Pancreatic cancer remains largely refractory to immune checkpoint inhibitors. High-intensity focused ultrasound (HIFU) may modulate the immunosuppressive tumor microenvironment via immunogenic cell death, yet clinical evidence on HIFU combined with programmed cell death protein 1 (PD-1) inhibitors in elderly patients is scarce.

The gut microbiome shapes chemotherapy efficacy and outcomes in several cancers, but evidence in ovarian cancer (OC) remains limited and largely cross-sectional. Despite high initial response rates, long-term relapse in OC remains frequent, while conventional markers capture only short-term therapeutic sensitivity. Whether longitudinal gut-microbiome trajectories during chemotherapy are associated with long-term recurrence remains unknown.

Two series of 1,2,3-triazole-based molecules were synthesized. Their physical properties were documented, and cytotoxicity was evaluated against normal lymphocytes, leukemic, adherent, and nontumor cell lines. Compounds 11, 15, and 16 were inactive, while compound 17 affected both normal and cancer cells. Compounds 18 and 20 showed activity against BJ and A549 cell lines, with compound 20 being selective for T-cell leukemias and compound 18 moderately affecting B-cell leukemia. Compound 12 specifically affected the HCTp53 KO cell line, while compounds 13 and 14 were selective for U2O2 and HCT116 cell lines, respectively. Compound 14 was highly specific for T-cell leukemia, whereas compound 19 was specific for A549 and moderately specific for B-cell lines. Compound 22 affected all tumor cell lines except A549. The active compound induces apoptosis since it activates caspase 3. Spheroid testing revealed that compounds 13 and 22 specifically affected HCT116 spheroids, while compound 19 affected A549 spheroids. Both in vitro and computational analyses demonstrated that compounds 11, 12, and 13 exhibit high affinity for the A Cα subunit of protein kinase A. This suggests a kinase-targeted mechanism of action, providing a structural foundation for future design strategies to optimize the potency of these lead compounds.

Lung squamous cell carcinoma (LUSC) is a difficult cancer to treat, with few targeted therapies to improve its poor prognosis. The goal of this study was to use a drug repurposing strategy to evaluate and compare drug sensitivities using 2D adherent and 3D spheroid models of NCI-H2170 LUSC cells. Both 2D adherent and 3D spheroid models were used to grow NCI-H2170 lung squamous cell carcinoma cells and evaluate their sensitivity to a large library of food and drug administration (FDA)-approved drugs, including many not typically used as anti-cancer agents. Cell death was assessed in the 2D adherent models, and for the top drugs half maximal effective concentration (EC50) values were determined. For the 3D spheroid models, drugs reducing spheroid size after 4 days of treatment were identified. There were 263 drugs that reduced the cell viability to <20% when cells were grown in 2D in 10 µM drug. When grown in 3D the cells were generally more drug resistant, with 87 drugs capable of reducing spheroid volume when grown over 4 days in 10 µM drug. Interestingly, 60 drugs proved effective in both model systems including many drugs that typically associated with anti-cancer properties. Of these 60, four were further found to have selective effects towards metastatic NCI-H2170 cells as compared to a much less metastatic matched cell line expressing the metastasis suppressor CREB3L1, in both 2D and 3D model systems. These included the hypoxia-inducible factor 1-alpha (HIF-1α inhibitor 2-methoxyestradiol, and three anti-infection agents (cetylpyridinium chloride, chlorhexidine-2HCl, zinc pyrithione).

Recent studies have shown that while chemotherapy kills tumor cells, it may also induce adaptive changes in cells within the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), which could paradoxically promote tumor progression. This study aimed to investigate the role of CAFs exposed to paclitaxel (PTX) or doxorubicin (DOX) in tumor progression and explore the underlying mechanisms.

Cancer remains one of the leading causes of mortality worldwide. Dysregulated cellular signaling pathways play a pivotal role in tumorigenesis, tumor progression, and metastasis. Among these, tyrosine kinases (TKs) constitute a critical class of enzymes that catalyze the phosphorylation of tyrosine residues on target proteins, thereby regulating key cellular processes including growth, differentiation, and survival. TKs have revolutionized cancer therapy by selectively targeting these enzymes, resulting in suppressed tumor growth and improved clinical outcomes for patients. Urea-containing motifs represent one of the most important bioactive functional groups in medicinal chemistry. In particular, unsymmetrical alkyl- and benzylureas are widely employed as key structural components in numerous approved drugs. This structural feature enables versatile modifications that enhance physicochemical properties, including solubility, metabolic stability, and bioavailability. This review explores the current landscape of antineoplastic urea-based tyrosine kinase inhibitors, presenting an exhaustive examination of contemporary urea-containing compounds that inhibit TKs while elucidating their mechanisms of action and molecular targets. In recent years, computational technologies have become indispensable in modern drug discovery. They significantly accelerate the identification of new TKIs and support the repurposing of established pharmaceuticals. Ultimately, the review addresses the prevailing challenges and future opportunities in the advancement of urea-containing tyrosine kinase inhibitors.

This study aimed to identify the incidence rate, severity and distribution characteristics of symptoms in ovarian cancer patients during first-line maintenance therapy, and to determine the composition of symptom clusters, so as to provide evidence for clinical medical staff to optimize symptom management strategies for ovarian cancer patients receiving first-line maintenance therapy.

Chemotherapy scheduling poses a challenging control problem due to the need to suppress tumour growth whilst maintaining systemic toxicity within clinically acceptable limits. This study develops a double Q-learning-based controller for optimising daily dosing of a three-drug regimen consisting of cisplatin, docetaxel and irinotecan. A pharmacokinetics-pharmacodynamics (PK/PD) tumour model with eight resistance states is used as the simulation environment. The controller aims to minimise tumour burden whilst enforcing strict toxicity constraints aligned with clinical dosing guidelines. Simulation results show that double Q-learning substantially outperforms classical Q-learning, achieving near-complete tumour suppression within the simulation framework, corresponding to a residual tumour fraction on the order of 10-6 (approximately six orders of magnitude reduction) whilst maintaining toxicity within predefined constraints. Robustness analyses under physiological parameter variations of up to ±50% and under abrupt disturbance events further demonstrate that the double Q-learning policy preserves stable closed-loop behaviour within the simulation environment and exhibits strong resilience to uncertainty. Overall, the results indicate that double Q-learning provides a proof-of-concept framework for adaptive chemotherapy optimisation, with potential for future investigation in reinforcement learning-based chemotherapy optimisation frameworks.

Bispecific antibodies (BisAbs) have transformed the management of relapsed and refractory multiple myeloma (MM), achieving high response rates in heavily pretreated patients. However, these therapies induce profound immune perturbation, including plasma cell aplasia, hypogammaglobulinemia, and T-cell exhaustion, predisposing patients to serious infections. Progressive multifocal leukoencephalopathy (PML) has rarely been reported in this setting.

Gastric cancer is among the most common cancers and represents a major public health problem worldwide. New therapeutic strategies and drugs are needed. Anti-angiogenic agents targeting the Vascular Endothelial Growth Factor (VEGF) are used in combination therapy in the clinic, although their efficacy remains modest. We believe that these large anti-VEGF antibodies could be advantageously replaced by smaller peptides with better tissue penetration. In this study, we evaluate the efficacy of a previously described dimer peptide ligand of VEGF, D6, in inhibiting the proliferation of gastric cancer cells and the growth of the corresponding murine xenograft. The activity of the D6 peptide in these assays was comparable to that of bevacizumab, the positive control antibody, although the peptide required repeated injections at higher molar concentrations. These promising results justify the continued optimization of the peptide dimer, currently under investigation in our laboratory.

Dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene, plays an important role in the metabolism of fluoropyrimidine (FP) drugs, including tegafur, in S-1. A decrease in DPD activity can cause severe FP-related toxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for FP and DPYD polymorphisms recommend FP dose adjustments based on the four major DPYD polymorphisms. However, multiple rare variants of DPYD have been reported. We present the case of a man in his 50s with cT3N0M0 tongue squamous cell carcinoma who developed severe myelosuppression and diarrhea after the initiation of S-1 (tegafur/gimeracil/oteracil) despite appropriate dosing. On day 20 of treatment, the patient developed grade 4 neutropenia and septic shock and required ICU admission. Genetic testing identified a rare heterozygous DPYD variant (c. 812delT) that causes a frameshift and a presumed loss of enzyme function, suggesting an underlying cause of the severe adverse events. Although severe toxicity occurred, marked tumor shrinkage allowed for less invasive surgery. This case highlights the need for expanded genetic screening beyond the guideline-listed variants, particularly in Asian populations, where common variants differ. Combining genotypic and phenotypic evaluations of DPD activity may improve the prediction and prevention of FP-related toxicities, supporting safer and more effective use of FP drugs.

We reported LINGO1 as a potential marker on Ewing sarcoma cells that could enable targeted drug delivery, improving treatment effectiveness while reducing side effects.

BRAF inhibitors have advanced treatment for patients with BRAF-altered high and low-grade glioma (HGG and LGG, respectively). Clinically-available therapies are effective but require selection by mutation type and careful, proactive toxicity management to maximize patient quality of life and treatment duration. While pediatric LGG patients often experience durable responses, adults with LGG and patients with HGG frequently develop treatment resistance and disease progression while on treatment. Strategies to prevent or overcome resistant disease are under active preclinical and clinical investigation. This review serves as a primer to BRAF-altered therapy in glioma, outlines best practices for using available BRAF inhibitors, and highlights emerging therapeutic approaches aimed at improving outcomes in resistant disease. It serves as a forward-looking, practical guide for clinicians treating patients with BRAF-altered glioma.Article highlightsBRAF inhibitors are effective in both pediatric and adult low- and high-grade gliomas (LGG and HGG), but treatment should be tailored to the specific BRAF alteration (Table 1).Dabrafenib combined with trametinib is FDA-approved for BRAF V600E-mutant gliomas, while tovorafenib is approved for pediatric LGGs harboring BRAF V600 mutations or BRAF fusions.Proactive management, including anticipatory guidance and dose reduction for some patients, is essential to mitigate toxicity and avoid treatment interruptions.Tumor progression can occur during treatment interruptions or drug cessation; however, some patients may respond to BRAF inhibitor rechallenge.Emerging strategies focus on combination with other therapies including radiation, autophagy inhibitors, additional targeted agents, and others to overcome acquired resistance.Next-generation BRAF inhibitors-including paradox breakers, dimer disruptors, and protein degraders-are under clinical investigation (Table 2).

FTA is a new FT derivative developed by our team by modifying FT with aspirin, and it has been shown to boost anti-breast cancer activity.

Childhood cancer survivors (CCSs) are at increased risk of cancer therapy-related cardiac dysfunction following anthracycline chemotherapy. Although left atrial (LA) strain assessed by speckle-tracking echocardiography has emerged as a sensitive marker of diastolic dysfunction, it remains unclear when during survivorship LA dysfunction becomes detectable in CCSs treated with anthracyclines.In this retrospective observational case-control study, 92 CCSs (aged 4-32 years) and 96 age-matched healthy controls underwent echocardiography. Participants were stratified into three age groups (4-12, 13-18, and 19-32 years). LA reservoir, conduit, and pump strains were measured using two-dimensional speckle-tracking echocardiography from the apical four-chamber view. Conventional echocardiographic parameters, including mitral inflow velocities (E and A waves), E/A ratio, and tissue Doppler-derived e' and E/e', as well as left ventricular longitudinal strain (LVLS), were assessed.Conventional diastolic parameters did not significantly differ between CCSs and controls within corresponding age groups. However, in young adult CCSs (19-32 years), all three components of LA phasic strain (reservoir, conduit, and pump strains) were significantly reduced compared with age-matched controls. LVLS was also significantly lower in this group, whereas younger CCSs showed no significant differences in LA strain.LA phasic dysfunction was most evident in young adult CCSs despite preserved conventional diastolic indices, suggesting that age-stratified LA strain assessment may help identify survivorship stages at which atrial dysfunction becomes detectable.

Patients diagnosed with metastatic or recurrent cancer experience uncertainty and distress; however, their consultation needs remain insufficiently quantified. We conducted a web survey in Japan (January 23-29, 2025) among adults (≥18 years) with a history of metastatic or recurrent cancer (n=522). Participants selected concerns from 21 items across four domains, and for each endorsed concern, they indicated whether they wished to consult hospital and/or community pharmacists; consultation intention was calculated among those endorsing each item. Hospital-community differences were evaluated using McNemar's test or Mid-P exact test using a significance threshold of p<0.001. The mean age was 58.9±12.9 years; cancers were colorectal (22.2%), breast (18.2%), lung (11.9%), and gastric (11.1%). 88.7% reported at least one concern. The most common concerns were treatment-related side effects (51.0%), anticancer drug mechanism/efficacy (46.9%), treatment costs (42.1%), mental distress (35.1%), and medications used to alleviate cancer- or treatment-related physical discomfort (34.7%). Consultation intention was higher for hospital than community pharmacists for issues including side effects (43.2 vs. 16.2%), mechanism/efficacy (42.9 vs. 18.0%), and symptom-relief medications (48.6 vs. 24.9%). Although concerns regarding medications other than cancer treatment were uncommon (<10% each), consultation intention exceeded 40% when present. These findings indicate that patients with metastatic or recurrent cancer may perceive different consultation roles for hospital and community pharmacists, particularly according to the type of concern. Because these results are based on self-reported consultation intentions rather than actual consultation behavior, they should be regarded as hypothesis-generating and as a basis for future studies on coordinated pharmacist support.

Managing adverse events is important for optimizing cancer treatment and ensuring high patient satisfaction. Studies have assessed (1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody-induced skin toxicities, (2) development of severe neutropenia by renally excreted anticancer drugs in patients with renal impairment (RI), and (3) pharmaceutical care in the treatment of immune checkpoint inhibitors (ICIs). We identified liver metastasis as a risk factor and preemptive systemic antibiotic administration with anti-inflammatory effect as a preventive factor for grade ≥2 overall skin toxicities in anti-EGFR treatment for metastatic colorectal cancer (mCRC). Additional prophylactic topical steroids to systemic minocycline significantly prevented grade ≥2 rashes, but did not mitigate overall skin toxicities. Patients receiving trifluridine/tipiracil (FTD/TPI)-based chemotherapy for mCRC were assessed, resulting in significantly higher early severe neutropenia development among patients with RI. Additionally, we assessed the impact of RI on severe neutropenia development in carboplatin+pemetrexed-based chemotherapy for thoracic cancer. Consequently, severe neutropenia in the first cycle and all-treatment cycles was significantly more confirmed in patients with RI. We assessed the usefulness of pharmaceutical interventions in ICI treatment, which suggested that pharmaceutical care may improve quality of outpatient ICI treatment, and pharmaceutical intervention during the first three months after initiation of ICI treatment is crucial. Our studies have found clinically important outcomes that support the provision of less onerous chemotherapy.

Immune checkpoint inhibitors-induced diabetes mellitus (ICI-DM) is a rare but potentially life-threatening endocrine immune-related adverse event, often characterized by abrupt onset of insulin deficiency and frequent presentation with diabetic ketoacidosis and difficulty with daily management with the available therapies. Lung cancer patients represent a substantial proportion of reported cases, reflecting the widespread use of PD-1/PD-L1 inhibitors in thoracic oncology. We report on the case of an elderly patient with metastatic lung adenocarcinoma treated with pembrolizumab who developed severe DM requiring permanent insulin therapy and leading to treatment discontinuation. The patient was subsequently followed over a prolonged period, during which oncological disease remained under sustained control despite immunotherapy interruption. We describe the clinical course, diagnostic workup, and multidisciplinary management, and review current guideline recommendations addressing acute metabolic management, diabetic treatment, and decision-making regarding continuation of immunotherapy. This case highlights the complexity of managing ICI-DM in real-world clinical practice. The current guidelines may help in broad terms. Although guidelines have been published, they remain cursory. Nevertheless, therapeutic decisions should ultimately be individualized through close multidisciplinary collaboration.

Parasite-derived molecules have emerged as a promising source of natural bioactive compounds with immunomodulatory and antitumor properties, attracting increasing attention in cancer research. Derived from both protozoan and helminth parasites, these molecules exhibit diverse biological activities that extend beyond parasite survival and represent a novel resource for cancer therapy. Accumulating evidence demonstrates that parasite-derived molecules suppress tumor progression through complementary immune-mediated and non-immune mechanisms, including activation of innate and adaptive antitumor immunity, remodeling of the tumor microenvironment, induction of apoptosis and autophagy, inhibition of angiogenesis and metastasis, and regulation of tumor metabolism. Recent preclinical studies have demonstrated encouraging therapeutic efficacy across multiple tumor models, including melanoma, lung cancer, colorectal cancer, breast cancer, hepatocellular carcinoma, and other malignancies. In addition to summarizing the major classes of parasite-derived molecules and their mechanisms of action, this review highlights recent advances in translational research, including combination therapeutic strategies, immunogenicity and safety, delivery system optimization, and manufacturing and regulatory considerations. Despite encouraging preclinical findings, substantial challenges remain before clinical translation can be achieved. By integrating current mechanistic evidence with emerging translational perspectives, this review provides a comprehensive overview of parasite-derived molecules as potential anticancer agents and offers insights to facilitate their future development and clinical application in cancer therapy.

Malignancy remains a major cause of late morbidity and mortality in kidney transplant recipients, largely due to chronic immunosuppression and impaired tumor immune surveillance. Mammalian target of rapamycin inhibitors have antiproliferative and antiangiogenic properties and are frequently used in recipients considered to be at increased oncologic risk. However, their protective effect against de novo malignancy is not absolute. Here, we report 2 cases of severe malignancies that developed in kidney transplant recipients after conversion from calcineurin inhibitors to sirolimus following polyomavirus-associated nephropathy. The first patient, a 55-year-old man, developed prostate adenocarcinoma 6 years after transplant and 4 years after conversion to sirolimus. The diagnosis was established during evaluation for severe anemia and graft dysfunction. The second patient, a 35-year-old woman, developed primary central nervous system posttransplant lymphoproliferative disorder 4 years after transplant and 2 years after conversion to sirolimus. Histopathologic examination confirmed an aggressive lymphoma without detectable Epstein-Barr virus infection. These cases illustrate that mammalian target of rapamycin inhibitor-based immunosuppression does not eliminate the risk of solid or hematologic malignancy. Cumulative immunosuppressive exposure, viral complications, and delayed conversion may contribute to persistent oncogenic risk. Careful long-term oncologic surveillance and individualized immunosuppressive management remain essential in kidney transplant recipients.