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- HepatoPredict Accurately Selects Hepatocellular Carcinoma Patients for Liver Transplantation Regardless of Tumor Heterogeneity.Publication . Andrade, Rita; Perez-Rojas, Judith; da Silva, Sílvia Gomes; Miskinyte, Migla; Quaresma, Margarida C; Frazão, Laura P; Peixoto, Carolina; Cubells, Almudena; Montalvá, Eva M; Figueiredo, António; Cipriano, Augusta; Gonçalves-Reis, Maria; Proença, Daniela; Folgado, André; Pereira-Leal, José B; Oliveira, Rui Caetano; Pinto-Marques, Hugo; Tralhão, José Guilherme; Berenguer, Marina; Cardoso, JoanaBackground/objectives: Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths rising worldwide. This is leading to an increased demand for liver transplantation (LT), the most effective treatment for HCC in its initial stages. However, current patient selection criteria are limited in predicting recurrence and raise ethical concerns about equitable access to care. This study aims to enhance patient selection by refining the HepatoPredict (HP) tool, a machine learning-based model that combines molecular and clinical data to forecast LT outcomes. Methods: The updated HP algorithm was trained on a two-center dataset and assessed against standard clinical criteria. Its prognostic performance was evaluated through accuracy metrics, with additional analyses considering tumor heterogeneity and potential sampling bias. Results: HP outperformed all clinical criteria, particularly regarding negative predictive value, addressing critical limitations in existing selection strategies. It also demonstrated improved differentiation of recurrence-free and overall survival outcomes. Importantly, the prognostic accuracy of HP remained largely unaffected by intra-nodule and intra-patient heterogeneity, indicating its robustness even when biopsies were taken from smaller or non-dominant nodules. Conclusions: These findings support the usage of HP as a valuable tool for optimizing LT candidate selection, promoting fair organ allocation and enhancing patient outcomes through integrated analysis of molecular and clinical data.
- Metabolism-Targeted Therapy in NSCLC - A New Theranostics Inhalation Approach Using Lactate Functionalized and Selenium-Chrysin Loaded Nanoparticles (SeChry@PURE-LA).Publication . Mendes, Cindy; Martins, Filipa; Granja, Sara; Gonçalves, Joana; Barros, Hélio; Casimiro, Teresa; Aguiar-Ricardo, Ana; Silva, Fernanda; Abreu, Bruna; Cristovão, Miguel; André, Saudade; Pereira, Sofia A; Baltazar, Fátima; Cabral-Marques, Helena; Gaspar, Maria Manuela; Gonçalves, Luís G; Bonifácio, Vasco D B; Serpa, JacintaLung cancer is one of the most lethal cancers globally, primarily due to delayed diagnosis and lack of specific and effective therapy. Increased lactate production and consumption, along with cysteine metabolic reliance, are features identified in NSCLC in our recent studies. Cancer metabolic remodeling leads to excessive ROS production, triggering oxidative stress, promoting angiogenesis, causing cellular and tissue damage, and contributing to various pathophysiological changes. This study aimed to investigate the therapeutic potential of selenium-chrysin (SeChry), a cysteine metabolism inhibitor, and its delivery targeted at MCT1 by encapsulation in fourth-generation polyurea dendrimers functionalized with lactic acid (PURE-LA), the nanoformulation SeChry@PURE-LA, in NSCLC. We explored the impact of SeChry nanoformulation on cell death mechanisms, including ferroptosis, and its influence on angiogenesis in in vitro and in vivo models. SeChry@PURE-LA induces cell death through the induction of intracellular ROS and lipid peroxides, resulting in distinct expression patterns of ferroptosis-associated genes across cell lines. Experiments using chicken embryo chorioallantoic membrane (CAM) and mouse orthotopic xenograft models revealed a trend toward decreased tumor growth and angiogenesis with SeChry@PURE-LA administration. These findings suggest the potential of SeChry@PURE-LA as an innovative therapeutic approach for NSCLC, highlighting its impact on cell death mechanisms and anti-angiogenic effects.
- Welcoming the New, Revisiting the Old: a Brief Glance at Cytopathology Reporting Systems for Lung, Pancreas, and Thyroid.Publication . Luis, Rita; Thirunavukkarasu, Balamurugan; Jain, Deepali; Canberk, SuleThis review addresses new reporting systems for lung and pancreatobiliary cytopathology as well as the most recent edition of The Bethesda Reporting System for Thyroid Cytopathology. The review spans past, present, and future aspects within the context of the intricate interplay between traditional morphological assessments and cutting-edge molecular diagnostics. For lung and pancreas, the authors discuss the evolution of reporting systems, emphasizing the bridge between past directives and more recent collaborative efforts of the International Academy of Cytology and the World Health Organization in shaping universal reporting systems. The review offers a brief overview of the structure of these novel systems, highlighting their strengths and pinpointing areas that require further refinement. For thyroid, the authors primarily focus on the third edition of The Bethesda System for Reporting Thyroid Cytopathology, also considering the two preceding editions. This review serves as an invaluable resource for cytopathologists, offering a panoramic view of the evolving landscape of cytopathology reporting and pointing out the integrative role of the cytopathologist in an era of rapid diagnostic and therapeutic advancements.
- Multidisciplinary Approaches and Molecular Diagnostics in New-Onset Refractory Status Epilepticus and Nontuberculous Mycobacterial CNS Infections in the ICU: A Case Report.Publication . Batarda Sena, Pedro Manuel; Ferro, Margarida; Alves Cabrita, Joana; Pontinha, Carlos; Mestre, Ana; Oliveira, Mário; Bento, LuisThe diagnosis and management of complex neurological conditions such as New-Onset Refractory Status Epilepticus (NORSE) and central nervous system (CNS) infections caused by non-tuberculous mycobacteria (NTM) pose substantial difficulties in intensive care units (ICUs). This article combines a case report and a literature review that explores the diagnostic dilemmas and therapeutic strategies for these critical conditions. We report the case of an 83-year-old female with chronic granulomatous meningitis secondary to NTM, presenting a challenging diagnostic and complex management complexity typical of such a rare disease through a period time of five years. Her case emphasized the importance of a multidisciplinary approach in such cases, as the interplay between neurology and intensive care was vital. The need for new molecular diagnostic technologies is shown to be of high significance in identifying the causative pathogens and improving patient outcomes in these rare but critical conditions.
- Calcium Polystyrene Sulfonate-Induced Colitis: Advanced Characterization of Crystal Nature With Infrared Spectroscopy.Publication . Vidal, Helena; Salgado, Vilma; Alves, Patrícia; Fonseca, Nuno Moreira; Frochot, Vincent; Ferreira, Aníbal; OxfordClassical potassium binders are used in the treatment of hyperkalemia and are widely associated with gastrointestinal side effects, with crystal colonic injury being rare but potentially fatal. In this report, we describe the case of an 82-year-old male with hyperkalemia and calcium polystyrene sulfonate crystal-associated colonic necrosis. Traditionally, this diagnosis has relied on the examination of crystal morphology and polarization through microscopy. Our study enhances crystal identification by incorporating an analysis of the physical characteristics of the crystals using infrared spectroscopy. This is the first description, to our knowledge, of the calcium polystyrene sulfonate infrared spectrum.
- Primary Liver Lymphoma Presenting as Liver NodulesPublication . Silva, JM; Ornelas Saraiva, R; Simões, G; Araújo, C; Calinas, F; Coimbra, JThe liver is usually affected in advanced stages of lympho-proliferative diseases, but primary liver lymphomas (PLLs) are rare. The diagnosis is usually late, especially in patients without identifiable risk factors, with consequent worse prognosis. We report the case of a 59-year-old female with progressive worsening pain in the right hypochondrium and weight loss. She was previously healthy and had a family history of gastrointestinal and gynecologic neoplasms. During the initial investigation, three liver nodules suggestive of liver metastases were found. Nevertheless, no primary neoplasm was identified in a subsequent evaluation with imaging and endoscopic exams. Laboratory exams excluded hepatic infections, metabolic diseases, and acquired immunosuppression. Biopsy of the lesions revealed diffuse large B-cell lymphoma. Lymph node and medullar involvement were excluded, and the diagnosis of PLL was assumed. The patient started chemotherapy with R-CHOP. With this case, we intend to alert for this differential diagnosis of liver nodules, even in the absence of predisposing conditions for lymphoma. We point out the need to define universal diagnosis criteria for this pathology.
- Presence of Multilobular Necrosis on Liver Biopsy Identifies Corticosteroid Responsiveness in Acute Indeterminate HepatitisPublication . Lin, S; Araújo, C; Hall, A; Kumar, R; Phillips, A; Hassan, M; Engelmann, C; Quaglia, A; Jalan, RBackground and aims: Treatment of patients with severe indeterminate hepatitis (IAH) is an unmet need. Corticosteroids are often used in the management of these patients but criteria for the selection of patients for this intervention are arbitrary. The aims of this study were to analyse the clinical and pathological features of patients with IAH to define predictors of corticosteroid responsiveness. Methods: This study included consecutive patients with acute indeterminate hepatitis admitted to a single hospital and underwent a liver biopsy. The clinical manifestation and histopathological features of steroid and non-steroid groups were compared and their relationship with corticosteroids response was evaluated. Results: Forty-eight patients were included, 24 (50%) recovered and the other half underwent liver transplantation or died within 3-months. Of the 48 cases, 24 received corticosteroids (initial dose of 45 ± 12 mg prednisolone). Corticosteroids were initiated 2.7 ± 3.8 days after admission. Liver biopsy was performed 2-days (median, IQR 1-3) after admission. Fifteen (62.5%) patients receiving corticosteroids survived without transplantation compared with 9 (37.5%) that did not receive steroids (P = .149). In those with multilobular necrosis, 50% reduction in the death/transplantation rate was observed after steroid treatment (P = .018). In patients without multilobular necrosis and with or without perivenulitis, corticosteroids did not impact the outcome. Response to corticosteroids was independent of the MELD score. Conclusions: The presence of multilobular necrosis on liver biopsy helps identify a subgroup of IAH cases who may benefit from the administration of corticosteroids.
- The Modern Value of Clinical AutopsiesPublication . Marques Pontinha, C
- Hyperleukocytosis in Solid Tumors: a Rare Paraneoplastic Syndrome Associated with Poor PrognosisPublication . Ferrão, J; Sardinha, M; Dutra, EHematological paraneoplastic syndromes are fairly uncommon. While mild leukocytosis in solid tumors is well reported, white blood cell (WBC) count over 50,000 u/L, described as paraneoplastic leukemoid reaction (PLR), is not. Indeed, when found, it is usually associated with a higher burden of disease, tumor activity and worse clinical outcomes. We report the case of a challenging and burdensome diagnosis of a presumptive hematological paraneoplastic syndrome in a patient with a locally advanced lung cancer admitted in the Internal Medicine ward. After the end of chemotherapy, clinical and laboratory benefit was observed; however, the aggressive course of the disease became clear, with progression and downhill course that was unresponsive to treatment.
- Anatomical Basis, Histological Findings and Hemodinamics in the Modern Perfusion Model for Human CorpsesPublication . Júnior, E; Bettencourt-Pires, M; Alves, S; Casal, D; Pais, D; Goyri O’neill, J; Vassilenko, VsSeveral modern human cadaveric fixation methods are subject to permanent evaluation. Formaldehyde is the oldest and still the most widely used method of embalming. However, the International Agency for Research on Cancer has proven its high carcinogenic potential and its use was banned, with the recommendation of research for better alternatives in the conservation of corpses. The embalming method of excellence, which preserves all features, while keeping the disinfectant properties against cadaveric decomposition was proposed by João Goyri O’Neill. Their method was considered “the most modern and efficient technique in cadaveric preservation”. The aim of this present study was to analyze the quality of this original perfusion technique, at the organic level, based on central and peripheral hemodynamics. The cadaveric material was embalmed through a pulsed arterial perfusion system, connected to an automatic intermittent pump, that permits stability of the microvascular network, as well as the computerized measurement of the main perfusion parameters, such as flow and pressure. This procedure ensures good preservation of color, elasticity, texture, flexibility and fresh appearance, for several years. The morphological characteristics of the organs exhibited astonishing similarity to the living organic tissues, even several years after embalming and high freezing. Microscopic analysis demonstrated preservation of the structure of vessels, such as the aorta. Further studies on the integrity of the endocardial layer of the heart will enable to adapt the intermittent perfusion pump system to best simulate cardiac rhythm and arterial pulse, during cadaveric surgical training.