SEOM clinical guideline for management of adult medulloblastoma (2020).

Recent advances in molecular profiling, have reclassified medulloblastoma, an undifferentiated tumor of the posterior fossa, in at least four diseases, each one with differences in prognosis, epidemiology and sensibility to different treatments. The recommended management of a lesion with radiological characteristics suggestive of MB includes maximum safe resection followed by a post-surgical MR < 48 h, LCR cytology and MR of the neuroaxis. Prognostic factors, such as presence of a residual tumor volume > 1.5 cm2, presence of micro- or macroscopic dissemination, and age > 3 years as well as pathological (presence of anaplastic or large cell features) and molecular findings (group, 4, 3 or p53 SHH mutated subgroup) determine the risk of relapse and should guide adjuvant management. Although there is evidence that both high-risk patients and to a lesser degree, standard-risk patients benefit from adjuvant craneoespinal radiation followed by consolidation chemotherapy, tolerability is a concern in adult patients, leading invariably to dose reductions. Treatment after relapse is to be considered palliative and inclusion on clinical trials, focusing on the molecular alterations that define each subgroup, should be encouraged. Selected patients can benefit from surgical rescue or targeted radiation or high-dose chemotherapy followed by autologous self-transplant. Even in patients that are cured by chemorradiation presence of significant sequelae is common and patients must undergo lifelong follow-up.

Gender differences and health inequality: Evolution of cardiovascular risk in workers.

The aim was to find out if there are any such differences due to gender in a cohort of workers followed for ten years, comparing their lifestyles and following the evolution of the main cardiovascular risk factors (CVRF) and their impact on cardiovascular risk. An observational longitudinal study of 698 civil servants workers (186 women and 512 men) of a local government office from Córdoba (Spain), was conducted over the period 2003-2014. We compared the initial and final prevalence of physical activity, smoking, obesity, hypertension, metabolic syndrome and diabetes. Cardiovascular risk was also assessed using the REGICOR (Registre Gironí del Cor) and SCORE (Systematic Coronary Risk Evaluation) equations. There was a greater rise in the prevalence of hypertension and hypercholesterolemia in the cohort in women than in men (94.2% vs. 38% and 92% vs 21.1%), while the reduction in smoking also differed by gender (26.4% vs. 36.5%). It could be that since women present a lower cardiovascular risk profile, they are treated less or less effort is made to keep the risk factors low, resulting in a worse evolution of smoking, hypercholesterolemia and hypertension in women.

Resultados y complicaciones de la enfermedad del segmento adyacente tratada mediante artrodesis intersomática lateral mínimamente invasiva / Results and complications of adjacent segment disease treated by minimally invasive lateral intersomatic arthrodesis

Resumen: Introducción: Se ha realizado un estudio clínico comparativo sobre los pacientes intervenidos mediante artrodesis intersomática lateral para tratamiento de la enfermedad del segmento adyacente utilizando dispositivos intersomáticos de titanio y de PEEK. Material y métodos: Se han analizado y comparado los resultados clínicos (EVA y oswestry disability index ODI) y radiológicos (alineamiento y fusión), las complicaciones (mayores y menores) y la calidad de vida (EQ5D) de 32 pacientes intervenidos desde Septiembre de 2015 hasta Septiembre de 2018, con un seguimiento medio de 25 meses (46-18). La edad media en la cirugía fue de 66 años (39-89) y 68% de los pacientes fueron mujeres. El segmento intervenido con más frecuencia fue L3-L4 (62%) abordaje retroperitoneal derecho 86%. La EVA lumbar mejoró de 6.2 ± 2.12 a 4.1 ± 1.71 (p = 0.028). La EVA de la pierna descendió de 5.3 ± 2.26 a 1.9 ± 1.58 (p = 0.02). La escala ODI mejoró de 50.2 ± 18.9 a 33.3 ± 10.2 (p = 0.025) y la EQ5D pasó de 0.52 a 0.73 (p = 0.039) sin diferencias estadísticamente significativas entre los grupos (ODI p = 0.18, EQ5D p = 0.293). Radiológicamente aumentó la altura intervertebral, la lordosis lumbar y segmentaria, disminuyó el ángulo de Cobb y la tasa de fusión global fue de 84.3% (88% Ti/82% PEEK), sin diferencias entre los grupos. Conclusiones: La artrodesis intersomática lumbar lateral Lateral Lumbar Interbody Fusion es un método eficaz para el tratamiento de la enfermedad del segmento adyacente con resultados clínicos-radiológicos y complicaciones similares a la literatura. No se han encontrado diferencias entre los implantes de Ti y de PEEK.

Abstract: Introduction: A comparative clinical study has been conducted on patients involved using lateral intersomatic arthrodesis for the treatment of adjacent segment disease using titanium and PEEK intersomatic devices. Material and methods: Clinical (EVA and oswestry disability index ODI) and radiological (alignment and fusion), complications (major and minor) and quality of life (EQ5D) of 32 patients intervened from September 2015 to September 2018 have been analyzed and compared, with an average follow-up of 25 months (46-18). The average age in surgery was 66 years (39-89) and 68% of patients were women. Results: The most common segment involved was L3-L4 (62%) right retroperitoneal approach 86%. Lumbar EVA improved from 6.2 ± 2.12 to 4.1 ± 1.71 (p = 0.028). The LEG EVA descended from 5.3 ± 2.26 to 1.9 ± 1.58 (p = 0.02). The ODI scales improved from 50.2 ± 18.9 to 33.3 ± 10.2 (p = 0.025) and the EQ5D went from 0.52 to 0.73 (p = 0.039) with no statistically significant differences between the groups (ODI p = 0.18, EQ5D p = 0.293). Radiologically increased intervertebral height, lumbar and segmental lordosis, decreased Cobb's angle and the overall melting rate was 84.3% (88% Ti/82% PEEK), with no differences between the groups. Conclusion: Lateral lumbar interbody fusion is an effective method for treating adjacent segment disease with clinical-radiological results and literature-like complications. No differences have been found between Ti and PEEK implants.

[Results and complications of adjacent segment disease treated by minimally invasive lateral intersomatic arthrodesis]. / Resultados y complicaciones de la enfermedad del segmento adyacente tratada mediante artrodesis intersomática lateral mínimamente invasiva.

INTRODUCTION: A comparative clinical study has been conducted on patients involved using lateral intersomatic arthrodesis for the treatment of adjacent segment disease using titanium and PEEK intersomatic devices. MATERIAL AND METHODS: Clinical (EVA and oswestry disability index ODI) and radiological (alignment and fusion), complications (major and minor) and quality of life (EQ5D) of 32 patients intervened from September 2015 to September 2018 have been analyzed and compared, with an average follow-up of 25 months (46-18). The average age in surgery was 66 years (39-89) and 68% of patients were women. RESULTS: The most common segment involved was L3-L4 (62%) right retroperitoneal approach 86%. Lumbar EVA improved from 6.2 ± 2.12 to 4.1 ± 1.71 (p = 0.028). The LEG EVA descended from 5.3 ± 2.26 to 1.9 ± 1.58 (p = 0.02). The ODI scales improved from 50.2 ± 18.9 to 33.3 ± 10.2 (p = 0.025) and the EQ5D went from 0.52 to 0.73 (p = 0.039) with no statistically significant differences between the groups (ODI p = 0.18, EQ5D p = 0.293). Radiologically increased intervertebral height, lumbar and segmental lordosis, decreased Cobb's angle and the overall melting rate was 84.3% (88% Ti/82% PEEK), with no differences between the groups. CONCLUSION: Lateral lumbar interbody fusion is an effective method for treating adjacent segment disease with clinical-radiological results and literature-like complications. No differences have been found between Ti and PEEK implants.

INTRODUCCIÓN: Se ha realizado un estudio clínico comparativo sobre los pacientes intervenidos mediante artrodesis intersomática lateral para tratamiento de la enfermedad del segmento adyacente utilizando dispositivos intersomáticos de titanio y de PEEK. MATERIAL Y MÉTODOS: Se han analizado y comparado los resultados clínicos (EVA y. CONCLUSIONES: oswestry disability index ODI) y radiológicos (alineamiento y fusión), las complicaciones (mayores y menores) y la calidad de vida (EQ5D) de 32 pacientes intervenidos desde Septiembre de 2015 hasta Septiembre de 2018, con un seguimiento medio de 25 meses (46-18). La edad media en la cirugía fue de 66 años (39-89) y 68% de los pacientes fueron mujeres. El segmento intervenido con más frecuencia fue L3-L4 (62%) abordaje retroperitoneal derecho 86%. La EVA lumbar mejoró de 6.2 ± 2.12 a 4.1 ± 1.71 (p = 0.028). La EVA de la pierna descendió de 5.3 ± 2.26 a 1.9 ± 1.58 (p = 0.02). La escala ODI mejoró de 50.2 ± 18.9 a 33.3 ± 10.2 (p = 0.025) y la EQ5D pasó de 0.52 a 0.73 (p = 0.039) sin diferencias estadísticamente significativas entre los grupos (ODI p = 0.18, EQ5D p = 0.293). Radiológicamente aumentó la altura intervertebral, la lordosis lumbar y segmentaria, disminuyó el ángulo de Cobb y la tasa de fusión global fue de 84.3% (88% Ti/82% PEEK), sin diferencias entre los grupos. La artrodesis intersomática lumbar lateral.

Delay in starting radiotherapy due to neoadjuvant therapy does not worsen survival in unresected glioblastoma patients.

PURPOSE: We retrospectively examined the potential effect on overall survival (OS) of delaying radiotherapy to administer neoadjuvant therapy in unresected glioblastoma patients. PATIENTS AND METHODS: We compared OS in 119 patients receiving neoadjuvant therapy followed by standard treatment (NA group) and 96 patients receiving standard treatment without neoadjuvant therapy (NoNA group). The MaxStat package of R identified the optimal cut-off point for waiting time to radiotherapy. RESULTS: OS was similar in the NA and NoNA groups. Median waiting time to radiotherapy after surgery was 13 weeks for the NA group and 4.2 weeks for the NoNA group. The longest OS was attained by patients who started radiotherapy after 12 weeks and the shortest by patients who started radiotherapy within 4 weeks (12.3 vs 6.6 months) (P = 0.05). OS was 6.6 months for patients who started radiotherapy before the optimal cutoff of 6.43 weeks and 19.1 months for those who started after this time (P = 0.005). Patients who completed radiotherapy had longer OS than those who did not, in all 215 patients and in the NA and NoNA groups (P = 0.000). In several multivariate analyses, completing radiotherapy was a universally favorable prognostic factor, while neoadjuvant therapy was never identified as a negative prognostic factor. CONCLUSION: In our series of unresected patients receiving neoadjuvant treatment, in spite of the delay in starting radiotherapy, OS was not inferior to that of a similar group of patients with no delay in starting radiotherapy.

SEOM clinical guidelines for diagnosis and treatment of glioblastoma (2017).

Glioblastoma (GB) is the most common brain malignancy and accounts for over 50% of all high-grade gliomas. Radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ) chemotherapy is the current standard of care for patients with newly diagnosed GB up to age 70. Recently, a new standard of care has been adopted for elderly patients (≥ 65 years) based on short course of RT and TMZ. Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified. The treatment for recurrent GB is not well defined, and decision-making is usually based on prior strategies as well as several clinical and radiological factors. The presence of neurologic deficits and seizures can significantly impact quality of life.

Adult spinal deformity treated with minimally invasive surgery. Description of surgical technique, radiological results and literature review. / Deformidad del adulto tratada mediante cirugía mínimamente invasiva. Técnica quirúrgica, resultados radiológicos y revisión de la literatura.

The prevalence of adult spinal deformity has been increasing exponentially over time. Surgery has been credited with good radiological and clinical results. The incidence of complications is high. MIS techniques provide good results with fewer complications. This is a retrospective study of 25 patients with an adult spinal deformity treated by MIS surgery, with a minimum follow-up of 6 months. Radiological improvement was SVA from 5 to 2cm, coronal Cobb angle from 31° to 6°, and lumbar lordosis from 18° to 38°. All of these parameters remained stable over time. We also present the complications that appeared in 4 patients (16%). Only one patient needed reoperation. We describe the technique used and review the references on the subject. We conclude that the MIS technique for treating adult spinal deformity has comparable results to those of the conventional techniques but with fewer complications.

Results of a multicenter survey showing interindividual variability among neurosurgeons when deciding on the radicality of surgical resection in glioblastoma highlight the need for more objective guidelines.

PURPOSE: We assessed agreement among neurosurgeons on surgical approaches to individual glioblastoma patients and between their approach and those recommended by the topographical staging system described by Shinoda. METHODS: Five neurosurgeons were provided with pre-surgical MRIs of 76 patients. They selected the surgical approach [biopsy, partial resection, or gross total resection (GTR)] that they would recommend for each patient. They were blinded to each other's response and they were told that patients were younger than 50 years old and without symptoms. Three neuroradiologists classified each case according to the Shinoda staging system. RESULTS: Biopsy was recommended in 35.5-82.9%, partial resection in 6.6-32.9%, and GTR in 3.9-31.6% of cases. Agreement among their responses was fair (global kappa = 0.28). Nineteen patients were classified as stage I, 14 as stage II, and 43 as stage III. Agreement between the neurosurgeons and the recommendations of the staging system was poor for stage I (kappa = 0.14) and stage II (kappa = 0.02) and fair for stage III patients (kappa = 0.29). An individual analysis revealed that in contrast to the Shinoda system, neurosurgeons took into account T2/FLAIR sequences and gave greater weight to the involvement of eloquent areas. CONCLUSIONS: The surgical approach to glioblastoma is highly variable. A staging system could be used to examine the impact of extent of resection, monitor post-operative complications, and stratify patients in clinical trials. Our findings suggest that the Shinoda staging system could be improved by including T2/FLAIR sequences and a more adequate weighting of eloquent areas.

Extreme lateral lumbar interbody fusion. Surgical technique, outcomes and complications after a minimum of one year follow-up. / Artrodesis intersomática lumbar extralateral. Técnica quirúrgica, resultados y complicaciones con un seguimiento mínimo de un año.

«Minimally invasive¼ techniques have been recently been developed in order to achieve good clinical results with a low incidence of complications. The extralateral interbody fusion or direct transpsoas is a minimally invasive anterior arthrodesis. A total of 97 patients with 138 segments received surgery between May 2012 and May 2015. The follow-up was from 12-44 months. The mean age was 68 years (41-86). The most common cause of intervention was the adjacent segment (30%), deformity (22%), and lumbar disc disease (21%). The interbody cage was implanted as: Single (stand-alone) in 33%, and additional fixation was used in the others: Screws, percutaneous unilateral (11%), bilateral (27%), or with a lateral plate (62%). The mean stay was 3.2 days (2-6). The score on a lumbar visual analogue scale decreased from 9 to 4.1, and dropped to 3 after one year. The improvement in disc height was from 8.4mm to 13.8mm, and a larger increase in the foramen diameter from 10.5 to 13.1mm, which were statistically significant. The early major complications recorded were, three motor femoral nerve injuries and retroperitoneal haematoma (4%), and the early minor were: two fractures (2%). As major late complications there was an abdominal hernia, a mobilization of 10mm and three radiculopathy (5%), and as minor late, three fracture, two mobilisations greater than 10mm, four mobilisations of less than 10mm, and one mobilisation of a screw plate (10%). The extralateral interbody fusion technique is a safe and reliable when performing a lumbar fusion by an alternative minimally invasive route.

Luxación congénita de rodilla: a propósito de un caso / Congenital knee dislocation: case report

Resumen: La luxación congénita de rodilla es una patología poco frecuente con una etiología desconocida. En algunos casos se le considera una patología aislada mientras que en otros pueden observarse patologías asociadas o síndromes. El tratamiento de la luxación congénita de rodilla depende de la gravedad y flexibilidad de la deformidad y en la bibliografía pueden encontrarse desde enyesados seriados o arnés de Pavlik hasta plastías del tendón cuadricipital u osteotomías femorales. Presentamos un caso de una luxación congénita que se trató mediante enyesado seriado y que evolucionó favorablemente.

Abstract: Congenital knee dislocation is an infrequent condition with unknown etiology. In some cases it occurs as an isolated condition, while in others it coexists with associated conditions or syndromes. The treatment of congenital knee dislocation is driven by the severity and flexibility of the deformity. The literature includes from serial casting or the Pavlik harness to quadriceps tendon plasty or femoral osteotomies. We report herein the case of a congenital dislocation treated with serial casting with a good outcome.

Historia natural del carcinoma ductal invasivo frente a carcinoma lobulillar invasivo. Nuestra experiencia / Natural history of invasive ductal carcinoma versus invasive lobular carcinoma. Our experience

Introducción: La subclasificación histológica del cáncer de mama infiltrante, ya sea ductal (CDI) o lobulillar (CLI) se correlaciona aparentemente con una biología tumoral distinta. Los datos de nuestro análisis m ostraron que los carcinomas lobulillares invasivos son generalmente de tipo luminales, tienen mayor tamaño al momento del diagnóstico clínico y un superior índice de cirugías radicales. Siendo superior la tasa de recurrencia local. Tanto la supervivencia global como la libre de enfermedad no tuvieron diferencia significativa en ambos grupos. Conclusión: La clasificación histológica del cáncer invasivo de mama, ya sea ductal o lobulillar, no se correlaciona con la supervivencia de la enfermedad. Sin embargo, en nuestro trabajo encontramos diferencias en la recidiva local, no así a distancia, lo que podría deberse a un comportamiento biológico diferente.

Familial isolated pituitary adenoma caused by a Aip gene mutation not described before in a family context.

The cause of familial isolated pituitary adenomas (FIPA) remains unknown in a high percentage of cases, but the AIP gene plays an important role in the etiology. The aim of the study is to describe a family with FIPA syndrome and the results of genomic studies. A 16-year-old man had a giant prolactinoma resistant tomedical treatment with delayed growth and pubertal development. His mother had been previously diagnosed with a nonfunctioning pituitary macroadenoma. Transsphenoidal endoscopic resection was performed and a genetic study revealed a heterozygous mutation in exon 6: 974G>A (p.Arg325Gln). Because the AIP gene is a tumor suppressor gene, we searched for loss of heterozygosity within the AIP gene by amplifying exon 6 from tumor tissue of the patient. In the electropherogram, only the A allele was amplified (hemizygous state), indicating loss of the normal allele. We report a Spanish family with FIPA in whom a mutation in the AIP gene previously unreported in a familiar context was identified.

A cellular and molecular basis for the selective desmopressin-induced ACTH release in Cushing disease patients: key role of AVPR1b receptor and potential therapeutic implications.

CONTEXT: Desmopressin is a synthetic agonist of vasopressin receptors (AVPRs). The desmopressin stimulation test is used in the diagnosis and postsurgery prognosis of Cushing disease (CD). However, the cellular and molecular mechanisms underlying the desmopressin-induced ACTH increase in patients with CD are poorly understood. OBJECTIVE: The objectives of this study were to determine, for the first time, whether desmopressin acts directly and exclusively on pituitary corticotropinoma cells to stimulate ACTH expression/release and to elucidate the cellular and molecular mechanisms involved in desmopressin-induced ACTH increase in CD. DESIGN: A total of 8 normal pituitaries (NPs), 23 corticotropinomas, 14 nonfunctioning pituitary adenomas, 17 somatotropinomas, and 3 prolactinomas were analyzed for AVPR expression by quantitative real-time RT-PCR. Primary cultures derived from corticotropinomas, nonfunctioning pituitary adenomas, somatotropinomas, prolactinomas, and NPs were treated with desmopressin, and ACTH secretion/expression, [Ca(2+)]i kinetics, and AVPR expression and/or proliferative response were evaluated. The relationship between AVPR expression and plasma adrenocorticotropin/cortisol levels obtained from desmopressin tests was assessed. RESULTS: Desmopressin affects all functional parameters evaluated in corticotropinoma cells but not in NPs or other pituitary adenomas cells. These effects might be due to the dramatic elevation of AVPR1b expression levels found in corticotropinomas. In line with this notion, the use of an AVPR1b antagonist completely blocked desmopressin stimulatory effects. Remarkably, only AVPR1b expression was positively correlated with elevated plasma adrenocorticotropin levels in corticotropinomas. CONCLUSIONS: The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and postsurgery prognosis of CD. Furthermore, our data indicate that AVPR1b is responsible for the direct/exclusive desmopressin stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b antagonists as potential therapeutic tools for CD treatment.

The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells.

Somatostatin receptors (sst1-5) are present in different types of tumors, where they inhibit key cellular processes such as proliferation and invasion. Although ssts are densely expressed in breast cancer, especially sst2, their role and therapeutic potential remain uncertain. Recently, we identified a new truncated sst5 variant, sst5TMD4, which is related to the abnormal response of certain pituitary tumors to treatment with somatostatin analogs. Here, we investigated the possible role of sst5TMD4 in breast cancer. This study revealed that sst5TMD4 is absent in normal mammary gland, but is abundant in a subset of poorly differentiated human breast tumors, where its expression correlated to that of sst2. Moreover, in the MCF-7 breast cancer model cell, sst5TMD4 expression increased malignancy features such as invasion and proliferation abilities (both in cell cultures and nude mice). This was likely mediated by sst5TMD4-induced increase in phosphorylated extracellular signal-regulated kinases 1 and 2 and p-Akt levels, and cyclin D3 and Arp2/3 complex expression, which also led to mesenchymal-like phenotype. Interestingly, sst5TMD4 interacts physically with sst2 and thereby alters its signaling, enabling disruption of sst2 inhibitory feedback and providing a plausible basis for our findings. These results suggest that sst5TMD4 could be involved in the pathophysiology of certain types of breast tumors.

Somatostatin dramatically stimulates growth hormone release from primate somatotrophs acting at low doses via somatostatin receptor 5 and cyclic AMP.

Somatostatin and cortistatin have been shown to act directly on pituitary somatotrophs to inhibit growth hormone (GH) release. However, previous results from nonprimate species indicate that these peptides can also directly stimulate GH secretion, at low concentrations. The relevance of this phenomenon in a nonhuman primate model was investigated in the present study by testing the impact of somatostatin/cortistatin on GH release in primary pituitary cell cultures from baboons. High doses (> 10(-10) m) of somatostatin/cortistatin did not alter basal GH secretion but blocked GH-releasing hormone (GHRH)- and ghrelin-induced GH release. However, at low concentrations (10(-17)-10(-13) m), somatostatin/cortistatin dramatically stimulated GH release to levels comparable to those evoked by GHRH or ghrelin. Use of somatostatin receptor (sst) specific agonists/antagonists, and signal transduction blockers indicated that sst2 and sst1 activation via intact adenylate cylcase and mitogen-activated protein kinase systems mediated the inhibitory actions of high-concentration somatostatin. By contrast, the stimulatory actions of low-dose somatostatin on GH release were mediated by sst5 signalling through adenylate cylcase/cAMP/protein kinase A and intracellular Ca(2+) pathways, and were additive with ghrelin (not GHRH). Notably, low-concentrations of somatostatin, similar to sst5-agonists, inhibited prolactin release. These results clearly demonstrate that the ultimate impact of somatostatin/cortistatin on hormone release is dose-dependent, cell type-selective and receptor-specific, where the stimulatory effects of low-concentration somatostatin/cortistatin on GH release extend to primates, thereby supporting the notion that this action is relevant in regulating GH secretion in humans.

Somatotroph tumor progression during pegvisomant therapy: a clinical and molecular study.

CONTEXT: There is concern that pegvisomant could be associated with a higher risk of tumor growth. The rate and possible determinants of this tumor growth are unknown. OBJECTIVE: The objective of the study was to investigate the clinical, immunohistological, and molecular factors conditioning tumor growth in patients taking pegvisomant. DESIGN AND SETTING: This was a cross-sectional study performed from 2004 to 2010 in four university hospitals in Spain. PATIENTS: Seventy-five acromegalic patients with active disease resistant to somatostatin analogs treated with pegvisomant were followed up for a mean of 29 ± 20 months. MAIN OUTCOME MEASURES: Magnetic resonance images before initiation of pegvisomant, at 6 months, and then yearly were examined in all patients. Immunohistological and molecular studies were performed in tumors that grew. RESULTS: A significant increase in tumor size was observed in five patients (6.7%). Absence of previous irradiation (P = 0.014) and shorter duration of prepegvisomant somatostatin analog therapy (P < 0.001) were associated with an increased risk of tumor growth. A stepwise multivariate linear regression analysis (R(2) = 0.334, P < 0.001) identified the duration of somatostatin analog therapy prior to pegvisomant (beta = -4.509, P = 0.014) as the only significant predictor of tumor growth. In those tumors that grew, GH expression and insulin receptor expression were higher (P = 0.033 in both cases) than in the control group. CONCLUSIONS: No previous radiotherapy, shorter duration of prepegvisomant somatostatin analog therapy, and higher tumor expression of GH and insulin receptor could be risk factors for tumor growth during pegvisomant therapy.

Bacillary angiomatosis with atypical clinical presentation in an immunocompetent patient.

Bacillary angiomatosis is a recently described infectious disease that usually affects immunosupressed hosts with a previous history of contact with cats. We report a rare case of bacillary angiomatosis in an immunocompetent 59-year-old woman with no history of previous exposure to cats, and atypical clinical features (fever and subcutaneous nodules with ulceration on the left ankle). Histopathology of the lesion showed extensive ulceration and reactive tumor-like vascular proliferation of the blood vessels with swollen endothelial cells and an inflammatory infiltrate including neutrophils and lymphocytes in the dermis and subcutis. Staining with the Warthin-Starry method demonstrated the presence of clustered bacilli located in the extracellular matrix adjacent to the proliferating endothelial cells. Diagnosis was confirmed with the detection of Bartonella spp. DNA in the affected skin and in bone marrow using polymerase chain reaction.

Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors.

Infection of gastric mucosa by Helicobacter pylori induces an inflammatory response with increased levels of proinflammatory cytokines. Among them, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 induce the activation of signaling pathways that regulate genes expression, such as MUC2 and MUC4 intestinal mucins ectopically detected in gastric tumors. This study evaluated if the predominant inflammatory cell type correlates with MUC2 and MUC4 expression in human intestinal gastric tumors (n=78). In addition, we analyzed the regulatory effects of the associated inflammatory signaling pathways on their expression in gastric cancer cell lines, and in a mouse model with hyperactivated STAT3 signaling pathway. Tumors with predominant lymphoplasmocytic infiltrate (chronic inflammation), presented higher levels of MUC2 and were more differentiated than tumors with predominant polymorphonuclear infiltrate (acute inflammation). These differences can be attributed to specific cytokines, because TNF-alpha and IL-1beta induced MUC2 but no MUC4 expression in gastric cancer cell lines. The two groups of tumors expressed similar levels of MUC4 that correlated with the expression of STAT3 transcription factor, implicated in the activation of genes through the IL-6 pathway. In gastric tissues from gp130(+/+), gp130(Y757F/Y757F) and gp130(Y757F/Y757F) Stat3(-/+) mice, Muc2 was not detected, whereas Muc4 was found in the gastric tumors developed in the gp130(Y757F/Y757F) mice, with hyperactivated STAT3. These data indicate that the signaling pathways associated with the inflammatory response can modulate the expression of MUC2 and MUC4 intestinal mucin genes, in human and mouse gastric tumors.

KiSS-1/kisspeptins and the metabolic control of reproduction: physiologic roles and putative physiopathological implications.

It is well established that reproductive function is gated by the state of energy reserves of the organism; conditions of metabolic stress and energy insufficiency being frequently coupled to disturbed reproductive maturation and/or infertility. In addition, obesity is also commonly linked to altered puberty onset and reproductive impairment. Such an impact of energy status on the reproductive axis is conveyed through a number of neuropeptide hormones and metabolic cues, whose nature and mechanisms of action have begun to be deciphered only in recent years. In this context, the emergence of kisspeptins, encoded by the KiSS-1 gene, and their receptor, GPR54, as indispensable signals for normal pubertal maturation and gonadal function, has raised the possibility that the KiSS-1/GRP54 system might also participate in coupling body energy status and reproduction. We revise herein the experimental evidence, gathered in rodent models, supporting the contention that the hypothalamic KiSS-1 system operates as a central conduit for conveying metabolic information onto the centers governing reproductive function, through a putative leptin-kisspeptin-GnRH pathway. Admittedly, key aspects of this 'metabolic' network involving the KiSS-1 system, such as its different peripheral regulators and central effectors, have not been fully elucidated. Nonetheless, the proposed hypothalamic circuitry, responsible for transmitting metabolic information onto the reproductive axis through KiSS-1 neurons, might explain, at least in part, the mechanisms for the well-known alterations of fertility linked to conditions of disturbed energy balance in humans, from anorexia nervosa to morbid obesity.

Loss of heterozygosity at 9q32-33 (DBC1 locus) in primary non-invasive papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma of the bladder and their associated normal urothelium.

Tumour recurrence has a major impact on patients with non-invasive papillary urothelial tumours of the bladder. To explore the role of DBC1 (deleted in bladder cancer 1 locus), a candidate tumour suppressor gene located at 9q32-33, as prognostic marker we have performed loss of heterozygosity (LOH) testing in 49 patients with primary papillary urothelial tumours and associated normal urothelium. Data from the 38 tumours and 11 specimens of normal urothelium that were informative in the LOH study (D9S195 marker) showed that LOH in urothelium (45.4%) but not in non-invasive tumours (60.5%) was associated with tumour recurrence (p = 0.026) but not to grade or progression. Also, tumours whose normal urothelium had LOH were larger (p = 0.020) and showed cyclin D1 over-expression (p = 0.032). Non-significant increased expression of p53, p21Waf1, apoptotic index and tumour proliferation, and decreased expression of p27Kip1 or cyclin D3 also characterized tumours whose normal urothelium had LOH. The expression of these G1-S modulators, apoptotic index and tumour proliferation was more heterogeneous in papillary urothelial tumours, irrespective of having retained heterozygosity or LOH. Also, Bax expression decreased in papillary urothelial tumours having LOH (p = 0.0473), but Bcl-2 was unrelated to LOH status. In addition, FGFR3 protein expression decreased in LOH tumours (p = 0.036) and in those having LOH in their normal urothelium (p = 0.022). FGFR3 immunohistochemical expression was validated by western blot in selected cases. The survival analysis selected LOH in normal urothelium as a marker of disease-free survival (log-rank 5.32, p = 0.021), progression-free survival (log-rank 3.97, p = 0.046) and overall survival (log-rank 4.26, p = 0.038); LOH in tumours was significant in progression-free survival (log-rank 3.83, p = 0.042). It is concluded that LOH at the DBC1 locus in normal urothelium seems to be relevant in the prognosis of non-invasive papillary tumours of the bladder via selecting cases with increased proliferation, frequent alterations of the G1-S phase modulators, and decreased FGFR3 protein expression.