Pancreatic enzyme replacement therapy (PERT) is essential for the management of pancreatic exocrine insufficiency. Since June 2023, the United Kingdom has been affected by a global shortage of PERT. We investigated the impact of this shortage on national prescribing trends for Creon, Nutrizym, Pancrex and Pangrol.

We analysed primary and secondary care prescribing data in England from January 2019 to February 2026 and used linear regression with an interrupted time series approach to assess the impact of the shortage.

Creon 25 000 was the most prescribed PERT with an increasing trend. Following the onset of the shortage, prescribing in primary care increased to 12 192 (95% CI: 11 682-12 702) thousand capsules across 43 203 (41 549-44 856) prescriptions per month but remained below predicted levels (p < 0.001). Secondary care prescribing was higher than predicted (p < 0.001). Prescribing of Creon 10 000 also increased, with an excess of 912 (493-1330) thousand capsules and 2202 (1308-3097) prescriptions per month in primary care and 235 (192-279) thousand capsules in secondary care (approximately threefold higher than predicted, p < 0.001). Nutrizym more than doubled in primary care to 841 (743-940) and tripled in secondary care to 30 (24-35) thousand capsules per month (p < 0.001). Pancrex doubled in primary care (p = 0.001) but remained below predicted levels in secondary care (p = 0.005). The number of capsules per prescription increased for Creon 10 000 by 15 (6-23; p = 0.002) but decreased for all other formulations (p < 0.001).

Although prescribing remained highest for Creon 25 000, the shortage was associated with a shift towards Creon 10 000 and an increase in alternative products, particularly Nutrizym.

MAPK-pathway inhibitors including BRAF, MEK, and type II RAF inhibitors are now integral to treatment of pediatric low-grade glioma (pLGG), BRAF V600-mutant glioma, NF1-associated tumors, and melanoma brain metastases. Intratumoral and intracranial hemorrhage has emerged as a clinically relevant safety signal, but drug-specific incidence estimates, phenotypic definitions, and contributing mechanisms remain incompletely characterized. We systematically reviewed the evidence and synthesized contributing mechanisms.

We performed a systematic review of PubMed/MEDLINE and Embase from database inception through May 2026, supplemented by FDA prescribing information, to identify studies reporting intratumoral or intracranial hemorrhage with MAPK-pathway targeted agents across tumor types. Results were synthesized narratively given heterogeneity in reporting definitions and study designs.

CNS hemorrhage signals were identified across agents. Dabrafenib-based regimens in melanoma brain metastases produced ICH rates of 6% (BREAK-MB monotherapy) and a fatal hemorrhage in 0.8% (COMBI-MB combination). In the phase 2 FIREFLY-1 trial of tovorafenib in BRAF-altered pLGG (n = 137), any-site hemorrhage of any grade occurred in 42% of patients with grade 3-4 hemorrhage in 7 patients (5%) and, separately, one fatal grade 5 intratumoral hemorrhage; in the overlapping pooled FDA-label safety population (N = 140), intratumoral hemorrhage specifically was reported in 9%. Combining BRAF inhibitors with stereotactic radiosurgery was associated with 3-fold higher odds of ICH versus radiosurgery alone (OR 3.16; 95% CI 1.43-6.96).

MAPK-pathway inhibitors are associated with a consistent but heterogeneous CNS hemorrhage signal. Reported incidence varies by agent, population, and hemorrhage ascertainment method (active imaging-based surveillance versus clinical reporting), from < 1% symptomatic ICH with dabrafenib in adult melanoma to 9% intratumoral hemorrhage in the pooled pediatric tovorafenib safety population. Standardized definitions, CNS-specific CTCAE capture, and prospective imaging surveillance are needed to define true incidence and risk as MAPK-directed therapy expands in neuro-oncology.

This systematic review was not prospectively registered in PROSPERO.

Colorectal cancer (CRC) is a major cause of cancer-related death due to recurrence and therapeutic resistance. This study evaluates whether combining panobinostat, a histone deacetylase (HDAC) inhibitor, with epigallocatechin gallate (EGCG), a green tea-derived polyphenol, enhances anti-tumor activity through modulation of HDAC expression in CRC cell lines.

Cytotoxicity and migration were assessed in HCT-116 and HT-29 cells. Combination studies were performed using sub-cytotoxic concentrations (less than IC₂₅), and HDAC1, HDAC2, and HDAC4 expression levels were quantified by qPCR.

The combination of panobinostat and EGCG produced synergistic cytotoxic effects at low, sub-cytotoxic doses. Compared with single-agent treatment, co-treatment enhanced the cytotoxic activity of panobinostat. In HT-29 cells, EGCG inhibited migration, while 5 nM panobinostat alone showed minimal effect. Higher panobinostat doses (10 nM) and certain combination treatments significantly reduced migration. In HCT-116 cells, migration responses were limited, although selected combinations produced significant inhibition at 72 h. Mechanistically, EGCG downregulated HDAC1 in HT-29 cells and HDAC2 and HDAC4 in HCT-116 cells. In contrast, panobinostat and combination treatments upregulated HDAC expression, suggesting compensatory transcriptional feedback in response to HDAC inhibition.

Panobinostat combined with EGCG exerts synergistic cytotoxic effects in CRC, accompanied by time-and cell line-specific inhibition of cell migration and modulation of HDAC expression.

CAR-T cell therapy has revolutionized the treatment of hematologic malignancies, yet its translation to solid tumors remains a formidable challenge. A central determinant of this limitation is the hypoxic tumor microenvironment, which imposes profound immunosuppressive pressure on infiltrating CAR-T cells, impairing their persistence, effector function, and metabolic fitness. Rather than viewing hypoxia purely as an obstacle, emerging engineering paradigms are reframing it as a tumor-selective switch one that can be harnessed to spatially confine CAR-T cell activation, enhance metabolic fitness, and reduce off-tumor toxicity. This review critically examines how hypoxia subverts CAR-T cell immunity, and how next-generation hypoxia-responsive constructs, metabolic reprogramming strategies, and armored cytokine-secreting designs are beginning to turn this hostile microenvironment into a therapeutic advantage. We further discuss unresolved clinical challenges and the translational outlook for hypoxia-adapted CAR-T cells in solid tumor immunotherapy.

Hepatocellular carcinoma (HCC) progression is strongly influenced by hypoxia-driven HIF-1α signaling, which promotes EMT, invasion, angiogenesis, and metabolic adaptation. This study investigated whether miR-885-3p regulates HCC malignant phenotypes through the TASP1/HIF-1α axis.

Huh7 cells were transfected with miR-885-3p mimic, inhibitor, or controls. RT-qPCR, Western blotting, immunofluorescence, and dual-luciferase reporter assays were performed to assess miR-885-3p, TASP1, and HIF-1α regulation. Functional assays evaluated EMT, migration, invasion, angiogenesis, oxidative stress, metabolism, colony formation, adhesion, focal adhesion formation, and cytoskeletal remodeling. TASP1 restoration was used to test rescue effects. GEO datasets and 30 HCC patient samples were analyzed for clinical correlations.

Hypoxia increased miR-885-3p expression and enhanced HIF-1α nuclear accumulation. miR-885-3p directly targeted the TASP1 3'-UTR, suppressed TASP1 expression, and promoted HIF-1α activation. miR-885-3p overexpression induced EMT, migration, invasion, angiogenesis, oxidative stress, glycolytic activity, clonogenicity, adhesion, and F-actin remodeling, whereas miR-885-3p inhibition produced opposite effects. TASP1 restoration reduced HIF-1α activation and partially reversed migration, invasion, and angiogenesis. Clinical analyses showed inverse correlations between miR-885-3p and TASP1 and positive correlations with VIM, VEGFA, MMP2, and HMOX1.

miR-885-3p promotes HCC malignant phenotypes partly by targeting TASP1 and activating HIF-1α-associated signaling. Further in vivo validation is required.

Adenosine, a common cellular metabolite, can remodel the tumor immune microenvironment. Although gastric juice is considered a potential biomarker for gastric cancer (GC), sufficient verification is still lacking. This study aims to explore the potential of gastric juice-derived adenosine as a cancer biomarker. Adenosine levels in gastric juice, blood, and tissues from patients with GC and normal controls were quantified using non-targeted metabolomics and assay kits. Structure-explorative-interactive-SAR algorithm was used to analyze and predict the binding between adenosine and adenosine A1 receptor (ADORA1). Tumor immune estimation resource algorithm was employed to examine the correlation between ADORA1 and M2 macrophage infiltration and interleukin-6 (IL-6) levels. The binding affinity between adenosine and ADORA1 was validated using the cellular thermal shift assay. The messenger RNA and protein expression levels of ADORA1, CD86, and CD206 were examined via reverse transcription-quantitative polymerase chain reaction and Western blot. The protein expression of ADORA1 in tissue samples was assessed by immunohistochemistry. Flow cytometry was employed to measure the expression of surface markers on macrophages. Levels of cytokines and IL-6 were determined using an enzyme-linked immunosorbent assay. The chemotaxis of M2 macrophages was evaluated through Transwell. In vivo validation was conducted using a primary GC mouse model. Adenosine was highly expressed in gastric juice and tissues of patients with GC, while no significant difference was observed in the blood. Adenosine showed a strong binding affinity for ADORA1, and its expression level was positively correlated with adenosine concentration. Moreover, ADORA1 expression in GC cells was significantly and positively associated with M2 macrophage polarization and IL-6 secretion. However, the polarization of M1 macrophages and migration of M2 macrophages remained largely unchanged during this process. Our study innovatively reveals that gastric juice adenosine holds promise as a biomarker for GC diagnosis and the cancer immune landscape.

This report describes a rare case of recurrent hyperparathyroidism due to ectopic parathyroid hyperplasia in a 35-year-old woman with a CDC73 c.271C > T mutation. This case highlights the importance of multimodal imaging, intraoperative monitoring, and genetic evaluation in the management of recurrent primary hyperparathyroidism.

Prolactinomas are the most common neuroendocrine tumors of the pituitary and the leading cause of hyperprolactinemia. Dopamine Receptor Agonists (DAs), particularly cabergoline (CAB), effectively reduce prolactin levels and tumor volume, and are therefore the first-line therapy for prolactinomas. With long-term cabergoline use, adverse effects may become more consequential for some patients. Cabergoline-Associated Valvulopathy (CAV) primarily affects the mitral, tricuspid, and aortic valves, although its underlying mechanisms remain unclear. The potential link between CAB use and Valvular Heart Disease (VHD) in patients with prolactinomas remains controversial. This review summarizes current understanding of CAV and explores potential molecular mechanisms, including CAB's modulation of catecholaminergic, serotonergic, and Transforming Growth Factor-beta (TGF-β) related signaling pathways, along with inflammatory pathways. By integrating clinical patterns with mechanistic plausibility, we aim to support practical surveillance decisions and improve the long-term safety of CAB therapy in patients with prolactinomas.

Parathyroid carcinoma (PC) is a rare but clinically aggressive endocrine malignancy with limited treatment options and a poorly defined tumor microenvironment (TME). To elucidate its cellular heterogeneity and spatial architecture, we integrated single-cell and spatial transcriptomic profiling with whole-exome sequencing and multiplex immunohistochemistry on eight parathyroid neoplasm specimens, including PC, parathyroid adenoma (PA), and atypical parathyroid tumor (APT). We identified a distinct progenitor-like endocrine subpopulation (Ca-1) enriched in CDC73-mutant PC, exhibiting stem-like properties, elevated cell cycle activity, and pronounced genomic instability. Spatial mapping revealed that Ca-1 cells preferentially localize at the leading edge, forming a fibroinflammatory niche characterized by the enrichment of inflammatory cancer-associated fibroblasts (iCAFs) and SPP1+ macrophages. Within this niche, the dipeptidyl peptidase DPP4 is selectively expressed in Ca-1 cells and iCAFs, implicating a potential paracrine axis driving stromal remodeling and immunosuppression. These findings suggest that a spatially organized ecosystem may promote PC progression through TME remodeling and highlight the DPP4-CXCL2 axis as a candidate pathway for future investigation in aggressive parathyroid neoplasms.

Resistance to antiangiogenics is a major challenge in cancer therapy. These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we showed that hypoxia-inducing anti-VEGF therapy upregulated programmed cell death ligand 1 (PD-L1), yet failed to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggered epithelial osteopontin (SPP1) production, which recruited monocytes and skewed macrophages toward M2 states, suppressing T cell cytotoxicity. Pharmacological SPP1 depletion impeded the development of hypoxia, reduced M2 infiltration, restored T cell activity, and enabled synergy between antiangiogenics and anti-PD-L1. Genetic dissection - tumor-epithelial Spp1-KO grafts and bone marrow chimeras generated by lethal irradiation and reconstitution with Spp1-/- or WT hematopoietic donors - showed that myeloid SPP1 contributed only marginally compared with epithelial SPP1. These findings identified SPP1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contributed to a comprehensive model of antiangiogenic resistance, and supported SPP1-targeted strategies to personalize immunotherapy and antiangiogenic therapy according to tumor hypoxia.