Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline alterations in mismatch repair (MMR) genes leading to increased risk of colon cancer as well as other cancer types. Non-small cell lung cancer (NSCLC) is not among typical Lynch syndrome-associated tumors: pembrolizumab, an immune checkpoint inhibitor, is actually approved for the treatment of NSCLC patients and represents a promising treatment option for patients with advanced metastatic MMR-deficient cancer, regardless of tumor origin. This case report describes the clinical presentation and management of a 74-year-old female with a history of rectal adenocarcinoma and ovarian cancer, who has a documented frameshift pathogenic variant in the exon 8 of MSH6 gene and an intronic variant in the BRCA2 gene (classified as a variant of uncertain significance), affected by NSCLC with brain metastases. Despite these premises, the patient was treated with pembrolizumab and she did not benefit from this kind of treatment.

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Systemic inflammatory rheumatic disorders are associated with an increased risk of malignancy. The mechanism linking malignancy and rheumatic diseases is complex and multidirectional, and is only partially understood. This review focused on the incidence of neoplastic diseases in patients with the most common systemic rheumatic disorders. Rheumatoid arthritis is associated with a risk of malignancy that is about 10% higher than in the general population, and this is more related to the disease itself than to medication. Systemic lupus erythematosus is associated with an increased risk of neoplasms, particularly haematological malignancies such as non-Hodgkin lymphoma. The risk increases with long-lasting active disease. Systemic sclerosis is associated with an increased risk of lung and liver cancer, as well as malignancies of the haematological system. Men and patients with RNA polymerase III antibodies are at a higher risk. Dermatomyositis and polymyositis are subgroups of idiopathic inflammatory myopathy associated with a high risk of malignancy. Male gender and old age are additional risk factors. Other rheumatic diseases are also thought to be associated with an increased risk of cancer. Currently, the data are insufficient for a clear distinction to be made between subgroups at risk. Most patients with systemic autoimmune disorders are at enhanced risk of malignancy to some degree. The management of these patients should include procedures for the early detection of age- and population-specific malignancies, as well as those which are more prevalent in the patient population suffering from the individual rheumatic disease. It is important to note that an atypical disease course or increased treatment resistance for a rheumatic disorder may indicate that the observed changes are an expression of a paraneoplastic syndrome or that a new neoplasm is modifying the clinical course of an already diagnosed rheumatic disease.

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Primary biliary cholangitis (PBC) is an autoimmune cholangiopathy that affects mainly women and, if untreated, can evolve into biliary cirrhosis. Its prevalence varies worldwide, depending on race, and accounts for 22.27 cases/100,000 habitants in Europe. To establish the diagnosis of PBC according to the European Association for the Study of the Liver (EASL) guidelines, two criteria must be satisfied among alkaline phosphatase (ALP) alterations, autoantibody positivity, and histologic abnormalities. Early treatment is effective in prolonging survival. Current guidelines do not suggest hepatic biopsy in patients with autoantibody positivity without cholestasis alterations. However, many patients with these characteristics have been diagnosed with PBC disease only histologically, mainly patients with normal ALP and elevated gamma-glutamyl transferase (GGT), whose normalization has been used as a marker for the follow-up. In contrast, this is the case of a patient with autoantibody positivity and both ALP and GGT within the range, diagnosed for PBC by histology. The manuscript wants to propose the re-evaluation of the role of liver biopsy in PBC diagnosis and the need for a serological or histological biomarker in the follow-up of patients without cholestatic alterations.

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Steatotic liver disease (SLD) has been known for a long time, but our understanding of this disease has remained poor until the past decade. Despite extensive research, our ability to comprehend the etiopathogenesis and natural course of SLD is far from the desired level of comprehension. This is required to develop a universally effective novel therapeutic agent. This review aims to concisely elaborate the conceptual approach and advancement in the understanding of global disease burden and etiopathogenic process, identifying the gaps and the pathophysiologic mechanism behind developing novel therapeutic agents. We searched two major databases, PubMed and Google Scholar, to identify publications related to the abovementioned topics. All publications, including original papers, reviews, and commentaries, were reviewed. Findings: Metabolic dysfunction-associated steatotic liver disease (MASLD) is not limited to obese individuals, rather, it may develop in any individual independent of weight. Visceral adiposity is strongly associated with MASLD and subsequent risks of cirrhosis, hepatocellular carcinoma, and cardiovascular disease. MASLD is associated with diabetes mellitus independent of underlying pathogenic mechanisms, and there is a bidirectional connection between MASLD and diabetes mellitus, making the situation quite challenging. Not all patients with MASLD exhibit atherogenic dyslipidemia and thus do not have a higher risk of cardiovascular disease. The overlap of these metabolic risk factors is not straightforward. There is a differential contribution of these risk factors based on age, gender, race, ethnicity, alcohol consumption, and microbiota composition. Poor dietary habits and lifestyle directly affect the microbiota, modulators, and mediators, thereby affecting the final biochemical processes leading to steatosis, steatohepatitis, fibrosis, and oncogenesis. In conclusion, MASLD is a complex and pathogenically heterogeneous disease with significant interpatient variation in the natural course and outcome. Understanding the precise mechanism of variability is the key gap and a limiting factor in the development of a novel therapeutic agent.

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder affecting motor neurons. The complex etiopathogenetic mechanism of ALS can lead to extensive alterations, including cortical changes, neuroinflammation, and changes in muscular structure. These ALS-derived alterations may contribute to fatigue, a symptom severely impacting patients’ quality of life that is commonly associated with muscular exercise. Intriguingly, muscular exercise can be at once a promoter of motor neuron degeneration in predisposed patients as well as an effective non-pharmacological treatment of ALS. To fully disclose its therapeutic potential, muscular exercise must be tailored to patients’ phenotypes, balancing potential benefits and risks that are unique to each ALS case. Biomarkers of muscular fatigue, with their potential for insight into inflammation and oxidation, can be used to ensure that the intensity of physical activity remains below the threshold level beyond which exercise might become harmful. In this review, the authors explore the concept of fatigue in ALS patients, focusing on fatigue generation, definition, detection, quantification, and treatment. The study discusses the most important fatigue biomarkers, putting them in relation to the mechanism of fatigue generation and with monitoring of muscular exercise as a possible treatment of fatigue.

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Histone deacetylases (HDACs) are a class of zinc (Zn)-dependent metalloenzymes that are responsible for epigenetic modifications. HDACs are largely associated with histone proteins that regulate gene expression at the DNA level. This tight regulation is controlled by acetylation [via histone acetyl transferases (HATs)] and deacetylation (via HDACs) of histone and non-histone proteins that alter the coiling state of DNA, thus impacting gene expression as a downstream effect. For the last two decades, HDACs have been studied extensively and indicated in a range of diseases where HDAC dysregulation has been strongly correlated with disease emergence and progression—most prominently, cancer, neurodegenerative diseases, HIV, and inflammatory diseases. The involvement of HDACs as regulators in these biochemical pathways established them as an attractive therapeutic target. This review summarizes the drug development efforts exerted to create HDAC inhibitors (HDACis), specifically class I HDACs, with a focus on the medicinal chemistry, structural design, and pharmacology aspects of these inhibitors.

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Catatonia is a neuropsychiatric syndrome characterized by a broad range of motor, behavioral and cognitive abnormalities. Catatonia and Parkinson’s disease (PD) may show partially overlapping symptomatology. For this reason, catatonia could be misdiagnosed and overlooked in patients with severe PD, leading to a delay in proper treatment with benzodiazepines or electroconvulsive therapy (ECT). Two cases of women with PD and catatonia who have been admitted and treated with ECT at the University Hospital of Pisa are described here. Both had a history of bipolar disorder and developed withdrawn catatonia, in the context of affective episodes, approximately one year after the diagnosis of PD. In both cases, ECT was needed and successfully led to the remission of catatonic symptoms, without cognitive worsening. Since ECT appears to effectively treat catatonia in patients with PD, clinicians should consider it as a therapeutic option.

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Mitochondria are present in all mammalian cells except matured red blood cells. Mitochondria consist of several metabolic pathways for glucose, fatty acids, amino acids, and bioenergetic pathways for ATP synthesis, membrane potential, and reactive oxygen production. In the liver, hepatic mitochondria play a key role in hepatic steatosis because mitochondrial metabolism produces acetyl-CoA which is the building block for synthesis of lipids and cholesterol. Mitochondria inner membrane is impermeable of metabolites, reducing equivalents, and small molecules such as phosphate, and sulfate. Thus, mitochondrial shuttles and carriers function as the routes of influx and efflux of these metabolites and molecules across the inner membrane. The signal regulation of these shuttles and mitochondrial enzymes could play a key role in coordinating the mitochondrial metabolism to adapt the cytosolic part of metabolic pathways in liver metabolic stress. Intriguingly, the interaction of mitochondria protein SH3 domain-binding protein 5 (SAB/SH3BP5) and c-Jun N-terminal kinase (JNK) was found as a pivotal role in sustained activation of JNK and phosphorylated-JNK (P-JNK) mediated activation of lipogenic pathway in nutritional excess. Knockout or knockdown of SAB prevented or reversed the hepatic steatosis, inflammation, and fibrosis, and improved metabolic intolerance and energy expenditure. Moreover, blocking the SAB peptide prevents palmitic acid-induced P-JNK interaction with SAB and inhibition of mitochondrial bioenergetics, implying the P-JNK effect on mitochondrial metabolism. This review focuses on the flow of mitochondrial metabolites in metabolic stress conditions and the contribution of mitochondria and mitochondrial stress signals in hepatic steatosis.

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging and rapidly growing health problem that currently affects more than one-third of the world general population and more than two-thirds of patients with obesity or type 2 diabetes. MASLD is associated with one or more cardio-metabolic risk factors (CMRFs) that determine the complexity of its natural history and management. Although the term MASLD encompasses a single disease, each CMRF has a different impact on MASLD, and the number of overlapping CMRFs results in a different rate of progression and outcomes of both liver and systemic disease. Its pathogenesis is characterized by insulin resistance, lipotoxicity and a complex cross-talk between liver, adipose tissue, muscle, intestine through the release of hepatokines, cytokines, myokines and inflammatory products. The stage of liver fibrosis is the best predictor of liver outcomes, such as liver failure and mortality, and also predicts the high risk of all-cause mortality associated with the disease. In many cases, the development of hepatocellular carcinoma (HCC) is associated with advanced fibrosis or cirrhosis, although it can occur at all stages of the disease, making prevention difficult. MASLD is characterized by increasing very low-density lipoprotein (VLDL) secretion and chronic low-grade systemic inflammation, which increase the risk of cardio-vascular, renal, and endocrine diseases and extrahepatic cancer. Thus, the management of MASLD requires a holistic approach and treatment of CMRFs through multispecialty collaboration. Currently, diet and physical activity are the effective first-line approaches. There are no approved drugs for the treatment of MASLD, apart from resmetirom, which in a percentage of cases improves metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. We summarize the wide and varied recent literature on the complex etiopathogenetic, clinical and therapeutic aspects of MASLD, connecting and interpreting it to facilitate clinical and management approaches.

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Nonalcoholic fatty liver disease (NAFLD) is a serious condition that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is associated with metabolic syndrome (MetS) and all of its components. According to data, around 25–30% of population has NAFLD. Giving the growing incidence of MetS, obesity and diabetes mellitus type 2, NAFLD related terminal-stage liver disease is becoming prevailing indication for liver transplantation. In order to prevent terminal stage of this disease, it is crucial to determine those that are in risk group, to modify their risk factors and monitor their potential progression. In the absence of other causes of chronic liver disease, the prime diagnosis of NAFLD in daily clinical practice includes anamnesis, laboratory results (increased levels of aminotransferases and gammaglutamil transferases) and imaging methods. The biggest challenge with NAFLD patients is to differentiate simple steatosis from nonalcoholic steatohepatitis, and detection of fibrosis, that is the main driver in NAFLD progression. The gold standard for NAFLD diagnosis still remains the liver biopsy (LB). However, in recent years many noninvasive methods were invented, such as transient elastography (TE). TE (FibroScan®, Echosens, Paris, France) is used for diagnosis of pathological differences of liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). Investigations in the last years have confirmed that elastographic parameters of steatsis (CAP) and fibrosis (LSM) are reliable biomarkers to non-invasively assess liver steatosis and fibrosis respectively in NAFLD patients. A quick, straightforward and non-invasive method for NAFLD screening in patients with MetS components is TE-CAP. Once diagnosed, the next step is to determine the presence of fibrosis by LSM which should point out high risk patients. Those patients should be referred to hepatologists. LB may be avoided in a substantial number of patients if TE with CAP is used for screening.

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Diffuse idiopathic skeletal hyperostosis (DISH) and axial spondyloarthritis (axSpA) are diseases with inflammatory involvement of the axial skeleton that can result in new bone formation that may lead to total ankylosis of the spine and functional impairment of different extent in individual patients. In these diseases, the new bone formation may lead to total ankylosis of the spine and impaired mobility with functional impairment. This review will highlight the similarities and differences of these two conditions. In axSpA, the genetic background with the association with human leukocyte antigen-B27 (HLA-B27) is known for 50 years, while in DISH, a genetic contribution is not yet proven. The phenotype of new bone formation and its anatomic features are different between these diseases. In axSpA symmetric, thin and marginal syndesmophytes representing an ossification of enthesitic inflammation at the area of the attachment of the annulus fibrosus that may extend to the adjacent deeper layers anterior longitudinal ligament and are typical, while in DISH the so-called “chunky bridging osteophytes” grow as an additional layer on the anterior longitudinal ligament. Besides distinct anamnestic and clinical features, magnetic resonance imaging is helpful differentiating the two diseases since inflammatory changes with the typical pattern of axSpA are reliably visualized. Similar in both diseases is the high prevalence of vertebral fractures, which are mainly caused by the local osteoporosis and decreased flexibility of the affected bones, and therefore may occur even after minor traumata. The presence of extraarticular manifestations like uveitis, inflammatory bowel disease or psoriasis are only linked to axSpA. In contrast, DISH is associated with obesity, diabetes mellitus, and other metabolic diseases. Although DISH and axSpA are distinct conditions, the cooccurrence of these two diseases exists in some patients. Various therapeutic options are becoming available for axSpA, but no therapy has been approved for DISH yet.

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