Endothelial Growth Factor Tyrosine Kinase Research Articles

Tumor growth velocity: A modified tumor growth rate defining tumor progression during sorafenib treatment in patients with metastatic renal cell carcinoma.

To investigate the role of tumor growth velocity in defining tumor progression in metastatic renal cell carcinoma patients treated with the vascular endothelial growth factor tyrosine kinase inhibitor, sorafenib. A modified calculation for tumor growth velocity was introduced to evaluate the tumor growth velocity, before and after sorafenib withdrawal. Known prognostic factors together with tumor growth velocity before drug withdrawal and tumor growth velocity after drug withdrawal were compared using a χ2 -test from a contingency table, and partial likelihood test from a Cox regression model for overall survival. A total of 114 patients who reached progressive disease and withdrew from sorafenib were enrolled after a median follow-up period of 107.8months. Tumor growth velocity before drug withdrawal was 7.347±4.040, and tumor growth velocity after drug withdrawal was 11.647±5.937 (P<0.001). Higher tumor growth velocity before drug withdrawal was correlated with a higher risk Memorial Sloan Kettering Cancer Center score (P=0.022), Karnofsky Performance Status<80 (P=0.028), non-clear cell carcinoma (P=0.037), higher tumor nucleus grade (P<0.001) and best treatment response (P<0.001). Patients with tumor growth velocity before drug withdrawal>5.0 had shorter overall survival (P<0.001). On multivariate analysis, factors associated with overall survival were high/intermediate Memorial Sloan Kettering Cancer Center risk score (hazard ratio 2.119, P=0.006), non-clear histological subtype (hazard ratio 1.900, P=0.031), tumor growth velocity before drug withdrawal≥5.0 (hazard ratio 2.758, P<0.001) and progressive disease as best response (hazard ratio 2.069, P=0.001). Significantly faster tumor growth can be observed if sorafenib is discontinued in the case of disease progression. Thus, we suggest not to withdraw targeted agents until tumor growth velocity is>5.0.

Gebe sıçanlara bevacizumab uygulayarak preeklampsi çalışmalarında kullanılabilecek deneysel hayvan modeli oluşturulabilir.

INTRODUCTION: To develop a rat model of preeclampsia by administering bevacizumab, an angiogenesis inhibitor. METHODS: Sixteen pregnant rats were randomly allocated to intraperitoneal injection of 10 mg/kg bevacizumab or 0.1 cc intraperitoneal serum physiologic on the 4th and 8th days of gestation. Blood pressure, body weight, and proteinuria were measured on both day 0 (D0) and day 20 (D20). Blood samples were collected on D20 for analysis, including for determining vascular endothelial growth factor (VEGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) levels. On the same day, the mice were euthanized, the placentas and pups were weighted, and the angiogenesis markers and microvessel density were evaluated using immunohistochemical methods. RESULTS: Lower serum VEGF (p = 0.038) and higher SFlt-1 (p = 0.015) levels were observed in bevacizumab-treated pregnant rats. Bevacizumab-treated pregnant rats had significantly higher systolic (p = 0.050) and diastolic (p = 0.046) blood pressures compared to the controls. Additionally, the bevacizumab group showed a significant increase in proteinuria on D20 compared to that on D0 (p = 0.026). Although higher serum AST, ALT, BUN, and creatinine levels and renal glomerular endotheliosis scores as well as lower placental VEGF and microvessel density were noted in bevacizumab-treated rats, these differences were not statistically significant (p > 0.05 for each). DISCUSSION AND CONCLUSION: The promising results of this trial show that bevacizumab treatment in pregnant rats might provide a model to study human preeclampsia

Protective effect of human umbilical cord mesenchymal stem cell exosomes on preserving the morphology and angiogenesis of placenta in rats with preeclampsia.

This study aims to investigate the effect of human umbilical cord mesenchymal stem cell exosomes (hucMSC-Ex) on placental tissue and angiogenesis in rats with preeclampsia (PE). The expression of MSC surface markers were identified by flow cytometry. Alizarin red staining and oil red O staining were used to examine osteogenic and adipogenic differentiation of hucMSCs. Western blotting was used to determine expressions of CD63 and CD81 in hucMSC-Ex. PE rat models were established using endothelial nitric oxide synthase, eNOS)NG-Nitro-l-arginine Methyl Ester, which were then treated with exosome (Exo) of low dosage (L-Exo), Exo of medium dosage (M-Exo) and Exo of high dosage (H-Exo). The blood pressure at the 15d, 17d and 19d of pregnancy and 24-h urinary protein were measured. TUNEL staining and immunohistochemistry were applied to detect the cell apoptosis and micro-vascular density (MVD) in placental tissues, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to examine serum levels of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase receptor-1 (sFlt1). In vitro cultured hucMSCs showed expression of MSC surface markers (CD29, CD90 and CD105), and no expression of CD34 and CD45. Besides, the isolated exosomes expressed the exosome markers (CD63 and CD81). In response to the treatment of L-Exo, M-Exo and H-Exo, the blood pressure of PE rat models on the 17 d and the 19 d as well as the 24-h urinary protein were substantially decreased. Moreover, at the 21 d, PE rat models treated with L-Exo, M-Exo and H-Exo exhibited an increase in the number and quality of fetuses, placenta quality, MVD and VEGF expression, but substantial decreased cell apoptosis and expression of sFlt1. The influence of Exos was exerted in a dosage dependent manner. hucMSC-Ex, in a dose-dependent manner, can improve the morphology of placental tissue in rats with PE, by inhibiting cell apoptosis and promoting angiogenesis in placental tissue.

Targeting Bacteroides in Stool Microbiome and Response to Treatment With First-Line VEGF Tyrosine Kinase Inhibitors in Metastatic Renal-Cell Carcinoma.

Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are a mainstay of treatment for metastatic renal-cell carcinoma. Stool microbiome composition is predictive of response to immunotherapy and cytotoxic chemotherapy. We sought to investigate whether antibiotics targeting Bacteroides species affect progression-free survival (PFS) while receiving first-line VEGF-TKI therapy. Using a retrospective cohort of intermediate- and poor-risk metastatic renal-cell carcinoma patients from the University of Utah, we categorized patients receiving first-line VEGF-TKIs by receipt of antibiotics (Bacteroides spp., non-Bacteroides spp., or none) and assessed PFS by Kaplan-Meier and Cox proportional hazard models. Of 145 patients, 17 received antibiotics with Bacteroides spp. coverage and 32 patients received antibiotics without Bacteroides spp. coverage. When compared to patients not receiving antibiotics, improved PFS was seen with each additional day antibiotics were prescribed with Bacteroides spp. coverage (hazard ratio= 0.92; 95% confidence interval, 0.83-0.99; P= .04). Targeting stool Bacteroides spp. with antibiotics improves PFS in patients receiving first-line VEGF-TKIs in a duration-dependent manner.

A meta-analysis of randomized controlled trials for efficacy and safety of vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) adjuvant therapy in high-risk renal cell cancer (RCC).

4567Background: Three large randomized placebo controlled trials (RCTs) (ASSURE, S-TARC, PROTECT) with adjuvant VEGF-TKIs in high risk RCCs have provided variable results for improving disease free...

Neuropathy as an adverse effect of vascular endothelial growth factor tyrosine kinase inhibitors, a meta-analysis of randomized clinical trials (P6.098)

Neuropathy as an adverse effect of vascular endothelial growth factor tyrosine kinase inhibitors, a meta-analysis of randomized clinical trials (P6.098)

Genomic alterations to refine prognostication of patients with metastatic renal cell carcinoma.

626 Background: The IMDC risk score is a valid and simple tool to prognosticate patients (pts) with metastatic renal cell carcinoma (mRCC). Some non-VHL common genomic alterations may be associated with outcomes. We therefore assessed the prognostic value of most commonly mutated genes in mRCC beside VHL overall, and within IMDC risk groups. Methods: We identified patients treated at Dana-Farber Cancer Institute (n = 65) or part of TCGA (n = 33) who had genomic data available and were treated with first line vascular endothelial growth factor tyrosine kinase inhibitors. Information on genomic alterations (GA) focused on PBRM1, BAP1, SETD2, KDM5C and TP53 was extracted. Cox regression was performed to assess the association of each GA with overall survival (OS), adjusting for IMDC risk groups and age. Results: Overall, 98 pts were identified. 96/98 pts had clear-cell histology. Pts distribution by IMDC risk groups was: 7% good, 58% intermediate, 27% poor and 8% unknown. Mutation rates were 27% PBRM1, 17% BAP1, 29% SETD2, 9% KDM5C and 8% TP53. In multivariable models, there was an association between GA and worse OS for BAP1 and BAP1 or TP53 combined (Table). When stratified by IMDC risk groups, GA in BAP1 or TP53 was associated with shorter median OS in poor risk pts [12.1 mo (95%CI 8.3- 24.0) v. 27.6 mo (95%CI 18.9- 53.4), aHR 4.64 (95%CI 1.32-16.4), p = 0.017] and a trend toward worse median OS in intermediate risk pts [20.5 mo (95%CI 7.4-54.6) v. 36.3 mo (95%CI 21.1, NR), aHR 2.11 (95%CI 0.94-4.74)] compared to pts without GA in BAP1 or TP53. Too few death events were observed in good risk pts to assess the prognostic value of GA in BAP1 or TP53. Conclusions: GA in BAP1 or TP53 are prognostic in mRCC and further discriminate pts with distinct outcomes within IMDC risk groups. Validation in larger dataset is ongoing. [Table: see text]

Association of age and sex with mortality following adjuvant therapy for renal cell cancer (RCC): Subgroup analysis of the ASSURE (E2805) trial.

575 Background: The benefit of vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) as adjuvant therapy for RCC remains a subject of controversy. Given the uncertain risk-benefit ratio, identifying subgroups expected to derive benefit or harm from therapy could lead to a more precise approach to therapy. Because of known sex-differences in the pharmacokinetics and tissue distribution of VEGF-TKIs, we assessed the interaction of age and sex on treatment outcomes among patients in the phase III ASSURE trial (Adjuvant Sorafenib or Sunitinib for Unfavorable RCC). Methods: ASSURE included 1,943 patients with ≥ pT1b resected RCC. There was no OS or DFS benefit with adjuvant sunitinib or sorafenib relative to placebo. In this post-hoc subgroup analysis of age and sex based on the median age of 56 years, Cox regression computed hazard ratios (HR) and 95% confidence intervals (CIs) for OS and DFS with sunitinib or sorafenib compared to placebo across age- and sex-specific strata (males ≤ 56 years [n = 689], males &gt; 56 years [n = 620], females ≤ 56 years [n = 317], and females &gt; 56 years [n = 317]). Models were adjusted for race, histology, and UISS risk group. A 3-way interaction term was calculated for sex, age, and treatment. Results: Treatment with sunitinib was associated with increased mortality among women &gt; 56 years (sunitinib vs placebo [HR OS 2.38; 95% CI, 1.39-4.07]), but not in women ≤ 56 years or in men of any age. Similarly, among women &gt; 56 years, the risk of disease recurrence was increased with sunitinib relative to placebo (HR DFS 1.53; 95% CI, 1.03-2.28). There were no statistically significant differences in OS or DFS associated with sorafenib (women &gt; 56 years: HR OS 1.50, 95% CI, 0.83-2.71; HR DFS 1.23, 95% CI, 0.81-1.89). The 3-way interaction between age, sex, and sunitinib treatment on mortality was statistically significant (p = 0.0166). Conclusions: Adjuvant sunitinib after nephrectomy was associated with increased mortality among older women, which may be explained by increased risk of RCC recurrence. These findings, if validated, highlight the importance of considering sex and age on VEGF-TKI treatment outcomes, future study designs, and RCC tumor biology. Clinical trial information: NCT00326898.

Phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma.

364 Background: Sorafenib has been the only FDA-approved medication for inoperable HCC (iHCC) as first line. Agents with better tolerability and potential to improve progression-free-survival (PFS) are needed. Tivozanib (TIVO) is an inhibitor of vascular endothelial growth factor (VEGF) tyrosine kinase, inhibiting angiogenesis critical in HCC. Methods: This is a phase 1b/2 study with HCC patients (pts) having a measurable disease, Child-Pugh class A, and no prior systemic therapy. Phase 1b portion followed a modified 3 + 3 design; phase 2 portion was a two-stage, single arm, un-blinded study. Adverse events were categorized based on CTCAE, and tumor imaging was assessed per RECIST. Results: At 3 centers with IRB approval, 21 eligible pts were enrolled. In phase 1b, 8 pts were enrolled at a starting dose of 1mg once daily q21days with one week off. Upon escalation to 1.5mg, two pts had dose limiting toxicities (DLTs, grade 3 mucositis and hypertension) and came off study without completing the DLT period. The dose of TIVO was de-escalated to 1 mg, and the accrual of remaining patients to phase 2 portion occurred at 1 mg. In a total of 19 pts, median follow up was 16.9 months (mo). The primary endpoint of median PFS was 5.5 mo. Partial response (PR) was seen in 4/19 (21%) and stable disease (SD) in 8/19 (42%): disease control rate was 63%. Overall survival (OS) at 6 and 12 mo was 58% and 25%. Median OS was 7.5 mo. Three pts have remained on TIVO for &gt; 2 years. Viral loads of hepatitis B and C remained stable during the study. Adverse events (AEs) related to TIVO included grade 3 fatigue (15.7%), decreased appetite (5.3%), pulmonary embolism (5.3%), hand-foot syndrome (5.3%), elevated LFT (10.5%), and grade 4 hypertension (5.3%). Conclusions: TIVO is tolerable at 1 mg in iHCC. In few pts, TIVO had deep and durable responses. Biomarker driven studies of TIVO in the context of immunotherapy are warranted. Acknowledgment: We appreciate support from NCCN. Clinical trial information: NCT01835223.

Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment. High-dose interleukin-2 (HDIL-2) therapy remains a reasonable treatment option in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and have minimal comorbid conditions. In the near future, these agents are likely to be surpassed by cabozantinib and by combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab. Independent review has recently confirmed superiority of first-line cabozantinib over sunitinib in a phase 2 trial of 157 patients with intermediate or poor risk mccRCC (progression-free survival [PFS] 8.6 vs 5.3months, hazard ratio [HR] 0.48, p = 0.0008). In a separate study of 1096 patients treated with either upfront sunitinib or the combination of nivolumab and ipilimumab, those with intermediate and poor risk had significant improvement in both PFS (11.6 vs 8.4months, HR 0.82, p = 0.0331) and OS (not reached vs 26months, p < 0.0001). Responses were greater in patients with positive programmed death receptor ligand-1 (PD-L1) tumor staining, and pending regulatory approval may become standard of care in untreated patients with intermediate to poor risk disease with positive PD-L1 status. This likely represents the beginning of additional novel immunotherapy combinations for the first-line treatment of mccRCC.

Advances in the Treatment of Metastatic Renal Cell Carcinoma.

The treatment landscape for metastatic renal cell carcinoma has constantly been in flux. In 2005, with the advent of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy, the standard of care shifted to agents such as sunitinib and pazopanib. However, more recently there have been datasets, suggesting that next-generation TKIs such as cabozantinib may play an important role in therapy. Furthermore, immunotherapy has had resurgence with the FDA approval of nivolumab with ipilimumab. In the current chapter, we attempt to contextualize available frontline therapies for metastatic renal cell carcinoma with a focus on the CABOSUN and CheckMate 214 clinical trials.

Therapeutic Effect of Long-Term Epidural Block in Rats with Pregnancy Induced Hypertension

Background Pregnancy induced hypertension (PIH) causes a variety of systemic disorders that negatively affect the maternal placenta and fetal growth. Epidural sympathetic block elicits symptoms of decreased blood pressure. This study was designed to determine the therapeutic effect of long-term epidural block in rats with PIH. Methods Forty healthy pregnant Sprague Dawley rats were randomized into four groups with each group consisting of 10 rats. On gestation day (GD) 14, rats in control group underwent a sham procedure; rats in RUPP group were operated on to obtain reduced uterine perfusion pressure (RUPP); rats in RUPP plus normal saline (NS) group were also subjected to the RUPP procedure and underwent epidural block with 25 μl normal saline twice daily until delivery; rats in RUPP plus epidural block (EB) group were treated as those in RUPP plus NS group except that an epidural block with 25 μl of 0.125% bupivacaine was administered two times per day until delivery. On GD 20, blood pressure was measured in all groups before delivery, and blood samples were collected in order to quantify the serum concentrations of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase 1 (sFlt-1). Results The mean arterial pressure (MAP) of rats in RUPP group (147.6 ± 6.0 mmHg) was markedly increased when compared with control group (80.8 ± 4.6 mmHg) (p < 0.05). The MAP of rats in RUPP plus EB group (114.4 ± 7.2 mmHg) was clearly decreased in contrast with RUPP group but was still higher than in control group (p < 0.05). The variation of fetal weight in all groups followed a similar trend to that of MAP. However, there were no significant differences between control group and RUPP plus EB group with respect to placental weight (p = 0.186). Variation in MAP was positively correlated with the expression of sFlt-1 in each group but was negatively correlated with VEGF. Conclusion This study demonstrates that long-term epidural block decreases blood pressure in PIH rats and improves the serum concentrations of VEGF and sFlt-1. Taken together, long-term epidural block may have a potential role in PIH treatment.

Transplantation of Human Umbilical Cord Blood Mononuclear Cells Attenuated Ischemic Injury in MCAO Rats via Inhibition of NF-κB and NLRP3 Inflammasome

Accumulated evidence displayed that transplantation of stem cells may be a promising approach for the treatment of neurological disorders. However, the underlying mechanisms remain to be well elucidated. Moreover, some investigators cannot reproduce similar results as the previous. The present results showed that transplantation of fresh human umbilical cord blood mononuclear cells (cbMNCs) attenuated ischemic damage in middle cerebral artery occlusion (MCAO) rats, accompanied with improvement of neurologic deficits, learning and memory function. The increase in neovascularization and related molecules such as vascular endothelial growth factor (VEGF), Angiopoietin-1 (Ang-1) and endothelium-specific receptor tyrosine kinase 2 (Tie-2) in the injured brain was observed in cbMNCs-treated rats. Moreover, nuclear factor-κB (NF-κB) activation and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome were also inhibited by the cells graft, resulting in reduction in cleaved caspase-1 and mature interleukin-1β (IL-1β) content. These results suggested that the protective actions of the cells on the cerebral ischemia may be related to inhibition of NF-κB pathway and NLRP3 inflammasome.

Pro-angiogenic effects of Ilexsaponin A1 on human umbilical vein endothelial cells in vitro and zebrafish in vivo

BackgroundIlexsaponin A1 is the major bioactive ingredient of Ilex pubescens Hook. et Arn. This plant has been conventionally used in Traditional Chinese Medicine for the treatment of cardiovascular diseases including stroke, coronary arterial disease, and peripheral vascular diseases. PurposeTo investigate the pro-angiogenic effect of Ilexsaponin A1 and its mechanism of action. Study designHuman umbilical vein endothelial cells (HUVECs) and transgenic zebrafish Tg(fli1:EGFP) were employed as an in vitro and in vivo model respectively. MethodsPro-angiogenic effects of Ilexsaponin A1 were examined by assessing endothelial cell proliferation, migration, invasion and tube formation. The mechanism of pro-angiogenic effects was investigated by measuring the expression level of various signalling proteins. Furthermore, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor II (VRI)-induced vascular insufficient transgenic zebrafish model was used to confirm the results of the HUVECs results in vivo. ResultsIlexsaponin A1 significantly promoted cell proliferation, migration, invasion and tube formation in HUVECs, and rescued blood vessel loss in VRI-induced vascular insufficient zebrafish. Ilexsaponin A1 upregulated p-Akt, p-mTOR, p-Src, p-FAK, p-MEK, and p-Erk1/2 in HUVECs. ConclusionThis study showed that Ilexsaponin A1 exhibits pro-angiogenic activity in HUVECs and VRI-induced vascular insufficient zebrafish, probably by activating Akt/mTOR, MAPK/ERK and Src- and FAK-dependent signalling pathways. The findings suggest that Ilexsaponin A1 and probably I. pubescens, a major source of Ilexsaponin A1, could be developed as a potential therapeutic agent for preventing or treating cardiovascular diseases and/or other diseases related to vascular insufficiency.

Proton Pump Inhibitors and Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma.

Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and can affect the optimal absorption of concomitant oral medications, such as vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs). The purpose of this study was to investigate the effect of PPI use on survival in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. We conducted a pooled analysis of mRCC patients treated in phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. We identified 2188 patients treated with sunitinib (n= 952), axitinib (n= 626) or sorafenib (n= 610), of whom 120 were PPI users. Overall, PPI users showed similar overall survival compared with non-PPI users (hazard ratio [HR], 1.051; 95% confidence interval [CI], 0.769-1.438; P= .754; median, 24.1 vs. 21.3 months). Similarly, progression-free survival (HR, 1.016; 95% CI, 0.793-1.301; P= .902; median, 5.5 vs. 8.0 months) and objective response rates (23.3% vs. 27.4%; P= .344) were not different between PPI users and nonusers. These findings were consistent across International mRCC Database Consortium risk groups and according to line of therapy. Adverse events were similar between PPI users and nonusers. We showed that PPI use does not appear to negatively affect the efficacy and safety of select VEGF-TKIs in patients with mRCC. Documentation of concomitant medications and patient education on potential drug interactions are critical for optimizing the use of oral cancer-targeting therapy.

Proton pump inhibitors (PPIs) and survival outcomes in patients with metastatic renal cell carcinoma (mRCC).

493 Background: PPIs are potent inhibitors of gastric acid secretion and can affect the bioavailability of orally administered cancer targeting therapies, such as vascular endothelial growth factor tyrosine-kinase inhibitors (VEGF-TKIs). Smaller preclinical and clinical studies have attempted to assess the interaction between VEGF-TKIs and PPIs in patients with advanced cancers; however, these studies are limited and larger analyses from rigorous datasets have been lacking. We investigate the impact of PPI use on survival in patients with mRCC treated with oral VEGF-TKIs. Methods: A pooled analysis of mRCC patients treated on phase II and III clinical trials was conducted. The primary outcome was to assess overall survival (OS) between PPI users, defined as patients receiving a PPI at baseline, compared to non-PPI users. Secondary outcomes included progression-free survival (PFS), objective response rates (ORR), and adverse events. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. Results: Our cohort consisted of 2,188 patients treated with sunitinib (n = 952), axitinib (n = 626), or sorafenib (n = 610), of whom 120 were PPI users. Overall, PPI users demonstrated similar OS compared to non-PPI users (median 24.1 vs. 21.3 months, adjusted hazard ratio [aHR] 1.051, 95% confidence interval (CI) 0.769-1.438, p = 0.754). Similarly, PFS (5.5 vs. 8.0 months, aHR 1.016, 95% CI 0.793-1.301, p = 0.902) and ORR (23.3% versus 27.4%, p = 0.344) were not different between PPI users and non-users. These findings were consistent across International mRCC Database Consortium risk groups and by line of therapy. Adverse events were also similar between both groups. Conclusions: In this analysis, we demonstrate that PPI use does not appear to negatively impact the efficacy of VEGF-TKIs in mRCC patients treated in the targeted therapy era. Given the current landscape expanding to include more self-administered treatments, documentation of concomitant medications, and patient education on potential drug interactions are critical for optimizing the utilization of oral cancer targeting therapy.

VEGF, Flt-1, and microvessel density in primary tumors as predictive factors of colorectal cancer prognosis.

Angiogenesis in the primary tumor is known to be necessary for tumor progression in adenocarcinomas of the colon. However, whether angiogenesis in the primary tumors of patients with colorectal cancer affects their prognosis has yet to be fully elucidated. The aim of the present study was to assess the association between selected pathoclinical parameters and overall survival of resectable colorectal cancer patients with the expression of angiogenesis-promoting factors, including vascular endothelial growth factor (VEGF) and Fms-like tyrosine kinase receptor (Flt-1), and microvessel density (MVD) in the primary tumor. VEGF and Flt-1 expression were assessed, as well as MVD (with anti-CD34) by immunohistochemistry in 139 archived primary colorectal cancer tissue samples. These results were compared with the overall survival of the patients and potential prognostic pathoclinical parameters. A higher MVD in the tumors expressing Flt-1 (P=0.04) was identified. However, there was no correlation between the pathoclinical parameters of colon cancer and Flt-1 expression, VEGF expression, or MVD in the tumor. Furthermore, the intensity of VEGF expression, Flt-1 expression and tumor MVD did not correlate with the overall survival of the patients. Therefore, although increased expression of VEGF and Flt-1 was correlated with an increased expression of MVD in the primary tumors of resectable colorectal cancer patients, these factors were not correlated with prognostic pathoclinical factors and overall survival.

1436PD - Risk of serious adverse events (SAEs) and fatal adverse events (FAEs) with sorafenib use in patients with solid cancers: a meta-analysis of phase 3 RCTs

Sorafenib is a commonly used vascular endothelial growth factor-tyrosine kinase inhibitor in a variety of cancers. There are concerns about the increased risk of SAEs and FAEs with sorafenib. We performed an up-to-date meta-analysis of all phase 3 randomized controlled trials (RCTs) of sorafenib to quantify the increased risk of SAEs and FAEs. We carried out a systematic search on PubMed for studies published in English. Eligibility criteria included phase 3 RCTs of solid tumors comparing sorafenib, alone or in combination with non-targeted chemotherapy (Sorafenib arm) versus placebo or non-targeted chemotherapy (control arm). Data on SAEs and FAEs for both the arms were extracted from each study and pooled to determine the overall incidence, relative risks (RRs) and 95% Confidence Intervals (CIs). Of 471 studies identified, a total of 12 phase 3 RCTs involving 6,797 solid cancer patients comparing sorafenib with control met the eligibility criteria and included in this meta-analysis. 8 RCTs compared sorafenib alone with a placebo and 4 RCTs compared sorafenib plus chemotherapy with chemotherapy plus placebo. The RCTs involved Hepatocellular carcinoma (HCC, n = 5), Melanoma (n= 2), non-small cell lung cancer ( n = 2), pancreatic cancer, renal cell carcinoma and thyroid cancer ( n = 1 each). The overall incidence of SAEs and FAEs with sorafenib were 24.5% (95% CI: 16.0%-35.5%) and 1.6% (95% CI: 0.7%- 3.3%) respectively. Compared with control, sorafenib use significantly increased the risk of both SAEs ( RR : 1.51, 95% CI: 1.20-1.92, P < 0.001) and FAEs ( RR : 1.84, 95% CI: 1.29-2.64, P = 0.001). This association varied significantly with cancer types ( P = 0.001) and approval status ( P = 0.018) for SAEs but no evidence for heterogeneity was found for FAEs. The risk for SAEs was significantly higher for HCC (RR: 2.20, 95%CI: 1.18-4.10, P = 0.013) and non-approved use of sorafenib (RR: 1.68, 95% CI: 1.24-2.29, P = 0.001). This meta-analysis of phase 3 RCTs demonstrates an increased risk of SAEs and FAEs with sorafenib use in patients with solid cancers. Special vigilance is recommended while using sorafenib in non-approved settings.

Conditional survival of metastatic renal cell carcinoma patients treated with high-dose interleukin-2.

Conditional survival (CS) is a clinically useful prediction measure which adjusts a patient’s prognosis based on their duration of survival since initiation of therapy. CS has been described in numerous malignancies, and recently described in patients with metastatic renal cell carcinoma (mRCC) who received vascular endothelial growth factor tyrosine kinase inhibitor (VEGFTKI) therapy. However, CS has been not reported in the context of mRCC treated with high-dose interleukin-2 therapy (HDIL-2). A total of 176 patients with histologically confirmed metastatic clear cell RCC (mccRCC) treated with HDIL-2 at the University of Utah Huntsman Cancer Institute from 1988–2012 were evaluated. Using the Heng/IMDC model, they were stratified by performance status and prognostic risk groups. Two-year CS was defined as the probability of surviving an additional two years from initiation of HDIL-2 to 18 months after the start of HDIL-2 at three-month intervals. The median overall survival (OS) was 19.9 months. Stratifying patients into favourable (n = 35; 20%), intermediate (n = 110; 63%), and poor (n = 31; 18%) prognostic groups resulted in median OS of 47.5 (HR 0.57, 95% CI 0.35–0.88, p = 0.0106 versus intermediate), 19.6 (HR 0.33, 95% CI 0.10–0.33, p < 0.0001 versus poor), and 8.8 (HR 5.34, 95% CI 3.00–9.62, p < 0.0001 versus favourable) months respectively. Two-year overall CS increased from 43% at therapy initiation to 100% at 18 months. These results have significant ramifications in prognostication. Furthermore, it is important when counseling patients with mccRCC who have completed treatment with HDIL-2 and are in active follow-up.

Effect of Metformin Use on Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma

IntroductionObservational studies have suggested that metformin use is associated with favorable outcomes in several cancers. For renal cell carcinoma (RCC), data have been limited. Therefore, we investigated the effect of metformin on survival in metastatic RCC (mRCC) using a large clinical trial database. Patients and MethodsWe conducted a retrospective analysis of patients with mRCC in phase II and III clinical trials. The overall survival (OS) in metformin users was compared with that of users of other antidiabetic agents and those not using antidiabetic agents. Progression-free survival, objective response rate, and adverse events were secondary endpoints. Subgroup analyses were conducted after stratifying by class of therapy, type of vascular endothelial growth factor tyrosine kinase inhibitors, and International Metastatic RCC Database Consortium (IMDC) risk groups. ResultsWe identified 4736 patients with mRCC, including 486 with diabetes, of whom 218 (4.6%) were taking metformin. Metformin use did not affect OS when compared with users of other antidiabetic agents or those without diabetes. Furthermore, metformin use did not confer an OS advantage when stratified by class of therapy and IMDC risk group. However, in diabetic patients receiving sunitinib (n = 128), metformin use was associated with an improvement in OS compared with users of other antidiabetic agents (29.3 vs. 20.9 months, respectively; hazard ratio, 0.051; 95% confidence interval, 0.009-0.292; P = .0008). ConclusionIn the present study, we found a survival benefit for metformin use in mRCC patients treated with sunitinib. Clinical and preclinical studies are warranted to validate our results and guide the use of metformin in the clinic.