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Background: Drug-induced acute interstitial nephritis (DI-AIN) represents a common cause of acute kidney injury. Early withdrawal of the culprit drug and corticosteroid therapy remains the mainstay of treatment.This study aimed to develop and validate a predictive nomogram to assess the probability of recovery of kidney function at 6 months after treatment., Methods: Multicenter, retrospective, observational study in 13 nephrology departments. Patients with biopsy proven DI-AIN treated with corticosteroids between 1996-2023 were included. Dataset was randomly divided into training (n=164) and validation sets (n=60). Least absolute shrinkage and selection operator regression was used to screen the main predictors of complete (creatinine increase <25% of the last value before DI-AIN) or no recovery of kidney function (serum creatinine ≥75% or need for dialysis)., Results: The study group comprised 224 patients with DI-AIN: 51 (31%) in the training group and 19 (32%) in the validation set, achieved complete recovery at 6 months. Conversely, 33 (20%) and 8 (13%) patients in each set showed no recovery at 6 months. Clinical characteristics were well balanced between training and validation sets. The selected variables were age (under/above 65 years), gender, degree of interstitial fibrosis and time to corticosteroids initiation (under/above 7 days). Based on multivariable logistic regression model, a nomogram was developed. The area under the curve (AUC) of the nomogram was 0.79 (95% confidence interval: 0.71-0.88) indicating a good discriminative power. Bootstrap self-sampling was performed 1000 times for validation of the model. Calibration plot revealed that the predicted outcomes aligned well with the observations. Decision curve analysis suggested that the model had clinical benefit., Conclusions: We developed and validated a nomogram to predict kidney recovery at 6 months in DI-AIN patients treated with corticosteroids. This tool helps clinicians estimate prognosis and optimize corticosteroid therapy's intensity and duration for better treatment outcomes., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 12% survival rate, highlighting the need for novel therapies. c-MYC overexpression, driven by upstream mutations and amplifications, reprograms tumor metabolism and promotes proliferation, migration and metastasis. This study identifies ELOVL6, a fatty acid elongase regulated by c-MYC, as a potential therapeutic target. Using PDAC mouse models and cell lines, we show that c-MYC directly upregulates ELOVL6 during tumor progression. Genetic or chemical inhibition of ELOVL6 reduces proliferation and migration by altering fatty acid composition, affecting membrane rigidity, permeability and pinocytosis. These changes increase Abraxane uptake and show a synergistic effect when combined with ELOVL6 inhibition in vitro. In vivo, ELOVL6 interference significantly suppresses tumor growth and improves Abraxane response, prolonging survival. These findings position ELOVL6 as a promising target for improving PDAC treatment outcomes., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Genetic defects affecting steroid biosynthesis cause cortisol deficiency and differences of sex development; among these defects are recessive mutations in the steroidogenic enzymes CYP11A1 and CYP11B, whose function is supported by reducing equivalents donated by ferredoxin reductase (FDXR) and ferredoxin. So far, mutations in the mitochondrial flavoprotein FDXR have been associated with a progressive neuropathic mitochondriopathy named FDXR-related mitochondriopathy (FRM), but cortisol insufficiency has not been documented. However, patients with FRM often experience worsening or demise following stress associated with infections. We investigated 2 female patients with FRM carrying the potentially novel homozygous FDXR mutation p.G437R with ambiguous genitalia at birth and sudden death in the first year of life; they presented with cortisol deficiency and androgen excess compatible with 11-hydroxylase deficiency. In addition, steroidogenic FDXR-variant cell lines reprogrammed from 3 patients with FRM fibroblasts displayed deficient mineralocorticoid and glucocorticoid production. Finally, Fdxr-mutant mice allelic to the severe p.R386W human variant showed reduced progesterone and corticosterone production. Therefore, our comprehensive studies show that human FDXR variants may cause compensated but possibly life-threatening adrenocortical insufficiency in stress by affecting adrenal glucocorticoid and mineralocorticoid synthesis through direct enzyme inhibition, most likely in combination with disturbed mitochondrial redox balance.

Introduction: Heart transplant (HT) survival has barely improved in the last decades, which is unsatisfactory for many HT recipients. The development of anti-human leukocyte antigen (anti-HLA) antibodies in HT patients is associated with a cardiac allograft dysfunction. The mechanisms leading to this damage are unclear. The Multimodality Evaluation Of Antibody-Mediated Injury In Heart Transplantation (LEONE-HT) study aimed to thoroughly describe the damage inflicted on the myocardium by anti-HLA antibodies., Methods and Analysis: The LEONE-HT study is a cohort study with a cross-sectional approach in which HT patients with positive anti-HLA antibodies are compared with coetaneous HT patients with negative anti-HLA antibodies. All patients will undergo a state-of-the-art multimodal assessment, including imaging techniques, coronary anatomy and physiology evaluations and histological and immunological analyses. The individual and combined primary outcomes of structural graft injuries and longitudinal secondary outcomes are to be compared between the exposed and non-exposed groups with univariate and multivariable descriptive analyses., Ethics and Dissemination: The LEONE-HT study is carried out in accordance with the principles set out in the Declaration of Helsinki and the International Conference on Harmonization guidelines for good clinical practice and following national laws and regulations. The study design, objectives and participant centers have been communicated to clinicaltrials.gov (NCT05184426). The LEONE-HT study counts on the support of patient associations to disseminate the objectives and results of the research. This study was funded by the Spanish Ministry of Science and Innovation and the Spanish Society of Cardiology.

Objectives: The aim of this study was to evaluate the potential biologic effects caused by the successive placement of biodegradable polydioxanone (PDO) stents in the rabbit trachea. PDO stents could eventually induce a fibroproliferative reaction in the submucosa that could be beneficial in the treatment of malacia due to an increase in its consistency without impairing the tracheal lumen., Methods: Sixteen adult NZ rabbits were distributed into 3 groups with different survival times according to the number of stents placed: 1 stent (14 weeks), 2 stents (28 weeks) and 3 stents (42 weeks). Stent insertion was performed endoscopically in the cervical trachea of the animal. Histopathological studies included Masson's trichrome staining for submucosal fibrosis and Safranin O to assess the structural integrity of cartilage. Potential inflammatory changes were analysed by means of immunohistochemistry determining the number of CD45-positive cells., Results: Stent placement was successful in every case. Histological studies did not show a statistically significant increase in tracheal wall collagen area and cartilage structure was not modified in those rabbits with 1 or more PDO stents inserted compared to non-stented tracheal sections. Furthermore, no statistically significant changes in the number of CD45+ cells were observed in stented tracheal segments compared to normal tracheal tissues., Conclusions: According to our data, successive PDO stenting caused mild inflammatory changes in the tracheal wall and no increase in the collagen matrix, and the cartilaginous support was not modified during a long follow-up period (up to 42 weeks). These findings suggest that they may be safe and show good biocompatibility in the long term., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Metastatic disease in the kidney is relatively uncommon compared to other body sites. In most cases it presents as a unilateral and unifocal mass in the tubulointerstitial region. Intraglomerular metastases are even rarer, and their diagnosis is hampered by the limitations of imaging techniques in detecting them. We describe the finding of intraglomerular metastases in a patient affected by a malignant melanoma considered to be in partial remission, with no evidence of melanoma progression on the previously performed computed tomography scan. This patient developed rapidly progressive kidney failure, proteinuria, and hematuria with dysmorphic red blood cells in the urine sediment. Kidney biopsy showed a marked crescentic proliferation caused by tumor cells, which even invaded the proximal convoluted tubule. Melanoma cells were also found in the lumina of the glomerular capillaries, distending their basement membranes. Our case describes the histologic and electron microscopic findings of this form of intraglomerular metastasis and reminds us of its inclusion in the differential diagnosis of rapidly progressive kidney failure., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The exact role of viral replication in patients with severe COVID-19 has not been extensively studied, and it has only been possible to demonstrate the presence of replicative virus for more than 3 months in a few cases using different techniques. Our objective was to study the presence of RNA SARS-CoV-2 in autopsy samples of patients who died from COVID-19 long after the onset of symptoms. Secondary superimposed pulmonary infections present in these patients were also studied. We present an autopsy series of 27 COVID-19 patients with long disease duration, where pulmonary and extrapulmonary samples were obtained. In addition to histopathological analysis, viral genomic RNA (gRNA) and viral subgenomic RNA (sgRNA) were detected using RT-PCR and in situ hybridization, and viral protein was detected using immunohistochemistry. This series includes 26 adults with a median duration of 39 days from onset of symptoms to death (ranging 9-108 days), 92% of them subjected to immunomodulatory therapy, and an infant patient. We detected gRNA in the lung of all but one patient, including those with longer disease duration. SgRNA was detected in 11 out of 17 patients (64.7%) with illness duration up to 6 weeks and in 3 out of 9 patients (33.3%) with more than 6 weeks of disease progression. Viral protein was detected using immunohistochemistry and viral mRNA was detected using in situ hybridization in 3 out of 4 adult patients with illness duration of <2 weeks, but in none of the 23 adult patients with an illness duration of >2 weeks. A remarkable result was the detection of viral protein, gRNA and sgRNA in the lung cells of the pediatric patient after 95 days of illness. Additional pulmonary infections included: 9 acute bronchopneumonia, 2 aspergillosis, 2 cytomegalovirus, and 1 BK virus infection. These results suggest that in severe COVID-19, SARS-CoV-2 could persist for longer periods than expected, especially in immunocompromised populations, contributing to the persistence of chronic lung lesions. Additional infections contribute to the fatal course of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Caniego-Casas, Martínez-García, Alonso-Riaño, Pizarro, Carretero-Barrio, Martínez-de-Castro, Ruz-Caracuel, de Pablo, Saiz, Royo, Santiago, Rosas, Rodríguez-Peralto, Pérez-Mies, Galán and Palacios.)

From 2000, Mesoamerican region has reached an important rate of chronic kidney disease of unknown etiology. Under the name of Meroamerican Nephropathy (MeN) several hypotheses (including dehydration, heat stress, environmental or toxic exposure or even infections) have tried to explain the etiology this new disease. MeN affects young men, agricultural workers exposed to high temperatures. MeN courses with unspecific symptoms as low-grade fever and dysuria and progressive kidney disease with impaired renal function and hydroelectrolyte disturbances. The diagnosis requires kidney biopsy showing tubule-interstitial nephritis (usually at chronic stage). Although MeN conditions a high morbi-mortality in endemic regions, there is a lack of specific treatment and only preventive measures have demonstrated some effect of prognosis (avoid heat stress, constant hydration). In this review we aim to summarize the available information of MeN, illustrating the information in a case report., (Copyright © 2021. Published by Elsevier España, S.L.U.)

Introduction: In 1842 William Bowman described the microvascular system of the Malpighian body. Electron microscopic studies definitively revealed the spatial structure of its mesangial-capillary-epithelial component. In 1952-54 Trabucco and Marquez challenged the ideas of Bowman, demonstrating the existence of a single glomerular arteriole. Our study supports the finding of a single glomerular arteriole, leading to a definitive interpretation of the Malpighian body structure., Materials and Methods: Serial histological studies were carried out of the vascular pole in a case of oligomeganephrotic renal hypoplasia and the immunohistochemical study of embryonal glomerular development (15 embryos aged between 7 and 11weeks), with alpha-actin (smooth muscle marker), CD31 and CD34 (endothelial markers) and CD10 (podocyte marker)., Results: The study of the glomerular vascular pole in the case of oligomeganephrotic renal hypoplasia supports the existence of a single glomerular arteriole. Our immunohistochemical study confirmed this finding and provided data on the morphogenesis of the mesangial-capillary-epithelial component of the Malpighian body., Conclusions: There exist a single glomerular arteriole. Mesangial and endothelial cells originating from a single glomerular arteriole interact with an epithelial component derived from the nephrogenic vesicle which then generate the lobular glomerular tuft, providing the basis for a definitive interpretation of the structure of the Malpighian body. There is no scientific base to the interpretation of the glomerular microvascular system as having two glomerular arterioles with an intercalated capillary network., (Copyright © 2021 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.)

From 2000, Mesoamerican region has reached an important rate of chronic kidney disease of unknown etiology. Under the name of Meroamerican Nephropathy (MeN) several hypotheses (including dehydration, heat stress, environmental or toxic exposure or even infections) have tried to explain the etiology this new disease. MeN affects young men, agricultural workers exposed to high temperatures. MeN courses with unspecific symptoms as low-grade fever and dysuria and progressive kidney disease with impaired renal function and hydroelectrolyte disturbances. The diagnosis requires kidney biopsy showing tubule-interstitial nephritis (usually at chronic stage). Although MeN conditions a high morbi-mortality in endemic regions, there is a lack of specific treatment and only preventive measures have demonstrated some effect of prognosis (avoid heat stress, constant hydration). In this review we aim to summarize the available information of MeN, illustrating the information in a case report., (Copyright © 2021 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

One key feature of pancreatic ductal adenocarcinoma (PDAC) is a dense desmoplastic reaction that has been recognized as playing important roles in metastasis and therapeutic resistance. We aim to study tumor-stromal interactions in an in vitro coculture model between human PDAC cells (Capan-1 or PL-45) and fibroblasts (LC5). Confocal immunofluorescence, Enzyme-Linked Immunosorbent Assay (ELISA), and Western blotting were used to evaluate the expressions of activation markers; cytokines arrays were performed to identify secretome profiles associated with migratory and invasive properties of tumor cells; extracellular vesicle production was examined by ELISA and transmission electron microscopy. Coculture conditions increased FGF-7 secretion and α-SMA expression, characterized by fibroblast activation and decreased epithelial marker E-cadherin in tumor cells. Interestingly, tumor cells and fibroblasts migrate together, with tumor cells in forming a center surrounded by fibroblasts, maximizing the contact between cells. We show a different mechanism for tumor spread through a cooperative migration between tumor cells and activated fibroblasts. Furthermore, IL-6 levels change significantly in coculture conditions, and this could affect the invasive and migratory capacities of cells. Targeting the interaction between tumor cells and the tumor microenvironment might represent a novel therapeutic approach to advanced PDAC.

The novel coronavirus disease (COVID-19) is a rapidly spreading pandemic, secondary to severe acute respiratory syndrome coronavirus 2. The severity and the little knowledge that we have of the disease have made us focus mostly on the respiratory symptoms. As we bend the curve, other findings reported in association with COVID-19 become of importance for specialists to recognize. We describe the spectrum of clinicopathologic lesions in the skin that can be the only symptom or the first manifestation of COVID-19 and demonstrate the origin of the virus. We collected 25 patients with skin lesions in this context. We recognized 5 types of cutaneous manifestations including acute acroischemic or chilblain-like lesions (11), purpura palpable (2), exanthemas (9), urticarial eruptions (1), and other lesions (2) that might appear with more unspecific pictures. Chilblain-like lesions were the most common form of presentation, which tend to appear as self-healing, erythematous-necrotic plaques mostly on the feet, in young patients with no systemic symptoms associated. Importantly, we visualized viral particles with electron microscopy in 5 of 13 cases analyzed. In this study, we seek to draw a picture of the spectrum of clinicopathologic lesions that may appear in the skin in the context of COVID-19. Although apparently skin lesions are not correlated with disease severity, it may help in some cases to recognize and control the spread of the infection sooner., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The spectrum of COVID-19 infection includes acute respiratory distress syndrome (ARDS) and macrophage activation syndrome (MAS), although the histological basis for these disorders has not been thoroughly explored. Post-mortem pulmonary and bone marrow biopsies were performed in 33 patients. Samples were studied with a combination of morphological and immunohistochemical techniques. Bone marrow studies were also performed in three living patients. Bone marrow post-mortem studies showed striking lesions of histiocytic hyperplasia with hemophagocytosis (HHH) in most (16/17) cases. This was also observed in three alive patients, where it mimicked the changes observed in hemophagocytic histiocytosis. Pulmonary changes included a combination of diffuse alveolar damage with fibrinous microthrombi predominantly involving small vessels, in particular the alveolar capillary. These findings were associated with the analytical and clinical symptoms, which helps us understand the respiratory insufficiency and reveal the histological substrate for the macrophage activation syndrome-like exhibited by these patients. Our results confirm that COVID-19 infection triggers a systemic immune-inflammatory disease and allow specific therapies to be proposed.

Background: Chilblains ('COVID toes') are being seen with increasing frequency in children and young adults during the COVID-19 pandemic. Detailed histopathological descriptions of COVID-19 chilblains have not been reported, and causality of SARS-CoV-2 has not yet been established., Objectives: To describe the histopathological features of COVID-19 chilblains and to explore the presence of SARS-CoV-2 in the tissue., Methods: We examined skin biopsies from seven paediatric patients presenting with chilblains during the COVID-19 pandemic. Immunohistochemistry for SARS-CoV-2 was performed in all cases and electron microscopy in one., Results: Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and thrombosis. Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen. SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy., Conclusions: Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relation of the lesions with SARS-CoV-2. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains and perhaps also in a group of patients severely affected by COVID-19 presenting with features of microangiopathic damage. What is already known about this topic? Despite the high number of cases of chilblains seen during the COVID-19 pandemic, a definite causative role for SARS-CoV-2 has not yet been proven. Different pathogenetic hypotheses have been proposed, including coagulation anomalies, interferon release and external factors. What does this study add? The demonstration of SARS-CoV-2 in endothelial cells of skin biopsies by immunohistochemistry and electron microscopy confirms that these lesions are part of the spectrum of COVID-19. Virus-induced vascular damage and secondary ischaemia could explain the pathophysiology of COVID-19 chilblains. Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a pathogenetic role in the severe forms of COVID-19. Linked Comment: Wetter. Br J Dermatol 2020; 183:611., (© 2020 British Association of Dermatologists.)

We fully agree that the interpretation of electron microscopy findings can be challenging, even for experts. Differences between viral pathogens and normal subcellular organelles may be subtle, and some cellular components can masquerade as viruses. The size and shape of the particle shown in our paper fit with other descriptions of SARS-CoV-2, but there may be a bias in interpretation., (This article is protected by copyright. All rights reserved.)

Lung cancer during pregnancy is a very rare disease with less than 70 cases published to date. Information about specific lung cancer as adenocarcinoma is even more limited. Genetic techniques can detect oncogene mutations which seem to be more frequent among cases of lung cancer in pregnant women and could determine both the treatment and prognosis. We present a recent case seen at our hospital and a literature review.

Background and Aims: endoscopic submucosal dissection (ESD) in the Western setting remains a challenge. Therefore, other simplified techniques such as knife-assisted snare resection (KAR) have been reported to overcome this issue., Methods: patients who underwent an ESD for the treatment of gastrointestinal neoplasms were included in a retrospective cross-sectional observational study. Factors associated with the end of ESD as a salvage p-KAR were identified and a logistic regression model was developed., Results: a total of 136 lesions in 133 patients were analyzed. Operator experience of under 50 cases and the combination of lesion size > 30 mm and colorectal location were independent predictive factors for switching to a salvage p-KAR according to the multivariate logistic regression analysis. We developed a risk scoring system based on these four variables (experience, size, location and the combination of size and location) with a receiver operating characteristic curve of 0.81 (95% CI: 0.74-0.89). The diagnostic accuracy of the score for a cut-off point ≥ 5 had a sensitivity of 0.79 (95% CI: 0.66-0.93) and a specificity of 0.71 (95% CI: 0.61-0.80)., Conclusion: a simple predictive score system that includes four preoperative factors accurately predicts ESD to finish as a p-KAR. A careful selection of cases considering these variables could be useful to achieve better outcomes in the Western setting.

Objectives: Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) is commonly altered in many human tumors, leading to the activation of p110α enzymatic activity that stimulates growth factor-independent cell growth. PIK3CA alterations such as mutation, gene amplification and overexpression are common in head and neck squamous cell carcinoma (HNSCC) and. We aim to explore how these alterations and clinical outcome are associated, as well as the molecular mechanisms involved., Material and Methods: Mutation and copy-number variation in PIK3CA, and whole-genome expression profiles, were analyzed in primary HNSCC tumors from The Cancer Genome Atlas (TCGA) cohort (n = 243). The results were validated in an independent cohort form the University Hospital of A Coruña (UHAC, n = 62). Expression of the PIK3CA gene protein product (PI3K p110α) and nuclear YAP were assessed in tissue microarrays in a cohort from the University Hospital 12 de Octubre (UH12O, n = 91)., Results: Only high expression of the PIK3CA gene was associated with poor clinical outcome. The study of gene expression, transcription factor and protein signatures suggested that the activation of the Hippo-YAP pathway, involved in organ size, stem cell maintenance and tumorigenesis, could underlie tumor progression in PI3KCA overexpressing tumors. Tissue arrays showed that PI3K p110α levels correlated with YAP nuclear localization in HNSCC tumors., Conclusions: High expression of PIK3CA in HNSCC primary tumors identifies patients at high risk for recurrence. In these tumors, progression could rely on the Hippo-YAP pathway instead of the canonical Akt/mTOR pathway. This observation could have important implications in the therapeutic options for patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We report the case of a 77-year-old diabetic patient with asymptomatic papular eruption developed over a cutaneous scar after the resection of a squamous cell carcinoma. Histological examination revealed a clear cell proliferation involving the secretory portion of the eccrine glands. This entity has been previously named as papular clear cell hyperplasia of the eccrine duct. This clear cell change might be caused by glycogen deposition because of diabetes. We postulate that papular clear cell hyperplasia could be a precursor lesion of clear cell syringoma.

Subepithelial gastric tumours comprise a heterogeneous group of lesions. Endoscopic ultrasonography with fine-needle aspiration (EUS-FNA) is a useful approach but cannot always offer a definitive diagnosis to guide future therapeutic decisions. In the case we describe, biopsy samples of an antral subepithelial lesion and cytological analysis obtained with an EUS-FNA suggested the diagnosis of an adenocarcinoma. Endoscopic submucosal dissection (ESD) allowed en bloc resection of the tumour ensuring diagnosis and providing a definitive treatment.