Enhanced Risk Stratification in Early-Stage Endometrial Cancer: Integrating POLE through Droplet Digital PCR and L1CAM.

AIM: In order to enhance risk stratification in early-stage endometrial cancer (EC), we conducted molecular classification using surrogate markers, including the POLE droplet digital polymerase chain reaction (ddPCR) and L1CAM immunohistochemistry (IHC). METHOD: We analyzed archival tumor tissue from 183 early-stage EC patients. POLE pathogenic mutations of P286R, V411L, S297F, A456P, and S459F within exons 9, 13, and 14 were detected using a ddPCR, while the mismatch repair (MMR) status was determined by MMR protein IHC and MSI tests. Additionally, we conducted IHC for p53 and L1CAM. RESULTS: The 183 ECs were categorized into four subgroups: POLE-mutated (15.9%), MMR-deficient (29.0%), p53-abnormal (8.7%), and non-specific molecular profile (NSMP, 46.4%). We further subcategorized the NSMP subgroup into NSMP-L1CAMneg (41.5%) and NSMP-L1CAMpos (4.9%), which we refer to as the molecular L1CAM classification. The molecular L1CAM classification was an independent prognostic factor for recurrence-free survival (RFS) and overall survival (OS) (p < 0.001, each). CONCLUSION: Integrating molecular L1CAM classification can enhance risk stratification in early-stage EC, providing valuable prognostic information to guide treatment decisions and improve patient outcomes. POLE ddPCR might be a cost-effective and easy-to-perform test as an alternative to POLE NGS.

Early Increase in Circulating PD-1+CD8+ T Cells Predicts Favorable Survival in Patients with Advanced Gastric Cancer Receiving Chemotherapy.

The clinical significance of PD-1 expression in circulating CD8+ T cells in patients with gastric cancer (GC) receiving chemotherapy remains unelucidated. Therefore, we aimed to examine its prognostic significance in blood samples of 68 patients with advanced GC who received platinum-based chemotherapy. The correlation between peripheral blood mononuclear cells, measured using fluorescence-activated cell sorting, was evaluated. Patients were divided into two groups according to the changes in PD-1+CD8+ T-cell frequencies between day 0 and 7. They were categorized as increased or decreased PD-1+CD8+ T-cell groups. The increased PD-1+CD8+ T-cell group showed longer progression-free survival (PFS) and overall survival (OS) than the decreased PD-1+CD8+ T-cell group (PFS: 8.7 months vs. 6.1 months, p = 0.007; OS: 20.7 months vs. 10.8 months, p = 0.003). The mean duration of response was significantly different between the groups (5.7 months vs. 2.5 months, p = 0.041). Multivariate analysis revealed that an increase in PD-1+CD8+ T-cell frequency was an independent prognostic factor. We concluded that the early increase in PD-1+CD8+ T-cell frequency is a potential predictor of favorable prognoses and durable responses in patients with advanced GC receiving chemotherapy.

Prognostic value of soluble PD-L1 and exosomal PD-L1 in advanced gastric cancer patients receiving systemic chemotherapy.

The prognostic role of soluble PD-L1 (sPD-L1) and exosomal PD-L1 (exoPD-L1) in patients with gastric cancer (GC) receiving systemic chemotherapy remains unelucidated. Thus, we examined their prognostic significance in patients with advanced GC. Blood samples were obtained from 99 patients with advanced GC receiving first-line chemotherapy. Serum-derived exosomes were isolated by centrifugation and polymer precipitation. The correlation between serum-derived exoPD-L1, plasma sPD-L1, immune-related markers, and circulating immune cells was evaluated. Patients were divided into two groups according to pretreatment sPD-L1 and exoPD-L1 levels: low sPD-L1 and high sPD-L1 groups, low exoPD-L1 and high exoPD-L1 groups. Patients with low sPD-L1 level before treatment (< 9.32 pg/mL) showed significantly better overall survival (OS) and progression-free survival (PFS) than those with high sPD-L1 level (≥ 9.32 pg/mL). The low exoPD-L1 group (< 10.21 pg/mL) showed a tendency of longer PFS than the high exoPD-L1 group (≥ 10.21 pg/mL). Pretreatment sPD-L1 was an independent prognostic factor for OS in multivariate analysis. exoPD-L1 was associated with systemic inflammation markers, immunomodulatory cytokines, and T cells, while sPD-L1 was associated with tumor markers. Pretreatment plasma-derived sPD-L1 level could be used as a prognostic marker for patients receiving cytotoxic chemotherapy. Serum-derived exoPD-L1 may reflect the immunosuppressive state of patients with advanced GC.

EGFR-Tyrosine Kinase Inhibitors Induced Activation of the Autocrine CXCL10/CXCR3 Pathway through Crosstalk between the Tumor and the Microenvironment in EGFR-Mutant Lung Cancer.

CXCL10 is a cytokine that is elevated during EGFR-TKI treatment in the tumor microenvironment of lung cancer. Here, we report an original study that the impact of the CXCL10/CXCR3 pathway on EGFR-TKI resistance in EGFR-mutant lung cancer through a cytokine array analysis during in vitro coculture with tumor cells and activated PBMCs treated with EGFR-TKI, as well as the serial analysis of CXCL10 in EGFR-mutant lung cancer transgenic mice during EGFR-TKI treatment. In EGFR-mutant tumor cells cocultured with activated PBMCs, EGFR-TKI treatment increased CXCL10 in the supernatant; this activated CXCR3 in the tumor cells to induce the phosphorylation of Src and the NF-κB subunit, p65, and the expression of HIF-1α. CXCL10 siRNA treatment of EGFR-mutant tumor cells also decreased CXCL10 in the supernatant from coculturing with activated PBMCs, suggesting that the effects of CXCL10 occur via autocrine and paracrine pathways. Importantly, elevated CXCL10/CXCR3 signaling was recapitulated in a transgenic lung cancer mouse model. Our results show that increased CXCL10 levels during early EGFR-TKI treatment stimulate oncogenic signaling of persistent tumor cells to contribute to EGFR-TKI resistance via autocrine and paracrine pathways.

Slug and CD133 expression are associated with peritoneal carcinomatosis and survival in gastric cancer.

BACKGROUND: Slug is an activating transcription factor involved in epithelial-mesenchymal transition, and CD133 is a cancer stem cell marker found in various cancers, including gastric cancer (GC). We investigated the relationship between Slug and CD133 and the occurrence of peritoneal carcinomatosis and survival in patients with GC. METHODS: This retrospective study included 196 patients with stage 2 or 3 GC who underwent curative surgery with D2 lymph node dissection and adjuvant chemotherapy between 2001 and 2009. We analyzed the expression of Slug, CD133, ABCG2, E-cadherin, vimentin, NEDD9, and SMAD4 in surgical tissue specimens using immunohistochemical analysis to determine their prognostic value. RESULTS: Among the 196 patients, expression of Slug was elevated in 157 tumors (81%) while the expression of CD133 was high in 153 tumors (81%). The expression of Slug and CD133 in combination significantly predicted peritoneal relapse (P=0.002). High Slug and high CD133 expression were significantly associated with poor peritoneal relapse-free survival [hazard ratio (HR), 7.239; P=0.007] and overall survival (HR, 1.682; P=0.027) in multivariate Cox analysis. CONCLUSIONS: Our study shows that a high Slug and high CD133 expression status is predictive of peritoneal recurrence in high-risk resected GC patients. They are also a poor prognostic factor for peritoneal relapse-free survival and overall survival.

A Monocentric, Retrospective Analysis of 61 Patients with Generalized Granuloma Annulare.

BACKGROUND: Granuloma annulare is a chronic noninfectious granulomatous skin condition with variable clinical presentations. Generalized granuloma annulare, defined as widespread disease with >10 skin lesions, accounts for 15% of all cases. Numerous associated diseases have been controversially discussed, most importantly diabetes mellitus, dyslipidemia, thyroid disease, malignancy and systemic infections. OBJECTIVES: The objective of our study is to describe disease characteristics, treatment outcome and associated diseases in patients treated at the Department of Dermatology of the University Hospital Zurich during the last 20 years. METHODS: The hospital database was searched for patients with generalized granuloma annulare in the last 20 years (January 1, 1998, to December 31, 2017). Overall, 61 patients, 14 males and 47 females, were included in our study. The mean age was 58 years at first consultation. The diagnosis was verified clinically and histologically. RESULTS: Generalized granuloma annulare occurred at a mean age of 55 years, more commonly in females. Pruritus was absent in 51% of all patients. Metabolic diseases including diabetes mellitus, hypercholesterinemia and hypertriglyceridemia were present in 10.5, 8.2 and 4.9%, respectively. Thyroid disease was present in 9.8% and malignant disease in 23%, including colorectal cancer, lymphoproliferative disease, squamous cell carcinoma of the esophagus, basal cell carcinoma and gynecological malignancy. Therapy was initiated in 92%, while second- and third-line therapy was performed in 70 and 39%, respectively. Benefit during therapy (e.g., full and partial remission) was achieved in 39.3% during first-line, in 39.4% during second-line and in 33.8% during third-line treatment. Topical corticosteroids were the most commonly prescribed treatment, mostly leading to stable disease (46.6%). Combined full and partial remission occurred in a large proportion of patients receiving UVA1 (45%), PUVA (63.6%) and intralesional triamcinolone acetonide (100%). CONCLUSIONS: Generalized granuloma annulare is a mostly asymptomatic and benign disease with a strong tendency for treatment resistance. We suggest to screen all patients for dyslipidemia, thyroid disease and malignant disease. While randomized trials are needed, we suggest topical corticosteroids as the first-line treatment, intralesional triamcinolone acetonide for persistent solitary lesions and, if further treatment is needed, UVA1 or PUVA.

Evaluation of Two EGFR Mutation Tests on Tumor and Plasma from Patients with Non-Small Cell Lung Cancer.

Epidermal growth factor receptor (EGFR) mutation testing is essential for individualized treatment using tyrosine kinase inhibitors. We evaluated two EGFR mutation tests, cobas v2 and PANAMutyper, for detection of EGFR activating mutations Ex19del, L858R, and T790M in tumor tissue and plasma from 244 non-small cell lung cancer (NSCLC) patients. The Kappa coefficient (95% CI) between the tests was 0.82 (0.74-0.92) in tumor samples (suggesting almost perfect agreement) and 0.69 (0.54-0.84) in plasma (suggesting substantial agreement). In plasma samples, both tests showed low to moderate sensitivity depending on disease stage but high diagnostic precision (86%-100%) in all disease stages (sensitivity: percentage of mutations in tumors that are also detected in plasma; precision: percentage of mutations in plasma which are also detected in tumors). Among the 244 patients, those previously diagnosed as T790M carriers who received osimertinib treatment showed dramatically better clinical outcomes than T790M carriers without osimertinib treatment. Taken together, our study supports interchangeable use of cobas v2 and PANAMutyper in tumor and plasma EGFR testing. Both tests have high diagnostic precision in plasma but are particularly valuable in late-stage disease. Our clinical data in T790M carriers strongly support the clinical benefits of osimertinib treatment guided by both EGFR mutation tests.