The roles of tertiary lymphoid structures in genitourinary cancers: molecular mechanisms, therapeutic strategies, and clinical applications.

The presence of tertiary lymphoid structures (TLSs) associated with distinct treatment efficacy and clinical prognosis has been identified in various cancer types. However, the mechanistic roles and clinical implications of TLSs in genitourinary (GU) cancers remain incompletely explored. Despite their potential role as predictive markers described in numerous studies, it is essential to comprehensively evaluate the characteristics of TLSs, including drivers of formation, structural foundation, cellular compositions, maturation stages, molecular features, and specific functionality to maximize their positive impacts on tumor-specific immunity. The unique contributions of these structures to cancer progression and biology have fueled interest in these structures as mediators of antitumor immunity. Emerging data are trying to explore the effects of therapeutic interventions targeting TLSs. Therefore, a better understanding of the molecular and phenotypic heterogeneity of TLSs may facilitate the development of TLSs-targeting therapeutic strategies to obtain optimal clinical benefits for GU cancers in the setting of immunotherapy. In this review, the authors focus on the phenotypic and functional heterogeneity of TLSs in cancer progression, current therapeutic interventions targeting TLSs and the clinical implications and therapeutic potential of TLSs in GU cancers.

Safety and Effectiveness of Irreversible Electroporation in Lymph Node Metastases.

PURPOSE: Demonstrating the safety and efficacy of percutaneous irreversible electroporation (IRE) for the treatment of lymph node metastases. MATERIALS AND METHODS: An IRB-approved, single-center retrospective review was performed on patients with lymph node metastases gastrointestinal, and genitourinary primary cancers. Primary objective safety was evaluated by assessing complications graded according to the Clavien-Dindo Classification, and efficacy was determined by tumor response on follow-up imaging and local progression-free survival (LPFS). Secondary outcome measures were technical success (complete ablation with an adequate ablative margin > 5 mm), length of hospital stay and distant progression-free survival (DPFS). RESULTS: Nineteen patients underwent percutaneous IRE between June 2018 and February 2023 for lymph node metastases, close to critical structures, such as vasculature, bowel, or nerves. The technical success was achieved in all cases. Complications occurred in four patients (21.1%), including two self-limiting grade 1 hematomas, a grade 1 abdominal pain, and grade 2 nerve pain treated with medication. Seventeen patients were hospitalized overnight, one patient stayed two nights and another patient stayed fourteen nights. Median follow-up was 25.5 months. Median time to local progression was 24.1 months (95% CI: 0-52.8) with 1-, 2-, and 5-year LPFS of 57.9%, 57.9% and 20.7%, respectively. Median time to distant progression was 4.3 months (95% CI: 0.3-8.3) with 1-, 2-, and 5-year DPFS of 31.6%, 13.2% and 13.2%, respectively. CONCLUSION: IRE is a safe and effective minimally-invasive treatment for lymph node metastases in locations, where temperature dependent ablation may be contraindicated. Care should be taken when employing IRE near nerves.

Understanding and overcoming resistance to immunotherapy in genitourinary cancers.

The introduction of novel immunotherapies has significantly transformed the treatment landscape of genitourinary (GU) cancers, even becoming the standard of care in some settings. One such type of immunotherapy, immune checkpoint inhibitors (ICIs) like nivolumab, ipilimumab, pembrolizumab, and atezolizumab play a pivotal role by disturbing signaling pathways that limit the immune system's ability to fight tumor cells. Despite the profound impact of these treatments, not all tumors are responsive. Recent research efforts have been focused on understanding how cancer cells manage to evade the immune response and identifying the possible mechanisms behind resistance to immunotherapy. In response, ICIs are being combined with other treatments to reduce resistance and attack cancer cells through multiple cellular pathways. Additionally, novel, targeted strategies are currently being investigated to develop innovative methods of overcoming resistance and treatment failure. This article presents a comprehensive overview of the mechanisms of immunotherapy resistance in GU cancers as currently described in the literature. It explores studies that have identified genetic markers, cytokines, and proteins that may predict resistance or response to immunotherapy. Additionally, we review current efforts to overcome this resistance, which include combination ICIs and sequential therapies, novel insights into the host immune profile, and new targeted therapies. Various approaches that combine immunotherapy with chemotherapy, targeted therapy, vaccines, and radiation have been studied in an effort to more effectively overcome resistance to immunotherapy. While each of these combination therapies has shown some efficacy in clinical trials, a deeper understanding of the immune system's role underscores the potential of novel targeted therapies as a particularly promising area of current research. Currently, several targeted agents are in development, along with the identification of key immune mediators involved in immunotherapy resistance. Further research is necessary to identify predictors of response.

Immunotherapy has transformed the treatment landscape for many cancer types, including genitourinary malignancies such as renal and bladder cancers.However, not all patients or tumor types, such as prostate cancer, respond to this type of treatment.Understanding the mechanisms of immunotherapy resistance is critical for developing strategies to overcome these challenges.Primary resistance, which is present at the onset of treatment, can bedue to genetic abnormalities or immune system dysregulation. These factors alter the interactions between host cells and cancer cells.Adaptive resistance develops during therapy due to dynamic changes in the levels of growth factors, cytokines, and the tumor microenvironment (TME).Acquired resistance mainly occurs at the genetic and translational levels, involving the downregulation of critical human leukocyte antigen (HLA) molecules and interference with mutational repair.Future therapies may focus on detailed genetic profiling of patients to guide treatment selection and on the use of immune profile monitoring to assist in assessing responsiveness, alongside developing novel targeted therapies and ICIs.Further research is needed to identify predictors of response to ICIs.

Integrating Palliative Care Into the Management of Genitourinary Malignancies.

Palliative care (PC) plays a critical role in managing the difficulties associated with genitourinary malignancies. Its primary aim is to improve the overall health of patients, provide support to both patients and their caregivers, and help individuals to navigate the complex decisions about treatment and end-of-life care. PC takes a holistic approach to patient care, recognizing that genitourinary malignancies affect multiple aspects of a person's life. By addressing physical, emotional, social, and spiritual needs, PC aims to provide comprehensive support that is consistent with the patient's values and preferences. The goal is to optimize comfort, minimize distress, and enhance the patient's quality of life throughout the course of the illness. PC is not a one-off intervention, but an ongoing source of support. This article aims to provide a thorough overview of the critical elements involved in addressing the challenges posed by genitourinary cancers, emphasizing the importance of palliative interventions. We will highlight the multifaceted aspects of care and explore strategies to optimize the overall well-being of patients throughout the course of treatment for genitourinary malignancies.

Role of Metastasis-Directed Therapy in Genitourinary Cancers.

OPINION STATEMENT: The treatment of oligometastatic genitourinary cancers is a rapidly advancing field with ablative radiotherapy as one of the critical treatment components. The oligometastatic disease state, which can be defined as 1-5 metastatic sites with a controlled primary, represents a distinct clinical state where comprehensive ablative local therapies may provide improved outcomes. Enhanced imaging has increased the number of patients identified with oligometastatic disease. Evidence for improved outcomes with metastasis-directed therapy (MDT) in oligometastatic genitourinary cancers is increasing, and previously published outcome data continues to mature with an increasing body of prospective data to inform the role of MDT in histology-specific settings or in the context of systemic therapy. In select patients, MDT can offer benefits beyond improved local control and allow for time off of systemic therapy, prolonged time until next therapy, or even the hope of cure. However, treatment decisions for locally ablative therapy must be balanced with consideration towards safety. There are exciting advances in technologies to target and adapt treatment in real-time which have expanded options for safer delivery and dose escalation to metastatic targets near critical organs at risk. The role of systemic therapies in conjunction with MDT and incorporation of tumor genetic information to further refine prognostication and treatment decision-making in the oligometastatic setting is actively being investigated. These developments highlight the evolving field of treatment of oligometastatic disease. Future prospective studies combining MDT with enhanced imaging and integrating MDT with evolving systemic therapies will enable the optimal selection of patients most likely to benefit from this "all-or-none" approach and reveal settings in which a combination of therapies could result in synergistic outcomes.

Gender inequality in genitourinary malignancies clinical trials leadership.

BACKGROUND: Over the past 2 decades, there has been a growing interest in the significance of gender roles in healthcare and several efforts and initiatives have focused on increasing female representation in the medical field. Clinical trials play a very important role in shaping medical practice; moreover, the leaders of clinical trials often represent the upper echelon of researchers in any designated field. Presently, there is no data regarding women's representation in urological oncology clinical trials leadership. Therefore, the aim of this study is to examine the extent of female representation in leading urological clinical trials. METHODOLOGY: To thoroughly examine the representation of females as principal investigators (PIs) in urological cancer clinical trials between 2000 and 2020, we conducted a comprehensive search of completed trials focused on kidney, prostate, and bladder cancer on ClinicalTrials.gov. We extracted relevant information regarding the PIs and analyzed the data using univariate analyses to identify any significant differences between male and female PIs. RESULTS: A total of 9145 cancer clinical trials were conducted over the last 2 decades, and 11.3% (n = 1033) of them were urological cancer clinical trials. We were able to obtain detailed information about the principal investigators (PI) in 79.0% (n = 816) of the clinical trials, and we found that 16.8% (n = 137) of them were led by female investigators. Upon evaluating the characteristics of the PIs, female PIs had a significantly lower median age and median total citations as compared to male PIs (55.0 vs 59.0 and 5333 vs 7902; p-value < 0.001 and 0.006, respectively). However, there was no statistically significant difference between the termination rate, publication rate, funding source, cancer type, and the subject of conducting the clinical trials between male and female PIs. CONCLUSION: Between 2000 and 2020, only 16.8% of urological cancer clinical trials were led by a female PI, perhaps reflective of a low percentage of senior female researchers in the fields of urology, oncology and radiation oncology. Universities, research institutes and funding agencies should work to improve mentorship, representation and opportunities for female investigators to encourage more involvement for female researchers in these clinical trials.

Criteria and indicators to evaluate quality of care in genitourinary tumour boards.

PURPOSE: Genitourinary (GU) multidisciplinary tumour boards (GUMTBs) are key components of patient care, as they might lead to changes in treatment plan, improved survival, and increased adherence to guidelines. However, there are no guidelines on how GUMTBs should operate or how to assess their quality of performance. METHODS: A systematic literature review was conducted to identify criteria and indicators to evaluate quality in GUMTBs. A scientific committee-comprising 12 GU cancer specialists from seven disciplines-proposed a list of criteria and developed indicators, evaluated in two rounds of Delphi method. Appropriateness and utility of indicators were scored using a 9-point Likert scale. Consensus was defined as at least two-thirds of Delphi respondents selecting a score sub-category that encompassed the median score of the group. RESULTS: Forty-five criteria were selected to evaluate the quality of GUMTBs covering five dimensions: organisation, personnel, protocol and documentation, resources, and interaction with patients. Then, 33 indicators were developed and evaluated in the first round of Delphi, leading to a selection of 26 indicators in two dimensions: function, governance and resources, and GUMTB sessions. In the second round, consensus was reached on the appropriateness of all 26 indicators and on the utility of 24 of them. Index cards for criteria and indicators were developed to be used in clinical practice. CONCLUSIONS: Criteria and indicators were developed to evaluate the quality of GUMTBs, aiming to serve as a guide to improve quality of care and health outcomes in patients with GU cancer.

Redefining Rare Genitourinary Cancers: An Initiative Led by the Global Society of Rare Genitourinary Tumors.

Rare cancers account for 20-25% of all cancers diagnosed annually but there is no consensus on the definition of a rare cancer and substantial geographic heterogeneity. The Global Society of Rare Genitourinary Tumors is dedicated to education and research for rare genitourinary tumors.

A clinical overview of people living with HIV and genitourinary cancer care.

The number of people living with HIV infection has been increasing globally. Administration of antiretroviral therapy is effective in controlling the infection for most patients and, as a consequence, people living with HIV (PLWH) now often have a long life expectancy. However, their risk of developing cancer - most notably virus-related cancers - has been increasing. To date, few studies have assessed the risk of genitourinary cancers in PLWH, and robust scientific data on their treatment-related outcomes are lacking. Previous studies have noted that PLWH are at a reduced risk of prostate cancer; however, low adoption and/or availability of prostate cancer screening among these patients might be confounding the validity of this finding. In genitourinary cancers, advanced stage at diagnosis and reduced cancer-specific mortality have been reported in PLWH. These data likely reflect, at least in part, the inequity of health care access for PLWH. Notably, systemic chemotherapy and/or radiotherapy could decrease total CD4+ cell counts, which could, therefore, increase the risk of morbidity and mortality from cancer treatments in PLWH. Immune checkpoint inhibitors have become the therapeutic backbone for many advanced malignancies in the general population; however, most studies validating their efficacy have excluded PLWH owing to concerns of severe adverse effects from immune checkpoint inhibitors themselves and/or related to their immunosuppressed status. To our knowledge, no genitourinary cancer survivorship programme exists that specifically caters to the needs of PLWH. By including PLWH in ongoing cancer trials, we can gain invaluable insights that will help to improve cancer care specifically for PLWH.

Genitourinary cancers updates: highlights from ASCO 2023.

Significant scientific advances in immunotherapy and targeted therapy approaches have improved clinical outcomes and increased treatment options for patients with genitourinary (GU) malignancies. We highlight the clinical trial developments released at the ASCO 2023 annual meeting, including PARP inhibitors for prostate cancer, antibody drug conjugates and fibroblast growth factor receptor inhibitors for urothelial cancer, and HIF2a inhibitors for renal cell carcinoma. Novel agents such as bispecific antibodies, chimeric antigen receptor T-cells, and radiopharmaceuticals are currently in early phase development and also have high potential impact for the GU cancer landscape. With more treatment options, the field will need to define best treatment sequencing to optimize outcomes for each patient.

Prognostic value of various nutritional risk markers in patients hospitalized for the treatment of genitourinary cancer: A retrospective study.

BACKGROUND & AIMS: Because malnutrition adversely affects the prognosis of patients with cancer, accurate nutritional status assessment is important. Therefore, this study aimed to verify the prognostic value of various nutritional assessment tools and compare their predictability. METHODS: We retrospectively enrolled 200 patients hospitalized for genitourinary cancer between April 2018 and December 2021. Four nutritional risk markers, namely, Subjective Global Assessment (SGA) score, Mini-Nutritional Assessment-Short Form (MNA-SF) score, Controlling Nutritional Status (CONUT) score, and Geriatric Nutritional Risk Index (GNRI), were measured at admission. The endpoint was all-cause mortality. RESULTS: SGA, MNA-SF, CONUT, and GNRI values were all independent predictors of all-cause mortality (hazard ratio [HR] = 7.72, 95% confidence interval [CI]: 1.75-34.1, P = 0.007; HR = 0.83, 95% CI: 0.75-0.93, P = 0.001; HR = 1.29, 95% CI: 1.16-1.43, P < 0.001; and HR = 0.95, 95% CI: 0.93-0.98, P < 0.001, respectively) even after adjustment for age, sex, cancer stage, and surgery or medication. However, in the model discrimination analysis, the net reclassification improvement of the CONUT model (vs. SGA: 0.420, P = 0.006 and vs. MNA-SF: 0.57, P < 0.001) and GNRI model (vs. SGA: 0.59, P < 0.001 and vs. MNA-SF: 0.671, P < 0.001) were significantly improved compared to the SGA and MNA-SF models, respectively. The combination of CONUT and GNRI models also had the highest predictability (C-index = 0.892). CONCLUSIONS: Objective nutritional assessment tools were superior to subjective nutritional tools in predicting all-cause mortality in inpatients with genitourinary cancer. Measurement of both the CONUT score and GNRI might contribute to a more accurate prediction.

CD24 targeting with NK-CAR immunotherapy in testis, prostate, renal and (luminal-type) bladder cancer and identification of direct CD24 interaction partners.

Alternative therapeutic options targeting urologic malignancies, such as germ cell tumours, as well as urothelial, renal and prostate carcinomas, are still urgently needed. The membrane protein CD24 represents a promising immunotherapeutical approach. The present study aimed to decipher the molecular function of CD24 in vitro and evaluate the cytotoxic capacity of a third-generation natural killer (NK) cell chimeric antigen receptor (CAR) against CD24 in urologic tumour cell lines. Up to 20 urologic tumour cell lines and several non-malignant control cells were included. XTT viability assays and annexin V/propidium iodide flow cytometry analyses were performed to measure cell viability and apoptosis rates, respectively. Co-immunoprecipitation followed by mass spectrometry analyses identified direct interaction partners of CD24. Luciferase reporter assays were used to functionally validate transactivation of CD24 expression by SOX2. N- and O-glycosylation of CD24 were evaluated by enzymatic digestion and mass spectrometry. The study demonstrates that SOX2 transactivates CD24 expression in embryonal carcinoma cells. In cells of different urological origins, CD24 interacted with proteins involved in cell adhesion, ATP binding, phosphoprotein binding and post-translational modifications, such as histone acetylation and ubiquitination. Treatment of urological tumour cells with NK-CD24-CAR cells resulted in a decreased cell viability and apoptosis induction specifically in CD24+ tumour cells. Limitations of the study include the in vitro setting, which still has to be confirmed in vivo. In conclusion, we show that CD24 is a promising novel target for immune therapeutic approaches targeting urologic malignancies.

Adaptive Immunity in Genitourinary Cancers.

CONTEXT: While urothelial and renal cell cancers have exhibited modest responses to novel immune checkpoint inhibitors targeting the programmed death ligand 1 and its receptor, response rates in patients with prostate cancer have remained poor. The factors underlying suboptimal outcomes observed in patients treated with novel immunotherapies are still to be resolved. OBJECTIVE: To review the literature and describe the key adaptive immune physiological events associated with cancer progression and therapeutic response in genitourinary (GU) cancers. EVIDENCE ACQUISITION: We performed a nonsystematic, collaborative narrative review to highlight recent advancements leading to the current state of knowledge on the critical mediators of antitumor adaptive immunity to GU cancers. Further, we discuss the findings on the pre- and post-treatment immunological events that either are unique to each of the three cancer types or exhibit overlapping clinical associations. EVIDENCE SYNTHESIS: Aging-associated immune function decline is a major factor underlying poor outcomes observed in patients treated with both conventional and novel immunotherapies. Other cancer immunobiological aspects associated with suboptimal responses in GU cancers include the overall tumor mutational burden, mutations in specific tumor suppressor/DNA damage repair genes (KDM6A, PTEN, STAG2, TP53, ATM, and BRCA2), and abundance of multiple functional states of adaptive immune cells and their spatiotemporal localization within the tumor immune microenvironment. Understanding these mechanisms may potentially lead to the development of prognostic and predictive biomarkers such as immune cell infiltration profiles and tertiary lymphoid structures (TLSs) that associate with variable clinical outcomes depending on the nature of the novel immunotherapeutic approach. Implementation of newer immune-monitoring technologies and improved preclinical modeling systems will augment our understanding of the host and tumor intrinsic factors contributing to the variability of responses to immunotherapies. CONCLUSIONS: Despite the tremendous progress made in the understanding of dynamic and static adaptive immune elements within the tumor immune landscape, several knowledge gaps remain. A comprehensive knowledge thus gained will lead to precision immunotherapy, improved drug sequencing, and a therapeutic response. PATIENT SUMMARY: We performed a collaborative review by a diverse group of experts in the field to examine our understanding of the events and crosstalk between cancer cells and the patient's immune system that are associated with responses to novel immunotherapies. An evolving understanding of tumor-intrinsic and host-related immune alterations, both before and after therapy, will aid in the discovery of promising markers of responses to immunotherapy as well as the development of unique therapeutic approaches for the management of genitourinary cancers.

[Alternative medicine in uro-oncology]. / Alternativmedizin in der Uroonkologie.

BACKGROUND: Alternative medicine is used instead of conventional therapy. Some patients use it in parallel with conventional medicine. OBJECTIVE: Narrative compilation of the evidence on alternative medicine in the (uro)oncological context. MATERIALS AND METHODS: A selective literature search in MEDLINE via PubMed was performed. RESULTS: The data on 3­bromopyruvate, Miracle Mineral Supplement (MMS), insulin-potentiated therapy, base therapy, hyperthermia, Artemisia annua, amygdalin (vitamin B17), Amanita therapy, homeopathy, apitherapy, dendritic cells, galavit, Germanic new medicine, and spiritual healing show either no or little clinical evidence of efficacy or clearly exhibit a negative benefit-risk profile. CONCLUSIONS: Alternative medicine is pseudo-medicine that may have a positive effect on mental well-being in the short term, but is mostly associated with disadvantages for the patient in the long term.