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Article ; Online: HUS1 as a Potential Therapeutic Target in Urothelial Cancer

Andrea Katharina Lindner / Tobias Furlan / Jacob J. Orme / Gennadi Tulchiner / Nina Staudacher / David D’Andrea / Zoran Culig / Renate Pichler

Journal of Clinical Medicine, Vol 11, Iss 2208, p

2022 Volume 2208

Abstract: Platinum-based chemotherapy is the standard of care with concern to first-line systemic therapy for metastatic disease in urothelial cancer (UC). Resistance to chemotherapy despite an initial response is linked with the ability to remove platinum-based ... ...

Abstract	Platinum-based chemotherapy is the standard of care with concern to first-line systemic therapy for metastatic disease in urothelial cancer (UC). Resistance to chemotherapy despite an initial response is linked with the ability to remove platinum-based DNA adducts and to repair chemotherapy-induced DNA lesions by various DNA repair proteins. The Rad9-Rad1-HUS1 complex that is loaded onto DNA at sites of damage is involved in checkpoint activation as well as DNA repair. Here, we addressed for the first time the potential influence of HUS1 expression in urothelial carcinogenesis (using two human basal urothelial cancer cell lines UM-UC-3 and HT1197) and its role as a potential therapeutic target for predicting responses to platinum-based chemotherapy. Specific inhibition of HUS1 expression in both cell lines was achieved by specific siRNA and validated by Western blot. In order to define the possible importance of HUS1 in the regulation of cellular proliferation, parental and resistant cells were treated with increasing concentrations of either control or HUS1 siRNA. HUS1 protein expression was observed in both human basal urothelial cancer cell lines UM-UC-3 and HT1197. In cisplatin-sensitive cells, knock-down of HUS1 inhibited cellular proliferation in the presence of cisplatin. On the contrary, knock-down of HUS1 in resistant cells did not result in a re-sensitization to cisplatin. Finally, RNAseq data from the Cancer Genome Atlas provided evidence that HUS1 expression is a significant prognostic factor for poor survival in UC patients. In summary, HUS1 may acts as an oncogene in UC and might be a key determinant of the cellular response to cisplatin-based chemotherapy.
Keywords	bladder cancer ; prognosis ; biomarker ; chemotherapy ; platinum-based ; HUS1 ; Medicine ; R
Subject code	610 ; 616
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Sex hormones influence survival of patients with metastatic urothelial carcinoma undergoing immune checkpoint therapy

Andrea Katharina Lindner / Felizian Lackner / Piotr Tymoszuk / Dominik Andreas Barth / Andreas Seeber / Florian Kocher / Bettina Toth / Margarethe Hochleitner / Martin Pichler / Renate Pichler

Biology of Sex Differences, Vol 14, Iss 1, Pp 1-

2023 Volume 17

Abstract: Abstract 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 ... ...

Abstract	Abstract 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 < 0.001) and OS (p = 0.039). Conclusion Increased LH and LH/FSH values ...
Keywords	Metastatic urothelial carcinoma ; Immunotherapy ; Overall survival ; Sex hormones ; Gonadotropins ; Prognostic ; Medicine ; R ; Physiology ; QP1-981
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Organ-Sparing Surgery in Testicular Tumor

Nina Staudacher / Gennadi Tulchiner / Katie Bates / Michael Ladurner / Mona Kafka / Friedrich Aigner / Renate Pichler / Wolfgang Horninger

Journal of Clinical Medicine, Vol 9, Iss 2911, p

Is This the Right Approach for Lesions ≤ 20 mm?

2020 Volume 2911

Abstract: Background: This study was conducted in order to analyze factors predicting malignancy in patients undergoing organ-sparing surgery (OSS) for small testicular lesions. Methods: Patients with small (£20 mm) marker-negative clinical stage I testicular ... ...

Abstract	Background: This study was conducted in order to analyze factors predicting malignancy in patients undergoing organ-sparing surgery (OSS) for small testicular lesions. Methods: Patients with small (£20 mm) marker-negative clinical stage I testicular tumors were managed by OSS with tumor enucleation and frozen section examination (FSE) for the past 15 years at our institution. Benign and malignant cases were compared, focusing on preoperative and postoperative lesion sizes. Results: Eighty-nine patients were enrolled in this retrospective study. Ten (11.2%) of them were treated for synchronous bilateral tumors. Sixty-seven (67.7%) of ninety-nine lesions were benign, confirming a high concordance rate (98%) between FSE and final histology. Patients with benign tumors were significantly older than patients with malignant tumors ( p = 0.026), and benign tumors were detected more frequently during urologic work-up of hormone disorders ( p = 0.001). Preoperative tumor size was a strong predictor of malignancy (area under the curve (AUC) = 0.726; p < 0.001). According to the Youden index, the best cutoff to predict tumor dignity was 13.5 mm, resulting in a sensitivity and specificity of 53% and 85%, respectively. No cases of local recurrence or distant metastasis were confirmed after a median follow-up of 42 months. Conclusion: Our findings are consistent with previous reports, supporting an OSS approach in small testicular tumors whenever possible. Most tumors ≤ 20 mm were benign, and in the case of malignancy, OSS with FSE and consecutive orchiectomy is oncologically safe due to the high concordance rate of FSE and final histology, thus preventing a two-stage procedure.
Keywords	testicular cancer ; small testicular tumors ; organ-sparing surgery ; scrotal ultrasonography ; frozen section examination ; Medicine ; R
Subject code	616
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Lynch Syndrome

Andrea Katharina Lindner / Gert Schachtner / Gennadi Tulchiner / Martin Thurnher / Gerold Untergasser / Peter Obrist / Iris Pipp / Fabian Steinkohl / Wolfgang Horninger / Zoran Culig / Renate Pichler

International Journal of Molecular Sciences, Vol 22, Iss 2, p

Its Impact on Urothelial Carcinoma

2021 Volume 531

Abstract: Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1 , MSH2 , ...

Abstract	Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1 , MSH2 , MSH6 , and PMS2 , and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.
Keywords	Lynch syndrome ; urothelial cancer ; upper urinary tract ; DNA mismatch repair genes ; MMR ; microsatellite instability ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Expression of ADAM Proteases in Bladder Cancer Patients with BCG Failure

Renate Pichler / Andrea Katharina Lindner / Georg Schäfer / Gennadi Tulchiner / Nina Staudacher / Martin Mayr / Eva Comperat / Jacob J. Orme / Gert Schachtner / Martin Thurnher

Journal of Clinical Medicine, Vol 10, Iss 4, p

A Pilot Study

2021 Volume 764

Abstract: Although Bacillus Calmette Guérin (BCG) remains a mainstay of adjuvant treatment in high-risk, non-muscle-invasive bladder cancer, BCG failure occurs in up to 40% of patients, with radical cystectomy (RC) as the inevitable therapeutic consequence. ... ...

Abstract	Although Bacillus Calmette Guérin (BCG) remains a mainstay of adjuvant treatment in high-risk, non-muscle-invasive bladder cancer, BCG failure occurs in up to 40% of patients, with radical cystectomy (RC) as the inevitable therapeutic consequence. Current data suggest that PD-L1 immunosuppressive signaling is responsible for BCG failure, supporting the therapeutic rationale of combining checkpoint inhibitors with BCG. To address the immune cascade in 19 RC specimens obtained after BCG failure, we applied a small immunohistochemical (IHC) panel consisting of selected markers (PD-L1, GATA-3, a disintegrin and metalloproteinase (ADAM) proteases, IL-10/IL-10R). A modified quick score was used for IHC semi-quantification of these markers in tumor cells (TC) and immune cells (IC) within two different regions: muscle-invasive bladder cancer (MIBC) and primary/concurrent carcinoma in situ (CIS). Contrary to expectation, PD-L1 was consistently low, irrespective of tumor region and cell type. Intriguingly, expression of ADAM17, which has been reported to release membrane-bound PD-L1, was high in both tumor regions and cell types. Moreover, expression of GATA3, IL-10, and IL-10R was also increased, indicative of a generally immunosuppressive tumor microenvironment in BCG failure. ADAM10 expression was associated with advanced tumor disease at RC. Our findings raise the possibility that ADAM proteases may cleave PD-L1 from the surface of bladder TC and possibly also from IC. Therefore, IHC assessment of PD-L1 expression seems to be insufficient and should be supplemented by ADAM10/17 in patients with BCG failure.
Keywords	bacillus calmette guéri (BCG) failure ; bladder cancer ; a disintegrin and metalloproteinase (ADAM) proteases ; soluble PD-L1 ; PD-L1 biomarkers ; checkpoint inhibition ; Medicine ; R
Subject code	610 ; 616
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Synergies of Targeting Tumor Angiogenesis and Immune Checkpoints in Non-Small Cell Lung Cancer and Renal Cell Cancer

Andreas Pircher / Dominik Wolf / Axel Heidenreich / Wolfgang Hilbe / Renate Pichler / Isabel Heidegger

International Journal of Molecular Sciences, Vol 18, Iss 11, p

From Basic Concepts to Clinical Reality

2017 Volume 2291

Abstract: In recent years, considerable advances concerning therapeutic strategies in patients with metastatic cancer have been achieved. Particularly in renal cell cancer (RCC) and advanced stage non-small cell lung cancer (NSCLC), immune-activating and ... ...

Abstract	In recent years, considerable advances concerning therapeutic strategies in patients with metastatic cancer have been achieved. Particularly in renal cell cancer (RCC) and advanced stage non-small cell lung cancer (NSCLC), immune-activating and antiangiogenic (AA) drugs (i.e., checkpoint antibodies and vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) targeting compounds, respectively) have been successfully developed. As immune-effector cells have to enter the tumor, it is tempting to speculate that the combination of immunotherapy with AA treatment may induce synergistic effects. In this short review, we explore the theoretical background and the therapeutic potential of this novel treatment option for patients with advanced RCC or NSCLC. We discuss the growing body of evidence that pro-angiogenic factors negatively modulate the T-cell-mediated immune response and examine the preclinical evidence for testing combined immune-activating and AA therapy concepts in clinical practice. Particular attention will also be paid to potential novel treatment-related adverse events induced by combination treatment.
Keywords	angiogenesis ; immunotherapy ; checkpoint inhibition ; VEGF inhibition ; renal cell cancer ; non-small cell lung cancer ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616 ; 610
Language	English
Publishing date	2017-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Adenomatoid tumor of the testis mimicking malignant testicular cancer on multiparametric ultrasound

Renate Pichler / Gennadi Tulchiner / Fabian Steinkohl / Afschin Soleiman / Wolfgang Horninger / Isabel Maria Heidegger / Friedrich Aigner

European Journal of Medical Research, Vol 23, Iss 1, Pp 1-

2018 Volume 4

Abstract: Abstract Background Adenomatoid tumor is one of the most common histological subtypes of paratesticular cancer arising from the epididymis. In very rare cases, these tumors appear as intratesticular lesions originating in the tunica albuginea, ... ...

Abstract	Abstract Background Adenomatoid tumor is one of the most common histological subtypes of paratesticular cancer arising from the epididymis. In very rare cases, these tumors appear as intratesticular lesions originating in the tunica albuginea, representing a diagnostic challenge. Case presentation We present a case of a 51-year-old man with a small (0.9 cm) hyperechoic lesion of the left testicle mimicking testicular cancer on multiparametric ultrasound. The lesion was localized in the peripheral zone, confirming vascularization and increased stiffness on contrast-enhanced ultrasound and real-time elastography. Preoperative tumor markers and hormone levels were within normal ranges. Staging computed tomography was negative. Organ-sparing surgery with tumor enucleation and frozen section analysis was performed, confirming testicular adenomatoid tumor. Conclusion Currently, no typical ultrasound features can definitively distinguish intratesticular adenomatoid tumors from malignant testicular masses. Thus, a surgical approach is almost always considered in such a case for both diagnostic and therapeutic purposes.
Keywords	Adenomatoid tumor ; Testis ; Tunica albuginea ; Ultrasound ; Elastography ; Medicine ; R
Subject code	616
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Age-Adjusted PSA Levels in Prostate Cancer Prediction

Isabel Heidegger / Josef Fritz / Helmut Klocker / Renate Pichler / Jasmin Bektic / Wolfgang Horninger

PLoS ONE, Vol 10, Iss 7, p e

Updated Results of the Tyrol Prostate Cancer Early Detection Program.

2015 Volume 0134134

Abstract: To reduce the number of unnecessary biopsies in patients with benign prostatic disease, however, without missing significant PCa the present study re-evaluates the age-dependent PSA cut-offs in the Tyrol Prostate Cancer (PCa) early detection program.The ... ...

Abstract	To reduce the number of unnecessary biopsies in patients with benign prostatic disease, however, without missing significant PCa the present study re-evaluates the age-dependent PSA cut-offs in the Tyrol Prostate Cancer (PCa) early detection program.The study population included 2225 patients who underwent prostate biopsy due to elevated PSA levels at our department. We divided our patient collective into four age groups: ≤49 years (n = 178), 50-59 years (n = 597), 60-69 years (n = 962) and ≥70 years (n = 488). We simulated different scenarios for PSA cut-off values between 1.25 and 6 ng/mL and fPSA% between 15 and 21% for all four age groups and calculated sensitivity, specificity, confidence intervals and predictive values.PCa was detected in 1218 men (54.7%). We found that in combination with free PSA ≤21% the following PSA cut-offs had the best cancer specificity: 1.75 ng/ml for men ≤49 years and 50-59 years, 2.25 ng/ml for men aged 60-69 years and 3.25 ng/ml for men ≥70 years. Using these adjusted PSA cut-off values all significant tumors are recognized in all age groups, yet the number of biopsies is reduced. Overall, one biopsy is avoided in 13 to 14 men (number needed to screen = 13.3, reduction of biopsies = 7.5%) when decision regarding biopsy is done according to the "new" cut-off values instead of the "old" ones. For the different age groups the number needed to screen to avoid one biopsy varied between 9.2 (≤49 years) and 17.4 (50-59 years).With "new", fine-tuned PSA cut-offs we detect all relevant PCa with a significant reduction of biopsies compared to the "old" cut-off values. Optimization of age-specific PSA cut-offs is one step towards a smarter strategy in the Tyrol PCa Early Detection Program.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: High risk of under-grading and -staging in prostate cancer patients eligible for active surveillance.

Isabel Heidegger / Viktor Skradski / Eberhard Steiner / Helmut Klocker / Renate Pichler / Andreas Pircher / Wolfgang Horninger / Jasmin Bektic

PLoS ONE, Vol 10, Iss 2, p e

2015 Volume 0115537

Abstract: BACKGROUND:Active surveillance (AS) is increasingly offered to patients with low risk prostate cancer. The present study was conducted to evaluate the risk of tumor under-grading and -staging for AS eligibility. Moreover, we analyzed possible biomarkers ... ...

Abstract	BACKGROUND:Active surveillance (AS) is increasingly offered to patients with low risk prostate cancer. The present study was conducted to evaluate the risk of tumor under-grading and -staging for AS eligibility. Moreover, we analyzed possible biomarkers for predicting more unfavorable final tumor histology. METHODS:197 patients who underwent radical prostatectomy (RPE) but would have met the EAU (European Association of Urology) criteria for AS (PSA<10 ng/ml, biopsy GS ≤ 6, ≤ 2 cancer-positive biopsy cores with ≤ 50% of tumor in any core and clinical stage ≤ T2a) were included in the study. These AS inclusion parameters were correlated to the final histology of the RPE specimens. The impact of preoperative PSA level (low PSA ≤ 4 ng/ml vs. intermediate PSA of >4-10 ng/ml), PSA density (<15 vs. ≥ 15 ng/ml) and the number of positive biopsy cores (1 vs. 2 positive cores) on predicting upgrading and final adverse histology of the RPE specimens was analyzed in uni- and multivariate analyses. Moreover, clinical courses of undergraded patients were assessed. RESULTS:In our patient cohort 41.1% were found under-graded in the biopsy (final histology 40.1% GS7, 1% GS8). Preoperative PSA levels, PSA density or the number of positive cores were not predictive for worse final pathological findings including GS >6, extraprostatic extension and positive resection margin (R1) or correlated significantly with up-grading and/or extraprostatic extension in a multivariate model. Only R1 resections were predictable by combining intermediate PSA levels with two positive biopsy cores (p = 0.004). Sub-analyses showed that the number of biopsy cores (10 vs. 15 biopsy cores) had no influence on above mentioned results on predicting biopsy undergrading. Clinical courses of patients showed that 19.9% of patients had a biochemical relapse after RPE, among all of them were undergraded in the initial biopsy. CONCLUSION:In summary, this study shows that a multitude of patients fulfilling the criteria for AS are under-diagnosed. The ...
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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