INTRODUCTION: Homologous recombination (HR) deficiency (HRD) and replication stress (RS) are increasingly recognized as interconnected hallmarks of genomic instability in cancer, offering promising avenues for therapeutic targeting. As novel combination therapies targeting these hallmarks continue to emerge, understanding how these processes interact in therapeutic contexts and comparing the relative efficacy and toxicity of combination therapy is critical in advancing precision oncology. AREAS COVERED: We investigate current and emerging assays that assess HRD and RS in cancer treatment and provide an exploration of related pathways. We also provide a high-level comparative pan-cancer analysis from results available on clinicaltrials.gov for common mono poly ADP-ribose polymerase inhibitor (PARPi), RS, and immune checkpoint blockade (ICB) therapies as well as their pairwise combinations, demonstrating efficacy and toxicity of current combination therapies. EXPERT OPINION: Integrating functional assessment of HRD and RS with immune contexture and considering these processes as outputs of their interconnected pathways in response to targeted agents could establish a unified therapeutic axis. Targeting this collective axis comprehensively may provide a promising foundation for next-generation, functionally guided treatment strategies capable of achieving durable responses with acceptable toxicity across diverse cancer types.

Locoregional breast cancer recurrence remains a significant therapeutic challenge, largely driven by limited drug selectivity and toxicity to surrounding healthy tissues. This Mini-Review examines the emerging potential of pH- and temperature-responsive formulations as injectable drug delivery systems designed to achieve preferential targeting of malignant cells. A range of advanced platforms─from smart hydrogels to hybrid constructs such as pH-sensitive liposomes embedded within thermoresponsive hydrogel matrices─are discussed, with emphasis on key design principles and synthesis strategies enabling environmental responsiveness. Among the technologies reviewed, liposome-in-hydrogel hybrid systems─still largely unexplored in breast cancer therapy─stand out for their capacity to enhance encapsulation of lipophilic therapeutics, improve formulation stability, streamline manufacturing, and provide sustained, spatially controlled drug release. Finally, critical physicochemical, mechanical, and biological characterization studies that are needed to rigorously evaluate the translational and clinical potential of these materials for the treatment of locoregional recurrent breast cancer are outlined.

Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancer. Despite recent advances in treating BRAFV600E-driven ATC, therapy resistance remains a significant challenge, often resulting in disease progression and death. Leveraging a focused CRISPR/KO screen in parallel with a CRISPR/activation screen, both tailored on response to BRAFV600E inhibitor treatment, we identified TAZ (encoded by WWTR1 gene) deficiency as synthetically lethal with BRAF inhibitor in ATC. TAZ is overexpressed in ATC compared to well-differentiated thyroid tumors. We demonstrate that TAZ-deficient ATC cells display heightened sensitivity to BRAF inhibitors. Using gene essentiality score across cancer cell lines, we found that BRAFV600E-driven cancers are highly sensitive to TAZ loss, unlike their counterparts with wild-type BRAF and non-BRAFV600E. Mechanistically, we demonstrate that dabrafenib triggers the Unfolded Protein Response (UPR) under ER stress and suppresses protein synthesis. TAZ loss represses the UPR, reverses the inhibition of protein synthesis, and triggers increased cell death by ferroptosis in dabrafenib-treated ATC. Collectively, our findings unveil TAZ as a new target to overcome resistance to BRAF inhibitors in undifferentiated thyroid cancer.

Managing deep, irregular wounds remains challenging due to poor suturability, persistent bleeding-induced wet environments, and neuropathic pain. Here, we have developed a sprayable dual-network microgel adhesive (PR) that rapidly covers complex wound geometries, combining strong wet tissue adhesion with sustained ropivacaine release. The sprayable powder format allows PR microgels to penetrate and adhere to irregular wound beds that conventional dressings cannot reach, with uniform particle size ensuring complete wound protection. Notably, PR maintains exceptional wet adhesion (∼40 kPa, over four times stronger than fibrin glue), enabling reliable sealing even under active bleeding conditions where liquid adhesives fail. The spray application simultaneously delivers liposomal ropivacaine, providing sustained analgesia (240 h release) that maintains pain-free mobility for over 168 h post-operation in rodent models. This on-demand sprayable platform addresses key limitations in wound management by integrating instant hemostatic adhesion with prolonged pain relief in a single conformable format, demonstrating significant potential for clinical application.

The authors provide an overview of the effects of physiotherapy on the immune response. Immunomodulation plays a decisive role in the analgesic and anti-inflammatory mechanisms underlying physiotherapy. Exercise is the most prominent physiotherapy treatment, for which the most evidence exists. The skeletal muscle is a secretory organ that releases myokines in response to movement. One of the best-known of these is irisin, a movement-induced myokine. Irisin plays an important role in inhibiting oxidative stress, reducing systemic inflammatory responses, and providing neuroprotection. It also has a positive effect on the functions of regulatory T cells, modulates immune cells, and increases the production of anti-inflammatory cytokines. Physiotherapy plays a significant role in improving the clinical condition of patients with autoimmune diseases. The beneficial tumor-immunological effects of regular physical activity are not accompanied by harmful side effects. Physiotherapy increases the number of natural killer cells, which play an important role in the defense against tumors. Massage, electrotherapy, and photomodulation treatments also affect the immune response. Following radon and sulfur bath treatments, statistically significant reductions in cytokine levels and other inflammatory biomarkers were observed. The anti-inflammatory effect of whole-body cryotherapy may also be due to a decrease in interleukin-6 and tumor necrosis factor levels. Knowledge of the effects of physiotherapy treatments on the immune response may be an important consideration when choosing a treatment strategy for these diseases. Orv Hetil. 2026; 167(17): 651-660.

BACKGROUND: Breast cancer (BC) is a biologically heterogeneous disease, and no single imaging modality captures the full spectrum of phenotypes across all stages of the disease. This review summarizes advances in receptor-targeted nuclear imaging approaches that support patient stratification, treatment selection and response monitoring. MAIN BODY: We provide a comprehensive review of preclinical and clinical studies of PET and SPECT radiopharmaceuticals targeting BC-relevant biomarkers on tumor cells and within the tumor microenvironment, with emphasis on clinical use cases, practical limitations and theranostic translational readiness. Conventional imaging modalities and [F]FDG PET/CT remain central to staging but can be limited by poor specificity and reduced sensitivity for small lesions. Although anatomical (RECIST) and metabolic (PERCIST) response criteria remain central in routine response assessment, their application in BC can be challenging, particularly in bone-predominant disease and in the presence of marked inter-lesional heterogeneity. Receptor-mediated nuclear imaging enables non-invasive, whole-body phenotyping beyond biopsy and maps spatial heterogeneity. Clinical progress has been achieved for steroid receptors (ER/PR/AR), HER2, GRPR and SSTR2 imaging, and extends to stromal targets such as FAP (FAPI tracers). Emerging targets, including CXCR4, NTSR1, NPY1R and TROP-2, further broaden the theranostic landscape, particularly in settings where biomarker profiles are heterogeneous or evolve over time. CONCLUSION: Multi-target imaging strategies may better address intra- and inter-lesional heterogeneity. Larger prospective cohorts are needed to define diagnostic performance, clinical relevance and theranostic value in BC.

Therapeutic options for relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) are limited, and the clinical activity and central nervous system (CNS) pharmacology of CD20 × CD3 bispecific antibody glofitamab remain poorly defined. This multicenter real-world study evaluated the efficacy, CNS penetration, and molecular response dynamics of glofitamab in 16 adults with R/R PCNSL treated with glofitamab monotherapy. Paired plasma and cerebrospinal fluid (CSF) samples were analyzed to assess CNS drug penetration. Serial CSF circulating tumor DNA (ctDNA) profiling was performed during glofitamab monotherapy, and chimeric antigen receptor T (CAR-T) cell kinetics were examined in patients receiving CAR-T consolidation. Glofitamab monotherapy achieved an interim overall response rate of 75%, including 50% complete responses. Median progression-free survival was 15.4 months, and median overall survival was not reached. In several patients, glofitamab was used as a bridge to subsequent CAR-T and/or autologous stem cell transplantation (ASCT), which may have influenced long-term outcomes. Glofitamab was detectable in the CSF of 60% of patients, with CSF/plasma ratios up to 0.44%. Longitudinal ctDNA analysis demonstrated that early molecular clearance was associated with radiographic response, while persistent or re-emergent ctDNA preceded clinical progression. The safety profile of glofitamab monotherapy was manageable, with most adverse events being Grade 1-2. Two patients (11%) experienced Grade ≥ 3 neurotoxicity and recovered after corticosteroid treatment. Two additional patients developed fatal immune effector cell-associated neurotoxicity syndrome following CAR-T consolidation. Glofitamab demonstrates early clinical activity and measurable CNS penetration in R/R PCNSL. Serial CSF ctDNA profiling may aid treatment monitoring, warranting prospective validation.

BACKGROUND This report describes the case of a 78-year-old man with neuroendocrine carcinoma of the submandibular gland. This is an exceptionally rare and aggressive malignancy, with only a limited number of cases reported in the literature. Due to its low incidence and histopathologic overlap with other tumors, its diagnosis and management remain challenging. CASE REPORT We report the case of a 78-year-old White man with no history of smoking or alcohol use and with no relevant comorbidities, who presented with a painless, rapidly enlarging left submandibular mass measuring approximately 6×4.5 cm. Contrast-enhanced CT revealed a large tumor with central necrosis extending into the subcutaneous plane. The patient underwent en bloc surgical resection of the tumor with associated cervical lymph nodes. Histopathological examination demonstrated a high-grade neuroendocrine carcinoma, characterized by large nests and trabeculae of tumor cells with a high nucleus-to-cytoplasm ratio, nuclear hyperchromasia, high mitotic activity, and areas of necrosis. Immunohistochemistry showed positivity for chromogranin A, cytokeratin AE1/AE3, and CD56, supporting the diagnosis of neuroendocrine carcinoma. Postoperative management included adjuvant medical therapy, and long-term radiological follow-up demonstrated no evidence of recurrence at 4 years. In addition, a systematic review of the literature was performed, identifying 27 well-documented cases of submandibular gland neuroendocrine carcinoma. CONCLUSIONS Submandibular gland neuroendocrine carcinoma is a rare and highly aggressive neoplasm requiring a multidisciplinary diagnostic and therapeutic approach. Given the lack of standardized treatment protocols, further research, molecular profiling, and multicentric studies are needed to develop personalized therapeutic strategies and improve patient outcomes.

INTRODUCTION: Ultraviolet B (UVB) phototherapy is recommended in clinical guidelines for atopic dermatitis, but it is uncertain whether narrowband or broadband UVB is more effective and better tolerated. OBJECTIVES: The objective of this parallel-group randomized clinical trial was to compare the efficacy and safety of broadband vs. narrowband UVB for the treatment of moderate-to-severe atopic dermatitis. METHODS: Participants were 18 years and older with moderate-to-severe atopic dermatitis refractory to topical corticosteroids. Participants were randomized 1:1 via a centralized computer randomization scheme to full-body broadband or narrowband UVB phototherapy, with ongoing concomitant topical therapy. Participants were blinded but treating and assessing clinicians were not. The primary outcome was change in Eczema Area and Severity Index (EASI) at 12 weeks. Secondary outcomes included achieving 0 or 1 and improvement of 2 or more on the validated Investor Global Assessment scale (vIGA) and change in Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numeric Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI) and Recap of atopic eczema RECAP). Efficacy analyses were conducted on a modified intention-to-treat population, including all randomized participants who receive at least one dose of phototherapy. RESULTS: 34 participants were randomized to broadband UVB and 35 to narrowband UVB. 32 participants received at least one dose of broadband UVB and 34 received at least one dose of narrowband UVB and were included in the modified intention-to-treat analysis. The mean age was 37.1 years in the broadband UVB arm and 33.2 in the narrowband UVB arm. The mean (95% credible interval) change in EASI score in the broadband UVB arm was -8.1 (-12.1 to -4.1) and in the narrowband UVB arm was -8.9 (-13.0 to -4.9). In the adjusted analysis, the difference between arms in change in EASI was -0.7 (-5.6 to 4.1). There were no significant differences between arms for any of vIGA, POEM, PP-NRS, DLQI or RECAP. There were 4 withdrawals from phototherapy due to adverse events in the broadband arm and 0 in the narrowband arm. CONCLUSIONS: In this study, broadband and narrowband UVB were similarly effective and narrowband UVB was better tolerated for the treatment of moderate-to-severe atopic dermatitis.

Exhausted T cells (Tex), characterized by impaired cytotoxic function, play a detrimental role in anti-tumor and anti-infection immunity but represent promising therapeutic targets for autoimmune diseases. Persistent exposure to auto-antigens drives autoreactive CD8+ or CD4+T cells toward an exhausted state, thereby mitigating excessive damage to healthy tissues. Inducing T cell exhaustion may offer a targeted approach to suppress pathological autoimmunity. In this review, we describe the markers, characteristics, and developmental phases of T cell exhaustion, discuss its close association with autoimmune diseases, and highlight Tex as a potential biomarker. We also summarize Tex-targeted therapeutic strategies, including inhibitory receptor activation, TCR overstimulation, and metabolic intervention, to provide insights for future treatments. The clinical translation gap of Tex-targeted therapy has also been proposed from stability, safety, and disease-specific considerations. Although challenges remain in areas such as antigen specificity and tenuous tolerance, therapies targeting Tex hold considerable potential to disrupt pathogenic circuits, realize disease remission, and reduce the risk of relapse in autoimmune diseases.

Venetoclax-based low-intensity regimens have improved the outcomes of older or unfit patients with acute myeloid leukemia (AML). This phase II study investigated the combination of cladribine plus low-dose cytarabine and venetoclax alternating with azacitidine plus venetoclax for older or unfit patients with newly diagnosed AML. A total of 190 patients were included; the median age was 68 years (range, 47-84 years; 13% ≥ 75 years). By the European LeukemiaNet 2022 classification, 16%, 20%, and 64% were stratified as favorable, intermediate, and adverse risk, respectively. The rates of complete remission (CR)/CR with incomplete blood count recovery (CRi) and minimal residual disease (MRD) negative CR/CRi were 84% and 75% overall and 91% and 77% among patients with TP53-wild type AML, respectively. The 4- and 8-week mortality rates were 1% and 3%, respectively. Among responders, 44% proceeded to allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) and event free survival (EFS) were 52 and 50 months, respectively. The 2- and 5-year OS rates were 60% and 45%, respectively. The 2-and 5-year EFS rates were 56% and 43%, respectively. Patients achieving MRD-negative CR had a median OS not reached and a 2-year OS rate of 70%. The median time to absolute neutrophil count recovery (> 1 × 10/L) and platelet count recovery (> 100 × 10/L) after induction was 27 and 24 days, respectively. Overall, the treatment was safe and most grade 3 and 4 adverse events were infectious complications. The combination produced a high rate of remissions, translating into favorable outcomes for older patients with newly diagnosed AML. Trial Registration: ClinicalTrials.gov idetifier: NCT03586609.

BACKGROUND: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcemia (FHH) are key differential diagnoses in parathyroid hormone (PTH)-mediated hypercalcemia. While PHPT often arises from single-gland parathyroid adenomas, CaSR mutations are typically associated with FHH. However, the coexistence of CaSR mutations and PHPT represents an unusual presentation, and the variability in their clinical impact remains underexplored. This report highlights two distinct cases of heterozygous CaSR mutations, including a novel mutation, shedding light on their potential roles in disease pathogenesis and management. CASE PRESENTATION: The first case involves a 54-year-old Caucasian female with a heterozygous Ala986Ser CaSR mutation, PHPT due to a parathyroid adenoma, and autoimmune Graves' disease. She presented with recurrent sicca syndrome, fatigue, hypercalcemia, elevated PTH, and hypercalciuria. Post-parathyroidectomy, persistent hypercalcemia and abnormal laboratory findings, alongside TRAK and TG antibodies, suggested a multifactorial pathogenesis. Imaging showed patchy hypoechoic thyroid parenchyma and recurrent adenoma. DXA revealed mild osteopenia, while calcimimetic therapy with cinacalcet was initiated but subsequently discontinued due to gastrointestinal intolerance. This unusual overlap of autoimmune and genetic factors emphasizes the complexity of managing PHPT with coexisting CaSR mutations. The second case describes a 52-year-old Caucasian male with a heterozygous Glu1011Gln CaSR mutation. He presented with severe hypercalcemia, elevated PTH, nausea, and diffuse musculoskeletal pain. Imaging revealed no adenomas, but sonography later identified a hypoechoic lesion with central vascularization, suggestive of a potential adenoma. Initial symptomatic improvement occurred despite persistently elevated biochemical markers; however, clinical worsening with recurrent abdominal symptoms and progressive bone mineral density loss was observed during follow-up. This case highlights a possible association between CaSR variants and sporadic adenomas, underscoring diagnostic complexity rather than direct causality. CONCLUSIONS: These cases highlight the complex clinical presentations in patients carrying CaSR variants and autoimmune components, suggesting a broader spectrum of clinical phenotypes and pathogenesis than previously understood. The findings emphasize the importance of genetic analysis in atypical cases and underscore the need for further research into the role of CaSR mutations in PHPT, which may inform future diagnostic and therapeutic strategies.

BACKGROUND: Gastric cancer (GC) is the fifth most prevalent cancer and the fifth leading cause of cancer-related mortality worldwide. The current gold standard for clinical diagnosis is gastroscopy, which, despite its high sensitivity and specificity, is limited by its invasive nature and high cost, making it unsuitable for large-scale screening. Furthermore, the diagnostic process lacks biomarkers that offer both high sensitivity and specificity. A screening model incorporating five methylation-based biomarkers (ELMO1, FGF12, NPY, SEPTIN9, ZNF671) was developed. Using these methylation profiles, GC risk prediction models were constructed employing Random Forest. RESULTS: In the training cohort of 605 subjects (259 patients with gastric cancer, 346 controls), the model demonstrated an area under the curve (AUC) of 0.9585, accuracy of 87.93%, sensitivity of 81.85%, and specificity of 92.49%. In an independent validation cohort of 152 subjects (73 patients with gastric cancer, 79 controls), the model achieved an AUC of 0.8868, accuracy of 81.58%, sensitivity of 82.19%, and specificity of 81.01%. The model showed strong screening capability across various pathological stages (0 + IA + IB, IIA + IIB, IIIA + IIIB + IIIC, IV), with AUCs of 0.8210, 0.9149, 0.9357, and 0.9383, respectively. Validation results were consistent with those from the training cohort, indicating significant potential for early-stage detection. CONCLUSIONS: This study establishes a minimally invasive, peripheral blood DNA methylation-based detection method for GC screening. The model demonstrates robustness, high sensitivity, and specificity, offering an effective strategy for population-level screening. The primary limitations of this study include the relatively small size of the validation cohort and a significant imbalance in TNM stage distribution. Additionally, there is a potential limitation in accurately discriminating gastric cancer risk within high-risk precancerous populations based solely on the current model. It is necessary to formulate a larger-scale prospective verification plan in the future.

BACKGROUND: Miller Fisher syndrome is a rare and challenging condition to diagnose. This article presents the case of a patient with severe and rapidly progressing symptoms who was initially misdiagnosed with cerebral infarction. Following methylprednisolone treatment, the patient's prognosis improved significantly. CASE PRESENTATION: The patient was a 63-year-old east Asian female farmer who was admitted with complaints of "dizziness, double vision, and unsteady gait for 14 hours." She subsequently developed respiratory distress, requiring ventilatory support and experienced a drop in blood pressure, which was managed with vasopressors. Initially misdiagnosed as having cerebral infarction, she received treatment with 3-butylphthalide, aspirin, and atorvastatin, but her symptoms did not improve. Serum tests were positive for anti-GQ1b and anti-GT1a IgG antibodies. This, combined with her history of a preceding infection and the presence of the clinical triad (ophthalmoplegia evidenced by diplopia and nystagmus, ataxia evidenced by unsteady gait and incoordination, and areflexia/hyporeflexia evidenced by absent pharyngeal reflex and diminished tendon reflexes), led to a final diagnosis of Miller Fisher syndrome (anti-GQ1b antibody-positive). Following treatment with methylprednisolone, her symptoms improved significantly. CONCLUSION: This report not only shares valuable clinical management experiences related to Miller Fisher syndrome, but also aims to enhance readers' understanding of the condition. Furthermore, this case is noteworthy as it documents the emergence of life-threatening symptoms such as respiratory distress and hypotension, which are atypical for Miller Fisher syndrome and highlight the potential for severe disease progression.

BACKGROUND: Hypoxia is a hallmark of the hepatocellular carcinoma (HCC) microenvironment, promoting tumor progression, therapy resistance, and poor prognosis. Central mediators of the hypoxic response are the hypoxia-inducible factors (HIFs), particularly HIF-1α, whose functional relevance in clinically representative models remains incompletely understood. METHODS: In this study, we performed an in-depth characterization and functional analysis of HIF-1α by generating HIF1A knockout (KO) models in two-dimensional (2D) and three-dimensional (3D) HCC culture systems, including tumor spheroids and fibrotic-like collagen-fibrin hydrogels, to better recapitulate the complexity of the tumor microenvironment (TME). RESULTS: Analyses of publicly available transcriptomic datasets revealed that HIF1A was significantly upregulated in tumor tissues and associated with higher grade, stage, and poor survival. In contrast, EPAS1 was downregulated and correlated with improved outcomes. Functional silencing and KO experiments confirmed that HIF-1α promoted tumor cell survival, invasion, and adaptation to hypoxia, while HIF-2α played only a limited role. HIF1A deletion impaired the expression of downstream targets such as VEGF and BNIP3 and altered ABCB1 levels. Importantly, HIF-1α loss markedly reduced viability and structural integrity in 3D cultures, highlighting the added value of using physiologically relevant models to uncover microenvironment-driven phenotypes. CONCLUSIONS: Altogether, our results identify HIF-1α as a central regulator of hypoxia-mediated tumor behavior in HCC and provide a strong rationale for its therapeutic targeting to disrupt tumor adaptation and improve patient outcomes. Moreover, these findings underscore the relevance of integrating both advanced 3D and complex 2D culture systems to better capture the structural, biochemical, and mechanical features of the TME.

Glioblastoma (GBM) remains incurable due to the blood-brain barrier (BBB) limiting drug delivery and intrinsic/acquired resistance to temozolomide (TMZ), the first-line chemotherapy. Here, we developed Angiopep-2 (Ang)-modified natural killer cell-derived extracellular vesicles (Ang-NK-EV) for targeted TMZ delivery (Ang-NK-EV@TMZ) to address these bottlenecks. NK-EV were prepared via freeze-thaw extrusion of NK-92 cells, loaded with TMZ, and surface-functionalized with Ang to target LRP1 (highly expressed at the BBB and on GBM cells). Characterization confirmed Ang-NK-EV@TMZ exhibited spherical morphology, preserved EV markers (TSG101, CD9/63/81), and retained NK cell-derived immune factors (IFN-γ, GZMB). In vitro, Ang modification enhanced GBM cell uptake (2.5-3.2-fold vs. NK-EV) and BBB transcytosis (2.8-3.5-fold vs. free TMZ). Ang-NK-EV@TMZ reversed TMZ resistance by modulating STING/ mTOR/ MGMT signaling (via IFN-γ) and inducing apoptosis (elevated cleaved caspase-3, γ-H2AX). It also triggered immunogenic cell death (increased ATP, HMGB1) and polarized macrophages to M1-like phenotypes. In orthotropic GBM models, Ang-NK-EV@TMZ accumulated in brain tumors, inhibited growth (7.2-fold lower bioluminescence vs. PBS), and extended median survival (42 days vs. 18 days for PBS). No significant organ toxicity or hemolysis was observed. This platform integrates targeted chemotherapy and immune modulation, highlighting NK-EV' potential for GBM therapy.