Cancer and neoplasms
Yale Urology Research [Q3: July-September 2023]
Oct
The following is a comprehensive list of Yale Urology faculty publications for the 3rd quarter of calendar year 2023. The listing is separated into primary and secondary faculty sections, then in descending published date order. Listed items include cite details and portions of each abstract/summary.
Primary Faculty
Wang C, Meriggiola MC, Amory JK, Barratt CLR, Behre HM, Bremner WJ, Ferlin A, Honig S, Kopa Z, Lo K, Nieschlag E, Page ST, Sandlow J, Sitruk-Ware R, Swerdloff RS, Wu FCW, Goulis DG. Practice and development of male contraception: European Academy of Andrology and American Society of Andrology guidelines. Andrology. 2023 Sep 20. doi: 10.1111/andr.13525. Epub ahead of print. PMID: 37727884.
Sixty evidence-based and graded recommendations were produced on couple-centered communication, behaviors, barrier methods, semen analysis and contraceptive efficacy, physical agents, surgical methods, actions before initiating male contraception, hormonal methods, non-hormonal methods, vaccines, and social and ethical considerations.
Park J, Hall C, Hubbard B, LaMoia T, Gaspar R, Nasiri A, Li F, Zhang H, Kim J, Haeusler RA, Accili D, Shulman GI, Yu H, Choi E. MAD2-dependent insulin receptor endocytosis regulates metabolic homeostasis. Diabetes. 2023 Sep 19:db230314. doi: 10.2337/db23-0314. Epub ahead of print. PMID: 37725942.
Our findings establish the function of cell division regulators in insulin signaling and provide insights into the metabolic functions of IR endocytosis.
Press BH, Olawoyin O, Arlen AM, Silva CT, Weiss RM. Heresy – Is there a role for ultrasound in management of the non-palpable testicle? J Pediatr Urol. 2023 Sep 9:S1477-5131(23)00390-X. doi: 10.1016/j.jpurol.2023.08.032. Epub ahead of print. PMID: 37749009.
US in the evaluation of cryptorchidism can guide surgical management in select cases in which a testis is non-palpable following careful examination by a urologist.
Burgio KL, Cunningham SD, Newman DK, Low LK, Nodora J, Lipman TH, Klusaritz H, James AS, Rickey L, Gahagan S, Hebert-Beirne J, Kenton KS, Williams BR. Preferences for Public Health Messaging Related to Bladder Health in Adolescent and Adult Women. J Womens Health (Larchmt). 2023 Oct;32(10):1120-1135. doi: 10.1089/jwh.2022.0463. Epub 2023 Aug 22. PMID: 37610853; PMCID: PMC10541935.
This article reports an analysis of the “Public Health Messaging” code, which includes participants’ views on what information is needed about bladder health, attributes of messaging, and preferred locations and delivery methods.
Soum D. Lokeshwar, Ather Ali, Theresa R. Weiss et al. A Randomized Controlled Trial of a Fermented Soy Beverage Among Patients with Localized Prostate Cancer Prior to Radical Prostatectomy, 17 August 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3240223/v1]
Fermented soy products have shown to possess inhibitory effects on prostate cancer (PCa). We evaluated the effect of a fermented soy beverage (Q-Can®), containing medium-chain triglycerides, ketones and soy isoflavones, among men with localized PCa prior to radical prostatectomy.
Leapman MS, Sutherland R, Gross CP, Ma X, Seibert TM, Cooperberg MR, Catalona WJ, Loeb S, Schulman-Green D. Patient experiences with tissue‐based genomic testing during active surveillance for prostate cancer. BJUI compass. 08/2023. doi: 10.1002/bco2.277.
Patients interact with and are influenced by the results of biopsy-based genomic testing during active surveillance for prostate cancer, despite gaps in understanding about test results. Our findings indicate areas for improvement in patient counselling in order to increase patient knowledge and comfort with genomic testing.
Ślusarczyk A, Baboudjian M, Zapała P, Yanagisawa T, Miszczyk M, Chlosta M, Krumpoeck P, Moschini M, Gandaglia G, Ploussard G, Rivas JG, Życzkowski M, Karakiewicz PI, Radziszewski P, Leapman MS, Shariat SF, Rajwa P. Survival outcomes of patients treated with local therapy for nonmetastatic prostate cancer with high prostate-specific antigen concentrations. Prostate. 2023 Nov;83(15):1504-1515. doi: 10.1002/pros.24609. Epub 2023 Aug 7. PMID: 37545342.
Patients treated with local therapy for nmPCa with very high PSA at diagnosis have relatively good long-term oncological outcomes. Therefore, among well-selected patients with nmPCa, high PSA levels alone should not preclude the use of radical local therapy. Potential selection bias limits inferences about the relative effectiveness of specific local therapies in this setting.
Buller D, Harnisch B, Lyall V, Goltzman M, Neuber E, Bartolucci A, Honig S. Attitudes towards disposition of cryopreserved sperm in the event of death. Can J Urol. 2023 Aug;30(4):11613-11618. PMID: 37633289.
A majority of male patients seeking sperm cryopreservation for ART elected to transfer their sperm to their partner if future death should occur. There does not appear to be a clear factor that would impact this decision based on demographic characteristics.
Pak DH, Liu M, Kim T, Liang L, Caballero A, Onofrey J, Ahn SS, Xu Y, McKay R, Sun W, Gleason R, Duncan JS. Patient-specific Heart Geometry Modeling for Solid Biomechanics using Deep Learning. IEEE Trans Med Imaging. 2023 Jul 11;PP. doi: 10.1109/TMI.2023.3294128. Epub ahead of print. PMID: 37432807.
In this work, we present DeepCarve (Deep Cardiac Volumetric Mesh): a novel deformation-based deep learning method that automatically generates patient-specific volumetric meshes with high spatial accuracy and element quality. The main novelty in our method is the use of minimally sufficient surface mesh labels for precise spatial accuracy and the simultaneous optimization of isotropic and anisotropic deformation energies for volumetric mesh quality.
Kc M, Fan J, Hyslop T, Hassan S, Cecchini M, Wang SY, Silber A, Leapman MS, Leeds I, Wheeler SB, Spees LP, Gross CP, Lustberg M, Greenup RA, Justice AC, Oeffinger KC, Dinan MA. Relative Burden of Cancer and Noncancer Mortality Among Long-Term Survivors of Breast, Prostate, and Colorectal Cancer in the US. JAMA Netw Open. 2023 Jul 3;6(7):e2323115. doi: 10.1001/jamanetworkopen.2023.23115. PMID: 37436746; PMCID: PMC10339147.
This study is the first to date to examine competing oncologic and nononcologic risks focusing on long-term adult survivors of cancer. Knowledge of the relative risks facing long-term survivors may help provide pragmatic guidance to patients and clinicians regarding the importance of ongoing primary and oncologic-focused care.
Secondary Faculty
Nyman J, Denize T, Bakouny Z, Labaki C, Titchen BM, Bi K, Hari SN, Rosenthal J, Mehta N, Jiang B, Sharma B, Felt K, Umeton R, Braun DA, Rodig S, Choueiri TK, Signoretti S, Van Allen EM. Spatially aware deep learning reveals tumor heterogeneity patterns that encode distinct kidney cancer states. Cell Rep Med. 2023 Sep 19;4(9):101189. doi: 10.1016/j.xcrm.2023.101189. PMID: 37729872; PMCID: PMC10518628.
Our work reveals spatially interacting tumor-immune structures underlying ccRCC biology that may also inform selective response to ICI.
Sridhar SS, Powles T, Climent Durán MÁ, Park SH, Massari F, Thiery-Vuillemin A, Valderrama BP, Ullén A, Tsuchiya N, Aragon-Ching JB, Gupta S, Petrylak DP, Bellmunt J, Wang J, Laliberte RJ, di Pietro A, Costa N, Grivas P, Sternberg CN, Loriot Y. Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance. Eur Urol. 2023 Sep 13:S0302-2838(23)03020-8. doi: 10.1016/j.eururo.2023.08.001. Epub ahead of print. PMID: 37714742.
Post hoc analyses of OS and PFS in subgroups defined by first-line chemotherapy duration and interval before maintenance were generally consistent with the results in the overall population, with similar safety findings. Prospective trials are warranted to confirm these findings.
Santasusagna S, Zhu S, Jawalagatti V, Carceles-Cordon M, Ertel A, Garcia-Longarte S, Song WM, Fujiwara N, Li P, Mendizabal I, Petrylak DP, Kelly WK, Reddy EP, Wang L, Schiewer MJ, Lujambio A, Karnes J, Knudsen KE, Cordon-Cardo C, Dong H, Huang H, Carracedo A, Hoshida Y, Rodriguez-Bravo V, Domingo-Domenech J. Master transcription factor reprograming unleashes selective translation promoting castration resistance and immune evasion in lethal prostate cancer. Cancer Discov. 2023 Sep 7. doi: 10.1158/2159-8290.CD-23-0306. Epub ahead of print. PMID: 37676710.
These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy refractory lethal PCa and provide a druggable mechanism that may transcend into effective combined therapeutic strategies.
Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin vs chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Sep 5:S0923-7534(23)00832-3. doi: 10.1016/j.annonc.2023.08.016. Epub ahead of print. PMID: 37678672.
This exploratory analysis evaluated efficacy and safety data for enfortumab vedotin versus chemotherapy over median follow-up of approximately 2 years from EV-301.
Saliby RM, El Zarif T, Bakouny Z, Shah V, Xie W, Flippot R, Denize T, Kane MH, Madsen KN, Ficial M, Hirsch L, Wei XX, Steinharter JA, Harshman LC, Vaishampayan UN, Severgnini M, McDermott DF, Lee GM, Xu W, Van Allen EM, McGregor BA, Signoretti S, Choueiri TK, McKay RR, Braun DA. Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma. Cancer Immunol Res. 2023 Aug 3;11(8):1114-1124. doi: 10.1158/2326-6066.CIR-22-0996. PMID: 37279009; PMCID: PMC10526700.
Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.
Saad E, Labaki C, Saliby RM, Bakouny Z, Song L, Wall M, Pan W, Semaan K, Eid M, Gwo-Shu ML, Braun D, Liu XS, Choueiri T. Host immune signatures as predictors of response to immunotherapy-based regimens in patients with metastatic renal cell carcinoma (mRCC). Oncologist. 2023 Aug 23;28(Suppl 1):S4–5. doi: 10.1093/oncolo/oyad216.007. PMCID: PMC10445570.
We were successfully able to characterize T-cell receptor and B-cell IgH repertoires in a large cohort of patients with mRCC, and evaluate their associations with ICI response. Our results show that baseline TCR clonality and IgG1 antibody fraction are associated with the response to ICI regimens, suggesting a potential role for immune biomarker development.
Labaki C, Al-Choueiry M, Nyman J, Hou Y, Bi K, Zhang L, Hobeika C, Bakouny Z, Priolo C, Khabibullin D, Schindler N, Fu J, Camp S, Maria Saliby R, Saad E, Van Allen EM, Shukla S, Henske EP, Choueiri T, Braun D. Characterization of the Cellular Origin and Oncogenic Mechanisms of Chromophobe Renal Cell Carcinoma (ChRCC) and Renal Oncocytic Neoplasms. Oncologist. 2023 Aug 23;28(Suppl 1):S7–8. doi: 10.1093/oncolo/oyad216.011. PMCID: PMC10445568.
ChRCC is a rare form of kidney cancer and presents with a poor prognosis in the metastatic setting, with limited response to immune checkpoint inhibitors (ICI) and targeted therapy. While previous studies suggested that ChRCC originates from intercalated cells of the kidney, its exact cellular origin has not been clearly defined. We therefore investigated the cellular origin of ChRCC and renal oncocytic neoplasms at single-cell resolution.
Schoenfeld DA, Moutafi M, Martinez S, Djureinovic D, Merkin RD, Adeniran A, Braun DA, Signoretti S, Choueiri TK, Parisi F, Hurwitz M, Rimm DL, Wei W, Jilaveanu L, Kluger HM. Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases. J Immunother Cancer. 2023 Aug;11(8):e007240. doi: 10.1136/jitc-2023-007240. PMID: 37586773; PMCID: PMC10432651.
Compared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies.
Michel Alchoueiry, Chris Labaki, Long Zhang, Yue Hou, Kevin Bi, Charbel Hobeika, J. Connor Wells, Kosuke Takemura, Ziad Bakouny, Sabrina Camp, Carmen Priolo, Damir Khabibullin, Nicholas Schindler, Renee Maria Saliby, Eddy Saad, Samer Salem, Melissa Daou, Rana McKay, Sumanta Pal, Daniel Heng, Eliezer Van Allen, Sachet Shukla, Toni Choueiri, David Braun, Elizabeth Henske. Clinical and molecular characterization of chromophobe renal cell carcinoma: A focus on immunotherapy based regimens and the tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B019.
Patients with metastatic ChRCC appear to display poor clinical outcomes when treated with IO-based regimens, compared to ccRCC. Renal oncocytic tumors, including ChRCC, exhibit a low infiltration of immune cells, and a non-exhausted immune phenotype.
David A. Braun, Derin B. Keskin, Sachet A. Shukla, Bradley A. McGregor, Nicholas R. Schindler, Eryn Blass, Susan Klaeger, Lucas Pomerance, Siranush Sarkizova, Shuqiang Li, Jackson Southard, Giorgia Moranzoni, Christina B. Pedersen, Yiwen Liu, Steven L. Chang, Michelle S. Hirsch, Nicole R. LeBoeuf, Matthew Mossanen, Vipheaviny Chea, Isabel Carulli, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Giacomo Oliveira, J. Bryan Iorgulescu, Sabina Signoretti, Jon C. Aster, Liudmila Elagina, Ignaty Leshchiner, Gad Getz, Maegan Harden, Stacey Gabriel, Lars R. Olsen, Donna S. Neuberg, Edward F. Fritsch, Nir Hacohen, Kenneth J. Livak, Steven Carr, Patrick A. Ott, Catherine J. Wu, Toni K. Choueiri. Tumor-specific immunity generated by a personalized neoantigen vaccination incorporating locally delivered ipilimumab in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR015.
Personalized cancer vaccines can generate circulating immune responses against predicted neoantigen targets, but whether such responses lead to actual immune recognition of a patient’s tumor and consequent clinical activity is largely unknown. To investigate this, we conducted a phase I clinical trial of a personalized neoantigen vaccine as adjuvant therapy in high-risk, completely surgically resected, stage III/IV clear cell renal cell carcinoma (RCC; NCT02950766).
Karl Semaan, Talal El Zarif, Marc Eid, Valisha Shah, Brad Fortunato, Renee Maria Saliby, Amin H. Nassar, Sarah Abou Alaiwi, Ji-Heui Seo, Chris Labaki, Ziad Bakouny, Sayed Matar, Nourhan El Ahmar, Yasmin Nabil Laimon, Gwo-Shu Mary Lee, Mark Pomerantz, Jacob Berchuck, Sabina Signoretti, Eliezer Van Allen, Toni Choueiri, David Braun, Matthew Freedman, Sylvan Baca. Epigenomic profiling nominates master transcription factors (TFs) driving sarcomatoid differentiation of renal cell carcinoma (RCC) [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A029.
This is the first study to analyze the epigenomic landscape of sRCC by integrating ChIP-seq and RNA-seq data. Our findings implicated FOSL1 & E2F7 as transcriptional regulators of SD with prognostic relevance. Further studies are underway to validate these results.
David A. Braun, Derin B. Keskin, Sachet A. Shukla, Bradley A. McGregor, Nicholas R. Schindler, Eryn Blass, Susan Klaeger, Lucas Pomerance, Siranush Sarkizova, Shuqiang Li, Jackson Southard, Giorgia Moranzoni, Christina B. Pedersen, Yiwen Liu, Steven L. Chang, Michelle S. Hirsch, Nicole R. LeBoeuf, Matthew Mossanen, Vipheaviny Chea, Isabel Carulli, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Giacomo Oliveira, J. Bryan Iorgulescu, Sabina Signoretti, Jon C. Aster, Liudmila Elagina, Ignaty Leshchiner, Gad Getz, Maegan Harden, Stacey Gabriel, Lars R. Olsen, Donna S. Neuberg, Edward F. Fritsch, Nir Hacohen, Kenneth J. Livak, Steven Carr, Patrick A. Ott, Catherine J. Wu, Toni K. Choueiri. Tumor-specific immunity generated by a personalized neoantigen vaccination incorporating locally delivered ipilimumab in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A013.
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR015) of the Conference Program/Proceedings.
Miya B. Hugaboom, Neil Ruthen, Opeyemi Jegede, Nicholas R. Schindler, Lena Wirth, Sasha Kyrysyuk, David F. McDermott, Elizabeth R. Plimack, Jeffrey A. Sosman, Naomi B. Haas, Michael E. Hurwitz, Hans J. Hammers, Sabina Signoretti, Michael B. Atkins, Catherine J. Wu, David A. Braun, Kelly Street. T cell clonotype expansion is common in advanced renal cell carcinoma but is not associated with altered response to PD-1 blockade [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B013.
The localization of most expanded clonotypes to a single T cell lineage suggests a low degree of phenotypic plasticity. Enrichment of these clonotypes along an exhausted lineage is consistent with prior findings of lower TCR diversity in terminally exhausted CD8+ T cells. Future directions will focus on inferring the tumor specificity of infiltrating T cells along the diverging lineages.
Henske EP, [Braun DA]. Chromophobe renal cell carcinoma. Cancer cell. 08/2023;41(8):1383-1388. doi: 10.1016/j.ccell.2023.07.006.
For ccRCC, clinical breakthroughs were preceded by fundamental biologic discoveries, including the roles of the VHL gene and HIF2α. ChRCC is poised for similar biologic and therapeutic progress, with the identification of pathways providing a path toward the first targeted therapies. Significant barriers remain, including the limited cellular and preclinical models that likely do not recapitulate all aspects of the human disease and the challenges of clinical trial design for rare cancers. Concerted and collaborative scientific and clinical efforts are needed to address these challenges.
Sachet Shukla, Tejas Jammihal, Renée-Maria Saliby, [David Braun] et al. Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma, 06 July 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3088575/v1].
Although immune checkpoint inhibitors can lead to “exceptional”, durable clinical responses in a subset of patients, the molecular mechanisms underlying exceptional responses (ERs) are still unknown. We analyzed pre-therapy genomic and transcriptomic data in treatment-naive patients with mccRCC treated with standard-of-care immunotherapies.
Antonarakis ES, Subudhi SK, Pieczonka CM, Karsh LI, Quinn DI, Hafron JM, Wilfehrt HM, Harmon M, Sheikh NA, Shore ND, Petrylak DP. Combination Treatment with Sipuleucel-T and Abiraterone Acetate or Enzalutamide for Metastatic Castration-Resistant Prostate Cancer: STAMP and STRIDE Trials. Clin Cancer Res. 2023 Jul 5;29(13):2426-2434. doi: 10.1158/1078-0432.CCR-22-3832. PMID: 37058234; PMCID: PMC10320463.
Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.
Labaki C, Saliby RM, Bakouny Z, Saad E, Semaan K, Eid M, Lalani AK, Choueiri TK, Braun DA. Emerging Biomarkers of Response to Systemic Therapies in Metastatic Clear Cell Renal Cell Carcinoma. Hematol Oncol Clin North Am. 2023 Oct;37(5):937-942. doi: 10.1016/j.hoc.2023.05.021. Epub 2023 Jul 3. PMID: 37407357.
Patients with metastatic clear cell renal cell carcinoma (mccRCC) experience highly heterogeneous outcomes when treated with standard-of-care systemic regimens. Therefore, valid biomarkers are needed to predict the clinical response to these therapies and help guide management. In this review, the authors outline relevant and promising biomarkers for patients with mccRCC receiving systemic therapies, with a focus on immunotherapy-based regimens.
