Publications by authors named "Philippe E Spiess"

323 Publications

Systemic treatment of penile squamous cell carcinoma-hurdles and hopes of preclinical models and clinical regimens: a narrative review.

Transl Androl Urol 2021 Oct;10(10):4085-4098

Department of Urology and Pediatric Urology, University Medicine Mainz, Mainz, Germany.

Despite contemporary research efforts, the prognosis of penile squamous cell carcinoma (PeSCC) has not significantly improved over the past decade. Despite frequently encountered patient-related delayed medical consultations impairing outcomes, several other aspects contribute to the lack of advancement in the treatment of this condition. One essential reason is that translational research, a prerequisite for the clinically successful disease management, is still at an early stage in PeSCC as compared to many other malignancies. Preclinical experimental models are indispensable for the evaluation of tumor biology and identification of genomic alterations. However, since neither commercial PeSCC cell lines are available nor xenograft models sustainably established, such analyses are challenging in this field of research. In addition, systemic therapies are less effective and toxic without decisive breakthroughs over recent years. Current systemic management of PeSCC is based on protocols that have been investigated in small series of only up to 30 patients. Thus, there is an unmet medical need for new approaches necessitating research efforts to develop more efficacious systemic strategies. This review aims to highlight the current state of knowledge in the molecular alterations involved in the etiology and ensuing steps for cancer progression, existing preclinical models of translational research, clinically relevant systemic protocols, and ongoing clinical trials.
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http://dx.doi.org/10.21037/tau-20-945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575571PMC
October 2021

Impact of the COVID-19 pandemic on treatment patterns for US patients with metastatic solid cancer.

medRxiv 2021 Sep 23. Epub 2021 Sep 23.

Background: The COVID-19 pandemic has led to delays in patients seeking care for life-threatening conditions; however, its impact on treatment patterns for patients with metastatic cancer is unknown. We assessed the COVID-19 pandemic's impact on time to treatment initiation (TTI) and treatment selection for patients newly diagnosed with metastatic solid cancer.

Methods: We used an electronic health record-derived longitudinal database curated via technology-enabled abstraction to identify 14,136 US patients newly diagnosed with de novo or recurrent metastatic solid cancer between January 1 and July 31 in 2019 or 2020. Patients received care at ∼280 predominantly community-based oncology practices. Controlled interrupted time series analyses assessed the impact of the COVID-19 pandemic period (April-July 2020) on TTI, defined as the number of days from metastatic diagnosis to receipt of first-line systemic therapy, and use of myelosuppressive therapy.

Results: The adjusted probability of treatment within 30 days of diagnosis [95% confidence interval] was similar across periods: January-March 2019 41.7% [32.2%, 51.1%]; April-July 2019 42.6% [32.4%, 52.7%]; January-March 2020 44.5% [30.4%, 58.6%]; April-July 2020 46.8% [34.6%, 59.0%]; adjusted percentage-point difference-in-differences 1.4% [-2.7%, 5.5%]. Among 5,962 patients who received first-line systemic therapy, there was no association between the pandemic period and use of myelosuppressive therapy (adjusted percentage-point difference-in-differences 1.6% [-2.6%, 5.8%]). There was no meaningful effect modification by cancer type, race, or age.

Conclusions: Despite known pandemic-related delays in surveillance and diagnosis, the COVID-19 pandemic did not impact time to treatment initiation or treatment selection for patients with metastatic solid cancers.
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http://dx.doi.org/10.1101/2021.09.22.21263964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491856PMC
September 2021

Lynch syndrome in urological practice: diagnosis, therapeutic strategies, and screening for upper tract urothelial carcinoma.

Curr Opin Urol 2022 Jan;32(1):40-47

University Vita-Salute San Raffaele.

Purpose Of Review: To provide a comprehensive overview of diagnosis, treatment, and screening for upper tract urothelial carcinoma (UTUC) among Lynch syndrome patients.

Recent Findings: Lynch syndrome is an autosomal dominant disorder resulting from the germline mutation in the mismatch repair (MMR) system. The Lynch syndrome predisposes to early onset of a broad spectrum of tumours, among which UTUC represents the third most frequent malignancy. Since up to 10% of UTUC can be attributed to Lynch syndrome, a correct recognition of this disease provides the opportunity for patients and their relatives to be properly treated for UTUC and to be followed up for other Lynch syndrome-related malignancies.

Summary: UTUC patients less than 65 years, or UTUC patients with personal history of Lynch syndrome-related cancer, or with one first-degree relative (FDR) less than 50 years with Lynch syndrome-related cancer, or two FDRs with Lynch syndrome-related cancer regardless of age should be referred to molecular testing and subsequent DNA sequencing to confirm Lynch syndrome diagnosis. Considering the increased risk of metachronous recurrence, treatments other than radical nephroureterectomy, such as ureteroscopic laser ablation may represent valuable therapeutic strategies. As Lynch syndrome patients exhibit an approximate 14-fold increased risk of developing UTUC compared with general population, expert recommendations are urgently required in order to point out appropriate screening protocols.
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http://dx.doi.org/10.1097/MOU.0000000000000936DOI Listing
January 2022

Risk factors and survival outcomes for upstaging after inguinal lymph node dissection for cN1 penile squamous cell carcinoma.

Urol Oncol 2021 Dec 30;39(12):838.e7-838.e13. Epub 2021 Sep 30.

Department of Genitourinary Oncology, H Lee Moffitt Cancer Center, Tampa, FL.

Objectives: To identify incidence and risk factors for upstaging from cN1 to pN2/N3 at inguinal lymphadenectomy (ILND) for penile cancer (pSCC). Our secondary objective is to assess survival outcomes and associations for cN1 patients undergoing ILND.

Subjects/patients And Methods: Patients with pT≥1cN1cM0 pSCC who underwent bilateral ILND and had complete data were identified in a multi-institutional international cohort from 8 referral centers in 7 countries diagnosed from 1980 to 2017. Upstaging was defined as pN2/N3 at ILND. Multivariable logistic regression analysis was used to determine associations with upstaging, and Cox multivariable logistic regression analysis to determine associations with overall survival (OS).

Results: Of 144 patients were included in the final study population. 84 patients (58%) were upstaged from cN1 to pN2/N3, and 25 (17%) were down staged to pN0. Upstaging was associated with pT3/T4 (OR 4.1, 95%CI 1.5-11.7, P < 0.01) and pTX (OR 7.1, 95CI 1.6-51.1, P = 0.02). Age, smoking status, HPV status, and LVI were not associated with upstaging. Age (HR 1.03/y, 95%CI 1.01-1.06, P < 0.01) and upstaging (HR 2.8, 95%CI 1.3-5.9, P < 0.01) were associated with worse OS. Upstaged patients had a 5-year OS of 49%, compared with 86% for patients who were not upstaged.

Conclusion: The majority of cN1 pSCC patients harbor a higher-risk disease state than their clinical staging suggests, especially those with higher pT stages. More intensive pre-operative workup may be warranted for these patients to identify upstaging prior to ILND and potentially qualify them for neoadjuvant chemotherapy or clinical trials.
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http://dx.doi.org/10.1016/j.urolonc.2021.08.028DOI Listing
December 2021

Identifying the Optimal Number of Neoadjuvant Chemotherapy Cycles in Patients with Muscle Invasive Bladder Cancer.

J Urol 2021 Aug 27:101097JU0000000000002190. Epub 2021 Aug 27.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose: We investigated the pathological response rates and survival associated with 3 vs 4 cycles of cisplatin-based neoadjuvant chemotherapy (NAC) in patients with cT2-4N0M0 muscle invasive bladder cancer.

Materials And Methods: In this cohort study we analyzed clinical data of 828 patients treated with NAC and radical cystectomy between 2000 and 2020. A total of 384 and 444 patients were treated with 3 and 4 cycles of NAC, respectively. Pathological objective response (pOR; ypT0-Ta-Tis-T1 N0), pathological complete response (pCR; ypT0 N0), cancer-specific survival and overall survival were investigated.

Results: pOR and pCR were achieved in 378 (45%; 95% CI 42, 49) and 207 (25%; 95% CI 22, 28) patients, respectively. Patients treated with 4 cycles of NAC had higher pOR (49% vs 42%, p=0.03) and pCR (28% vs 21%, p=0.02) rates compared to those treated with 3 cycles. This effect was confirmed on multivariable logistic regression analysis (pOR OR 1.46 p=0.008, pCR OR 1.57, p=0.007). On multivariable Cox regression analysis, 4 cycles of NAC were significantly associated with overall survival (HR 0.68; 95% CI 0.49, 0.94; p=0.02) but not with cancer-specific survival (HR 0.72; 95% CI 0.50, 1.04; p=0.08).

Conclusions: Four cycles of NAC achieved better pathological response and survival compared to 3 cycles. These findings may aid clinicians in counseling patients and serve as a benchmark for prospective trials. Prospective validation of these findings and assessment of cumulative toxicity derived from an increased number of cycles are needed.
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http://dx.doi.org/10.1097/JU.0000000000002190DOI Listing
August 2021

Impact of radiation therapy on perineal urethrostomy for penile cancer.

Clin Transl Radiat Oncol 2021 Sep 9;30:84-87. Epub 2021 Aug 9.

Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, United Kingdom.

Objective: A lack of demonstrated clinical benefit precludes radiotherapy (RT) from being recommended for pN1/pN2 penile cancer (PeCa) lesions; but it may be recommended in case of extranodal (pN3) disease or for positive resection margins. Perineal urethrostomy (PU) is a technique of urinary diversion in patients with PeCa requiring total or subtotal penectomy as primary therapy. Prior studies suggest PU failure rates of up to 30%, without specific mention of the potential role of RT. When RT is delivered for PeCa it is usually to the pre-pubic fat, groin and lateral pelvis, and not to the region of the PU. Here we describe the role of perioperative RT in a large, multi-institutional registry of PU for PeCa.

Methods: In our cohort, 299 patients from seven international, high-volume centers in Belgium, Brazil, China, Netherlands, United Kingdom and the United States underwent PU as urinary diversion for PeCa between 2000 and 2020. Demographic and clinicopathologic characteristics were reviewed.

Results: Median patient age was 67 years and median follow-up was 19 months. Seven patients (2.3%) received pre-operative RT; six of them with chemotherapy. 37 received RT post-operatively, 21 (57%) with chemotherapy. Stenosis of the PU occurred in 35 (12%) of the total population. The majority of these patients (74%) required surgical revision at a median of 6.1 months post-operatively. RT delivery was neither significantly related to PU stenosis (p = 0.16) or to subsequent revision ( = 0.75).

Conclusion: Receipt of RT was not significantly associated with increased stenosis risk in PeCa patients who underwent PU.
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http://dx.doi.org/10.1016/j.ctro.2021.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367760PMC
September 2021

Contrasting genomic profiles from metastatic sites, primary tumors, and liquid biopsies of advanced prostate cancer.

Cancer 2021 Aug 11. Epub 2021 Aug 11.

Upstate Medical University, State University of New York, Syracuse, New York.

Background: This study assessed the contrasting genomic profiles from the primary tumors (PTs), metastatic (MET) sites, and circulating tumor DNA (ctDNA) of patients with prostate cancer (PC).

Methods: A total of 1294 PC tissue specimens and 2462 ctDNA specimens underwent hybrid capture-based comprehensive genomic profiling (CGP). Specimens included tissue from PTs; MET biopsies from bone, liver (LIV), lung (LU), brain (BN), lymph node, and soft tissue sites; and ctDNA.

Results: Differences in alteration frequencies between PT, MET, and ctDNA specimens for selected genes were observed. TMPRSS2:ERG fusion frequencies were similar between PTs and MET sites (35% vs 33%) but varied among MET sites. Genomic alterations (GAs) in AR were lowest in PTs (2%) and highest in MET sites (from 24% in LU to 50% in LIV). BN had the highest genomic alterations/tumor (8) and enrichment for PTEN GAs. The BRCA2 GA frequency varied from 0% in BN to 15% in LIV. ERBB2 amplification was increased in MET sites in comparison with PTs. RB1 GAs were increased in LIV. Biomarkers potentially associated with an anti-PD(L)1 response included CDK12 GAs (16% in LU) and a microsatellite instability-high status (29% in BN). Analyses of ctDNA featured a broad spectrum of GAs similar to those detected across MET sites.

Conclusions: CGP of PTs, MET sites, and ctDNA in PC exhibited differences most likely associated with tumor progression, clonal evolution, and exposure to systemic therapies; ctDNA can also capture a broad range of potential therapeutic opportunities for patients with PC.
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http://dx.doi.org/10.1002/cncr.33865DOI Listing
August 2021

Association of age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer.

World J Urol 2021 Dec 9;39(12):4345-4354. Epub 2021 Aug 9.

Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD, USA.

Purpose: To assess the association of patient age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer (MIBC).

Materials And Methods: We analyzed data from 1105 patients with MIBC. Patients age was evaluated as continuous variable and stratified in quartiles. Pathologic objective response (pOR; ypT0-Ta-Tis-T1N0) and pathologic complete response (pCR; ypT0N0), as well survival outcomes were assessed. We used data of 395 patients from The Cancer Genome Atlas (TCGA) to investigate the prevalence of TCGA molecular subtypes and DNA damage repair (DDR) gene alterations according to patient age.

Results: pOR was achieved in 40% of patients. There was no difference in distribution of pOR or pCR between age quartiles. On univariable logistic regression analysis, patient age was not associated with pOR or pCR when evaluated as continuous variables or stratified in quartiles (all p > 0.3). Median follow-up was 18 months (IQR 6-37). On Cox regression and competing risk regression analyses, age was not associated with survival outcomes (all p > 0.05). In the TCGA cohort, patient with age ≤ 60 years has 7% less DDR gene mutations (p = 0.59). We found higher age distribution in patients with luminal (p < 0.001) and luminal infiltrated (p = 0.002) compared to those with luminal papillary subtype.

Conclusions: While younger patients may have less mutational tumor burden, our analysis failed to show an association of age with response to preoperative chemotherapy or survival outcomes. Therefore, the use of preoperative chemotherapy should be considered regardless of patient age.
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http://dx.doi.org/10.1007/s00345-021-03793-4DOI Listing
December 2021

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

Cancers (Basel) 2021 Jul 26;13(15). Epub 2021 Jul 26.

Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

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 apoptotic tumor cells in the ccRCC tumor microenvironment and determine associations with survival and systemic treatment. Pre-treatment primary tumor samples were collected from 96 patients with metastatic ccRCC. Three adjacent slices were obtained from 2 tumor-core regions of interest (ROI) per patient, and immunohistochemistry (IHC) staining was performed for αSMA, Ki-67, and caspase-3 to detect CAFs, proliferating cells, and apoptotic cells, respectively. H-scores and cellular density were generated for each marker. ROIs were aligned, and spatial point patterns were generated, which were then used to perform spatial analyses using a normalized Ripley's K function at a radius of 25 μm (nK(25)). The survival analyses used an optimal cut-point method, maximizing the log-rank statistic, to stratify the IHC-derived metrics into high and low groups. Multivariable Cox regression analyses were performed accounting for age and International Metastatic RCC Database Consortium (IMDC) risk category. Survival outcomes included overall survival (OS) from the date of diagnosis, OS from the date of immunotherapy initiation (OS-IT), and OS from the date of targeted therapy initiation (OS-TT). Therapy resistance was defined as progression-free survival (PFS) <6 months, and therapy response was defined as PFS >9 months. CAFs exhibited higher cellular clustering with Ki-67 cells than with caspase-3 cells (nK(25): Ki-67 1.19; caspase-3 1.05; = 0.04). The median nearest neighbor (NN) distance from CAFs to Ki-67 cells was shorter compared to caspase-3 cells (15 μm vs. 37 μm, respectively; < 0.001). Multivariable Cox regression analyses demonstrated that both high Ki-67 density and H-score were associated with worse OS, OS-IT, and OS-TT. Regarding αSMA+CAFs, only a high H-score was associated with worse OS, OS-IT, and OS-TT. For caspase-3, high H-score and density were associated with worse OS and OS-TT. Patients whose tumors were resistant to targeted therapy (TT) had higher Ki-67 density and H-scores than those who had TT responses. Overall, this ex vivo geospatial analysis of CAF distribution suggests that close proximity clustering of tumor cells and CAFs potentiates tumor cell proliferation, resulting in worse OS and resistance to TT in metastatic ccRCC.
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http://dx.doi.org/10.3390/cancers13153743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345222PMC
July 2021

Outcomes of perineal urethrostomy for penile cancer: A 20-year international multicenter experience.

Urol Oncol 2021 08 13;39(8):500.e9-500.e13. Epub 2021 Jun 13.

Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL. Electronic address:

Purpose: Perineal urethrostomy (PU) is often the definitive form of urinary diversion in patients with locally-advanced or anatomically unfavorable penile cancer (PC) requiring total penectomy. Here, we report post-operative PU-related complications and PU stenosis rates after total penectomy with PU in a large multicenter cohort of PC patients.

Methods: We retrospectively reviewed the medical records of 299 patients who underwent PU as a means of urinary diversion for primary PC across seven international centers from 2000 to 2020. The Clavien-Dindo grading system was used to record 30-day post-operative complications. Cumulative incidence of stenosis was evaluated using the Kaplan-Meier method.

Results: Median patient age was 67 years (interquartile range (IQR) 58-74), and median follow-up was 19 months (IQR 7.2-57). A total of 58 patients (19%) developed a 30-day post-operative complication, of which 45 (79%) were deemed minor (CD Grade I and II). Wound infection (11%; CD grade I-III) and dehiscence (4.0%; CD grade I-III) were the more common complications. The overall incidence of stenosis was 12% (35/299 patients), of which 26 (74%) needed surgical revision (probability of stenosis revision at one year of 9.3%, median time until the revision: 6.1 months (IQR 3.0-13)). Only two stenoses were seen after two years of follow-up.

Conclusion: We present the most extensive series of PU in the management of PC to date. Wound infections of the primary surgical site were the most common complication. Stenosis occurred mostly within one and a half years after treatment.
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http://dx.doi.org/10.1016/j.urolonc.2021.04.023DOI Listing
August 2021

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

JAMA Netw Open 2021 May 3;4(5):e2111329. Epub 2021 May 3.

Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Importance: 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 unclear.

Objective: To assess the association of first-line TT, IT, and combination TT and IT regimens with OS in a real-world cohort of patients with metastatic clear cell RCC.

Design, Setting, And Participants: This retrospective propensity-matched cohort study identified 5872 patients with metastatic clear cell RCC in the National Cancer Database from January 1, 2015, to December 31, 2017, who received first-line TT, IT, or combination TT and IT and were not treated on a clinical trial protocol. Patients were stratified by first-line systemic treatment. Statistical analysis was conducted from October 1 to December 1, 2020.

Main Outcomes And Measures: The primary outcome was OS from the date of diagnosis to death or censoring at last follow-up. After 1:1:1 nearest-neighbor caliper matching of propensity scores, survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates.

Results: The final study population included 5872 patients (TT group: n = 4755 [81%]; 3332 men [70%]; median age, 64 years [interquartile range, 57-71 years]; IT group: n = 638 [11%]; 475 men [74%]; median age, 61 years [interquartile range, 54-69 years]; and combination TT and IT group: n = 479 [8%]; 321 men [67%]; median age, 62 years [interquartile range, 55-69 years]), and the matched cohort included 1437 patients (479 per treatment group). Patients in the IT and combination TT and IT groups were younger than those in the TT group, had fewer comorbid conditions (Charlson-Deyo score of 0, 480 of 638 [75%] in the TT group, 356 of 479 [74%] in the IT group, and 3273 of 4755 [69%] in the combination TT and IT group), and were more often treated at academic centers (315 of 638 [49%], 216 of 479 [45%], and 1935 of 4755 [41%], respectively). Both first-line IT and combination TT and IT were associated with improved OS compared with first-line TT for patients with metastatic clear cell RCC (IT group: hazard ratio [HR], 0.60 [95% CI, 0.48-0.75]; P < .001; combination TT and IT group: HR, 0.74 [95% CI, 0.60-0.91]; P = .005). No survival difference was seen between the IT and combination TT and IT groups (combination TT and IT: HR, 1.24 [95% CI, 0.98-1.56]; P = .08).

Conclusions And Relevance: This study suggests that both first-line IT and combination TT and IT were associated with improved OS compared with first-line TT for patients with metastatic clear cell RCC. These findings are similar to those identified in recently reported clinical trials, lending confidence to the broader applicability of these findings outside of a clinical trial setting.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.11329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150693PMC
May 2021

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

J Urol 2021 10 25;206(4):960-969. Epub 2021 May 25.

H. Lee Moffitt Cancer Center, Department of Genitourinary Oncology, Tampa, Florida.

Purpose: Our primary objective is to detail the incidence, site, and timing of penile squamous cell carcinoma (pSCC) recurrence after inguinal lymph node dissection (ILND).

Materials And Methods: We performed a 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 logistic regression analysis determined associations with recurrence. Multivariable Cox regression analysis determined associations with overall survival (OS). Sub-group analysis of the distant recurrences analyzed timing and OS by site of distant recurrence.

Results: After ILND pSCC recurred in 176 (31.9%) patients. Median time to recurrence was 10 months for distant recurrences, 12 for inguinal, 10.5 for pelvic, and 44.5 for local. Greater than 95% of distant, inguinal, and pelvic recurrences occurred within 48 months of ILND, versus 127 months for local recurrences. Post-ILND recurrence was associated with pN2 (OR 1.99, 95% CI 1.0-4.1), and pN3 (OR 7.2, 95% CI 4.0-13.7). Patients who had local recurrence had similar OS to those without (HR 1.5, 95% CI 0.6-3.8), and worse OS was identified in patients with inguinal (HR 4.5, 95% CI 2.8-7.1), pelvic (HR 2.6, 95% CI 1.5-4.5), or distant (HR 4.0, 95% CI 2.7-5.8) recurrences. Patients with lung recurrences had worse OS than other sites (HR 2.2, 95% CI 1.1-4.3).

Conclusions: Of the patients 31.9% had post-ILND recurrence associated with high pN staging. Greater than 95% of distant, inguinal, and pelvic recurrences occurred within 48 months, suggesting surveillance beyond this is low yield. Local recurrences occurred over a longer timeline, emphasizing necessity of long-term surveillance of the primary site.
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http://dx.doi.org/10.1097/JU.0000000000001790DOI Listing
October 2021

Pretreatment Risk Stratification for Endoscopic Kidney-sparing Surgery in Upper Tract Urothelial Carcinoma: An International Collaborative Study.

Eur Urol 2021 Oct 20;80(4):507-515. Epub 2021 May 20.

Department of Urology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

Background: Several groups have proposed features to identify low-risk patients who may benefit from endoscopic kidney-sparing surgery in upper tract urothelial carcinoma (UTUC).

Objective: To evaluate standard risk stratification features, develop an optimal model to identify ≥pT2/N+ stage at radical nephroureterectomy (RNU), and compare it with the existing unvalidated models.

Design, Setting, And Participants: This was a collaborative retrospective study that included 1214 patients who underwent ureterorenoscopy with biopsy followed by RNU for nonmetastatic UTUC between 2000 and 2017.

Outcome Measurements And Statistical Analysis: We performed multiple imputation of chained equations for missing data and multivariable logistic regression analysis with a stepwise selection algorithm to create the optimal predictive model. The area under the curve and a decision curve analysis were used to compare the models.

Results And Limitations: Overall, 659 (54.3%) and 555 (45.7%) patients had ≤pT1N0/Nx and ≥pT2/N+ disease, respectively. In the multivariable logistic regression analysis of our model, age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.0-1.03, p = 0.013), high-grade biopsy (OR 1.81, 95% CI 1.37-2.40, p < 0.001), biopsy cT1+ staging (OR 3.23, 95% CI 1.93-5.41, p < 0.001), preoperative hydronephrosis (OR 1.37 95% CI 1.04-1.80, p = 0.024), tumor size (OR 1.09, 95% CI 1.01-1.17, p = 0.029), invasion on imaging (OR 5.10, 95% CI 3.32-7.81, p < 0.001), and sessile architecture (OR 2.31, 95% CI 1.58-3.36, p < 0.001) were significantly associated with ≥pT2/pN+ disease. Compared with the existing models, our model had the highest performance accuracy (75% vs 66-71%) and an additional clinical net reduction (four per 100 patients).

Conclusions: Our proposed risk-stratification model predicts the risk of harboring ≥pT2/N+ UTUC with reliable accuracy and a clinical net benefit outperforming the current risk-stratification models.

Patient Summary: We developed a risk stratification model to better identify patients for endoscopic kidney-sparing surgery in upper tract urothelial carcinoma.
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http://dx.doi.org/10.1016/j.eururo.2021.05.004DOI Listing
October 2021

Prevalence of Preoperative Iron Deficiency Anemia: A Case Series Among Patients Undergoing Radical Cystectomy.

A A Pract 2021 May 17;15(5):e01477. Epub 2021 May 17.

Department of Genitourinary Oncology.

Anemia occurs in a significant group of patients with bladder cancer before radical cystectomy. Iron deficiency is a readily identifiable cause of anemia, which can be treated before surgery. The proportion of patients with bladder cancer with iron deficiency anemia is unknown. Laboratory and clinical outcomes were collected on 47 consecutive patients presenting for radical cystectomy. Iron studies found 30% of patients had iron deficiency anemia. These findings present an opportunity to treat anemia before surgery, to reduce blood transfusions during radical cystectomy.
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http://dx.doi.org/10.1213/XAA.0000000000001477DOI Listing
May 2021

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

Eur Urol Focus 2021 May 11. Epub 2021 May 11.

Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Background: 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.

Objective: To analyze the associations between common ccRCC somatic mutations and immune cell infiltration patterns within the tumor immune microenvironment (TIME).

Design, Setting, And Participants: The study included tumor samples (24 primary and 24 metastatic) from 48 patients with stage IV ccRCC. Targeted sequencing was performed for well-characterized recurrent somatic mutations in ccRCC, with the analysis focusing on the six most common ones: VHL, BAP1, PBRM1, SETD2, TP53, and KDM5C. For each sample, multiplex immunofluorescence (IF) was performed in lymphoid and myeloid panels, for seven regions of interest in three zones (tumor core, stroma, and tumor-stroma interface). IF-derived cellular densities were compared across patients, stratified by their somatic mutation status, using a linear mixed-model analysis. External validation was pursued using RNA-seq enrichment scoring from three large external data sources.

Results And Limitations: Tumors with SETD2 mutations demonstrated significantly decreased levels of FOXP3+ T cells in the tumor core, stroma, and tumor-stroma interface. PBRM1 mutations were associated with decreased FOXP3+ T cells in the tumor core. Primary KDM5C mutations were associated with significantly increased CD206+ macrophage tumor infiltration in the tumor core. A computational method estimating immune cell types in the TIME using bulk RNA-seq data, xCell scoring, failed to validate associations from the IF analysis in large external data sets. A major limitation of the study is the relatively small patient population studied.

Conclusions: This study provides evidence that common somatic mutations in ccRCC, such as SETD2, PBRM1, and KDM5C, are associated with distinct immune infiltration patterns within the TIME.

Patient Summary: In this study, we analyzed tumor samples from patients with metastatic kidney cancer to determine whether common genetic mutations that arise from the cancer cells are associated with the density of immune cells found within those tumors. We found several distinct immune cell patterns that were associated with specific genetic mutations. These findings provide insight into the interaction between cancer genetics and the immune system in kidney cancer.
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May 2021

Editorial Comment.

J Urol 2021 08 6;206(2):362-363. Epub 2021 May 6.

Department of GU Oncology, Moffitt Cancer Center, Tampa, Florida.

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http://dx.doi.org/10.1097/JU.0000000000001775.02DOI Listing
August 2021

Preoperative immunonutrition and carbohydrate loading associated with improved bowel function after radical cystectomy.

Nutr Clin Pract 2021 Apr 26. Epub 2021 Apr 26.

Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

Background: Preoperative malnourishment has been consistently associated with poor outcomes after radical cystectomy and other major abdominal surgeries. Most enhanced recovery after surgery (ERAS) studies have examined preoperative nutrition and its relationship to outcomes after gastrointestinal surgery. Although numerous studies have demonstrated the benefits of using an ERAS protocol, this study in unique in comparing 2 ERAS protocols, with and without a nutrition component.

Methods: A formalized preoperative nutrition protocol (PNP) recommending use of preoperative immunonutrition and carbohydrate drink was introduced in June 2018. A total of 78 consecutive patients who drank both beverages were compared with 92 historical controls. Multivariable logistic regression analyses were sequentially performed to determine if preoperative nutrition was associated with binary outcome variables (30-day complication, infectious complication, and readmission within 30 days).

Results: The preoperative nutrition group and control group were statistically similar in distribution of age, sex, American Society of Anesthesiologists physical status classification, clinical stage, and body mass index. Return of bowel function was found to occur earlier in the preoperative nutrition group than in the control group (3.12 vs 3.74 days; relative risk, 0.82; CI, 0.73-0.93; P = .0029). Complications within 30 days were similar in both groups (63.6% vs 55.4%; P = 0.36). Infectious complications (42.9% vs 37%; P = .53) and readmission within 30 days (22.1% vs 15.2%; P = .34) were also similar in both groups.

Conclusions: Use of a PNP including immunonutrition and carbohydrate drink may be associated with earlier return of bowel function after radical cystectomy.
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http://dx.doi.org/10.1002/ncp.10661DOI Listing
April 2021

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

PLoS One 2021 21;16(4):e0245415. Epub 2021 Apr 21.

Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.

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 cellular clustering for myeloid cell markers in 129 regions of interest from 55 samples from 35 patients with metastatic ccRCC. CD68+ cells were found to be clustered with tumor cells and dispersed from stromal cells, while CD163+ and CD206+ cells were found to be clustered with stromal cells and dispersed from tumor cells. CD68+ density was not associated with OS, while high tumor/CD68+ cell clustering was associated with significantly worse OS. These novel findings would not have been identified if immune infiltrate was assessed using cellular density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors. Significance: Increased clustering of CD68+ TAMs and tumor cells was associated with worse overall survival for patients with metastatic ccRCC. This effect would not have been identified if immune infiltrate was assessed using cell density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245415PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059840PMC
September 2021

Current practice patterns of society of urologic oncology members in performing inguinal lymph node staging/therapy for penile cancer: A survey study.

Urol Oncol 2021 07 26;39(7):439.e9-439.e15. Epub 2021 Mar 26.

Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Objectives: Inguinal lymph node (ILN) staging and therapeutic procedures are important for the diagnosis and management of suspected Inguinal lymph node metastasis in the setting of penile cancer. Morbidity associated with inguinal lymph node dissection (ILND) and the lack of standardization in its perioperative management are both significant. In this study, we aimed to define current management approaches and potential opportunities for improving outcomes.

Methods And Materials: A questionnaire was developed with 16 questions regarding pre, peri, and postoperative management of patients undergoing ILND. The questionnaire was approved by the Society of Urologic Oncology (SUO) Questionnaire Committee, which facilitated its dissemination through an initial email and a follow-up reminder to 1,003 members. The study was conducted from July to August, 2020.

Results: Of the 1,003 SUO members invited to participate, 93 responded (9.3% response rate); 49% performed 1 to 2 ILNDs annually, and 60% chose open ILND for high-risk primary cancer cN0. For suspicious lymph nodes > 2 cm, 69% preferred ILND, 86% preoperative systemic neoadjuvant chemotherapy, followed by surgery for bulky inguinal metastasis, and 84% used perioperative antibiotics (ABX), 53% of whom discontinued ABX 24 hours after surgery. Prophylactic anticoagulation was used by 78% of respondents, and 60% stopped it after ambulation. Specific ligation of lymphatics (versus none) was used by 82% of respondents, 55% obtained frozen sections, and 94% used inguinal drains. A saphenous sparing technique was used by 75% of respondents. An incisional wound vacuum device was used by 17% of respondents. Compression stockings and/or referral to a lymphedema specialist were used to manage postoperative lymphedema by 61% of respondents.

Conclusions: Responses to a penile lymphadenectomy survey were relatively low and were primarily from the academic surgeon subset of the SUO. Significant consensus ( ≥ 70%) was noted for neoadjuvant chemotherapy for bulky nodal metastasis prior to surgery, perioperative antibiotic use, ligation of lymphatics, drain placement, and saphenous sparing dissection techniques. Other evidenced-based strategies that could decrease morbidity were rarely used, including dynamic sentinel node biopsy, incisional wound vacuums, and lymphedema prevention. Prospective trials are needed to validate and resolve existing treatment paradigms and to optimize perioperative pathways to reduce complications in penile cancer management.
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http://dx.doi.org/10.1016/j.urolonc.2021.03.007DOI Listing
July 2021

Novel Classification for Upper Tract Urothelial Carcinoma to Better Risk-stratify Patients Eligible for Kidney-sparing Strategies: An International Collaborative Study.

Eur Urol Focus 2021 Mar 24. Epub 2021 Mar 24.

Department of Urology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

Background: The European Association of Urology risk stratification dichotomizes patients with upper tract urothelial carcinoma (UTUC) into two risk categories.

Objective: To evaluate the predictive value of a new classification to better risk stratify patients eligible for kidney-sparing surgery (KSS).

Design, Setting, And Participants: This was a retrospective study including 1214 patients from 21 centers who underwent ureterorenoscopy (URS) with biopsy followed by radical nephroureterectomy (RNU) for nonmetastatic UTUC between 2000 and 2017.

Outcome Measurements And Statistical Analysis: A multivariate logistic regression analysis identified predictors of muscle invasion (≥pT2) at RNU. The Youden index was used to identify cutoff points.

Results And Limitations: A total of 811 patients (67%) were male and the median age was 71 yr (interquartile range 63-77). The presence of non-organ-confined disease on preoperative imaging (p < 0.0001), sessile tumor (p < 0.0001), hydronephrosis (p = 0.0003), high-grade cytology (p = 0.0043), or biopsy (p = 0.0174) and higher age at diagnosis (p = 0.029) were independently associated with ≥pT2 at RNU. Tumor size was significantly associated with ≥pT2 disease only in univariate analysis with a cutoff of 2 cm. Tumor size and all significant categorical variables defined the high-risk category. Tumor multifocality and a history of radical cystectomy help to dichotomize between low-risk and intermediate-risk categories. The odds ratio for muscle invasion were 5.5 (95% confidence interval [CI] 1.3-24.0; p = 0.023) for intermediate risk versus low risk, and 12.7 (95% CI 3.0-54.5; p = 0.0006) for high risk versus low risk. Limitations include the retrospective design and selection bias (all patients underwent RNU).

Conclusions: Patients with low-risk UTUC represent ideal candidates for KSS, while some patients with intermediate-risk UTUC may also be considered. This classification needs further prospective validation and may help stratification in clinical trial design.

Patient Summary: We investigated factors predicting stage 2 or greater cancer of the upper urinary tract at the time of surgery for ureter and kidney removal and designed a new risk stratification. Patients with low or intermediate risk may be eligible for kidney-sparing surgery with close follow-up. Our classification scheme needs further validation based on cancer outcomes.
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http://dx.doi.org/10.1016/j.euf.2021.03.018DOI Listing
March 2021

Intermediate- and high-risk nonmuscle invasive bladder cancer: Where do we stand?

Urol Oncol 2021 10 22;39(10):631-641. Epub 2021 Mar 22.

Department of Medical Oncology, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy.

Introduction: The standard of care for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) patients is transurethral resection of bladder tumor followed by intravesical adjuvant immunotherapy with Bacillus Calmette-Guerin (BCG). However, a non-negligible portion of patients is doomed to fail BCG-therapy and, consequently, undergo radical cystectomy as only treatment option available. In this context, effective options to improve tumor response, thus delaying or even avoiding radical cystectomy, are urgently needed. A narrative review of the literature was performed to summarize the rationale and the clinical outcomes regarding the use of immunotherapy and novel therapeutic perspectives both for BCG-treated and BCG-naïve NMIBC patients.

Results: Several clinical trials are currently investigating immune checkpoint inhibitors and novel targeted approaches, including cancer vaccines, for NMIBC patients with BCG-naïve and BCG-unresponsive disease. Despite the lack of long-term safety data, novel therapeutic options, both by systemic and intravesical delivery, demonstrated a good tolerability, antitumor efficacy, and low rates of recurrence and/or progression to muscle-invasive disease.

Conclusions: Although clinical data available are mostly limited to phase I/II trials, novel targeted therapies have raised as an effective and reliable approach for patients failing BCG and for those who are therapy naïve. Phase III trials will be crucial in order to change the current clinical practice, after many years in which BCG was the only therapy available for intermediate- and high-risk NMIBC patients.
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http://dx.doi.org/10.1016/j.urolonc.2021.02.020DOI Listing
October 2021

Salvage therapy for localized recurrences of penile cancer.

Curr Opin Urol 2021 05;31(3):214-219

Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Purpose Of Review: To review the current literature and guidelines regarding salvage therapy for local and regional recurrence of primary penile cancer.

Recent Findings: While invasive surgical management has not significantly changed, penile sparing treatments (PSTs) may have a promising role in the management of local recurrence. Penile sparing surgeries do appear to have higher rates of recurrence. However, the overall survival rate is comparable to that of partial and total penectomies. Additionally, a combination of therapies may have a more profound effect on management of penile cancer.

Summary: Clinicians must discuss the role of each type of therapy for penile cancer with their patients, and tailor their management to the extent of disease in each patient. While it is important to discuss the balance between quality of life and rates of relapse, one must also emphasize the rates of overall survival in patients with local recurrence who are treated with PSTs.
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http://dx.doi.org/10.1097/MOU.0000000000000871DOI Listing
May 2021

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

Int Braz J Urol 2021 Sep-Oct;47(5):943-956

Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Purpose: 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 of diagnosis. Therefore, we performed a literature review of studies evaluating factors, both clinical and pathological, predictive of lymph node metastases in penile SCC.

Materials And Methods: Studies were identified using PubMed and search terms included the following: penile cancer, penile tumor, penile neoplasm, penile squamous cell carcinoma, inguinal lymph node metastasis, lymph node metastases, nodal metastasis, inguinal node metastasis, inguinal lymph node involvement, predictors, and predictive factor. The number of patients and predictive factors were identified for each study based on OR, HR, or RR in multivariate analyses, as well as their respective significance values. These were compiled to generate a single body of evidence supportive of factors predictive of ILNM in penile SCC.

Results: We identified 31 studies, both original articles and meta-analyses, which identified factors predictive of metastases in penile SCC. The following clinical factors were predictive of ILNM in penile SCC: lymphovascular invasion (LVI), increased grade, increased stage (both clinical and pathological), infiltrative and reticular invasion, increased depth of invasion, perineural invasion, and younger patient age at diagnosis. Biochemically, overexpression of p53, SOD2, Ki-67, and ID1 were associated with spread of SCC to inguinal lymph nodes. Diffuse PD-L1 expression, increased SCC-Ag expression, increased NLR, and CRP >20 were also associated with increased ILNM.

Conclusions: A multitude of factors are associated with metastasis of SCC of the penis to inguinal lymph nodes, which is associated with poor clinical outcomes. The above factors, most strongly LVI, grade, and node positivity, may be considered when constructing a nomogram to risk-stratify patients and determine eligibility for prophylactic inguinal lymphadenectomy.
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http://dx.doi.org/10.1590/S1677-5538.IBJU.2020.0959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321459PMC
August 2021

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

Front Oncol 2020 10;10:627025. Epub 2021 Feb 10.

Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.

Background: 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.

Methods: Patients with clear cell RCC or non-clear cell RCC underwent cytoreductive nephrectomy in efforts to improve overall survival (OS). Patients were stratified by presence or absence of histologic sarcomatoid features within tumor samples.

Results: Of 167 patients who underwent cytoreductive nephrectomy, 127 had clear cell RCC, of whom 14 had sarcomatoid features, and 40 had non-clear cell RCC, of whom 13 had sarcomatoid features. Median age of the cohort was 62 years (range, 56.5-69 years). The cohort included 119 male (71.3%) and 48 (28.7%) female patients. Among all patients with advanced RCC, having sRCC had a significantly worse OS after cytoreductive nephrectomy (30 vs 8 months; hazard ratio [HR], 2.88; <0.0001). Additionally, favorable-risk patients had significantly longer OS compared to intermediate- or poor-risk patients (56 vs 30 vs 10 months; HR, 0.21; =0.00016). For patients with clear cell RCC, having sRCC conferred a significantly poorer survival (30 vs 9 months; HR, 2.82; =0.0035). Patients with non-clear cell sRCC also had significantly worse outcomes compared to patients whose tumors did not have sarcomatoid features (30 vs 6.5 months; HR, 3; =0.009). When patients with sRCC were stratified by whether there was >10% or ≤10% sarcomatoid features present within the sample, there was no significant difference in OS (8 vs 8.5 months; =0.32).

Conclusions: Sarcomatoid features within tumor histology confer significantly poor prognosis. Patients with sRCC, regardless of clear cell vs non-clear cell histology, have significantly shorter OS. Even among patients with 10% or less sarcomatoid features, there was no OS benefit to cytoreductive nephrectomy. Based on our findings, there appears to be a limited to no role of cytoreductive nephrectomy if sRCC is identified on pretreatment biopsy. The role of radiomics and pre-operative biopsies may confer significant benefit in this patient population.
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http://dx.doi.org/10.3389/fonc.2020.627025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902859PMC
February 2021

Expansion of tumor-infiltrating lymphocytes (TIL) from penile cancer patients.

Int Immunopharmacol 2021 May 23;94:107481. Epub 2021 Feb 23.

Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA; Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA; Center for Immunization and Infection Research in Cancer (CIIRC), Moffitt Cancer Center, Tampa, FL, USA. Electronic address:

Penile cancer is a rare but highly lethal cancer, and therapeutic options for patients presenting with lymph nodal disease are very limited. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) was shown to provide durable objective response in patients with metastatic melanoma and TIL have been expanded from solid tumors at rates between 70 and 90% depending on the specific diagnosis. We evaluated whether TIL could be expanded from surgical specimens of patients with penile cancer. Tumor samples from metastatic lymph nodes obtained at the time of inguinal lymph node dissection were collected, minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. The phenotype of expanded TILs was assessed by flow cytometry and their anti-tumor reactivity was assessed by IFN-γ ELISA. TIL were expanded from 11 out of 12 (91.6%) samples of metastatic lymph nodes. Expanded TIL were predominantly CD3 (mean 67.5%, SD 19.4%) with a mean of 46.8% CD8 T cells (SD 21.1%). Five out of 11 samples (45.4%) from expanded TIL secreted IFN-γ in response to autologous tumor. TIL expansion and phenotype of expanded T cell lymphocytes were independent of previous HPV infection and treatment with neoadjuvant chemotherapy. This is the first report demonstrating successful expansion of tumor-reactive TIL from penile cancer patients, which support development of ACT strategies using TIL for the treatment of advanced and recurrent penile cancer.
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http://dx.doi.org/10.1016/j.intimp.2021.107481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205103PMC
May 2021

Reliability of Serum Tumor Marker Measurement to Diagnose Recurrence in Patients with Clinical Stage I Nonseminomatous Germ Cell Tumors Undergoing Active Surveillance: A Systematic Review.

J Urol 2021 Jun 22;205(6):1569-1576. Epub 2021 Feb 22.

Department of Urology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy.

Purpose: Men with nonseminomatous germ cell tumors of the testicle without evidence of residual disease after radical orchiectomy (clinical stage I) are increasingly managed with active surveillance. The guideline-recommended cornerstones of surveillance are conventional serum tumor markers and computerized tomography. The reliability of serum tumor markers as a tool to diagnose early recurrence of clinical stage I nonseminomatous germ cell tumors is unclear. The study objective was to conduct a systematic review of the currently available evidence assessing the reliability of serum tumor markers as a test to diagnose recurrence in patients with clinical stage I nonseminomatous germ cell tumors under active surveillance.

Materials And Methods: A systematic review was conducted in accordance with PRISMA guidelines, with no language or date restrictions. Studies were included that readily identified the tumor marker status of patients with clinical stage I nonseminomatous germ cell tumors who had a recurrence on active surveillance. The primary outcome was marker positivity at the time of recurrence. Risk of bias assessment was undertaken.

Results: A total of 2,157 studies were identified and independently screened by 2 reviewers, with 37 studies ultimately being included. A relatively high risk of bias was identified among the studies, with the vast majority being retrospective series. The total population for the included studies was 8,545 patients with clinical stage I nonseminomatous germ cell tumors managed by active surveillance, and 2,254 ultimately relapsed. Serum tumor markers were elevated in 28% to 75% of patients at the time of recurrence and were the only indication of recurrence in 4% to 39%. The unavailability of patient-level data is the major limitation to the present findings.

Conclusions: In patients with clinical stage I nonseminomatous germ cell tumors managed by active surveillance, the use of serum tumor markers cannot obviate the need for computerized tomography. More reliable serum markers are needed in order to limit radiation exposure for these patients.
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http://dx.doi.org/10.1097/JU.0000000000001685DOI Listing
June 2021

Should Upper-tract Urothelial Carcinoma and Bladder Carcinoma Be Treated the Same or Different?

Eur Urol Oncol 2021 04 16;4(2):180-181. Epub 2021 Feb 16.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

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http://dx.doi.org/10.1016/j.euo.2021.01.009DOI Listing
April 2021

Penile cancer.

Nat Rev Dis Primers 2021 02 11;7(1):11. Epub 2021 Feb 11.

Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

Penile squamous cell carcinoma (PSCC) is a rare cancer with orphan disease designation and a prevalence of 0.1-1 per 100,000 men in high-income countries, but it constitutes up to 10% of malignancies in men in some African, Asian and South American regions. Risk factors for PSCC include the absence of childhood circumcision, phimosis, chronic inflammation, poor penile hygiene, smoking, immunosuppression and infection with human papillomavirus (HPV). Several different subtypes of HPV-related and non-HPV-related penile cancers have been described, which also have different prognostic profiles. Localized disease can be effectively managed by topical therapy, surgery or radiotherapy. As PSCC is characterized by early lymphatic spread and imaging is inadequate for the detection of micrometastatic disease, correct and upfront surgical staging of the inguinal lymph nodes is crucial in disease management. Advanced stages of disease require multimodal management. Optimal sequencing of treatments and patient selection are still being investigated. Cisplatin-based chemotherapy regimens are the mainstay of systemic therapy for advanced PSCC, but they have poor and non-durable responses and high rates of toxic effects, indicating a need for the development of more effective and less toxic therapeutic options. Localized and advanced penile cancers and their treatment have profound physical and psychosexual effects on the quality of life of patients and survivors by altering sexual and urinary function and causing lymphoedema.
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http://dx.doi.org/10.1038/s41572-021-00246-5DOI Listing
February 2021

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

Front Oncol 2020 23;10:615298. Epub 2020 Dec 23.

Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, United States.

Background: 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 expression in patients with PSCC, and its biological similarities to other squamous cell carcinomas, we present two patient cases treated with pembrolizumab with extraordinary durable treatment response far beyond treatment with standard therapy.

Main Body: The first patient is a 64 year old male with PSCC who was treated with neoadjuvant chemotherapy, partial penectomy, and adjuvant radiation prior to developing metastatic disease. He had a high TMB (14 mutations/Mb) and was started on pembrolizumab with a complete response, which has been maintained for 38 months. The second patient is an 85 year old male with PSCC who was treated with partial penectomy and adjuvant chemotherapy and radiation prior to developing metastatic disease. He had positive PD-L1 expression CPS 130) and was started on pembrolizumab with a partial response, which has been maintained for 18 months after starting treatment.

Conclusions: These two cases of extreme durable response with pembrolizumab (with molecular data including TMB and PD-L1 status) represent a significant clinical benefit in this patient population. With limited treatment options that result in a median OS of less than 6 months, along with the toxicity profile of chemotherapy which may not be tolerated in elderly patients with comorbidities, this survival benefit with pembrolizumab, along with advances in tumor sequencing and clinical trials shows that there is a potentially significant benefit with novel therapies in this patient population.
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http://dx.doi.org/10.3389/fonc.2020.615298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793656PMC
December 2020
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