Cabozantinib Plus Nivolumab in Patients with Non-Clear Cell Renal Cell Carcinoma: Updated Results from a Phase 2 Trial.

Treatment options are limited for patients with non-clear cell renal cell carcinoma (nccRCC). Patients with nccRCC experienced a favorable objective response rate (ORR) in a phase 2 trial of cabozantinib plus nivolumab. We now report updated efficacy and safety results at median follow-up of 34 mo for patients with papillary, unclassified, or translocation-associated RCC. Cabozantinib and nivolumab were administered at standard doses to patients with metastatic nccRCC that had progressed on zero or one line of systemic therapy. The primary endpoint was the ORR according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Forty patients were treated. At median follow-up of 34 mo for survivors, the ORR was 48% (95% confidence interval [CI] 31.5-63.9%). Median PFS was 13 mo (95% CI 7-16); the 12-mo and 24-mo PFS rates were 51% (95% CI 34-65%) and 23% (95% CI 11-37%), respectively. Median OS was 28 mo (95% CI 23-43); the 18-mo and 36-mo OS rates were 70% (95% CI 53-82%) and 44% (95% CI 28-60%), respectively. No new safety signals were seen with cabozantinib and nivolumab. This extended follow-up analysis demonstrates promising efficacy, and highlights the potential for sustained responses with cabozantinib plus nivolumab in patients with metastatic nccRCC. PATIENT SUMMARY: We evaluated outcomes for patients with metastatic kidney cancer of the non-clear cell (NCC) type who were treated with cabozantinib + nivolumab. We found that 48% of the patients responded to the treatment, and there were no unexpected side effects. Among patients who responded to the treatment, the response lasted for a median of 17 months. We conclude that cabozantinib + nivolumab is a safe and effective treatment for NCC kidney cancer.

Edge roughness quantifies impact of physician variation on training and performance of deep learning auto-segmentation models for the esophagus.

Manual segmentation of tumors and organs-at-risk (OAR) in 3D imaging for radiation-therapy planning is time-consuming and subject to variation between different observers. Artificial intelligence (AI) can assist with segmentation, but challenges exist in ensuring high-quality segmentation, especially for small, variable structures, such as the esophagus. We investigated the effect of variation in segmentation quality and style of physicians for training deep-learning models for esophagus segmentation and proposed a new metric, edge roughness, for evaluating/quantifying slice-to-slice inconsistency. This study includes a real-world cohort of 394 patients who each received radiation therapy (mainly for lung cancer). Segmentation of the esophagus was performed by 8 physicians as part of routine clinical care. We evaluated manual segmentation by comparing the length and edge roughness of segmentations among physicians to analyze inconsistencies. We trained eight multiple- and individual-physician segmentation models in total, based on U-Net architectures and residual backbones. We used the volumetric Dice coefficient to measure the performance for each model. We proposed a metric, edge roughness, to quantify the shift of segmentation among adjacent slices by calculating the curvature of edges of the 2D sagittal- and coronal-view projections. The auto-segmentation model trained on multiple physicians (MD1-7) achieved the highest mean Dice of 73.7 ± 14.8%. The individual-physician model (MD7) with the highest edge roughness (mean ± SD: 0.106 ± 0.016) demonstrated significantly lower volumetric Dice for test cases compared with other individual models (MD7: 58.5 ± 15.8%, MD6: 67.1 ± 16.8%, p < 0.001). A multiple-physician model trained after removing the MD7 data resulted in fewer outliers (e.g., Dice ≤ 40%: 4 cases for MD1-6, 7 cases for MD1-7, Ntotal = 394). While we initially detected this pattern in a single clinician, we validated the edge roughness metric across the entire dataset. The model trained with the lowest-quantile edge roughness (MDER-Q1, Ntrain = 62) achieved significantly higher Dice (Ntest = 270) than the model trained with the highest-quantile ones (MDER-Q4, Ntrain = 62) (MDER-Q1: 67.8 ± 14.8%, MDER-Q4: 62.8 ± 15.7%, p < 0.001). This study demonstrates that there is significant variation in style and quality in manual segmentations in clinical care, and that training AI auto-segmentation algorithms from real-world, clinical datasets may result in unexpectedly under-performing algorithms with the inclusion of outliers. Importantly, this study provides a novel evaluation metric, edge roughness, to quantify physician variation in segmentation which will allow developers to filter clinical training data to optimize model performance.

Genomic ancestry in kidney cancer: Correlations with clinical and molecular features.

INTRODUCTION: Genetic ancestry (GA) refers to population hereditary patterns that contribute to phenotypic differences seen among race/ethnicity groups, and differences among GA groups may highlight unique biological determinants that add to our understanding of health care disparities. METHODS: A retrospective review of patients with renal cell carcinoma (RCC) was performed and correlated GA with clinicopathologic, somatic, and germline molecular data. All patients underwent next-generation sequencing of normal and tumor DNA using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, and contribution of African (AFR), East Asian (EAS), European (EUR), Native American, and South Asian (SAS) ancestry was inferred through supervised ADMIXTURE. Molecular data was compared across GA groups by Fisher exact test and Kruskal-Wallis test. RESULTS: In 953 patients with RCC, the GA distribution was: EUR (78%), AFR (4.9%), EAS (2.5%), SAS (2%), Native American (0.2%), and Admixed (12.2%). GA distribution varied by tumor histology and international metastatic RCC database consortium disease risk status (intermediate-poor: EUR 58%, AFR 88%, EAS 74%, and SAS 73%). Pathogenic/likely pathogenic germline variants in cancer-predisposition genes varied (16% EUR, 23% AFR, 8% EAS, and 0% SAS), and most occurred in CHEK2 in EUR (3.1%) and FH in AFR (15.4%). In patients with clear cell RCC, somatic alteration incidence varied with significant enrichment in BAP1 alterations (EUR 17%, AFR 50%, SAS 29%; p = .01). Comparing AFR and EUR groups within The Cancer Genome Atlas, significant differences were identified in angiogenesis and inflammatory pathways. CONCLUSION: Differences in clinical and molecular data by GA highlight population-specific variations in patients with RCC. Exploration of both genetic and nongenetic variables remains critical to optimize efforts to overcome health-related disparities.

Exploring published and novel pre-treatment CT and PET radiomics to stratify risk of progression among early-stage non-small cell lung cancer patients treated with stereotactic radiation.

PURPOSE: Disease progression after definitive stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) occurs in 20-40% of patients. Here, we explored published and novel pre-treatment CT and PET radiomics features to identify patients at risk of progression. MATERIALS/METHODS: Published CT and PET features were identified and explored along with 15 other CT and PET features in 408 consecutively treated early-stage NSCLC patients having CT and PET < 3 months pre-SBRT (training/set-aside validation subsets: n = 286/122). Features were associated with progression-free survival (PFS) using bootstrapped Cox regression (Bonferroni-corrected univariate predictor: p ≤ 0.002) and only non-strongly correlated predictors were retained (|Rs|<0.70) in forward-stepwise multivariate analysis. RESULTS: Tumor diameter and SUVmax were the two most frequently reported features associated with progression/survival (in 6/20 and 10/20 identified studies). These two features and 12 of the 15 additional features (CT: 6; PET: 6) were candidate PFS predictors. A re-fitted model including diameter and SUVmax presented with the best performance (c-index: 0.78; log-rank p-value < 0.0001). A model built with the two best additional features (CTspiculation1 and SUVentropy) had a c-index of 0.75 (log-rank p-value < 0.0001). CONCLUSIONS: A re-fitted pre-treatment model using the two most frequently published features - tumor diameter and SUVmax - successfully stratified early-stage NSCLC patients by PFS after receiving SBRT.

'Ageing well': Discursive constructions of ageing and health in the public reach of a national longitudinal study on ageing.

Established in 2006, the Irish Longitudinal Study on Ageing (TILDA) investigates the health, economic and social circumstances of a nationally-representative sample of people aged fifty years and older in a series of biennial data collection waves. Irish newspapers have been reporting the results of TILDA for over a decade and a half, and their texts represent reports of scientific research distilled through the pen of journalists. In their totality, their texts constitute a public discourse on ageing and health. Using critical discourse analysis, we examined the discourse within the texts of a purposive sample of two national daily newspapers. As sites of public discourse, newspapers reflect social life and are influential in forming and legitimating public attitudes. Like other sites of discourse, their language-in-use is contextually located, is rarely neutral and may employ strategies to discursively construct, sustain and privilege particular social identities, including ageing identities. Discursively constructed as 'ageing well', our analysis of newspaper texts revealed a discernible meta-discourse on ageing and health in which ageing was framed as a life course stage that may be cultivated, diligently self-nurtured and exploited for its positive aspects. When considered in light of literature on health and social inequalities, the consequences of this broadly positive ageing discourse can, somewhat perversely, frame older adults in unintended negative ways, including homogenising them and attributing to them capacities for ageing well that they may not possess. Discursively constructing older adults as a social and economic resource can also impose unrealistic expectations on them and may legitimise exploitation and demonstrate how normative ideologies of ageism and ableism are conveyed through legitimising language. Despite these potentially unintended consequences, the available media resources associated with TILDA may represent one of the most important contributions of the study, in terms of informing positive public attitudes towards ageing.

Amplification of Wild-Type RET Represents a Novel Molecular Subtype of Several Cancer Types With Clinical Response to Selpercatinib.

PURPOSE: RET rearrangements and RET activating point mutations represent targetable genomic alterations in advanced solid tumors. However, the frequency and clinicopathologic characteristics of wild-type RET amplification in cancer and its potential role as a targetable oncogenic driver are not well-characterized. METHODS: In two institutional cohorts of patients with solid cancers from the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC) whose tumors underwent next-generation sequencing (NGS), the frequency and clinicopathologic features of wild-type RET amplification in the absence of RET rearrangements or activating mutations was assessed. The findings were validated using merged data from The Cancer Genome Atlas (TCGA), Genomics Evidence Neoplasia Information Exchange (GENIE), and China Pan-Cancer data sets. RESULTS: The frequency of wild-type RET amplification across all solid cancers was 0.08% (26 of 32,505) in the DFCI cohort, 0.05% (26 of 53,152) in the MSKCC cohort, and 0.25% (71 of 28,623) in the cohort from TCGA, GENIE, and China Pan-Cancer. Cancer types with RET amplification included non-small-cell lung cancer (NSCLC), hepatobiliary cancer, prostate cancer, breast cancer, and others. The median RET copy number in RET-amplified cases was 7.5 (range, 6-36) in the DFCI cohort and 5.7 (range, 4-27.7) in the MSKCC cohort. Among 11 RET-amplified NSCLCs, eight had no other concurrent driver mutations. Finally, we report on a 69-year-old man with recurrent NSCLC harboring high-level wild-type RET amplification (22-28 copies) as the only identified putative genomic driver who experienced both a systemic and intracranial confirmed response to the RET inhibitor selpercatinib. CONCLUSION: Amplification of wild-type RET represents a novel, targetable molecular subset of cancer.

Pneumonitis in Patients Receiving Thoracic Radiotherapy and Osimertinib: A Multi-Institutional Study.

Introduction: Thoracic radiotherapy (TRT) is increasingly used in patients receiving osimertinib for advanced NSCLC, and the risk of pneumonitis is not established. We investigated the risk of pneumonitis and potential risk factors in this population. Methods: We performed a multi-institutional retrospective analysis of patients under active treatment with osimertinib who received TRT between April 2016 and July 2022 at two institutions. Clinical characteristics, including whether osimertinib was held during TRT and pneumonitis incidence and grade (Common Terminology Criteria for Adverse Events version 5.0) were documented. Logistic regression analysis was performed to identify risk factors associated with grade 2 or higher (2+) pneumonitis. Results: The median follow-up was 10.2 months (range: 1.9-53.2). Of 102 patients, 14 (13.7%) developed grade 2+ pneumonitis, with a median time to pneumonitis of 3.2 months (range: 1.5-6.3). Pneumonitis risk was not significantly increased in patients who continued osimertinib during TRT compared with patients who held osimertinib during TRT (9.1% versus 15.0%, p = 0.729). Three patients (2.9%) had grade 3 pneumonitis, none had grade 4, and two patients had grade 5 events (2.0%, diagnosed 3.2 mo and 4.4 mo post-TRT). Mean lung dose was associated with the development of grade 2+ pneumonitis in multivariate analysis (OR = 1.19, p = 0.021). Conclusions: Although the overall rate of pneumonitis in patients receiving TRT and osimertinib was relatively low, there was a small risk of severe toxicity. The mean lung dose was associated with an increased risk of developing pneumonitis. These findings inform decision-making for patients and providers.

Gerontological education: a pathway towards advancing the rights of older people.

Following the UN Human Rights Declaration in 1948, much effort has been undertaken to formalize the rights of older people. This article aims to highlight the role of education in advancing the rights of older people. Raising awareness and sharing knowledge about the rights of older people through rights-based education can empower students, when entering their field of work, to be advocates for rights within their employment settings and local communities. The effectiveness of a rights-based educational training for organizations working with refugees in Jordan, which took place in Amman in January 2020, is analyzed using the participant-focused Transformative Human Rights Education (THRED) as a framing structure. Our analysis found that training participants became active in promoting the rights of older people in their workplaces. The rights of older people need to be more than a conversation, and transformational change that promotes rights can occur when people feel empowered to undertake action-oriented advocacy. The case study analysis provides an example of how influential participant-centered pedagogy, such as THRED, can be to help students in gerontology programs become active agents in promoting rights of older people in their workplaces, communities, and ultimately influencing the international dialogue.

Radiotherapy Dose in Patients Receiving Immunotherapy.

There is significant rationale for combining radiation therapy (RT) and immuno-oncology (IO) agents, but the optimal radiation parameters are unknown. This review summarizes key trials in the RT and IO space with a focus on RT dose. Very low RT doses solely modulate the tumor immune microenvironment, intermediate doses both modulate the tumor immune microenvironment and kill some fraction of tumor cells, and ablative doses eliminate the majority of target tumor cells and also possess immunomodulatory effects. Ablative RT doses may have high toxicity if targets are adjacent to radiosensitive normal organs. The majority of completed trials have been conducted in the setting of metastatic disease and direct RT to a single lesion with the goal of generating systemic antitumor immunity termed the abscopal effect. Unfortunately, reliable generation of an abscopal effect has proved elusive over a range of radiation doses. Newer trials are exploring the effects of delivering RT to all or most sites of metastatic disease, with dose personalization based on the number and location of lesions. Additional directions include testing RT and IO in earlier stages of disease, sometimes in further combination with chemotherapy and surgery, where lower doses of RT may still contribute substantially to pathologic responses.

Adjuvant therapy options in renal cell carcinoma - targeting the metastatic cascade.

Localized renal cell carcinoma (RCC) is primarily managed with nephrectomy, which is performed with curative intent. However, disease recurs in ~20% of patients. Treatment with adjuvant therapies is used after surgery with the intention of curing additional patients by disrupting the establishment, maturation or survival of micrometastases, processes collectively referred to as the metastatic cascade. Immune checkpoint inhibitors and vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitors (TKIs) have shown efficacy in the treatment of metastatic RCC, increasing the interest in the utility of these agents in the adjuvant setting. Pembrolizumab, an inhibitor of the immune checkpoint PD1, is now approved by the FDA and is under review by European regulatory agencies for the adjuvant treatment of patients with localized resected clear cell RCC based on the results of the KEYNOTE-564 trial. However, the optimal use of immunotherapy and VEGFR-targeting TKIs for adjuvant treatment of RCC is not completely understood. These agents disrupt the metastatic cascade at multiple steps, providing biological rationale for further investigating the applications of these therapeutics in the adjuvant setting. Clinical trials to evaluate adjuvant therapeutics in RCC are ongoing, and clinical considerations must guide the practical use of immunotherapy and TKI agents for the adjuvant treatment of localized resected RCC.

Progression-free Survival After Second Line of Therapy for Metastatic Clear Cell Renal Cell Carcinoma in Patients Treated with First-line Immunotherapy Combinations.

Immunotherapy (IO)-based combinations used to treat metastatic clear cell renal cell carcinoma (ccRCC) include dual immune checkpoint inhibition with ipilimumab and nivolumab (IO/IO) and several combinations of vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (TKIs) with an immune checkpoint inhibitor (TKI/IO). IO/IO and TKI/IO approaches have not been compared directly, and it is unknown whether patients who do not respond to first-line IO/IO can salvage long-term survival by receiving a second-line TKI. Progression-free survival after second-line therapy (PFS-2) evaluates the ability to be salvaged by second-line therapy. We retrospectively evaluated 173 patients treated with first-line IO/IO or TKI/IO for metastatic ccRCC at Memorial Sloan Kettering Cancer Center and report PFS-2, overall survival, and response to second line of therapy (ORR2nd) for groups defined by first-line category. Although ORR2nd was significantly higher with IO/IO than with TKI/IO (47% vs 13%, p < 0.001), there was no significant difference in median PFS-2 for TKI/IO versus IO/IO (44 vs 23 mo, log-rank p = 0.1) or restricted mean survival time (RMST) for PFS-2 when adjusted for propensity score (33 vs 30 mo; difference 2.6 mo [95% confidence interval {CI}: -2.6, 7.9]; p = 0.3). There was also no significant difference in RMST for overall survival when adjusted for propensity score (38 vs 37 mo; group difference 1.0 mo [95% CI: -3.4, 5.5]; p = 0.7). These findings do not support a change in current utilization practices for IO/IO and TKI/IO treatment strategies for ccRCC. PATIENT SUMMARY: In cases of metastatic clear cell renal cell carcinoma, no significant difference was observed in progression-free survival after second line of therapy between patients receiving ipilimumab plus nivolumab and those receiving a combination of a tyrosine kinase inhibitor and an immune checkpoint inhibitor.

Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade.

In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53-dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule-based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.

Perioperative Antibiotics and Other Factors Associated with Postcesarean Infections: A Case-Control Study.

OBJECTIVE: Our objective was to determine modifiable risk factors associated with surgical site infection (SSI) and postpartum endometritis. We hypothesized that inappropriate surgical antibiotic prophylaxis would be a risk factor for both types of infections. STUDY DESIGN: This was a single-center case-control study of SSI and endometritis after cesarean delivery over a 2-year period from 2016 to 2017. Cases were identified by International Classification of Diseases, 10th Revision diagnosis codes, infection control surveillance, and electronic medical records search and were subsequently confirmed by chart review. Three controls were randomly selected for each case from all cesareans ± 48 hours from case delivery. Demographic, pregnancy, and delivery characteristics were abstracted. Separate multivariable logistic regression models were used to assess factors associated with SSI and endometritis. Postpartum outcomes, including length of stay and readmission, were also compared. RESULTS: We identified 141 cases of SSI and endometritis with an overall postpartum infection rate of 4.0% among all cesarean deliveries. In adjusted analysis, factors associated with both SSI and endometritis were intrapartum delivery, classical or other (non-low-transverse) uterine incision, and blood transfusion. Factors associated with SSI only included inadequate antibiotic prophylaxis, public insurance, hypertensive disorder of pregnancy, and nonchlorhexidine abdominal preparation; factors only associated with endometritis included ß-lactam allergy, anticoagulation therapy, and chorioamnionitis. Among cases, 34% of those with SSI and 25% of those with endometritis did not receive adequate antibiotic prophylaxis, compared with 12.9 and 13.5% in control groups, respectively. Failure to receive appropriate antibiotic prophylaxis was associated with an increased risk of SSI (adjusted odds ratio [aOR]: 4.4, 95% confidence interval [CI]: 1.3-15.6) but not endometritis (aOR 0.9, 95% CI 0.4-2.0). CONCLUSION: Inadequate surgical antibiotic prophylaxis was associated with an increased risk of SSI but not postpartum endometritis, highlighting the different mechanisms of these infections and the importance of prioritizing adequate surgical prophylaxis. Additional potentially modifiable factors which emerged included blood transfusion and chlorhexidine skin preparation. KEY POINTS: · Inadequate antibiotic prophylaxis is associated with a four-fold risk in surgical site infections.. · The most common cause for failure to achieve adequate surgical prophylaxis was inappropriate timing of antibiotics at or after skin incision.. · Blood transfusions are strongly associated (>10-fold risk) with both SSI and endometritis..

Comparison of vaginal and buccal misoprostol after mifepristone for medication abortion through 70 days of gestation: A retrospective chart review.

OBJECTIVE: To determine the proportion of complete abortion without surgical intervention for patients who chose medication abortion with vaginal compared to buccal misoprostol following oral mifepristone through 70 days of gestation. METHODS: We performed a retrospective cohort study. We reviewed charts via electronic medical record data abstraction of patients receiving medication abortion with mifepristone and buccal or vaginal misoprostol between September 1, 2017 and August 1, 2019. Primary outcome was complete abortion without surgical intervention for any indication. Secondary outcomes were ongoing pregnancy and uterine aspiration for indications other than ongoing pregnancy. RESULTS: There were 14,504 encounters included in the data set. Of the 4814 patients who took vaginal misoprostol and the 4011 patients who took buccal misoprostol for whom follow up data is available, 4640 (96.4%) and 3917 (97.7%) had a complete abortion without surgical intervention, respectively (p = 0.002). At <64 days of gestation, complete abortion was 96.6% for vaginal administration compared to 98.0% for buccal (p = 0.001). At 64 to 70 days of gestation, complete abortion was 92.7% for vaginal administration compared to 93.2% for buccal (p = 0.08). Of the 1128 patients who took vaginal misoprostol at less than 6 hours after mifepristone, 95.3% experienced a complete abortion. CONCLUSION: Buccal administration of misoprostol is associated with a higher proportion of complete abortion before 64 days of gestation compared to vaginal misoprostol. Clinically, vaginal misoprostol is an effective route of administration through 70 days of gestation. IMPLICATIONS: Medication abortion with vaginal misoprostol is effective when administered through 70 days of gestation and with shorter intervals between mifepristone and misoprostol. Prospective research to better estimate effectiveness is warranted. Expanding medication abortion options promotes patient autonomy amid increasing restrictions and bans on abortion.

Engaged Scholarship in Gerontology: Frank Caro's Lifetime Contributions.

Dr. Francis G. Caro, retired Professor of Gerontology at the University of Massachusetts Boston, Co-editor (1996-2005) and Editor-in-Chief (2005-2016) of the Journal of Aging and Social Policy, passed away on October 2, 2020. Caro dedicated most of his nearly 60 years of academic and professional activity to gerontology and services for older adults. This article offers a review of his contributions in four central areas of gerontology: the strengthening of long-term services and supports through integration of home care services with other domains, the expansion of how productive aging was socially understood and economically valued, the importance of rigorous program evaluation and ongoing methodological innovation, and the significance of age-friendly cities and communities, both in the United States and internationally. This review of Caro's work highlights his integral role in helping to place several topics on the gerontological agenda that are still relevant today, establishing him as an important contributor to the field. He also exemplified productive aging and how scholarship can be theoretically rigorous but also applied in meaningful ways to make a difference in individual lives and within communities.

Personalizing First-Line Management of Metastatic Renal Cell Carcinoma: Leveraging Current and Novel Therapeutic Options.

The treatment of metastatic renal cell carcinoma (RCC) has been revolutionized by advances in immunotherapeutic and targeted agents. Therapeutic approaches to RCC in these categories have recently evolved to include immune checkpoint inhibitors, novel vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors, and combinations of those agents. Multiple regimens within each category have been approved for use in the first-line treatment of clear cell and non-clear cell RCC. However, few of these regimens have been directly compared, leading to a new clinical challenge for physicians: how to select a first-line treatment regimen for an individual patient from among multiple approved options. In the modern era of RCC management, the initial treatment selection therefore becomes highly personalized and depends on numerous patient-specific factors, including histopathologic and clinical features of the disease, comorbid conditions, and psychosocial and economic factors. This review details current first-line treatment options for the management of metastatic RCC and proposes a framework whereby treatment selection can be optimized for individual patients.

Genomic and Metabolic Hallmarks of SDH- and FH-deficient Renal Cell Carcinomas.

BACKGROUND: Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of TCA cycle enzymes. OBJECTIVE: To define and compare the genomic and metabolomic hallmarks of SDHRCC and FHRCC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Somatic alterations were identified using clinical pipelines, with allele-specific copy number alterations (CNAs) identified using FACETS. Mass spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors. RESULTS AND LIMITATIONS: Tumors were analyzed for 42 patients (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCCs harbored a germline alteration in SDHB, whereas only 17/22 FHRCCs had pathogenic germline FH variants. SDHRCCs had a lower mutation burden (p = 0.02) and CNA burden (p = 0.0002) than FHRCCs. All SDHRCCs presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCCs demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCCs and FHRCCs exhibited significant idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC tumors had elevation of numerous acylcarnitines. These characteristic metabolic changes allowed identification of a previously unrecognized SDH-deficient RCC. CONCLUSIONS: Despite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities. PATIENT SUMMARY: Kidney cancers driven by loss of the gene encoding either the succinate dehydrogenase or fumarate hydratase enzyme are rare. We sought to define and compare the genetic and metabolic features of these cancer entities.