Breast cancer has become one of the most common malignant tumors in women, and the incidence rate is increasing annually in men. This study focused on exploring the prognostic significance of the combined detection of serum ALP and LDH in patients with breast cancer. We enrolled 80 individuals with male breast cancer (MBC), female breast cancers (FBCs) were randomly matched via propensity score matching (PSM). In the MBC cohort, the optimal cutoff values for ALP and LDH were determined to be 114 U/L and 207 U/L, respectively, whereas in the FBC cohort, they were 68 U/L and 133 U/L, respectively. There was a difference in median survival between patient groups classified by the optimal cutoff values of ALP and LDH in the FBC cohort. However, in the FBC cohort, there was no significant correlation between the levels of ALP or LDH and patient prognosis. We developed a "joint score" system that incorporates the values of both ALP and LDH and separates MBCs into three groups. Survival was significantly different among the three groups. In the multivariate analysis, the "joint score" was identified as an independent prognostic factor for both disease-free survival(DFS) and overall survival (OS).

The CBFA2T3::GLIS2 (CG) fusion protein causes aggressive pediatric acute megakaryoblastic leukemia (AMKL). Although dysregulated molecular pathways in AMKL have been identified, their role in early pre-leukemic transformation remains poorly understood. We developed a disease model utilizing genetically modified human induced pluripotent stem cells (hiPSC) physiologically and conditionally expressing CG. Using in vitro differentiation and single-cell multi-omics, we captured the impact of oncogene activity on gene-regulatory networks during hematopoiesis. We discovered that CG interferes with myelopoiesis through two alternative routes: by locking aberrant megakaryocyte progenitors (aMKP) in a proliferative state, or by impeding differentiation of aberrant megakaryocytes (aMK). Transcriptionally and functionally, aMKPs mimic CG-AMKL cells and establish a self-renewal network with co-factors GATA2, ERG, and DLX3. In contrast, aMKs partially sustain regulators of MK maturation but fail to complete differentiation due to repression of factors like NFE2, SPI1, GATA1 and LYL1. These insights may inform new strategies for targeting AMKL cell states.

Gastric cancer is the fourth most common cancer globally and the leading cause of cancer-related deaths in Peru. Current synthetic treatments often fail to distinguish cancerous cells from healthy cells, resulting in severe side effects and drug resistance. This study aimed to evaluate the effects of the chloroform fraction of Dracontium spruceanum bulb (DSBCl) on cancer stem cells (CSCs) from AGS and KATO III gastric cancer cell lines, which represent primary and metastatic cancers. The methanolic extract was prepared and characterized via thin-layer chromatography to isolate the chloroform fraction. CSCs were identified via the CD44 marker and isolated via magnetic assisted cell sorting. The cytotoxic effect of DSBCl was evaluated to determine the IC50, revealing its ability to modulate CSC markers and genes associated with tumorigenesis, chemoresistance, and metastasis. In AGS CSCs, DSBCl reduced CD24 expression and downregulated the expression of genes, including ID1, BCL2L2, ABCC2, NANOG, and OCT4, while it upregulated KLF17, BAX, and KLF4. In KATO III CSCs, DSBCl increased ID1 and MYC but decreased BCL2L1 and BAX. These findings suggest that DSBCl modulates critical markers and genes in gastric CSCs, highlighting its potential for gastric cancer treatment.

Gastric MALT lymphoma diagnosis relies on histopathological findings and immunoglobulin H gene (IgHr) rearrangement testing, which reflects monoclonal immunoglobulin proliferation. This study aimed to clarify the role of IgHr in the diagnosis, treatment prediction, and surveillance of gastric MALT lymphoma. Of the 152 suspected cases, 131 were definitively diagnosed using a combination of IgHr and pathology, with pathological findings considered the gold standard. Patients with discrepancies between IgHr and pathology underwent re-evaluation. The relationship between IgHr status, clinicopathological features, and treatment outcomes was analyzed. IgHr and histopathology were assessed over 2 years in 41 patients after pathological complete remission (pCR). IgHr positivity was 69.5% at initial biopsy and 90.8% after two biopsies. IgHr-positive cases had higher H. pylori infection rates and better CR rates post-eradication. Patients with IgHr positivity at pCR had higher recurrence rates (16.7%). IgHr positivity gradually declined among 37 non-recurrent cases (CR: 56.8%, 6 M: 45.9%, 1Y: 21.6%, 2Y: 10.8%), indicating a delay between pCR and IgH-negative conversion. Repeated biopsies may improve the accuracy of gastric MALT lymphoma diagnosis. IgHr-positive status at pCR may signal higher recurrence risk, underscoring the need for careful post-CR surveillance. Surveillance should account for potential delays in IgHr-negative conversion.

Intratumoral low oxygen tension promotes cancer cell invasion and metastasis. Hypoxia-Inducible Factor 1-alpha (HIF1α) is the principal transcription factor orchestrating cellular responses to hypoxic stress, mediating the regulation of genes implicated in adapting to perturbations in oxygen homeostasis. Here, we describe our findings that functionally demonstrate a nucleolar localization domain in HIF1ɑ that enables HIF1ɑ to translocate to the nucleolus. Nucleolar HIF1ɑ binds the ribosomal DNA promoter and upregulates RNA Polymerase I activity leading to dysregulated ribosomal RNA transcription and consequently enhanced ribosome biogenesis. Ribosome biogenesis is important in supporting cellular metabolic processes and invasion and metastasis. Our findings are recapitulated in breast tumors wherein upregulated HIF1ɑ and rRNA biogenesis are associated with poor prognosis. Finally, our studies demonstrate that inhibition of RNA Polymerase I impedes aggressive traits of hypoxia-driven cancer progression, highlighting the potential of this approach as a therapeutic strategy in breast cancer. Cumulatively our work unravels an unprecedented role of HIF1ɑ in regulating rRNA biogenesis in breast cancer.

Recent evidence has highlighted immune checkpoint inhibitors as among the most promising immunotherapies for various malignancies. However, a significant proportion of HCC patients exhibit poor responses. Lipid metabolic heterogeneity is considered a key driver of cancer progression. However, the role of lipid metabolic reprogramming in HCC immunotherapy resistance remains poorly understood. Herein, we aimed to illuminate the potential relationship between lipid metabolic reprogramming and ICI resistance and provide novel strategies to increase the HCC immunotherapy response. Patients who received PD-1/PD-L1 inhibitors were enrolled. The effect of TACC3 on the tumor microenvironment was validated via single-cell RNA sequencing in HCC-bearing mouse models. Targeted metabolomics was performed to analyze the regulatory role of TACC3 in HCC metabolism. To address HCC immunotherapy resistance, we developed a targeted nucleic acid therapeutic utilizing N-acetylgalactosamine (GalNAc) to conjugate siTACC3. Through clinical cohort analysis, we found that TACC3 was overexpressed in HCC patients with poor response to immunotherapy. Furthermore, we demonstrated that silencing tumor-derived TACC3 optimizes the cytotoxicity of infiltrating CD8+ T lymphocytes. Both in vitro and in vivo assays suggested that TACC3 maintains ACSL4-mediated polyunsaturated fatty acid (PUFA) metabolism in HCC cells. Additionally, TACC3 accelerates ACSL4 expression by interacting with LARP1 and PABPC1, which stabilize ACSL4 mRNA. The results of preclinical models demonstrated the satisfactory efficacy of GalNAc-conjugated siTACC3 combined with PD-1 inhibitor therapy for HCC. In summary, tumor-derived TACC3 impairs the tumor-killing activity of CD8+ T lymphocytes through PUFA metabolism-associated crosstalk. Targeting TACC3 represents a novel and practicable strategy to augment ICI efficacy against HCC.

Mitosis is a critical phase of the cell cycle and a vulnerable point where cancer cells can be disrupted, causing cell death and inhibiting tumor growth. Challenges such as drug resistance persist in clinical applications. During mitosis, mRNA translation is generally downregulated, while non-canonical translation of specific transcripts continues. Here, we show that mitotic cancer cells redistribute ribosomes toward the 5' untranslated region (5' UTR) and beginning of the coding sequence (CDS), enhancing translation of thousands of upstream open reading frames (uORFs) and upstream overlapping open reading frames (uoORFs). This mitotic induction of uORF/uoORF enriches human leukocyte antigen (HLA) presentation of non-canonical peptides on the surface of cancer cells after mitotic inhibitor treatment. Functional assays indicate these epitopes provoke cancer-cell killing by T cells. Our findings highlight the therapeutic potential of targeting uORF/uoORF-derived epitopes with mitotic inhibitors to enhance immune recognition and tumor cell elimination.

Repeated oncogenic mutations and polyclonal proliferation are evident in cancers. However, little is known about the polyclonal principles governing the systemic cancerous lineage during immunotherapy. Here, we examine a unique autopsy case of metastatic urothelial carcinoma that exhibits different treatment responses to anti-PD-1 therapy at each tumor site. By performing in-depth analyses of different multiregional bulk tumor masses, we reveal that subsets of subclones acquire potential driver mutations under treatment selection pressure. Spatial transcriptomics analysis reveals that subclones resistant to immunotherapy form distinct immunosuppressive environments consistent with their habitats. Furthermore, different cancer hallmarks are identified in each of the subclones that expand under immunotherapy at single-cell level; for example, one subclone is more proliferative, and another is more stem-cell-like. In summary, this study provides an overall picture of the polyclonal competition and changes in the immune microenvironment that are related to resistance to immunotherapy in patients with malignancies.

The efficacy, safety and ideal treatment duration of an adjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for patients with resected EGFR-mutated non-small-cell lung cancer (NSCLC) were not known until 2014, when this study was initiated. In this phase 3 ICTAN trial (GASTO1002, NCT01996098), patients with completely resected, EGFR-mutated, stage II-IIIA NSCLC after adjuvant chemotherapy were assigned in a 1:1:1 ratio to receive icotinib (125 mg, three times daily) for 12 months, to receive icotinib for 6 months, or to undergo observation. The primary endpoint was disease-free survival (DFS). This trial was terminated early. A total of 251 patients were randomized. Adjuvant icotinib for 12 months significantly improved DFS (hazard ratio [HR]: 0.40, 95% confidence interval [CI], 0.27-0.61; P < 0.001) and overall survival (OS; HR: 0.55, 95% CI, 0.32-0.96; P = 0.032) compared with observation. Adjuvant icotinib of 6 months also significantly improved DFS (HR: 0.41, 95% CI, 0.27-0.62; P < 0.001) and OS (HR: 0.56, 95% CI, 0.32-0.98; P = 0.038) compared with observation. Adjuvant icotinib for 12 months did not improve DFS (HR: 0.97; P = 0.89) or OS (HR: 1.00; P = 0.99) compared with 6 months of this drug. Rates of adverse events of grade 3 or higher were 8.3%, 6.0% and 2.4% for the 12-month icotinib, 6-month icotinib, and observation groups, respectively. Adjuvant icotinib for 12 months or 6 months following adjuvant chemotherapy improved DFS and OS compared with observation in patients with resected EGFR-mutated stage II-IIIA NSCLC with a manageable safety profile, supporting it as a potential treatment option.

Lymph node metastasis (LNM) is a crucial risk factor influencing an unfavorable prognosis in specific cancers. Fundamental research illuminates our understanding of tumor behavior and identifies valuable therapeutic targets. Nevertheless, the exploration of fundamental theories and the validation of clinical therapies hinge on preclinical experiments. Preclinical models, in this context, serve as the conduit connecting fundamental theories to clinical outcomes. In vivo models established in animals offer a valuable platform for comprehensively observing interactions between tumor cells and organisms. Using various experimental animals, including mice, diverse methods, such as carcinogen-induced tumorigenesis, tumor cell line or human tumor transplantation, genetic engineering, and humanization, have been used effectively to construct numerous models for tumor LNM. Carcinogen-induced models simulate the entire process of tumorigenesis and metastasis. Transplantation models, using human tumor cell lines or patient-derived tumors, offer a research platform closely mirroring the histology and clinical behavior of human tumors. Genetically engineered models have been used to delve into the mechanisms of primary tumorigenesis within an intact microenvironment. Humanized models are used to overcome barriers between human and murine immune systems. Beyond mouse models, various other animal models have unique advantages and limitations, all contributing to exploring LNM. This review summarizes existing in vitro and animal preclinical models, identifies current bottlenecks in preclinical research, and offers an outlook on forthcoming preclinical models.

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.