Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer.

BACKGROUND: Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study. PATIENTS AND METHODS: Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints. RESULTS: Thirty-nine patients were enrolled in DE [n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3)] and 134 in DC [n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR. CONCLUSIONS: Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.

Immune checkpoint inhibitors-related encephalitis in melanoma and non-melanoma cancer patients: a single center experience.

BACKGROUND: Treatment with immune checkpoint inhibitors (ICI) has greatly improved survival for patients with a number of malignant diseases in recent years. Neurological immune-related adverse events (n-irAE) of varying severity have been reported in the literature. We aimed to identify the incidence of n-irAE, focusing on immune-related encephalitis (IRE), in patients treated with ICI for multiple non-hematological malignancies in our institution. METHODS: All patients with histologically verified cancer that received treatment with ICI at the Sheba Medical Center between January 2017 and August 2019 were surveyed. Medical records for each patient were reviewed and information regarding n-irAE was recorded. RESULTS: In total, 1993 patients were included. Eleven cases of IRE were recorded, affecting 0.55% of patients overall, eight had non-melanoma cancer. Eight patients had made a full recovery. CONCLUSIONS: IRE is a n-irAE more frequent than previously reported, particularly in non-melanoma patients. The diagnostic criteria and optimal treatment needs to be determined. ICI re-challenge after IRE can be considered for selected patients.

Evidence for cutaneous dysbiosis in dystrophic epidermolysis bullosa.

BACKGROUND: The human microbiome project addresses the relationship between bacterial flora and the human host, in both healthy and diseased conditions. The skin is an ecosystem with multiple niches, each featuring unique physiological conditions and thus hosting different bacterial populations. The skin microbiome has been implicated in the pathogenesis of many dermatoses. Given the role of dysbiosis in the pathogenesis of inflammation, which is prominent in dystrophic epidermolysis bullosa (DEB), we undertook a study on the skin microbiome. AIM: To characterize the skin microbiome in a series of patients with DEB. METHODS: This was a case-control study of eight patients with DEB and nine control cases enrolled between June 2017 and November 2018. The skin of patients with DEB was sampled at three different sites: untreated wound, perilesional skin and normal-appearing (uninvolved) skin. Normal skin on the forearm was sampled from age-matched healthy controls (HCs). We used a dedicated DNA extraction protocol to isolate microbial DNA, which was then analysed using next-generation microbial 16S rRNA sequencing. Data were analysed using a series of advanced bioinformatics tools. RESULTS: The wounds, perilesional and uninvolved skin of patients with DEB demonstrated reduced bacterial diversity compared with HCs, with the flora in DEB wounds being the least diverse. We found an increased prevalence of staphylococci species in the lesional and perilesional skin of patients with DEB, compared with their uninvolved, intact skin. Similarly, the uninvolved skin of patients with DEB displayed increased staphylococcal content and significantly different microbiome diversities (other than staphylococci) compared with HC skin. CONCLUSIONS: These findings suggest the existence of a unique DEB-associated skin microbiome signature, which could be targeted by specific pathogen-directed therapies. Moreover, altering the skin microbiome with increasing colonization of bacteria associated with nonchronic wounds may potentially facilitate wound healing in patients with DEB.

Association between p53 protein phosphorylated at serine 20 expression and ovarian carcinoma stem cells phenotype: correlation with clinicopathological parameters of ovarian cancer.

Biological behavior of ovarian carcinomas might be the result of cellular diversity existing in tumor tissue, which consists of differentiated and undifferentiated cells showing stem cells biological properties and function. We examined correlation between p53 protein phosphorylated at serine 20 (p-p53(Ser20)) and CD133, SOX2, Notch1 expression, in order to reveal p-p53(Ser20) stemness function in ovarian cancer. p-p53(Ser20), CD133, Notch1, SOX2 expression was analyzed on 104 ovarian carcinomas using immunohistochemical staining. The positive correlation between p53 and p-p53(Ser20) (p=0.02), p53 and SOX2 (p=0.02), p-p53(Ser20) and Notch1 (p=0.03), p-p53(Ser20) and CD133 (p=0.01) expression was observed in ovarian carcinomas. The parallel expression of p-p53(Ser20)/CD133, p-p53(Ser20)/Notch1 reflecting co-expression of these proteins in single carcinoma cell, and p-p53(Ser20)/SOX2 expression was associated with advanced stage and p-p53(Ser20)/Notch1, p53/SOX2, p-p53(Ser20)/SOX2 parallel expression correlated with high tumor grade. The correlation between p-p53(Ser20) and CD133, Notch1, SOX2 expression and clinical parameters indicate, that malignancy and biological behavior of ovarian carcinomas depend on interaction between p-p53(Ser20) and carcinoma stem cells biomarkers expression.

The effectiveness of chemotherapy and electrochemotherapy on ovarian cell lines in vitro.

The presented study aimed to evaluate in vitro the effectiveness of improvement standard chemotherapy with bleomycin by electroporation in two various ovarian cancer cell lines. Two human ovarian cell lines OvBH-1 and SKOV-3 were used. The lines were selected because of their resistance to several therapeutic methods. As anticancer drug we use range of concentrations of bleomycin. In EP and ECT experiments different voltage values: from 0 to 1200 V/cm, 8 pulses with duration of 100µs and intervals between pulses 1s long were used. The cells viability after applied treatments was evaluated by MTT assay. The expression of heat shock proteins - HSP27 was examined by immunocytochemical ABC method.The cytotoxicity with different concentrations of bleomycin alone was not significantly decrease in both cell lines. It confirms resistance of these cells to conventional chemotherapy. The highest decrease of cell proliferation was observed after EP with bleomycin after 48h of incubation for 1000 V/cm. The intensity of expression of small heat shock proteins HSP27 slightly increased after ECT in both treated cell lines, in particular in OvBH-1. The presented study indicated that application of electroporation may effectively enhance chemotherapy with bleomycin, particularly in the case of treating ovarian cancer resistant to standard therapy.

Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R.

BACKGROUND: Based on the findings of the PACIFIC trial, consolidation durvalumab following platinum-based chemoradiotherapy (CRT) is a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). An earlier analysis from the ongoing PACIFIC-R study (NCT03798535) demonstrated the effectiveness of this regimen in terms of progression-free survival (PFS). Here, we report the first planned overall survival (OS) analysis. PATIENTS AND METHODS: PACIFIC-R is an observational/non-interventional, retrospective study of patients with unresectable, stage III NSCLC who started durvalumab (10 mg/kg intravenously every 2 weeks) within an AstraZeneca-initiated early access program between September 2017 and December 2018. Primary endpoints are OS and investigator-assessed PFS, estimated using the Kaplan-Meier method. RESULTS: By 30 November 2021, the full analysis set included 1154 participants from 10 countries (median follow-up in censored patients: 38.7 months). Median OS was not reached, and the 3-year OS rate was 63.2% (95% confidence interval 60.3% to 65.9%). Three-year OS rates were numerically higher among patients with programmed death-ligand 1 (PD-L1) expression on ≥1% versus <1% of tumor cells (TCs; 67.0% versus 54.4%) and patients who received concurrent CRT (cCRT) versus sequential CRT (sCRT) (64.8% versus 57.9%). CONCLUSIONS: PACIFIC-R data continue to provide evidence for the effectiveness of consolidation durvalumab after CRT in a large, diverse, real-world population. Better outcomes were observed among patients with PD-L1 TCs ≥1% and patients who received cCRT. Nevertheless, encouraging outcomes were still observed among patients with TCs <1% and patients who received sCRT, supporting use of consolidation durvalumab in a broad population of patients with unresectable, stage III NSCLC.

The expression of BRCA1, P53, KAI1, and Nm23 in ovaries of BRCA1 mutation carriers after prophylactic adnexectomy.

INTRODUCTION: High mortality rate, absence of reliable methods for early diagnosis and poor prognosis of advanced ovarian cancer prompted to investigate the role of prophylactic oophorectomy in BRCA1 mutation carriers as well as evaluate the expression of BRCA1, p53, Nm23, and KAI1 proteins in ovarian tissue from these patients. MATERIALS AND METHODS: Ovaries from BRCA1 mutation carriers underwent prophylactic adnexectomy and control group of patients were operated from other than cancer reasons. The expression of selected proteins was studied using immunohistochemical staining. The intensity of immunostaining and the number of tumor cells showing the reaction for selected proteins were analyzed. RESULTS: We have analyzed ovarian tissues from 18 BRCA1 mutation carriers and 11 women included in control group. Positive expression of BRCA1 protein was presented in 83.3 % cases in BRCA1 mutation carriers and in 72.7 % in the control group (p > 0.05). Positive expression of p53 protein was observed, respectively, in 27.8 vs. 36.4 % (p > 0.05), Nm23 protein 77.7 vs. 90.9 % (p > 0.05), and KAI1 in 72.2 vs. 72.7 % (p > 0.05). Mean percent of tumor cells that showed the reaction for selected proteins as well as the intensity of immunostaining for all analyzed proteins seems to be lower in BRCA1 mutation carriers. CONCLUSIONS: However, any significant differences between study group and control group have not been found; there were similar trends showing reduced expression of studied proteins in BRCA1 mutation carriers.

Effect of vaginal progesterone, administered to prevent preterm birth, on impedance to blood flow in fetal and uterine circulation.

OBJECTIVE: To evaluate the effect on the maternal and fetal circulation of progesterone administered to prevent preterm birth. METHODS: We used an observational cohort study design. The study group included 44 women at 18-32 weeks' gestation who presented with an episode of preterm labor, with or without history of delivery before 34 weeks' gestation, or an incidental finding of short cervix (≤ 25 mm). Doppler flow assessment of the umbilical artery, fetal middle cerebral artery and uterine arteries was performed before and 24 h after vaginal administration of progesterone. RESULTS: Seventeen (38.6%) women gave birth before term, but only nine (20.4%) did so before 34 weeks' gestation. Following progesterone treatment, there was a statistically significant decrease in the pulsatility index of the fetal middle cerebral artery (mean reduction, 18.2%; mean change in pulsatility index, 0.44 (95% CI, 0.25-0.63), P < 0.001), with no changes in the other vessels. Comparison of the women who gave birth before with those who delivered at term yielded no significant differences in Doppler flow parameters in any vessel examined, either before or after progesterone treatment. CONCLUSION: Treatment with vaginal progesterone is associated with a lower pulsatility index in the fetal middle cerebral artery, suggesting a vasodilatory effect on the fetal circulation.

Clinical activity of brigatinib in ROS1-rearranged non-small cell lung cancer.

BACKGROUND: Brigatinib is a potent ROS1 inhibitor. The existing data on its clinical activity in ROS1-rearranged non-small cell lung cancer (NSCLC) are limited to four cases. METHODS: Six patients with ROS1-rearranged advanced NSCLC treated with brigatinib were identified through search of the internal databases of four participating cancer centers. Four additional patients were selected by PubMed and Google Scholar search. The objective response rate (ORR), progression-free survival (PFS) (RECIST v.1.1), duration of treatment (DOT), and safety were assessed. RESULTS: Of eight patients evaluable for response assessment (crizotinib naive-1, crizotinib resistant -7), three patients demonstrated a partial response (ORR-37%). One crizotinib-naive patient had an ongoing response at 21.6 months. Of seven crizotinib-resistant patients, two patients demonstrated a partial response (ORR-29%), and one patient (14%) had stable disease. PFS, available in four crizotinib-resistant patients, was 7.6 + , 2.9, 2.0, and 0.4 months. In crizotinib-resistant patients, DOT was 9.7 + , 7.7 + , 7.6 + , 4.0, 2.0, 1.1, 0.4 months, and was not reported in two patients. Genomic profiling in one responder revealed no ROS1 alteration, suggesting that the response was attributable to "off-target" brigatinib activity. In two patients with progressive disease, genomic profiling demonstrated a cMET exon 14 mutation + KRAS G12A mutation in one case, and a persisting ROS1-CD74 fusion + TP53 K139N, FGFR2 E250G, ATM G2695D, and NF1 R2258Q mutations in the other. No grade 3-5 toxicity was observed. CONCLUSION: Brigatinib demonstrated modest activity in crizotinib-resistant ROS1-rearranged NSCLC. Its intracranial and systemic activity should be assessed in correlation with the underlying molecular mechanism of crizotinib resistance.

Our series is the first to describe brigatinib activity in ROS1-altered NSCLC. In crizotinib-resistant patients, ORR with brigatinib was 29%. PFS with brigatinib was 7.6+, 2.9, 2.0, and 0.4 months. DOT with brigatinib was 9.7+, 7.7+, 7.6+, 4.0, 2.0, 1.1, 0.4 months. The correlation between response and molecular resistance needs further exploration.

L3 skeletal muscle index (L3SMI) is a surrogate marker of sarcopenia and frailty in non-small cell lung cancer patients.

Background: Non-small cell lung cancer (NSCLC) is a common and highly lethal disease. As advanced treatment modalities are being developed, improved prognostication methods are sought. L3 skeletal muscle index (L3SMI) and alanine aminotransferase (ALT) levels are accepted surrogate markers of sarcopenia and related frailty. We aimed to evaluate the potential association of these markers with NSCLC patients' survival. Methods: A retrospective, single-center study of an NSCLC patients' cohort. L3SMI was calculated based on skeletal muscle area on computed tomography scans at the level of the L3 vertebra. Clinical data were extracted from clinical charts. Results: A total of 140 patients (56.4% males, median age 66 [range 37-86]) were included in this study, 32% were diagnosed at stage 3 and 45% at stage 4. During the follow-up duration (median of 1.9 years; range 1 month to 6.4 years), 102 patients (72.8%) died. Patients' characteristics that were found to be associated with increased mortality were performance status, albumin and tumor stage at diagnosis. Sarcopenia, defined as low L3SMI (lower than 41 cm2/m2 for women and lower than 53 cm2/m2 for men) was significantly associated with higher risk of mortality compared with patients with normal L3SMI values (77.2%, vs 64.6%, p=0.013) in univariate analysis, but not in a multiple regression analysis. Conclusion: Low L3SMI could serve as a surrogate marker for sarcopenia and frailty and, as such, facilitate the prognostication process of NSCLC patients.

Autonomic dysfunction of gastric motility in major depression.

BACKGROUND: Patients suffering from major depressive disorder (MDD) often complain about somatic symptoms. Cardiac complaints have been examined predominantly. However, gastrointestinal complaints are also reported frequently and are associated with worse outcomes. The research concerning changes in gastric motility of these patients is rather sparse. The aim of our study was to determine dysfunction of gastric motility and gastrointestinal symptoms in MDD. The duration and severity of MDD were examined regarding its influence over gastric emptying. METHODS: Gastric emptying was determined by a 13C-acetate breath test in patients with MDD (n = 29) and healthy control subjects (n = 51). Prior to this, depressive illness was operationalized using external and self-assessment scales (HAMD-21, MADRS, BDI, CGI). Whether the severity or duration of MDD influenced the gastric emptying parameters was examined using Spearman's correlation. In addition, autonomic complaints were recorded by means of an ANS score. Each ANS score item was determined using a Mann-Whitney U or Kruskal-Wallis test concerning the gastric emptying parameters. RESULTS: There was a significant difference in the parameters of the maximum gastric emptying rate (Tmax) and gastric half emptying time T1/2b between patients with MDD and healthy control subjects (Tmax 66.21min vs 53.35min, p < 0.006, T1/2b 207.59min vs 133.27min, p < 0.005). There was a significant negative correlation between Tmax and the severity of MDD determined with the depression rating scales BDI (Spearman's rank - 0.521, p = 0.013) and HAMD-21 (r - 0.384, p = 0.048). No correlation was found between the duration of MDD and the maximum gastric emptying rate (r - 0.125, p = 0.519) and gastric half emptying time (r - 0.62, p = 0.749). CONCLUSION: Gastrointestinal motility is significantly impaired in patients with MDD compared to healthy control subjects. Autonomic complaints were indicated frequently in MDD patients. The duration of MDD had no influence over the time of gastric emptying. There was a significant negative correlation between the severity of MDD and Tmax, indicating that the Tmax was reached earlier with the progression of MDD. The slowing of gastric motility in MDD patients is likely a result of a dysfunction of the autonomic nervous system.

Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53.

Tumor-associated mutant forms of p53 can exert an antiapoptotic gain of function activity, which confers a selective advantage upon tumor cells harboring such mutations. We report that mutant p53 suppresses the expression of the MSP (MST-1/HGFL) gene, encoding the ligand of the receptor tyrosine kinase RON, implicated in a variety of cellular responses. Mutant p53 associates with the MSP gene promoter and represses its transcriptional activity, leading to a decrease in mRNA levels and a subsequent decrease in the levels of secreted MSP protein. Forced downregulation of MSP expression in H1299 cells, derived from a large-cell lung carcinoma, confers increased resistance against etoposide-induced cell death. These antiapoptotic consequences of MSP downregulation seemingly conflict with the well-documented ability of the RON receptor to promote cell survival and tumor progression when aberrantly hyperactive. Yet, they are consistent with the fact that reduced MSP expression was observed in many types of human cancer, including large-cell lung carcinoma. Thus, repression of MSP gene expression by mutant p53 may contribute to oncogenesis in a cell type-specific manner.

The PI3K inhibitor LY294002 prevents p53 induction by DNA damage and attenuates chemotherapy-induced apoptosis.

The p53 tumor suppressor plays a key role in the natural protection against cancer. Activation of p53 by DNA-damaging agents can contribute to successful elimination of cancer cells via chemotherapy-induced apoptosis. The phosphatidylinositol-3 kinase (PI3K) pathway, triggered in normal cells upon exposure to growth factors, regulates a cascade of proliferation and survival signals. The PI3K pathway is abnormally active in many cancers, thus making it an attractive target for inactivation in an attempt to achieve better cancer therapy. We report here that exposure to LY294002, a potent PI3K inhibitor, aborts the activation of p53 by several drugs commonly used in cancer chemotherapy. Concomitantly, LY294002 attenuates p53-dependent, chemotherapy-induced apoptosis of cancer cells. These findings invoke an unexpected positive role for PI3K in p53 activation by anticancer agents, and suggest that the efficacy of PI3K inhibitors in cancer therapy may be greatly affected by the tumor p53 status.

Characteristics of the expression of KAI1/CD82 and PDGFRß and their impact on glioma progression.

The biological features of glioma cells may define their clinical outcome. Little is known about the interactions between KAI1/CD82 metastatic suppressor protein and PDGFR in gliomas. The aim of the study was to examine KAI1/CD82 and PDGFR expression in gliomas in order to find the impact of these proteins on progression of the tumors. PDGFR, KAI1/CD82 protein expression and mRNA of genes were evaluated on eighty four paraffin-embedded tissue of gliomas using immunohistochemical staining and RT-PCR analysis. The PDGFR expression was higher in IV/III than in I/II glioma grades (p = 0.0004). The level of mRNA PDGFR was associated with the degree of PDGFR immunoreactivity. Downregulation of KAI1/CD82 was associated with tumor malignancy (p = 0.007). The increased level of KAI1/CD82 gene expression (3-4-fold) was found in gliomas with strong KAI1/CD82 immunoreactivity. The parallel KAI1/CD82 and PDGFR expression was more significantly associated with cases in a group graded as III and IV than in a group graded as I/II (p = 0.002). We found that a loss of KAI1/CD82 and an increase in PDGFR expression in gliomas relate to a progressive tumor growth. The correlation between PDGFR and KAI1 expression in high grade gliomas suggests that a direct or indirect interaction between these proteins might have an impact on cell motility and invasive behavior of the tumor.

The effect of placenta previa on fetal growth and pregnancy outcome, in correlation with placental pathology.

OBJECTIVE: To compare the clinical characteristics and placental histopathology between pregnancies complicated by placenta previa and controls. STUDY DESIGN: Between 2009 and 2015, cesarean deliveries (CDs) of 119 pregnancies with placenta previa were identified from which maternal outcomes, neonatal outcomes and placental pathology were reviewed. Results were compared with CDs matched for maternal age and pregnancy complications (control group, n=119). Placental lesions were classified into maternal and fetal vascular supply lesions and inflammatory response. Composite neonatal outcome was defined as one or more of early neonatal complications. Small-for-gestational age (SGA) was defined as birth weight ⩽10th percentile. RESULTS: Placentas from the previa group had higher rates of weights <10th percentile (P<0.001) and of maternal and fetal vascular supply lesions (P<0.001, for both). Higher rate of SGA (P=0.003) and worse composite neonatal outcome (P<0.001) were also observed in the previa group as compared with controls. After controlling for potential confounding bias using multivariable logistic regression models, placenta previa remained statistically significantly associated with placental maternal (adjusted odds ratio (aOR) 2.48, 95% confidence interval (CI) 1.2-4.9, P=0.009) and fetal (aOR 7.05, 95% CI 2.4-20.2, P<0.001) vascular supply lesions, SGA (aOR 10, 95% CI 2.3-44.2, P=0.002) and adverse neonatal outcome (aOR 6.87, 95% CI 2.9-11.8, P<0.001). CONCLUSIONS: More placental vascular supply lesions, higher rate of SGA and worse neonatal outcome characterized pregnancies with placenta previa in the current study. These findings may suggest that abnormal placentation is accompanied by suboptimal implantation that interferes with fetal growth.

Serum resistin levels of obese and lean children and adolescents: biochemical analysis and clinical relevance.

OBJECTIVE: It was hypothesized that resistin links obesity with diabetes, but this has not been studied in children and adolescents to date. PATIENTS: We determined serum resistin levels of 135 obese (body mass index, 32.0 +/- 6.2 kg/m2; age, 12.6 +/- 3.4 yr) and 201 lean children (body mass index, 18.7 +/- 2.4 kg/m2; age, 12.5 +/- 2.5 yr) by a newly developed and extensively evaluated in-house immunoassay. These results were controlled for their association with markers of puberty, obesity, and insulin sensitivity. RESULTS: The analytical evaluation of our assay revealed different resistin isoforms with major peaks of higher than 660 and 55 kDa in the size exclusion chromatography. Using this assay system we found no difference in the resistin levels of obese compared with lean subjects (P = 0.48). However, resistin was significantly higher in girls than in boys (6.74 +/- 2.42 vs. 5.79 +/- 2.45; P < 0.001). Interestingly, in both obese and lean children, resistin correlated with age (P < 0.01), Tanner stage, and testosterone and estradiol levels (P < 0.05). In contrast, no significant correlation was found with parameters of insulin resistance such as homeostasis model assessment, insulin sensitivity index, or insulin, proinsulin, and glucose concentrations in obese subjects. CONCLUSIONS: Resistin appears to be not the main link between obesity and insulin resistance in children and adolescents but because of its association with Tanner stage, it may be related to the maturation of children during pubertal development. Additionally, we have demonstrated the presence of different molecular isoforms of resistin in human blood, and this may raise problems in comparing data from diverse assay systems.

The pharmacologic approach to the prevention of preeclampsia: from antiplatelet, antithrombosis and antioxidant therapy to anticonvulsants.

Preeclampsia has been suggested to be a two-stage disorder of an alteration in placental perfusion (stage 1) leading to generalized vascular endothelial damage (stage 2). Because the mechanism linking the two stages remains unclear, effective primary prevention is still impossible. However, advances made in our understanding of the pathophysiology of preeclampsia have paved the way for secondary and tertiary prevention approaches. Platelets are known to be activated in early pregnancy. They also play a pivotal role in the process of inflammation, as demonstrated by the finding that CD40 ligand is shed from activated platelets to directly initiate inflammation of the vessel wall. According to the Cochrane Library Update summarizing data from over 30,000 women, secondary prevention with antiplatelet drugs is associated with a 19% decrease in the risk of preeclampsia. Additional randomized controlled trials are needed to establish the association between preeclampsia and thrombophilia. The effect of the antithrombotic agent heparin on pregnancy outcome in preeclampsia and its potential preventive action in high-risk patients need to be elucidated. One of the several hypotheses of the pathogenesis of preeclampsia focuses on the oxidative stress caused by the imbalance in prooxidant and antioxidant forces. Preliminary findings on vitamin E and vitamin C supplementation in preeclamptic women are encouraging, and suggest a rationale for larger clinical trials. Although there is currently no explanation for the positive effect of magnesium sulfate on eclamptic seizures, studies have provided enough evidence to encourage its worldwide use as the primary anticonvulsant of choice in the tertiary prevention of maternal and perinatal death in severe preeclampsia/eclampsia. In conclusion, secondary and tertiary prevention of preeclampsia is possible when targeted at reducing maternal and neonatal morbidity and mortality.

Antepartum management protocol. Timing and mode of delivery in gestational diabetes.

We sought to determine whether strict glycemic control during diabetic pregnancy combined with elective early induction of labor reduces the rate of cesarean delivery and fetal birth trauma. We used a population-based longitudinal design covering three periods corresponding to changes in the management protocol for diabetic pregnancy at our center: 1) 1980-1989: no set level of maternal glycemia, elective cesarean section when estimated fetal weight was 4,500 g or more, and no elective early induction; 2) 1990-1992: desired mean maternal glycemia < or = 5.8 mmol/l, elective cesarean section when estimated fetal weight was 4,000 g or more, and elective early induction at 40 weeks for large-for-gestational-age fetuses; 3) 1993-1995: desired mean maternal glycemia < or = 5.3 mmol/l, elective cesarean section when estimated fetal weight was 4,000 g or more, and elective early induction at 38 weeks for large-for-gestational-age fetuses. Outcome of diabetic pregnancies was compared for the three periods, relative to that of the normal population. There was a gradual, constant, and significant decline in the incidence of macrosomia (17.9, 14.9, and 8.8%, respectively; P < 0.05) and large-for-gestational-age fetuses (23.6, 21.0, and 11.7%; P < 0.05) coupled with a gradual, nonsignificant decrease in cesarean deliveries (20.6, 18.4, and 16.2%) and in cases of shoulder dystocia (1.5, 1.2, and 0.6%), to rates close to those of the normal population. Our data show that maintaining strict control of maternal diabetes and adhering to an active management protocol for early elective delivery based on the estimated fetal weight have a significant effect on reducing the rate of macrosomia, thereby affecting the incidence of both traumatic births and cesarean deliveries.

The association between umbilical cord abnormalities and the development of non-reassuring fetal heart rate leading to emergent cesarean deliveries.

OBJECTIVE: To study the contribution of umbilical cord (UC) abnormalities in emergent cesarean deliveries (ECDs) for non-reassuring fetal heart rate (NRFHR) and to explore their association with placental histopathology and neonatal outcome. STUDY DESIGN: Data from 530 ECDs for NRFHR were reviewed for the occurrence of UC abnormalities. Those included the presence of UC entanglements, the number and location of loops, true knots and short cord (<50 cm). Multiple UC entanglements were defined as ⩾ 2 UC loops. Results were compared with 530 vaginal deliveries (VD group) matched for maternal age, parity and gestational age. Additionally, we compared neonatal outcome and placental histopathology in cases of ECDs with a single vs multiple UC entanglements. Neonatal outcome consisted of low Apgar score (⩽ 7 at 5 min), cord blood pH ⩽ 7.1 and composite neonatal outcome that was defined as one or more of respiratory distress, necrotizing enterocolitis, sepsis, transfusion, ventilation, seizure, hypoxic-ischemic encephalopathy, phototherapy or death. Placental lesions were classified as: lesions related to maternal vascular supply, lesions related to fetal vascular supply (consistent with fetal thrombo-occlusive disease), and maternal and fetal inflammatory responses. RESULTS: UC entanglements, true knots and short cords were all more common in the ECD group compared with the VD group, P<0.001, P=0.002, P=0.004, respectively. The rate of one loop entanglement did not differ between the groups. The rate of multiple UC entanglements was higher in the ECD group compared with the VD group, 20.6% vs 6.4%, respectively, P<0.001. ECDs with multiple compared with single UC entanglement had higher rate of adverse neonatal outcome, P=0.031, and more placental fetal vascular lesions 19.3% vs 8.1%, P=0.027, respectively. CONCLUSION: Multiple UC entanglements, true knots and short cords were more common in ECDs for NRFHR, suggesting their role in the development of fetal placental vascular lesions and adverse neonatal outcome.