Search Results (336)

Multidrug resistance (MDR) is defined as resistance to apparently unrelated drugs with different mechanisms of action, a phenomenon that seriously decreases the efficacy of many anticancer therapeutic regimens. MDR is mainly associated with a high expression of ATP-binding cassette (ABC) transporters, including ABCB1, ABCG2, and members of the ABCC subfamily, which actively extrude many anticancer drugs of various classes out of the cells. Protein kinase inhibitors (PKIs) were developed as therapies targeting oncogenic kinases but later appeared to be both substrates and inhibitors of ABC transporters and thus can potentially reverse MDR. This comprehensive review evaluates how PKIs regulate ABC transporters through three key mechanisms: altering expression, modifying subcellular localization, and inhibiting the efflux function. We evaluated the effect of PKIs that target tyrosine and serine/threonine kinases, such as EGFR/ErbB, JAK, VEGFR, BCR-Abl, ALK, FGFR, MEK1/2, B-RAF, BTK, CDK4/6, MET, RET, PDGFR and SYK. We have collected both computational studies and experimental reports, including functional assays, mechanistic studies of inhibition, and structural approaches that have evaluated PKIs’ effects on ABC transporters. We conclude that although PKIs can be ABC substrates, they mainly inhibit drug efflux, with minimal and context-dependent effects on transporter expression or localization. Full article

Background/objectives: Renal-cell carcinoma (RCC) accounts for approximately 4% of all solid tumours worldwide. Oligometastatic RCC, frequently defined as the presence of fewer than five metastatic lesions, is increasingly recognised as a clinically and prognostically distinct disease state, yet standardised treatment algorithms remain lacking. Method: This narrative review summarises current local and systemic treatment strategies for oligometastatic RCC and identifies patient populations most likely to benefit based on 26 studies published within the past ten years. Results: Stereotactic ablative radiotherapy (SABR) was the most frequently evaluated local modality, consistently demonstrating high local control rates with favourable toxicity profiles. Systemic therapies showed mixed efficacy and greater treatment-related adverse events, while evidence for radiofrequency ablation, cryoablation, and metastasectomy remains limited but suggests feasibility in selected patients. Conclusions: Overall, current evidence supports local therapy—particularly SABR—in appropriately selected patients with oligometastatic RCC, though most available evidence is retrospective and concentrated in favourable-risk ccRCC populations, limiting generalizability. Further prospective research is needed to refine patient selection criteria and optimise treatment sequencing. Full article

Background: Oligometastatic non-small cell lung cancer (OMD NSCLC) represents a distinct clinical state with limited metastatic spread, where local ablative therapies (LAT) combined with systemic treatment may improve outcomes. Accurate staging and prognostic assessment are critical, with ¹⁸F-FDG PET/CT emerging as a valuable tool for detecting metabolically active tumor burden. Results: We retrospectively analyzed 38 patients with synchronous OMD NSCLC who received radiotherapy. All patients underwent ¹⁸F-PET/CT and brain imaging for staging. Semi-quantitative ¹⁸F-PET/CT parameters, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of primary tumor and metastatic lesions, were measured and associated with progression-free survival (PFS) and overall survival (OS) using Cox proportional hazard models. The median PFS and OS were 8.28 and 21.62 months, respectively. Higher MTV and TLG values of metastases were significantly associated with shorter PFS and OS (p < 0.01). In multivariable analysis, TLG of metastases above the median remained an independent predictor of worse PFS (HR = 2.78, p = 0.031) and OS (HR = 3.12, p = 0.024), alongside clinical factors such as ECOG performance status 2 and having multiple metastases. The metabolic parameters of the primary tumor did not predict survival outcomes. Conclusions:¹⁸F-PET/CT-derived metabolic parameters, particularly the TLG of metastatic lesions, may provide significant prognostic information in oligometastatic NSCLC beyond clinical variables. These findings may support the integration of ¹⁸F-PET/CT metrics for future trials involving patients treated with LAT in oligometastatic NSCLC. Full article

Background and Clinical Significance: Bone involvement is a common and debilitating manifestation of advanced malignancies, with a substantial negative impact on patients’ functional status, quality of life, and overall prognosis. Management is primarily palliative and may include several locoregional approaches such as radiotherapy, surgical stabilization, cementoplasty, thermal or cryoablation, and high-intensity focused ultrasound. Electrochemotherapy (ECT) is an emerging non-thermal ablative technique that combines limited invasiveness with short procedural times and a favorable safety profile. Case Presentation: We report the case of a patient with oligometastatic lung cancer presenting with a painful rib metastasis refractory to radiotherapy. The patient had previously undergone radiotherapy to the right femoral head and the eighth rib, followed by cryoablation combined with cementoplasty for the femoral lesion and cryoablation of the rib. At one-year follow-up after cryoablation combined with bone cementoplasty, computed tomography demonstrated progression with the appearance of a new symptomatic rib lesion unresponsive to further radiotherapy. Percutaneous ECT was therefore performed under general anesthesia, supplemented with an erector spinae plane block. A total of twelve 18-gauge needle electrodes were accurately positioned under fluoroscopic guidance. Follow-up imaging at three months showed complete local tumor resolution, accompanied by marked and sustained pain relief. Conclusions: This experience supports the role of ECT as an effective salvage locoregional treatment option in selected patients with bone metastases resistant to conventional therapies. Full article

Background: Local recurrence of rectal cancer is a challenging problem for patients and clinicians. Surgical resection is associated with good outcomes if R0 margins are achieved; however, it is often complex, requires suitable patient fitness, and is associated with long term physical and psychological consequences. Meanwhile, continuing technical advances in radiotherapy have enabled the delivery of highly conformal treatment, thereby enabling dose escalation or pelvic reirradiation to be safely considered—either as definitive management or in the neoadjuvant setting—for patients with locally recurrent rectal cancer. Pelvic reirradiation may refer to patients who have received primary rectal radiotherapy with the aim of neoadjuvant downstaging or reducing the risk of locoregional recurrence, versus radiotherapy for a previous unrelated non-rectal pelvic malignancy. Methods: A literature search of pelvic reirradiation for non-metastatic, locally recurrent rectal cancer was conducted for full text articles published over the last 20 years. Additional papers were identified within the references of these papers. Studies focusing on non-rectal cancers, and patients having primary radiotherapy for locally recurrent rectal cancer were excluded. Due to the heterogenicity of the data, no meta-analysis was performed. Results: A total of 15 papers were included, containing a cohort of 840 patients. Several reirradiation modalities were reported, including external beam radiotherapy, brachytherapy, stereotactic ablative radiotherapy and heavy particle therapy (carbon ion). Carbon ion radiotherapy was the most common reirradiation treatment modality utilised with a median cumulative dose of 70.4 Gray (Gy). Treatment response, defined as either complete or partial improvement in tumour size, was only reported in seven studies, and varied from 14 to 88%. Overall 3-year survival was also variable with rates reported between 18 and 85%. These observations may be due to variation in patient selection, treatment intent, and technique. Pelvic reirradiation was associated with acceptable toxicity, low rates of G3+ toxicity, and improved symptom control. Conclusions: Our review describes the multitude of approaches to pelvic reirradiation for locally recurrent rectal cancer. Reviewing the radiobiological and patient outcomes is challenging in view of the degree of heterogeneity in patient selection, treatment approach, and reported outcomes. However, there is consensus that pelvic reirradiation—either for long term control or to downstage prior to definitive surgery—is feasible with potential utility in this setting. Full article

Background: Liver metastases from breast cancer (BCLM) are associated with poor prognosis and represent a significant clinical challenge in the era of modern systemic therapies. Local ablative therapies (LATs), including microwave ablation (MWA) and transarterial chemoembolization (TACE), have emerged as potentially beneficial locoregional approaches in selected patients. However, data on survival outcomes and prognostic determinants of LAT in BCLM remain limited. This study aimed to evaluate the survival outcomes and prognostic factors of LAT in patients with breast cancer liver metastases at a tertiary care center. Methods: Patients with de novo or metachronous breast cancer liver metastases who underwent LAT (MWA and/or TACE) between 2013 and October 2023 at a single tertiary center were retrospectively analyzed. Primary endpoints were overall survival (OS), defined as the time from LAT initiation to death from any cause, and progression-free survival (PFS), defined as the time from LAT initiation to the first radiographically confirmed progression. Treatment response was assessed per RECIST 1.1 criteria. Results: A total of 20 female patients were included. Median age at diagnosis was 42 years (IQR: 37–53). The majority had invasive ductal carcinoma (90%) and grade 3 disease (60%). Hormone receptor-positive, HER2-positive, and triple-negative subtypes comprised 45%, 25%, and 30% of the cohort, respectively. MWA was performed in 16 patients (80%), TACE was performed in 2 patients (10%), and both modalities were performed in 2 patients (10%). Complete response per RECIST 1.1 was achieved in 40% of patients. No grade 3–4 adverse events were recorded. Median OS was 20 months (95% CI: 14.9–25.1), and median PFS was 6 months (95% CI: 0–17.5). In univariate analysis, factors associated with improved OS included LM size < 18 mm (23 vs. 11 months, p < 0.001), unilateral lobar involvement (23 vs. 5 months, p = 0.025), and LAT application during first-line therapy (48 vs. 19 months, p = 0.021). Factors associated with improved PFS included LM size < 18 mm (19 vs. 5 months, p < 0.001) and achievement of complete ablative response per RECIST 1.1 (18 vs. 5 months, p = 0.005). Conclusions: LAT is a safe and feasible treatment modality in selected BCLM patients. In univariate analysis, smaller lesion size, unilateral hepatic involvement, and early-line LAT applications are associated with improved OS, while complete ablative response is associated with improved PFS. These findings warrant validation in prospective studies with larger cohorts. Multidisciplinary patient selection is essential to optimize outcomes. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide despite advances in screening, navigational bronchoscopy, and systemic therapies. Diagnostic and therapeutic limitations persist, including uncertainty regarding intraprocedural tissue adequacy during biopsy sampling and constraints of existing ablative modalities for tumors located near critical thoracic structures. This review examines two emerging technologies: Full-Field Optical Coherence Tomography-based Dynamic Cell Imaging (DCI) and monopolar biphasic Pulsed Electric Field (PEF) ablation as complementary emerging technologies that may address these gaps. The Van Gogh™ Microscopy System (CellTivity Scientific, Inc.) utilizes DCI to enable real-time visualization of cellular metabolic activity without tissue destruction, providing functional information regarding tissue viability and microstructural morphology. The Aliya^® PEF ablation system (Galvanize Therapeutics, Inc.) delivers biphasic high-voltage electrical pulses that induce non-thermal tumor cell death while preserving extracellular matrix architecture, potentially allowing treatment near sensitive thoracic structures such as airways, vasculature, and pleura. Early preclinical studies and initial clinical experience suggest that DCI can facilitate rapid intraprocedural assessment of biopsy adequacy, while PEF ablation may provide reproducible focal tumor destruction with a favorable safety profile near critical structures. Although the current evidence base remains limited to early-phase studies and feasibility trials, the convergence of real-time biologic tissue assessment with structurally preserving ablation technologies introduces the possibility of integrating diagnostic confirmation and local therapy within a single procedural workflow. This review summarizes the mechanistic rationale, emerging evidence, and potential clinical applications of these technologies and proposes a conceptual “See and Strike” framework within these two emerging technologies. The methodological limitations, workflow considerations, and future research directions required to validate this approach are also discussed. Prospective multicenter trials and long-term oncologic outcomes will be necessary before widespread clinical adoption. Full article

Background: The management of localized prostate cancer (PCa) suffers from the dilemma between the overtreatment associated with radical surgery and the uncertainty of active surveillance, highlighting a significant therapeutic gap specifically for intermediate-risk patients and selected low-risk patients. Focal therapy (FT) emerges as an advanced technological solution to balance rigorous oncological control with anatomical and functional preservation. Methods: A narrative review of the literature was conducted to analyze the physical principles underlying various ablative energies (thermal, cryogenic, and non-thermal) as well as radiation-based focal approaches. The review examines the oncological rationale of targeted ablation, recent innovations in imaging, and the expanding clinical scenarios for FT application. Results: Evidence supports the oncological rationale of “Index Lesion” ablation as a targeted curative strategy for clinically significant disease, rather than merely a palliative one. The review highlights the emerging concept of “pushing the disease” and demonstrates the valuable role of salvage focal therapy in the setting of radio-recurrent carcinoma. Furthermore, recent innovations in multiparametric magnetic resonance imaging (mpMRI) and fusion systems have significantly refined patient selection, rendering this minimally invasive approach highly targeted. Conclusions: The current barrier to the universal adoption of focal therapy is the lack of a standardized consensus on the definitions of therapeutic failure and the inadequacy of traditional PSA-based criteria. However, evidence suggests that FT represents a promising, organ-sparing alternative for carefully selected patients with localized PCa, though long-term comparative data are still required. Full article

Background/Objectives: Non-ablative local therapies are increasingly used in the conservative management of human papillomavirus (HPV) infection. Coriolus versicolor, an immunomodulatory medicinal mushroom, is one such approach. This study aimed to investigate the effect of a Coriolus versicolor–based vaginal gel on HPV clearance and cervical cytological outcomes. Methods: This retrospective cohort study included 600 women with cervical HPV infection (300 treated with a Coriolus versicolor–based vaginal gel and 300 receiving standard follow-up). Baseline and six-month follow-up assessments included HPV DNA testing and cervical cytology. Results: Baseline demographic characteristics, HPV genotype distribution, infection type, and cytological findings were comparable between the groups. Overall HPV clearance was significantly higher in the treatment group than in the controls (89.3% vs. 44.7%, p < 0.001). Complete clearance of high-risk HPV genotypes, including HPV 16 (77.0% vs. 25.4%, p < 0.001) and HPV 18 (73.9% vs. 18.5%, p = 0.017), was also significantly more frequent among treated women. Cytological normalization occurred more often in the treatment group (88.4% vs. 60.4%, p < 0.001). Multivariable analysis identified use of the vaginal gel as the strongest independent factor associated with HPV clearance (adjusted odds ratio [aOR] = 10.19; 95% confidence interval [CI]: 3.52–29.47; p < 0.001). Conclusions: Treatment with a Coriolus versicolor–based vaginal gel was associated with significantly higher rates of high-risk HPV clearance and cervical cytological normalization. These findings suggest that this therapy may represent an effective adjunct in the conservative management of HPV infection; however, randomized controlled trials are warranted to confirm these results. Full article

Arginase 1 (ARG1) deficiency (ARG1-D) is a rare genetic disorder due to loss of ARG1, the final enzyme in the urea cycle. ARG1-D hepatocytes are impaired in converting arginine into urea, resulting in elevated peripheral arginine and ammonia, which leads to progressive neurological symptoms. Current therapeutic strategies mainly focus on managing plasma arginine and ammonia level, but long-term outcomes remain poor. While no approved treatment specific for ARG1-D is available in the United States, a recombinant protein-based enzyme replacement therapy is available in Europe. Recently, extracellular vesicles (EVs) are emerging as a powerful therapeutic vehicle. By using Capricor’s StealthX^TM platform, EVs were engineered to express human ARG1 on their surface or encapsulated within. Regardless of their localization on the EV membrane, nanograms of ARG1 carried by EVs were biologically active and able to convert arginine into urea as potent as micrograms of human recombinant ARG1 (rHuArg1). Furthermore, ARG1-encapsulating EVs (STX-Arg1-in) were able to deliver ARG1 intracellularly but not EVs carrying ARG1 on their surface or rHuArg1. STX-Arg1-in EVs were further evaluated in a series of in vivo studies, and the results showed that STX-Arg1-in EVs were non-toxic and able to restore arginase activities in the liver of Arg1^−/− mice, which led to a lowered plasma arginine concentration similar to that in wild-type mice. Most importantly, Arg1-in EVs expanded the lifespan of the lethal neonatal Arg1 deficiency mouse model. Taken together, our data suggested StealthX^TM-engineered STX-Arg1-in EVs have a better safety profile due to the extremely low dosage and have great potential as a novel enzyme replacement strategy for patients suffering from ARG1-D. Significance statement: Intracellular delivery of recombinant protein and improved llifespanare endpoints of successful enzyme replacement therapy for the treatment of ARG1-D. Using the StealthX platform, a fully functional ARG1 enzyme was engineered to be carried inside of the extracellular vesicles, which allowed for the intracellular delivery of ARG1 protein in vitro and in vivo, with an improvement of lifespan in a lethal neonatal mouse model of Arg1 deficiency. More importantly, no toxicity was observed, and efficacy was achieved with a low dose, setting the base for an improved therapeutic approach. Full article

Soft-tissue sarcomas (STSs) comprise a rare, heterogeneous group of mesenchymal malignancies in which histologic grade remains the strongest determinant of outcome, metastatic risk, and therapeutic strategy. Intermediate/high-grade STSs exhibit a pronounced propensity for early distant relapse, yet growing evidence indicates that metastatic behaviour is not uniform. Within this spectrum, an oligometastatic phenotype, characterised by a limited number of metastases, often confined to the lung, has emerged as a clinically and biologically distinct state associated with more indolent metastatic kinetics and improved survival when treated with aggressive local interventions. However, the criteria that define true oligometastatic STSs remain unsettled, and prospective evidence is lacking. Emerging molecular and immunological correlates provide a potential framework for biological triage. Low genomic complexity (low-risk CINSARC), a B-cell/TLS-rich tumour microenvironment, high immune-cytotoxic signatures, and persistently low or undetectable circulating tumour DNA (ctDNA) are each linked to reduced metastatic competence and may underpin oligometastatic trajectories. Conversely, high chromosomal instability, immunosuppressive microenvironments, and elevated ctDNA levels align with covertly polymetastatic biology despite limited radiographic disease. In this context, artificial intelligence and machinelearning approaches applied to computational genomics, immune profiling, imaging, and liquid-biopsy data offer a powerful strategy to integrate these multi-dimensional features and refine predictions of metastatic behaviour in STS. Oligometastatic STS therefore represents a biologically definable subset amenable to multimodal management integrating local ablative therapies, systemic agents, and immune-based strategies. Prospective, biomarker-stratified trials are needed to validate selection frameworks and optimise treatment sequencing in this evolving therapeutic space. Full article

Oligoprogressive disease (OPD) in non-small-cell lung cancer (NSCLC) is a clinical entity with peculiar behavior and treatment. OPD patients, during systemic therapy, may receive local ablative treatment (LAT) with survival benefit. The importance of OPD and the role of LAT has been comprehensively assessed in the setting of EGFR mutant and ALK-rearranged NSCLC during tyrosine kinase inhibitor (TKI) treatment, but it is still almost unexplored in the context of NSCLC harboring actionable oncogenic drivers other than EGFR and ALK. The aim of our review is to collect and discuss the available data about standard treatment in this latter setting, with special consideration given to the role of LAT in case of OPD in systemic treatment. Through a comprehensive PubMed and ClinicalTrials.gov search, we identified the available data and ongoing clinical trials addressing these aims. To date, only limited evidence supports the use of LAT in OPD involving NSCLC driven by these molecular alterations, mainly deriving from case reports and retrospective series. This highlights an unmet clinical need that warrants systematic and multicentric data collection to generate more robust evidence. Full article

Background/Objectives: Patients with early-stage non-small cell lung cancer (NSCLC) or limited lung metastases and compromised lung function, such as those with interstitial lung disease (ILD) or chronic obstructive pulmonary disease (COPD), or other factors rendering them high-risk for surgery or medically inoperable, face increased risks of treatment-related toxicity from stereotactic ablative radiation therapy (SABR). This study evaluated a novel treatment approach to mitigate these risks. Methods: We investigated Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy (PULSAR), delivered as pulsed radiation every three weeks, in patients with <5 cm lung tumors and ILD, COPD, or prior therapy. Treatment occurred between 2022 and 2024. Online adaptive radiotherapy (o-ART) was employed in 20 patients (80%) to modify treatment plans when anatomical changes warranted replanning. Primary outcomes included volumetric tumor response, changes in dose to organs at risk (OARs) and acute events, while secondary outcomes included local and tumor control, and overall survival. Results: Twenty-three patients received PULSAR treatment at doses between 40 Gy and 60 Gy in 5 fractions and one patient received 54 Gy in 3 fractions, with a median follow-up time of 16.2 months. Approximately half of treated patients demonstrated volumetric tumor response, with median residual volume of 70% (range 36–100%) at maximal response. Among the 20 patients (80%) who underwent online adaptive replanning, significant reductions in OAR dosimetry were observed for all organs assessed including the Dmax for heart (p = 0.0053), bronchus (p = 0.0003), esophagus (p = 0.0005), spinal cord (p = 0.025), and the lung V20 Gy and V12.5 Gy (p < 0.0001). Treatment-related toxicity included two grade 1–2 adverse events and six grade 3 events consisting of pneumonitis, dyspnea or lung infection, with no grade 4 or 5 events. Median progression-free survival was 21.1 months, with 1-year overall survival of 74% and 1-year local control of 100%. Conclusions: PULSAR shows promise as a feasible treatment option for high-risk patients with NSCLC or lung metastases, demonstrating no grade 5 events and complete tumor control. Additional research is needed to fully evaluate the safety profile of PULSAR in the high-risk subgroups and whether PULSAR’s treatment intervals and adaptive planning advantages lead to improved long-term outcomes compared to conventional, uninterrupted SABR regimens. Full article

Background/Objectives: Oral surgical procedures in patients at risk of/diagnosed with MRONJ require systemic antibiotic therapy, which can fail to achieve an adequate local drug concentration. This research aims to design mucoadhesive buccal patches (containing erythromycin or the erythromycin–resveratrol combination) tailored to the therapeutic needs of patients at risk of MRONJ undergoing oral surgery. Methods: Erythromycin (ERY) and resveratrol (RSV) were embedded into lipid-based microparticles prepared via hot melt dispersion. The microparticles, recovered in the form of dry powders, were characterized in terms of yield, softening/melting temperature, active(s) content, physical state (amorphous vs. crystalline), and individual and bulk properties. Then, they were loaded into a hydrophilic gel, which was dried, obtaining microparticle-loaded buccal patches. The optimized patches were characterized in terms of uniformity, folding endurance, swelling, mucoadhesion, and oromucosal permeation/retention. Results: The microparticles were efficiently produced via a green approach, resulting in reproducible pharmaceutical powders with high loading efficacy (≈90%), spherical morphology, particle sizes in the range of approximately 106–425 μm, and a softening temperature close to body temperature. The buccal patches were also obtained via a green approach, and were found to be thin, flexible, homogeneous, highly swellable, extremely mucoadhesive, and able to promote ERY and RSV accumulation in the buccal tissue (≈25% and 2% of ERY and RSV, respectively, after 2 h) while avoiding active(s) absorption. Conclusions: The proposed buccal patches are viable candidates for further clinical trials aimed at evaluating both the effectiveness of locoregional antibiotic treatment and the usefulness of the co-administration of RSV and ERY. Full article

Background/Objectives: Although Tumor-Treating Fields (TTFields) therapy is an established treatment modality for adult glioblastoma, clinical data on its efficacy in pediatric brain tumors are extremely scarce. The present study aimed to evaluate the safety of TTFields therapy for pediatric diffuse high-grade glioma (HGG) and to conduct an exploratory analysis of its efficacy. Methods: A prespecified, interim analysis was performed to determine whether the study should be continued on the basis of safety and feasibility data on the first three patients. The target population was children aged 5 to 17 years with newly diagnosed, supratentorial HGG or its first recurrence following frontline therapy. After completion of initial, local treatment for the tumor (surgical removal and/or radiotherapy), all patients received TTFields therapy using Optune^TM for 28 days per course for up to 26 courses until disease progression. Results: The interim analysis, which was completed in October 2022, included three female patients aged 14, 17, and 9 years. All had a histological grade 4 tumor, two of which were radiation-induced, secondary HGG. No serious, treatment-related toxicities or device-related issues were observed. All three patients were able to continue using the device for 75% or more of the time in accordance with the protocol, suggesting that the treatment was feasible. The MRI findings of two patients indicated that the treatment has a potential antitumor effect. Based on these results, the study was resumed and is currently being continued at multiple centers. Conclusions: The initial results of the prespecified, interim analysis demonstrated that TTFields therapy was safe and feasible for children with HGG. This study was funded by the Japan Agency for Medical Research and Development (AMED) and was registered with the Japan Registry of Clinical Trials (jRCTs032200423). Full article