Growth Factor Tyrosine Research Articles

Predicting Preeclampsia Pregnancy Termination Time Using sFlt-1

BackgroundThe aim of this study was to determine the usefulness of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in predicting the time for pregnancy termination in pregnant women with known preeclampsia (PE) onset.MethodsForty-four pregnant women diagnosed with PE (22 weeks 0 days to 33 weeks 6 days gestation) were included in this study. The levels of sFlt-1 and PlGF, and the sFlt-1/PlGF ratio were compared between the women that delivered in <24 h (T group) and those that delivered in more than 24 h (P group), and between women that delivered in <1 week (T group) and those that delivered in more than 1 week (P group). Cutoff values were calculated for the three markers that were the most significantly correlated with predicting pregnancy termination at <24 h and <1 week.ResultsAmong sFlt-1, PlGF, and sFlt-1/PlGF, sFlt-1 was the most significantly associated with the timing of pregnancy termination. sFlt-1 cutoff values of 8682.1 pg/ml (AUC 0.71; 95%Cl, 0.5191–0.9052) and 7,394.5 pg/ml (AUC 0.78; 0.78, 95%Cl, 0.6394–0.9206) for delivery in <24 h and delivery within 1 week, respectively, were important predictive values. The positive predictive value for delivery within 24 h was 43.9%, with a sensitivity of 72.3% and specificity of 69.0%, when sFlt−1 was <8,682 pg/ml. A sFlt-1 level of 7,394 pg/ml or greater would result in delivery within 1 week, with a positive predictive value of 67.2%; the sensitivity was 79.0% and specificity was 72.0%.ConclusionThis study showed that sFlt-1 may be effective in predicting the timing of pregnancy termination. However, the number of cases was small and, thus, the results were not definitive. This finding should be researched further in order to predict the optimal timing of pregnancy termination in PE to reduce severe maternal complications.

PREGNANCY OUTCOMES IN WOMEN WITH EXTREMELY HIGH SFLT-1/PIGF RATIO: CASE SERIES

Preeclampsia (PE) is a multisystem disorder, usually defined as the development of hypertension and proteinuria after 20 weeks of pregnancy. The sFlt-1/PlGF ratio has been widely studied as a diagnostic and prognostic marker of preeclampsia and other manifestations of placental dysfunction. A sFlt-1/PlGF ratio greater than 85 for early PE, &lt;34 weeks of gestation suggests a high risk of PE requiring close clinical monitoring. Our main aim was to evaluate the maternal and perinatal outcomes of pregnancies with an extremely high sFlt-1/PlGF ratio. The analysis included data on placental growth factor and soluble fms-like tyrosine kinase serum levels, measured during 2017–2020 in 128 pregnant women. Here we present 8 cases of women with a numerical ratio greater than 850. In all 100% of cases, the signs of obstetric angiogenic catastrophe requiring imminent delivery developed soon. We observed a trend for worsening perinatal outcomes in women with an extremely high sFlt-1/PlGF of ≥850.

Ефективність превентивних методів їх комбінацій у профілактиці передчасних пологів

Prediction and prevention of premature birth is a significant problem of modern obstetrics. The use of ultrasound cervicometry and the index of placental angiogenesis for the prediction of premature birth is promising. The aim of the study was to investigate the effectiveness of cerclage, pessary, intravaginal progesterone or their combinations in the prevention of premature birth. A total of 292 pregnant women were examined. They were divided into several groups according to the results of the detection of cervical length and the level of the ratio between placental growth factor (PlGF) and fms-like tyrosine kinase (sFlt-1). Group I included women with a negative screening’ resuls. Other groups included women with a «short» cervix and disturbed placental angiogenesis. In group II, women with cervical cerlage were observed. In group III — used a pessary; Group IV — vaginal progesterone; V — cobined use of cerclage and pessary; and in VI — use of cerclage and vaginal progesterone. The pregnancy was completed at term in 159 patients, and 133 women had preterm delivery. Among patients who had positive miscarriage screening results, the use of preventive measures or combinations resulted in fairly equal results. However, the use of progesterone and cervical cerclage has shown the best efficacy. Some limitations in this study were the small sample size and the lack of information on the use of anticoagulants, disaggregants and tocolytics in the examined women.

DNA damage repair (DDR) pathway alteration in advanced renal cell carcinoma (RCC) is association with good progression-free survival with tyrosine kinase inhibitor (TKI) therapy.

346 Background: Alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may be as potential biomarkers for vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy in renal cell carcinoma. However, biologic significance and relevance to TKI targeted therapy in metastatic RCC are unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic RCC. Tumor and germline DNA were subject to targeted next generation sequencing across 642 genes of interest, including 60 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) DDR gene alterations present (Mut DDR); (2) wildtype (WT) DDR gene alterations present (WT DDR). Association between DDR status and therapeutic benefit was investigated separately for and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy. Results: Mut DDR were detected in 17/40 patients (42.5%). The most frequently DDR altered genes were TP53. For patients with TKI treatment, Mut DDR status was associated with superior progression free survival (log-rank p = 0.048), but not with superior overall survival (log-rank p = 0.39); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Mut DDR was 2.68 (95% CI: 0.96–7.46; p = 0.059). Conclusions: DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Dysfunction events in these genes may affect outcome with TKI therapy in adanced RCC, and these hypothesis-generating results deserve further study.

ASSET: Alternative schedule sunitinib in metastatic renal cell carcinoma (RCC)—Cardiopulmonary exercise testing (CPET).

300 Background: Sunitinib (SUN) is a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) approved for treatment of advanced RCC and high risk RCC after nephrectomy. Evidence suggests that a 2 week (wk) on, 1 wk off schedule (2/1) of SUN administration may be more tolerable than the standard 4 wk on, 2 wk off schedule (4/2). We investigated changes in cardiopulmonary function and related parameters over time in RCC patients treated with both schedules of SUN. Methods: Patients starting SUN for RCC, with KPS ≥80 and normal organ and marrow function, were enrolled and randomized 1:1 to schedule 4/2 or 2/1. Subjects were required to be able to walk and jog on a treadmill and to complete an acceptable CPET at baseline (BL). Primary endpoint was change in peak oxygen uptake (VO2peak) on both schedules at 12 wk from BL. Key secondary endpoints were change from BL to 12 wk in: left ventricular ejection fraction (LVEF), upper and lower body strength (1-RM), functional measures (chair stand, timed up-and-go [TUG], 6-minute walk test [6MWT], quality of life (QOL; FACT-Fatigue, FKSI-19), anxiety and depression (HADS) and exercise behavior (Godin Leisure Score). ANCOVA models controlling for baseline values were used to analyze the primary and secondary endpoints. Results: Between 11/20/2017 and 6/24/2019, 9 out of a planned 30 patients consented to participate at Duke. Two patients declined to participate and 7 patients were enrolled on study: 4 on Arm A and 3 on Arm B. All 7 patients completed the 12 wk study. Median age, BMI, and VO2peak were 65 yrs, 30.5 kg/m2, and 19.2 ml kg−1 min−1. We observed no difference in the primary endpoint of VO2peak between arms (p=0.84). We report BL to 12 wk change scores for all patients starting SUN (Table). In addition, mean change scores (SE) for QOL by FACIT-Fatigue and FKSI-19 were -2.88 (1.5) and 1.2 [9.8]; anxiety and depression by HADS 1.14 (1.3); and physical activity 1.14 (1.7). Conclusions: We observed non-significant declines in most measures of physical fitness and function during the first 12 wk of treatment with SUN. To our knowledge, this is the first reported study of these parameters in patients with RCC. Given that a VEGF TKI, alone and with an immune checkpoint inhibitor, remains a standard of care for metastatic ccRCC, studies should be undertaken to examine whether exercise training can prevent declines in physical fitness and function. Clinical trial information: NCT03109015 . [Table: see text]

Clinical value of serum VEGF and sFlt-1 in pernicious placenta previa

This study was designed to explore the expression and the diagnostic value of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in pernicious placenta previa (PPP) combined placental accreta/increta. A total of 140 PPP patients were enrolled and divided into two groups: 56 patients with placenta accreta/increta (PA group), and 84 patients without placenta accreta/increta (non-PA group). In the same period, 46 pregnant women without PPP who had undergone caesarean section were selected as controls. The levels of VEGF and sFlt-1 in serum were detected by enzyme-linked immunosorbent assay. Diagnostic efficiency of VEGF and sFlt-1 in serum were evaluated by receiver operating characteristics curve. It was found that both VEGF and sFlt-1 had diagnostic value for PPP and placenta accreta/increta combined PPP. In addition, the levels of VEGF and sFlt-1 could be used to distinguish placenta accreta from placenta increta. VEGF was negatively correlated with sFlt-1 in PPP patients. In summary, the levels of VEGF and sFlt-1 could be used as auxiliary indicators to diagnose PPP and distinguish between placenta accreta and increta. KEY POINTS The levels of VEGF and sFlt-1 could be used to distinguish placenta accreta from placenta increta. VEGF is negatively correlated with sFlt-1 in PPP patients. The levels of VEGF and sFlt-1 could be used as auxiliary indicators to diagnose PPP and distinguish between placenta accreta and increta.

Increasing efficiency of preterm birth prediction

Abstract. The disturbed placentation in a certain way plays an important role in the pathogenesis of great obstetric syndromes. Therefore, the possibility of using biochemical indicators of the level of placental growth factor (PlGF) and fms-like tyrosine kinase (sFlt-1) for predicting preterm labor is of great interest. The aim of the study was developing criteria for predicting preterm labor based on the combined use of ultrasound cervicometry and the concentration of PlGF and sFlt-1. Materials and methods. A total of 227 pregnant women were examined, 190 of whom had preterm birth. Group I included 48 women whose pregnancy completed at 23 to 27 weeks. In group II, 142 women with prematurity in terms of 28 to 36 weeks were observed. Group III included 37 women with a healthy pregnancy, which completed at 38–41 weeks. All patients involved in the study underwent ultrasound cervicometry on a Voluson 730 (GE Healthcare, USA) at 16 weeks, and also the concentration of PlGF and sFlt-1 in blood serum by electrochemiluminescence immunoassay using a Cobas e411 analyzer was studied (Roche diagnostics, Switzerland). Results. The study revealed a significant (p &lt; 0.001) decrease in the average concentration of PlGF in the blood serum by 65 % associated with an increased level of sFlt-1 by 93% in women with early termination of pregnancy – 23–27 weeks (group I) in relation to women with a healthy pregnancy. In women with preterm birth at 28–36 weeks of gestation (group II), a similar trend of changes was observed: the PlGF level significantly (p = 0.014) decreased on average by 68 % in relation to women with a healthy pregnancy. In women of group I, the value of the sFlt-1 / PlGF ratio exceeded (p &lt; 0.001) the values of patients in group III by 14 times. But an even more pronounced imbalance of angiogenic factors was observed in women of group II – on average 16 times. Two main markers were used to predict premature birth: shortening of the cervix according to ultrasound cervicometry data of less than 30 mm, as well as the sFlt-1/PlGF ratio of more than 50 conv. units. The odds ratio (OR) of preterm birth in the case of using only the length of the cervix was 34,133 (95 % confidence interval – 12.308–94.660). OR in the case of combined use of cervicometry data and angiogenesis variables was 148.750 (95 % confidence interval – 33.243–665.593). Conclusion. Thus, the use of an additional biochemical marker significantly improved the accuracy of preterm labor prediction.

No association between early antiretroviral therapy during pregnancy and plasma levels of angiogenic factors: a cohort study

BackgroundEarly antiretroviral therapy (ART) during pregnancy has dramatically reduced the risk of perinatal HIV transmission. However, studies have shown an association between premature delivery and the use of ART during pregnancy (particularly protease inhibitor (PI)-based therapies), which could be explained by placental dysfunction. The objective of this study was to evaluate the association of ART (class, duration of exposure and time of initiation) with placental function by using angiogenic factors placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) as biomarkers.MethodsClinical and biological data from 159 pregnant women living with HIV were analyzed. Levels of each biomarker were measured in the first and second trimester of pregnancy. After logarithmic transformation, we compared these using generalized estimating equations according to (a) the type of ART; (b) the duration of exposure to ART; and (c) the time of initiation of ART.ResultsAfter adjusting for variables such as ethnicity, maternal age, gestational age, body mass index, parity, smoking status, and sex of the fetus, we found no significant association between the class of ART (PI-based or not) and serum concentrations of PlGF or sFlt-1. Furthermore, no significant association was found between biomarker levels and the duration of ART exposure or the timing of ART initiation (pre- or post-conception).ConclusionsThis study suggests that first and second trimester angiogenic factor levels are not significantly associated with ART, regardless of the duration or type (with or without PI). These observations seem reassuring when considering the use of ART during early pregnancy.

223. CD163-mediated hemoglobin-scavenging system, haptoglobin phenotype and preeclampsia risk

Introduction Preeclampsia (PE) is a multisystemic disorder which complex pathophysiology involves both oxidative stress and endothelial dysfunction as key factors. The CD163-mediated haptoglobin (HP) hemoglobin-scavenging system has been proposed as an important pathway for diverse disease states due to its anti-inflammatory and pro-angiogenic effects. The human HP locus is polymorphic, yielding three distinct phenotypes characterized by different antioxidant and pro-angiogenic properties. Objective We aimed to determine whether HP phenotype was associated with PE risk and to assess the relationship between HP phenotype and first-trimester concentrations of HP, soluble form of the hemoglobin-scavenger receptor CD163 (sCD163), placental growth-factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). Methods Case-control study of 452 pregnant women selected from a prospective cohort of singleton pregnancies that underwent first-trimester aneuploidy screening in a routine care low-risk setting. The study sample included 204 women who subsequently developed PE and 248 women with normal pregnancies who were matched for gestational age. HP phenotypes were determined by polyacrylamide gel electrophoresis (PAGE). First-trimester serum PlGF, sFlt-1 and HP concentrations were determined by automated electrochemiluminescence/immunoturbidimetric methods (Roche Diagnostics), while sCD163 levels were determined by enzyme-linked immunosorbent assay (R&D Systems). Results Although HP phenotype alone did not affect overall PE risk, we found significantly higher HP concentrations between preeclamptic and normal women with HP2-1 (122.0/107.1 mg/dL, P = 0.01) and HP2-2 (101.0/82.0 mg/dL, P = 0.001) phenotypes. HP2-2 phenotype was also associated with high levels of sCD163 (472.6/418.6 ng/mL, P = 0.02) that were significantly higher among women who subsequently developed PE (511.5/430.8 ng/mL, P = 0.04). Finally, PlGF and sFlt-1 levels presented significantly different patterns between preeclamptic and normal pregnancies, being the strongest association in women with HP2-1 and HP2-2 phenotypes. Conclusion These findings suggest that HP phenotype could be useful in combination with first-trimester inflammatory and angiogenic markers to identify subsets of women with increased risk of PE development since early pregnancy.

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.

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.

P 12 Treatment of very preterm preeclampsia by heparin-mediated extracorporeal LDL-Precipitation (H.E.L.P) apheresis results in favorable fetal outcome and weight gain without lowering soluble FMS-like Tyrosine Kinase-1 (sFlt-1) – The Freiburg preeclampsia HELP-Apheresis study

Background Preeclampsia (PE) is a life-threatening complication of pregnancy. To date the only therapy of severe PE consists in timely delivery of the fetus. In PE a deranged lipoprotein metabolism considered to impair endothelial function is observed. Heparin-mediated extracorporeal LDL-precipitation (H.E.L.P.)-apheresis is an established method for lipoprotein removal and has already been successfully applied in PE. Recently, angiogenetic and anti-angiogenetic factors like placenta growth factor (PlGF) and soluble Fms-like tyrosine kinase-1 (sFlt-1) are discussed as risk factors and removal of sFlt-1 by dextran sulfate column (DCS) apheresis is suggested as specific cure for PE. By contrast, H.E.L.P.-apheresis does not remove sFlt-1. The present clinical trial revaluates the clinical efficacy of H.E.L.P.-apheresis in PE with focus on sFlt-1 and PlGF. Methods Open pilot study assessing the prolongation by H.E.L.P.-apheresis in 6 women (30–41 years) with very preterm PE (24 + 4 to 27 + 0 gestational weeks (GW)) (NCT01967355) compared to a historic untreated PE-group matching treated patients by GW at admission ( Results Women with PE received apheresis 2–6 times. In treated patients the average time from admission to birth was 15.0 days compared to 6.3 days in controls (p = 0.027). In treated patients the prolongation of gestation by apheresis converted to a mean fetal weight gain of 101 grams (p = 0.029). Lung maturation could be induced in all treated cases and all children could be dismissed in healthy condition. Apheresis significantly reduced levels of total cholesterol (−33%), triglycerides (−43%), and LDL-cholesterol (−44%). However, sFlt-1 was not reduced but levels significantly increased initially by H.E.L.P.-apheresis and dropped to almost pre-apheresis levels before next apheresis, with sFlt-1/PLGF ratio remaining unaffected. Conclusions H.E.L.P.-apheresis proved again to be a safe therapeutic option to prolong pregnancies in PE and results in significant fetal weight gain. However, H.E.L.P.-apheresis does not reduce circulating sFlt-1 levels. Thus, reducing lipids and other pro-inflammatory factors may be more relevant than reducing circulating sFlt-1 to improve outcome in PE.

Angiogenesis Factors and Uterine Artery Doppler Ultrasound Resistance Index and Pulsatility Index in Pregnancies with High-Risk of Preeclampsia

Background: Endothelial dysfunction in the maternal circulation is an early finding during preeclampsia. Early diagnosis is very important to protect from maternal and neonatal morbidity we aimed to investigate the Vascular Endothelial Growth Factor (VEGF), anti-angiogenic VEGFR-1 (sVEGFR-1) or soluble FMS-like tyrosine kinase-1 (sFlt-1), and angiogenic PlGF using uterine artery Doppler ultrasonography and to evaluate placental vascular and fetomaternal blood flow changes.Methods: This cross-sectional study included a total of 64 pregnant women aged between 15 and 40 years who were in their 20 to 24 weeks of gestation and who were at a risk of developing preeclampsia. The patients were reexamined after delivery and divided into two groups according to those who developed preeclampsia/IUGR (n=9/7) and those who did not (n=48). We compared the VEGF, sFlt1 and PlGF using uterine artery Doppler ultrasonography changes.Results: Univariate analysis results of potential factors for preeclampsia were insignificant except age (p=0.047) and body mass index (0.004). In our ROC curve, the pvalue was found to be significant.Conclusion: Our study results demonstrated that biochemical and radiologic markers did not give any clues for early diagnosis at the 20 to 24 weeks of gestation.

Association of first-trimester angiogenic factors with placental histological findings in late preeclampsia

Objective To explore in women with late preeclampsia (PE) the association between maternal levels of angiogenic/antiangiogenic factors in the first trimester of pregnancy and histological findings attributable to placental underperfusion (PUP). Methods A nested case-control cohort study was conducted in 73 women with pregnancies complicated by late PE (⩾34 weeks at delivery) matched with controls. First trimester uterine artery Doppler (UtA); maternal levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were retrieved. Placentas were histologically evaluated using a hierarchical and standardized classification system. One-way ANOVA with linear polynomial contrast or linear-by-linear association test was performed to test the hypothesis of a linear association across study groups (controls, PE without PUP and PE with PUP). Results In 54 (74%) placentas, 89 placental histological findings qualifying for PUP were found. Across study groups, significant values were observed in maternal levels of PlGF (MoM values: 1.53, 1.41 and 1.37; p Discussion In late-onset PE an imbalance of circulating angiogenic and anti-angiogenic factors already present at 8–10 weeks of pregnancy was associated with histological findings reflecting placental insufficiency. An early first trimester screening by angiogenic factors might help to identify patients with placental involvement among late PE cases. Conclusion In late-onset preeclampsia, first-trimester uterine Doppler and circulating levels of angiogenic/antiangiogenic factors are associated with placental underperfusion.

A clinical study of interstitial lung disease induced by TKI concurrent radiotherapy

Objective To investigate the influence of radiotherapy with concurrent oral epidermal growth factor receptor (EGFR) and tyrosine kinase inhibitor (TKI) for advanced non-small cell lung cancer (NSCLC) on the incidence of interstitial lung disease (ILD), and to analyze the risk factors for the pathogenesis of ILD. Methods The incidence of ILD in 72 patients with NSCLC who were admitted to Department of Radiotherapy Oncology of Lu'an Hospital of Traditional Chinese Medicine and treated with radiotherapy with concurrent oral EGFR-TKI from January 2010 to January 2014 was analyzed retrospectively, and some patients were selected as controls to compare the difference in the incidence of ILD between the TKI concurrent radiotherapy group and the other groups. The univariate analysis using chi-square test and multivariate logistic regression analysis were applied to analyze the risk factors for the incidence of ILD in the patients receiving TKI concurrent radiotherapy. Results The TKI concurrent radiotherapy group had a significantly higher incidence rate of ILD than the palliative chemotherapy group, single TKI group, and concurrent chemoradiotherapy group (19.4% vs. 2.5%, 12%, and 7.5%, P=0.045). The multivariate regression analysis showed that male sex, long-term smoking, underlying lung disease, tumor volume>5 cm, and application of conventional radiotherapy were the risk factors for the pathogenesis of ILD in the TKI concurrent radiotherapy group. Conclusions Radiotherapy with concurrent TKI for advanced NSCLC may increase the incidence of ILD. Key words: Tyrosine kinase inhibitors; Interstitial lung disease; Lung neoplasms/radiotherapy; Lung neoplasms/chemotherapy

Geographic tongue (benign migratory glossitis) in a patient treated with Pazopanib for metastatic renal cell carcinoma

Abstract Significant advances in the last decade have been made in the management of patients with metastatic renal cell carcinoma (RCC) with targeted therapies, however the toxicities from these new agents are still being discovered. Vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors (TKI) have been associated with many oral mucocutaneous toxicities including the development of Geographic Tongue (GT). We present the first reported case of GT in a 58 year old male patient being treated with Pazopanib as a monotherapy for metastatic RCC which resolved after cessation of the medication during an acute infection. However, GT is a benign condition that often does not require dose reduction or discontinuation of Pazopanib. Although it can be alarming to patients, treatment is focused on reassurance of the benign nature of the disease to patients and the ability to continue on treatment. This case illustrates the continued discovery of new toxicities during a time in which we are seeing rapid development of new therapies. We suspect GT is a class effect of VEGF inhibitors and TKIs due to their disruption of buccal mucosa homeostasis and although GT is considered rare it is likely underreported in the literature.

Association of hand-foot syndrome (HFS), treatment dose reductions (TDRs), and outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs).

4580 Background: HFS is a common toxicity of VEGF TKIs, often requiring TDRs. Correlation between HFS, in the context of TDRs, with survival outcomes has not been reported in mRCC. Methods: From a ...

Incidence and severity of hypothyroidism and survival outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs).

e15580 Background: Thyroid dysfunction is a common adverse effect of VEGF TKIs. There are conflicting reports on survival benefit in association with hypothyroidism. Moreover, severity of hypothyro...

Abstract IA10: Molecular testing to personalized EGFR and ALK inhibitor therapies in lung cancer.

Abstract The concept of “oncogene addiction” led to the realization that not all patients respond equally to each targeted therapy, and best therapeutic results are obtained when the therapy is given to patients whose tumor harbors the “driver mutation” that is sensitive to the drug. In lung cancer, two currently approved new therapies require patient selection based on the presence of sensitizing epidermal growth factor (EGFR) tyrosine kinase domain (TKD) mutation or the anaplastic lymphoma kinase (ALK) gene rearrangement. EGFR mutations occur almost always in lung cancer of adenocarcinoma histology, and uncommonly in other histologies except when they also contain adenocarcinoma component. They are more common in East Asian (~45%) compared to Caucasian (~15-25%) patients, in never/light smokers and in female patients. Ninety percent of EGFR sensitizing mutations involve the 3-5 amino acid deletions on exon 19 and the L858R mutation on exon 21. Although ALK rearrangement also occurs mainly in lung adenocarcinoma and never/light smokers, it is not associated with sex or ethnicity. A great majority of the ALK gene rearrangements that occur in lung cancer involve a fusion between the C-terminal of ALK containing the kinase domain and the N-terminal of echinoderm microtubule-associated protein-like 4 (EML4), which results from an inversion on the short arm of chromosome 2. While EGFR mutations are detected by mainly by sequencing or PCR-based techniques, ALK rearrangement is best detected by the fluorescent in situ hybridization (FISH). However, recent data suggest that the oncogenic ALK fusion proteins can be detected with close to 100% sensitivity and specificity in lung cancer by immunohistochemistry using commercially available ALK specific antibodies, while the native ALK protein is not expressed in normal lung cells. Based on a systematic review of the published literatures, experts representing the International Association for the Study of Lung Cancer (IASLC), in collaboration with the College of American Pathologists (CAP) and the Association of Molecular Pathologists (AMP) recently issued a guideline on Molecular Testing of EGFR and ALK in Lung Cancer. The testing algorithm reported in this guideline will be discussed. Citation Format: Ming Sound Tsao. Molecular testing to personalized EGFR and ALK inhibitor therapies in lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA10.