Perivascular Epithelioid Cell Neoplasm (PEComa) harboring TFE3 gene rearrangements in a patient with Lynch syndrome.

A 38-year-old male with a history of Lynch syndrome was diagnosed with a rectal mucinous adenocarcinoma 6 years earlier. In the follow-up a pelvic nodule radiologically suggestive of a lymph node recurrence was found, and was surgically removed. Histopathological studies were suggestive of PEComa. Immunohistochemical studies showed diffuse positivity for HMB45 and TFE3, with scattered cells expressing MELAN A and actin. TFE3 gene rearrangement was confirmed with fluorescence in situ hybridization. Intact nuclear expression was observed for MLH1, MSH2, MSH6 and PMS2, and genetic studies confirmed microsatellite stability, arguing against a relation with Lynch syndrome. After 29 months, the patient remains alive with no evidence of recurrence of either the adenocarcinoma or the PEComa. Although some sarcomas have been described in Lynch syndrome families, cumulative evidence suggests that Lynch syndrome patients might also develop non-Lynch syndrome tumors. To the best of our knowledge, this is the first report of a PEComa in a patient with Lynch syndrome. TFE3-rearranged PEComas are a recently described variant defined by the translocation of TFE3, the features of which are poorly defined. This tumor adds to the list of sporadic non-Lynch syndrome-related tumors, and to the data of TFE3 rearrangement-associated PEComas.

EEG before chimeric antigen receptor T-cell therapy and early after onset of immune effector cell-associated neurotoxicity syndrome.

BACKGROUND: Immune effector cell-associated neurotoxicity syndrome (ICANS) is common after chimeric antigen receptor T-cell (CAR-T) therapy. OBJECTIVE: This study aimed to assess the impact of preinfusion electroencephalography (EEG) abnormalities and EEG findings at ICANS onset for predicting ICANS risk and severity in 56 adult patients with refractory lymphoma undergoing CAR-T therapy. STUDY DESIGN: EEGs were conducted at the time of lymphodepleting chemotherapy and shortly after onset of ICANS. RESULTS: Twenty-eight (50%) patients developed ICANS at a median time of 6 days after CAR-T infusion. Abnormal preinfusion EEG was identified as a risk factor for severe ICANS (50% vs. 17%, P = 0.036). Following ICANS onset, EEG abnormalities were detected in 89% of patients [encephalopathy (n = 19, 70%) and/or interictal epileptiform discharges (IEDs) (n = 14, 52%)]. Importantly, IEDs seemed to be associated with rapid progression to higher grades of ICANS within 24 h. CONCLUSIONS: If confirmed in a large cohort of patients, these findings could establish the basis for modifying current management guidelines, enabling the identification of patients at risk of neurotoxicity, and providing support for preemptive corticosteroid use in patients with both initial grade 1 ICANS and IEDs at neurotoxicity onset, who are at risk of neurological impairment.

Gastric metaplasia as a precursor of nonconventional dysplasia in inflammatory bowel disease.

Gastric metaplasia in colonic mucosa with inflammatory bowel disease (IBD) develops as an adaptation mechanism. The association between gastric metaplasia and nonconventional and/or conventional dysplasia as precursors of colitis-associated colorectal cancer is unknown. To address this question, we retrospectively reviewed a series of 33 IBD colectomies to identify gastric metaplasia in 76 precursor lesions. We obtained 61 nonconventional and 15 conventional dysplasias. Among nonconventional dysplasia, 31 (50.8 %) were low-grade (LGD), 4 (6.5 %) were high-grade (HGD), 9 (14.8 %) had both LGD and HGD, and 17 (27.9 %) had no dysplasia (ND), while 14 (93 %) conventional dysplasias had LGD, and 1 (7 %) had LGD and HGD. Gastric metaplasia was assessed by concomitant immunoexpression of MUC5AC and loss of CDX2 staining. Expression of a p53-mut pattern was considered as a surrogate for gene mutation, and complete loss of MLH1 staining as presence of MLH1 hypermethylation. In nonconventional dysplasia, MUC5AC immunoexpression decreased as the degree of dysplasia increased, being 78 % in LGD and 39 % in HGD (p = 0.006). CDX2 was lost in epithelial glands with high expression of MUC5AC (p < 0.001). The p53-mut pattern was observed in 77 % HGD, 45 % LGD, and in 6 % with ND (p < 0.001). Neither nonconventional nor conventional dysplasia showed complete loss of MLH1 staining. Gastric metaplasia was also present in mucosa adjacent to nonconventional dysplasia with chronic changes or active inflammation. Our results show that gastric metaplasia appears in IBD-inflamed colon mucosa, it is the substrate of most nonconventional dysplasia and occurs prior to p53 alterations.

The prognostic potential of CDX2 in colorectal cancer: Harmonizing biology and clinical practice.

Adjuvant chemotherapy following surgical intervention remains the primary treatment option for patients with localized colorectal cancer (CRC). However, a significant proportion of patients will have an unfavorable outcome after current forms of chemotherapy. While reflecting the increasing complexity of CRC, the clinical application of molecular biomarkers provides information that can be utilized to guide therapeutic strategies. Among these, caudal-related homeobox transcription factor 2 (CDX2) emerges as a biomarker of both prognosis and relapse after therapy. CDX2 is a key transcription factor that controls intestinal fate. Although rarely mutated in CRC, loss of CDX2 expression has been reported mostly in right-sided, microsatellite-unstable tumors and is associated with aggressive carcinomas. The pathological assessment of CDX2 by immunohistochemistry can thus identify patients with high-risk CRC, but the evaluation of CDX2 expression remains challenging in a substantial proportion of patients. In this review, we discuss the roles of CDX2 in homeostasis and CRC and the alterations that lead to protein expression loss. Furthermore, we review the clinical significance of CDX2 assessment, with a particular focus on its current use as a biomarker for pathological evaluation and clinical decision-making. Finally, we attempt to clarify the molecular implications of CDX2 deficiency, ultimately providing insights for a more precise evaluation of CDX2 protein expression.

Alterations in p53, Microsatellite Stability and Lack of MUC5AC Expression as Molecular Features of Colorectal Carcinoma Associated with Inflammatory Bowel Disease.

Colitis-associated colorectal carcinoma (CAC) occurs in inflammatory bowel disease (IBD) because of the "chronic inflammation-dysplasia-cancer" carcinogenesis pathway characterized by p53 alterations in the early stages. Recently, gastric metaplasia (GM) has been described as the initial event of the serrated colorectal cancer (CRC) process, resulting from chronic stress on the colon mucosa. The aim of the study is to characterize CAC analyzing p53 alterations and microsatellite instability (MSI) to explore their relationship with GM using a series of CRC and the adjacent intestinal mucosa. Immunohistochemistry was performed to assess p53 alterations, MSI and MUC5AC expression as a surrogate for GM. The p53 mut-pattern was found in more than half of the CAC, most frequently stable (MSS) and MUC5AC negative. Only six tumors were unstable (MSI-H), being with p53 wt-pattern (p = 0.010) and MUC5AC positive (p = 0.005). MUC5AC staining was more frequently observed in intestinal mucosa, inflamed or with chronic changes, than in CAC, especially in those with p53 wt-pattern and MSS. Based on our results, we conclude that, as in the serrated pathway of CRC, in IBD GM occurs in inflamed mucosa, persists in those with chronic changes and disappears with the acquisition of p53 mutations.

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy.

A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.

[Undergraduate Pathology: Results of a Survey on Undergraduate Teaching of Pathology in Spanish Medical Schools]. / Docencia de pregrado en Anatomía Patológica: Resultados de la encuesta sobre la docencia de la asignatura de Anatomía Patológica en los estudios de pregrado de las facultades de medicina españolas.

In order to ascertain the present state of undergraduate pathology teaching in Spain, the Spanish Society of Pathology sent a survey to the coordinators of the subject in every Medical School. The survey consisted of a form created using Google Forms tool and covered various aspects of teaching, such as the different syllabi, methodology and resources. 62% of the 55 Medical Schools contacted participated in the study (76% public and 25% private). In about half of cases, Pathology was taught as a single subject, while in the rest it was divided into General and Special Pathology. Only 18% integrated other clinical subjects into Pathology teaching and only 55% coordinated the timing of the course in order to coordinate with the content of other clinical subjects. We present the results of the survey together with all the accompanying comments and reflections, which highlight the heterogeneity of the Pathology syllabus in Spanish Medical Schools. We consider that if undergraduate Pathology is taught in an attractive, stimulating and clinically relevant manner, more students would be motivated to choose Pathology as their future speciality. Our main recommendations would be to emphasize the clinical application of Pathology and offer opportunities to gain practical, hands-on experience in Pathology departments.

"Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction".

BACKGROUND: Patient-derived organoids (PDOs) from advanced colorectal cancer (CRC) patients could be a key platform to predict drug response and discover new biomarkers. We aimed to integrate PDO drug response with multi-omics characterization beyond genomics. METHODS: We generated 29 PDO lines from 22 advanced CRC patients and provided a morphologic, genomic, and transcriptomic characterization. We performed drug sensitivity assays with a panel of both standard and non-standard agents in five long-term cultures, and integrated drug response with a baseline proteomic and transcriptomic characterization by SWATH-MS and RNA-seq analysis, respectively. RESULTS: PDOs were successfully generated from heavily pre-treated patients, including a paired model of advanced MSI high CRC deriving from pre- and post-chemotherapy liver metastasis. Our PDOs faithfully reproduced genomic and phenotypic features of original tissue. Drug panel testing identified differential response among PDOs, particularly to oxaliplatin and palbociclib. Proteotranscriptomic analyses revealed that oxaliplatin non-responder PDOs present enrichment of the t-RNA aminoacylation process and showed a shift towards oxidative phosphorylation pathway dependence, while an exceptional response to palbociclib was detected in a PDO with activation of MYC and enrichment of chaperonin T-complex protein Ring Complex (TRiC), involved in proteome integrity. Proteotranscriptomic data fusion confirmed these results within a highly integrated network of functional processes involved in differential response to drugs. CONCLUSIONS: Our strategy of integrating PDOs drug sensitivity with SWATH-mass spectrometry and RNA-seq allowed us to identify different baseline proteins and gene expression profiles with the potential to predict treatment response/resistance and to help in the development of effective and personalized cancer therapeutics.

Docencia de pregrado en Anatomía Patológica: Resultados de la encuesta sobre la docencia de la asignatura de Anatomía Patológica en los estudios de pregrado de las facultades de medicina españolas / Undergraduate Pathology: Results of a Survey on Undergraduate Teaching of Pathology in Spanish Medical Schools

Desde la Sociedad Española de Anatomía Patológica se ha realizado una encuesta entre las facultades de medicina españolas con el fin de obtener una imagen global del estado de la docencia de la asignatura de Anatomía Patológica en pregrado valorando los diferentes planes de estudio, la metodología empleada y la dotación de recursos. La encuesta se envió a los coordinadores de la asignatura en las diferentes facultades de medicina españolas a través de un formulario creado con la herramienta Formularios de Google.El 62% de las 55 unidades docentes encuestadas participaron en el estudio (76% universidades públicas y 24% privadas). Prácticamente en la mitad de los casos, la Anatomía Patológica se imparte como asignatura única, y en la otra mitad como una asignatura general y otra especial. Solo un 18% de las facultades contempla la asignatura especial integrada con otras asignaturas clínicas, y en general, solo en un 55% de los centros con Anatomía Patológica Especial, el contenido está coordinado con el de otras asignaturas clínicas.Los resultados de este estudio ponen en evidencia la heterogeneidad de la formación ofrecida en la asignatura de Anatomía Patológica para los estudiantes de Medicina en las diversas universidades españolas. Solamente planteando una asignatura en pregrado que sea atractiva y estimulante podremos motivar suficientemente a los estudiantes para elegir Anatomía Patológica como especialidad. En este artículo presentamos los resultados de la encuesta con todos los comentarios recogidos y las reflexiones planteadas a partir de los mismos. Las principales medidas propuestas están relacionadas con insistir en el carácter asistencial de la especialidad y en ofrecer rotaciones prácticas en los servicios de Anatomía Patológica.(AU)

In order to ascertain the present state of undergraduate pathology teaching in Spain, the Spanish Society of Pathology sent a survey to the coordinators of the subject in every Medical School. The survey consisted of a form created using Google Forms tool and covered various aspects of teaching, such as the different syllabi, methodology and resources.62% of the 55 Medical Schools contacted participated in the study (76% public and 25% private). In about half of cases, Pathology was taught as a single subject, while in the rest it was divided into General and Special Pathology. Only 18% integrated other clinical subjects into Pathology teaching and only 55% coordinated the timing of the course in order to coordinate with the content of other clinical subjects.We present the results of the survey together with all the accompanying comments and reflections, which highlight the heterogeneity of the Pathology syllabus in Spanish Medical Schools. We consider that if undergraduate Pathology is taught in an attractive, stimulating and clinically relevant manner, more students would be motivated to choose Pathology as their future speciality. Our main recommendations would be to emphasize the clinical application of Pathology and offer opportunities to gain practical, hands-on experience in Pathology departments.(AU)

Integrative immune transcriptomic classification improves patient selection for precision immunotherapy in advanced gastro-oesophageal adenocarcinoma.

BACKGROUND: Advanced gastro-oesophageal cancer (GEA) treatment has been improved by the introduction of immune checkpoint inhibitors (CPIs), yet identifying predictive biomarkers remains a priority, particularly in patients with a combined positive score (CPS) < 5, where the benefit is less clear. Our study assesses certain immune microenvironment features related to sensitivity or resistance to CPIs with the aim of implementing a personalised approach across CPS < 5 GEA. DESIGN: Through integrative transcriptomic and clinicopathological analyses, we studied in both a retrospective and a prospective cohort, the immune tumour microenvironment features. We analysed the cell types composing the immune infiltrate highlighting their functional activity. RESULTS: This integrative study allowed the identification of four different groups across our patients. Among them, we identified a cluster whose tumours expressed the most gene signatures related to immunomodulatory pathways and immunotherapy response. These tumours presented an enriched immune infiltrate showing high immune function activity that could potentially achieve the best benefit from CPIs. Finally, our findings were proven in an external CPI-exposed population, where the use of our transcriptomic results combined with CPS helped better identify those patients who could benefit from immunotherapy than using CPS alone (p = 0.043). CONCLUSIONS: This transcriptomic classification could improve precision immunotherapy for GEA.

Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors.

About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients' response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.

[Undergraduate Pathology: Video tutorials including digital pathology make teaching more practical and the subject more attractive]. / Anatomía Patológica para el estudiante de Medicina: videotutoriales con integración de Patología digital como una valiosa herramienta para hacer la asignatura más práctica y atractiva.

INTRODUCTION AND OBJECTIVES: Although pathology is one of the cornerstone subjects of the medical curriculum, for many students it can prove too theoretical and remote from clinical relevance. We present the results of a new distance learning project designed to make the teaching of pathology more practical and render the subject more attractive to the medical student. MATERIALS AND METHODS: We developed a teaching programme which included digital pathology images and video tutorials of clinical cases; the students were required to arrive at a final diagnosis. An explanatory video of how biopsies are processed was also included. Twitter was used for rapid interaction with the students. A questionnaire was then completed by the participants evaluating the various aspects of the project. RESULTS: All the students reached a correct diagnosis for the clinical cases. 89% of the participants were extremely satisfied with the project. The majority agreed that the different activities were interesting and useful for improving their understanding of pathology and thus recommended that they should be continued. CONCLUSIONS: Our results support the inclusion of digital pathology into the curriculum together with video tutorials to enhance undergraduate pathology teaching. In the future, such distance learning could prove a useful resource in combination with conventional face-to-face lectures and tutorials.

[Three cases of urachal cyst in adults]. / Quistes de uraco en adultos. Presentación de 3 casos y revisión de la literatura.

The urachus is a thick fibrous cord that appears in the fifth month of pregnancy as a result of the allantois obliteration. Urachal cysts occur as a result of a defect in the obliteration of the duct, anomaly detected mainly in children and very rarely in adults. We present three cases of urachal cysts in adults, one of them detected during the study of abdominal pain and the other two, found incidentally during the study of other pathologies. In any case the possibility of urachal cysts was clinically suspected. Histologically, these lesions are lined by epithelium of urothelial type with expression of CK7, CK20, CK5/6, P63 and GATA3. The diagnosis of urachal cysts certainty lies in the histopathological study where the morphology, immunohistochemistry and a proper clinical-pathological correlation, allow to differentiate it from other more frequent abdominal cystic lesions in adults.

Anatomía Patológica para el estudiante de Medicina: videotutoriales con integración de Patología digital como una valiosa herramienta para hacer la asignatura más práctica y atractiva / Undergraduate Pathology: Video tutorials including digital pathology make teaching more practical and the subject more attractive

Introducción y objetivo: La asignatura de Anatomía Patológica es fundamental en la formación del estudiante de Medicina. Sin embargo, para muchos estudiantes la asignatura presenta un excesivo contenido teórico, poco trasladable a la práctica clínica. Presentamos los resultados de un proyecto de innovación docente dirigido a facilitar la transmisión del conocimiento a distancia y hacer de la Anatomía Patológica una asignatura más práctica y atractiva para el estudiante de Medicina. Materiales y métodos: Elaboramos material didáctico integrando imágenes de enfermedad digital con videotutoriales para la exposición de casos clínicos donde los alumnos debían llegar al diagnóstico final. Creamos un vídeo explicativo donde exponemos como se procesan las biopsias y utilizamos redes sociales (Twitter) para mantener una comunicación más fluida con los estudiantes. Finalmente, valoramos la percepción del estudiante sobre las actividades realizadas a través de una encuesta. Resultados: Al final de la actividad todos los alumnos resolvieron los casos clínicos y llegaron al diagnóstico correcto de manera exitosa. El 89% de los alumnos mostró un alto nivel de satisfacción con la actividad. Para la mayoría de los participantes la actividad resultó interesante y didáctica, mejorando su experiencia de aprendizaje, por lo que recomendaban mantenerla en el futuro. Conclusiones: Nuestros resultados soportan la integración de la enfermedad digital en combinación con video tutoriales como una herramienta exitosa en el aprendizaje de la Anatomía Patológica. Este modelo podría mantenerse en el futuro como un recurso útil en combinación con el aprendizaje presencial.(AU)

Introduction and objectives: Although pathology is one of the cornerstone subjects of the medical curriculum, for many students it can prove too theoretical and remote from clinical relevance. We present the results of a new distance learning project designed to make the teaching of pathology more practical and render the subject more attractive to the medical student. Materials and methods: We developed a teaching programme which included digital pathology images and video tutorials of clinical cases; the students were required to arrive at a final diagnosis. An explanatory video of how biopsies are processed was also included. Twitter was used for rapid interaction with the students. A questionnaire was then completed by the participants evaluating the various aspects of the project. Results: All the students reached a correct diagnosis for the clinical cases. 89% of the participants were extremely satisfied with the project. The majority agreed that the different activities were interesting and useful for improving their understanding of pathology and thus recommended that they should be continued.Conclusions: Our results support the inclusion of digital pathology into the curriculum together with video tutorials to enhance undergraduate pathology teaching. In the future, such distance learning could prove a useful resource in combination with conventional face-to-face lectures and tutorials.(AU)

Quistes de uraco en adultos. Presentación de 3 casos y revisión de la literatura / Three cases of urachal cyst in adults

El uraco es un grueso cordón fibroso que aparece a partir del quinto mes de gestación como consecuencia de la obliteración de la alantoides. Los quistes de origen uracal se producen como consecuencia de un defecto en la obliteración de dicho conducto, anomalía que se detecta principalmente en niños y raramente en adultos. Presentamos 3 casos de quistes uracales en adultos, uno de ellos detectado durante el estudio de dolor abdominal y los otros 2 hallados de forma incidental durante el estudio de otras patologías. En ningún caso se sospechó clínicamente la posibilidad de quistes uracales. Histológicamente, estas lesiones se encuentran revestidas por epitelio de tipo urotelial con expresión de CK7, CK20, CK5/6, P63 y GATA3. El diagnóstico de certeza recae en el estudio histopatológico donde la morfología, la inmunohistoquímica y un adecuado correlato clínico-patológico, permiten diferenciarlo de otras lesiones quísticas mucho más frecuentes en el adulto.(AU)

The urachus is a thick fibrous cord that appears in the fifth month of pregnancy as a result of the allantois obliteration. Urachal cysts occur as a result of a defect in the obliteration of the duct, anomaly detected mainly in children and very rarely in adults. We present three cases of urachal cysts in adults, one of them detected during the study of abdominal pain and the other two, found incidentally during the study of other pathologies. In any case the possibility of urachal cysts was clinically suspected. Histologically, these lesions are lined by epithelium of urothelial type with expression of CK7, CK20, CK5/6, P63 and GATA3. The diagnosis of urachal cysts certainty lies in the histopathological study where the morphology, immunohistochemistry and a proper clinical-pathological correlation, allow to differentiate it from other more frequent abdominal cystic lesions in adults.(AU)

Molecular profiling of advanced solid tumours. The impact of experimental molecular-matched therapies on cancer patient outcomes in early-phase trials: the MAST study.

INTRODUCTION: Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution. METHODS: Patients with advanced solid tumors were molecularly selected to receive a molecular-matched treatment into early phase clinical trials versus best investigators choice, according to the evaluation of a multidisciplinary molecular tumor board. The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1). RESULTS: Of a total of 231 molecularly screened patients, 87 were eligible for analysis. Patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24-14.43) compared to those who received standard therapy (2.76 months; 95% CI, 2.14-3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008). DISCUSSION: We demonstrate the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies, improving disease control. Prospective randomized trials are needed to confirm this approach and open the door to expanded drug access.