The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors.

Testicular germ cell tumors (TGCTs) are cancers with very good prognosis, even in the metastatic setting, with high curative potential mainly attributed to the introduction of cisplatin-based chemotherapy. However, approximately 15% of the patients develop platinum-refractory disease and suffer multiple relapses. Therefore, there is an unmet need for novel therapeutic agents with improved efficacy and minimal long-term side effects. Recent advances in the development of immunotherapeutic agents, particularly immune checkpoint inhibitors (ICIs), have offered an opportunity to test their activity in various tumor types, including GCTs. This review aims to analyze the immune microenvironment of these tumors and present the most recently available data from studies that have tested immunotherapeutic agents against GCTs. The majority of the available knowledge derives from case reports or small cohort studies, particularly those involving ICIs of the PD-1/PD-L1 axis alone or in combination with anti-CTLA-4 monoclonal antibodies. Other immunotherapeutic targeted approaches, including antibody-drug conjugates, antibody prodrugs, vaccines, tyrosine kinase inhibitors, chimeric antigen receptor (CAR) T-cell therapy, have biological rationales and have shown preliminary activity or are currently being tested. Growing evidence on these and other approaches will assist in broadening the currently limited treatment armamentarium against platinum-refractory TGCTs.

Characterization of a miRNA Signature with Enhanced Diagnostic and Prognostic Power for Patients with Bladder Carcinoma.

Bladder carcinoma is globally among the most prevalent cancers and is associated with a high mortality rate at advanced stages. Its detection relies on invasive diagnostic methods that are unpleasant for the patient. Non-invasive molecular biomarkers, such as miRNAs, could serve as alternatives for early detection and prognosis of this malignancy. We designed a computational approach that combines transcriptome profiling, survival analyses, and calculation of diagnostic power in order to isolate miRNA signatures with high diagnostic and prognostic utility. Our analysis of TCGA-BLCA data from 429 patients yielded one miRNA signature, consisting of five upregulated and three downregulated miRNAs with cumulative diagnostic power that outperforms current diagnostic methods. The same miRNAs have a strong prognostic significance since their expression is associated with the overall survival of bladder cancer patients. We evaluated the expression of this signature in 19 solid cancer types, supporting its unique diagnostic utility for bladder carcinoma. We provide computational evidence regarding the functional implications of this miRNA signature in cell cycle regulation, demonstrating its abundance in body fluids, including peripheral blood and urine. Our study characterized a novel miRNA signature with the potential to serve as a non-invasive method for bladder cancer diagnosis and prognosis.

Radiofrequency-assisted, laparoscopic, clampless partial nephrectomy in patients with low-complexity small renal tumors: A retrospective cohort study.

Background: This single-center, retrospective study was performed to investigate the safety and efficacy of radiofrequency-assisted (RF), laparoscopic partial nephrectomy (PN) with zero ischemia in patients with low-complexity small renal tumors. Materials and Methods: Patients with small renal masses (SRMs) who underwent laparoscopic, clampless laparoscopic partial nephrectomy - radiofrequency assisted (LPN-RFA) between January 2016 and June 2020 were studied. Demographics, clinical and pathological characteristics, recurrence-free survival, and overall survival were recorded. Results: Fifty-two SRMs were excised from corresponding patients using RFA-LPN. The median tumor size was 2.5 cm and all specimens involved low-complexity masses according to the renal nephrometry score. No conversions to radical nephrectomy were recorded. Postoperatively, there were one patient with fever, one with hematuria, and two with urinary leakage treated endoscopically. The majority of tumors (48/52, 86.2%) were clear-cell carcinomas. According to the glomerular filtration rate postoperatively and 12 months' posttreatment, adequate renal function was preserved in all patients. There were no positive surgical margins identified postoperatively and no recurrences during a median follow-up 24 months. All patients were alive at the last follow-up. Conclusions: This study suggests that RFA laparoscopic clampless PN represents an effective method for managing patients with low-complexity SRMs. It offers adequate intraoperative safety and excellent mid-term oncological control and functional preservation.

Upper Tract Urothelial Carcinoma: A Rare Malignancy with Distinct Immuno-Genomic Features in the Era of Precision-Based Therapies.

Upper tract urothelial carcinoma (UTUC) is a rare malignancy, occurring in 5-10% of patients diagnosed with UC, and involves the renal pelvis, calyces, or ureters. UTUC can be sporadic or hereditary as a clinical manifestation of Lynch syndrome. Therapeutic management of these patients is challenging. Following risk stratification of localized disease, patients with low-grade UTUC may undergo kidney-sparing surgery or radical nephroureterectomy (RNU) and/or chemoablation with mitomycin-c instillation to reduce recurrence. In high-grade disease, RNU followed by adjuvant chemotherapy remains the standard of care. For decades, platinum-based chemotherapy has been the cornerstone of treatment for locally advanced and metastatic disease. The aim of the present review is to summarize recent advances in UTUC's therapeutic management through the lens of its genomic and immune landscape. Accumulating knowledge on the genetic and immune aspects of UTUC tumors has increased our understanding of their underlying biology, supporting a luminal papillary, T-cell depleted contexture and enrichment in fibroblast growth factor receptor (FGFR) expression. These advances have fueled successful clinical testing of several precision-based therapeutic approaches, including immune checkpoint inhibitors (ICIs), the antibody-drug conjugates (ADCs) enfortumab vedotin and sacituzumab govitecan, and agents targeting the FGFR axis such as erdafitinib and other kinase inhibitors, allowing their entry into the therapeutic armamentarium and improving the prognosis of these patients. Not all patients respond to these precision-based targeted therapies; thus, validating and expanding the toolkit of potential biomarkers of response or resistance, including molecular subtypes, FGFR pathway gene alterations, DNA repair gene defects, tumor mutational burden (TMB), circulating tumor DNA (ctDNA), nectin-4, TROP2, and programmed death ligand-1 (PD-L1), are key to maximizing the benefit to these particular subgroups of patients.

Complete Vascular Replacement of the Infrarenal Inferior Vena Cava and Abdominal Aorta during Post-Chemotherapy Retroperitoneal Lymph Node Dissection for a Non-Seminomatous Germ Cell Tumor.

Testicular germ cell tumors (TGCTs) are the leading cause of cancer-related death in males between the ages of 20 and 40. In the advanced stages, the combination of cisplatin-based chemotherapy and surgical excision of the remaining tumor can cure many of these patients. Vascular procedures may be required during retroperitoneal lymph node dissection (RPLND) in order to achieve the complete excision of all residual retroperitoneal masses. Careful assessment of pre-operative imaging and the identification of patients who could benefit from additional procedures are important for minimizing peri- and postoperative complications. We report on a case of a 27-year-old patient with non-seminomatous TGCT, who successfully underwent post-chemotherapy RPLND with additional infrarenal inferior vena cava (IVC) and complete abdominal aorta replacement using synthetic grafts.

Mutational profile of primary clear cell renal cell carcinoma predicts recurrence and potential candidacy for adjuvant immune checkpoint inhibition.

Background: The risk of recurrence after nephrectomy for primary clear cell renal cell carcinoma (ccRCC) is estimated in daily practice solely based on clinical criteria. The aim of this study was to assess the prognostic relevance of common somatic mutations with respect to tumor aggressiveness and outcomes of ccRCC patients after definitive treatment. Methods: Primary tumors from 37 patients with ccRCC who underwent radical nephrectomy were analyzed for presence of somatic mutations using a 15-gene targeted next-generation sequencing (NGS) panel. Associations to histopathologic characteristics and outcomes were investigated in the study cohort (n=37) and validated in The Cancer Genome Atlas (TCGA) ccRCC cohort (n=451). Results: VHL was the most frequently mutated gene (51%), followed by PBRM1 (27%), BAP1 (13%), SETD2 (13%), KDM5C (5%), ATM (5%), MTOR (5%), and PTEN (3%). One-third of patients did not have any somatic mutations within the 15-gene panel. The vast majority of tumors harboring no mutations at all or VHL-only mutations (51%) were more frequently of smaller size (pT1-2) and earlier stage (I/II), whereas presence of any other gene mutations in various combinations with or without VHL was enriched in larger (pT3) and higher stage tumors (III) (p=0.02). No recurrences were noted in patients with unmutated tumors or VHL-only mutations as opposed to three relapses in patients with non- VHL somatic mutations (p=0.06). Presence of somatic mutations in PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, or PTEN genes in 451 TCGA ccRCC patients was associated with a significantly shorter disease-free survival (DFS) compared to those with unaltered tumors (q=0.01). Conclusions: Preliminary findings from this ongoing study support the prognostic value of non- VHL mutations including PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, and PTEN in primary ccRCC tumors as surrogates of earlier recurrence and potential selection for adjuvant immune checkpoint inhibition.

Hypoxia-Inducible Factor-2-Altered Urothelial Carcinoma: Clinical and Genomic Features.

Background: Hypoxia is recognized as a key feature of cancer growth and is involved in various cellular processes, including proliferation, angiogenesis, and immune surveillance. Besides hypoxia-inducible factor 1-alpha (HIF-1α), which is the main mediator of hypoxia effects and can also be activated under normoxic conditions, little is known about its counterpart, HIF-2. This study focused on investigating the clinical and molecular landscape of HIF-2-altered urothelial carcinoma (UC). Methods: Publicly available next-generation sequencing (NGS) data from muscle-invasive UC cell lines and patient tumor samples from the MSK/TCGA 2020 cohort (n = 476) were interrogated for the level of expression (mRNA, protein) and presence of mutations, copy number variations, structural variants in the EPAS1 gene encoding HIF-2, and findings among various clinical (stage, grade, progression-free and overall survival) and molecular (tumor mutational burden, enriched gene expression) parameters were compared between altered and unaltered tumors. Results: 19% (7/37) of UC cell lines and 7% (27/380) of patients with muscle-invasive UC display high EPAS1 mRNA and protein expression or/and EPAS1 alterations. EPAS1-altered tumors are associated with higher stage, grade, and lymph node metastasis as well as with shorter PFS (14 vs. 51 months, q = 0.01) and OS (15 vs. 55 months, q = 0.01). EPAS1 mRNA expression is directly correlated with that of its target-genes, including VEGF, FLT1, KDR, DLL4, CDH5, ANGPT1 (q < 0.001). While there is a slightly higher tumor mutational burden in EPAS1-altered tumors (9.9 vs. 4.9 mut/Mb), they are enriched in and associated with genes promoting immune evasion, including ARID5B, SPINT1, AAK1, CLIC3, SORT1, SASH1, and FGFR3, respectively (q < 0.001). Conclusions: HIF-2-altered UC has an aggressive clinical and a distinct genomic and immunogenomic profile enriched in angiogenesis- and immune evasion-promoting genes.

Boosting artificial nicotinamide cofactor systems.

Developing inexpensive nicotinamide cofactor biomimetics to replace the expensive NAD(P)/H cofactors is an ongoing research activity. Here we present mutational studies on a thermostable glucose dehydrogenase from Saccharolobus solfataricus (SsGDH) using a novel set of synthetic cofactors. Furthermore, we show the successful oxidation of a variety of different sugars in the context of cofactor regeneration. This combined approach resulted in an 160-fold improved system compared to the native enzyme with the standard biomimetic BNA+. These findings pave the way towards competitive industrial utilization of artificial cofactor regeneration systems.

Clear-cell renal cell carcinoma single urinary bladder metastasis: a case report and review of the literature.

Renal cell carcinoma (RCC) is the most frequent solid lesion accounting for ~90% of all kidney malignancies. Clear-cell RCC (ccRCC) represents the most frequent subtype. Urinary bladder is a rare metastatic site either synchronous or metachronous. Hereby, we report the case of an 85-year-old male patient with a single urinary bladder metastasis due to ccRCC and we present a review of the literature.

Mixed epithelial and stromal tumor-adult cystic nephroma of the kidney: a case report with immunohistochemical analysis.

The mixed epithelial and stromal tumor family of kidney contain neoplasms with biphasic epithelial and stromal component. According to the 2016 World Health Organization Classification, they encompasses a spectrum of tumors ranging from predominantly cystic tumors (adult cystic nephroma) to tumors that are variably solid (Mixed epithelial and stromal tumor-MESTs). We present the case of a 20-year-old woman with an adult cystic nephroma which was verified by immunohistochemical examination.

Learning curves in laparoscopic and robot-assisted prostate surgery: a systematic search and review.

PURPOSE: To perform a systematic search and review of the available literature on the learning curves (LCs) in laparoscopic and robot-assisted prostate surgery. METHODS: Medline was systematically searched from 1946 to January 2021 to detect all studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, reporting on the LC in laparoscopic radical prostatectomy (LRP), laparoscopic simple prostatectomy (LSP), robot-assisted radical prostatectomy (RARP) and robot-assisted simple prostatectomy (RSP). RESULTS: In total, 47 studies were included for qualitative synthesis evaluating a single technique (LRP, RARP, LSP, RSP; 45 studies) or two techniques (LRP and RARP; 2 studies). All studies evaluated outcomes on real patients. RARP was the most widely investigated technique (30 studies), followed by LRP (17 studies), LSP (1 study), and RSP (1 study). In LRP, the reported LC based on operative time; estimated blood loss; length of hospital stay; positive surgical margin; biochemical recurrence; overall complication rate; and urinary continence rate ranged 40-250, 80-250, 58-200, 50-350, 110-350, 55-250, 70-350 cases, respectively. In RARP, the corresponding ranges were 16-300, 20-300, 25-200, 50-400, 40-100, 20-250, 30-200, while LC for potency rates was 80-90 cases. CONCLUSIONS: The definition of LC for laparoscopic and robot-assisted prostate surgery is not well defined with various metrics used among studies. Nevertheless, LCs appear to be steep and continuous. Implementation of training programs/standardization of the techniques is necessary to improve outcomes.

Biomarkers in Prostate-Specific Membrane Antigen Theranostics.

Theranostics of prostate cancer (PC) represents a growing area of development of imaging agents and targeted radionuclide therapeutics against a major target, prostate specific membrane antigen (PSMA). In view of the encouraging efficacy from the use of 177Lu and other radionuclides in metastatic castration-resistant prostate cancer (mCRPC), it is becoming increasingly important to identify surrogate markers that can help predict which patients are more likely to respond and experience improved survival. This review discusses potential predictors of efficacy of PSMA-targeted radionuclide therapies (TRT) segregated in three major categories: imaging, clinical and molecular.

Endothelin-1 indicates unfavorable prognosis in primary high-grade non-muscle-invasive urothelial bladder cancer.

OBJECTIVE: To conduct a prospective study of the potential prognostic role of endothelin-1 (ET-1) in a cohort of primary high-grade non-muscle-invasive urothelial bladder cancer patients, who were treated with adjuvant intravesical Bacillus Calmette-Guérin (BCG). MATERIAL AND METHODS: Patients with primary high-grade nonmuscle- invasive urothelial bladder cancer, who received postoperatively induction and maintenance BCG therapy, were prospectively included. Recurrence and progression were histologically proven. Immunohistochemical staining for ET-1 was assessed. Epidemiological, pathological and clinical parameters as well as the expression of ET-1 in tumor specimens were statistically analyzed for recurrence, progression, recurrence-free survival (RFS) and progression-free survival (PFS). RESULTS: ET-1 associates significantly with recurrence (p = 0.000), progression (p = 0.000), RFS (p = 0.000) and PFS (p = 0.000). The patient's age is also significant for recurrence (p = 0.003, OR = 1.273 95% CI: 1.086-1.492) and RFS (p = 0.013). CONCLUSIONS: ET-1 seems to deteriorate prognosis in patients suffering from primary high-grade non-muscle-invasive urothelial bladder cancer, who are treated with adjuvant BCG instillations. Furthermore, the patient's age associates with an increased likelihood for recurrence.

carba Nicotinamide Adenine Dinucleotide Phosphate: Robust Cofactor for Redox Biocatalysis.

Here we report a new robust nicotinamide dinucleotide phosphate cofactor analog (carba-NADP+ ) and its acceptance by many enzymes in the class of oxidoreductases. Replacing one ribose oxygen with a methylene group of the natural NADP+ was found to enhance stability dramatically. Decomposition experiments at moderate and high temperatures with the cofactors showed a drastic increase in half-life time at elevated temperatures since it significantly disfavors hydrolysis of the pyridinium-N-glycoside bond. Overall, more than 27 different oxidoreductases were successfully tested, and a thorough analytical characterization and comparison is given. The cofactor carba-NADP+ opens up the field of redox-biocatalysis under harsh conditions.

Adverse effects of androgen deprivation therapy in patients with prostate cancer: Focus on muscle and bone health.

Androgen deprivation therapy (ADT) is the most effective systemic treatment for prostate cancer and can be succeeded either surgically or pharmaceutically. Both approaches lead to hypogonadism with a large variety of adverse events, including obesity, metabolic syndrome, osteoporosis, sarcopenia, diabetes mellitus, cardiovascular disease, gynecomastia and sexual dysfunction. In addition, undesirable effects on muscle and bone health may have a significant impact not only on the quality of life but also on life expectancy. Currently, supervised exercise seems to be the only intervention that could prevent the adverse effects of the ADT and improve quality of life. Lifestyle modification, supplementation of calcium, vitamin D and when indicated antiosteoporotic treatments improve bone health. However, patients receiving ADT must be well informed about the potential benefits as well as the risks of the treatment.

Production of Propene from n-Butanol: A Three-Step Cascade Utilizing the Cytochrome P450 Fatty Acid Decarboxylase OleTJE.

Propene is one of the most important starting materials in the chemical industry. Herein, we report an enzymatic cascade reaction for the biocatalytic production of propene starting from n-butanol, thus offering a biobased production from glucose. In order to create an efficient system, we faced the issue of an optimal cofactor supply for the fatty acid decarboxylase OleTJE , which is said to be driven by either NAD(P)H or H2 O2 . In the first system, we used an alcohol and aldehyde dehydrogenase coupled to OleTJE by the electron-transfer complex putidaredoxin reductase/putidaredoxin, allowing regeneration of the NAD+ cofactor. With the second system, we intended full oxidation of n-butanol to butyric acid, generating one equivalent of H2 O2 that can be used for the oxidative decarboxylation. As the optimal substrate is a long-chain fatty acid, we also tried to create an improved variant for the decarboxylation of butyric acid by using rational protein design. Within a mutational study with 57 designed mutants, we generated the mutant OleTV292I , which showed a 2.4-fold improvement in propene production in our H2 O2 -driven cascade system and reached total turnover numbers >1000.

Management of Patients with Liver Cirrhosis and Invasive Bladder Cancer: A Case-series.

Liver cirrhosis is a major risk factor for increased mortality and morbidity in patients undergoing non-hepatic surgery with overall mortality rates as high as 45-50%. However, cirrhotic patients are often in need of surgical procedures including urological surgeries like cystectomies for muscle invasive bladder cancer. Data on the prognosis of these patients undergoing cystectomy for bladder cancer are scarce in the literature. In the present case-study, we describe the outcomes of 3 patients with liver cirrhosis who underwent radical cystectomy for muscle invasive bladder cancer. To the best of our knowledge, this is the first study reporting on this kind of urological surgery in patients with liver cirrhosis. Accordingly, we provide a review in the literature on prognosis and factors influencing the survival of cirrhotic patients who undergo surgical procedures.

Primary High-Grade Non-Muscle-Invasive Bladder Cancer: High NFκB Expression in Tumor Specimens Distinguishes Patients Who are at Risk for Disease Progression.

To investigate the potential prognostic role of NFκB expression in primary high-grade non-muscle-invasive bladder cancer. Patients with primary high-grade non-muscle-invasive bladder cancer who received induction and maintenance BCG therapy were retrospectively included. Recurrence and progression were histologically proven. Intensity and extent of immunochemistry were assessed. The final evaluation of the NFκB staining was done by combining intensity and extent as ΄΄product΄΄ and expressing it as ΄΄low NFκΒ expression΄΄ or ΄΄high NFκB expression΄΄. Epidemiological, pathological, clinical parameters and NFκB expression were statistically analyzed for recurrence (REC), progression (PR), recurrence-free survival (RFS) and progression-free survival (PFS). NFκB is significantly associated with disease progression (p < 0,001 in univariate analysis and p = 0,001, Odds Ratio = 14,484, 95% Confidence Interval = 3187-65,821 in multivariate analysis), but not with recurrence. The median value of NFκB expression as ΄΄product΄΄ is significantly higher for the patients with progression in comparison to patients with recurrence only (p = 0,003) and patients without recurrence or progression (p = 0,001). Patients' age is significantly associated (p = 0,001 in univariate analysis and p = 0,003, Odds Ratio = 1273, 95% Confidence Interval = 1086-1492 in multivariate analysis) with disease recurrence. High NFκB expression in primary high-grade non-muscle-invasive bladder cancer, treated with postoperative intravesical BCG immunotherapy, could represent an unfavorable prognostic factor.