Incidence of hand-foot syndrome with protein kinase inhibitors in advanced hepatocellular carcinoma patients who received atezolizumab-bevacizumab combination.

INTRODUCTION: Treatment of advanced HepatoCellular Carcinoma (HCC) is based on first-line (L1) combination of atezolizumab and high-dose (HD) bevacizumab while second-line (L2) refers one antiangiogenic protein kinase inhibitors (aaPKI). This prolonged antiangiogenic pressure let us to observe an increasing occurrence of Hand-Foot Syndromes (HFS) in patients receiving aaPKI after HD bevacizumab combination. This study reports observations and discussions about the evidence and hypothesis that could be made. METHODS: Patients who received the L1 combination from September 1st 2020 to December 31st 2022 to identify L2 aaPKI. Demographic, biological, oncological data and occurrence of HFS were collected. In addition were collected the number of L1 combination cycles, type of aaPKI, and delay between last L1 cycle and L2 initiation. This study had a purely exploratory purpose, so no statistical analysis was planned. RESULTS: 17 patients received an aaPKI after the L1 HD bevacizumab combination with a median time of 26 days from last L1 cycle to L2 start. Five patients experienced HFS including grade 3 (n = 2) with sorafenib and cabozantinib. The HFS occurred with a median delay of 23 days (IQR: 21-28) from aaPKI start. Three patients experienced aaPKI-related dose-limiting toxicity. CONCLUSIONS: Proportion of patients experienced HFS in our cohort did not differ from pivotal trials data and the sample size do not allow to conclude. Hypotheses include timing of aaPKI start in HCC treatment, vascular toxicity at aaPKI start after HD bevacizumab discontinuation instead combination, patient-related outcome for a better understanding of these aaPKI-related HFS post HD bevacizumab.

Analysis of Immune-Related Adverse Events of Atezolizumab and Bevacizumab in Patients with Hepatocellular Carcinoma: A Multicentre Cohort Study.

Introduction: Despite the emergence of atezolizumab and bevacizumab (A + B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A + B treatment. Methods: This multicentre retrospective study included consecutive patients with HCC who were treated with the A + B regimen from September 2020 to December 2022. Patients were categorized into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs. Results: This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: group 1 (n = 84) had no irAEs, group 2 (n = 37) had mild irAEs (grade 1-2), and group 3 (n = 29) had severe irAEs (grade ≥3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to group 1 (9.5 months) and group 3 (5.6 months), with a median OS of 23.0 months (p < 0.001). Furthermore, group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both group 1 and group 3 (p < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; p = 0.010), ALBI grade 1 (HR, 0.389; p = 0.006), Child-Pugh class A (HR, 0.338; p = 0.002), and the absence of PVTT (HR, 0.556; p = 0.043) as independent predictors of better OS. Conclusion: Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A + B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis.

Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study.

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs). Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated. Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis. Discussion/Conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab.

Combination Therapy of Lenvatinib and Hepatic Arterial Infusion Chemotherapy Using Cisplatin With Lipiodol and 5-Fluorouracil: A Potential Breakthrough Therapy for Unresectable Advanced Hepatocellular Carcinoma.

INTRODUCTION: In 2021, the LEOPARD trial reported that the combination of lenvatinib+one-shot cisplatin infusion might contribute to improving the results of conventional advanced hepatocellular carcinoma (HCC) treatment. Thus, combination therapy with lenvatinib and catheterization has emerged as a focal point in treating advanced HCC. Conversely, the New FP regimen consists of low-dose cisplatin (CDDP) combined with 5-fluorouracil (5-FU) and lipiodol via hepatic arterial infusion chemotherapy (HAIC), with a high response rate of approximately 70%. Therefore, lenvatinib+New FP (LEN-New FP) may be a more promising treatment for HCC. Here, we report six patients who were administered LEN+New FP and achieved high therapeutic efficacy. Among them, one case had an interesting clinical course, which has been described in detail. MATERIALS AND METHODS: This study included six patients who were administered 12 mg or 8 mg of lenvatinib once daily based on a body weight of ≥60 kg or <60 kg, respectively, along with 50 mg of cisplatin in 5-10 mL lipiodol, and a continuous infusion of 5-FU (1500 mg/5 days) infused every 2-4 weeks. Tumor evaluations were performed 4-8 weeks after the initiation of New FP administration and every 8-12 weeks thereafter. RESULTS: The median patient age was 65 years. All patients had a history of prior treatment with atezolizumab and bevacizumab and one of the factors associated with poor overall survival for New FP monotherapy, such as a maximum tumor diameter ≥7 cm and bilobular multifocal distribution. Four (67%) patients had severe vascular invasion. The best objective response and disease control rates were 83% and 100%, respectively. The best response of the target lesion was complete remission in four out of six patients. CONCLUSION: The LEN-New FP combination for advanced HCC showed a high response rate and was more effective in high-risk patients with factors associated with poor overall survival than that reported with conventional New FP monotherapy. Additionally, LEN-New FP exhibited extremely high objective response and disease control rates and was well tolerated, including in cases where it was considered second- or third-line systemic chemotherapy for advanced HCC. Thus, LEN-New FP can serve as a breakthrough therapy for advanced HCC based on appropriate case selection.

Fatal intratumoral hemorrhage in a patient with hepatocellular carcinoma following successful treatment with atezolizumab/bevacizumab: A case report.

BACKGROUND: Atezolizumab/bevacizumab is emerging as the new standard for advanced hepatocellular carcinoma (HCC), with ongoing real-world implementation to study its effectiveness. As the use of atezolizumab/bevacizumab increases, various side effects have been reported in clinical practice, most notably increased bleeding caused by bevacizumab. CASE SUMMARY: In this case report, we present a rare and fatal case of intratumoral hemorrhage in a patient with advanced HCC following successful treatment with atezolizumab/bevacizumab. A 63-year-old male diagnosed with HCC initially underwent four cycles of intra-arterial chemotherapy. However, follow-up abdominal computed tomography (CT) revealed disease progression. Subsequently, the treatment plan was modified to atezolizumab/bevacizumab. After the fifth cycle of atezolizumab/bevacizumab, CT showed partial regression of HCC. One week later, he visited the emergency room due to severe abrupt abdominal pain. Abdominal CT revealed focal rupture of HCC in the medial segment inferior portion with active bleeding and a large amount of hemoperitoneum. Angiography was performed on the same day, and embolization of A4 and A8 branches using lipiodol and gelfoam was implemented. Despite successful hemostasis, the patient subsequently developed liver failure and died. CONCLUSION: Atezolizumab/bevacizumab for advanced HCC suggests that intratumoral hemorrhage may be crucial despite good tumor response after immunotherapy, emphasizing the continuous monitoring of this side effect.

A Consensus Statement on the Administration of Systemic Bevacizumab in Patients with Recurrent Respiratory Papillomatosis.

OBJECTIVE: To provide detailed guidance on the administration of systemic bevacizumab in patients with recurrent respiratory papillomatosis (RRP) based on a detailed review of the scientific literature and a consensus of experts with real-world clinical experience. METHODS: A bevacizumab consensus working group (N = 10) was composed of adult and pediatric otolaryngologists, adult and pediatric oncologists, and a representative from the RRP Foundation (RRPF), all with experience administering systemic bevacizumab in patients with RRP. After extensive review of the medical literature, a modified Delphi method-based survey series was utilized to establish consensus on the following key areas: clinical and patient characteristics ideal for treatment candidacy, patient perspective in treatment decisions, treatment access, initial dosing, monitoring, guidelines for tapering and discontinuation, and reintensifying therapy. RESULTS: Seventy-nine statements were identified across nine critical domains, and 45 reached consensus [clinical benefits of bevacizumab (3), patient and disease characteristics for treatment consideration (7), contraindications for treatment (3), shared decision-making (incorporating the patient perspective) (5), treatment access (3), initial dosing and administration (8), monitoring (7), tapering and discontinuation (6), and reintensification (3)]. CONCLUSION: This consensus statement provides the necessary guidance for clinicians to initiate systemic administration of bevacizumab and represents a potential paradigm shift toward nonsurgical treatment options for patients with RRP. LEVEL OF EVIDENCE: 5 Laryngoscope, 2024.

Efficacy and safety of PD-1/L1 inhibitors as first-line therapy for metastatic colorectal cancer: a meta-analysis.

Objective: To evaluate the efficacy and safety of PD-1/L1 inhibitors as first-line therapy in metastatic colorectal cancer(mCRC). Method: Articles evaluating first-line PD-1/L1 inhibitors for mCRC were sought in four databases (Pubmed, Embase, Web of Science, and the Cochrane Library) from the inception of the databases until 11 November 2023. Meta-analyses were conducted to assess the rates of progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), disease control rate (DCR), and grade ≥ 3 treatment-related adverse events (trAEs). Results: Totally nine studies were included for meta-analysis. A subgroup analysis was performed based on mismatch repair(MMR) status and regimens. In patients diagnosed with mismatch repair-deficient(dMMR) mCRC who received PD-1/L1 inhibitors as their first-line treatment, the ORR was 0.54 (95% CI, 0.39 to 0.68), the median PFS was 53.2 months, the Grade≥ 3 TRAEs rate was 0.33(95% CI, 0.12 to 0.60) and the median OS was not determined. For patients with proficient mismatch repair (pMMR) mCRC who underwent a combined treatment of PD-1/L1 inhibitors, anti-VEGF monoclonal antibody and chemotherapy as their first-line therapy, the ORR was 0.62 (95% CI, 0.56 to 0.68), the median PFS was 10.1 months, the median OS was 26.7 months, and the Grade≥ 3 TRAEs rate was 0.59(95% CI, 0.39 to 0.77). Conclusion: Our results revealed that the utilization of PD-1/L1 inhibitors as first-line therapy for dMMR mCRC yielded highly favorable outcomes, while maintaining an acceptable level of safety. Administering a combination of PD-1/L1 inhibitors, anti-VEGF monoclonal antibody, and chemotherapy as first-line treatment in patients with pMMR mCRC led to an improved ORR. However, there was no significant improvement in the long-term prognosis of the tumor. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024506196, identifier CRD42024506196.

Combination of pemetrexed with bevacizumab for non-small-cell lung cancer: a meta-analysis study.

BACKGROUND: Combining pemetrexed with bevacizumab may have some potential in improving the efficacy in patients with non-small-cell lung cancer (NSCLC), and this meta-analysis aims to explore the impact of pemetrexed addition to bevacizumab on treatment efficacy for NSCLC. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched, and we included randomized controlled trials (RCTs) assessing the effect of pemetrexed addition to bevacizumab on treatment efficacy in patients with NSCLC. Overall survival and progression-free survival were included in this meta-analysis. RESULTS: Four RCTs were finally included in the meta-analysis. Overall, compared with bevacizumab for NSCLC, pemetrexed addition showed significantly improved overall survival (hazard ratio [HR] = 0.87; 95% confidence interval [CI] = 0.76 to 0.99; P = 0.03), survival rate (odd ratio [OR] = 1.41; 95% CI = 1.06 to 1.86; P = 0.02), progression-free survival (HR = 0.63; 95% CI = 0.55 to 0.72; P < 0.00001) and progression-free survival rate (OR = 1.92; 95% CI = 1.38 to 2.67; P < 0.00001), but led to the increase in grade ≥ 3 adverse events (OR = 2.15; 95% CI = 1.62 to 2.84; P < 0.00001). CONCLUSIONS: Pemetrexed addition may be effective to improve treatment efficacy for NSCLC compared to bevacizumab treatment.

First-Line Treatment with Atezolizumab plus Bevacizumab and Chemotherapy for US Patients with Metastatic, Persistent, or Recurrent Cervical Cancer: A Cost-Effectiveness Analysis.

OBJECTIVE: The BETAcc clinical trial demonstrated that chemotherapy combined with bevacizumab plus atezolizumab (CBA) significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with metastatic, persistent, or recurrent cervical cancer. However, to our knowledge, the economic value of using this new therapy for this indication is currently unknown. Therefore, our study aims to evaluate the cost-effectiveness of CBA for the first-line treatment of metastatic, persistent, or recurrent cervical cancer from the United States healthcare payers perspective. METHODS: A state-transition Markov model over a 10-year lifetime horizon was developed to compare the cost and effectiveness of CBA versus chemotherapy plus bevacizumab (CB). The primary outcomes of our study included costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the results. RESULTS: CBA was associated with an additional 0.58 QALY at an extra cost of $172,495.90 compared to CB. The ICER was $295,972.43/QALY, significantly higher than the willingness-to-pay (WTP) threshold value of $150,000/QALY. One-way sensitivity analyses revealed that results were most sensitive to the PFD utility, the unit cost of atezolizumab, and PD utility. Probabilistic sensitivity analysis indicated that CBA achieved a 4.3% probability of cost-effectiveness at a $150,000/QALY threshold. To achieve cost-effectiveness, the unit price of atezolizumab must be reduced by approximately 56.6%. CONCLUSIONS: CBA treatment is unlikely to be a cost-effective option compared with CB for patients with persistent, recurrent, or metastatic cervical cancer in the United States.

Association of serum lactate dehydrogenase with prognosis and tumor metabolism in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy.

PURPOSE: Treatment outcomes are predicted by analyzing peripheral blood markers such as serum lactate dehydrogenase (LDH). We conducted this study to investigate whether serum LDH levels can predict the prognosis of patients treated with atezolizumab plus bevacizumab (ATZ/BEV) therapy for hepatocellular carcinoma (HCC) and whether LDH levels correlate with metabolic changes. METHODS: We enrolled 66 HCC patients treated with ATZ/BEV. Based on the change in serum LDH levels before and after treatment, the patients were divided into two groups, and the prognosis of each group was examined. Moreover, the association of LDH levels with tumor metabolism was analyzed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). RESULTS: There were 32 patients categorized as the LDH-decrease group. Kaplan-Meier survival analysis indicated worse progression-free survival (PFS) in the LDH-increase group than in the LDH-decrease group (p = 0.0029). Multivariate analysis showed that an increase in the LDH level was an independent risk factor for worse PFS (p = 0.0045). The baseline LDH level correlated significantly with a high maximum standardized uptake value of 18F-FDG, according to the PET/CT findings. Transcriptomic analyses of specimens resected after ATZ/BEV therapy showed downregulated mitochondria-related pathways. CONCLUSION: Serum LDH levels are a potential prognostic marker and an indicator of tumor metabolism.

Cost-effectiveness analysis of bevacizumab biosimilars versus originator bevacizumab for metastatic colorectal cancer: a comparative study using real-world data.

OBJECTIVE: MVASI (Amgen) and Zirabev (Pfizer) are two of the earliest bevacizumab biosimilars approved for the first-line treatment of metastatic colorectal cancer (mCRC). We aimed to confirm and quantify the real-world cost-savings and cost-effectiveness of MVASI and Zirabev relative to originator bevacizumab for patients with mCRC. METHODS: We conducted a population-based, retrospective cohort study in Ontario, Canada, where originator and biosimilar bevacizumab are universally publicly funded. All mCRC patients who received originator bevacizumab between January 2008 and August 2019 or biosimilar bevacizumab between August 2019 and March 2021 were propensity score-matched (1:4) to adjust for baseline differences. Total 1-year patient-level costs (CAD) and effects (life years (LY) and quality-adjusted life years (QALY)) were calculated from the public health payer's perspective. Primary outcomes included incremental net monetary benefit (INMB) and incremental net health benefit (INHB). Sensitivity analyses included a subgroup analysis by biosimilar type (MVASI/Zirabev) and a 2-year analysis. RESULTS: The matched cohort included 747 biosimilar cases and 2,945 comparators. Bevacizumab biosimilars were associated with an incremental cost of -$6,379 (95%CI: -9,417, -3,537) (i.e., cost-saving) and incremental effect of 0.0 (95% CI: -0.02, 0.02) LY and -0.01 (95%CI: -0.03, 0) QALY gained. INMB and INHB estimates were $6,331 (95% CI: 6,245, 6,417) and 0.127 LY (95% CI: 0.125, 0.128), respectively, at a willingness-to-pay threshold of $50,000/LYG, with all estimates indicating the cost-effectiveness of biosimilar bevacizumab. Cost-effectiveness remained consistent across biosimilar brand subgroups and 2-year sensitivity analyses. CONCLUSION: Bevacizumab biosimilars demonstrated real-world cost-savings while providing similar survival benefit as originator bevacizumab, confirming the initial expectations of their implementation and supporting health system sustainability.

Mechanism and rational combinations with GP-2250, a novel oxathiazine derivative, in ovarian cancer.

BACKGROUND: GP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models. METHODS: We carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP-2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP-2250 alone and in combination with standard-of-care drugs (e.g., paclitaxel, cisplatin, topotecan, and poly ADP-ribose polymerase [PARP] inhibitors). RESULTS: We investigated the cytotoxic effect of GP-2250 in 10 ovarian cancer cell lines and found GP-2250 combined with a PARP inhibitor had the greatest synergy. RPPA revealed that GP-2250 inhibited hypoxia-inducible factor-1α, AKT, and mammalian target of rapamycin (mTOR) activation and expression. High-resolution mass spectrometry revealed that hexokinase2 activity and protein expression were significantly reduced by GP-2250 exposure. Furthermore, GP-2250 reduced glycolysis and ATP synthesis in cancer cells. An in vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that 500 mg/kg GP-2250 was effective in downregulating AKT and mTOR activation and expression. In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP-2250 with either PARP inhibitors or bevacizumab showed a significant reduction of tumor weights and nodules compared to those treated with a vehicle, control IgG groups, or monotherapy groups. CONCLUSIONS: Taken together, our data indicate that GP-2250 exerts profound effects on tumor metabolism and, in combination with PARP inhibitors or bevacizumab, showed promising anti-tumor efficacy. These findings could have implications for the clinical development of GP-2250.

Effects of PARP Inhibitors on Subsequent Platinum-Based Chemotherapy in Patients with Recurrent Ovarian Cancer.

The clinical outcomes in patients with ovarian cancer have been significantly improved by Poly(adenosine diphosphate-ribose) polymerase inhibitors (PARP-is). However, the best therapeutic strategy for recurrence during PARP-i maintenance therapy remains unknown. Herein, we elucidated the efficacy of platinum-based chemotherapy after PARP-i treatment in recurrent ovarian cancer. Eligible patients had experienced relapses during PARP-i maintenance therapy lasting at least 6 months and had received subsequent platinum-based chemotherapy at our institution between January 2019 and March 2024. Progression-free survival (PFS), overall survival (OS), and risk factors for PFS were evaluated. Sixty-six patients were assessed for eligibility and eighteen were enrolled. The median follow-up period was 14.5 months. The PFS and OS of all patients were 6.5 and 17.6 months, respectively. The evaluation of the risk factors for PFS revealed that age, pathological type, duration of PARP-i maintenance therapy, prior lines of chemotherapy, and PARP-i dose reduction were not significant prognostic markers. However, bevacizumab use in subsequent therapies significantly extended the PFS. The median PFS was 3.1 months in the chemotherapy-alone group and 8.9 months in the chemotherapy with bevacizumab group (log-rank p = 0.022). Platinum-based chemotherapy with bevacizumab in subsequent therapies would provide substantial benefits in the PFS of patients with recurrent ovarian cancer.

Secondary glaucoma after bevacizumab injection in Type-1 retinopathy of prematurity.

Purpose: The authors report three separate cases of type 1 retinopathy of prematurity (ROP) treated with intravitreal bevacizumab before, or at 34 weeks postmenstrual age (PMA), with subsequent development of secondary glaucoma. Observations: All three cases involve patients born ≤24 weeks and meeting the American Academy of Pediatrics criteria for ROP screening. Prior to treatment, each patient was noted to have normal anterior chamber structures with no signs of glaucoma. Each patient developed type 1 ROP and was treated with intravitreal bevacizumab, which was administered at or before 34 weeks PMA. Following the administration of intravitreal anti-vascular endothelial growth factor (VEGF), each patient developed a suspected open-angle glaucoma (OAG) within an approximate 4-week time frame. In these cases, the presentation of glaucoma differed from those that have been previously reported in the literature. Conclusion and importance: Based on similar timing of glaucoma development following intravitreal bevacizumab injections, we hypothesize that the administration of anti-VEGF agents to very premature infants (≤24 weeks) at or before 34 weeks PMA, may predispose them to the development of secondary glaucoma through an unknown and possibly novel pathway.

Is add-on Bevacizumab therapy to Temozolomide and radiotherapy associated with clinical utility for newly diagnosed Glioblastoma? A systematic review and meta-analysis.

Bevacizumab, temozolomide (TMZ), and radiotherapy are three therapeutic methods, but the combination of them as a new approach for the treatment of newly diagnosed high-grade gliomas (HGGs) is still under investigation. Therefore, this study aims to evaluate the safety, efficacy, and clinical utility of this treatment approach for patients with glioblastoma (GBM). PubMed/Medline, Scopus, Embase, and Web of Science were systematically reviewed from inception to 24 August 2023. Relevant studies evaluating the therapeutic effect of adding Bevacizumab to TMZ-based chemotherapy and radiation therapy were enrolled. All statistical analysis was performed using the "meta" package of R. A total of 21 studies were included in this study. Our meta-analysis found that adding bevacizumab to standard therapy improved progression-free survival (PFS) in patients with newly diagnosed GBM. The pooled 6-month PFS rate was significantly higher with bevacizumab (79% vs. 56%, odds ratio 3.17). Overall survival (OS) showed modest improvements, with 2-year OS rates of 39% vs. 20% favoring bevacizumab. Radiological response rates varied, with a pooled overall response rate of 44% for bevacizumab-treated patients. The complete response rate was 16%, partial response 32%, and progressive disease 25%. Adverse events occurred in 62% of bevacizumab-treated patients. Common complications included fatigue, thrombocytopenia, and thromboembolic events. When added to standard therapy, bevacizumab demonstrates modest improvements in PFS and OS for newly diagnosedGBM. While it shows promise in short-term outcomes and radiological responses, long-term survival benefits remain limited. The risk of adverse events, particularly CNS hemorrhage, necessitates careful patient selection. These findings suggest that bevacizumab may have a role in treating high-grade gliomas, but its use should be individualized based on patient characteristics and risk-benefit assessment.

Successful radical surgery for lymph node metastasis in a patient with hepatocellular carcinoma following atezolizumab plus bevacizumab combination therapy: a case report and literature review.

A woman in her early 80 s was followed up in our hospital for chronic hepatitis C after viral eradication. We detected rapid-growing lymph node metastasis of hepatocellular carcinoma (HCC) after treatment with transcatheter arterial chemoembolization and/or radiofrequency ablation. We found that the metastasis was operable, but the size and location of the metastasis obliged the patient to receive pancreatoduodenectomy, which was too invasive. Then we initiated systemic chemotherapy to perform radical minimally invasive surgery. We treated the patient with 3 weekly cycles of atezolizumab 1200 mg plus bevacizumab 15 mg/kg. The patient tolerated the treatment well, and treatment-emergent adverse events included deterioration of hypertension and increased uric protein. After a total of 4 cycles of therapy, abdominal computed tomography findings showed that the metastasis evidently decreased, and a complete response was achieved based on the Revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Seventeen days later, the metastasis was dissected. Subsequently, we confirmed that there was no pathological metastatic lesion in the resected lymph node. Our case is the first report of successful application of the radical therapy to lymph node metastasis of HCC via combination therapy with atezolizumab/bevacizumab.

Antitumor effects of IOX1 combined with bevacizumab-induced apoptosis and immunity on colorectal cancer cells.

Colorectal cancer (CRC), as a fatal cancer, is one of the most common cancers worldwide. Although the standard treatment for colorectal cancer is well researched and established, long-term patient survival remains poor, and mortality remains high. Therefore, more and more effective treatment options are needed. To evaluate the efficacy of bevacizumab, the histone demethylase inhibitor IOX1, or their combination for the treatment of colorectal cancer, we examined the effects of IOX1, bevacizumab, and IOX1 combined with bevacizumab on cell activity, proliferation, and migration of colorectal cancer cell lines HCT116, RKO, and CT26 by CCK8, colony formation assay, wound healing assay, and transwell assay. The effects of the drugs alone as well as in combination on apoptosis in colorectal cancer cell lines were examined by flow cytometry and further validated by Western blotting for apoptosis-related proteins. The antitumor effects of treatment alone or in combination on colorectal cancer cells were examined in animal models. Mice were injected subcutaneously with CT26 cells and the growth and immune infiltration in tumor tissues were detected by IHC after drug treatment. We found that IOX1 could effectively inhibit the activity of CRC cells and had a significant inhibitory effect on the proliferation and migration of CRC cells. The apoptosis rate increased in a dose-dependent manner after IOX1 treatment on colorectal cancer cells, and the expression of apoptosis-related proteins changed accordingly. Further combination with bevacizumab revealed that the combination had a more significant effect on the proliferation, migration, and apoptosis of CRC cells than either IOX1 or bevacizumab alone. In vivo experiments have found that both alone and combination drugs can inhibit the growth of mouse tumors, but the effect of combination inhibition is the most obvious. Combination therapy significantly inhibited the expression of proliferative marker (Ki67) in tumor xenograft models, and increased content of antigen-specific CD4+, CD8+T cell growth, and granzymeB (GZMB), which is associated with T cell cytotoxicity, was detected in combination therapy. Immunoassays suppressed the expression of relevant PD-1 and decreased. The anticancer drug bevacizumab and the histone demethylase inhibitor IOX1 may inhibit colon cancer cell growth by regulating apoptosis. The inhibitory effect of combination therapy on tumor growth may be achieved, in part, through upregulation of infiltration-mediated tumor immunity by T lymphocytes. The combination of IOX1 and bevacizumab produced significant synergistic effects. This study aims to provide a new direction for CRC combination therapy.

Variceal bleeding following treatment with atezolizumab plus bevacizumab in two patients with unresectable hepatocellular carcinoma.

Bleeding-related adverse events may occur due to anti-vascular endothelial growth factors. Here, we report two cases of variceal rupture during atezolizumab plus bevacizumab (ATZ/BV) treatment for unresectable hepatocellular carcinoma (u-HCC).Case 1 involved a man in his 60 s with alcoholic liver cirrhosis (LC) and u-HCC. Seventy-four days after ATZ/BV administration, the patient was admitted for hematemesis. Upper esophagogastroduodenoscopy (EGD) revealed worsening of the esophageal varices (EVs) to F2 grade with active bleeding. Endoscopic variceal ligation successfully achieved hemostasis.Case 2 involved a man in his 70 s with alcoholic LC and u-HCC. The patient was admitted with hematemesis 114 days after ATZ/BV administration. During EGD, the EVs deteriorated to F3 grade, although hemostasis had already been achieved. The evaluation was discontinued during the observation stage because of the worsening hepatic reserve.Neither patient had EVs warranting prophylactic treatment before ATZ/BV administration, showed a partial tumor response, or had portal vein tumor thrombus. Both patients demonstrated increased total diameters of the collateral veins and splenic volume compared to those before treatment. These findings suggest that ATZ/BV treatment may increase portal pressure. In conclusion, the administration of ATZ/BV to patients with LC and u-HCC necessitates careful management of EVs aggravation and rupture.

Molecular Imaging of Melanoma VEGF-expressing Tumors through [99mTc]Tc-HYNIC-Fab(Bevacizumab).

BACKGROUND: Angiogenesis is a process that many tumors depend on for growth, development, and metastasis. Vascular endothelial growth factor (VEGF) is one of the major players in tumor angiogenesis in several tumor types, including melanoma. VEGF inhibition is achieved by bevacizumab, a humanized monoclonal antibody that binds with high affinity to VEGF and prevents its function. In order to successfully enable in vivo VEGF expression imaging in a murine melanoma model, we previously labeled bevacizumab with [99mTc]Tc. We observed that this was feasible, but it had prolonged blood circulation and delayed tumor uptake. OBJECTIVE: The aim of this study was to develop a radiolabeled Fab bevacizumab fragment, [99mTc]Tc-HYNICFab( bevacizumab), for non-invasive in vivo VEGF expression molecular imaging. METHODS: Flow cytometry was used to examine VEGF presence in the murine melanoma cell line (B16-F10). Bevacizumab was digested with papain for six hours at 37°C to produce Fab(bevacizumab), which was then conjugated to NHS-HYNIC-Tfa for radiolabeling with [99mTc]Tc. Stability and binding affinity assays were also evaluated. Biodistribution and single photon emission computed tomography/computed tomography (SPECT/CT) were performed at 1, 3, and 6 h (n = 4) after injection of [99mTc]Tc-HYNIC-Fab(Bevacizumab) in normal and B16-F10 tumor-bearing C57Bl/6J mice. RESULTS: Using flow cytometry, it was shown that the B16-F10 murine melanoma cell line has intracellular VEGF expression. Papain incubation resulted in the complete digestion of bevacizumab with good purity and homogeneity. The radiolabeling yield of [99mTc]Tc-HYNIC-Fab(bevacizumab) was 85.00 ± 6.06%, with a specific activity of 291.87 ± 18.84 MBq/mg (n=3), showing in vitro stability. Binding assays demonstrated significant intracellular in vitro VEGF expression. Fast blood clearance and high kidney and tumor uptake were observed in biodistribution and SPECT/CT studies. CONCLUSIONS: We present the development and evaluation of [99mTc]Tc-HYNIC-Fab(bevacizumab), a novel molecular VEGF expression imaging agent that may be used for precision medicine in melanoma and potentially in other VEGF-expressing tumors.