The aim of our study was to investigate expression levels and the prognostic value of multiple growth factors and their receptors in the primary tumor cells of renal cell carcinoma (RCC).
Expression ...of vascular endothelial growth factor (VEGF)A, fibroblast growth factor (FGF)2, vascular endothelial growth factor receptor (VEGFR)1, VEGFR2, FGFR1, FGFR2, platelet-derived growth factor receptor (PDGFR)α, and PDGFRβ was investigated in 65 primary RCC specimens by immuhistochemical staining using the appropriate antibodies. Expression levels were evaluated by the semi-quantitative method. A search for correlations of expression levels of investigated growth factors and receptors with RCC features and patients outcomes was performed.
Expression of all growth factors and their receptors was detected both on the surface and in the cytoplasm of the primary tumor cells in RCC patients. The expression of all analyzed factors was interconnected. FGFR2 expression correlated with the largest number of other growth factors and receptors. A strong correlation was revealed between high expression of the studied markers, high Fuhrman grade, and advanced RCC stages. In a univariate analysis overexpression of VEGFR2 (p <0.0001) and FGFR2 (p = 0.014) had negative influence on cancer-specific survival.
Expression of growth factors and tyrosine kinase receptors in the primary tumor cells is strongly interconnected and associated with unfavorable features of RCC.
Summay
Purpose
Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. We ...investigated antitumor activity of alofanib (RPT835), a novel allosteric FGFR2 inhibitor, in ovarian cancer in vitro and in vivo.
Methods
Equal amounts of ovarian cancer cell (SKOV3) lysates were analyzed for FGFR1–3 protein expression using Wes. To assess the efficacy of alofanib on FGF-mediated cell proliferation, SKOV3 cells were incubated and were treated with serially diluted alofanib. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega’s Cell Titer-Glo® assay. Immunocompromised mice were used for xenotransplantation of SKOV3 cancer cells. Seventy animals with measurable tumors were selected on day 10 and randomized into control groups (no treatment or chemotherapy alone (paclitaxel + carboplatin) and treatment groups (alofanib orally or intravenously (different dose levels) in combination with chemotherapy). Measurements of tumor volume (mm3) were performed by digital calipers every 3 days during 31 days after tumor inoculation. Number of tumor vessels and Ki-67 index were calculated.
Results
SKOV3 cells express FGFR1 and FGFR2 but not FGFR3. Basic FGF increased proliferation of the ovarian cancer cells in untreated control group (
P
= 0.001). Alofanib inhibited growth of FGFR2-expressing SKOV3 cells with GI50 value of 0.37 μmol/L. Treatment with alofanib in combination with paclitaxel/carboplatin resulted in tumor growth delay phenotype in all treatment groups compared to control non-treatment groups. Compound exhibited a dose-dependent effect on tumor growth. Daily intravenous regimen of alofanib (total maximum dose per week was 350 mg/kg) demonstrated significant effect (inhibiting growth by 80 % and by 53 % in comparison with vehicle and chemotherapy group alone, respectively (
P
< 0.001). Alofanib decreased number of vessels in tumor (−49 %;
P
< 0.0001) and number of Ki-67-positive SKOV3 cells (−42 %,
P
< 0.05
)
. There were tumor necrosis and cell degeneration in alofanib group.
Conclusions
We suggest that FGFR2 inhibition has potent effects on ovarian cancer growth in preclinical studies.
Objectives
To evaluate the role of cytoreductive radiofrequency ablation (cRFA) in patients with metastatic renal cell carcinoma (RCC) with small primary tumours treated with immuno‐ or targeted ...therapy.
To assess the efficacy of sunitinib in patients with metastatic RCC with unresected small primary tumours.
Patients and Methods
Three parallel single‐arm prospective studies were conducted. Eligibility criteria were nearly identical for all trials and included: histopathologically confirmed RCC; metastatic measurable disease; size of primary tumour <5 cm; good or intermediate prognosis according to the Memorial Sloan‐Kettering Cancer Center model; and no previous therapy.
Study 1: Patients were treated with percutaneous cRFA under computed tomography guidance followed by interferon (IFN)‐α, 9 MIU, s.c., three times per week. Study 2: Patients received cRFA followed by sunitinib in repeated 6‐week cycles of 50 mg/day orally for 4 weeks, then 2 weeks off treatment. Study 3: Patients with unresected primary RCC received sunitinib alone. The primary endpoint was progression‐free survival (PFS).
Results
Baseline patient characteristics (age, gender, histology, Eastern Cooperative Oncology Group performance status, metastatic sites, primary tumour size) were similar in all three studies.
Efficacy data for 114 evaluable patients showed an objective response rate of 8% (95% confidence interval CI 4.5, 10.5) for study 1, 28.9% (95% CI 15.2, 34) for study 2, and 31.6% (95% CI 20.3, 38.9) for study 3. The median (95% CI) PFS times were 9.1 (6.9, 10.2), 13.4 (9.8, 14.4) and 12.7 (11.3, 13.5) months for studies 1, 2 and 3, respectively.
Objective response rate was significantly higher and PFS significantly longer in the sunitinib trials than in study 1 (P < 0.01 all differences); no differences were found between studies 2 and 3 (objective response rate, P = 0.1; PFS, P = 0.6). Study 1 met its primary endpoint, showing that PFS was significantly longer than the expected 5 months (P = 0.02).
The median (95% CI) overall survival (OS) times were greater in study 2 (cRFA/sunitinib) and study 3 (sunitinib‐alone) than in study 1 (IFN‐α) at 27.2 (22.6, 31.8) and 22.5 (20.7, 24.3) vs 19.5 (16.3, 22.7) months, respectively. Differences were significant (study 1 vs 2, hazard ratio HR = 0.55; P = 0.003; study 1 vs study 3 HR = 0.6, P = 0.01). OS was significantly longer in the cRFA/sunitinib group compared with the sunitinib‐alone group (HR = 0.71; P = 0.04).
There were no unexpected toxicities of medical treatment or complications of cRFA.
Conclusions
cRFA is a safe and effective approach for select patients with metastatic RCC treated with immunotherapy.
The cRFA technique did not improve PFS in patients treated with sunitinib; cRFA probably has impact on OS in these patients. This needs to be tested in a larger trial.
Sunitinib was effective in patients with metastatic RCC with unresected small primary tumours.
We report on a family with von Hippel-Lindau (VHL) disease and atypically aggressive renal cell carcinoma. A woman and her brother had progressive VHL disease with multiple tumors in their kidneys. ...One patient developed pulmonary metastases. The patient who had localized disease received radiofrequency ablation with complete destruction of tumors. Cytoreductive nephrectomy was performed in the case of metastatic disease, following which sunitinib maleate (50 mg orally daily, 4 weeks on, 2 weeks off) was given. Examination after two treatment cycles showed complete regression of all metastases. For 19 months, the patients have been under active observation without disease progression. Also, we detected high immunohistochemical expression of vascular endothelial growth factor receptors 1 and 2 in the cytoplasm and nuclei of tumor cells.
Radiation oncologists in Russia face a number of unique professional difficulties including lack of standardized training and continuing medical education. To combat this, under the auspices of the ...Russian Society of Clinical Oncology (RUSSCO), our group has developed a series of ongoing in-person interactive contouring workshops that are held during the major Russian oncology conferences in Moscow, Russia. Since November 2016 during each workshop, we utilized a web-based open-access interactive three-dimensional contouring atlas as part of our didactics. We sought to determine the impact of this resource on radiation oncology practice in Russia. We distributed an IRB-approved web-based survey to 172 practicing radiation oncologists in Russia. We inquired about practice demographics, RUSSCO contouring workshop attendance, and the clinical use of open-access English language interactive contouring atlas (eContour). The survey remained open for 2 months until November 2017. Eighty radiation oncologists completed the survey with a 46.5% response rate. Mean number of years in practice was 13.7. Sixty respondents (75%) attended at least one RUSSCO contouring workshop. Of those who were aware of eContour, 76% were introduced during a RUSSCO contouring workshop, and 81% continue to use it in their daily practice. The greatest obstacles to using the program were language barrier (51%) and internet access (38%). Nearly 90% reported their contouring practices changed since they started using the program, particularly for delineation of clinical target volumes (57%) and/or organs at risk (46%). More than 97% found the clinical pearls/links to cooperative group protocols in the software helpful in their daily practice. The majority used the contouring program several times per month (43%) or several times per week (41%). Face-to-face contouring instruction in combination with open-access web-based interactive contouring resource had a meaningful impact on perceived quality of radiation oncology contours among Russian practitioners and has the potential to have applications worldwide.
Fibroblast growth factor (FGF) receptors (FGFRs) play a key role in tumor growth and angiogenesis. The present report describes our search for an extracellularly binding FGFR inhibitor using a ...combined molecular modeling and de novo design strategy.
Based upon crystal structures of the receptor with its native ligand and knowledge of inhibiting peptides, we have developed a computational protocol that predicts the putative binding of a molecule to the extracellular domains of the receptor. This protocol, or scoring function, was used in combination with the de novo synthesis program 'SYNOPSIS' to generate high scoring and synthetically accessible compounds.
Eight compounds belonging to 3 separate chemical classes were synthesized. One of these compounds, alofanib (RPT835), was found to be an effective inhibitor of the FGF/FGFR2 pathway. The preclinical in vitro data support an allosteric inhibition mechanism of RPT835. RPT835 potently inhibited growth of KATO III gastric cancer cells expressing FGFR2, with GI50 value of 10 nmol/L.
These results provide strong rationale for the evaluation of compound in advanced cancers.
We report on a family with von Hippel-Lindau (VHL) disease and
atypically aggressive renal cell carcinoma. A woman and her brother had
progressive VHL disease with multiple tumors in their kidneys. ...One
patient developed pulmonary metastases. The patient who had localized
disease received radiofrequency ablation with complete destruction of
tumors. Cytoreductive nephrectomy was performed in the case of
metastatic disease, following which sunitinib maleate (50 mg orally
daily, 4 weeks on, 2 weeks off) was given. Examination after two
treatment cycles showed complete regression of all metastases. For 19
months, the patients have been under active observation without disease
progression. Also, we detected high immunohistochemical expression of
vascular endothelial growth factor receptors 1 and 2 in the cytoplasm
and nuclei of tumor cells.
Background
A paraneoplastic syndrome is observed in 5% to 10% of cancer patients. Paraneoplastic vasculitis (PV) in metastatic renal cell carcinoma (mRCC) patients has been poorly investigated.
Aims
...In our case series study, we evaluated the incidence and development of PV in patients with mRCC.
Methods and results
Patients were required to have previously untreated clear‐cell or papillary mRCC and no evidence of autoimmune diseases or venous thrombosis in history. Patients had a careful examination including Doppler ultrasonography of the blood vessels and skin punch biopsy in the presence of suspicious skin rash. Sixteen (8.2%) of 196 patients were diagnosed with PV, which was manifested clinically by leukocytoclastic vasculitis on the lower extremities. Skin biopsy confirmed vasculitis. Progression‐free survival and overall survival were significantly better in patients without PV.
Conclusions
PV is not rare paraneoplastic syndrome in mRCC. Leukocytoclastic vasculitis was the most common type of PV in this study.
Introduction: Metastatic renal cell carcinoma (mRCC) can cause hypogonadism as an adverse effect in male patients. Hypogonadism can also result from adverse effects of targeted therapy of mRCC, such ...as fatigue, pain, anorexia, asthenia or hypothyroidism. The objective of this multicenter randomized phase 2 study was to determine efficacy and safety of testosterone undecanoate (T) in mRCC patients with hypogonadism. Methods: Eighty-two male patients with clear cell mRCC were screened. Patients with low testosterone level and normal PSA level receiving first-line sunitinib or pazopanib were randomly assigned (1:1) to either T (Nebido®, 1,000 mg) and targeted therapy or targeted therapy alone (control group). T was injected intramuscular deeply on Day 1 of a new treatment cycle. Symptom index (FKSI-19), fatigue score (FACIT-Fatigue), erectile function (IIEF-5), testosterone serum concentrations, red blood cells (RBC) count and hemoglobin level were evaluated. The assessments were performed at baseline and Day 28 of a treatment cycle. Results: Sixty (75.6%) patients had hypogonadism. Mean age was 52 years (range 33-71) in the T group (N=30) and 55 years (42-69) in the control group (N=30). 45 (75%) patients reported a negative change in their sexual life, and 16 (27%) patients had no sexual activity since the start of the targeted therapy. T was well tolerated in mRCC patients. No unexpected toxicity was observed. The health-related quality-of-life scores in the T group were better than those in the control group, respectively (mean (SD) - FKSI-19: baseline, 46.5 (12.2) vs. 44.2 (9.4), Day 28, 27.5 (12.5) vs. 39.9 (9.8); FACIT-Fatigue: baseline, 37 (4.7) vs. 35.3 (3.1), Day 28, 20.3 (8.1) vs. 42.5 (8.4), all P≤0.01). Therapy with T improved significantly sexual function (IIEF-5: baseline, 16 (3.3) vs. 19 (2.6), Day 28, 21 (1.5) vs. 8 (1.9), P=0.003). There was non-significant positive trend in hemoglobin level between 2 groups (baseline, 124.5 (11.7) g/l vs. 119 (10.4), Day 28, 133 (13.5) vs. 108 (17). Testosterone level increased significantly in T group (baseline, 6.21 (1.78) nmol/l, Day 28, 33.2 (14.3). Conclusions: Male patients with mRCC receiving targeted therapy had significantly less fatigue, better symptom control, and better erectile function with T. T therapy was safe. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.
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