Dose Of Bevacizumab Research Articles

ANGI-07. A CASE OF HYPERBARIC OXYGEN USED AS A TREATMENT MODALITY FOR ANAPLASTIC ASTROCYTOMA

Abstract Although its precise mechanism is unclear, hyperbaric oxygen is thought to impede the growth of tumor cells by inhibiting tumor hypoxia, a known driver for angiogenesis. We present a case of a 32-year-old pilot who developed sudden onset aphasia and disorientation which led to hospitalization and imaging. He was diagnosed with anaplastic astrocytoma and underwent resection, radiation, and chemotherapy with temozolomide. Approximately one year later, MRI showed enlarging non-enhancing T2/FLAIR hyperintense mass in the right temporal lobe. He received 4 cycles of lomustine. Four months later, MRI showed slight increase in the size of ring enhancement around the treatment area. These findings were thought to be related to treatment-related changes. After 4 doses of bevacizumab every 2 weeks, there was improvement in surrounding vasogenic edema. However, after 7 doses, his MRI brain demonstrated increase in treatment-related changes with more vasogenic edema. He also had worsening left-sided weakness, unable to lift his left arm against gravity, dysarthria, and cognitive slowing. MRI perfusion supported treatment-related changes rather than tumor growth. He then started hyperbaric oxygen treatments and after 20 sessions of treatment, his vasogenic edema and his left-sided weakness improved. After 60 sessions of hyperbaric oxygen, he noticed further improvement in his strength and short-term memory. Four months after completion of his hyperbaric oxygen, he was found to have increasing size of ring-enhancing lesion and was restarted on hyperbaric oxygen treatments in addition to bevacizumab and low-dose temozolomide. He completed a total of 100 rounds of hyperbaric treatments. MRI showed improvement and stability. His left-sided weakness continued to improve. Hyperbaric oxygen alone or combined with other treatment modalities may be a promising therapy to improve quality of life. Further research will assist with mechanisms through which hyperbaric oxygen works and patient outcomes.

INNV-07. IVOSIDENIB AND BEVACIZUMAB IN HEAVILY PRETREATED PATIENTS WITH IDH1 MUTANT GLIOMAS

Abstract Isocitrate dehydrogenase 1 (IDH1) inhibitors are transforming the treatment of patients with non-enhancing IDH1 mutant gliomas that have only undergone surgical resection. Questions remain on the utility of IDH1 inhibitors in patients that have received prior therapies such as radiation therapy (RT) and chemotherapy (e.g. temozolomide (TMZ)) and have progressive disease. We evaluated the safety and efficacy of ivosidenib, an oral IDH1 inhibitor, in combination with bevacizumab (BEV), a monoclonal antibody targeting VEGF-A, in IDH1 mutant glioma patients that were heavily pretreated. Fourteen patients received combination ivosidenib and bevacizumab starting between February 2021 to July 2023. In our small cohort, patient age range was 26 to 73 years with seven female patients and seven male patients. Diagnoses represented were astrocytoma, IDH1 mutant (n=10) and oligodendroglioma, IDH1 mutant (n=4). At the time of IDH1 therapy initiation, the majority of patients (n=10) had a grade 3 tumor. All patients (n=14) had canonical IDH1 mutation (p.Arg132His) and had enhancing disease. Therapies initiated prior to ivosidenib therapy included: prior RT (n=12), prior TMZ (n=14) and prior BEV (n=10). The median number of progressions prior to initiation of ivosidenib combination therapy was 3 (range 2 to 6). All patients received ivosidenib dosed at 500 mg daily with bevacizumab doses varying from 5 to 15 mg/kg IV dosed every 2 to 3 weeks. Combination therapy was well tolerated with minimal patients experiencing toxicities requiring dose interruptions; diarrhea (n=2), creatine phosphokinase elevations (n=1), QTc prolongation (n=1), and thrombocytopenia (n=1). The median treatment duration on ivosidenib combination therapy was 4.42 months (range 0.69 to 11.4 months). In this cohort, the combination of ivosidenib and bevacizumab was well tolerated. More information is needed on the benefit of ivosidenib in combination with other therapies and in heavily pretreated patients with IDH1 mutant gliomas.

Efficacy and safety of osimertinib plus bevacizumab versus osimertinib alone for advanced non-small-cell lung cancer with EGFR mutations: A meta-analysis of randomized controlled trials.

To systematically evaluate the efficacy and safety of osimertinib plus bevacizumab in treating advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Up to May 26, 2024, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, Chinese Biomedical Literature, China Science and Technology Journal, and Wanfang were searched, and the randomized controlled clinical trials (RCTs) of osimertinib plus bevacizumab in the treatment of advanced EGFR-mutant NSCLC were included. Two researchers independently screened the literature, assessed the quality of the included literature, and extracted the literature data. Revman5.4 software was used for meta-analysis. A total of 824 patients were included in 10 RCTs. The results of meta-analysis showed that compared with the control group (osimertinib alone), the experimental group (osimertinib plus bevacizumab) had a higher objective response rate (ORR) (relative risk [RR] = 1.23, 95% confidence interval [CI] = 1.03-1.47, P = .02), and the experimental group could significantly reduce the expression levels of carcinoembryonic antigen (mean difference [SMD] = 0.82, 95% CI = 0.30-1.35, P = .002), vascular endothelial growth factor (SMD = 0.43, 95% CI = 0.13-0.73, P = .005), neuron-specific enolase (SMD = 0.88, 95% CI = 0.60-1.17, P < .00001), cytokeratin 19 fragments (SMD = 1.33, 95% CI = 0.34-2.33, P = .009), and carbohydrate antigen 125 (SMD = 0.46, 95% CI = 0.15-0.77, P = .004) in serum. However, the experimental group did not significantly improve the disease control rate (DCR) (RR = 1.17, 95% CI = 1.00-1.36, P = .05), 1- and 2-year progression-free survival (PFS) rates (RR = 1.15, 95% CI = 1.00-1.33, P = .05; RR = 1.02, 95% CI = 0.74-1.40, P = .92), 1- and 2-year overall survival (OS) rates (RR = 1.11, 95% CI = 0.92-1.36, P = .28; RR = 0.99, 95% CI = 0.84-1.18, P = .95). Interestingly, the results of subgroup analysis showed that the experimental group significantly improved ORR, DCR, 1-year PFS, and OS rates in the Chinese population and patients under 65 years old (P < .05). In addition, when the dose of bevacizumab was 7.5 mg/kg q3w in the experimental group, ORR, DCR, 1-year PFS, and OS rates were significantly better than those in the control group (P < .05). In terms of adverse events of drugs, the incidence of proteinuria, hypertension, oral mucositis, bleeding, nausea, and vomiting in the experimental group was higher than that in the control group (P < .05). For patients with advanced EGFR-mutant NSCLC, osimertinib plus bevacizumab has some clinical benefit compared with osimertinib alone. Still, it does not provide additional long-term survival benefits and has higher toxicity. More well-designed, multicenter RCTs are needed to identify the subgroups of patients most likely to benefit from this combination regimen and to validate the optimal dose of this combination regimen.

Comparison of eGFR Levels in Patients Before and After Intravitreal Bevacizumab (Anti-VEGF) Injection

Background: Estimated glomerular filtration rate (eGFR) is a vital indicator of kidney function, particularly in patients receiving treatments that may impact renal health, such as intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections like bevacizumab. Bevacizumab, commonly used to treat retinal diseases like diabetic retinopathy, has raised concerns about its potential systemic effects, including its impact on kidney function due to the role of VEGF in maintaining glomerular integrity. This study investigates the effect of bevacizumab injections on renal function in patients with diabetic kidney disease (DKD) and those without. Objective: To assess changes in eGFR before and after intravitreal bevacizumab injections in patients with and without diabetic kidney disease, evaluating whether these injections significantly affect renal function. Methodology: This quasi-experimental study was conducted in the Department of Ophthalmology, Bangabandhu Sheikh Mujib Medical University (BSMMU), from April 2019 to August 2021. Forty patients with diabetic retinopathy were selected, divided equally into DKD and non-DKD groups. Serum creatinine and eGFR were measured within 30 days before the injection and one month after the third dose of intravitreal bevacizumab. eGFR was calculated using the CKD-EPI equation, and statistical analysis was performed using SPSS. Results: The mean pre-injection eGFR was 69.35±25.91 ml/min/1.73m² in the DKD group and 96.7±30.59 ml/min/1.73m² in the non-DKD group. Post-injection, the mean eGFR was 73.3±33.87 ml/min/1.73m² in DKD patients and 93.6±29.7 ml/min/1.73m² in non-DKD patients. The mean differences in eGFR were not statistically significant between pre- and post-injection measurements in either group (p&gt;0.05). Conclusion: Intravitreal bevacizumab injections did not cause significant changes in eGFR in both DKD and non-DKD patients, suggesting that the treatment is unlikely to have a detrimental impact on renal function in the short term. Further studies are needed to assess the long-term effects of repeated injections.

Dose and Efficacy of Bevacizumab in Recurrent High-Grade Gliomas: A Retrospective Study

Dose and Efficacy of Bevacizumab in Recurrent High-Grade Gliomas: A Retrospective Study

Treatment of epistaxis in Osler-Weber-Rendu disease by bevacizumab nasal spray. The EROSB study: Determining the effective dose

Treatment of nosebleeds in Osler-Weber-Rendu disease (OWRD) is a therapeutic challenge. Intranasal anti-angiogenic sprays are a promising solution, requiring scientific validation, leading us to conduct the present study. ObjectiveThe main objective was to determine the minimum effective dose of bevacizumab by intranasal spray to treat epistaxis in OWRD: i.e., the dose resulting in≥50% reduction in the number of nosebleeds at 1 month of treatment compared to the month prior to inclusion for 60% of patients. The secondary objectives were to assess treatment efficacy at 3 and 6 months and progression in the number and impact of nosebleeds, and to document pharmacokinetics. Materials and methodsThe study, named EROSB (treatment of epistaxis in patients with OWRD using a bevacizumab intranasal spray), under the French Hospitals Clinical Research Program (PHRC-I 2013), was selected by the Inter-regional Clinical Research and Innovation Group (GIRCI). It was a phase I/II prospective single-blind study based on 10 cohorts of 3 patients each, using the Continual Reassessment Method (CRM) to determine the minimum effective dose of bevacizumab. ResultsDue to difficulties in recruiting enough patients, the study was stopped after inclusion of 15 subjects. The CRM method identified 64mg as the minimum effective dose. However, this result is not interpretable due to the small number of subjects. ConclusionThe EROSB study did not succeed in identifying a minimum effective dose of bevacizumab, administered as intranasal spray that could reduce the number of nosebleeds compared to the month prior to inclusion. However, the initial results indicated almost no systemic passage of the substance.

Re-irradiation of anaplastic meningioma: higher dose and concomitant Bevacizumab may improve progression-free survival

IntroductionAnaplastic meningiomas, categorized as WHO grade 3 tumors, are rare and highly aggressive, accounting for 1-2% of all meningioma cases. Despite aggressive treatment, including surgery and Radiation, they exhibit a high recurrence rate and poor survival outcomes. The aggressive histopathological features emphasize the urgent need for effective management strategies.MethodsA retrospective multi-institutional analysis was conducted on patients with recurrent anaplastic meningioma who underwent re-irradiation between 2017 and 2023. Clinical, dosimetric, and outcome data were collected and analyzed, focusing on local control, progression free survival and treatment-related adverse events.ResultsThirty-four cases were analyzed, with a median follow-up 11 months after re-irradiation. Progression-free survival at 12 months was 61.9%, with higher doses correlating with better outcomes. Concomitant Bevacizumab improves progression-free survival and reduces the risk of radiation necrosis. CDKN2A homozygote deletion correlated with a higher risk of local failure. Symptomatic radiation necrosis occurred in 20.5% of cases, but its incidence was lower with concomitant Bevacizumab treatment.ConclusionRe-irradiation presents a viable option for recurrent anaplastic meningioma despite the associated risk of radiation necrosis. Higher doses with concomitant Bevacizumab improve clinical outcomes and reduce toxicity. Individualized treatment approaches are necessary, emphasizing the importance of further research to refine management strategies for this challenging disease.

Phase I study of trifluridine/tipiracil (TAS-102) plus irinotecan in combination with bevacizumab as a second-line therapy for patients with metastatic colorectal cancer.

This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment. A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m2 twice daily on days 1-5) and irinotecan (150-165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose. Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease. The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.

VAMANA: A phase 2 study of low-dose bevacizumab plus CCNU in relapsed/recurrent glioblastoma.

LBA2064 Background: There are limited systemic therapy options for recurrent glioblastomas (rGBM). CCNU and/or Bevacizumab are often used to treat rGBM not amenable to local therapy. The addition of Bevacizumab (10 mg/kg) to CCNU failed to improve overall survival in the EORTC 26101 study. The question is whether the failure was due to the high dose of Bevacizumab used in the study. High doses of Bevacizumab may lead to excessive pruning &amp; destruction of blood vessels, hampering the delivery of CCNU. In vitro &amp; in vivo studies showed that a lower dose of Bevacizumab (1-1.5 mg/kg) has the potential to normalize tumor vasculature leading to improved drug delivery &amp; outcomes. To test this hypothesis, we conducted this study to evaluate the efficacy of low-dose Bevacizumab in combination with CCNU in rGBM. Methods: This was a phase 2 open-label, single-arm trial that included adults with rGBM with an ECOG PS 0-2 and adequate organ &amp; marrow function. The participants received CCNU 110 mg/m2 PO once a day, on day 1 of a 42-day cycle (max. 8 cycles) with Bevacizumab 1.5 mg/kg intravenously every 3 weeks (max.16 cycles). Appropriate anti-emetic prophylaxis was given. Treatment continued until disease progression, clinical deterioration, or development of intolerable side effects. Response assessment was done with MRI Brain +/- spine at 2 monthly intervals till disease progression. The modified RANO criteria were used for response assessment. Safety assessments were done on day 8 of cycle 1, &amp; days 21 &amp; 42 of each cycle. The primary end-point of this study was overall survival (OS) and secondary end-points were progression-free survival (PFS) &amp; safety. A 6-month OS ≥ 40% was the signal to explore this regimen further and if the 6-month OS &lt;20% it would be considered futile. Descriptive statistics were performed and the Kaplan-Meier method was used for time-to-event analysis. Results: Forty-six patients were enrolled in this study. The median age was 42 years (IQR 33-52.75) and 78.3% (36/46) were males. Most patients (76.1%, 35/46) had an ECOG PS of 1. The median follow-up duration was 15.27 months (95% CI 13.47-17.06). The median number of doses of Bevacizumab and CCNU were 4 and 2 respectively. Three (6.5%) patients completed all planned doses of Bevacizumab and CCNU. The objective response rate (ORR) was 15.2 % (7/46). The median OS was 6.133 months (95% CI 5.474-6.793). The 6-month OS was 57.1%. The median PFS was 3.267 months (95% CI 0.850-5.684). The most frequent grade 3 or higher toxicities seen were neutropenia (7/46, 15.2%), thrombocytopenia (5/46,10.8%), elevated ALT levels (3/46, 6.5%), anemia (2/46, 4.3%) and hyponatremia (2/46, 4.3%). Conclusions: This study demonstrates the efficacy of low-dose Bevacizumab in combination with CCNU in rGBM (the median OS exceeded the preplanned cut-off of 40%) with an acceptable toxicity profile and no new safety signals. This combination should be explored further in a phase III randomized study. Clinical trial information: CTRI/2020/07/026696 .

PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer.

Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies. In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics. By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10-8). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively). Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.

Stereotactic body radiation therapy combined with atezolizumab and bevacizumab for hepatocellular carcinoma with extrahepatic metastasis: Preliminary result of a single-arm study.

e16205 Background: IMbrave150 study confirmed the clinical benefit of atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma (HCC). However, patients with extrahepatic metastasis (EHS) had a poorer prognosis. Studies suggested “abscopal effect” of synchronous radiotherapy and immunotherapy may improve antitumor activity. This study aimed to evaluate efficacy and safety of stereotactic body radiation therapy (SBRT) combined with atezolizumab and bevacizumab in HCC patients with EHS. Methods: This single-arm study included HCC patients with EHS from January 2022 to November 2023 in Fudan University Shanghai Cancer Center. Prior tyrosine kinase inhibitor and/or immune checkpoint inhibitor treatment were eligible. After first dose atezolizumab and bevacizumab, SBRT was performed with a total dose of 25-50 Gy. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), and duration of response (DOR). Results: Thirty-nine patients were included. Fourteen patients were treated as first-line therapy and 25 patients were treated as later-line therapy. The mean age was 56.69±11.21 years and 89.7% were male. Of these patients, 66.7% had hepatitis viral infection and 25.6% had vascular invasion. 53.8% of patients had ≥2 extrahepatic spread lesions. In addition, 33.3% of patients had received prior immunotherapy and 23.1% of patients had received tyrosine kinase inhibitor therapy. The median follow-up was 6.50 (range: 1.43-22.17) months. The ORR and DCR were 43.6% and 92.3%, respectively. The ORR was 57.1% and 36.0% in first-line subgroup and later-line subgroup, respectively. The 12-month OS rates was 54.7%. The median PFS, median TTP and median DOR were 6.73 months, 8.67 months, and 7.17 months, respectively. The incidence of all grade TRAE and grade ≥3 TRAE were 38.5% and 12.8%, respectively. The most common grade ≥3 TRAEs were decreased platelet count (7.7%), decreased white blood cell count (2.6%), pruritus (2.6%) and rectal bleeding (2.6%). No serious adverse events occurred. Conclusions: SBRT combined with systemic atezolizumab and bevacizumab showed encouraging efficacy with manageable safety profile for HCC patients with EHS regardless of prior treatment. Further studies are warranted. Clinical trial information: NCT05396937 . [Table: see text]

Intravitreal bevacizumab improves trabeculectomy survival at 12 months: the bevacizumab in trabeculectomy study—a randomised clinical trial

AimsTo evaluate the effect of an intraoperative dose of intravitreal bevacizumab (Avastin) on surgical success following trabeculectomy with mitomycin-C (MMC) over 12 months.MethodsA single centre, parallel, double-blinded randomised, placebo-controlled trial...

501 Systemic Immunological Suppression in Glioblastoma Is Targeted by Concurrent VEGF and PD-1 Inhibition in a Dose-Dependent Manner: Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) From a Randomized Controlled Trial

INTRODUCTION: Anti-PD1 blockade has had poor efficacy in recurrent glioblastoma (rGBM) across three RCTs. VEGF, a proangiogenic factor that is upregulated in rGBM, contributes to tumor-associated immunosuppression and is widely targeted through bevacizumab. Preclinical data indicate a potential dose-dependent effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD-1 and anti-VEGF agents is a promising approach for rGBM, for which an RCT was conducted. METHODS: Patients with rGBM were administered nivolumab (240mg IV q2weeks) plus either standard dose bevacizumab (10mg/kg) or low dose bevacizumab (3mg/kg) IV q2weeks, with 1:1 randomization. Stratification factors were age, performance status, extent of resection, and MGMT methylation status. Primary endpoint was overall survival (OS) at 12 months. CITE-Seq was performed on 16 patients across trial arms, both pre- and on-therapy, yielding total 32 immunological profiles. For control, CITE-seq was done on three patients receiving anti-VEGF therapy alone. RESULTS: 90 patients were enrolled with median age of 60.6 years and 45 patients per arm. Both arms had similar OS at 12 months (P = 0.14). Significantly higher OS was found in posthoc analysis for patients aged = 60 years with standard dose. Distinct immune cell populations were identified and differential changes in myeloid-derived suppressor cells (MDSCs) found across trial arms on-therapy. Network medicine approach identified VEGF as target to reduce MDSCs, with VEGF primarily expressed by responders’ MDSCs. Differential gene expression analysis identified increased pro-inflammatory signatures in standard dose arm. CONCLUSIONS: Standard dose bevacizumab was associated with increased inflammatory response and reduction of immunosuppressive MDSC. These mechanistic insights potentially explain survival benefit seen with concurrent VEGF and PD-1 inhibition in elderly rGBM patients.

Comparing reactivation and retreatment for three doses of bevacizumab in type 1 retinopathy of prematurity

To determine timing and rates of reactivation and retreatment of type 1 retinopathy of prematurity (ROP) after treatment with either 0.125 mg, 0.250 mg, or 0.500 mg of intravitreal bevacizumab (IVB). Retrospective data, including demographic information, past medical history, and ROP characteristics were analyzed for babies with type 1 ROP treated with IVB at Riley Hospital for Children for the perioed 2014-2021. A total of 84 patients met inclusion criteria: 29 patients received 0.125 mg of IVB; 39, 0.250 mg; and 16, 0.500 mg. Of the 84, 67 (80%) had additional laser treatment because of late reactivation (n = 52) or persistent avascular retina (PAR) (n = 15). Subsequent laser treatment was more common with lower doses: 0.125 mg (n = 27 [93%]); 0.250 mg (n = 31 [80%]); 0.500 mg (n = 9 [57%]) (P = 0.012). There was no difference between groups with regard to reason for subsequent laser treatment (reactivation vs PAR). The 0.125 mg group required retreatment because of reactivation 3.8 weeks sooner than the other dosing groups (P = 0.047). The outcomes comparing three doses of IVB for severe ROP showed a difference in the timing of secondary treatment, with the lower dosing group requiring laser for reactivation earlier.

Perioperative Chemotherapy Including Bevacizumab in Potentially Curable Metastatic Colorectal Cancer: Long-Term Follow-Up of the ASSO-LM1 Trial.

In 2007, the ASSO-LM1 trial, a multicenter prospective study, was initiated to investigate the resectability (R0) rate following preoperative combination therapy with XELOX and bevacizumab in patients with potentially resectable colorectal liver metastases. Six cycles of systemic therapy were administered preoperatively, although the sixth cycle did not include bevacizumab, resulting in 5 weeks between the last bevacizumab dose and surgery. Treatment with bevacizumab plus XELOX was restarted for another six cycles postoperatively. In total, 43 patients were enrolled in the ASSO-LM1 trial. Eight patients were ineligible for resection due to protocol violation and progression in two patients. The resectability of operated patients was 97% with 34 R0 resections and one R1 resection. Postoperative morbidity occurred in 22% of patients, of which three operative revisions were related to the primary tumor resection. Efficacy results for response in 38 eligible patients confirmed an ORR of 66%, 31% SD and 3% PD according to RECIST. Preoperative grade 3/4 adverse events were 17% diarrhea, 5% HFS and 5% thromboembolic events. Overall survival significantly differed depending upon the fulfillment of adjuvant treatment in curative resected patients (59.1 mo vs. 30.8 mo). In conclusion, the ASSO-LM1 trial is a hypothesis-generating study confirming the prognostic benefits of perioperative therapy with XELOX and bevacizumab in patients with metastatic colorectal cancer confined to the liver.

Promising Remission with Reduced Bevacizumab and Pembrolizumab Dosage in a Patient with AT-rich Interaction Domain 1A Mutated Ovarian Clear-cell Carcinoma Refractory to Chemotherapy

Abstract Patients with ovarian clear-cell carcinoma have limited treatment choices, because they are resistant to the standard chemotherapeutic agents used in ovarian cancer. The phase II KEYNOTE-100 trial revealed that pembrolizumab monotherapy demonstrated a 15.8% objective response in patients with ovarian clear-cell carcinoma in the subgroup analysis, which is much higher than that of other histology subtypes of ovarian cancer. Immune checkpoint inhibitors may play a new role in the treatment of these malignancies. Genetic analyses revealed a significant proportion of ovarian clear-cell carcinoma carrying the AT-rich interaction domain 1A protein (ARID1A) mutation. The association between a higher frequency of ARID1A mutation and a higher response to immune checkpoint inhibitors in ovarian clear-cell carcinoma opens a new research topic. Herein, we report a patient with ovarian clear-cell carcinoma refractory to platinum-based chemotherapy, who was treated with a reduced dose of bevacizumab and pembrolizumab combination therapy and achieved a complete treatment response.

A case of chemotherapy efficacy with atezolizumab plus bevacizumab dose reduction for hepatocellular carcinoma against nasal hemorrhage as bevacizumab-related adverse event

A case of chemotherapy efficacy with atezolizumab plus bevacizumab dose reduction for hepatocellular carcinoma against nasal hemorrhage as bevacizumab-related adverse event

Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients.

The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4nM), steady-state dissociation constant (KSS = 10 nM) and antibody-target complexes elimination constant (kint = 0.52 day-1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship.

Effect of Bevacizumab on traumatic penumbra brain edema in rats at different time points

ABSTRACT Traumatic penumbra (TP) is a secondary injury area located around the core area of traumatic brain injury after brain trauma, and is an important factor affecting the outcome of traumatic brain injury (TBI). The main pathological change caused by TP is brain edema, including (cellular brain edema and vascular brain edema). The formation and development of brain edema in the TP area are closely related to the blood-brain barrier (BBB) and vascular endothelial growth factor (VEGF). VEGF is a vascular permeability factor that can promote angiogenesis and increase BBB permeability, and there is a debate on the pros and cons of its role in early TBI. Therefore, in the early stage of TBI, when using the VEGF inhibitor bevacizumab to treat TP area brain edema, the timing of bevacizumab administration is particularly important, and there are currently no relevant literature reports. This article explores the treatment time window and optimal treatment time point of bevacizumab in the treatment of cerebral edema in the TP area by administering the same dose of bevacizumab at different time points after brain injury in rats. The results showed that there was traumatic brain edema in TP area, BBB structure and function were damaged, VEGF expression and angiogenesis were increased. Compared with TBI + NS Group, after Bevacizumab treatment, brain edema in TP area was alleviated, BBB structure and function were improved, VEGF expression and angiogenesis were decreased in each treatment group, and the effect of TBI + Bevacizumab 1 h group was the most significant. Bevacizumab can be used as a targeted therapy for traumatic brain edema. The therapeutic time window of bevacizumab for traumatic brain edema is within 12 hours after TBI, and 1 h is the optimal therapeutic time point.

Decellularized plant-derived vasculature-on-a-chip interacting with breast cancer spheroids to evaluate a dual-drug therapy

Breast cancer progression is a complex process involving the primary tumor and its microenvironment supported by a vascular network. Multicellular spheroids closely mimic in vivo-like tumor conditions, paving the way for effective treatments. Although spheroid formation by simulated microgravity emerges as a promising technique for cancer spheroids, the lack of a perfusable vascular network still limits the evaluation of tumor progression. Recently, decellularized plant structures with hierarchically formed vasculatures similar to the human vascular system gained interest as engineered vascular networks. In this study, breast cancer spheroids co-cultured with endothelial cells were grown both under unit-gravity and simulated microgravity conditions, whereas vasculature was formed by the decellularization of spinach leaf. The optimized spheroids and plant-derived vasculature populated with endothelial cells were integrated into a microplatform, where fibroblasts were embedded into the extracellular matrix (ECM) to mimic the tumor microenvironment (TME). The vasculature-on-a-chip was used to assess the response of breast cancer spheroids to a combinatorial dose of Doxorubicin (DOX) and Bevacizumab (BMAB) treatment administered to circulating flow emulating intravenous administration. The developed platform offers a biomimetic model to recapitulate key aspects of breast cancer progression and evaluate the responses of both the tumor and the vasculature to chemotherapeutic drugs.