Assessment of melanocytic skin lesions with a high-definition laser Doppler imaging system.

BACKGROUND: Early detection is a major goal in the management of malignant melanoma. Besides clinical assessment many noninvasive technologies such as dermoscopy, digital dermoscopy and in vivo laser scanner microscopy are used as additional methods. Herein we tested a system to assess lesional perfusion as a tool for early melanoma detection.¦METHODS: Laser Doppler flow (FluxExplorer) and mole analyser (MA) score (FotoFinder) were applied to histologically verified melanocytic nevi (33) and malignant melanomas (12).¦RESULTS: Mean perfusion and MA scores were significantly increased in melanoma compared to nevi. However, applying an empirically determined threshold of 16% perfusion increase only 42% of the melanomas fulfilled the criterion of malignancy, whereas with the mole analyzer score 82% of the melanomas fulfilled the criterion of malignancy.¦CONCLUSION: Laser Doppler imaging is a highly sensitive technology to assess skin and skin tumor perfusion in vivo. Although mean perfusion is higher in melanomas compared to nevi the high numbers of false negative results hamper the use of this technology for early melanoma detection.

Dopamine reverses reward insensitivity in apathy following globus pallidus lesions.

Apathy is a complex, behavioural disorder associated with reduced spontaneous initiation of actions. Although present in mild forms in some healthy people, it is a pathological state in conditions such as Alzheimer's and Parkinson's disease where it can have profoundly devastating effects. Understanding the mechanisms underlying apathy is therefore of urgent concern but this has proven difficult because widespread brain changes in neurodegenerative diseases make interpretation difficult and there is no good animal model. Here we present a very rare case with profound apathy following bilateral, focal lesions of the basal ganglia, with globus pallidus regions that connect with orbitofrontal (OFC) and ventromedial prefrontal cortex (VMPFC) particularly affected. Using two measures of oculomotor decision-making we show that apathy in this individual was associated with reward insensitivity. However, reward sensitivity could be established partially with levodopa and more effectively with a dopamine receptor agonist. Concomitantly, there was an improvement in the patient's clinical state, with reduced apathy, greater motivation and increased social interactions. These findings provide a model system to study a key neuropsychiatric disorder. They demonstrate that reward insensitivity associated with basal ganglia dysfunction might be an important component of apathy that can be reversed by dopaminergic modulation.

Novel immunotherapeutic strategies against human papillomavirus type 16 (HPV 16) induced lesions and cervical cancer

RESUME Le cancer du col de l'utérus, deuxième cause de mort par cancer chez la femme, a pu être associé à une infection par plusieurs types de virus du Papillome Humain (HPV), et en particulier HPV 16. Les vaccins prophylactiques sont efficaces à prévenir le cancer du col utérin alors que les lésions de haut grade sont généralement traitées par ablation chirurgicale et par d'éventuels traitements additionnels. Les risques de récurrence liés aux ablations et le taux de mortalité (50%) lié au cancer, démontrent le besoin de développer des stratégies alternatives afin de cibler les lésions précancéreuses. A ce jour, les vaccins thérapeutiques ont démontré peu de résultats cliniques, contrastant avec les régressions de tumeurs ectopiques observées après vaccination dans des modèles murins avec tumeurs associées à HPV. L'induction de réponses immunitaires protectrices dans la muqueuse génitale semble être cruciale pour l'efficacité des vaccins thérapeutiques HPV et évaluer leur efficacité dans un modèle murin avec tumeurs-HPV génitales représente un pré-requis important avant de procéder à des études cliniques. Par conséquent, nous avons établi un modèle murin orthotopique où des tumeurs se développent dans (a muqueuse génitale après une instillation intra-vaginale (i.vag) de cellules tumorales exprimant les oncogènes E6/E7 d'HPV 16 et transduites par un vecteur lentiviral codant la luciferase afin de suivre le développement de ces tumeurs in vivo par imagerie. La caractérisation histologique a démontré que les tumeurs grandissaient dans l'épithélium vaginal et en accord avec leur localisation, des cellules Τ CD8 spécifiques à E7 induites par la tumeur n'étaient détectées que dans la muqueuse génitale et les ganglions drainants. Une infiltration de cellules Τ régulatrices a aussi été mise en évidence, empêchant la régression spontanée de ces tumeurs. Par conséquent, ce modèle devrait être plus adéquat pour tester des stratégies thérapeutiques, étant donné qu'il partage certaines similarités immunologiques avec les lésions génitales naturelles causées par HPV. Etant donné que les oncogènes E6 et E7 d'HPV sont nécessaires à la maintenance du phénotype cancéreux des cellules cervicales, elles représentent des antigènes cibles pour la vaccination thérapeutique. Nous avons démontré que des souris immunisées par voie sous-cutanée (s.c.) avec une dose d'un vaccin à base de polypeptide E7 d'HPV 16 et d'adjuvants, présentaient de nombreuses cellules Τ CD8 sécrétant de l'IFN-γ spécifiquement à E7 dans leurs organes lymphatiques mais également dans la muqueuse génitale. De plus, le manque de corrélation entre les réponses spécifiques mesurées dans la périphérie et dans la muqueuse génitale souligne la nécessité et l'importance de déterminer les réponses immunitaires localement là où les lésions dues à HPV se développent. Si une vaccination par voie muqueuse est plus propice à traiter/régresser des infections génitales/tumeurs que le voie parentérale est un sujet débattu. Nos données montrent que seule la voie s.c. était capable de régresser la quasi totalité des tumeurs génitales chez la souris bien que des réponses CD8 spécifiques à E7 similaires étaient mesurées dans la muqueuse génitale après des vaccinations intra-nasale et i.vag. Afin d'augmenter la réponse spécifique au vaccin dans la muqueuse génitale, des immunostimulants ont été administrés par voie i.vag après vaccination. Nous avons démontré qu'une application i.vag d'agonistes des Toll like receptors après une vaccination s.c. induisait de manière significative une augmentation des cellules Τ CD8 sécrétant de l'IFN-γ spécifiquement à E7 dans la muqueuse génitale. Plus précisément et concernant les CpG et Poly l:C, l'effet était probablement associé à une attraction locale des cellules Τ CD8 et deuxièmement dépendait respectivement des voies de signalisation TLR9 et TLR3/Mda5. Finalement, cette stratégie combinatoire a permis de régresser des grosses tumeurs génitales chez la souris, suggérant qu'une telle immunothérapie pourrait adéquatement traiter des lésions dues à HPV chez les femmes. SUMMARY Cervical cancer is the second leading cause of cancer mortality in women worldwide and results from an infection with a subset of Human Papillomavirus (HPV), HPV 16 representing the most prevalent type. The available prophylactic vaccines are an effective strategy to prevent cervical cancer while already established high grade lesions usually require surgical ablation of lesion with possible additional treatments. Recurrence risks linked to conventional ablations and the high mortality (50%) related to cervical cancer demonstrate the need for alternative strategies like immunotherapies to target pre¬cancerous lesions. Until now, therapeutic vaccines only showed limited clinical results, which strongly contrast with the regression of ectopic tumors observed in the available murine HPV tumor models after vaccination. Induction of protective immune responses in the genital mucosa (GM) may be crucial for efficacy of HPV therapeutic vaccines and evaluating their efficacy in a murine model with genital HPV- tumors represents an important prerequisite for clinical trials. Thus, we have here established an orthotopic mouse model where tumors in the GM develop after an intravaginal (i.vag) instillation of HPV 16 E6/E7 oncogenes-expressing tumor cells transduced with a luciferase encoding lentivirus vector for in vivo imaging of tumor growth. Histological characterization showed that tumor grew within the vaginal epithelium and according to their mucosal location tumor- induced E7-specific CD8 Τ cells were restricted to the GM and genital draining lymph nodes together with high Τ regulatory cells infiltrates preventing spontaneous regression. Consequently, sharing several immunological similarities with natural genital HPV lesions, this novel genital tumor model may be more adequate to test therapeutic strategies. As E6 and/or E7 HPV oncogenes expression is required for the maintenance of the cancerous phenotype of cervical cells, they represent target antigens for therapeutic vaccination. We reported that mice subcutaneously (s.c.) immunized once with an adjuvanted HPV 16 E7 polypeptide vaccine harbored high E7-specific IFN-γ secreting CD8 Τ cells in their lymphoid organs and more importantly in the GM. In addition, the lack of correlation between specific responses measured in the periphery with those measured in the GM highlighted the necessity and relevance to determine the immune responses locally where HPV 16-induced lesions develop. Whether a mucosal route of immunization is better to treat/regress genital infections/tumors than parenteral immunization is still debated. Our data shows that although similar E7-specific IFN-γ secreting CD8 Τ cells responses were measured in the GM upon mucosal routes of E7 vaccine delivery (nasal and vaginal immunizations), only the s.c immunization was able to regress at least all genital tumors in mice. To further increase the vaccine-specific responses in the GM, immunostimulatory agents were i.vag administrated after vaccination. We demonstrated that a single i.vag application of toll like receptor (TLR) agonists after a s.c. E7 vaccination induced a significant increase of E7-specific IFN-γ secreting CD8 Τ cells in the GM. More precisely, regarding CpG and Poly l:C, the effect is most probably associated with a local attraction of total CD8 Τ cells and secondly depends on TLR9 and TLR3/Mda5 signaling pathways, respectively. Finally, this combinatorial strategy induced tumor regression in mice harboring large genital tumors, suggesting that such an immunotherapy could be adequate to treat HPV-induced lesions in women.

Carotid Dose Spring in Definitive Irradiation of T1N0 Squamous Cell Laryngeal Carcinoma Using Helical Tomotherapy

Purpose/Objective(s): To implement a carotid dose sparing protocol using helical Tomotherapy in T1N0 squamous cell laryngeal carcinoma.Materials/Methods: Between July and August 2010, 7 men with stage T1N0 laryngeal carcinoma were included in this study. Age ranged from 47 - 74 years. Staging included endoscopic examination, CT-scan and MRI when indicated. Planned irradiation dose was 70 Gy in 35 fractions over 7 weeks. A simple treatment planning algorithm for carotid sparing was used: maximum point dose to the carotids 35 Gy, to the spinal cord 30 Gy, and 100% PTV volume to be covered with 95% of the prescribed dose. Carotid volume of interest extended to 1 cm above and below of the PTV. Doses to the carotid arteries, to the critical organs, and to the planned target volume (PTV) with our standard laryngeal irradiation protocol was compared. Daily megavoltage scans were obtained before each fraction. When necessary, the Planned Adaptive software (TomoTherapy Inc., Madison, WI) was used to evaluatethe need for a re-planning, which has never been indicated. Dose data were extracted using the VelocityAI software (Atlanta, GA), and data normalization and dose-volume histogram (DVH) interpolation were realized using the Igor Pro software (Portland, OR).Results:A significant (p\0.05) carotid dose sparing compared to our standard protocol with an average maximum point dose of 38.3 Gy (standard deviation [SD] 4.05 Gy), average mean dose of 18.59 Gy (SD 0.83 Gy) was achieved. In all patients, 95% of the carotid volume received less than 28.4 Gy (SD 0.98 Gy). The average maximum point dose to the spinal cord was 25.8 Gy (SD 3.24 Gy). PTV was fully covered with more than 95% of the prescribed dose for all patients with an average maximum point dose of 74.1 Gy and the absolute maximum dose in a single patient of 75.2 Gy. To date, the clinical outcomes have been excellent. Three patients (42%) developed stage 1 mucositis that was conservatively managed, and all the patients presented a mild to moderate dysphonia. All adverse effects resolved spontaneously in the month following the end of treatment. Early local control rate is 100% considering a 4 - 5 months post treatment follow-up.Conclusions: Helical Tomotherapy allows a clinically significant decrease of carotid irradiation dose compared to standard irradiation protocols with an acceptable spinal cord dose tradeoff. Moreover, this technique allows the PTV to be homogenously covered with a curative irradiation dose. Daily control imaging brings added security margins especially when working with high dose gradients. Further investigations and follow-up are underway to better evaluate the late clinical outcomes especially the local control rate, late laryngeal and vascular toxicity, and expected potential impact on cerebrovascular events.

Diagnostic Accuracy of (18)F-FDG-PET and PET/CT in the Differential Diagnosis between Malignant and Benign Pleural Lesions: A Systematic Review and Meta-Analysis.

RATIONALE AND OBJECTIVES: To systematically review and meta-analyze published data about the diagnostic accuracy of fluorine-18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and PET/computed tomography (CT) in the differential diagnosis between malignant and benign pleural lesions. METHODS AND MATERIALS: A comprehensive literature search of studies published through June 2013 regarding the diagnostic performance of (18)F-FDG-PET and PET/CT in the differential diagnosis of pleural lesions was carried out. All retrieved studies were reviewed and qualitatively analyzed. Pooled sensitivity, specificity, positive and negative likelihood ratio (LR+ and LR-) and diagnostic odds ratio (DOR) of (18)F-FDG-PET or PET/CT in the differential diagnosis of pleural lesions on a per-patient-based analysis were calculated. The area under the summary receiver operating characteristic curve (AUC) was calculated to measure the accuracy of these methods. Subanalyses considering device used (PET or PET/CT) were performed. RESULTS: Sixteen studies including 745 patients were included in the systematic review. The meta-analysis of 11 selected studies provided the following results: sensitivity 95% (95% confidence interval [95%CI]: 92-97%), specificity 82% (95%CI: 76-88%), LR+ 5.3 (95%CI: 2.4-11.8), LR- 0.09 (95%CI: 0.05-0.14), DOR 74 (95%CI: 34-161). The AUC was 0.95. No significant improvement of the diagnostic accuracy considering PET/CT studies only was found. CONCLUSIONS: (18)F-FDG-PET and PET/CT demonstrated to be accurate diagnostic imaging methods in the differential diagnosis between malignant and benign pleural lesions; nevertheless, possible sources of false-negative and false-positive results should be kept in mind.

Selective accumulation of differentiated FOXP3(+) CD4 (+) T cells in metastatic tumor lesions from melanoma patients compared to peripheral blood

Precise identification of regulatory T cells is crucial in the understanding of their role in human cancers. Here, we analyzed the frequency and phenotype of regulatory T cells (Tregs), in both healthy donors and melanoma patients, based on the expression of the transcription factor FOXP3, which, to date, is the most reliable marker for Tregs, at least in mice. We observed that FOXP3 expression is not confined to human CD25(+/high) CD4(+) T cells, and that these cells are not homogenously FOXP3(+). The circulating relative levels of FOXP3(+) CD4(+) T cells may fluctuate close to 2-fold over a short period of observation and are significantly higher in women than in men. Further, we showed that FOXP3(+) CD4(+) T cells are over-represented in peripheral blood of melanoma patients, as compared to healthy donors, and that they are even more enriched in tumor-infiltrated lymph nodes and at tumor sites, but not in normal lymph nodes. Interestingly, in melanoma patients, a significantly higher proportion of functional, antigen-experienced FOXP3(+) CD4(+) T was observed at tumor sites, compared to peripheral blood. Together, our data suggest that local accumulation and differentiation of Tregs is, at least in part, tumor-driven, and illustrate a reliable combination of markers for their monitoring in various clinical settings.

Fissures du labrum glénoïdal postérieur et lésions associées de l'épaule: une étude en arthroscanner [Fissures of the posterior labrum and associated lesions: CT arthrogram evaluation]

PURPOSE: To describe osseous, chondral and tendinous lesions associated with fissures of the posterior labrum. To better understand the pathological processes leading to fissure of the posterior labrum. Materials and methods. Retrospective study of 43 CT arthrograms performed in 43 patients that showed a fissure of the posterior labrum. The following associated lesions were noted: osseous and chondral remodeling of the humeral head and/or glenoid and articular surface fissures of the rotator cuff. Based on type of associated lesions, patients were separated into one of four pathological subgroups: posterior instability, posterosuperior or internal impingement, anterior instability and isolated fissure of the posterior labrum. RESULTS: Sixteen patients (37.2%) of patients showed posterior instability, 12 (27.9%) showed lesions of internal impingement, and 11 (25.6%) showed lesions of anterior instability. Only 4 patients (9.3%) had an isolated fissure of the posterior labrum. CONCLUSION: Posterior instability, internal impingement and anterior instability are the main pathologies leading to fissure of the posterior labrum, which seldom occurs in isolation. Evaluation of these associated lesions allows understanding of the underlying pathological processes leading to fissure of the posterior labrum.

Interobserver and intraobserver variability of the apparent diffusion coefficient in treated malignant hepatic lesions on a 3.0T machine: measurements in the whole lesion versus in the area with the most restricted diffusion.

PURPOSE: To assess the inter/intraobserver variability of apparent diffusion coefficient (ADC) measurements in treated hepatic lesions and to compare ADC measurements in the whole lesion and in the area with the most restricted diffusion (MRDA). MATERIALS AND METHODS: Twenty-five patients with treated malignant liver lesions were examined on a 3.0T machine. After agreeing on the best ADC image, two readers independently measured the ADC values in the whole lesion and in the MRDA. These measurements were repeated 1 month later. The Bland-Altman method, Spearman correlation coefficients, and the Wilcoxon signed-rank test were used to evaluate the measurements. RESULTS: Interobserver variability for ADC measurements in the whole lesion and in the MRDA was 0.17 x 10(-3) mm(2)/s [-0.17, +0.17] and 0.43 x 10(-3) mm(2)/s [-0.45, +0.41], respectively. Intraobserver limits of agreement could be as low as [-0.10, +0.12] 10(-3) mm(2)/s and [-0.20, +0.33] 10(-3) mm(2)/s for measurements in the whole lesion and in the MRDA, respectively. CONCLUSION: A limited variability in ADC measurements does exist, and it should be considered when interpreting ADC values of hepatic malignancies. This is especially true for the measurements of the minimal ADC.

Immunoscintigraphic localization of inflammatory lesions: concept, radiolabelling and in vitro testing of a granulocyte specific antibody.

Current nuclear medicine techniques for the localization of inflammatory processes are based on injection of 111In labelled autologous granulocytes which need to be isolated and radiolabelled in vitro before reinjection. A new technique is presented here that obviates the need for cell isolation by the direct intravenous injection of a granulocyte specific 123I labelled monoclonal antibody. In this publication the basic parameters of the antibody granulocyte interaction are described. Antibody binding does not inhibit vital functions of the granulocytes, such as chemotaxis and superoxide generation. Scatchard analysis of binding data reveals an apparent affinity of the antibody for granulocytes of 6.8 X 10(9) l/mol and approximately 7.1 X 10(4) binding sites per cell. Due to the high specificity of the antibody, the only expected interference is from CEA producing tumors.

Cricotracheal resection for laryngeal invasion by thyroid carcinoma: our experience.

Invasion of the laryngeal framework by thyroid carcinoma requires specific surgical techniques and carries a higher rate of complications that deserve to be highlighted. We reviewed our data from 1995 to 2012 and found six patients with laryngotracheal invasion by thyroid carcinoma. All underwent total thyroidectomy and single-stage cricotracheal resection, plus anterolateral neck dissection. Three had airway obstruction that necessitated prior endoscopic debulking. None of the patients needed a tracheotomy. There were four cases of papillary carcinoma, and two cases of undifferentiated carcinoma. One patient died of complications of the procedure (anastomotic dehiscence and tracheo-innominate artery fistula). Another died 2 months after the procedure from local recurrence and aspiration pneumonia. One case presented recurrence at 15 months, which was managed by re-excision and adjuvant radiotherapy; after 26 months of follow-up, he has no evidence of locoregional recurrence. The three other patients are alive without evidence of disease at 6, 18 and 41 months, respectively. Cricotracheal resection for subglottic invasion by thyroid carcinoma is an effective procedure, but carries significant risks of complications. This could be attributed to the devascularisation of the tracheal wall due to the simultaneous neck dissection, sacrifice of the strap muscles or of a patch of oesophageal muscle layer. We advocate a sternocleidomastoid flap to cover the anastomosis. Cricotracheal resection for subglottic invasion can be curative with good functional outcomes, even for the advanced stages of thyroid cancer. Endoscopic debulking of the airway prior to the procedure avoids tracheotomy.

El patró “no dipper” i la rigidesa arterial, poden estar relacionats amb les lesions glomerulars incipients dels pacients amb obesitat mòrbida?

La monitorització ambulatòria de la pressió arterial (MAPA) és la millor tècnica pel diagnòstic d’hipertensió arterial i es relaciona millor amb l’afectació d’òrgans diana respecte la pressió arterial clínica. Recentment, s’ha descrit un indicador de rigidesa arterial que s’ estima a partir de la MAPA, l’ Ambulatory Arterial Stiffnes Index (AASI). En aquest treball es valora si els pacients amb obesitat mòrbida presenten rigidesa arterial mesurada a través de la MAPA i s’identifiquen factors de risc associats amb la lesió glomerular i vascular.

Placental vascular obstructive lesions: risk factor for developing necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a severe neonatal disease affecting particularly preterm infants. Its exact pathogenesis still remains unknown. In this study, we have compared the prevalence of vascular obstructive lesions in placentae of premature newborns which developed NEC and of a control group. We further compared separately the findings of placentae of infants of less than 30 weeks of gestation, the age group in which NEC occurs most frequently. We found signs of fetal vascular obstructive lesions in 65% of the placentae of preterm patients developing NEC, compared to only 17% of the placentae of preterm patients in the control group. In the age groups below 30 weeks of gestation, 58.5% of placentae of later NEC patients presented such lesions compared to 24.5% in the control group. The significant difference between NEC and control group suggests a strong association between fetal vascular obstructive lesions and NEC. Therefore, we propose that fetal vascular obstructive lesions might be considered as a risk factor for the development of NEC in premature infants.

Treatment of skin lesions in newborn children: meeting the needs of nursing staff

Objective To understand, together with nursing staff, the care needed to treat skin lesions in newborn children hospitalized in a neonatal unit. Method Qualitative research, of the convergent care type. The data was collected through semi-structured interviews, which were conducted from November to December 2012, in the neonatal unit of a hospital in southern Brazil. The participants were four auxiliary nurses, six nursing technicians and four nurses. Results The following three categories were designated: questions about what can be used in relation to newborn children; hospitalization can cause lesions on the skin of newborn children; and knowledge about care promotes professional autonomy. Conclusion There is an urgent need for staff to know more about the treatment of skin lesions, which would provide safer care for newborn children and would also support the autonomy of professional nurses in providing that care.