Abstract
Tumor budding is defined as a single cell or a cluster of up to 5 tumor cells at the invasion front. Due to the difficulty of identifying patients at high risk for pT1 non-muscle-invasive ...bladder cancer (NMIBC) and the difficulties in T1 substaging, tumor budding was evaluated as a potential alternative and prognostic parameter in these patients. Tumor budding as well as growth pattern, invasion pattern and lamina propria infiltration were retrospectively evaluated in transurethral resection of the bladder (TURB) specimens from 92 patients with stage pT1 NMIBC. The presence of tumor budding correlated with multifocal tumors (
p
= 0.003), discontinuous invasion pattern (
p
= 0.039), discohesive growth pattern (
p
< 0.001) and extensive lamina propria invasion (
p
< 0.001). In Kaplan–Meier analysis, tumor budding was associated with significantly worse RFS (
p
= 0.005), PFS (
p
= 0.017) and CSS (
p
= 0.002). In patients who received BCG instillation therapy (n = 65), the absence of tumor budding was associated with improved RFS (
p
= 0.012), PFS (
p
= 0.011) and CSS (
p
= 0.022), with none of the patients suffering from progression or dying from the disease. Tumor budding is associated with a more aggressive and invasive stage of pT1 NMIBC and a worse outcome. This easy-to-assess parameter could help stratify patients into BCG therapy or early cystectomy treatment groups.
Introduction and objectives
Checkpoint inhibition has emerged as new therapeutic option in muscle-invasive bladder cancer. The objective of the present study was to evaluate the prognostic role of ...PD1 and PDL1 expression in non-muscle-invasive bladder cancer (NMIBC) and establish an objective measuring method using RNA quantification.
Materials and methods
We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder. mRNA expression of PD1, PDL1 and CD3 was measured by single step RT-qPCR and correlated to clinicopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS) and carcinoma-specific survival (CSS).
Results
We have analyzed 334 patients with NMIBC at stage pT1 for mRNA analysis. Data from 296 patients (79% male, median age: 72 years) could be used. Spearman correlation revealed significant associations between mRNA expressions of PD1/PDL1 (
ρ
: 0.6024,
p
< 0.0001), CD3/PDL1 (
ρ
: 0.5728,
p
< 0.0001) and CD3/PD1 (
ρ
: 0.7005,
p
< 0.0001). Kaplan–Meier analysis revealed that high PDL1 mRNA expression (≥ 33.83) is a favorable prognostic factor with regard to better RFS (
p
= 0.0018), PFS (
p
= 0.021) and CSS (
p
= 0.012). Multivariate Cox-regression analysis proved PDL1 expression to be an independent prognosticator for RFS HR 0.48 (0.31–0.72),
p
= 0.0005, PFS HR 0.45 (0.24–0.80),
p
= 0.0059 and CSS HR 0.31 (0.13–0.67),
p
= 0.0021.
Conclusion
High mRNA expression of PDL1 predicts improved RFS, PFS and CSS of pT1 NMIBC. Following prospective validation, this objective measurement of PD-L1 might help stratify patients with NMIBC for immunotherapy and identify patients who might benefit from early cystectomy.
Recently, muscle-invasive bladder cancer (MIBC) has been subclassified by gene expression profiling, with a substantial impact on therapy response and patient outcome. We tested whether these complex ...molecular subtypes of MIBC can be determined by mRNA detection of keratin 5 (
) and keratin 20 (
). Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was applied to quantify gene expression of
and
using TaqMan
-based assays in 122 curatively treated MIBC patients (median age 68.0 years). Furthermore, in silico analysis of the MD Anderson Cancer Center (MDACC) cohort (GSE48277 + GSE47993) was performed. High expression of
and low expression of
were associated with significantly improved recurrence-free survival (RFS) and disease-specific survival disease specific survival (DSS: 5-year DSS for
high: 58%; 5-year DSS for
high: 29%).
and
were associated with rates of lymphovascular invasion and lymphonodal metastasis. The combination of
and
allowed identification of patients with a very poor prognosis (
⁺/
, 5-year DSS 0%,
< 0.0001). In silico analysis of the independent MDACC cohorts revealed congruent results (5-year DSS for
low vs. high: 84% vs. 40%,
= 0.042). High
-expressing tumors as well as
⁺/
tumors were significantly enriched with aggressive urothelial carcinoma variants (micropapillary, plasmacytoid, nested).
Abstract
To determine whether Xpert bladder cancer monitor, a noninvasive PCR-based biomarker test, can predict the need for 2nd transurethral resection of the bladder (TURB) better than clinical ...assessment. Patients scheduled for TURB were prospectively screened. After initial TURB, patients were assigned to 2nd TURB or follow-up cystoscopy at 3 months (FU) by clinicians’ discretion. Central urine cytology and Xpert monitor tests were performed prior to the 1st TURB and 2nd TURB or FU, respectively. Statistical analysis to compare clinical assessment and Xpert monitor comprised sensitivity (SENS), specificity (SPEC), NPV and PPV. Of 756 screened patients, 171 were included (114 with 2nd TURB, 57 with FU). Residual tumors were detected in 34 patients who underwent 2nd TURB, and recurrent tumors were detected in 2 patients with FU. SENS and SPEC of Xpert monitor were 83.3% and 53.0%, respectively, PPV was 32.6% and NPV was 92.1%. Clinical risk assessment outperformed Xpert monitor. In patients with pTa disease at initial TURB, Xpert monitor revealed a NPV of 96%. Xpert monitor was not superior than clinical assessment in predicting the need for 2nd TURB. It might be an option to omit 2nd TURB for selected patients with pTa disease.
Stage pT1 bladder cancer (BC) shows highly diverse outcomes. Predictive markers are required to stratify patients for personalized treatment. The present study aimed to validate immune response ...quantification as a prognostic marker. Patients with pT1 BC (
= 167) treated by transurethral resection of the bladder (TURB) were enrolled. Formaldehyde-fixed paraffin-embedded material was stained for CD3 and CD8. Corresponding T cells were counted in three regions with the highest immune response. Numbers of tertiary lymphoid structures (TLS) and lymphocyte aggregates (LA) were quantified. High CD3
stroma T-cell infiltration was associated with improved survival (
= 0.045), especially in the G3 subgroup (
= 0.01). Cluster with higher immune response showed less recurrence (
= 0.034) and favorable overall survival (OS) (
= 0.019). In contrast, higher CD3
and CD8
tumor T-cell infiltration seemed to have a negative impact on prognosis. TLS and LA were more frequently observed in G3 tumors, indicating an increased anti-tumoral immune response. We proved the role of immune cell infiltration and showed that higher infiltration numbers of CD3
(not CD8
) lymphocytes in the stroma are associated with favorable outcome. Immune cell quantification could be used as a marker to help stratify patients' risk and therefore, to optimize patients' management and follow-up examination as well as possible therapies.
To study the expression pattern, localisation and potential clinical significance of aquaporin water channels (AQP) both in prostate cancer (PC) cell lines and in benign and malignant human prostate ...tissue.
The AQP transcript and protein expression of HPrEC, LNCaP, DU-145 and PC3 cell lines was investigated using reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence (IF) microscopy labelling. Immunohistochemistry (IHC) was performed to assess AQP protein expression in surgical specimens of benign prostatic hyperplasia as well as in PC. Tissue mRNA expression of AQPs was quantified by single-step reverse transcriptase quantitative polymerase chain reaction (qPCR). Relative gene expression was determined using the 40-ΔC
method and correlated to clinicopathological parameters.
Transcripts of AQP 1, 3, 4, 7, 8, 10 and 11 were expressed in all four cell lines, while AQP 9 transcripts were not detected in malignant cell lines. IF microscopy confirmed AQP 3, 4, 5, 7 and 9 protein expression. IHC revealed highly heterogeneous AQP 3 protein expression in PC specimens, with a marked decrease in expression in tumours of increasing malignancy. Loss of AQP 9 was shown in PC specimens. mRNA expression of AQP3 was found to be negatively correlated to PSA levels (ρ = - 0.354; p = 0.013), D'Amico risk stratification (ρ = - 0.336; p = 0.012), ISUP grade (ρ = - 0.321; p = 0.017) and Gleason score (ρ = - 0.342; p = 0.011).
This is the first study to systematically characterize human prostate cell lines, benign prostatic hyperplasia and PC in relation to all 13 members of the AQP family. Our results indicate the differential expression of several AQPs in benign and malignant prostate tissue. A significant correlation was observed between AQP 3 expression and tumour grade, with progressive loss in more malignant tumours. Taken together, AQPs may play a role in the progression of PC and AQP expression patterns may serve as a prognostic marker.
BackgroundAssessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to ...develop a clinically applicable immune gene expression assay to predict prognosis and adjuvant chemotherapy benefit.Patients and methodsGene expression of CD3Z, CD8A and CXCL9, immune cell (IC) populations including stromal tumor infiltrating lymphocytes (sTILs), T-cells, natural killer cells (NK-cells), macrophages, Programmed cell death protein 1 positive (PD-1) IC and tumor subtypes (MD Anderson Cancer Center/MDACC-approach) were assessed in 187 MIBC patients (Comprehensive Cancer Center Erlangen-EMN/CCC-EMN-cohort). A gene expression signature was derived by hierarchical-clustering and validated in The Cancer Genome Atlas (TCGA)-cohort. IC populations in the TCGA cohort were assessed via CIBERSORT. Benefit of platinum-containing adjuvant chemotherapy was assessed in a pooled cohort of 125 patients. Outcome measurements were disease specific survival, disease-free survival and overall survival.ResultsThe gene expression signature of CXCL9, CD3Z and CD8A correlates with quantitative amounts of specific IC populations and sTILs (CCC-EMN: ρ-range: 0.44–0.74; TCGA: ρ-range: 0.56–0.82) and allows stratification of three different inflammation levels (inflamed high, inflamed low, uninflamed). Highly inflamed tumors are preferentially basal subtype and show favorable 5-year survival rates of 67.3% (HR=0.27; CCC-EMN) and 55% (HR=0.41; TCGA). Uninflamed tumors are predominantly luminal subtypes and show low 5-year survival rates of 28% (CCC-EMN) and 36% (TCGA). Inflamed tumors exhibit higher levels of PD-1 and Programmed cell death 1 ligand 1 (PD-L1). Patients undergoing adjuvant platinum-based chemotherapy with ‘inflamed high’ tumors showed a favorable 5-year survival rate of 64% (HR=0.27; merged CCC-EMN and TCGA cohort).ConclusionThe gene expression signature of CD3Z, CD8A and CXCL9 can assess the immune status of MIBC and stratify the survival of MIBC patients undergoing surgery and adjuvant platinum-based chemotherapy. Furthermore, the assay can identify patients with immunological hot tumors with particular high expression of PD-L1 potentially suitable for immunotherapy.
Owing to the morbidity of established radical treatment options for prostate cancer, alternative whole-gland and focal treatment strategies have emerged. High-intensity focused ultrasound (HIFU) is ...one of the most studied sources for tissue ablation and has been used since the 1990s.
To provide 21-yr oncological long-term follow-up data of an unselected series of patients who underwent whole-gland HIFU for nonmetastatic prostate cancer.
A total of 674 patients were treated between November 1997 and November 2012 in one university center.
The oncological outcome was assessed by biopsy failure–free survival (BFFS), salvage treatment–free survival (STFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Multivariable Cox proportional hazard regression analyses were performed to estimate the prognostic relevance of clinical variables.
In total, 560 patients were included into the evaluation and the median follow-up was 15.1 yr, with a range up to 21.4 yr. At 15 yr, CSS rates for low-, intermediate-, and high-risk patients were 95%, 89%, and 65%, respectively; MFS, STFS-1 (salvage treatment other than HIFU), STFS-2 (salvage treatment including repeat HIFU), and BFFS rates were 91%, 85%, and 58%; 77%, 63%, and 29%; 67%, 52%, and 28%; and 82%, 73%, and 47%, respectively. Preoperative high-risk category was an independent predictor of inferior OS, CSS, MFS, STFS, and BFFS.
Although whole-gland HIFU achieved good long-term cancer control in low- and intermediate-risk patients, high-risk patients should not be treated routinely by HIFU. Intermediate-risk patients achieve high CSS and MFS rates, but a relevant salvage treatment rate has to be reckoned with. Long-term data after whole-gland therapy might help derive implications for focal treatment sources and patient selection.
Long-term data after whole-gland high-intensity focused ultrasound (HIFU) therapy are crucial to prove its oncological efficacy, and may help derive implications for focal treatment strategies and patient selection. In this context, whole-gland HIFU achieved good long-term cancer control up to 21 yr in low- and intermediate-risk prostate cancer (PCa) patients. Owing to considerably inferior long-term cancer control, it should not routinely be used in high-risk PCa patients.
While high-intensity focused ultrasound (HIFU) achieved good long-term cancer control in low- and intermediate-risk patients, its performance in high-risk patients was considerably inferior and such patients should not be treated routinely by HIFU. In intermediate-risk patients, a relevant risk of salvage treatment has to be expected.
We assessed a wide array of body composition parameters to identify those most relevant as prognostic tools for patients undergoing radical cystectomy (RC) due to bladder cancer (BC).
In this ...retrospective, single-center study, preoperative computed tomography (CT) scans of 657 patients were measured at the level of the 3rd lumbar vertebra (L3) to determine common body composition indices including sarcopenia, myosteatosis, psoas muscle index (PMI), subcutaneous and visceral fat index (SFI and VFI), visceral-to-subcutaneous fat ratio (VSR), and visceral obesity. Predictors of overall survival (OS) and cancer-specific survival (CSS) were identified in univariate and multivariate survival analysis.
Sarcopenia and a low PMI were independently associated with shorter OS (Sarcopenia: HR 1.30; 95% CI 1.02-1.66;
= 0.04 and a low PMI: HR 1.32; 95% CI 1.02-1.70;
= 0.03) and CSS (Sarcopenia: HR 1.64; 95% CI 1.19-2.25;
< 0.01 and a low PMI: HR 1.41; 95% CI 1.02-1.96;
= 0.04). Myosteatosis, measured as decreasing average Hounsfield units of skeletal muscle, was an independent risk factor for OS (HR 0.98; 95% CI 0.97-1.00;
= 0.01) and CSS (HR 0.98; 95% CI 0.96-1.00;
< 0.05). The assessed adipose tissue indices were not significant predictors for OS and CSS.
Sarcopenia, a low PMI, and myosteatosis are independent predictors for OS and CSS in patients undergoing radical cystectomy for bladder cancer.
Background: Immune checkpoint inhibitors (ICI) are standard of care in patients with metastatic urothelial carcinoma (mUC) ineligible for cisplatin, and as second-line therapy after platinum-based ...chemotherapy. To date, few data exist about the efficacy of the former second-line chemotherapeutic agent vinflunine after the failure of sequential platinum-based chemotherapy and ICI treatment. The aim of this analysis was to examine the efficacy of vinflunine in a post-ICI third- or later-line setting. Methods: In this retrospective German multicenter study, data of mUC patients treated with vinflunine were reviewed in six centers between February 2010 and December 2021. All of the 105 included patients had radiologic progression after first-line platinum-based chemotherapy. The objective was to describe the efficacy of vinflunine in terms of overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and progression-free survival (PFS) for post-ICI and ICI-naïve patients, respectively. Results: In our cohort, 61 patients (58.1%) had preceding immunotherapy before vinflunine administration, and 44 patients (41.9%) were ICI-naïve. Patients with ICI pretreatment showed an ORR of 22.4% compared to 15.6% within ICI-naïve patients (p = 0.451), and CBR was 51.0% vs. 25.0% (p = 0.020), respectively. Post-ICI patients showed longer OS (8.78 vs. 5.72 months; p = 0.467) and longer PFS (3.09 vs. 2.14 months; p = 0.105). Conclusion: This analysis supports the sequential use of vinflunine in post-ICI patients since the vinca-alkaloid retains a measurable clinical activity in these heavily pretreated patients. The therapeutic benefit may be higher than demonstrated in previous studies.
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