Clinicopathological characteristics, molecular landscape, and biomarker landscape for predicting the efficacy of PD-1/PD-L1 inhibitors in Chinese population with mismatch repair deficient urothelial carcinoma: a real-world study.

Urothelial carcinoma (UC) with deficient mismatch repair (dMMR) is a specific subtype of UC characterized by the loss of mismatch repair (MMR) proteins and its association with Lynch syndrome (LS). However, comprehensive real-world data on the incidence, clinicopathological characteristics, molecular landscape, and biomarker landscape for predicting the efficacy of PD-1/PD-L1 inhibitors in the Chinese patients with dMMR UC remains unknown. We analyzed 374 patients with bladder urothelial carcinoma (BUC) and 232 patients with upper tract urothelial carcinoma (UTUC) using tissue microarrays, immunohistochemistry, and targeted next-generation sequencing. Results showed the incidence of dMMR UC was higher in the upper urinary tract than in the bladder. Genomic analysis identified frequent mutations in KMT2D and KMT2C genes and LS was confirmed in 53.8% of dMMR UC cases. dMMR UC cases displayed microsatellite instability-high (MSI-H) (PCR method) in 91.7% and tumor mutational burden-high (TMB-H) in 40% of cases. The density of intratumoral CD8+ T cells correlated with better overall survival in dMMR UC patients. Positive PD-L1 expression was found in 20% cases, but some patients positively responded to immunotherapy despite negative PD-L1 expression. Our findings provide valuable insights into the characteristics of dMMR UC in the Chinese population and highlights the relevance of genetic testing and immunotherapy biomarkers for treatment decisions.

Characteristics of glioblastomas and immune microenvironment in a Chinese family with Lynch syndrome and concurrent porokeratosis.

Background: Lynch syndrome (LS)-associated glioblastoma (GBM) is rare in clinical practice, and simultaneous occurrence with cutaneous porokeratosis is even rarer. In this study, we analyzed the clinicopathological and genetic characteristics of LS-associated GBMs and concurrent porokeratosis, as well as evaluated the tumor immune microenvironment (TIME) of LS-associated GBMs. Methods: Immunohistochemical staining was used to confirm the histopathological diagnosis, assess MMR and PD-1/PD-L1 status, and identify immune cell subsets. FISH was used to detect amplification of EGFR and PDGFRA, and deletion of 1p/19q and CDKN2A. Targeted NGS assay analyzed somatic variants, MSI, and TMB status, while whole-exome sequencing and Sanger sequencing were carried out to analyze the germline mutations. Results: In the LS family, three members (I:1, II:1 and II:4) were affected by GBM. GBMs with loss of MSH2 and MSH6 expression displayed giant and multinucleated bizarre cells, along with mutations in ARID1A, TP53, ATM, and NF1 genes. All GBMs had TMB-H but not MSI-H. CD8+ T cells and CD163+ macrophages were abundant in each GBM tissue. The primary and recurrent GBMs of II:1 showed mesenchymal characteristics with high PD-L1 expression. The family members harbored a novel heterozygous germline mutation in MSH2 and FDPS genes, confirming the diagnosis of LS and disseminated superficial actinic porokeratosis. Conclusion: LS-associated GBM exhibits heterogeneity in clinicopathologic and molecular genetic features, as well as a suppressive TIME. The presence of MMR deficiency and TMB-H may serve as predictive factors for the response to immune checkpoint inhibitor therapy in GBMs. The identification of LS-associated GBM can provide significant benefits to both patients and their family members, including accurate diagnosis, genetic counseling, and appropriate screening or surveillance protocols. Our study serves as a reminder to clinicians and pathologists to consider the possibility of concurrent genetic syndromes in individuals or families.

Corrigendum: Case report: Potential predictive value of MMR/MSI status and PD-1 expression in immunotherapy for urothelial carcinoma.

[This corrects the article DOI: 10.3389/pore.2022.1610638.].

Case Report: Potential Predictive Value of MMR/MSI Status and PD-1 Expression in Immunotherapy for Urothelial Carcinoma.

Immune checkpoint inhibitors (ICIs) have shown encouraging outcomes against Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H). However, there is as yet no clarity on the safety and efficacy of immunotherapy combined with chemotherapy in LS-associated urothelial carcinoma (UC). Here, we report a patient with recurrent and metastatic LS-associated UC who achieved sustained response to programmed death protein 1 (PD-1) inhibitor combined with chemotherapy over 31 months, during which the side effects of immunotherapy could be controlled and managed. Our findings indicate that the dMMR/MSI status and PD-1 expression in UC may have potential predictive value for the response to PD-1-targeted immunotherapy. Our case supports the inclusion of such combination and/or monotherapy for UC in clinical studies and using dMMR/MSI status and PD-1 expression as potential predictive biomarkers for assessment of the therapeutic response.

A practical screening strategy for Lynch syndrome and Lynch syndrome mimics in colorectal cancer.

OBJECTIVES: The objective of the study is to provide an efficient and practical screening strategy to distinguish a broader spectrum of Lynch syndrome (LS) and LS mimics-associated colorectal cancer (CRC), including Lynch-like syndrome (LLS), constitutional mismatch repair-deficiency, familial CRC type X (FCCTX), and polymerase proofreading-associated polyposis syndrome. MATERIALS AND METHODS: 1294 cases of CRC samples were detected mismatch repair (MMR) status using immunohistochemistry (IHC) staining, in which the cases with MLH1-deficient CRC underwent BRAF mutation analysis by IHC. Following the personal and/or family history survey, next-generation sequencing (NGS) was used to detect gene variants. RESULTS: 1294 CRC patients were dichotomized into tumors caused by a deficient MMR (dMMR) system and a proficient MMR (pMMR) system after MMR status analysis. 45 patients with suspected sporadic dMMR CRC were then separated from MLH1-deficient CRC though BRAF mutation status analysis by IHC. Following the personal and/or family history survey for 1294 patients, as well as germline genetic testing by NGS, 34 patients were diagnosed as LS (8 cases), SLS (13 cases), LLS ( 6 cases), FCCTX (3 cases), and sporadic CRC (4 cases). CONCLUSIONS: Our screening strategy, which consists of clinical and molecular analyses, is expected to improve the screening efficiency and management for the LS and LS mimics.

LBH589 Inhibits Glioblastoma Growth and Angiogenesis Through Suppression of HIF-1α Expression.

Glioblastoma (GBM) is an angiogenic malignancy with a highly unfavorable prognosis. Angiogenesis in GBM represents an adaptation to a hypoxic microenvironment and is correlated with tumor growth, invasion, clinical recurrence, and lethality. LBH589 (also called panobinostat) is a histone deacetylase (HDAC) inhibitor with potent antitumor activity. In the current study, we investigated the mechanism and effects of LBH589 on GBM growth and hypoxia-induced angiogenesis in vitro and in vivo. To determine the antitumor and angiogenesis activity and mechanism of LBH589, we used cell proliferations in vitro and GBM xenografts in vivo. To clarify mechanisms of LBH589 on angiogenesis, HDAC assay, RT-PCR, Western blot, and co-immunoprecipitation assays were performed. We found LBH589 displayed significant antitumor effects on GBM as demonstrated by inhibited cell proliferation, slower tumor growth, and decreased microvessel density of subcutaneous xenografts. These actions of LBH589 resulted from the disruption of heat shock protein 90/HDAC6 complex, increased HIF-1α instability and degradation, and decreased VEGF expression. Our results indicate the potential antiangiogenic activity of LBH589 in human GBM and provide some preclinical data to warrant further exploration of HDAC inhibitors for the treatment of advanced glioma. Moreover, our study supports the role of HDAC inhibitors as a therapeutic strategy to target tumor angiogenesis.

Valproic acid ameliorates olfactory dysfunction in APP/PS1 transgenic mice of Alzheimer's disease: Ameliorations from the olfactory epithelium to the olfactory bulb.

Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Alzheimer's disease (AD) and mild cognitive impairment, pointing to the progression to dementia. Recent studies have revealed that valproic acid (VPA) has neuroprotective effects in rodent models of AD. In this study, we investigated the effects of VPA on olfactory dysfunction of APP/PS1 double transgenic mouse models of AD. After continuous treatment with a 100mg/kg daily dose of VPA for 3 months, APP/PS1 mice showed improved olfactory performances. In agreement with the behavioral findings, VPA treatment reduced amyloid ß (Aß) burden in the olfactory epithelium (OE) of transgenic mice. And, VPA increased epithelial thickness of the olfactory mucosa through decreased cell apoptosis and increased cell proliferation. In the olfactory bulb (OB), VPA administration also reduced senile plaques and levels of soluble and insoluble Aß42 peptides. Besides, VPA promoted the increase of mitral cells and decrease of neurofilament immunostaining. In hence, VPA treatment completely improved the olfactory performances and prevented degenerative changes of the OE and OB. Our study raises the possibility of AD diagnosis by OE biopsy. Moreover, VPA may provide a novel therapeutic strategy for the treatment of olfactory dysfunction in AD patients.

Cardiac structural and functional changes in old elderly patients with obstructive sleep apnoea-hypopnoea syndrome.

OBJECTIVE: To investigate cardiac structural changes in elderly patients with obstructive sleep apnoea-hypopnoea syndrome (OSAHS) and the impact on left ventricular systolic and diastolic function. METHODS: The study enrolled elderly patients with OSAHS and age-matched healthy control subjects. Cardiac structure, left ventricular diastolic function and left ventricular systolic function were measured using a Doppler ultrasound scanner and compared between the two groups. RESULTS: The study included 136 patients with OSAHS and 50 healthy control subjects. There were significant differences in the echocardiography indicators that reflect cardiac structure, including interventricular septum, left ventricle posterior wall thickness, and left ventricular mass and mass index between the two groups. There were significant differences between the two groups in the ventricular septal early diastolic myocardial peak velocity/late diastolic myocardial peak velocity (Em/Am), mitral annulus Em/Am, and left ventricle posterior wall Em/Am. There were also significant differences in the indicators of interventricular septum, mitral annulus and left ventricular posterior wall systolic peak velocity between the two groups. CONCLUSION: Elderly patients with OSAHS demonstrated cardiac structural changes and their left ventricular diastolic and systolic functions were significantly diminished.

Investigations on the clinical significance of FOXP3 protein expression in cervical oesophageal cancer and the number of FOXP3+ tumour-infiltrating lymphocytes.

OBJECTIVES: Investigations of FOXP3 protein expression in cervical oesophageal cancer cells and the number of FOXP3 + lymphocytes infiltrating tumour tissue were undertaken. METHODS: FOXP3 protein expression and FOXP3 + tumour-infiltrating lymphocytes were studied immunohistochemically, in cervical oesophageal cancer tissue samples from 42 cases and paracancerous tissue samples from 30 of these cases. RESULTS: The percentage of parenchymal cells expressing FOXP3 protein was significantly higher in cancer tissue (42.9%, 18/42) than in paracancerous tissue 6.67% (two of 30). FOXP3 + lymphocyte infiltration was significantly more frequent in cancer (38.1%, 16/42) than in paracancerous (13.33%, four of 30) tissue. FOXP3 protein expression in cancer parenchymal cells in patients with lymph node metastasis was significantly greater than expression in those without lymph node metastasis. FOXP3 protein expression was significantly higher in cancer tissue samples from clinical stage III or IV than those from stage I or II disease. FOXP3 + lymphocyte infiltration of tumours was significantly greater in patients with lymph node metastasis than in those without metastasis. CONCLUSIONS: Abnormal FOXP3 expression in cervical oesophageal cancer parenchyma and FOXP3 + lymphocyte infiltration might be closely related to metastasis of this cancer by promoting immune escape of the tumour. FOXP3 might be a potential marker for the assessment of postoperative metastasis in cervical oesophageal cancer.

The correlation between tumor-infiltrating Foxp3+ regulatory T cells and cyclooxygenase-2 expression and their association with recurrence in resected head and neck cancers.

The aim of this study was to investigate the correlation between tumor-infiltrating CD4+ CD25(high) Foxp3+ naturally occurring regulatory T cells (Foxp3+ nTregs) and cyclooxygenase-2 (COX-2) expression and their association with local recurrence in resected head and neck cancers. Intratumoral COX-2 and Foxp3+ nTregs expressions were retrospectively assessed using immunohistochemistry. Associations between the clinicopathological characteristics and either intratumoral COX-2 expression or number of Foxp3+ nTregs were tested using the Chi-square test. The correlation between the number of Foxp3+ nTregs and COX-2 expression was tested using Spearman's rank correlation test. Associations between recurrence-free survival (RFS) and either intratumoral COX-2 expression or number of Foxp3+ nTregs were calculated using the Kaplan-Meier method, and factors that may influence the RFS were analyzed by Cox regression. The five-year RFS for all patients was 35.09%. Patient clinicopathological characteristics had no relationship with intratumoral COX-2 expression or the number of Foxp3+ nTregs. However, a positive correlation between intratumoral COX-2 expression and the number of Foxp3+ nTregs was observed (P < 0.001). The RFS of patients with elevated COX-2 expression was significantly worse than that of patients without intratumoral COX-2 expression (P = 0.0228). The RFS of patients with tumors containing >6 Foxp3+ cells was significantly worse than that of patients with tumors containing ≤6 Foxp3+ cells (P = 0.0020). However, by Cox regression analysis, the RFS of all patients was not influenced by intratumoral COX-2 expression (P = 0.100) or the number of Foxp3+ nTregs (P = 0.071). Tumor-infiltrating CD4+ CD25(high) Foxp3+ nTregs were positively correlated with intratumoral COX-2 expression and were associated with a worse RFS in univariate analysis.

Littoral cell angioma of the spleen: report of three cases and a review of the literature.

Littoral cell angioma is a recently described rare vascular tumor of the spleen. The clinical course of this benign tumor is asymptomatic in most patients. Herein, we described three patients with littoral cell angioma detected during physical examination. A brief discussion and review of a handful of cases of splenic littoral cell angioma, which have been previously reported in the English language literature, are performed in this paper.

[Effects of mast cell infiltration on the development and metastasis of gastric carcinoma].

OBJECTIVE: To investigate the relationship between mast cell infiltration and the development and metastasis of gastric carcinoma. METHODS: Alcian blue-Safranin O staining and image analysis system were employed to observe, classify and quantify the mast cells in 74 gastric carcinoma specimens. RESULTS: Mast cells resided predominantly in the marginal area of the tumor and most of them were mature type, active and capable of discharging granules into the cytoplasm. The mast cells in the marginal area of the tumor were significantly more numerous than those in the matrix of the tumor (P<0.01) and there was a positive correlation between them (r=0.303, P<0.01). The density of the mast cells was inversely correlated to the depth of tumor invasion and the number of lymph node metastasis. CONCLUSIONS: Mast cell infiltration in the matrix of the tumor plays an important role in preventing the invasion and metastasis of gastric carcinoma possibly by release of heparin and other bioactive substances. Mast cell quantity in the marginal area of the tumor may serve as an indicator for prognostic assessment of gastric carcinoma.

[Ligustrazine and Salvia miltiorrhiza injection solution in complementary therapy of pregnancy-induced hypertension: clinical analysis of 60 cases].

OBJECTIVE: To compare the clinical effects of ligustrazine and Salvia miltiorrhiza injection solutions in the complementary therapy of pregnancy-induced hypertension (PIH). METHODS: Sixty patients with PIH were equally divided into 2 groups to receive intravenous infusion of 80 mg ligustrazine and 16 ml Salvia miltiorrhiza injection solution respectively, in addition to the conventional therapies. The effects of the two complementary treatments were compared. RESULTS: After a treatment course of 10 days, ligustrazine produced obvious effect in inhibiting fibrinolysis and promoting microcirculation of the patients. Salvia miltiorrhiza injection resulted in obvious reduction of blood viscosity, cholesterol and lipoprotein. CONCLUSION: Ligustrazine and Salvia miltiorrhiza injections produce obvious therapeutic effects on PIH, but they are used for different clinical purposes as their in pharmacological action difference.