Search Results (3,530)

Cisplatin, a platinum-based compound, is a cornerstone of modern chemotherapy and remains widely used against a variety of solid tumors, including testicular, ovarian, lung, bladder, and head and neck cancers. Its anticancer activity is primarily attributed to the formation of DNA crosslinks, which obstruct replication and repair, ultimately leading to apoptosis. However, the clinical value of cisplatin is constrained by two major challenges: its toxic profile and the development of resistance. Cisplatin toxicity arises from its interaction not only with tumor DNA but also with proteins and nucleic acids in healthy tissues, resulting in a range of adverse effects, including, but not limited to, nephrotoxicity, ototoxicity, neurotoxicity, and gastrointestinal injury. In pediatric patients, permanent hearing loss represents a particularly debilitating complication. On the other hand, tumor cells can evade cisplatin cytotoxicity through diverse mechanisms, including reduced intracellular drug accumulation, enhanced DNA repair, detoxification by thiol-containing molecules, and alterations in apoptotic signaling. These resistance pathways severely compromise treatment outcomes and often necessitate alternative or combination strategies. This review examines the chemical structure of cisplatin, the molecular mechanisms of cisplatin cytotoxicity and cisplatin-induced resistance, as well as the main applications in cancer management and the complications associated with its clinical use. Full article

Background/Objectives: Endometrial cancer is one of the most common gynecological malignancies, with increasing incidence and mortality rates, particularly in developed countries. L1 cell adhesion molecule (L1CAM) has been identified as a poor prognostic factor for human endometrial cancer; however, the molecular mechanisms underlying its role in tumor progression remain unclear. Methods: We investigated the biological significance of L1CAM in human endometrial cancer using multiple cell lines. Functional analyses, including cell proliferation, cell cycle, and apoptosis assays, were performed after L1CAM knockdown or overexpression. Results: L1CAM promoted the transition of endometrial cancer cells from the G0/G1 phase and enhanced cell proliferation. L1CAM knockdown inhibited NF-κB signaling by reducing NF-κB (p65) phosphorylation and downregulating the expression of downstream targets such as TNF. Overexpression of constitutively active IKKβ restored the proliferation defect caused by L1CAM knockdown, supporting the role of NF-κB as a key downstream effector of L1CAM. Immunohistochemical analysis revealed a significant correlation between L1CAM expression and nuclear NF-κB (p65) positivity rates in human patient samples. Furthermore, combination therapy with cisplatin and an IKK inhibitor enhanced the anti-proliferative effect. Conclusions: Our study demonstrated that L1CAM promotes proliferation and chemotherapy resistance in human endometrial cancer through activation of the NF-κB signaling pathway. Therapeutic strategies targeting the L1CAM-NF-κB pathway may represent a promising treatment option for improving prognosis in L1CAM-positive human endometrial cancer. Full article

Every year, the scientific community continues to drive advances in healthcare, opening up new perspectives in the treatment and management of various diseases. Despite vast strides being made in the quality of life and longevity, we still face an equally significant growth in the burden of oncological pathologies. Although current trends lean towards preventive and personalized medicine, numerous hurdles remain to be cleared to develop robust strategies in the field of oncology. Among all types of tumors, one of the prominent positions is occupied by hepatocellular carcinoma (HCC), which is one of the most widespread primary cancers with a high mortality rate. Conventional approaches to HCC therapy, such as surgery or chemotherapy, rarely provide steady performance due to the highly polymorphous nature of the cancerous process. In this study, we suggest an alternative methodological framework for designing potent siRNAs targeting genes implicated in hepatocellular carcinoma, implementing RNA interference mediated by synthetic small interfering RNAs (siRNAs) against mRNAs of ITGB1 and CD47 genes. Products of these genes are renowned drivers of tumor progression. We have developed a software algorithm for the design of unmodified and modified siRNAs, carried out solid-phase synthesis of the most promising molecules, and proved their capability to perform a more than 50-fold suppression of expression of the target genes in vitro. Full article

Bladder urothelial carcinoma (BUC) ranks among the most common malignant tumors of the urinary system, with alarmingly high incidence and mortality rates. Current clinical treatments face challenges such as strong chemotherapy resistance and limited response rates to immunotherapy, creating an urgent need for novel alternative therapies. Natural products, characterized by multi-targeted antitumor activity, low toxicity, and broad availability, have emerged as highly promising adjunctive or alternative strategies in cancer treatment. Extensive research has elucidated the antitumor activities of natural products, including inhibition of cancer cell proliferation, induction of apoptosis, and modulation of the immune microenvironment. What’s more, their bioactive components, such as terpenoids and polyphenols, can synergistically enhance therapeutic efficacy while reducing toxicity risks associated with traditional therapies. This review will examine the roles of terpenoids, phenolics, alkaloids, and other natural products in BUC treatment, to provide directions for future research. Full article

Background/Objectives: Colorectal cancer (CRC) is associated with anorexia–cachexia syndrome, which negatively affects health-related quality of life (HRQoL). This study aimed to evaluate HRQoL and functional status in CRC patients undergoing chemotherapy who were eligible for oral nutritional supplementation (ONS). Methods: In this prospective, randomized study, 72 patients with stage II–IV CRC were enrolled (40 intervention group [IG], 32 control group [CG]). IG received ONS (2 × 125 mL/day, 600 kcal, 36 g protein) for 12 weeks, while CG received dietary counseling only. HRQoL was assessed every 4 weeks with the Functional Assessment of Anorexia/Cachexia Therapy (FAACT, version 4.0). Functional status was evaluated with the Karnofsky scale. Nutritional status was assessed using the Subjective Global Assessment (SGA), Nutritional Risk Screening (NRS-2002), and body mass index (BMI), and appetite was assessed on a visual analogue scale (VAS). Clinical Trial Registration: ClinicalTrials.gov, NCT02848807. Results: Mean FAACT score did not differ significantly between groups over 12 weeks (101.0 ± 22.8, 95% CI: 94.6–107.4 vs. 105.1 ± 21.4, 95% CI: 99.1–111.1; p = 0.06). However, the observed difference corresponded to an effect size at the lower bound of the moderate range. However, minimally important difference (MID) analysis demonstrated that clinically meaningful improvement was significantly more frequent in IG than in CG for global FAACT (32% vs. 8%; p = 0.03, OR = 5.50, 95% CI: 1.10–27.62, φ = 0.29), physical well-being (32% vs. 8%; p = 0.03, OR = 5.50, 95% CI: 1.10–27.62, φ = 0.29), and emotional well-being (38% vs. 4%; p = 0.002, OR = 14.86, 95% CI: 1.79–123.36, φ = 0.40). Functional well-being and anorexia/cachexia concerns showed favorable, but nonsignificant, trends (FWB improvement: 29% vs. 8%, p = 0.05, OR = 4.79, 95% CI: 0.95–24.27, φ = 0.26; ACS deterioration: 3% vs. 20%, p = 0.07, OR = 0.12, 95% CI: 0.01–1.11, φ = 0.28). HRQoL correlated positively with nutritional status, appetite, and functional performance, while Karnofsky scores remained stable in both groups. Conclusions: ONS did not significantly change the mean QoL scores at the group level but increased the proportion of patients achieving clinically meaningful improvement, particularly in the physical and emotional domains. These findings suggest that ONS may benefit selected patients who respond to nutritional interventions, underscoring the clinical relevance of individualized nutrition strategies in oncology. Full article

Ionizing radiation remains the primary approach for treating brain cancer and is frequently used in combination with chemotherapy. However, when it comes to gliomas, the effective delivery of therapeutic agents is hindered by the limited permeability of the blood–brain barrier (BBB). Consequently, selecting the most suitable and least harmful type of ionizing radiation is essential, given its potential side effects on healthy cells within the tumor microenvironment. In this study, we explored the impact of X-ray exposure on two in vitro BBB endothelial cell models—murine and human. Post-irradiation, we evaluated cell viability, clonogenic capacity, cell cycle progression, reactive oxygen species (ROS) levels, formation of micronuclei and γ-H2AX foci, as well as alterations in cytoskeletal organization, cell migration, and intracellular calcium dynamics. The results demonstrate notable differences between the two endothelial cell lines, suggesting the human cell line is more sensitive to X-rays. In conclusion, our study provides valuable insights into the brain microvascular endothelial cells' response to radiation, laying the groundwork for strategies to protect healthy brain tissue. Full article

Background: Peritoneal metastasis represents an aggressive disease pattern in pancreatic ductal adenocarcinoma (PDAC), traditionally associated with poor survival and limited therapeutic options. Emerging intraperitoneal chemotherapy strategies—including hyperthermic intraperitoneal chemotherapy (HIPEC), normothermic intraperitoneal paclitaxel (NIPEC/IP-PTX), and pressurized intraperitoneal aerosol chemotherapy (PIPAC)—have been investigated to improve local tumor control and survival outcomes. Methods: We systematically reviewed published studies evaluating HIPEC, NIPEC/IP-PTX, and PIPAC in PDAC, including adjuvant, cytoreductive, and palliative settings. Study characteristics, feasibility, perioperative outcomes, oncologic outcomes, and risk of bias were analyzed. Results: Across modalities, intraperitoneal treatment strategies demonstrated acceptable feasibility and safety profiles in appropriately selected patients. Adjuvant HIPEC following pancreatectomy showed reduced local–regional recurrence signals in limited cohorts. CRS + HIPEC among patients with isolated peritoneal metastases yielded encouraging multi-year survival in highly selected candidates achieving complete cytoreduction. NIPEC/IP-PTX demonstrated favorable ascites control, symptom relief, and potential conversion to resection in select patients. PIPAC was primarily used in unresectable, heavily pretreated, palliative peritoneal metastasis settings, with goals centered on disease stabilization, histologic regression, and symptom control rather than curative intent. Conclusions: Intraperitoneal chemotherapy strategies in PDAC appear feasible with signals of meaningful clinical benefit in select settings. While CRS + HIPEC may benefit carefully selected metastatic patients, NIPEC/IP-PTX and PIPAC hold value primarily in symptom control and disease stabilization. Larger prospective trials are needed to define patient selection, optimize treatment protocols, and clarify survival benefit. Full article

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting adverse effect of paclitaxel and is characterized by cold and mechanical allodynia. Effective therapeutic strategies for CIPN remain limited. This study evaluated the analgesic potential of Corydalis yanhusuo (CY) and Evodia rutaecarpa (ER), as well as their major alkaloids tetrahydropalmatine (THP) and rutaecarpine, in a mouse model of paclitaxel-induced neuropathic pain. Methods: Neuropathic pain was induced by paclitaxel administration (2 mg/kg, i.p., four injections). CY and ER extracts were orally administered at doses of 100 or 300 mg/kg, either alone or in combination, and cold and mechanical allodynia were assessed from days 0 to 8. The analgesic effects of THP and rutaecarpine were also examined. Gene and protein expression analyses were performed to evaluate the involvement of TRPV1 and TRPM8 signaling pathways, and high-performance liquid chromatography (HPLC) was used to confirm the presence of THP in CY and rutaecarpine in ER. Results: Paclitaxel reliably induced robust cold and mechanical hypersensitivity. Oral administration of CY or ER significantly alleviated allodynia in a dose-dependent manner, with greater efficacy at 300 mg/kg. Combined CY–ER treatment produced stronger anti-allodynic effects than either extract alone. THP and rutaecarpine also exhibited dose-dependent analgesic effects, and their co-administration yielded the most pronounced inhibition of paclitaxel-evoked hypersensitivity. Molecular analyses confirmed the involvement of TRPV1- and TRPM8-related pathways in these analgesic effects. Collectively, these findings indicate that CY, ER, and their representative alkaloids effectively attenuate paclitaxel-induced neuropathic pain and highlight CY–ER-based natural products as promising candidates for managing CIPN through modulation of TRPV1/TRPM8 signaling. Full article

Chemotherapy causes primordial follicle apoptosis, resulting in premature ovarian insufficiency (POI) and infertility. In this study, we found that intraperitoneal injection of retinoic acid (RA) and calcitriol partially reversed the cyclophosphamide and doxorubicin treatment-induced decrease in primordial follicles in neonatal mouse ovaries. Furthermore, RA and calcitriol co-treatment reversed cyclophosphamide treatment-induced PI3K/Akt activity and FOXO3a nuclear export in the oocytes within primordial follicles, suggesting that the oocyte transcriptional activity was decreased, which in turn reduced the binding of chemotherapeutic drugs to DNA. Consistent with these findings, RA and calcitriol co-treatment reversed cyclophosphamide treatment-induced changes in reactive oxygen species (ROS), DNA damage response proteins (γH2AX, p-CHK2, p-p53, PUMA, BAX, Cleaved Caspase-3, and cPARP), and antioxidant proteins (NRF2, HO-1, and GPX4). Moreover, RA and calcitriol co-treatment preserved fertility in cyclophosphamide-treated mice without impairing cyclophosphamide’s antitumor efficacy in MCF-7 tumor-bearing mice. Thus, RA and calcitriol protect mouse primordial follicles from cyclophosphamide treatment-induced apoptosis by inhibiting cyclophosphamide treatment-induced oocyte transcriptional activity and enhancing antioxidant capacity. Our results suggest a potential strategy for preserving ovarian reserve during chemotherapy in female cancer patients. Full article

Background and Objectives: HER2-positive metastatic colorectal cancer (mCRC) represents a biologically distinct and clinically aggressive subtype associated with poor response to standard first-line chemotherapy. Reliable, low-cost prognostic biomarkers are urgently needed to identify early non-responders and guide treatment decisions. This real-world cohort study evaluated the prognostic value of carcinoembryonic antigen (CEA) kinetics and systemic inflammatory markers (SIMs) in HER2-positive mCRC treated with first-line chemotherapy. Materials and Methods: We retrospectively analyzed 98 patients with HER2-positive mCRC treated between 2015 and 2024. Serial CEA values were measured at baseline, after three cycles (week 6), and at radiologic progression. Early CEA change was categorized as ≥50% decline, 10–49% decline, or any increase. Baseline SIMs—including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII)—were calculated from pretreatment blood counts. Progression-free survival (PFS) was analyzed using Kaplan–Meier and Cox regression models. Results: Among patients with evaluable CEA kinetics (n = 60), early CEA increase occurred in 30% of patients (n = 18) and was strongly associated with inferior PFS (HR 2.84; 95% CI 1.81–4.44; p < 0.001). ROC analysis identified a ≥38% CEA reduction as the optimal predictor of radiologic response (AUC 0.79). High baseline NLR (≥3) and high SII (≥900) were also significantly associated with shorter PFS (median PFS: 5.2 vs. 9.1 months for NLR; 4.7 vs. 10.3 months for SII; both p < 0.01). In multivariate analysis, early CEA increase, high NLR, and high SII remained independent predictors of poor PFS. Conclusions: CEA dynamics and inflammation-based biomarkers provide robust, complementary prognostic information in HER2-positive mCRC. Early CEA increase is the strongest independent predictor of poor outcome, while high baseline NLR and SII further refine risk stratification. These inexpensive and widely accessible biomarkers may help identify early non-responders, optimize monitoring strategies, and support timely therapeutic adjustments in routine clinical practice. Full article

Background/Objectives: Breast cancer is the most common cancer among women worldwide. Surgical treatments include breast-conserving therapy (BCT) and mastectomy, often followed by reconstruction, but the impact of reconstruction on locoregional recurrence (LRR) remains unclear. This study evaluated LRR, survival, and risk factors following primary breast reconstruction performed simultaneously with mastectomy compared with mastectomy without reconstruction. Methods: This population-based, retrospective cohort included 2475 women with breast cancer treated between 2004 and 2018 at the Tumor Center and Caritas St. Josef Hospital in Regensburg, Germany. Patients were grouped into not primarily reconstructed, primary autologous reconstruction, primary allogeneic reconstruction, and primary combined reconstruction. Overall survival (OS), recurrence-free survival (RFS), and cumulative recurrence rates (CRR) were assessed using Kaplan–Meier methods and Cox proportional hazards models adjusted for age, nodal status, tumor biology, and adjuvant therapies. Results: Of 14,046 eligible cases, 2475 met inclusion criteria: no primary reconstruction (87%), autologous reconstruction (3.1%), allogeneic reconstruction (9.0%), and combined reconstruction (0.4%). Patients undergoing reconstruction were younger and more likely to receive chemotherapy. The 5-year OS was 71.8% without primary reconstruction, 82.1% after autologous reconstruction, and 90.0% after allogeneic reconstruction. Allogeneic reconstruction was associated with improved OS (HR 0.570, p = 0.015) and RFS (HR 0.669, p = 0.039), whereas autologous reconstruction was associated with higher hazards of LRR and distant metastases compared to no primary reconstruction. Conclusions: The 5-year cumulative LRR was 5.2%, 13.5%, and 4.8%, respectively. Immediate allogeneic reconstruction after mastectomy was therefore associated with favorable survival and recurrence outcomes, while autologous reconstruction was linked to higher LRR and distant metastasis rates in this cohort. The retrospective design, small autologous subgroup, and absence of detailed lifestyle and metabolic data are important limitations of these findings. These associations likely reflect differences in tumor stage, biology, and unmeasured risk factors, and should be interpreted as hypothesis generating. Prospective multicenter studies with detailed risk profiling are needed to clarify the oncologic safety of different reconstructive strategies. Full article

Triple-Negative Breast Cancer (TNBC) remains the most aggressive breast cancer subtype, characterized by profound heterogeneity and a lack of effective targeted therapies. Although cytotoxic chemotherapy is the standard of care, the rapid emergence of resistance driven by cancer stem cells (CSCs), metabolic plasticity, and the tumor microenvironment limits long-term survival. This review highlights the paradigm shift in TNBC treatment from 2021 to 2025, moving beyond broad cytotoxicity to precision medicine. We first examine the limitations of earlier targeted therapies, such as PI3K/AKT/mTOR inhibitors, which failed due to compensatory feedback loops and toxicity. We then discuss emerging synthetic lethality strategies targeting the G2/M checkpoint (WEE1, ATR) and mitotic kinases (PLK1, TTK) to exploit genomic instability in TP53-mutant tumors. Furthermore, we explore how novel modalities like PROTACs and Antibody–Drug Conjugates (ADCs) are unlocking the “undrugged kinome,” including targets like TNIK, PTK7, and PAK4, which were previously inaccessible. Finally, we propose that future success lies in combinatorial strategies integrating these next-generation kinase inhibitors with ADCs and immunotherapies to dismantle therapeutic resistance. Full article

Background: Mediastinal gray zone lymphoma (MGZL) is a rare B-cell lymphoma characterized by overlapping clinicopathologic and molecular features of primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL). Under current WHO-HEMA5 and International Consensus Classification (ICC) frameworks, MGZL is restricted to EBV-negative lymphomas arising in the mediastinum. Methods: This review summarizes current evidence on epidemiology, clinical presentation, pathology, molecular characteristics, diagnostic challenges, and therapeutic approaches to MGZL, with data derived from retrospective series, limited prospective cohorts, and recent molecular studies. Results: MGZL predominantly affects young adults and commonly presents with bulky mediastinal disease. Diagnosis is challenging due to transitional morphology, pleomorphic Reed–Sternberg-like cells, and variable expression of B-cell and activation markers. Molecular studies demonstrate shared alterations with PMBL and CHL, including 9p24.1 (JAK2/PD-L1/PD-L2) gains, while additional reported features such as HOXA5 hypomethylation and MYC copy number gains support its biological distinctiveness, although evidence remains limited. Frontline treatment commonly involves intensive chemoimmunotherapy regimens such as DA-EPOCH-R; however, outcomes remain inferior to PMBL and CHL, with 5-year overall survival rates of approximately 40–60%. Relapsed or refractory disease frequently requires salvage chemotherapy and autologous stem cell transplantation. Immune-based therapies, including brentuximab vedotin and PD-1 inhibitors, have shown promising activity, particularly in combination. Conclusions: MGZL remains a diagnostically challenging and therapeutically complex lymphoma with inferior outcomes compared with related mediastinal lymphomas. Advances in molecular profiling and immunotherapy offer promising avenues toward more personalized treatment; however, prospective clinical trials and international collaboration are urgently needed to establish evidence-based management strategies for this rare entity. Full article

Background: Immune checkpoint inhibitors (ICIs) are a new anti-cancer therapy that have improved survival rates in many aggressive cancers. However, while rare, a significant number of patients develop ICI-induced cardiotoxicity. Clinical manifestations are non-specific and underlying cellular mechanisms remain unknown, making diagnosis and treatment of these ICI-induced cardiac side effects difficult. Exercise has shown protective effects against chemotherapy-induced cardiotoxicity but has not been investigated in combination with ICIs. High-intensity exercise has shown greatest cardioprotective effects in preclinical (animal) models, but human cancer patients prefer low-intensity exercise in the clinical setting. Therefore, the purpose of this study was to further identify the cardioprotective effects of low-intensity exercise as a treatment strategy against ICI-induced cardiotoxicity. Methods: Female mice were randomly selected and separated into four groups: sedentary (SED), sedentary ICI-treated (SED + ICI), low-intensity treadmill-exercised (TM), and low-intensity treadmill-exercised ICI-treated mice (TM + ICI). Mice either underwent a 4-week low-intensity treadmill exercise protocol (TM) or remained sedentary (SED). During the 4 weeks, ICI mice received anti-PD-1 treatment (200 μg/mouse) via intraperitoneal injections twice each week. Echocardiography was performed at baseline and sacrifice to determine changes in cardiac structure and function. At sacrifice, cardiac tissue was collected, weighed, and frozen for further biochemical analysis. Underlying metabolic signaling pathways were assessed via Western Blot, and autophagic flux was analyzed via fluorescent microscopy. Results: Echocardiography at sacrifice revealed significantly decreased fractional shortening as a measure of cardiac function (−20%), 1.5-fold dilation of the left ventricle, and thinning of the posterior cardiac wall at systole and diastole in SED + ICI mice compared to SED controls (p < 0.05), indicative of a phenotype of ICI-induced dilated cardiomyopathy. TM + ICI mice did not show a significant difference in these cardiac structural and functional parameters, suggesting cardioprotective effects of low-intensity exercise. In line with these findings, Western Blot and fluorescent microscopy analyses revealed upregulation of autophagic flux (p < 0.05), as well as dysfunctional metabolic pathways (p < 0.05) in ICI-treated mice compared to non-ICI controls. Low-intensity exercise was associated with regulation of dysfunctional metabolism and autophagy in TM + ICI compared to SED + ICI mice. Conclusions: The clinically relevant ICI treatment protocol used in this study led to significant cardiac dysfunction and remodeling, accompanied by underlying dysfunctional metabolism and autophagy. Low-intensity exercise was capable of regulating abnormal protein synthesis and degradation and protecting against ICI-induced cardiotoxicity. This study adds knowledge to the characterization of still unclear clinical manifestations of ICI-induced cardiotoxicity, underlying signaling pathways that could shed light on potential pharmacological treatment targets, as well as the protective effects of low-intensity exercise as a non-pharmacological treatment strategy. Full article

Immunotherapy (IT) and especially immune checkpoint blockade (ICB) changed the therapeutic approach in non-small cell lung cancer (NSCLC). Nevertheless, primary or secondary resistance and a percentage of long responders and survivors have been observed. The aim of this study is to gain a deeper understanding of the complex mechanisms of primary and secondary resistance to IT, involving tumor cells, the tumor microenvironment (TME), and the host, in order to find strategies to overcome it. With this aim in mind, a search for key words has been performed to identify relevant evidence in the literature. The most widely used approach is the combination of IT with chemotherapy (CT) and/or radiotherapy (RT), relying on the synergistic effect on the enhancement of immunogenic cell death. Since a dual role has been observed, a lot of questions are yet to be answered regarding the complex effect of these therapies, especially on the TME. Preclinical and clinical studies investigate the best sequencing and timing of chemoradiation with IT, and the optimal RT volumes, sites, and dose/fractionation regimens to favor immune stimulation over suppression on the TME. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors on immune or tumor cells are under evaluation. The huge potential of combination therapies becoming apparent. Questions regarding targets, selection of patients, and time and sequence of administration are yet to be answered, considering the complex mechanisms of resistance. Dynamic biomarkers to guide personalized treatment decisions are needed. Full article