Triple-negative breast cancer (TNBC) is an aggressive subtype with high recurrence risk. The KEYNOTE-522 trial demonstrated improved pathological complete response (pCR) rates and survival outcomes with the addition of pembrolizumab to neoadjuvant chemotherapy. However, long-term immune-related adverse events (irAEs) remain a concern, particularly in curative settings. We report a case of a woman in her early 40s with node-positive TNBC who achieved a pCR following neoadjuvant chemoimmunotherapy. After completing adjuvant pembrolizumab, she developed acquired lipodystrophy, an under-recognised irAE, manifesting as progressive subcutaneous fat loss, dyslipidaemia, and hepatic steatosis. Histology demonstrated adipocyte necrosis with lymphohistiocytic infiltration. Corticosteroids stabilised progression but did not reverse changes. This case highlights the need for long-term surveillance of irAEs and raises important questions about immunotherapy de-escalation in patients achieving pCR, against a rapidly evolving systemic treatment landscape for TNBC.

Lipodystrophy is a rare group of metabolic disorders characterized by the abnormal distribution of body fat, which can lead to various metabolic complications due to the body's inability to adequately process carbohydrates and fat. We report the case of a female, aged 53 years, who was admitted as an outpatient for progressive weight loss of the upper part of the body (face, neck, arms, and chest), dyspeptic complaints, fatigue, mild insomnia, and anxious behavior. Her medical history was characterized by the presence of dyslipidemia, hypertension, and a minor stroke episode. However, she denied any family-relevant medical history. Although the clinical perspective suggested a possible late onset of partial acquired lipodystrophy, due to the imaging exam that revealed an enlarged liver with inhomogeneous structure with multiple nodular lesions, scattered over both lobes, a lot of lab work-ups and complementary studies were performed. Eventually, a liver biopsy was performed by a laparoscopic approach during cholecystectomy, the histology consistent with metabolic disease-associated steatohepatitis (MASH). In conclusion, given their heterogeneity and rarity, lipodystrophies may be either overlooked or misdiagnosed for other entities. Barraquer-Simons syndrome (BSS) may be associated with liver disease, including cirrhosis and liver failure. Liver lipodystrophy in BSS may sometimes feature steatosis with a focal, multi-nodular aspect, multiplying the diagnostic burden. Liver lipodystrophy may manifest as asymptomatic fat accumulation but may progress to severe conditions, representing one of the major causes of mortality in BSS, apart from the cardio-vascular comorbidities. Given the potential of severe outcomes, it is mandatory to correctly assess the stage of liver disease since the first diagnosis.

Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is a salient feature of skin fibrosis, and is followed by accumulation of extracellular matrix (ECM). Lipodystrophy syndromes, often associated with metabolic co-morbidities, are estimated to affect 1 in 20,000 people. We recently showed that fibrosis-associated lipodystrophy is dependent on sustained Wnt signaling, but the mechanism is unclear. Transcriptomic profiling of mature dermal adipocytes in vivo reveal that Wnt activation downregulates the de novo -lipogenesis (DNL) axis enzymes within 48 hours. We found that protein expression of Fatty Acid Synthase (FASN), a key DNL enzyme, is dependent on sustained Wnt activation in vitro and in vivo . In human systemic sclerosis, FASN mRNA is significantly downregulated during two years of disease. Remarkably, pharmacological inhibition of FASN enzyme during reversal from Wnt induced fibrosis impedes recovery of DWAT lipid content as well as ECM accumulation and topography. All together, we demonstrate that acquired lipodystrophy in the context of skin fibrosis is mediated by a new role of the Wnt-DNL axis. These findings underscore the importance of this pathway in lipodystrophy and fibrosis, opening new avenues for therapeutic targets in skin fibrosis.

This review aims to introduce the latest developments in etiology and classification of lipodystrophy syndromes. Recent developments in genetic assessment with deeper sequencing have increased the number of specific etiologies of lipodystrophy with known single-gene associations. Despite this, more than 50% of patients diagnosed with partial and most of acquired lipodystrophy do not have a precise disease mechanism. Regardless of the cause of lipodystrophy, patients present with multiple important comorbidities. Complications impact not only metabolic endpoints but the entire body, akin to what happens in extreme obesity. As research advances, new subtypes of lipodystrophy are being identified, with recent studies shifting focus from adipocyte differentiation to the role of cellular structures, survival pathways, and immune regulation in the disease etiology. These metabolic diseases pose significant clinical challenges, underscoring the need for further research to understand the mechanisms more precisely, identify new subtypes, and develop targeted therapies.

Insulin glargine is a long-acting drug and the first synthetic insulin to mimic human metabolism. The safety of insulin glargine in the real world remains to be further investigated. This study aims to analyze insulin glargine-related adverse events (ADEs) to guide its safe clinical use. This study collected ADE reports from the FDA Adverse Event Reporting System (FAERS) between the first quarter of 2004 and the third quarter of 2024, where insulin glargine was identified as the primary suspect drug. Four disproportionate analytical methods were employed to analyze positive signals for drug-related ADEs, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). The study also describes the time to onset of ADEs and uses the Weibull distribution to analyze the temporal trend of ADEs occurrence over time. This study included 97,350 ADE reports, containing 228,258 ADEs, and identified 130 ADEs with positive signal. The study confirmed several known ADEs, such as hypoglycemia, injection site pain and acquired lipodystrophy. Additionally, several unexpected ADEs were identified, including pancreatic neoplasm, medullary thyroid cancer, and bone marrow tumor cell infiltration. 28.13% of ADEs occurred within the first month. The Weibull distribution indicated that the occurrence of ADEs decreased over time. This study explored the real-world safety of insulin glargine and revealed several unexpected ADEs. These findings provide new insights into the safety profile of insulin glargine for clinicians."