Advanced Female Primary Urethral Carcinoma with Nodal Extension Managed with Exclusive Use of Chemoradiotherapy: Report of a Case and Review of the Relevant Current Literature.

Primary urethral carcinoma (PUC) is a rare disease with frequent nodal metastasis at the time of diagnosis. Few risk factors have been established and overall prognosis remains poor. As of now, no clear therapeutic guidelines are established and management of advanced PUC often involves surgery which can have negative functional and psychological outcomes for the patient. Few authors have already reported the use of chemoradiotherapy alone to avoid surgery with some good short-term results. We report the case of a 48-year-old woman with advanced high-grade urothelial carcinoma of distal urethra associated to bilateral inguinal nodal metastasis. She was similarly and successfully treated using chemoradiotherapy exclusively without significant adverse effects. This experience reinforces benefits of a surgery-sparing management, when possible, as recommended in current guidelines.

Evaluation of the multimorbidity network and its relationship with clinical phenotypes in chronic obstructive pulmonary disease: The GALAXIA study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous condition, in which taking into consideration clinical phenotypes and multimorbidity is relevant to disease management. Network analysis, a procedure designed to study complex systems, allows to represent connections between the distinct features found in COPD. METHODS: Network analysis was applied to a cohort of patients with COPD in order to explore the degree of connectivity between different diseases, taking into account the presence of two phenotypic traits commonly used to categorize patients in clinical practice: chronic bronchitis (CB+ /CB- ) and the history of previous severe exacerbations (Ex+ /Ex- ). The strength of association between diseases was quantified using the correlation coefficient Phi (ɸ). RESULTS: A total of 1726 patients were included, and 91 possible links between 14 diseases were established. Although the four phenotypically defined groups presented a similar underlying comorbidity pattern, with special relevance for cardiovascular diseases and/or risk factors, classifying patients according to the presence or absence of CB implied differences between groups in network density (mean ɸ: 0.098 in the CB- group and 0.050 in the CB+ group). In contrast, between-group differences in network density were small and of questionable significance when classifying patients according to prior exacerbation history (mean ɸ: 0.082 among Ex- subjects and 0.072 in the Ex+ group). The degree of connectivity of any given disease with the rest of the network also varied depending on the selected phenotypic trait. The classification of patients according to the CB- /CB+ groups revealed significant differences between groups in the degree of conectivity between comorbidities. On the other side, grouping the patients according to the Ex- /Ex+ trait did not disclose differences in connectivity between network nodes (diseases). CONCLUSIONS: The multimorbidity network of a patient with COPD differs according to the underlying clinical characteristics, suggesting that the connections linking comorbidities between them vary for different phenotypes and that the clinical heterogeneity of COPD could influence the expression of latent multimorbidity. Network analysis has the potential to delve into the interactions between COPD clinical traits and comorbidities and is a promising tool to investigate possible specific biological pathways that modulate multimorbidity patterns.

Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma.

Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E-cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)-positive/HER2-negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)-stained sections. In set B (62 cases), participants were provided with HE-stained sections and E-cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non-lobular BC versus mixed BC versus ILC. Pairwise inter-observer agreement and agreement with a pre-defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E-cadherin mutation status. Thirty-five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter-observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48-0.66) and substantial in set B (median κ = 0.75, IQR: 0.56-0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57-0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73-0.93, p < 0.001). The median frequency of CDH1/E-cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56-72%) and 73% in set B (IQR: 65-75%, p < 0.001). Cases with variable subtype calls included E-cadherin-positive ILCs harboring CDH1 missense mutations, and E-cadherin-negative ILCs with tubular elements and focal P-cadherin expression. ILCs with trabecular growth pattern were often misclassified as non-lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre-defined reference standard, if assessment is supported by E-cadherin IHC. CDH1 missense mutations associated with preserved E-cadherin protein expression, E- to P-cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification.

Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study.

High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.

La pandemia por SARS-CoV-2 y la tercera revolución sanitaria de Sir Muir Gray / No disponible

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Can the COPD-comorbidome Be Applied to All Outpatients With Chronic Obstructive Pulmonary Disease? A Single-center Analysis / ¿El comorbidoma de COPD se puede aplicar a todos los pacientes ambulatorios con enfermedad pulmonar obstructiva crónica? Un estudio unicéntrico

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The COPD Comorbidome in the Light of the Degree of Dyspnea and Risk of Exacerbation.

The BODE group designed a bubble chart, analogous to the solar system, which depicts the prevalence of each disease and its association with mortality and called it a "comorbidome". Although this graph was used to represent mortality and, later, the risk of needing hospital admission, it was not applied to visualize the association between a set of comorbidities and the categories of the GOLD 2017 guidelines, neither according to the degree of dyspnea nor to the risk of exacerbation. For the purpose of knowing to which extent each comorbidity associates with each of the two conditions-most symptomatic group (groups B and D) and highest risk of exacerbation (groups C and D)-we performed a analysis based on the comorbidome. 439 patients were included. Cardiovascular comorbidity (especially cardiac and renal disease) is predominantly observed in patients with a higher degree of dyspnea, whereas bronchial asthma and stroke occur more frequently in subjects at higher risk of exacerbation. This is the first time that the comorbidome is presented based on the categories of the GOLD 2017 document, which we hope will serve as a stimulus for scientific debate.

Health Status in Patients with COPD According to GOLD 2017 Classification: Use of the COMCOLD Score in Routine Clinical Practice.

The COMCOLD score was developed to quantify the impact of comorbidities on health status in patients with chronic obstructive pulmonary disease (COPD). The objective of this study is to evaluate the association between health status in outpatients with COPD according to COMCOLD score and the GOLD 2017 groups according to symptoms (B and D vs. A and C) and exacerbations (C and D vs. A and B). 439 patients were included. The average score was 2.4 ± 3. 48% of cases had a COMCOLD score >0. The most symptomatic patients (B and D vs. A and C) had a higher score: 3 ± 3.3 vs. 1.3 ± 2.1 (p < 0.001), in contrast with the groups with a higher risk of exacerbation (C and D vs. A and B) in which there was no significant difference: 3 ± 3.5 vs. 2.2 ± 3.0 (p = 0.055). The most symptomatic patients (B and D) showed a greater prevalence of depression, peripheral artery disease and heart disease with an adjusted OR of 3.04 [CI95%: 1.36; 6.86], 2.49 [CI95%: 1.17; 5.29], and 4.41 [CI95%: 2.50; 7.75], respectively. Moreover, no relationship was found between the comorbidities defined by the COMCOLD score and the GOLD 2017 groups with the greatest risk of exacerbation (C and D). The greatest effect on health status was found in those patients with COPD belonging to the most symptomatic groups (B and D), with depression, peripheral artery disease, and heart disease being the main comorbidities involved.

Molecular Detection of the Frequent Allele F52del in Alpha 1 Antitrypsin Deficiency / Detección molecular del alelo F52del frecuente en la deficiencia de alfa-1-antitripsina

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Espectro de mutaciones deficitarias de alfa-1 antitripsina detectadas en Tenerife / Spectrum of Alpha-1 Antitripsin Deficiency Mutations Detected in Tenerife

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Déficit de alfa-1-antitripsina asociado a la variante Mmalton. Descripción de una familia / Alpha-1 antitrypsin deficiency associated with the Mmalton variant. Description of a family

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Aquaporin expression in blood-retinal barrier cells during experimental autoimmune uveitis.

PURPOSE: Blood-retinal barrier (BRB) breakdown and retinal edema are major complications of autoimmune uveitis and could be related to deregulation of aquaporin (AQP) expression. We have therefore evaluated the expression of AQP1 and AQP4 on BRB cells during experimental autoimmune uveitis (EAU) in mice. METHODS: C57Bl6 mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) peptide 1-16. The disease was graded clinically, and double immunolabeling using glial fibrillary acidic protein (GFAP; a marker of disease activity) and AQP1 or AQP4 antibodies was performed at day 28. AQP1 expression was also investigated in mouse retinal pigment epithelium (RPE) cells (B6-RPE07 cell line) by reverse transcriptase PCR and western blot under basal and tumor necrosis factor alpha (TNF-alpha)-stimulated conditions. RESULTS: In both normal and EAU retina, AQP1 and AQP4 expression were restricted to the photoreceptor layer and to the Müller cells, respectively. Retinal endothelial cells never expressed AQP1. In vasculitis and intraretinal inflammatory infiltrates, decreased AQP1 expression was observed due to the loss of photoreceptors and the characteristic radial labeling of AQP4 was lost. On the other hand, no AQP4 expression was detected in RPE cells. AQP1 was strongly expressed by choroidal endothelial cells, rendering difficult the evaluation of AQP1 expression by RPE cells in vivo. No major differences were found between EAU and controls at this level. Interestingly, B6-RPE07 cells expressed AQP1 in vitro, and TNF-alpha downregulated AQP1 protein expression in those cells. CONCLUSIONS: Changes in retinal expression of AQP1 and AQP4 during EAU were primarily due to inflammatory lesions, contrasting with major modulation of AQP expression in BRB detected in other models of BRB breakdown. However, our data showed that TNF-alpha treatment strongly modulates AQP1 expression in B6-RPE07 cells in vitro.

Nodal-stage classification in invasive lobular breast carcinoma: influence of different interpretations of the pTNM classification.

PURPOSE Application of current nodal status classification is complicated in lobular breast carcinoma metastases. The aim of this study was to define the optimal interpretation of the pTNM classification in sentinel node (SN) -positive patients to select patients with limited or with a high risk of non-SN involvement. PATIENTS AND METHODS SN metastases of 392 patients with lobular breast carcinoma were reclassified according to interpretations of the European Working Group for Breast Screening Pathology (EWGBSP) and guidelines by Turner et al, and the predictive power for non-SN involvement was assessed. Results Reclassification according to definitions of EWGBSP and Turner et al resulted in different pN classification in 73 patients (19%). The rate of non-SN involvement in the 40 patients with isolated tumor cells according to Turner et al and with micrometastases according to EWGBSP was 20%, which is comparable to the established rate for micrometastases. The rate of non-SN involvement in the 29 patients with micrometastases according to Turner et al and with macrometastases according to EWGBSP was 48%, which is comparable to the established rate for macrometastases. Therefore, the EWGBSP method to classify SN tumor load better reflected the risk of non-SN involvement than the Turner et al system. CONCLUSION Compared with the guidelines by Turner et al, the EWGBSP definitions better reflect SN metastatic tumor load and allow better differentiation between patients with lobular breast carcinoma who have a limited or a high risk of non-SN metastases. Therefore, we suggest using the EWGBSP definitions in these patients to select high-risk patients who may benefit from additional local and/or systemic therapy.

Recombinant adenovirus administration in rat peritoneum: endothelial expression and safety concerns.

BACKGROUND: Initial studies of adenovirus-mediated gene transfer to the peritoneum have shown transgene expression in the mesothelium from the parietal peritoneum. Using a replication-deficient adenovirus encoding beta-galactosidase (Ad beta Gal), we investigated the expression efficiency and the distribution of the transgene to different areas of both visceral and parietal peritoneum and to extra-peritoneal tissues. METHODS: Male Wistar rats received an intraperitoneal injection of 15 ml of 0.9% NaCl alone or containing 1 x 10(9) or 3 x 10(9) p.f.u. of Ad beta Gal. Evaluations of the histology of the peritoneum, the transgene expression and the safety of adenovirus-mediated gene transfer, using measurement of both beta Gal activity and staining, were performed 1, 3 and 5 days post-injection. RESULTS: At 1 day post-injection of 3 x 10(9) p.f.u. of Ad beta Gal, significant beta Gal activity and staining were detected in the omentum and mesenteric peritoneum. beta Gal staining was observed in endothelial cells, mesothelial cells and adipocytes. Focal mononuclear infiltrates restricted to the submesothelial area of the visceral peritoneum were also observed. No expression was detected in the mesocolon and parietal peritoneum, where the mesothelium was damaged. Significant beta Gal activity and staining were observed in lymph nodes, lungs, liver, heart and kidneys, in the absence of inflammatory changes. CONCLUSIONS: Intraperitoneal delivery of adenoviral vectors allows highly efficient transgene expression in mesothelial cells, but also in endothelial cells and adipocytes of the visceral peritoneum. Adverse focal mononuclear infiltrates, as well as spreading of the adenoviral vector from the abdominal cavity to the systemic circulation, were observed in parallel. Transgene expression in endothelial cells is potentially important since the latter play a key role in the alterations of the peritoneal membrane associated with long-term peritoneal dialysis. However, these data emphasize the need for less immunogenic adenoviral vectors, ideally containing an endothelial cell-specific promoter, to overcome immune response-related problems and spreading to extra-peritoneal tissues.