[Malignant melanotic nerve sheath tumor of the posterior mediastinum]. / Tumor maligno melanocítico de la vaina neural en mediastino posterior.

Melanotic schwannoma (MS) is a rare and infrequent subtype of schwannoma characterized by cytoplasmic deposits of melanosomes (melanin). Unlike the other schwannomas, it could have malignant transformation. Due to distinctive characteristics and atypical behavior from classic schwannomas subtypes, MS were renamed and reclassified as "melanocytic malignant neural sheath tumor" in the 5th ed. of the World Health Organization's classification of central nervous system tumors in 2021. We present two cases of MS that underwent complete surgical resection.

El schwannoma melanótico (SM) es una variante rara e infrecuente caracterizada por el depósito citoplasmático de melanosomas (melanina). A diferencia de las otras variantes de schwannomas, tienen capacidad de malignización. Por poseer características y comportamiento distintos al resto de los schwannomas, fue reclasificado como "tumor maligno melanocítico de la vaina neural" en la 5ta edición de la clasificación de los tumores del sistema nervioso central de la Organización Mundial de la Salud en 2021. Presentamos dos casos de SM de ubicación mediastinal en los que se realizó una resección quirúrgica completa.

[PEComa of the lung]. / PEComa pulmonar.

Clear cell "sugar" tumor of the lung is a rare benign tumor arising from perivascular epithelioid cells (PECs). They belong to a group of mesenchymal neoplasms called PEComas. Although widely presumed as benign, due to their rich vascular stroma they are usually avid for the different types of contrast agents used in imaging studies, mimicking a malignant lesion. We report the case of a 66-year-old man in whom a solitary pulmonary nodule was discovered during oncological staging for an adenocarcinoma of the prostate who underwent an anatomical pulmonary segmentectomy. The final pathology result was a perivascular epithelioid cell tumor (pulmonary PEComa or clear "sugar" cell tumor).

Los tumores de células claras "de azúcar" (CCTL) son lesiones benignas muy infrecuentes. Forman parte de un grupo de neoplasias mesenquimales denominadas PEComas que se originan de las células epiteloides perivasculares. Por su rico estroma vascular, suelen tener avidez por los distintos tipos de contrastes utilizados en los estudios de diagnóstico por imágenes, simulando lesiones de estirpe maligna. Presentamos el caso de un paciente de 66 años con hallazgo de un nódulo pulmonar durante la estadificación oncológica por adenocarcinoma de próstata al que se le realizó una segmentectomía pulmonar anatómica. El resultado definitivo de anatomía patológica fue tumor de células epiteloides perivasculares (PEComa pulmonar o tumor de células claras "de azúcar").

PEComa pulmonar / PEComa of the lung

Resumen Los tumores de células claras "de azúcar" (CCTL) son lesiones benignas muy infrecuentes. Forman parte de un grupo de neoplasias mesenquimales denominadas PEComas que se originan de las células epiteloides perivasculares. Por su rico estroma vascular, suelen tener avidez por los distintos tipos de contrastes utilizados en los estudios de diagnóstico por imágenes, simulando lesiones de estirpe maligna. Presentamos el caso de un paciente de 66 años con hallazgo de un nódulo pulmonar durante la estadificación oncológica por adenocarcinoma de próstata al que se le realizó una segmentectomía pulmonar anatómica. El resultado definitivo de anatomía patológica fue tumor de células epiteloides perivasculares (PEComa pulmonar o tumor de células claras "de azúcar").

Abstract Clear cell ''sugar'' tumor of the lung is a rare benign tumor arising from perivascular epithelioid cells (PECs). They belong to a group of mesenchymal neoplasms called PEComas. Although widely presumed as benign, due to their rich vascular stroma they are usually avid for the different types of contrast agents used in imaging studies, mimicking a malignant lesion. We report the case of a 66-year-old man in whom a solitary pul monary nodule was discovered during oncological staging for an adenocarcinoma of the prostate who underwent an anatomical pulmonary segmentectomy. The final pathology result was a perivascular epithelioid cell tumor (pulmonary PEComa or clear "sugar" cell tumor).

Resultados del tratamiento quirúrgico en neoplasias epiteliales de timo / Outcomes of surgical treatment for thymic epithelial neoplasms

Resumen Las neoplasias epiteliales del timo (NET) son tumores infrecuentes. El manejo inicial de las mismas se basa en el análisis de la resecabilidad del tumor en los estudios por imágenes, siendo la resección completa el tratamiento estándar para cualquier estadio. El objetivo principal fue evaluar la supervivencia global y la supervivencia libre de enfermedad de los pacientes con diagnóstico de NET sometidos a tratamiento quirúrgico. El objetivo secundario fue comparar la supervivencia global de acuerdo al tipo de resección quirúrgica, el estadio de Masaoka-Koga y subtipo histológico. Estudio observacional descriptivo realizado en el Hospital Británico de Buenos Aires desde 2004 a 2020. Se incluyeron 42 pacientes operados de tumores en mediastino anterior con diagnóstico histopatológico definitivo de NET. Treinta y nueve eran timomas y 3 carcinomas tímicos. La cirugía realizada en todos los pacientes fue una timectomia total. La mediana de seguimiento fue de 63.5 meses (RIQ 32-97.5). La supervivencia global estimada a los cinco y diez años fue del 87% (95% IC, 0.69-0.95) y 78% (95% IC, 0.5-0.92), respectivamente. La supervivencia libre de enfermedad estimada a cinco y diez años fue del 90% (95% IC, 0.74-0.96). Los pacientes a los que se le realizó una resección completa y que tenían estadios tem pranos de Masaoka-Koga presentaron una supervivencia global superior en comparación con las resecciones incompletas y estadios avanzados (p = 0.0097 y p = 0.0028, respectivamente). Al contar con un bajo número de pacientes en el grupo de carcinomas tímicos, no pudimos sacar conclusiones en cuanto a supervivencia entre éstos y los timomas.

Abstract Thymic epithelial tumors are a group of rare neoplasms of the mediastinum. When resectable, complete resection is considered the gold standard for any stage. The primary endpoint was to evaluate overall survival and disease-free survival of patients with thymus epithelial tumors who underwent surgical treatment. The secondary endpoint was to evaluate and compare the overall survival according to: resection type (complete vs. incomplete), Masaoka-Koga stage and tumor histology according to WHO classification. This is a descriptive observational study from January 2004 to December 2020, in which 42 patients with a postoperative histopathological diagnosis of thymic epithelial tumours were included. Thirty-nine were thymomas (92.9%) and 3 were thymic carcinomas (7.1%). In all patients a total thymectomy was performed. The median follow-up was 63.5 months (IQR 32-97.5). The estimated overall survival at five and ten years was 87% (95% CI, 0.69-0.95) and 78% (95% CI, 0.5-0.92), respectively. Estimated disease-free survival at five and ten years was 90% (95% CI, 0.74-0.96). Patients who underwent complete resection and with early Masaoka-Koga stages had superior overall survival compared to incomplete resections and advanced Masaoka-Koga stages (p = 0.0097 and p = 0.0028, respectively). We found no differences in terms of survival between histological subtypes due to a low number of patients in the thymic carcinoma group.

[Outcomes of surgical treatment for thymic epithelial neoplasms]. / Resultados del tratamiento quirúrgico en neoplasias epiteliales de timo.

Thymic epithelial tumors are a group of rare neoplasms of the mediastinum. When resectable, complete resection is considered the gold standard for any stage. The primary endpoint was to evaluate overall survival and disease-free survival of patients with thymus epithelial tumors who underwent surgical treatment. The secondary endpoint was to evaluate and compare the overall survival according to: resection type (complete vs. incomplete), Masaoka-Koga stage and tumor histology according to WHO classification. This is a descriptive observational study from January 2004 to December 2020, in which 42 patients with a postoperative histopathological diagnosis of thymic epithelial tumours were included. Thirty-nine were thymomas (92.9%) and 3 were thymic carcinomas (7.1%). In all patients a total thymectomy was performed. The median follow-up was 63.5 months (IQR 32-97.5). The estimated overall survival at five and ten years was 87% (95% CI, 0.69-0.95) and 78% (95% CI, 0.5-0.92), respectively. Estimated diseasefree survival at five and ten years was 90% (95% CI, 0.74-0.96). Patients who underwent complete resection and with early Masaoka-Koga stages had superior overall survival compared to incomplete resections and advanced Masaoka-Koga stages (p = 0.0097 and p = 0.0028, respectively). We found no differences in terms of survival between histological subtypes due to a low number of patients in the thymic carcinoma group.

Las neoplasias epiteliales del timo (NET) son tumores infrecuentes. El manejo inicial de las mismas se basa en el análisis de la resecabilidad del tumor en los estudios por imágenes, siendo la resección completa el tratamiento estándar para cualquier estadio. El objetivo principal fue evaluar la supervivencia global y la supervivencia libre de enfermedad de los pacientes con diagnóstico de NET sometidos a tratamiento quirúrgico. El objetivo secundario fue comparar la supervivencia global de acuerdo al tipo de resección quirúrgica, el estadio de Masaoka-Koga y subtipo histológico. Estudio observacional descriptivo realizado en el Hospital Británico de Buenos Aires desde 2004 a 2020. Se incluyeron 42 pacientes operados de tumores en mediastino anterior con diagnóstico histopatológico definitivo de NET. Treinta y nueve eran timomas y 3 carcinomas tímicos. La cirugía realizada en todos los pacientes fue una timectomia total. La mediana de seguimiento fue de 63.5 meses (RIQ 32-97.5). La supervivencia global estimada a los cinco y diez años fue del 87% (95% IC, 0.69-0.95) y 78% (95% IC, 0.5-0.92), respectivamente. La supervivencia libre de enfermedad estimada a cinco y diez años fue del 90% (95% IC, 0.74-0.96). Los pacientes a los que se le realizó una resección completa y que tenían estadios tempranos de Masaoka-Koga presentaron una supervivencia global superior en comparación con las resecciones incompletas y estadios avanzados (p = 0.0097 y p = 0.0028, respectivamente). Al contar con un bajo número de pacientes en el grupo de carcinomas tímicos, no pudimos sacar conclusiones en cuanto a supervivencia entre éstos y los timomas.

Incidental pulmonary carcinoid tumorlet associated with lung cancer / Tumorlet carcinoide pulmonar incidental asociado a cáncer de pulmón

Abstract Lung tumorlets are rare neuroendocrine neoplasms of 0.5 cm or less in diameter that extend beyond the basement membrane. Although they are associated with bronchiectasis and fibrosis they tend to be asymptomatic and behave in a benign way, usually being diagnosed as incidental microscopic nests of neuroendocrine cells in lung tissue. We present a case of a pulmonary tumorlet finding after right upper lobectomy for lung cancer.

Resumen. Los tumorlets pulmonares son neoplasias neuroendocrinas poco frecuentes, que se extienden más allá de la membrana basal y miden 0.5 cm o menos de diámetro. Aunque suelen asociarse a bronquiectasias y fibrosis pulmonar, suelen ser asintomáticas comportándose de una manera indolente, siendo usualmente diagnosticadas de forma incidental en el estudio microscópico de una pieza pulmonar. Presentamos el caso de un tumorlet pulmonar incidental luego de una lobectomía superior derecha por cáncer de pulmón.

Incidental pulmonary carcinoid tumorlet associated with lung cancer.

Lung tumorlets are rare neuroendocrine neoplasms of 0.5 cm or less in diameter that extend beyond the basement membrane. Although they are associated with bronchiectasis and fibrosis they tend to be asymptomatic and behave in a benign way, usually being diagnosed as incidental microscopic nests of neuroendocrine cells in lung tissue. We present a case of a pulmonary tumorlet finding after right upper lobectomy for lung cancer.

Los tumorlets pulmonares son neoplasias neuroendocrinas poco frecuentes, que se extienden más allá de la membrana basal y miden 0.5 cm o menos de diámetro. Aunque suelen asociarse a bronquiectasias y fibrosis pulmonar, suelen ser asintomáticas comportándose de una manera indolente, siendo usualmente diagnosticadas de forma incidental en el estudio microscópico de una pieza pulmonar. Presentamos el caso de un tumorlet pulmonar incidental luego de una lobectomía superior derecha por cáncer de pulmón.

Neumotórax catamenial / Catamenial pneumothorax

Resumen El síndrome de endometriosis torácica (TES) es un trastorno poco común caracterizado por la presencia de tejido endometrial ectópico en la cavidad torácica. La manifestación clínica típica es un neumotórax espontáneo, que generalmente se presenta con dolor torácico, disnea y/o tos. El diagnóstico requiere un alto nivel de sospecha clínica junto con una historia ginecológica completa. Los estudios de imáge nes pueden ayudar con el diagnóstico, pero el gold standard es la cirugía toracoscópica videoasistida (VATS). Se ha demostrado que el tratamiento quirúrgico en combinación con al menos 6 meses de tratamiento médico hormonal mejora el pronóstico y reduce la recurrencia de esta entidad. Presentamos el caso de una paciente de 40 años con antecedentes de endometriosis pélvica y múltiples episodios de neumotórax, que consultó en nuestra institución por un nuevo episodio de neumotórax espontáneo. Se realizó una VATS donde se identificaron nódulos en la pleura parietal y orificios diafragmáticos. En el postoperatorio continuó con tratamiento hormonal. A los 6 meses de seguimiento refirió mejoría del dolor y no presentó nuevos episodios de neumotórax.

Abstract. Thoracic endometriosis syndrome (TES) is a rare disorder characterized by the presence of ectopic endometrial tissue in the chest cavity. The typical clinical manifestation is a spontaneous pneumothorax, which usually presents with chest pain, dyspnea, and/or cough. The diagnosis requires a high level of clinical suspicion and a complete gynecological history. Imaging studies can help with the diagnosis, although the gold standard is video-assisted thoracoscopic surgery (VATS). Surgical treatment in combination with at least 6 months of hormonal medical treatment has been shown to improve the prognosis and reduce the recurrence of this entity. We present the case of a 40-year-old patient with a history of pelvic endometriosis and multiple episodes of pneumothorax, who consulted at our institution for a new episode of spon taneous pneumothorax. A VATS was performed where nodules in the parietal pleura and diaphragmatic orifices were identified. In the postoperative period, she continued with hormonal treatment. At 6 months of follow-up, she reported improvement in pain and did not present new episodes of pneumothorax.

[Catamenial pneumothorax]. / Neumotórax catamenial.

Thoracic endometriosis syndrome (TES) is a rare disorder characterized by the presence of ectopic endometrial tissue in the chest cavity. The typical clinical manifestation is a spontaneous pneumothorax, which usually presents with chest pain, dyspnea, and/or cough. The diagnosis requires a high level of clinical suspicion and a complete gynecological history. Imaging studies can help with the diagnosis, although the gold standard is video-assisted thoracoscopic surgery (VATS). Surgical treatment in combination with at least 6 months of hormonal medical treatment has been shown to improve the prognosis and reduce the recurrence of this entity. We present the case of a 40-year-old patient with a history of pelvic endometriosis and multiple episodes of pneumothorax, who consulted at our institution for a new episode of spontaneous pneumothorax. A VATS was performed where nodules in the parietal pleura and diaphragmatic orifices were identified. In the postoperative period, she continued with hormonal treatment. At 6 months of follow-up, she reported improvement in pain and did not present new episodes of pneumothorax.

El síndrome de endometriosis torácica (TES) es un trastorno poco común caracterizado por la presencia de tejido endometrial ectópico en la cavidad torácica. La manifestación clínica típica es un neumotórax espontáneo, que generalmente se presenta con dolor torácico, disnea y/o tos. El diagnóstico requiere un alto nivel de sospecha clínica junto con una historia ginecológica completa. Los estudios de imágenes pueden ayudar con el diagnóstico, pero el gold standard es la cirugía toracoscópica videoasistida (VATS). Se ha demostrado que el tratamiento quirúrgico en combinación con al menos 6 meses de tratamiento médico hormonal mejora el pronóstico y reduce la recurrencia de esta entidad. Presentamos el caso de una paciente de 40 años con antecedentes de endometriosis pélvica y múltiples episodios de neumotórax, que consultó en nuestra institución por un nuevo episodio de neumotórax espontáneo. Se realizó una VATS donde se identificaron nódulos en la pleura parietal y orificios diafragmáticos. En el postoperatorio continuó con tratamiento hormonal. A los 6 meses de seguimiento refirió mejoría del dolor y no presentó nuevos episodios de neumotórax.

Visual Analysis of Hyperproperties for Understanding Model Checking Results.

Model checkers provide algorithms for proving that a mathematical model of a system satisfies a given specification. In case of a violation, a counterexample that shows the erroneous behavior is returned. Understanding these counterexamples is challenging, especially for hyperproperty specifications, i.e., specifications that relate multiple executions of a system to each other. We aim to facilitate the visual analysis of such counterexamples through our HyperVis tool, which provides interactive visualizations of the given model, specification, and counterexample. Within an iterative and interdisciplinary design process, we developed visualization solutions that can effectively communicate the core aspects of the model checking result. Specifically, we introduce graphical representations of binary values for improving pattern recognition, color encoding for better indicating related aspects, visually enhanced textual descriptions, as well as extensive cross-view highlighting mechanisms. Further, through an underlying causal analysis of the counterexample, we are also able to identify values that contributed to the violation and use this knowledge for both improved encoding and highlighting. Finally, the analyst can modify both the specification of the hyperproperty and the system directly within HyperVis and initiate the model checking of the new version. In combination, these features notably support the analyst in understanding the error leading to the counterexample as well as iterating the provided system and specification. We ran multiple case studies with HyperVis and tested it with domain experts in qualitative feedback sessions. The participants' positive feedback confirms the considerable improvement over the manual, text-based status quo and the value of the tool for explaining hyperproperties.

[Synchronous pulmonary adenocarcinoma and primary lymphoma of lung mucosa-associated lymphoid tissue]. / Adenocarcinoma pulmonar sincrónico y linfoma primario de tejido linfoide asociado a mucosa pulmonar.

The lymphomas of mucosa-associated lymphoid tissue (MALT), are uncommon entities, of low grade of malignancy with very infrequent or no lymph node involvement. They represent about 80% of the primary pulmonary lymphomas. The synchronous appearance with lung adenocarcinoma is an extremely rare finding. We present the case of an ex-smoker 68-year-old man, in whom, in the follow-up of a pulmonary nodule, a second pulmonary nodule was found. The surgical biopsy confirmed the diagnosis of both neoplasms.

Los linfomas derivados del tejido linfoide asociado a las mucosas (MALT) son entidades poco frecuentes, de bajo grado de malignidad con escaso o nulo compromiso ganglionar y representan cerca del 80% de los linfomas primarios pulmonares. La aparición sincrónica con adenocarcinoma de pulmón es un hallazgo extremadamente infrecuente. Presentamos el caso de un hombre de 68 años, ex-tabaquista, en quien durante el seguimiento de un nódulo pulmonar se identificó un segundo nódulo y la biopsia quirúrgica confirmó el diagnóstico de ambas neoplasias.

Adenocarcinoma pulmonar sincrónico y linfoma primario de tejido linfoide asociado a mucosa pulmonar / Synchronous pulmonary adenocarcinoma and primary lymphoma of lung mucosa-associated lymphoid tissue

Los linfomas derivados del tejido linfoide asociado a las mucosas (MALT) son entidades poco frecuentes, de bajo grado de malignidad con escaso o nulo compromiso ganglionar y representan cerca del 80% de los linfomas primarios pulmonares. La aparición sincrónica con adenocarcinoma de pulmón es un hallazgo extremadamente infrecuente. Presentamos el caso de un hombre de 68 años, ex-tabaquista, en quien durante el seguimiento de un nódulo pulmonar se identificó un segundo nódulo y la biopsia quirúrgica confirmó el diagnóstico de ambas neoplasias.

The lymphomas of mucosa-associated lymphoid tissue (MALT), are uncommon entities, of low grade of malignancy with very infrequent or no lymph node involvement. They represent about 80% of the primary pulmonary lymphomas. The synchronous appearance with lung adenocarcinoma is an extremely rare finding. We present the case of an ex-smoker 68-year-old man, in whom, in the follow-up of a pulmonary nodule, a second pulmonary nodule was found. The surgical biopsy confirmed the diagnosis of both neoplasms.

Pancreatoblastoma in a paediatric patient: anatomo-pathological aspects of a case with multiple hepatic metastases.

Pancreatoblastoma is a rare paediatric malignant neoplasm. The treatment of choice is complete surgical resection. However, it is often unresectable due to its large size, local infiltration or distant metastasis. Since the condition is rare, there is currently no standard treatment regimen. We outline the case of a 4-year-old child who presented with abdominal pain and distention, together with an enlarged liver and elevated serum α-fetoprotein levels. Imaging studies showed the presence of an abnormal pancreatic tumour and multiple nodular lesions in the liver, the biopsies from which led to a diagnosis of pancreatoblastoma. In this case, the patient received cycles of neoadjuvant chemotherapy, combining cisplatin and doxorubicin. The patient subsequently underwent scheduled surgery in which the primary pancreatic lesion was resected, obtaining a circumscribed and nodular specimen measuring 7 × 6 cm and weighing 150 g. Given the extent of the metastasis, the child is currently awaiting a liver transplant.

Malignant extra-adrenal pelvic paraganglioma in a paediatric patient.

The extra-adrenal paraganglioma is a neoplasm originating in regional structures, uncommon in paediatrics. We report on a case of a 13-year-old patient who began with severe arterial hypertension, tachycardia, dilated cardiomyopathy and elevated levels of catecholamines in the blood and urine. The presence of a retrovesical pelvic mass in contact with the right vaginal dome was determined by imaging studies. A diagnosis of malignant extra-adrenal pelvic paraganglioma with lymph node metastases was reached through biopsy and the surgical resection of subsequent local recurrences. Paragangliomas are usually located in the paravertebral zones from the base of the skull to the retroperitoneum and are benign in 90% of cases. This kind of neoplasia is uncommon in paediatrics, especially those located in the pelvis. In cases of masses of a gynaecological origin, a differential diagnosis should be considered, and a histological and immunohistochemical study is essential in certifying the diagnosis.

Hepatic metastasis of thymoma: case report and immunohistochemical study.

Thymomas are rare tumours characterised by their slow growth and capacity to invade directly by contiguity. While distant dissemination is infrequent, all sub-types of thymoma have the capacity to metastasise to extrathoracic organs. We present here the case of a female patient with a liver mass discovered 13 years after the removal of a mediastinal thymoma and after ten years from thyroidectomy for papillary carcinoma. The histopathological study showed that the lesion contained an epithelial component, which was immunohistochemically positive for pankeratin. It was accompanied by numerous small lymphocytes testing positive for TdT, CD3, CD4, CD5, CD8, CD99, and CD43. The result was consistent with hepatic metastatic thymoma sub-type B1, according to the World Health Organisation classification (WHO). Our case highlights the importance of morphological and immunohistological examinations in the differential diagnosis of visceral masses in patients with a history of thymoma. Given the infrequency of its metastasis and the increased risk of developing other primary tumours that these patients have, these studies play a significant role.

The regulatory role of residues 226-232 in phosphoenolpyruvate carboxylase from maize.

The regulatory properties of maize phosphoenolpyruvate carboxylase were significantly altered by site-directed mutagenesis of residues 226 through 232. This conserved sequence element, RTDEIRR, is part of a surface loop at the dimer interface. Mutation of individual residues in this sequence caused various kinetic changes, including desensitization of the enzyme to key allosteric effectors or alteration of the K(0.5 PEP) for the substrate phosphoenolpyruvate. R231A, and especially R232Q, displayed decreased apparent affinity for the activator glucose-6-phosphate. Apparent affinity for the activator glycine was reduced in D228N and R232Q, while the maximum activation caused by glycine was greatly reduced in R226Q and E229A. R226Q and E229A also showed significantly lower sensitivity to the inhibitors malate and aspartate. E229A exhibited a low K(0.5 PEP), while the K(0.5 PEP )of R232Q was significantly higher than that of wild type. Thus these seven residues are critical determinants of the enzyme's kinetic responses to activators, inhibitors and substrate. The present results support an earlier suggestion that Arg 231 contributes to the binding site of the allosteric activator glucose-6-phosphate, and are consistent with other proposals that the substrate phosphoenolpyruvate allosterically activates the enzyme by binding at or near the glucose-6-phosphate site. The results also suggest that the glycine binding site may be contiguous with the glucose-6-phosphate binding site. Glu 229, which extends from this interface region through the interior of the protein and emerges near the aspartate binding site, may provide a physical link for propagating conformational changes between the allosteric activator and inhibitor binding regions.

Type 1 diabetes in the Spanish population: additional factors to class II HLA-DR3 and -DR4.

BACKGROUND: The Major Histocompatibility Complex is the main genetic contributor to susceptibility to type 1 diabetes (T1D); genome-wide scans have consistently mapped increased predisposition to this region. The highest disease risk has been associated with HLA-DR3 and HLA-DR4. In particular, the DR3-positive ancestral haplotype 18.2 was reported as highly diabetogenic. We aimed to corroborate whether this haplotype increases the susceptibility conferred by the DQ2-DR3 alleles in a Mediterranean population. We also searched for additional susceptibility factors to the classic DQ2-DR3 and DQ8-DR4. RESULTS: Genetic MHC markers were analysed in a case-control study with 302 T1D patients and 529 ethnically matched controls. DR3-TNFa1b5 carrier rate was significantly higher in DR3-positive heterozygous T1D patients than in DR3-positive heterozygous controls (p = 0.0019; odds ratio OR [95% confidence interval CI] = 2.26 [1.3-3.93]). This data was confirmed analysing the allelic frequency, which includes the information corresponding to the DR3-homozygous individuals (p = 0.001; OR = 2.09) and by using the Arlequin software to check the DR3-positive haplotypes (p = 0.004;OR = 1.93). The present results provide strong evidence of a second susceptibility region in the ancestral haplotype 18.2 in the Spanish population. Moreover, we searched for T1D susceptibility factors in addition to the MHC classical ones, within the DR2-DQ6/DR3-DQ2/DR4-DQ8 negative population. Several genetic markers in both MHC class II (DQA1*0101-DQB1*0501 [p = 0.007;OR = 2.81], DQA1*0201-DQB1*0202 [p = 0.03; OR = 2.35]) and III (TNFa2b1 [p = 0.01 OR = 2.74], BAT-2*2 [p = 0.004; OR = 3.19]) were found. These different alleles associated with T1D were not independent and we observed linkage disequilibrium among them leading us to describe two new risk haplotypes (DQA1*0101-DQB1*0501-TNFa2b1 and DQA1*0201-DQB1*0202- BAT-2*2). Finally, we studied a T1D susceptibility/protection marker located in extended class I, D6S2223; however, no association was observed in our population. CONCLUSION: Our results suggest that other associated MHC haplotypes might present susceptibility factors in loci different from HLA-class II and that the class II molecules are not necessarily the universal etiologic factor in every MHC haplotype.