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Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.

Upper tract urothelial carcinoma (UTUC) is an aggressive disease that is managed by radical or organ-sparing surgery. High recurrence rates require early detection and strict follow-up (FU) protocols. Recommendations are assigned to a low level of evidence. Our aim was to identify time-to-tumor recurrence, analyze the temporal relation to recommended FU regimens, and provide a critical proposal for further surveillance. This retrospective study included 54 patients receiving radical nephroureterectomy (RNU) in high-risk UTUC and 14 patients assigned to kidney-sparing surgery (KSS) with low-risk disease. FU surveillance protocols consisted of close intervals irrespective of the received type of surgery. In total, 68 patients were included with a median FU of 23 months. Mean overall survival (OS) was significantly shorter in RNU compared to KSS (P = .027). Recurrence in the bladder and/or upper urinary tract (UUT) was 57.1% in KSS and 38.9% after RNU (P = .241). Mean recurrence-free survival (RFS) was significantly shorter in RNU patients compared to KSS (22.4 vs. 47.9 months, P = .013), and 76.2% of the recurrences in the RNU group occurred in the first postoperative year. UUT recurrence was diagnosed after a median of 3.0 (RNU) and 25.0 (KSS) months. There was a frequent onset of metastases in the RNU group, with 85.7% in the first year compared to the KSS group with 50%. Multivariable regression analysis showed that the tumor stage was the parameter independently related to OS (P = .002), RFS (P = .008), and metastasis-free survival (MFS, P = .002). In conclusion, surveillance of UTUC should be adapted to real-time occurrence patterns. Strict imaging protocols are recommended in the first two years irrespective of the method of surgery. As recurrence is equally distributed over the years after KSS, cystoscopy should be offered regularly for five years and diagnostic URS for three years. After RNU, cystoscopies should be decreased to yearly intervals after year three. Contralateral UUT should also be examined after RNU.

Introduction Clinical trials investigating efficacy of immune checkpoint inhibitors (ICI) revealed sex-specific divergent outcomes in urothelial cancer (UC), suggesting that sex hormones might play an important role in gender-specific dimorphisms of response upon ICI. However, further clinical investigations are still needed to understand the influence of sex hormones in UC. The aim of this study was to get further insights on the prognostic and predictive value of sex hormone levels in patients with metastatic UC (mUC) who underwent ICI. Material and methods Sex hormone levels of patients with mUC including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, prolactin, testosterone and 17β-estradiol (E2) were evaluated at baseline and during ICI at 6/8 weeks and 12/14 weeks. Results Twenty-eight patients (10 women, 18 men) with a median age of 70 years were included. Metastatic disease was confirmed in 21 patients (75%) after radical cystectomy while seven patients showed mUC at first diagnosis. Twelve patients (42.8%) received first line and 16 patients second line pembrolizumab. The objective response rate (ORR) was 39% (CR in 7%). The median progression-free survival (PFS) and overall survival (OS) was 5.5 and 20 months. Focusing on changes of sex hormone levels during ICI, a significant increase in FSH levels and decrease of the LH/FSH ratio was noticed in responders (p = 0.035), yet without sex-specific significance. When adjusted for sex and treatment line, a significant increase of FSH levels was confirmed in men during second line pembrolizumab. Focusing on baseline levels, LH/FSH ratio was significantly higher in female responders (p = 0.043) compared to non-responders. In women, increased LH levels and LH/FSH ratio were associated with better PFS (p = 0.014 for LH, p = 0.016 for LH/FSH ratio) and OS (p = 0.026 and p = 0.018). In male patients, increased E2 levels were linked with improved PFS (p

Additional file 1. Changes in blood levels of luteinizing hormone, follicle-stimulating hormone, LH to FSH ratio, prolactin, estrogen and testosterone prior to the therapy start, after 6/8 weeks and 12/14 weeks after the therapy begin in females and males. Statistical significance was assessed by Friedman test with Kendall’s W effect size statistic. Points represent single observations. Gray lines connect observations belonging to the same participant. Numbers of complete observations are displayed in the plot captions. Effect size and p values are presented in the plot facets. Female, male.

Fragestellung: In Anbetracht der Tatsache, dass Anämie mit einer reduzierten Lebensqualität und schlechterem Überleben von WeichteilsarkompatientInnen vergesellschaftet ist, kann die perioperative Gabe von leukozytenfreien Erythrozytenkonzentraten (EKs) sowohl lebensrettend als auch -verlängernd [zum vollständigen Text gelangen Sie über die oben angegebene URL]

Background The advanced lung cancer inflammation index (ALI) was first introduced for prognosis prediction in lung cancer patients and since then evaluated in several other malignancies. However, in pancreatic cancer (PC) the ALI and its prognostic utility were only investigated in a comparably small and specific cohort of locally advanced PC patients treated with chemoradiotherapy. Methods In our single‐center cohort study, we included 429 patients with histologically verified PC who were treated between 2003 and 2015 at our academic institution. The ALI was defined as body mass index (BMI; kg/m2) × serum albumin levels (g/dL)/neutrophil‐lymphocyte ratio (NLR) and we defined the optimal cutoff for biomarker dichotomization by ROC‐analysis. Kaplan‐Meier method as well as uni‐ and multivariate Cox regression Hazard proportional models were implemented to assess the prognostic potential of ALI in PC patients. We considered cancer‐specific survival (CSS) as the primary endpoint of the study. Results The ALI showed a significant negative correlation with CA19‐9 levels and C‐reactive protein levels whereas we found an association with localized tumor stage and better performance status (P, The advanced lung cancer inflammation index (ALI) was originally established as a prognostic tool in lung cancer patients and consequently validated in various other types of cancer. To date, however, in pancreatic cancer (PC) patients, the prognostic value of the ALI has only been investigated in a relatively small cohort of chemoradiotherapy‐treated patients with locally advanced PC. Converse to previous results, in this large cohort of PC patients, the ALI does not add additional prognostic value to the established clinicopathological prognostic factors.

The microRNA-200 family has wide-ranging regulatory functions in cancer development and progression. Above all, it is strongly associated with the epithelial-to-mesenchymal transition (EMT), a process during which cells change their epithelial to a mesenchymal phenotype and acquire invasive characteristics. More recently, miR-200 family members have also been reported to impact the immune evasion of cancer cells by regulating the expression of immunoinhibitory immune checkpoints (ICs) like PD-L1. Therefore, we aimed to comprehensively characterize this miR-200 family as a regulatory interface between EMT and immune evasion mechanisms in biliary tract cancer. Initial correlation analyses and transient overexpression experiments using miRNA mimics suggested miR-200c-3p as a putative regulator of ICs including PD-L1, LGALS9, and IDO1. However, these effects could not be confirmed in stable miR-200c-3p overexpression cell lines, nor in cells transiently transfected with miR-200c-3p mimic from an independent manufacturer. By shifting our efforts towards dissecting the mechanisms leading to these disparate effects, we observed that the initially used miR-200c-3p mimic triggered a double-stranded (ds)RNA-dependent antiviral response. Besides upregulating the ICs, this had substantial cellular consequences including an induction of interferon type I and type III expression, increased levels of intracellular dsRNA sensors, and a significantly altered cellular growth and apoptotic activity.Our study highlights the capability of miRNA mimics to non-specifically induce a dsRNA-mediated antiviral interferon response. Consequently, phenotypic alterations crucially distort physiological miRNA functions and might result in a major misinterpretation of previous and future miRNA studies, especially in the context of IC regulation.

We present a technique for computing multi-branch-point covers with prescribed ramification and demonstrate the applicability of our method in relatively large degrees by computing several families of polynomials with symplectic and linear Galois groups. As a first application, we present polynomials over \(\mathbb{Q}(\alpha,t)\) for the primitive rank-3 groups \(PSp_4(3)\) and \(PSp_4(3).C_2\) of degree 27 and for the 2-transitive group \(PSp_6(2)\) in its actions on 28 and 36 points, respectively. Moreover, the degree-28 polynomial for \(PSp_6(2)\) admits infinitely many totally real specializations. Next, we present the first (to the best of our knowledge) explicit polynomials for the 2-transitive linear groups \(PSL_4(3)\) and \(PGL_4(3)\) of degree 40, and the imprimitive group \(Aut(PGL_4(3))\) of degree 80. Additionally, we negatively answer a question by König whether there exists a degree-63 rational function with rational coefficients and monodromy group \(PSL_6(2)\) ramified over at least four points. This is achieved due to the explicit computation of the corresponding hyperelliptic genus-3 Hurwitz curve parameterizing this family, followed by a search for rational points on it. As a byproduct of our calculations we obtain the first explicit \(Aut(PSL_6(2))\)-realizations over \(\mathbb{Q}(t)\). At last, we present a technique by Elkies for bounding the transitivity degree of Galois groups. This provides an alternative way to verify the Galois groups from the previous chapters and also yields a proof that the monodromy group of a degree-276 cover computed by Monien is isomorphic to the sporadic 2-transitive Conway group \(Co_3\)., Wir stellen eine Technik zur Berechnung von Mehrpunktüberlagerungen mit vorgeschriebener Verzweigung vor und demonstrieren die Anwendbarkeit unserer Methode in relativ großen Graden durch die Berechnung mehrerer Familien von Polynomen mit symplektischen und linearen Galoisgruppen. Als erste Anwendung präsentieren wir Polynome über \(\mathbb{Q}(\alpha,t)\) für die primitiven Rang-3-Gruppen \(PSp_4(3)\) und \(PSp_4(3).C_2\) vom Grad 27 und für die 2-fach transitive Gruppe \(PSp_6(2)\) in ihren Operationen auf 28 bzw. 36 Punkten. Außerdem lässt das Polynom vom Grad 28 für \(PSp_6(2)\) unendlich viele total-reelle Spezialisierungen zu. Als Nächstes präsentieren wir die (unseres Wissens nach) ersten expliziten Polynome für die 2-fach transitiven linearen Gruppen \(PSL_4(3)\) und \(PGL_4(3)\) vom Grad 40 und die imprimitive Gruppe \(Aut(PGL_4(3))\) vom Grad 80. Zusätzlich geben wir eine negative Antwort auf die Frage von König, ob es eine rationale Funktion vom Grad 63 mit rationalen Koeffizienten gibt, die über mindestens vier Punkten verzweigt ist und Monodromiegruppe \(PSL_6(2)\) besitzt. Dies wird durch die explizite Berechnung der entsprechenden hyperelliptischen Geschlecht-3 Hurwitzkurve erreicht, die diese Familie parametrisiert, gefolgt von einer Suche nach rationalen Punkten auf ihr. Als Nebenprodukt unserer Berechnungen erhalten wir die ersten expliziten \(Aut(PSL_6(2))\)-Realisierungen über \(\mathbb{Q}(t)\). Schließlich stellen wir eine Technik von Elkies zur Beschränkung des Transitivitätsgrades von Galoisgruppen vor. Diese bietet einen alternativen Weg, die Galoisgruppen aus den vorherigen Kapiteln zu verifizieren und liefert auch einen Beweis dafür, dass die Monodromiegruppe einer von Monien berechneten Grad-276 Überlagerung isomorph zur sporadischen 2-fach transitiven Conway-Gruppe \(Co_3\) ist.

Biliary tract cancer is a major global health issue in cancer-related mortality. Therapeutic options are limited, and cisplatin-based treatment schedules represent the mainstay of first-line therapeutic strategies. Although the gain of survival by the addition of cisplatin to gemcitabine is moderate, acquired cisplatin resistance frequently leads to treatment failures with mechanisms that are still poorly understood. Epithelial–mesenchymal transition (EMT) is a dynamic process that changes the shape, function, and gene expression pattern of biliary tract cancer cells. In this study, we explored the influence of the EMT-regulating miR-200c-3p on cisplatin sensitivity in biliary tract cancer cells. Using gain of function experiments, we demonstrated that miR-200c-3p regulates epithelial cell markers through the downregulation of the transcription factor ZEB1. MiR-200c-3p upregulation led to a decreased sensitivity against cisplatin, as observed in transient overexpression models as well as in cell lines stably overexpressing miR-200c-3p. The underlying mechanism seems to be independent of miR-200c-3p’s influence on ZEB1 expression, as ZEB1 knockdown resulted in the opposite effect on cisplatin resistance, which was abolished when ZEB1 knockdown and miR-200c-3p overexpression occurred in parallel. Using a gene panel of 40 genes that were previously associated with cisplatin resistance, two (Dual Specificity Phosphatase 16 (DUSP16) and Stratifin (SFN)) were identified as significantly (&gt, 2 fold, p-value &lt, 0.05) up-regulated in miR-200c-3p overexpressing cells. In conclusion, miR-200c-3p might be an important contributor to cisplatin resistance in biliary tract cancer, independently of its interaction with ZEB1.