Germline Pathogenic Variants Identified in Patients With Genitourinary Malignancies Undergoing Universal Testing: A Multisite Single-Institution Prospective Study.

PURPOSE: This study aimed to investigate the prevalence of pathogenic germline variants (PGVs) in hereditary cancer genes utilizing a universal testing approach and to determine the rate of PGVs that would have been missed based on National Comprehensive Cancer Network (NCCN) guidelines in genitourinary (GU) malignancies. MATERIALS AND METHODS: A multisite, single-institution prospective germline genetic test (GGT) was universally offered to patients with new or active diagnoses of GU malignancies (prostate, bladder, and renal) from April 2018 to March 2020 at Mayo Clinic sites. Participants were offered GGT using a next-generation sequencing panel of > 80 genes. Demographic, tumor characteristics, and genetic results were evaluated. NCCN GU cancer guidelines were used to identify whether patients had incremental findings, defined as PGV-positive patients who would not have received testing based on NCCN guidelines. RESULTS: Of 3095 individuals enrolled in the study, 601 patients had GU cancer (prostate = 358, bladder = 106, and renal = 137). The mean enrollment age was 67 years (SD 9.1), 89% were male, and 86% of patients were non-Hispanic White. PGVs were identified in 82 (14%) of all GU patients. PGV prevalence breakdown by cancer type was: 14% prostate, 14% bladder, and 13% renal cancer. Nearly one-third of identified PGVs were high penetrance, and the majority of these (67%) were clinically actionable. Incremental PGVs were identified in 28 (57%) prostate, 15 (100%) bladder, and 14 (78%) renal cancer patients. Of the 82 patients with PGV findings, 29 (35%) had at least 1 relative undergo cascade testing for the familial variant(s) identified. CONCLUSIONS: More than 1 in 8 patients with GU malignancies were found to carry a PGV, with 67% of patients with high-penetrance PGVs undergoing clinically actionable changes. The majority of these PGVs would not have been identified based on current testing criteria. These findings support universal GGT for GU malignancies and underscore its potential to enhance risk assessment and guide precision interventions in urologic oncology.

Optimal systemic therapy in men with low-volume prostate cancer.

PURPOSE OF REVIEW: Low-volume prostate cancer is an established prognostic category of metastatic hormone-sensitive prostate cancer. However, the term is often loosely used to reflect the low burden of disease across different prostate cancer states. This review explores the definitions of low-volume prostate cancer, biology, and current evidence for treatment. We also explore future directions, including the impact of advanced imaging modalities, particularly prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scans, on refining patient subgroups and treatment strategies for patients with low-volume prostate cancer. RECENT FINDINGS: Recent investigations have attempted to redefine low-volume disease, incorporating factors beyond metastatic burden. Advanced imaging, especially PSMA PET, offers enhanced accuracy in detecting metastases, potentially challenging the conventional definition of low volume. The prognosis and treatment of low-volume prostate cancer may vary by the timing of metastatic presentation. Biomarker-directed consolidative therapy, metastases-directed therapy, and de-escalation of systemic therapies will be increasingly important, especially in patients with metachronous low-volume disease. SUMMARY: In the absence of validated biomarkers, the management of low-volume prostate cancer as defined by CHAARTED criteria may be guided by the timing of metastatic presentation. For metachronous low-volume disease, we recommend novel hormonal therapy (NHT) doublets with or without consolidative metastasis-directed therapy (MDT), and for synchronous low-volume disease, NHT doublets with or without consolidative MDT and prostate-directed radiation. Docetaxel triplets may be a reasonable alternative in some patients with synchronous presentation. There is no clear role of docetaxel doublets in patients with low-volume disease. In the future, a small subset of low-volume diseases with oligometastases selected by genomics and advanced imaging like PSMA PET may achieve long-term remission with MDT with no systemic therapy.

Intolerance of uncertainty and psychological flexibility as predictors of mental health from adolescence to old age.

PURPOSE: The COVID-19 pandemic brought with it significant social, economic and health uncertainties. These were proposed to impact young people more compared to adults, leading adolescents to report more mental health problems during the pandemic. The current study examined whether differences in cognitive risk (tolerance of uncertainty) and protective (psychological flexibility) factors accounted for age-related differences in depression and anxiety. METHODS: These associations were investigated in the COVID-19 Risks Across the Lifespan (CORAL) cohort (N = 2280, 11-89 years). RESULTS: The results showed that adolescents experienced greater intolerance of uncertainty and lower psychological flexibility compared to adults and older adults. Tolerance of uncertainty did not account for age-related differences in depression or anxiety. However, psychological flexibility conferred more protective advantage for anxiety in adults compared to adolescents. CONCLUSION: The observed age-related differences in risk and protective factors advance our understanding of developmental vulnerabilities to depression and anxiety. Implications for mental health interventions in the context of future pandemics are discussed.

Mental Health Provider Reach and Engagement in a Countywide Training Initiative.

Many training initiatives are underway to increase implementation of evidence-based practice (EBPs) in mental healthcare. However, little is known about what types of trainings and supports yield the highest reach and engagement. Supported by a tax-funded, countywide initiative to improve access to quality care for youths, the current mixed methods study evaluates mental health (MH) provider reach, or registering for the training initiative, and engagement, or participation in training activities, for several EBP training and implementation supports. MH providers were offered free 1) formal EBP workshops, 2) a biweekly learning community, 3) individual case consultation, and 4) confidential online clinical feedback system. To register, interested providers (N = 698) completed a web-based assessment measuring clinical practice information, organizational implementation climate, and EBP knowledge, attitudes, and practices. Thirteen providers, selected via purposeful sampling stratified by level of participation, completed semi-structured qualitative interviews. While the training initiative achieved high reach (66% of county agencies had a provider register), far fewer providers engaged substantially in training. Quantitative results indicated that providers whose professional discipline was not psychology, had higher baseline EBP knowledge, more extensive use of common evidence-based strategies, and less extensive use of other therapy strategies, engaged in more training. Rapid qualitative analysis of interviews expanded upon these findings and illuminated provider, organizational, system, practical, and training activity-specific barriers and facilitators to engagement. Findings suggest the importance of identifying strategies for improving provider engagement in training activities beyond workshops. Implications for future research and training initiatives are discussed.

Mapping the role of sexuality in adolescent mental health and substance use.

Individuals who belong to a sexual minority are at greater risk of adverse health and social outcomes. These effects are observed during adolescence when many mental health problems, such as depression, first emerge. Here, we used a network analytic approach to better understand the role that sexual minority status plays in the association between depression, interpersonal difficulties and substance use in a large sample of mid-adolescents. In doing so, we used data from 8017 fourteen year olds from the UK's Millennium Cohort Study, of which 490 self-identified as belonging to a sexual minority. We found that sexual minority status was highly central in the network and connected to multiple adverse outcomes, sometimes directly and sometimes indirectly. The largest single association was between sexual minority status and depression, and this link mediated multiple negative associations with being in a sexual minority. The shortest path to drinking, poor social support and closeness with parents and victimization occurred via depression. The shortest path to smoking and drug use occurred via conduct problems. We also identified three distinct profiles of adverse outcomes among those belonging to a sexual minority, highlighting the heterogeneous nature of this group.

Low PSA radiographic disease progression on C11-choline PET.

Background: For men with prostate cancer, radiographic progression may occur without a concordant rise in prostate-specific antigen (PSA). Our study aimed to assess the prevalence of radiographic progression using C-11 choline positron emission tomography (PET) imaging in patients achieving ultra-low PSA values and to evaluate clinical outcomes in this patient population. Methods: In a single institution study, we reviewed the prospectively maintained Mayo Clinic C-11 Choline PET metastatic prostate cancer registry to identify patients experiencing radiographic disease progression (rDP) on C-11 choline PET scan while the PSA value was less than 0.5 ng/mL. Disease progression was confirmed by tissue biopsy or response to subsequent therapy. Clinicopathologic variables were abstracted by trained research personnel. Overall survival was estimated using the Kaplan-Meier method. Intergroup differences were assessed using the log-rank test. A univariate and multivariate Cox regression model was performed to investigate variables associated with poor survival after rDP. Results: A total of 1323 patients within the registry experienced rDP between 2011 and 2021, including 220 (16.6%) men with rDP occurring at low PSA level. A median (interquartile range [IQR]) of 54.7 (19.7-106.9) months elapsed between the time of prostate cancer diagnosis and low PSA rDP, during which 173 patients (78%) developed castration-resistant prostate cancer (CRPC). Sites of low PSA rDP included local recurrence (n = 17, 8%), lymph node (n = 90, 41%), bone (n = 94, 43%) and visceral metastases (n = 19, 9%). Biopsy at the time of rDP demonstrated small-cell or neuroendocrine features in 21% of patients with available tissue. Over a median (IQR) follow-up of 49.4 (21.3-95.1) months from the time of low PSA rDP, 46% (n = 102) of patients died. Factors associated with poorer survival outcomes include advanced age at rDP, CRPC status, bone and visceral metastasis (p value <0.05). Visceral metastases were associated with decreased overall survival (p = 0.009 by log-rank) as compared with other sites of rDP. Conclusions: Men with prostate cancer commonly experience metastatic progression at very low or even undetectable PSA levels. Periodic imaging, even at low absolute PSA values, may result in more timely identification of disease progression.

Survival Patterns Based on First-site-specific Visceral Metastatic Prostate Cancer: Are Outcomes of Visceral Metastases the Same?

Background and objective: Visceral metastatic disease in prostate cancer patients conveys a poor prognosis. Using advanced imaging techniques, studies have demonstrated increasing detection rates of visceral metastasis. Visceral metastases are now seen in up to 30-60% of prostate cancer patients. Survival patterns of site-specific visceral metastasis are described poorly in the literature. Here, we sought to investigate survival patterns in prostate cancer patients according to their first detected site of visceral metastasis. Methods: Retrospectively, we identified 203 prostate cancer patients with visceral metastases from the Mayo Clinic Advanced Prostate Cancer Registry. Patients were divided into three groups according to the first site of visceral metastases detected: lung, brain, or liver. Visceral metastases were detected primarily on either metabolic imaging (C-11 choline) or prostate-specific membrane antigen positron emission tomography computed tomography (CT) scan. Confirmation of visceral metastasis diagnosis was established with either biopsy when feasible or focused conventional imaging, including focused CT or magnetic resonance imaging. Overall survival and cancer-specific survival were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression model was conducted to assess different variables that affect overall and cancer-specific survival. Key findings and limitations: Over a median (interquartile range) follow-up duration of 16.2 (3.9-49.8) mo, the overall and cancer-specific survival of the entire cohort suggests better survival patterns in patients with first-site lung metastases than in patients with first-site brain or liver metastases (p < 0.0001). In univariate and multivariate analyses of factors impacting patients' overall and cancer-specific survival, a high prostate-specific antigen level at diagnosis of visceral metastasis, concomitant bone and lymph node disease, and more than four visceral metastases were associated with poor overall and cancer-specific survival (p < 0.05). On the contrary, first-site lung metastasis was associated with improved overall and cancer-specific survival, compared with first-site liver and brain metastases (p < 0.001). Conclusions and clinical implications: These data suggest that prostate cancer patients with visceral metastatic disease have varying survival patterns according to first-site detected visceral metastasis. In our cohort, patients with first-site lung metastasis demonstrated better survival outcomes than patients with first-site brain or liver metastasis. Patient summary: Our study explored the survival outcomes among patients with visceral metastatic prostate cancer employing cutting-edge imaging methods. Prostate cancer patients with metastases to different organs have different survival rates. Patients with cancer spreading to the lungs first showed better survival than those with cancer spreading to the brain or liver first.

Salivary toxicity from PSMA-targeted radiopharmaceuticals: What we have learned and where we are going.

Clinical trials of prostate-specific membrane antigen (PSMA) targeted radiopharmaceuticals have shown encouraging results. Some agents, like lutetium-177 [177Lu]Lu-PSMA-617 ([177Lu]Lu-PSMA-617), are already approved for late line treatment of metastatic castration-resistant prostate cancer (mCRPC). Projections are for continued growth of this treatment modality; [177Lu]Lu-PSMA-617 is being studied both in earlier stages of disease and in combination with other anti-cancer therapies. Further, the drug development pipeline is deep with variations of PSMA-targeting radionuclides, including higher energy alpha particles conjugated to PSMA-honing vectors. It is safe to assume that an increasing number of patients will be exposed to PSMA-targeted radiopharmaceuticals during the course of their cancer treatment. In this setting, it is important to better understand and mitigate the most commonly encountered toxicities. One particularly vexing side effect is xerostomia. In this review, we discuss the scope of the problem, inventories to better characterize and monitor this troublesome side effect, and approaches to preserve salivary function and effectively palliate symptoms. This article aims to serve as a useful reference for prescribers of PSMA-targeted radiopharmaceuticals, while also commenting on areas of missing data and opportunities for future research.

Prostate Cancer Lung Metastasis: Clinical Insights and Therapeutic Strategies.

Prostate cancer lung metastasis represents a clinical conundrum due to its implications for advanced disease progression and the complexities it introduces in treatment planning. As the disease progresses to distant sites such as the lung, the clinical management becomes increasingly intricate, requiring tailored therapeutic strategies to address the unique characteristics of metastatic lesions. This review seeks to synthesize the current state of knowledge surrounding prostate cancer metastasis to the lung, shedding light on the diverse array of clinical presentations encountered, ranging from subtle radiological findings to overt symptomatic manifestations. By examining the diagnostic modalities utilized in identifying this metastasis, including advanced imaging techniques and histopathological analyses, this review aims to provide insights into the diagnostic landscape and the challenges associated with accurately characterizing lung metastatic lesions in prostate cancer patients. Moreover, this review delves into the nuances of therapeutic interventions employed in managing prostate cancer lung metastasis, encompassing systemic treatments such as hormonal therapies and chemotherapy, as well as metastasis-directed therapies including surgery and radiotherapy.

First-in-human controlled inhalation of thin graphene oxide nanosheets to study acute cardiorespiratory responses.

Graphene oxide nanomaterials are being developed for wide-ranging applications but are associated with potential safety concerns for human health. We conducted a double-blind randomized controlled study to determine how the inhalation of graphene oxide nanosheets affects acute pulmonary and cardiovascular function. Small and ultrasmall graphene oxide nanosheets at a concentration of 200 µg m-3 or filtered air were inhaled for 2 h by 14 young healthy volunteers in repeated visits. Overall, graphene oxide nanosheet exposure was well tolerated with no adverse effects. Heart rate, blood pressure, lung function and inflammatory markers were unaffected irrespective of graphene oxide particle size. Highly enriched blood proteomics analysis revealed very few differential plasma proteins and thrombus formation was mildly increased in an ex vivo model of arterial injury. Overall, acute inhalation of highly purified and thin nanometre-sized graphene oxide nanosheets was not associated with overt detrimental effects in healthy humans. These findings demonstrate the feasibility of carefully controlled human exposures at a clinical setting for risk assessment of graphene oxide, and lay the foundations for investigating the effects of other two-dimensional nanomaterials in humans. Clinicaltrials.gov ref: NCT03659864.

Deferred cytoreductive nephrectomy in the management of metastatic renal cell carcinoma: A systematic review and meta-analysis.

Deferred cytoreductive nephrectomy (dCN) after upfront systemic therapy has been utilized in the management of select patients with metastatic renal cell carcinoma (mRCC). Herein, we sought to review the current evidence and define oncologic and perioperative outcomes associated with deferred surgical management of newly diagnosed mRCC. Our objective was to critically evaluate the role of dCN in the targeted and immunotherapy eras, comparing oncologic and perioperative outcomes between dCN and upfront CN. Medline, OVID, and Scopus databases were searched for studies evaluating patients undergoing dCN following systemic therapy (ST). PRISMA guidelines were referenced and followed. Outcomes of interest included overall survival (OS), progression free survival (PFS), percent of patients proceeding to dCN, reduction in primary tumor size, complication rates, and perioperative mortality. Random effects meta-analysis was performed comparing overall survival between dCN vs. ST alone and dCN vs. upfront CN. Nineteen studies were included to assess the primary outcomes. The percent of patients proceeding to planned dCN after planned pre-surgical ST ranged from 60.5% to 84%. The most common reason for not undergoing dCN was disease progression on upfront ST. Of patients undergoing dCN, 76% to 96% were able to resume ST postoperatively. OS and PFS ranged from 12.4 to 46 months and 4.5 to 11 months, respectively. Pooled results demonstrated significantly improved OS favoring dCN over upfront CN (hazard ratio, HR = 0.56; 95% CI 0.45-0.69) and ST alone (HR = 0.45; 95% CI 0.38-0.53). Deferred CN represents a potential treatment option in appropriately selected patients with mRCC with a favorable response to upfront systemic therapy. Future randomized trials will be needed to clarify how much this is due to the surgery vs. patient selection.