Aggressive Tumor Research Articles

Ferrocenyl Aminocresols Display Multimodal Activity Against Triple‐Negative Breast Cancer Cells In Vitro

AbstractTriple‐negative breast cancer (TNBC) lacks expression of the oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu), has an aggressive tumor phenotype, shows only a partial response to chemotherapy, and lacks clinically established targeted therapies. Therefore, there is a need to develop more effective drugs for the treatment of TNBC. The ferrocenyl benzoxazine and α‐aminocresols class of compounds gave a potential source of multimodal inhibitors of cancer based on previous studies. In this study, a set of ferrocenyl benzoxazines and α‐aminocresols were screened and characterized as potential inhibitors of TNBC in vitro. A panel of 11 compounds was screened for selective cytotoxicity to cancer cells over normal cell equivalents. Focusing on the previously proposed modes of action of their building blocks, α‐aminocresols 3a and 3b exhibited significant DNA binding capabilities and caused robust DNA damage in TNBC cells. In addition, both compounds exhibited significant ROS generation capability; however, introducing a ROS quencher in a cell viability assay only partially rescued the cells from the cytotoxicity effects of the α‐aminocresols. This, together with the observation that compounds 3a and 3b triggered significant protein aggregation in HCC1806 cells, supports a mixed mode of action for these compounds.

Extracellular vesicles powered cancer immunotherapy: Targeted delivery of adenovirus-based cancer vaccine in humanized melanoma model.

Malignant melanoma, a rapidly spreading form of skin cancer, is becoming more prevalent worldwide. While surgery is successful in treating early-stage melanoma, patients with advanced disease have only a 20% chance of surviving beyond five years. Melanomas with mutations in the NRAS gene are characterized for a more aggressive tumor biology, poorer prognosis and shorter survival. Hence, new therapeutic strategies are needed, especially for this specific group of patients. Novel approaches, such as cancer vaccines, offer promising solutions by stimulating the anti-tumor immune response. Nevertheless, their clinical efficacy is still modest and more effective approaches are required. Herein, we propose the systemic administration of the adenovirus-based cancer vaccine complexed in extracellular vesicles (EVs) with the aim of achieving a targeted therapeutic effect. The vaccine was based on previously tested oncolytic adenovirus Ad5/3-D24-ICOSL-CD40L in combination with melanoma-specific antigens targeting NRAS mutations to enhance the anticancer effect. The antineoplastic properties of the oncolytic vaccine were evaluated in xenograft MUG Mel-2 melanoma BALB/c nude mice. Moreover, to mimic the tumor microenvironment, while investigating at the same time immune cell infiltration and drug penetration, we established a 3D co-culture model based on human NRAS mutated MUG Mel-2 spheroids and PBMCs (HLA matched), which displayed a synergistic effect when treated with the cancer vaccine compared to relative controls. Subsequently, we investigated the systemic delivery of the vaccine in EV formulations in a humanized NSG MUG Mel-2 melanoma mouse model. Our study provides a promising strategy for a tumor-targeted vaccine delivery by EVs, resulting in improved anticancer efficacy and increased infiltration of tumor-infiltrating lymphocytes. This study explores the potential of EVs for the selective delivery of cancer vaccines against malignancies, such as NRAS melanoma. Overall, this research could pave the way for applying autologous EVs as a safe and efficacious tool for targeted cancer therapy.

Preliminary Study of Radionuclide-Labeled MerTK-Targeting PET Imaging Agents for the Diagnosis of Melanoma.

MerTK PET imaging holds potential as a promising approach for assessing tumor aggressiveness and monitoring treatment response. In this study, we synthesized a series of 18F- and 68Ga-labeled tracers derived from MerTK inhibitors for detection of MerTK expression. Among the synthesized agents, the dimeric compounds [68Ga]10 and [68Ga]12 demonstrated good in vivo and in vitro stability, high affinities to the MerTK receptor, and good MerTK-targeting specificity. Notably, [68Ga]10 exhibited a tumor uptake of 2.6 ± 0.2%ID/g at 1 h p. i. in B16F10 tumor-bearing mice, nearly tripling the uptake of its monomeric counterpart [68Ga]3. A similar enhancement was observed with [68Ga]12 compared to its monomeric analog [68Ga]6. Additionally, [18F]14 achieved a tumor uptake of 7.6 ± 0.5%ID/g at 2 h p. i., outperforming the previously reported [18F]15. Biodistribution analysis further validated the results, highlighting their potential for clinical investigation.

Primary Small Cell Carcinoma of Left Maxillary Sinus: A Case Report of Rare Tumor on Rare Location

Introduction: Primary extrapulmonary small cell carcinoma (EPSCC) is a rare and aggressive tumor with diverse clinical manifestations. In the realm of head and neck pathology, EPSCC most commonly presents in the larynx or oral cavity. Sinonasal small cell neuroendocrine carcinoma represents a particularly infrequent and aggressive neoplasm affecting the nasal cavity and paranasal sinuses. Case Presentation: Here in, we are presenting a case of a 40-year-old nonsmoking male with left maxillary sinus EPSCC, demonstrating extensive local invasion and regional lymphadenopathy. The patient presented with nasal obstruction, ocular swelling, visual loss, and multiple neck swellings. Diagnosis was challenging, requiring a multidisciplinary approach and histopathological confirmation. Immunohistochemistry revealed positive cytokeratin AE1/AE3 and synaptophysin markers validating the diagnosis of small cell carcinoma. Conclusion: This case underscores the diagnostic complexities and highlights the importance of swift intervention and a multidisciplinary treatment approach for optimizing patient outcomes in rare and aggressive tumors like EPSCC. Early detection and prompt management are crucial in resource-limited settings to mitigate morbidity and mortality.

CHORIOCARCINOME GESTATIONNEL DECOUVERT A J46 DUN ACCOUCHEMENT NORMAL

The choriocarcinoma is a rare and aggressive tumor that can grow quickly and spread easily to other parts of the body, sometimes occurring after spontaneous or elective abortion, tubal pregnancy or, more rarely, normal pregnancy. In our case, we reported abnormal uterine bleeding following vaginal delivery at day46. The post-partum period was unremarkable, and the diagnosis of gestational choriocarcinoma was evoked and retained in view of the clinical, biological and radiological picture, management was multidisciplinary and timely, and the prognosis was favorable.

Tumor-targeted glutathione oxidation catalysis with ruthenium nanoreactors against hypoxic osteosarcoma

The majority of anticancer agents have a reduced or even complete loss of a therapeutic effect within hypoxic tumors. To overcome this limitation, research efforts have been devoted to the development of therapeutic agents with biological mechanisms of action that are independent of the oxygen concentration. Here we show the design, synthesis, and biological evaluation of the incorporation of a ruthenium (Ru) catalyst into polymeric nanoreactors for hypoxic anticancer therapy. The nanoreactors can catalyze the oxidation of glutathione (GSH) to glutathione disulfide (GSSG) in hypoxic cancer cells. This initiates the buildup of reactive oxygen species (ROS) and lipid peroxides, leading to the demise of cancer cells. It also stimulates the overexpression of the transient receptor potential melastatin 2 (TRPM2) ion channels, triggering macrophage activation, leading to a systemic immune response. Upon intravenous injection, the nanoreactors can systemically activate the immune system, and nearly fully eradicate an aggressive osteosarcoma tumor inside a mouse model.

ZNF143-mediated upregulation of MEX3C promotes hepatocellular carcinoma progression

BackgroundMicrovascular invasion is strongly associated with aggressive tumor behavior and recurrence in hepatocellular carcinoma (HCC) patients. Zinc finger protein 143(ZNF143) is a transcription factor involved in a wide variety of physiological and developmental processes. This study primarily focuses on the exact biological role and mechanism of ZNF143 in HCC migration and invasion. MethodsThe expression and prognosis of ZNF143 in HCC patients were analyzed. The levels of ZNF143, mex-3 RNA binding family member C (MEX3C) were quantified by western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell migration ability was detected by wound- healing assay. Matrigel transwell assay was conducted to evaluate the invasion of HCC cells. The differential expression genes of ZNF143 overexpression and knockdown were screened by mRNA profiling analysis. Dual luciferase assay was performed to determine the promoter activity of MEX3C. The enrichment of ZNF143 at MEX3C promoter was determined by chromatin immunoprecipitation (ChIP). ResultsZNF143 is overexpressed in HCC tissues and that its overexpression is correlated with poorer prognosis, especially in HCC patients with higher tumor grades and microvascular invasion. Gain- and loss-of function experiments showed that ZNF143 promotes migration and invasion in HCC cells. mRNA profiling showed that ZNF143 significantly upregulates MEX3C. ZNF143 was positively correlated with MEX3C expression in HCC tissue. ZNF143 activates MEX3C transcription by directly binding to its promoter. MEX3C knockdown inhibited migration and invasion induced by ZNF143 overexpression in HCC cells. ConclusionZNF143 promotes HCC cell migration and invasion by binding to MEX3C promoter and activating its expression.

Liver Transplantation for Intrahepatic Cholangiocarcinoma After Chemotherapy and Radioembolization: An Intention-To-Treat Study.

Liver transplantation (LT) is a potentially curative experimental treatment for unresectable intrahepatic cholangiocarcinoma (iCC). Pre-transplant downstaging may help defining tumor aggressiveness and drive patient selection. We report the preliminary results of LT for liver-limited unresectable iCC after sequential downstaging with systemic chemotherapy and radioembolization (SYS-TARE). In case of sustained disease stability after SYS-TARE, patients underwent surgical nodal sampling and, if negative, were listed for LT. In this study, 13 patients with unresectable iCC underwent downstaging with SYS-TARE. The median age was 70years and 77% were female. All had single bulky lesions at diagnosis. After SYS-TARE, 9 (69%) dropped out: 3 due to progressive disease after TARE with no response to second-line, 4 due to extrahepatic disease development and 2 due to positive nodal disease at pre-listing abdominal exploration. The median OS after dropout was 11.5 months. Four (31%) were successfully listed and transplanted. At pathology, viable tumor ranged from 30% to less than 5%. All four patients are alive and disease-free at 73, 40, 12, and 8months from LT. LT for unresectable iCC after downstaging with SYS-TARE appears to select suitable patients for LT, achieving optimal oncological outcomes in case of response to therapy and no lymphnodal spread.

Role of Apparent Diffusion Coefficient Value and Apparent Diffusion Coefficient Ratio as Prognostic Factors for Prostate Cancer Aggressiveness.

Prostate cancer is one of the most prevalent cancers in the male population. To determine the aggressiveness of suspected lesions precisely, predictive models are increasingly being developed using quantitative MRI measurements, and particularly the ADC value. This study aimed to determine whether ADC values could be used to establish the aggressiveness of prostate cancer. A retrospective single-center study included 398 patients with prostate cancer who underwent a multiparametric MRI prior to radical prostatectomy. DWI ADC values were measured (µm2/s) using b values of 50 and 1000. The dominant lesion best visualized on MRI was analyzed. The ADC values of the index lesion and reference tissue were compared to tumor aggressivity according to the Gleason grade groups based on radical prostatectomy results. Statistical analysis was performed using the Mann-Whitney U test, Kruskal-Wallis H test, Spearman's rank correlation, and ROC curves. A very strong negative correlation (rs = -0.846, p < 0.001) between ADC and GS was found. ROC analysis revealed an AUC of 0.958 and an ADC threshold value of 758 µm2/s in clinically significant prostate cancer diagnoses using the absolute ADC value, with no advantage of using the ADC ratio over the absolute ADC value being identified. DWI ADC values and the calculated ADC ratio have a significant inverse correlation with GS. The findings indicate a strong capability in determining prostate cancer aggressiveness, as well as the possibility of assisting with assigning PI-RADS categories using ADC as quantitative metrics.

Switch/Sucrose Non-Fermentable (SWI/SNF) Complex—Partial Loss in Sinonasal Squamous Cell Carcinoma: A High-Grade Morphology Impact and Progression

Sinonasal carcinomas are aggressive neoplasms that present a high morbidity and mortality rate with an unfavorable prognosis. This group of tumors exhibits morphological and genetic diversity. Genetic and epigenetic alterations in these neoplasms are the current targets for diagnosis and treatment. The most common type of cancer originating in the sinonasal tract is sinonasal squamous cell carcinomas (SNSCCs), which present different histological patterns and variable histological aggressiveness. A significant number of alterations have been reported in sinonasal tumors, including deficiencies in the Switch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex. In the sinonasal tract, deficiencies of the subunits SMARCB1/INI1, SMARCA4/BRG1, and SMARCA2 have been noted in carcinomas, adenocarcinomas, and soft tissue tumors with a distinctive high-grade morphology and a fatal prognosis. Objective: The objective of this study is to identify the status of the SWI/SNF complex using immunohistochemistry in sinonasal squamous cell carcinomas and their association with morphology and survival. Methods: A total of 103 sinonasal carcinomas with different grades of squamous differentiation were analyzed; the selection was based on those cases with high-grade morphology. The carcinomas were then evaluated immunohistochemically for SMARCB1 and SMARCA4 proteins. Their expression was compared with the biological behavior and survival of the patients. Results: Among the SNSCCs, 47% corresponded to the non-keratinizing squamous cell carcinoma (NKSCC) type with high-grade characteristics, 40% were keratinizing squamous cell carcinomas (KSCCs), 9% were SMARCB1-deficient carcinomas, and 4% were SMARCA4-deficient carcinomas. Mosaic expression for SMARCB1 (NKSCC—33%; KSCC—21.9%) and SMARCA4 (NKSCC—14.6%; KSCC—12.2%) was identified, showing an impact on tumor size and progression. Conclusions: We identified that that the partial loss (mosaic expression) of SMARCB1 in SNSCCs is associated with high-grade malignant characteristics and a negative effect on patient survival; meanwhile, SMARCA4-mosaic expression in SNSCCs is associated with high-grade malignant characteristics and an increase in tumor size concerning the intact SMARCA4.

18F]FDG and [68Ga]Ga-FAPI-04-Directed Imaging for Outcome Prediction in Patients with High-Grade Neuroendocrine Neoplasms.

We aimed to quantitatively investigate the prognostic value of PET-based biomarkers on [18F]FDG and [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 PET/CT in patients with highly aggressive neuroendocrine neoplasms (NENs) and to compare the visually assessed differences in uptake on both examinations with progression-free survival (PFS). Methods: In this single-center retrospective analysis, 20 patients with high-grade NENs had undergone [18F]FDG and [68Ga]Ga-FAPI-04 PET. Both PET scans were visually compared, and the presence of [18F]FDG-positive, [68Ga]Ga-FAPI-04-negative (FDG+/FAPI-) lesions was noted. In addition, we assessed maximum, peak, and mean SUV; tumor volume (TV); and total lesion uptake (TLU = TV × SUVmean) for both radiotracers using a 40% lesion-based threshold. The results of quantitative and visual analysis were correlated with PFS using log-rank analysis or univariate Cox regression. PFS was defined radiographically using RECIST 1.1., clinically using signs of disease progression, or as death. Results: Most primary tumors were located in the gastrointestinal tract (13/20 patients, 65%) or were cancer of unknown primary (5/20 patients, 25%). FDG+/FAPI- lesions were found in 9 of 20 patients (45%). Patients with FDG+/FAPI- lesions had a significantly decreased PFS of 4 mo, compared with 9 mo for patients without FDG+/FAPI- metastases (P = 0.0063 [log-rank test]; hazard ratio [HR], 5.637; 95% CI 1.619-26.16; P = 0.0110 [univariate Cox regression]). On univariate analysis, a significant correlation was also found between PFS and TV for both radiotracers ([18F]FDG: mean TV, 258 ± 588 cm3; HR, 1.024 [per 10 cm3]; 95% CI, 1.007-1.046; P = 0.0204) ([68Ga]Ga-FAPI-04: mean TV, 130 ± 192 cm3; HR, 1.032 [per 10 cm3]; 95% CI, 1.001-1.062; P = 0.0277) and TLU on [18F]FDG PET (mean TLU, 1,931 ± 4,248 cm3; HR, 1.004 [per 10 cm3]; 95% CI, 1.001-1.007; P = 0.0135). Conclusion: The presence of discordant FDG+/FAPI- lesions is associated with a significantly shorter PFS, which might indicate more aggressive disease prone to early progression. Dual-tracer PET/CT of patients with highly aggressive NENs could help guide treatment decisions or identify high-risk lesions for additional local therapeutic approaches.

Successful management of refractory Cushing's disease with severe hypercortisolemia using etomidate and temozolomide in post-surgical failure.

Corticotropinomas account for 20% of all aggressive pituitary tumors and pituitary carcinomas and are associated with high mortality. These tumors not only cause neurovascular compromise but can also be fatal due to severe hypercortisolemia itself. Although surgery is considered the primary treatment modality, it is often partially successful or unsuccessful. Moreover, these tumors frequently recur and may be resistant to conventional treatments, including surgery and radiotherapy. Therefore, early multimodal treatment and regular follow-up are necessary. We present a case of aggressive Cushing's disease managed with combined temozolomide therapy and radiotherapy following an unsuccessful transsphenoidal surgery, resulting in significant long-term radiological and biochemical remission. In addition, etomidate infusion was administered to achieve rapid cortisol reduction, highlighting its role as a bridging therapy to other modalities in treating life-threatening and severe hypercortisolemia outside an intensive care setting.

Losartan-based nanocomposite hydrogel overcomes chemo-immunotherapy resistance by remodeling tumor mechanical microenvironment

Preclinical studies demonstrating high cure rates with PD1/PD-L1 combinations have led to numerous clinical trials, but emerging results are disappointing. These combined immunotherapies are commonly employed for patients with refractory tumors following prior treatment with cytotoxic agents. Here, we uncovered that the post-chemotherapy tumor presents a unique mechanical microenvironment characterized by an altered extracellular matrix (ECM) elasticity and increased stiffness, which facilitate the development of aggressive tumor phenotypes and confer resistance to checkpoint blocking therapy. As thus, we rationally designed an in situ nanocomposite hydrogel system, LOS&FeOX@Gel, which enabled effective and specific delivery of the therapeutic payloads (losartan [LOS] and oxaliplatin [OX]) into tumor. We demonstrate that sustained release of LOS effectively remodels the tumor mechanical microenvironment (TMM) by reducing ECM deposition and its associated “solid stress”, thereby augmenting the efficacy of OX and its immunological effects. Importantly, this hydrogel system greatly sensitized post-chemotherapy tumor to checkpoint blocking therapy, showing synergistic therapeutic effects against cancer metastasis. Our study provides mechanistic insights and preclinical rationale for modulating TMM as a potential neoadjuvant regimen for tumor to optimize the benefits of chemo-immunotherapy, which lays the groundwork for leveraging “mechanical-immunoengineering” strategies to combat refractory tumors.Graphical

Perivascular epithelioid cell tumor of the uterus and pelvic cavity.

Primary perivascular epithelioid cell tumors (PEComas) of the female reproductive tract have been primarily reported as case reports owing to their clinical rarity. Limited incidence rates and clinical case data hinder a comprehensive understanding of the risks and invasiveness of this disease. We discuss herein the diagnosis, treatment, and prognosis of this disease to enhance comprehension and therapeutic strategies. We conducted a clinical analysis of patients with PEComa treated at the Gynecology Department of The West China Second University Hospital of Sichuan University between May 2018 and January 2024. Diagnosis and treatment were evaluated based on pertinent literature. Overall, eight patients (seven patients with tumors in the uterus and one patient with tumors in the pelvic cavity) were evaluated. One patient with PEComa of unknown malignant potential and two patients with malignant PEComa underwent hysterectomy and bilateral adnexectomy with or without adjuvant therapy and did not develop recurrence. Meanwhile, three patients who underwent lesion resection only exhibited radiological evidence of new lesions. Furthermore, postoperative imaging identified new pulmonary nodules in three patients. Although the current criteria are generally effective in assessing the tumor invasiveness of PEComa, emphasizing the significance of complete lesion resection remains crucial. Inadequate treatment significantly increases the risks of recurrence and metastasis. Additionally, the prevalence of pulmonary metastases may have been underestimated. Refining risk stratification to prevent overtreatment of low-grade malignancies or overlooking highly aggressive tumors is an important area for further study.

Radiomics in precision medicine for colorectal cancer: a bibliometric analysis (2013–2023)

BackgroundThe incidence and mortality of colorectal cancer (CRC) have been rising steadily. Early diagnosis and precise treatment are essential for improving patient survival outcomes. Over the past decade, the integration of artificial intelligence (AI) and medical imaging technologies has positioned radiomics as a critical area of research in the diagnosis, treatment, and prognosis of CRC.MethodsWe conducted a comprehensive review of CRC-related radiomics literature published between 1 January 2013 and 31 December 2023 using the Web of Science Core Collection database. Bibliometric tools such as Bibliometrix, VOSviewer, and CiteSpace were employed to perform an in-depth bibliometric analysis.ResultsOur search yielded 1,226 publications, revealing a consistent annual growth in CRC radiomics research, with a significant rise after 2019. China led in publication volume (406 papers), followed by the United States (263 papers), whereas the United States dominated in citation numbers. Notable institutions included General Electric, Harvard University, University of London, Maastricht University, and the Chinese Academy of Sciences. Prominent researchers in this field are Tian J from the Chinese Academy of Sciences, with the highest publication count, and Ganeshan B from the University of London, with the most citations. Journals leading in publication and citation counts are Frontiers in Oncology and Radiology. Keyword and citation analysis identified deep learning, texture analysis, rectal cancer, image analysis, and management as prevailing research themes. Additionally, recent trends indicate the growing importance of AI and multi-omics integration, with a focus on improving precision medicine applications in CRC. Emerging keywords such as deep learning and AI have shown rapid growth in citation bursts over the past 3 years, reflecting a shift toward more advanced technological applications.ConclusionsRadiomics plays a crucial role in the clinical management of CRC, providing valuable insights for precision medicine. It significantly contributes to predicting molecular biomarkers, assessing tumor aggressiveness, and monitoring treatment efficacy. Future research should prioritize advancing AI algorithms, enhancing multi-omics data integration, and further expanding radiomics applications in CRC precision medicine.

Phase II study of uPAR-PET/CT for staging of primary breast cancer in comparison with ultrasound and fine needle biopsies

Accurate initial staging of patients with breast cancer is essential for planning optimal treatment strategies. However, currently, no imaging modality is able to detect lymph node metastases preoperatively with sufficient reliability; therefore, the N status depends on the sentinel node procedure for ~ 70% of patients. In a prospective clinical trial of breast cancer patients, we compared head-to-head uPAR-PET/CT with current standard-of-care, ultrasound (US) and fine needle biopsy (FNB) as staging methods. Forty-nine patients (48 women and 1 man) with biopsy-proven early breast cancer underwent uPAR-PET/CT prior to surgery. All image data were analyzed by two separate teams, each consisting of a highly experienced certified specialist in nuclear medicine and a highly experienced certified specialist in radiology for visualization of primary tumor lesions and detection of lymph node and distant metastases. Histopathological assessment and verification of malignancy in the excised tissues (primary tumors and lymph nodes) were considered standard-of-truth. On a per patient basis, uPAR PET/CT demonstrated a sensitivity of 94% [CI: 83–99%] for detecting the primary tumor (both teams). For the detection of axillary lymph nodes the pooled sensitivity of uPAR PET/CT was 33.3% [CI: 16.5–54.0%], specificity 87.0% [CI: 66.4–97.2%] and accuracy 58.0% [CI: 43.2–71.8%]. In comparison, the standard-of-care preoperative clinical staging algorithm with US and FNB had a sensitivity of 41% [CI: 22–61%] and specificity of 100% [CI: 85–100%] for axillary lymph node metastases. We conclude that the results do not support the use of uPAR PET/CT for staging in breast cancer patients. However, the finding that 94% of primary tumors were uPAR-PET positive may be encouraging for pursuing uPAR theranostics in localized disease. Additionally, other potential applications, such as using uPAR-PET as a prognostic imaging biomarker of tumor aggressiveness, remain to be investigated.

The value of multiple diffusion metrics based on whole-lesion histogram analysis in evaluating the subtypes and proliferation status of non-small cell lung cancer.

Limited studies have explored the utility of whole-lesion histogram analysis in discerning the subtypes and proliferation status of non-small cell lung cancer (NSCLC), despite its potential to provide comprehensive tissue assessment through the computation of additional quantitative metrics. This study sought to assess the significance of intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) histogram parameters in discriminating between squamous cell carcinoma (SCC) and adenocarcinoma (AC), and to examine the correlation of each parameter with the proliferative marker Ki-67. Patients with space-occupying lesions detected by chest CT examination and with further routine MRI, DKI and IVIM functional sequence scans were enrolled. Based on the pathological results, seventy patients with NSCLC were selected and divided into AC and SCC groups. Histogram parameters of IVIM (D, D*, f) and DKI (Dapp, Kapp) were calculated, and the Mann-Whitney U test or independent samples t test was used to analyze the differences in each histogram parameter of the SCC and AC groups. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of the histogram parameters. The correlation coefficient between histogram parameters and Ki-67 was calculated using Spearman's or Pearson's methods. The D 10th percentile, D 90th percentile, D mean, D median, Dapp 10th percentile, Dapp 90th percentile, Dapp mean, Dapp median, Dapp skewness, Dapp SD of the AC groups were significantly higher than those of the SCC groups, while the Kapp entropy and Kapp SD of the SCC groups were significantly higher than those of the AC groups. All the above differences were statistically significant (all P < 0.05). ROC curve analysis revealed that Dapp mean showed the best performance for differentiating AC from SCC lesions, with an area under the ROC curve of 0.832 (95% confidence interval [CI]: 0.707-0.919). But there was no statistically significant difference in diagnostic efficacy compared to other histogram parameters (all P>0.05). Dapp 90thpercentile, Dapp mean, Kapp skewnes showed a slight negative correlation with Ki-67 expression (r value -0.340, -0.287, -0.344, respectively; P< 0.05), while the other histogram parameters showed no significant correlation with Ki-67 (all P > 0.05). Our study demonstrates the utility of IVIM and DKI histogram analyses in differentiating NSCLC subtypes, particularly AC and SCC. Correlations with the Ki-67 index suggest that Dapp mean, Dapp 90th percentile, and Kapp skewness may serve as markers of tumor aggressiveness, supporting their use in NSCLC diagnosis and treatment planning.

A method for in silico exploration of potential glioblastoma multiforme attractors using single-cell RNA sequencing

We presented a method to find potential cancer attractors using single-cell RNA sequencing (scRNA-seq) data. We tested our method in a Glioblastoma Multiforme (GBM) dataset, an aggressive brain tumor presenting high heterogeneity. Using the cancer attractor concept, we argued that the GBM’s underlying dynamics could partially explain the observed heterogeneity, with the dataset covering a representative region around the attractor. Exploratory data analysis revealed promising GBM’s cellular clusters within a 3-dimensional marker space. We approximated the clusters’ centroid as stable states and each cluster covariance matrix as defining confidence regions. To investigate the presence of attractors inside the confidence regions, we constructed a GBM gene regulatory network, defined a model for the dynamics, and prepared a framework for parameter estimation. An exploration of hyperparameter space allowed us to sample time series intending to simulate myriad variations of the tumor microenvironment. We obtained different densities of stable states across gene expression space and parameters displaying multistability across different clusters. Although we used our methodological approach in studying GBM, we would like to highlight its generality to other types of cancer. Therefore, this report contributes to an advance in the simulation of cancer dynamics and opens avenues to investigate potential therapeutic targets.

Targeting the undruggable in glioblastoma using nano-based intracellular drug delivery.

Glioblastoma (GBM) is a highly prevalent and aggressive brain tumor in adults with limited treatment response, leading to a 5-year survival rate of less than 5%. Standard therapies, including surgery, radiation, and chemotherapy, often fall short due to the tumor's location, hypoxic conditions, and the challenge of complete removal. Moreover, brain metastases from cancers such as breast and melanoma carry similarly poor prognoses. Recent advancements in nanomedicine offer promising solutions for targeted GBM therapies, with nanoparticles (NPs) capable of delivering chemotherapy drugs or radiation sensitizers across the blood-brain barrier (BBB) to specific tumor sites. Leveraging the enhanced permeability and retention effect, NPs can preferentially accumulate in tumor tissues, where compromised BBB regions enhance delivery efficiency. By modifying NP characteristics such as size, shape, and surface charge, researchers have improved circulation times and cellular uptake, enhancing therapeutic efficacy. Recent studies show that combining photothermal therapy with magnetic hyperthermia using AuNPs and magnetic NPs induces ROS-dependent apoptosis and immunogenic cell death providing dual-targeted, immune-activating approaches. This review discusses the latest NP-based drug delivery strategies, including gene therapy, receptor-mediated transport, and multi-modal approaches like photothermal-magnetic hyperthermia combinations, all aimed at optimizing therapeutic outcomes for GBM.

Amino Acid Deprivation in Glioblastoma: The Role in Survival and the Tumour Microenvironment—A Narrative Review

Background: Glioblastoma is the most common and aggressive primary brain tumour, characterised by its invasive nature and complex metabolic profile. Emerging research highlights the role of amino acids (AAs) in glioblastoma metabolism, influencing tumour growth and the surrounding microenvironment. Methods: This narrative review synthesises recent pre-clinical studies focusing on the metabolic functions of AAs in glioblastoma. Key areas include the effects of AA deprivation on tumour growth, adaptive mechanisms, and the tumour microenvironment. Results: The effects related to arginine, glutamine, methionine, and cysteine deprivation have been more extensively reported. Arginine deprivation in arginine-auxotrophic glioblastomas induces apoptosis and affects cell adhesion, while glutamine deprivation disrupts metabolic pathways and enhances autophagy. Methionine and cysteine deprivation impact lipid metabolism and ferroptosis. Tumour adaptive mechanisms present challenges, and potential compensatory responses have been identified. The response of the microenvironment to AA deprivation, including immune modulation, is critical to determining therapeutic outcomes. Conclusions: Targeting AA metabolism offers a promising approach for glioblastoma treatment, with potential targeted drugs showing clinical promise. However, the complexity of tumour adaptive mechanisms and their impact on the microenvironment necessitates further research to optimise combination therapies and improve therapeutic efficacy.