PCDHGC3 hypermethylation as a potential biomarker of intestinal neuroendocrine carcinomas.

Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and paraganglia. Despite advancements, accurately predicting the aggressiveness of gastroenteropancreatic (GEP) NENs based solely on pathological data remains challenging, thereby limiting optimal clinical management. Our previous research unveiled a crucial link between hypermethylation of the protocadherin PCDHGC3 gene and neuroendocrine tumors originating from the paraganglia and adrenal medulla. This epigenetic alteration was associated with increased metastatic potential and succinate dehydrogenase complex (SDH) dysfunction. Expanding upon this discovery, the current study explored PCDHGC3 gene methylation within the context of GEP-NENs in a cohort comprising 34 cases. We uncovered promoter hypermethylation of PCDHGC3 in 29% of GEP-NENs, with a significantly higher prevalence in gastrointestinal (GI) neuroendocrine carcinomas (NECs) compared with both pancreatic (Pan) NECs and neuroendocrine tumors (NETs) of GI and Pan origin. Importantly, these findings were validated in one of the largest multi-center GEP-NEN cohorts. Mechanistic analysis revealed that PCDHGC3 hypermethylation was not associated with SDH mutations or protein loss, indicating an SDH-independent epigenetic mechanism. Clinically, PCDHGC3 hypermethylation emerged as a significant prognostic factor, correlating with reduced overall survival rates in both patient cohorts. Significantly, whereas PCDHGC3 hypermethylation exhibited a strong correlation with TP53 somatic mutations, a hallmark of NEC, its predictive value surpassed that of TP53 mutations, with an area under the curve (AUC) of 0.95 (95% CI 0.83-1.0) for discriminating GI-NECs from GI-NETs, highlighting its superior predictive performance. In conclusion, our findings position PCDHGC3 methylation status as a promising molecular biomarker for effectively stratifying patients with GI-NENs. This discovery has the potential to advance patient care by enabling more precise risk assessments and tailored treatment strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

In-stent restenosis is associated with proliferative skin healing and specific immune and endothelial cell profiles: results from the RACHEL trial.

Introduction: In-stent restenosis (ISR) is a major challenge in interventional cardiology. Both ISR and excessive skin healing are aberrant hyperplasic responses, which may be functionally related. However, the cellular component underlying ISR remains unclear, especially regarding vascular homeostasis. Recent evidence suggest that novel immune cell populations may be involved in vascular repair and damage, but their role in ISR has not been explored. The aims of this study is to analyze (i) the association between ISR and skin healing outcomes, and (ii) the alterations in vascular homeostasis mediators in ISR in univariate and integrative analyses. Methods: 30 patients with ≥1 previous stent implantation with restenosis and 30 patients with ≥1 stent without restenosis both confirmed in a second angiogram were recruited. Cellular mediators were quantified in peripheral blood by flow cytometry. Skin healing outcomes were analyzed after two consecutive biopsies. Results: Hypertrophic skin healing was more frequent in ISR patients (36.7%) compared to those ISR-free (16.7%). Patients with ISR were more likely to develop hypertrophic skin healing patterns (OR 4.334 [95% CI 1.044-18.073], p=0.033), even after correcting for confounders. ISR was associated with decreased circulating angiogenic T-cells (p=0.005) and endothelial progenitor cells (p<0.001), whereas CD4+CD28null and detached endothelial cells counts were higher (p<0.0001 and p=0.006, respectively) compared to their ISR-free counterparts. No differences in the frequency of monocyte subsets were found, although Angiotensin-Converting Enzyme expression was increased (non-classical: p<0.001; and intermediate: p<0.0001) in ISR. Despite no differences were noted in Low-Density Granulocytes, a relative increase in the CD16- compartment was observed in ISR (p=0.004). An unsupervised cluster analysis revealed the presence of three profiles with different clinical severity, unrelated to stent types or traditional risk factors. Conclusion: ISR is linked to excessive skin healing and profound alterations in cellular populations related to vascular repair and endothelial damage. Distinct cellular profiles can be distinguished within ISR, suggesting that different alterations may uncover different ISR clinical phenotypes.

Liposarcoma pleomórfico originado en una localización inusual. Presentación de caso / Pleomorphic liposarcoma arising in an unusual site. A case report

Los liposarcomas son el grupo más común de las neoplasias mesenquimatosas malignas. Suelen aparecer en las extremidades y en el retroperitoneo. Es excepcional su localización intestinal. Se presenta el caso de un varón de 75 años que fue hospitalizado por anemia severa, en cuya TC se objetivó un engrosamiento de asa yeyunal de 5cm sospechoso de neoplasia. Se realizó resección parcial de intestino delgado. Macroscópicamente se identificó una tumoración polipoide ulcerada de 12×6cm. Microscópicamente se observó una neoplasia bien delimitada, ulcerada, de transición abrupta con una mucosa circundante normal, compuesta por lipoblastos pleomórficos sobre un fondo sarcomatoso. Existen muy pocos casos publicados de liposarcomas intestinales, la mayoría de los cuales eran liposarcomas bien diferenciados o desdiferenciados. Se presenta el caso de un liposarcoma pleomórfico de intestino delgado por su excepcional localización y la importancia en su diagnóstico diferencial.(AU)

Liposarcomas are the most common group of malignant mesenchymal neoplasms. They usually occur in the extremities and the retroperitoneum and only rarely in the intestine. We report the case of a 75-year-old man presenting with severe anaemia. A CAT scan revealed a 5cm thickening of the jejunal loop, arousing the suspicion of a neoplasm. A partial resection of the small intestine was performed. Macroscopy showed a 12×6cm ulcerated, polypoid mass. Microscopically, a well circumscribed, ulcerated tumour was seen, which had well-defined margins with the surrounding normal mucosa. It consisted of pleomorphic lipoblasts within a sarcomatous background. Very few cases of intestinal liposarcomas have been published and the majority report well-differentiated or undifferentiated liposarcomas. We present a case of a pleomorphic liposarcoma of the small intestine, which is an unusual location and emphases the importance of a comprehensive differential diagnosis.(AU)

[Pleomorphic liposarcoma arising in an unusual site. A case report]. / Liposarcoma pleomórfico originado en una localización inusual. Presentación de caso.

Liposarcomas are the most common group of malignant mesenchymal neoplasms. They usually occur in the extremities and the retroperitoneum and only rarely in the intestine. We report the case of a 75-year-old man presenting with severe anaemia. A CAT scan revealed a 5cm thickening of the jejunal loop, arousing the suspicion of a neoplasm. A partial resection of the small intestine was performed. Macroscopy showed a 12×6cm ulcerated, polypoid mass. Microscopically, a well circumscribed, ulcerated tumour was seen, which had well-defined margins with the surrounding normal mucosa. It consisted of pleomorphic lipoblasts within a sarcomatous background. Very few cases of intestinal liposarcomas have been published and the majority report well-differentiated or undifferentiated liposarcomas. We present a case of a pleomorphic liposarcoma of the small intestine, which is an unusual location and emphases the importance of a comprehensive differential diagnosis.

AA amyloidosis associated with morbid obesity (clinical case) / Amiloidosis AA asociada a la obesidad mórbida (caso clínico)

We present the case of a 45-year-old woman who was hospitalized due to severe macrocytic anemia and renal failure. The patient presented a morbid obesity. The immunological study showed anti-ENA anti-SSA (Ro52) positive, with negative antinuclear antibodies. Also in the proteinogram (serum immunofixation) the presence of monoclonal bands IgG lambda and IgG kappa, monoclonal component 7.2% (4.68g/L), with elevation of free light chains (kappa 95.94mg/L (3.3-19.4), evidenced, lambda 145.17mg/L (5.71-26.3)). The bone marrow study showed an infiltration of 5% of plasma cells and positive for AA amyloid. Finally, a percutaneous renal biopsy was performed, which again showed amyloid infiltration. In the genetic study, 2 mutations of the family Mediterranean fever gene (MEFV) have been identified. Secondary AA amyloidosis has been described associated with obesity, in addition to a percentage of cases of unknown etiology

Presentamos el caso de una mujer de 45 años que fue hospitalizada debido a una anemia macrocítica severa e insuficiencia renal. El paciente presentaba una obesidad mórbida. El estudio inmunológico mostró positividad para anti-ENA, anti-SSA (Ro52) y negatividad para anticuerpos antinucleares. También en el proteinograma (inmunofijación sérica) se detectó la presencia de bandas monoclonales IgG lambda e IgG kappa, con un componente monoclonal del 7,2% (4,68g/l) y la elevación de cadenas ligeras libres (kappa 95,94mg/l [3,3-19,4]; lambda 145,17mg/l [5,71-26,3]). El estudio de biopsia de médula ósea mostró una infiltración del 5% de células plasmáticas y positividad para amiloide AA. Finalmente, se realizó una biopsia renal que nuevamente mostró infiltración amiloide. En el estudio genético se identificaron 2 mutaciones del gen de la fiebre mediterránea familiar (MEFV). La amiloidosis secundaria AA se ha descrito asociada a la obesidad, además de un porcentaje de casos de etiología desconocida

AA amyloidosis associated with morbid obesity (clinical case).

We present the case of a 45-year-old woman who was hospitalized due to severe macrocytic anemia and renal failure. The patient presented a morbid obesity. The immunological study showed anti-ENA anti-SSA (Ro52) positive, with negative antinuclear antibodies. Also in the proteinogram (serum immunofixation) the presence of monoclonal bands IgG lambda and IgG kappa, monoclonal component 7.2% (4.68g/L), with elevation of free light chains (kappa 95.94mg/L (3.3-19.4), evidenced, lambda 145.17mg/L (5.71-26.3)). The bone marrow study showed an infiltration of 5% of plasma cells and positive for AA amyloid. Finally, a percutaneous renal biopsy was performed, which again showed amyloid infiltration. In the genetic study, 2 mutations of the family Mediterranean fever gene (MEFV) have been identified. Secondary AA amyloidosis has been described associated with obesity, in addition to a percentage of cases of unknown etiology.