Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) continue to face a substantial risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which remains a leading cause of treatment failure. In our previous study, maintenance therapy with a combination of venetoclax and decitabine has shown potential in reducing relapse rates; however, its efficacy and safety, particularly in relation to drug concentration levels, are not yet fully elucidated. This study aimed to evaluate the influence of venetoclax blood concentrations on the efficacy and toxicity of venetoclax plus decitabine as maintenance therapy in high-risk AML/MDS patients after allo-HSCT. We retrospectively analyzed clinical data from 58 high-risk AML/MDS patients who received this maintenance regimen at our center between April 2018 and June 2023, with a focus on the association between venetoclax blood levels, treatment response, and adverse effects. The results demonstrated that the venetoclax-decitabine maintenance regimen was effective and generally well-tolerated, improving remission rates without significantly increasing intolerable toxicities or the risk of graft-versus-host disease (GVHD). Notably, substantial interindividual variability in venetoclax blood concentrations was observed. Patients with concentrations maintained within the range of 2605-4060 ng/mL achieved superior outcomes and higher safety profiles. In conclusion, this study provides key evidence for establishing a target concentration window for venetoclax, highlighting the importance of therapeutic drug monitoring in guiding post-transplant maintenance therapy for high-risk AML/MDS patients.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design kinase inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 determined co-crystal structures, including a structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazoline-based inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure shows the molecular basis for targeting solvent-front mutations across oncogenic kinases.

Pancreatic acinar cell carcinoma (ACC) is a rare and aggressive malignancy whose molecular basis remains poorly understood. N6-methyladenosine (m⁶A) RNA modification, mediated particularly through methyltransferase 3 (METTL3), has emerged as a critical regulator in various cancers. Here, we investigated the role of METTL3-mediated RNA methylation in ACC development and progression. We used transgenic mouse models overexpressing Mettl3 and SV40 large T antigen under the pancreatic elastase I promoter. Comprehensive analyses included m⁶A-methylated RNA immunoprecipitation sequencing (MeRIP-seq), single-cell RNA sequencing (scRNA-seq), functional studies using the METTL3 inhibitor STM2457, and S-adenosylmethionine (SAM)-binding domain deletion mutants to assess functional requirements. Mettl3 overexpression significantly accelerated ACC development and increased tumor aggressiveness. The SAM-binding domain was essential for tumor formation, as deletion mutants failed to promote carcinogenesis. MeRIP-seq revealed preferential methylation of cell cycle and DNA replication genes in Mettl3-overexpressing tumors. scRNA-seq analysis demonstrated enhanced malignancy signatures, including epithelial-to-mesenchymal transition and transforming growth factor-β signaling. METTL3 also promoted PRSS1-mediated signaling from ACC cells to inflammatory cancer-associated fibroblasts, creating a feed-forward loop involving IGF1 that amplifies tumor growth. Conditional Mettl3 deletion induced rapid tumor apoptosis. Pharmacological inhibition with STM2457 similarly triggered caspase-3/7-dependent apoptosis in pancreatic tumors. METTL3-mediated RNA methylation drives ACC pathogenesis through tumor-intrinsic cell cycle regulation and tumor-extrinsic stromal interactions. These findings establish METTL3 as a promising therapeutic target and provide mechanistic insights supporting the clinical development of METTL3 inhibitors for ACC treatment.

Cancer metabolism is characterized by profound reprogramming, yet the mechanisms enabling rapid and precise adaptation remain incompletely understood. This review establishes post-translational modifications (PTMs) as the central processing unit of oncogenic metabolic reprogramming. PTMs execute a conserved three-tiered regulatory logic: they interpret oncogenic and environmental signals, command metabolic flux, and cement malignant phenotypes through epigenetic and feedback mechanisms. We systematically demonstrate how this PTM-driven logic governs key pillars of cancer metabolism-glucose, lipid, amino acid, and nucleotide utilization-and extends its command to critical cell fate execution programs, including mitochondrial dynamics, autophagy, and ferroptosis. Furthermore, we delineate how PTMs act as master regulators of immunometabolic reprogramming within the tumor microenvironment (TME), directly linking tumor metabolism to T cell exhaustion, myeloid cell polarization, and immune evasion. By integrating recent advances on the determinants and crosstalk of PTM networks, we describe how metabolic plasticity and heterogeneity are encoded at the PTM level, with metabolic gradients shaping distinct "PTM geographies" within tumors. Finally, we translate these insights into clinical prospects, highlighting PTM-based biomarkers, PTM-targeted drugs and emerging therapeutic strategies, including targeted protein degradation, PTM-targeted vaccines and dietary interventions. Deciphering this PTM-encoded program reveals a new landscape of therapeutic vulnerabilities, shifting the paradigm toward rationally targeting the fundamental computational logic that sustains tumors.

Ameloblastoma is a benign yet locally aggressive odontogenic neoplasm characterized by a significant propensity for local recurrence. Soft-tissue recurrence following mandibular resection and reconstruction represents a distinct clinical entity, often posing diagnostic and therapeutic challenges. In contrast, ameloblastic carcinoma may arise de novo or through malignant transformation of a pre-existing ameloblastoma, reflecting a spectrum of biological behaviour. We report a case of post-resection soft-tissue recurrence with subsequent malignant transformation, underscoring the unpredictable clinical course and complexities in management of this tumour.

A 36-year-old woman with a prior history of segmental mandibulectomy and free fibula flap reconstruction followed by Reconstruction plate fixation for mandibular ameloblastoma presented with a progressively enlarging submental swelling three years postoperatively. Radiological evaluation was suggestive of recurrent disease, and incisional biopsy indicated follicular ameloblastoma. However, definitive histopathological examination following surgical excision revealed features consistent with ameloblastic carcinoma. The patient underwent complete excision of the involved soft tissue with concurrent neck dissection and remains under close surveillance, with consideration for adjuvant therapy guided by histopathological risk factors.

Carcinoma ex ameloblastoma may manifest as soft-tissue recurrence following prior surgical management, reflecting its potential for aggressive behaviour and delayed malignant transformation. Such presentations necessitate a multidisciplinary management strategy prioritizing complete oncologic excision, appropriate cervical nodal evaluation, and judicious use of adjuvant therapy. Vigilant long-term clinical and radiological surveillance is imperative given the risk of delayed recurrence and disease progression.

Radiopharmaceutical therapy (RPT) uses radionuclides linked to targeting ligands to bind tumor-associated receptors or antigens and deliver ionizing radiation to malignant cells. Approved agents include [¹⁷⁷Lu]Lu-DOTATATE for gastroenteropancreatic neuroendocrine tumors, [¹⁷⁷Lu]Lu-PSMA-617 for metastatic castration-resistant prostate cancer, and ²²³Ra-dichloride for bone-predominant metastatic castration-resistant prostate cancer. Accumulating evidence suggests that RPT may impose genotoxic stress on the hematopoietic system, resulting in prolonged cytopenias and, in some patients, therapy-related myeloid neoplasms (tMNs). This review synthesizes evidence regarding hematologic toxicities associated with [¹⁷⁷Lu]Lu-based RPT, emphasizing mechanisms of marrow injury, limitations of dose-only frameworks, host susceptibility factors, and emerging strategies for risk stratification, monitoring, and mitigation. We propose an integrated radiogenomic framework in which hematologic toxicity and tMN risk after RPT may arise from interactions among prior genotoxic exposure, heterogeneous red marrow radiation delivery, host genomic susceptibility-including clonal hematopoiesis and germline predisposition-and baseline marrow reserve. As RPT moves into earlier lines of therapy and populations with a longer expected survival, anticipating hematologic consequences will be essential for safe and precise clinical implementation.

A woman in her 40s presented with a 2-day history of progressive left lower limb swelling and dyspnoea. She had a background of heavy menstrual bleeding and previously underwent insertion of an intrauterine device 2 years earlier, at which time pelvic imaging was not performed. On presentation, imaging demonstrated bilateral deep vein thromboses and a large saddle pulmonary embolism in the absence of conventional thromboembolic risk factors. Further evaluation revealed a markedly enlarged multifibroid uterus causing compression of the inferior vena cava (IVC) and bilateral iliac veins, resulting in venous stasis and thromboembolism. She was treated with therapeutic anticoagulation and managed non-surgically with two uterine artery embolisations, achieving symptom resolution and radiological improvement in venous compression on follow-up imaging. This case highlights uterine fibroid-related IVC compression as a rare cause of extensive venous thromboembolism and underscores the importance of early pelvic examination and imaging in women with abnormal uterine bleeding.

The process of excising and repairing skin cancers has the potential to be highly complex. This is especially the case on the head and neck or where a complex closure is required. To optimise decision making, it is important that at the planning stage all of the various, potentially competing, considerations are made explicit and appropriately ranked in relation to the four surgical hierarchical goals which are: (1) curing the cancer; (2) avoiding functional disturbance; (3) avoiding complications; and (4) achieving good cosmesis.

We wished to design an easily remembered formal process that would not only assist doctors ensure they had considered all the relevant variables but that would also help rank these in terms of surgical importance prior to making a surgical plan. An appropriate acronym is an efficient means of ensuring the most important considerations are made explicit first (establishing the hierarchy) and that all the relevant information is gathered. Only then does the solution phase proceed. This is the basis of 'CHAIRS' which stands for: Cure the Cancer; Hole; Area/Alignment; Icebergs/Incidents; Reservoirs; Solution(s)/Salvage.

CHAIRS enables structured, orderly preoperative planning crucial for achieving favourable outcomes in skin cancer surgery. It provides less experienced doctors a framework to work with, and more experienced ones with a back-up first principles approach. It is easy to learn, remember and teach.

The tumor microbiota critically shapes responses to immunotherapy; however, the mechanisms by which specific microbial species drive immune checkpoint blockade (ICB) resistance in gastric cancer (GC) remain poorly defined.

Streptococcus anginosus enrichment was assessed in ICB-unresponsive GC tissues from patients and multiple preclinical models. Orthotopic, subcutaneous, and germ-free mono-colonized mouse models were employed to evaluate the impact of S. anginosus on antitumor immunity and programmed cell death protein 1 (PD-1) blockade efficacy. Integrated multi-omics analyses were performed to identify microbiota-derived metabolites, and mechanistic studies investigated their effects on CD8⁺ T-cell function. Therapeutic targeting of integrin α2 (ITGA2) was tested to assess restoration of cytotoxic T-cell activity and sensitization to PD-1 blockade.

S. anginosus was markedly enriched in ICB-non-responsive GC tissues. Colonization with S. anginosus impaired antitumor immunity and promoted PD-1 blockade resistance by suppressing CD8⁺ T-cell effector function. Multi-omics analyses identified kynurenic acid (KA) as a microbiota-derived metabolite selectively enriched following S. anginosus colonization. KA induced ITGA2 expression and inhibited an mTOR-dependent signaling cascade, sustaining cathepsin V expression and attenuating interferon-γ and granzyme B production in CD8⁺ T cells. Therapeutic inhibition of ITGA2 restored CD8⁺ T-cell cytotoxicity and sensitized tumors to PD-1 blockade.

A microbiota-metabolite-immune signaling axis involving S. anginosus, KA, and ITGA2 drives immunotherapy resistance in GC. Therapeutic inhibition of ITGA2 represents a potential strategy to overcome ICB resistance in GC.

Immune checkpoint blockade (ICB) therapy has emerged as a pivotal cancer treatment by activating antitumor immunity. However, its clinical efficacy remains limited in many patients, highlighting the need for combination strategies to overcome resistance. Inducing immunogenic cell death (ICD) represents a promising approach to remodel the immunosuppressive tumor microenvironment and improve ICB efficacy.

A high-throughput screen of a natural compound library identified potent ICD inducers. Polyphyllin II (PPII), a bioactive component from Paris polyphylla, was selected for further investigation. Its effects on ICD markers, tumor growth, and immune activation were evaluated in vitro and in vivo. Limited proteolysis-mass spectrometry was employed to identify the direct target of PPII, followed by mechanistic studies using molecular and immunological assays.

PPII was identified as a potent ICD inducer, stimulating the release of high mobility group box 1, ATP, and calreticulin from tumor cells. PPII suppressed tumor growth and enhanced antitumor immunity by promoting dendritic cell maturation and antigen cross-presentation, leading to CD8⁺ T-cell activation. Mechanistically, PPII directly bound to glucose-regulated protein 75 (GRP75), enhancing endoplasmic reticulum-mitochondrial tethering, provoking endoplasmic reticulum stress and mitochondrial calcium overload, and promoting cytochrome c release and caspase-3 activation. This cascade ultimately triggered gasdermin E (GSDME)-mediated pyroptosis. Furthermore, PPII synergized with anti-programmed cell death protein 1 therapy by reprogramming the tumor immune microenvironment and promoting systemic antitumor immunity.

Our findings identify GRP75 as a novel therapeutic target for cancer immunotherapy and highlight PPII-driven immune reprogramming as a translatable strategy to potentiate ICB efficacy through the induction of immunogenic pyroptosis.