Shorter Recurrence-free Survival Research Articles

Predicting Metastatic Potential in Pheochromocytoma and Paraganglioma: A Comparison of PASS and GAPP Scoring Systems.

The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP) are scoring systems to predict metastatic potential in pheochromocytomas (PCC) and paragangliomas (PGLs). The goal of this study is to assess PASS and GAPP as metastatic predictors and to correlate with survival outcomes. The cohort included PCC/PGL with ≥5 years of follow-up or known metastases. Surgical pathology slides were rereviewed. PASS and GAPP scores were assigned. Univariable and multivariable logistic regression, Kaplan-Meier survival analysis, and Cox proportional hazards were performed to assess recurrence-free survival (RFS) and disease-specific survival (DSS). From 143 subjects, 106 tumors were PCC and 37 were PGL. Metastases developed in 24%. The median PASS score was 6.5 (interquartile range [IQR]: 4.0-8.0) and median GAPP score was 3.0 (IQR: 2.0-4.0). Interrater reliability was low-moderate for PASS (intraclass correlation coefficient [ICC]: 0.6082) and good for GAPP (ICC 0.7921). Older age (OR: 0.969, P = .0170) was associated with longer RFS. SDHB germline pathogenic variant (OR: 8.205, P = .0049), extra-adrenal tumor (OR: 6.357, P < .0001), Ki-67 index 1% to 3% (OR: 4.810, P = .0477), and higher GAPP score (OR: 1.537, P = .0047) were associated with shorter RFS. PASS score was not associated with RFS (P = .1779). On Cox regression, a GAPP score in the moderately differentiated range was significantly associated with disease recurrence (HR: 3.367, P = .0184) compared with well-differentiated score. Higher GAPP scores were associated with aggressive PCC/PGL. PASS score was not associated with metastases and demonstrated significant interobserver variability. Scoring systems for predicting metastatic PCC/PGL may be improved by incorporation of histopathology, clinical data, and germline and somatic tumor markers.

Relationship between post-void residual urine volume, preoperative pyuria and intravesical recurrence after transurethral resection of bladder carcinoma.

To evaluate the relationship between residual urine volume, pyuria and bladder carcinoma recurrence. The clinical data of 305 patients who had post-void residual urine volume measured and preoperative pyuria were retrospectively collected. The patients were classified into three risk groups based on the presence of residual urine and pyuria: good (negative residual urine and pyuria), intermediate (positive residual urine or pyuria) and poor (positive residual urine and pyuria). Predictive factors for intravesical recurrence-free survival were statistically analyzed using Cox proportional hazard models and Kaplan-Meier methods. The propensity score matching method was used to adjust the patients' backgrounds. The median follow-up period for all patients was 44months. The presence of residual urine (P=0.0164) and pyuria (P=0.0233) were two independent prognostic factors for recurrence. After patients were classified into risk groups, the poor-risk group showed significantly shorter recurrence-free survival compared with that of the good- (P=0.0002) and intermediate-risk groups (P=0.0090). Even after matching, the presence of residual urine was related to short recurrence-free survival in male patients (P=0.0012). When stratified by European Organization for Research and Treatment of Cancer risk groups, the presence of pyuria was related to short recurrence-free survival, especially for intermediate-risk patients without bacillus Calmette-Guérin treatment. Post-void residual urine and preoperative pyuria are two risks for recurrence-free survival in non-muscle-invasive bladder cancer.

Overexpression of chitinase-3-like protein 1 is associated with structural recurrence in patients with differentiated thyroid cancer.

We previously identified that the expression of chitinase-3-like protein 1 (CHI3L1) was upregulated during thyroid cancer progression. Here, we investigated the prognostic significance of CHI3L1 expression in thyroid neoplasms and examined the potential oncogenic roles. CHI3L1 immunochemical staining was performed on tissue microarrays of benign and malignant thyroid tumours. Compared with normal thyroid tissue and benign thyroid lesions that had low or no detectable CHI3L1 expression, CHI3L1 was overexpressed in both differentiated and undifferentiated thyroid cancer. High CHI3L1 expression was associated with extrathyroidal extension, lymph node metastasis, and shorter recurrence-free survival in differentiated thyroid cancer. The biological roles of CHI3L1 were further investigated by gain- and loss-of-function assays. CHI3L1 silencing suppressed clonogenicity, migration, invasion, anoikis resistance, and angiogenesis in thyroid cancer cells, although exogenous CHI3L1 treatment promoted these malignant phenotypes. Cysteine-rich angiogenic inducer 61 (CYR61) was identified as a downstream target of CHI3L1 by RNA-seq analysis. CYR61 silencing or treatment reversed the alterations induced by CHI3L1 modulation. Our results demonstrate that CHI3L1 is overexpressed in thyroid cancer and is associated with an increased risk of disease recurrence. Additionally, CYR61 may participate in CHI3L1-mediated tumour progression. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Predictive Effectiveness of the Glasgow Prognostic Score for Gastrointestinal Stromal Tumors

The aim of this study was to evaluate the significance of the Glasgow prognostic score (GPS) in patients with resected gastrointestinal stromal tumors (GISTs). Forty-six GIST patients who underwent radical resection between January 2004 and December 2011 were enrolled in this retrospective study. The clinicopathological parameters examined included predictors of recurrence-free survival (RFS). Univariate and multivariate analysis of prognostic factors related to RFS were calculated using Cox proportional hazards model. The GPS classification system revealed 37 (80.4%), 6 (13.1%), and 3 (6.5%) patients with a GPS of 0, 1, and 2, respectively. Patients with GPS 1/2 had a significantly shorter RFS compared to those with GPS 0 (P = 0.01). The 3- and 5-year RFS rates for patients with GPS 0 were 94.0% and 90.9%, respectively, compared to 66.7% and 53.3%, respectively, for patients with GPS 1/2. Univariate analyses indicated that tumor size (P < 0.01), mitotic rate (P < 0.01), higher GPS (P < 0.01), and platelet count (P = 0.04) were prognostic factors for RFS; tumor size (P = 0.01) and GPS (P = 0.04) were independent prognostic factors in multivariate analysis. Preoperative high GPS were predictors of long-term prognosis in patients with resected GISTs.

The loss of nuclear expression of single-stranded DNA binding protein 2 of gastric adenocarcinoma and its prognostic role: Analysis of molecular subtype

Single-stranded DNA binding protein 2 (SSBP2) is ubiquitously expressed, with several studies reporting it to be a tumor suppressor. We investigated SSBP2 expression and its clinicopathological significance in gastric cancer. SSBP2 expression was examined by immunohistochemistry in 539 gastric cancer sections. The cases were divided into three subtypes, namely, Epstein–Barr virus-associated (EBV), microsatellite unstable, and others (microsatellite stable and EBV negative), based on the molecular classification of The Cancer Genome Atlas (TCGA). Cases were also divided into two subgroups according to the amplification status of human epidermal growth factor receptor 2 (HER2). Most cases showed SSBP2 positivity, and only 24 (4.5%) cases displayed negative nuclear expression. Loss of nuclear expression correlated significantly with high pT category (P = 0.001), nodal metastasis (P = 0.002), and stage of progression (P = 0.005), with no correlation between molecular characteristics and SSBP2 expression. All HER2 amplification cases displayed positive SSBP2 expression. Negative SSBP2 cases showed significantly shorter recurrence-free survival (RFS) compared to positive SSBP2 cases (P = 0.008). Loss of nuclear expression of SSBP2 was significantly associated with shorter RFS in the microsatellite stable and EBV negative groups (P = 0.002), as well as the HER2 negative group (P = 0.007). However, there were no statistically significant differences in multivariate analyses. Loss of nuclear expression of SSBP2 was a poor prognostic factor, associated with stage of progression and recurrence, and showed no significant difference in molecular characteristics, including TCGA subtype and HER2 status.

Clinical Significance of Trk Receptor Expression as a New Therapeutic Target in Hepatocellular Carcinoma.

Oncogenic fusion of the tropomyosin receptor kinase (Trk) receptor family encoded by the NTRK gene has been found in several carcinomas. About ten targeted therapies have been developed and clinical trials are in progress. However, the results of studies on expression of the Trk receptor in HCC have not yet been published. Immunohistochemical staining was performed using anti-TrkA+B+C antibody (ab181560, Abcam) in 288 curatively resected primary HCC samples, and the correlation between Trk expression and NTRK copy number was assessed. Targeted next generation sequencing was performed in cases with Trk overexpression to detect NTRK fusion genes. Overexpression of Trk protein was observed in 21 (7.3%) of 288 cases. The Trk overexpression group showed a trend toward shorter recurrence-free survival (RFS) (p = 0.092) and overall survival (OS) (p = 0.079) than the low expression group, with frequent multicentric occurrence. Differences in RFS and OS were statistically significant in specific sub-populations including AJCC T1 stage HCCs, tumors less than 5cm, patients without cirrhosis, tumors without vascular invasion, or Edmondson grades I and II. Trk expression was also an independent prognostic factor in both RFS and OS. Trk expression was not associated with copy number of each NTRK gene, and NTRK fusion was not detected in HCCs with Trk overexpression. Trk expression might play an important role in the development and progression of HCC, and emerging target therapy against the Trk protein could be applicable in patients with Trk-overexpressing HCC.

Identification of Key Differentially Expressed Transcription Factors in Glioblastoma.

Glioblastoma (GBM) is the most frequent malignant brain tumor in adults. Our study focused on uncovering differentially expressed genes (DEGs) and their methylation in order to identify novel diagnostic biomarkers and potential treatment targets. Using GBM RNA-sequencing data from The Cancer Genome Atlas (TCGA) database, DEGs between GBM samples and paracancer tissue samples were analyzed. Enrichment analysis for DEGs and transcription factors (TFs) was performed. A total of 1029 upregulated genes and 1542 downregulated genes were identified, which were associated mainly with multiple tumor-related and immune-related pathways such as cell cycle, mitogen-activated protein kinase signaling pathway, leukocyte transendothelial migration, and autoimmune thyroid disease. These DEGs were enriched for 174 TFs, and six TFs were differentially expressed and identified as key TFs in GBM: HOXA3, EN1, ZIC1, and FOXD3 were upregulated, while HLF and EGR3 were downregulated. A total of 1978 DEGs were involved in the regulatory networks of the six key differentially expressed TFs. High expression of EN1 was associated with shorter overall survival, while high expression of EGR3 was associated with shorter recurrence-free survival. The six TFs were differentially methylated in GBM samples compared with paracancer tissues. Our study identifies numerous DEGs and their associated pathways as potential contributors to GBM, particularly the TFs EN1, EGR3, HOXA3, ZIC1, FOXD3, and HLF. The differential expression of these TFs may be unlikely driven by aberrant methylation. These TFs may be useful as diagnostic markers and treatment targets in GBM, and EN1 and EGR3 may have predictive prognostic value.

Prognostic Significance of Circulating CD28 Negative Suppressor T Cells and Memory B Cells in Patients with Breast Cancer.

It has been suggested that routine assessment and quantification of different lymphocyte subsets can provide clinically meaningful prognostic information in breast cancer (BC). To determine the relationship between peripheral blood lymphocyte subsets and pathological parameters and response to therapy in patients with BC. Thirty patients with operable breast cancer treated surgically with either modified radical mastectomy or breast conservative surgery, and 20 healthy controls were included. For detection of lymphocyte subsets in peripheral blood; Fluorochrome-labeled monoclonal antibodies were used andcells were analyzed by flow cytometry. Patients were treated with chemotherapy, radiotherapy and hormonal treatment, and followed up to determine relapse and recurrence-free survival (RFS). Significant differences were found in the frequencies of B, T, NK, NKT, and CD28‒T cells between patients with BC and controls. Moreover, a significant difference was found in the percentage of CD8+CD28‒ T cells between patients with different pathologic subtypes of BC and negative correlations were observed between the frequency of CD8+CD28‒T cells and memory B cells, and RFS. Also, a significant difference in the frequency of naïve B cells was found in patients with different tumor grades and a negative correlation was found between the frequencies of B cells and NKT cells. NK, NKT, lymphocytes, and CD28‒ T cells significantly differed between healthy controls and BC patients. Also, memory B cells were associated with good response to treatment while CD28‒ T cells were associated with shorter RFS.

SRC-homology 2 domain-containing phosphatase 2 (SHP2) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD).

9540 Background: Epidermal growth factor (EGFR)-mutant lung adenocarcinomas (LUADs) display impaired phosphorylation of extracellular signal-regulated kinase (ERK) and SRC-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. However, the function of SHP2 in early EGFR-mutant LUADs and EGFR wild-type LUADs has not been reported. We posit that SHP2 mRNA expression could be a predictive marker in resected EGFR-mutant LUADs versus EGFR wild-type patients (pts). Methods: We examined 267 resected LUADs from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1 and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction (PCR). EGFR mutant cell lines were investigated for their activity of SHP2. Results: Among the 267 enrolled pts, 100 (37.3%) were EGFR-mutant LUADs. Five-year recurrence-free survival (RFS) and overall survival (OS) were lower for EGFR-mutant LUADs with high SHP2 mRNA levels (hazard ratio = 1.83 and 2.28, respectively. p = 0.03 and p = 0.04). However, SHP2 was not associated with RFS nor OS in the 167 wild-type EGFR LUADs. In EGFR-mutant cells, RMC-4550 (SHP2 inhibitor) plus erlotinib showed synergism via inhibition of AKT (S473) and ERK1/2 (T202/Y204). While erlotinib translocates SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocalizes SHP2 into the cytoplasm membrane, limiting AKT and ERK activation. Conclusions: High SHP2 mRNA is related to shorter RFS and OS in EGFR-mutant LUADs, but not in EGFR wild-type LUADs. The findings indicate that the addition of SHP2 inhibitors could improve adjuvant therapy in EGFR-mutant LUADs.

Elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis of patients with primary gastrointestinal stromal tumor

BackgroundThe neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are considered to reflect the systemic inflammatory response and clinical prognosis. However, the independent prognostic values of the NLR and PLR for patients with gastrointestinal stromal tumor (GIST) remain debatable. This study aims to evaluate the prognostic value of preoperative NLR and PLR in GIST patients.MethodsWe retrospectively reviewed all GIST patients diagnosed and surgically treated at Union Hospital between 2005 and 2018. The preoperative NLR and PLR were calculated to evaluate recurrence-free survival (RFS) and overall survival (OS) by Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were performed to estimate the independent prognostic values.ResultsThe median follow-up time was 49 months (interquartile range, 22–74 months). The preoperative PLR was significantly increased in the GIST patients with intermediate and high tumor risks. Increases in the NLR (≥2.34) and PLR (≥185.04) were associated with shorter RFS and OS (P < 0.01). Moreover, the multivariate analysis revealed that elevated PLR was an independent factor for shorter RFS (hazard ratio [HR]: 3.041; 95% confidence interval [CI]: 2.001–4.622; P < 0.001) and OS (HR: 1.899; 95% CI: 1.136–3.173; P = 0.014).ConclusionsThe preoperative PLR is a potential biomarker of GIST and is related to the clinical outcome. An elevated preoperative PLR predicts poor prognosis of patients with primary GIST after complete surgical resection.

Frailty is an independent risk factor for recurrence and mortality following curative resection of stage I-III colorectal cancer.

AimWith population aging, the number of frail patients with colorectal cancer has increased. The Clinical Frailty Scale (CFS) is a validated tool for assessing frailty, and higher scores indicate worse clinical outcomes following cardiovascular procedures. This retrospective study aimed to examine preoperative frailty in relation to recurrence and mortality following curative resection of colorectal cancer.MethodsWe retrospectively analyzed data for 729 consecutive patients undergoing curative resection of stage I–stage III colon and rectal adenocarcinoma between January 2009 and December 2016. Frailty was assessed using the CFS: 1 (very fit) to 9 (terminally ill), and frailty was defined as CFS ≥ 4. Recurrence‐free survival (RFS) and overall survival (OS) were compared between frail and nonfrail patients. Cox proportional hazards model was used to calculate hazard ratios (HRs), controlling for potential confounders.ResultsCFS score was negatively correlated with the Barthel index of activities of daily living (Spearman's ρ = −0.83). Of the 729 patients, 253 (35%) were frail. In multivariable analyses adjusting for potential confounders including age and disease stage, frailty was independently associated with shorter RFS (multivariable HR: 1.70, 95% confidence interval: 1.25‐2.31, P < .001) and OS (multivariable HR: 2.04, 95% confidence interval: 1.40‐2.99, P < .001). There were no significant interactions of frailty with age and disease stage regarding RFS and OS (P interaction > .72).ConclusionPreoperative frailty was independently associated with shorter RFS and OS following resection of nonmetastatic colorectal cancer, regardless of age and disease stage. Further trials are needed to establish treatment strategies for frail patients with colorectal cancer.

Tumor-Infiltrating Neutrophils Predict Poor Survival of Non-Functional Pancreatic Neuroendocrine Tumor.

This study retrospectively characterized the immune infiltrating profile in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs). Tumor tissues from the 109-patient Fudan cohort and a 73-patient external validation set were evaluated by immunohistochemistry for 9 immune cell types: tumor-infiltrating neutrophils (TINs), tumor-associated macrophages (TAMs), CD11c+ dendritic cells, anti-NCR1+ natural killer (NK) cells, CD4+ and CD8+ T cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells (Tregs), and CD20+ B cells. TINs were primarily distributed in the intratumoral area, dendritic cells and NK cells were scattered evenly in intratumoral and stromal areas, and Tregs were rarely detected. The remaining 5 cell types were primarily present in peritumoral stroma. Total TINs (P < .001) and TAMs (P = .002) increased as NF-PanNET grade rose. Kaplan-Meier analyses showed that high intratumoral TINs, total TAMs, and stromal CD4+ T-cell infiltration correlated with shorter recurrence-free survival (RFS, P = .010, P = .027, and P = .035, respectively) and overall survival (OS, P = .017, P = .029, and P = .045, respectively). Additionally, high intratumoral CD8+ T cell infiltration correlated with prolonged RFS (P = .039). Multivariate Cox regression demonstrated that intratumoral TINs, World Health Organization (WHO) classification, and eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8th TNM) were independent factors for RFS (P = .043, P = .023, and P = .029, respectively), whereas intratumoral TINs and WHO classification were independent factors for OS (P = .010 and P = .007, respectively). Furthermore, the combination of TINs, WHO classification, and AJCC8th TNM remarkably improved prognostic accuracy for RFS. These results have been verified in the external validation set. Intratumoral TINs are an independent and unfavorable predictor of postoperative NF-PanNETs. A combination of TINs, WHO classification, and AJCC8th TNM could improve prognostic accuracy for RFS.

Postoperative C-reactive protein/albumin ratio is a biomarker of risk of recurrence and need for adjuvant chemotherapy for stage III colorectal cancer.

Adjuvant chemotherapy is generally recommended for patients with stage III colorectal cancer. Even with adjuvant chemotherapy, 20-30% of such patients develop recurrences; the risk factors for recurrence are currently unclear. The preoperative systemic inflammation index has been linked to poor prognoses in patients with colorectal cancer; however, the relationship between postoperative systemic inflammation index and recurrence is unclear. We aimed to evaluate the association between preoperative and postoperative systemic inflammation indexes and recurrence in patients with stage III colorectal cancer. The following laboratory data of 133 patients with stage III colorectal cancer were analyzed: preoperative and postoperative C-reactive protein/albumin ratios (CAR); neutrophil to lymphocyte ratios (NLR); and platelet to lymphocyte ratios (PLR) and their relationships with recurrence analyzed. The optimal cutoff values for systemic inflammation indexes were determined by examining receiver operating characteristic curves. Multivariate analyses indicated that N-stage, postoperative complications, preoperative NLR, and postoperative CAR were independent predictors of recurrence-free survival (RFS). Postoperative CAR was also an independent predictor of overall survival (OS). Patients with postoperative CAR ≥ 0.035 who did not receive adjuvant chemotherapy had shorter RFS and OS than those who did. There were no significant differences in RFS and OS between patients with postoperative CAR < 0.035 who did and did not receive adjuvant chemotherapy. Postoperative CAR is strongly associated with poor prognosis in patients with stage III colorectal cancer and is a useful biomarker for determining whether adjuvant chemotherapy should be administered.

Synaptopodin-2 promotes hepatocellular carcinoma metastasis via calcineurin-induced nuclear-cytoplasmic translocation.

Hepatocellular carcinoma (HCC), a type of malignant liver tumor, has a grim prognosis. As a functional protein, synaptopodin-2 (SYNPO2) has been associated with malignancy; however, the expression profile and function of SYNPO2 in HCC remains unknown. Herein, we revealed that SYNPO2 was transcriptionally downregulated in HCC tissues from both The Cancer Genome Atlas cohort and our cohort, and was also decreased at the translational level as determined by western blotting and immunohistochemical staining. Furthermore, reduced SYNPO2 expression correlated significantly with short overall survival and recurrence free survival of HCC patients. Restoring SYNPO2 expression inhibited the proliferation and aggressiveness of hepatocarcinoma cells. Mechanistically, increasing the ratio of cytoplasmic SYNPO2 to nuclear SYNPO2 was positively associated with recurrence rate in HCC patients; calcineurin (CaN) activity positively correlated with cytoplasmic SYNPO2 levels in HCC tissues; and nuclear-cytoplasmic translocation of SYNPO2 was induced by CaN to facilitate metastasis of HCC through assembly of peripheral actin bundles. In short, our findings uncover a novel role of SYNPO2 in HCC metastasis via the CaN/SYNPO2/F-actin axis, and indicate that SYNPO2 may serve as a possible prognostic marker and novel therapeutic target.

Overexpression of SLC6A1 associates with drug resistance and poor prognosis in prostate cancer

BackgroundSolute Carrier Family 6 Member 1 (SLC6A1) has been identified as a cancer-promoting gene in various human cancers, such as clear cell renal cell carcinoma and ovarian cancer. However, its roles in prostate cancer (PCa) has not been fully elucidated. The aim of this study was to investigate the expression and clinical significance of SLC6A1 in PCa tissues and its effect on drug resistance to docetaxel in PCa.MethodsExpression patterns of SLC6A1 protein in PCa tissues were examined by immunohistochemistry based on Tissue microarray. Associations of SLC6A1 protein expression with various clinicopathological features and patients’ prognosis of PCa were also statistically evaluated based on TCGA data. Roles of SLC6A1 deregulation in prostate carcinogenesis and drug resistance was further determined in vitro and in vivo experiments.ResultsBased on TCGA Dataset, SLC6A1 expression was markedly higher in patients with high Gleason score, advanced clinical stage and positive biochemical recurrence than those with control features (all P < 0.05). Both unvariate and multivariate analyses demonstrated that SLC6A1 expression was significantly associated with biochemical recurrence-free survival in PCa patients. In addition, enforced expression of SLC6A1 effectively promoted cell proliferation, migration and invasion of PCa cells in vitro. Moreover, the inhibition of SLC6A1 suppressed the tumor growth in vivo. Additionally, immunohistochemical notches of PCNA and MMP-9 in the low-expression cluster were pointedly lower compared to those of NC group. Finally, the cell viability revealed that the overexpression of SLC6A1 obviously promoted the PCa cell resistant to docetaxel (DTX), and the transplanted tumor in the overexpression group had no significant reduction compared with the untreated group.ConclusionsOur data suggest that SLC6A1 overexpression may be associated with aggressive progression and short biochemical recurrence-free survival of PCa, and may be related to the resistance to docetaxel therapy.

Risk factors for short recurrence-free survival after resection of pancreatic neuroendocrine tumor (PanNET) liver metastases: which patients should undergo resection?

Background: In the treatment of metastatic pancreatic neuroendocrine tumors (PanNETs), surgical resection is the first choice if curative resection is expected. However, most patients develop recurrence after resection of liver metastasis. Because one of the benefits of resection is to gain a tumor-free period for the patients, it is important to identify which patients achieve longer recurrence-free survival (RFS) by resection. In this study, the clinicopathological factors associated with RFS after resection of metastatic PanNETs in the liver were evaluated to identify the patient group that is suitable for resection.Methods: Consecutively diagnosed patients with PanNET liver metastasis with resection at our hospital from January 2000 to July 2019 were evaluated. A total of 26 metastatic PanNET patients with primary liver resections were evaluated. The median follow-up time was 48.3 months.Results: There were 18 NET recurrences of the total 26 resections, with a median RFS of 17.9 months. Independent risk factors for short RFS were a high Ki67 index (p = .009) and the number of resected tumors (p = .045). When the cut-off value for the Ki67 index was 5.0% and that for the number of resected tumors was 6, Ki67 > 5.0% tumors had shorter RFS (4.9 months vs. 38.2 months p = .006), and patients with tumors > = 7 tumors had shorter RFS (4.7 months vs. 27.5 months p = .001).Conclusions: These findings indicate that good candidates for resection of metastatic tumors of PanNETs could be patients with low Ki67 tumors and a small number of metastatic tumors.

Immune phenotype and histopathological growth pattern in patients with colorectal liver metastases

BackgroundPatients with desmoplastic (angiogenic) histopathological growth pattern (HGP) colorectal liver metastases (CLM) might derive more benefit from bevacizumab-based chemotherapy than those with replacement (non-angiogenic) HGP. This study investigated the association of HGP with the immune phenotype (IP) and clinical outcome after liver resection.MethodsCLM of patients treated with perioperative bevacizumab-based chemotherapy and liver resection were investigated. Association of HGP and IP with response, recurrence-free survival (RFS) and overall survival (OS) was investigated.ResultsOne hundred and eighteen patients (M/F 66/52, median age 62.3 (31.0–80.4) years, median follow-up 32.2 (5.0–92.7) months) were enrolled. The inflamed IP was associated with the desmoplastic HGP. The desmoplastic HGP was associated with better radiological and histological response compared to the replacement HGP, respectively. The replacement HGP was associated with shorter RFS (8.7 versus 16.3 months, HR 2.60, P = 0.001) and OS (36.6 months versus not reached, HR 2.32, P = 0.027), respectively. The non-inflamed IP was associated with shorter RFS (10.8 versus 16.5 months, HR 1.85, P = 0.029). The HGP but not the IP remained significant in multivariable analysis for RFS.ConclusionsThe desmoplastic HGP is associated with the inflamed IP and HGP may be a potential biomarker for adjuvant treatment that includes targeting the immune contexture.

Lower airway bacterial microbiome may influence recurrence after resection of early-stage non–small cell lung cancer

ObjectiveThe lower airway bacterial microbiome influences carcinogenesis and response to immunotherapy in non–small cell lung cancer (NSCLC). We investigated the association of this microbiome with recurrence in early NSCLC. MethodsMicrobiomes of presurgery bronchoalveolar lavage (BAL) and saliva, and resected stage I NSCLC tumor and adjacent lung tissues of 48 patients were examined by 16S gene sequencing. Tumor gene expression was measured by RNA sequencing. ResultsSpatial relationships of the different biospecimen types was reflected in their microbiomes, with microbiomes of BAL intermediate to those of saliva and lung tissue. BAL and saliva microbiomes were less dissimilar in patients with high α-amylase levels in BAL, indicating oral aspiration as a source of lower airway microbiota. BAL microbiomes of patients with recurrence within 32 months of surgery differed from those without recurrence during ≥32 months of follow-up (n = 18 each), despite no difference for age, sex, smoking history, and tumor histology and grade. The recurrence-associated BAL microbiome signature was present in 16 of the 18 recurrence cases but in only two of the others. Signature presence was associated with shorter recurrence-free survival (log-rank test P < .001; hazard ratio = 14.5), and greater expression in tumors of genes for cell proliferation and epithelial mesenchymal transition. Immune cellular composition of the tumor microenvironment was not different between patients with and without the signature. ConclusionsPresurgery composition of lower airway microbiome may be associated with recurrence of early NSCLC. This association may reflect an influence of the microbiome on tumor biology.

The prognostic value of the urokinase-plasminogen activator system (uPA) in bladder cancer patients treated with radical cystectomy (RC)

PurposeUrokinase-plasminogen activator (uPA), its receptor (uPAR), and the plasmin-activator inhibitor type 1 (PAI-1) have been associated with oncologic outcomes in various malignancies and could help identify bladder cancer (BC) patients treated with radical cystectomy (RC) who are likely to benefit from intensification of therapy to prevent disease progression. Our aim was to assess the value of uPA, uPAR, and PAI-1 for prognosticating survival outcomes of patients treated with RC for BC. Materials and methodsTumor specimens from 272 consecutive patients treated with RC for advanced BC were assessed with immunohistochemical staining for uPA, uPAR, and PAI-1. Overexpression was assessed by pathological image analysis. Kaplan-Meier estimates and multivariable Cox-regression were used to analyze survival. Harrell's C-index was used to assess for clinical impact of the uPA system. ResultsuPA, uPAR, and PAI-1 were overexpressed in 48.2%, 51.1%, and 52.2% of patients, respectively. uPA overexpression was associated with lymphovascular invasion (P = 0.034) and nodal status (P = 0.013); PAI-1 overexpression was associated with primary muscle-invasive BC (P = 0.015) and lymphovascular invasion (P = 0.024). uPA, uPAR, and the number of overexpressed markers were all 3 significantly associated with shorter overall recurrence-free-, distant recurrence-free-, and cancer-specific survival. In multivariable analyses, uPA overexpression remained associated with shorter recurrence-free survival (hazard ratio [HR] = 1.79; P = 0.036) in the entire cohort, in patients without lymph node metastasis (HR = 1.98; P = 0.018) and those with nonorgan-confined disease (HR = 1.98; P = 0.022). uPAR overexpression was associated with shorter recurrence-free survival in patients without lymph node metastasis (HR = 2.01; P = 0.021) and those with organ-confined disease (HR = 4.11; P = 0.037). ConclusionMembers of the uPA system are associated with features of biologically aggressive BC and oncologic outcomes. However, their value beyond currently available information remains limited.

Comparison of outcomes following segmentectomy or lobectomy for patients with clinical N0 invasive lung adenocarcinoma of 2cm or less in diameter.

Previous studies have reported similar survival between segmentectomy and lobectomy for patients with small-sized non-small cell lung cancer. However, part of those patients were with adenocarcinoma in situ or minimally invasive adenocarcinoma, which were considered to have a favorable prognosis. We compared survival outcomes of patients with clinical N0 invasive lung adenocarcinomas of no more than 2cm who underwent segmentectomy or lobectomy. Between June 1, 2008, and May 31, 2018, 1018 patients with clinical N0 invasive lung adenocarcinomas of no more than 2cm in diameter on thin-section chest CT scans were retrospectively included in this study. Of them, 214 underwent segmentectomy and 804 underwent lobectomy. Propensity-score matching of preoperative factors, such as gender, age, smoking status, forced expiratory volume in 1 s predicted%, tumor's CT appearance, tumor size on CT scan and tumor location was used to compare survival outcomes of those patients receiving different surgical treatments. Cox proportional hazard regression model was used to identify independent prognostic factors. This study was approved by the Committee for Ethical Review of Research (Fudan University Shanghai Cancer Center IRB# 090977-1). Informed consent was waived because of the retrospective nature of this study. Average follow-up time was 42.5months. Before matching, the lobectomy group had a shorter recurrence-free survival (P = 0.02), but similar overall survival (P = 0.60). After matching, no significant difference of overall survival or recurrence-free survival was found between the two groups (P = 0.70 and P = 0.40, respectively). Our results suggest that segmentectomy achieved similar recurrence-free and overall survival compared with lobectomy for patients with clinical N0 invasive lung adenocarcinomas of no more than 2cm. Therefore, segmentectomy could be an alternative approach. These results need to be further validated by randomized trials.