Bulky Isolated Adrenal Metastasis as First Presentation of Occult Hepatocellular Carcinoma (HCC) in a Patient with a Synchronous Squamous Carcinoma of the Tongue.

BACKGROUND: The diagnostic workup of an adrenal mass should always rule out the possibility of an adrenal metastasis, especially in a patient followed-up for a known primitive cancer. Sometimes, however, the incidental finding of a bulky lesion in a cancer patient can lead to the unexpected diagnosis of metastasis from a second occult cancer. Here, we report the case of a voluminous, isolated left adrenal metastasis from unknown and persistently occult hepatocellular carcinoma (HCC), incidentally found during the follow-up for squamous carcinoma of the tongue. CASE DESCRIPTION: A 72-year-old HBV/HCV-negative male patient with a history of alcohol abuse was referred to our hospital for gastric bleeding. Some weeks before, the patient was operated on for a locally advanced squamous cell carcinoma of the tongue, which required cervical lymph node neck dissection, temporary tracheostomy, jejunostomy, and plastic reconstruction. Subsequent diagnostic imaging revealed a left adrenal mass sized 9x15 cm with suspicious features. The hormonal workout was negative for pheochromocytoma and a hyperfunctioning adrenal lesion. The patient underwent laparotomic left adrenalectomy. The exploration of the liver was compatible with alcoholic cirrhosis and did not reveal any other palpable lesion. The adrenal mass histologically turned out to be a poorly differentiated G3 HCC. Subsequent radiological exams were unable to identify the primary liver lesion or any other neoplasms. Conversely, α-FP levels were initially high but reduced after treatment with sorafenib. After 2 years of follow-up, the patient is alive and well, albeit with evidence of locoregional inter-aortocaval lymphadenopathy. The primary HCC has never been identified, thus suggesting the hypothesis of a diffuse cirrhosis-like HCC. CONCLUSION: The suspicion of an adrenal metastasis in a patient with primary cancer with a low potential for adrenal metastatic spreading must raise the diagnostic suspect for another synchronous occult cancer beyond that for primary adrenal cancer. HCC can rarely first manifest as a metastatic adrenal lesion.

COVID19 infection and vaccination and the risk of pituitary apoplexy: an entangled yarn.

PURPOSE: Pituitary apoplexy (PA) has been increasingly reported in association with both infection from and vaccination for COVID19. Our aim was to analyse the available published cases and compare the clinical characteristics in the two groups (infection vs vaccination). METHODS: We systematically reviewed the published literature for all cases of PA associated with COVID19 infection or vaccination. We also presented two cases managed at our Centre. RESULTS: Collectively, fortythree cases were analysed. Patients with PA after COVID19 vaccination (n = 7), compared with patients with PA after COVID19 infection (n = 36), were significantly younger (p = 0.009) and had a more abrupt onset of PA (p = 0.022), but showed a milder hormonal involvement (p = 0.008) and a lower rate of persistent hypopituitarism during follow-up (p = 0.001). Patients in the vaccination group did not have clinical risk factors for PA, although this difference did not reach statistical significance. CONCLUSIONS: PA associated with COVID19 is a rare but clinically significant entity, although pathophysiological details of this association are lacking. Given the significantly different clinical presentation, we could speculate that PA induced by COVID19 vaccination might represent a distinct clinical entity, with different pathophysiological mechanism, compared to PA from COVID19 infection.

CASCADES, a novel SOX2 super-enhancer-associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults, with a median survival of just over 1 year. The failure of available treatments to achieve remission in patients with glioblastoma (GBM) has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence. In fact, the property of "stemness" itself may be responsible for treatment resistance. In this study, we identify a novel long noncoding RNA (lncRNA), cancer stem cell-associated distal enhancer of SOX2 (CASCADES), that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in isocitrate dehydrogenase (IDH)-wild-type GBM and is significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell- and cancer-specific manner. Bioinformatics analysis reveals that CASCADES functions as a super-enhancer-associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs that represents a novel epigenetic and therapeutic target for disrupting the CSC compartment in glioblastoma.

On the"Staple" Effect in the d-Glucose Acetylation by Choline-Chloride Ethylene Glycol and Choline-Chloride Urea Deep Eutectic Solvents.

This work employs hybrid quantum mechanics molecular mechanics simulations coupled with an umbrella sampling technique to investigate the acetylation of d-glucose with acetic anhydride in two deep eutectic solvents (DESs): choline-chloride ethylene glycol (ChCl/Etg) and choline-chloride urea (ChCl/U). The reaction proceeds spontaneously, with activation free energy barriers of 18.19 ± 0.15 and 19.83 ± 0.15 kcal/mol for ChCl/Etg and ChCl/U, respectively. These values align with literature data for similar reactions in ionic liquids, highlighting the potential of DESs as green reaction media for wood modifications, while minimizing lignocellulosic matrix degradation. Energy pair distribution analysis, radial distribution functions, and noncovalent interactions reveal a more solvated transition state compared to the initial reactant state within ChCl/Etg, facilitating the acetylation reaction. Interestingly, combined distribution function analysis unveils a "staple" effect in both solvents, potentially hindering efficient product separation. The work further explores hydrogen bond networks and Kamlet-Taft solvatochromic parameters to elucidate the role of solvents in the reaction mechanism. It was observed that a notable decrease in activation energy is accompanied by increasing net basicity, along with a reduction in the "staple" effect. This suggests that solvent parameters could serve as an effective screening tool for identifying novel and efficient DESs for wood modifications.

Expanded Hemodialysis Enhancement in Middle Molecule Clearance for Patients With Low Blood Flow Rates of Tunneled Dialysis Catheters.

INTRODUCTION: Expanded hemodialysis (HDx), being based on medium cut-off (MCO) membranes, improves the removal of medium molecule uremic toxins. HDx efficacy has been proven with blood flow rates (Qb) of 350-400 ml/min, while low Qb have only been assessed in single sessions. We evaluated the effectiveness of HDx in patients with tunneled central venous catheters (CVCs) and low Qb over six months, comparing it with high-flux hemodialysis (HF-HD). METHODS: The study included 10 patients with a mean age of 79±12 years and mean Qb of 237 ± 12 ml/min. Reduction ratios (RRs) and predialysis serum levels were measured for ß2-microglobulin (B2M), free κ and λ light chains (FLC), prolactin (PRL), interleukin-6 (IL-6), albumin, and urea after HF-HD and at one, three, and six months of HDx. Erythropoiesis-stimulating agent (ESA) resistance index (ERI) was also evaluated. RESULTS: B2M, κ-FLC, λ-FLC, and PRL RRs were significantly higher with HDx. IL-6, albumin, and urea RRs did not show a statistical difference between the two treatments. Predialysis B2M concentrations were significantly lower after three and six months of HDx, matching up to increased B2M clearance (spKt/V). A decrease in albumin concentrations was observed, with median levels significantly reduced at months seven and eight (35.3 and 35.5 g/L, respectively) but recovering afterwards. ERI was significantly lower during HDx, reaching a 30% reduction at month six. CONCLUSIONS: HDx was feasible, safe, and superior to HF-HD in patients with low Qb rates of tunneled dialysis catheters. The present data expand options for HDx prescription, with particular regard for patients who cannot achieve high convective volumes due to inadequate vascular access.

TULIPs decorate the three-dimensional genome of PFA ependymoma.

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in the 3D nuclear space with surprising strength. TULIPs occur in all PFA samples and recur at predictable genomic coordinates, and their formation is induced by expression of EZHIP. The universality of TULIPs across PFA samples suggests a conservation of molecular principles that could be exploited therapeutically.

Diabetes and Cancer: The Perfect Storm and a PRICE to Pay.

Diabetes, obesity, cardiovascular diseases, and cancer are noncommunicable diseases representing the main global health challenges of the current century [...].

Endocrine-metabolic assessment checklist for cancer patients treated with immunotherapy: A proposal by the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE) and Italian Society of Pharmacology (SIF) multidisciplinary group.

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy.

SARS-Cov-2 Infection: A New Risk Factor for Pituitary Apoplexy?

BACKGROUND: Pituitary apoplexy (PA) can arise from haemorrhage or ischaemia of pituitary tissue and is characterized by abrupt onset of headache, visual impairment and hypopituitarism. COVID-19 may be associated with various degrees of vascular complications and, recently, its relationship with PA has been suggested. Cases Presentation Case 1: A 64-year-old male with type 2 diabetes, hypertension and coronary heart disease was admitted to the ER, after several days of asymptomatic COVID-19 infection, with symptoms of PA of a known non-functioning pituitary macroadenoma. The hormonal panel was consistent with anterior panhypopituitarism and the sellar MRI showed haemorrhagic changes of macroadenoma tissue. Transsphenoidal resection of the pituitary lesion was carried out seven days after admission. Although a volumetric reduction of the lesion was apparent during follow-up, some degree of visual symptoms endured. Case 2: An 18-year-old, otherwise healthy, female presented to the ER with symptoms of PA of a recently-diagnosed non-functioning pituitary macroadenoma, after ten days of asymptomatic COVID-19 infection. Central hypocortisolism and hypothyroidism were diagnosed and, after six days, the lesion was surgically resected. At two months follow-up, clinical symptoms had completely resolved, and the hormonal panel was normal. CONCLUSION: Alongside known risk factors (hypertension, anticoagulation, pregnancy, surgery, etc.), COVID-19 infection might represent an emerging predisposing factor for PA onset. The two cases hereby presented are both significant: the first confirms the role of "classic" vascular predisposing factors for PA, while the second demonstrates that PA might arise also in young patients without known risk factors.

Cancer stem cell hypothesis 2.0 in glioblastoma: Where are we now and where are we going?

Over the past 2 decades, the cancer stem cell (CSC) hypothesis has provided insight into many malignant tumors, including glioblastoma (GBM). Cancer stem cells have been identified in patient-derived tumors and in some mouse models, allowing for a deeper understanding of cellular and molecular mechanisms underlying GBM growth and therapeutic resistance. The CSC hypothesis has been the cornerstone of cellular heterogeneity, providing a conceptual and technical framework to explain this longstanding phenotype in GBM. This hypothesis has evolved to fit recent insights into how cellular plasticity drives tumor growth to suggest that CSCs do not represent a distinct population but rather a cellular state with substantial plasticity that can be achieved by non-CSCs under specific conditions. This has further been reinforced by advances in genomics, including single-cell approaches, that have used the CSC hypothesis to identify multiple putative CSC states with unique properties, including specific developmental and metabolic programs. In this review, we provide a historical perspective on the CSC hypothesis and its recent evolution, with a focus on key functional phenotypes, and provide an update on the definition for its use in future genomic studies.

Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

Preventing Ventricular Catheter Displacement and Infection with the "Catheter-Locking Device-Assisted" Technique: A Retrospective Study of 231 Patients.

BACKGROUND: Inserting cerebrospinal fluid diversion devices such as external ventricular drains (EVDs) and ventriculoperitoneal shunts (VPSs) is a critical procedure. Unfortunately, complications such as catheter misplacement, dislocation, or infection can occur. Various surgical strategies aim to reduce these risks. One recent innovation is the "catheter-locking device-assisted" technique for EVD surgery. In this study, we examined its application in a larger group of cases encompassing both EVDs and VPSs over a 30-month period, with a focus on these complications. METHODS: All adult patients who underwent a shunt procedure for noninfectious hydrocephalus at our institution from January 2021 to June 2023 were reviewed. We compared complications between those treated with the "standard" technique (subgroup A) and those managed with the "catheter-locking device-assisted" approach (subgroup B). RESULTS: In the EVD surgical group (initial procedures, n = 161), 6 patients (3.7%) required reoperation owing to the catheter misplacement caused by inadvertent migration of the ventricular catheter within the operating room ("early" migration), while 11 patients (6.8%) experienced unintentional postoperative dislodgement ("delayed" migration). Seven patients (4.3%) developed an EVD-related infection after an average duration of 7.4 days. None of these complications were observed in subgroup B patients (P < 0.05). Among VPS patients (n = 137), 4 (2.9%), all in subgroup A, required reoperation due to intraoperative migration of the catheter (P = 0.121); no other complications were identified. CONCLUSIONS: The "catheter-locking device-assisted" technique may significantly decrease the occurrence of the most common EVD complications and can also prove beneficial in VPS surgery. However, further investigation is necessary.

Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials.

AIM: To conduct a meta-analysis of randomized clinical trials (RCTs) to investigate whether there is an association between glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and thyroid cancer. MATERIALS AND METHODS: In this meta-analysis of RCTs, we included studies comparing a GLP-1RA with any comparator, lasting at least 52 weeks, and reporting the incidence of adverse events independently of the principal endpoint and population. All cases of thyroid cancer were collected. RESULTS: We retrieved 64 trials, 26 of which reported at least one incident case of thyroid cancer. GLP-1RA treatment was associated with a significant increase in the risk of overall thyroid cancer (Mantel-Haenzel odds ratio [MH-OR] 1.52 [95% confidence interval {CI} 1.01, 2.29]; P = 0.04, I2 = 0%), with a fragility index of 1, and a 5-year number needed to harm of 1349. The association remained significant when including only trials lasting at least 104 weeks (MH-OR 1.76 [95% CI 1.00, 3.12]; P = 0.05). No significant association was found for papillary thyroid cancer (MH-OR 1.54 [95% CI 0.77, 3.06]; P = 0.22) or medullary thyroid cancer (MH-OR 1.44 [95% CI 0.23, 9.16]; P = 0.55). CONCLUSIONS: Our meta-analysis showed that GLP-1RA treatment could be associated with a moderate increase in relative risk for thyroid cancer in clinical trials, with a small increase in absolute risk. Studies of longer duration are required to assess the clinical implications of this finding.

H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs.

Polycomb Repressive Complex 2 (PRC2)-mediated histone H3K27 tri-methylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, polycomb-regulated genes are connected through long-range 3D interactions which resolve upon differentiation. Here, we report that polycomb looping is controlled by H3K27me3 spreading and regulates target gene silencing and cell fate specification. Using glioma-derived H3 Lys-27-Met (H3K27M) mutations as tools to restrict H3K27me3 deposition, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened 3D interactions mirroring chromatin architecture of pluripotency, and stringent gene repression that maintains cells in progenitor states to facilitate tumor development. Conversely, H3K27me3 spread in pluripotent stem cells, following neural differentiation or loss of the H3K36 methyltransferase NSD1, dilutes cPRC1 concentration and dissolves polycomb loops. These results identify the regulatory principles and disease implications of polycomb looping and nominate histone modification-guided distribution of reader complexes as an important mechanism for nuclear compartment organization. Highlights: The confinement of H3K27me3 at PRC2 nucleation sites without its spreading correlates with increased 3D chromatin interactions.The H3K27M oncohistone concentrates canonical PRC1 that anchors chromatin loop interactions in gliomas, silencing developmental programs.Stem and progenitor cells require factors promoting H3K27me3 confinement, including H3K36me2, to maintain cPRC1 loop architecture.The cPRC1-H3K27me3 interaction is a targetable driver of aberrant self-renewal in tumor cells.

Thrombotic Microangiopathy and Multiple Organ Failure in Scleroderma Renal Crisis: A Case Report.

This case report can be considered a rare occurrence of scleroderma renal crisis (SRC) presenting with a severe clinical course and multiple organ failure. A patient diagnosed with systemic sclerosis four years earlier was admitted to the hospital because of severe malignant systolic-diastolic arterial hypertension and acute kidney injury (AKI). Exacerbating disease suggested thrombotic microangiopathy (TMA) and the PLASMIC (Platelet count; combined hemoLysis variable; absence of Active cancer; absence of Stem-cell or solid-organ transplant; MCV; INR; Creatinine) score was used in the differential diagnosis. Despite the timely initiation of therapy with ACE inhibitors (ACE-I), the progressive renal failure required hemodialysis treatment, but renal function never recovered. Disease duration, skin involvement, and previous specific pharmacological therapy represented multiple risk factors that determined a clinical course complicated by pericardial tamponade with acute heart failure, acute pancreatitis, and ischemic stroke, with fatal evolution. These complications presented a challenging clinical sequence of events requiring an interdisciplinary course of action. Timely ascertainment of the SRC is important given the possible severe organ involvement as well as mortality. A diagnosis of scleroderma renal crisis should be considered in cases of acute kidney injury associated with known risk factors. Early treatment and collaboration between rheumatology and renal physicians can improve patient outcomes.

Polybrominated Diphenyl Ethers (PBDEs) and Human Health: Effects on Metabolism, Diabetes and Cancer.

There is increasing evidence of the role of endocrine disruptors (EDs) derived from commonly employed compounds for manufacturing and processing in altering hormonal signaling and function. Due to their prolonged half-life and persistence, EDs can usually be found not only in industrial products but also in households and in the environment, creating the premises for long-lasting exposure. Polybrominated diphenyl ethers (PBDEs) are common EDs used in industrial products such as flame retardants, and recent studies are increasingly showing that they may interfere with both metabolic and oncogenic pathways. In this article, a multidisciplinary panel of experts of the Italian Association of Medical Diabetologists (AMD), the Italian Society of Diabetology (SID), the Italian Association of Medical Oncology (AIOM), the Italian Society of Endocrinology (SIE) and the Italian Society of Pharmacology (SIF) provides a review on the potential role of PBDEs in human health and disease, exploring both molecular and clinical aspects and focusing on metabolic and oncogenic pathways.

Role of Prehabilitation and Rehabilitation on Functional Recovery and Quality of Life in Thyroid Cancer Patients: A Comprehensive Review.

BACKGROUND: This narrative review aims to provide a comprehensive overview of the current prehabilitation and rehabilitation strategies for thyroid cancer survivors to optimize functional outcomes and enhance their quality of life. METHODS: The review follows the SANRA quality criteria and includes an extensive literature search conducted in PubMed/Medline, Web of Science, and Scopus. RESULTS: The review emphasizes the role of a comprehensive rehabilitation approach in targeting the different domains that generate disability in thyroid cancer patients. In this context, physical activity, range of motion exercises, myofascial release, joint mobilization, and postural exercises are crucial for improving functional outcomes and reducing treatment-related discomfort and disability. Moreover, tailored rehabilitative management addressing dysphonia and dysphagia might have a positive impact on the quality of life of these patients. Despite these considerations, several barriers still affect the implementation of a multimodal rehabilitative approach in common clinical practice. Thus, sustainable and effective strategies like digital innovation and patient-centered approaches are strongly needed in order to implement the rehabilitative treatment framework of these subjects. CONCLUSIONS: This narrative review provides valuable insights into the current prehabilitation and rehabilitation strategies to treat thyroid cancer survivors, addressing physical, psychological, and vocational needs to optimize functional outcomes and enhance their quality of life.

Linked-read based analysis of the medulloblastoma genome.

Introduction: Medulloblastoma is the most common type of malignant pediatric brain tumor with group 4 medulloblastomas (G4 MBs) accounting for 40% of cases. However, the molecular mechanisms that underlie this subgroup are still poorly understood. Point mutations are detected in a large number of genes at low incidence per gene while the detection of complex structural variants in recurrently affected genes typically requires the application of long-read technologies. Methods: Here, we applied linked-read sequencing, which combines the long-range genome information of long-read sequencing with the high base pair accuracy of short read sequencing and very low sample input requirements. Results: We demonstrate the detection of complex structural variants and point mutations in these tumors, and, for the first time, the detection of extrachromosomal DNA (ecDNA) with linked-reads. We provide further evidence for the high heterogeneity of somatic mutations in G4 MBs and add new complex events associated with it. Discussion: We detected several enhancer-hijacking events, an ecDNA containing the MYCN gene, and rare structural rearrangements, such a chromothripsis in a G4 medulloblastoma, chromoplexy involving 8 different chromosomes, a TERT gene rearrangement, and a PRDM6 duplication.