Hypothetically, intratumoral genomic heterogeneity has the potential to foster tumor-infiltrating lymphocyte (TIL) diversity; however, no study has directly tested this hypothesis by simultaneously investigating somatic mutations, TIL diversity, and immune response activity. Thus, we performed whole-exome sequencing, immune repertoire sequencing and gene expression on ten spatially separated tumor samples obtained from two tumor masses excised from a glioblastoma multiforme (GBM) patient, and we included peripheral blood as control. We found that although the multi-region samples from one tumor shared more common mutations than those from different tumors, the TIL populations did not. TIL repertoire diversity did not significantly correlate with the number of non-synonymous mutations; however, TIL diversity was highly correlated with local immune activity, as the pathways were all immune-related pathways that highly positive correlated with local TIL diversity. Twenty-three genes with expression largely unaffected by the intratumor heterogeneity were extracted from these pathways. Fifty GBM patients were stratified into two clusters by the expression of these genes with significant difference in prognosis. This finding was validated by The Cancer Genome Atlas (TCGA) GBM dataset, which indicated that despite the heterogeneity of intra-tumor immune status, the overall level of the immune response in GBM could be connected with prognosis.

Object: Skull base meningiomas with extracranial extensions are rarely described. This study describes the clinical features, surgical management and clinical outcomes of these rare tumors and investigates risk factors associated with progression-free survival (PFS). Methods: The clinical data of 34 consecutive patients who underwent surgery for skull base meningiomas with extracranial extensions from 2007 to 2018 were retrospectively collected and analyzed. Results: The mean patient age was 47.9 ± 13.9 years; 50.0% were male. The most common symptoms on admission were ophthalmic. All patients underwent a multidisciplinary consultation before surgery, and received individualized surgical management. The gross total resection (GTR) rate was 55.9% (19/34). Twelve patients received post-operative adjuvant radiotherapy (RT). Twelve patients experienced tumor recurrence during the follow-up period. The median PFS duration was 54 months. The mean overall survival (OS) duration was 111 months. By univariate analysis, a higher histological grade (WHO grade II and III), Ki-67 LI ≥ 5 and the extent of resection (EOR) were significantly associated with tumor recurrence. Multivariate analysis revealed Ki-67 LI ≥ 5, the EOR and adjuvant RT as prognostic factor of PFS. Conclusions: These relatively rare meningiomas are difficult to resect and have a poor prognosis; they are more common in males and have a higher histological grade than intracranial meningiomas. Multidisciplinary collaboration and individualized surgical strategies are crucial for surgically managing these complex tumors. Total removal of the tumor remains challenging. Subtotal resection (STR) or partial resection (PR) followed by RT is a reasonable strategy when radical resection is infeasible. Adjuvant RT should be recommended especially for tumors with histopathological risk factors (Ki-67 LI ≥ 5 or high histological grade).

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The organic alkylphenol 4-nonylphenol (NP) is regarded to be an endocrine disrupting chemical (EDC), one of the widely diffused and stable environmental contaminants. Due to its hydrophobicity and long half-life, NP can easily accumulate in living organisms, including humans, where it displays a series of toxic effects. It has been widely reported that NP affects male reproduction. In addition, there is increasing evidence suggesting that NP is detrimental to various organs, including the pancreas. This study investigated the adverse effects of NP exposure on the pancreas. Sprague-Dawley rats were treated with different doses of NP for 90 consecutive days. The data suggested that the body weights of the rats treated with NP decreased, and the highest dose of NP treatment (180 mg kg) dramatically increased water consumption by rats. Meanwhile, H&E staining and immunohistochemistry indicated that islets in the pancreases shrunk when the rats were treated with the indicated doses of NP. TUNEL staining demonstrated that NP exposure up-regulated the level of apoptosis in the pancreases in a dose-dependent manner. Besides this, NP exposure inhibited the secretion of insulin and disrupted glucose tolerance. The levels of reactive oxygen species (ROS) and intracellular calcium ([Ca]) in the islets were up-regulated in the groups of rats treated with NP, but the levels of Mitochondrial Membrane Potential (MMP) were down-regulated. These results suggest that NP-induced pancreatic damage in rats occurs through mitochondrial dysfunction and oxidative stress, which causes disruption of glucose tolerance and decrease in insulin secretion.

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