C‐reactive protein flare‐response predicts long‐term efficacy to first‐line anti‐PD‐1‐based combination therapy in metastatic renal cell carcinoma

Objectives Immune checkpoint blockade (IO) has revolutionised the treatment of metastatic renal cell carcinoma (mRCC). Early C-reactive protein (CRP) kinetics, especially the recently introduced CRP flare-response phenomenon, has shown promising results to predict IO efficacy in mRCC, but has only been studied in second line or later. Here, we aimed to validate the predictive value of early CRP kinetics for 1st-line treatment of mRCC with αPD-1 plus either αCTLA-4 (IO+IO) or tyrosine kinase inhibitor (IO+TKI). Methods In this multicentre retrospective study, we investigated the predictive potential of early CRP kinetics during 1st-line IO therapy. Ninety-five patients with mRCC from six tertiary referral centres with either IO+IO (N = 59) or IO+TKI (N = 36) were included. Patients were classified as CRP flare-responders, CRP responders or non-CRP responders as previously described, and their oncological outcome was compared. Results Our data validate the predictive potential of early CRP kinetics in 1st-line immunotherapy in mRCC. CRP responders, especially CRP flare-responders, had significantly prolonged progression-free survival (PFS) compared with non-CRP responders (median PFS: CRP flare-responder: 19.2 months vs. responders: 16.2 vs. non-CRP responders: 5.6, P < 0.001). In both the IO+IO and IO+TKI subgroups, early CRP kinetics remained significantly associated with improved PFS. CRP flare-response was also associated with long-term response ≥ 12 months. Conclusions Early CRP kinetics appears to be a low-cost and easy-to-implement on-treatment biomarker to predict response to 1st-line IO combination therapy. It has potential to optimise therapy monitoring and might represent a new standard of care biomarker for immunotherapy in mRCC

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

Prognostic impact of molecular muscle-invasive bladder cancer subtyping approaches and correlations with variant histology in a population-based mono-institutional cystectomy cohort

Purpose Recently discovered molecular classifications for urothelial bladder cancer appeared to be promising prognostic and predictive biomarkers. The present study was conducted to evaluate the prognostic impact of molecular subtypes assessed by two different methodologies (gene and protein expression), to compare these two approaches and to correlate molecular with histological subtypes in a consecutively collected, mono-institutional muscle-invasive bladder cancer (MIBC) cohort. Methods 193 MIBC were pathologically re-evaluated and molecular subtypes were assessed on mRNA (NanoString technology, modified 21-gene-containing MDACC approach) and protein levels (immuno-histochemical [IHC] analysis of CK5, CK14, CD44, CK20, GATA3 and FOXA1). Descriptive statistical methods and uni-/multi-variable survival models were employed to analyze derived data. Results Neither gene expression nor protein-based subtyping showed significant associations with disease-specific (DSS) or recurrence-free survival (RFS). Agreement between mRNA (reference) and protein-based subtyping amounted 68.6% for basal, 76.1% for luminal and 50.0% for double-negative tumors. Histological subtypes associated with RFS in uni-variable (P = 0.03), but not in multivariable survival analyses. Tumors with variant histology predominantly showed luminal subtypes (gene expression subtyping: 36/55 cases, 65.5%; protein subtyping: 44/55 cases, 80.0%). Squamous differentiation significantly associated with basal subtypes (gene expression subtyping: 44/45 squamous cases, 97.8%; protein subtyping: 36/45 cases, 80.0%). Conclusion In our consecutive cystectomy cohort, neither gene, protein expression-based subtyping, nor histological subtypes associated with DSS or RFS in multi-variably adjusted survival analyses. Application of a limited IHC subtyping marker panel showed high concordance of 83.9% with gene expression-based subtyping, thus underlining the utility for subtyping in pathological routine diagnostics. In addition, histological MIBC subtypes are strong indicators for intrinsic subtypes

How Octogenarians with Bladder Cancer Are Treated in a Maximum-Care Hospital: The Real-Life Experience

Introduction: With increasing life expectancy, curative treatment of octogenarians with urothelial carcinoma of the bladder (UCB) becomes more important. Materials and Methods: The treatment modalities of 276 octogenarians with UCB who were treated at the University Hospital of Erlangen between 1982 and 2011 were assessed retrospectively. Results: One hundred forty-six patients had non-muscle invasive bladder cancer (NMIBC) while 71 had muscle invasive bladder cancer (MIBC). No data was available for 59 patients. Eighty-five (58.2%) of the 146 patients with NMIBC received transurethral resection of the bladder tumor (TURBT) only, another 38 patients (26%) underwent additional intravesical therapy; and 8.9% were treated with radiochemotherapy (RCT), 4.1% with radiotherapy (RT), 1.4% with systemic chemotherapy and 1.4% with radical cystectomy (RC). Of the 71 patients suffering from MIBC, 39 (54.9%) received TURBT alone. A potentially curative therapy was performed on 31 of the 71 patients with MIBC (43.7%). Of these, 16 patients (51.6%) received RCT, 9 patients (29.0%) RT and 6 patients (19.4%) RC. In Kaplan-Meier analysis, patients with MIBC had better median overall survival with curative treatment compared to TURBT alone (28 vs. 9 months; p < 0.001, log-rank test). Conclusions: By offering a wide range of treatment options, over 43% of octogenarians with MIBC received a curative therapy at a maximum care hospital

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

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

mRNA-Expression of KRT5 and KRT20 Defines Distinct Prognostic Subgroups of Muscle-Invasive Urothelial Bladder Cancer Correlating with Histological Variants

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 (KRT5) and keratin 20 (KRT20). Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was applied to quantify gene expression of KRT5 and KRT20 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 KRT5 and low expression of KRT20 were associated with significantly improved recurrence-free survival (RFS) and disease-specific survival disease specific survival (DSS: 5-year DSS for KRT5 high: 58%; 5-year DSS for KRT20 high: 29%). KRT5 and KRT20 were associated with rates of lymphovascular invasion and lymphonodal metastasis. The combination of KRT5 and KRT20 allowed identification of patients with a very poor prognosis (KRT20+/KRT5−, 5-year DSS 0%, p < 0.0001). In silico analysis of the independent MDACC cohorts revealed congruent results (5-year DSS for KRT20 low vs. high: 84% vs. 40%, p = 0.042). High KRT20-expressing tumors as well as KRT20+/KRT− tumors were significantly enriched with aggressive urothelial carcinoma variants (micropapillary, plasmacytoid, nested)

Serum miRNAs Support the Indication for MRI-Ultrasound Fusion-Guided Biopsy of the Prostate in Patients with Low-PI-RADS Lesions

Multiparametric MRI (mpMRI) and targeted biopsy of the prostate enhance the tumor detection rate. However, the prediction of clinically significant prostate cancer (PCa) is still limited. Our study tested the additional value of serum levels of selected miRNAs in combination with clinical and mpMRI information for PCa prediction and classification. A total of 289 patients underwent targeted mpMRI-ultrasound fusion-guided prostate biopsy complemented by systematic biopsy. Serum miRNA levels of miRNAs (miR-141, miR-375, miR-21-5p, miR-320b, miR-210-3p, let-7c, and miR-486) were determined by quantitative PCR. Detection of any PCa and of significant PCa were the outcome variables. The patient age, pre-biopsy PSA level, previous biopsy procedure, PI-RADS score, and serum miRNA levels were covariates for regularized binary logistic regression models. The addition of miRNA expression of miR-486 and let-7c to the baseline model, containing only clinical parameters, increased the predictive accuracy. Particularly in patients with PI-RADS ≤3, we determined a sensitivity for detecting significant PCa (Gleason score ≥ 7a corresponding to Grade group ≥2) of 95.2%, and an NPV for absence of significant PCa of 97.1%. This accuracy could be useful to support patient counseling in selected cases

Klinische Untersuchung der Determinanten der zerebralen Oxygenierung während aortokoronarer Bypassoperationen unter Verwendung der Herz-Lungen-Maschine

Neurologische und kognitive Störungen gehören zu den häufigsten Komplikationen nach aortokoronaren Bypassoperationen (ACB). Während Emboli und Vorhofflimmern als Ursachen für postoperative neurokognitive Störungen anerkannt sind, wird zunehmend der Einfluss der intraoperativen zerebralen Perfusion und Oxygenierung diskutiert. Ziel dieser Studie war das Aufzeigen der Veränderungen der zerebralen Oxygenierung sowie die Feststellung möglicher intraoperativer Einflussfaktoren auf die regionale und globale zerebrale Oxygenierung während ACB unter Einsatz der Herz-Lungen-Maschine. Insgesamt wurden 53 Patienten, die sich einer elektiven ACB unter Verwendung der Herz-Lungen-Maschine unterzogen, in die Studie aufgenommen. Als Parameter der zerebralen Oxygenierung wurden die über Nahinfrarot-Spektroskopie (NIRS) gemessene regionale zerebrale Sauerstoffsättigung (rSO2), welche die regionale Oxygenierung in der Grenzzone zwischen A. cerebri media und A. cerebri anterior misst, sowie die jugularvenöse Sauerstoffsättigung (SjO2), welche die globale Oxygenierung des Gehirns widerspiegelt, verwendet. Als mögliche Einflussfaktoren wurden die Temperatur, der mittlere arterielle Blutdruck (MAP), die Hb-Konzentration, der CO2-Partialdruck (PaCO2), der Herzindex (CI), sowie der zentrale Venendruck (ZVD) berücksichtigt. Sowohl die Parameter der zerebralen Oxygenierung als auch die Einflussfaktoren wurden zeitgleich zu sechs Zeitpunkten während der Operation gemessen. Die Messzeitpunkte im Einzelnen waren: vor Sternotomie als Ausgangswert, nach Gabe der Kardioplegielösung (Zeitpunkt der tiefsten Hypothermie), 30 Minuten nach Beginn des kardiopulmonalen Bypasses (frühe Wiedererwärmung), 60 Minuten nach Beginn des kardiopulmonalen Bypasses (späte Wiedererwärmung), unmittelbar nach Beendigung der extrakorporalen Zirkulation (EKZ), sowie nach Thoraxverschluss. Die Korrelation der zerebralen Oxygenierung mit den Einflussfaktoren wurde über verallgemeinerte Schätzgleichungen (GEE) bestimmt. Die rSO2 sank nach Gabe der Kardioplegielösung signifikant von 69,20 ± 7,86% auf 62,26 ± 8,67% ab und stieg nach Beendigung der EKZ erneut signifikant auf 67,83 ± 7,26% an. Die SjO2 sank nach Gabe der Kardioplegielösung signifikant von 72,34 ± 8,64% auf 65,31 ± 12,57%. Nach Beendigung der EKZ stieg die SjO2 signifikant auf 70,51 ± 9,45% an. Die Temperatur sank nach Gabe der Kardioplegielösung signifikant von 35,7 ± 0,5°C auf ihren niedrigsten Wert 33,9 ± 1,1°C ab. Im weiteren Verlauf stieg die Temperatur kontinuierlich bis auf den Höchstwert 36,7 ± 0,5°C nach Beendigung der EKZ an. Der MAP sank nach Gabe der Kardioplegielösung signifikant von 85,29 ± 10,12mmHg auf 56,67 ± 13,64mmHg, intraoperativ kam es zu weiteren signifikanten Veränderungen. Nach Beendigung der EKZ stieg der Wert auf 77,84 ± 12,99mmHg an. Der Hb-Wert sank nach Gabe der Kardioplegielösung signifikant von 13,0 ± 1,4g/dl auf 10,1 ± 1,8g/dl ab, im weiteren Verlauf gab es keine signifikanten Veränderungen. Der Ausgangswert der PaCO2 betrug 39,7 ± 2,9mmHg und sank erst 30 Minuten nach Anschluss an die EKZ signifikant ab. Nach Beendigung der EKZ stieg der PaCO2 erneut signifikant auf 38,2 ± 3,6mmHg. Der CI betrug zum Zeitpunkt der Sternotomie 2,00 ± 0,54 l/min/m2. Erst nach Beendigung der EKZ stieg der CI signifikant auf 3,31 ± 1,28 l/min/m2 an. Der ZVD betrug zum ersten Messzeitpunkt 10,73 ± 3,12mmHg. Erst nach Beendigung der EKZ ergab sich ein signifikanter Anstieg des ZVD auf 11,91 ± 2,97mmHg. Mit Ausnahme des ZVD korrelierten alle gemessenen Einflussgrößen mit der zerebralen Oxygenierung. Der PaCO2 und der CI korrelierten sowohl mit der rSO2 als auch mit der SjO2 (jeweils P<0,01). Der MAP korrelierte nur mit der globalen (P<0,01), jedoch nicht mit der regionalen Oxygenierung (P=0,71). Die Temperatur und der Hb-Wert korrelierten nur mit der regionalen Oxygenierung (jeweils P<0,01). Es gab keine Korrelation der SjO2 mit der Temperatur (P=0,99) und dem Hb-Wert (P=0,31). Die zerebrale Oxygenierung während ACB mit Herz-Lungen-Maschine ist somit von mehreren intraoperativen Einflussfaktoren abhängig. Unter den vorliegenden Bedingungen führten die Temperatur und der Hb-Wert nur zu regionalen Veränderungen, die über eine Messung der globalen Oxygenierung nicht erfasst werden konnten. Der MAP konnte nur die globale zerebrale Oxygenierung verändern, während der PaCO2 und der CI sowohl die regionale als auch die globale zerebrale Oxygenierung beeinflussten

Dynamic Mean-Variance Optimization Problems with Deterministic Information

We solve the problems of mean-variance hedging (MVH) and mean–variance portfolio selection (MVPS) under restricted information. We work in a setting where the underlying price process S is a semimartingale, but not adapted to the filtration G which models the information available for constructing trading strategies. We choose as G=Fdet the zero-information filtration and assume that S is a time-dependent affine transformation of a square-integrable martingale. This class of processes includes in particular arithmetic and exponential Lévy models with suitable integrability. We give explicit solutions to the MVH and MVPS problems in this setting, and we show for the Lévy case how they can be expressed in terms of the Lévy triplet. Explicit formulas are obtained for hedging European call options in the Bachelier and Black-Scholes models