Grade G3 Research Articles

The relationship between 6-thioguanine levels and remission outcomes in children with autoimmune hepatitis. Single center experience.

The treatment of autoimmune hepatitis (AIH) is based on steroids and azathioprine (AZA). AZA is a pro-drug which is converted among others into 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP). The aim of the study was to determine the relationship between the AZA active metabolite 6-TG and both the biochemical and histological remission outcomes. The authors conducted a retrospective analysis of a single chart review. The sample size consisted of 44 pediatric patients with AIH. Biochemical remission was defined as an alanine aminotransferase (ALT) level below 40 U/l and histological remission was defined as a situation when the control biopsy revealed inflammation grade G1 (or lower) in the Batts-Ludwig score. Statistical analysis was applied to assess the difference in remission outcomes in patients with different levels of 6-TG. In the benchmark variant of our statistical analysis, we found that the correlation between 6-TG and ALT in the sample was not statistically significant. Moreover, the difference between the mean levels of ALT in the populations in and without remission was not statistically significant (the p-value of the t-test was 0.16). Our results tend to support the claim that there is no statistically significant relationship between 6-TG concentration and remission (both biochemical and histological) in pediatric patients with AIH.

Significance of dorsal bladder neck involvement in predicting the progression of non-muscle-invasive bladder cancer.

Accurately predicting of progression is important for patients with non-muscle-invasive bladder cancer (NMIBC). We previously reported that bladder neck involvement (BNI) was significantly associated with progression of NMIBC. In this study, we evaluated the prognostic significance of the detailed BNI location in NMIBC patients. We retrospectively reviewed 651 patients diagnosed with primary NMIBC at a single center between 2000 and 2018. Using the detailed BNI location, patients were divided into the following three groups: dorsal BNI (BNId; 4 to 8 o'clock position), ventral BNI (BNIv; 8 to 4 o'clock but not 4 to 8 o'clock position), and non-BNI group. Both time to progression to muscle-invasive disease and distant metastasis was compared among the three groups. A prognostic model was developed and its discriminative ability was evaluated. Dorsal bladder neck involvement and BNIv were observed in 43 (6.6%) and 36 (5.5%) patients, respectively. During a median follow-up of 61months, 35 (5.4%) patients progressed. The cumulative incidence at 5 years was 12%, 0%, and 5.0% in BNId, BNIv, and non-BNI groups, respectively. On multivariate analysis, BNId was a significant and independent risk factor for progression, tumor stage pT1, and histologic grade G3. One point was assigned to each factor, and patients were classified into four well-stratified prognostic groups based on the total score. Dorsal bladder neck involvement was an independent and significant risk factor for progression in primary NMIBC. Our simple and practical prognostic model including BNId is easy to use and may help selecting the optimal treatment and its timing.

The use of Ctrough for the therapeutic drug monitoring of olaparib in patients with ovarian cancer.

Olaparib is the poly-[Adenosine diphosphate ribose (ADP-ribose)] polymerase inhibitor (PARPI) used in maintenance therapy of patients with platinum-sensitive ovarian cancer with mutations in breast cancer genes 1/2 (BRCA1/2). Oncologists still do not have recommendations of treatment depending on efficient plasma concentrations of the PARP inhibitor. The aim of the study was the assessment of plasma trough concentrations of olaparib at steady state (Ctrough) in ovarian cancer patients. The severity of olaparib adverse effects (AEs) was noted. The retrospective study involved 33 patients [mean standard deviation (SD)]; age 57.0 (8.4) years; weight 68.7 (13.7) kg; and body mass index (BMI) 26.4 (4.9) kg/m2, with ovarian cancer treated with olaparib (tablets in dose 300 mg/12 h, 250 mg/12 h, 200 mg/12 h or capsules 400 mg/12 h, 200 mg/12 h, 100 mg/12 h). Plasma drug levels were measured by HPLC-UV method (λ = 254 nm; Symmetry C8 column; gradient flow). The severity of olaparib AEs was assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale. Drug interactions were analyzed. In total, 130 measurements (n) of Ctrough were determined in 33 patients (median sample frequency per patient was 4). The olaparib Ctrough in patients with AEs was 87.840-7,213.262 ng/mL [coefficient of variation (CV) = 91%], in patients without AEs 48.021-7,073.350 ng/mL (CV = 88%). AEs were the following: fatigue (modest, n = 4, severe, n = 2), anemia (grade G1 n = 66, G2 n = 6, G3 n = 3), neutropenia (grade G1 n = 15, G2 n = 4), prediabetes (n = 1). There was a correlation between Ctrough and olaparib-induced fatigue (p = 0.0015). The lower values of dose-adjusted olaparib concentrations (p = 0.0121) and dose/kg-adjusted olaparib concentrations (p = 0.0389) were correlated with higher grade of neutropenia. There was a correlation between Ctrough, expressed as ng/ml, ng/ml/mg or ng/ml/mg/kg, and fatigue degree, but not anemia. Patients with neutropenia had statistically significant lower plasma concentrations of olaparib.

MAIT cells in chronic HBV infection‐related liver fibrosis: Friends or foes?

MAIT cells in chronic HBV infection‐related liver fibrosis: Friends or foes?

Sporadic and MEN1-related gastrinoma and Zollinger–Ellison syndrome: differences in clinical characteristics and survival outcomes

PurposeGastrinoma with Zollinger–Ellison syndrome (ZES) may occur sporadically (Sp) or as part of the inherited syndrome of multiple endocrine neoplasia 1 (MEN-1). Data comparing Sp and MEN-1/ZES are scanty. We aimed to identify and compare their clinical features.MethodsConsecutive patients with ZES were evaluated between 1992 and 2020 among a monocentric Italian patient cohort.ResultsOf 76 MEN-1 patients, 41 had gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), 18 of whom had ZES; of 320 Sp-GEP-NEN, 19 had Sp-ZES. MEN-1/ZES patients were younger (p = 0.035) and the primary MEN-1/ZES gastrinoma was smaller than Sp-ZES (p = 0.030). Liver metastases occurred in both groups, but only Sp-ZES developed extrahepatic metastases. 13 Sp-ZES and 8 MEN-1/ZES underwent surgery. 8 Sp-ZES and 7 MEN-1/ZES received somatostatin analogs (SSAs). Median overall survival (OS) was higher in MEN-1/ZES than in Sp-ZES (310 vs 168 months, p = 0.034). At univariate-logistic regression, age at diagnosis (p = 0.01, OR = 1.1), G3 grading (p = 0.003, OR = 21.3), Sp-ZES (p = 0.02, OR = 0.3) and presence of extrahepatic metastases (p = 0.001, OR = 7.2) showed a significant association with OS. At multivariate-COX-analysis, none of the variables resulted significantly related to OS. At univariate-logistic regression, age (p = 0.04, OR = 1.0), size (p = 0.039, OR = 1.0), G3 grade (p = 0.008, OR = 14.6) and extrahepatic metastases (p = 0.005, OR = 4.6) were independently associated with progression-free survival (PFS). In multivariate-COX-analysis, only extrahepatic metastases (p = 0.05, OR = 3.4) showed a significant association with PFS. Among SSAs-treated patients, MEN-1/ZES showed better PFS (p = 0.0227). After surgery, the median PFS was 126 and 96 months in MEN-1 and Sp, respectively.ConclusionMEN-1/ZES patients generally show better OS and PFS than Sp-ZES as well as better SSAs response.

Survival in Breast Cancer Patients with Bone Metastasis: A Multicenter Real-World Study on the Prognostic Impact of Intensive Postoperative Bone Scan after Initial Diagnosis of Breast Cancer (CSBrS-023).

The prognostic value of intensive postoperative bone scan (BS) screening, which is performed in asymptomatic patients with breast cancer (BC) after surgery, remained unclear. Patients diagnosed with BC with bone metastasis (BM) from five medical centers in China during the years 2005−2013 were retrospectively collected. Propensity score matching (PSM) was performed to balance the baseline characteristics. The survival outcomes were overall survival (OS) and overall survival after BM (OSABM). Among 1059 eligible patients, 304 underwent intensive postoperative BS while 755 did not. During a median follow-up of 6.67 years (95%CI 6.45, 7.21), intensive postoperative BS prolonged the median OS by 1.63 years (Log-Rank p = 0.006) and OSABM by 0.66 years (Log-Rank p = 0.002). Intensive postoperative BS was an independent prognostic factor for both OS (adjusted HR 0.77, 95%CI 0.64, 0.93, adjusted p = 0.006) and OSABM (adjusted HR 0.71, 95%CI 0.60, 0.86, adjusted p < 0.001). The prognostic value of intensive postoperative BS was consistently favorable for OS among clinical high-risk patients, including those with ages younger than 50, stage II, histology grade G3 and ER-Her2- subtype. This multicenter real-world study showed that intensive postoperative BS screening improved survival for BC patients with BM and should probably be recommended for postoperative surveillance, especially for patients at clinical high-risk.

The Glasgow Prognostic Score Predicts Survival Outcomes in Neuroendocrine Neoplasms of the Gastro-Entero-Pancreatic (GEP-NEN) System.

Across a variety of solid tumors, prognostic implications of nutritional and inflammation-based risk scores have been identified as a complementary resource of risk stratification. In this retrospective study, we performed a comparative analysis of several established risk scores and ratios, such as the Glasgow Prognostic Score (GPS), in neuroendocrine neoplasms of the gastro-entero-pancreatic (GEP-NEN) system with respect to their prognostic capabilities. Clinicopathological and treatment-related data for 102 GEP-NEN patients administered to the participating institutions between 2011 and 2021 were collected. Scores/ratios significantly associated with overall or progression-free survival (OS, PFS) upon univariate analysis were subsequently included in a Cox-proportional hazard model for the multivariate analysis. The median age was 62 years (range 18-95 years) and the median follow-up period spanned 51 months. Pancreatic or intestinal localization at the initial diagnosis were present in 41 (40.2%) and 44 (43.1%) cases, respectively. In 17 patients (16.7%), the primary manifestation could not be ascertained (NNUP; neuroendocrine neoplasms of unknown primary). Histological grading (HG) revealed 24/102 (23.5%) NET/NEC (poorly differentiated; high grade G3) and 78/102 (76.5%) NET (highly or moderately differentiated; low-high grade G1-G2). In total, 53/102 (51.9%) patients presented with metastatic disease (UICC IV), 11/102 (10.7%) patients presented with multifocal disease, and 56/102 (54.9%) patients underwent a primary surgical or endoscopic approach, whereas 28 (27.5%) patients received systemic cytoreductive treatment. The univariate analysis revealed the GPS and PI (prognostic index), as well as UICC-stage IV, HG, and the Charlson comorbidity index (CCI) to predict both the PFS and OS in GEP-NEN patients. However, the calculation of the survival did not separate GPS subgroups at lower risk (GPS 0 versus GPS 1). Upon the subsequent multivariate analysis, GPS was the only independent predictor of both OS (p &lt; 0.0001; HR = 3.459, 95% CI = 1.263-6.322) and PFS (p &lt; 0.003; HR = 2.119, 95% CI = 0.944-4.265). In line with previous results for other entities, the present study revealed the GPS at baseline to be the only independent predictor of survival across all stages of GEP-NEN, and thus supports its clinical utility for risk stratification in this group of patients.

Accuracy of the CUETO, EORTC 2016 and EAU 2021 scoring models and risk stratification tables to predict outcomes in high-grade non-muscle-invasive urothelial bladder cancer.

Non-muscle-invasive bladder cancers (NMIBC) constitute 3-quarters of all primary diagnosed bladder tumors. For risk-adapted management of patients with NMIBC, different risk group systems and predictive models have been developed. This study aimed to externally validate EORTC2016, CUETO and novel EAU2021 risk scoring models in a multi-institutional retrospective cohort of patients with high-grade NMIBC who were treated with an adequate BCG immunotherapy. The Kaplan-Meier estimates for recurrence-free survival and progression-free survival were performed, predictive abilities were assessed using the concordance index (C-index) and area under the curve (AUC). A total of 1690 patients were included and the median follow-up was 51 months. For the overall cohort, the estimates recurrence-free survival and progression-free survival rates at 5-years were 57.1% and 82.3%, respectively. The CUETO scoring model had poor discrimination for disease recurrence (C-index/AUC for G2 and G3 grade tumors: 0.570/0.493 and 0.559/0.492) and both CUETO (C-index/AUC for G2 and G3 grade tumors: 0.634/0.521 and 0.622/0.525) EAU2021 (c-index/AUC: 0.644/0.522) had poor discrimination for disease progression. Both the CUETO and EAU2021 scoring systems were able to successfully stratify risks in our population, but presented poor discriminative value in predicting clinical events. Due to the lack of data, model validation was not possible for EORTC2016. The CUETO and EAU2021 systems overestimated the risk, especially in highest-risk patients. The risk of progression according to EORTC2016 was slightly lower when compared with our population analysis.

The evolution of PRRT for the treatment of neuroendocrine tumors; What comes next?

Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure no-carrier-added Lu-177 has a high specific activity and has waste disposal advantages over the first generation carrier-added Lu-177. PRRT has recently been developed for the treatment of neuroendocrine tumors (NETs). The majority of pancreatic and gastroenteric NETs (GEP-NETs) express the somatostatin receptors (SSTRs) 2 and 5. These receptors can be specifically targeted with a somatostatin peptide analogue (DOTATOC/DOTATATE) which can be chelated to a positron emission tomography (PET) emitting radioisotope such as Ga-68 for imaging or to a β-emitting radioisotope Lu-177 for therapy. A key advantage of this approach is that the receptor expression can be demonstrated by PET imaging before the patient is treated. Clinical studies in G1 and G2 GEP-NETS have demonstrated that PRRT is extremely effective in terms of progression free survival (PFS), symptom control and quality of life, with a well-established safety profile. A beneficial effect on outcome survival awaits to be confirmed. The first commercially available product Lu-177-DOTATATE was approved following the NETTER-1 trial in G1 and G2 GE-NETS. Lu-177-DOTATATE 7,4 GBq every 8 weeks for 4 cycles, together with octreotide LAR 30 mg monthly, demonstrated a median PFS of 28,4 months compared to 8,5 months for octreotide LAR 60 mg monthly. A second pivotal study COMPETE is currently in progress, comparing no carrier-added (n.c.a.) Lu-177-DOTATOC to the m-TOR inhibitor Everolimus in both GE-NETs and PNETs. Two studies, NETTER-2 and COMPOSE are currently underway in patients with high grade G2 and G3 NETs. Novel SSTR antagonists are being developed as next generation targeting molecules for SSTR2-expressing tumors. Antagonists have a higher tumor binding to receptors than agonists, opening up the potential indications for SSTR2 targeting to tumors which have a relatively lower expression of SSTR2 compared to NET such as small cell lung cancer, hepatocellular carcinoma and breast cancer. In addition to Lu-177, radioisotopes with different radiation properties such as Tb-161 and the α-emitter Ac-225 are being developed which have the potential to improve treatment efficacy across the range of G1 to G3 NETs.

Development of a 4-miRNA prognostic signature for endometrial cancer.

To develop an effective uterine corpus endometrial carcinoma (UCEC) risk assessment tool to monitor treatment outcomes. Limma package was used to analyze differentially expressed microRNAs (miRNAs) between UCEC tissues and normal tissues in the TCGA database. According to univariate Cox risk regression, least absolute shrinkage, and selection operator (LASSO) Cox analysis were performed to screen prognostic miRNAs and construct a risk scoring model. The prognostic performance of signature was evaluated by Kaplan–Meier and receiver operating characteristic. Multivariate Cox regression analysis was used to determine the independent prognostic factors of UCEC. Nomogram was constructed according to age, clinical stage, and risk score. A 4-miRNA signature based on miR-31-5p, miR-34a-5p, miR-26a-1-3p and miR-4772-3p was established. Risk scores of each patient were calculated by the 4-miRNA signature. After z-score, the patients were divided into high- and low-risk groups. The overall survival of high-risk patients was significantly shorter than that of low-risk patients, pointing to the high performance and independence of the 4-miRNA signature in predicting UCEC prognosis. The nomogram showed a high accuracy in predicting overall survival of UCEC patients. We developed a 4-miRNA signature that could effectively predict the prognosis of UCEC.

MMP-1, UCH-L1, and 20S Proteasome as Potential Biomarkers Supporting the Diagnosis of Brain Glioma.

The diagnosis of brain gliomas is mainly based on imaging methods. The gold standard in this area is MRI. Recommendations for the prevention, diagnosis, and treatment of gliomas are periodically modified and updated. One of the diagnostic techniques used when a brain glioma is suspected is liquid biopsy. However, this technique requires further development to confirm its effectiveness. This paper presents a proposal of three potential biomarkers of brain gliomas—extracellular matrix metalloproteinase-1 (MMP-1), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and the 20S proteasome—which were quantified in blood plasma using SPRi biosensors. A statistical analysis of the results indicated no significant changes in the concentrations between the control group (K) and grades G1 and G2, and similarly between grades G3 and G4. However, the differences in the concentrations between the groups K/G1/G2 and G3/G4 were statistically significant. A positive average correlation was found between the concentrations of the proteins and the patient’s age. The individual tested proteins were also highly correlated with each other. Our work proposes a new diagnostic technique that may aid in the diagnosis of brain gliomas.

A novel tool to predict nodal metastasis in small pancreatic neuroendocrine tumors: A multicenter study

BackgroundNonfunctional pancreatic neuroendocrine tumors display a wide range of biological behavior, and nodal disease is associated with metastatic disease and poorer survival. The aim of this study was to develop a tool to predict nodal disease in patients with small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors. MethodsA multicenter retrospective study was performed on patients undergoing resection for small nonfunctional pancreatic neuroendocrine tumors. Patients with genetic syndromes, metastatic disease at diagnosis, neoadjuvant therapy, or positive resection margin were excluded. Factors associated with nodal disease were identified to develop a predictive model. Internal validation was performed using bootstrap with 1,000 resamples. ResultsNodal disease was observed in 39 (11.1%) of the 353 patients included. Presence of nodal disease was significantly associated with lower 5-year disease-free survival (71.6% vs 96.2%, P < .001). Two predictors were strongly associated with nodal disease: G2 grade (odds ratio: 3.51, 95% confidence interval: 1.71–7.22, P = .001) and tumor size (per mm increase, odds ratio: 1.14, 95% confidence interval: 1.03–1.25, P = .009). Adequate discrimination was observed with an area under the curve of 0.71 (95% confidence interval: 0.63–0.80). Based on risk distribution, 3 risk groups of nodal disease were identified; low (<5%), intermediate (≥5% to <20%), and high (≥20%) risk. The observed mean risk of nodal disease was 3.7% in the low-risk patients, 9.6% in the intermediate-risk patients, and 30.4% in the high-risk patients (P < .001). The 10-year disease-free survival in the low, intermediate, and high-risk groups was 100%, 88.8%, and 50.1%, respectively. ConclusionOur model using tumor grade and size can predict nodal disease in small nonfunctional pancreatic neuroendocrine tumors. Integration of this tool into clinical practice could help guide management of these patients.

Alpha2,3 sialic acid processing enzymes expression in gastric cancer tissues reveals that ST3Gal3 but not Neu3 are associated with Lauren's classification, angiolymphatic invasion and histological grade.

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Despite progress in the last decades, there are still no reliable biomarkers for the diagnosis of and prognosis for GC. Aberrant sialylation is a widespread critical event in the development of GC. Neuraminidases (Neu) and sialyltransferases (STs) regulate the ablation and addition of sialic acid during glycoconjugates biosynthesis, and they are a considerable source of biomarkers in various cancers. This study retrospectively characterized Neu3 and ST3Gal3 expression by immunohistochemistry in 71 paraffin-embedded GC tissue specimens and analyzed the relationship between their expression and the clinicopathological parameters. Neu3 expression was markedly increased in GC tissues compared with non-tumoral tissues (p<0.0001). Intratumoral ST3Gal3 staining was significantly associated with intestinal subtype (p=0.0042) and was negatively associated with angiolymphatic invasion (p=0.0002) and higher histological grade G3 (p=0.0066). Multivariate analysis revealed that ST3Gal3 positivity is able to predict Lauren's classification. No associations were found between Neu3 staining and clinical parameters. The in silico analysis of mRNA expression in GC validation cohorts corroborates the significant ST3Gal3 association with higher histological grade observed in our study. These findings suggest that ST3Gal3 expression may be an indicator for aggressiveness of primary GC.

Laminin-5, Fibronectin, and Type IV Collagen as Potential Biomarkers of Brain Glioma Malignancy.

The presented work is based on the quantification of LN-5, FN, and COL IV in blood plasma as potential biomarkers in patients diagnosed with glioma in grades G1 to G4. The obtained concentration results were compared with the protein content in the control group, which consisted of smokers of different ages. The obtained results were statistically analysed and interpreted based on the available clinical description. Quantitative determinations of LN-5, FN, and COL IV were performed with the use of SPRi biosensors specific to the tested proteins. Comparing groups K and G4, as well as G2 and G4, statistically significant relationships between changes in the concentration of individual proteins, were observed. The analysis showed significant correlations between FN and LN-5, between FN and COL IV, and between LN-5 and COL IV. There was a moderate positive correlation between individual proteins and the age of the patient. The ROC analysis distinguished patients with advanced disease from the control group. The results of the research show that LN-5, FN, and COL IV are effective biomarkers of brain glioma that may be helpful in non-invasive diagnosis and determining the grade of the disease.

597P Endometrial carcinoma and mismatch repair deficiency: Clinical association and universal screening for Lynch syndrome

Endometrial carcinoma (EC) is characterised by a high rate of DNA Mismatch Repair deficiency (dMMR). Testing for dMMR might have implications for EC prognosis and is part of Universal Screening (US) for Lynch syndrome (LS) diagnosis. However, this is not widely implemented yet, and LS is still underdiagnosed. For these reasons, we aimed to evaluate dMMR prevalence, its association with clinicopathological variables and its role for LS diagnosis for EC patients. This is a monocentric retrospective study on 368 consecutive EC cases (stages I-IV). From 2013 to 2020 they underwent surgery and immunohistochemistry (IHC) analysis for dMMR. We collected age, date of surgery, tumor histotype, grading, FIGO stage at diagnosis, lymphovascular invasion (LVSI), and survival status. We then assessed the proportion of dMMR patients on the entire cohort. Major outcome were OS and RFS in the dMMR patients compared to MMR proficient cases (pMMR). Among the dMMR cases, we reported those who underwent genetic testing and had LS. dMMR was found in 91/368 EC patients (25%). 84 had endometroid histotype, 7 other histotypes (92% vs 8% p= 0.010), 50 had G2 nuclear grading vs 19 G1 and 22 G3 (55% vs 21% vs 24%; p=0.005). As compared to pMMR at a 4-year follow-up an unfavorable trend in OS and RFS was observed for patients with dMMR (4 y OS 82% vs 74% p=0.115, 4 y RFS 70% vs 54% p-value=0.153). In multivariate analysis, age (p<0.001), histotype and grade (p<0.001), stage (p=0.003) and LVSI (p=0.010) were independently associated to OS. dMMR only showed a trend in worse OS (p=0.10). Among the 91 patients with dMMR, only 5 underwent genetic counseling (GC)(6.6%): LS was diagnosed in 1 patient (20%) with loss of MSH2/MSH6 expression. This is the largest Italian cohort of US for LS. dMMR prevalence was 25%, mainly associated with endometrioid type, G2 grading and a worse 4 y OS, as compared to pMMR cases, consistent with the literature. Unfortunately, oncologists' compliance with US for LS is still very poor, with a 6.6% GC referral. This should be implemented according to international guidelines, to increase LS diagnosis, reduce mortality in relatives and incidence of second cancers in survived patients.

High GPER expression in triple-negative breast cancer is linked to pro-metastatic pathways and predicts poor patient outcomes

Triple-negative breast cancer (TNBC) is a particularly aggressive and heterogeneous disease with few effective targeted therapies and precision therapeutic options over a long period. It is generally considered that TNBC is an estrogen-independent breast cancer, while a new estrogen receptor, namely G protein-coupled estrogen receptor (GPER), is demonstrated to mediate estrogenic actions in TNBC. Based on our transcriptomic analysis, expression of GPER was correlated with clinicopathological variables and survival of 360 TNBC patients. GPER expression at mRNA level was significantly correlated with immunohistochemistry scoring in 12 randomly chosen samples. According to the cutoff value, 26.4% (95/360) of patients showed high GPER expression and significant correlation with the mRNA subtype of TNBC (P = 0.001), total metastatic events (P = 0.019) and liver metastasis (P = 0.011). In quantitative comparison, GPER abundance is correlated with the high-risk subtype of TNBC. At a median follow-up interval of 67.1 months, a significant trend towards reduced distant metastasis-free survival (DMFS) (P = 0.014) was found by Kaplan–Meier analysis in patients with high GPER expression. Furthermore, univariate analysis confirmed that GPER was a significant prognostic factor for DMFS in TNBC patients. Besides, high GPER expression was significantly linked to the worse survival in patients with lymph node metastasis, TNM stage III as well as nuclear grade G3 tumors. Transcriptome-based bioinformatics analysis revealed that GPER was linked to pro-metastatic pathways in our cohort. These results may supply new insights into GPER-mediated estrogen carcinogenesis in TNBC, thus providing a potential strategy for endocrine therapy of TNBC.

Proliferating Lymphatic Endothelial Cells as a Prognostic Marker in Head and Neck Squamous Cell Carcinoma.

Podoplanin and Ki-67 are two important markers of cancer progression. The aim of this study is to evaluate double immunostaining for Ki-67 and podoplanin in head and neck squamous cell carcinoma (HNSCC), and to observe the involvement of lymphagiogenesis in tumoral and peritumoral areas, as well as the density of tumor proliferation correlated with histopathological grading. A total of 50 patients with HNSCC were included in this study. We carried out a morphological evaluation of tissue samples, after that, cases were selected for double Ki-67 and podoplanin immunostaining. Podoplanin expression was significantly correlated with histopathological grade (p < 0.05; p = 0.037) and expression of Ki-67 (p < 0.05; p = 0.050). A high expression of podoplanin, as well as of the proliferation factor Ki-67, was observed in histopathological grade G3 and the correlation between these (p < 0.05; p = 0.028), and implication of LMVD and LVI was not significant (LMVD p = 0.577; LVI p = 0.976). This study demonstrated the importance of double immunolabeling in assessing lymphagiogenesis and tumor proliferation in correlation with histopathological grades in HNSCC.

Establishment of three heterogeneous subtypes and a risk model of low-grade gliomas based on cell senescence-related genes.

BackgroundCellular senescence is a key element in the occurrence and progression of a variety of tumors. As a result, cellular senescence-related markers can be categorized based on the prognosis status of patients. Due to the heterogeneity and the complexity of the tumor microenvironment (TME), the long-term effectiveness of low-grade glioma (LGG) treatment remains a clinical challenge. Consequently, developing and refining effective treatment approaches to aid with LGG management is critical.MethodsBased on the expressions of cell senescence-related genes (CSRGs) acquired from the cellAge database, consensus clustering was utilized to identify stable molecular subtypes. Clinical features, immune infiltration, route modifications, and genetic changes of various subtypes were also assessed. Following that, the least absolute shrinkage and selection operator (LASSO) regression and univariate Cox regression analysis were used for developing the cell senescence-related risk score (CSRS) model. Finally, a correlation study of the CSRS model with molecular, immunological, and immunotherapy parameters was performed.ResultsC1, C2, and C3, are the three senescence-related subtypes that were identified. Patients belonging to the C1 subtype had poor prognoses and a substantial proportion of them was in the grade G3. The differentially expressed genes (DEGs) among the three subtypes were used to develop the CSRS model. In both the training and independent validation cohort, the model had a high area under the receiver operating characteristic (ROC) curve in predicting the overall survival (OS) of patients. As a result, this model can predict clinical features and responses to immunotherapy in a variety of patients and it is a potential independent prognostic factor for LGG.ConclusionThis research discovered three LGG subtypes related to cell senescence and created a CSRS model for six genes. Cell senescence was highly associated with unfavorable prognosis in LGG. The CSRS model can be used to predict the prognosis of patients and identify patients who would benefit from immunotherapy.

Normofractionated and moderately hypofractionated proton therapy: comparison of acute toxicity and early quality of life outcomes

AimData on the safety of moderately hypofractionated proton beam therapy (PBT) are limited. The aim of this study is to compare the acute toxicity and early quality of life (QoL) outcomes of normofractionated (nPBT) and hypofractionated PBT (hPBT).Material and methodsWe prospectively compared acute toxicity and QoL between patients treated with nPBT (dose per fraction 1.8–2.3 Gy, n = 90) and hPBT (dose per fraction 2.5–3.1 Gy, n = 49) in following locations: head and neck (H&N, n = 85), abdomen and pelvis (A&P, n = 43), and other soft tissue (ST, n = 11). The toxicities were grouped into categories—mucosal, skin, and other sites—and evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at baseline, treatment completion, and 3 months after PBT completion. QoL was evaluated with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 scale for all locations and additionally with EORTC QLQ-HN35 for H&N patients.ResultsOverall, the highest toxicity grades of G0, G1, G2, and G3 were observed in 7 (5%), 40 (28.8%), 78 (56.1%), and 15 (10.8%) patients, respectively. According to organ and site, no statistically significant differences were detected in the majority of toxicity comparisons (66.7%). For A&P, hPBT showed a more favorable toxicity profile as compared to nPBT with a higher frequency of G0 and G1 and a lower frequency of G2 and G3 events (p = 0.04), more patients with improvement (95.7% vs 70%, p = 0.023), and full resolution of toxicities (87% vs 50%, p = 0.008). Skin toxicity was unanimously milder for hPBT compared to nPBT in A&P and ST locations (p = 0.018 and p = 0.025, respectively). No significant differences in QoL were observed in 97% of comparisons for QLQ-C30 scale except for loss of appetite in H&N patients (+33.3 for nPBT and 0 for hPBT, p = 0.02) and role functioning for A&P patients (0 for nPBT vs +16.7 hPBT, p = 0.003). For QLQ-HN35, 97.9% of comparisons did not reveal significant differences, with pain as the only scale varying between the groups (−8.33 vs −25, p = 0.016).ConclusionHypofractionated proton therapy offers non-inferior early safety and QoL as compared to normofractionated irradiation and warrants further clinical investigation.

Serum levels of neuron-specific enolase as a prognostic factor for disease progression in patients with GET/NEN in the pancreas and the small intestine.

The aim of this study was to assess the usefulness of neuron-specific enolase (NSE) concentrations as a prognostic factor in patients with neuroendocrine neoplasms and to determine the relationship between NSE and clinicopathological features. Serum NSE levels were measured in 179 NEN patients before treatment. It was found that NSE levels in patients with a primary pancreatic location were higher compared to patients with a small intestine lesion (P = 0.015). NSE levels were significantly higher in patients with primary pancreatic location with histological grade G2 compared with the group with low-grade G1 (P = 0.047). Patients with initial liver involvement showed significantly higher NSE levels compared to patients with tumour location in the pancreas (P = 0.009). Statistical analysis confirmed that higher NSE levels were associated with disease progression (P = 0.001) in both the overall study group and in patients with tumours in the pancreas and small intestine. During treatment monitoring, an increase in median NSE concentrations was observed in patients with persistent progression with subsequent blood draws, and a decrease in NSE concentrations was observed in patients with disease stabilisation. We showed that NSE concentrations have prognostic value for progression-free survival in addition to primary liver involvement. In conclusion, the most important results of the study include the demonstration of an association between NSE concentrations and clinical status, which confirms its usefulness in patient monitoring and as a potential predictive indicator for progression-free survival in patients with NENs.