Emmanuelle Dantony

Prognostic Factors in Prolactin Pituitary Tumors: Clinical, Histological, and Molecular Data from a Series of 94 Patients with a Long Postoperative Follow-Up

CONTEXT AND OBJECTIVE Predicting pituitary tumor behavior remains a challenge. This multiparameter investigation aimed to identify markers for recurrence and progression in prolactin tumors. DESIGN From a cohort of patients treated for prolactin tumors by surgery, we retrospectively studied clinical data, tumor characteristics, clinical outcome, and the expression of nine genes by quantitative RT-PCR. RESULTS This study included 94 patients (62 females and 32 men), with long postoperative follow-up periods (mean, 138 +/- 46 months); 54.3% of patients had a macro or giant adenoma. Tumors were classified into three pathological groups based on their radiological and histological characteristics (noninvasive, 61; invasive, 22; and aggressive-invasive, 11). Immediately after surgery, 60 patients (63.8%) went into remission (prolactin level normalization). Persistently elevated prolactin levels (36.2%) were associated with increasing age, male sex, high preoperative prolactin levels, large tumor size on univariate analysis, and invasion and pathological classification on univariate and multivariate (P = 8 x 10(-10) and 3 x 10(-8)) analysis. During follow-up, 19 patients (20%) had tumors that recurred or progressed under dopamine agonist treatment. Invasion and pathological classification were associated with recurrence or progression on univariate analysis. Seven genes (ADAMTS6, CRMP1, PTTG, ASK, CCNB1, AURKB, and CENPE) were associated with tumor recurrence or progression and five of these (ADAMTS6, CRMP1, ASK, CCNB1, and CENPE) were associated with the pathological classification. CONCLUSION This study identifies both the clinical and histological factors that relate to prolactin tumor recurrence or progression. Molecular markers give additional information for prognosis of such tumors. Altogether, our results could influence the management of patients with pituitary tumors.

Prostate Cancer Ablation with Transrectal High-Intensity Focused Ultrasound: Assessment of Tissue Destruction with Contrast-enhanced US

PURPOSE To assess contrast material-enhanced ultrasonographic (US) findings seen after high-intensity focused ultrasound (HIFU) ablation of prostate cancer and correlate the US findings with post-HIFU biopsy findings. MATERIALS AND METHODS The study was ethics committee approved. Written informed consent was obtained from all patients. Twenty-eight patients referred for HIFU prostate cancer ablation underwent contrast-enhanced prostate US before treatment, gadolinium-enhanced magnetic resonance (MR) imaging and repeat contrast-enhanced US 1-3 days after treatment, and contrast-enhanced US-guided biopsy 30-45 days after treatment. The contrast-enhanced US enhancement patterns of the biopsy sites--assigned a score of S0 for no enhancement, S1 for mild and/or patchy enhancement, or S2 for marked enhancement--were compared with corresponding biopsy findings, which were assigned a score of B0 for necrosis and/or fibrosis without viable prostate gland tissue, B1 for vascularized tissue without viable gland tissue, or B2 for viable gland tissue (benign or malignant). Then, six additional patients underwent contrast-enhanced prostate US 15-30 minutes and 1 day after HIFU ablation, and the results of these two US examinations were compared. RESULTS Contrast-enhanced US performed on days 1-3 and days 30-45 after HIFU ablation depicted a large devascularized zone with peripheral enhancing areas that were localized anteriorly in all 28 patients, posteriorly in nine, laterally in five, and at the apex in 20 patients. MR findings were concordant. At biopsy, viable gland tissue was found at nine (6.2%) of 146 S0 sites, 10 (34%) of 29 S1 sites, and 44 (60%) of 73 S2 sites. The odds ratios for finding viable tissue (score B1 or B2) at S1 and S2 sites as opposed to S0 sites were 21 (95% confidence interval [CI]: 6, 71) and 73 (95% CI: 22, 243), respectively (P < .0001). Contrast-enhanced US performed 15-30 minutes and 1 day after treatment in the six additional patients had similar findings. CONCLUSION Contrast-enhanced US is a promising tool for distinguishing between ablated (devascularized) and viable (enhancing) tissue immediately after HIFU treatment.

Clonidine and dexmedetomidine increase the pressor response to norepinephrine in experimental sepsis: a pilot study.

Objective:During septic shock, vasopressors are a cornerstone of therapy. In septic shock, very high doses of vasopressors sometimes have to be used due to vascular desensitization, the mechanisms of which are poorly understood. This study assesses whether &agr;-2 agonists increase pressor responsiveness following lipopolysaccharide administration. Design:Parallel groups of animals (n = 7 per group) subjected to pharmacologic interventions. Setting:Physiology laboratory. Subjects:Rats. Interventions:In anesthetized rats, the pressor responses to increasing doses of norepinephrine (norepinephrine-systolic pressure curve) were assessed during a baseline period, after injection of saline or lipopolysaccharide, and after subsequent injection of saline, dexmedetomidine (100 &mgr;g/kg IV), or clonidine (200 &mgr;g/kg IV). Measurements and Main Results:Differences in the slopes of the norepinephrine-pressure curves were assessed across drug treatments and intervals. The pressor dose of norepinephrine necessary to increase systolic pressure by 33 and 100 mm Hg (pressor dose 33 and pressor dose 100) was determined. Pressor responsiveness to norepinephrine decreased slightly over time in the saline-saline group (saline 1 or 2 vs baseline: mean decrease of the slope, 2 mm Hg/&mgr;g/kg norepinephrine; p < 0.05), whereas there was a large decrease after lipopolysaccharide (lipopolysaccharide vs baseline: mean decrease of the slope, 7.2; p < 0.001). Clonidine alone had no effect, but when administered following lipopolysaccharide, it caused a striking increase in pressor responsiveness (mean slope after lipopolysaccharide, 10.7 [95% CI, 9.9–11.6]; after clonidine, 17.5 [95% CI, 16.7–18.4]). Similarly, dexmedetomidine administered after lipopolysaccharide caused a large increase in pressor responsiveness above lipopolysaccharide values. Accordingly the pressor dose 33 and pressor dose 100 values were lowered following lipopolysaccharide and restored by &agr;-2 agonists. Conclusions:The pressor response to norepinephrine was reduced following lipopolysaccharide and increased to baseline levels following &agr;-2 agonists.

Occupational Exposures Obtained by Questionnaire in Clinical Practice and Their Association With Semen Quality

In industrial countries, evidence suggests that semen quality has been steadily decreasing over the past 5 decades. We employed a short questionnaire to examine the association between self-reported physical or chemical occupational exposures and semen quality. The study included 402 men consulting for couple infertility (314 with oligospermia, asthenospermia, or teratospermia and 88 with normal semen; World Health Organization criteria). Exposure effects on global sperm quality and total sperm count, sperm motility, and sperm morphology were investigated. We found significant associations between semen impairment and occupational risk factors such as exposure to heavy metals (adjusted odds ratio [OR] = 5.4; 95% confidence interval [CI], 1.6-18.1), solvents (OR = 2.5; 95% CI, 1.4-4.4), fumes (OR = 1.9; 95% CI, 1.1-3.4), and polycyclic aromatic hydrocarbons (OR = 1.9; 95% CI, 1.1-3.5). Exposure to pesticides or cement was nearly significant (OR = 3.6; 95% CI, 0.8-15.8, and OR = 2.5; 95% CI, 0.95-6.5, respectively). Physical risk factors were associated with some sperm anomalies, such as mechanical vibrations with oligospermia and teratospermia as well as excess heat and extended sitting periods with impaired motility. Exposure to ionizing radiation and electromagnetic fields was not associated with semen impairment; these results, however, may be skewed, because very few subjects reported such exposure. Despite the small dataset, self-reported exposures were correlated with semen impairment. This approach may be recommended in routine clinical practice to seek relationships between occupational exposures to reprotoxic agents and impaired semen parameters. This knowledge would allow preventive measures in the workplace to be established and could be complemented by the use of biomarkers to better characterize exposure to chemical substances and their spermiotoxic effects.

Toxicity Associated with Stavudine Dose Reduction from 40 to 30 mg in First-Line Antiretroviral Therapy

Background To compare the incidence and timing of toxicity associated with the use of a reduced dose of stavudine from 40 to 30 mg in first-line antiretroviral therapy (ART) for HIV treatment and to investigate associated risk factors. Methods Multicohort study including 23 HIV programs in resource-limited countries. Adults enrolled between January 2005 and December 2009. Four-year rates of all-cause and stavudine-specific toxicity were estimated. Multilevel mixed-effect Poisson and accelerated failure models were used to investigate factors associated with toxicity and timing of diagnosis. Findings A total of 48,785 patients contributed 62,505 person-years of follow-up. Rate of all-cause toxicity was 7.80 (95%CI 7.59–8.03) per 100 person-years, but varied greatly across sites (range 0.41–21.76). Patients treated with stavudine 40 mg had higher rates of toxicity (adjusted rate ratio [aRR] 1.18, 95%CI 1.06–1.30 during the first year of ART; and 1.51, 95%CI 1.32–1.71 during the second year). Women, older age, initial advanced clinical stage, and low CD4 count were associated with increased toxicity rate ratios. Timing of lipodystrophy and peripheral neuropathy diagnosis were 12% and 13% shorter, respectively, in patients treated with stavudine 40 mg than in those receiving 30 mg stavudine dose (P = 0.03 and 0.07, respectively). Insterpretation Higher rates of drug-related toxicity were reported in patients receiving stavudine 40 mg compared with 30 mg, and the time to toxicity diagnosis was shorter in patients treated with the higher dose. Higher rates of toxicity were observed during the first two years of ART.

ED50 and ED95 of intrathecal levobupivacaine with opioids for Caesarean delivery

BACKGROUND This prospective randomized double-blind dose-response study aimed to determine the ED₅₀ and ED₉₅ of intrathecal levobupivacaine combined with morphine and sufentanil for elective Caesarean delivery. METHODS Parturients undergoing elective Caesarean delivery were included and allocated to five levobupivacaine dose groups (6, 8, 10, 12, or 14 mg). Combined spinal-epidural (CSE) anaesthesia was performed, allowing intrathecal administration of the allocated dose of levobupivacaine with intrathecal morphine 100 µg and intrathecal sufentanil 2.5 µg, and insertion of epidural catheter for completing anaesthesia in the case of failure. The dose was considered as successful if a bilateral T6 sensory block to pinprick occurred in 15 min and if no epidural supplement was required during surgery. A probit regression analysis was performed to calculate the ED₅₀ and ED₉₅ of intrathecal levobupivacaine for Caesarean delivery. RESULTS Eighty-five parturients were included. A block to T6 sensory level was reached in 15 min for most of the patients. The ED₅₀ and ED₉₅ of levobupivacaine were 6.2 mg (95% CI: 2.6-7.6) and 12.9 mg (11.1-17.9), respectively. Haemodynamic stability and the rate of nausea and vomiting were similar among groups. Greater doses of levobupivacaine were associated with increased motor block duration. CONCLUSIONS When combined with intrathecal sufentanil 2.5 µg and intrathecal morphine 100 µg, the ED₉₅ of intrathecal levobupivacaine is 12.9 mg for Caesarean delivery. If doses of levobupivacaine less than the ED₉₅, particularly near the ED₅₀, are used, these doses should be administered under a CSE technique.

Risk of Recurrence in Pituitary Neuroendocrine Tumors: A Prospective Study Using a Five-Tiered Classification

Background: Most pituitary neuroendocrine tumors (PitNETs) show benign behavior, but a substantial number are invasive, recur, or resist medical treatment. Based on a retrospective case‐control study, we recently proposed a classification of PitNETs of prognostic relevance. This prospective study aims to test the value of this classification in an independent patient cohort. Methods: All patients who underwent PitNET surgery from 2007 to 2012 in one single center were included. Using a grading system based on invasion on magnetic resonance imaging, immunocytochemical profile, Ki‐67, mitotic index, and p53 positivity, tumors were classified. Progression‐free survival of the graded tumors was calculated by the Kaplan‐Meier method and compared using the log‐rank test. A multivariate analysis, using a Cox regression model, was also performed. Results: In total, 365 patients had grade 1a PitNETs (51.2%), followed by grade 2a (32.3%), 2b (8.8%), and 1b tumors (7.7%). Of 213 patients with a follow‐up, 42% had recurrent (n = 52) or progressive disease (n = 37) at 3.5 years. Grade was a significant predictor of progression‐free survival (P < 0.001). Multivariate analysis indicated grade (P < 0.001), age (P = 0.035), and tumor type (P = 0.028) as independent predictors of recurrence and/progression. This risk was 3.72‐fold higher for a grade 2b tumor compared with grade 1a tumor. Conclusions: Our data suggest that classification of PitNETs into five grades is of prognostic value to predict postoperative tumor behavior and identifies patients who have a high risk of early recurrence or progression. It therefore will allow clinicians to adapt their therapeutic strategies and stratify patients in future clinical trials.

Pelvic-Floor Muscle Rehabilitation in Erectile Dysfunction and Premature Ejaculation

Background In men, involuntary or voluntary ischiocavernosus muscle contractions after erection lead to intracavernous blood pressures far higher than the systolic pressure, which builds and maintains penile rigidity. Thus, erectile dysfunction may be partly due to ischiocavernosus muscle atrophy and may be treated by rehabilitation interventions. Objective The purpose of this study was to determine whether pelvic-floor muscle strengthening interventions could be associated with increases in intracavernous pressure that would increase penile rigidity. Design An observational study was conducted. Methods One hundred twenty-two men with isolated erectile dysfunction and 108 men with isolated premature ejaculation participated (no neuromuscular diseases or previous perineal rehabilitation). Thirty-minute sessions of voluntary contractions coupled with electrical stimulation were designed to increase ischiocavernosus muscle strength (monitored through intracavernous pressure increase). A linear mixed-effects model per group analyzed separately, then jointly, the maximum change in pressure (ΔP) and the maximum baseline (ie, respectively, the average contraction-generated difference in intracavernous pressure and the intracavernous pressure plateau at full erection, both measured during the highest moving average of the best 2 minutes of each session). Results Over 20 sessions, the maximum ΔP increased in erectile dysfunction as well as in premature ejaculation (87% and 88%, respectively, in men with positive trends). The maximum baseline also increased (99% and 72%, respectively, in men with positive trends). The joint modeling indicated that the mean expected progressions of the intracavernous pressure after 5 sessions in erectile dysfunction and premature ejaculation were 62.85 and 64.15 cm H2O, respectively. Limitations Indirect measurements were obtained of intracavernous pressure and ischiocavernosus muscle force. Conclusions Pelvic-floor muscle rehabilitation was found to be beneficial in erectile dysfunction. However, its effects on symptoms of premature ejaculation, despite intracavernous pressure gains, were much more difficult to assess. The definitive proof of its benefits requires rather difficult-to-design clinical trials.

Morphometric analysis of the distal femur in total knee arthroplasty and native knees

AIMS Analysis of the morphology of the distal femur, and by extension of the femoral components in total knee arthroplasty (TKA), has largely been related to the aspect ratio, which represents the width of the femur. Little is known about variations in trapezoidicity (i.e. whether the femur is more rectangular or more trapezoidal). This study aimed to quantify additional morphological characteristics of the distal femur and identify anatomical features associated with higher risks of over- or under-sizing of components in TKA. METHODS We analysed the shape of 114 arthritic knees at the time of primary TKA using the pre-operative CT scans. The aspect ratio and trapezoidicity ratio were quantified, and the post-operative prosthetic overhang was calculated. We compared the morphological characteristics with those of 12 TKA models. RESULTS There was significant variation in both the aspect ratio and trapezoidicity ratio between individuals. Femoral trapezoidicity was mostly due to an inward curve of the medial cortex. Overhang was correlated with the aspect ratio (with a greater chance of overhang in narrow femurs), trapezoidicity ratio (with a greater chance in trapezoidal femurs), and the tibio-femoral angle (with a greater chance in valgus knees). DISCUSSION This study shows that rectangular/trapezoidal variability of the distal femur cannot be ignored. Most of the femoral components which were tested appeared to be excessively rectangular when compared with the bony contours of the distal femur. These findings suggest that the design of TKA should be more concerned with matching the trapezoidal/rectangular shape of the native femur. TAKE HOME MESSAGE The distal femur is considerably more trapezoidal than most femoral components, and therefore, care must be taken to avoid anterior prosthetic overhang in TKA

Circulating Klotho associates with cardiovascular morbidity and mortality during hemodialysis

Background: Klotho gene was identified as an aging suppressor. In animals, klotho overexpression extends life span, and defective klotho results in rapid aging and early death. The kidney is the main contributor to circulating klotho levels, and, during chronic kidney disease, renal klotho gene expression is drastically reduced in animals and humans as well. Objective: We aimed to determine the consequences of a serum klotho (seKL) defect on cardiovascular morbidity and mortality during chronic dialysis. Design: The ARNOGENE study was designed to prospectively follow a cohort of hemodialysis patients for 2 years without specific intervention. A total of 769 patients was recruited and followed from the end of 2008 until January 2011. A total of 238 patients was analyzed due to a technical sample conservation issue with other samples. Results: The median seKL was markedly reduced, 360.4 ng/L (interquartile range 176.5) as compared with nondialysis chronic kidney disease patients or healthy volunteers. Patients with a seKL above the first quartile (≥280 ng/L) had a significantly reduced occurrence of outcome combining cardiovascular events and cardiovascular death [odds ratio (OR) = 0.39; 0.19 to 0.78, P = 0.008] compared with patient with klotho <280 ng/L. This effect persisted (OR = 0.86; 0.76 to 0.99, P = 0.03) after adjustment on age, sex, diabetes, cardiac insufficiency, dialysis vintage, and serum hemoglobin, albumin, fibroblast growth factor‐23, phosphate, and calcium. Conclusions: These results suggest that, during chronic hemodialysis, conservation of seKL >280 ng/L is associated with a better 2‐year cardiovascular protection. Thus, a preserved klotho function supports cardiovascular protection and may represent a prognostic tool and therapeutic target for cardiovascular disease.