efficacy in the treatment of cardiovascular diseases. This study aimed to examine the impact of SMI on the proliferation, migration, invasion, and angiogenesis of tumor-derived endothelial cells (Td-EC).

Human umbilical vein endothelial cells (HUVEC) induced Td-EC, and HUVEC were treated with conditioned media from the human colorectal carcinoma cells (HCT116). The effects of HCT116 on the proliferation, migration, and invasion of hepatocellular carcinoma cells after treatment of SMI were observed by MTS assay and Transwell techniques. Additionally, an angiogenesis experiment was used to investigate Td-EC tube formation capacity.

SMI had a significant inhibiting effect on the proliferation, migration, and invasion of HCT116. SMI was also able to inhibit the angiogenesis of Td-EC. Notably, SMI did not have any effect on the normal endothelium.

SMI has obvious antiproliferation, migration, infiltration, and neogenesis effects on HCT116.

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.

Colorectal cancer (CRC) continues to be a major worldwide health issue, with elevated death rates linked to late stages of the illness. Immunotherapy has made significant progress in developing effective techniques to improve the immune system's capacity to identify and eradicate cancerous cells. This study examines the most recent advancements in CAR-T cell treatment and exosome-based immunotherapy for CRC. CAR-T cell therapy, although effective in treating blood cancers, encounters obstacles when used against solid tumours such as CRC. These obstacles include the presence of an immunosuppressive tumour microenvironment and a scarcity of tumour-specific antigens. Nevertheless, novel strategies like dual-receptor CAR-T cells and combination therapy involving cytokines have demonstrated promise in surmounting these obstacles. Exosome-based immunotherapy is a promising approach for targeted delivery of therapeutic drugs to tumour cells, with high specificity and minimal off-target effects. However, there are still obstacles to overcome in the field, such as resistance to treatment, adverse effects associated with the immune system, and the necessity for more individualised methods. The current research is focused on enhancing these therapies, enhancing the results for patients, and ultimately incorporating these innovative immunotherapeutic approaches into the standard treatment protocols for CRC.

The large and rapid increase in the incidence and mortality of colorectal cancer (CRC) demonstrates the urgent need for new drugs with higher efficacy to treat CRC. However, the lack of applicable and reliable preclinical models significantly hinders the progress of drug development. Patient-derived xenograft (PDX) models are currently considered reliable in vivo preclinical models for predicting drug efficacy in cancer patients. This study successfully uses the CRC PDX model to develop clinical indications for the new multi-target kinase inhibitor BPR1J481 and demonstrated the anti-cancer mechanism and competitive advantages of this drug candidate. The results demonstrate that BPR1J481 exhibits significant anticancer efficacy by inducing apoptosis in CRC PDX tumor tissues and corresponding PDX-derived CRC cells. Through kinase competitive binding and kinase activity assays, we discover that BPR1J481 effectively inhibits SRC kinase activity by directly binding to its active site. The reduction in SRC phosphorylation observed in CRC PDX tumor tissues and derived cells upon treatment with BPR1J481 further validates its inhibitory potential. Furthermore, the decrease in viable cells after SRC knockout and the poorer prognosis observed in patients with higher SRC expression, emphasizes the critical significance and clinical relevance of SRC in CRC. Additionally, BPR1J481 exhibits robust anti-angiogenic effects by suppressing VEGF- and PDGF-induced endothelial cell proliferation, migration, and capillary-like tube formation through inhibition of VEGFR2 and PDGFRβ phosphorylation. Remarkably, BPR1J481 appears to demonstrate greater efficacy against CRC compared to regorafenib. These findings highlight the therapeutic potential of BPR1J481 for patients with CRC.

Colorectal cancer (CRC) represents a significant cause of cancer-related mortality on a global scale. It is a highly heterogeneous cancer, and the response of patients to homogeneous drug therapy varies considerably. Patient-derived tumor organoids (PDTOs) represent an optimal preclinical model for cancer research. A substantial body of evidence from numerous studies has demonstrated that PDTOs can accurately predict a patient's response to different drug treatments. This article outlines the utilization of PDTOs in the management of CRC across a range of therapeutic contexts, including postoperative adjuvant chemotherapy, palliative chemotherapy, neoadjuvant chemoradiotherapy, targeted therapy, third-line and follow-up treatment, and the treatment of elderly patients. This article delineates the manner in which PDTOs can inform therapeutic decisions at all stages of CRC, thereby assisting clinicians in selecting treatment options and reducing the risk of toxicity and resistance associated with clinical drugs. Moreover, it identifies shortcomings of existing PDTOs, including the absence of consistent criteria for assessing drug sensitivity tests, the lack of vascular and tumor microenvironment models, and the high cost of the technology. In conclusion, despite their inherent limitations, PDTOs offer several advantages, including rapid culture, a high success rate, high consistency, and high throughput, which can be employed as a personalized treatment option for CRC. The use of PDTOs in CRC allows for the prediction of responses to different treatment modalities at various stages of disease progression. This has the potential to reduce adverse drug reactions and the emergence of resistance associated with clinical drugs, facilitate evidence-based clinical decision-making, and guide CRC patients in the selection of personalized medications, thereby advancing the individualized treatment of CRC.

Vascular endothelial growth factor (VEGF) inhibitors are widely used in oncology and ophthalmology. Although these agents have been shown to increase the risk of cardiovascular events in systemic use, the effect of local applications is unclear. In our study, we aimed to investigate the effects of anti-VEGF agents on left heart functions after intravitreal injection using speckle tracking echocardiography.

In this prospectively designed study, 44 patients who were going to start intravitreal anti-VEGF treatment were included in the study. Patients were evaluated with speckle tracking echocardiography before the first anti-VEGF administration and at three months of anti-VEGF treatment.

Global longitudinal strain (GLS) values at three months were lower in the patients who participated in the study and this was statistically significant (-18.77±2.17, -18.60±2.01, p=0.001). Also, there was a statistically significant decrease in the mean values of GLS (GLS4CH) obtained from apical four space image, GLS (GLSAPLAX) obtained from apical long axis image and GLS (GLS2CH) obtained from apical 2 space image at month 0 and month 3 (-19.08±2.39, -18.93±2.26, p=0.004; -18.81±2.29, -18.60±2.12, p=0.001; -18.44±2.31, -18.27±2.12, p=0.013, respectively).

The slight decrease in GLS in our study suggests that the use of intravitreal anti-VEGF agents may have cardiac effects.

The discovery of immune checkpoints and the development of immune checkpoint inhibitors (ICI) have achieved a durable response in advanced-stage cancer patients. However, there is still a high proportion of patients who do not benefit from ICI therapy due to a lack of response when first treated (primary resistance) or detection of disease progression months after objective response is observed (acquired resistance). Here, we review the current FDA-approved ICI for the treatment of certain solid malignancies, evaluate the contrasting responses to checkpoint blockade in different cancer types, explore the known mechanisms associated with checkpoint blockade resistance (CBR), and assess current strategies in the field that seek to overcome these mechanisms. In order to improve current therapies and develop new ones, the immunotherapy field still has an unmet need in identifying other molecules that act as immune checkpoints, and uncovering other mechanisms that promote CBR.

Metastatic colorectal cancer (mCRC) is mainly treated with 5-Fluoro-Uracil (5-FU), Oxaliplatin and Irinotecan chemotherapies and anti-Epidermal Growth Factor Receptor (EGFR) or anti-Vascular Endothelial Growth Factor (VEGF) targeted therapies. Due to chemotherapy-related toxicity, patients receive induction treatment to achieve tumour response followed by maintenance therapy with less cytotoxic molecules or a chemotherapy-free interval to reduce chemotherapy-related toxicity. In this study, the aim was to determine the patient, cancer and treatment factors that influence the duration of maintenance therapy (DMT).

We collected retrospective data on a cohort of 133 patients treated at the Centre Georges François Leclerc (CGFL) cancer centre in Dijon between March 2014 and June 2022. Patients had unresectable or potentially resectable diseases. They received first-line induction treatment with chemotherapy and/or targeted therapy and maintenance treatment, defined as the interruption of at least one chemotherapy agent.

In the multivariate analysis, age (HR: 1.02, 95% CI 1.00-1.04, p = 0.031), N2 nodal status (HR: 1.78, 95% CI 1.09-2.89, p = 0.021) and the presence of peritoneal metastases (HR: 2.05, 95% CI 1.25-3.36, p = 0.004), as well as baseline carcino-embryonic antigen (CEA) level (HR: 1.10, 95% CI 1.00-1.20, p = 0.052), were significantly associated to poor DMT. Local treatment of liver metastases also significantly reduced the DMT (HR: 0.49, 95% CI 0.28-0.86, p = 0.013). In our cohort, induction triplet chemotherapy significantly increased the CEA delta (70% vs. 44%, p = 0.047) compared to doublet chemotherapy and led to a higher rate of liver surgery (40% vs. 21%, p = 0.014) and a trend for a higher rate of local treatment of metastases (62% vs. 45%, p = 0.059).

Duration of maintenance therapy is determined by the initial patient and colorectal cancer characteristics. However, it is significantly increased by local treatment of liver metastases. By reducing the tumour burden, a triplet induction chemotherapy regimen increases the rate of liver metastase resection.

The optimal second-line systemic treatment for metastatic colorectal cancer (mCRC) is inconclusive.

We searched PubMed, Web of Science, EMBASE, and Cochrane Library for RCTs comparing second-line systemic treatments for mCRC from the inception of each database up to February 3, 2024. Markov Chain Monte Carlo (MCMC) technique was used in this network meta-analysis (NMA) to generate the direct and indirect comparison results among multiple treatments in progression-free survival (PFS), overall response rate (ORR), overall survival (OS), complete response (CR), partial response (PR), grade 3 and above adverse events (Grade ≥ 3AE), and any adverse events (Any AE). The surface under the cumulative ranking curve (SUCRA) was adopted to evaluate the probability of each treatment being the optimum intervention. Subgroup analyses were performed based on the RAS gene status.

A total of 47 randomized controlled trials were included, involving 16,925 patients and 44 second-line systemic treatments. In improving OS, FOLFOX + Bevacizumab + Erlotinib exhibited significant superiority (SUCRA:92.7%). In improving PFS, Irinotecan + CMAB009 (SUCRA:86.4%) had advantages over other treatments. FOLFIRI + Trebananib (SUCRA:88.1%) had a significant advantage in improving ORR. Among multiple second-line treatments, the SUCRA values of FOLFOX + Bevacizumab in PFS, OS, ORR, and PR were 83.4%, 74.0%, 81.1%, and 86.1%, respectively, and the safety was not significantly different from other interventions. Subgroup analyses showed that FOLFIRI + Bevacizumab + panitumumab ranked among the top in survival outcomes in the RAS-mutant population (OS SUCRA: 87.9%; PFS SUCRA: 70.2%); whereas in the RAS-wild-type population, FOLFIRI + Bevacizumab significantly improved survival outcomes (OS SUCRA: 73.2%; PFS SUCRA: 65.1%).

For most people, FOLFOX + Bevacizumab may be the best second-line systemic treatment regimen for mCRC. For RAS-mutant populations, FOLFIRI + Bevacizumab + Panitumumab is recommended. However, the therapeutic effect may be affected by the patient's physiological state, and clinicians should apply it based on actual conditions.

Cancer has become one of the major diseases threatening human health in the twenty-first century due to its incurability. In 2022, new cases of esophageal and gastrointestinal cancers accounted for 17.1% of all newly diagnosed cancer cases worldwide. Despite significant improvements in early cancer screening, clinical diagnostics, and treatments in recent years, the overall prognosis of digestive system cancer patients remains poor. The DEAD-box helicase family, a crucial member of the RNA helicase family, participates in almost every aspect of RNA metabolism, including transcription, splicing, translation, and degradation, and plays a key role in the occurrence and progression of various cancers. This article aims to summarize and discuss the role and potential clinical applications of DEAD-box helicase family proteins in digestive system cancers. The discussion includes the latest progress in the occurrence, development, and treatment of esophageal and gastrointestinal tumors; the main functions of DEAD-box helicase family proteins; their roles in digestive system cancers, including their relationships with clinical factors; effects on cancer proliferation, migration, and invasion; and involved signaling pathways; as well as the existing inhibitory strategies targeting DDX family proteins, are discussed. Additionally, outlooks on future research directions are provided.

VEGF-A concentrations were measured in the blood of bevacizumab-treated cancer patients in previous studies, but a consensus has not formed that would develop VEGF-A into a clinical biomarker. Recently, methods to strictly distinguish between the VEGF-A isoforms have been developed but have not yet been applied to cancer patients undergoing bevacizumab treatment.

An ELISA that strictly distinguishes between VEGF-A121 and VEGF-A165-the major isoforms of VEGF-A-and a commercially available ELISA for VEGF-A are used to determine the concentration of VEGF-A121, VEGF-A165, and VEGF-A in the blood of 12 patients with advanced colorectal cancer receiving bevacizumab therapy.

The serum and plasma concentrations of VEGF-A121 increased substantially post-bevacizumab administration; the median increase in serum was 860.8 pg/mL, 95% confidence interval (CI) [468.5, 1128.9], p = 0.0024, and in plasma was 808.6 pg/mL, 95% CI [748.7, 874.0], p = 0.00049. In stark contrast, VEGF-A165 after bevacizumab administration decreased in serum by a medium change of -73.8 pg/mL, 95% CI [-149.4, -10.2], p = 0.0034, with 83.3% of the post-bevacizumab concentrations falling below the high-accuracy threshold of 38 pg/mL; in plasma, all pre and post VEGF-A165 concentrations fell below this threshold. Concentrations of VEGF-A121 and VEGF-A165 in platelets did not change to a statistically significant degree. Adding recombinant VEGF-A121 (and -A165) or bevacizumab to plasma in patients post-bevacizumab administration increased or decreased, respectively, VEGF-A121 and VEGF-A165 levels. The increase in VEGF-A121 in plasma and serum after bevacizumab administration may be due to the dissociation of the complex of tumor-derived VEGF-A121 and bevacizumab when it moves from the stroma into the blood.

The VEGF-A121 isoform has been uniquely demonstrated as a clear marker of bevacizumab therapy in both plasma and serum, motivating further research on pursuing these isoforms as biomarkers in cancer care.