Stereotactic radiosurgery offers long-term tumor control for craniopharyngioma: a multi-institutional analysis of clinical and imaging outcomes from the International Radiosurgery Research Foundation (IRRF)

Abstract: Craniopharyngioma is histologically benign yet locally aggressive, with frequent recurrence. Long-term multicenter outcomes after stereotactic radiosurgery (SRS) remain incompletely defined. We performed a retrospective multi-institutional cohort study through the International Radiosurgery Research Foundation including 296 patients from 13 centers. Median age at first SRS was 33.6 years. Median tumor volume was 1.32 cm³ and median margin dose was 12.0 Gy. The primary endpoint was local control (LC); secondary endpoints were progression-free survival (PFS) and overall survival (OS). Kaplan-Meier methods estimated outcomes, and Cox proportional hazards models evaluated predictors of LC. Actuarial 1-, 5-, and 10-year LC was 93.5%, 76.2%, and 70.1%. Actuarial 1-, 5-, and 10-year OS was 98.2%, 93.6%, and 85.2%, and PFS was 92.4%, 73.6%, and 64.8%. Mixed solid-cystic phenotype had worse LC than non-mixed tumors (log-rank p = 0.025); non-mixed phenotype remained independently associated with improved LC (HR 0.53, p = 0.026). Visual fields improved in 10%, were unchanged in 86%, and deteriorated in 4%; visual acuity improved in 6%, was unchanged in 91%, and worsened in 3%. Ten-year freedom from endocrine deterioration was 96.7%. Diabetes insipidus improved in 6.3%, worsened in 0.5% and other pituitary dysfunction was noted in 2.6%, CONCLUSION: In this international multi-institutional experience, SRS achieved durable long-term control with favorable survival and low incidence of visual and endocrinologic dysfunction. Mixed phenotype was an important determinant of LC. Not applicable.

Niranjan A
Reyes JS
Hadjipanayis CG
Bernstein K
Speckter H
Gonzalez I
Chytka T
Liscak R
Bowden GN
Sumi T
Narita K
Kano H
Martínez-Moreno N
Martínez-Álvarez R
Picozzi P
Franzini A
Tripathi M
Rai A
Kumar N
Douri K
Mathieu D
Dono A
Amezquita-Contreras C
Blanco AI
Esquenazi Y
Tos SM
Mantziaris G
Peker S
Samanci Y
Duzkalir AH
Meng Y
Sheehan JP
Kondziolka D
Lunsford LD

Humans
Craniopharyngioma
Radiosurgery
Female
Pituitary Neoplasms
Retrospective Studies
Male
Adult
Adolescent
Child
Young Adult
Middle Aged
Follow-Up Studies
Child, Preschool
Treatment Outcome
Aged


Noise-Driven Tipping in a Tumor-Immune Model with Optimal Combination Therapy

Abstract: Cancer mortality remains high in part because tumor-immune interactions can be unpredictable and may exhibit multistability, making malignant progression difficult to anticipate. We develop and analyze a tumor-immune model incorporating chemotherapy-induced toxicity and a Norton-Simon type tumor response, and show via deterministic analysis and continuation that increasing toxicity can generate hysteresis and bistability separating tumor dormancy from an uncontrolled full-growth state, so that small perturbations may precipitate abrupt progression. To capture uncertainty, we study environmental and demographic stochasticity and observe noise-induced switching in both cases; however, demographic noise sustains higher resilience of the tumor-dominant state under bistability, whereas stronger environmental noise tends to suppress uncontrolled tumor growth. We further assess early-warning signals using single and composite rolling-window indicators and find that they can provide advance warning of transitions from dormancy to full growth, with composite measures offering greater robustness across noise levels. Finally, we formulate an optimal control problem for combination immunotherapy and radiotherapy and demonstrate that appropriately timed treatment can substantially reduce tumor burden when initiated from either dormancy or full-growth conditions, highlighting how stochasticity-aware monitoring and optimized interventions may help prevent catastrophic tumor progression.

Panda S
Karmakar S
Halder S
Chattopadhyay J
Wang H

Neoplasms
Stochastic Processes
Humans
Mathematical Concepts
Immunotherapy
Combined Modality Therapy
Models, Immunological
Computer Simulation
Animals
Disease Progression
Tumor Microenvironment


Pelvic lymph node dissection during robot-assisted radical prostatectomy: a bibliometric analysis of surgical extent, nodal staging, and lymphatic morbidity

Abstract: Pelvic lymph-node dissection (PLND) during robot-assisted radical prostatectomy (RARP) is important for nodal staging, but its optimal extent, morbidity profile, and integration with precision-guided techniques remain unsettled. This study mapped the knowledge structure and thematic evolution of RARP-associated PLND research. A single-database search of the Web of Science Core Collection was performed for English-language articles and reviews formally published through 2025. Two reviewers independently screened records directly evaluating PLND, nodal staging, lymphatic morbidity, or related preventive and guidance strategies during RARP according to predefined eligibility criteria. Bibliometrix, VOSviewer, CiteSpace, and Scimago Graphica were used to assess publication trends, collaboration patterns, citation structure, and keyword evolution. The final dataset comprised 225 eligible records, including 208 original research articles and 17 review articles published during 2006-2025. Output increased markedly after 2019 and peaked at 27 publications in 2024. The United States received the most citations, whereas the Netherlands Cancer Institute was the most productive institution. van der Poel H.G. was the most productive author. The knowledge base initially focused on PLND templates, anatomical extent, and lymph-node yield, then expanded toward risk-adapted nodal staging, oncologic implications, lymphatic morbidity, and precision-guided nodal assessment. Keyword analysis identified eight thematic clusters and showed recent attention to peritoneal flap and fixation strategies, node-positive disease, and image- or radioguided nodal approaches. This bibliometric analysis characterizes a shift in RARP-associated PLND research from surgical extent and staging yield toward individualized selection, morbidity reduction, and precision-guided nodal strategies. Further prospective studies are needed to clarify how preventive reconstruction and targeted nodal techniques should be integrated with anatomically defined extended PLND.

Lymph Node Excision
Humans
Male
Prostatectomy
Robotic Surgical Procedures
Pelvis
Bibliometrics
Prostatic Neoplasms
Lymph Nodes
Neoplasm Staging
Lymphatic Metastasis


Upregulation of paraoxonase-2 enzyme in human osteosarcoma and its involvement in mechanisms promoting the aggressive behavior of tumor cells

Abstract: Osteosarcoma (OS) is the most common bone cancer, known for its aggressive nature, high chemoresistance, and strong metastatic potential responsible for poor clinical outcomes. In this context, identifying reliable biomarkers and therapeutic targets is therefore critical. This study investigates the role of paraoxonase-2 (PON2), an intracellular enzyme known for its anti-oxidative and anti-apoptotic properties. PON2 overexpression has been observed in various cancers and is implicated in tumor development and progression. PON2 expression was evaluated by immunohistochemistry in bone tissue samples from OS patients and control subjects. shRNA-mediated PON2 silencing was performed in U-2 OS and Saos-2 cells to assess proliferation, viability, migration, chemosensitivity, ROS production, apoptosis activation, glucose uptake, and GLUT1 expression. PON2 overexpression and N-acetylcysteine (NAC) pre-treatment in CDDP-treated U-2 OS cells were used as rescue approaches. Preliminary analyses showed markedly higher PON2 expression in OS than in control bone specimens. PON2 knockdown reduced proliferation, viability, and migration, while enhancing sensitivity to cisplatin (U-2 OS and Saos-2) and doxorubicin (U-2 OS only); these effects were reversed by PON2 upregulation. PON2 silencing also increased ROS levels and caspase expression, and impaired glucose uptake by reducing GLUT1 expression and intracellular glucose levels. Since NAC did not fully rescue these alterations, PON2 appears to sustain chemoresistance by affecting important mechanisms related to ROS detoxification, glucose metabolism, and anti-apoptotic signaling. Obtained data clearly illustrate the potential of PON2 as promising biomarker and molecular therapeutic target for human OS.

Gerini E
Pompei V
Cecati M
Campagna R
Pozzi V
Filosa A
Goteri G
Salvolini E
Emanuelli M
Sartini D

Humans
Osteosarcoma
Aryldialkylphosphatase
Cell Line, Tumor
Bone Neoplasms
Cell Proliferation
Apoptosis
Up-Regulation
Gene Expression Regulation, Neoplastic
Cell Movement
Female
Reactive Oxygen Species
Male
Cell Survival
Cisplatin
Doxorubicin
Drug Resistance, Neoplasm
Glucose Transporter Type 1


Synergistic magnetic nano-chemotherapy overcomes chemoresistance in 3D breast cancer models

Abstract: Monodispersed highly magnetic iron oxide nanocubes and nanospheres with magnetization (78.72 emu/gcubic and 72.08 emu/gsphere with an average size of 17.45 ± 5.13 nm for spherical (IONPs) and with edge lengths ranging from 20.85 ± 6.60 nm for nanocubes (IONCs) have been successfully synthesized and functionalized with methoxy-polyethylene glycol (m-PEG). The specific absorption rate (SAR) has been observed to be 351.5 W/g for IONPs and 415.06 W/g for the IONCs. The antimicrobial activity of the synthesized nanoparticles (NPs) against Staphylococcus aureus and Escherichia coli was evaluated using the agar well diffusion method. Anti-angiogenic effects were evaluated via the Chick Chorioallantoic Membrane (CAM) assay, an extensively used in vivo model. Additionally, m-PEG-coated IONCs were functionalized with doxorubicin (DOX) and the tumor-targeting aptamer AS1411 to enable targeted magneto-chemotherapy (MCT) in 3D breast cancer models. The results show that magneto-chemotherapy (MCT) reduces cancer cell viability to 76.41% in 2D cultures and 77.27% in 3D cultures, highlighting the potential of 3D models for enhancing the effectiveness of targeted therapies in breast cancer.

Phalake SS
Patil AP
Patil AR
Salunkhe AB
Park JP
Thorat ND
Khot VM

Doxorubicin
Humans
Female
Breast Neoplasms
Animals
Polyethylene Glycols
Cell Survival
Drug Resistance, Neoplasm
Staphylococcus aureus
Escherichia coli
Magnetite Nanoparticles
Magnetic Iron Oxide Nanoparticles
Anti-Bacterial Agents
Antineoplastic Agents
Cell Line, Tumor


Robotic-assisted resection of pediatric intracavitary lesions: expanding the boundaries of minimally invasive surgery

Abstract: Describe the implementation of robotic-assisted surgery for pediatric cysts and neoplasms and characterize perioperative outcomes. A retrospective review was performed of pediatric patients undergoing robotic-assisted resection of cysts or neoplasms at a quaternary children's hospital from 2011 to 2026. Demographic, lesion, operative, and outcome data were analyzed. Thirty-eight pediatric robotic cases were reviewed. Median age was 13 years (IQR 8.25-16). Eighteen intracavitary cysts and 20 neoplasms were resected. Operations for solid neoplasms consisted of thymectomies (n = 3), mediastinal teratoma excision, lung lobectomy, partial gastrectomy, left hepatectomy, distal pancreatectomy (n = 2), pancreatic uncinate resection, pancreaticoduodenectomy, nephrectomies (2 partial, 2 radical), adrenalectomy, periadrenal mass resection, ovarian cystectomy (n = 2), and radical cystoprostatectomy. Median EBL was 15 mL (IQR 5-25) and day of discharge 1 (IQR 0-2). The median opioid dose prescribed at discharge was 0.28 mg/kg oral morphine equivalents with duration of 1 (0-3) day. Thirty-one (82%) patients experienced no complications. Major complications occurred after pancreatic resections, including hemorrhagic pancreatitis following uncinate resection and delayed biliary stenosis with ductal leak after pancreaticoduodenectomy requiring revision 1.5 years later. Robotic-assisted surgery is a safe and feasible option for selected pediatric cysts and neoplasms, offering low blood loss, short hospitalization, and minimal postoperative opioid requirements.

Chara AO
Gupta VS
Rogers JL
D'Cruz RJ
Stout M
Frainey B
Corona L
Clayton DB
Lovvorn HN
Zamora IJ

Humans
Robotic Surgical Procedures
Retrospective Studies
Female
Child
Adolescent
Minimally Invasive Surgical Procedures
Male
Treatment Outcome
Neoplasms


[Radioiodine-Refractory Differentiated Thyroid Carcinoma in Children and Adolescents: A Retrospective Study]

Abstract: Differentiated thyroid carcinoma (DTC) in children is a rare malignancy characterized by a high propensity for regional and distant metastases yet generally associated with a favorable long-term prognosis. Radioiodine-refractory (RAIR) disease represents a distinct clinical challenge, accounting for approximately 10-30% of pediatric DTC cases, and warrants comprehensive investigation of its clinical course, prognostic factors, and therapeutic options. This study aimed to perform an integrated assessment of treatment outcomes in children undergoing combined therapy for DTC (surgery and radioiodine therapy, RAI), with a particular focus on advanced and RAIR disease. We retrospectively analyzed medical records of 278 patients aged 5-18 years who underwent primary surgical treatment between 2008 and 2022, followed by one or more courses of RAI at the Endocrinology Research Centre (Moscow, Russia) from December 2015 to March 2024. The study included patients with advanced disease (high risk of recurrence at diagnosis) fulfilling at least one RAIR criterion, with a median follow-up of 48.0 months [21.5; 62.0]. Among 278 patients, 39 (14%) were diagnosed with advanced disease. Of these, 4 achieved remissions, 29 had stable disease, and 6 experienced biochemical and/or structural progression. Progression-free survival in the RAIR cohort was 85%, while the 5-year overall survival reached 100%. Based on study findings, we propose a novel classification system integrating both the baseline ability of metastases to accumulate ¹³¹I and the dynamic response to RAI (progression vs. stabilization). This framework is designed to optimize treatment and follow-up algorithms. The management of RAIR pediatric DTC should remain balanced: avoiding overtreatment in stable disease, while ensuring timely initiation of modern systemic therapies in patients with risk factors for progression.

Slaschuk KY
Reinberg MV
Rumyantsev PO
Nikiforovich PA
Konokikhina AP
Pershina-Milyutina AP
Aredov AV
Sheremeta MS
Degtyarev MV
Trukhin AA
Chikulaeva OA
Nagaeva EV
Brovin DN
Chernikov RA
Bezlepkina OB
Peterkova VA
Mokrysheva NG
Dedov II

Humans
Adolescent
Child
Thyroid Neoplasms
Iodine Radioisotopes
Retrospective Studies
Female
Child, Preschool
Male
Prognosis
Treatment Outcome


Combined Occupational Exposure to Lead and Other Metals and Risk of Lung Cancer

Abstract: The evidence linking occupational exposure to lead and cancer in humans is suggestive. Existing studies examine individual exposure to lead, ignoring the potential joint effects of mixed metal exposure. We analyzed the data of a case-control study of lung cancer conducted in seven European countries and comprising 2,861 cases and 2,936 controls, with a detailed assessment of occupational exposure to arsenic, cadmium, chromium (VI), and lead, to estimate the odds ratio (OR) of lung cancer for combined exposure to lead and these other carcinogenic metals, after adjustment for potential confounders. The results suggested a synergism between lead and arsenic or cadmium: ORs were around 1.0 for lead alone and above 2.0 for combined exposure. No interaction was suggested between lead and chromium (VI). Our results provide suggestive evidence of a possible interaction between occupational exposure to lead, arsenic, or cadmium and lung cancer risk, and highlight the importance of considering mixed metal exposures in occupational epidemiology.

Boffetta P
Zaridze D
Świątkowska B
Pándics T
Lissowska J
Fabiánová E
Field JK
Mates D
Schejbalová M
Foretova L
Janout V
Mukheria A
Yang C
Seyyedsalehi MS

Humans
Lung Neoplasms
Occupational Exposure
Lead
Occupational Diseases
Cadmium
Case-Control Studies
Arsenic
Male
Middle Aged
Chromium
Female
Europe
Risk Factors
Aged


Evaluation of AI-derived LAD artery dose metrics for survival stratification in stage III NSCLC: A secondary analysis of RTOG 0617 trial

Abstract: While the radiation dose to left anterior descending (LAD) artery is associated with overall survival (OS) in NSCLC patients, manual segmentation is labor-intensive. Several auto-segmentation models were developed on average 4DCT with promising geometric agreement, yet their feasibility in clinical outcome analysis on lung CT remains unclear. This study evaluates whether automated LAD segmentation can reproduce, at the group level, the established dose-survival association in a multi-institutional clinical trial dataset. Three deep learning-based auto-segmentation (DLAS) models for automatic segmentation of the LAD coronary artery were applied to 460 patients from the NRG Oncology/RTOG 0617 dataset. Kaplan-Meier curves and Cox proportional hazard ratio (HR) were calculated using each model's segmentation. The LAD V15 Gy was used to stratify patients into high-and low-risk groups, and the cut-off values were determined by minimizing mean absolute error (MAE) between DLAS-derived and manual OS curves. All three models demonstrated significantly different OS curves between the high risk and low risk groups (p < 0.05). The HR was 1.40 (95% CI: 1.02-1.93; p = 0.0381; MAE = 7.1%), 1.32 (95% CI: 1.03-1.68; p = 0.0258; MAE = 9.6%), and 1.37 (95% CI: 1.03-1.84; p = 0.0331; MAE = 7.9%) for the three models using a common V15 Gy ≥ 10% cut-off. After optimizing the cut-off, one model aligned well with what was derived from manual segmentation (MAE = 4.3%). Among the evaluated models, one DL model showed the strongest performance of survival groups separation and achieved group-level overall survival stratification comparable to that previously reported using manual contours in the multi-institutional cohort. Further validation with paired manual contours and pre-specified cutoffs is warranted.

Humans
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Coronary Vessels
Radiation Dosage
Neoplasm Staging
Survival Analysis
Image Processing, Computer-Assisted
Artificial Intelligence
Radiotherapy Dosage
Deep Learning

Journal Article
Evaluation Study
Multicenter Study


Real-world assessment of a deep learning neural network algorithm for prostate cancer detection in MRI using true de novo data

Abstract: Deep-learning neural network algorithms for detecting prostate cancer in MRI have proliferated in the literature. However, out of 30+ studies published since the PROSTATEx challenge, no studies tested the performance of their algorithm against using true external image data sets (studies came from an outside institution that did not supply any training data to the algorithm) while validating against MR-US fusion biopsy or whole-mount prostatectomy. Using true external data sets paints a much clearer picture of real-world clinical performance of an algorithm. This work will assess the performance of a published deep learning (DL) neural network algorithm to detect prostate cancer using external studies. The main difference from other studies is the combination of using only MR-US fusion biopsy results as a gold standard; using test data from an institution that did not supply any training data for this version of the algorithm (including studies acquired with an endorectal coil, which were not in the original training set); and comparing the performance of algorithm-generated regions-of-interest (ROIs) versus algorithm heat maps. Patients were included in the study if they had a prostate MRI with at least one radiologist-drawn target on MRI and underwent MR-US fusion biopsy where the target was sampled for pathological analysis. Patients were excluded if they had any history of prostate cancer treatment, had previously undergone MR-US fusion biopsy at our institution, were missing MRI acquisitions, had artifacts in image sets, or if the study had been shared for future algorithm development. MR image data was assessed using a DL research prototype (XProstate) from Siemens Healthineers that produced (a) ROIs in suspected cancer areas with a level of suspicion (LoS) score and (b) heat maps with LoS scores across the entire gland. The XProstate prototype had been trained with 2170 studies from eight different academic institutions. Clinical radiologist, XProstate ROI, and XProstate Heat Map scores were assessed with ROC analysis using pathology results from biopsy as a gold standard. 202 unique patients were included for assessment of the XProstate research prototype. The ROC curve for the XProstate Heat Map LoS score generated the highest AUC (0.76, 95% CI: 0.70, 0.82) followed by clinical radiologist PI-RADS score (0.73, 95% CI: 0.68, 0.79) and by XProstate ROI LoS score (0.71, 95% CI: 0.65, 0.77). Neither the XProstate Heat Map (AUC difference = 0.03, 95% CI: -0.04, 0.10, p = 0.38) nor the XProstate ROI (AUC difference = -0.02, 95% CI: -0.09, 0.04, p = 0.43) was significantly different from the radiologist PI-RADS score. The XProstate prototype demonstrated equivalent performance as clinical radiologists when presented with de novo cases that would mirror a real-world clinical deployment. The automatic ROI delineation more closely matched clinical radiologist performance when using a cutoff of PI-RADS 5 for annotating suspicious regions. Overall, the XProstate prototype provided reasonable clinical performance and this study demonstrated the need to assess Deep Learning prototypes with external institutional test data.

Shea SM
Wesolowski M
Hashem A
Goldberg A
Joyce C
Gupta G
Grimm R
von Busch H
Lou B
Kamen A

Prostatic Neoplasms
Humans
Male
Deep Learning
Magnetic Resonance Imaging
Image Processing, Computer-Assisted
Algorithms


NOTCH1 gene signaling pathway in the development and progression of carcinomas: an integrative review in cellular and molecular contexts

Abstract: The NOTCH1 gene and its signaling pathway play a critical role in the oncogenesis and progression of various carcinomas through complex cellular and molecular mechanisms. This integrative literature review examines 21 selected studies across multiple carcinoma types, including head and neck, prostate, penis, breast, and hepatocellular carcinomas, to elucidate the functional impact of notch1 alterations on tumor behavior and clinical outcomes. NOTCH1 functions as a context-dependent regulator, acting either as an oncogene or tumor suppressor according to cellular environment and molecular context. Aberrations in notch1 signaling influence cell proliferation, differentiation, apoptosis, and angiogenesis, thereby contributing to cancer initiation and progression. Despite some variability in findings, the majority of studies indicate that notch1-related molecular changes have significant implications for prognosis and potential therapeutic targeting. This review highlights the importance of understanding notch1 signaling pathways in the cellular and molecular biology of carcinomas, aiming to pave the way for novel diagnostic and treatment strategies.

Cellular and molecular biology (Noisy-le-Grand, France)

Silva LMSD
Matos AGM
Kwang Ii Marciaga Teófilo
Carvalho JV
Duarte DRD
Sousa BLN
Carmo JMDGRD
Beltrammi DGM
Lages JS
Frazão RDGC
Teixeira Júnior AAL
Pinho JD
Silva GEB

Humans
Receptor, Notch1
Signal Transduction
Disease Progression
Carcinoma
Animals
Gene Expression Regulation, Neoplastic


Pomegranate seed oil combined with low-frequency electromagnetic field enhances apoptosis in HT29 colon cancer cells via modulating caspase-3, caspase-9, Bax, and Bcl-2 expression

Abstract: Colon cancer is one of the most prevalent cancers globally, characterized by the abnormal growth of cells in the intestines. Numerous studies have explored the effects of pomegranate-derived products, such as pomegranate seed oil (PSO), as anti-proliferative, anti-invasive, and pro-apoptotic agents against various cancer cell lines. Additionally, previous research has highlighted the anti-cancer properties of low-frequency electromagnetic fields (LF-EMF). In the present study, we investigated the combined effects of these two factors on the expression of the Caspase 3, Caspase 9, BAX, and Bcl2 genes. Human colon cancer cells of the HT29 line were sourced from the Pasteur Institute of Iran cell bank and maintained in a complete culture medium. The cells were categorized into four groups: control, PSO, EMF, and PSO+EMF. To assess cell viability and the type of cell death, MTT and Annexin V-FITC assays were employed. Changes in the expression levels of Caspase 3, Caspase 9, BAX, and Bcl2 were analyzed using Real-Time PCR. The results from the MTT and Annexin V-FITC assays indicated that both PSO and EMF reduced cell viability and promoted apoptosis in colon cancer cells. The Real-Time PCR results showed an upregulation of Caspase 3, Caspase 9, and BAX genes, along with a downregulation of Bcl2 expression in the treatment groups compared to the control group. This study demonstrated that the combination of PSO and EMF enhances apoptotic gene expression, thereby diminishing the proliferation and viability of cancer cells. Based on these findings, both PSO and LF-EMF exhibit cytotoxic effects on colon cancer cells, suggesting their potential as candidates for future research in the field of colon cancer.

Humans
Apoptosis
bcl-2-Associated X Protein
Caspase 3
Proto-Oncogene Proteins c-bcl-2
Plant Oils
Caspase 9
HT29 Cells
Pomegranate
Seeds
Colonic Neoplasms
Electromagnetic Fields
Gene Expression Regulation, Neoplastic
Cell Survival
Cell Proliferation


The pivotal role of mitochondrial disorders in cancer development with a special focus on mitochondria-mediated apoptosis

Abstract: Emerging evidence indicates that mitochondrial dysfunction is not merely a consequence but a driving force in cancer progression. Unlike normal cells, cancer cells rewire their mitochondrial metabolism to support uncontrolled proliferation, a process that includes aerobic glycolysis, persistent reactive oxygen species production, and adaptation to hypoxic conditions. A common hallmark across many tumors is the suppression of the intrinsic apoptotic pathway, primarily achieved through an imbalance between anti-apoptotic and pro-apoptotic BCL-2 family proteins. This evasion of cell death not only facilitates tumor initiation and metastasis but also contributes to resistance against conventional therapies. Here, we provide an overview of major mitochondrial alterations in cancer, with a detailed focus on how the mitochondrial apoptotic machinery is disabled in malignant cells. We then discuss current therapeutic strategies designed to re-activate mitochondria-mediated apoptosis, including BH3 mimetics, direct activators of pro-apoptotic proteins like BAX, immune checkpoint inhibitors, CAR‑T cell therapy, and mitochondria-targeted nanomedicine. Finally, we address the limitations and safety concerns of existing pro-apoptotic drugs and propose future directions to develop more selective and effective cancer treatments. Understanding the molecular mechanisms that govern mitochondrial apoptosis may open new avenues for inducing tumor cell death while minimizing harm to normal tissues.

Blagov AV
Orekhov NA
Rozhkova U
Antonov S
Utkina A
Orekhov AN

Humans
Apoptosis
Mitochondria
Neoplasms
Animals
Mitochondrial Diseases
Proto-Oncogene Proteins c-bcl-2
Reactive Oxygen Species


Transcriptomic Association of COL3A1(+) Fibroblasts With Mechanical Pain-Related Gene Signatures in Triple-Negative Breast Cancer

Abstract: Epidemiological data show that approximately 80% of cancer patients experience pain of varying degrees throughout the course of their disease, with nearly one-third experiencing severe pain, significantly impacting their quality of life and the effectiveness of antitumor treatment. Triple-negative (TN) breast cancer tissues typically exhibit increased stromal stiffness and abnormally elevated mechanical stress; these biomechanical alterations may amplify pain signals by activating mechanosensitive channels. Utilizing single-cell RNA sequencing analysis, this study aims to elucidate the potential biological links between fibroblast mechanotransduction and cancer-associated pain, thereby providing a theoretical basis for clinical diagnosis and treatment. Dimensionality reduction and unsupervised clustering were used to identify cell types in TN breast cancer single-cell RNA sequencing data. To assess the association between pain and mechanical stimulation, we constructed a set of gene signatures associated with mechanical stimulation and pain and calculated scores using the Area Under the Curve Cell (AUCell). CellChat and SCENIC were used to reveal the communication networks and transcription factor regulatory mechanisms of fibroblast subtypes. COL3A1+ fibroblasts derived from TN breast cancer are highly involved in biological processes such as extracellular matrix remodeling, collagen fiber formation, and mechanotransduction. To assess the association between pain and mechanical stimulation, we constructed a gene signature set related to mechanical stimuli and pain and calculated corresponding scores using the AUCell tool. Cell communication studies showed that COL3A1+ fibroblasts interact extensively with epithelial cells and other cells through laminin and collagen signaling pathways, potentially leading to mechanotransduction remodeling of the TN breast cancer microenvironment. COL3A1+ fibroblasts demonstrate enhanced transcriptional profiles pertinent to collagen deposition and cytoskeletal reorganization, which are correlated with mechanotransduction signaling and may be connected with mechanical sensitivity in cancer-related pain. This study systematically characterizes the potential relationship between fibroblast-associated mechanotransduction characteristics and pain-related gene signatures at the single-cell level in TN breast cancer. These findings offer hypothesis-generating insights into the molecular landscape of tumor-associated pain, although additional experimental and clinical validation is necessary.

Humans
Triple Negative Breast Neoplasms
Female
Fibroblasts
Transcriptome
Pain
Mechanotransduction, Cellular
Collagen Type III


Ultrasound-based thyroid nodule segmentation with deep hybrid convolutional network

Abstract: Automatic segmentation of ultrasound-based thyroid nodules can assist physicians in more efficiently and accurately assessing thyroid diseases. However, thyroid ultrasound imaging presents certain unique challenges, such as blurred boundaries of nodules, strong heterogeneity in tissue echoes, and limited contrast between the lesions and adjacent normal thyroid tissue, which hinder the precise identification of nodules in clinical assessment. To overcome these obstacles, we propose a deep hybrid convolutional network, named UTNseg, for precisely automatic segmentation of ultrasound-based thyroid nodules. UTNseg contains four newly designed modules upon TransUNet: (1) the spatial-channel feature strong capture (STransformer) module is designed to reinforce the ability of encoder on capturing spatial and channel features, (2) the redundant feature map utilization (RMU) module is devised to mitigate redundant information in the skip connections, (3) the composite convolution (CConv) module is newly designed to further preserve the key multi-scale features of the target thyroid nodules, (4) the lightweight edge refinement (LER) module is newly proposed to refine the initial segmentation outputs. UTNseg was evaluated on two publicly available ultrasound datasets of thyroid nodules (TN3K with 3493 images and DDTI with 637 images). Datasets were divided at the patient level, with 4000 training images (2000 images from TN3K and 2000 images from DDTI, augmented by random rotation, scaling, and horizontal flipping on 445 images), 761 validation images (698 images from TN3K and 63 images from DDTI), and 924 test images (795 images from TN3K and 129 images from DDTI). Additionally, separate experiments were performed on these two datasets in comparative experiments. And the performance was compared with six state-of-the-art segmentation methods (U-Net, TransUNet, TRFENet, UNeXt, TRFE+ and BPAT-UNet). Evaluation metrics mainly included Dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (HD95). Statistical significance level was analyzed through the Wilcoxon signed-rank test, and the effect size was quantified by Cohen's d . Holm-Bonferroni correction was employed to correct for multiple comparisons. On the TN3K dataset, UTNseg achieved 79.52% DSC and 16.32 HD95. On the DDTI dataset, UTNseg achieved 86.21% DSC and 12.76 HD95. On the hybrid dataset, UTNseg achieved 80.77% DSC and 14.56 HD95. These results showed that UTNseg achieved superior performance. Compared with state-of-the-art approaches, UTNseg was statistically significant ( p < 0.05  ), and the corresponding effect sizes were mostly medium or large, further quantifying the practical importance of the improvements. UTNseg demonstrated excellent segmentation performance on the public dataset. Statistical significance and effect size analysis both indicate that the improvements are reliable and have practical significance.

Lu F
Sun H
Jiang B
Zhang Z
Ren G
Cai J
Gu Y
Ren P
Peng T

Thyroid Nodule
Ultrasonography
Humans
Image Processing, Computer-Assisted
Convolutional Neural Networks


Real-World Outcomes of Radium-223 Therapy in Metastatic Castration-Resistant Prostate Cancer: Predictive Value of PSA Doubling Time and Enzalutamide Continuation

Abstract: Radium-223 dichloride (Ra-223) is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. However, predictive factors associated with treatment efficacy remain unclear. This study evaluated prognostic factors associated with the efficacy of Ra-223 and investigated outcomes according to enzalutamide (ENZ) combination patterns. We retrospectively analyzed 34 patients with mCRPC treated with Ra-223 between 2016 and 2024. Progression-free survival (PFS) and overall survival (OS) were evaluated according to time to CRPC, pre-treatment prostate-specific antigen (PSA), PSA doubling time (PSADT), metastatic burden, and ENZ treatment patterns. Cutoff values were determined using the Contal-O'Quigley method. This study was approved by the Institutional Review Board of Gunma University (Approval No. 1662). The median time to CRPC, pre-treatment PSA level, and PSADT were 17 months, 6.2 ng/mL, and 2.2 months, respectively. Shorter time to CRPC (≤ 19 months), higher pre-treatment PSA (> 2.67 ng/mL), and shorter PSADT (≤ 2 months) were significantly associated with shorter PFS. Patients with ≥ 4 bone metastatic regions had significantly worse OS than those with ≤ 3 regions. Among the ENZ treatment patterns, continuous ENZ administration combined with Ra-223 was associated with significantly longer PFS than discontinuation of ENZ. Time to CRPC, pre-treatment PSA, and PSADT may represent potentially useful candidate markers for identifying patients more likely to benefit from Ra-223 therapy. Continued ENZ administration during Ra-223 therapy was associated with favorable PFS in selected patients; however, this finding should be considered exploratory and requires validation in larger cohorts.

International journal of urology : official journal of the Japanese Urological Association

Abe K
Miyazawa Y
Nakazawa S
Onose M
Maeno Y
Tsuji Y
Kanayama A
Ohtsu A
Fujizuka Y
Arai S
Nomura M
Sekine Y
Koike H
Matsui H
Suzuki K


[Study on the Resistance Mechanism of Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia--Review]

Abstract: Blinatumomab is the first globally approved bispecific T cell engager targeting the B-cell surface antigen CD19, and numerous clinical trials have demonstrated its significant efficacy in B-acute lymphoblastic leukemia (B-ALL) patients. However, with its widespread application, the problem of drug resistance is gradually becoming apparent. The specific mechanisms of drug resistance mainly include antigen escape, lineage switch, immune checkpoint pathway dysregulation and T cell exhaustion. In this review, the mechanisms of resistance to blinatumomab in B-ALL are systematically described, and relevant therapeutic strategies targeting these resistance factors are summarized to provide a reference for clinical diagnosis and treatment.

Precursor Cell Lymphoblastic Leukemia-Lymphoma


[Cellular Senescence in Hematological Malignancies: Pathogenesis and Traditional Chinese Medicine Treatment Strategies--Review]

Abstract: Cellular senescence is fundamentally characterized as an irreversible cell cycle arrest state. Studies have revealed that cellular senescence plays a significant role in the pathogenesis and progression of hematological malignancies. Consequently, inducing cellular senescence has emerged as a therapeutic strategy for these malignancies. Traditional Chinese herbal medicine, characterized by its high efficacy and relatively low toxicity, has shown unique potential in inducing senescence in hematological tumor cells. Previous studies have shown that traditional Chinese herbal medicine can induce cellular senescence through mechanisms such as telomere shortening, DNA damage induction, and regulation of the senescence-associated secretory phenotype (SASP) to treat hematological malignancies. This review aims to summarize the recent advances in the mechanisms by which cellular senescence contributes to the pathogenesis of hematological malignancies and the role of traditional Chinese herbal medicine in inducing cellular senescence for therapeutic purposes, thereby providing novel insights and theoretical support for the application of traditional Chinese herbal medicine in the treatment of hematological malignancies.

Cellular Senescence
Humans
Hematologic Neoplasms
Drugs, Chinese Herbal
Medicine, Chinese Traditional


[Advances in the Study of Factors Influencing the Efficacy of CAR-T Cell Therapy in Hematologic Oncology Treatment--Review]

Abstract: Chimeric antigen receptor T cell (CAR-T) therapy is a revolutionary progress in the current field of tumor treatment, especially showing remarkable potential in relapsed/refractory hematological malignancies. However, there are significant differences in efficacy among different patients, and such differences are affected by multiple clinical and biomedical factors. This review will discuss the current application status of CAR-T therapy in hematological malignancies, analyze the key factors influencing the efficacy, and summarize the latest research trends and development directions in this field, so as to provide references for clinical decision - making and scientific research innovation.

Humans
Hematologic Neoplasms
Immunotherapy, Adoptive
Receptors, Chimeric Antigen
T-Lymphocytes


[Research Progress on Epigenetic Regulation of the Leukemia Microenvironment --Review]

Abstract: The development and progression of leukemia are driven not only by intrinsic genetic and epigenetic alterations in leukemia cells, but also by the dynamic remodeling of immune niches within the bone marrow microenvironment (BMM). Accumulating evidence has indicated that leukemic cells can reshape the immune microenvironment through cytokine secretion, metabolic reprogramming, and other mechanisms, inducing T-cell dysfunction/exhaustion, impaired NK-cell effector functions, and immunosuppressive polarization of myeloid cells, thereby establishing a protective niche that facilitates disease progression, drug resistance, and relapse. In parallel, epigenetic mechanisms such as DNA methylation, histone modification, and RNA modifications bridge the phenotypic plasticity of leukemic cells and immune evasion processes by regulating antigen presentation, interferon signaling pathways, chemokine profiles, and immune checkpoint expression, thereby influencing the response to immunotherapy. This review centers on the core conceptual framework of "immune microenvironment remodeling - epigenetic regulation - drug resistance and relapse - combination therapy strategies". It systematically outlines the key immunosuppressive networks and their epigenetic foundations across different leukemia subtypes. Emphasis is placed on the advances and challenges in combining epigenetic drugs, such as demethylating agents and histone deacetylase inhibitors, with immune checkpoint inhibitors, BCL-2 inhibitors, and microenvironment-targeted therapies. Furthermore, it outlines future directions in microenvironment subtyping and precision interventions driven by single-cell and spatial multi-omics technologies, aiming to provide a theoretical basis for optimizing combination treatment strategies in leukemia.

Tumor Microenvironment
Epigenesis, Genetic
Humans
Leukemia
DNA Methylation
Immunotherapy


[Research Progress of CDK Inhibitors in Acute Myeloid Leukemia --Review]

Abstract: Acute myeloid leukemia (AML) is a highly heterogeneous disease. This heterogeneity often leads to treatment failure or unsustainable efficacy, and high relapse rates as well as short progression-free survival (PFS) are closely associated with poor prognosis. Cyclin-dependent kinases (CDKs) play a central role in cell cycle regulation, transcription regulation, and metabolic processes, and their aberrant expression or dysfunction is considered as one of the key drivers of AML progression. Recent studies have increasingly focused on CDK inhibitors, aiming to address drug resistance and improve prognosis. Although some CDK inhibitors have shown promising anti-AML potential, challenges such as off-target effects and systemic toxicity remain daunting. This review systematically summarized the research progress of CDK inhibitors in the treatment of AML, with a particular focus on the results of preclinical studies and clinical trials targeting CDKs in AML, such as CDK2, CDK4/6, CDK7, and CDK9. In addition, the limitations of current therapeutic applications of CDK inhibitors were discussed, and potential strategies to overcome these challenges were explored, aiming to provide a reference for optimizing AML treatment regimens.

Leukemia, Myeloid, Acute
Humans
Protein Kinase Inhibitors
Cyclin-Dependent Kinases


[Clinical Characteristics, Drug Resistance, and Prognosis Analysis of Enterobacteriaceae Bloodstream Infection in Children with Acute Leukemia]

Abstract: To investigate the clinical characteristics, drug resistance and prognosis of Enterobacteriaceae bloodstream infection (BSI) in children with acute leukemia (AL) following chemotherapy. A retrospective analysis was performed on children with Enterobacteriaceae BSI after AL chemotherapy in four hospitals in Fujian Province from January 2015 to December 2023. The clinical characteristics, drug resistance and prognosis of these children were analyzed. A total of 140 children were enrolled, including 117 cases of acute lymphoblastic leukemia and 23 cases of acute myeloid leukemia. BSI occurred in 52.14% of the children during the induction chemotherapy phase, 35.00% during the intensive chemotherapy phase, and 12.86% during the maintenance chemotherapy phase. All children manifested fever, 81.43% had neutropenia, 21.43% had septic shock, 16.43% had no clear infectious lesions, 83.57% had infectious lesions, and 45.71% had two or more multi-site infections. Among the 140 strains of Enterobacteriaceae bacteria, 50.71% were Klebsiella bacteria, 35.00% were Escherichia bacteria, 10.00% were Enterobacter bacteria, and 4.29% were Salmonella bacteria. The highest proportion of multidrug-resistant bacteria (MDRB) and carbapenem-resistant Enterobacteriaceae (CRE) were found in Escherichia (68.89% and 14.89%). Amikacin had the lowest resistance rate among Klebsiella, Escherichia, and Enterobacter. There were no significant differences in pathogen distribution, proportions of MDRB and CRE between the first 4 year group (2015-2018) and the last 5 year group (2019-2023) (P >0.05). There were significant differences in albumin levels, the proportion of anti-infective treatment one week before BSI, proportion of carbapenem anti-infective treatment before BSI, and proportion of deaths between CRE group and non-CRE group (all P <0.05). Among the 140 children, except for 2 children who gave up treatment and the outcomes were unknown, 123 children were cured and 15 children died of BSI. The attributable mortality rate was 10.87% (15/138), and the mortality related to septic shock was 33.33% (10/30). Univariate analysis showed that gender, proportion of septic shock, proportion of CRE strain, albumin level, C-reactive protein (CRP) level and procalcitonin level were significantly different between the cure group and the death group (all P <0.05). Multivariate logistic regression analysis showed that septic shock, lower albumin level and higher CRP level were independent risk factors for death in children with Enterobacteriaceae BSI. In children with Enterobacteriaceae BSI following AL chemotherapy, CRE infection is associated with higher mortality. Septic shock, low albumin, and high CRP are independent risk factors for death caused by Enterobacteriaceae BSI.

Huang SX
Wu CP
LE SH
Zhuang SQ
Wang XF
Guo BY
Lian ZL
Zheng YZ
Weng KZ


[Impact of TP53 and MYD88 Mutations on Treatment Efficacy in Diffuse Large B-Cell Lymphoma]

Abstract: To investigate the relationship between TP53 and MYD88 mutations and treatment efficacy in patients with diffuse large B-cell lymphoma (DLBCL) who received rituximab-based standard chemoimmunotherapy. The clinical data of 92 patients with newly diagnosed DLBCL who were treated in the Department of Hematology of the Huai'an No.1 People's Hospital and Yancheng No.1 People's Hospital from January 1, 2015 to December 30, 2023 were retrospectively analyzed. Chi-square test, univariate and multivariate logistic regression analyses were used to identify risk factors associated with treatment efficacy, and a predictive model was further established. Survival curves were plotted using the Kaplan-Meier method, and differences in survival between groups were compared by the log-rank test. Among the 92 patients, 71 (77.2%) achieved post-induction remission (remission group) and 21 (22.8%) did not respond to treatment (non-remission group). The proportions of patients with elevated lactate dehydrogenase (LDH) (P =0.022) and those with MYD88 mutation (P =0.021) were significantly higher in the non-remission group than in the remission group. Univariate analysis showed that LDH (OR =3.482, P =0.027) and MYD88 mutation (OR =3.175, P =0.024) were factors influencing treatment efficacy in DLBCL patients receiving chemoimmunotherapy. Multivariate analysis showed that TP53 mutation （P =0.031） and MYD88 mutation （P =0.010） were independent risk factors for poor treatment efficacy in DLBCL patients. A treatment efficacy prediction model for DLBCL was established based on TP53 and MYD88 mutations, with an area under the receiver operating characteristic (ROC) curve of 0.705. According to the novel predictive model, the enrolled patients were divided into high-risk and low-risk groups. Treatment efficacy analysis showed that the objective response rate (ORR) of the low-risk group was significantly higher than that of the high-risk group (92.3% vs. 66.0%, P =0.006), and the progression-free survival (PFS) and overall survival (OS) of patients in the high-risk group were significantly poorer than those in the low-risk group (PFS: P =0.024; OS: P =0.004). TP53 mutation and MYD88 mutation are independent risk factors for poor efficacy in DLBCL patients receiving first-line immunochemotherapy. The novel predictive model constructed based on these two mutations can identify patients with potential poor response to first-line chemoimmunotherapy, which may provide a reference for optimizing the first-line individualized treatment strategy for DLBCL.

Yao YM
Shi YY
Deng Y
Li YJ
Chen QN
Miao YQ
Wang CL

Lymphoma, Large B-Cell, Diffuse
Humans
Myeloid Differentiation Factor 88
Tumor Suppressor Protein p53
Mutation
Retrospective Studies
Treatment Outcome
Rituximab
Female
Male
Prognosis


[The Impact of CD4(+)/CD8(+) Ratio on the Efficacy of CAR-T Therapy in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma]

Abstract: To evaluate the predictive value of peripheral blood CD4+/CD8+ ratio immediately prior to chimeric antigen receptor T-cell (CAR-T) infusion (Day 0) for treatment efficacy in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). A retrospective analysis was conducted on data from 49 R/R DLBCL patients who received CAR-T therapy at The First Affiliated Hospital of Soochow University between January 2017 and June 2024. The relationship between the Day 0 peripheral blood CD4+/CD8+ ratio and treatment efficacy was evaluated. At 3 months post-CAR-T infusion, the objective response rate of the 49 patients was 75.5% (37/49), comprising a complete response rate of 55.1% (27/49) and a partial response rate of 20.4% (10/49). Patients with a Day 0 peripheral blood CD4+/CD8+ ratio ≥1 had a significantly higher 90-day response rate than those with a ratio <1 (88.2% vs. 46.7%, P =0.002). Multivariate analysis showed that the Day 0 peripheral blood CD4+/CD8+ ratio was an independent predictor of both progression-free survival (PFS) and overall survival (OS) (P =0.025； P =0.037). Patients with a ratio ≥1 had significantly longer median PFS (11.0 vs. 3.0 months, P =0.011) and median OS (32.1 vs. 8.5 months, P =0.003) compared to those with a ratio <1. Peripheral blood CD4+/CD8+ ratio ≥1 immediately prior to CAR-T infusion can predict a higher CAR-T treatment response rate and superior survival outcomes in R/R DLBCL patients.

Humans
Lymphoma, Large B-Cell, Diffuse
Retrospective Studies
Immunotherapy, Adoptive
CD4-CD8 Ratio
Receptors, Chimeric Antigen
Treatment Outcome
Female
CD8-Positive T-Lymphocytes


[Clinical Characteristics and Survival Analysis of Pediatric Non-Hodgkin Lymphoma in Fujian Province]

Abstract: To summarize the clinicopathological characteristics and survival outcomes of pediatric non-Hodgkin lymphoma (NHL) in Fujian Province. Clinical data of 294 newly diagnosed pediatric NHL patients treated at multiple centers in Fujian Province from January 2011 to December 2023 were collected. The characteristics of different pathological subtypes were summarized, Kaplan-Meier survival analysis were performed and Cox proportional hazards regression model was used for prognostic analysis. A total of 294 pediatric NHL patients were included in this study, with a male-to-female ratio of 3.03∶1 and a median age of 7 years (range, 0.9-14 years). The most common subtype was mature B-cell lymphoma, accounting for 59.2% of cases. The majority of patients were diagnosed at stage III/IV (86.2%), with 32 cases (10.9%) involving central nervous system (CNS) infiltration and 89 cases (30.3%) showing bone marrow involvement. The rate of voluntary abandonment significantly decreased after 2018 (abandonment rates before and after 2018: 6/110 (5.45%) vs. 1/184 (0.54%), P =0.012). Furthermore, excluding cases of voluntary abandonment, the 5-year EFS and OS of newly diagnosed pediatric NHL patients from 2018 to 2023 were still significantly higher than those diagnosed from 2011 to 2017 (EFS: 79.3%±3.7% vs. 70.2%±4.5%, P =0.032; OS: 87.7%±2.6% vs. 70.2%±4.5%, P < 0.001). OS improvements after 2018 were significant in patients with BL and LBL (BL: 89.3%±3.6% vs. 73.5%±7.6%, P =0.033; LBL: 89.3%±5.3% vs. 56.5%±10.3%, P =0.001). However, there were no statistically significant differences in EFS or OS for patients with ALCL or DLBCL (all P >0.05). Multivariate survival analysis identified concurrent hemophagocytic lymphohistiocytosis syndrome was an independent risk factors for both EFS and OS in pediatric NHL patients. Over the past six years, OS and EFS in children with NHL in Fujian Province have improved markedly, with more pronounced gains in BL and LBL. This trend may be related to the combined effects of reduced voluntary treatment abandonment, more standardized diagnostic and therapeutic pathways, treatment optimization, and updated protocols. HLH at initial diagnosis is an independent risk factor for poor prognosis in pediatric NHL, while remission after two chemotherapy cycles suggests a favorable outcome.

Pan LL
Zheng YZ
Li J
Guo BY
Zhu Y
Weng KZ
Luo JH
Zhuang SQ
Wang XF
Sun GY
Wu XG
LE SH

Humans
Lymphoma, Non-Hodgkin
Child
Male
Prognosis
Adolescent
China
Child, Preschool
Female
Infant
Survival Analysis
Survival Rate
Proportional Hazards Models