Socioeconomic Factors Associated with Poor Prognosis in Patients with Alcoholic Liver Cirrhosis

Background: Alcohol liver cirrhosis is a life-threatening condition, especially if alcohol cessation is not accomplished. Past studies have shown that alcohol abuse is closely linked to low socioeconomic status and social marginalization. Public assistance (PA), or Seikatsu-hogo, a Japanese public assistance ensuring medical care to low-income population, was employed as a proxy for social marginalization. This study aims to investigate the prognostic effect of being a PA recipient on overall mortality in patients with alcoholic cirrhosis.Methods: Patients diagnosed as alcoholic liver cirrhosis in a community hospital between 2006 to 2017 were included in this retrospective cohort study. Baseline demographics and mortality data were extracted from electronic health records. Cirrhosis severity at baseline was measured by mean model for end-stage liver disease (MELD) score and Albumin-Bilirubin (ALBI) score. Primary outcome was survival probability obtained by the Kapan Meier method and Cox proportional hazards regression. Results: 244 participants were included, among which 62 were PA recipients. Baseline cirrhosis severity score was not different between the two groups. Incidence proportion for overall mortality was 48.4% and 31.9% for PA recipients and non-PA recipients, respectively (p=0.002). In cox regression model, adjusted for age, ALBI score and HCV infection, hazard ratio for PA reception was1.57 (95% CI: 0.97-2.5, p=0.06). Conclusions: Being a PA recipient may be a poor prognostic factor of mortality in patients with alcoholic liver cirrhosis.

Follicular Helper T-Cell-Based Classification of Endometrial Cancer Promotes Precise Checkpoint Immunotherapy and Provides Prognostic Stratification

Despite the fact that management of EC is moving towards four TCGA-based molecular classifications, a pronounced variation in immune response among these molecular subtypes limits its clinical use. We aimed to investigate the determinant biomarker of ICI response in endometrial cancer (EC). We characterized transcriptome signatures associated with tumor immune microenvironment in EC. Two immune infiltration signatures were identified from the TCGA database (n = 520). The high- and low-infiltration clusters were compared for differences in patient clinical characteristics, genomic features, and immune cell transcription signatures for ICI prediction. A Lasso Cox regression model was applied to construct a prognostic gene signature. Time-dependent receiver operating characteristic curve, Kaplan–Meier curve, nomogram, and decision curve analyses were used to assess the prediction capacity. The efficacy of potential biomarker was validated by the Karolinska endometrial cancer cohort (n = 260). Immune signature profiling suggested that T follicular helper–like cells (Tfh) may be an important and favorable factor for EC; high Tfh infiltration showed potential for clinical use in the anti-PD-1 treatment. A Tfh Infiltration Risk Model (TIRM) established using eight genes was validated, and it outperformed the Immune Infiltration Risk Model. The TIRM had a stable prognostic value in combination with clinical risk factors and could be considered as a valuable tool in a clinical prediction model. We identified CRABP1 as an individual poor prognostic factor in EC. The Tfh-based classification distinguishes immune characteristics and predicts ICI efficacy. A nomogram based on Tfh-related risk score accurately predicted the prognosis of patients with EC, demonstrating superior performance to TCGA-based classification.

Androgen Receptor as an Emerging Feasible Biomarker for Breast Cancer

Biomarkers can be used for diagnosis, prognosis, and prediction in targeted therapy. The estrogen receptor α (ERα) and human epidermal growth factor receptor 2 (HER2) are standard biomarkers used in breast cancer for guiding disease treatment. The androgen receptor (AR), a nuclear hormone receptor, contributes to the development and progression of prostate tumors and other cancers. With increasing evidence to support that AR plays an essential role in breast cancer, AR has been considered a useful biomarker in breast cancer, depending on the context of breast cancer sub-types. The existing survival analyses suggest that AR acts as a tumor suppressor in ER + ve breast cancers, serving as a favorable prognostic marker. However, AR functions as a tumor promoter in ER-ve breast cancers, including HER2 + ve and triple-negative (TNBC) breast cancers, serving as a poor prognostic factor. AR has also been shown to be predictive of the potential of response to adjuvant hormonal therapy in ER + ve breast cancers and to neoadjuvant chemotherapy in TNBC. However, conflicting results do exist due to intrinsic molecular differences between tumors and the scoring method for AR positivity. Applying AR expression status to guide treatment in different breast cancer sub-types has been suggested. In the future, AR will be a feasible biomarker for breast cancer. Clinical trials using AR antagonists in breast cancer are active. Targeting AR alone or other therapeutic agents provides alternatives to existing therapy for breast cancer. Therefore, AR expression will be necessary if AR-targeted treatment is to be used.

Serotonin 5-HT7 Receptor Is A Biomarker Poor Prognostic Factor And Induces Proliferation of Triple Negative Breast Cancer Cells Through FOXM1

Purpose: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and associated with poor prognosis and shorter survival due to significant genetic heterogeneity, drug resistance and lack of effective targeted therapeutics. Therefore, novel molecular targets and therapeutic strategies are needed to improve patient survival. Serotonin (5-hydroxytriptamine, 5-HT) has been shown to induce growth stimulatory effects in breast cancer. However, the molecular mechanisms by which 5-HT exerts its oncogenic effects in TNBC still are not well understood. Methods: Normal breast epithelium (MCF10A) and two TNBC cells (MDA-MB-231, BT-546) and MCF-7 cells (ER+) were used to investigate effects of 5-HT7 receptor. Small interfering RNA (siRNA)-based knockdown and metergoline (5-HT7 antagonist) were used to inhibit the activity of 5-HT7. Cell proliferation and colony formation were evaluated using MTS cell viability and colony formation assays, respectively. Western blotting was used to investigate 5-HT7, FOXM1 and its downstream targets protein expressions.Results: We demonstrated that 5-HT induces cell proliferation of TNBC cells and expression of 5-HT7 receptor and FOXM1 oncogenic transcription factor. We found that expression of 5-HT7 receptor is upregulated in TNBC cells and higher 5-HT7 expression is associated with poor patient prognosis and shorter patient survival. Genetic and pharmacological inhibition of 5-HT7 by siRNA and metergoline, respectively, suppressed TNBC cell proliferation and FOXM1 and its downstream mediators, including eEF2-Kinase (eEF2K) and cyclin-D1. Conclusion: Our findings suggest for the first time that the 5-HT7 receptor promotes FOXM1, eEF2K and cyclin D1 signaling to support TNBC cell proliferation, thus inhibition of 5-HT7/FOXM1 signaling may be used as a potential therapeutic strategy for targeting TNBC.

Ringed Fluorodeoxyglucose Uptake Predicted Poor Prognosis After Resection of Pulmonary Pleomorphic Carcinoma

Background:Pulmonary pleomorphic carcinoma (PPC) is a relatively rare and poorly differentiated non-small cell carcinoma. This study aimed to investigate the clinicopathological features including programmed cell death ligand 1 (PD-L1) expression status in patients with PPC who underwent curative resection.Methods:We retrospectively studied 29 consecutive patients who had undergone anatomical lung resections for PPC. Perioperative and pathological variables, including radiological findings, were investigated to define prognostic factors.Results:Overall survival (OS) rates were 71.8% at 1 year and 60.0% at 5 years. Disease-free survival (DFS) rates were 54.8% at 1 year and 43.6% at 5 years. Univariate analysis revealed that ringed fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT) (p=0.003), a cavity in the tumor on CT (p=0.004), and tumor size (>40mm) (p=0.014) were poor prognostic factors for OS. Regarding DFS, ringed FDG uptake (p=0.002), a cavity on CT (p<0.001), tumor size (p=0.007), and pleural invasion (p=0.014) were poor prognostic factors. PD-L1 expression was not a prognostic factor. Conclusion:Early relapse was frequently observed. This study showed for the first time that ringed FDG uptake on PET/CT is a poor prognostic factor of PPC. PD-L1 expression status was not related to the prognosis. Trial registration:The study was approved by the Kobe City Medical Center General Hospital’s ethics board (No. 20112) on August 20, 2020.

Hemoglobin, albumin, lymphocytes and platelets (HALP) score is a useful predictor of survival in patients with recurrent glioblastoma multiforme treated with bevacizumab plus irinotecan

Backgrounds: We aimed to investigate whether the HALP score is a predictive marker in patients with recurrent GBM who were given bevacizumab plus irinotecan.Methods: We compared the survival of patients followed up in our clinic with the diagnosis of recurrent GBM and treated with bevacizumab plus irinotecan, according to HALP score.Results: Median PFS and OS were 4.5 (0.9-14.9) and 8 (0.9-21.3) months, respectively. The median PFS of the low HALP score group was 1.85 (1.3-3.37) months, and of the high HALP score group was 4.96 (0.9-14.9) months (p=0.03). The OS of the high HALP score group (9.63 [7.28-11.9]) was statistically higher compared with low HALP score group (2.26 [0.88-3.65]) (p<0.001). In univariate analysis HALP score was a significant prognostic factor; patients with low HALP score had a poorer prognosis than high HALP score (HR: 0.063, p<0.001). The multivariate analysis showed that HALP score (p=0.003), and residual tumor (p=0.029) were significant prognostic factors. In multivariate Cox regression analysis, low HALP score was a significant poor prognostic factor for OS compared with high HALP score (HR: 0.063, p<0.001). Conclusion: We showed that the HALP score at the start of treatment is an independent prognostic factor for PFS and OS in patients with recurrent GBM treated with bevacizumab plus irinotecan. The HALP score, which can be easily calculated by routine tests before chemotherapy, can be used as a predictive marker for bevacizumab treatment decision.

Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma

Glofitamab, a novel CD20xCD3, T-cell-engaging bispecific antibody, demonstrated single-agent activity in study NP30179, a first-in-human, phase 1 trial in relapsed/refractory B-cell non-Hodgkin lymphoma. Preclinical studies showed that glofitamab leads to T-cell activation, proliferation and tumor cell killing upon binding to CD20 on malignant cells. Here, we provide evidence of glofitamab's clinical activity, including pharmacodynamics, mode of action and factors associated with clinical response, by evaluating biomarkers in patient samples from the dose-escalation part of this trial. Patients enrolled in NP30179 received single-dose obinutuzumab pretreatment (1000 mg; Gpt) 7 days prior to intravenous glofitamab (5 µg-25 mg). Glofitamab treatment lasted ≤12 cycles once every 2 or 3 weeks. Blood samples were collected at predefined time points per clinical protocol; T-cell populations were evaluated centrally by flow cytometry, and cytokine profiles were analyzed. Immunohistochemical and genomic biomarker analyses were performed on tumor biopsies. Pharmacodynamic modulation was observed with glofitamab treatment including dose-dependent induction of cytokines, and T-cell margination, proliferation and activation in peripheral blood. Gene expression analysis of pre-treatment tumor biopsies indicated that tumor cell intrinsic factors like TP53 signaling are associated with resistance to glofitamab, but may also be interlinked with a diminished effector T-cell profile in resistant tumors and thus represent a poor prognostic factor per se. This integrative biomarker data analysis provides clinical evidence of glofitamab's mode of action, supports optimal biological dose selection, and will further guide clinical development. This trial was registered at www.clinicaltrials.gov as #NCT03075696.

Combination of Endogenous Estradiol and Adipokine Leptin in Breast Cancer Risk and Prognosis Assessment in Postmenopausal Chinese Women

ObjectiveOur study aims to clarify the role of estradiol and leptin in breast cancer risk and prognostic assessment in postmenopausal Chinese women.DesignThe serum circulating estradiol and leptin level was detected by ELISA. Then the correlation between estradiol, leptin level, and clinical characteristics was analyzed using Fisher’s exact test. Next, the Kaplan-Meier model was used to analyze the association between estradiol, leptin, and prognosis of postmenopausal breast cancer patients in our cohort and the TCGA dataset.SettingThe study was conducted at the National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College.PatientsA total of 182 postmenopausal breast cancer patients and 111 healthy subjects from January 2010 to August 2010 were included in the analysis. Another 702 cases with breast cancer were retrieved from The Cancer Genome Atlas (TCGA) database for subsequent analysis.Main Outcome MeasureSerum circulating estradiol and leptin level.ResultsThe level of estradiol was significantly higher (P&lt;0.001) but the level of leptin had no significant difference (P = 0.764) in postmenopausal breast cancer patients compared with healthy subjects. The level of estradiol and leptin was not significantly different between estrogen receptor (ER) positive and ER-negative groups (P&gt;0.05). Estradiol was significantly correlated with tumor T stage (P = 0.002) and leptin was significantly associated with perineural invasion (P = 0.014). In addition, the disease-free survival of patients with a high level of estradiol was significantly shorter (P = 0.025) but leptin tended to be a protective factor for overall survival in TCGA analysis (P = 0.038).ConclusionCirculating estradiol and leptin played important roles in the risk of postmenopausal breast cancer even in low-estrogen nations with an independent expression of ER status. High circulating estradiol was a poor prognostic factor and leptin may be a protection signal in Chinese postmenopausal patients with breast cancer.

Epigenetic upregulation of TET2 is an independent poor prognostic factor for intrahepatic cholangiocarcinoma

Mutations in IDH1/2 and the epigenetic silencing of TET2 occur in leukaemia or glioma in a mutually exclusive manner. Although intrahepatic cholangiocarcinoma (iCCA) may harbour IDH1/2 mutations, the contribution of TET2 to carcinogenesis remains unknown. In the present study, the expression and promoter methylation of TET2 were investigated in iCCA. The expression of TET2 was assessed in 52 cases of iCCA (small-duct type, n = 33; large-duct type, n = 19) by quantitative PCR, immunohistochemistry (IHC) and a sequencing-based methylation assay, and its relationships with clinicopathological features and alterations in cancer-related genes (e.g., KRAS and IDH1) were investigated. In contrast to non-neoplastic bile ducts, which were negative for TET2 on IHC, 42 cases (81%) of iCCA showed the nuclear overexpression of TET2. Based on IHC scores (area × intensity), these cases were classified as TET2-high (n = 25) and TET2-low (n = 27). The histological type, tumour size, lymph node metastasis and frequency of mutations in cancer-related genes did not significantly differ between the two groups. Overall and recurrence-free survival were significantly worse in patients with TET2-high iCCA than in those with TET2-low iCCA. A multivariate analysis identified the high expression of TET2 as an independent prognostic factor (HR = 2.94; p = 0.007). The degree of methylation at two promoter CpG sites was significantly less in TET2-high iCCA than in TET2-low iCCA or non-cancer tissue. In conclusion, in contrast to other IDH-related neoplasms, TET2 overexpression is common in iCCA of both subtypes, and its high expression, potentially induced by promoter hypomethylation, is an independent poor prognostic factor.