The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance.

Cysteine cathepsins are lysosomal enzymes belonging to the papain family. Their expression is misregulated in a wide variety of tumors, and ample data prove their involvement in cancer progression, angiogenesis, metastasis, and in the occurrence of drug resistance. However, while their overexpression is usually associated with highly aggressive tumor phenotypes, their mechanistic role in cancer progression is still to be determined to develop new therapeutic strategies. In this review, we highlight the literature related to the role of the cysteine cathepsins in cancer biology, with particular emphasis on their input into tumor biology.

Biomarkers of Renal Tumors: the Current State and Clinical Perspectives.

Renal cell carcinoma (RCC) ranks the first death rate among the urogenital tumors, whereas its incidence follows the incidences of prostate and bladder cancer. The diagnosis of RCC at early stages allows immediately undertaking appropriate treatment, which significantly increases patients' survival rate. Early and accurate diagnosis avoids inadequate treatment, provides the disease progression forecast, and permits to apply more efficient therapy. Unfortunately, the small renal tumors are usually asymptomatic resulting in the late diagnosis and, therefore, low efficacy of treatment. Thus, sensible and preventive biomarkers are essential for early RCC detection and monitoring of its progression. So far, many attempts were performed aimed at recognizing novel informative kidney tumor biomarkers applicable for early detection of the disease and possessing prognostic and predictive capabilities. This review summarizes recent advances in renal tumor biomarkers recognition, their diagnostic and prognostic values, and clinical feasibility.

The cancer-retina antigen recoverin as a potential biomarker for renal tumors.

The renal cell carcinoma is the ninth most common cancer with an increasing occurrence and mortality. Recoverin is the first retina-specific photoreceptor protein that was shown to undergo aberrant expression, due to its promoter demethylation, as a cancer-retina antigen in a number of malignant tumors. In this work, we demonstrated that recoverin is indeed expressed in 68.4 % of patients with different subtypes of renal cell carcinoma, and this expression has tendency to correlate with tumor size. Interestingly, 91.7 % of patients with the benign renal tumor, oncocytoma, express recoverin as well in their tumor. Epigenetic analysis of the recoverin gene promoter revealed a stable mosaic methylation pattern with the predominance of the methylated state, with the exception of -80 and 56 CpG dinucleotides (CpGs). While the recoverin expression does not correlate withoverall survival of the tumor patients, the methylation of the recoverin gene promoter at -80 position is associated with better overall survival of the patients. This work is the first report pointing towards the association of overall survival of renal cell carcinoma (RCC) patients with promoter methylation of a cancer-retina antigen. Taken together, these data allow to consider recoverin as a potential therapeutic target and/or marker for renal tumors.

Markers of local kidney cancer recurrence: A surgeon's mistake or a pattern? Review.

The influence of various morphological, anatomical, genetic and other factors on the local recurrence-free survival of patients who have undergone different renal cell cancer (RCC) treatment is still a rather complex, ambiguous and controversial issue for practicing oncourologists. This review evaluates the effect of several factors on both recurrence-free survival and local recurrence-free survival. The review includes articles, clinical cases, literature reviews, and meta-analyses highlighting the analysis of independent and interrelated predisposing factors for developing local recurrence of RCC from 1984 to 2020. The PubMed, Web of Science, and Scopus databases were searched in English, Spanish, and German. A review of the literature showed the role of the following indices in the local recurrence RCC: microvascular invasion (p = 0.001), tumor necrosis (p = 0.0001), high malignancy (Fuhrman III or IV) (HR = 38.3, 95% CI 3.1-467, p = 0.004) as histological factors, tumor size as an anatomical factor. Thus, the authors state that every centimeter of the tumor increases the risk of local recurrence (p < 0.05). A group from the Mayo Clinic showed the equivalence of different treatment methods in local RCC recurrence. Thus, in the group of patients with cT1a stage kidney cancer, the 5-year local recurrence-free survival rates were 97.7% (96.7-98.6), 95.9% (92.3-99.6), and 95.9% (92.3-99.6) for renal resection, RFA, and cryoablation, respectively. Surgical margin status is the most studied and controversial marker of local renal cell carcinoma recurrence. Researchers found a direct effect of PSM on the risk of local RCC recurrence (p < 0.01). The personalized approach with the search and evaluation of predisposing factors for the local recurrence, as well as further selection of the most optimal treatment, will allow oncourologists to improve both the effectiveness of primary treatment and the recurrence-free survival of patients.

Surgical treatment of renal cell carcinoma with tumor thrombosis of the inferior vena cava and the right heart: How we do it.

OBJECTIVE: Renal cell carcinoma with inferior vena cava thrombosis is a rare disease with a poor prognosis without surgical treatment. We report our 11-year experience in the surgical treatment of renal cell carcinoma with extension of the inferior vena cava. METHODS: We conducted a retrospective analysis of patients undergoing surgical treatment for renal cell carcinoma with invasion of the inferior vena cava in two hospitals from May 2010 to March 2021. To assess the spread of the tumor process invasion, we used the Neves and Zincke classification. RESULTS: A total of 25 people underwent surgical treatment. Sixteen patients were men, nine were women. Thirteen patients underwent cardiopulmonary bypass (CBP) surgery. The following postoperative complications were recorded: two cases of disseminate intravascular coagulation (DIC), two cases of acute myocardial infarction (MI) and one case of coma of unknown reason, Takotsubo syndrome and postoperative wound dehiscence. Three patients deceased (16.7%) of DIC syndrome and AMI. After discharge, one of the patients had a recurrence of tumor thrombosis 9 months after surgery, and another patient had the same 16 months later, presumably due to the neoplastic tissue in the adrenal gland on the contralateral side. CONCLUSION: We believe that this problem should be dealt with by an experienced surgeon with a multidisciplinary team in the clinic. The use of CPB provides benefits and reduces blood loss.

In Silico, In Vitro, and Clinical Investigations of Cathepsin B and Stefin A mRNA Expression and a Correlation Analysis in Kidney Cancer.

The cysteine protease Cathepsin B (CtsB) plays a critical role in multiple signaling pathways, intracellular protein degradation, and processing. Endogenous inhibitors regulate its enzymatic activity, including stefins and other cystatins. Recent data proved that CtsB is implicated in tumor extracellular matrix remodeling, cell invasion, and metastasis: a misbalance between cathepsins and their natural inhibitors is often considered a sign of disease progression. In the present study, we investigated CtsB and stefin A (StfA) expression in renal cell carcinoma (RCC). mRNA analysis unveiled a significant CTSB and STFA increase in RCC tissues compared to adjacent non-cancerogenic tissues and a higher CtsB expression in malignant tumors than in benign renal neoplasms. Further analysis highlighted a positive correlation between CtsB and StfA expression as a function of patient sex, age, tumor size, grade, lymph node invasion, metastasis occurrence, and survival. Alternative overexpression and silencing of CtsB and StfA confirmed the correlation expression between these proteins in human RCC-derived cells through protein analysis and fluorescent microscopy. Finally, the ectopic expression of CtsB and StfA increased RCC cell proliferation. Our data strongly indicated that CtsB and StfA expression play an important role in RCC development by mutually stimulating their expression in RCC progression.

Emergency versus elective ureteroscopy for the management of ureteral stones.

OBJECTIVE: To assess the safety and efficacy of emergency ureteroscopy (URS) compared with elective URS. METHODS: We conducted a retrospective analysis of patients who underwent URS for isolated ureteral stones in a single center from October 2001 to February 2014. Our patient cohort was divided into two groups: an emergency URS group (Group A), which consisted of patients who underwent URS within the first 24 h of admission, and an elective or planned URS group (Group B). The URS success rate was defined as being the incidence of successful stone fragmentation and whether there was resolution of renal obstruction. RESULTS: A total of 2957 patients' medical records were available for analysis. Of these, 704 (21%) comprised of emergency cases and the remaining 2253 (79%) were elective cases. Patients in Group A were younger, had a smaller BMIs, and had smaller stone sizes (p < 0.001). The URS success rate was found to be 97% in Group A and 96% in Group B (p = 0.35). Intraoperative or postoperative complication rates were not found to vary significantly between the groups (8% vs 7%, respectively, p = 0.50). The incidence of ureteral stenting was nearly twice as high if URS was performed during night hours (85% vs 45%, p < 0.001). However, ureteral stenting was more prevalent in Group B compared to Group A patients (57% vs 25%, p < 0.001), possibly as a result of the number of pre-stented patients (73%). CONCLUSIONS: Emergency URS is an effective and safe option for patients with renal colic. Younger patients without pre-existing obesity and with stone sizes up to 8 mm located in the distal ureter might be a better match for emergency URS.

Long Non-Coding PROX1-AS1 Expression Correlates with Renal Cell Carcinoma Metastasis and Aggressiveness.

Long non-coding RNAs (lncRNAs) can be specifically expressed in different tissues and cancers. By controlling the gene expression at the transcriptional and translational levels, lncRNAs have been reported to be involved in tumor growth and metastasis. Recent data demonstrated that multiple lncRNAs have a crucial role in renal cell carcinoma (RCC) progression-the most common malignant urogenital tumor. In the present study, we found a trend towards increased PROX1 antisense RNA 1 (PROX1-AS1) expression in RCC specimens compared to non-tumoral margins. Next, we found a positive correlation between PROX1-AS1 expression and the occurrence of distant and lymph node metastasis, higher tumor stage (pT1 vs. pT2 vs. pT3-T4) and high-grade (G1/G2 vs. G3/G4) clear RCC. Furthermore, global demethylation in RCC-derived cell lines (769-P and A498) and human embryonic kidney 293 (HEK293) cells induced a significant increase of PROX1-AS1 expression level, with the most remarkable change in HEK293 cells. In line with this evidence, bisulfite sequencing analysis confirmed the specific demethylation of bioinformatically selected CpG islands on the PROX1-AS1 promoter sequence in the HEK293 cell line but not in the tumor cells. Additionally, the human specimen analysis showed the hemimethylated state of CG dinucleotides in non-tumor kidney tissues, whereas the tumor samples presented the complete, partial, or no demethylation of CpG-islands. In conclusion, our study indicated that PROX1-AS1 could be associated with RCC progression, and further investigations may define its role as a new diagnostic marker and therapeutic target.

Autoantibody against arrestin-1 as a potential biomarker of renal cell carcinoma.

Renal cell carcinoma (RCC) is the second-most common uronephrological cancer. In the absence of specific symptoms, early diagnosis of RCC is challenging. Monitoring of the aberrant expression of tumour-associated antigens (TAAs) and related autoantibody response is considered as a novel approach of RCC diagnostics. The aim of this study was to examine the aberrant expression of arrestin-1 in renal tumours, to investigate the possible epigenetic mechanism underlying arrestin-1 expression, and to assess the frequency of anti-arrestin-1 autoantibody response. Immunohistochemistry was used to assess the presence of arrestin-1 in primary tumours and metastases of 39 patients with RCC and renal oncocytoma. Bisulfite sequencing was employed to analyse the methylation status of the promoter of the SAG gene encoding arrestin-1. Western blot analysis was performed to detect autoantibodies against arrestin-1 in serum samples of 36 RCC and oncocytoma patients. Arrestin-1 was found to be expressed in RCC (58.7% of cases) and renal oncocytoma (90% of cases) cells, while being absent in healthy kidney. The expression of arrestin-1 in RCC metastases was more prominent than in primary tumours. Hypomethylation of the SAG gene promoter is unlikely to be the mechanism for the aberrant expression of arrestin-1. Autoantibodies against arrestin-1 were detected in sera of 75% of RCC patients. Taken together, our findings suggest employment of autoantibody against arrestin-1 as biomarker of RCC.

Transurethral contact ureterolithotripsy in gas (СО2) medium.

BACKGROUND: Transurethral intracorporeal lithotripsy is the modality of choice for the endoscopic disintegration of large, long-standing, radiolucent or high-density stones. Despite several advantages and proven benefits of contact ureterolithotripsy/ureterolithoextraction (CULT), the application of irrigation carries significant risks of untoward perioperative events including retrograde stone migration and postoperative pyelonephritis. METHODS: We describe a new technique - endoscopic intracorporeal lithotripsy in the gas (СО2) medium. It is a prospective randomized, single blinded pilot study that included total of (n = 60) patients with urolithiasis who were allocated to either experimental or control group. Out of the total pool of patients, 30 underwent treatment with the new approach (experimental group) and other 30 (control group) had contact ureterolithotripsy in a standard of care 0.9% NaCL medium. We included patients >18 years old, with known symptomatic renal calculi disease who were eligible and scheduled for CULT and free from significant coexisting pathologies of urinary tract. RESULTS: No retrograde migration of the stone fragments into the kidney was reported in the experimental group [complications rate 0%, confidence interval (CI): 0-11.6%]. In the control group, complications were observed in eight cases (complications rate 26.7%, CI: 14.7-42.3%); retrograde migration was in five patients (16.6%), and acute pyelonephritis/exacerbation of chronic pyelonephritis was seen in three (10%) patients. There was not any acute pyelonephritis in the experimental group. Reliability of frequency differences - p = 0.0023 (χ2). CONCLUSIONS: The novel method of contact ureterolithotripsy is a safe and promising alternative to the conventional contact ureterolithotripsy in a fluid medium in a carefully selected patient population.