Role of fibroblast growth factor-23 as an early marker of metabolic bone disease of prematurity.

PURPOSE: Metabolic bone disease of prematurity (MBDP) remains a significant cause of morbidity in extremely premature newborns. In high-risk patients, suspected diagnosis and subsequent treatment modifications, with limitations in terms of sensitivity and specificity, rely on low phosphorus levels and/or high levels of alkaline phosphatase (ALP). We investigated the potential of fibroblast growth factor-23 (FGF23) as an early marker for MBDP when measured at 3-4 weeks of life in at-risk patients. METHODS: A single-center prospective observational non-interventional study including preterm newborns of both sexes, with a gestational age of less than 32 weeks and/or a birth weight of less than 1500 g. In the standard biochemical screening for MBDP performed between 3 and 4 weeks of life within a nutritional profile, the determination of FGF23 was included along with other clinical and metabolic studies. The study was conducted at Marqués de Valdecilla University Hospital in Santander, Spain, from April 2020 to March 2021. Participants provided informed consent. Biochemical analyses were conducted using various platforms, and follow-up evaluations were performed at the discretion of neonatologists. Patients at high risk for MBDP received modifications in treatment accordingly. The sample was descriptively analyzed, presenting measures of central tendency and dispersion for continuous variables, and absolute numbers/percentages for categorical ones. Tests used included t-tests, Mann‒Whitney U tests, chi-square tests, logistic regressions, Pearson correlation, and ROC curve analysis (IBM SPSS Statistics version 19). Significance level: P < 0.05. RESULTS: In the study involving 25 at-risk premature newborns, it was found that 20% (n = 5) were diagnosed with MBDP. Three of these patients (60%) were identified as high-risk based on standard biochemical evaluation at 3-4 weeks of age, while the other two patients (40%) were diagnosed in subsequent weeks. However, in all 5 patients, measurement of FGF23 levels would allow for early identification and optimization of treatment before other markers become altered. Low levels of FGF23 at 3-4 weeks, even with normal phosphorus and ALP levels, indicate the need for modifications in nutritional supplementation. CONCLUSIONS: MBDP remains a significant concern in extremely premature newborns. Current diagnostic methods rely on limited biochemical markers. Early detection of low FGF23 levels enables timely interventions, potentially averting demineralization.

Time of leaving work pregnancy results during COVID-19 pandemic. The MOACC-19 cohort from Spain.

BACKGROUND: COVID-19 pandemic has changed the way pregnancies have been controlled as well as working conditions. In countries with paid leave of work, leaving earlier has been a relevant measure for controlling the pandemic. No study has been published on factors associated with earlier leaving work in pregnancy and the consequences it could have on pregnancy outcomes. OBJECTIVE: We aimed to identify woman and pregnancy characteristics associated with leaving work earlier and its consequences on pregnancy results. METHOD: A cohort study was carried out in Cantabria, Northern Spain, including 760 women who were pregnant in 2020 and were working at the beginning of their pregnancy. Data on pregnancy characteristics and results were obtained from medical records and gestational age at leaving work was self-reported. In a logistic regression analysis, leaving work before 26th week of pregnancy was the main effect variable. RESULTS: Several factors were associated with lower probability of leaving work before 26th week, including university studies (OR = 0.49, 95% CI: 0.36, 0.68), having presential work (OR = 0.57, 95% CI: 0.40, 0.81), women born in non-European countries (OR = 0.55, 95% CI: 0.30, 1.01) and non-smokers (OR for smokers = 1.79, 95% CI: 1.12, 2.87). Neither type of delivery, gestational age at delivery nor other pregnancy results were associated with the gestational age of leaving work. CONCLUSION: Several pregnancy and women characteristics were associated with leaving work earlier in the COVID-19 pandemic, although it was not associated with any pregnancy outcome.

Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer.

BACKGROUND: Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of BRCA mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS: Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS: Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).

Acute coronary syndrome and recurrent colitis as immune-related adverse events in a lung cancer patient.

Immune checkpoint inhibitors have become a target for pharmacological research in lung cancer. Immune-related adverse events (irAEs) such as pneumonitis, colitis, hepatitis and endocrinopathies have been well characterized in immune checkpoint inhibitors, but coronary toxicities, like acute coronary syndrome, are poorly described. Herein, we report a possible acute coronary syndrome as immune-related adverse event in a lung cancer patient.

Usefulness of Ultrasound in the Diagnosis of Intestinal Anisakiasis.

OBJECTIVES: To evaluate the ultrasound (US) findings of gastrointestinal anisakiasis and the utility of US in its early diagnosis. METHODS: We retrospectively assessed the imaging findings and clinical data of 21 patients with gastrointestinal anisakiasis. Diagnosis was confirmed by a positive antigen (n = 16), endoscopy (n = 2), or a compatible clinical presentation, physical examination, and history of raw fish consumption (n = 3). Ultrasound findings reviewed included segmental circumferential bowel wall thickening, segmental edema of the valvulae conniventes, dilated small bowel loops with hyperperistalsis or hypoperistalsis, free fluid, and color Doppler hyperemia. RESULTS: Segmental circumferential bowel wall thickening was present in all 21 patients, whereas segmental edema of the valvulae conniventes was visualized in 13 patients, moderately dilated small-bowel loops proximal to the affected segment with increased peristalsis in 14 patients, small-to-moderate ascites in 18 patients, and color Doppler hyperemia in 7 patients. The US evaluation ruled out a surgical pathologic examination in all patients, and the diagnosis of anisakiasis was suggested by the radiologist on the basis of US findings in 12 patients. CONCLUSIONS: Familiarity with the suggestive US presentation of intestinal anisakiasis may allow the radiologist to propose the diagnosis of this overlooked cause of abdominal pain and may also prompt an investigation of recent raw or lightly cooked seafood ingestion. Ultrasound findings of bowel wall thickening, especially segmental edema of the valvulae conniventes, hyperperistalsis, and dilatation of small-bowel loops proximal to the affected segment, ascites, and color Doppler hyperemia, along with a history of raw fish ingestion should aid the radiologist in the diagnosis of anisakiasis.

Metabolic Changes in Children that Received Chemotherapy.

Cancer treatments are associated with short and long-effects. Epidemiological reports have revealed clinical features of metabolic syndrome (MS), obesity or overweight in young cancer survivors. The aim of the study was to examine the prevalence of unhealthy weight status and risk factors associated with MS related to chemotherapy. We study 52 pediatric cancer patients and analyze cholesterol, triglycerides, glycosylated hemoglobin, body mass index, waist circumference (WC), FINDRISC test. All the parameters were analyzed according to the percentile corresponding to sex and age of each child. The data show an important modification in weight, body mass index, and WC as in triglycerides, and cholesterol that could be associated with the development of MS. The variance analysis showed that the WC, triglycerides, and cholesterol are statistically correlated in our population. A follow-up for MS in children cancer survivor should be considered necessary.

P-glycoprotein Activity Correlates With Treatment Response in 2 Leukemia Child Patients.

Acute lymphoblastic leukemia is the most important childhood cancer. Multidrug resistance is an important factor of poor prognosis. We present the P-glycoprotein (P-gp) activity in 2 patients with different outcomes. Both patients had B-cell acute lymphoblastic leukemia; they were responding properly to the treatment, but one of them had an increment in the P-gp activity that correlates with an increment in the disease manifestation, the patient had to be hospitalized and developed sepsis and subsequently died. P-gp levels were correlated with disease progression. P-gp activity needs to be evaluated during treatment to assess and prevent disease relapse or the patient´s death.

Dysregulation of autophagy in rat liver with mitochondrial DNA depletion induced by the nucleoside analogue zidovudine.

The nucleoside reverse transcriptase inhibitor zidovudine (AZT), used in HIV infection treatment, induces mitochondrial DNA (mtDNA) depletion. A cause-effect relationship between mtDNA status alterations and autophagy has been reported. Both events are common in several liver diseases, including hepatocellular carcinoma. Here, we have studied autophagy activation in rat liver with mtDNA depletion induced by AZT administration in drinking water for 35 days. AZT at a concentration of 1 mg/ml, but not 0.5 mg/ml in the drinking water, decreased mtDNA levels in rat liver and extrahepatic tissues. In liver, mtDNA-encoded cytochrome c oxidase 1 protein levels were decreased. Although serum biomarkers of liver and kidney toxicity remained unaltered, ß-hydroxybutyrate levels were increased in liver of AZT-treated rats. Moreover, autophagy was dysregulated at two levels: (i) decreased induction signalling of this process as indicated by increases in autophagy inhibitors activity (AKT/mTOR), and absence of changes (Beclin-1, Atg5, Atg7) or decreases (AMPK/ULK1) in the expression/activity of pro-autophagy proteins; and (ii) reduced autophagosome degradation as indicated by decreases in the lysosome abundance (LAMP2 marker) and the transcription factor TFEB controlling lysosome biogenesis. This resulted in increased autophagosome abundance (LC3-II marker) and accumulation of the protein selectively degraded by autophagy p62, and the transcription factor Nrf2 in liver of AZT-treated rats. Nrf2 was activated as indicated by the up-regulation of antioxidant target genes Nqo1 and Hmox-1. In conclusion, rat liver with AZT-induced mtDNA depletion presented dysregulations in autophagosome formation and degradation balance, which results in accumulation of these structures in parenchymal liver cells, favouring hepatocarcinogenesis.

Angiotensin-(1-7) protects from brain damage induced by shiga toxin 2-producing enterohemorrhagic Escherichia coli.

Shiga toxin 2 (Stx2)-producing enterohemorrhagic induced brain damage. Since a cerebroprotective action was reported for angiotensin (Ang)-(1-7), our aim was to investigate whether Ang-(1-7) protects from brain damage induced by Stx2-producing enterohemorrhagic Escherichia coli The anterior hypothalamic area of adult male Wistar rats was injected with saline solution or Stx2 or Stx2 plus Ang-(1-7) or Stx2 plus Ang-(1-7) plus A779. Rats received a single injection of Stx2 at the beginning of the experiment, and Ang-(1-7), A779, or saline was administered daily in a single injection for 8 days. Cellular ultrastructural changes were analyzed by transmission electron microscopy. Stx2 induced neurodegeneration, axonal demyelination, alterations in synapse, and oligodendrocyte and astrocyte damage, accompanied by edema. Ang-(1-7) prevented neuronal damage triggered by the toxin in 55.6 ± 9.5% of the neurons and the Stx2-induced synapse dysfunction was reversed. In addition, Ang-(1-7) blocked Stx2-induced demyelination in 92 ± 4% of the axons. Oligodendrocyte damage caused by Stx2 was prevented by Ang-(1-7) but astrocytes were only partially protected by the peptide (38 ± 5% of astrocytes were preserved). Ang-(1-7) treatment resulted in 50% reduction in the number of activated microglial cells induced by Stx2, suggesting an anti-inflammatory action. All these beneficial effects elicited by Ang-(1-7) were blocked by the Mas receptor antagonist and thus it was concluded that Ang-(1-7) protects mainly neurons and oligodendrocytes, and partially astrocytes, in the central nervous system through Mas receptor stimulation.

Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity.

Acetaminophen (APAP) is a well-known analgesic and antipyretic drug. It is considered to be safe when administered within its therapeutic range, but in cases of acute intoxication, hepatotoxicity can occur. APAP overdose is the leading cause of acute liver failure in the northern hemisphere. Historically, studies on APAP toxicity have been focused on liver, with alterations in brain function attributed to secondary effects of acute liver failure. However, in the last decade the pharmacological mechanism of APAP as a cannabinoid system modulator has been documented and some articles have reported "in situ" toxicity by APAP in brain tissue at high doses. Paradoxically, low doses of APAP have been reported to produce the opposite, neuroprotective effects. In this paper we present a comprehensive, up-to-date overview of hepatic toxicity as well as a thorough review of both toxic and beneficial effects of APAP in brain.

Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn's disease.

BACKGROUND & AIMS: We assessed the accuracy of magnetic resonance enterography (MRE) in monitoring response to therapy in patients with Crohn's disease (CD) using ileocolonoscopy as a reference standard. METHODS: We performed a prospective multicenter study of 48 patients with active CD and ulcers in at least one ileocolonic segment. All patients underwent ileocolonoscopy and MRE at baseline and 12 weeks after completing treatment with corticosteroids (CS) or anti-tumor necrosis factor agents. Disease activity was quantified using Crohn's Disease Endoscopic Index of Severity (CDEIS) and Magnetic Resonance Index of Activity (MaRIA). The primary analysis was to determine the accuracy of MRE in identification of healing, defined as the disappearance of ulcers in endoscopy examination. Additional analyses established the accuracy of MRE in determining endoscopic remission (a CDEIS score <3.5) and change in severity based on consideration of all segments. RESULTS: MRE determined ulcer healing with 90% accuracy and endoscopic remission with 83% accuracy. The mean CDEIS and MaRIA scores significantly changed at week 12 in segments with ulcer healing, based on endoscopic examination (CDEIS: 21.28 ± 9.10 at baseline vs 2.73 ± 4.12 at 12 weeks; P < .001 and MaRIA: 18.86 ± 9.50 at baseline vs 8.73 ± 5.88 at 12 weeks; P < .001). The MaRIA score accurately detected changes in lesion severity (Guyatt score: 1.2 and standardized effect size: 1.07). MRE was as reliable as endoscopy in assessing healing; no significant changes in CDEIS or MaRIA scores were observed in segments with persistent ulcers, based on endoscopic examination (CDEIS: 26.43 ± 9.06 at baseline vs 20.77 ± 9.13 at 12 weeks; P = .18 and MaRIA: 22.13 ± 8.42 at baseline vs 20.77 ± 9.17 at 12 weeks; P = .42). The magnitude of change in CDEIS scores correlated with those in MaRIA scores (r = 0.51; P < .001). CONCLUSIONS: MRE evaluates ulcer healing with a high level of accuracy when ileocolonoscopy is used as the reference standard. The MaRIA is a valid, responsive, and reliable index assessing response to therapy in patients with CD.

The effect of acetaminophen on the expression of BCRP in trophoblast cells impairs the placental barrier to bile acids during maternal cholestasis.

Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis.

The expression of genes involved in hepatocellular carcinoma chemoresistance is affected by mitochondrial genome depletion.

Deletions and mutations in mitochondrial DNA (mtDNA), which are frequent in human tumors, such as hepatocellular carcinoma (HCC), may contribute to enhancing their malignant phenotype. Here we have investigated the effect of mtDNA depletion in the expression of genes accounting for mechanisms of chemoresistance (MOC) in HCC. Using human HCC SK-Hep-1 cells depleted of mtDNA (Rho), changes in gene expression in response to antitumor drugs previously assayed in HCC treatment were analyzed. In Rho cells, a decreased sensitivity to doxorubicin-, SN-38-, cisplatin (CDDP)-, and sorafenib-induced cell death was found. Both constitutive and drug-induced reactive oxygen species generation were decreased. Owing to activation of the NRF2-mediated pathway, MDR1, MRP1, and MRP2 expression was higher in Rho than in wild-type cells. This difference was maintained after further upregulation induced by treatment with doxorubicin, SN-38, or CDDP. Topoisomerase-IIa expression was also enhanced in Rho cells before and after treatment with these drugs. Moreover, the ability of doxorubicin, SN-38 and CDDP to induce proapoptotic signals was weaker in Rho cells, as evidenced by survivin upregulation and reductions in Bax/Bcl-2 expression ratios. Changes in these genes seem to play a minor role in the enhanced resistance of Rho cells to sorafenib, which may be related to an enhanced intracellular ATP content together with the loss of expression of the specific target of sorafenib, tyrosine kinase receptor Kit. In conclusion, these results suggest that mtDNA depletion may activate MOC able to hinder the efficacy of chemotherapy against HCC.

Association Between Assisted Reproductive Technology and Cerebral Palsy: A Meta-Analysis.

BACKGROUND: Since 1978 many children are born thanks to assisted reproductive technology (ART). However, the long-term effects of these therapies are still not fully known. Our objective is to evaluate the risk of cerebral palsy (CP) after ART compared with that in those spontaneously conceived (SC) and to examine this risk in single, multiple, and preterm births and the evolution of the risk over the years. METHODS: PubMed, Embase, and Web of Science databases were searched until December 2022. Studies were included if they studied CP cases in children born through ART. 16 studies were finally selected. Quality of studies was assessed using Newcastle Ottawa Scale. Pooled OR was estimated by weighting individual OR/RR by the inverse of their variance. A random-effect model was applied. To assess the causes of heterogeneity, we performed meta-regression analyses. RESULTS: A significantly high risk of CP was found (OR = 1.27; 95% CI 1.12 to 1.43) in children born through ART compared with those SC. This risk increased in singletons (OR = 1.48; 95% CI 1.23 to 1.79) but disappeared in multiple (OR = 1.05; 95% CI 0.93 to 1.18) and preterm births (OR = 1.09; 95% CI 0.87 to 1.37). We found a higher risk of CP in children born before the year 2000 (OR = 3.40; 95% CI 2.49 to 4.63). CONCLUSIONS: ARTs slightly increase the risk of CP once the effect of multiple gestation is controlled. Further studies are needed to clarify whether the techniques themselves, fertility problems, or associated maternal comorbidities are responsible for this risk.

Sonographic diagnosis of symptomatic ureteral calculi: usefulness of the twinkling artifact.

PURPOSE: Our aim was to analyze the value of ultrasound using the twinkling sign in the diagnosis of ureteral stones in patients with renal colic in the emergency setting. MATERIALS AND METHODS: Prospective study of 100 patients with suspected renal colic who underwent an US examination, including color Doppler mode. We analyzed sensitivity, specificity, predictive values, and accuracy. We evaluated whether the stone was observed before or after the twinkling artifact, and whether the use of the Doppler color increased the examination time. RESULTS: US including color Doppler detected 76 of the 84 confirmed lithiasis. The sensitivity and specificity were 90 % and 100 %, respectively. The positive predictive value was 100 % and the negative 67 %. The accuracy was 92 %. A total of 59 calculi (78 %) examined by color Doppler sonography showed the twinkling artifact. Seventy percent of the twinkling-positive calculi showed the artifact before the stone itself was detected. Considering the location of the stones the twinkling sign was seen before the stone in 92 % of lithiasis located in the mid lumbar ureter (p = 0.02). The use of the twinkling artifact showed a trend to facilitate the detection of smaller calculi (<10 mm) (p = 0.08). The average examination time was 5.8 min [± 4.3] (without differences between the stones detected before or after the twinkling artifact, p = 0.75). CONCLUSION: Doppler US examination shows good sensitivity and specificity for the diagnosis of symptomatic ureteral stones. The twinkling artifact is useful for the early detection of the calculi, especially in the middle tract of the ureter, usually the most difficult place in sonographic diagnosis. It also seems helpful for the detection of smaller stones. The use of color Doppler does not increase the exploration time.

Macro1 domain residue F156: A hallmark of SARS-CoV-2 de-MARylation specificity.

SARS-CoV-2 is a large, enveloped and positive sense single stranded RNA virus. Its genome codes for 16 non-structural proteins. The largest protein of this complex is nsp3, that contains a well conserved Macro1 domain. Viral Macro domains were shown to bind to mono-ADP-ribose (MAR) and poly-ADP-ribose (PAR) in their free form or conjugated to protein substrates. They carry ADP-ribose hydrolase activities implicated in the regulation of innate immunity. SARS-CoV-2 and SARS-CoV show widely different induction and handling of the host interferon response. Herein, we have conducted a mutational study on the key amino-acid residue F156 in SARS-CoV-2, pinpointed by bioinformatic and structural studies, and its cognate residue N157 in SARS-CoV. Our data suggest that the exchange of these residues slightly modifies ADP-ribose binding, but drastically impacts de-MARylation activity. Alanine substitutions at this position hampers PAR binding, abolishes MAR hydrolysis of SARS-CoV-2, and reduces by 70% this activity in the case of SARS-CoV.

Sensitization to Aeroallergens in a Mexican Cohort with Allergic Conjunctivitis: A Cross-sectional Retrospective Study Conducted in Ángeles Puebla Hospital.

This study aims to evaluate the sensitization distribution of aeroallergens in patients with allergic conjunctivitis (AC) living in a temperate subhumid region and to describe the prevalence in a Mexican cohort. A total of 761 patient records were revisited, including the results of the skin prick test (SPT) for 45 aeroallergens. We found 292 patients with AC and a positive SPT in a 5-year period. The most frequent aeroallergens include dust mites (69.2% for Dermatophagoides pteronyssinus and 47.6% for Dermatophagoides farinae), trees (36% for cypress and 22.6% for ash), animals (33.9% for dogs and 26.7% for cats), and grasses (21.2% for Paspalum notalum and 19.9% for Poa pratensis). Among the studied population, a prevalence of 38.4% for the disease was calculated. House dust mites were responsible for most sensitizations found in the studied population. There is a high prevalence of AC in the selected cohort during the period studied.

Maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced high-grade ovarian cancer: Main analysis of second progression-free survival in the phase III PAOLA-1/ENGOT-ov25 trial.

BACKGROUND: PAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. We report the prespecified main second progression-free survival (PFS2) analysis for PAOLA-1. METHODS: This randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were randomised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was reported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure. RESULTS: After a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64-0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64-0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymerase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab. CONCLUSION: In newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevacizumab provided continued benefit beyond first progression, with a significant PFS2 improvement and a time to second subsequent therapy or death delay versus placebo plus bevacizumab.

Further characterization of the electrogenicity and pH sensitivity of the human organic anion-transporting polypeptides OATP1B1 and OATP1B3.

Organic anion-transporting polypeptides (OATPs) are involved in the liver uptake of many endogenous and xenobiotic compounds, such as bile acids and drugs, respectively. Using Xenopus laevis oocytes and Chinese hamster ovary (CHO) cells expressing rat Oatp1a1, human OATP1B1, or OATP1B3, the sensitivity of these transporters to extracellular/intracellular pH (pHo/pHi) and changes in plasma membrane potential (ΔΨ) was investigated. In X. laevis oocytes, nonspecific plasma membrane permeability increased only at pHo below 4.5. Above this value, both using oocytes and CHO cells, extracellular acidification affected differently the specific transport of taurocholic acid (TCA) and estradiol 17ß-d-glucuronide (E(2)17ßG) by Oatp1a1 (stimulation), OATP1B1 (inhibition), and OATP1B3 (stimulation). Changes in substrate uptake in the presence of valinomycin (K(+)-ionophore), carbonyl cyanide 3-chlorophenylhydrazone and nigericin (protonophores), and amiloride (Na(+)/H(+)-inhibitor) and cation replacement in the medium were studied with fluorescent probes for measuring substrate uptake (cholylglycyl amidofluorescein) and changes in pHi (SNARF-4F) and ΔΨ [DilC(1)(5)]. The results suggest that activity of these three carriers is sodium/potassium-independent and affected differently by changes in pHo and ΔΨ: Oatp1a1 was confirmed to be an electroneutral anion exchanger, whereas the function of both OATP1B1 and OATP1B3 was markedly affected by the magnitude of ΔΨ. Moreover, electrophysiological measurements revealed the existence of a net anion influx associated to OATP1B1/OATP1B3-mediated transport of TCA, E(2)17ßG, and estrone-3-sulfate. Furthermore, a leakage of Na(+) through OATP1B1 and OATP1B3, which is not coupled to substrate transport, was found. In conclusion, these results suggest that OATP1B1 and OATP1B3 are electrogenic transporters whose activity may be strongly affected under circumstances of displacement of local pH.

Ultrasound findings of Crohn's disease: correlation with MR enterography.

Crohn's disease is a chronic inflammatory bowel disease characterized by periods of relative inactivity alternating with acute flare-ups. Imaging techniques play a fundamental role in the diagnosis and follow-up of Crohn's disease, providing information on the extent of disease, disease activity, and the presence of extramural complications. Because of the frequent re-evaluation required by the relapsing nature of Crohn's disease and the relative young age at which most patients are diagnosed, techniques that use ionizing radiation are best avoided in monitoring this population. Thus, magnetic resonance enterography (MRE) and ultrasonography (US) are the preferable techniques. Various studies have demonstrated that US is accurate in assessing the gut. Despite some clear advantages over MRE, US has long been underused in the evaluation of intestinal disease. This review presents an overview of the main imaging findings in Crohn's disease, correlating representative US images with MRE and surgical pathology specimens. We conclude that US reliably depicts both bowel-related and mesenteric features of Crohn's disease and US findings correlate strongly with MRE findings.