Search Results (434)

Background and Clinical Significance: Hemophagocytic lymphohistiocytosis (HLH) and autoimmune hemolytic anemia (AIHA) are both life-threatening hematologic syndromes that rarely present together outside of malignancy. Advanced acquired immunodeficiency syndrome (AIDS) creates a milieu of profound immune dysregulation and hyperinflammation, predisposing patients to atypical overlaps of these disorders. Case Presentation: A 30-year-old woman with poorly controlled AIDS presented with three weeks of jaundice, fever, and fatigue. Initial labs revealed pancytopenia, hyperbilirubinemia, and elevated ferritin level. Direct anti-globulin testing confirmed warm AIHA (IgG⁺/C3d⁺) with transient cold agglutinins. Despite intravenous immunoglobulin (IVIG), rituximab, and transfusions, she developed hepatosplenomegaly, extreme hyperferritinemia, and sIL-2R > 10,000 pg/mL, meeting HLH-2004 criteria. Bone marrow biopsy excluded malignancy; further work-up revealed Epstein–Barr virus (EBV) viremia and cytomegalovirus (CMV) reactivation. Dexamethasone plus reduced-dose etoposide transiently reduced soluble interleukin-2 receptor (sIL-2R) but precipitated profound pancytopenia, Acute respiratory distress syndrome (ARDS) from CMV/parainfluenza pneumonia, bilateral deep vein thrombosis (DVT), and an ST-elevation myocardial infarction (STEMI). She ultimately died of hemorrhagic shock after anticoagulation despite maximal supportive measures. Conclusions: This case underscores the diagnostic challenges of HLH-AIHA overlap in AIDS, where cytopenias and hyperferritinemia mask the underlying cytokine storm. Pathogenesis likely involved IL-6/IFN-γ overproduction, impaired cytotoxic T-cell function, and molecular mimicry. While etoposide remains a cornerstone of HLH therapy, its myelotoxicity proved catastrophic in this immunocompromised host, highlighting the urgent need for cytokine-targeted agents to mitigate treatment-related mortality. Full article

Malignant mediastinal tumors are a group representing some of the most demanding oncological challenges for early, multi-level, and successful management. The timely identification of any suspicious clinical symptomatology is urgent in achieving an accurate, staged histological diagnosis, in order to follow up with an equally detailed medical therapeutic plan (interventional or not) and determine the principal goals regarding efficient overall treatment in these patients. We report a case of a 24-year-old male patient with an incident-free prior medical history. An initial chest X-ray was performed after the patient reported short-term, consistent moderate chest pain symptomatology, early work fatigue, and shortness of breath. The following imaging procedures (chest CT, PET-CT) indicated the presence of an anterior mediastinal mass (meas. ~11 cm × 10 cm × 13 cm, SUV: 8.7), applying additional pressure upon both right heart chambers. The Alpha-Fetoprotein (aFP) blood levels had exceeded at least 50 times their normal range. Two consecutive diagnostic attempts with non-specific histological results, a negative-for-malignancy fine-needle aspiration biopsy (FNA-biopsy), and an additional tumor biopsy, performed via mini anterior (R) thoracotomy with “suspicious” cellular gatherings, were performed elsewhere. After admission to our department, an (R) Video-Assisted Thoracic Surgery (VATS) was performed, along with multiple tumor biopsies and moderate pleural effusion drainage. The tumor’s measurements had increased to DMax: 16 cm × 9 cm × 13 cm, with a severe degree of atelectasis of the Right Lower Lobe parenchyma (RLL) and a pressure-displacement effect upon the Superior Vena Cava (SVC) and the (R) heart sinus, based on data from the preoperative chest MRA. The histological report indicated elements of a combined, non-seminomatous germ-cell mediastinal tumor, posthuberal-type teratoma, and embryonal carcinoma. The imminent chemotherapeutic plan included a “BEP” (Bleomycin^®/Cisplatin^®/Etoposide^®) scheme, which needed to be modified to a “VIP” (Cisplatin^®/Etoposide^®/Ifosfamide^®) scheme, due to an acute pulmonary embolism incident. While the aFP blood levels declined, even reaching normal measurements, the tumor’s size continued to increase significantly (DMax: 28 cm × 25 cm × 13 cm), with severe localized pressure effects, rapid weight loss, and a progressively worsening clinical status. Thus, an emergency surgical intervention took place via median sternotomy, extended with a complementary “T-Shaped” mini anterior (R) thoracotomy. A large, approx. 4 Kg mediastinal tumor was extracted, with additional RML and RUL “en-bloc” segmentectomy and partial mediastinal pleura decortication. The following histological results, apart from verifying the already-known posthuberal-type teratoma, indicated additional scattered small lesions of combined high-grade rabdomyosarcoma, chondrosarcoma, and osteosarcoma, as well as numerous high-grade glioblastoma cellular gatherings. No visible findings of the previously discovered non-seminomatous germ-cell and embryonal carcinoma elements were found. The patient’s postoperative status progressively improved, allowing therapeutic management to continue with six “TIP” (Cisplatin^®/Paclitaxel^®/Ifosfamide^®) sessions, currently under his regular “follow-up” from the oncological team. This report underlines the importance of early, accurate histological identification, combined with any necessary surgical intervention, diagnostic or therapeutic, as well as the appliance of any subsequent multimodality management plan. The diversity of mediastinal tumors, especially for young patients, leaves no place for complacency. Such rare examples may manifest, with equivalent, unpredictable evolution, obliging clinical physicians to stay constantly alert and not take anything for granted. Full article

Background: Often, neoadjuvant therapy, which relies on the induction of double-strand breaks (DSBs), is used prior to surgery to shrink tumors by inducing cancer cell apoptosis. However, recent studies have suggested that this treatment may also induce a fluctuating state between senescence and stemness in PA-1 embryonal carcinoma cells, potentially affecting therapeutic outcomes. Thus, the respective epigenetic pathways are up or downregulated over a time period of days. These fluctuations go hand in hand with changes in spatial DNA organization. Methods: By means of Single-Molecule Localization Microscopy in combination with mathematical evaluation tools for pointillist data sets, we investigated the organization of euchromatin and heterochromatin at the nanoscale on the third and fifth day after etoposide treatment. Results: Using fluorescently labeled antibodies against H3K9me3 (heterochromatin tri-methylation sites) and H3K4me3 (euchromatin tri-methylation sites), we found that the induction of DSBs led to the de-condensation of heterochromatin and compaction of euchromatin, with a peak effect on day 3 after the treatment. On day 3, we also observed the co-localization of euchromatin and heterochromatin, which have marks that usually occur in exclusive low-overlapping network-like compartments. The evaluation of the SMLM data using topological tools (persistent homology and persistent imaging) and principal component analysis, as well as the confocal microscopy analysis of H3K9me3- and H3K4me3-stained PA-1 cells, supported the findings that distinct shifts in euchromatin and heterochromatin organization took place in a subpopulation of these cells during the days after the treatment. Furthermore, by means of flow cytometry, it was shown that the rearrangements in chromatin organization coincided with the simultaneous upregulation of the stemness promotors OCT4A and SOX2 and senescence promotors p21Cip1 and p27. Conclusions: Our findings suggest potential applications to improve cancer therapy by inhibiting chromatin remodeling and preventing therapy-induced senescence. Full article

Purpose: Neuroendocrine carcinomas (NECs) are aggressive tumors treated with cisplatin-based chemotherapy, though responses vary. As DNA damage response (DDR) pathways influence cisplatin sensitivity, this single-center retrospective study evaluates the efficacy of first-line cisplatin in recurrent or metastatic NEC based on DDR mutation status. Materials and Methods: This study analyzed patients with grade 3 recurrent or metastatic NEC treated with first-line etoposide plus cisplatin at Samsung Medical Center between January 2019 and September 2023. All patients underwent next-generation sequencing to determine DDR mutation status, defined by pathogenic alterations in major DNA repair pathways. Clinical outcomes were assessed per RECIST v1.1. Survival analyses were conducted using Kaplan–Meier methods and Cox regression models, with significance set at p ≤ 0.05. Results: A total of 40 patients with NEC were included in this study. There were 16 patients with DDR wild-type (WT) and 24 patients with DDR mutant type (MT). The most common primary tumor sites were the pancreas (25.0%), stomach (20.0%), and gallbladder/duct (12.5%). Among 40 patients, those with DDR mutations (n = 24) showed significantly higher objective response (58.3% vs. 12.5%) and disease control rates (91.7% vs. 50.0%) compared to patients with DDR WT (n = 16). The median progression-free survival (PFS) showed the favorable trend in the DDR mutant group (8.0 vs. 4.3 months; p = 0.15), with similar trends observed across homologous recombination repair (HRR), Fanconi anemia (FA), and mismatch repair (MMR) subgroups. Conclusions: This study revealed that patients with DDR mutations had significantly higher response to first-line etoposide–cisplatin, suggesting DDR mutation status as a potential predictive marker to guide treatment and improve outcomes in recurrent or metastatic NEC. Full article

Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis despite initial responsiveness to chemotherapy. Platinum-based chemotherapy with etoposide has long been the standard first-line treatment, but recent advances in immunotherapy have improved outcomes. Phase III trials, including IMpower133 and CASPIAN, demonstrated that adding immune checkpoint inhibitors, such as atezolizumab and durvalumab, to chemotherapy significantly enhances overall survival (OS) and progression-free survival (PFS). This case report describes a 76-year-old former smoker diagnosed with extensive-stage SCLC (ES-SCLC) following the detection of a left lower lung mass. The patient underwent combination therapy with carboplatin, etoposide, and atezolizumab, followed by maintenance atezolizumab. The patient demonstrated a sustained response to treatment, with significant tumor regression and no evidence of disease progression. Despite advanced age and comorbidities, treatment was well-tolerated, with no severe adverse events. Serial imaging over 24 months confirmed sustained disease stability, with regression of mediastinal lymphadenopathy and no new lesions. This case highlights the potential for prolonged disease control in select SCLC patients treated with chemo-immunotherapy. The absence of significant toxicities underscores the feasibility of immunotherapy even in elderly patients with comorbidities. These findings support the role of atezolizumab as a key component of ES-SCLC treatment and suggest the need for further research on predictors of durable response. Full article

Background: Betulinic acid (BA) and some derivatives are well-known antiproliferative compounds. Literature precedents suggest that incorporating triphenylphosphonium (TPP⁺) salts on this triterpenoid scaffold enhances its biological activity. In the present study, we carried out a simple synthesis of C-28 ester derivatives of this triterpenoid conjugated with TPP⁺ bromide salts through 4- to 6-carbon chains via nucleophilic substitution of the corresponding ω-TPP⁺bromoalkanes. Tests for antiproliferative activity in nine cancer cell lines and normal human fibroblasts showed that TPP⁺ incorporation enhanced the potency of BA by more than an order of magnitude, up to 100-fold. BA-C₄-TPP⁺Br⁻, with a four-carbon chain separating the TPP⁺ moiety from the BA, showed remarkable antiproliferative effects, sometimes more potent than the reference drug (Etoposide). This compound exhibited the strongest mitochondrial uncoupling effect in human cancer cells. No significant LDH release was noted in colorectal carcinoma cells at low micromolar concentrations of BA-C₄-TPP⁺Br⁻, and sub-micromolar concentrations were sufficient for inducing apoptosis. The in silico prediction of pharmacokinetic properties suggested high oral absorption (88%), as well as a non-inhibitor and non-substrate profile vs. cytochrome isoenzymes. These results point to this compound as a promising lead for the development of novel anticancer drugs. Full article

The accumulation of senescent cells is a major contributor to aging and various age-related diseases, making developing senolytic compounds that are capable of clearing these cells an important area of research. However, progress has been hampered by the limited number of known senolytics and the incomplete understanding of their mechanisms. This study presents a powerful senolytic predictor built using phenotypic data and machine learning techniques to identify compounds with potential senolytic activity. A comprehensive training dataset consisting of 111 positive and 3951 negative compounds was curated from the literature. The dataset was used to train machine learning models, incorporating traditional molecular fingerprints, molecular descriptors, and MoLFormer molecular embeddings. By applying MoLFormer-based oversampling and testing different algorithms, it was found that the Support Vector Machine (SVM) and Multilayer Perceptron (MLP) models with MoLFormer embeddings exhibited the best performance, achieving Area Under the Curve (AUC) scores of 0.998 and 0.997, and F1 scores of 0.948 and 0.941, respectively. This senolytic predictor was then used to perform virtual screening of compounds from the DrugBank and TCMbank databases. In the DrugBank database, 98 structurally novel candidate compounds with potential senolytic activity were identified. For TCMbank, 714 potential senolytic compounds were predicted and 81 medicinal herbs with possible senolytic properties were identified. Moreover, pathway enrichment analysis revealed key targets and potential mechanisms underlying senolytic activity. In an experimental screening of predicted compounds, panaxatriol was found to exhibit senolytic activity on the etoposide-induced senescence of the IMR-90 cell line. Additionally, voclosporin was found to extend the lifespan of C. elegans more effectively than metformin, demonstrating the value of our model for drug repurposing. This study not only provides an efficient framework for discovering novel senolytic agents, but also highlights the predicted novel senolytic compounds and herbs as valuable starting points for future research into senolytic drug development. Full article

Background: Glioblastoma (GBM) remains a significant challenge in oncology due to its resistance to standard treatments including temozolomide. This study aimed to develop and validate an integrated model for predicting GBM sensitivity to alternative chemotherapeutics and identifying new drugs and combinations with therapeutic potential. Research Design and Methods: We analyzed drug sensitivity data for 272 compounds from CancerRxTissue and employed in silico algorithms to assess blood-brain barrier permeability. The model was used to predict GBM sensitivity to various drugs, which was then validated using GBM cellular models. Alternative drugs targeting overexpressed and negative prognostic biomarkers in GBM were experimentally validated. Results: The model predicted that GBM is more sensitive to Etoposide and Cisplatin compared to Temozolomide, which was confirmed by experimental validation in GBM cells. We also identified novel drugs with high predicted sensitivity in GBM. Daporinad, a NAMPT inhibitor that permeates the blood-brain barrier was selected for further preclinical evaluation. This evaluation supported the in silico predictions of high potential efficacy and safety in GBM. Conclusions: Our findings using different cellular models suggest that this computational prediction model could constitute a valuable tool for drug repurposing in GBM and potentially in other tumors, which could accelerate the development of more effective cancer treatments. Full article

Cancer remains one of the leading causes of morbidity and mortality worldwide, driving the search for innovative and selective therapeutic agents. Topoisomerases I and II are essential enzymes involved in key cellular processes such as DNA replication and transcription. They have emerged as valuable anticancer targets; thus, many inhibitors of topoisomerases have been designed and some of them are considered to be major anticancer agents such as anthracyclines, etoposide or irinotecan. A great deal of attention is currently being paid to chalcones, a class of naturally occurring compounds, since they exhibit a wide range of biological activities, including anticancer properties. These compounds are characterized by an open-chain structure and an α,β-unsaturated carbonyl moiety that enables interaction with cellular targets. Recent studies aiming to design anti-topoisomerase agents have identified both natural and synthetic chalcones, including chalcone-based hybrids. This review highlights the structural diversity of chalcones as topoisomerase inhibitors and particular attention is given to structure–activity relationship studies and molecular hybridization strategies aimed at optimizing the pharmacological profile of chalcones. These findings underline the potential of chalcones as promising scaffolds in the design of next-generation anticancer agents. Full article

Neuroendocrine transformation in non-small-cell lung cancer (NSCLC) is an uncommon but clinically significant resistance mechanism to targeted therapy, immunotherapy, and chemotherapy. This phenomenon, primarily observed in adenocarcinoma (ADC) with EGFR mutations under tyrosine kinase inhibitor (TKI) treatment, leads to histological transformation into small-cell lung cancer (SCLC), commonly associated with an aggressive clinical course and poor prognosis. Standard platinum–etoposide chemotherapy provides only transient disease control, highlighting the urgent need for improved therapeutic strategies. Early identification of transformation through biopsy, liquid biopsy, or biomarkers like neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (pro-GRP) may allow for early intervention. As targeted therapies continue to develop, understanding the molecular drivers of neuroendocrine transformation is crucial for optimizing treatment. Further research into novel treatment approaches, including combination therapies with TKIs, chemotherapy, immunotherapy, and epigenetic modulators, is required to improve outcomes for these patients. Full article

Background: Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal syndrome of immune dysregulation with primary (genetic) and secondary (acquired) forms, including malignancy-associated HLH (m-HLH). The condition often presents significant diagnostic and therapeutic challenges due to overlapping symptoms with underlying malignancies and the absence of standardized guidelines for refractory cases. The established standard of care is dexamethasone and etoposide, but no guidelines exist for refractory HLH or cases triggered by malignancy. Case presentations: This case series describes three adolescent patients with m-HLH, focusing on complexities in diagnosis, treatment regimens, and toxicity management. While dexamethasone and etoposide remain a standard of care, their efficacy in refractory cases is limited. We highlight the novel use of targeted therapies, including emapalumab, an interferon-gamma inhibitor, and ruxolitinib, a JAK1/2 inhibitor, which showed potential in modulating immune hyperactivation. Conclusions: Our findings emphasize the need for individualized treatment approaches in adolescent m-HLH and importance of further research to establish evidence-based therapeutic guidelines for refractory cases. Full article

Background: Testicular germ cell tumors (GCTs) are highly curable malignancies, particularly when diagnosed early. However, cardiac metastases are exceedingly rare—occurring in less than 1% of cases—and pose significant diagnostic and therapeutic challenges. Intracardiac involvement is exceptionally uncommon and typically necessitates a multidisciplinary approach for optimal management. Objective: To present a rare case of metastatic testicular GCT with intracardiac extension in a young male, underscoring the diagnostic complexity and therapeutic considerations of this unusual clinical scenario. Case Report: A 23-year-old male presented with diffuse abdominal pain, dyspnea, and a palpable right testicular mass. Imaging revealed a testicular tumor with metastases to the lungs, liver, retroperitoneal lymph nodes, and a large intracardiac mass extending from the inferior vena cava into the right atrium. Histopathology confirmed a mixed-germ cell tumor consisting of 75% seminoma, 20% embryonal carcinoma, and 5% teratoma. The patient underwent radical right orchiectomy followed by chemotherapy with the BEP regimen (bleomycin, etoposide, cisplatin). Cardiac magnetic resonance imaging confirmed the intracardiac mass, which significantly decreased in size after treatment. Serum tumor markers (AFP and β-hCG) also showed substantial post-treatment declines, corresponding with clinical improvement. Conclusions: This case highlights a rare presentation of metastatic testicular GCT with intracardiac involvement, emphasizing the importance of recognizing atypical metastases. Despite its complexity, the patient responded well to chemotherapy, reinforcing the effectiveness of current treatments. Long-term follow-up and a multidisciplinary approach are essential for monitoring recurrence and complications, contributing to the understanding of rare metastatic patterns and the need for further research. Full article

Glioblastoma (GBM) presents significant therapeutic challenges due to its invasive nature and resistance to standard chemotherapy, i.e., temozolomide (TMZ). This study aimed to identify gene signatures that predict poor TMZ response and high PD−L1/PD−1 tumor expression, and explore potential sensitivity to alternative drugs. We analyzed The Cancer Genome Atlas (TCGA) biopsy data to identify differentially expressed genes (DEGs) linked to these characteristics. Among 33 upregulated DEGs, 5 were significantly correlated with overall survival. A risk score model was built using these 5 DEGs, classifying patients into low-, medium-, and high-risk groups. We assessed immune cell infiltration, immunosuppressive mediators, and epithelial–mesenchymal transition (EMT) markers in each group using correlation analysis, Gene Set Enrichment Analysis (GSEA), and machine learning. The model demonstrated strong predictive power, with high-risk patients exhibiting poorer survival and increased immune infiltration. GSEA revealed upregulation of immune and EMT-related pathways in high-risk patients. Our analyses suggest that high-risk patients may exhibit limited response to PD−1 inhibitors, but could show sensitivity to etoposide and paclitaxel. This risk score model provides a valuable tool for guiding therapeutic decisions and identifying alternative chemotherapy options to enable the development of personalized and cost-effective treatments for GBM patients. Full article

Objective: To evaluate treatment outcomes and prognostic factors in patients with ultra-high-risk gestational trophoblastic neoplasia (GTN) compared to those with low-risk and high-risk GTN. Methods: A retrospective review of medical records was conducted for GTN patients treated at Chiang Mai University Hospital, Chiang Mai, Thailand, between January 1999 and December 2019. Overall and risk-specific survival rates were estimated using the Kaplan–Meier method, and prognostic factors were analyzed through univariate and multivariate analyses. Results: During the study period, 160 patients with GTN were identified, including 98 (61.2%) classified as low-risk, 31 (19.4%) as high-risk, and 31 (19.4%) as ultra-high-risk. One patient in the low-risk group and one in the high-risk group underwent hysterectomy without adjuvant chemotherapy due to spontaneous regression of serum β-hCG (human chorionic gonadotropin). Additionally, one patient with ultra-high-risk GTN died before receiving chemotherapy. Among the 97 low-risk GTN patients, 80 (82.5%) were treated with either single-agent methotrexate or actinomycin D. Among the 30 high-risk GTN patients, 20 (66.7%) received EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) as first-line chemotherapy, while 24 (80%) of the 30 ultra-high-risk GTN patients received EMA/CO as first-line treatment. Following first-line chemotherapy and/or salvage treatment, patients with ultra-high-risk GTN had significantly worse outcomes compared with those with low- and high-risk GTN, with remission rates of 63.3%, 96.9%, and 80.0%, respectively (p < 0.01). The five-year overall survival rate for patients with ultra-high-risk GTN was significantly lower than that for patients with low- and high-risk GTN (56% vs. 96% and 80%, respectively; p < 0.001). On multivariable analysis, significant prognostic factors included antecedent term pregnancy (hazard ratio [HR] = 11.50; 95% confidence interval [CI], 3.56–37.22; p < 0.01) and brain metastasis (HR = 4.61; 95% CI, 1.73–12.28; p < 0.01). Conclusions: Ultra-high-risk GTN accounts for only a small proportion of GTN cases but it is associated with poor survival rate and responsible for the majority of GTN-related deaths. Antecedent term pregnancy and brain metastasis were identified as significant prognostic factors. Full article

The cornerstone of first-line treatment in extensive-stage small cell lung cancer (ES-SCLC) is platinum- and etoposide-based chemotherapy. Platinum compounds could immunomodulate the tumor microenvironment in addition to their cytotoxic effect. Genetic variation in immune checkpoint (IC) pathways may predict chemotherapy efficacy. Polymorphisms in the IC genes were determined, and their association with survival was analyzed in 78 patients with ES-SCLC treated with chemotherapy. PD-L1 protein expression in tumor tissue was determined. Three variants in CD274 were associated with better median progression-free survival (mPFS): rs2297136 (hazard ratio [HR] 0.52, 95% CI 0.29–0.93; p = 0.03), rs2282055 (HR 0.23, 95% CI 0.09–0.64; p = 0.005), and rs822336 (HR 0.41, 95% CI 0.23–0.73; p = 0.002). CTLA4 rs231775 was also associated with mPFS (HR 0.30, 95% CI 0.14–0.63; p = 0.002). The variants CD274 rs2297136 and CD274 rs822336 were associated with platinum sensitivity (odds ratio [OR] 0.13, 95% CI 0.02–0.70; p = 0.02, and OR 0.08, 95% CI 0.01–0.46; p = 0.005, respectively). CD274 rs2297136 was also associated with better overall survival (p = 0.02), but not after adjustment for covariates. No association was found between CD274 germline variants and PD-L1 tumor expression. Our results suggest that CD274 and CTLA4 variants may be predictive biomarkers for platinum plus etoposide treatment in ES-SCLC. Full article