Jose Ignacio Lopez

The B7‐H family of immune checkpoint proteins plays a central role in tumor immune regulation, yet their prognostic and predictive significance in metastatic clear cell renal cell carcinoma (ccRCC) remains incompletely defined. We analyzed a retrospective cohort of primary tumor specimens from 145 patients with synchronous or metachronous metastatic ccRCC to evaluate the expression of B7‐H3, B7‐H4, B7‐H5, and B7‐H7 and their association with tumor aggressiveness, treatment response, and long‐term survival. Immunohistochemistry revealed marked intratumoral heterogeneity and distinct compartmentalized expression patterns, with B7‐H3 detected in both tumor cells and stromal compartments, B7‐H4 exclusively expressed in tumor cells, B7‐H5 localized to tumor cells and tumor‐infiltrating lymphocytes (TILs), and B7‐H7 detected in both tumor cells and TILs. We did not detect any overlap in expression between B7‐H proteins and PD‐L1 positivity in TILs. High B7‐H3 expression in tumor and stroma was significantly associated with higher histological grade, increased local invasion, lymph node involvement, and advanced stage. B7‐H5 expression in TILs correlated with impaired Eastern Cooperative Oncology Group performance status. Elevated B7‐H3 predicted unfavorable response to tyrosine kinase inhibitors, mechanistic target of rapamycin inhibitors, and immune checkpoint inhibitors, whereas B7‐H5 negativity in tumor cells associated with more favorable treatment outcomes. B7‐H4 and B7‐H7 expression in tumor cells were associated with features of tumor aggressiveness and immune suppression, further highlighting the potential role of multiple B7‐H family checkpoints in metastatic ccRCC. In multivariable Cox regression models, B7‐H3 expression in tumor and stroma independently predicted shorter disease‐free and overall survival. B7‐H5 expression in TILs independently predicted reduced overall survival. These findings identify B7‐H3 as a robust biomarker of tumor aggressiveness, therapeutic resistance, and adverse prognosis in metastatic ccRCC, while B7‐H5 in TILs provides complementary prognostic information. Integrated profiling of B7‐H immune checkpoints in primary tumors may refine clinical risk stratification and support the development of biomarker‐guided immunotherapeutic strategies.

Despite advances in the management of advanced clear cell renal cell carcinoma (ccRCC), robust biomarkers for prognosis and therapeutic response prediction remain elusive. Fibroblast activation protein-α (FAP), a marker of activated cancer-associated fibroblasts (CAFs), has emerged as a potential indicator of tumor aggressiveness and resistance to systemic therapies in various solid tumors. This study evaluated the clinical relevance of stromal FAP expression in a cohort of 137 patients with advanced ccRCC and long-term follow-up. FAP immunohistochemistry (IHC) was performed on primary tumor specimens and correlated with key clinicopathological features, disease-free survival (DFS), overall survival (OS), and radiological response to first-line tyrosine kinase inhibitors (TKIs). A significantly higher percentage of FAP-positive CAFs was observed in primary tumors with high histological grade, extensive local invasion (pT3–4), and advanced clinical stage (NCCN stage III–IV). Stromal FAP expression was associated with shorter DFS and OS. Moreover, tumors lacking FAP expression were more likely to achieve complete response to TKI therapy as defined by RECIST criteria. These findings highlight the potential of FAP IHC as a prognostic and predictive tool in advanced ccRCC and support further clinical validation.

Background/Objectives: Osteoporosis is considered a surgical indication in primary hyperparathyroidism (PHPT), regardless of menopausal status. This pilot study aimed to evaluate the impact of menopause and PHPT on bone mineral density (BMD) and to explore additional clinical factors that may influence bone health. Methods: We conducted an observational pilot study including 204 postmenopausal women with osteopenia or osteoporosis who underwent surgery for sporadic PHPT between 2009 and 2021 at Cruces University Hospital (Spain). Demographic data, anthropometric data, date of last menstrual period, years since menopause (YSM), and the clinical history of bone fragility were collected prior to parathyroidectomy. Biochemical parameters and months with hypercalcemia (MHCa)—as a surrogate for PHPT exposure—were analyzed. BMD results were expressed as a densitometric index, the T-Score. Results: Higher age (p = 0.043), greater body mass index (BMI) (p = 0.039), more YSM (p = 0.027), lower serum calcium levels (s-Ca) (p = 0.04), and glucocorticoid treatment antecedents (GcT) (p = 0.029) were all significantly associated with femoral osteoporosis. Similarly, higher weight (p = 0.004), greater MHCa (p = 0.01), lower height (p = 0.01) and s-Ca levels (p = 0.002) were significantly associated with spinal osteoporosis. Furthermore, logistic regression multivariate analysis determined that femur density was independently influenced by YSM (p < 0.001), s-Ca (p = 0.018), BMI (p = 0.002) and GcT (p = 0.006). Osteoporosis of the spine was also independently associated with YSM (p = 0.036), s-Ca (p = 0.031) and also with body weight (p = 0.003). Conclusions: The duration of menopause (YSM), rather than PHPT severity, is an independent predictor of osteoporosis in postmenopausal women.

Locomotion movements are a fundamental characteristic of a variety of species, including prokaryotic and eukaryotic, that has a high impact in essential physiological and pathological processes. For decades, many different authors have focused on studying specific individual processes and their corresponding biomolecular components involved in cellular locomotion movements. Recently, we have shown that locomotion movements are regulated by integrative self-organized molecular processes operating at systemic level. Here, to verify that said systemic behavior also exists in extreme critical physiological conditions such as those corresponding to enucleated cells, we carried out an extensive study with 200 enucleated cells (cytoplasts) belonging to the Amoeba proteus species. The migratory movements of both enucleated and non-enucleated cells (400 in total) have been individually studied in four different scenarios: in absence of stimuli, under a galvanotactic field, in a chemotactic gradient, and under complex conditions such as simultaneous galvanotactic and chemotactic stimuli. All the experimental trajectories were analyzed using non-linear quantitative metrics for individual cell trajectories. The results show that both non-enucleated amoebas and cytoplasts display the same type of dynamic migratory patterns. The locomotion displacements of enucleated cells are a consequence of complex self-organized molecular dynamics, modulated at a systemic-cytoplasmic level. We have also quantitatively detected that enucleation clearly affects the correlation times and the intensity of the migratory responses of cytoplasts. The fact that cytoplasts preserved the dynamic properties of their migratory trajectories as compared to non-enucleated cells suggests that nuclear activity has a minor role in regulating the locomotion displacements of cells.

Urogenital cancer is very common in the male population of Western countries, a problem of major concern for public health systems, and a frequent test subject for oncological research. In this narrative, we identify the main hot topics for clinics and the basic science of urological cancer in the last few years (from 2021 onwards), considering the information given in the abstracts of almost 300 original articles published in outstanding journals of pathology, urology, and basic science. Once defined, for the top ten list of hot topics (the 2022 WHO update on the classification of urinary and male genital tumors, new entities in kidney cancer, urinary cancer-omics, update on the Gleason grading system, targeted therapies and other novel therapies in renal cancer, news on non-muscle invasive urothelial carcinoma, artificial intelligence in urologic cancer, intratumor heterogeneity influence in therapeutic failures in urologic neoplasms, intratumor microbiome and its influence in urologic tumor aggressiveness, and ecological principles and mathematics applied to urogenital cancer study), each issue is independently reviewed in an attempt to put together the most relevant updates and/or useful features accompanied by selected illustrations. This review article addresses some of the most interesting and current hot spots in urogenital basic cancer research and clinics and is mainly aimed toward clinicians, including pathologists, urologists, and oncologists. Readers are invited to explore each topic for further, more detailed information, in addition to the references provided.

Despite advances in the management of advanced clear cell renal cell carcinoma (ccRCC), robust biomarkers for prognosis and therapeutic response prediction remain elusive. Dysregulation of the intrarenal renin–angiotensin system (RAS) has been implicated in renal carcinogenesis but little explored, particularly regarding biomarker discovery and therapeutic innovation. Consequently, this study investigates the immunohistochemical expression and clinical relevance of the Mas-related G-protein-coupled receptor D (MrgD) in patients with ccRCC who developed metastatic disease (mccRCC). A cohort of 132 patients treated between 2008 and 2018 with nephrectomy and tyrosine kinase inhibitor (TKI)-based sequential therapy was analyzed. Treatment response was assessed using both the MASS and RECIST scoring systems. High MrgD expression in primary tumors was significantly associated with larger size, advanced stage, higher histological grade, and worse overall survival. Among 81 patients with metachronous metastases, high MrgD expression independently predicted shorter disease-free survival. High MrgD staining intensity correlated with poorer TKI responses in first-line therapy but improved outcomes with second-line mTORC1 inhibitors. These findings suggest that MrgD may be a useful biomarker of RAS linked to tumor aggressiveness in ccRCC. MrgD holds potential for identifying high-risk patients and guiding treatment selection in advanced disease. Further research is needed to unlock its clinical potential.

Urological cancer is very common in the male population of Western countries, a problem of major concern for public health systems, and a frequent test bench for oncological research. In this narrative we identify the main hot topics on clinics and basic science of urological cancer in the last few years (from 2021 onwards) considering the information given in the abstracts of almost 300 original articles published in outstanding journals of Pathology, Urology, and Basic Science. Once defined the top-ten list of hot topics (2022 WHO update in the classification of urinary and male genital tumors, new entities in kidney cancer, urinary cancer -omics, update on Gleason grading system, targeted therapies and other novel therapies in renal cancer, news on non-muscle invasive urothelial carcinoma, artificial intelligence in urologic cancer, intratumor heterogeneity influence in therapeutic failures in urologic neoplasms, intratumor microbiome and its influence in urologic tumor aggressiveness, and ecological principles and mathematics applied to urological cancer study), each issue is independently overviewed trying to put together in a succinct manner the most relevant updates and/or useful features accompanied by selected illustrations. This review article goes through some of the most interesting and current hot spots in urological basic cancer research and clinics, and is mainly oriented for clinicians, including pathologists, urologists, and oncologists. Readers are invited to deep into every topic for further, more detailed, information, with the references provided.

Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors (TKIs) are improving the response rates of advanced renal cancer patients. However, many treated patients do not respond, making novel immune checkpoint-based immunotherapies potentially clinically beneficial only for specific groups of patients. We detected high expression of the immune checkpoint protein B7-H3 in clear cell renal cell carcinomas (ccRCCs) and evaluated B7-H3 immunohistochemistry staining in tissue microarray samples from two distinct renal cancer cohorts. B7-H3 was highly expressed in approximately 50% of primary tumors and in 30% of metastatic lesions. B7-H3 expression in primary tumors correlated with tumor necrosis, sarcomatoid transformation, disease-free survival, and synchronous metastasis, while B7-H3 expression in metastasis correlated with metastases to the lymph nodes. Gene expression analysis revealed the association of B7-H3 expression with gene expression scores involved in T cell exhaustion and myeloid immune evasion, as well as with PI3K/AKT and JAK/STAT pathways. Furthermore, knocking down B7-H3 expression in renal cancer cells by siRNA and CRISPR/Cas resulted in lower 2D and 3D cell proliferation and viability as well as increased sensitivity to TKI axitinib. Together, our findings suggest a pro-oncogenic and immune evasive role for B7-H3 in ccRCC and highlight B7-H3 as an actionable novel immune checkpoint protein in combination with TKI in advanced renal cancer.

(1) Objective: To develop a clinically useful nomogram that may provide a more individualized and accurate estimation of cancer-specific survival (CSS) for patients with clear-cell (CC) metastatic renal cell carcinoma (mRCC) treated with nephrectomy and vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI)-based sequential therapy. (2) Methods: A prospectively maintained database of 145 patients with mRCC treated between 2008 and 2018 was analyzed to predict the CSS of patients receiving sunitinib and second- and third-line therapies according to current standards of practice. A nomogram based on four independent clinical predictors (Eastern Cooperative Oncology Group status, International Metastatic RCC Database Consortium score, the Morphology, Attenuation, Size and Structure criteria and Response Evaluation Criteria in Solid Tumors response criteria) was calculated. The corresponding 1- to 10-year CSS probabilities were then determined from the nomogram. (3) Results: The median age was 60 years (95% CI 57.9–61.4). The disease was metastatic at diagnosis in 59 (40.7%), and 86 (59.3%) developed metastasis during follow-up. Patients were followed for a median 48 (IQR 72; 95% CI 56–75.7) months after first-line VEGFR-TKI initiation. The concordance probability estimator value for the nomogram is 0.778 ± 0.02 (mean ± SE). (4) Conclusions: A nomogram to predict CSS in patients with CC mRCC that incorporates patient status, clinical risk classification and response criteria to first-line VEGFR-TKI at 3 months is presented. This new tool may be useful to clinicians assessing the risk and prognosis of patients with mRCC.

(1) Objective: To develop a clinically useful nomogram that may provide a more individualized and accurate estimation of cancer-specific survival (CSS) for patients with clear-cell (CC) metastatic renal cell carcinoma (mRCC) treated with nephrectomy and tyrosine kinase Inhibitor (TKI) based sequential therapy; (2) Methods: A prospectively maintained database of 145 patients with mRCC treated between 2008-2018 was analyzed to predict CSS of patients receiving sunitinib and 2nd and 3rd line therapies according to current standards of practice. A nomogram taking into account four independent clinical predictors (ECOG status, IMDC score, MASS and RECIST response criteria) was calculated. The corresponding 1- to 10-year CSS probabilities were then determined from the nomogram; (3) Results: The median age was 60 years (95% CI 57.9-61.4). Disease was metastatic at diagnosis in 59 (40.7%) and 86 (59.3%) developed metachronous metastasis after nephrectomy. Patients were followed for a median 48 (IQR 72; 95% CI 56-75.7) months after first-line TKI initiation. Concordance probability estimator for the nomogram is 0.778 ± 0.02 (mean ± SE); (4) Conclusions: A nomogram to predict CSS in patients with CC mRCC that incorporates patient status, clinical risk classification and response criteria to first-line TKI at 3 months is presented. This new tool may be useful to clinicians assessing risk and prognosis of patients with mRCC.