Epidermal autophagy and beclin 1 regulator 1 and loricrin: a paradigm shift in the prognostication and stratification of the American Joint Committee on Cancer stage I melanomas.

BACKGROUND: The updated American Joint Committee on Cancer (AJCC) staging criteria for melanoma remain unable to identify high-risk stage I tumour subsets. OBJECTIVES: To determine the utility of epidermal autophagy and beclin 1 regulator 1 (AMBRA1)/loricrin (AMLo) expression as a prognostic biomarker for AJCC stage I cutaneous melanoma. METHODS: Peritumoral AMBRA1 expression was evaluated in a retrospective discovery cohort of 76 AJCC stage I melanomas. AMLo expression was correlated with clinical outcomes up to 12 years in two independent powered, retrospective validation and qualification cohorts comprising 379 AJCC stage I melanomas. RESULTS: Decreased AMBRA1 expression in the epidermis overlying primary melanomas in a discovery cohort of 76 AJCC stage I tumours was associated with a 7-year disease-free survival (DFS) rate of 81·5% vs. 100% survival with maintained AMBRA1 (P < 0·081). Following an immunohistochemistry protocol for semi-quantitative analysis of AMLo, analysis was undertaken in validation (n = 218) and qualification cohorts (n = 161) of AJCC stage I melanomas. Combined cohort analysis revealed a DFS rate of 98·3% in the AMLo low-risk group (n = 239) vs. 85·4% in the AMLo high-risk cohort (n = 140; P < 0·001). Subcohort multivariate analysis revealed that an AMLo hazard ratio (HR) of 4·04 [95% confidence interval (CI) 1·69-9·66; P = 0·002] is a stronger predictor of DFS than Breslow depth (HR 2·97, 95% CI 0·93-9·56; P = 0·068) in stage IB patients. CONCLUSIONS: Loss of AMLo expression in the epidermis overlying primary AJCC stage I melanomas identifies high-risk tumour subsets independently of Breslow depth. What's already known about this topic? There is an unmet clinical need for biomarkers of early-stage melanoma. Autophagy and beclin 1 regulator 1 (AMBRA1) is a proautophagy regulatory protein with known roles in cell proliferation and differentiation, and is a known tumour suppressor. Loricrin is a marker of epidermal terminal differentiation. What does this study add? AMBRA1 has a functional role in keratinocyte/epidermal proliferation and differentiation. The combined decrease/loss of peritumoral AMBRA1 and loricrin is associated with a significantly increased risk of metastatic spread in American Joint Committee on Cancer (AJCC) stage I tumours vs. melanomas, in which peritumoral AMBRA1 and loricrin are maintained, independently of Breslow depth. What is the translational message? The integration of peritumoral epidermal AMBRA1/loricrin biomarker expression into melanoma care guidelines will facilitate more accurate, personalized risk stratification for patients with AJCC stage I melanomas, thereby facilitating stratification for appropriate follow-up and informing postdiagnostic investigations, including sentinel lymph node biopsy, ultimately resulting in improved disease outcomes and rationalization of healthcare costs.

Characterization of the Physiological Displacement of the Aortic Arch Using Non-Rigid Registration and MR Imaging.

OBJECTIVES: The aim of this work was to study physiological aortic arch three-dimensional displacement using non-rigid registration methods and magnetic resonance imaging (MRI). MATERIALS AND METHODS: Ten healthy volunteers underwent thoracic MRI. Prospective cardiac gating was performed with a 3D turbo field echo sequence to obtain end-systolic and end-diastolic MR images. The rigid and elastic behavior between these two cardiac phases was detected and compared using either an affine or an elastic registration method. To assess reproducibility, a second MRI acquisition was performed 14 days later. RESULTS: Affine registration between the end-systolic and end-diastolic MR images showed significant global translations of the aortic arch and the supra-aortic vessels in the x, y, and z directions (2.02 ± 1.6, -0.71 ± 1.1, and -1.21 ± 1.4 mm, respectively). Corresponding elastic registration indicated significant local displacement with a vector magnitude of 5.1 ± 0.89 mm for the brachiocephalic artery (BCA), of 4.26 ± 0.83 mm for the left common carotid artery (LCCA), and of 4.8 ± 0.86 mm for the left subclavian artery (LSCA). There was a difference in displacement between the supra-aortic trunks of the order of 2 mm. Vector displacement was not statistically different between the repeated acquisitions. CONCLUSIONS: The present results showed important deformations in the ostia of supra-aortic vessels during the cardiac cycle. It seems that aortic arch motions should be taken into account when designing and manufacturing fenestrated endografts. The elastic registration method provides more precise results, but is more complex and time-consuming than other methods.

Heterogeneity in resistant fecal Bacteroides fragilis group collected from healthy people.

Normal nonpathogenic flora would represent a constant lake of resistance genes potentially transferable to human pathogens. To assess the prevalence of resistance genes and genetic variability of Bacteroides fragilis group (BFG) from normal flora, 177 Bacteroides isolates obtained from the fecal samples of healthy individuals. These isolates were subjected to antibiotic susceptibility testing and pulsed field gel electrophoresis (PFGE). The isolates were further tested for the presence of ermF, tetQ and bft genes by PCR. Our results indicated the presence of different clonal strains (1 common type and 57 single types) among the resistant isolates. The resistance rate for the six antibiotics in this study was between 1% and 95%. Most of the isolates (99%) were susceptible to metronidazole. ermF and tetQ were detected in all erythromycin and tetracycline resistant isolates. None of the isolates were carried bft gene. These data suggest dissemination of heterogenic clonal groups in healthy persons and resistance to 5 high commonly used antibiotics.

A nomogram for perioperative prognostic risk-assessment in twin-twin transfusion syndrome.

OBJECTIVE: Prognostic assessment in twin-to-twin transfusion syndrome (TTTS) is ill-defined. The objective of this study is to define a perioperative prognostic score for TTTS treated by percutaneous laser coagulation. METHODS: Consecutive cases of TTTS treated by percutaneous fetoscopic laser coagulation over a 6-year period were reviewed. Twin survival at 28 days was considered using a 3-level polytomous variable defined by 0, 1, or 2 fatal events. A multivariate prognostic analysis with internal validation was conducted using gestational age at diagnosis, weight discordance, umbilical artery, and ductus venosus abnormalities in the donor and the recipient respectively, cervical length, selectivity of surgery, and transplacental approach. RESULTS: On the basis of 507 cases, the perinatal survival rate of 2 and 1 twin was 46.2% and 31.5%, respectively. Statistically significant factors included umbilical artery abnormalities in the donor, gestational age, and transplacental approach, but with different effects regarding survival of 0, 1, or 2 twins. A scoring chart was subsequently constructed together with a nomogram for both a preoperative and immediate post-operative prognostic assessment. CONCLUSION: Part of the prognosis can be anticipated by perioperative findings. Although further validation is required, the presented nomogram should help unify the prognostic assessment in TTTS.

Perinatal outcome in prenatally diagnosed cardiac rhabdomyoma case series.

OBJECTIVE: This study aims to determine the characteristics and outcome of prenatally diagnosed cardiac rhabdomyomas. STUDY DESIGN: This retrospective descriptive study includes cases referred to our university hospital. We studied sonographic characteristics of rhabdomyoma along with the neonatal outcome. RESULTS: Eight cases were included, with a mean gestational age at diagnosis at 31 weeks of gestation and five patients diagnosed after 32 weeks. We noted a male gender in 75%, multiple rhabdomyoma in 50%, mostly situated in the interventricular septum (41%) and valvular regurgitation in 25%. Most patients delivered at term, including five cesareans (62.5%). Six babies survived (75%); three of them were later diagnosed with tuberous sclerosis (50%). CONCLUSION: Cardiac rhabdomyoma have variable ultrasound features. The usual favorable outcome can however be complicated by neonatal death (12%), valvular regurgitation and cerebral tuber.

Evaluation of the CHOP cardiovascular score as a prognostic predictor of outcome in twin-twin transfusion syndrome after laser coagulation of placental vessels in a prospective cohort.

OBJECTIVE: To investigate the prognostic value of cardiac function assessment by the previously reported CHOP (Children's Hospital of Philadelphia) cardiovascular score in twin-twin transfusion syndrome (TTTS). METHODS: All consecutive monochorionic pregnancies presenting with TTTS over a 24-month period were evaluated by preoperative echocardiography before percutaneous laser coagulation of chorionic vessels. Each of the 12 items of the CHOP score was evaluated prospectively and the cardiovascular score was categorized into stages using previously published cut-offs. The outcome considered for this study was neonatal survival of neither, one or both twins. RESULTS: In total, 215 pregnancies were enrolled. Due to technical issues, CHOP evaluation was incomplete in 16% of cases and follow-up was unavailable in 12%. Overall, there was a significant relationship between the CHOP score and the Quintero staging system, although this relationship was significantly reduced when parameters used in the Quintero system were removed from the CHOP score. Based upon neonatal survival, the CHOP score did not show any prognostic value regarding overall pregnancy outcome or individual recipient survival. CONCLUSION: Cardiac function assessment using the CHOP score is not of clinical use as a prognostic marker in TTTS. This suggests that cardiac function may not be of interest for preoperative staging when laser coagulation is the first-line treatment, other than to confirm the diagnosis of TTTS requiring surgery.

Profiling fetal cardiac function in twin-twin transfusion syndrome.

OBJECTIVES: Cardiomyopathy in the recipient twin is a marker of severity in twin-twin transfusion syndrome (TTTS), making it a potentially valuable tool for staging the disease. This study aimed to provide a quantitative description of cardiac function in the recipient twin. METHODS: Consecutive monochorionic pregnancies complicated with TTTS and treated by percutaneous laser coagulation underwent fetal echocardiography before surgery. An unsupervised classification analysis was conducted to identify groups of twins with similar cardiac profiles. The predictive value of the recipient twin's preoperative cardiac function based on these profiles was assessed, using perinatal death of at least one twin as the main outcome. The cardiac function profiles that we identified were compared with the current Quintero staging. RESULTS: A total of 107 pregnancies were included, with six of these lost to follow-up; 63/107 complete cases were available for multivariate description of the recipient's cardiac function. Three different preoperative cardiac profiles were identified with increasing right and left myocardial performance index, decreasing right and left shortening fraction, and increasing ductus venosus pulsatility index. Although the three groups represented progressive stages of the syndrome-related cardiomyopathy, no correlation was found with pregnancy outcome. Of Quintero Stage 1 cases, 55% showed significant alterations of cardiac function in the recipient twin. CONCLUSIONS: Progressive cardiomyopathy can be assessed quantitatively in the recipient twin and does not influence pregnancy outcome when fetoscopic laser coagulation is the first-line treatment. Compared with the current staging, cardiac profiling allows discrimination of cases with significant myocardial dysfunction.

Outcome of anaemic monochorionic single survivors following early intrauterine rescue transfusion in cases of feto-fetal transfusion syndrome.

OBJECTIVE: To evaluate the outcome of severely anaemic monochorionic (MC) twins surviving the death of their co-twin following early intrauterine rescue transfusion in cases of feto-fetal transfusion syndrome (FFTS). STUDY DESIGN: We reviewed all MC pregnancies complicated with FFTS following primary management, in which a single intrauterine fetal death (IUFD) was diagnosed with certainty within 24 hours between January 1999 and December 2006. We included MC survivors who presented ultrasound or Doppler features of fetal anaemia following the death of their co-twin. Intrauterine transfusion (IUT) was given to all survivors who were anaemic. RESULTS: Nineteen MC twin pregnancies presented a single intrauterine death (IUD) associated with an anaemic co-twin. Median gestational age at IUD was 23 [20-28] weeks. The median interval between IUD and IUT was 12 [8-24] hours. There were 58% (11/19) healthy survivors. Perinatal death rate was 26% (5/19) including 16% (3/19) intrauterine and 10% (2/19) neonatal deaths. Abnormal prenatal cerebral findings developed in 21% (4/19) cases, always within 1 month after the death of the co-twin. Considering occlusive techniques and other management separately, there were 64% (7/11) and 50% (4/8) healthy survivors, respectively, and perinatal death occurred in 36% (4/11) and 12.5% (1/8) of fetuses, respectively. Prenatal fetal cerebral lesions developed in 9% (1/11) of cases following occlusive techniques and in 37.5% (3/8) of fetuses when managed differently. The median gestational age at delivery in the survivors was 31 [25-38] weeks. CONCLUSION: In cases of FFTS with single anaemic survivors, early IUT could be offered following extensive counselling and close follow up.

Electrochemical treatment of the pollutants generated in an ink-manufacturing process.

The effluents of ink-manufacturing processes contain a large variety of pollutants such as dyes, surfactants, biocides, water soluble solvents, etc. In this work, the electrochemical oxidation of several dyes (methylene blue and rhodamine B), solvents (monoethylene glycol, diethylene glycol and glycerol) and surfactants (sodium dodecylbenzenesulfonate) has been studied. To carry out the electrolyses, a bench-scale plant with a single-compartment electrochemical flow-cell was used. Boron doped diamond (BDD) was used as anode and stainless steel (AISI 304) as cathode. For all the compounds tested, the conductive diamond electrooxidation allows achieving the almost complete removal of COD of the waste with a very high current efficiency. The efficiencies of the electrochemical processes seem to depend on the current density and on the nature of the anions contained in the waste (chlorine, sulphate, phosphate). Thus, it has been observed that the use of chloride media favours the treatment of dyes. On the contrary, the use of sulphate- or phosphate-containing solutions improves the removal of the aliphatic compounds studied (solvents). These results suggest an important role of the mediated electrochemical processes on the overall performance of the reaction system.

State-of-the-art treatment of common femoral artery disease.

Atherosclerotic common femoral artery (CFA) disease is a well-known and frequent cause of symptomatic peripheral artery disease (PAD). Not so long ago, surgical treatment was considered the gold standard and the main treatment option. Therapeutic advances have, however, provided a wide and suitable armamentarium. These advances concern medical treatment and the direct treatment of lesions by open surgery or endovascular treatment. The aim of this manuscript was to summarize therapeutic updates and to describe the current endovascular and open surgical procedures used to treat common femoral artery disease.

Luminal concentrations of orally ingested 4-aminosalicylic acid as determined by in-vivo equilibrium dialysis.

We measured 4-aminosalicylic acid (4-ASA) levels in faecal water by in-vivo equilibrium dialysis during oral ingestion of drug by two different dose protocols (A and B). In Protocol A, 5 normal subjects ingested 3 g of 4-ASA as the free acid and 20 mg of metaclopromide per day. On Day 5, small dialysis sacs filled with dextran 40 were ingested and the oral drug was continued until the sacs were retrieved from the stool. Protocol B followed the same format except that 3 g of 4-ASA was ingested twice daily and metaclopromide was omitted. In both protocols concentrations of 4-ASA and N-acetylated 4-ASA in sac contents were measured by HPLC. In-vitro dialysis studies showed bi-directional equilibrium was reached within 120 min. During Protocol A, intraluminal concentrations of total 4-ASA ranged from 14.0 to 32.2 mmol/L with a mean of 20.6 mmol/L. With Protocol B, total 4-ASA levels ranged from 20.1 to 41.3 mmol/L with a mean of 33.9 mmol/L. From 90 to 99% of the drug in the dialysates was N-acetylated. These concentrations of total 4-ASA are similar to those of 5-ASA after ingestion of therapeutic doses of sulphasalazine or absorption-resistant formulations of 5-ASA. Thus, oral 4-ASA could have a role in the treatment of inflammatory bowel disease.

[Hypophyseal tuberculosis. A case report]. / Tuberculose hypophysaire. A propos d'un cas.

The authors present a case of hypophyseal tuberculosis. It is the case of a patient with abnormal sella turcica, erosion of sella and hypopituitarism. At intervention, they ascertain a lesion of sphenoïdal sinus with the lesion of hypophysis. The authors made the review of literature and ascertain the singularity of the both lesion. Generally, the tuberculosis of adenohypophysis is associated with tuberculosis meningitis. They think that it is an extension of sinusal lesion.

A comparison of first trimester measurements for prediction of delivery date.

OBJECTIVE: We evaluated the biometric values of first trimester measurements for prediction of delivery date by computing new dating formulas and evaluating them within the same settings in a large population. METHODS: We studied unselected pregnancies undergoing first trimester ultrasound examination by a single experimented sonographer. We used 331 pregnancies conceived by assisted reproductive treatment to build a new dating formula and another 3667 normal pregnancies with spontaneous delivery to test the accuracy of these measurements and formulas. The reproducibility of the two measurements which performed best was done. RESULTS: Crown-rump length (CRL) had the lowest random and systematic errors. The mean (SD) of errors in predicting day of delivery were 0.023 (7.873), 0.092 (7.928), 0.088 (8.208) and 0.269 (8.310) for CRL, biparietal diameter (BPD), head circumference (HC) and abdominal circumference (AC) respectively. CRL and BPD proved to be highly reproducible. The percentages of deliveries within ±10 and ±14 days of the predicted term were comparable for CRL and BPD but were significantly smaller when using HC, AC. CONCLUSIONS: Both CRL and BPD proved to be highly reproducible and able to predict with good precision the date of delivery. However, CRL has significantly lower random and systematic errors than all other biometric parameters.

Emergency cerclage in cases of twin-to-twin transfusion syndrome with a short cervix at the time of surgery and relationship to perinatal outcome.

OBJECTIVE: To evaluate the impact of emergency cerclage on perinatal outcome in cases presenting with cervical length less than fifth centile at the time of laser surgery. POPULATION AND METHODS: Observational study of severe twin-to-twin transfusion syndrome (TTTS) cases diagnosed before 26 weeks of gestation and treated by fetoscopic selective laser coagulation (FSLC). Transvaginal sonographic measurement of cervical length prior to treatment identified cases with cervical length less than fifth centile (15 mm). Expectant management was followed in these cases prior to 2004, and a McDonald suture was performed immediately after laser surgery from 2004 onwards. Outcome was compared in patients with and without cerclage. RESULTS: Cervical length was a strong predictor for gestational age (GA) at delivery (p = 0.005). Mean GA at laser therapy was comparable [22.4 ( +/- 2.1) and 22.1 ( +/- 2) in patients with (n = 9) and without cerclage (n = 5), respectively, (p = 0.8)], whereas mean (SD) GA at delivery was 30.5 ( +/- 4.3) and 23.1 ( +/- 2.6) weeks in patients with and without cerclage, respectively, (p = 0.004). There were 16 (89%) and 4 (40%) surviving twins in cases with and without cerclage, respectively (p = 0.01). CONCLUSIONS: In TTTS treated by laser, cervical length before treatment is significantly associated with GA at delivery. In cases with cervix < 15 mm, emergency cerclage may prolong the pregnancy and allow for better outcome.

First-trimester ultrasound examination and the outcome of monochorionic twin pregnancies.

OBJECTIVE: To refine the incidence of abnormal first-trimester ultrasound measurements and their correlation with the outcome of monochorionic diamniotic pregnancies. METHODS: First-trimester crown-rump length (CRL) and nuchal translucency thickness (NT) measurements were studied in three subgroups of a total of 200 monochorionic twin gestations referred to our center between June 2002 and February 2006. Intertwin CRL discordance was defined as > 10% and the 95th percentile of NT thickness for gestational age was used. The first group of 103 consecutive unselected monochorionic diamniotic twin pregnancies was prospectively followed up from 11-14 weeks onwards, throughout the pregnancy. The second group of 136 nonconsecutive monochorionic diamniotic twin pregnancies including 64 that developed TTTS was studied retrospectively. The third group of 100 consecutive cases of TTTS studied retrospectively for the correlation between first trimester measurements and staging and timing of occurrence of TTTS. RESULTS: In group 1, the incidence of TTTS was 5 in 103 (5%, 95CI [0.7-9]). Large intertwin CRL discordance and increased NT were correlated with perinatal death. In group 2, no significant association was found between first-trimester parameters and the development of TTTS but discordance in early second trimester biometry and Doppler were. In group three, a positive correlation was found between the intertwin discordance in CRL and early occurrence of TTTS before 20 weeks of gestation (p = 0.02). CONCLUSION: Monochorionic twin gestations who ultimately develop TTTS may exhibit intertwin difference in growth as early as 11-14 weeks of gestation. The earlier the discordance the earlier the development of the disease.

Intertwin discordance in umbilical venous volume flow: a reflection of blood volume imbalance in twin-to-twin transfusion syndrome.

OBJECTIVES: To compare umbilical venous volume flow (UVVF) between donor and recipient twins in twin-to-twin transfusion syndrome (TTTS) using an index that is independent of gestational age and to correlate changes in this index with outcome following endoscopic laser surgery. METHODS: UVVF was calculated in 84 cases of TTTS by multiplying the umbilical vein cross-sectional area at its entry into the fetal abdomen by time averaged blood velocity. All cases were classified according to the Quintero staging system. The ratio between UVVF in recipients and donors (R/D-UVVF) in each pair of twins was calculated before and 48 h after laser treatment, and changes in R/D-UVVF were correlated with pregnancy outcome. Intraobserver and interobserver UVVF measurement reliability was assessed in 19 singletons, and 13 donor and recipient twins before laser treatment using the intraclass correlation coefficient (ICC). RESULTS: Twenty-five, 32, 21 and six cases presented as Quintero Stages 1, 2, 3 and 4, respectively, at a median gestational age of 20 (range, 15-26) weeks. Intraobserver and interobserver ICC for UVVF measurement in twins were 0.97 and 0.67, respectively. UVVF was a median of 2.13-fold (range, 0.3-19-fold) higher in recipients than in donors (137 mL/min vs. 64 mL/min, P < 0.001) and increased with gestational age (r = 0.58, P < 0.001 for recipients, r = 0.62, P < 0.001 for donors). From 68 cases in which R/D-UVVF could be measured 48 h following laser surgery, cases with a favorable outcome showed a significant decrease in R/D-UVVF from a median of 1.97 to 1.27 (P < 0.01) and cases with recurrent TTTS (n = 6) did not (decrease in R/D-UVVF from a median of 2.32 to 2.19, P = 0.17). Using a cut-off of < 30% reduction of R/D-UVVF, 66% of the cases with recurrence could be predicted, and the odds ratio for recurrence was 3.13 (95% CI, 0.52-18.29). A significant UVVF imbalance between recipient and donor twins was found in cases with Quintero Stages 1-3 but not in those with Stage 4. CONCLUSIONS: In TTTS, UVVF is significantly higher in recipients than in their donor cotwins and the R/D-UVVF seems adequately to indicate the flow imbalance between twins, regardless of gestational age. A decrease in R/D-UVVF could be predictive of a favorable evolution following laser treatment.

Three-dimensional sonographic assessment of fetal urine production before and after laser surgery in twin-to-twin transfusion syndrome.

OBJECTIVE: Fetal urine production in twin-to-twin transfusion syndrome (TTTS) reflects the hemodynamic imbalance between the donor and recipient twins but it has not been measured in this particular condition. The aim of this study was to measure fetal urine production using three-dimensional (3D) ultrasound in donor and recipient twins before and after laser treatment for TTTS and to correlate this with umbilical venous volume flow (UVVF). METHODS: Urine production rate (UPR) was measured using 3D ultrasound with Virtual Organ Computer-aided AnaLysis (VOCAL) in 106 cases of severe TTTS. The rotation angle was set at 30 degrees . The bladder volume was measured twice in each fetus (V(1) and V(2)), with an interval of 5-30 min between measurements, in order to calculate the UPR. When V(2) > V(1), UPR was calculated using the formula: V(2) - V(1) /time interval. Together with UPR, UVVF was measured before and after treatment. Both parameters were corrected for fetal weight. Inter- and intraobserver variability were calculated in 16 cases using the intraclass correlation coefficient. RESULTS: Before laser treatment, UPR was significantly higher in recipients compared with donors (median, 14.8 and 0 mL/h/kg, mean 23.8 and 2.3 mL/h/kg, respectively, P < 0.001), and UPR was positively correlated with UVVF in both twins. Following laser treatment (48 h later), UPR decreased to 9 mL/h/kg (P < 0.001) in recipients, while there was no change in donors. UVVF increased significantly from a median value of 92 to 132 mL/min/kg (P < 0.01) in donors and decreased significantly from 150 to 99 mL/min/kg (P < 0.001) in recipients. CONCLUSIONS: In TTTS UPR is correlated to UVVF and reflects the hemodynamic imbalance between donor and recipient twins. Following laser treatment, UPR decreases in recipients but is unaffected in donors. However, changes in UVVF occur in both twins. This suggests that although fetal renal function is driven by fetal hemodynamics, there may be a lag in the recovery of renal function in the donor twin.