Multiregion WES of metastatic pancreatic neuroendocrine tumors revealed heterogeneity in genomic alterations, immune microenvironment and evolutionary patterns.

Pancreatic neuroendocrine tumors (PanNETs), though uncommon, have a high likelihood of spreading to other body parts. Previously, the genetic diversity and evolutionary patterns in metastatic PanNETs were not well understood. To investigate this, we performed multiregion sampling whole-exome sequencing (MRS-WES) on samples from 10 patients who had not received prior treatment for metastatic PanNETs. This included 29 primary tumor samples, 31 lymph node metastases, and 15 liver metastases. We used the MSK-MET dataset for survival analysis and validation of our findings. Our research indicates that mutations in the MEN1/DAXX genes might trigger the early stages of PanNET development. We categorized the patients based on the presence (MEN1/DAXXmut, n = 7) or absence (MEN1/DAXXwild, n = 3) of these mutations. Notable differences were observed between the two groups in terms of genetic alterations and clinically relevant mutations, confirmed using the MSK-MET dataset. Notably, patients with mutations in MEN1/DAXX/ATRX genes had a significantly longer median overall survival compared to those without these mutations (median not reached vs. 43.63 months, p = 0.047). Multiplex immunohistochemistry (mIHC) analysis showed a more prominent immunosuppressive environment in metastatic tumors, especially in patients with MEN1/DAXX mutations. These findings imply that MEN1/DAXX mutations lead PanNETs through a unique evolutionary path. The disease's progression pattern indicates that PanNETs can spread early, even before clinical detection, highlighting the importance of identifying biomarkers related to metastasis to guide personalized treatment strategies.

The functional verification of EGFR-CAR T-cells targeted to hypopharyngeal squamous cell carcinoma.

BACKGROUND: The aim of this study was to validate the antitumor function of EGFR-chimeric antigen T-cells (CART) targeted to FaDu cells, a hypopharyngeal squamous cell carcinoma cell line, and to provide a preclinical basis for the application of CART cell technology in hypopharyngeal squamous cell carcinoma. METHODS: Detection of cytokine secretions of EGFR-CAR T and CART-controls in the presence of target cells and nontarget cells as an indicator of CART cell activation. Detection of the cytotoxic effects of EGFR-CAR T on specific tumors in the presence of target cells was evaluated by LDH release and CART cell proliferation. RESULTS: The results showed that cytokine secretion increased significantly after EGFR-CAR T-cells were incubated with target cells, and EGFR-CAR T-cells has higher cytotoxic effect on target cells than the CART-control group. The target cell lysis rate was 52.66%. The proliferation of EGFR-CAR T-cells in the presence of target cells was not distinctly observed. CONCLUSION: In this study, we validated the antitumor function of EGFR-CAR T-cells targeted to the FaDu cell line and provided the foundation for application of the CART technique in the treatment of hypopharyngeal carcinoma.

The effects of fibroblast growth factor-2 delivered via a Gelfoam patch on the regeneration of myringosclerotic traumatic eardrum perforations lying close to the malleus.

OBJECTIVE: We evaluated the effects of fibroblast growth factor-2 (FGF-2) delivered via a Gelfoam patch on the regeneration of myringosclerotic traumatic tympanic membrane perforations (TMPs) lying close to the malleus. STUDY DESIGN: A prospective, randomized, controlled clinical study. SETTING: A university-affiliated teaching hospital. SUBJECTS AND METHODS: We prospectively analyzed, in a randomized manner, the outcomes of treatment for traumatic TMPs constituting >25% of the tympanic membrane. The closure rates, closure times, and otorrhea rates were compared among patients treated via FGF-2-containing Gelfoam patches, Gelfoam patches alone, and observation only. RESULTS: We analyzed data from 138 patients. The perforation closure rates in the FGF-2 plus Gelfoam patch, Gelfoam patch, and observation alone groups were 97.9, 89.8, and 70.7%, respectively. Both the FGF-2 plus Gelfoam and Gelfoam alone groups exhibited significantly higher closure rates than the observational group (both p<0.05).The mean closure times were 15.7±5.1, 24.8±4.9, and 35.7±9.2days in the FGF-2 plus Gelfoam patch, Gelfoam patch alone, and observation alone groups, respectively. The FGF-2 plus Gelfoam patch group exhibited a significantly shorter closure time than the Gelfoam patch alone and observation alone groups (p<0.05). The incidences of purulent otorrhea were 14.6, 6.1, and 4.9% in the FGF-2 plus Gelfoam patch, Gelfoam patch alone, and observation alone groups, respectively. Surprisingly, 7 of 7 (100.0%) perforations associated with purulent otorrhea completely closed in the FGF-2 plus Gelfoam patch group; however, no such perforation healed in either the Gelfoam alone or observation alone group. CONCLUSIONS: FGF-2 plus Gelfoam patching significantly shortened the closure time compared to observation and Gelfoam patching alone, and it significantly improved the closure rate (compared to observation alone) of myringosclerotic perforations lying close the malleus. FGF-2 plus Gelfoam patching is a valuable, minimally invasive alternative treatment that may be readily applied to outpatient settings.