Electrophilic nitro-fatty acids suppress allergic contact dermatitis in mice.

BACKGROUND: Reactions between nitric oxide (NO), nitrite (NO2-), and unsaturated fatty acids give rise to electrophilic nitro-fatty acids (NO2 -FAs), such as nitro oleic acid (OA-NO2 ) and nitro linoleic acid (LNO2 ). Endogenous electrophilic fatty acids (EFAs) mediate anti-inflammatory responses by modulating metabolic and inflammatory signal transduction reactions. Hence, there is considerable interest in employing NO2 -FAs and other EFAs for the prevention and treatment of inflammatory disorders. Thus, we sought to determine whether OA-NO2 , an exemplary nitro-fatty acid, has the capacity to inhibit cutaneous inflammation. METHODS: We evaluated the effect of OA-NO2 on allergic contact dermatitis (ACD) using an established model of contact hypersensitivity in C57Bl/6 mice utilizing 2,4-dinitrofluorobenzene as the hapten. RESULTS: We found that subcutaneous (SC) OA-NO2 injections administered 18 h prior to sensitization and elicitation suppresses ACD in both preventative and therapeutic models. In vivo SC OA-NO2 significantly inhibits pathways that lead to inflammatory cell infiltration and the production of inflammatory cytokines in the skin. Moreover, OA-NO2 is capable of enhancing regulatory T-cell activity. Thus, OA-NO2 treatment results in anti-inflammatory effects capable of inhibiting ACD by inducing immunosuppressive responses. CONCLUSION: Overall, these results support the development of OA-NO2 as a promising therapeutic for ACD and provides new insights into the role of electrophilic fatty acids in the control of cutaneous immune responses potentially relevant to a broad range of allergic and inflammatory skin diseases.

Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE).

BACKGROUND: Neuroendocrine tumors (NETs) are an unusual family of neoplasms with a wide and complex spectrum of clinical behavior. Here, we present the first report of a National Cancer Registry of gastroenteropancreatic neuroendocrine tumors from a Southern European country. PATIENTS AND METHODS: Data was provided online at www.retegep.net by participating centers and assessed for internal consistency by external independent reviewers. RESULTS: The study cohort comprised 907 tumors. The most common tumor types were carcinoids (55%), pancreatic nonfunctional tumors (20%), metastatic NETs of unknown primary (9%), insulinomas (8%) and gastrinomas (4%). Forty-four percent presented with distant disease at diagnosis, most often those from small intestine (65%), colon (48%), rectum (40%) and pancreas (38%), being most unusual in appendix primaries (1.3%). Stage at diagnosis varied significantly according to sex, localization of primary tumor, tumor type and grade. Overall 5-year survival was 75.4% (95% confidence interval 71.3% to 79.5%) and was significantly greater in women, younger patients and patients with hormonal syndrome and early stage or lower grade tumors. Prognosis also differed according to tumor type and primary tumor site. However, stage and Ki-67 index were the only independent predictors for survival. CONCLUSION: This national database reveals relevant information regarding epidemiology, current clinical practices and prognosis of NETs in Spain, providing valuable insights that may contribute to understand regional disparities in the incidence, patterns of care and survival of this heterogeneous disease across different continents and countries.

[Malignant peripheric nerve sheath tumor of the orbit: first description of orbital location in a patient with NF1]. / Tumor maligno de la vaina del nervio periférico (MPNST) glandular de la órbita: primera descripción de la literatura de localización orbitaria en un paciente con neurofibromatosis tipo 1.

INTRODUCTION: The malignant peripheric nerve sheath tumor (MPNST), is a malignant neoplastic lesion originated in Schwann cells of the lining sheath of peripheral nerves. This neoplasia may appear with benign or malignant heterologous components, with divergent differentiation, as the glandular one. AIM: To describe for the first time in the literature, a case of a glandular MPNST, located at the orbit and to revise the literature on this tumoral lesion. CLINICAL CASE: Nine year old male, with a base diagnosis of NF1, who had exophthalmos, retro-ocular pain, headache, facial asymmetry and descent of the right eyeball, that started 1 year earlier. This patient showed in the Computed Tomography an Magnetic Resonance, a well delimited, lobulated, solid mass at the eyeball, which extended to the fontal and temporal brain parenchyma. A right Fronto-temporal craniotomy was made with fronto -orbital- zygomatic resection of the tumoral lesion. Later, a dural plasty and reconstruction with titanium mesh was made at the skull base. At present, the patient is asymptomatic after 4 months of follow up. A malignant biphasic neoplastic lesion was observed, reactive in the mesenchymal elements S100, PGP 9.5, neurofilaments and vimentin. The glandular component was positive for AE1/AE3, EMA, CEA and focally for CD57. There was also reactivity to cromogranin, synaptophysin, serotonin and somatostatin. The diagnosis of Glandular MPNST was made. CONCLUSION: For the first time in the literature a case of Glandular MPNST located at the orbit, which occurred in child with NF1, is described. This extremely uncommon neoplasia must be taken into account, in the study of biphasic malignant lesions, as its diagnosis is of great importance because of the bad prognosis of the affected patients.

Bexarotene activates the p53/p73 pathway in human cutaneous T-cell lymphoma.

BACKGROUND: Bexarotene is the first synthetic retinoid X receptor-selective retinoid (rexinoid) approved for the treatment of cutaneous T-cell lymphoma (CTCL). However, little is known about the signalling pathways by which it exerts its anticarcinogenic effect. OBJECTIVES: To characterize the effects of bexarotene in CTCL cell lines and elucidate the underlying molecular pathways of its antineoplastic effect. METHODS: The cell lines Hut-78, HH and MJ were used. Cell viability was assessed with the XTT assay. The self-renewal potential of cells after bexarotene treatment was studied with the methylcellulose clonogenic assay. Flow cytometry was used to analyse the effects on cell cycle, Ki-67 expression and apoptosis induction. Cell cycle and apoptosis-related protein expression were determined by Western blot and immunofluorescence. RESULTS: Bexarotene induced a loss of viability and more pronounced inhibition of clonogenic proliferation in HH and Hut-78 cells, whereas the MJ line exhibited resistance. Bexarotene upregulated and activated Bax in sensitive lines, although not enough to signal significant apoptosis. Instead, all data point to the inhibition of proliferation, rather than apoptosis, as the main mechanistic action of the rexinoid. Bexarotene signals both G(1) and G(2)/M arrest by the modulation of critical checkpoint proteins. We further found that bexarotene activates p53 by phosphorylation at Ser15, which influences the binding of p53 to promoters for cell cycle arrest, induces p73 upregulation, and, in concordance, also modulates some p53/p73 downstream target genes, such as p21, Bax, survivin and cdc2. Bexarotene-mediated ataxia telangiectasia mutated protein (ATM) activation in all studied lines suggests that ATM is likely to be the p53/p73 upstream activator. CONCLUSIONS: Our data indicate for the first time that bexarotene exerts its effect in CTCL mainly by triggering the p53/p73-dependent cell cycle inhibition pathway, probably by upstream ATM activation. Therefore, bexarotene-modulated genes represent potential biomarkers to assess the response to treatment of patients with CTCL.

Cutaneous metastases of hepatocellular carcinoma.

Cutaneous metastases are an unusual finding that may present as the first sign of an internal neoplasia. A case of cutaneous metastases of hepatocellular carcinoma, which may often involve other organs but very rarely metastases to the skin, is reported.

[Clinical experience with efalizumab in the Hospital of Cruces]. / Experiencia clínica con efalizumab en el Hospital de Cruces.

Efalizumab (Raptiva) is one of the biological agents approved recently for the treatment of patients with moderate-severe psoriasis who have not responded to conventional treatments. It is a humanized IgG1 monoclonal antibody which, due to its anti-D11 effect, is capable of blocking the endothelial migration and T cell activation on the skin, fundamental processes in the etiopathogeny of psoriasis. We present the experience we have had in our hospital over the last two years with 23 patients who have initiated treatment with efalizumab.

[Antibiotic diffusion to central nervous system]. / Difusión de los antibióticos en el sistema nervioso central.

Central nervous system (CNS) infections caused by pathogens with a reduced sensitivity to drugs are a therapeutic challenge. Transport of fluid and solutes is tightly controlled within CNS, where vasculature exhibits a blood-brain barrier (BBB).The entry of drugs, including antibiotics, into the cerebro-spinal fluid (CSF) is governed by molecular size, lipophilicity, plasma protein binding and their affinity to transport systems at the BBB. The ratio of the AUCCSF (Area under the curve in CSF)/AUCS (Area under the curve in serum) is the most accurate parameter to characterize drug penetration into the CSF. Linezolid, some fluoroquinolones and metronidazole get high CSF concentrations and are useful for treating susceptible pathogens. Some highly active antibiotic compounds with low BBB permeability can be directly administered into the ventricles together with concomitant intravenous therapy. The ideal antibiotic to treat CNS infections should be that with a small moderately lipophilic molecule, low plasma protein binding and low affinity to efflux pumps at BBB. Knowledge of the pharmacokinetics and pharmacodynamics of antibiotics at the BBB will assist to optimize antibiotic treatment in CNS infections. This article reviews the physicochemical properties of the main groups of antibiotics to assess which compounds are most promising for the treatment of CNS infections and how to use them in the daily clinical practice.

Fine-needle aspiration biopsy of pancreatic neuroendocrine tumors: Correlation between Ki-67 index in cytological samples and clinical behavior.

BACKGROUND: Mitotic count in hematoxylin-eosin stained slides and Ki-67 index allow stratification of patients for prognosis and therapeutic decision making in pancreatic neuroendocrine tumors (PNETs). However, the utility of Ki-67 determination in cytological material and its association to PNET prognosis are under discussion. METHODS: We have retrospectively reviewed all cases of EUS-FNA cytology of pancreatic lesions performed in the Hospital Clínico San Carlos (Madrid) between 2006 and 2016. We have analyzed the potential association between the Ki-67 estimation in PNET cytological material and patient outcomes. RESULTS: We identified 24 PNET cases. Mean age was 56.8 years and most patients were males (54%). PNETs were mainly located in the head and tail of the pancreas and the mean tumor size was 36 mm. Cell block from cytology was available in 12 cases (50%), and there were 19 G1, 2 G2, and 3 G3 tumors. All cases graded as G2 (2 patients) or G3 (three patients) on cytology were stage IV, and the 19 cases graded as G1 ranged from stages IA to IV. All patients with G2 tumors on cytology died due to PNET. Of the three patients with G3 lesions, two died of disease and the other died 2 months after diagnosis from causes other than PNET. 78% of the patients with G1 tumors are stable and currently being followed-up. CONCLUSION: Higher Ki-67 index in cytology specimens portends a worse outcome, although some G1 tumors may progress or cause death. Diagn. Cytopathol. 2017;45:29-35. © 2016 Wiley Periodicals, Inc.

Reliability of Ki-67 Determination in FNA Samples for Grading Pancreatic Neuroendocrine Tumors.

Neuroendocrine pancreatic tumors (PanNETs) are graded on the basis of their proliferative activity. Cytological samples are commonly the only samples available, but the determination of Ki-67 in cytology and its reliability as a measure of tumor mitotic activity is not well settled. We have retrospectively reviewed all the cases of FNA under EUS control of PanNETs in a 10-year period (2006-2016) in the Hospital Clínico San Carlos (Madrid). We identified 10 PanNET cases with histological correlation. Median age was 49.4 years and the patients were mainly women. PanNETs were located more frequently in the tail of the pancreas, with a median size of 33.8 mm. None of our cases was a grade 3 tumor. The seven grade 1 tumors confirmed in histology had consistent Ki-67 in cytology. In three cases (30 %), there were discrepancies between the Ki-67 index measured in cytology and histology, and the differences ranged from 2 to 15 %; all these cases were grade 2 tumors in histology and were graded as grade 1 tumors in FNA material. Our results are consistent with previous studies which showed understaging when tumor grade was assessed in cytological samples, mainly in G2 tumors. Previous literature has shown that Ki-67 assessment in EUS-FNA samples is a useful tool to rule out G3 tumors, but can be problematic for distinguishing G1 and G2 tumors.

Prostaglandins and chemotaxis: enhancement of polymorphonuclear leukocyte chemotaxis by prostaglandin F2alpha.

Prostaglandins E1, E2, F1alpha, and F2alpha did not demonstrate direct in vitro chemotactic properties either to rabbit peritoneal polymorphonuclear leukocytes or to rabbit or human polymorphonuclear leukocytes isolated from blood. Prostaglandin F2alpha, however, enhanced the chemotactic responsiveness of human polymorphonuclear leukocytes to the chemotactic agent casein.

Cost-effectiveness analysis of interferon as adjuvant therapy in high-risk melanoma patients in Spain.

In the randomised clinical trial E1684, the administration of interferon (IFN) alpha-2b resulted in prolonged disease-free and overall survival in high-risk melanoma patients following surgical resection. However, and considering the cost and toxicity of IFN, the convenience of its widespread use should be evaluated. The aim of this study was to analyse the cost-effectiveness ratio of adjuvant therapy with IFN alpha-2b in melanoma patients versus an untreated control group. A Markov model was used to compare two hypothetical cohorts of 1000 patients aged 50 years, according to the clinical outcome of the E1684 study. The cohort of patients treated with IFN alpha-2b has an increased overall survival of 1.90 years during the patient's lifetime. The incremental discounted cost per life year gained of IFN versus observation is 9015 Euros according to the projection generated by the model. The sensitivity analysis demonstrated that changes in the most relevant study end-points do not modify the study outcome. In conclusion, in high-risk melanoma patients following surgical resection, the cost-effectiveness of IFN alpha-2b (at a dose of 20 MU/m2/day, 5 days per week for one month, followed by 10 MU/m2 TIW, up to one complete year of therapy) versus an untreated control group is within the limits established in health economics to determine if adoption of a new treatment is economically justified and is comparable with other interventions in which cost-effectiveness is acceptable to the National Health System.

Toxic doses of vitamin A for pityriasis rubra pilaris.

Seven patients who were disabled by pityriasis rubra pilaris were given toxic doses of oral vitamin A (1 million IU/day in six of the seven patients) for five to 14 days. Within 72 hours, the patients began to exfoliate the hyperkeratotic and keratodermatous lesions. The desquamative process was completed between ten and 14 days. The skin remained erythematous for several months before assuming a normal color. The skin of six of the seven patients was virtually cleared by the treatment, and none suffered a relapse of the pityriasis rubra pilaris. Serial skin biopsy specimens showed evidence suggestive of an accelerated turnover rate of epidermal cells during treatment. Transient abnormalities of liver function test results were noted in two patients.

Disabling pansclerotic morphea of children.

Fourteen children with generalized morphea involving all levels of the skin and soft tissues were examined. The term "acral pansclerotic morphea" describes the distribution and the multiple levels of sclerosis. Lymphocytic inflammation and hyaline pannicultitis were observed on biopsy specimens in some cases. Laboratory data were characterized by a polyclonal elevation of gamma-globulin level and by peripheral eosinophilia. Pulmonary changes in five patients and esophageal changes in one imply that acral pansclerotic morphea may be assoicated with mild nonprogressive visceral change. Although cyclophosphamide may retard the process, no satisfactory treatment for progressive, mutilating acral pansclerotic morphea has been found.

Cutaneous periarteritis nodosa: immunofluorescence studies.

The study of ten cases of cutaneous periarteritis nodosa by direct immunofluorescence microscopy of excision biopsy specimens revealed positive findings in nine. Deposition of IgM was found in the vessel walls in six cases, and C3 was observed in four; however, only in two cases was C3 found with IgM in the vessel walls. Deposits of IgM in the superficial vessels were found in five cases, although only the deep muscular vessels showed evidence of the vasculitis in cutaneous periarteritis nodosa. Serum hepatitis B antigen was absent in the nine cases that were tested. Positive immunofluorescence findings in superficial as well as in deep vessels suggest that although periarteritis nodosa is characterized by an inflammatory panarteritis, occasional vasculitis of small vessels might be expected.

Serum IgE in dermatitis and dermatosis: an analysis of 497 cases.

Serum IgE values from 497 patients with various forms of dermatitis, dermatosis, and tinea pedis were analyzed statistically and compared with values from 95 normal controls. The median and geometric mean values were significantly elevated (except in acne without atopy, lichen planus, and tinea pedis), even after exclusion of patients with a history of atopy or of cutaneous reaction to food or drugs. Serum IgE levels and atopic dermatitis have a close correlation. A modest positive correlation (p approximately equal to .05) appeared between the log serum IgE level and peripheral blood absolute eosinophil count in 80 cases of atopic dermatitis. A unique group of adult nonatopic patients had acquired generalized dermatitis and markedly elevated serum IgE levels (greater than 12,000 ng/ml). Our results suggest that, in most common dermatologic disorders, elevated serum IgE is a secondary phenomenon rather than a primary causative factor.

Livedo vasculitis (the vasculitis of atrophie blanche). Immunohistopathologic study.

Hyalinizing segmental vasculitis or livedo vasculitis (atrophie blanche) is a clinical entity with a distinctive immunohistopathologic morphology that can be distinguished from other forms of cutaneous vasculitis by histologic and direct immunofluorescent studies. Our studies showed that immunoglobulins and complement components (C-1g, C-3, and properdin) were localized in diseased vessel walls, suggesting an immune pathogenesis.

Interleukin-2 enhances the growth of human melanoma cells derived form primary but not from metastatic tumours.

Previously, we demonstrated that in vitro treatment of B16F10 murine melanoma cells with interleukin-2 (IL-2) enhances proliferation and metastasis. To further investigate the role played by IL-2 in human melanomas, we studied the expression of IL-2/IL-2 receptor and the effect of IL-2 on the proliferation of melanoma cell lines derived from primary (A375 and RMS cell lines) and metastatic (Hs294T cell line) tumours. We found a constitutive expression of cytoplasmic IL-2 and alpha, beta and gamma-subunits of the IL-2R on the surface of the three melanoma cell lines. The presence of IL-2 in the culture increased the proliferation rate in A375 and RMS cell lines, but no effect was observed in Hs294T metastatic cells. Biologically active IL-2 could be found in the supernatant of the three melanoma cell lines, particularly in A375 and RMS cells, in which an inhibition of the proliferation rate was observed when IL-2 was blocked. Moreover, the combination of anti-IL-2R beta and anti-IL-2R gamma blocking antibodies induced a significant down-regulation of cell proliferation in the three melanoma cell lines, and the combination of anti-IL-2R alpha, anti-IL-2R beta and anti-IL-2R gamma blocking antibodies inhibited IL-2-mediated growth stimulation in A375 and Hs294T cell lines. In RMS cells, a more significant effect was observed when only IL-2R gamma was blocked. Finally, exogenous IL-2 modulated the IL-2 endogenously produced by melanoma cells. These data show that IL-2 may modulate the growth of melanoma cells through autocrine or/and paracrine mechanisms.

First Report of Tomato spotted wilt virus Infection of Tomatillo in Georgia.

During the 2000 spring season, tomatillo (Physalis ixocarpa) plants showing chlorotic streaks on leaves were observed in an experimental plot of the University of Georgia's Coastal Plain Experiment Station in Tift County, GA. Leaf samples from 192 plants were collected. These included plants that had chlorotic streaks and those without obvious symptoms. Samples were tested by ELISA using a commercially available Tomato spotted wilt virus (TSWV) detection kit (Agdia Inc., Elkhart, IN). TSWV was found in 10 samples that had chlorotic streaks on leaves, and the remaining plants with no obvious symptoms were negative for TSWV. Infected plants were found in both cultivars, Verde Puebla and Toma Verde. The presence of the virus had no apparent effect on plant size or fruit appearance. TSWV infection of the ELISA-positive samples was further verified by immunocapture reverse transcription-polymerase chain reaction (IC-RT-PCR) (1). The primer pair (5'-ATGTCTAAGGTTAAGCTC-3' and 5' TTAAGCAAGTTCTGTGAG-3') represented the first and last 18 bases of the coding region of the nucleocapsid gene of TSWV, respectively, and produced approximately 800-bp PCR product (1). IC-RT-PCR gave a single DNA band of expected size and no amplification was found in the uninfected control. This is the first report of TSWV on tomatillo in Georgia. Reference: (1) R. K. Jain et al. Plant Dis. 82:900, 1998.

Natural Infestation of Onion Seed by Pantoea ananatis, Causal Agent of Center Rot.

An immunomagnetic separation and polymerase chain reaction (IMS-PCR) assay was used to detect Pantoea ananatis in naturally infested onion seeds. Using species-specific PCR primers and polyclonal antibodies, IMS-PCR consistently demonstrated detection thresholds of 101 to 103 CFU/ml. There was no significant difference between the numbers of CFU recovered from onion seed wash by IMS (after repeated rinses) and by direct plating, indicating that IMS effectively captured P. ananatis cells from heterogeneous bacterial populations. Using IMS-PCR and IMS followed by plating on nutrient agar, P. ananatis was detected in 19.7% of onion seed samples harvested from two onion fields in which center rot developed naturally in 2000. When planted in germination boxes, 53% of the seed samples that tested positive for P. ananatis produced seedlings with symptoms of center rot. There was no significant difference in germination between infested and noninfested seed samples. This is the first report of natural infestation and transmission of P. ananatis in onion seed.