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Disease-specific U1 spliceosomal RNA mutations in mature B-cell neoplasms
No full textRecurrent mutations in the third base of U1 spliceosomal RNA responsible for marked splicing and expression abnormalities have been described in chronic lymphocytic leukemia (CLL) and some solid tumors. However, the clinical significance of these mutations in large and independent CLL cohorts as well as their presence in other B-cell neoplasms is unknown. Here we characterized U1 mutations in 1670 CLL and 363 mature B-cell lymphomas. We confirmed that the g.3A>C U1 mutation is found in 3.5% of CLL, which conferred rapid disease progression independently of the main biological and clinical prognostic markers of the disease. Additionally, a recurrent g.9C>T mutation was found in 1.5% of CLL causing downstream splicing alterations and associated with adverse prognosis. We also identified a g.4C>T mutation in 10% of diffuse large B-cell lymphomas of the germinal center subtype and a g.7A>G mutation in 30% of EBV-negative Burkitt lymphomas, both of which altered the splicing pattern of multiple genes. This study reveals novel, recurrent, and tumor-specific U1 mutations in mature B-cell neoplasms with biological and prognostic implications, thus establishing U1 as a novel pan-B-cell malignancy driver gene. (Figure presented.
TENT5/FAM46: An Enigmatic Family of Secretory Tuners
No full text: Human TENT5 family comprises four members (A-D) associated with different diseases of secretory cells. Homozygous mutations in TENT5A cause a rare form of osteogenesis imperfecta due to impaired collagen deposition by osteoblasts. TENT5C is frequently mutated or deleted in patients with multiple myeloma, the cancer of antibody-secreting plasma cells, and TENT5D alterations result in male infertility. TENT5 members are noncanonical poly(A)polymerases that selectively stabilize mRNAs encoding endoplasmic reticulum-imported proteins, thus promoting the expression of secretory cargoes and proteins involved in folding, glycosylation, and trafficking along the secretory apparatus. This specificity has been proposed to be linked to TENT5 localization at the membrane of the endoplasmic reticulum, thanks to their interaction with transmembrane FNDC3 proteins. Recently, key roles of TENT5 proteins have been described in cancer, bone homeostasis, immunity, stemness, and fertility. This review will comprehensively analyze the identified cellular functions of this novel family of secretory tuners in physiological and pathological conditions, highlighting the proposed molecular mechanisms and the remaining open questions
Radioguided Surgery for Prostate Cancer
No full textProstate-specific membrane antigen radioguided surgery (PSMA-RGS) is an emerging technique that provides real-time intraoperative guidance for identification of lymph node metastases (LNMs) in patients with prostate cancer (PC). PSMA-RGS uses PSMA ligands labeled with radionuclides that emit γ or β particles and has shown promise in enhancing the accuracy of surgery. Introduced for salvage lymph node dissection in patients experiencing biochemical recurrence, PSMA-RGS has demonstrated high specificity and positive predictive value, although sensitivity remains limited for micrometastatic disease. Recent studies on PSMA-RGS during extended pelvic lymph node dissection in the primary setting showed that it is safe and feasible, with superior accuracy in comparison to preoperative PSMA positron emission tomography. Despite its advantages, PSMA-RGS has limited sensitivity for micrometastatic LNMs because of spatial resolution for the probe. PSMA-RGS represents a promising tool for optimizing surgical management in PC. However, future studies with long-term follow-up are needed to refine detection strategies and evaluate its oncological impact. Patient summary: Radioguided surgery using radioactive compounds that bind to a protein called PSMA (prostate-specific membrane antigen) is a safe procedure that may help surgeons in identifying metastasis in lymph nodes during robot-assisted surgery for prostate cancer. While this technique has potential to enhance treatment outcomes, further studies are necessary to confirm its long-term benefits
PCSK9 expression and cancer survival: a prognostic biomarker at the intersection of oncology and geroscience
Get PDFProprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in cholesterol metabolism; however, emerging evidence suggests it plays a broader role in the regulation of cellular aging mechanisms and the pathogenesis of age-related diseases. Given that cancer is an age-related disease, PCSK9 has garnered attention for its potential impact on tumor progression and patient survival. In this study, we conducted a comprehensive analysis of PCSK9 expression across multiple tumor types, assessing its prognostic significance using RNA sequencing data from The Cancer Genome Atlas (TCGA) and gene expression microarray data from the Gene Expression Omnibus (GEO). Cox proportional hazards regression models and Kaplan–Meier survival analyses were employed to evaluate overall survival (OS) associations. Our findings reveal that elevated PCSK9 expression is associated with improved OS in breast and ovarian cancers, particularly in Luminal B breast cancer subtypes. Conversely, high PCSK9 expression correlates with worse OS in bladder cancer, renal clear cell carcinoma, melanoma, and pancreatic cancer. Notably, while PCSK9 expression is significantly upregulated in melanoma and bladder tumors, it is downregulated in renal clear cell carcinoma, yet relatively higher expression among renal tumors still predicts poorer survival. No significant associations between PCSK9 expression and OS were observed in colon, liver, gastric, lung, prostate, head and neck cancers, or low-grade gliomas in the available datasets.In conclusion, our study identifies PCSK9 as a prognostic biomarker with distinct, tumor-specific survival implications. Its dual role—associating with improved survival in some cancers while correlating with worse outcomes in others—suggests that PCSK9 may influence cancer progression through context-dependent mechanisms. Future research should focus on elucidating the mechanistic underpinnings of these associations and exploring the diagnostic and therapeutic potential of targeting PCSK9 in oncology
Pancreatic resection for metachronous colorectal cancer metastases: a case series multicenter study
No full textBackground: Pancreas resection for metachronous colorectal cancer metastasis is episodic and the role of surgery in the management of these patients is still debated. Methods: We recruited seven patients from three different centres and analyzed 30-day morbidity and mortality, oncological outcomes at 6 and 12 months. Results: There was no postoperative mortality. Complications occurred in two patients (28,6%). All patients completed at least a 12-months follow-up. At 6-month follow-up, only one patient had a recurrence. At 12-month follow-up, no patients died for disease recurrence and one more patient had a new recurrence. Conclusion: Our series supports the feasibility and safety of pancreas resection in metastatic colorectal cancer suggesting that radical resection may improve the patient's prognosis
Open-label evaluation of oral trehalose in patients with neuronal ceroid lipofuscinoses
No full textThe neuronal ceroid lipofuscinoses (NCLs) are incurable pediatric neurodegenerative diseases characterized by accumulation of lysosomal material and dysregulation of autophagy. Given the promising results of treatment with trehalose, an autophagy inducer, in cell and animal models of NCL, we conducted an open-label, non-placebo-controlled, non-randomized 12-month prospective study in NCL patients receiving oral trehalose (4 g/day). All were treated with a commercially available formulation for 6 months, followed by a 6-month washout. The primary endpoint was the presence of severe adverse reactions during treatment; secondary endpoints were clinical changes documented using the validated Unified Batten Disease Rating Scale and the Hamburg scale. Leveraging on our recent multiomic studies identifying convergent biomarkers in NCLs, fluid biomarker changes were taken as additional secondary endpoints. Of the 17 patients enrolled, 11 completed the study. Oral intake of trehalose in NCL patients with different genetic forms and at different disease stages was found to be well tolerated over 6 months. Oral trehalose is associated with subjective benefits reported by caregivers, but not with improvement or worsening on clinical scales. Analysis of potential biomarkers demonstrated significant differences between patients and controls at baseline, but we observed no modifications over time, or correlations with clinical scales and treatment. In our pilot experience in a heterogeneous disease group of NCL, oral trehalose seemed safe for patients. While subjective improvements were reported by caregivers, larger multicenter randomized placebo-controlled studies, and perhaps additional clinical tools covering multiple functions affected by the disease, will be needed to identify possible improvements in clinical scale scores and biomarkers
Tamuzimod in patients with moderately-to-severely active ulcerative colitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 induction trial
No full textBackground: Tamuzimod (VTX002) is a selective sphingosine 1-phosphate receptor 1 modulator in development for ulcerative colitis. We aimed to assess the safety and efficacy of tamuzimod in patients with moderately-to-severely active ulcerative colitis. Methods: This double-blind, randomised, placebo-controlled, phase 2 induction trial was conducted at 122 centres across 15 countries in Asia, Europe, and North America. Patients aged 18–80 years with a modified Mayo score (MMS) of 4–9 and an inadequate response or a loss of response, or intolerance to one or more approved ulcerative colitis therapies were randomly assigned (1:1:1) to once-daily oral tamuzimod (60 mg or 30 mg) or placebo for 13 weeks. Randomisation was stratified by previous advanced therapy, baseline corticosteroid, and baseline MMS. The primary endpoint was clinical remission (defined as an MMS stool frequency subscore of ≤1, rectal bleeding subscore of 0, and endoscopic subscore ≤1, excluding friability) at week 13. Adverse events and laboratory abnormalities were assessed for safety. Efficacy and safety analyses included all randomly assigned patients who received at least one study dose, with the efficacy analysis restricted to patients with a baseline MMS of 5–9 based on regulatory feedback. The study was registered with ClinicalTrials.gov, NCT05156125, and EudraCT, 2021-003050-23. Findings: Between Nov 4, 2021, and Aug 30, 2023, 367 patients were screened, and 213 (mean age 40·6 years [SD 14·2]; 116 [54%] males and 97 [46%] females) were randomly assigned to tamuzimod 60 mg (n=70), tamuzimod 30 mg (n=73), or placebo (n=70). Two in the tamuzimod 30 mg group and two in the tamuzimod 60 mg group with baseline modified Mayo score of 4 were excluded from the efficacy analysis. At week 13, clinical remission was reached by 19 (28%) of 68 patients receiving tamuzimod 60 mg, 17 (24%) of 71 patients receiving tamuzimod 30 mg, and eight (11%) of 70 patients receiving placebo (risk difference 16·5% [95% CI 3·2 to 29·4], p=0·018, for tamuzimod 60 mg vs placebo and 12·5% [–0·2 to 24·9], p=0·041, for tamuzimod 30 mg vs placebo). Treatment-emergent adverse events occurred in 33 (47%) of 70 patients receiving tamuzimod 60 mg, 34 (47%) of 73 patients receiving tamuzimod 30 mg, and 24 (34%) of 70 patients receiving placebo. Most adverse events were mild or moderate. The most frequently reported treatment-emergent adverse events (in ≥5% of in any treatment group) were upper respiratory tract infection (six [9%] of 70 patients in the tamuzimod 60 mg group, one [1%] of 73 in the tamuzimod 30 mg group, and one [1%] of 70 in the placebo group), anaemia (three [3%], four [5%], and six [9%]), and headache (four [6%], five [7%], and two [3%]). No adverse events of atrioventricular block, bradycardia, macular oedema, severe or opportunistic infections, malignancies, or deaths occurred. Interpretation: Induction therapy with tamuzimod was effective and well tolerated in patients with ulcerative colitis. These results and the favourable risk−benefit profile of tamuzimod collectively support the continued clinical development of tamuzimod for the treatment of moderately-to-severely active ulcerative colitis. Funding: Ventyx Biosciences
An integrated clinical pathway for pancreatic and periampullary tumor management within the Pancreas Unit network in Lombardy, Italy
No full text: This study presents a novel clinical pathway framework developed to standardize care protocols across the Pancreas Units network in the Lombardy region, which was established in 2024. The primary goal is to improve the quality of care across hub-and-spoke units by ensuring consistency in diagnosis, treatment, and follow-up. A key feature is the early integration of palliative care, aiming to enhance patient well-being throughout the treatment journey. The framework establishes a comprehensive care continuum, from patient admission to post-treatment follow-up, with local and regional case managers coordinating care and ensuring timely access to services. Their role is essential in maintaining continuity and optimizing treatment. The framework also emphasizes the importance of continuous professional development for healthcare providers and the implementation of a digital platform to enhance care coordination and track treatment outcomes. Additionally, patient rights and ethical considerations are emphasized throughout the care process. This study contributes to the growing body of literature on standardized care pathways in oncology, particularly in the context of regionalized healthcare systems. Future research should focus on evaluating the long-term impacts of this framework on patient outcomes and healthcare system efficiency
Correction: Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia (Leukemia, (2022), 36, 4, (1171-1175), 10.1038/s41375-021-01485-x)
No full textCorrection to: Leukemiahttps://doi.org/10.1038/s41375-021-01485-x, published online 01 January 2022 The wrong Supplementary file was originally published with this article; it has now been replaced with the correct file. The original article has been corrected
