Penile squamous cell carcinoma (pSCC) is a rare tumour with a variable prognosis. More prognostic markers linked to mutational signatures and the tumour immune microenvironment are needed. A cohort made up of 165 invasive pSCC was retrospectively analysed using formalin-fixed, paraffin-embedded tumour tissue, focusing on tumour mutational burden (TMB), programmed death ligand 1 (PD-L1) expression, microsatellite instability (MSI), the number of tumour infiltrating lymphocytes (TILs) expressing cytotoxic T-lymphocyte-associated protein 4 (CTLA4), HPV status determined by p16 immunohistochemistry, and several traditional histopathological variables. High TMB (>10 mut/Mb) was associated with high PD-L1 expression (TPS 50-100%), and HPV-negative status. High PD-L1 expression was linked to HPV negativity, a high number of intratumoural CTLA4+ cells, and brisk lymphocytic infiltrate. High TMB was a significant predictor of shorter overall survival (OS) in both univariate and multivariate analysis when using a median cut-off value of 4.3 mut/Mb, but not when using an arbitrary cut-off of 10 mut/Mb. Low CTLA4+ cell infiltration at the tumour invasion front was a marker of shorter OS and cancer-specific survival in both univariate and multivariate analysis. PD-L1 expression had no significant impact on prognosis. Only two cases were MSI high. The results support the hypothesis of two aetiological pathways in pSCC cancerogenesis: (1) SCC linked to HPV infection characterised by low TMB, less common PD-L1 expression, and a lower number of TILs; and (2) SCC linked to chronic inflammation leading to a high number of acquired mutations (high TMB), HPV negativity, increased neoantigen production (i.e., PD-L1), and high immune cell infiltration.
- MeSH
- antigen CTLA-4 MeSH
- antigeny CD274 metabolismus MeSH
- infekce papilomavirem * komplikace MeSH
- lidé MeSH
- nádorové mikroprostředí MeSH
- nádory penisu * genetika MeSH
- retrospektivní studie MeSH
- spinocelulární karcinom * MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Soft tissue sarcomas harboring EWSR1::PATZ1 are a recently recognized entity with variable morphology and a heterogeneous immunohistochemical profile. We studied 17 such tumors. The tumors occurred in 12 men and 5 women (median age, 50 years; range, 15-71 years), involved the thoracoabdominal soft tissues (14 cases; 82%), lower extremities (2 cases; 12%), and tongue (1 case; 6%), and ranged from 0.7 to 11.3 cm (median, 4.7 cm). All but 1 patient received complete surgical resection; 7 were also treated with neoadjuvant chemo/radiotherapy. All cases showed typical features of EWSR1::PATZ1 sarcoma, including uniform round to spindled cells, fibromyxoid matrix, fibrous bands, hyalinized vessels, and pseudoalveolar/microcystic spaces. Unusual features, seen in a subset of cases, included degenerative-appearing nuclear atypia, epithelioid cytomorphology, mature fat, abundant rhabdomyoblasts, high mitotic activity, and foci with increased cellularity and nuclear atypia. Positive immunohistochemical results were desmin (16/17, 94%), MyoD1 (13/14, 93%), myogenin (6/14, 43%), GFAP (10/10, 100%), S100 protein (15/17, 88%), SOX10 (7/13, 54%), keratin (10/17, 59%), CD99 (4/11, 36%), H3K27me3 (retained expression 9/9, 100%), p16 (absent expression 1/4, 25%), and p53 (wild type 3/3, 100%). Fusion events included EWSR1 exon 8::PATZ1 exon 1 (14/17, 82%), EWSR1 exon 9::PATZ1 exon 1 (2/17, 12%), and EWSR1 exon 7::PATZ1 exon 1 (1/17, 6%). No evaluated tumor had alterations of CDKN2A/B and/or TP53, or MDM2 amplification. Clinical follow-up (16 patients: median, 13.5 months; range, 1-77 months) showed distant metastases in 3 patients (1/3 at time of presentation) and no local recurrences. At the time of last follow-up, 14 patients were disease free, 1 was alive with disease, 1 was dead of disease (at 13 months), and 1 had an indeterminant pulmonary nodule. We conclude that the morphologic spectrum of EWSR1::PATZ1 is broader than has been previously appreciated. Although more long-term follow-up is needed, the prognosis of these very rare sarcomas may be more favorable than previously reported.
- MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery genetika MeSH
- nádory měkkých tkání * genetika terapie patologie MeSH
- prognóza MeSH
- protein EWS vázající RNA genetika MeSH
- proteiny S100 MeSH
- represorové proteiny genetika MeSH
- sarkom * genetika terapie patologie MeSH
- transkripční faktory Krüppel-like MeSH
- transkripční faktory MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
T-type calcium channels perform crucial physiological roles across a wide spectrum of tissues, spanning both neuronal and non-neuronal system. For instance, they serve as pivotal regulators of neuronal excitability, contribute to cardiac pacemaking, and mediate the secretion of hormones. These functions significantly hinge upon the intricate interplay of T-type channels with interacting proteins that modulate their expression and function at the plasma membrane. In this review, we offer a panoramic exploration of the current knowledge surrounding these T-type channel interactors, and spotlight certain aspects of their potential for drug-based therapeutic intervention.
BACKGROUND: Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. METHODS: In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). FINDINGS: Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. INTERPRETATION: Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. FUNDING: Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.
- MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- erytropoéza MeSH
- lidé MeSH
- mladiství MeSH
- myelodysplastické syndromy * farmakoterapie MeSH
- oligonukleotidy * MeSH
- protokoly antitumorózní kombinované chemoterapie MeSH
- trombocytopenie * farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: In recent decades, magnetic resonance imaging (MRI) has gained prominence as a standard diagnostic method for preoperative assessment in patients with anorectal malformations and a colostomy, with the potential to replace the classic fluoroscopic distal pressure colostogram (FDPC). Three MRI techniques are available: MRI-distal pressure colostogram with gadolinium (MRI-DPCG) or saline (MRI-DPCS) instillation into the colostomy and native MRI without colostomy instillation. OBJECTIVE: To evaluate and compare the diagnostic accuracy of MRI (native MRI, MRI-DPCG and MRI-DPCS) in the preoperative workup of boys with an anorectal malformation and a colostomy and to compare it to FDPC. MATERIALS AND METHODS: Sixty-two boys with preoperative MRI using one of the three approaches and 43 with FDPC met the inclusion criteria for this retrospective study. The presence and localization of rectal fistulas according to the Krickenbeck classification were evaluated and compared with intraoperative findings. RESULTS: The accuracy of fistula detection for MRI in general (regardless of the technique), MRI-DPCS, MRI-DPCG, native MRI and FDPC was 95% (59/62, P<0.001), 100% (12/12, P=0.03), 100% (30/30, P<0.001), 85% (17/20, P=0.41) and 72% (31/43, P=0.82), respectively. The accuracy of describing fistula type in patients with a correctly detected fistula using these methods was 96% (45/47, P<0.001), 100% (9/9, P<0.001), 100% (23/23, P<0.001), 87% (13/15, P<0.001) and 67% (13/21, P=0.002), respectively. CONCLUSION: MRI is a reliable method for detecting and classifying fistulas in boys with an anorectal malformation and a colostomy and can be considered the modality of first choice for preoperative workup.
- MeSH
- anorektální malformace * diagnostické zobrazování chirurgie MeSH
- kolostomie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- magnetická rezonanční tomografie metody MeSH
- rektální píštěl * chirurgie MeSH
- rektum diagnostické zobrazování chirurgie abnormality MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diagnostic work-up and risk stratification in patients with bladder cancer before and after treatment must be refined to optimize management and improve outcomes. MRI has been suggested as a non-invasive technique for bladder cancer staging and assessment of response to systemic therapy. The Vesical Imaging-Reporting And Data System (VI-RADS) was developed to standardize bladder MRI image acquisition, interpretation and reporting and enables accurate prediction of muscle-wall invasion of bladder cancer. MRI is available in many centres but is not yet recommended as a first-line test for bladder cancer owing to a lack of high-quality evidence. Consensus-based evidence on the use of MRI-VI-RADS for bladder cancer care is needed to serve as a benchmark for formulating guidelines and research agendas until further evidence from randomized trials becomes available.
The synchronous research and analysis of total and active soil microbial communities can provide insight into how these communities are impacted by continuous cropping years and pathogen infection. The diversity of total and active bacteria in rhizospheric soil of 2-year-old and 3-year-old healthy and diseased Panax notoginseng can comprehensively reveal the bacterial response characteristics in continuous cropping practice. The results showed that 4916 operational taxonomic units (OTUs) were found in the rhizospheric soil bacterial community of P. notoginseng at the DNA level, but only 2773 OTUs were found at the RNA level. The rhizospheric environment had significant effects on the active and bacterial communities, as indicated by the number of OTUs, Shannon, Chao1, Faith's phylogenetic diversity (Faith's PD), and Simpson's diversity indexes. The DNA level can better show the difference in diversity level before and after infection with root rot. The bacterial Chao1 and Faith's PD diversity indexes of 2-year-old root rot-diseased P. notoginseng rhizospheric soil (D2) were higher than that of healthy plants, while the bacterial Shannon diversity index of 3-year-old root rot-diseased P. notoginseng rhizospheric soil (D3) was the lowest in the total bacteria. Principal coordinate analysis (PCoA) illustrated that the total bacterial species composition changed markedly after root rot disease. There were significant differences in the composition of active bacterial species between the 2-year and 3-year rhizospheres. In conclusion, the total and active edaphic rhizospheric bacterial communities could provide important opportunities to understand the responses of bacteria to continuous cropping of P. notoginseng.
- MeSH
- Bacteria * klasifikace genetika izolace a purifikace MeSH
- biodiverzita * MeSH
- DNA bakterií genetika MeSH
- fylogeneze * MeSH
- kořeny rostlin mikrobiologie MeSH
- nemoci rostlin mikrobiologie MeSH
- Panax notoginseng * mikrobiologie MeSH
- půda chemie MeSH
- půdní mikrobiologie * MeSH
- rhizosféra * MeSH
- RNA ribozomální 16S genetika MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- fibromyalgie * diagnóza psychologie terapie MeSH
- lidé MeSH
- psychosomatické a relaxační terapie MeSH
- somatoformní poruchy psychologie terapie MeSH
- syndrom chronické únavy * diagnóza psychologie terapie MeSH
- syndrom dráždivého tračníku * diagnóza psychologie terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
