Quantitative analysis of the effect of docetaxel-induced edema on quality of life in patients with breast cancer and related factors: a prospective cohort study.

BACKGROUND: Systemic edema is an adverse effect of docetaxel chemotherapy and causes distress to patients, including those receiving this agent for breast cancer. However, its characteristics and factors related to its effect on quality of life (QoL) have not been adequately investigated. In this study, we assessed systemic edema quantitatively, explored related factors, and evaluated QoL in patients receiving docetaxel for breast cancer. METHODS: The study had a prospective cohort design and included 37 patients with no known history of swelling who were treated with docetaxel between September 2019 and April 2022. Patients were examined at the start, middle, and end of their course of treatment and 1 and 2 months later. Body water content, body mass, fat mass, and muscle mass were quantified using bioelectrical impedance analysis. Systemic edema was evaluated with reference to the Common Terminology Criteria for Adverse Events. The timing of development of systemic edema at any anatomical site that was grade 2 or worse was recorded. QoL was assessed using the Quality of Life-Anti Cancer Drug scale. Nutrition was evaluated using the Brief-type self-administered diet history questionnaire. Multivariable logistic regression analysis was performed to identify related factors. QoL was also compared between patients with edema and those without edema. RESULTS: Systemic edema developed in 67% of the study participants and was most prevalent at the end of treatment. Body fat mass (adjusted odds ratio [aOR] 0.802, 95% confidence interval [CI] 0.651-0.988, p = 0.038), disease stage (aOR 3.279, 95% CI 0.493-21.793, p = 0.219), and history of alcohol consumption (aOR 0.141, 95% CI 0.013-1.521, p = 0.106) were identified as risk factors for docetaxel-induced edema. Participants who developed systemic edema experienced more physical, vital, and emotional distress 1 month after treatment than those who did not. There was no association between systemic edema and nutrition. CONCLUSIONS: Systemic edema may develop after treatment with docetaxel and increase distress in patients with a high body fat mass. Patients at risk of systemic edema should be informed in advance about the potential frequency, location, and timing of its onset and encouraged to self-manage this condition.

The relation between mindfulness and the fatigue of women with breast cancer: path analysis.

BACKGROUND: Although fatigue is a common and distressing symptom in cancer survivors, the mechanism of fatigue is not fully understood. Therefore, this study aims to investigate the relation between the fatigue and mindfulness of breast cancer survivors using anxiety, depression, pain, loneliness, and sleep disturbance as mediators. METHODS: Path analysis was performed to examine direct and indirect associations between mindfulness and fatigue. Participants were breast cancer survivors who visited a breast surgery department at a university hospital in Japan for hormonal therapy or regular check-ups after treatment. The questionnaire measured cancer-related-fatigue, mindfulness, anxiety, depression, pain, loneliness, and sleep disturbance. Demographic and clinical characteristics were collected from medical records. RESULTS: Two-hundred and seventy-nine breast cancer survivors were registered, of which 259 answered the questionnaire. Ten respondents with incomplete questionnaire data were excluded, resulting in 249 participants for the analyses. Our final model fit the data well (goodness of fit index = .993; adjusted goodness of fit index = .966; comparative fit index = .999; root mean square error of approximation = .016). Mindfulness, anxiety, depression, pain, loneliness, and sleep disturbance were related to fatigue, and mindfulness had the most influence on fatigue (ß = - .52). Mindfulness affected fatigue not only directly but also indirectly through anxiety, depression, pain, loneliness, and sleep disturbance. CONCLUSIONS: The study model helps to explain the process by which mindfulness affects fatigue. Our results suggest that mindfulness has both direct and indirect effects on the fatigue of breast cancer survivors and that mindfulness can be used to more effectively reduce their fatigue. It also suggests that health care professionals should be aware of factors such as anxiety, depression, pain, loneliness, and sleep disturbance in their care for fatigue of breast cancer survivors. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN number. 000027720) on June 12, 2017.

Synergistic effects of tumor necrosis factor-α and insulin-like growth factor-I on survival of human trophoblast-derived BeWo cell line.

OBJECTIVE: Trophoblast survival is regulated by cytokines and growth factors. While the pharmacological levels (10-100 ng/mL) of tumor necrosis factor (TNF)- α affect trophoblasts survival in vitro, the effects of the physiological levels (1-10 pg/mL) of TNF-α remain unknown. We investigated the effects of the physiological levels of TNF-α on proliferation and apoptosis of human trophoblast cells by using BeWo cells. Insulin-like growth factor (IGF)-I is also a potent regulator of trophoblast survival and has been known to exert synergistic effects with other hormones. The interaction of IGF-I and TNF-α on BeWo cells survival was also examined. METHODS: After incubating BeWo under the presence of TNF-α (10-105 pg/mL) and IGF-I (102 ng/mL), we assessed cell number by WST-1 assay and cell proliferation by BrdU uptake assay and immunocytochemistry with anti-Ki67 antibody. Apoptosis was evaluated by TUNEL assay and caspase-3, 8 activity assays. RESULTS: Under the presence of IGF-I, cell number, BrdU uptake, and Ki-67 expression of BeWo were dose-dependently enhanced by low TNF-α (10-102 pg/mL), while no such effects were detected without IGF-I. Higher levels of TNF-α (104-105 pg/mL) showed inhibiting effects on cell number and cell proliferation. The number of TUNEL positive cells were decreased and caspase activities were suppressed by lower levels (10-102 pg/mL) of TNF-α and IGF-I independently. Higher levels of TNF-α (104-105 pg/mL) showed promoting effects on apoptosis irrespective of IGF-I. CONCLUSION: The physiological levels of TNF-α and IGF-I had synergetic effects on enhancing cell proliferation and also independently inhibited apoptosis of Bewo cells.

Significance of gestational weight gain in spontaneous onset of labor at term.

AIM: To investigate the significance of gestational weight gain (GWG) in association with the spontaneous onset of labor at term. METHODS: A retrospective cohort study on 985 pregnant women (629 nullipara and 356 pluripara) who delivered singleton babies at term was conducted. We reviewed the maternal demographics (age, parity, prepregnancy body mass index [BMI]) and the perinatal outcomes (gestational age [GA] and the type [spontaneous or induced] of labor onset, and GWG). The subjects were categorized by prepregnancy BMI and GWG. The rates of spontaneous onset of labor were compared between the nullipara and pluripara groups. Kaplan-Meier survival analysis was applied to evaluate the time to spontaneous labor according to prepregnancy BMI and GWG. A Cox proportional hazards model was used to determine the independent predictive factor for spontaneous onset of labor. RESULTS: In both the nullipara and pluripara group, women with prepregnancy obesity were less likely to enter spontaneous labor. In nullipara, women with excessive weight gain were less likely to enter spontaneous labor. In pluripara, women with poor gain were more likely to enter spontaneous labor. In the multivariate model, GWG was independently associated with the spontaneous onset of labor in both nullipara (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75-0.98, P = 0.03) and pluripara (HR 0.82, 95% CI 0.64-0.93, P = 0.005). CONCLUSION: Greater maternal weight gain was significantly associated with longer gestation and a decreased likelihood of spontaneous onset of labor at term.

Influence of maternal obesity on fetal growth at different periods of pregnancies with normal glucose tolerance.

AIM: We aimed to examine the influence of maternal obesity on fetal growth in utero at different periods of pregnancies with normal glucose tolerance. METHODS: A retrospective cohort study on 356 pregnant women with normal glucose tolerance was conducted. The women were categorized by pre-pregnancy body mass index (BMI) as obese (OB; BMI ≥ 25.0 kg/m2 ) or non-obese (n-OB). Z-scores of the fetal abdominal circumference (AC) and the rate of fetal macrosomia (AC ≥ 90th percentile) at 19, 30, and 36 gestational weeks (GW) were compared between the two groups. Maternal demographics (age, parity, height, pre-pregnancy BMI, history of prior large-for-gestational-age delivery) were compared between the pregnancies with and without fetal macrosomia at each gestational age. Multiple logistic regression analysis was performed to determine the independent risk factors for fetal macrosomia. RESULTS: Birthweights of the neonates were significantly higher in the OB group. Z-scores of the fetal AC were significantly higher in the OB group at 30 and 36 GW, while no significant difference was found at 19 GW. The rates of fetal macrosomia in the OB group were also higher at 30 and 36 GW, while maternal obesity was not associated with fetal macrosomia at 19 GW. Pre-pregnancy BMI was detected as the independent predictor of fetal macrosomia at 30 GW (odds ratio, 1.19 [95% CI]) and 36 GW (odds ratio, 1.13 [95% CI]). CONCLUSION: Maternal pre-pregnancy obesity has a promoting effect on fetal growth from the third trimester through birth.

Increased maternal insulin resistance promotes placental growth and decreases placental efficiency in pregnancies with obesity and gestational diabetes mellitus.

AIM: Homeostasis model assessment for insulin resistance (HOMA-IR) was measured during pregnancy to analyze placental weight and efficiency in relation to maternal insulin resistance. METHODS: A retrospective study of 510 pregnant women (130 with gestational diabetes mellitus [GDM], 380 with normal glucose tolerance) was conducted. We reviewed the patients' demographic data (age, parity, pre-pregnancy body mass index [BMI]) and perinatal outcomes (birth weight, placental weight, BMI at delivery, maternal weight gain, HOMA-IR). The birth weight to placental weight (B/P) ratio was calculated for placental efficiency. The subjects were categorized by BMI at delivery, and maternal, neonatal and placental characteristics were compared between the groups to investigate the determinants of placental weight and B/P ratios. RESULTS: Obesity was significantly associated with heavier placental weight and lower B/P ratios. The presence of GDM did not affect placental weight, whereas the B/P ratios in women with GDM were significantly lower than in women with normal glucose tolerance. HOMA-IR was positively correlated with placental weight (ρ = 0.217, P < 0.001) and negatively with B/P ratio (ρ = -0.181, P < 0.001). CONCLUSIONS: Increased maternal insulin resistance promoted placental growth and inhibited placental efficiency. Maternal insulin resistance may be one of the pathophysiological conditions responsible for altered placental size and function in pregnancies with obesity and GDM.

Role of the inner-membrane histidine kinase RcsC and outer-membrane lipoprotein RcsF in the activation of the Rcs phosphorelay signal transduction system in Escherichia coli.

The Rcs phosphorelay signal transduction system of Escherichia coli controls genes for capsule production and many other envelope-related functions and is implicated in biofilm formation. The outer-membrane lipoprotein RcsF is an essential component of the Rcs system. Mislocalization of RcsF to the periplasm or the cytoplasmic membrane leads to high activation of the Rcs system, suggesting that RcsF functions by interacting with the cytoplasmic membrane component(s) of the system in activating the system. This is consistent with the result reported by Cho et al. (Cell159, 1652-1664, 2014) showing that RcsF interacts with the periplasmic domain (YrfFperi) of the inner-membrane protein YrfF (IgaA in Salmonella enterica serovar Typhimurium), which is a negative regulator of the Rcs system. In this study we show that RcsF also interacts with the periplasmic domain of the innermembrane-localized histidine kinase RcsC (RcsCperi). RcsCperi, which was secreted to the periplasm by fusion to maltose-binding protein, titrated RcsF's activating effect. A bimolecular fluorescence complementation experiment showed interaction of RcsF with RcsCperi, as well as with YrfFperi. We conclude that RcsF interacts with the periplasmically exposed region of RcsC, as well as with that of YrfF.

Non-essential and branched-chain amino acids differentially regulate insulin-like growth factor binding protein-1 production and phosphorylation in HepG2 cells.

Deprivation of branched-chain amino acids (BCAAs) induces insulin-like growth factor binding protein-1 (IGFBP-1) production in HepG2 cells, while the role of non-essential amino acids (NEAAs) remains unknown. We investigated changes in IGFBP-1 production and phosphorylation induced by NEAAs and also examined its significance on IGF-I activity in HepG2 cells. We demonstrated that decreased BCAAs and increased NEAAs stimulated phosphorylated IGFBP-1 secretion. We also revealed that decreased BCAA-to-NEAA ratios enhanced phosphorylated IGFBP-1 secretion, while changes in the total amount of amino acids (AAs) had no effect. Phosphorylation of IGF-I receptor ß-subunits mediated by exogenous IGF-I in HepG2 cells was inhibited by decreased BCAAs, increased NEAAs, and decreased BCAA-to-NEAA ratios, while the total amount of AAs had no effect. In addition to BCAAs, NEAAs are also responsible for the regulation of IGFBP-1 secretion and phosphorylation in HepG2 cells. Moreover, the balance of BCAAs and NEAAs regulated IGFBP-1 secretion and phosphorylation.

Ramelteon, a selective MT1/MT2 receptor agonist, suppresses the proliferation and invasiveness of endometrial cancer cells.

The incidence of endometrial cancer is increasing, making it the fifth most common cancer worldwide. To date, however, there is no standard therapy for patients with recurrent endometrial cancer. Melatonin, a hormone secreted by the pineal gland, has been shown to have anti-tumor effects in various tumor types. Although melatonin is available as a supplement, it has not been approved for cancer treatment. Ramelteon, a selective melatonin receptor type 1 and 2 (MT1/MT2) receptor agonist, has been approved to treat sleep disorders, suggesting that ramelteon may be effective in the treatment of endometrial cancer. To determine whether this agent may be effective in the treatment of endometrial cancer, this study investigated the ability of ramelteon to suppress the proliferation and invasiveness of HHUA cells, an estrogen receptor-positive endometrial cancer cell line. Ramelteon at 10-8 M maximally suppressed the proliferation of HHUA cells, reducing the percentage of Ki-67 positive proliferating cells. This effect was completely blocked by luzindole, a MT1/MT2 receptor antagonist. Furthermore, ramelteon inhibited HHUA cell invasion and reduced the expression of the MMP-2 and MMP-9 genes. These results suggested that ramelteon may be a candidate for the treatment of recurrent endometrial cancer, with activity similar to that of melatonin.

Prediction of spontaneous preterm delivery in asymptomatic twin pregnancies using cervical length and granulocyte elastase.

OBJECTIVE: The purpose of this study was to evaluate sonographic cervical length (CL) and granulocyte elastase (GE) in cervical secretion as predictors of preterm delivery in asymptomatic twin pregnancies. MATERIALS AND METHODS: This study prospectively enrolled asymptomatic twin pregnancies with CL < 25 mm at 22-29 weeks of gestation. All women were hospitalized for preterm labor, and the cervical secretion was obtained for GE testing on admission. The results of CL measurement and GE testing were reviewed, and the relationship between each variables and preterm delivery prior to 34 weeks of gestation was assessed. RESULTS: Overall, we included 54 women with twin pregnancies, of which 12 (22.2%) had preterm deliveries prior to 34 weeks of gestation. A CL of <20 mm was significantly associated with preterm delivery with an odds ratio of 4.88 (95% confidence limit, 1.15-20.73). GE was not an independent predictive marker for preterm delivery. We also performed a subgroup analysis on the combination of CL and GE for predicting preterm delivery. Among the patients with GE(-), CL < 20 mm markedly increased the risk of preterm delivery with an odds ratio of 10.89 (95% confidence limit, 1.40-77.10). CL was not associated with preterm delivery among those with GE(+). Those with negative GE and shorter CL demonstrated the shortest duration of pregnancy after admission. CONCLUSION: The combination of sonographic CL and GE of cervical secretion is useful to predict the risk of preterm delivery in asymptomatic twin pregnancies.

Branched-chain amino acids regulate insulin-like growth factor-binding protein 1 (IGFBP1) production by decidua and influence trophoblast migration through IGFBP1.

STUDY QUESTION: Do branched-chain amino acids (BCAAs) influence the migration of human extravillous trophoblast (EVT) cells through changes in insulin-like growth factor-binding protein 1 (IGFBP1) production in decidual cells? STUDY FINDING: Decidua-derived IGFBP1 had a stimulating effect on migration of EVT. WHAT IS KNOWN ALREADY: IGFBP1 is abundantly secreted from human decidual cells and influences trophoblast migration in human placenta of early pregnancy. In hepatic cells, the expression of IGFBP1 is influenced by nutritional status and BCAAs regulate IGFBP1 production. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: This is a laboratory-based study using human decidual cells and trophoblast cells isolated from placental tissue of early pregnancy (n = 50) and grown as primary cultures. Production of IGFBP1 from decidual cells was examined by enzyme-linked immunosorbent assay and immunoblotting after incubation with or without BCAAs. EVT migration was evaluated using the media conditioned by decidual cells. The effect of conditioned media on phosphorylation of focal adhesion kinase (FAK) in EVT was also analyzed by immunoblotting. The same experiments were repeated in the presence of RGD peptide, which inhibits IGFBP1 binding to α5ß1 integrin. An EVT migration assay and the immunoblotting of phosphorylated FAK were also conducted with exogenous IGFBP1. The effect of the conditioned media on cytotrophoblast cell number was also assessed using WST-1 in a cell proliferation assay. MAIN RESULTS AND THE ROLE OF CHANCE: Deprivation of BCAAs on decidual cells significantly suppressed IGFBP1 secretion (P < 0.05, versus BCAA+). Exogenous IGFBP1-stimulated EVT migration (P < 0.05) and phosphorylation of FAK (P < 0.05), and the RGD peptide inhibited these effects. EVT migration and phosphorylation of FAK were stimulated by the conditioned media, presumably by IGFBP1 in the media. RGD treatment abrogated the stimulating effects of conditioned media. The conditioned media deprived of BCAAs had suppressive effects on EVT migration (P < 0.05, versus BCAA+) and phosphorylation of FAK (P < 0.05, versus BCAA+). The conditioned media did not affect number of cytotrophoblast cells. LIMITATIONS, REASONS FOR CAUTION: The conclusions are based on in vitro experiments with human decidual cells and trophoblast cells isolated from placental tissue of early pregnancy, and we were unable to ascertain whether these mechanisms actually operate in vivo. We investigated the effect of decidua-derived IGFBP1 on EVT migration, however, we cannot completely rule out the possibility that endogenous IGF could also influence cell migration. WIDER IMPLICATIONS OF FINDINGS: Interruption of the BCAA supply to uterine decidual cells in early pregnancy may suppress EVT migration through reduced IGFBP1 secretion, which may be one of the pathophysiological conditions responsible for pre-eclampsia. LARGE SCALE DATA: None. STUDY FUNDING/ AND COMPETING INTERESTS: All funds were obtained through Kyorin University School of Medicine. The authors have no conflict of interest to declare.

Intrapartum group B Streptococcus screening using real-time polymerase chain reaction in Japanese population.

OBJECTIVE: The objective of this study was to analyze the diagnostic accuracy of a commercial real-time polymerase chain reaction (PCR) assay for group B streptococcus (GBS) colonization status and to compare results of the intrapartum PCR with the antepartum conventional GBS culture in Japanese pregnant women. METHODS: This prospective observational study enrolled Japanese pregnant women at 35-37 weeks' gestation. Paired recto-vaginal swabs were obtained for PCR and conventional culture, both at 35-37 weeks' gestation and at admission for delivery. Performance of PCR was analyzed by comparing with the culture results. Furthermore, using the intrapartum culture results as the gold standard, the test of both the antepartum culture and the intrapartum PCR were characterized. RESULTS: We prospectively enrolled 79 pregnant women at 35-37 weeks' gestation, and the intrapartum results were obtained from 73 of those women. The sensitivity of PCR was 86.2%, and concordance rate with the conventional culture was 96.7% overall. Compared with the intrapartum culture, the sensitivity and the specificity of the intrapartum PCR were 83.3% and 98.4%, respectively, while the sensitivity and the specificity of the antepartum culture were 100.0% and 95.1%. CONCLUSIONS: The intrapartum real-time PCR assay for GBS screening has the accuracy similar to the antepartum conventional culture method.

Prenatal diagnosis of Klippel-Trenaunay-Weber syndrome with Kasabach-Merritt syndrome in utero.

Klippel-Trenaunay-Weber syndrome (KTWS), a congenital disease characterized by cutaneous hemangiomas, soft tissue and bone hypertrophy, and occasionally arteriovenous malformations, is extremely rare and its natural history in utero is unknown. We present a prenatally diagnosed case of KTWS complicated with Kasabach-Merritt syndrome in utero and fetal hydrops from acute anemia. The fetus was diagnosed with KTWS at 24 weeks of gestation based on the ultrasound findings of hemangiomas and unilateral hypertrophy of the lower extremity. Acute enlargement of the hemangiomas and the appearance of new retroperitoneal hemangiomas were detected at 27 weeks, along with skin edema and cardiomegaly. Doppler examination showed elevated peak systolic velocity in the middle cerebral artery, indicating acute fetal anemia. We believe the fetus's condition was complicated with Kasabach-Merritt syndrome in utero, which caused acute hemolytic anemia leading to high-output cardiac failure and fetal hydrops.

Antepartum reversible cerebral vasoconstriction syndrome with pre-eclampsia and reversible posterior leukoencephalopathy.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headache and diffuse segmental constriction of the cerebral arteries that resolves spontaneously within a few months. Pregnancy is one of the precipitating factors of RCVS and most of the reported cases occurred in the post-partum period. We report a case of RCVS that occurred in a pregnant women with pre-eclampsia during her antepartum period. A 34-year-old woman in full-term pregnancy presented with a severe and acute headache. Magnetic resonance angiography (MRA) showed multiple segmental constrictions of the cerebral arteries. Magnetic resonance imaging revealed a high-intensity lesion in the left occipital lobe, consistent with reversible posterior leukoencephalopathy syndrome, on fluid attenuated inversion recovery sequences. The case was also complicated by severe pre-eclampsia and the patient underwent emergency cesarean section. Although her symptoms resolved rapidly, MRA revealed new lesions of arterial constriction 4 days after onset. The vasoconstriction completely resolved on MRA after 10 days and the patient was discharged without neurological sequelae.

Assessment of reasons for referral and activities of hospital palliative care teams using a standard format: a multicenter 1000 case description.

CONTEXT: The many benefits of hospital palliative care teams (PCTs) are well known. However, their specific activities have not been fully clarified, and no standardized methods for reporting PCT activities are available. OBJECTIVES: The aim of this study was to investigate, through the use of a standard format, the activities performed by hospital PCTs in Japan. METHODS: This was a prospective observational study. A total of 21 hospital PCTs were included in this study, and each recruited approximately 50 consecutively referred patients. Participating PCTs filled in a standard form for reporting activities. RESULTS: We obtained data from 1055 patients who were referred to PCTs. Of the 1055 patients, 1005 patients (95%) had cancer. The median number of reasons for referral and problems identified by PCTs was two (0-22) and four (0-18), respectively. The two major reasons for referral were pain (63%) and anxiety/depression/grief/emotional burden (22%). The major recommendations were pharmacological treatment (74%), care for the patient's physical symptoms (49%), and support for patient's decision making (38%). The major activities performed by the PCTs were comprehensive assessment (90%), care for the patient's physical symptoms (77%), and pharmacological treatment (74%). CONCLUSION: The components of hospital PCT activities were successfully measured using the Standard Format for Reporting Hospital PCT Activity. The results of this study and the format for reporting hospital PCT activity could be effective in improving hospital PCT practice and for the education of new hospital PCT members.

Prenatal diagnosis of umbilical artery thrombosis.

Umbilical artery thrombosis (UAT) is rare and few prenatally diagnosed cases have been reported. We describe 2 cases of fetal growth restriction prenatally diagnosed as UAT by ultrasound examination. In each case the cross section of the umbilical cord showed one normal artery and a small echogenic area which was suspected as an occluded thrombotic artery and they were surrounded by a highly curving 'C-shaped' vein. UAT was confirmed by histological examinations after deliveries in both cases. The characteristic ultrasound finding of the umbilical vessel, which is the so-called 'orange grabbed sign', enables the prenatal diagnosis of UAT and it is valuable with respect to perinatal fetal management because UAT is associated with increased perinatal morbidity and mortality.

Improvement of insulin sensitivity promotes extravillous trophoblast cell migration stimulated by insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) has been shown to stimulate extravillous trophoblast (EVT) cell migration and invasion, and to play a crucial role in placental function, thereby, influencing placental development and fetal growth. Insufficient invasion of EVT cells into the uterine endometrium leads to pregnancy-related complications, including spontaneous abortion, fetal growth restriction (FGR), and pregnancy-induced hypertension (PIH). Insulin-resistant conditions such as polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) have also been associated with abortion and PIH. However, the effects of IGF-I on EVT cells under insulin-resistant conditions have not been elucidated yet. The current study was undertaken to analyze the effects of IGF-I under insulin-resistant conditions and to determine whether improvement in insulin sensitivity alters IGF signaling and cell migration in the EVT. Incubation with pioglitazone, an insulin sensitizer, increased peroxisome proliferator-activated receptor-γ (PPARγ) expression after 48 h. A 48-h pre-incubation with insulin reduced the phosphorylation and concentration of the insulin receptors, which were increased by insulin treatment. Long-term exposure to insulin reduced phosphorylation of the IGF-I receptor, insulin receptor substrate-1 (IRS-1), and Akt, and also reduced EVT cell migration. However, when the cells were incubated with pioglitazone in addition to insulin for 48 h, the phosphorylation of these proteins was restored. This combination partially reversed the inhibitory effect of insulin on EVT cell migration. These results suggest that abnormalities in pregnancy that are induced by loss of insulin sensitivity can be treated by improving insulin sensitivity.