CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

Bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide. Although there are several well-established molecular and immunological classifications, markers for tumor cells and immune cells that are associated with prognosis are still needed. The chemokine CC motif ligand 2 (CCL2) could be such a marker. We analyzed the expression of CCL2 by immunohistochemistry (IHC) in 168 muscle invasive BCa samples using a tissue microarray. Application of a single cut-off for the staining status of tumor cells (TCs; positive vs. negative) and immune cells (ICs; ≤6% of ICs vs. >6% of ICs) revealed 57 cases (33.9%) and 70 cases (41.7%) with CCL2-positive TCs or ICs, respectively. IHC results were correlated with clinicopathological and survival data. Positive CCL2 staining in TCs was associated with shorter overall survival (OS), disease-specific survival (DSS), and relapse-free survival (RFS) (p = 0.004, p = 0.036, and p = 0.047; log rank test) and appeared to be an independent prognostic factor for OS (RR = 1.70; p = 0.007; multivariate Cox’s regression analysis). In contrast, positive CCL2 staining in the ICs was associated with longer OS, DSS, and RFS (p = 0.032, p = 0.001, and p = 0.001; log rank test) and appeared to be an independent prognostic factor for DSS (RR = 1.77; p = 0.031; multivariate Cox’s regression analysis). Most interestingly, after separating the patients according to their lymph node status (N0 vs. N1+2), CCL2 staining in the ICs was differentially associated with prognosis. In the N0 group, CCL2 positivity in the ICs was a positive independent prognostic factor for OS (RR = 1.99; p = 0.014), DSS (RR = 3.17; p = 0.002), and RFS (RR = 3.10; p = 0.002), whereas in the N1+2 group, CCL2 positivity was a negative independent factor for OS (RR = 3.44; p = 0.019)) and RFS (RR = 4.47; p = 0.010; all multivariate Cox’s regression analyses). In summary, CCL2 positivity in TCs is a negative prognostic factor for OS, and CCL2 can mark ICs that are differentially associated with prognosis depending on the nodal stage of BCa patients. Therefore, CCL2 staining of TCs and ICs is suggested as a prognostic biomarker for BCa patients.

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Analysis of CXCL9, PD1 and PD-L1 mRNA in Stage T1 Non-Muscle Invasive Bladder Cancer and Their Association with Prognosis

Cancers ◽

10.3390/cancers12102794 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2794 ◽

Cited By ~ 1

Author(s):

Jennifer Kubon ◽

Danijel Sikic ◽

Markus Eckstein ◽

Veronika Weyerer ◽

Robert Stöhr ◽

...

Keyword(s):

Bladder Cancer ◽

Regression Analysis ◽

Prognostic Factor ◽

Patient Group ◽

Independent Prognostic Factor ◽

Invasive Bladder Cancer ◽

Immune Markers ◽

Muscle Invasive Bladder Cancer ◽

Cox's Regression ◽

Muscle Invasive

Non-muscle invasive bladder cancer (NMIBC), which is characterized by a recurrence rate of approximately 30% and very long treatment times, remains a major unresolved problem for patients and the health care system. The immunological interplay between tumor cells and the immune environment is important for tumor development. Therefore, we analyzed the mRNA of three immune markers, CXCL9, PD1 and PD-L1, in NMIBC by qRT-PCR. The results were subsequently correlated with clinicopathological parameters and prognostic data. Altogether, as expected, higher age was an independent prognostic factor for overall survival (OS) and disease-specific survival (DSS), but not for recurrence-free survival (RFS). Lower CXCL9 mRNA was observed in multivariate Cox’s regression analysis to be an independent prognostic parameter for reduced OS (relative risk; RR = 2.08; p = 0.049), DSS (RR = 4.49; p = 0.006) and RFS (RR = 2.69; p = 0.005). In addition, PD-L1 mRNA was an independent prognostic factor for DSS (RR = 5.02; p = 0.042) and RFS (RR = 2.07; p = 0.044). Moreover, in univariate Cox’s regression analysis, the stratification of patients revealed that low CXCL9 or low PD1 mRNA was associated with reduced RFS in the younger patient group (≤71 years), but not in the older patient group (>71 years). In addition, low CXCL9 or low PD-L1 was associated with shorter RFS in patients with higher tumor cell proliferation and in patients without instillation therapy. In conclusion, the characterization of mRNA levels of immune markers differentiates NIMBC patients with respect to prognosis.

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Combination of GP88 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Is an Independent Prognostic Factor for Bladder Cancer Patients

Cells ◽

10.3390/cells10071796 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1796

Author(s):

Markus Eckstein ◽

Verena Lieb ◽

Rudolf Jung ◽

Danijel Sikic ◽

Katrin Weigelt ◽

...

Keyword(s):

Bladder Cancer ◽

Prognostic Factor ◽

Tumor Cells ◽

Immune Cells ◽

Potential Candidate ◽

Poor Prognostic Factor ◽

Risk Of Death ◽

Increased Risk ◽

Muscle Invasive ◽

Disease Specific

Urothelial bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide and accounts for approximately 3% of global cancer diagnoses. We are interested in prognostic markers that may characterize tumor cells (TCs) and immune cells (ICs) and their relationship in BCa. A potential candidate marker that meets these criteria is progranulin (GP88), which is expressed separately in TCs and ICs. We analyzed GP88 expression by immunohistochemistry (IHC) in 196 muscle-invasive BCa samples using a tissue microarray. The immunoreactive score for GP88 staining in TCs and the percentage of GP88-positive ICs was determined. An easy cutoff for the staining status of TCs (positive vs. negative) and ICs (0% vs. >0%) and, more generally, negative vs. positive GP88 staining could be applied. We detected 93 patients (47.4%) and 92 patients (46.9%) with GP88-positive TCs or ICs, respectively. The IHC results were correlated with clinicopathological and survival data. Positive GP88 staining in TCs appeared to be an independent poor prognostic factor for disease-specific survival (DSS) (RR (relative risk) = 1.74; p = 0.009) and recurrence-free survival (RFS) (RR = 1.92; p = 0.002). In contrast, negative GP88 staining in ICs was an independent negative predictor for overall survival (OS) (RR = 2.18; p < 0.001), DSS (RR = 2.84; p < 0.001) and RFS (RR = 2.91; p < 0.001) in multivariate Cox’s regression analysis. When combining GP88 staining in TCs and ICs, a specific combination of GP88-positive TCs and GP88-negative ICs was associated with a 2.54-fold increased risk of death, a 4.21-fold increased risk of disease-specific death and a 4.81-fold increased risk of recurrence compared to GP88-negative TCs and GP88-positive ICs. In summary, GP88 positivity in TCs is a negative prognostic factor for DSS and RFS. In addition, GP88 positivity can mark ICs that are associated with a good prognosis (OS, DSS and RFS). The combination of GP88 staining in TCs and ICs appears to be a significant independent prognostic biomarker in muscle-invasive BCa.

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Expression of AR-V7 (Androgen Receptor Variant 7) Protein in Granular Cytoplasmic Structures Is an Independent Prognostic Factor in Prostate Cancer Patients

Cancers ◽

10.3390/cancers12092639 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2639

Author(s):

Paul König ◽

Markus Eckstein ◽

Rudolf Jung ◽

Amer Abdulrahman ◽

Juan Guzman ◽

...

Keyword(s):

Prostate Cancer ◽

Regression Analysis ◽

Androgen Receptor ◽

Prognostic Factor ◽

Cancer Biology ◽

Splice Variants ◽

Independent Prognostic Factor ◽

Cytoplasmic Granules ◽

Cox's Regression ◽

Cytoplasmic Structures

Prostate cancer (PCa) is the second most common cancer, causing morbidity and mortality among men world-wide. The expression of the androgen receptor (AR) and its splice variants is a crucial factor of prostate cancer biology that has not been comprehensively studied in PCa tumors. The aim of this study was to characterize the protein expression of the AR and its splice variant, AR-V7, and their subcellular distributions in PCa by immunohistochemistry and to correlate the results to the clinicopathological data and prognosis. Immunohistochemical staining for AR and AR-V7 was performed on a tissue microarray (TMA) with specimens from 410 PCa patients using an immunoreactive score (IRS) or only the percentage of AR-V7 staining in cytoplasmic granules. Nuclear or cytoplasmic AR staining was not associated with prognosis. AR-V7 staining was only occasionally observed in the nucleus. However, AR-V7 staining in the cytoplasm or in cytoplasmic granules was associated with relapse-free survival (RFS). AR-V7 staining of the cytoplasm was associated with a shorter RFS, whereas AR-V7 staining of cytoplasmic granules was associated with a longer RFS. In a multivariate Cox’s regression analysis, only negative (<5%) AR-V7 staining of cytoplasmic granules remained an independent prognostic factor for RFS (HR = 5.3; p = 0.006). In a further subgroup analysis by multivariate Cox’s regression analysis, AR-V7 was an independent prognostic factor in the following groups: age ≤ 65 (HR = 9.7; p = 0.029), negative CK20 staining (HR = 7.0; p = 0.008), and positive perineural invasion (HR = 3.7; p = 0.034). Altogether, AR-V7 protein in granular cytoplasmic structures is an independent prognostic factor for RFS in PCa patients.

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Comorbidity Is An Independent Prognostic Factor in AML: Comparison of Two Comorbidity Scores.

Blood ◽

10.1182/blood.v114.22.3106.3106 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3106-3106

Author(s):

Juergen Novotny ◽

Achim Aisenbrey ◽

Holger Nückel ◽

Ulrich Dührsen

Keyword(s):

Prognostic Factor ◽

Median Survival ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Risk Groups ◽

Independent Prognostic Factor ◽

Rank Test ◽

Log Rank Test ◽

Comorbidity Scores ◽

Comorbidity Index

Abstract Abstract 3106 Poster Board III-43 Objective Many factors have been studied to predict outcome and allocate treatment in AML. The best established prognostic factors are karyotype and age. However, comorbidity may play an important role in the outcome of AML. We applied two comorbidity scores at the time of first admission in order to test this hypothesis. Methods We retrospectively analysed 198 consecutive patients with AML. All patients were included irrespective of the applied therapy. Karyotype risk group was 11.6 % good, 68.0 intermediate and 20.4 % poor risk, respectively. The median survival was 382 days. The median age was 62 years (range 20 – 81), 95 were male, 103 were female. The criteria of the Charlson Comorbidity Index (CCI) and the recently developed Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) were applied. However, the cut-offs were set lower than in the original publication in order to detect the possible impact of minor comorbidity. Results In our study, the HCT-CI (left figure) separated clearly between patients with a score of more than one (dotted line), one (dashed line) and zero (continous line) (median survival: 100 vs 328 vs 718 days; log rank test p<0.0001). Similarly, the CCI separated the patients with more than one (dotted line), one (dashed line) and none (continous line) (median survival: 94 vs 293 vs 515 days; log rank test p<0.0001). Karyotype (p < 0.001), HCT-CI (p = 0.003) and age (cut-off 60 years; p = 0.006) we shown as independent risk factors by multivariate analysis. The CCI (right figure) separated only between patients with a score of zero (continous line) and those with at least one score point. Patients with one (dashed line) and patients more than one (dotted line) were not separated. Conclusions Our findings show that HCT-CI is an additional prognostic factor in AML, at least in our cohort. We extend previous findings severalfold. Firstly, our analysis includes 90 patients younger than 60 years and was not restricted to patients older than 60 years. Secondly, we directly compared two comorbidity indices, showing that the HCT-CI discriminaates between three risk groups. Thirdly, we showed that comorbidity is an independent predictor for survival. In conclusion comorbidity seems to be an independent prognostic factor and should be studied prospectively to clarify its use for stratification in therapeutic studies. Disclosures No relevant conflicts of interest to declare.

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Circulating proteasome levels are an independent prognostic factor for survival in multiple myeloma

Blood ◽

10.1182/blood-2006-04-016360 ◽

2006 ◽

Vol 109 (5) ◽

pp. 2100-2105 ◽

Cited By ~ 89

Author(s):

Christian Jakob ◽

Karl Egerer ◽

Peter Liebisch ◽

Seval Türkmen ◽

Ivana Zavrski ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factor ◽

Prognostic Significance ◽

Independent Prognostic Factor ◽

Rank Test ◽

Ubiquitinated Proteins ◽

Intracellular Degradation ◽

Log Rank Test ◽

Cycle Regulation ◽

First Time

Abstract The proteasome is a proteolytic complex for intracellular degradation of ubiquitinated proteins which are involved in cell-cycle regulation and apoptosis. A constitutively increased proteasome activity has been found in myeloma cells. We studied circulating proteasome levels and their prognostic significance in sera of 50 control subjects, 20 persons with monoclonal gammopathies of undetermined significance (MGUS), and 141 previously untreated patients with multiple myeloma (MM) by an anti-20S proteasome enzyme-linked immunoabsorbent assay (ELISA). Serum proteasome concentrations were significantly elevated in MM compared with controls (P < .001), in MM versus MGUS (P = .03), and in active (n = 101) versus smoldering (n = 40) MM (P < .001). In patients with active MM, there was a significant (P < .001) decrease from pretreatment to post-treatment proteasome concentrations in responders to chemotherapy, but not in nonresponders. Circulating proteasome levels were identified as a prognostic factor for overall survival in the univariate (P < .001 log-rank test) and in the multivariate (hazard ratio, 4.38) survival analysis in patients with active MM. We demonstrate for the first time that increased serum proteasome concentrations correlate with advanced disease and are an independent prognostic factor in MM.

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The prognostic significance of lymphatic invasion in primary melanoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.9050 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 9050-9050

Author(s):

X. Xu ◽

L. Chen ◽

W. Hwang ◽

P. Dawson ◽

D. Guerry ◽

...

Keyword(s):

Prognostic Factor ◽

Prognostic Significance ◽

Primary Melanoma ◽

Risk Groups ◽

Lymphatic Invasion ◽

Independent Prognostic Factor ◽

Rank Test ◽

Survival Curves ◽

Cox Models ◽

Log Rank Test

9050 Background: Lymphatic invasion (LI) is an under-observed phenomenon in primary malignancies that can be better detected by immunostaining and that may associate with prognosis. In this study we sought to test the hypothesis that LI was associated with melanoma-specific survival (MSS) and was an independent prognostic factor. Methods: This study included 277 patients with stage I/II melanomas in vertical growth phase (VGP) who had at least 10 years of follow up. The log-rank test was used to test the study hypothesis - 72 melanoma-specific deaths were needed for 80% power to detect an odds ratio of 2.1. Paraffin sections were stained with antibodies to podoplanin (lymphatic vessels) and S-100 (melanoma cells) to identify LI. Univariate and multivariate Cox models were used to evaluate the prognostic significance of LI. An independent cohort of 106 similar patients was used for validation of the 10-year MSS rates. Results: LI was observed in 44.5% (95% CI: 38.6% - 50.4%) of the melanomas and its presence was significantly associated with thickness, mitotic rate, gender, age, and ulceration (U). The Kaplan-Meier survival curves for those with and without LI were significantly different (log-rank test p=0.022). The final multivariate model for time to MSD identified 4 independent prognostic factors: thickness (HR=1.5, p<0.001), U (HR=2.2 p=0.013), site (HR=3.9, p<0.001) and LI (HR=1.9, p=0.015). These factors were used to define a prognostic tree with 5 risk groups defined by melanomas that were thin (≤1.0mm) with no LI or U; thin with LI but no U; 1–3mm with no U; 1–3mm with U; and >3mm. Respectively, MSS rates were 100%, 88.6%, 77%, 48% and 42%. In the validation set, observed 10-year MSS rates in each risk group were not significantly different from those predicted from the survival curves for the tree-based risk groups. Conclusions: LI is an independent prognostic factor for MSS. Among patients with thin melanomas without U the 10-year MSS was lower for those patients with LI (89%, 95% CI=78% - 99%; n=41) compared to those without (100%, n=78). LI is an important prognostic factor that needs further validation in a population of patients from the sentinel node biopsy era. No significant financial relationships to disclose.

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Extracapsular Extension of Pelvic Lymph Node Metastasis is an Independent Prognostic Factor in Bladder Cancer: A Systematic Review and Meta-analysis

Annals of Surgical Oncology ◽

10.1245/s10434-014-4359-1 ◽

2015 ◽

Vol 22 (11) ◽

pp. 3745-3750 ◽

Cited By ~ 16

Author(s):

Tae Sik Ahn ◽

Hyung Suk Kim ◽

Chang Wook Jeong ◽

Cheol Kwak ◽

Hyeon Hoe Kim ◽

...

Keyword(s):

Systematic Review ◽

Bladder Cancer ◽

Lymph Node ◽

Prognostic Factor ◽

Lymph Node Metastasis ◽

Meta Analysis ◽

Independent Prognostic Factor ◽

Extracapsular Extension ◽

Node Metastasis ◽

Pelvic Lymph Node Metastasis

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Effect of Tumor Size on Long-Term Survival After Resection for Solitary Intrahepatic Cholangiocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2020.559911 ◽

2021 ◽

Vol 10 ◽

Author(s):

Junjie Kong ◽

Yukun Cao ◽

Jiawei Chai ◽

Xihan Liu ◽

Cunhu Lin ◽

...

Keyword(s):

Regression Analysis ◽

Prognostic Factor ◽

Intrahepatic Cholangiocarcinoma ◽

Tumor Size ◽

Cox Regression ◽

Independent Prognostic Factor ◽

Rank Test ◽

Term Survival ◽

Cox Regression Analysis ◽

Size Groups

BackgroundThe relationship between tumor size and survival in intrahepatic cholangiocarcinoma (ICC) is still controversial. This study aimed to evaluate the prognostic ability of tumor size for solitary ICC after resection and explore optimal cut-off values in different subgroups.MethodsPatients with solitary ICC who underwent liver resection from the Surveillance, Epidemiology, and End Results Program and Shandong Provincial Hospital were retrospectively analyzed. Kaplan-Meier and Cox regression analysis were used to assess the prognostic ability of tumor size. The log-rank test was used to determine the optimal cut-off values, and a minimum P was regarded as the optimal one in different subgroups.ResultsLarge tumor size groups had worse overall survival (OS) than small tumor size groups. Cox regression analysis suggested that tumor size was an independent prognostic factor for OS for solitary ICC after resection. Subgroup analysis showed tumor size was associated with OS for both solitary ICC with and without vascular invasion (VI). Furthermore, the optimal cut-off values for solitary ICC with and without VI were found to be 8 and 3 cm, respectively, which could divide the patients into two groups with significant differences in OS.ConclusionTumor size was an independent prognostic factor for solitary ICC after resection. The existing American Joint Committee on Cancer (AJCC) staging system could be improved if the cut-off value of the T1 stage was changed to 8 cm and if the T2 stage incorporated a tumor size with a cut-off value of 3 cm. Further studies with more cases are needed to validate these findings.

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