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Geospatial Cellular Distribution of Cancer-Associated Fibroblasts Significantly Impacts Clinical Outcomes in Metastatic Clear Cell Renal Cell Carcinoma

Nicholas Chakiryan, Gregory Kimmel, Youngchul Kim, Joseph Johnson, Noel Clark, Ali Hajiran, Andrew Chang, Ahmet Aydin, Logan Zemp, Esther Katende, Jad Chahoud, Meghan Ferrall-Fairbanks, Philippe Spiess, Natasha Francis, Michelle Fournier, Jasreman Dhillon, Jong Park, Liang Wang, James Mule, Philipp Altrock, Brandon Manley,

Cancer-associated fibroblasts (CAF) are highly prevalent cells in the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). CAFs exhibit a pro-tumor effect in vitro and have been implicated in tumor cell proliferation, metastasis, and treatment resistance. Our objective is to analyze the geospatial distribution of CAFs with proliferating and ... Read more >>

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Pathologic Downstaging and Survival Outcomes Associated with Neoadjuvant Chemotherapy for Variant Histology Muscle Invasive Bladder Cancer.

Nicholas H Chakiryan, Da David Jiang, Kyle A Gillis, Elizabeth Green, Ali Hajiran, Lee Hugar, Logan Zemp, Jingsong Zhang, Rohit Jain, Jad Chahoud, Michael Poch, Brandon J Manley, Roger Li, Wade Sexton, Scott M Gilbert,

<h4>Purpose</h4>Patients with muscle invasive bladder cancer (MIBC) of variant histology have a poor prognosis. It is unclear if neoadjuvant chemotherapy prior to radical cystectomy is associated with pathologic downstaging or improved overall survival (OS) for patients with variant histology. Our objective was to assess for associations between receipt of neoadjuvant ... Read more >>

J Urol (The Journal of urology)
[2021, :101097JU0000000000001855]

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Correlating Immune Cell Infiltration Patterns with Recurrent Somatic Mutations in Advanced Clear Cell Renal Cell Carcinoma.

Nicholas H Chakiryan, Ali Hajiran, Youngchul Kim, Ahmet M Aydin, Logan Zemp, Esther Katende, Jonathan Nguyen, Wenyi Fan, Chia-Ho Cheng, Neale Lopez-Blanco, Jad Chahoud, Philippe E Spiess, Michelle Fournier, Jasreman Dhillon, Liang Wang, Carlos Moran-Segura, James Mulé, Dongliang Du, Sean J Yoder, Anders Berglund, Jamie K Teer, Brandon J Manley,

<h4>Background</h4>Clear cell renal cell carcinoma (ccRCC) tumors have low frequencies of genetic alterations compared with other malignancies, but very high levels of immune cell infiltration and favorable response rates to immunotherapy. Currently, the interplay between specific ccRCC somatic mutations and immune infiltration pattern is unclear.<h4>Objective</h4>To analyze the associations between common ... Read more >>

Eur Urol Focus (European urology focus)
[2021, :]

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Patterns of Recurrence Following Inguinal Lymph Node Dissection for Penile Cancer: Optimizing Surveillance Strategies.

Nicholas H Chakiryan, Aaron Dahmen, Marco Bandini, Filippo Pederzoli, Laura Marandino, Maarten Albersen, Eduard Roussel, Yao Zhu, Ding-Wei Ye, Antonio A Ornellas, Mario Catanzaro, Oliver W Hakenberg, Axel Heidenreich, Friederike Haidl, Nick Watkin, Michael Ager, Jad Chahoud, Alberto Briganti, Roberto Salvioni, Francesco Montorsi, Andrea Necchi, Philippe E Spiess,

<h4>Purpose</h4>Our primary objective is to detail the incidence, site, and timing of pSCC recurrence after ILND.<h4>Methods</h4>Retrospective analysis of 551 patients who underwent ILND for pSCC, from 2000 to 2017. The primary outcome was pSCC recurrence after ILND. Recurrences were identified and stratified by site. Timing of recurrence was determined. Multivariable ... Read more >>

J Urol (The Journal of urology)
[2021, :101097JU0000000000001790]

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Real-World Survival Outcomes Associated With First-Line Immunotherapy, Targeted Therapy, and Combination Therapy for Metastatic Clear Cell Renal Cell Carcinoma.

Nicholas H Chakiryan, Da David Jiang, Kyle A Gillis, Elizabeth Green, Ali Hajiran, Lee Hugar, Logan Zemp, Jingsong Zhang, Rohit K Jain, Jad Chahoud, Philippe E Spiess, Wade Sexton, Scott M Gilbert, Brandon J Manley,

<h4>Importance</h4>Clinical trials have shown an overall survival (OS) benefit associated with first-line immunotherapy (IT) and combination targeted therapy (TT) and IT regimens compared with TT among patients with metastatic clear cell renal cell carcinoma (RCC). Generalizability of these findings in a real-world cohort outside of a clinical trial setting is ... Read more >>

JAMA Netw Open (JAMA network open)
[2021, 4(5):e2111329]

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Spatial clustering of CD68+ tumor associated macrophages with tumor cells is associated with worse overall survival in metastatic clear cell renal cell carcinoma.

Nicholas H Chakiryan, Gregory J Kimmel, Youngchul Kim, Ali Hajiran, Ahmet M Aydin, Logan Zemp, Esther Katende, Jonathan Nguyen, Neale Lopez-Blanco, Jad Chahoud, Philippe E Spiess, Michelle Fournier, Jasreman Dhillon, Liang Wang, Carlos Moran-Segura, Asmaa El-Kenawi, James Mulé, Philipp M Altrock, Brandon J Manley,

Immune infiltration is typically quantified using cellular density, not accounting for cellular clustering. Tumor-associated macrophages (TAM) activate oncogenic signaling through paracrine interactions with tumor cells, which may be better reflected by local cellular clustering than global density metrics. Using multiplex immunohistochemistry and digital pathologic analysis we quantified cellular density and ... Read more >>

PLoS One (PloS one)
[2021, 16(4):e0245415]

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Patient-Reported Outcomes in Clinical Trials Leading to Cancer Immunotherapy Drug Approvals From 2011 to 2018: A Systematic Review.

Houssein Safa, Monica Tamil, Philippe E Spiess, Brandon Manley, Julio Pow-Sang, Scott M Gilbert, Firas Safa, Brian D Gonzalez, Laura B Oswald, Adele Semaan, Adi Diab, Jad Chahoud,

<h4>Background</h4>Patient-reported outcomes (PROs) promote patient centeredness in clinical trials; however, in the field of rapidly emerging and clinically impressive immunotherapy, data on PROs are limited.<h4>Methods</h4>We systematically identified all immunotherapy approvals from 2011 through 2018 and assessed the analytic tools and reporting quality of associated PRO reports. For randomized clinical trials ... Read more >>

J Natl Cancer Inst (Journal of the National Cancer Institute)
[2021, 113(5):532-542]

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Pembrolizumab for advanced penile cancer: a case series from a phase II basket trial.

Andrew W Hahn, Jad Chahoud, Matthew T Campbell, Daniel D Karp, Jennifer Wang, Bettzy Stephen, Shi-Ming Tu, Curtis A Pettaway, Aung Naing,

<h4>Background</h4>Treatment options for unresectable, locally advanced or metastatic penile squamous cell carcinoma (SCC) are limited. Previous studies have shown that 40-62% of patients with penile SCC express PD-L1. We report three cases of locally advanced or metastatic penile SCC treated with pembrolizumab.<h4>Case presentations</h4>Herein, we present three patients with recurrent, locally ... Read more >>

Invest New Drugs (Investigational new drugs)
[2021, :]

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Spatial Clustering of CD68+ Tumor Associated Macrophages with Tumor Cells is Associated with Worse Overall Survival in Metastatic Clear Cell Renal Cell Carcinoma

Nicholas Chakiryan, Gregory Kimmel, Youngchul Kim, Ali Hajiran, Ahmet Aydin, Logan Zemp, Esther Katende, Jonathan Nguyen, Neale Lopez-Blanco, Jad Chahoud, Philippe Spiess, Michelle Fournier, Jasreman Dhillon, Liang Wang, Carlos Moran-Segura, Asmaa El-Kenawi, James Mulé, Philipp Altrock, Brandon Manley,

<h4>ABSTRACT</h4> Immune infiltration is typically quantified using cellular density, not accounting for cellular clustering. Tumor-associated macrophages (TAM) activate oncogenic signaling through paracrine interactions with tumor cells, which may be better reflected by local cellular clustering than global density metrics. Using multiplex immunohistochemistry and digital pathologic analysis we quantified cellular density ... Read more >>

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Whole-exome Sequencing in Penile Squamous Cell Carcinoma Uncovers Novel Prognostic Categorization and Drug Targets Similar to Head and Neck Squamous Cell Carcinoma.

Jad Chahoud, Frederico O Gleber-Netto, Barrett Z McCormick, Priya Rao, Xin Lu, Ming Guo, Maggaret B Morgan, Randy A Chu, Magaly Martinez-Ferrer, Agda Karina Eterovic, Curtis R Pickering, Curtis A Pettaway,

<h4>Purpose</h4>Penile squamous cell carcinoma (PSCC) is rare with limited treatment options. We report the first whole-exome sequencing (WES) analysis and compare the molecular landscape of PSCC with other squamous cell carcinomas (SCC), with the goal to identify common novel targets.<h4>Experimental design</h4>PSCC and matched normal penile tissues from 34 prospectively followed ... Read more >>

Clin Cancer Res (Clinical cancer research : an official journal of the American Association for Cancer Research)
[2021, 27(9):2560-2570]

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Prognostic predictors of lymph node metastasis in penile cancer: a systematic review.

David S Zekan, Ahmad Dahman, Ali J Hajiran, Adam M Luchey, Jad Chahoud, Philippe E Spiess,

<h4>Purpose</h4>Squamous cell carcinoma (SCC) of the penis is a rare disease in developed countries but is associated with significant morbidity and mortality. A crucial prognostic factor is the presence of inguinal lymph node metastases (ILNM) at the time of diagnosis. At least 25% of cases have micrometastases at the time ... Read more >>

Int Braz J Urol (International braz j urol : official journal of the Brazilian Society of Urology)
[2021, 47:]

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Case Report: Two Cases of Chemotherapy Refractory Metastatic Penile Squamous Cell Carcinoma With Extreme Durable Response to Pembrolizumab.

Jad Chahoud, William Paul Skelton, Philippe E Spiess, Christine Walko, Jasreman Dhillon, Kenneth L Gage, Peter A S Johnstone, Rohit K Jain,

<h4>Background</h4>Penile squamous cell carcinoma (PSCC) is a rare malignancy, and those patients with metastatic disease have limited treatment options. Treatment is largely comprised of platinum-based chemotherapy; however, patients progressing after initial chemotherapy have a median overall survival (OS) of less than 6 months. Based on a high percentage of PD-L1 ... Read more >>

Front Oncol (Frontiers in oncology)
[2020, 10:615298]

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Management of Advanced Penile Cancer.

Jad Chahoud, Manish Kohli, Philippe E Spiess,

Penile squamous cell carcinoma (PSCC) is a rare cancer, with approximately 2000 new cases in the United States and 35,000 globally every year. Multiple risk factors are involved in PSCC, but most importantly, the high-risk human papillomavirus infection is thought to be present in approximately 50% of cases. Penile squamous ... Read more >>

Mayo Clin Proc (Mayo Clinic proceedings)
[2021, 96(3):720-732]

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Outcomes of patients with metastatic renal cell carcinoma with sarcomatoid dedifferentiation to immune checkpoint inhibitors.

Jad Chahoud, Pavlos Msaouel, Jeremy A Ross, Barrett Z McCormick, Tharakeswara K Bathala, Jianjun Gao, Robert Horn, Lianchun Xiao, Kanishka Sircar, Matthew T Campbell, Amishi Y Shah, Sangeeta Goswami, Amado J Zurita, Eric Jonasch, Surena F Matin, Christopher G Wood, Jose A Karam, Padmanee Sharma, Nizar M Tannir,

<h4>Introduction</h4>Metastatic renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is associated with poor survival outcomes. We aimed to analyze the efficacy and safety of immune checkpoint inhibitors (ICI) in patients with sRCC comparing clear-cell (sccRCC) to non-clear cell epithelial histology (snccRCC).<h4>Methods</h4>We performed retrospective analysis of sRCC patients who received ICI at ... Read more >>

Urol Oncol (Urologic oncology)
[2021, 39(2):134.e9-134.e16]

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Topical chemotherapy for penile carcinoma in situ: Contemporary outcomes and reported toxicity.

Ali Hajiran, Logan Zemp, Ahmet M Aydin, Salim K Cheryian, Julio M Pow-Sang, Jad Chahoud, Phillippe E Spiess,

<h4>Purpose</h4>The toxicity of topical chemotherapeutics has been well-characterized in extra-genital squamous cell carcinoma; however, there is limited data regarding the use of topical agents for penile squamous cell carcinoma in situ (CIS). We aim to describe the clinical outcomes and toxicities associated with the use of topical fluorouracil and imiquimod ... Read more >>

Urol Oncol (Urologic oncology)
[2021, 39(1):72.e1-72.e5]

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The Immune Microenvironment in Penile Cancer and Rationale for Immunotherapy.

Mohamed E Ahmed, Shayan Falasiri, Ali Hajiran, Jad Chahoud, Philippe E Spiess,

Penile cancer is an extremely rare malignancy that accounts for approximately 1% of cancer deaths in the United States every year. While primary penile cancer can be managed surgically, advanced and metastatic forms of the disease require more aggressive management plans with systemic chemotherapy and/or radiotherapy. Despite the meaningful response ... Read more >>

J Clin Med (Journal of clinical medicine)
[2020, 9(10):]

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Influence of gene expression on survival of clear cell renal cell carcinoma.

Anders Berglund, Ernest K Amankwah, Young-Chul Kim, Philippe E Spiess, Wade J Sexton, Brandon Manley, Hyun Y Park, Liang Wang, Jad Chahoud, Ratna Chakrabarti, Chang D Yeo, Hung N Luu, Giuliano D Pietro, Alexander Parker, Jong Y Park,

Approximately 10%-20% of patients with clinically localized clear cell renal cell carcinoma (ccRCC) at time of surgery will subsequently experience metastatic progression. Although considerable progression was seen in the systemic treatment of metastatic ccRCC in last 20 years, once ccRCC spreads beyond the confines of the kidney, 5-year survival is less ... Read more >>

Cancer Med (Cancer medicine)
[2020, 9(22):8662-8675]

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Evaluation, diagnosis and surveillance of renal masses in the setting of VHL disease.

Jad Chahoud, Melissa McGettigan, Nainesh Parikh, Ronald S Boris, Othon Iliopoulos, W Kimryn Rathmell, Anthony B Daniels, Eric Jonasch, Philippe E Spiess, ,

This brief report focuses on the evaluation and diagnosis of clinically localized renal masses in children and adults with Von Hippel-Lindau (VHL) disease. Counseling considerations pertinent to the urologists, medical oncologists, and multidisciplinary teams involved in the care of these patients are addressed. As practice patterns regarding the evaluation and ... Read more >>

World J Urol (World journal of urology)
[2020, :]

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Second line salvage systemic therapy for advanced penile cancer.

Jad Chahoud, Monica Tamil, Andrea Necchi,

Most patients with advanced penile cancer will have relapsed disease after cisplatin-based combination chemotherapy. Unfortunately, these patients have dismal outcomes with salvage chemotherapy, surgery, or radiation. In this review we will discuss the available chemotherapy and targeted therapies for salvage second line systemic treatment for patients with penile cancer. We ... Read more >>

Urol Oncol (Urologic oncology)
[2020, :]

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Understanding genomics and the immune environment of penile cancer to improve therapy.

Ahmet Murat Aydin, Jad Chahoud, Jacob J Adashek, Mounsif Azizi, Anthony Magliocco, Jeffrey S Ross, Andrea Necchi, Philippe E Spiess,

The incidence of penile squamous cell carcinoma (PSCC) has increased in developed countries over the past decades owing to increased human papilloma virus (HPV) exposure. Despite successful surgical treatment of locoregional PSCC, effective treatment options for advanced disease are limited. The prognosis of patients with bulky nodal and metastatic PSCC ... Read more >>

Nat Rev Urol (Nature reviews. Urology)
[2020, 17(10):555-570]

Cited: 2 times

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Effective combinatorial immunotherapy for penile squamous cell carcinoma.

Tianhe Huang, Xi Cheng, Jad Chahoud, Ahmed Sarhan, Pheroze Tamboli, Priya Rao, Ming Guo, Ganiraju Manyam, Li Zhang, Yu Xiang, Leng Han, Xiaoying Shang, Pingna Deng, Yanting Luo, Xuemin Lu, Shan Feng, Magaly Martinez Ferrer, Y Alan Wang, Ronald A DePinho, Curtis A Pettaway, Xin Lu,

Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and ... Read more >>

Nat Commun (Nature communications)
[2020, 11(1):2124]

Cited: 3 times

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Reply by Authors.

Mounsif Azizi, Ahmet M Aydin, Ali Hajiran, Andrew Lai, Ambuj Kumar, Charles C Peyton, Suks Minhas, Guru P Sonpavde, Jad Chahoud, Lance C Pagliaro, Andrea Necchi, Philippe E Spiess,

J Urol (The Journal of urology)
[2020, 203(6):1155]

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Dissecting Outcomes: Should Cytoreductive Nephrectomy Be Performed for Patients With Metastatic Renal Cell Carcinoma With Sarcomatoid Dedifferentiation?

Jacob J Adashek, Yumeng Zhang, William Paul Skelton, Alyssa Bilotta, Jad Chahoud, Logan Zemp, Jiannong Li, Jasreman Dhillon, Brandon Manley, Philippe E Spiess,

<h4>Background</h4>It is highly contested whether cytoreductive nephrectomy for treating advanced renal cell carcinoma (RCC) with sarcomatoid features (sRCC) benefits overall survival. Patients with sRCC are known to have a poor prognosis, and these tumors have a more aggressive biology than those without sarcomatoid features.<h4>Methods</h4>Patients with clear cell RCC or non-clear ... Read more >>

Front Oncol (Frontiers in oncology)
[2020, 10:627025]

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Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-analysis of Individual Patient Data From Randomized Clinical Trials.

Safae Terrisse, Eleni Karamouza, Chris C Parker, A Oliver Sartor, Nicholas D James, Sarah Pirrie, Laurence Collette, Bertrand F Tombal, Jad Chahoud, Sigbjørn Smeland, Bjørn Erikstein, Jean-Pierre Pignon, Karim Fizazi, Gwénaël Le Teuff, ,

<h4>Importance</h4>Both α-emitting and β-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an α-emitting RI, radium 223 (223Ra), vs standard of care. Yet no head-to-head comparison has been ... Read more >>

JAMA Oncol (JAMA oncology)
[2020, 6(2):206-216]

Cited: 1 time

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Systematic Review and Meta-Analysis-Is there a Benefit in Using Neoadjuvant Systemic Chemotherapy for Locally Advanced Penile Squamous Cell Carcinoma?

Mounsif Azizi, Ahmet M Aydin, Ali Hajiran, Andrew Lai, Ambuj Kumar, Charles C Peyton, Suks Minhas, Guru P Sonpavde, Jad Chahoud, Lance C Pagliaro, Andrea Necchi, Philippe E Spiess,

PURPOSE:Neoadjuvant chemotherapy is a recommended treatment for patients with penile cancer with bulky inguinal lymphadenopathy or unresectable primary tumors, although there is no evidence of its benefit from randomized trials. MATERIALS AND METHODS:We conducted a systematic search in Embase® and MEDLINE® for studies reporting on patients who received preoperative neoadjuvant ... Read more >>

J Urol (The Journal of urology)
[2020, 203(6):1147-1155]

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