Effects of local administration of allogenic adipose tissue-derived mesenchymal stem cells on functional recovery in experimental traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in paediatric patients after the first year of life. The aim of this study was to evaluate effects of locally administered allogeneic mesenchymal stem cells (MSC), in the acute period after a TBI. METHODOLOGY: MSC were isolated from peritoneal fat of healthy rats, expanded in vitro and labelled with the green fluorescent protein. Rats were placed in one of three experimental groups: (1) CONTROL: TBI, (2) IP-CONTROL: TBI + local saline and (3) IP-Treat: TBI + 2 × 10(5) MSC 24 hours after receiving a moderate, unilateral, controlled cortical impact. Motor and cognitive behavioural tests were performed to evaluate functional recovery. Histological examination and immunohistochemistry were used to identify cell distribution. MAIN RESULTS: Improved performance was found on motor tests in the MSC-treated group compared to control groups. MSC were found in the perilesional area and their number decreased with time after transplantation. MSC treatment increased the cell density in the hippocampus (CA3 pyramidal cells and granule cells in the dentate gyrus) and enhanced neurogenesis in this area. CONCLUSION: MSC cell therapy resulted in better recovery of motor function compared with the control group. This cellular therapy might be considered for patients suffering from TBI.

Fibromyalgia and non-celiac gluten sensitivity: a description with remission of fibromyalgia.

Fibromyalgia (FM) syndrome is a disabling clinical condition of unknown cause, and only symptomatic treatment with limited benefit is available. Gluten sensitivity that does not fulfill the diagnostic criteria for celiac disease (CD) is increasingly recognized as a frequent and treatable condition with a wide spectrum of manifestations that overlap with the manifestations of FM, including chronic musculoskeletal pain, asthenia, and irritable bowel syndrome. The aim of this report was to describe 20 selected patients with FM without CD who improved when placed on a gluten-free diet. An anti-transglutaminase assay, duodenal biopsy, and HLA typing were performed in all cases. CD was ruled out by negative anti-transglutaminase assay results and absence of villous atrophy in the duodenal biopsy. All patients had intraepithelial lymphocytosis without villous atrophy. Clinical response was defined as achieving at least one of the following scenarios: remission of FM pain criteria, return to work, return to normal life, or the discontinuation of opioids. The mean follow-up period was 16 months (range 5-31). This observation supports the hypothesis that non-celiac gluten sensitivity may be an underlying cause of FM syndrome.

Epithelioid angiomyolipoma presenting as an urothelial.

OBJECTIVE: Renal angiomyolipoma is a mesenchymal neoplasm composed of dysmorphic blood vessels, smooth muscle, and adipose tissue. Epithelioidangiomyolipoma is an uncommon variant considered potentially malignant. We report a case of renal epithelioid angiomyolipoma suspicious for urothelialcarcinoma of renal pelvis. METHODS: A 50-year-old woman with a 3-day history of macroscopic hematuria and CT-scan showing a tumor arising from the left renal pelvis suspicious for urothelialcarcinoma. Nephrectomy was analysed in multiple slides of hematoxilin-eosin and immunohistochemistry. RESULTS: Left nephrectomy was performed. Tumor sized 8 cm and showed pathologic findings of epithelioid angiomyolipoma with a little component of classic angiomyolipoma. We studied differential diagnosis and pathologic characteristics for the prognosis. CONCLUSIONS: Pathologic study in detail is fundamental for differential diagnosis and prognosis of this tumor. Our patient's pathology showed good prognosis, however follow-up is important due the malignant potential of the neoplasm.

Non-celiac gluten sensitivity and chronic refractory low back pain with spondyloarthritis features.

OBJECTIVE: To propose the hypothesis that non-celiac gluten sensitivity is associated with chronic low-back pain related to spondyloarthritis, and a gluten free diet has a therapeutic benefit in a subgroup of patients. Gut involvement is a well-known association of spondyloarthritis but limited to a few disorders such as inflammatory bowel disease. Currently the therapeutic implication of this association is pharmacologic treatment for inflammation with immunosupresive drugs for both diseases. Here is a case series of patients with chronic low-back pain, spondyloarthritis related features, and response to gluten free diet despite celiac disease being ruled out. METHODS: Retrospective case report of 110 patients from a tertiary hospital rheumatology clinic specialized in chronic pain and gluten sensitivity. These are patients with refractory low-back pain and spondyloarthritis features who followed a gluten free diet despite celiac disease being ruled out. Demanding improvement was defined based on the achievement of at least one of the following objectives: asymptomatic status, remission of chronic low-back pain, returning to normal life, returning to work, changing from confinement to bed/wheelchair to being able to walk, returning to self-sufficiency for hygiene and personal care, discontinuation of opioids. RESULTS: Average age at low-back onset pain was 30. Average disease duration was 15 years. 87 (79%) of the patients experienced improvement. 69 (62%) of the patients achieved demanding improvement. Average duration of gluten-free diet in patients with demanding improvement was 60 months. 56 out of 69 patients with demanding improvement ingested gluten. Of these 56 patients, 54 experienced clinical worsening and were considered as having non-celiac gluten sensitivity. Oral aphthae and having a relative with celiac disease were associated with demanding improvement. Out of 28 patients retrospectively classified as having axial spondyloarthritis, 23 had demanding improvement. Out of 16 patients with uveitis, 13 had demanding improvement. Out of 83 patients with fibromyalgia, 48 had demanding improvement. CONCLUSION: These observational data support the proposed hypothesis and offer information regarding possible clinical predictors of response to diet.

Outcome of patients with retinoblastoma and postlaminar optic nerve invasion.

PURPOSE: To evaluate the outcome of patients with retinoblastoma and postlaminar optic nerve invasion (PLONI). DESIGN: Retrospective interventional case series. PARTICIPANTS: Sixty-one consecutive patients included in 3 successive protocols were analyzed. METHODS: Pathologic review was done in each case. Patients were stratified into 2 risk groups: the high-risk group included those with concomitant full choroidal and/or scleral invasion and were given adjuvant chemotherapy. Those without these features were considered low risk and chemotherapy was withheld after 1994. MAIN OUTCOME MEASURES: Extraocular relapse and survival according to stratification. RESULTS: The probability of event-free survival (pEFS) was 0.91 and the probability of overall survival (pOS) was 0.94 at 5 years. Patients in the high-risk group (n = 22) had pEFS of 0.86. Three had extraocular relapse (involving the central nervous system; all died of disease). Microscopic scleral invasion was associated to extraocular relapse (P = 0.05). Lower risk patients (n = 39) had a pEFS of 0.94 and pOS of 1. Eighteen received postenucleation chemotherapy and none relapsed. Twenty-one received no adjuvant therapy and 2 had a systemic relapse but were successfully retrieved. Relapsing patients had a higher ratio of affected optic nerve (>25% of it overall length; P = 0.02). CONCLUSIONS: Patients with PLONI have an excellent outcome with current therapy. Risk stratification according to the presence of concomitant choroidal and/or scleral invasion may help in the decision of giving adjuvant therapy.

Influence of carrier cells on the clinical outcome of children with neuroblastoma treated with high dose of oncolytic adenovirus delivered in mesenchymal stem cells.

We report here our clinical experience of a program of compassionate use of Celyvir--autologous marrow-derived mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus--for treating children with advanced metastatic neuroblastoma. Children received weekly doses of Celyvir with no concomitant treatments. The tolerance was excellent, with very mild and self-limited viral-related symptoms. Patients could be distinguished based on their response to therapy: those who had a clinical response (either complete, partial or stabilization) and those who did not respond. We found differences between patients who responded versus those who did not when analyzing their respective MSCs, at the expression levels of adhesion molecules (CCR1, CXCR1 and CXCR4) and in migration capacities in transwell assays, and in immune-related molecules (IFNγ, HLA-DR). These results suggest interpatient differences in the homing and immune modulation capacities of the therapy administered. In addition, the pretherapy immune T cell status and the T effector response were markedly different between responders and non-responders. We conclude that multidoses of Celyvir have an excellent safety profile in children with metastatic neuroblastoma. Intrinsic patients' and MSCs' factors appear to be related to clinical outcome.

[Lymphoepithelioma-like gastric carcinoma: unusual variant in postgastrectomy stump]. / Carcinoma gástrico de tipo linfoepitelioma: variante inusual en muñón post-gastrectomía.

Gastric lymphoepithelioma--like carcinoma, undifferentiated with lymphoid or medullary stroma, constitutes a 3.8% of gastric carcinomas. Microscopically it is similar to other lymphoepitheliomas, it has an expansive growth and better prognosis than other histologic types. A possible relation to Epstein Barr virus is presumed. A 56 year old female, gastrectomized due to a cancer (Billroth II) 31 years before, showed an ulcer lesion close to the anastomosis at endoscopy. A biopsy was taken with positive result and gastrectomy was performed. The surgical specimen included gastric stump, jejunoanastomosis, omentum and lymph nodes. It had a 4.5 cm, protruded ulcerated lesion, located in anterior wall, 1.5 cm from stomy. It was fixed in buffered formalin, routinely processed and stained with Hematoxilin--Eosin. Immunohistochemistry techniques for CKAE1-AE3, EMA, CEA, CD45, CD20, CD3 and CD45Ro, and PCR for Epstein Barr virus were performed. Microscopically it was constituted by an expansive proliferation of polygonal cells with barely eosinophylic cytoplasm and vesicular nuclei, arranged in small clusters or isolated, positive for CKAE1-AE3, EMA and CEA, with dense mature lymphoid infiltrate, both follicular and diffuse, positive for CD45, CD45Ro, CD3 and CD20. PCR technique for Epstein Barr virus was positive. This has been the first case of this type in our department since 1989. In addition to the peculiar characteristics of this variety, whose differential diagnosis must be made with lymphomas, the origin from gastric stump, where this complication appears with variable rates, the risk being related to the type of surgery and the time elapsed are relevant.

Exercise benefits in chronic graft versus host disease: a murine model study.

INTRODUCTION: Chronic graft versus host disease (cGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation that generates considerable morbidity and compromises the physical capacity of patients. We determined the effects of an exercise training program performed after allogeneic hematopoietic stem cell transplantation on clinical and biological variables in a minor histocompatibility antigen-driven murine model of cGVHD treated with cyclosporine A. METHODS: Recipient BALB/C female mice (age 8 wk) received bone marrow cells and splenocytes from donor B10.D2 male mice and were randomly assigned to an exercise (n = 11) or control group (n = 12). For approximately 11 wk after transplant, the exercise group completed a moderate-intensity treadmill program. Variables assessed were clinical severity scores, survival, physical fitness, cytokine profile, immune cell reconstitution, molecular markers of muscle exercise adaptations, and histological scores in affected tissues. RESULTS: Exercise training increased survival (P = 0.011), diminished total clinical severity scores (P = 0.002), improved physical fitness (P = 0.030), and reduced blood IL-4 and tumor necrosis factor α levels (P = 0.03), while increasing circulating B220 (P = 0.008) and CD4 lymphocytes (P = 0.043). CONCLUSIONS: A moderate-intensity exercise program that mimics widely accepted public health recommendations for physical activity in human adults was well tolerated and positive effects on survival as well as on clinical and biological indicators of cGVHD.

Effects of exercise interventions in graft-versus-host disease models.

Graft-versus-host-disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is associated with high morbimortality and decreased patients' physical capacity. We evaluated the effects of an 11-week moderate-intensity exercise (treadmill) training program performed after allo-HSCT in a murine acute (aGVHD) and chronic GVHD model (cGVHD). Female mice (aged 8-12 weeks) were randomly assigned to the exercise or the control group. They completed a maximal treadmill test before allo-HSCT (with donor bone marrow cells and splenocytes) and after the 11-week period, during which we evaluated clinical severity scores and survival (Kaplan-Meier method). Before allo-HSCT and at days +21, +52 and +83 (upon sacrifice), we collected blood samples for immune cell reconstitution and cytokine analysis. The main results were that (i) in aGVHD, exercise improved maximal physical capacity over the 11-week period compared with pre-allo-HSCT conditions (p < 0.001 for the between-group comparison) and benefited total clinical score evolution (p = 0.05 for the group × time interaction effect), without altering immune reconstitution; (ii) in cGVHD, exercise training resulted in a lesser deterioration of physical capacity after 11 weeks (p = 0.023). Our results highlight the potential beneficial effects of exercise as coadjuvant intervention against GVHD, especially in the acute form of the disease.

Molecular findings of nasopharyngeal carcinoma in a European population.

OBJECTIVE: To explore biomolecular characteristics of a group of patients with nasopharyngeal carcinoma from European (Spanish) hospitals, addressing the pathogenesis of the tumor and the response to treatment. STUDY DESIGN: Cyclin D1 and p16 expression were evaluated immunohistochemically in 33 tissue samples of nasopharyngeal carcinoma. CCDN1 gene amplification and p16 gene deletion were studied by fluorescence in situ hybridization. Patient clinical data were examined, and tissues were evaluated histologically using hematoxylin-eosin staining. RESULTS: Cyclin D1 overexpression was found in 19 cases, and p16 expression was undetected in 30 cases. An association was observed between impaired p16 expression and cyclin D1 overexpression (p = 0.034). Eleven patients displayed p16 gene deletion and CCDN1 gene amplification. CONCLUSION: Cyclin D1 overexpression and CCDN1 amplification, loss of p16 expression and p16 deletion may be among the genetic alterations involved in the pathogenesis of nasopharyngeal carcinoma.

Spindle epithelial tumor with thymuslike differentiation in a 2-year-old boy: a case report.

BACKGROUND: The spindle epithelial tumor with thymuslike differentiation (SETTLE) is a rare thyroid tumor believed to be derived from ectopic thymus tissue or the embryonic remnants of branchial pouches, which displays primitive thymic differentiation. Histologic observation of spindle cells may lead to confusion with other tumors the development and prognosis of which are very different. Differential diagnosis using histochemical markers is essential since although there is a tendency to develop blood-borne metastases, tumor growth is slow and the survival rate in patients followed up is as high as 70%. It mainly affects children and young adults (mean age 15), although cases have been reported in patients ranging from 2 to 59. CASE: A 2-year-old boy presented with a tumor on the anteroinferior aspect of the neck, which had been growing since birth, suggesting a congenital origin. Histologic examination showed spindle cell nodules separated by fibrous bands containing mucous glands and cysts filled with mucoid material. Immunohistochemical markers revealed primitive differentiation; tumor cells stained positive for cytokeratin and vimentin but negative for markers indicative of greater differentiation, such as calcitonin, chromogranin, calretinin, synaptophysin and S-100 protein. CONCLUSION: This is the first reported case of SETTLE in the youngest patient which had been growing since birth.

An aggressive bone marrow evaluation including immunocytology with GD2 for advanced retinoblastoma.

There is general agreement that bone marrow (BM) examination for staging in patients with retinoblastoma should be limited to cases with advanced disease. However, there are limited data about the yield of sampling multiple sites with aspirations and biopsies and immunocytology. Our policy for BM examination included: 2 aspirates and 2 biopsies at the posterior iliac crest scheduled only for cases with postlaminar optic nerve extension (n=56), scleral invasion (n=10) or orbital (n=5) or metastatic disease at diagnosis (n=7) or at extraocular relapse (n=18). Immunocytology with the antibodies 3A7 or 3F8 for the ganglioside GD2 was performed. From 1/1994 to 3/2005, 277 newly diagnosed patients and 5 at extraocular relapse were included. BM invasion was not found in any of the 66 patients enucleated with disease confined to the globe, but was found in 11/27 of those with overt extraocular disease. There were 2/11 cases with at least 1 negative aspirate with positive biopsy and/or immunocytology for GD2. GD2 positivity was found in 9/9 cases. A more aggressive BM evaluation has a low yield in enucleated patients with high-risk features but disease limited to the globe. However, in cases with overt extraocular dissemination, the use of BM biopsy and immunocytology for GD2 allowed for the detection of cases that would have been missed by aspirations alone. GD2 was intensively expressed and it may also be used to monitor disease response and the presence of minimal residual disease.

Angiomiolipoma epitelioide presentado como un carcinoma urotelial de pelvis renal / Epithelioid angiomyolipoma presenting as an urothelial Carcinoma of renal pelvis

OBJETIVO: El angiomiolipoma renal es una neoplasia compuesta de vasos sanguíneos dismórficos, músculo liso y tejido adiposo. El angiomiolipoma epitelioide es una variante rara potencialmente maligna. Aportamos un caso de angiomiolipoma epitelioide renal sospechoso de carcinoma urotelial de pelvis. MÉTODO: Mujer de 50 años con hematuria y masa, en la tomografía axial computerizada, sospechosa de carcinoma urotelial de pelvis renal. Se analiza patológicamente la pieza de nefrectomía, con múltiples cortes histológicos de hematoxilina-eosina y técnicas inmunohistoquímicas. RESULTADOS: Se realiza nefrectomía izquierda. El riñón muestra tumor de 8cm con rasgos morfoinmunohistoquímicos de angiomiolipoma epitelioide, con escaso componente de angiomiolipoma clásico. Planteamos diagnóstico diferencial y analizamos los datos patológicos de pronóstico. CONCLUSIONES: El estudio patológico detallado del tumor es fundamental para el diagnóstico diferencial y su pronóstico. En este caso la paciente no presentaba rasgos indicativos de mal pronóstico, aunque el seguimiento es fundamental dado el potencial maligno de la neoplasia (AU)

OBJECTIVE: Renal angiomyolipoma is a mesenchymal neoplasm composed ofdysmorphic blood vessels, smooth muscle, and adipose tissue. Epithelioidangiomyolipoma is an uncommon variant considered potentially malignant. Wereport a case of renal epithelioid angiomyolipoma suspicious for urothelialcarcinoma of renal pelvis. METHODS: A 50-year-old woman with a 3-day history of macroscopic hematuria and CT-scan showing a tumor arising from the left renal pelvis suspicious for urothelialcarcinoma. Nephrectomy was analysed in multiple slides of hematoxilin-eosinand immunohistochemistry. RESULTS: Left nephrectomy was performed. Tumor sized 8cm and showed pathologic findings of epithelioid angiomyolipoma with a little component of classic angiomyolipoma. We studied differential diagnosis and pathologic characteristics for the prognosis. CONCLUSIONS: Pathologic study in detail is fundamental for differential diagnosisand prognosis of this tumor. Our patient`spathology showed good prognosis, however follow-up is important due the malignant potential of the neoplasm (AU)

Carcinoma gástrico de tipo linfoepitelioma: variante inusual en muñón post-gastrectomía / Lymphoepithelioma-like gastric carcinoma: unusual variant in postgastrectomy stump

El carcinoma de tipo linfoepitelioma, indiferenciado con estroma linfoide o medular, constituye un 3,8% de los carcinomas gástricos. Microscópicamente es similar a linfoepiteliomas de otras localizaciones, tiene crecimiento expansivo y mejor pronóstico que otros tipos histológicos. Se postula probable relación con el virus de Epstein Barr. Una mujer de 56 años gastrectomizada por cáncer hacía 31 años (Billroth) mostró en la endoscopía lesión ulcerada próxima a neboca. Se biopsió con resultado positivo y se realizó gastrectomía. Se recibió pieza que incluía muñón gástrico, yeyuno anastomosis, epiplón y glanglios. Presentaba lesión sobreelevada, ulcerada, de 4,5 cm ubicada en cara anterior a 1,5 cm de neoboca. Se efectuó fijación en formol buffer, procesamiento según métodos habituales y coloración con Hematoxilina-Eosina. Se realizaron técnicas de Inmunohistoquímica para CKAE1-AE3, EMA, CEA, CD45, CD20, CD3 y CD45Ro, y de PCR para virus de Epstein Barr. Microscópicamente estaba constituida por una proliferación expansiva de células poligonades con citoplasma ligeiramente eosinófilo y núcleos vesiculares, dispuestas en pequeños nidos o asiladas, positivas para CKES1-AE3, EMA y CEA, con denso infiltrado linfoide maduro, de disposición folicular y difuso, positivo para CD45, CD45Ro, CD3 y CD20. La técnica de PCR fue positiva. Éste es el primer caso de este tipo registrado en nuestro servicio desde 1989. Además de las características peculiares de esta variedad, cuyo diagnóstico diferencial debe haceres con los linfomas. es relevante su origen en muñón gástrico, donde esta complicación aparece con cifras variables, estando el riesgo vinculado al tipo de cirgía y tiempo transcurrido.

Carcinoma gástrico de tipo linfoepitelioma: variante inusual en muñón post-gastrectomía / Lymphoepithelioma-like gastric carcinoma: unusual variant in postgastrectomy stump

El carcinoma de tipo linfoepitelioma, indiferenciado con estroma linfoide o medular, constituye un 3,8% de los carcinomas gástricos. Microscópicamente es similar a linfoepiteliomas de otras localizaciones, tiene crecimiento expansivo y mejor pronóstico que otros tipos histológicos. Se postula probable relación con el virus de Epstein Barr. Una mujer de 56 años gastrectomizada por cáncer hacía 31 años (Billroth) mostró en la endoscopía lesión ulcerada próxima a neboca. Se biopsió con resultado positivo y se realizó gastrectomía. Se recibió pieza que incluía muñón gástrico, yeyuno anastomosis, epiplón y glanglios. Presentaba lesión sobreelevada, ulcerada, de 4,5 cm ubicada en cara anterior a 1,5 cm de neoboca. Se efectuó fijación en formol buffer, procesamiento según métodos habituales y coloración con Hematoxilina-Eosina. Se realizaron técnicas de Inmunohistoquímica para CKAE1-AE3, EMA, CEA, CD45, CD20, CD3 y CD45Ro, y de PCR para virus de Epstein Barr. Microscópicamente estaba constituida por una proliferación expansiva de células poligonades con citoplasma ligeiramente eosinófilo y núcleos vesiculares, dispuestas en pequeños nidos o asiladas, positivas para CKES1-AE3, EMA y CEA, con denso infiltrado linfoide maduro, de disposición folicular y difuso, positivo para CD45, CD45Ro, CD3 y CD20. La técnica de PCR fue positiva. Este es el primer caso de este tipo registrado en nuestro servicio desde 1989. Además de las características peculiares de esta variedad, cuyo diagnóstico diferencial debe haceres con los linfomas. es relevante su origen en muñón gástrico, donde esta complicación aparece con cifras variables, estando el riesgo vinculado al tipo de cirgía y tiempo transcurrido.(AU)

Carcinoma gástrico de tipo linfoepitelioma: variante inusual en muñón post-gastrectomía. / [Lymphoepithelioma-like gastric carcinoma: unusual variant in postgastrectomy stump]

Gastric lymphoepithelioma--like carcinoma, undifferentiated with lymphoid or medullary stroma, constitutes a 3.8

of gastric carcinomas. Microscopically it is similar to other lymphoepitheliomas, it has an expansive growth and better prognosis than other histologic types. A possible relation to Epstein Barr virus is presumed. A 56 year old female, gastrectomized due to a cancer (Billroth II) 31 years before, showed an ulcer lesion close to the anastomosis at endoscopy. A biopsy was taken with positive result and gastrectomy was performed. The surgical specimen included gastric stump, jejunoanastomosis, omentum and lymph nodes. It had a 4.5 cm, protruded ulcerated lesion, located in anterior wall, 1.5 cm from stomy. It was fixed in buffered formalin, routinely processed and stained with Hematoxilin--Eosin. Immunohistochemistry techniques for CKAE1-AE3, EMA, CEA, CD45, CD20, CD3 and CD45Ro, and PCR for Epstein Barr virus were performed. Microscopically it was constituted by an expansive proliferation of polygonal cells with barely eosinophylic cytoplasm and vesicular nuclei, arranged in small clusters or isolated, positive for CKAE1-AE3, EMA and CEA, with dense mature lymphoid infiltrate, both follicular and diffuse, positive for CD45, CD45Ro, CD3 and CD20. PCR technique for Epstein Barr virus was positive. This has been the first case of this type in our department since 1989. In addition to the peculiar characteristics of this variety, whose differential diagnosis must be made with lymphomas, the origin from gastric stump, where this complication appears with variable rates, the risk being related to the type of surgery and the time elapsed are relevant.