BJC reports最新文献

Background: Emerging HER2-targeted therapies provide new treatment options for patients with HER2-expressing tumors. This study investigates the prevalence of HER2 amplification and HER2 low expression across a well-characterized cohort of endometrial carcinoma.

Methods: HER2 chromogenic in situ hybridization (CISH) was used to detect HER2 amplification in endometrial carcinoma samples. Chromogenic HER2 immunohistochemistry (IHC) was performed. HER2 low was defined as IHC 1 + /2+ and negative CISH.

Results: CISH confirmed HER2 amplification in 2% (n = 26) of the 1239 endometrial carcinoma samples including all the IHC 3+ cases (n = 13) and 20% of the 2+ cases (n = 55). Amplified cases presented various histotypes but consisted almost exclusively of p53 abnormal tumors. HER2 low 2+ category (n = 44) was heterogeneous with regard to molecular subgroup and histotype with 64.3% of the patients having high-risk disease. HER2 status did not independently predict disease-specific survival.

Conclusions: p53 abnormal molecular subgroup predicts HER2 amplification better than histotype. HER2 low cases present a wide range of histotypes and molecular subgroups including many patients with high-risk uterine cancer. Future trials of anti-HER2 therapies will clarify the clinical relevance of HER2 low status, treatment indications and guidelines for HER2 testing in endometrial carcinoma.

Background: In cancer cachexia the relationship between the tumour, its environment and the systemic inflammatory response is not clear. This study aims to examine this relationship in greater detail.

Methods: Host characteristics included the presence of a Systemic Inflammatory Response (SIR) as measured by Systemic Inflammatory Grade (SIG), sarcopenia (SMI) and myosteatosis (SMD) were measured. Categorical variables were analysed using χ² test for linear-by-linear association, or χ² test for 2 by 2 tables. Survival analysis was carried out using univariate and multivariate Cox regression.

Results: A total of 473 patients were included. Of these, 70.4% were over 65 years of age, 54.8% were male and 49.8% had an ASA grade of 1 or 2. Pathological examination showed that the majority of patients had a T3 (53.7%) or a T4 (34.0%) cancer and 73.0% had evidence of necrosis. A SIG score of 0 or 1 was present in 57.7% of patients. Tumour necrosis was associated with age (p < 0.01), tumour location (p < 0.01), T-stage (p < 0.001), margin involvement (p < 0.05), SIG (p < 0.001), SMI (p < 0.01), SMD (p < 0.05) and 5-year survival (p < 0.001). On multivariate survival analysis in patients with T3 cancers age (HR: 1.45 95% CI 1.13-1.86 p < 0.01), ASA grade (HR: 1.50 95% CI 1.15-1.95 p < 0.01) and SIG (HR: 1.28 95% CI 1.11-1.48 p < 0.001) remained independently associated with survival.

Conclusion: These results suggest that tumour necrosis and the subsequent SIR could result in profound changes in body composition and survival. Further pre-clinical and clinical work is required to prove causation.

Background: Osteosarcoma is the most common malignant bone tumour with limited treatment options and poor outcomes in advanced metastatic cases. Current immunotherapies show limited efficacy, highlighting the need for novel therapeutic approaches. Systemic immune activation by Toll-like receptor 4 (TLR4) immunostimulants has shown great promise; however, current TLR4 agonists' toxicity hinders this systemic approach in patients with osteosarcoma.

Methods: We compared the antitumour effect of lipopolysaccharides (LPS) with that of an innovative chemically detoxified TLR4 agonist (Lipo-MP-LPS) in a syngeneic metastatic osteosarcoma mouse model. Lipo-MP-LPS exhibited an optimal safety and solubility profile for systemic administration at an effective dose. We evaluated tumour growth, lung metastases, and immune cell infiltration in wild-type and TLR4-mutant mice and performed selective immunodepletion.

Results: Lipo-MP-LPS exhibited antitumour effects against localised osteosarcoma tumours and lung metastases, like those of natural LPS. Lipo-MP-LPS promoted CD8⁺ T cells and M1 macrophages infiltration in primary tumours and CD8⁺ T cells in metastases, with an M1-phenotype macrophage shift. The Lipo-MP-LPS antitumour effects were found to depend on TLR4 and CD8⁺ T cells, but not on macrophages.

Conclusion: Lipo-MP-LPS inhibited tumour growth and lung metastasis of osteosarcoma by promoting CD8 + T cell infiltration, indicating its therapeutic potential for advanced osteosarcoma.

The author transitions his career in oncology to one in planetary health. The career pivot begins after he recognizes similarities between the pandemic and the climate crisis. The author determines that stepping away from his role as chair of radiology for a one-year sabbatical is the most efficient way to learn about sustainability. The author explains the process of his sabbatical and offers guidance for those in oncology who are also considering sabbaticals. He concludes by listing five lessons about sustainability and describing his future plans.

Single-use plastics (SUPs) are used widely in cancer research laboratories. They are cheap, durable, and lightweight, and until now have been considered disposable items. This, however, contributes significantly to unsustainable waste production. SUP waste is typically diverted to landfill or incineration, which contributes to greenhouse gas emissions, taking many years to degrade. Lack of robust SUP waste disposal streams, particularly in cancer research labs has long term effects on the environment. Having identified that a single laboratory researcher in our group generates at least 15 kg SUP tissue culture waste alone each year, we explore some of the issues associated with SUPs in pre-clinical oncology research, discussing potential reuse routes, alternative materials for labware and developing circular approaches to plastic consumption to address the green agenda. We also propose recommendations for improving sustainability in cancer research labs.

Background: Endothelin 1 receptors are one of the drivers of tumor progression in many cancers. Inhibition of their signaling pathways with antagonist drugs has been the subject of numerous clinical trials, but the results have not met expectations probably due to the high endothelin concentrations in the tumor microenvironment and their unusually high affinity for their receptors.

Methods: We previously reported the rendomab B49 antibody (RB49) exhibiting a preferential affinity for the activated conformation of human endothelin B receptor (ET_B), not displaced by high endothelin levels, and without any pharmacological properties that could inhibit the division of melanoma cells. In this context, we have developed xiRB49-MMAE, a chimeric antibody-drug conjugated (ADC) to monomethyl auristatin E. We have characterized its physicochemical properties, studied its binding mechanisms, and evaluated its therapeutic potential in a preclinical model. Immunohistochemical analysis of metastatic melanoma lymph nodes evaluated RB49 as a diagnostic tool for patient stratification.

Results: xiRB49-MMAE showed high efficacy against melanoma cells and ET_B⁺ xenograft tumor models. IHC studies indicated that 100% of melanoma patient lymph node biopsies were RB49-positive.

Conclusions: xiRB49-MMAE is a promising drug candidate for clinical trials in ET_B⁺ tumors. RB49 could be used as a diagnostic tool for patient stratification.

Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine was synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT).

Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of ribociclib plus gemcitabine in patients with advanced solid tumors. Patients received gemcitabine intravenously on days 1 and 8 followed by ribociclib days 8-14, with treatment repeated every 3 weeks.

Results: The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800 mg daily and gemcitabine 1000 mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease.

Conclusions: The addition of ribociclib to gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Biomarkers such as Rb status and activity of CDK2 and CDK4/6 complexes may help to select patients who may respond better to the combination of gemcitabine and ribociclib.

Clinical trial registration: NCT03237390.

Background: The identification of effective diagnostic and prognostic biomarkers is critical to improving the outcomes of patients with pancreatic ductal adenocarcinoma (PDAC). We explored the potential of serum levels of laminin γ2 monomer (LG2m) as a biomarker in PDAC.

Methods: This study included two cohorts. Cohort 1 included 142 PDAC patients, 55 patients with intraductal papillary mucinous neoplasm (IPMN), and 46 healthy individuals. Cohort 2 included 518 PDAC patients. The medical records of patients were reviewed. Cut-off levels for LG2m were determined by receiver operating characteristic analysis.

Results: In Cohort 1, serum LG2m levels were significantly higher in PDAC patients compared with healthy individuals (P < 0.001) and IPMN patients (P < 0.001). Comparing PDAC patients and health individuals, the optimal cut-off level of LG2m was 9.55 pg/mL and the sensitivity, specificity, and area under the curve were 0.89, 0.87, and 0.88, respectively. High sensitivity of LG2m in PDAC patients were confirmed in Cohort 2. The sensitivity and specificity of LG2m was higher than that of CEA and CA19-9. In patients treated with resection or chemotherapy, high serum LG2m level indicated a significantly shorter survival (P = 0.042 and P < 0.001, respectively).

Conclusions: LG2m may be a useful diagnostic and prognostic marker for PDAC.