TP53 mutation

The final diagnosis was CD20-negative primary intestinal large B-cell lymphoma with a TP53 mutation arising in the context of poorly controlled CD, a combination that, to the best of our knowledge, has not been previously reported in the literature. This case highlights the diagnostic challenges posed by intestinal lymphomas associated with CD and emphasizes the importance of integrating histopathological, immunophenotypic, and molecular findings to achieve an accurate diagnosis and provide prognostic assessment.

Upfront CTx only regimens used were classified into three groups to reflect disease treatment conventions: standard-dose, high-dose (intensified regimens of sufficient dosage to require stem cell support) and those including intraventricular methotrexate (IVT-MTX)...With outcomes established, clinical trials are now encouraged to focus on quality-of-life following different intensified approaches to identify the kindest curative strategies. Cancer Research UK, Children with Cancer UK, Children's Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero and Blue Skye Thinking.

Using B-ALL cell lines and patient-derived xenografts, we show that FATP2-expressing TP53-mutant B-ALL resistance to CAR-T is dependent on exogenous lipid uptake to fuel fatty acid oxidation (FAO) and cell survival, which can be pharmacologically targeted through inhibition of neutral lipolysis and CPT1. These findings identify FATP2-mediated fatty acid uptake and downstream FAO as a potential target to improve existing CAR-T efficacy in human B-ALL.

Herein, we report the first documented case of phenotypic conversion to SCLC in a patient with advanced pulmonary sarcomatoid carcinoma (PSC) who received pemetrexed, carboplatin, and camrelizumab only, with no targeted agents administered. TP53 and RET mutations may be implicated in this phenotypic transition. This case provides new insights into the biological mechanism underlying the evolution of PSC to SCLC.

We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53/MDM2 negative feedback loop. KTX-049 was >100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling...Acquired resistance was strongly associated with acquisition of TP53 mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT TP53 MCC.

SBAs display genomic heterogeneity. The novel HGC stratifies these tumors based on homology to foregut or hindgut alterations and may be superior to anatomic location for characterizing pathology. Additional studies are needed to validate and further explore these findings.

Sonrotoclax demonstrated rapid, durable responses and manageable safety in heavily pretreated patients with R/R MCL, including high-risk subgroups, supporting its further clinical evaluation as an oral therapy for R/R MCL.

Despite histologic similarity, anogenital BCC demonstrates a distinct molecular profile, suggesting an alternative pathogenesis. Further genomic studies are warranted.

ZR-CHOP demonstrates encouraging activity and acceptable safety in molecularly selected high-risk DLBCL, particularly in the MCD-like subgroup. (ClinicalTrials.gov number, NCT05290337).

Clinically, elevated LFPM expression correlates with poorer survival, specifically in p53R175H-mutant cancers. Our work unveils a pivotal mechanism for mutant p53 stabilization and nominates the LFPM-p53R175H axis as a promising therapeutic target.

E6AP-mediated p53 degradation was severely impaired in the presence of the ATM inhibitor KU-55933, indicating that HBx-induced p53 phosphorylation plays a critical role in this process. Additionally, E6AP could target p53 phosphorylated by DNA-damaging agents like etoposide in the absence of HBx...Ser-15 phosphorylation was pivotal, as E6AP could degrade p53 S15D (phosphomimetic mutant) but failed to act on p53 S15A (a non-phosphorylatable mutant). These findings suggest that HBx-induced p53 phosphorylation enhances E6AP-mediated degradation while concurrently inhibiting MDM2-mediated pathways, thereby fine-tuning p53 levels to support cell survival, viral replication and potentially carcinogenesis during HBV infection in human hepatocytes.

Our findings support a monoclonal origin for ASC, with smoking influencing divergent evolutionary trajectories and immune microenvironment characteristics between ACC and SCCC. These insights provide a molecular framework for personalized ASC therapies.