Delphi techniques are used in health care and nursing to systematically bring together explicit and implicit knowledge from experts with a research or practical background, often with the goal of reaching a group consensus. Consensus standards and findings are important for promoting the exchange of information and ideas on an interdisciplinary and transdisciplinary basis, and for guaranteeing comparable procedures in diagnostic and therapeutic approaches. Yet, the development of consensus standards using Delphi techniques is challenging because it is dependent on the willingness of experts to participate and the statistical definition of consensus.

It has become evident that we cannot understand tumour growth without considering components of the stromal microenvironment, such as the vasculature. At the same time, the tumour phenotype determines the nature of the tumour vasculature. Much research is now devoted to determining the impact of angiogenesis on tumour development and progression, and the reciprocal influences of tumour products on the microvasculature. A more detailed understanding of the complex parameters that govern the interactions between the tumour and vascular compartments will help to improve anti-angiogenic strategies-- not only for cancer treatment, but also for preventing recurrence.

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

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Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.

Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. Antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. According to Jain et al., an alternative hypothesis could be that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. With emphasize on the research works of Jain et al., the aim of this review is to describe the impact of antivascular endothelial growth factor (VEGF) therapy on "pseudo-normalization" of tumor vasculature and tumor microenvironment, its role in early and metastatic breast cancer, and the clinical evidence supporting this original concept. The phase III clinical trials showed that extended tumors, metastatic or locally advanced, are likely to benefit from bevacizumab therapy in combination with chemotherapy, assuming that a high level of tumor neoangiogenesis as in triple-negative tumors is the best target. In adjuvant setting, the lower level of tumor vasculature could mask a potential benefit of anti-VEGF therapy. All these findings highlight the need to identify biomarkers to help in the selection of patients most likely to respond to anti-VEGF therapy, to better understand the mechanism of angiogenesis and of resistance to anti-VEGF therapy according to molecular subtypes.

Two thirds of patients with ovarian carcinoma have advanced disease at diagnosis and have poor prognoses because of the presence of highly invasive carcinoma cells and rapidly accumulating ascitic fluid. Vascular endothelial growth factor (VEGF), a potent mitogen of endothelial cells, is produced in elevated amounts by many tumors, including ovarian carcinomas. The known human receptors for VEGF, flt and KDR, are both cell surface tyrosine kinases and are expressed predominantly on endothelial cells. Acting through these receptors, VEGF may stimulate angiogenesis and promote tumor progression.We aimed to clarify the function of VEGF in tumor development by identifying the cells in ovarian carcinoma tissue that express VEGF and its receptors.VEGF, flt, and KDR expression was localized by in situ hybridization and immunohistochemistry in frozen sections of primary tumors from five patients with ovarian carcinoma and from metastases of ovarian carcinoma from three different patients. Reverse transcription followed by polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay were used to analyze VEGF, flt, and KDR expression in six epithelial cell lines derived from ovarian carcinoma ascites from five additional patients.Messenger RNAs (mRNAs) encoding VEGF, flt, and KDR were detected in primary ascitic cells and in three of four ovarian carcinoma cell lines examined by RT-PCR. Two novel complementary DNAs that may encode truncated, soluble forms of flt were cloned from one primary source. VEGF levels of 20-120 pM were found in culture media conditioned by the cell lines. Elevated expression of VEGF mRNA was found in all primary tumors and metastases, especially at the margins of tumor acini. VEGF immunoreactivity was concentrated in clusters of tumor cells and patches of stromal matrix. flt immunoreactivity was confined to tumor blood vessels, but flt mRNA was not detected by in situ hybridization. In contrast, KDR mRNA was detected not only in vascular endothelial cells but also in tumor cells at primary malignant sites.VEGF is expressed by tumor cells in primary and metastatic ovarian carcinoma and accumulates in the stromal matrix. Its receptors, flt and KDR, are expressed by some tumor cells that coexpress VEGF. This is the first localization of KDR expression in nonendothelial cells.Coexpression of VEGF and KDR by tumor cells in ovarian carcinoma raises the possibility of autocrine stimulation and of therapeutic strategies targeting this receptor-ligand interaction.

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Combination treatments with immune-checkpoint inhibitor and antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a notable therapeutic strategy in recurrent ovarian cancer (ROC). We report the results of camrelizumab (an anti-programmed cell death protein-1 antibody) in combination with famitinib (a receptor tyrosine kinase inhibitor) for the treatment of platinum-resistant ROC from an open-label, multicenter, phase 2 basket trial.

Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib is an anti-angiogenic drug active in ovarian cancer. We assessed the effect of adding pazopanib to paclitaxel for patients with platinum-resistant or platinum-refractory advanced ovarian cancer.We did this open-label, randomised phase 2 trial at 11 hospitals in Italy. We included patients with platinum-resistant or platinum-refractory ovarian cancer previously treated with a maximum of two lines of chemotherapy, Eastern Cooperative Oncology Group performance status 0-1, and no residual peripheral neurotoxicity. Patients were randomly assigned (1:1) to receive weekly paclitaxel 80 mg/m(2) with or without pazopanib 800 mg daily, and stratified by centre, number of previous lines of chemotherapy, and platinum-free interval status. The primary endpoint was progression-free survival, assessed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01644825. This report is the final analysis; the trial is completed.Between Dec 15, 2010, and Feb 8, 2013, we enrolled 74 patients: 37 were randomly assigned to receive paclitaxel and pazopanib and 37 were randomly assigned to receive paclitaxel only. One patient, in the paclitaxel only group, withdrew from the study and was excluded from analyses. Median follow-up was 16·1 months (IQR 12·5-20·8). Progression-free survival was significantly longer in the pazopanib plus paclitaxel group than in the paclitaxel only group (median 6·35 months [95% CI 5·36-11·02] vs 3·49 months [2·01-5·66]; hazard ratio 0·42 [95% CI 0·25-0·69]; p=0·0002). We recorded no unexpected toxic effects or deaths from toxic effects. Adverse events were more common in the pazopanib and paclitaxel group than in the paclitaxel only group. The most common grade 3-4 adverse events were neutropenia (11 [30%] in the pazopanib group vs one [3%] in the paclitaxel group), fatigue (four [11%] vs two [6%]), leucopenia (four [11%] vs one [3%]), hypertension (three [8%] vs none [0%]), raised aspartate aminotransferase or alanine aminotransferase (three [8%] vs none), and anaemia (two [5%] vs five [14%]). One patient in the pazopanib group had ileal perforation.Our findings suggest that a phase 3 study of the combination of weekly paclitaxel plus pazopanib for patients with platinum-resistant or platinum-refractory advanced ovarian cancer is warranted.National Cancer Institute of Napoli and GlaxoSmithKline.Copyright © 2015 Elsevier Ltd. All rights reserved.

Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC).

Camrelizumab is an antibody against programmed death protein 1. We assessed the activity and safety of camrelizumab plus apatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, in patients with advanced cervical cancer.

This phase 2 study assesses the efficacy and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (anti-angiogenic agent) in women with pretreated recurrent or metastatic cervical cancer (ClinicalTrials.gov NCT03827837). Patients with histologically or cytologically confirmed cervical squamous cell carcinoma experiencing relapse or progression during or after 1-2 lines of systemic therapy for recurrent or metastatic disease are enrolled. Eligible patients receive camrelizumab 200 mg intravenously on day 1 of each 3-week cycle plus famitinib 20 mg orally once daily. The primary endpoint is the objective response rate. Secondary endpoints are duration of response, disease control rate, time to response, progression-free survival, overall survival, and safety. The trial has met pre-specified endpoint. Thirty-three patients are enrolled; median follow-up lasts for 13.6 months (interquartile range: 10.0-23.6). Objective responses are observed in 13 (39.4%, 95% confidence interval [CI]: 22.9-57.9) patients; the 12-month duration of response rate is 74.1% (95% CI: 39.1-90.9). Median progression-free survival is 10.3 months (95% CI: 3.5-not reached) and the 12-month overall survival rate is 77.7% (95% CI: 58.9-88.7). All patients experience treatment-related adverse events; grade ≥3 events occur in 26 (78.8%) patients. Treatment-related serious adverse events and deaths are observed in 9 (27.3%) and 2 (6.1%) patients, respectively. Camrelizumab plus famitinib shows promising antitumor activity with a manageable and tolerable safety profile in patients with pretreated recurrent or metastatic cervical squamous cell carcinoma. This combination may represent a treatment option for this population.© 2022. The Author(s).

Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors.Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORR); secondary efficacy end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor assessments were evaluated by investigators per immune-related RECIST.At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORR was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORR (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)-high tumors (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumors (n = 94). For previously treated patients, regardless of tumor MSI status, the median DOR was 21.2 months (95% CI, 7.6 months to not estimable), median PFS was 7.4 months (95% CI, 5.3 to 8.7 months), and median OS was 16.7 months (15.0 months to not estimable). Grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients.Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile.

Although co-inhibition of the angiogenesis and programmed death 1 (PD-1) pathways is proposed as an effective anticancer strategy, studies in Chinese patients with endometrial cancer are sufficient. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor affecting tumor angiogenesis and proliferation; sintilimab is an anti-PD-1 monoclonal antibody.