Comprehensive Cancer Center Vienna

Pineoblastoma is a clinically aggressive childhood brain tumor composed of distinct molecular subgroups with divergent driver genes, demographics, and clinical outcomes. To identify developmental origins and mechanisms governing disease pathogenesis, we derive single-cell transcriptomes from pineal parenchymal tumors, aligning malignant cells with developmental counterparts to retrace cellular origins. Integrative computational analyses map pineoblastoma origins to transient, cycling pinealocyte progenitors during development. Lineage-specific perturbation of suspected drivers in the early pineal gland yields preclinical models representative of consensus molecular subgroups. Multi-omic characterization of patient tumors and these models uncover a tumor-associated photoreceptor signature (TAPS) common to pineoblastoma, retinoblastoma, and Group 3 medulloblastoma. Transcriptional activity of this signature within respective cellular origins establishes a developmental basis for molecular similarities between entities. Photoreceptor signature constituents are selective dependencies across these anatomically distinct central nervous system malignancies, motivating future studies evaluating developmentally encoded programs of malignancy as potential therapeutic liabilities.

Introduction: Sarcomatoid dedifferentiation may be identified in both clear cell renal cell carcinoma (ccRCC) and non-clear cell RCC (nccRCC). Within the SEER database (2010–2021), we tested the effect of sarcomatoid dedifferentiation in first ccRCC and subsequently in nccRCC on cancer-specific mortality (CSM). Methods: Separate propensity score matching (PSM) and multivariable competing risks regression (CRR) analyses were first applied to ccRCC with vs. without sarcomatoid dedifferentiation and subsequently to nccRCC with vs. without sarcomatoid dedifferentiation. Results: Sarcomatoid dedifferentiation was present in 2496 (3.0%) of 82,146 ccRCC patients and in 501 (1.9%) of 26,584 nccRCC. In ccRCC, after 1:2 PSM, 2496 (100%) patients with sarcomatoid dedifferentiation vs. 4992 (6.2%) patients without sarcomatoid dedifferentiation were included. At 60 months, CSM was 45.7% vs. 33.6% in ccRCC patients with vs. without sarcomatoid dedifferentiation. In CRR sarcomatoid dedifferentiation independently predicted 1.6-fold higher CSM (HR 1.6, p < 0.001). In nccRCC, after 1:2 PSM 501 (100%) patients with sarcomatoid dedifferentiation vs. 1002 (3.8%) patients without sarcomatoid dedifferentiation were included. At 60 months, CSM was 41.7% vs. 28.1% in nccRCC patients with vs. without sarcomatoid dedifferentiation. In CRR sarcomatoid dedifferentiation independently predicted 2.0-fold higher CSM (HR 2.0, p < 0.001). Conclusion: Sarcomatoid dedifferentiation is invariably associated with higher CSM in both ccRCC and nccRCC. However, the detrimental effect of sarcomatoid dedifferentiation in CSM is more pronounced in nccRCC than in ccRCC.

A deep-intronic single nucleotide variant in RUNX2 causes the characteristic clinical features of cleidocranial dysplasia (CCD) in a family via pseudo-exon inclusion into the mRNA. The pseudo-exon contains a premature stop codon and triggers mRNA decay, which results in RUNX2 haploinsufficiency, the known disease mechanism.

A 73-year-old man developed subacute cognitive impairment, status epilepticus and reduced level of consciousness requiring mechanical ventilation. An MR scan of the brain showed multifocal inflammatory lesions, but with normal cerebrospinal fluid (CSF); blood results showed positive antinuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibodies (Abs), but normal complement and urine analysis. Commercial kit for cell-surface antineuronal antibodies, including anti-NMDAR (anti-N-Methyl-D-Aspartate Receptor antibody), anti-LGI1 (anti-Leucine-Rich Glioma-Inactivated 1 antibody), anti-CASPR2 (anti-Contactin-Associated Protein-Like 2 antibody), anti-GABA-BR (anti-Gamma-Aminobutyric Acid Type B Receptor antibody), anti-AMPAR (anti-α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor antibody) and anti-DPPX (anti-Dipeptidyl-Peptidase-Like Protein-6 antibody), was negative in serum and CSF. We gave methylprednisolone, plasma exchange, rituximab and cyclophosphamide. However, despite initial improvement, he had five relapses. We reassessed the diagnosis and identified a thymoma; also, research laboratory testing with tissue-based and cell-based assays identified anti-GABA-AR Abs. He improved following thymectomy and with tocilizumab. This case underscores the complexity and varied presentations of anti-GABA-AR encephalitis with thymoma, emphasising the importance of comprehensive antibody testing in making this challenging diagnosis.

Next-generation human papillomavirus (HPV) vaccines encompass newly licensed and emerging formulations that employ alternative production platforms, expanded valency, or novel antigenic targets beyond conventional L1-based vaccines. These vaccines aim to address affordability challenges, supply limitations, and suboptimal vaccination coverage, particularly in low- and middle-income countries. This review aggregates current clinical, immunological, and programme-related evidence on newly licensed vaccines, including the World Health Organization (WHO)-prequalified bivalent formulations (Cecolin® and Walrinvax®), the quadrivalent Cervavac®, and the Escherichia coli-derived nonavalent Cecolin 9®, which received national licensure in 2025. Additionally, emerging high-valency candidates in Phase I-III trials-9-valent, 11-valent, and 14-valent formulations-are critically assessed. Clinical trials demonstrate that next-generation HPV vaccines provide robust protection; for example, Cecolin® showed 100% efficacy against HPV-16/18-associated high-grade squamous intraepithelial lesions (HSIL) and up to 97.8% efficacy against persistent HPV infection, while Walrinvax® demonstrated 78.6% protection against CIN2+ lesions. Cervavac® showed non-inferior immunogenicity compared with established vaccines. While comparative analyses of efficacy, immunogenicity, and safety indicate that these vaccines are strong alternatives to established products, robust long-term effectiveness and real-world impact data remain essential before full clinical equivalence can be definitively established. Advances in L2-based platforms further aim to broaden cross-type protection, simplify manufacturing, and enable thermostable formulations, thereby enhancing applicability in resource-limited settings. Economic evaluations demonstrating favorable cost-effectiveness emphasize the essential role of next-generation vaccines in improving access and reducing inequity. Overall, innovations in valency, technology, and delivery strategies have the potential to significantly expand global HPV prevention coverage and accelerate progress toward cervical cancer elimination.