[Alkaptonuria: evolution and course of the disease towards ochronotic arthropathy. Series of cases managed with joint replacement]. / Alcaptonuria: evolución y curso de la enfermedad hacia artropatía ocronótica. Serie de casos manejados con reemplazo articular.

INTRODUCTION: alkaptonuria is a very rare metabolic disease with autosomal recessive inheritance due to HGA oxidase deficiency. Classically described and diagnosed in the third to fourth decade of life, affecting both men and women; Its diagnostic impression is clinical based on the blue/black coloration of the conjunctivae, however it is confirmed by the specific analysis of the enzyme in the urine, to date there is no cure and its treatment is palliative and symptomatic. MATERIAL AND METHODS: descriptive, observational, case series study, the primary objective of which is to describe the progression of the disease and its involvement in the musculoskeletal system. RESULTS: two clinical cases are presented in women and men in which the broad clinic is illustrated, its progressive advance and the different alterations that it can generate in the musculoskeletal system. CONCLUSIONS: alkaptonuria is a rare disease which leads to a severe secondary arthropathy, currently without a specific management which is based on treating the symptoms, in its final stages joint replacements are a management option with satisfactory results for the relief of pain.

INTRODUCCIÓN: la alcaptonuria es una enfermedad metabólica inusual, de herencia autosómica recesiva dada por la deficiencia de la oxidasa de HGA. Clásicamente descrita y diagnosticada sobre la tercera a cuarta década de la vida, la cual tiene afectación en ambos sexos, su impresión diagnóstica es clínica, basándose en la coloración azul/negro de las conjuntivas; sin embargo, se confirma mediante el análisis específico de la enzima en la orina, actualmente no existe un tratamiento definitivo, sólo alternativas en cuanto a lo paliativo y sintomático. MATERIAL Y MÉTODOS: estudio descriptivo, observacional, de tipo serie de casos, como objetivo primario se describe la progresión de la enfermedad y su compromiso en el sistema musculoesquelético. RESULTADOS: se presentan dos casos clínicos en mujer y hombre, los cuales ilustran: variedad clínica, avance progresivo y las alteraciones que puede generar en el sistema musculoesquelético. CONCLUSIONES: la alcaptonuria es una enfermedad rara, la cual conlleva una artropatía secundaria severa, sin un tratamiento definitivo dirigido a tratar los síntomas, incluso en sus estadios finales los reemplazos articulares son una opción para proporcionar manejo del dolor obteniendo resultados satisfactorios.

Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).

Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed. Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002). Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.

Involvement of pp125FAK and p60SRC in the signaling through Fc gamma RII-Fc gamma RIII in murine macrophages.

Cross-linking the FcgammaRs can activate a wide variety of biological responses in macrophages. Receptor stimulation induces activation of protein tyrosine kinase cascades that result in phagocytosis, a process known to involve cytoskeletal rearrangements. Therefore, an involvement of non-receptor tyrosine kinases such as pp125FAK, in FcgammaR signaling is likely. Using the murine macrophage cell line J774, we demonstrate that FcgammaRII-RIII cross-linking induces a time- and dose-dependent increase in tyrosine phosphorylation of the focal adhesion kinase pp125FAK that correlates with an increase in its catalytic activity. Interestingly enough, pp125FAK activation results in its association both to the FcgammaRII-III and to p60Src. The results presented here define a novel-signaling pathway likely to be important in low affinity FcgammaRII-III mediated phagocytosis.

Low affinity Fc gamma receptors on murine macrophages: mitogen-activated protein kinase activation and AP-1 DNA binding activity.

Mouse macrophage cell lines such as J774 express Fc receptors for IgG2a immune complexes, which upon binding of the proper ligand, trigger several signal transduction pathways. A surface to nucleus signaling through these receptors has been demonstrated. We describe here the activation of the mitogen-activated protein kinase (MAPK) and an increase in the binding of the activator protein 1 (AP-1) to DNA upon receptor stimulation. The described effects are only partially blocked by inhibitors of the Ca2+/diacylglycerol-dependent protein kinase (PKC), suggesting that differential signaling pathways are activated upon receptor cross-linking and that they converge at or above the MAPK level. These results pave the way to our understanding of Fc gammaR cross-linking induced gene expression regulation.