Endothelial Growth Factor Inhibitors Research Articles

Screening for Coronary Artery Disease inCancer Survivors: JACC: CardioOncology State-of-the-ArtReview.

Coronary artery disease (CAD) is an important contributor to the cardiovascular burden in cancer survivors. This review identifies features that could help guide decisions about the benefit of screening to assess the risk or presence of subclinical CAD. Screening may be appropriate in selected survivors based on risk factors and inflammatory burden. In cancer survivors who have undergone genetic testing, polygenic risk scores and clonal hematopoiesis markers may become useful CAD risk prediction tools in the future. The type of cancer (especially breast, hematological, gastrointestinal, and genitourinary) and the nature of treatment (radiotherapy, platinum agents, fluorouracil, hormonal therapy, tyrosine kinase inhibitors, endothelial growth factor inhibitors, and immune checkpoint inhibitors) are also important in determining risk. Therapeutic implications of positive screening include lifestyle and atherosclerosis interventions, and in specific instances, revascularization may be indicated.

Efficacy and safety of a triple combination of atezolizumab, bevacizumab plus GEMOX for advanced biliary tract cancer: a multicenter, single-arm, retrospective study

Anti-programmed cell death ligand 1/vascular endothelial growth factor inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit, but it has not been investigated in advanced biliary tract cancer (BTC). We investigated the efficacy and safety of atezolizumab, bevacizumab, and gemcitabine plus oxaliplatin (GEMOX) in advanced BTC and explore the potential biomarkers related to the response. Multicenter, single-arm, retrospective study. Advanced BTC patients, who received a triple combination therapy at three medical centers between 18 March 2020 and 1 September 2021, were included. Treatment response was evaluated via mRECIST and RECIST v1.1. Endpoints included the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The whole exome sequencing of pathological tissues was conducted for bioinformatic analysis. In all, 30 patients were enrolled. The best ORR was 76.7% and the DCR was 90.0%. The median PFS was 12.0 months, and the median OS was not reached. During the treatment, 10.0% (3/30) of patients suffered from ⩾grade 3 treatment-related adverse events (TRAEs). Furthermore, fever (73.3%), neutropenia (63.3%), increased aspartate transaminase and alanine aminotransferase levels (50.0% and 43.3%, respectively) are the most common TRAEs. Bioinformatics analysis revealed patients with altered ALS2CL had a higher ORR. The triple combination of atezolizumab, bevacizumab, and GEMOX may be efficacious and safe for patients with advanced BTC. ALS2CL may be a potential predictive biomarker for the efficacy of triple combination therapy.

Atezolizumab and bevacizumab in patients with relapsed mesothelioma: MIST4—a phase IIa trial with cellular and molecular correlates of efficacy.

8560 Background: Targeting the PD1-PDL1 axis has demonstrated significant efficacy in patients with relapsed malignant mesothelioma (MM) however the factors that determine sensitivity are unknown. Combined inhibition of vascular endothelial growth factor (VEGF) may potentiate efficacy through remodelling of the tumour microenvironment and inhibition of angiogenesis. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis and to uncover cellular and molecular determinants of efficacy as arm 4 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST4). Methods: Patients with any histological subtype or site of MM (pleural or peritoneal) were enrolled. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Atezolizumab 1200mg iv q3w with bevacizumab 15mg/kg iv q3w (AtzBev). Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Baseline BAP1, p16ink4a, PD-L1 (DAKO22C3), gut microbiome 16s RNA metagenomics, multiplex immunofluorescence, and whole exome and RNA transcriptome sequencing was conducted to explore cellular and molecular correlates of sensitivity. Results: Between January 2020 and February 2021, 26 patients with MM started treatment and received at least one dose of AtzBev. The median age of pts was 68 (range, 44-80) years, 69% were male, 77% epithelioid, 85% ECOG PS1, > 1 prior systemic therapy 54%. The median cycles of Atz dosing was 4.5 (IQR, 2-8) and Bev dosing was 4.5 (IQR, 2-7). DCR12w: 53.8% (95% confidence limit (CI), 33.4% – 73.4%), DCR24w: 23.1% (95%CI, 9.0% – 43.6%). Best responses (evaluable within 24w): partial – 3.8% (95%CI, 0.1- 19.6%); stable disease – 69.2% (48.2 – 85.7%); progression – 15.4% (4.4 – 34.9%). Adverse events (any cause): ≥ grade 3 toxicities affected 35% of pts. Conclusions: MiST4 met its primary endpoint however responses were heterogeneous. Analysis of cellular and molecular correlates are ongoing and will be presented. Clinical trial information: NCT03654833.

Systemic bevacizumab for aggressive recurrent respiratory papillomatosis: A single center experience of five cases.

e22005 Background: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) driven benign neoplasm, affecting larynx, trachea, and even lung, leading to voice disorders, airway obstruction, and post-obstructive pneumonia. Currently, there is no curative therapy for RRP.Patients require frequent debulking operations for symptomatic palliation. However, several case reports documented promising results on inhibition of vascular endothelial growth factor (VEGF) by systemic administration of bevacizumab. Methods: We retrospectively analyzed clinical, radiological, and bronchoscopy data of aggressive RRP patients treated with systemic bevacizumab since January 2021. Results: 5 consecutive patients were included. Median age (range) was 8 (4-30), 60% (3/5) were male. The locations of RRP were as follows: localized in the major airway (including vocal cords, larynx, trachea, and main bronchus), n = 1; extensive from major airway to lung parenchyma, n = 4. The median number (range) of local interventions was 8 (2-17) throughout the 12 months prior to bevacizumab treatment. The administration of systemic therapeutic agents, such as HPV vaccine and interferon had been tried in two patients. Bevacizumab was administered at a dose of 5 mg/kg (n = 4) or 7.5 mg/kg (n = 1) intravenously. Treatment intervals were initiated every 2-3 weeks and subsequently extended after achieving the maximum response. The patients received median 6 cycles of bevacizumab (range 4-7). The bevacizumab was given as adjuvant therapy in 2 patients on the 3rd and 5th day after laser operation, and as salvage therapy in the other 3 patients. All patients with major airway RRP displayed improvement in disease burden. No patients required surgery during a medain 7 (range 3-8) months follow up periods after initiating bevacizumab treatment. A rapid response was demonstrated in a patient with long-standing extensive pulmonary disease. Except from mild and transit abdominal pain and hemoptysis in 2 patients, systemic treatment with bevacizumab was well tolerated. Conclusions: Inhibition of VEGF by systemic bevacizumab seems to be a well tolerated and effective treatment option for localized and extensive forms of RRP.

Cross-trial validation of molecular subtypes in patients with metastatic clear cell renal cell carcinoma (RCC): The JAVELIN Renal 101 experience.

4531 Background: Vascular endothelial growth factor (VEGF) and immune checkpoint inhibitors (IO) combinations are a standard in mRCC. Molecular clusters of patients have been identified and correlated with outcomes in the phase 3 IMmotion151 (IM151) trial of atezolizumab + bevacizumab (IO+VEGF) vs. sunitinib (Sun) (Motzer, Cancer Cell 2020 & JAMA Oncol 2021). Avelumab+axitinib (AA) is an approved IO+VEGF combination in mRCC. This work aims to evaluate these clusters in patients from the phase 3 JAVELIN Renal 101 (JR101; NCT02684006 ) trial of AA vs. Sun. Methods: Bulk RNA-sequencing of primary and metastatic samples and clinical data (data cutoff: 28 January 2019) from JR101 were obtained. A random forest model designed to predict molecular clusters based on transcriptomic data was trained on the IM151 dataset. Using this model, patients from JR101 study were categorized into previously defined molecular subgroups. We then evaluated treatment outcomes including progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) from JR101 in relation to molecular subgroups. Results: The proportion of patients in each molecular subtype and across MSKCC risk groups were largely comparable between the 2 trials (accuracy: 81.6%; p=0.2). AA was generally superior to Sun. for PFS and ORR across all molecular subsets, including angiogenic and immune-based clusters (Table). Combining immune and/or cell cycle-enriched clusters 4+5 resulted in improved PFS (HR: 0.65; 95% CI: 0.44-0.97) for AA vs. Sun. Conclusions: We were able to largely validate the molecular clusters classification and some of the associations with survival outcomes from IM151 in the JR101 clinical trial cohort. Biomarkers of specific VEGF+IO combinations in mRCC should be prospectively validated in randomized trials. [Table: see text]

Fumarate hydratase-deficient renal cell carcinoma: The real-world experience at Dana-Farber Cancer Institute and Moores Cancer Center.

e16522 Background: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare and aggressive tumor with limited clinical trials dedicated to therapeutics for this disease. This retrospective study aimed to report a multi-center experience in the systemic treatment of FH-deficient RCC. Methods: The medical records of patients undergoing systemic therapy for advanced or metastatic FH-deficient RCC at Dana-Farber Cancer Institute and Moores Cancer Center were reviewed from 2012 to 2021. Demographic, histologic, molecular, and survival parameters were collected. Response was assessed using RECIST 1.1 criteria. A confirmative initial diagnosis of FH-RCC was made utilizing FH/2SC immunohistochemistry (n = 12) and/or the presence of an FH mutation (n = 6). The primary endpoint of this study was to characterize patients with FH-deficient RCC in the modern era. Results: 18 patients were included; median age at diagnosis was 45 (interquartile range [IQR]: 40-55) years. All patients had a Karnofsky Performance Status (KPS) ≥ 80. Among 14 patients with evaluable IMDC criteria, 1 (7.4%) had favorable-risk disease, while 10 (71.4%) and 3 (21.4%) had intermediate- and poor-risk disease, respectively. Tumors at diagnosis were stage III (n = 6, 33.3%), and IV (n = 12, 66.7%). Median time from diagnosis to the start of systemic therapy was 2.8 months. Six types of regimens were given as first-line therapy (Table). Fourteen patients (78%) developed disease progression on frontline therapy and received subsequent therapy; two patients, initially treated with an mTOR inhibitor and combined vascular endothelial growth factor (VEGF) inhibitor and immune checkpoint inhibitor (ICI), are off therapy and still under surveillance with no recurrence to date; one patient passed away while on frontline therapy; and one patient has limited follow-up. For a median follow-up of 22 months (IQR:6.4-49), the 18-month-overall survival estimate was 81% (95% confidence interval [CI]: 53%-94%) and median progression-free survival (PFS) was 6.7 months (95%CI: 5.0-17.0). Conclusions: This study shows considerable heterogeneity in the treatment for FH deficient-RCC, with disparate clinical outcomes. Dedicated trials and guidelines on the management of FH-deficient RCC are needed.[Table: see text]

MO178: Renal Function Impairment in Diabetic Patients after Intravitreal Injection of Anti-Vascular endothelial Growth Factor

Abstract BACKGROUND AND AIMS Intravitreal administration of vascular endothelial growth factor (VEGF) inhibitors is the treatment of a wide variety of retinal diseases. Kidney damage caused by systemic administration is widely known. However, there is not enough information in the literature on the renal effect of these drugs after intravitreal injection. The aim of the study is to analyse the effect of intravitreal anti-VEGF on kidney function in diabetic patients. METHOD A prospective cohort study of diabetic patients with and without chronic kidney disease (CKD) who received intravitreal anti-VEGF from January 2018 to December 2019. Clinical and analytical parameters were analysed. The follow-up time was 24 months. RESULTS We included 45 patients (55.6% male) with a mean age of 74.4 ± 11.5 (50–91) years. Approximately 64.4% of patients had CKD [estimated glomerular filtration rate (eGFR) <60 mL/min]. The types of anti-VEGF used were: bevacizumab 57.8% and ranibizumab 42.2%. The average number of doses administered was 7.6 ± 4.8 (1–22). The initial eGFR was 48.7 ± 25.3 mL/min and the Alb/Cr ratio 145 (49.45) mg/g. A significant decrease in the eGFR was observed at 6, 12 and 24 months (Table 1). There was a significant increase in proteinuria at 12 and 24 months. This drop in eGFR was independent of the presence of CKD, the anti-VEGF type or the number of doses. After the admistration of the first dose, five patients (17.2%) in the CKD group required renal replacement therapy (mean time 22 ± 12 months). CONCLUSION A significant decrease in eGFR and an increase in proteinuria are observed after administration of anti-VEGF in diabetic patients. For this reason, a close monitoring of renal function is needed to establish an early diagnosis and management of possible complications.

Predictors of objective response to first-line immuno-oncology combination therapies in metastatic renal cell carcinoma: Results from the international metastatic renal cell database consortium (IMDC).

310 Background: Predictors of objective response to first-line (1L) immuno-oncology (IO) combination therapies remain elusive. We sought to characterise clinical variables and their association with investigator assessed best overall response. Methods: Using the IMDC, we retrospectively identified patients treated with 1L ipilimumab nivolumab (IPI-NIVO) or approved IO/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE). Patients were classified, per RECIST v1.1, as responders (complete or partial response (CR or PR)) or non-responders (stable or progressive disease (SD or PD)). Logistic regression was used to adjust for IMDC criteria. Results: Out of 1084 patients, 794 (73%) received IPI-NIVO and 290 (27%) received IOVE (axitinib+pembrolizumab, cabozantinib+nivolumab, axitinib+avelumab, lenvatinib+pembrolizumab). Favourable, intermediate and poor IMDC risk comprised 147 (16%), 517 (55%) and 272 (29%) respectively. Of the 898 patients with evaluable responses, 37 (4%) achieved a best response of CR, 343 (38%) PR, 315 (35%) SD and 203 (23%) PD. Corresponding median overall survival from time of 1L initiation was: not reached, 55.9, 48.1, and 13 months respectively (logrank p < 0.0001). In a multivariable model, lung metastases and cytoreductive nephrectomy (CN) (performed after diagnosis of metastatic disease and before 1L therapy) retained independent association with response, after adjustment for IMDC criteria. Factors not associated with response included (with univariable p values): gender (p = 0.58), age (p = 0.06), sarcomatoid histology (p = 0.99), smoking status (p = 0.39), liver (p = 0.63) and brain (p = 0.12) metastases. As in the VEGF monotherapy era, improved IMDC prognostic risk was associated with response. Results were similar when restricted to the IPI-NIVO cohort. Conclusions: Presence of lung metastases, CN and better IMDC risk group are associated with a higher probability of response to 1L immunotherapy combination regimens. Further work to identify reliable predictors of response to guide treatment selection and patient counselling is warranted.[Table: see text]

Multicenter retrospective study of ramucirumab-containing chemotherapy for gastrointestinal neuroendocrine carcinoma patients previously treated with platinum-based chemotherapy: RAM-NEC study (WJOG13420G).

511 Background: Platinum-based systemic chemotherapy (CTx) is recommended for poorly differentiated advanced gastrointestinal neuroendocrine carcinoma (GI-NEC). As second-line CTx various regimens are adopted according to the guidelines of GI adenocarcinoma or small cell lung cancer in daily practice. Recently, some clinical and preclinical reports suggest that vascular endothelial growth factor (VEGF) inhibitors are effective against NEC. In this study, we evaluated the efficacy of ramucirumab (RAM, anti-VEGF receptor 2 antibody)-containing CTx. Methods: We retrospectively evaluated gastric (G-) or colorectal (C-) NEC patients previously treated with first-line platinum-based CTx followed by second-line CTx between March 2015 and June 2020 (G-NEC) or between May 2016 and June 2020 (C-NEC). The main inclusion criteria were ECOG performance status (PS) of 0–2, pathologically diagnosed as G or C- NEC or mixed adenoneuroendocrine carcinoma. We compared the efficacy of RAM-containing CTx as second- or later-line treatment (Group A) with that of CTx without RAM as second-line treatment (Group B). A Cox proportional hazard model and inverse probability weighting of propensity scores were used to adjust the background factors between the two groups. Results: From 25 facilities, 139 patients were included in this study. Group A and B contained 50 (G/C, 43/7 patients) and 89 (G/C, 58/31 patients) patients, respectively. Patient characteristics were as follows (Group A/Group B): median age (range), 70 (28–83)/68 (39–86); ECOG PS 1–2, 66/69%, more than two prior regimens, 46/0%; response to previous platinum-based CTx, 46/38%. The regimen in combination with RAM in Group A was paclitaxel/nab-paclitaxel/FOLFIRI (62/26/12%). Second-line CTx in Group B were commonly amrubicin (58%) and irinotecan (11%). The efficacy (Group A/Group B) after a median follow-up time of 7.5/5.5 months were as follows: median overall survival (mOS), 8.6/5.8 months (HR, 0.68; 95% CI, 0.45–1.01; p = 0.058); median progression-free survival, 4.3/1.9 months (HR, 0.57; 95% CI, 0.39–0.84; p = 0.004); objective response rate, 50/8% ( p < 0.0001); disease control rate, 70/24% ( p < 0.0001); mOS in G-NEC, 8.6/5.3 months (HR, 0.62; 95% CI, 0.39–0.99; p = 0.047); and mOS in C-NEC, 5.4/6.8 months (HR, 0.66; 95% CI, 0.26–1.66; p = 0.378). The most common grade 3 or higher treatment-related adverse event that occurred in more than 5% of patients in Group A was neutropenia (32%). Conclusions: This study suggests that RAM-containing CTx as second- or later-line treatment is effective for GI-NEC patients, especially for G-NEC. Central pathological review and biomarker analyses using pretreated tissue specimens are ongoing. We will present updated data in the congress. Clinical trial information: UMIN000043200.

BTCRC-GI20-457: A phase II study of atezolizumab and bevacizumab in Child-Pugh B7 hepatocellular carcinoma (the AB7 Trial).

TPS493 Background: Both the incidence and death rate of hepatocellular carcinoma (HCC) are on the rise in the United States, and overall, the prognosis is grim. First-line treatment options for patients with advanced disease previously included tyrosine kinase inhibitors (TKIs) which have resulted in a median overall survival (OS) of less than a year. Combinations of immune checkpoint inhibitors (CPIs) with vascular endothelial growth factor (VEGFR) inhibitors are of interest given the known effects of VEGF in the tumor microenvironment, including promoting inhibitory immune cells, suppressing maturation of dendritic cells, decreasing cytotoxic T cell responses, and altering lymphocyte development and trafficking. The phase III IMbrave150 trial investigated the combination of atezolizumab (A) and bevacizumab (B) as compared to sorafenib (S) in previously untreated locally advanced or metastatic HCC patients, and resulted in significantly improved OS (mOS: 19.2 mos AB vs 13.4 mos S), PFS (mPFS: 6.9 mos AB vs 4.3 mos S), and response rates (ORR: 29.8% AB vs 11.3% S), and a meaningful improvement in duration of response (mDOR: 18.1 mos AB vs 14.9 mos S). Notably, patients with class Child-Pugh B liver dysfunction were excluded from this study, although they are clinically abundant. We hypothesize the combination of AB will be safe and well tolerated in patients with locally advanced or metastatic HCC with Child-Pugh class B7 liver dysfunction. In addition, we expect efficacy will be similar to that demonstrated by the IMbrave150 study, and that ctDNA will correlate with, and possibly predict, clinical outcomes. Methods: This will be a single arm phase II study investigating the safety of the combination of AB in patients with previously untreated locally advanced or metastatic HCC with Child-Pugh B7 liver dysfunction. Patients must also be ECOG PS 0-1 and without clinically significant ascites or hepatic encephalopathy, untreated esophageal/gastric varices (assessed by EGD within the prior 6 months), or recent significant bleeding. We will enroll 50 patients with the primary endpoint of grade 3-5 treatment-related adverse event rate by CTCAE v5. Secondary endpoints include ORR, disease control rate (DCR), DOR, progression free survival (PFS), and OS. Correlative studies include tumor molecular signature by next generation sequencing (NGS) tissue analysis and ctDNA levels to correlate both with each other and with clinical benefit. Patients will receive A 1,200 mg IV and B 15 mg/kg IV every 3 weeks until disease progression or intolerable toxicity. Tumor imaging reassessment will occur every 3 cycles. Archival or fresh tumor biopsy will be required at baseline, and plasma for ctDNA will be collected with each imaging reassessment. The trial is being conducted at sites throughout the Big Ten Cancer Research Consortium (Big Ten CRC) and is currently screening eligible subjects (NCT04829383). Clinical trial information: NCT04829383.

Features of angiogenesis in eye diseases

Based on the analysis of published data, the review provides information on the role and mechanisms of angiogenesis in the development of eye diseases. It has been shown that the developing inflammatory process associated with infections or damage to the organ of vision almost always leads to the appearance of newly formed vessels in the avascular cornea. The progression, in particular, of age-related macular degeneration is associated with the immune-mediated development of angiogenesis processes. A key inducer of angiogenesis is vascular endothelial growth factor (VEGF), whose activity can be enhanced by a number of pro-inflammatory cytokines (tumor necrosis factor alpha, TNF-), growth (fibroblast growth factor, FGF) and transforming factors (transforming growth factor beta, TGF- ). In addition, VEGF overproduction is mediated by an imbalance of pro-angiogenic (angiogenin) and anti-angiogenic (angiostatin, vasostatin, endostatin; tissue inhibitors of matrix metalloproteinases) factors. Antiangiogenic activity based on inhibition of vascular endothelial growth factor (VEGF) has been successfully used in the treatment of a number of eye diseases, such as exudative age-related macular degeneration and diabetic macular edema, the pathogenesis of which is based on the growth of newly formed vessels. The review presents information on the main anti-angiogenic drugs for intravitreal administration, used in ophthalmology.

Regulator-Requested Non-Interventional Postauthorization Safety and Effectiveness Studies for Oncology Drugs: A Systematic Review.

There has been a growing number of oncology drug approvals. Non-interventional postauthorization safety/effectives studies (PASSs/PAESs) aim to provide real-world evidence on the safety/effectiveness of oncology drugs postapproval. To understand the current landscape, a comprehensive search as of March 1, 2021, was conducted in major register/databases. We found that requested studies increased from 1 in 2006-2010 to 47 in 2016-2020. Of 78 total studies identified, 50 focused on safety/risk assessment (64.1%), 6 on effectiveness (7.7%), 3 on drug utilization (3.8%), 1 on disease epidemiology (1.3%), and 18 on effectiveness of additional risk minimization measures (23.1%). For safety/risk assessment studies, 58.9% focused on nonspecific end points (e.g., frequency of adverse events). For effectiveness studies, the leading primary outcome was overall survival. Overall, safety/risk assessment studies concerning nonspecific end points for vascular endothelial growth factor (receptor) inhibitors were most requested. Regarding data sources, though a majority (71.8%) used primary data collection, a growing proportion utilized secondary data sources. Among 23 studies with information available on study design, 10 (43.5%) were single-arm cohort studies, 9 (39.1%) were cross-sectional studies, 3 (13.1%) were comparative cohort studies, and 1 (4.3%) was a nested-case-control study. In conclusion, there was an increasing number of oncology-specific non-interventional PASSs/PAESs, with a majority on safety/risk assessment. Although most utilized primary data collection, there was an increasing use of secondary real-world data sources. Few conducted comparative analyses, and most used single-arm designs. Future efforts are needed to assess how findings of these studies would impact regulatory decisions and improve knowledge of toxicity for clinical/translational development.

Real-world prognosis of eyes with diabetic macular oedema receiving treatment with vascular endothelial growth factor (VEGF) inhibitors

Real-world prognosis of eyes with diabetic macular oedema receiving treatment with vascular endothelial growth factor (VEGF) inhibitors

Inhibition of vascular endothelial growth factor (VEGF)-induced cell proliferation in the first trimester trophoblast cell line by cinnamon extract

Inhibition of vascular endothelial growth factor (VEGF)-induced cell proliferation in the first trimester trophoblast cell line by cinnamon extract

Cabozantinib and nivolumab as first-line treatment in advanced renal cell carcinoma

ABSTRACT Introduction In the last decade, there have been substantial changes in the management of metastatic renal cell carcinoma (mRCC) with combined regimens with immune checkpoint inhibitors (ICI) replacing targeted therapies. These combined regimens include the combination of cabozantinib plus nivolumab. Areas covered Here, we provide an overview of clinical trials evaluating the combination of cabozantinib and nivolumab and the current clinical data on mechanism of action, pharmacokinetics, efficacy, and safety profile. Expert opinion Dual immune checkpoint inhibition with nivolumab and ipilimumab as well as the combination of a vascular endothelial growth factor (VEGF) inhibitor and an immune checkpoint inhibitor have shown to improve outcomes in phase III trials in comparison to sunitinib (axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumab, cabozantinib plus nivolumab, lenvatinib plus pembrolizumab). However, to date, there are no head-to-head trials comparing these new combination therapies and no biomarkers are available to guide the optimal choice of first line therapy.

Refractory systemic capillary leak syndrome treated with bevacizumab: a case report

Systemic capillary leak syndrome (SCLS) is a syndrome caused by many reasons and without a definitive mechanism. The main diagnostic criteria of SCLS are hemoconcentration, hypoalbuminemia, and hypotension. Though most SCLS improved spontaneously within a few days, it can be life-threatening without effective treatments. In previous literature, vascular endothelial growth factor (VEGF) inhibitor had shown its potential to be an effective treatment, but the treatment outcomes were inconsistent. This article was about a 58-year-old female suffering from refractory systemic capillary leak syndrome after bone marrow transplantation and being treated with bevacizumab, a VEGF inhibitor. In comparison with other successfully treated cases, this patient received four cycles of bevacizumab treatment without symptomatic improvement and eventually died in the intensive care unit. Further studies are needed to further confirm the role of bevacizumab in the management of SCLS.

Ischemic Stroke Risk Among Adult Brain Tumor Survivors: Evidence to Guide Practice.

INTRODUCTION: Primary brain tumors are the leading cause of cancer mortality in the United States affecting approximately 90,000 Americans each year. A major complication for brain tumor survivors is acute ischemic stroke (AIS). Currently, there are limited research to provide guidelines for AIS prevention and management in adult brain tumor survivors. The purpose of this review is to discuss the most common risk factors for AIS in adult brain tumor survivors along with best evidence for assessment, screening, and strategies to prevent AIS in this population. METHODS: Relevant literature was identified by searching CINAHL and PubMed databases using the following keywords: "brain tumor survivors," "adults," "stroke," "risk factors," "guidelines," "prevention," and "management". Articles not pertaining to adult brain tumor survivors and AIS were excluded. RESULTS: The location of the tumor, dose, extent, and type of radiation contribute to the development of vascular injury and subsequent carotid stenosis among brain tumor survivors. Endothelial growth factor inhibitor and chemotherapy drugs induces vascular remodeling. Other symptoms such as neurological impairments and co-morbidities are also present among brain tumor survivors. Furthermore, AIS increases from the time of primary brain tumor diagnosis and incidence further increases among patients who were diagnosed with a brain tumor as a child. CONCLUSION: Nurses play a key role in the assessment, prevention, and identifying individuals who are at risk of AIS during brain tumor survivorship. Engaging patients and their caregivers on minimizing their risks of AIS is crucial in the outpatient setting. Annual surveillance visits that include intracranial artery imaging should be used to identify individuals considered most at risk for developing AIS symptoms.

First-line therapy in patients with metastatic renal cell carcinoma (mRCC): Results from consecutive patients over 25 years in a single institution.

e16574 Background: Immune checkpoint inhibitors (ICI) have demonstrated improved activity in metastatic renal cell carcinoma (mRCC). Real-world data comparing the effectiveness of ICI with interleukin-2 (IL-2) is limited. Methods: We retrospectively assessed consecutive patients with biopsy-proven mRCC at our institution between 1994 and 2020. Patients were classified into four groups based on first-line therapy: vascular endothelial growth factor (VEGF) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, IL-2, or ICI. The primary endpoint was overall survival (OS). Kaplan-Meier method was used to compare OS between treatment groups. We used Cox proportional hazards models to adjust for prognostic covariates. Results: A total of 1424 patients were treated with first line therapy; 51% received VEGF, 3% received mTOR, 40% received IL-2, and 6% received ICI. Median follow-up was 97.6 months. Except for the mTOR group, baseline characteristics were largely balanced between the treatment groups. Median OS in the ICI group compared with IL-2, mTOR and VEGF was 40.1, 17.6, 6.3 and 14.7 months (p < 0.001), respectively, and the 5-year survival rate was 36%, 20%, 9% and 14%, respectively. After adjusting for IMDC and MSKCC individual risk factors, histology, age, gender, year of treatment initiation, low sodium, and location of metastases (lung, liver, bone, lymph node), the hazard ratio (HR) (95%CI) for OS with VEGF as reference was 0.50 (0.33-0.74, p = 0.001) for ICI, 0.81 (0.70-0.92, p = 0.002) for IL2, and 1.09 (0.79-1.52, p = 0.6) for mTOR. Conclusions: In this largest single institution cohort to date, patients with mRCC who received CPI achieved longer OS.[Table: see text]

Haem relieves hyperoxia-mediated inhibition of HMEC-1 cell proliferation, migration and angiogenesis by inhibiting BACH1 expression

BackgroundHyperoxia-mediated inhibition of vascular endothelial growth factor (VEGF) in the retina is the main cause of impeded angiogenesis during phase I retinopathy of prematurity (ROP). Human retinal angiogenesis involves the proliferation, migration and vessel-forming ability of microvascular endothelial cells. Previous studies have confirmed that BTB and CNC homology l (BACH1) can inhibit VEGF and angiogenesis, while haem can specifically degrade BACH1. However, the effect of haem on endothelial cells and ROP remains unknown.MethodsIn this report, we established a model of the relative hyperoxia of phase I ROP by subjecting human microvascular endothelial cells (HMEC-1) to 40% hyperoxia. Haem was added, and its effects on the growth and viability of HMEC-1 cells were evaluated. Cell counting kit 8 (CCK8) and 5-ethynyl-2′-deox-yuridine (EdU) assays were used to detect proliferation, whereas a wound healing assay and Matrigel cultures were used to detect the migration and vessel-forming ability, respectively. Western blot (WB) and immunofluorescence (IF) assays were used to detect the relative protein levels of BACH1 and VEGF.ResultsHMEC-1 cells could absorb extracellular haem under normoxic or hyperoxic conditions. The proliferation, migration and angiogenesis abilities of HMEC-1 cells were inhibited under hyperoxia. Moderate levels of haem can promote endothelial cell proliferation, while 20 μM haem could inhibit BACH1 expression, promote VEGF expression, and relieve the inhibition of proliferation, migration and angiogenesis in HMEC-1 cells induced by hyperoxia.ConclusionsHaem (20 μM) can relieve hyperoxia-induced inhibition of VEGF activity in HMEC-1 cells by inhibiting BACH1 and may be a potential medicine for overcoming stunted retinal angiogenesis induced by relative hyperoxia in phase I ROP.

Gene expression profiling (GEP) to identify metabolic gene signature predictive of recurrence after surgery in stage III clear-cell renal cell carcinoma (ccRCC).

355 Background: Management of patients with localized or locally advanced renal cell cancer (RCC) involves surgical resection. However, 20-40% of all localized kidney cancer patients experience a recurrence. Adjuvant treatment in high-risk kidney cancer has not proven to successfully improve overall survival (OS) and the only drug approved so far in this setting is vascular endothelial growth factor (VEGF) inhibitor, sunitinib. As multiple trials are evaluating drugs including immune checkpoint inhibitors in patients with high risk localized clear cell RCC, there is an urgent need to identify biomarkers to help with therapeutic decisions as well as for risk stratification. Here we present analysis pertaining to genes involved in metabolic reprogramming in kidney cancer. Methods: A deep transcriptomic analysis of patients with stage III ccRCC in the TCGA KIRC Firehose Legacy cohort was undertaken. Caucasian males with stage III ccRCC in the TCGA cohort for whom recurrence data was available with a minimum follow-up of 2 years were identified for the analysis. Expression profiles of differentially expressed genes were clustered using the Bayesian infinite mixture model and samples clustered using average linkage hierarchical clustering based on pairwise Pearson’s correlations as the measure of similarity. Enrichment analysis of up- and down-regulated genes was performed using logistic regression. R package was used to generate Kaplan-Meier curves and assess statistical significance of differences in overall and disease-free survival using log-rank test. Results: The cohort evaluated for this study included Caucasian male patients that remained disease free for at least 24 months after surgery (n = 22) and patients whose cancer recurred within 24 months (n = 20). We identified metabolic genes, encoding subunits of mitochondrial electron transport chain as well as malate aspartate shuttle (MAS), where loss of coordinated co-expression between these genes identified patients at risk of recurrence after surgery. The gene signature stratified the 42 patients into three subtypes: significantly enriched for a) recurrence (subtype 1), for b) disease free status (subtype 2) and b) intermediate (subtype 3). Work is underway to combine the use of individual gene expression and ratios of gene expression within the signature to optimize prognostic biomarkers for localized ccRCC. Conclusions: In this analysis, we have identified a novel metabolic gene signature which can help identify patients with localized ccRCC at high risk of recurrence after surgery to guide aggressive therapy. These findings require further validation in tumors collected from patients with stage III ccRCC.