doxorubicin (doxorubicin, Nanox / Doxonax)

Invasive thymoma with rapid response to cisplatin, doxorubicin and cyclophosphamide (PAC) chemotherapy, after an early postoperative recurrence-a case report.

Harada Chika C, Kitano Kentaro K, Umezawa Hiroki H, Kono Chiyoko C et al.

Thymomas generally exhibit indolent growth and local progression, with extrathoracic metastases being rare. Recurrence typically occurs months or years after surgical resection. We herein present a rare case of thymoma exhibiting rapid postoperative recurrence and abdominal lymph node metastasis, which showed a dramatic response to chemotherapy. A 66-year-old female was referred to our hospital for breast cancer treatment. A preoperative computed tomography (CT) scan coincidentally revealed a 7.5 cm anterior mediastinal tumor, suspected to be invading the pericardium and left lung. Extended thymothymectomy with partial resection of the left lung and pericardium was performed. Intraoperatively, no pleural dissemination was observed, and pleural effusion cytology was negative for malignant cells. The pathology was Type AB thymoma, Masaoka stage III [tumor, node, metastasis (TNM) 8th edition: pT3N0M0, Stage IIIA; TNM 9th edition: pT2N0M0, Stage II], with microscopically positive (R1) margins; thus, postoperative radiotherapy was planned. On postoperative day (POD) 18, she presented with dyspnea and massive left pleural effusion; after repeated thoracocentesis, the effusion recurred, and the patient was readmitted for continuous drainage. On POD 43, a CT scan showed a massive lesion along the left thoracic wall adjacent to the pericardium, with multiple small nodes in the left lung and two enlarged left gastric lymph nodes. A CT-guided needle biopsy of the thoracic wall performed on POD 47 confirmed recurrent thymoma. The patient received chemotherapy with cisplatin, doxorubicin, and cyclophosphamide (PAC), with biochemical evidence of rapid tumor lysis that did not meet formal tumor lysis syndrome criteria. Chest X-ray on day 3 of chemotherapy showed near-complete resolution of the thoracic lesions, and a complete response, including normalization of the abdominal lymph nodes, was achieved after four courses of PAC. Serial follow-up imaging has shown no evidence of recurrence for at least 18 months. This case illustrates the diagnostic complexity of thymoma, including atypical radiological and pathological features together with an unusually aggressive early recurrence. Incomplete resection can lead to early recurrence and progression, and clinicians must remain vigilant for such atypical courses. The tumor nonetheless proved highly sensitive to chemotherapy, underscoring the importance of prompt systemic treatment intervention when recurrence occurs.

Combined 2D and 3D cell culture models as a strategy to reduce the use of animals in antitumoral compound screening.

Fontão Ana Paula Gregório Alves APGA, E Silva Gustavo Werneck de Souza GWS, Barroso Wanise Borges Gouveia WBG, Barroso Gouveia G et al.

Advances in drug discovery and early clinical development depends fundamentally on robust pre-clinical research and a comprehensive understanding of cancer biology. There is an international effort to reduce the use of animals in research and product development, with a focus on technical advances to build better in vitro models. Three-dimensional (3D) cell culture mimics the architecture of solid tumors and could be validated as an alternative method to animal use in research and development, promoting faster and more. A workflow of assays and decision points was established in the FIOCRUZ Technological Platform of Bioassays for antitumoral drugs at Farmanguinhos - FIOCRUZ. The flow with increased complexity starts with simple 2D assays, going through assays for determination of apoptosis and finally 3D assays for cytotoxicity and biomarker modulation. This drug discovery flow was challenged by two molecules received by our platform. As first step, compounds were tested in a single concentration using cell lines in the 2D model, with cytotoxicity assessment performed by the MTT assay. This stage is intended for early-phase projects (TRL 1 and 2), including the screening of new molecules, development of nanopreparations, and activity-guided synthesis or natural product fractionation. When at least 30% of cytotoxicity is observed, samples are forwarded for IC50 determination and, if a good IC50 is observed (below 10 µM) the selectivity index (SI) is determined and apoptosis analysis is performed. At this stage, the projects are already at more advanced maturity levels, covering lead compounds, enriched fractions, isolated natural products and optimized nanopreparations. Samples with good performance (IC50 below 10 µM and SI above 3) are subsequently evaluated in 3D spheroid models using the forced suspension method, with the goal of complementing cytotoxicity data and then advancing to studies on biomarker expression. In this study, we have carried out assays on MCF-7 cell line. As expected, compounds RPT11M_10330 and RPT11M_10332 showed significant differences in IC50 values between the 2D and 3D models. We observed that both compounds were cytotoxic and were equally effective as doxorubicin in the 2D model. The 3D model exhibited greater intrinsic resistance compared to the 2D model, as described in the literature; the Ultra-low attachment spheroid culture environment changed the tumor cellular responses to drugs as IC50 values of these molecules were higher in the 3D model. Each approach has its own strengths and limitations and should be considered both individually and in an integrated manner. Recent advances in preclinical screening tools, which more reliably predict clinical effects and adverse events of drug candidates, have begun a new era in drug development and screening. We suggest a combination of well-established 2D models with emerging techniques, such as 3D models, in drug research and development that may lead to robust preclinical reports, accelerating drug discovery projects. The online version contains supplementary material available at https://doi.org/10.1007/s44164-026-00137-7.

Response to Letter "Dexamethasone for PEGylated liposomal doxorubicin cutaneous toxicity: Denominators, regimen identity, and implementation".

Ding Tianhao T

Cholesterol-mediated endoplasmic reticulum targeting to enhance the immune-activating capability of doxorubicin for hepatocellular carcinoma.

Wang Yanxia Y, Dou Yue Y, Chen Huan H, Qi Jianhong J et al.

Severe endoplasmic reticulum stress (ERS) activates ER autophagy and related apoptotic pathways, promoting cell death, a characteristic that has been applied in cancer treatment. Targeted delivery of immunogenic cell death (ICD) inducers, such as doxorubicin (DOX), to the ER can significantly enhance ERS and induce ICD in cells, thereby activating the body's anti-tumor immune response and effectively killing cancer cells. Based on the cholesterol metabolism and intracellular transport characteristics of Hepatocellular carcinoma (HCC) cells, this study designed a nanoparticle delivery system using cholesterol phosphate conjugates (CHP) as carriers for the delivery of DOX (DOX@HCCP). The results show that DOX@HCCP exhibits an endocytosis pathway similar to that of cholesterol, characterized by a high dependence on energy. The endocytosis pathways primarily involve caveolin-mediated endocytosis, macropinocytosis, and clathrin-mediated endocytosis, followed by lysosomal escape to the ER via the cholesterol-mediated intracellular transport pathway. The targeted delivery of DOX to the ER induces strong ERS, effectively triggers cell apoptosis, and promotes ICD, significantly activating the body's anti-tumor immune response, thereby enhancing the anti-tumor effects.