Risultati per: Carcinoma cutaneo a cellule squamose

Objective
Squalene epoxidase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in modulating the tumour immune microenvironment in MASH-HCC remains unclear.

Design
We established hepatocyte-specific Sqle transgenic (tg) and knockout mice, which were subjected to a choline-deficient high-fat diet plus diethylnitrosamine to induce MASH-HCC. SQLE function was also determined in orthotopic and humanised mice. Immune landscape alterations of MASH-HCC mediated by SQLE were profiled by single-cell RNA sequencing and flow cytometry.

Results
Hepatocyte-specific Sqle tg mice exhibited a marked increase in MASH-HCC burden compared with wild-type littermates, together with decreased tumour-infiltrating functional IFN-+ and Granzyme B+ CD8+ T cells while enriching Arg-1+ myeloid-derived suppressor cells (MDSCs). Conversely, hepatocyte-specific Sqle knockout suppressed tumour growth with increased cytotoxic CD8+ T cells and reduced Arg-1+ MDSCs, inferring that SQLE promotes immunosuppression in MASH-HCC. Mechanistically, SQLE-driven cholesterol accumulation in tumour microenvironment underlies its effect on CD8+ T cells and MDSCs. SQLE and its metabolite, cholesterol, impaired CD8+ T cell activity by inducing mitochondrial dysfunction. Cholesterol depletion in vitro abolished the effect of SQLE-overexpressing MASH-HCC cell supernatant on CD8+ T cell suppression and MDSC activation, whereas cholesterol supplementation had contrasting functions on CD8+ T cells and MDSCs treated with SQLE-knockout supernatant. Targeting SQLE with genetic ablation or pharmacological inhibitor, terbinafine, rescued the efficacy of anti-PD-1 treatment in MASH-HCC models.

Conclusion
SQLE induces an impaired antitumour response in MASH-HCC via attenuating CD8+ T cell function and augmenting immunosuppressive MDSCs. SQLE is a promising target in boosting anti-PD-1 immunotherapy for MASH-HCC.

Circulation, Volume 150, Issue Suppl_1, Page A4144779-A4144779, November 12, 2024. Case Presentation:A 76-year-old male, non-smoker, with history of HLD and NIDDM, presented with several weeks of dyspnea and cough, unresponsive to outpatient treatments. He was normotensive and found to have new onset atrial fibrillation at a rate of 110bpm and pulsus paradoxus with a difference of 15mmHg. CT chest showed a 2.2cm thyroid nodule along with a pericardial effusion (PE), confirmed to be tamponade on TTE (Fig.1). A TTE showed resolution of tamponade after the pericardial window (Fig.2). Pericardial fluid cytology was positive for malignant cells. Patient was discharged, had an outpatient PET CT which showed uptake in the thyroid, pericardial region&right supraclavicular lymph node (LN). The patient developed symptoms of heart failure, prompting his 2nd visit to the hospital after 3 weeks. A repeat TTE showed a small PE with effusive-constrictive physiology (Fig.3). He was started on high dose steroids and diuresed as tolerated, but his symptoms did not improve. He underwent thyroid nodule and right supraclavicular LN biopsy, which revealed high grade follicular thyroid carcinoma (FTC). His course was complicated by multiorgan failure, prompting transfer to another facility for pericardiectomy; during which he was found to have extensive tumor infiltration into the myocardium; he then went into shock and passed away shortly after.Discussion:Effusive-constrictive pericarditis (ECP) is a rare clinical condition characterized by PE with constrictive physiology1. Hancock defined ECP as a pathophysiological form of cardiac compression due to a constricted visceral pericardium and PE, with the hallmark sign of persistently elevated right atrial pressure despite removal of pericardial fluid2. ECP can rarely be caused by malignancies, attributing 5% of cases2. FTC is a well-differentiated thyroid malignancy that typically metastasizes to distant sites such as the lungs and bones, but pericardial involvement is extremely rare. To date, there has been one reported case of PE caused by FTC, but the PE did not reaccumulate, possibly due to early recognition and radiation therapy3. To our best knowledge, this case report represents the first documented case of ECP caused by FTC. Our case demonstrates the complexity of diagnosing/managing it, which underscores the need for a multidisciplinary approach and comprehensive diagnostic evaluation in patients with PE, especially when associated with malignancies that rarely metastasize to the pericardium.

Circulation, Volume 150, Issue Suppl_1, Page A4146814-A4146814, November 12, 2024. Background:The Fontan operation has been an effective treatment plan for patients with single ventricle anomalies, greatly improving survival into adulthood. Yet, Fontan patients are at increased risk of numerous cardiac and noncardiac complications, and premature mortality.Methods:A cohort of 735 patients with a prior Fontan surgery (median age 7.6yrs at first encounter, 57.4% male, 41.0% Black), with at least one healthcare encounter from a pediatric or adult healthcare system between 2010-2019, was linked to encounter data and death certificates. Heart failure (HF) was defined by ICD-9-CM and ICD-10-CM codes determined by clinicians. The primary composite outcome included heart transplant, hepatocellular carcinoma (HCC) and death. Hospitalizations were defined as an inpatient encounter spanning at least two consecutive days. Time to event was anchored at initial encounter.Results:Characteristics of those with and without HF are seen in Table 1. Median age was 17.1yrs [3.0-70.5] and 5.5yrs [3.0-56.0] for those with and without HF, respectively. The composite outcome occurred in 85 Fontan patients (11.6%) at median 3.26yrs after initial encounter. Of those with HF, 12.5% experienced a heart transplant compared to 0.9% without HF (p

Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis.

Objective
To evaluate the cost-effectiveness of risk-stratified hepatocellular carcinoma (HCC) screening in diabetic patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Design
A state-transition model from a healthcare payer perspective on a lifetime horizon.

Setting
Japan.

Population
A hypothetical cohort of 50-year-old diabetic patients with MASLD risk-stratified according to degree of obesity and progression to cirrhosis. Metabolic dysfunction-associated steatotic liver (MASL), metabolic dysfunction-associated steatohepatitis (MASH) and MASH cirrhosis are progressive manifestations of this specific type of liver disease.

Intervention
Abdominal ultrasound (US), US with alpha-fetoprotein (AFP), US with AFP and lectin-reactive alpha-fetoprotein (AFP-L3), CT, extracellular contrast-media-enhanced MRI (ECCM-MRI), gadoxetic acid-enhanced MRI (EOB-MRI) and no screening.

Main outcome measure
Costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), early-stage HCC cases, advanced-stage HCC cases and HCC-related deaths.

Results
EOB-MRI is the most cost-effective screening method for non-obese diabetic patients with MASH cirrhosis and for obese diabetic patients with MASH and MASH cirrhosis. Cost-effectiveness was sensitive to HCC incidence in non-obese diabetic patients with MASH cirrhosis and obese diabetic patients with MASH, and the adherence rate of HCC screening in obese diabetic patients with MASH. When the semiannual HCC incidence was between 0.008 and 0.0138 in non-obese diabetic patients with MASH cirrhosis, US with AFP was more cost-effective than EOB-MRI. Cost-effectiveness acceptability curves showed that EOB-MRI was 50.7%, 96.0% and 99.9% cost-effective in obese diabetic patients with MASH and non-obese diabetic patients with MASH cirrhosis, and obese diabetic patients with MASH cirrhosis at a willingness-to-pay level of $50 000 per QALY gained. Compared with no screening in 100 000 non-obese diabetic patients with MASH cirrhosis and obese diabetic patients with MASH cirrhosis, EOB-MRI reduced total costs by US$69 million and by US$142 million, increased lifetime effectiveness by 12 546 QALYs and by 15 815 QALYs, detected 17 873 and 21 014 early-stage HCC cases, and averted 2068 and 2471 HCC-related deaths, respectively.

Conclusions
Of all HCC screening methods for diabetic patients with MASH cirrhosis, EOB-MRI yields the greatest cost-saving with the highest QALYs, detects the greatest number of early-stage HCC cases and averts the greatest number of advanced-stage HCC cases and HCC-related deaths. The findings provide important insights for the precise implementation of risk-stratified HCC surveillance to reduce morbidity and mortality and improve the quality of life in diabetic patients with MASLD.

La ricerca degli atenei Tor Vergata e Ucla apre la strada ad ampie applicazioni in medicina e biotecnologia

La scoperta apre a terapie più mirate

Objective
Circulating tumour DNA (ctDNA) is a promising non-invasive biomarker in cancer. We aim to assess the dynamic of ctDNA in patients with hepatocellular carcinoma (HCC).

Design
We analysed 772 plasmas from 173 patients with HCC collected at the time of diagnosis or treatment (n=502), 24 hours after locoregional treatment (n=154) and during follow-up (n=116). For controls, 56 plasmas from patients with chronic liver disease without HCC were analysed. All samples were analysed for cell free DNA (cfDNA) concentration, and for mutations in TERT promoter, CTNNB1, TP53, PIK3CA and NFE2L2 by sequencing and droplet-based digital PCR. Results were compared with 232 corresponding tumour samples.

Results
In patients with active HCC, 40.2% of the ctDNA was mutated vs 14.6% in patients with inactive HCC and 1.8% in controls (p

We read with great interest the recent article by Choi et al.1 By analysing the data of a multicentre historical cohort including 4693 adult patients with chronic hepatitis B (CHB), they concluded that patients with moderate baseline viral loads, particularly around 6 log10 IU/mL, demonstrated the highest on-treatment hepatocellular carcinoma (HCC) risk. Because this conclusion is interesting and different from the findings of some previous studies,2 3 which may affect the timing of treatment initiation for many patients with CHB, findings of this study should be cautiously viewed. Here, we highlight some points that need further discussion. First, the authors investigated the association between on-treatment HCC risk and various baseline characteristics. However, some indicators (recently emerging biomarkers: quantified hepatitis B surface antigen (HBsAg)4 5; common clinical characteristics: serum albumin,2 diabetes mellitus,6 family history of HCC,

Condotto dall’Enea. Biomolecole ne inibiscono la proliferazione