Lower Recurrence-free Survival Rates Research Articles

Denosumab Induces Neoplastic Stromal Cell Apoptosis Via p62 Downregulation Dependent on Autophagy Pathway in Giant Cell Tumour of Bone.

As the only humanized monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL) for giant cell tumour of bone (GCTB) therapy, denosumab has limited antitumour effect on neoplastic stromal cells. Nevertheless, its mechanism of action has not yet been clarified. A previous study has revealed that p62 may play an important role in the antitumour activity of denosumab. The study aimed to investigate if the mechanism by which denosumab inhibits GCTB neoplastic stromal cells growth is via p62 modulation and other related mechanisms. p62 expression before and after denosumab therapy was analysed by RT‒qPCR, western blot, ELISA, and immunohistochemical assays. Two primary neoplastic stromal cells were isolated from fresh GCTB tumour tissue (L cell) and metastatic tissue (M cell). Cell proliferation, migration, apoptosis, and autophagy were investigated in p62 knockdown neoplastic stromal cells transfected by short hairpin RNA lentivirus in vitro. Tumor growth was evaluated in the chick chorioallantoic membrane model in vivo. p62 expression was found to be downregulated following denosumab therapy. The patients with a decrease in p62 expression had lower recurrence-free survival rates. The proliferation of M cells was not inhibited by denosumab therapy, but it was restored by p62 knockdown. Moreover, p62 knockdown inhibited tumour growth in vivo. Denosumab induced M cell apoptosis and arrested the cell cycle at the G1/G0 transition and these effects were also enhanced by p62 knockdown. Autophagic flux assays revealed p62 modulation to be dependent on autophagy following denosumab incubation. Denosumab induced neoplastic stromal cells apoptosis via p62 downregulation dependent on autophagy pathway. The combination of p62 and RANKL knockdown might be a better strategy than RANKL knockdown alone for GCTB targeted therapy.

Comparison of the Efficacy of Percutaneous Balloon Compression and Extracranial Non gasserian Ganglion Radiofrequency Thermocoagulation for Primary Multibranch Trigeminal Neuralgia

BACKGROUND: Both computed tomography-guided extracranial nongasserian ganglion radiofrequency thermocoagulation (RFT) and percutaneous balloon compression (PBC) have significant clinical efficacy in the treatment of trigeminal neuralgia, but a comparison of the efficacy of the 2 methods for pain in primary multibranch trigeminal neuralgia (TN) has not been studied clinically. OBJECTIVE: To compare the efficacy and safety of PBC with extracranial nongasserian ganglion RFT in the treatment of primary multibranch TN. STUDY DESIGN: This is a single-center, retrospective, observational study. SETTING: This study was conducted at the Pain Department of the Affiliated Hospital of Jiaxing College in Jiaxing, People’s Republic of China. METHODS: A total of 202 patients, including 112 patients in the RFT group and 90 patients in the PBC group, with multi-branch TN who visited the pain department of Jiaxing First Hospital for percutaneous minimally invasive surgery from April 2016 through June 2021 were retrospectively analyzed. Patients in both groups were followed-up regularly after surgery, and the Numeric Rating Scale, recurrence-free survival rate, Barrow Neurological Institute facial numbness score, and other postoperative complications were recorded before surgery (T0), immediately after surgery (T1) and at 3 months (T2), 6 months (T3), 12 months (T4), and 15 months (T5) postoperatively. RESULTS: All patients completed the operation successfully. No significant difference was found between the two groups in terms of gender, age, pain duration, preoperative Numeric Rating Scale (NRS-11), lateralization of pain and affected branches, and preoperative underlying disease (P > 0.05). There was a significant difference in preoperative and immediate postoperative NRS-11 scores between the 2 groups (P < 0.01). NRS-11 scores decreased at each time point (T1-T5) and were significantly different from preoperative scores (P < 0.001). Meanwhile, no significant difference was found in NRS-11 scores at T0, T1, and T2 between the RFT and PBC groups (P > 0.05). However, the differences were statistically significant at T3 (P < 0.05), T4 (P < 0.001), and T5 (P < 0.001). BNI-N scores decreased in both groups at T2, T3, T4, and T5 after surgery and were significantly different from preoperative scores (P < 0.05). BNI-N scores were significantly lower in the PBC group than in the RFT group at all time points (P < 0.05). In the long-term treatment of multibranch trigeminal neuralgia, the PBC group exhibited a lower recurrence rate than the RFT group. No severe complications or deaths were observed in either of the 2 groups. LIMITATIONS: A small sample size and being conducted at a single center are limitations of our study. CONCLUSION: Both RFT and PBC were effective in relieving primary multibranch TN, but patients in the PBC group had a lower recurrence-free survival rate, fewer complications, and a better safety profile. Follow-up studies with a larger patient sample held at multiple locations should be conducted. KEY WORDS: Radiofrequency thermocoagulation, percutaneous balloon compression, trigeminal neuralgia, extracranial nongasserian ganglion, multibranch pain

Factors influencing the prognosis patients with Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma undergoing salvage surgery after conversion therapy.

The aim of this study was to investigate the prognostic factors influencing the outcome of patients with Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma (HCC) receiving salvage surgery after conversion therapy based on tyrosine kinase inhibitors (TKIs) and anti-programmed death-1 (PD-1) antibodies. From June 2018 to December 2022, patients receiving salvage surgery after conversion therapy based on PD-1 and TKIs at the Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital were retrospectively recruited for this study. Overall survival (OS) and recurrence-free survival (RFS) were observed as the primary end point in the Cox analysis of prognostic factors among this study. The 6- and 12-month RFS rates were 77.0% and 64.8%, respectively, while the 6-, 12-, 24-, and 36-month OS rates were 98.4%, 93.4%, 76.8%, and 69.8%, respectively. The median OS and RFS were not reached. On multivariable Cox regression analyses, low serum alpha fetoprotein (AFP) level (≤20 ng/mL) after conversion therapy [hazard ratio (HR) 0.186, 95% CI: 0.039-0.887; P=0.035) and microvascular invasion (MVI) grade II (HR 3.054, 95% CI: 1.000-9.329; P=0.050) were independent factors associated with a higher OS and RFS. For patients with Barcelona Clinic Liver Cancer stage C (BCLC-C) HCC, lower AFP level after conversion therapy (<20 ng/mL) and MVI II were associated with a higher OS and lower RFS rate, respectively.

Clinical implications of m6A‐related regulators YTHDF1 and YTHDF2 in hepatocellular carcinoma

AbstractIt aims to examine the correlation between the expression of YTHDF1 and YTHDF2 and the clinical, pathological, and prognostic factors in HCC. The study was done using statistics from TCGA to establish the noted relationship. The degree of YTHDF1 and YTHDF2 protein expression in 88 HCC as well as the adjacent tissues was then determined through IHC examination, and we examined how that expression linked with other clinicopathological traits and clinical outcomes. Bioinformatics examination revealed that YTHDF1 and YTHDF2 expression was increased in HCC tissues, and poor pathology grade and prognosis were linked to high expression. YTHDF1 protein expression in IHC was notably higher in HCC tissue (p = .023). It was associated with age (p = .002) but not with other clinicopathological characteristics or prognoses. When compared to paraneoplastic tissues, the expression of the protein YTHDF2 was considerably higher in HCC tissues (p &lt; .0001); and its high expression due to worse pathological grading (p = .035), higher alpha fetoprotein expression (p = .04), higher tumor recurrence (p = .023), lower overall survival rate (p = .011), and lower recurrence free survival rate (p = .005). A separate predictive factor for determining recurrence‐free survival in HCC was YTHDF2. A novel molecular marker called YTHDF2 may be used to assess HCC patients' prognoses.

Role of Intrahepatic Regional Immunity in Post-Transplant Cancer Recurrence

Hepatic malignancy is a major indication for liver transplantation; however, post-transplant cancer recurrence is an emerging clinical challenge affecting long-term outcomes. Pre-transplant tumor biology, staging, and post-transplant immunosuppression regimens have been elucidated as risk factors for recurrent liver cancer. However, increasing evidence indicates that hepatic ischemia and reperfusion (IR) injury to allografts are crucial to providing a favorable immunologic microenvironment for cancer cell invasiveness and metastasis after liver transplantation. The association of severe graft injury in marginal grafts, such as small-for-size or fatty grafts, with lower recurrence-free survival rates in living donor liver transplantations, substantiates the correlation between hepatic IR injury and cancer recurrence. IR has been demonstrated to trigger intrahepatic immunological microenvironment remodeling, including pro-inflammatory responses exacerbating graft injury and anti-inflammatory responses promoting tissue repair. However, the role of regional immunity in post-transplant cancer recurrence is not comprehensively understood. This review describes the up-to-date evidence of the intrahepatic humoral microenvironment and regional regulatory immunological microenvironment induced by IR injury, as well as their roles in cancer recurrence after liver transplantation. A comprehensive understanding of regional immunity will provide novel precise diagnostic, therapeutic, and prognostic strategies for post-transplant cancer recurrence.

PBRM1 Immunohistochemical Expression Profile Correlates with Histomorphological Features and Endothelial Expression of Tumor Vasculature for Clear Cell Renal Cell Carcinoma.

Simple SummaryThe PBRM1 protein, whose gene is the most frequently mutated one in clear cell renal cell carcinoma (ccRCC) following von Hippel-Lindau, has been proposed as a potential biomarker for ccRCC. However, the association of the PBRM1 immunohistochemical expression with histomorphological features of ccRCC and the endothelial expression of tumor vasculature, which is an important role of the tumor microenvironment related to treatment response, is little known. Recently, our research team has established a vascularity-based architectural classification of ccRCC correlated with angiogenesis and immune gene expression signatures, which could provide prognostic information and function as a surrogate for treatment selection. In the present study, we found the PBRM1 expression was correlated with the architectural patterns. Furthermore, we demonstrated that endothelial expression tended to be lost in cases with low PBRM1 expression. This correlation implied the orchestrated expression of PBRM1, raising the possibility that the cancer cells and their microenvironment interact in ccRCC.Loss of the polybromo-1 (PBRM1) protein has been expected as a possible biomarker for clear cell renal cell carcinoma (ccRCC). There is little knowledge about how PBRM1 immunohistochemical expression correlates with the histomorphological features of ccRCC and the endothelial expression of tumor vasculature. The present study evaluates the association of architectural patterns with the PBRM1 expression of cancer cells using a cohort of 425 patients with nonmetastatic ccRCC. Furthermore, we separately assessed the PBRM1 expression of the endothelial cells and evaluated the correlation between the expression of cancer cells and endothelial cells. PBRM1 loss in cancer cells was observed in 148 (34.8%) patients. In the correlation analysis between architectural patterns and PBRM1 expression, macrocyst/microcystic, tubular/acinar, and compact/small nested were positively correlated with PBRM1 expression, whereas alveolar/large nested, thick trabecular/insular, papillary/pseudopapillary, solid sheets, and sarcomatoid/rhabdoid were negatively correlated with PBRM1 expression. PBRM1 expression in vascular endothelial cells correlated with the expression of cancer cells (correlation coefficient = 0.834, p < 0.001). PBRM1 loss in both cancer and endothelial cells was associated with a lower recurrence-free survival rate (p < 0.001). Our PBRM1 expression profile indicated that PBRM1 expression in both cancer and endothelial cells may be regulated in an orchestrated manner.

RON, ROR1 and SUSD2 expression in tissues of endometrial carcinoma patients. Clinicopathological and prognostic implications.

IntroductionEndometrial carcinoma is now considered a common female gynecologic cancer with increasing incidence, with 13–25% of patients being still liable to recurrence and metastasis, which needs further studies to detect novel targets and new therapies. The aim of the study was evaluate tissue expression of RON, ROR1 and SUSD2 in endometrial carcinoma and atypical endometrial hyperplasia using immunohistochemistry and correlate their expression with clinical, pathological and prognostic parameters of patients.Material and methodsWe included samples from 100 patients with endometrial carcinoma. Sections from paraffin blocks were stained with RON, ROR1 and SUSD2 using immunohistochemistry. Correlations between marker expression, clinicopathological features and prognostic samples were evaluated.ResultsUpregulation of RON and ROR1 and downregulation of SUSD2 expression were found in endometrial carcinoma more than atypical endometrial hyperplasia (p < 0.001). High RON and ROR1 expression levels were significantly associated with high grade (p < 0.001), presence of lymph node metastases (p = 0.003), distant metastases (p = 0.009), advanced International Federation of Gynecology and Obstetrics stage (p = 0.002), poor response to therapy (p = 0.046), and lower recurrence-free survival (RFS) rate (p = 0.002), progression-free survival (PFS) rate (p = 0.008), distant metastasis-free survival (DMFS) rate (p = 0.019) and overall survival rate (p < 0.001). Low SUSD2 expression was significantly associated with older patient age (p = 0.002), large tumor size (p = 0.003), high grade (p = 0.005), presence of adnexal invasion (p = 0.023), presence of lympho-vascular invasion (p = 0.021), extent of myometrial invasion (p = 0.002), lower RFS rate (p = 0.008), lower PFS rate (p = 0.023), and lower DMFS rate (p < 0.001).ConclusionsUpregulation of RON and ROR1 and downregulation of SUSD2 lead to promotion of endometrial cancer cell proliferation, migration, epithelial-mesenchymal transition, and invasion.

Novel Insights into the Prognosis and Immunological Value of the SLC35A (Solute Carrier 35A) Family Genes in Human Breast Cancer.

According to statistics 2020, female breast cancer (BRCA) became the most commonly diagnosed malignancy worldwide. Prognosis of BRCA patients is still poor, especially in population with advanced or metastatic. Particular functions of each members of the solute carrier 35A (SLC35A) gene family in human BRCA are still unknown regardless of awareness that they play critical roles in tumorigenesis and progression. Using integrated bioinformatics analyses to identify therapeutic targets for specific cancers based on transcriptomics, proteomics, and high-throughput sequencing, we obtained new information and a better understanding of potential underlying molecular mechanisms. Leveraging BRCA dataset that belongs to The Cancer Genome Atlas (TCGA), which were employed to clarify SLC35A gene expression levels. Then we used a bioinformatics approach to investigate biological processes connected to SLC35A family genes in BRCA development. Beside that, the Kaplan–Meier estimator was leveraged to explore predictive values of SLC35A family genes in BCRA patients. Among individuals of this family gene, expression levels of SLC35A2 were substantially related to poor prognostic values, result from a hazard ratio of 1.3 (with 95 percent confidence interval (95% CI: 1.18–1.44), the p for trend (ptrend) is 3.1 × 10−7). Furthermore, a functional enrichment analysis showed that SLC35A2 was correlated with hypoxia-inducible factor 1A (HIF1A), heat shock protein (HSP), E2 transcription factor (E2F), DNA damage, and cell cycle-related signaling. Infiltration levels observed in specific types of immune cell, especially the cluster of differentiation found on macrophages and neutrophils, were positively linked with SLC35A2 expression in multiple BRCA subclasses (luminal A, luminal B, basal, and human epidermal growth factor receptor 2). Collectively, SLC35A2 expression was associated with a lower recurrence-free survival rate, suggesting that it could be used as a biomarker in treating BRCA.

Feasibility and outcomes of bronchial artery embolization in patients with non-massive hemoptysis

PurposeTo evaluate the safety, efficacy, and long-term outcome of bronchial artery embolization (BAE) in the treatment of non-massive hemoptysis and the prognostic factors associated with recurrent bleeding.Materials and methodsFrom March 2005 to September 2014, BAE was performed in 233 patients with non-massive hemoptysis. All patients had a history of persistent or recurrent hemoptysis despite conservative medical treatment. We assessed the technical and clinical success, recurrence, prognostic factors related to recurrent bleeding, recurrence-free survival rate, additional treatment, and major complications in all the patients.ResultsTechnical success was achieved in 224 patients (96.1%), and clinical success was obtained in 219 (94.0%) of the 233 patients. In addition, 64 patients (27.5%) presented hemoptysis recurrence with median time of 197 days after embolization. Tuberculosis sequelae and presence of aberrant bronchial artery or non-bronchial systemic collaterals were significantly related to recurrent bleeding (p < 0.05). The use of Histoacryl-based embolic materials significantly reduced the recurrent bleeding rate (p < 0.05). Patient who had a tuberculosis sequelae showed a significantly lower recurrence-free survival rate (p = 0.013). Presence of aberrant bronchial artery or non-bronchial systemic collaterals showed a statistically significant correlation with recurrence-free survival rate (p = 0.021). No patients had major complications during follow-up.ConclusionsBAE is a safe and effective treatment to manage non-massive hemoptysis. The procedure may offer a better long-term control of recurrent hemoptysis and quality of life than conservative therapy alone.

Diagnostic and prognostic value of FOXD1 expression in head and neck squamous cell carcinoma.

FOXD1 has been reported to function as an oncogene in several types of cancer. This study evaluated the expression of FOXD1 and its role in head and neck squamous cell carcinoma (HNSCC). We mined the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases for expression profiles, clinical significance, and potential mechanisms of FOXD1in HNSCC. Our validation cohort consisted of FOXD1 mRNA expression in 162 paired HNSCC and adjacent normal tissues, as determined using quantitative real-time polymerase chain reaction. FOXD1 expression was upregulated in HNSCC in the public databases and in the validation cohort. The expression level of FOXD1 was associated with DNA amplification and methylation level. The areas under the curves (AUC) of TCGA cohort and the validation cohort were 0.855 and 0.843, respectively. Furthermore, higher FOXD1 expression was significantly associated with worse overall survival (hazard ratio [HR]: 1.849, 95% confidence interval [CI]: 1.280-2.670, P = 0.001) and a lower rate of recurrence-free survival (HR: 1.650, 95% CI: 1.058-2.575, P = 0.027) in patients with HNSCC. Moreover, gene set enrichment analysis showed that cases of HNSCC with FOXD1 overexpression were enriched in bladder cancer, cell cycle, DNA replication, glycosaminoglycan biosynthesis chondroitin sulfate, homologous recombination, glycan biosynthesis, nucleotide excision repair, p53 signaling pathway, pyrimidine metabolism, and spliceosome pathways. In summary, FOXD1 was significantly upregulated in HNSCC and was a good diagnostic biomarker and an independent predictor of poor survival and low rate of recurrence-free survival in patients with HNSCC.

Clinicopathologic characteristics and prognosis of upper tract urothelial carcinoma complicated with aristolochic acid nephropathy after radical nephroureterectomy

BackgroundThe purpose of this study was to identify the clinicopathologic characteristics and prognosis of upper tract urothelial carcinoma (UTUC) patients complicated with aristolochic acid nephropathy(AAN) after radical nephroureterectomy (RNU).MethodsThe clinical data of 42 UTUC patients with AAN (AAN group) and 238 UTUC patients without AAN (Non-AAN group) were retrospectively reviewed. All patients received a RNU with excision of bladder cuff. Demographic and clinical data, including preoperative indexes, intraoperative indexes and surgical outcomes were compared.ResultsThere were no significant differences in age, tumor location, surgery approach, tumor pathologic grade, stage, the mean operative time and estimated blood loss between the two groups (all p > 0.05). There were more female patients in the AAN group (p < 0.001), and 57.1% were high grade tumors. The AAN group showed a higher complications rate (p = 0.003). The median follow-up time was 43.2 months. The AAN group showed a worse estimated 5-year overall survival rate (35.1% vs. 63.0%, p = 0.014), however, no significant difference was found between the two groups with regard to disease specific survival (63.5% vs. 81.5%, p = 0.091). Multivariate binary logistic regression analysis showed that AAN was an independent factor related with overall and disease specific survival. 38.9% of all patients experienced any types of recurrence, and the estimated 5-year recurrence-free survival rate was lower in the AAN group (37.1% vs. 63.7%, p = 0.001). In the comparison of subgroups stratified by recurrence type, the AAN group had a higher intravesical (p = 0.030) and contralateral recurrence rate (p = 0.040).ConclusionUTUC with AAN occurred more frequently in female patients who were more likely to develop high-grade tumors. However, these patients showed a worse overall survival and a lower recurrence-free survival rate than the other patients. AA-related UTUC might be associate with an increased risk of intravesical and contralateral recurrence after RUN.

Conservative treatment of upper urinary tract carcinoma in patients with imperative indications.

To report our experience for endoscopic treatment of upper urinary tract carcinoma (UTUC) in patients with imperative indications for management. Retrospective data were collected for all patients who underwent endoscopic management of UTUC for imperative situations, from September 2013 to January 2019. Comorbidity was determined by using the age-adjusted Charlson Comorbidity Index (CCI). The primary endpoint of the study was overall survival (OS). Secondary outcomes were recurrence-free survival (RFS) rates, complication rates and global renal function. A total of 29 patients were enrolled in the study. The median age was 69.0 (IQR 63.0-79.0) years and the median CCI was 6 (IQR 4-8). Overall, 137 endoscopic procedures were performed; 117 (85.4%) had no complication. Clavien-Dindo grade III and IV complications were 3 (2.2%) and 1 (0.7%) respectively. The median follow-up of 23 months (IQR 14-35). During the follow-up, 2 (6.9%) patients died for cause not related to cancer. Recurrence of UTUC occurred in 18 patients (61.1%). The 24-month OS was 96.4±3.5% and the 24-month RFS was 31.7±9.4%. Lower RFS rates were found in high grade tumor patients (22.2±13.9%) compared to low grade tumor patients (35.6±12.3%) (P=0.237). There was statistical difference in creatinine and eGFR values when comparing baseline to last follow-up (P=0.018 and P=0.005, respectively). Endoscopic management of UTUC in patients with imperative indications appears to be a reasonable alternative to nephroureterectomy. However, stringent endoscopic follow-up is necessary due to the high risk of disease recurrence.

The value of transurethral thulium laser en bloc resection combined with a single immediate postoperative intravesical instillation of pirarubicin in primary non-muscle-invasive bladder cancer.

The objective of this study was to evaluate which patients might benefit from a single immediate postoperative intravesical instillation (SII) compared to maintenance intravesical instillations (MII) in primary non-muscle-invasive bladder cancer (NMIBC) after transurethral en bloc resection of bladder tumors (ERBT). A total of 141 patients with primary NMIBC who underwent ERBT with thulium laser between January 2012 and May 2016 were retrospectively enrolled. All the patients were categorized into two groups based on the duration of postoperative intravesical instillation of pirarubicin (THP): single intravesical instillation (SII) group, patients received a single immediate postoperative intravesical instillation of THP (30mg), and maintenance intravesical instillations (MII) group, patients received a 1-year MII of THP (30mg). Prognosis and recurrence data of each group were analyzed. One hundred and four (73.8%) patients received MII, and other 37 (26.2%) patients received SII. There was no significant difference in recurrence-free survival (RFS) between the two groups (P = 0.105). Following recurrence risk-stratified analysis, patients with high recurrence risk who accepted SII had a significantly lower RFS rate than those who received MII (P = 0.027). However, there were no significant differences in RFS rate between the two groups in patients with low and intermediate recurrence risk. In the multivariate analysis, the number of tumors was found to be an independent prognostic factor for RFS in NMIBC patients [hazard ratio, 5.665; 95% confidence interval (CI), 2.577-12.454; P < 0.001]. SII seems not to be inferior to MII in patients with initial low-risk and intermediate-risk NMIBC after ERBT.

Abstract 2812: Triple-negative breast cancer cell-intrinsic glucocorticoid receptor activity and modulation of the immune microenvironment

Abstract Background: Variation in the infiltration of TNBC immune microenvironment is not well understood. Our lab previously demonstrated that high glucocorticoid receptor (GR; nuclear hormone receptor) activity in TNBC models is associated with tumor cell-intrinsic anti-inflammatory gene expression pathways. In addition, high GR expression in early-stage TNBC is associated with a significantly lower rate of recurrence-free survival suggesting a role for GR-associated mechanisms in TNBC progression. GR activation in lymphocytes is well known to result in their apoptosis; however, a current gap in knowledge regarding GR biology is whether tumor-cell intrinsic GR activity modulates immune cells in the microenvironment. We hypothesized that TNBC cell-intrinsic GR activity may inhibit antitumor T cell activity in the tumor microenvironment. Methods and Results: We divided TCGA primary TNBC RNAseq expression data based on GR expression and determined enrichment for immune cells using two transcriptome parsing algorithms. We found that TNBCs with high GR expression are significantly enriched for the T cell-inflamed gene expression signature, suggesting the presence of T cells in the microenvironment. The xCell algorithm found that TNBCs with high GR expression are significantly enriched for the CD4+ naïve T cell transcriptome, which is absent in TNBCs with low GR-expression. To begin to determine whether GR activation in TNBC cells induces the secretion of cytokines and/or growth factors that result in the chemotaxis of CD4+ naïve T cells, we collected conditioned cell culture media from control versus GR-active TNBC cells and performed multiplex cytokine ELISA. We found that G-CSF secretion by TNBC cells was significantly increased following GR activation; G-CSF has been shown to promote immunosupressive Treg cell differentiation. Conclusions: Prior data suggest that breast tumor-infiltrating immunosuppressive Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Thus targeting GR in TNBC may be an important therapeutic approach to potentiate antitumor T cell responses and suppress the Treg population in the tumor microenvironment. Ongoing work is aimed at further delineating a mechanism by which GR can modulate the immune tumor microenvironment. Citation Format: Deniz N. Dolcen, Diana West Szymanski, Ananth Panchamukhi, Xiaomeng Wang, Randy F. Sweis, Rita Nanda, Suzanne Conzen. Triple-negative breast cancer cell-intrinsic glucocorticoid receptor activity and modulation of the immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2812.

JAB1-STAT3 activation loop is associated with recurrence following 5-fluorouracil-based adjuvant chemotherapy in human colorectal cancer.

Jun activation domain-binding protein 1 (JAB1) has been shown to have multiple roles in tumorigenesis, including the degradation of tumor suppressor proteins such as p53, Smad7, Runx3 and the cyclin-dependent kinase inhibitor p27Kip1, and the activation of oncogenic transcription factors, such as c-Jun and hypoxia-inducible factor-1α. In addition, our previous study revealed that JAB1 positively regulates signal transducer and activator of transcription 3 (STAT3) DNA-binding activity in human colon cancer cells. In turn, the oncogenic transcription factor STAT3 positively regulates JAB1 expression, indicative of a positive feedback loop. Furthermore, high JAB1 expression is associated with a poor prognosis in numerous malignant carcinomas. However, the association between JAB1 expression and prognosis in colorectal cancer remains unclear. The aim of the present study was to elucidate the association between JAB1 and STAT3 expression and recurrence in colorectal cancer. In the present study, it was found that high JAB1 expression in primary colorectal cancer tissues is an independent predictor of recurrence following 5-fluorouracil (5-FU)-based adjuvant chemotherapy in colorectal cancer patients, and that high expression of both JAB1 and STAT3 in primary colorectal cancer tissues is associated with a lower recurrence-free survival rate following 5-FU-based adjuvant chemotherapy compared to high expression of only JAB1 or STAT3. Overall, these results suggest that JAB1 is a novel predictive marker of recurrence following 5-FU-based adjuvant chemotherapy in colorectal cancer patients, and that the JAB1-STAT3 activation loop may be a potential therapeutic target in recurrent colorectal cancer following 5-FU-based adjuvant chemotherapy.

High expression of Parkin predicts easier recurrence of patients with adjuvant transarterial chemoembolization.

To investigate the clinical significance of E3 ubiquitin ligase Parkin in patients with adjuvant transarterial chemoembolization after curative resection of hepatocellular carcinoma. Parkin expression of hepatocellular carcinomas was detected and its correlation with clinicopathological factors was analyzed with χ2 test. The significance of Parkin in prognosis and recurrence was analyzed with log-rank test and the Cox-regression model. High expression of Parkin could result in lower recurrence-free survival rate instead of overall survival rate. Larger tumor size, positive tumor recurrence, advanced T, N, M and TNM stage were significantly associated with poorer prognosis. Larger tumor size, advanced T and TNM stage could lead to higher recurrence. High Parkin expression could predict easier recurrence to patients with adjuvant transarterial chemoembolization.

Impact of preoperative thrombocytosis on prognosis after surgical treatment in pathological T1 and T2 renal cell carcinoma: results of a multi-institutional comprehensive study.

BackgroundThe prognostic significance of preoperative thrombocytosis (TC) in renal cell carcinoma (RCC) is not without some debate. The aim of the present multi-institutional study was to determine the association of preoperative TC with the clinicopathological features and prognosis of localized RCC patients who underwent surgery in a large cohort.MethodsA study involving 8 institutions, and 4,376 patients with pT1 and pT2 RCC from the Korean renal cell carcinoma (KORCC) database, was conducted. TC was defined as a platelet count ≥400,000/μL. Patients were divided into 2 groups based on the presence of preoperative TC. Clinicopathological variables and survival rates were compared between the 2 groups.ResultsOut of the 4,376 patients in the study, 106 (2.4%) had preoperative TC. Compared to patients without TC, these patients had a lower body mass index. Additionally, these patients had more advanced stage tumors with a higher Fuhrman grade, and higher incidence of symptoms at the time of diagnosis. Kaplan-Meier curves revealed that patients with TC had a significantly lower rate of recurrence-free survival (RFS). Furthermore, a lower rate of overall survival (OS) was exhibited amongst patients with TC. Multivariate analysis revealed that TC was an independent prognostic factor in terms of the RFS and OS.ConclusionsTC appeared to be an important prognostic determinant in localized RCC. Furthermore, preoperative platelet count may be clinically useful for risk stratification of patients with surgically treated localized RCC.

Stereotactic body radiotherapy for patients with relapsing prostate cancer with bones or nodes oligometastases.

263 Background: To analyze patients treated by stereotactic body radiotherapy (SBRT) for node or bone oligometastatic recurrence of a prostate cancer previously locally treated, To identify possible pronostic factors of early biochemical failure (BF) after SBRT. Methods: We reviewed patients with a rising PSA treated by SBRT between November 2011 and April 2016 for bone or node oligometastases, diagnosed on a 18F Fluorocholine positron emission tomography-computed tomography (PET-CT) following biochemical failure of a prostate cancer after a local curative treatment. Recurrence-free survival (RFS) was the primary end-point defined as the time interval between SBRT and biochemical failure. Biochemical failure was defined as 2 consecutive elevations of PSA with last dosage superior to PSA dosage before treatment, or clinical failure. PSA value before SBRT, location of metastases, number of lesions treated, concomitant androgen deprivation therapy were analyzed to identify pronostic factors of poor response to SBRT. Results: With a median follow-up from time of SBRT of 12 months, we treated 40 patients and 56 metastatic lesions, with a local-control rate of 85%. 19 patients were treated for 1 to 3 bone lesions and 21 patients for 1 to 3 node lesions. 8 patients with bone oligometastases and 13 patients with node oligometastases had a recurrence (p=0.55). The main sites of failure after SBRT were lymph nodes only (7 ; 33%), bone only (7 ; 33 %), and synchronous node and bone (4 ; 19%). A 2nd and 3rdcourse of radiotherapy was delivered in 8 and 1 patients. Median RFS was 345 days (134-426) in the node SBRT group and 494 days (85-877) in the bone SBRT group (p=0.27). On bivariate analysis, a PSA nadir up to 0.51 ng/mL after SBRT was identified as a pronostic factor of a worse RFS (p=0.0038). This result was not confirmed in multivariate analysis (p=0.87). Conclusions: SBRT for node oligometastases showed a non significant lower rate of RFS when compared to SBRT in bone oligometastases. A larger cohort with a longer follow up is needed to determine whether node and bone oligometastases have similar outcomes after SBRT.

The Clinical Impact of Solid and Micropapillary Patterns in Resected Lung Adenocarcinoma

IntroductionSince the new adenocarcinoma (ADC) classification was presented in 2011, several authors have reported that patients with solid (S) and/or micropapillary (MP) predominant patterns showed a worse prognosis. On the other hand, there are several patients who have S and/or MP patterns even if their patterns are not predominant. However, the evaluation of these patients is uncertain. MethodsA total of 531 ADCs were examined. We classified the patients into five subgroups according to the proportion of S and/or MP patterns: (1) both patterns absent (S–/MP–), (2) S predominant (S pre), (3) MP predominant (MP pre), (4) S pattern present although not predominant and MP pattern absent (S+ not pre/MP–), and (5) MP pattern present although not predominant (MP+ not pre). ResultsOf the 531 ADCs, 384 (72.3%) were classified as S–/MP–, 55 (10.4%) as S pre, 11 (2.1%) as MP pre, 42 (7.9%) as S+ not pre/MP–, and 39 (7.3%) as MP+ not pre. In a univariate analysis, the recurrence-free survival (RFS) and overall survival differed significantly among the five subgroups (p < 0.01 and p < 0.01, respectively). In a multivariate analysis, patients with S–/MP– had significantly higher RFS rates than did those with other subgroups. On the other hand, patients with MP pre had lower RFS rates than did those with other subgroups. ConclusionPatients with S and/or MP patterns have a poorer prognosis even if their patterns are not predominant. The S and/or MP patterns must be treated at the time of diagnosis.

The association between preoperative serum C-reactive protein and hepatocellular carcinoma recurrence in patients with chronic hepatitis B virus (HBV) infection--a retrospective study.

The prognosis of the patients with hepatocellular carcinoma (HCC) recurrence following curative hepatectomy is usually dismal. Whether preoperative serum C-reactive protein (CRP) can predict the recurrence of HCC in patients with chronic HBV infection is not clear. Total 232 patients with chronic HBV infection were included in this retrospective study. We investigated the association between detailed preoperative serum CRP levels and early (≤ 2 year) and late (> 2 year) HCC recurrence following curative hepatectomy. After adjusting for potential confounders, we found a saturation effect for preoperative serum CRP of 2.1 mg/dl existed for early HCC recurrence (ER). The incidence of ER increased with preoperative serum CRP less than 2.1 mg/dl (OR = 3.5, 95% CI 1.6–7.6, P = 0.001), and higher preoperative serum CRP (>2.1 mg/dl) did not increase the incidence of ER (OR = 0.8, 95% CI 0.2–2.7, P = 0.703). Whereas there is a linear relationship between preoperative serum CRP and late HCC recurrence (LR) (OR = 0.2, 95% CI, 0.1- 0.4) (OR = 1.8, 95% CI, 1.2–2.5, P = 0.002). In addition, the optimal cutoff point for serum CRP level was 1.5 mg/dl, instead of 1.0 mg/dl, in predicting both ER and LR. Patients with higher preoperative serum CRP level (>1.5 mg/dl) had lower recurrence free survival rates and overall survival rates (P<0.01). These results suggest that preoperative serum CRP played different roles on ER and LR following curative hepatectomy, thus further predictingthe prognosis in patients with chronic HBV infection.