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

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

High CDKN2A/p16 and Low FGFR3 Expression Predict Progressive Potential of Stage pT1 Urothelial Bladder Carcinoma

Identifying pT1 bladder cancer with high risk for progression remains a challenge. Aberrations in cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16 and fibroblast growth factor receptor 3 (FGFR3) expression are the most common in urothelial bladder cancer. In the study at hand, we could show that high CDKN2A/p16 mRNA expression is associated with the luminal subtype and high CDKN2A/p16 as well as low FGFR3 mRNA expression are associated with worse progression-free survival. Background: A recent study on the comprehensive genomic profile of advanced urothelial bladder cancer (UBC) showed cyclin-dependent kinase inhibitor 2A (CDKN2A) and fibroblast growth factor receptor 3 (FGFR3) as the most often clinically relevant genomic alterations. Therefore, the prognostic role of FGFR3 and CDKN2A/p16 for pT1 UBC was studied. Patients and Methods: Clinical data and formal in-fixed paraffin-embedded tissues of pT1 UBC treated with an organ-preserving approach was analyzed retrospectively. Total RNA was isolated using commercial RNA extraction kits and mRNA expression of CDKN2A/p16 and FGFR3 was measured using single step reverse transcription quantitative real time polymerase chain reaction using RNA-specific TaqMan assays. Results: Data from 296 patients (79.4% male; median age: 72 years) could be used for the final evaluation. Spearman correlation revealed a statistically significant negative correlation between mRNA expression of CDKN2A/p16 and FGFR3. There was a positive correlation between CDKN2A/p16 and G3 tumors (rho = 0.1875; P = .0012) and associated carcinoma in situ (rho = 0.1703, P = .0033) and a negative correlation between FGFR3 and these factors (rho = -0.2791, P = 38.04) and low FGFR3 expression (= 3 cm (LR chi(2) = 6.03; P = .0141) as independent predictors for PFS. Conclusion: High expression of CDKN2A/p16 and low expression of FGFR3 show a correlation with established prognostic features for non-muscle-invasive bladder cancer and can predict progression of stage pT1 UBC

Analysis of the prognostic relevance of sex-steroid hormonal receptor mRNA expression in muscle-invasive urothelial carcinoma of the urinary bladder

Muscle-invasive urothelial carcinoma of the urinary bladder (UCB) often recurs following radical cystectomy (RC). An altered expression of sex-steroid hormone receptors has been associated with oncological outcomes of UCB and may represent therapeutic targets. Here the expression of different hormone receptors was measured on mRNA levels in patients treated by RC and associated with outcomes. Androgen receptor (AR), estrogen receptor 1 (ESR1), and progesterone receptor (PGR) mRNA expression was assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in RC samples of 87 patients with a median age of 66 (39-88) years. Univariate and multivariate analyses were performed to test associations with pathological and clinical characteristics as well as recurrence-free (RFS) and disease-specific survival (DSS). AR mRNA expression was lower in comparison with ESR1 and PGR expression (p<0.0001). In univariate analysis, high expression levels of AR were associated with reduced RFS (HR 2.8, p=0.015) and DSS (HR 2.8, p=0.010). High AR mRNA expression and a positive lymph node status were independent predictors for reduced RFS (HR 2.5, p=0.0049) and DSS (HR 3.4, p=0.009). In patients with low AR mRNA expression, an increased ESR1 and PGR mRNA expression were associated with reduced RFS and DSS. High expression levels of AR are significantly associated with adverse outcome in patients with muscle-invasive UCB following RC. ESR1 and PGR expression status can further stratify patients with low AR expression into subgroups with significantly reduced RFS and DSS. Therapeutic targeting of AR may influence outcomes in patients with UCB

Data from: Gonadotropin-releasing hormone antagonists versus standard androgen suppression therapy for advanced prostate cancer: a systematic review with meta-analysis

Objectives: To evaluate efficacy and safety of gonadotropin-releasing hormone (GnRH) antagonists compared to standard androgen suppression therapy for advanced prostate cancer. Setting: The international review team included methodologists of the German Cochrane Centre and clinical experts. Participants: We searched CENTRAL, MEDLINE, Web of Science, EMBASE, trial registries and conference books for randomised controlled trials (RCT) for effectiveness data analysis, and randomised or non-randomised controlled studies (non-RCT) for safety data analysis (March 2015). Two authors independently screened identified articles, extracted data, evaluated risk of bias and rated quality of evidence according to GRADE. Results: 13 studies (10 RCTs, 3 non-RCTs) were included. No study reported cancer-specific survival or clinical progression. There were no differences in overall mortality (RR 1.35, 95% CI 0.63 to 2.93), treatment failure (RR 0.91, 95% CI 0.70 to 1.17) or prostate-specific antigen progression (RR 0.83, 95% CI 0.64 to 1.06). While there was no difference in quality of life related to urinary symptoms, improved quality of life regarding prostate symptoms, measured with the International Prostate Symptom Score (IPSS), with the use of GnRH antagonists compared with the use of standard androgen suppression therapy (mean score difference −0.40, 95% CI −0.94 to 0.14, and −1.84, 95% CI −3.00 to −0.69, respectively) was found. Quality of evidence for all assessed outcomes was rated low according to GRADE. The risk for injection-site events was increased, but cardiovascular events may occur less often by using GnRH antagonist. Available evidence is hampered by risk of bias, selective reporting and limited follow-up. Conclusions: There is currently insufficient evidence to make firm conclusive statements on the efficacy of GnRH antagonist compared to standard androgen suppression therapy for advanced prostate cancer. There is need for further high-quality research on GnRH antagonists with long-term follow-up. Trial registration number: CRD42012002751

Gonadotropin-releasing hormone antagonists versus standard androgen suppression therapy for advanced prostate cancer: A systematic review with meta-analysis

Objectives To evaluate efficacy and safety of gonadotropin-releasing hormone (GnRH) antagonists compared to standard androgen suppression therapy for advanced prostate cancer. Setting The international review team included methodologists of the German Cochrane Centre and clinical experts. Participants We searched CENTRAL, MEDLINE, Web of Science, EMBASE, trial registries and conference books for randomised controlled trials (RCT) for effectiveness data analysis, and randomised or non-randomised controlled studies (non-RCT) for safety data analysis (March 2015). Two authors independently screened identified articles, extracted data, evaluated risk of bias and rated quality of evidence according to GRADE. Results 13 studies (10 RCTs, 3 non-RCTs) were included. No study reported cancer-specific survival or clinical progression. There were no differences in overall mortality (RR 1.35, 95% CI 0.63 to 2.93), treatment failure (RR 0.91, 95% CI 0.70 to 1.17) or prostate-specific antigen progression (RR 0.83, 95% CI 0.64 to 1.06). While there was no difference in quality of life related to urinary symptoms, improved quality of life regarding prostate symptoms, measured with the International Prostate Symptom Score (IPSS), with the use of GnRH antagonists compared with the use of standard androgen suppression therapy (mean score difference −0.40, 95% CI −0.94 to 0.14, and −1.84, 95% CI −3.00 to −0.69, respectively) was found. Quality of evidence for all assessed outcomes was rated low according to GRADE. The risk for injection-site events was increased, but cardiovascular events may occur less often by using GnRH antagonist. Available evidence is hampered by risk of bias, selective reporting and limited follow-up. Conclusions There is currently insufficient evidence to make firm conclusive statements on the efficacy of GnRH antagonist compared to standard androgen suppression therapy for advanced prostate cancer. There is need for further high-quality research on GnRH antagonists with long-term follow-up