Evaluation of Angiogenesis-Related Genes as Prognostic Biomarkers of Bevacizumab Treated Ovarian Cancer Patients: Results from the Phase IV MITO16A/ManGO OV-2 Translational Study

Background. Epithelial ovarian cancer (EOC) is a rare, highly lethal disease. In a subset of high grade EOC patients, maintenance therapy with the antiangiogenic drug Bevacizumab (BEV) is a valuable option. To date, no validated predictive or prognostic biomarkers exist for selecting EOC patients that might benefit from BEV treatment. Methods. Immunohistochemistry and RT-qPCR evaluated the expression of seven angiogenesis-related proteins and of a twelve microRNAs angio-signature in EOC patients, treated in first line with chemotherapy plus BEV (MITO16A/ManGO OV-2 phase IV trial). Centralized statistical analyses assessed the associations between each biomarker, clinical prognostic factors and survival outcomes. Results. High miR-484 expression was associated with longer progression-free and overall survival. Notably, the combined expression of miR-484 and its target VEGFB identified a subset of patients that might mostly benefit from BEV treatment. No other significant correlations were found between the other analyzed biomarkers and patients’ survival. The application of a shrinkage procedure to adjust for over-fitting hazard ratio estimates reduced the association significance. Conclusions. The analysis of angiogenesis related biomarkers in EOC patients homogenously treated with BEV in first line provides novel insight in their prognostic value and suggests that some of them might merit to be tested as predictive markers of drug activity in dedicated randomized trials.

Simulations on the efficacy of radiotherapy with different time schemes of antiangiogenic therapy

The combination of radiotherapy and antiangiogenic agents has been suggested to be potent in tumor growth control compared to the application of antiangiogenic therapy or radiotherapy alone. Since radiotherapy is highly dependent on the oxygen level of the tumor area, antiangiogenic agents are utilized for the reoxygenation of tumor vasculature. We present a mathematical framework to investigate the efficacy of radiotherapy combined with antiangiogenic treatment. The framework consists of tumor cells, vasculature, and oxygenation levels evolving with time to mimic a tumor microenvironment. Non-linear partial differential equations (PDEs) are employed to simulate each component of the framework. Different treatment schemes are investigated to see the changes in tumor growth and oxygenation. To test combination schedules, radiation monotherapy, neoadjuvant, adjuvant, and concurrent cases are simulated. The efficiency of each therapy scheme on tumor growth control, the changes in tumor cell density, and oxygen levels shared by tumor cells are represented. The simulation results indicate that the application of radiotherapy after antiangiogenic treatment is more efficient in tumor growth control compared to other therapy schemes. The present study gives an insight into the possible interaction and timing of the combination of radiotherapy and antiangiogenic drug treatment.

A retrospective study of anlotinib in patients with cervical cancer after chemoradiotherapy.

e17509 Background: Anlotinib is a novel small molecule antiangiogenic drug, which can inhibit multiple tyrosine kinase receptor activity. Its antitumor activity has been proved in various cancers, including gynecological tumors. This retrospective study explored the efficacy and safety of anlotinib monotherapy or anlotinib combined chemotherapy in cervical cancer patients who have disease progressed or metastasis after chemoradiotherapy. Methods: 28 patients with cervical cancer admitted to the Second Affiliated Hospital of Zhengzhou University were enrolled. These patients who had received radiotherapy and at least one line chemotherapy had tumor progression or metastasis. 13 patients received anlotinib monotherapy (12mg/d from day 1 to day 14 in a 21-day cycle) and 15 patients received chemotherapy combined with the anlotinib. Treatment was continued until disease progression or death or intolerable adverse events. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS) and safety. Results: As of Dec 31 2020, no one was lost follow up. 2 patients were still under treatment, and 26 patients were evaluable. 1 CR, 6 PR, 13 SD, 6 PD, yielding the ORR of 26.92%, and the DCR of 76.92%. The median PFS for receiving anlotinib monotherapy was 4.57 (95% CI, 3.85-5.29) months, and 8.47 (95% CI, 5.09-11.85) months for combination group. The most common adverse events (AEs)were grade 1, including hypertension (46.43%), anemia (42.85%) and fatigue (39.29%). Grade 3 AEs were hypertension(10.71%) and anemia(7.14%). No higher grade AEs occurred. Conclusions: Anlotinib is safe and effective for patients with advanced cervical cancer after chemoradiotherapy, and it is well tolerated.

Durable Response to Immunotherapy With Antiangiogenic Drug in Large-Cell Lung Carcinoma With Multiple Fulminant Postoperative Metastases: A Case Report

Immunotherapy alone or chemo-immunotherapy has recently been recommended for treating advanced lung carcinoma in patients without driver mutations. However, the efficacy of immunotherapy and molecular mechanism in large-cell lung cancer (LCLC) remains unclear. Here, we reported a rare case of multiple fulminant postoperative body and mouth metastases in LCLC treating with combination immunotherapy. Initially, the patient was diagnosed as early stage LCLC and underwent a radical resection of the right lower lobe. Just one month later, multiple fulminant body and mouth lesions appeared in the right upper arm, right elbow, right waist, and tongue root. Meanwhile, serum neuron specific enolase (NSE) concentration dramatically increased from 12.12 to 30.14 ng/ml. Immumohistochemistry findings demonstrated moderate PD-L1 expressions with tumor proportion score (TPS), while next-generation sequencing indicated moderate tumor mutational burden (TMB) levels and gene mutations in PBRM1 L1230P and TP53 L194R of both foci. Besides, loss of heterozygosity (LOH) at human leukocyte antigen (HLA) class I (HLA-A*02:03, HLA-B*55:02 and HLA-C*12:03) were detected in the right upper arm metastasis, which may facilitate malignant postoperative metastases in this case. Notably, this patient received combination therapy with anti-PD-1 antibody sintilimab plus anlotinib, and achieved a partial response for at least 12 months. Using an integrated computational method, the mutant peptide TEIPENDIPL derived from PBRM1 L1230P was predicted to be a specific neoantigen and could still be presented by HLA-B*40:01. This case suggests that immunotherapy plus antiangiogenic drug may provide an alternative therapeutic option for advanced LCLC patients without common gene mutations.

Treatment sequences of patients with advanced colorectal cancer and use of second-line FOLFIRI with antiangiogenic drugs in Japan: A retrospective observational study using an administrative database

The objectives were to describe treatment sequences for advanced colorectal cancer (CRC), use of second-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) plus antiangiogenic drug (bevacizumab, ramucirumab, aflibercept beta) therapy, and the factors associated with the duration of antitumor drug treatment from second-line antiangiogenic therapy in Japan. This retrospective observational study was conducted using a Japanese hospital-based administrative database. Patients were enrolled if they started adjuvant therapy (and presumably experienced early recurrence) or first-line treatment for advanced CRC between May 2016 and July 2019, and were analysed until September 2019. Factors associated with overall treatment duration from second-line treatment with FOLFIRI plus antiangiogenic drugs were explored with multivariate Cox regression analysis. The most common first-line treatments were FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) with bevacizumab (presumed RAS-mutant CRC) and FOLFOX with panitumumab (presumed RAS-wild type CRC). The most common second-line treatments were FOLFIRI-based. Many patients did not transition to subsequent lines of therapy. For second-line treatment, antiangiogenic drugs were prescribed more often for patients with presumed RAS-mutant CRC, right-sided CRC, and independent activities of daily living (ADL). The median duration of second-line FOLFIRI plus antiangiogenic drug treatment was 4.5 months; 66.2% of patients transitioned to third-line therapy. Low body mass index and not fully independent ADL were significantly associated with shorter overall duration of antitumor drug treatment from second-line therapy. Left-sided CRC, presumed RAS-wild type CRC, previous use of oral fluoropyrimidines and use of proteinuria qualitative tests, antihypertensives, or anticholinergics during second-line therapy were significantly associated with longer treatment. Treatment of advanced CRC in Japan is consistent with both international and Japanese guidelines, but transition rates to subsequent therapies need improvement. In addition to antitumor drug treatment, better ADL, higher body mass index, management of hypertension, and proteinuria tests were associated with continuation of sequential therapy that included antiangiogenic drugs.

Biomaterials Targeting AMD: Are We There Yet?

Age-related macular degeneration (AMD) is the leading cause of central blindness in developed countries. It affects people mainly over the age of 50 years. It is a disease of the macula, an area of the retina responsible for sharp central vision. It particularly affects the Bruch’s membrane (BM); a layer in the retina that acts as the basement upon which retinal pigment epithelial cells (RPE) attach and survive. The pathology of AMD is not fully understood, but age is considered the main risk factor. There are two forms; nonexudative, leading to the end-stage of the disease, called nonexudative (or dry) AMD (90% of cases) where fatty deposits called drusen form under the RPE on top of the BM lifting off the RPE, and neovascular (or wet) AMD (10% of cases) where abnormal new blood vessels grow and push through the BM, bleeding in and disrupting the RPE. Neovascular AMD is well controlled with regular antiangiogenic drug injections of anti-vascular endothelial growth factor (anti-VEGF) into the eye, whereas there is no current treatment for nonexudative AMD. Many research groups across the world are working on a treatment for nonexudative AMD. This review discusses the research currently being conducted including cell therapies, development of cell transplantation membranes, targeting other disease structures in affected retina (i.e. drusen), and drug delivery to the retina using nanoparticles. Finally, we include our research contributing to the field; developing a bioactive membrane intended to function two-fold: target diseased structures and transplant healthy RPE to the desired area.

Development and Validation of Dimeric Macrocyclic Tannin Assay Method in Dosage Forms

Introduction. Quantitative assessment of the active substance is necessary and perhaps the most significant part of the drug quality control. Validation of the analytical methods of quantitative assessment ensures their compliance with high requirements. The present study describes the development and validation of a spectrophotometry method for the quantitative evaluation of the active substance in the drug form of the national antitumor and antiangiogenic drug «Dimeric macrocyclic tannin (DMT) lyophilizate for solution for injection, 100 mg».Aim. The development and validation of the assay method for the standardization of «DMT lyophilizate for solution for injection, 100 mg».Materials and metods. The study used «DMT lyophilizate for solution for injection, 100 mg» and the active substance DMT. Method – spectrophotometry.Results and discussion. The methodof the quantitative assessment of the active substance in the DMT lyophilized drug by direct UV spectrophotometry was developed and the validation characteristics of the method were defined as a result of the study.Conclusion. The validation results showed that the assay method of DMT in the drug form has the appropriate accuracy, precision and linearity. The obtained results correspond to the approved criteria that allow the use of the developed methodology for evaluating the quality of the drug.