Post-acute phase and sequelae management of epidermal necrolysis: an international, multidisciplinary DELPHI-based consensus.

BACKGROUND: Long-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking. OBJECTIVES: We conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae. METHODS: Participants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method. RESULTS: Fifty-two healthcare professionals participated. After the first round, a consensus was obtained for 100% of 54 initially proposed statements (disagreement index < 1). Among them, 50 statements were agreed upon as 'appropriate'; four statements were considered 'uncertain', and ultimately finally discarded. CONCLUSIONS: Our DELPHI-based expert consensus should help guide physicians in conducting a prolonged multidisciplinary follow-up of sequelae in SJS-TEN.

Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

De la conjonctivite à l'ulcère de Mooren : errance diagnostique ou insuffisance des spécialistes

Nous rapportons une observation d'un homme âgé de 25 ans, mélanoderme sans antécédent médico-chirurgical connu, qui a consulté pour douleur oculaire,larmoiement, baisse de l'acuité visuelle, photophobie évoluant depuis environ huit mois, l'examen ophtalmologique note une hyperhémie conjonctivale, une ulcération cornéenne marginale compliquée de perforation cornéenne avec hernie de l'iris rongeant la moitié de la cornée, une excavation papillaire asymétrique.Le diagnostic d'ulcère de Mooren bilatéral est fortement suspecté, puis retenu sur la base d'argument épidémiologique ; clinique ophtalmologique (kératite ulcéreuse chronique inflammatoire qui affecte initialement la périphérie de la cornée, avec progression circonférentielle et centrale, puis perforation) ; paraclinique (la négativité de tous les examens complémentaires : les facteurs rhumatoïdes, les sérologies de l'hépatite B, C, VIH et de la syphilis, l'examen parasitologique des selles, la protéinurie de 24 h …) mais aussi après avoir exclu un certain nombre de diagnostics,notamment les maladies systémiques, les maladies infectieuses, les atteintes traumatiques des yeux.La collaboration entre ophtalmologiste et interniste a abouti à la mise en route immédiate d'un traitement à base de corticothérapie locale, d'antibiothérapie et des topiques locaux. L'évolution a été favorable avec récupération progressive de l'acuité visuelle au niveau des deux yeux deux semaines après la mise en route du traitement

Optical imaging of the propagation patterns of neural responses in the rat sensory cortex: comparison under two different anesthetic conditions.

Although many studies have reported the influence of anesthetics on the shape of somatic evoked potential, none has evaluated the influence on the spatio-temporal pattern of neural activity in detail. It is practically impossible to analyze neural activities spatially, using conventional electrophysiological methods. Applying our multiple-site optical recording technique for measuring membrane potential from multiple-sites with a high time resolution, we compared the spatio-temporal pattern of the evoked activity under two different anesthetic conditions induced by urethane or α-chloralose. The somatic cortical response was evoked by electrical stimulation of the hindlimb, and the optical signals were recorded from the rat sensorimotor cortex stained with a voltage-sensitive dye (RH414). The evoked activity emerged in a restricted area and propagated in a concentric manner. The spatio-temporal pattern of the evoked activity was analyzed using isochrone maps. There were significant differences in the latency and propagation velocity of the evoked activity, as well as the full width at half maximum of optical signal between the two anesthetic conditions. Differences in the amplitude and the slope of the rising phase were not significant.

MicroRNA-1246 expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer.

BACKGROUND: Pancreatic cancer has a poor prognosis because of its high refractoriness to chemotherapy and tumour recurrence, and these properties have been attributed to cancer stem cells (CSCs). MicroRNA (miRNA) regulates various molecular mechanisms of cancer progression associated with CSCs. This study aimed to identify the candidate miRNA and to characterise the clinical significance. METHODS: We established gemcitabine-resistant Panc1 cells, and induced CSC-like properties through sphere formation. Candidate miRNAs were selected through microarray analysis. The overexpression and knockdown experiments were performed by evaluating the in vitro cell growth and in vivo tumourigenicity. The expression was studied in 24 pancreatic cancer samples after laser captured microdissection and by immunohistochemical staining. RESULTS: The in vitro drug sensitivity of pancreatic cancer cells was altered according to the miR-1246 expression via CCNG2. In vivo, we found that miR-1246 could increase tumour-initiating potential and induced drug resistance. A high expression level of miR-1246 was correlated with a worse prognosis and CCNG2 expression was significantly lower in those patients. CONCLUSIONS: miR-1246 expression was associated with chemoresistance and CSC-like properties via CCNG2, and could predict worse prognosis in pancreatic cancer patients.

Clinical outcome of pancreas transplantation from marginal donors in Japan.

In Japan, absolute shortage of donors still continues even after the law allowing organ transplantation from deceased donors came into force in 1997. With the passage of the waiting period after registration for pancreas transplantation (PTx), both deaths and serious cases of diabetic complications necessitating withdrawal of the registration have undoubtedly increased. Therefore, so-called "marginal donor" (MD) has been considered as a potential solution for shortage of donors in Japan. The aim of the present study is to evaluate feasibility of MD in terms of post-PTx outcomes using data from Japan Organ Transplantation Network. A total of 148 PTx were performed from deceased donors in Japan from 2000 to 2012. MD was defined as follows: (1) >45 years old; (2) hemodynamically unstable at harvest using a high-dose dopamine or more than 2 vasopressors; or (3) non-heart-beating status. Postoperative outcomes after PTx were compared between the MD group and the non-MD group. Among the 148 PTx donors, 108 donors (73.0%) satisfied the criteria of MD. Early graft loss of pancreas graft during 3 months post-transplant was observed in 15 patients (10.1%), and the marginality (MD vs non-MD) was not significantly correlated with the early loss of pancreas graft. The overall patient survival of the MD group (1, 3, 5 years: 94.7%, 94.7%, 94.7%) was not significantly different from that of the non-MD group (1, 3, 5 years: 95.0%, 95.0%, 95.0%). Pancreas graft survival in the MD group (1, 3, 5 years: 80.9%, 73.2%, 66.0%) seemed to be slightly lower than that in the non-MD group (1, 3, 5 years: 92.5%, 85.2%, 77.4%), but no statistically significant differences were found between the 2 groups. These results suggest the feasibility of the use of MD for PTx.

miR-320c regulates gemcitabine-resistance in pancreatic cancer via SMARCC1.

BACKGROUND: Gemcitabine-based chemotherapy is the standard treatment for pancreatic cancer. However, the issue of resistance remains unresolved. The aim of this study was to identify microRNAs (miRNAs) that govern the resistance to gemcitabine in pancreatic cancer. METHODS: miRNA microarray analysis using gemcitabine-resistant clones of MiaPaCa2 (MiaPaCa2-RGs), PSN1 (PSN1-RGs), and their parental cells (MiaPaCa2-P, PSN1-P) was conducted. Changes in the anti-cancer effects of gemcitabine were studied after gain/loss-of-function analysis of the candidate miRNA. Further assessment of the putative target gene was performed in vitro and in 66 pancreatic cancer clinical samples. RESULTS: miR-320c expression was significantly higher in MiaPaCa2-RGs and PSN1-RGs than in their parental cells. miR-320c induced resistance to gemcitabine in MiaPaCa2. Further experiments showed that miR-320c-related resistance to gemcitabine was mediated through SMARCC1, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. In addition, clinical examination revealed that only SMARCC1-positive patients benefited from gemcitabine therapy with regard to survival after recurrence (P=0.0463). CONCLUSION: The results indicate that miR-320c regulates the resistance of pancreatic cancer cells to gemcitabine through SMARCC1, suggesting that miR-320c/SMARCC1 could be suitable for prediction of the clinical response and potential therapeutic target in pancreatic cancer patients on gemcitabine-based therapy.

Behavioral context-dependent modulation of descending statocyst pathways during free walking, as revealed by optical telemetry in crayfish.

Crustacean posture control is based on a complex interaction between the statocyst input and other sensory inputs as well as the animal's behavioral context. We examined the effects of behavioral condition on the activity of descending statocyst pathways using an optical telemetry system that allowed underwater recording of neuronal signals from freely behaving crayfish. A functionally identified statocyst-driven interneuron that directionally responded to body tilting without a footboard and to tilting of the footboard was found to show complicated responses depending upon the ongoing behavior of the animal when it freely walked around in water on the aquarium floor. The spike firing frequency of the interneuron increased significantly during walking. When the animal stood or walked on the tilted floor, the interneuron activity represented the tilt angle and direction if the abdomen was actively flexed, but not if it was extended. Two other statocyst-driven descending interneurons were found to be affected differently by the animal's behavioral condition: the spike activity of one interneuron increased during walking, but its directional response on the tilted floor was completely absent during abdominal posture movements, whereas that of another interneuron was enhanced during abdominal extension only, representing the tilt angle and direction. The results obtained in this study provide the first experimental demonstration that crustacean postural control under natural conditions is dependent on very fine aspects of the animal's locomotor behavioral context, suggesting far more complex control mechanisms than those expected from the experimental data obtained in isolated and fixed animals.

Alpha-fetoprotein mRNA detection in peripheral blood for prediction of hepatocellular carcinoma recurrence after liver transplantation.

The aim of this study was to assess the value of alphafeto protein (AFP) mRNA-expressing cells detected in peripheral blood for predicting tumor recurrence after living donor liver transplantation (LDLT) in patients with hepatocellular carcinoma (HCC). The test group consisted of 25 patients who underwent LDLT for end-stage liver disease with HCC while the control group consisted of 37 living donors. Quantitative real-time reverse-transcriptase polymerase chain reaction was used for detection of AFP mRNA-expressing cells in peripheral blood. Nine (36%) of 25 patients developed tumor recurrences (four lung; one liver; one peritoneum; two bone; one adrenal gland) during the follow-up period. Perioperatively, AFP mRNA was positive in peripheral blood of eight patients (32.0%) but only in 1 (2.7%) of the control. Preoperative AFP mRNA was positive in three cases. Univariate analyses revealed that preoperative and perioperative AFP mRNA and microscopical vascular invasion were the significant predictors for HCC recurrence (P = .007, .037, and .005, respectively). In the patients with HCC exceeding Milan criteria (n = 15), the presence of AFP mRNA-positive cells in the peripheral blood correlated significantly with HCC recurrence (P = .033). We concluded that the presence of AFP mRNA-expressing cells could be a useful predictor of HCC recurrence in liver transplant patients.

Risk factors for graft dysfunction after adult-to-adult living donor liver transplantation.

The aim of this study was to investigate the risk factors for graft dysfunction after adult-to-adult living donor liver transplantation (LDLT). Thirty-nine adults with chronic cirrhosis underwent LDLT between 1999 and 2004. Their postoperative courses were uneventful with no vascular or bile duct complications early after LDLT, except one mild hepatic artery stenosis. The preoperative MELD scores were significantly higher in the failed graft group (n=5) than the functioning graft group (n=34; P=.004), while the graft liver weight/standard liver volume ratio was similar between these groups. We concluded that a high preoperative MELD score was associated with postoperative graft failure and that graft size had little impact on graft outcome. Although large grafts would seem intuitively more suitable for sick recipients, we did not show a benefit among this cohort; the MELD score was the best predictor, a finding that is also most consistent with donor safety.

Modification of statocyst input to local interneurons by behavioral condition in the crayfish brain.

Posture control by statocysts is affected by leg condition in decapod crustaceans. We investigated how, in the crayfish brain, the synaptic response of local interneurons to statocyst stimulation was affected by leg movements on and off a substratum. The magnetic field stimulation method permitted sustained stimulation of statocyst receptors by mimicking body rolling. The statocyst-driven local interneurons were classified into four morphological groups (Type-I-IV). All interneurons except Type-IV projected their dendritic branches to the parolfactory lobe of the deutocerebrum where statocyst afferents project directly. Type-I interneurons having somata in the ventral-paired lateral cluster responded invariably to statocyst stimulation regardless of the leg condition, whereas others having somata in the ventral-unpaired posterior cluster showed response enhancement or suppression, depending on the cell, during leg movements on a substratum, but no response change during free leg movements off the substratum. The synaptic responses of Type-II and IV interneurons were also affected differently by leg movements depending on the substratum condition, whereas those of Type-III remained unaffected. These findings suggest that the statocyst pathway in the crayfish brain is organized in parallel with local circuits that are affected by leg condition and those not affected.

Elevated amount of human papillomavirus 31 DNA in a squamous cell carcinoma developed from bowenoid papulosis.

A 50-year-old woman presented with asymptomatic, multiple black macules on the genitalia for 6 months. She presented multiple, round to irregularly shaped, black macules on her labia major and perineum. A keratotic reddish nodule was found on one of the macules. The results of laboratory investigations showed pancytopenia and a decreased CD4/CD8 ratio. A lymphocyte stimulation test showed a decreased response. The histological examination of a biopsy specimen led us to the diagnosis of bowenoid papulosis (BP) for the macules and squamous cell carcinoma (SCC) for the nodule. The macules and nodule were removed successfully. An elevated amount of HPV DNA was demonstrated in SCC compared with that of BP. The HPV DNA in SCC and BP was shown to be HPV-31. These observations indicated that the elevated amount of HPV-31 DNA could have led to the emergence of SCC from BP under the condition of decreased cellular immunity.

Effects of leg movements on the synaptic activity of descending statocyst interneurons in crayfish, Procambarus clarkii.

Crustacean postural control is modulated by behavioral condition. In this study, we investigated how the responses of descending statocyst interneurons were affected during leg movements. Intracellular recording was made from an animal whose statoliths had been replaced with ferrite grains so that statocyst receptors could be activated by magnetic field stimulation. We identified 14 morphological types of statocyst-driven descending interneurons. Statocyst-driven descending interneurons always showed an excitatory response to statocyst stimulation on either ipsilateral or contralateral side to the axon. The response of each statocyst-driven descending interneuron to statocyst stimulation was differently modulated by leg movements in different conditions. During active leg movements, six statocyst-driven descending interneurons were activated regardless of whether a substrate was provided or not. In other two statocyst-driven descending interneurons, the excitatory input during leg movements was stronger when a substrate was provided than when it was not. One statocyst-driven descending interneuron received an excitatory input only during leg movements on a substrate, whereas another statocyst-driven descending interneuron did not receive any input during leg movements both on a substrate and in the air. These results suggest that the descending statocyst pathways are organized in parallel, each cell affected differently by behavioral conditions.

A case of concurrent vitiligo vulgaris and polymyositis.

Abstract We present a rare case of simultaneous muscle weakness and cutaneous depigmentation. Muscle and skin biopsies confirmed the diagnosis of polymyositis and generalized vitiligo vulgaris. All symptoms improved after steroid therapy. Immunohistochemical analyses revealed predominant CD8-positive T cell infiltration in both muscular and cutaneous lesions. This case suggests that a common autoimmune mechanism mediated by cytotoxic T lymphocytes underlies the pathogeneses of these two diseases.