Favorable Overall Survival In Patients Research Articles

Prognostic Role of Pre-Treatment Body Composition Parameters in Patients Undergoing First-Line Immunotherapy for Metastatic Renal Cell Carcinoma.

We investigated the relationship between body mass index (BMI), radiological body composition, and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) underwent first-line immune checkpoint inhibitor (ICI)-based therapy. Analyzing data from 102 patients treated between November 2019 and March 2023, pre-treatment computed tomography (CT) scans assessed fat and muscle areas. BMI and body composition indices were examined, including skeletal muscle index, subcutaneous fat index (SFI), visceral fat index, and total fat index. Kaplan-Meier curves and Log rank tests compared progression-free survival (PFS) and overall survival (OS), while multivariable Cox proportional regression analysis was performed to identify the variables significantly associated with survival outcomes. 54 patients (52.9%) experienced disease progression, and 26 (25.5%) died during a median follow-up of 17.4 months. High SFI was significantly associated with improved OS (p = 0.018) but not PFS (p = 0.090). Multivariable analysis confirmed the positive impact of high SFI on OS (adjusted HR: 0.37, p = 0.029) and suggested a trend towards improved PFS (adjusted HR: 0.61, p = 0.088). Notably, in the ipilimumab + nivolumab subgroup, high SFI significantly correlated with both PFS and OS (p = 0.047 and p = 0.012, respectively). High SFI predicts favorable OS in patients with mRCC receiving first-line ICI-based therapy, especially patients treated with ipilimumab + nivolumab displayed a significant association between high SFI and favorable PFS and OS.

A Phase II Trial of Bevacizumab in Patients with Recurrent/Progressive Solid Tumor Brain Metastases That Have Progressed Following Whole-Brain Radiation Therapy.

Patients with solid tumor brain metastases that progress after whole-brain radiation have limited options. This prospective trial investigated the efficacy, safety, and tolerability of bevacizumab as salvage therapy in this population. Eligible patients received bevacizumab 10 mg/kg intravenously every 2 weeks until progression. The primary endpoint was radiologic response using Response Assessment in Neuro-Oncology (RANO) criteria. The secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response, and safety. Quality of life (QOL) was studied using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) scale. Twenty-seven patients were enrolled, with twenty-four having evaluable data for response. The majority of histologies (n = 21, 78%) were breast cancer. The remaining histologies were non-small-cell lung cancer (n = 4, 15%), neuroendocrine cancer (n = 1, 3%), and papillary fallopian serous adenocarcinoma (n = 1, 3%). Eighteen patients had radiologic response, with two patients demonstrating partial response (8.33%) and sixteen patients demonstrating stable disease (66.7%). The median duration of response was 203 days. PFS at 6 months was 46%, median PFS was 5.3 m, and median OS was 9.5 m. Treatment was well tolerated, with six patients experiencing grade 3 lymphopenia and hypertension. There was one grade 3 thromboembolism. QOL was not negatively impacted. Bevacizumab is a safe and feasible salvage treatment with durable response and favorable overall survival for patients with progressive brain metastases after whole-brain radiation.

Stereotactic radiosurgery in the management of non-small cell lung cancer brain metastases: a prospective study using the NeuroPoint Alliance Stereotactic Radiosurgery Registry.

The literature on non-small cell lung cancer (NSCLC) brain metastases (BMs) managed using stereotactic radiosurgery (SRS) relies mainly on single-institution studies or randomized controlled trials (RCTs). There is a literature gap on clinical and radiological outcomes of SRS for NSCLC metastases in real-world practice. The objective of this study was to benchmark mortality and progression outcomes in patients undergoing SRS for NSCLC BMs and identify risk factors for these outcomes using a national quality registry. The SRS Registry of the NeuroPoint Alliance was used for this study. This registry included patients from 16 enrolling sites who underwent SRS from 2017 to 2022. Data are prospectively collected without a prespecified research purpose. The main outcomes of this analysis were overall survival (OS), out-of-field recurrence, local progression, and intracranial progression. All time-to-event investigations included Kaplan-Meier analyses and multivariable Cox regressions. Two hundred sixty-four patients were identified, with a mean age of 66.7 years and a female proportion of 48.5%. Most patients (84.5%) had a Karnofsky Performance Status (KPS) score of 80-100, and the mean baseline EQ-5D score was 0.539 quality-adjusted life years. A single lesion was present in 53.4% of the patients, and 29.1% of patients had 3 or more lesions. The median OS was 28.1 months, and independent predictors of mortality included no control of primary tumor (hazard ratio [HR] 2.1), KPS of 80 (HR 2.4) or lower (HR 2.4), coronary artery disease (HR 2.8), and 5 or more lesions present at the time of SRS treatment (HR 2.3). The median out-of-field progression-free survival (PFS) was 24.8 months, and the median local PFS was unreached. Intralesional hemorrhage was an independent risk factor of local progression, with an HR of 6.0. The median intracranial PFS was 14.0 months and was predicted by the number of lesions at the time of SRS (3-4 lesions, HR 2.2; 5-14 lesions, HR 2.5). In this real-world prospective study, the authors used a national quality registry and found favorable OS in patients with NSCLC BMs undergoing SRS compared with results from previously published RCTs. The intracranial PFS was mainly driven by the emergence of new lesions rather than local progression. A greater number of lesions at baseline was associated with out-of-field progression, while intralesional hemorrhage at baseline was associated with local progression.

In Silico Transcriptomic Expression of MSR1 in Solid Tumors Is Associated with Responses to Anti-PD1 and Anti-CTLA4 Therapies.

Immuno-oncology has gained momentum with the approval of antibodies with clinical activities in different indications. Unfortunately, for anti-PD (L)1 agents in monotherapy, only half of the treated population achieves a clinical response. For other agents, such as anti-CTLA4 antibodies, no biomarkers exist, and tolerability can limit administration. In this study, using publicly available genomic datasets, we evaluated the expression of the macrophage scavenger receptor-A (SR-A) (MSR1) and its association with a response to check-point inhibitors (CPI). MSR1 was associated with the presence of macrophages, dendritic cells (DCs) and neutrophils in most of the studied indications. The presence of MSR1 was associated with macrophages with a pro-tumoral phenotype and correlated with TIM3 expression. MSR1 predicted favorable overall survival in patients treated with anti-PD1 (HR: 0.56, FDR: 1%, p = 2.6 × 10-5), anti PD-L1 (HR: 0.66, FDR: 20%, p = 0.00098) and anti-CTLA4 (HR: 0.37, FDR: 1%, p = 4.8 × 10-5). When specifically studying skin cutaneous melanoma (SKCM), we observed similar effects for anti-PD1 (HR: 0.65, FDR: 50%, p = 0.0072) and anti-CTLA4 (HR: 0.35, FDR: 1%, p = 4.1 × 10-5). In a different dataset of SKCM patients, the expression of MSR1 predicted a clinical response to anti-CTLA4 (AUC: 0.61, p = 2.9 × 10-2). Here, we describe the expression of MSR1 in some solid tumors and its association with innate cells and M2 phenotype macrophages. Of note, the presence of MSR1 predicted a response to CPI and, particularly, anti-CTLA4 therapies in different cohorts of patients. Future studies should prospectively explore the association of MSR1 expression and the response to anti-CTLA4 strategies in solid tumors.

Abstract 962: Oncodrivers expression analysis in primary tumors: potential for development of targeted immunotherapies for triple negative breast cancer (TNBC)

Abstract Background and significance: Lack of targets, aggressive course, resistance to treatment and poor prognosis are typical characteristics of TNBC. Like other breast cancer (BC) types, TNBC cells are also dependent on oncodrivers that potentiate the malignancy by inducing proliferation. This dependency makes oncodrivers the target of choice for new BC therapies. Here, we focus on cellular distribution of HER3, EGFR, and MET in TNBC tumors. Analysis of oncodrivers expression along with immune cell landscape in TNBC tumors pre- and post-chemotherapy will help in understanding the interaction between immune response and oncodrivers status and how that correlates with therapeutic response(s) in patients to design future clinical trial using targeted immunotherapy.Methods: In an IRB-approved study, immunohistochemistry was performed using tissue microarray (TMA) on surgical blocks from a cohort of 90 TNBC patients. Two separate multiplex panels: (1) Oncodrivers (HER3, EGFR & MET); (2) Immune cells (CD4, CD8, CD20, CD56, CD45, & PD1) were used. Subsequently, oncodrivers expression was correlated to immune infiltration, clinical responses, and survival by reviewing the pathological data. Results: We analyzed total 208 QC-passed TMA cores. Irrespective of clinical outcome, EGFR (41.13% vs 15.09%, p<0.0001) and MET (35.67% vs 11.61%, p<0.0001) showed increase in the number of positive cells in tumor as compared to benign tissue. Curiously, limited expression of HER3 was significantly lower in stromal tissue (1.62% vs 0.59%, p=0.026). The distribution of MET and EGFR showed a significant correlation (r=0.32, p<0.0001) whereas HER3 expression was mutually exclusive to either MET (r=-0.006, p=0.931) or EGFR (r=-0.07, p=0.291). Analysis of clinical and pathological data demonstrated that HER3 expression was higher in patients treated with neoadjuvant chemotherapy (2.95% versus 0.79%, p=0.004). There was higher expression of HER3 in node positive disease (p=0.013) and MET in node negative disease (p=0.004). There was no change in expression between pre- and post-chemotherapy samples for MET (p=0.097) and EGFR (p=0.754). Interestingly, the intermediate strength of EGFR expression was significantly associated with favorable overall survival in patients treated with neoadjuvant chemotherapy (univariate Cox model, N=13, HR=0.28, p=0.024). Analysis of immune infiltrate showed a significant correlation between CD45 and EGFR (r=0.379, p<0.001) as well as MET (r=0.443, p<0.001). Conclusion: EGFR and MET overexpressed in tumor tissue of TNBC specimens while smaller proportion of HER3+ cells were limited to tumor as compared to stroma. HER3 appears to be altered by neoadjuvant chemotherapy. EGFR and MET expression correlated with CD45+ immune cells. To this end, HER3, EGFR, and MET remain viable options as potential targets for dendritic cell tumor vaccines. Citation Format: Saurabh K. Garg, Nicholas T. Champion, Amrita Basu, Junmin Whiting, Weihong Sun, Susan Hoover, Brian J. Czerniecki. Oncodrivers expression analysis in primary tumors: potential for development of targeted immunotherapies for triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 962.

Outcomes of laparoscopic radiofrequency ablation versus percutaneous radiofrequency ablation for hepatocellular carcinoma.

Few studies have compared the therapeutic outcomes in patients with HCC who underwent laparoscopic radiofrequency ablation (LRFA) versus percutaneous radiofrequency ablation (PRFA) for hepatocellular carcinoma (HCC). Therefore, this study compared the recurrence and survival outcomes of the two RFA methods in patients with HCC. Recurrence and overall survival outcomes were evaluated in 307 patients who underwent LRFA (n = 151) or PRFA (n = 156) as a treatment method for de novo HCC. Inverse probability of treatment weighting (IPTW) analysis was performed to reduce the impact of treatment selection bias. There were no significant differences in major baseline characteristics between the LRFA and PRFA groups. However, the proportion of cirrhotic patients was higher in the LRFA group, whereas the LRFA group had more tumors and a more advanced tumor-node-metastasis stage. Moreover, the mean tumor size was significantly larger in the LRFA group than in the PRFA group. In a multivariate analysis, serum albumin level, more than three tumors, and the RFA method were identified as significant predictors of recurrence-free survival. Moreover, for the overall survival of HCC patients, serum albumin levels, days of hospital stay during RFA, and the RFA method were independent predictors. In the IPTW-adjusted analysis, the LRFA group showed significantly higher recurrence-free survival and overall survival. Our study revealed that compared with PRFA, LRFA was associated with longer recurrence-free survival and favorable overall survival in patients with HCC. Therefore, LRFA should be considered the primary therapy in patients with HCC eligible for RFA.

Long-Term Outcomes and Prognosis Factors in Patients With Idiopathic Inflammatory Myopathies Based on Myositis-Specific Autoantibodies: A Single Cohort Study.

This study was undertaken to investigate the long-term survival rates and prognostic factors in patients with idiopathic inflammatory myopathies (IIMs) based on myositis-specific antibody (MSA) stratification. Exactly 628 patients with an IIM were included. Kaplan-Meier survival curves, univariate, and multivariate Cox regression were used to analyze the outcomes and risk factors. The cumulative 1-, 5-, and 10-year survival rates for IIM patients overall were 91.4%, 82.8%, and 75.6%, respectively. The survival rate in the MSA subset was significantly different (P < 0.001). The 1- and 10-year survival rates in the anti-melanoma differentiation-associated protein 5 (anti-MDA-5)-positive subgroup were 79.5% and 58.5%, respectively, which were the lowest among all subgroups. The 10-year survival rate of anti-signal recognition particle (anti-SRP)-positive patients was the highest (96.4%). Independent risk factors that impacted the long-term prognosis for IIM patients included rapidly progressive interstitial lung disease (RP-ILD), malignancy, and elevated serum ferritin levels (hazard ratio [HR] 17.47, 20.36, and 9.15, respectively, P < 0.01), whereas disease duration was a protective factor (HR 0.27, P=0.003). Among these subsets, the strongest independent risk factor for death in the anti-MDA-5-positive subgroup was RP-ILD (HR 3.4, P=0.017). Malignancy was an independent risk factor in the anti-aminoacyl-tRNA synthetase antibody-positive, anti-transcription intermediary factor 1γ-positive, and MSA-negative subgroups (HR 46.69, 6.65, and 4.48, respectively; P < 0.001). RP-ILD was also a risk factor in the prognosis of individuals in the MSA-negative subgroup (HR 72.28, P < 0.001). Despite favorable overall survival in patients with IIM, the anti-MDA-5-positive subgroup had the highest mortality rate among all MSA subgroups, highlighting the distinctive prognosis for patients with different MSAs. RP-ILD and malignancy are the most common causes of death in IIM patients.

Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients With Advanced Neuroendocrine Carcinoma of the Digestive System

Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for advanced neuroendocrine carcinoma (NEC). To identify whether EP or IP is a more effective regimen in terms of overall survival (OS) in patients with advanced NEC of the digestive system. This open-label phase 3 randomized clinical trial enrolled chemotherapy-naive patients aged 20 to 75 years who had recurrent or unresectable NEC (according to the 2010 World Health Organization classification system) arising from the gastrointestinal tract, hepatobiliary system, or pancreas. Participants were enrolled across 50 institutions in Japan between August 8, 2014, and March 6, 2020. In the EP arm, etoposide (100 mg/m2/d on days 1, 2, and 3) and cisplatin (80 mg/m2/d on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m2/d on days 1, 8, and 15) and cisplatin (60 mg/m2/d on day 1) were administered every 4 weeks. The primary end point was OS. In total, data from 170 patients were analyzed to detect a hazard ratio (HR) of 0.67 (median OS of 8 and 12 months in inferior and superior arms, respectively) with a 2-sided α of 10% and power of 80%. The pathologic findings were centrally reviewed following treatment initiation. Among the 170 patients included (median [range] age, 64 [29-75] years; 117 [68.8%] male), median OS was 12.5 months in the EP arm and 10.9 months in the IP arm (HR, 1.04; 90% CI, 0.79-1.37; P = .80). The median progression-free survival was 5.6 (95% CI, 4.1-6.9) months in the EP arm and 5.1 (95% CI, 3.3-5.7) months in the IP arm (HR, 1.06; 95% CI, 0.78-1.45). A subgroup analysis of OS demonstrated that EP produced more favorable OS in patients with poorly differentiated NEC of pancreatic origin (HR, 4.10; 95% CI, 1.26-13.31). The common grade 3 and 4 adverse events in the EP vs IP arms were neutropenia (75 of 82 [91.5%] patients vs 44 of 82 [53.7%] patients), leukocytopenia (50 of 82 [61.0%] patients vs 25 of 82 [30.5%] patients), and febrile neutropenia (FN) (22 of 82 [26.8%] patients vs 10 of 82 [12.2%] patients). While incidence of FN was initially high in the EP arm, primary prophylactic use of granulocyte colony-stimulating factor effectively reduced the incidence of FN. Results of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although AEs were generally manageable, grade 3 and 4 AEs were more common in the EP arm. Japan Registry of Clinical Trials: jRCTs031180005; UMIN Clinical Trials Registry: UMIN000014795.

Efficacy of Preoperative mFOLFIRINOX vs mFOLFIRINOX Plus Hypofractionated Radiotherapy for Borderline Resectable Adenocarcinoma of the Pancreas

National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear. To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC. This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021. Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; bolus fluorouracil, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2 over 46 hours). Each treatment arm's 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection. Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively. This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting. ClinicalTrials.gov Identifier: NCT02839343.

Attenuated ZHX3 expression is predictive of poor outcome for liver cancer: Indication for personalized therapy.

The zinc-fingers and homeoboxes (ZHX) family members have been characterized as master regulators in cancer initiation and development. The present study performed in silico data-mining with publicly available datasets and immunohistochemistry to assess the expression status of ZHX factors and the corresponding prognostic implications in liver cancer. Increased ZHX3 mRNA expression was associated with favorable overall survival in patients with liver cancer. Subgroups analyses revealed a significant association between the expression of ZHX factors and outcomes in select patient cohorts. Immunohistochemical analysis supported that ZHX3 expression was an independent prognostic indicator for patient survival. These results suggested that dysregulation of ZHX factors is involved in disease progression and ZHX3 expression may serve as a prognostic biomarker for liver cancer.

PD-1H Expression Associated With CD68 Macrophage Marker Confers an Immune-Activated Microenvironment and Favorable Overall Survival in Human Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal carcinoma (EC) in China. Although the PD-1 inhibitor pembrolizumab has been approved to treat patients with EC, its therapeutic efficacy is limited. Thus, additional immunotherapeutic targets for EC treatment are needed. Programmed Death-1 Homolog (PD-1H) is a negative checkpoint regulator that inhibits antitumor immune responses. Here, PD-1H expression in 114 patients with ESCC was evaluated by immunohistochemistry. Next, 12 randomly selected tumor tissue sections were used to assess the colocalization of PD-1H protein and multiple immune markers by multiplex immunohistochemistry. Our results demonstrated that PD-1H was expressed at high frequency in ESCC tumor tissues (85.1%). PD-1H protein was predominantly expressed in CD68+ tumor-associated macrophages and expressed at low levels in CD4+ T cells and CD8+ T cells in ESCC tumor tissues. Furthermore, based on ESCC data in The Cancer Genome Atlas (TCGA), the gene expression levels of PD-1H were positively associated with the infiltration levels of immune-activated cells especially CD8+ cytotoxic T cells. In contrast, the gene expression levels of PD-1H were negatively correlated with myeloid-derived suppressor cells (MDSCs). Importantly, PD-1H expression in tumor sites was significantly correlated with favorable overall survival in patients with ESCC. Collectively, our findings first provided direct information on the PD-1H expression pattern and distribution in ESCC, and positive correlation of PD-1H expression with overall survival suggested PD-1H expression levels could be a significant prognostic indicator for patients with ESCC. Future studies need to explore the immunoregulatory of PD-1H in the tumor microenvironment of ESCC.

LncRNA DSCAM-AS1 facilitates the progression of endometrial cancer via miR-136-5p.

Previous studies have indicated that long non-coding RNA (lncRNA) down syndrome cell adhesion molecule antisense 1 (DSCAM-AS1) serves an oncogenic role in numerous cancer types. However, its role in endometrial cancer (EC) remains largely unknown. In the present study, DSCAM-AS1 expression levels in EC tissues and cells and their normal counterparts were analyzed using reverse transcription-quantitative. In vitro and in vivo experiments were conducted to validate the functions of DSCAM-AS1 in EC. It was revealed that DSCAM-AS1 was expressed at a high level in EC tissues and cells after analyzing patient data and data obtained from The Cancer Genome Atlas. Notably, it was also revealed that high DSCAM-AS1 expression was associated with a less favorable overall survival in patients with EC. Knockdown of DSCAM-AS1 was able to suppress EC cell proliferation by upregulating cell apoptosis in vitro. Furthermore, it was revealed that DSCAM-AS1 acted as a microRNA (miR)-136-5p sponge to exert its oncogenic roles in EC. Collectively and to the best of our knowledge, the current results provided first evidence that DSCAM-AS1 stimulated EC progression by regulating miR-136-5p, which may improve the understanding of the roles of ncRNAs in EC, and may help identify novel targets for anticancer treatment.

TNFAIP3 mutation may be associated with favorable overall survival for patients with T-cell lymphoma

BackgroundT-cell lymphoma (TCL) is highly aggressive and has a poor prognosis; thus, it is worth exploring biomarkers that may predict clinical outcomes and investigate their potential role in developing targeted therapies. In this study, we characterized the mutation pattern of tumor necrosis factor-alpha-inducing protein 3 (TNFAIP3) and its role in the prognosis of TCL patients.MethodsCoding sequence (CDS) mutations in TNFAIP3 in TCL patients was explored using exome-sequencing data from 79 patients in our center (Guangdong Provincial People’s Hospital, GDPH) and 544 samples from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Additionally, non-CDS mutations in TNFAIP3 in 41 TCL patients from our center (JNU) were investigated by polymerase chain reaction (PCR) and Sanger sequencing. Furthermore, non-CDS mutations in TNFAIP3 in 47 TCL patients from Gene Expression Omnibus (GEO) dataset were explored.ResultsIn the COSMIC database, TNFAIP3 mutations in TCL patients were located in the CDS, and the overall mutation frequency was 2.2%. However, TNFAIP3 mutations were not detected in the CDS of any of the samples in our center’s datasets. Interestingly, non-CDS TNFAIP3 mutations were found in 14.6% and 4.3% of TCL patients in the JNU and GSE15842 dataset, respectively. Importantly, there was a clear trend showing that TCL patients with a TNFAIP3 mutation were associated with a longer 5-year restricted mean survival time (RMST) and favorable OS rate compared with those without a TNFAIP3 mutation in the JNU dataset [hazard ratio (HR) = 0.29, 95% confidence interval (CI) 0.07 to 1.31, P = 0.089]. Furthermore, TNFAIP3 mutations significantly correlated with T-cell large granular lymphocytic leukemia (T-LGLL) with a favorable prognosis in the JNU dataset (P = 0.002). Notably, the different mutation patterns of TNFAIP3 when comparing our center and the COSMIC datasets might be due to different ethnic and genetic backgrounds.ConclusionsTo the best of our knowledge, we for the first time describe that TNFAIP3 mutations in non-CDS regions are associated with favorable OS for TCL patients, which might be a potential biomarker for the prognostic stratification of Chinese TCL patients.

Low CBS expression can identify patients who benefit from adjuvant chemotherapy in gastric cancer

ABSTRACT Aim: To explore the clinical significance of Cystathionine beta-synthase (CBS) expression in gastric cancer (GC). Research design and methods: CBS expression and clinicopathological/follow-up information of patients with gastric cancer undergoing operation were collected from The Cancer Genome Atlas (TCGA) database. The association of CBS expression with patients’ overall survival (OS) was determined in the entire cohort and different subgroups. Validation was performed in two external cohorts from NCBI Gene Expression Omnibus (GEO) database. The estimated drug response of the tumors with different CBS expressions was characterized. The potential CBS-related cellular pathways in chemoresistance were explored. Results: High CBS was associated with poor OS in patients receiving adjuvant chemotherapy (ACT) but not those without ACT. And ACT was associated with favorable OS in patients with low CBS expression but not those with high CBS expression. The results were verified in two external cohorts. Drug response prediction suggested that patients with low CBS expression showed high sensitivity to 5-Fluorouracil. Gene Set Enrichment Analysis (GSEA) suggested that CBS might contribute to GC chemoresistance via modulating many cellular pathways, including down-regulating apoptosis and P53 pathways while up-regulating DNA repair pathway. Conclusion: Low CBS expression can predict the benefit from ACT in GC.

Metabolic features of cancer cells impact immunosurveillance

BackgroundTumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the...

Expression and prognostic value of SULT1A2 in bladder cancer.

Sulfotransferase Family 1A Member 2 (SULT1A2) is a protein coding gene. Several studies have reported that SULT1A2 may have a chemical carcinogenic effect if expressed as a functional protein. The present study aimed to investigate the expression and potential role of SULT1A2 in bladder cancer (BC). Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases were used to analyze SULT1A2 expression in BC. In addition, reverse transcription-quantitative PCR and western blot analyses were performed to detect SULT1A2 expression in BC cells and tissues. Immunohistochemistry analysis was performed on 100 formalin-fixed, paraffin-embedded BC tissues and corresponding adjacent normal bladder tissues (ANBTs) to verify SULT1A2 expression and determine the clinical significance of SULT1A2 in BC. Gene set enrichment analysis (GSEA) was performed to determine the potential biological processes and internal molecular mechanisms. The results demonstrated that SULT1A2 was highly expressed in BC tissues compared with ANBTs. Furthermore, high SULT1A2 expression was significantly associated with the staging of BC. Analyses of TCGA datasets and BC tissue microarray indicated that high SULT1A2 expression was significantly associated with a favorable overall survival in patients with BC. In addition, GSEA revealed pathways, diseases and biological processes associated with SULT1A2. Taken together, the results of the present study suggest that SULT1A2 acts as an oncogene in BC, and thus may serve as a biomarker for tumor staging and prognosis in patients with BC.

DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells

BackgroundConventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a...

A retrospective comparative study of S-IROX and modified FOLFIRINOX for patients with advanced pancreatic cancer refractory to gemcitabine plus nab-paclitaxel.

The aim of this study was to evaluate the efficacy and tolerability of S-IROX and modified FOLFIRINOX (mFFX) after gemcitabine plus nab-paclitaxel for advanced pancreatic cancer (PC) in the real world setting. Consecutive patients receiving S-IROX or mFFX as a second-line chemotherapy for advanced PC refractory to gemcitabine plus nab-paclitaxel were retrospectively studied. Patients were treated every 2weeks: S-1 40mg/m2 was administered orally twice daily on days 1 to 7 in S-IROX and 5-fluorouracil 2400mg/m2 was intravenously administered for 46h without bolus infusion in mFFX, in addition to intravenous oxaliplatin 85mg/m2 and irinotecan 150mg/m2 on day 1 in both regimens. Fifty-four patients with advanced PC who received S-IROX (n = 19) or mFFX (n = 35) were retrospectively studied. The disease control rate and response rate were 73.7% and 10.5% in the S-IROX group and 62.2% and 2.7% in the mFFX group, respectively. The median progression free survival (PFS) was 7.8 and 5.7months in the S-IROX and mFFX groups (p = 0.24). The median overall survival (OS) was 14.2 and 11.5months in the S-IROX and mFFX groups (p = 0.34). There were no significant differences in the incidences of grade 3-4 adverse effects. The subgroup analyses suggested S-IROX demonstrated favorable OS in patients with PFS ≥6months of first-line gemcitabine plus nab-paclitaxel (p for interaction = 0.02). S-IROX and mFFX were similarly tolerable and effective as a second-line chemotherapy in patients with PC refractory to gemcitabine plus nab-paclitaxel.

Optimal treatment strategy for adult patients with newly diagnosed glioblastoma: a systematic review and network meta-analysis

To compare the efficacy and safety of treatments based on the Stupp protocol for adult patients with newly diagnosed glioblastoma and to determine the optimal treatment option for patients with different O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation statuses. We estimated hazard ratios (HRs) for overall survival (OS) and odds ratios (ORs) for adverse events of grade 3 or higher (AEs ≥ 3). Twenty-one randomized controlled trials involving 6478 patients treated with 21 different treatment strategies were included. Results of the pooled HRs indicated tumor-treating fields (TTF) combined with the Stupp protocol resulted in the most favorable OS for patients with and without MGMT promoter methylation. Subgroup analyses by the two MGMT promoter statuses indicated that lomustine-temozolomide plus radiotherapy or TTF combination therapy was associated with the best OS for patients with methylated MGMT promoter (HR, 1.03; 95% credible interval [CI], 0.54-1.97), and standard cilengitide combination therapy or TTF combination treatment was associated with the best OS for patients with unmethylated MGMT promoter (HR, 1.05; 95% CI, 0.67-1.64). Regarding AEs ≥ 3, there were no significant differences in pooled ORs. However, Bayesian ranking profiles that demonstrated intensive cilengitide combination therapy and TTF combination therapy have a similar possibility to cause the least toxicity. These results indicated that TTF combination therapy was associated with increased survival, irrespective of the MGMT promoter methylation status, and a relatively tolerated safety profile compared with other combination treatments. The optimal treatment option for glioblastoma patients with different MGMT promoter methylation statuses was different.

Missed radiation therapy sessions in first three weeks predict distant metastasis and less favorable outcomes in surgically treated patients with oral cavity squamous cell carcinoma

BackgroundWe sought to investigate the prognostic impact of missed RT sessions in patients who had undergone surgery for oral cavity squamous cell carcinoma (OCSCC).MethodsThe study sample consisted of 905 patients with surgically treated OCSCC who fulfilled criteria of RT course ≤8 weeks. The study participants were divided into three groups based on the characteristics of missed RT, as follows: 1) early missed RT, 2) late missed RT, and 3) RT as scheduled.ResultsThe 5-year overall survival (OS) rates in the early missed RT, late missed RT, and RT as scheduled groups were 53.0, 58.1, and 64.5%, respectively (p = 0.046). In multivariate analysis, early missed RT was independently associated with both OS (hazard ratio (HR) = 1.486; 95% confidence interval (CI): 1.122–1.966; p = 0.006) and the occurrence of distant metastasis (HR = 1.644; 95% CI: 1.047–2.583; p = 0.031).ConclusionEarly missed RT was independently associated with a higher occurrence of distant metastasis and less favorable OS in patients who had undergone surgery for OCSCC.