Anti-programed cell death protein-1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies combined with anti-vascular endothelial growth factor (VEGF) or anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies are now standard therapeutic options for patients with treatment-naïve, advanced stage, hepatocellular carcinoma. Given the observed efficacy in the advanced setting, the unmet need for therapies for intermediate stage liver cancer, and compelling preclinical rationale for combination with liver-directed therapies, such as transarterial chemoembolization, immunotherapies have quickly moved into earlier stages of the disease. Several phase 1/2 clinical trials have collectively verified the safety of immune checkpoint blockade with regional therapy for intermediate stage, liver-limited, hepatocellular carcinoma. Recently, two global, randomized, double-blind, placebo-controlled studies have demonstrated superior efficacy, based on the surogate of progession free survial, for transarterial chemoembolization plus combination immunotherapy over chemoembolization alone. In this issue of the Journal, Li and colleagues present data for an anti-PD-1 inhibitor with chemoembolization in liver-limited hepatocellular carcinoma (HCC). This study, along with the status of the field, provides the opportunity to highlight key issues for implementation of combinatorial approaches in patients with liver-limited liver cancer, which are discussed in this Commentary. Regional treatment with immune checkpoint inhibition combinations for intermediate stage disease is now rightly at the forefront of HCC drug development, though specific biologic factors, ideal patient characteristics, and optimal combinations require deeper investigation prior to routine use for all patients.

T-cell activation and clonal expansion are essential to effective immunotherapy responses in non-small cell lung cancer (NSCLC). The distribution of T-cell clones may offer insights into immunogenic mechanisms and imply potential prognostic and predictive information.

Metastatic ovarian cancer patients who have recurrent disease after multiple lines of prior treatment have dismal prognosis. The Kristen rat sarcoma viral oncogene homologue (KRAS) G12C mutation is very rare in ovarian cancers and no approved KRAS G12C targeted treatment options exist for ovarian cancer. Here we present a case of metastatic ovarian serous adenocarcinoma in a female patient in her late 70s who was heavily pretreated with multiple lines of treatment before, showing an excellent durable response to KRAS G12C inhibitor sotorasib at reduced dose of 240 mg oral daily for over 26 months and ongoing. Our case highlights KRAS G12C as a driver mutation in ovarian cancer patients that is potentially targetable in certain subgroups of patients.

Cervical teratoblastoma in paediatric patients is an extremely rare and aggressive malignancy, with limited documentation in the medical literature. Teratoblastoma is a malignant variant of germ cell tumours, distinguished by its invasive growth pattern and poor cellular differentiation.A female child in early adolescence presented to our oncology hospital with complaints of persistent lower abdominal discomfort and abnormal uterine bleeding. These symptoms had been progressively worsening over time. On physical examination and imaging, pelvic ultrasonography and MRI revealed a complex cystic mass with hypoechoic features, located in the region between the cervix and the hymenal ring. Histopathological evaluation of a biopsy specimen confirmed the diagnosis of malignant cervical teratoblastoma. A multidisciplinary tumour board recommended surgical intervention. The patient underwent transvaginal excision of the cervical mass, with care taken to preserve reproductive anatomy.Postoperatively, adjuvant chemotherapy was initiated with the bleomycin, procarbazine (Natulan) and cisplatin regimen to reduce the risk of recurrence and metastasis. This case highlights the importance of early recognition, accurate diagnosis and a coordinated treatment approach in managing rare paediatric cervical malignancies.

Orbital metastasis is a rare manifestation of systemic malignancy, accounting for approximately 2%-5% of orbital tumours. The most common primary cancers associated with orbital metastases include breast carcinoma, malignant melanoma and prostate carcinoma. Hepatocellular carcinoma (HCC) is an uncommon source of all reported orbital metastases. We report the case of a man in his mid-50s with a history of alcoholic cirrhosis who presented with an acute onset of left periorbital pain, conjunctival injection, proptosis and restrictive ophthalmoplegia, in addition to abdominal discomfort. Orbital CT demonstrated a heterogeneously enhancing mass in the superolateral left orbit, associated with osseous erosion and displacement of adjacent orbital structures. Further imaging revealed multifocal hepatic lesions with evidence of portal vein invasion. A biopsy of the orbital mass confirmed metastatic HCC. The patient experienced rapid clinical deterioration before initiating treatment and ultimately passed away. This case highlights the importance of considering metastatic liver malignancy in the differential diagnosis of orbital masses, particularly in patients with risk factors for HCC.

This is a case of a man in his 60s initially diagnosed with gastric adenocarcinoma and treated with curative intent surgery and chemotherapy 6 years ago. Four years after initial treatment he had locoregional lymph node recurrence treated with curative chemoradiation and was on surveillance with no evidence of disease for 2 years. He presented to clinic with multiple 'bumps' on his head that had been increasing in size for the past 6 months. He has no other associated symptoms aside from 20 pounds of weight loss. The skin nodule was biopsied, and the pathology showed recurrence of his primary gastric adenocarcinoma. A positron emission tomography (PET)-CT showed a small area of metastasis in a single rib alongside this scalp lesion, without any areas of locoregional or intrathoracic recurrence. This is a rare case of cutaneous recurrence of primary gastric cancer without a high burden of intra-abdominal or visceral disease.

The RAPID-RT study is part of a large-scale research programme investigating the use of routinely collected real-world patient data to rapidly and prospectively evaluate and optimise the impact of changes in radiotherapy practice on clinical outcome, an approach often referred to as 'rapid learning'. As a proof of concept, a prospective, observational clinical study using realworld data is embedded within the programme. This study implements a new dose limit to a defined region of the heart in patients with stage I-III lung cancer treated with curative-intent radiotherapy at The Christie NHS Foundation Trust. The RAPID-RT study includes both methodological and clinical objectives. Its primary aim is to assess the feasibility and clinical acceptability of using rapid learning with real-world data to evaluate outcomes following modifications to standard-of-care radiotherapy protocols. This work has the potential to establish rapid learning as a robust, evidence-based approach for the continuous optimisation of radiotherapy workflows.

To describe long term risks of second non-breast primary cancers and contralateral breast cancers among women with early invasive breast cancer after primary surgery.

This study investigates two cases of stage IVb de novo multi-metastatic nasopharyngeal carcinoma (NPC) that responded to immunotherapy but resulted in different outcomes. Case 1 involved a multi-metastatic NPC patient (T4N3M1) with extensive bone and lymphatic metastases and severely impaired physical condition (ECOG PS 2) who showed significant tumor reduction after one cycle of immunotherapy combined with non-platinum chemotherapy, with no radiation exposure. Due to financial difficulties, the patient received intermittent immunotherapy plus chemotherapy and survived 28 months with a good quality of life. Case 2 describes a multi-metastatic NPC patient (T3N2M1) with multi-organ (bone and liver) metastases and good performance status (ECOG PS 0) who underwent standard chemotherapy, immunotherapy, and radiotherapy but experienced rapid progression and died after 21 months. Immunotherapy combined with chemotherapy remains the standard for multi-metastatic NPC patients. Patients responsive to induction chemotherapy gain survival benefits from subsequent radiotherapy. However, the advantages and disadvantages of radiotherapy for immunotherapy-sensitive multi-metastatic NPC patients are still unclear. Radiotherapy (RT) can enhance local control and promote tumor antigen release, thereby complementing immunotherapy; yet it can also damage immune cells, leading to exhaustion and resistance. Therefore, balancing RT and chemotherapy is vital for optimizing immune synergy and preventing immune exhaustion.

Osteosarcoma is one of the most common primary bone malignancies, typically occurring around the knee. However, the forearm is a rare site, with tumors in the proximal ulna being extremely uncommon. Primary sarcoma in this location presents a surgical challenge due to the complex anatomy and limited reconstructive options. We report a rare case of a 19-year-old female with non-metastatic, high-grade giant cell-rich osteosarcoma involving the right proximal ulna. To our knowledge, this is only the second reported adult case of this histological subtype in this location. The patient was treated at a specialized oncology center with neoadjuvant and adjuvant chemotherapy, along with wide intra-articular resection for local tumor control. Reconstruction was achieved using a novel, customized 3D-printed articulating cement spacer mold with plate osteosynthesis. Artificial elbow ligamentous reconstruction was performed using FiberTape and FiberWire sutures passed through drill holes, and the triceps tendon was reattached to the cement mold using an endobutton. This cost-effective and personalized surgical approach allowed successful joint reconstruction while maintaining elbow stability and function. Our case highlights a feasible reconstructive option for rare and anatomically challenging osteosarcoma presentations, contributing to the limited literature on proximal ulna giant cell-rich osteosarcoma.

Squamoid morules (SM) are rare in colorectal adenomas. Submucosal pseudoinvasion in adenomas is similar to that in invasive carcinomas and needs to be differentiated, especially in the presence of mucin spillage.

RAD18 is a crucial mismatch repair gene associated with the post-replication repair, and genetic variations in RAD18 gene are closely related to tumorigenesis. We selected 6 RAD18 SNP and performed mismatch amplification PCR on 650 cases of CIN III, 580 cervical squamous cell carcinoma (CSCC), and 1320 healthy controls. The RAD18 rs250403 GG and G allele (AG + GG) genotype risk in CIN III and CSCC were significantly increased. The results showed a significant correlation between the GG genotype of rs615967 and the risk of CIN III and CSCC. Carriers of the G allele (AG + GG) at RAD18 rs615967 also had an increased risk. More noteworthy was that the RAD18 rs250403 (A/G) and rs615967 (A/G) haplotypes associated with high risk of CIN III and CSCC were AG-GG, GG-AA, GG-AG, and GG-GG. Clinical data analysis further showed that the polymorphisms of RAD18 rs250403 and rs615967 were significantly correlated with prognostic indicators such as family history of tumor, differentiation grade, lymph node metastasis, and vascular involvement. RAD18 protein expression was significantly decreased in CSCCs with the rs615967-AG and rs615967-GG genotype. In summary, the 2 genetic polymorphisms of the RAD18 were associated with susceptibility and prognosis in CIN III and CSCC, and specific high-risk haplotypes of these 2 SNPs could serve as genetic predictive biomarkers.

Machine learning (ML) applied to radiomics has revolutionized neuro-oncological imaging, yet the diagnostic performance of ML models based specifically on ^18F-FDG PET features in glioma remains poorly characterized.

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is an autosomal dominant tumor predisposition syndrome with germline fumarate hydratase (FH) pathogenic variants. We describe the unusual clinical presentation, morphologic, and immunohistochemical features of bilateral renal cell carcinoma (RCC) occurring in polycystic kidneys in a 15-year-old male with HLRCC.

The location of nasopharyngeal carcinoma (NPC) is relatively hidden. Most patients are diagnosed at the middle or late stage of the disease, having missed the best time for treatment.

Solitary fibrous tumor (SFT) is a fibroblastic tumor characterized by a prominent staghorn vasculature and collagen deposition. However, little is known about SFTs with alveolar structures. Herein, we present a case of an alveolar pattern SFT in a 55-year-old woman. The tumor was present in the lumbosacral spinal canal and showed an alveolar architecture composed of ovoid to spindle-shaped cells. Immunohistochemical examination showed that the tumor cells were positive for STAT6 (nuclear expression), CD34, CD99, and Bcl-2, but negative for cytokeratins (CK-pan and AE1/AE3), EMA, GFAP, CD31, progesterone receptor, S-100 protein, and smooth muscle actin. Furthermore, NAB2::STAT6 fusion was detected using DNA-based next-generation sequencing, which established the diagnosis of SFT at a molecular level. The present case expands the morphological categories of SFT.

Patients with hepatocellular carcinoma (HCC) exhibit a high rate of recurrence and poor prognosis after surgery, and effective prognostic indicators and stratification strategies are currently lacking. Hence, this study proposes new prognostic markers to provide a theoretical basis for patients with HCC.

In alignment with the latest WHO classification system, which underscores the integration of molecular alterations in glioma diagnosis and grading, this study investigates the prognostic significance of MYCN amplification in IDH-mutant gliomas, a relationship that remains poorly characterized despite its established association with adverse outcomes in various malignancies. A cohort of 190 patients with IDH-mutant gliomas was analyzed for clinical and pathological characteristics. MYCN amplification status was determined using fluorescence in situ hybridization (FISH) with an MYCN-specific probe. Survival outcomes were assessed via Kaplan-Meier analysis, while independent prognostic factors were identified through multivariable Cox proportional hazards regression models. Tumor morphology was systematically evaluated in cases with MYCN amplification. MYCN amplification was identified in 28 of 190 cases (14.7%), demonstrating a significant correlation with advanced tumor grade and elevated Ki-67 proliferation indices (p < 0.05). Patients harboring MYCN amplification exhibited markedly reduced overall survival compared to non-amplified cases (112.13 ± 6.58 versus 91.14 ± 14.96 months, p = 0.001), with this association being particularly pronounced in lower-grade (WHO grades 2 and 3) IDH-mutant gliomas (122.12 ± 6.81 versus 47.76 ± 6.58 months, p < 0.001). To address limitations in current grading systems, we propose a refined classification approach that upgrades lower-grade IDH-mutant astrocytomas with MYCN amplification to high-grade status. This MYCN-based grading system demonstrated significant prognostic stratification (112.84 ± 10.40 versus 77.65 ± 11.15 months, p < 0.001). Morphological analysis revealed that 50% of MYCN-amplified cases (14/28) exhibited distinct epithelioid features, characterized by abundant eosinophilic cytoplasm and nuclear displacement. In conclusion, MYCN amplification emerges as a critical prognostic indicator in IDH-mutant gliomas, particularly in lower-grade tumors, and is frequently associated with unique epithelioid histological features. These findings highlight the necessity of incorporating MYCN amplification status into grading paradigms for IDH-mutant gliomas to enhance prognostic accuracy and inform clinical decision-making.

Pancreatic cancer (PC) is a highly lethal tumour of the gastrointestinal tract. New molecular targets are urgently needed for its treatment. Kinesin family member C1 (KIFC1) is implicated in the development and progression of several types of cancer. Previous studies from our group demonstrated that KIFC1 overexpression in hepatocellular carcinoma promotes malignant behaviours via the PI3K/AKT pathway. However, the molecular and functional mechanisms of KIFC1 in PC are not yet fully elaborated. In this study, KIFC1 and BUB1B were significantly upregulated in PC patient samples, and high KIFC1 expression was closely associated with the malignant phenotype and poorer overall survival (OS) in PC patients. Functional experiments showed that KIFC1 knockdown inhibited PC cell growth in vivo and in vitro, blocked cell cycle progression and hindered cell migration and invasion. In addition, rescue experiments showed that KIFC1 induced PC cell malignant behaviours dependent on BUB1B. Mechanistically, KIFC1 regulates BUB1B expression by competitively binding to BUB1B and reducing its ubiquitination and degradation. We have shown for the first time the molecular regulatory mechanism between KIFC1 and BUB1B on PC. Therefore, KIFC1 shows promise as an attractive therapeutic target for PC in the future.

Prostate cancer (PCa) is an extremely heterogeneous cancer and is highly prevalent in the older male population. Since intra-tumour heterogeneity (ITH) commonly results in PCa chemotherapy resistance and recurrence, it is critical to explore its effects on tumour behaviour. Prognostic genes related to ITH were identified, and a signature was constructed using Cox regression analyses and multiple machine learning algorithms. Single-cell RNA sequencing data extracted from PCa and CRPC samples were analysed via sub-clustering, pseudotime, cell communication and drug sensitivity approaches to elucidate their function. The oncogenic potential of hub genes was confirmed by immunohistochemistry and cell proliferation assays. An 11-gene signature underlying a prostate cancer meta-program (PCMP) was generated by selecting an optimal combination of machine learning methods. Survival assays and multivariate Cox regression analyses conducted in multiple cohorts revealed the superior prognostic value of the PCMP signature. Functional enrichment analyses indicated that it dysregulates the cell cycle. Using trajectory and cell-cell communication analyses, we illustrated that PCMP genes exert oncogenic effects by enhancing the proliferation and oxidative phosphorylation of epithelial cells. Intra-cellular assays also demonstrated that CENPA and CKS1B had promising malignant potential. In summary, our research not only establishes the association between the PCMP signature and reveals its malignant characteristics, but also deepens our understanding of the mechanisms underlying PCa progression and ITH. It holds promise for the development of targeted therapeutic interventions, thereby offering clinical benefits to patients.