Multifocality in Testicular Cancer: Clinicopathological Correlations and Prognostic Implications.

There are limited data regarding the significance of multifocality in testicular cancer patients. This study evaluated the relationship between multifocality and clinicopathological features determined at the time of radical orchiectomy. The study involved 280 consecutive patients who underwent radical orchiectomy between 2018 and 2023. Multifocality was defined as a distinct tumor focus characterized by a group of malignant cells > 1 mm, clearly differentiated from the primary tumor mass. Uni- and multivariate logistic regression analyses were employed to investigate the association between multifocality and histopathological parameters along with potential risk factors for clinical stages II + III. Multifocality was identified in 44 (15.7%) patients. Significantly smaller primary tumors were observed in subjects with multifocality (20.0 mm vs. 30.0 mm, p = 0.0001), while those exhibiting monofocality presented a markedly elevated rate of tumors exceeding 4 cm (40.3% vs. 18.2%, p = 0.005). Furthermore, multifocality was associated with a significantly higher rate of primary tumors < 2 cm (52.3% vs. 29.2%, p = 0.003). Univariate logistic regression analysis revealed a substantial decrease in the likelihood of multifocality occurrence in seminoma patients with tumors > 4 cm (OR = 0.38, p = 0.017). Meanwhile, in multivariate logistic regression, multifocality did not emerge as a significant risk factor for clinical stages II + III in either seminoma (p = 0.381) or non-seminoma (p = 0.672) cases. Our study suggests that multifocality holds no substantial prognostic relevance for clinically advanced disease in testicular cancer patients. The findings indicate that multifocality is associated with smaller primary tumors, particularly those measuring less than 2 cm.

The Polymorphisms in GSTO Genes (GSTO1 rs4925, GSTO2 rs156697, and GSTO2 rs2297235) Affect the Risk for Testicular Germ Cell Tumor Development: A Pilot Study.

Members of the omega class of glutathione transferases (GSTs), GSTO1, and GSTO2, catalyze a range of reduction reactions as a part of the antioxidant defense system. Polymorphisms of genes encoding antioxidant proteins and the resultant altered redox profile have already been associated with the increased risk for testicular germ cell cancer (GCT) development. The aim of this pilot study was to assess the individual, combined, haplotype, and cumulative effect of GSTO1rs4925, GSTO2rs156697, and GSTO2rs2297235 polymorphisms with the risk for testicular GCT development, in 88 patients and 96 matched controls, through logistic regression models. We found that carriers of the GSTO1*C/A*C/C genotype exhibited an increased risk for testicular GCT development. Significant association with increased risk of testicular GCT was observed in carriers of GSTO2rs2297235*A/G*G/G genotype, and in carriers of combined GSTO2rs156697*A/G*G/G and GSTO2rs2297235*A/G*G/G genotypes. Haplotype H7 (GSTO1rs4925*C/GSTO2rs2297235*G/GSTO2rs156697*G) exhibited higher risk of testicular GCT, however, without significant association (p > 0.05). Finally, 51% of testicular GCT patients were the carriers of all three risk-associated genotypes, with 2.5-fold increased cumulative risk. In conclusion, the results of this pilot study suggest that GSTO polymorphisms might affect the protective antioxidant activity of GSTO isoenzymes, therefore predisposing susceptible individuals toward higher risk for testicular GCT development.

P53 and survivin expression in renal cell carcinoma.

Objective: Mutation of p53 is detected in more than 50% of human cancers, expression of p53 has a potential prognostic value in patients with renal cell carcinoma (RCC). Survivin is a member of the inhibitor of apoptosis protein family, its overexpression is observed in many malignancies, including RCC. The aim of the study was to estimate a correlation between survivin and p53 expression in tumor samples and the histologic type of a tumor, tumor stage, tumor grade, and survival of patients. Materials and Methods: Tumor samples were collected from surgical specimens of 90 patients who underwent radical or partial nephrectomy for RCC between November 2017 and July 2020. Tumors were staged according to the UICC (The Union for International Cancer Control) TNM classification system and histopathologically graded according to Fuhrman nuclear grade system. Histopathological diagnosis was confirmed with standard light microscopic evaluation, using hematoxylin and eosin staining and standard p53 and survivin antibodies. Results: Positive p53 staining was observed in 36.7% of tumor specimens and 24.4% were survivin positive. There was a statistically significant correlation between p53 or survivin expression and histologic subtype of clear cell RCC as well as Type I and II of papillary RCC. There was a statistically significant correlation between p53 expression and tumor size, stage, and grade. The p53 or survivin expression was related to lower overall survival. Conclusion: The results of this study suggest that p53 overexpression and survivin positivity in RCC patients could be associated with poor prognosis. Thus, these proteins could be used as prognostic markers in RCC.

Prognostic Significance of Systemic Inflammation Markers in Testicular and Penile Cancer: A Narrative Review of Current Literature.

In contemporary clinical practice, biomarkers are indispensable in the assessment and management of oncological patients. Although established serum tumor markers (beta human chorionic gonadotropin (bHCG), alpha fetoprotein (AFP), and lactate dehydrogenase (LDH)) have an indisputably important role in the management of patients with testicular cancer (TC), the application of these tumor markers may be accompanied with certain limitations, implying the need for additional biomarkers. Contrary to TC, there is a lack of established serological biomarkers for penile cancer (PC) and the management of this urological malignancy is based on multiple clinicopathological parameters. Therefore, the identification and rigorous analytical and clinical validation of reliable biomarkers are considered pivotal for improving PC management. Inflammation may be associated with all stages of oncogenesis, from initial neoplastic transformation to angiogenesis, tissue invasion, and metastasis. Accordingly, an array of inflammation-related indices have gained increasing attention as emerging predictors of oncological outcomes. The clinical usefulness of systemic inflammation markers was reported in many urological and non-urological malignancies. The aim of this narrative review is to summarize current scientific data regarding the prognostic and predictive significance of systemic inflammation markers in TC and PC patients.

Electrospun polycaprolactone nanofibers functionalized with Achillea millefolium extract yield biomaterial with antibacterial, antioxidant and improved mechanical properties.

In this study, polycaprolactone (PCL), as a biocompatible polymer was functionalized by addition of medicinal plant extract- Achillea millefolium L. (yarrow). Nanofiber mats were fabricated from PCL solutions containing dry yarrow extract in four concentrations (5%, 10%, 15%, and 20% relative to the weight of the polymer) by using blend electrospinning method. The nanofibers were characterized for their biological, mechanical and drug release behavior. In vitro release of yarrow polyphenols from the electrospun PCL nanofibers over a period of 5 days showed the release of up to 98% of the total loaded polyphenols. The released polyphenols retained its antioxidant activity, which was determined by DPPH assay. Electrospun PCL/yarrow nanofiber mats exhibited the antibacterial effect against Staphylococcus aureus, but had no effect on the growth of Pseudomonas aeruginosa. All PCL/yarrow nanofiber mats had improved mechanical properties compared to the neat PCL nanofibers, as evident by an increase in Young's modulus of elasticity (up to 5.7 times), the tensile strength (up to 5.5 times), and the strain at break (up to 1.45 times). Based on our results, yarrow-loaded PCL nanofiber mats appeared to be multi-functional biomaterials suitable for the production of catheter-coating materials, patches, or gauzes with antibacterial and antioxidant properties.

Effectiveness of Outpatient Pulmonary Rehabilitation in Patients with Surgically Resected Lung Cancer: A Retrospective Real-World Analysis.

Patients with lung cancer frequently suffer from physical deconditioning, low exercise capacity, and reduced quality of life. There is little evidence on the effects of a structured outpatient pulmonary rehabilitation program (OPR) on exercise capacity and symptom load in these patients. We performed a retrospective, single-center analysis of surgically resected lung cancer patients, who underwent a multiprofessional 6-week OPR. The primary endpoint was a change in the six-minute walk test distance (6 MWT). Secondary endpoints included changes in maximal workload and constant work-rate test results during cycle-ergometry, upper and lower extremity strength, and inspiratory muscle strength. The COPD Assessment Test (CAT) was used to assess symptom burden. Fifty-seven patients were included. Of those, fifty-two (91.2%) completed the full 6 weeks of OPR. The mean age was 56.4 (SD 9.2) years, and 58% were female. At completion of OPR, there was a statistically significant mean of a 50 m (95% CI, 29.6−70.7; p < 0.001) increase in 6 MWT. Significant improvements were also seen in all other exercise and strength tests (p < 0.001), accompanied by a significant reduction in the CAT score (mean difference −3.1, p = 0.001). No adverse effects were reported. OPR for surgically resected lung cancer patients was safe and effective and showed high adherence in the current study.

Treatment options in stage I seminoma.

Seminomas are most commonly diagnosed in clinical stage I (CSI). After orchiectomy, approximately 15% of patients in this stage have subclinical metastases. Adjuvant radiotherapy (ART) delivered to the retroperitoneum and ipsilateral pelvic lymph nodes has been the mainstay of treatment for many years. Although highly efficient, with long-term cancer-specific survival (CSS) rates approaching almost 100%, ART is associated with considerable long-term consequences, particularly cardiovascular toxicity and increased risk of secondary malignancies (SMN). Therefore, active surveillance (AS) and adjuvant chemotherapy (ACT) were developed as alternative treatment options. While AS prevents patient overtreatment, it is associated with strict follow-up regimens and increased radiation exposure due to repeated imaging. Due to equivalent CSS rates to ART, and lower toxicity, one course of adjuvant carboplatin presents the cornerstone of chemotherapy for CSI patients. CSS is almost 100% for patients with CSI seminoma, regardless of the chosen treatment option. Therefore, a personalized approach in treatment selection is preferred. Currently, routine radiotherapy for CSI seminoma patients is no longer recommended. Instead, it should be reserved for patients who are unfit or unwilling for AS or ACT. Identification of prognostic factors for disease relapse allowed for the development of risk-adapted treatment strategy and stratification of patients in low-risk and high-risk groups. Although risk-adapted policy needs further validation, surveillance is currently recommended in low-risk patients, while ACT is reserved for patients with a higher risk of relapse.

The Correlation between Extracellular Heat Shock Protein 70 and Lipid Metabolism in a Ruminant Model.

Metabolic stress in early lactation cows is characterized by lipolysis, ketogenesis, insulin resistance and inflammation because of negative energy balance and increased use of lipids for energy needs. In this study the relationship between lipid metabolite, lipid-based insulin resistance, and hepatocyte functionality indexes and tumor necrosis factor alpha (TNF-α) with extracellular heat shock protein 70 (eHsp70) was investigated. The experiment included 50 cows and all parameters were measured in blood serum. In cows with a more pronounced negative energy balance, the following was determined: a higher concentration of eHsp70, TNF-α, non-esterified fatty acid (NEFA), beta-hydroxybutyrate (BHB), NEFA to insulin and NEFA to cholesterol ratio and lower concentration of cholesterol, very low-density lipoproteins (VLDL), low density lipoproteins (LDL) and liver functionality index (LFI). The eHsp70 correlated negatively with the values of cholesterol, VLDL, LDL, and triglycerides, while correlated positively with the level of NEFA and BHB. A higher concentration of eHsp70 suggests the development of fatty liver (due to a higher NEFA to cholesterol ratio and lower LFI) and insulin resistance (due to a lower revised quantitative insulin sensitivity check index RQUICKI-BHB and higher NEFA to insulin ratio). The eHsp70 correlated positively with TNF-α. Both TNF-α and eHsp70 correlated similarly to lipid metabolites. In cows with high eHsp70 and TNF-α values we found higher concentrations of NEFA, BHB, NEFA to insulin and NEFA to cholesterol ratio and a lower concentration of triglycerides and VLDL cholesterol compared to cows that had only high TNF-α values. Based on the positive correlation between eHsp70 and TNF-α, their similar relations, and the additional effect of eHsp70 (high TNF-α + eHsp70 values) on lipid metabolites we conclude that eHsp70 has pro-inflammatory effects implicating lipolysis, fatty liver, and fat tissue insulin resistance.

Cocaine Blocks Effects of Hunger Hormone, Ghrelin, Via Interaction with Neuronal Sigma-1 Receptors.

Despite ancient knowledge on cocaine appetite-suppressant action, the molecular basis of such fact remains unknown. Addiction/eating disorders (e.g., binge eating, anorexia, bulimia) share a central control involving reward circuits. However, we here show that the sigma-1 receptor (σ1R) mediates cocaine anorectic effects by interacting in neurons with growth/hormone/secretagogue (ghrelin) receptors. Cocaine increases colocalization of σ1R and GHS-R1a at the cell surface. Moreover, in transfected HEK-293T and neuroblastoma SH-SY5Y cells, and in primary neuronal cultures, pretreatment with cocaine or a σ1R agonist inhibited ghrelin-mediated signaling, in a similar manner as the GHS-R1a antagonist YIL-781. Results were similar in G protein-dependent (cAMP accumulation and calcium release) and in partly dependent or independent (ERK1/2 phosphorylation and label-free) assays. We provide solid evidence for direct interaction between receptors and the functional consequences, as well as a reliable structural model of the macromolecular σ1R-GHS-R1a complex, which arises as a key piece in the puzzle of the events linking cocaine consumption and appetitive/consummatory behaviors.

CFTR Genotype and Maximal Exercise Capacity in Cystic Fibrosis: A Cross-sectional Study.

RATIONALE: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human skeletal muscle cells. Variations of CFTR dysfunction among patients with cystic fibrosis may be an important determinant of maximal exercise capacity in cystic fibrosis. Previous studies on the relationship between CFTR genotype and maximal exercise capacity are scarce and contradictory. OBJECTIVES: This study was designed to explore factors influencing maximal exercise capacity, expressed as peak oxygen uptake (V.O2peak), with a specific focus on CFTR genotype in children and adults with cystic fibrosis. METHODS: In an international, multicenter, cross-sectional study, we collected data on CFTR genotype and cardiopulmonary exercise tests in patients with cystic fibrosis who were ages 8 years and older. CFTR mutations were classified into functional classes I­V. RESULTS: The final analysis included 726 patients (45% females; age range, 8­61 yr; forced expiratory volume in 1 s, 16 to 123% predicted) from 17 cystic fibrosis centers in North America, Europe, Australia, and Asia, all of whom had both valid maximal cardiopulmonary exercise tests and complete CFTR genotype data. Overall, patients exhibited exercise intolerance (V.O2peak, 77.3 ± 19.1% predicted), but values were comparable among different CFTR classes. We did not detect an association between CFTR genotype functional classes I­III and either V.O2peak (percent predicted) (adjusted ß = −0.95; 95% CI, −4.18 to 2.29; P = 0.57) or maximum work rate (Wattmax) (adjusted ß = −1.38; 95% CI, −5.04 to 2.27; P = 0.46) compared with classes IV­V. Those with at least one copy of a F508del-CFTR mutation and one copy of a class V mutation had a significantly lower V.O2peak (ß = −8.24%; 95% CI, −14.53 to −2.99; P = 0.003) and lower Wattmax (adjusted ß = −7.59%; 95% CI, −14.21 to −0.95; P = 0.025) than those with two copies of a class II mutation. On the basis of linear regression analysis adjusted for relevant confounders, lung function and body mass index were associated with V.O2peak. CONCLUSIONS: CFTR functional genotype class was not associated with maximal exercise capacity in patients with cystic fibrosis overall, but those with at least one copy of a F508del-CFTR mutation and a single class V mutation had lower maximal exercise capacity.

Treatment response according to small airway phenotypes: a real-life observational study.

OBJECTIVE: Scant clinical data are available on the effects of current treatments for asthma on different subgroups of patients with this disease. We conducted a prospective, noninterventional, multicenter real-life study in adult patients with persistent asthma, and we specifically analyzed the effects of treatment with extrafine beclometasone dipropionate/formoterol (BDP/F) in asthma patients categorized by phenotypes related to small airways (i.e. smoking habits, disease duration, and air trapping). METHODS: Patients received BDP/F as a fixed combination (100/6 µg), administered in 1-2 inhalations twice daily over a period of 12 weeks. Peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), number of asthma attacks, asthma control, and severity of asthma symptoms were evaluated in the overall population and in different subgroups at three different time points. RESULTS: Overall, 213 patients were enrolled. In the overall population the treatment resulted in a significant increase in the proportion of well controlled patients (from 6.1% to 66.3%; p<0.001), and a reduction of uncontrolled subjects (70.3% versus 10.0%; p<0.001). BDP/F was also associated with a reduction in asthma attacks and an improvement of symptoms. These results were confirmed in specific subgroups of patients identified as small airway phenotypes: smokers, elderly patients, those with long duration of disease and air trapping. CONCLUSIONS: This real-life observational study indicates that extrafine BDP/F in a fixed combination improves asthma control and symptoms in the overall population as well as specific subgroups of patients.

Homeostatic synaptic scaling is regulated by protein SUMOylation.

Homeostatic scaling allows neurons to alter synaptic transmission to compensate for changes in network activity. Here, we show that suppression of network activity with tetrodotoxin, which increases surface expression of AMPA receptors (AMPARs), dramatically reduces levels of the deSUMOylating (where SUMO is small ubiquitin-like modifier) enzyme SENP1, leading to a consequent increase in protein SUMOylation. Overexpression of the catalytic domain of SENP1 prevents this scaling effect, and we identify Arc as a SUMO substrate involved in the tetrodotoxin-induced increase in AMPAR surface expression. Thus, protein SUMOylation plays an important and previously unsuspected role in synaptic trafficking of AMPARs that underlies homeostatic scaling.

[Neo-urethroclitoroplasty according to Petrovic]. / La neouretroclitoridoplastica secondo Petrovic.

INTRODUCTION: We present a refinement to our original technique in MtF gender reassignment surgery. Our goal was to construct a neoclitoris, which is wet and covered with urethral neoprepuce. Since 1995 more than 300 transgender MtF patients have been operated at our institution. Our refinement has been applied to 12 cases and showed both excellent functional and cosmetic results during midterm follow-up. PATIENTS AND METHODS: During 2010 several sex reassignment surgeries have been performed using our new technique that includes: bilateral orchiectomy, removal of corpora cavernosa of the penis, formation of the neourethra with neomeatus, neovaginoplasty by inversion of penoscrotal skin flaps, construction of the neoclitoris with preservation of the neurovascular bundle and exterior vulva formation. The refinement consists in creating a neoclitoris embedded in urethral mucosa using urethral flaps. These flaps are in continuity with the previously spatulated urethra. The urethral plate is further incised distally in a Y fashion. The urethral flaps are sutured around the neoclitoris to form a neo-urethroclitoris covered by urethral neoprepuce, which resembles a real female clitoris. The neoclitoris is positioned in the anatomical position of the male suspensory ligament of the penis that is also the natural anatomical position of the female clitoris. RESULTS: With this method we are able to construct a clitoris with a normal sensitivity embedded in urethral mucosa that remains wet and hairless. It can be easily stimulated during sexual intercourse, as most of the patients reported great satisfaction and ability to reach orgasm. DISCUSSION: We want to emphasize how both the cosmetic results and functionality of the neovagina and neoclitoris are important in this type of surgery for the quality of life of our patients. We are still far from a perfect surgical solution, but we are further improving our technique and follow our aims step by step.

Properties of thiamine transport in isolated perfused hearts of chronically alcoholic guinea pigs.

The aim of this study was to determine the mechanism of transport of (14)C-thiamine in the hearts of healthy (nonalcoholic) and chronically alcoholic guinea pigs. We used the single-pass, paired-tracer dilution method on isolated and retrogradely perfused guinea pig hearts. The maximal cellular uptake (U(max)) and total cellular uptake (U(tot)) of (14)C-thiamine were determined under control conditions and under influence of possible modifiers. We tested how the presence of unlabeled thiamine, metabolic inhibitors, or absence of sodium ions influence the transport of (14)C-thiamine. The results of our experiments show that the transport of (14)C-thiamine is specific and energy-dependent and that its properties are significantly changed under the influence of chronic alcoholism. The latter effect occurs by increase in both U(max) and U(tot), as a manifestation of a compensatory mechanism in thiamine deficiency.