Publications by authors named "Lucia Nappi"

37 Publications

Primary pure carcinoid tumor of the testis: Radiology, pathology and molecular correlation.

Urol Case Rep 2021 Nov 21;39:101787. Epub 2021 Jul 21.

Department of Radiology, British Columbia Cancer Vancouver Centre, Vancouver, BC, Canada.

We describe a case of a primary carcinoid tumor of the testis in a 35-year-old man as an incidental finding. Testicular ultrasound showed a 1.1 cm hypoechoic/isoechoic mass with some calcification in the left testicle. The pathology examination of the radical orchiectomy demonstrated a pure carcinoid tumor, with the adjacent coarse calcification. Fluorescence in situ hybridization showed 35 % of the tumor cells had one additional chromosome 12p11.21 signal. This case adds to the rare reports in the literature of a primary pure carcinoid tumor of the testis, and provides additional insight into the radiological and pathological correlation of this disease.
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http://dx.doi.org/10.1016/j.eucr.2021.101787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326723PMC
November 2021

Effectiveness of first-line abiraterone versus enzalutamide among patients ≥80 years of age with metastatic castration-resistant prostate cancer: A retrospective propensity score-weighted comparative cohort study.

Eur J Cancer 2021 Jul 12;152:215-222. Epub 2021 Jun 12.

Department of Medicine, Medical Oncology Division, BC Cancer, Vancouver Centre, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background: Metastatic castration-resistant prostate cancer (mCRPC) disproportionately affects the elderly. There is limited data assessing the efficacy and tolerability of abiraterone acetate (AA) versus enzalutamide in this population.

Objective: To compare the clinical efficacy and tolerability of AA versus enzalutamide in patients ≥ 80 years with mCRPC.

Design, Setting And Participants: A retrospective propensity-weighted comparative cohort study of first-line AA versus enzalutamide among patients with mCRPC aged ≥80 years.

Outcome Measurements And Statistical Analysis: Inverse probability treatment weights based on propensity scores were generated to assess the treatment effect of AA versus enzalutamide on time to PSA progression (TTPP), time to progression (TTP) (first of PSA/radiographic/clinical progression) and overall survival using a weighted Cox proportional hazards model. PSA response rate (PSA RR) was compared between groups using Χ.

Results And Limitations: One hundred fifty-three patients received AA, and 125 received enzalutamide. Enzalutamide was associated with higher PSA RR (61.6% vs 43.8%, P < 0.004), and TTP (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.50-0.88, P = 0.01) but not TTPP (HR 0.73, 95% CI 0.53-1.01, P = 0.06). There were significantly more dose reductions with enzalutamide (22.9% vs 44.8%, P > 0.001) but there was no interaction between median proportion of full dose received and TTPP or TTP for either drug. Rates of treatment discontinuation (for reasons other than progression) were also significantly different between AA and enzalutamide (28.8% vs 40.8%, respectively, P = 0.04). The most common reason for dose reductions and discontinuation of enzalutamide was fatigue (30.4% and 5.6%, respectively).

Conclusions: Despite more dose reductions and a higher treatment discontinuation rate, enzalutamide was associated with a higher PSA RR and longer time to progression, than AA. Given that clinical outcomes were not adversely impacted by decreased treatment exposure, dose modification may be a useful treatment strategy to balance toxicity and tolerance.
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http://dx.doi.org/10.1016/j.ejca.2021.05.003DOI Listing
July 2021

Androgen receptor (AR) antagonism triggers acute succinate-mediated adaptive responses to reactivate AR signaling.

EMBO Mol Med 2021 May 11;13(5):e13427. Epub 2021 Mar 11.

Vancouver Prostate Centre, Vancouver, BC, Canada.

Treatment-induced adaptive pathways converge to support androgen receptor (AR) reactivation and emergence of castration-resistant prostate cancer (PCa) after AR pathway inhibition (ARPI). We set out to explore poorly defined acute adaptive responses that orchestrate shifts in energy metabolism after ARPI and identified rapid changes in succinate dehydrogenase (SDH), a TCA cycle enzyme with well-known tumor suppressor activity. We show that AR directly regulates transcription of its catalytic subunits (SDHA, SDHB) via androgen response elements (AREs). ARPI acutely suppresses SDH activity, leading to accumulation of the oncometabolite, succinate. Succinate triggers calcium ions release from intracellular stores, which in turn phospho-activates the AR-cochaperone, Hsp27 via p-CaMKK2/p-AMPK/p-p38 axis to enhance AR protein stabilization and activity. Activation of this pathway was seen in tissue microarray analysis on prostatectomy tissues and patient-derived xenografts. This adaptive response is blocked by co-targeting AR with Hsp27 under both in vitro and in vivo studies, sensitizing PCa cells to ARPI treatments.
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http://dx.doi.org/10.15252/emmm.202013427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103094PMC
May 2021

In Reply.

Oncologist 2021 02 9;26(2):e350. Epub 2021 Jan 9.

University of Naples "Federico II," Department of Clinical Medicine and Surgery, CRCTR Regional Rare Tumors Reference Center, Naples, Italy.

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http://dx.doi.org/10.1002/onco.13651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873323PMC
February 2021

Integrated Expression of Circulating miR375 and miR371 to Identify Teratoma and Active Germ Cell Malignancy Components in Malignant Germ Cell Tumors.

Eur Urol 2021 01 4;79(1):16-19. Epub 2020 Nov 4.

Department of Medicine, Medical Oncology Division, BC Cancer, Vancouver Centre, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Active germ cell malignancies express high levels of specific circulating micro-RNAs (miRNAs), including miR-371a-3p (miR371), which is undetectable in teratoma. Teratoma markers are urgently needed for theselection of patients and treatments because of the risk of malignant transformation and growing teratoma syndrome. To assess the accuracy of plasma miR375 alone or in combination with miR371 in detecting teratoma, 100 germ cell tumor patients, divided into two cohorts, were enrolled in a prospective multi-institutional study. In the discovery cohort, patients with pure teratoma and with no/low risk of harboring teratoma were compared; the validation cohort included patients with confirmed teratoma, active germ cell malignancy, or complete response after chemotherapy. The area under the receiver operating characteristic curve values for miR375, miR371, and miR371-miR375 were, respectively, 0.93 (95% confidence interval [CI]: 0.87-0.99), 0.59 (95% CI: 0.44-0.73), and 0.95 (95% CI: 0.90-0.99) in the discovery cohort and 0.55 (95% CI: 0.36-0.74), 0.74 (95% CI: 0.58-0.91), and 0.77 (95% CI: 0.62-0.93) in the validation cohort. Our study demonstrated that the plasma miR371-miR375 integrated evaluation is highly accurate to detect teratoma. PATIENT SUMMARY: The evaluation of two micro-RNAs (miR375-miR371) in the blood of patients with germ cell tumors is promising to predict teratoma. This test could be particularly relevant to the identification of teratoma in patients with postchemotherapy residual disease.
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http://dx.doi.org/10.1016/j.eururo.2020.10.024DOI Listing
January 2021

Impact of COVID-19 outbreak on cancer immunotherapy in Italy: a survey of young oncologists.

J Immunother Cancer 2020 10;8(2)

Oncology, Department of Precision Medicine, Università della Campania "L. Vanvitelli", Napoli, Campania, Italy.

Background: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region.

Methods: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ test for trends relative to the questions with 3 or more options.

Results: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones.

Conclusion: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.
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http://dx.doi.org/10.1136/jitc-2020-001154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565202PMC
October 2020

Avelumab and axitinib combination therapy for the treatment of advanced renal cell carcinoma.

Future Oncol 2020 Dec 28;16(36):3021-3034. Epub 2020 Aug 28.

Department of Medical Oncology, BC Cancer Vancouver Centre, Vancouver, BC, V5Z 4E6, Canada.

Owing to an improved understanding of the immunobiological profile of renal cell carcinoma (RCC), the past few years have ushered in significant changes in systemic therapies for advanced stage RCC. First-line treatment with single-agent tyrosine kinase inhibitors (TKI) has been virtually replaced for most patients by immunotherapy combinations. The first of such treatments was the dual immune checkpoint inhibitor combination of ipilimumab and nivolumab. More recently, the combination of an immune checkpoint inhibitor and a TKI has also moved into the first-line setting. This review summarizes the pharmacologic properties, evidence for use and safety of avelumab, a PD-L1 inhibitor and axitinib a small-molecule TKI, each as monotherapy, and in combination for the management of metastatic RCC.
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http://dx.doi.org/10.2217/fon-2020-0586DOI Listing
December 2020

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic: A Survey of International Expertise Centers.

Oncologist 2020 10 18;25(10):e1509-e1515. Epub 2020 Sep 18.

Center Hospitalier de l'Université de Montréal, Montreal, Canada.

Background: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs).

Materials And Methods: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options.

Results: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences.

Conclusion: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic.

Implications For Practice: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity.
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http://dx.doi.org/10.1634/theoncologist.2020-0420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543332PMC
October 2020

LIN28B promotes the development of neuroendocrine prostate cancer.

J Clin Invest 2020 10;130(10):5338-5348

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Therapy-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive subtype of prostate cancer with poor patient survival. Emerging evidence indicates that t-NEPC can develop when prostate adenocarcinoma cells acquire cancer stem-like cell signaling in the presence of androgen receptor inhibition, followed by redifferentiation toward neuroendocrine lineage and subsequent t-NEPC progression. Whether the stem-like signaling is controlled by the core pluripotency stem cell genes (e.g., LIN28 and SOX2) remains unknown. Here, we report that the transcription of the LIN28B isoform and SOX2 were co-upregulated in t-NEPC patient tumors, patient-derived xenografts, transgenic mice, and cell models. Immunohistochemistry validated that LIN28B and SOX2 protein expression were elevated in t-NEPC patient biopsies. Using prostate adenocarcinoma and t-NEPC cell models, we demonstrated that LIN28B induced a stem-like gene network, neuroendocrine biomarkers, and neuroendocrine cell morphology. LIN28B depletion by CRISPR inhibited t-NEPC tumorigenesis and xenograft growth. These LIN28B functions were mediated mainly through the suppression of let-7 miRNA expression, resulting in de-repression of the transcription factor HMGA2 and HMGA2-mediated SOX2 expression. This study revealed a mechanism by which t-NEPC can develop through the LIN28B/let-7/SOX2 axis that regulates a cancer cell stem-like gene network, highlighting LIN28B as a potential therapeutic target in t-NEPC.
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http://dx.doi.org/10.1172/JCI135373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524485PMC
October 2020

Zero, Some Chemotherapy Game in Early-Stage Germ Cell Tumors.

J Clin Oncol 2020 07 22;38(19):2214-2215. Epub 2020 Apr 22.

Craig Nichols, MD, Testicular Cancer Commons, and SWOG Group Chair's Office, Portland, OR; Lucia Nappi, PhD and Christian Kollmannsberger, MD, British Columbia Cancer, Division of Medical Oncology, Vancouver, British Columbia, Canada; Robert Hamilton, MD, MPH, Department of Surgery (Urology), Princess Margaret Cancer Centre, Toronto, Ontario, Canada; and Hamed Ahmadi, MD and Siamak Daneshmand, MD, University of Southern California/Norris Comprehensive Cancer Center, Institute of Urology, Los Angeles, CA.

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http://dx.doi.org/10.1200/JCO.20.00204DOI Listing
July 2020

Back to the Future-Moving Forward for Testicular Cancer Survivors.

JNCI Cancer Spectr 2020 Apr 8;4(2):pkz082. Epub 2019 Oct 8.

USC/Norris Comprehensive Cancer Center, Institute of Urology, Los Angeles, CA.

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http://dx.doi.org/10.1093/jncics/pkz082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065711PMC
April 2020

Plasma Circulating Tumor DNA and Clonal Hematopoiesis in Metastatic Renal Cell Carcinoma.

Clin Genitourin Cancer 2020 08 8;18(4):322-331.e2. Epub 2020 Jan 8.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; Department of Medical Oncology, BC Cancer, British Columbia, Canada.

Background: There is a lack of molecularly-informed biomarkers for patients with metastatic renal cell carcinoma (RCC). Plasma cell-free DNA (cfDNA) sequencing is a minimally-invasive alternative to tissue for profiling the genome in other cancers but relevance in metastatic RCC remains unclear.

Materials And Methods: Whole blood was collected from 55 patients with metastatic RCC. Plasma cfDNA and leukocyte DNA were subjected to targeted sequencing across 981 cancer genes. Matched tumor tissue from 14 patients was analyzed.

Results: Thirty-three percent of patients had evidence for RCC-derived circulating tumor DNA (ctDNA), significantly lower than patients with metastatic prostate or bladder cancer analyzed using the same approach. Among ctDNA-positive patients, ctDNA fraction averaged only 3.9% and showed no strong association with clinical variables. In these patients, the most commonly mutated genes were VHL, BAP1, and PBRM1, and matched tissue concordance was 77%. Evidence of somatic expansions unrelated to RCC, such as clonal hematopoiesis of indeterminate potential, were detected in 43% of patients. Pathogenic germline mutations in DNA repair genes were detected in 11% of patients. CtDNA-positive patients had shorter overall survival and progression-free survival on first-line therapy. Patients with evidence of clonal hematopoiesis of indeterminate potential had an intermediate prognosis compared with ctDNA-positive and -negative patients.

Conclusions: CfDNA sequencing enables straightforward characterization of the somatic RCC genome in a minority of patients with metastatic RCC. Owing to low ctDNA abundance, and the presence of non-RCC derived somatic clones in circulation, cfDNA sequencing may not be a simple pan-patient alternative to tissue biopsy in metastatic RCC.
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http://dx.doi.org/10.1016/j.clgc.2019.12.018DOI Listing
August 2020

The role of micro-RNAs in management of germ cell tumors: future directions.

Curr Opin Urol 2020 03;30(2):258-263

Testicular Cancer Commons, Beaverton.

Purpose Of Review: miRNAs 371 and 302/367 clusters are abundantly secreted in the blood of patients with active germ cell malignancy (aGCM), both seminoma and nonseminoma. The serum concentration of those micro-RNAs correlates with tumor burden and to the activity of specific treatments; therefore, representing attractive biomarkers for the diagnosis and follow-up of patients with germ cell tumors. This review summarizes the most relevant evidence supporting their clinical validity in germ cell tumors.

Recent Findings: Several retrospective studies have reported high sensitivity and specificity of those micro-RNAs in identifying aGCM prior to the orchiectomy or in patients with metastatic germ cell tumor prior to or during chemotherapy. Most recently, few prospective studies have confirmed their clinical validity during the follow-up of patients after surgery and/or chemotherapy. Large studies are panned across the spectrum of germ cell tumors to assess their clinical utility and several efforts to identify biomarkers of teratoma are underway.

Summary: The integration of those micro-RNAs in the management of germ cell tumors has the potential to refine the therapeutic decision, especially in some clinical situations characterized by high uncertainty, such as clinical stage I, clinical stage IIA with normal tumor markers and residual disease postchemotherapy.
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http://dx.doi.org/10.1097/MOU.0000000000000726DOI Listing
March 2020

Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models.

J Clin Invest 2020 02;130(2):699-714

Department of Urologic Sciences, Vancouver Prostate Centre, and.

HSP27 is highly expressed in, and supports oncogene addiction of, many cancers. HSP27 phosphorylation is a limiting step for activation of this protein and a target for inhibition, but its highly disordered structure challenges rational structure-guided drug discovery. We performed multistep biochemical, structural, and computational experiments to define a spherical 24-monomer complex composed of 12 HSP27 dimers with a phosphorylation pocket flanked by serine residues between their N-terminal domains. Ivermectin directly binds this pocket to inhibit MAPKAP2-mediated HSP27 phosphorylation and depolymerization, thereby blocking HSP27-regulated survival signaling and client-oncoprotein interactions. Ivermectin potentiated activity of anti-androgen receptor and anti-EGFR drugs in prostate and EGFR/HER2-driven tumor models, respectively, identifying a repurposing approach for cotargeting stress-adaptive responses to overcome resistance to inhibitors of oncogenic pathway signaling.
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http://dx.doi.org/10.1172/JCI130819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994194PMC
February 2020

Developing a Highly Specific Biomarker for Germ Cell Malignancies: Plasma miR371 Expression Across the Germ Cell Malignancy Spectrum.

J Clin Oncol 2019 11 25;37(33):3090-3098. Epub 2019 Sep 25.

BC Cancer, Vancouver Centre, University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: Our objective was to evaluate operating characteristics, particularly specificity and positive predictive value (PPV), by mapping plasma miR371 expression to actual clinical events in patients with a history of germ cell tumor.

Patients And Methods: One hundred eleven male patients with a history of or newly diagnosed germ cell tumors were evaluable. Biospecimens obtained before confirmed clinical events were analyzed for miR371 expression with blinding of providers and laboratory personnel to analytic results or clinical status, respectively. Cases (patients with clinically confirmed active germ cell malignancy [aGCM]) and controls (patients with no clinically confirmed aGCM) were assigned over the course of the management. Patients were assigned risk status (high, low, or moderate) based on the composite clinical picture at time points in management.

Results: Considering all cases and controls and results of prospectively obtained biosamples analyzed for miR371 expression, 46 (35%) of 132 samples had clinically confirmed aGCM over the course of management; 44 (96%) of these 46 patients had plasma miR371 expression (true positives) with no false positives. Two (4%) of 46 patients had no miRNA expression despite pathologic confirmation of aGCM (false negatives). Plasma miR371 expression in confirmed aGCM had a specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 96%, 100%, and 98%, respectively. Interpretation of sensitivity and negative predictive value is limited by modest follow-up. Specificity and sensitivity were 100% and 98%, 100% and 92%, and 100% and 97% in the low-, moderate-, and high-risk groups, respectively, with a median follow-up time of 15 months.

Conclusion: Plasma miR371 expression predicts aGCM with high specificity and positive predictive value. Although other operating characteristics of miR371 await longer follow-up for more complete definition, the findings of a highly specific liquid biopsy strongly support moving forward with large-scale, real-world clinical trials to further define full operating characteristics and to identify clinical utility and areas of patient benefit.
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http://dx.doi.org/10.1200/JCO.18.02057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351323PMC
November 2019

MicroRNAs as Biomarkers for Germ Cell Tumors.

Urol Clin North Am 2019 Aug 29;46(3):449-457. Epub 2019 May 29.

Testicular Cancer Commons, Vancouver, WA, USA; SWOG Group Chairs Office, 2611 Southwest 3rd Avenue MQ280, Portland, OR 97201, USA. Electronic address:

Two clusters of microRNAs have been discovered highly expressed by seminoma and nonseminoma germ cell tumors. They are secreted in blood of patients with testicular germ cell tumors and can be extracted from the serum or plasma and quantified by real-time-polymerase chain reaction. Results have confirmed the feasibility of the technique and demonstrated that sensitivity and specificity of those microRNAs in detecting viable germ cell tumors are higher than with current methods. If operation characteristics are confirmed in larger studies, those microRNAs will be valuable to manage equivocal clinical scenarios characterized by high uncertainty and high risk of over-treatment or under-treatment.
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http://dx.doi.org/10.1016/j.ucl.2019.04.011DOI Listing
August 2019

Management of Stage II Germ Cell Tumors: Be Sure, Be Patient, Be Safe.

J Clin Oncol 2019 08 10;37(22):1856-1862. Epub 2019 Jun 10.

2Testicular Cancer Commons, Vancouver, WA.

A healthy 27-year-old man discovered a left testicular mass. Several months later he saw an urologist, who palpated a suspicious mass on the left testicle; an ultrasound confirmed a 2-cm solid mass. Serum tumor marker testing disclosed a slightly elevated alpha-fetoprotein (AFP) of 12.3 µg/L (upper limit of normal, 8.0 µg/L), and a normal β-human chorionic gonadotropin (HCG). Staging imaging with a contrast-enhanced computed tomography (CT) scan of the chest/abdomen/pelvis showed no evidence for retroperitoneal lymphadenopathy or distant metastases. He underwent a left radical orchiectomy, and pathology showed a 1.5-cm mixed germ cell tumor with 85% embryonal, 10% yolk sac tumor, and 5% mature teratoma histologies. Lymphovascular invasion was present. His AFP normalized after surgery. After discussion of management alternatives, he chose active surveillance, but 4 months later a scheduled surveillance CT scan identified a 1.4-cm left para-aortic lymph node just below the left renal hilum (Fig 1). Serum tumor markers remained negative. He returns to discuss his results and potential management options.
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http://dx.doi.org/10.1200/JCO.19.00502DOI Listing
August 2019

Loss of Nuclear Functions of HOXA10 Is Associated With Testicular Cancer Proliferation.

Front Oncol 2018 7;8:594. Epub 2018 Dec 7.

Department of Urologic Sciences, Vancouver Prostate Centre, The University of British Columbia, Vancouver, BC, Canada.

HOXA10 is a key transcriptional factor that regulates testis development as reported from previous transgenic mouse models and human inherited diseases. However, whether it also plays important roles in promoting the development of testicular cancer is not well-understood. To study the expression of HOXA10 and its regulated signaling pathways in testicular cancers. A tissue microarray was constructed with benign and cancerous testis. TCam2, NT-2, and NCCIT cell models were applied in this study. Immunohistochemistry and immunofluorescence were performed to measure the expression and cellular localization of HOXA10 in testicular cancer tissues and cell models. Cell proliferation and cell cycling rates were determined by BrdU incorporation and flow cytometry assays. HOXA10 transcriptomes were profiled with Ampliseq RNA-seq in testicular cancer cells. Immunoblotting assays were used to detect HOXA10-regulated signaling. HOXA10 is a nuclear protein in benign spermatocytes. Reduced nuclear expression and increased cytoplasmic expression of HOXA10 are associated with testicular cancers. These changes are consistent in both seminoma and non-seminoma. Enhanced HOXA10 expression in testicular cancer cell models inhibits cell proliferation and delays cell cycle progression through G2/M phases. These functions of HOXA10 mainly affect the TP53, cKit, STAT3, AKT, and ERK signaling pathways. Loss of nuclear functions of HOXA10 enhances proliferation of testicular cancer cells, suggesting that downregulation of HOXA10 transcription activity may promote the development of testicular cancers.
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http://dx.doi.org/10.3389/fonc.2018.00594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292994PMC
December 2018

Clinical features and psychological aspects of the decision-making process in stage I testicular germ cell tumors.

Future Oncol 2018 Jul 29;14(16):1591-1599. Epub 2018 Jun 29.

CRTR Rare Tumors Reference Center, University of Naples Federico II, Naples, Italy.

Testicular germ cell tumors (TGCTs) are the most prevalent malignancies in young Caucasian men. Clinical stage I (CSI) TGCTs present the highest cure rate and treatment options after orchiectomy depend on histology and risk factors. Nevertheless, the management of CSI TGCTs is controversial due to the availability of multiple treatments and the lack of randomized trials. An integrated multidisciplinary approach that includes clinicians (surgeons, radiotherapists and oncologists) and psychologists is crucial to maximize the patients' compliance and must be acknowledged with appropriate tools. The aim of our work is to review the oncological and psychological aspects of the decision-making process, discussing the fundamental role of the patient involvement in the personalized management of CSI TGCTs.
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http://dx.doi.org/10.2217/fon-2017-0670DOI Listing
July 2018

Long term deficiency of vitamin D in germ cell testicular cancer survivors.

Oncotarget 2018 Apr 20;9(30):21078-21085. Epub 2018 Apr 20.

Department of Medicine and Surgery, Division of Medical Oncology, Centro di Riferimento Tumori Rari Regione Campania, University of Naples "Federico II", Napoli, Italy.

Background: Cisplatin-based chemotherapy significantly improved the survival of patients with germ cell testicular cancer. However, long term side effects of chemotherapy have non-negligible impact on the quality of life of these young patients, who have a long life expectancy after being successfully treated.

Materials And Methods: 25-OH vitamin D, testosterone, FSH and LH of patients with testicular cancer were retrospectively evaluated and for each patient clinical information were collected. The tissue of 52 patients with germ cell tumors was analyzed for VDR expression by immunohistochemistry. The serum 25-OH vitamin D and VDR expression were correlated to the patients 'clinical characteristics.

Results: 25-OH vitamin D was analyzed in 82 patients. Insufficient (< 30 ng/ml) levels were detected in 65%-85%, mild deficient (< 20 ng/ml) in 25%-36% and severe deficient (< 10 ng/ml) in 6%-18% of the patients over a median follow-up of 48 months. No difference in serum 25-OH vitamin D was detected over the follow-up time points. No correlation with histology, stage and type of treatment was found. The 25-OH vitamin D levels were not correlated to testosterone, FSH and LH levels. Interestingly, the expression of VDR was much higher in non seminoma than in seminoma tissue.

Conclusions: Patients with testicular cancer have reduced vitamin D levels after the treatment of the primary cancer. Since long term hypovitaminosis D leads to high risk of fractures, infertility and cardiovascular diseases, we envision that vitamin D should be regularly checked in patients with testicular cancer and replaced if needed.
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http://dx.doi.org/10.18632/oncotarget.24925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940414PMC
April 2018

New treatments for stage I testicular cancer.

Clin Adv Hematol Oncol 2017 Aug;15(8):626-631

Division of Medical Oncology, University of British Columbia, British Columbia, Canada.

Clinical stage I represents the most frequent presentation of both seminoma and nonseminoma testicular cancer. Despite a survival rate of close to 100%, the management of patients with this disease stage is controversial. The recurrence rate is 10% to 20% for patients with stage I seminoma and 15% to 50% for those with stage I nonseminoma. A highly sensitive and specific biomarker of relapse that is applicable to both seminoma and nonseminoma, and able to drive a definitive risk-adapted management of the patients, still is not available. Lymphovascular invasion (LVI) in the orchiectomy specimen has been used as a risk factor in patients with stage I nonseminoma. However, with a risk of recurrence of 50% for LVI-positive patients and 15% for LVI-negative patients, the discriminative power of LVI is modest at best. Various management options exist. In the absence of a predictive biomarker for recurrence, active surveillance avoids overtreatment in 50% to 85% of patients, with no risk of long-term side effects in nonrelapsing patients and a preserved overall survival of almost 100% after specific treatment for recurrent disease. However, although active surveillance has been accepted as the preferred option for stage I seminoma and low-risk stage I nonseminoma, its role in high-risk stage I nonseminoma remains controversial.
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August 2017

Lack of Effectiveness of Postchemotherapy Lymphadenectomy in Bladder Cancer Patients with Clinical Evidence of Metastatic Pelvic or Retroperitoneal Lymph Nodes Only: A Propensity Score-based Analysis.

Eur Urol Focus 2019 03 3;5(2):242-249. Epub 2017 Jun 3.

University of Southampton, Southampton, United Kingdom.

Background: Limited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma.

Objective: To compare the outcomes of operated versus nonoperated patients after first-line chemotherapy.

Design, Setting, And Participants: Data from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic±RP) only, first-line platinum-based chemotherapy given.

Intervention: LND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma.

Outcome Measures And Statistical Analysis: Overall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation.

Results And Limitations: Overall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p=0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p=0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations.

Conclusions: Although there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials.

Patient Summary: We found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies.
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http://dx.doi.org/10.1016/j.euf.2017.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712487PMC
March 2019

Clinical Outcomes of Perioperative Chemotherapy in Patients With Locally Advanced Penile Squamous-Cell Carcinoma: Results of a Multicenter Analysis.

Clin Genitourin Cancer 2017 10 27;15(5):548-555.e3. Epub 2017 Feb 27.

UAB Comprehensive Cancer Center, Birmingham, AL.

Background: The prognosis of patients with locally advanced penile squamous-cell carcinoma is primarily related to the extent of lymph node metastases. Surgery alone yields suboptimal results, and there is a paucity of data on these patients' outcomes.

Patients And Methods: This retrospective study evaluated patients who received neoadjuvant or adjuvant chemotherapy from 1990 onward at 12 centers. Cox models were used to investigate prognostic factors for relapse-free survival and overall survival (OS).

Results: Among the 201 included patients, 39 (19.4%) had disease of T3-4 and N0 clinical stage; the remaining patients had clinical lymph node involvement (cN+). Ninety-four patients received neoadjuvant chemotherapy (group 1), 78 received adjuvant chemotherapy (group 2), and 21 received both (group 3). Eight patients for whom the timing of perioperative chemotherapy administration was unavailable were included in the Cox analyses. Forty-three patients (21.4%) received chemoradiation. Multivariate analysis for OS (n = 172) revealed bilateral disease (P = .035) as a negative prognostic factor, while pelvic cN+ tended to be nonsignificantly associated with decreased OS (P = .076). One-year relapse-free survival was 35.6%, 60.6%, and 45.1% in the 3 groups, respectively. One-year OS was 61.3%, 82.2%, and 75%, respectively. No significant differences were seen on univariable analyses for OS between the groups (P = .45). Platinum type of chemotherapy and chemoradiation were not significantly associated with any outcome analyzed.

Conclusion: Benchmark survival estimates for patients receiving perioperative chemotherapy for locally advanced penile squamous-cell carcinoma have been provided, with no substantial differences observed between neoadjuvant and adjuvant administration. This analysis may result in improved patient information, although prospective studies are warranted.
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http://dx.doi.org/10.1016/j.clgc.2017.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854657PMC
October 2017

Prognostic and Predictive Factors in Patients with Advanced Penile Cancer Receiving Salvage (2nd or Later Line) Systemic Treatment: A Retrospective, Multi-Center Study.

Front Pharmacol 2016 20;7:487. Epub 2016 Dec 20.

Section of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham Comprehensive Cancer Center Birmingham, AL, USA.

Metastatic penile squamous cell carcinoma (PSCC) is associated with dismal outcomes with median overall survival (OS) of 6-12 months in the first-line and <6 months in the salvage setting. Given the rarity of this disease, randomized trials are difficult. Prognostic risk models may assist in rational drug development by comparing observed outcomes in nonrandomized phase II studies and retrospective data vs. predicted outcomes based on baseline prognostic factors in the context of historically used agents. In this retrospective study, we constructed a prognostic model in the salvage setting of PSCC patients receiving second or later line systemic treatment, and also explored differences in outcomes based on type of treatment. : We performed a chart review to identify patients with locally advanced unresectable or metastatic PSCC who received second or later line systemic treatment in centers from North America and Europe. The primary outcome was OS from initiation of treatment, with secondary outcomes being progression-free survival (PFS) and response rate (RR). OS was estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify prognostic factors for outcomes using univariable and multivariable models. Sixty-five patients were eligible. Seventeen of 63 evaluable patients had a response (27.0%, 95% confidence interval [CI] = 16.6-39.7%) and median OS and PFS were 20 (95% CI = 20-21) and 12 (95% CI = 12, 16) weeks, respectively. Visceral metastasis (VM) and hemoglobin (Hb) ≤ 10 gm/dl were consistently significant poor prognostic factors for both OS and PFS, and Hb was also prognostic for response. The 28 patients with neither risk factor had a median OS (95% CI) of 24 (20-40) weeks and 1-year (95% CI) OS of 13.7% (4.4-42.7%), while the 37 patients with 1 or 2 risk factors had median OS (95% CI) of 20 (16-20) weeks and 1-year (95% CI) OS of 6.7% (1.8-24.9%). Cetuximab-including regimens were associated with a trend for improved RR compared to other agents (Odds ratio = 5.05, 95% CI = 0.84-30.37, = 0.077). Taxanes vs. non-taxane, and combination vs. single agent therapy was not associated with improved outcomes. The study is limited by its modest sample size. This is the first prognostic classification proposed for patients receiving salvage systemic therapy for advanced PSCC. The presence of VM and Hb ≤ 10 gm/dl was associated with poor OS and PFS. Cetuximab appeared to be associated with better RR. This prognostic model may assist in salvage therapy drug development for this orphan disease by improving interpretation of outcomes seen in nonrandomized data.
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http://dx.doi.org/10.3389/fphar.2016.00487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5168461PMC
December 2016

Molecular Dissection of Complete Response to Receptor Tyrosine Kinase Inhibition in Type II Papillary Renal Cell Carcinoma.

Clin Genitourin Cancer 2017 02 27;15(1):e145-e150. Epub 2016 May 27.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.clgc.2016.05.019DOI Listing
February 2017

Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis.

EMBO Mol Med 2016 07 1;8(7):761-78. Epub 2016 Jul 1.

The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

Clusterin (CLU) is a stress-activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti-cancer therapies in preclinical models, progression to treatment-resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic-targeting agents such as taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells up-regulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdk1. In this study, we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A leading to relief of negative feedback inhibition and activation of Wee1-Cdk1 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU-regulated cell cycle effector Wee1 may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors.
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http://dx.doi.org/10.15252/emmm.201506059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931290PMC
July 2016

PARP inhibition in castration-resistant prostate cancer.

Future Oncol 2016 Mar 21;12(5):577-80. Epub 2016 Jan 21.

Vancouver Prostate Centre & Department of Urologic Science, University of British Columbia, Vancouver, British Columbia, Canada.

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http://dx.doi.org/10.2217/fon.16.1DOI Listing
March 2016

Hsp27 Inhibition with OGX-427 Sensitizes Non-Small Cell Lung Cancer Cells to Erlotinib and Chemotherapy.

Mol Cancer Ther 2015 May 4;14(5):1107-16. Epub 2015 Mar 4.

The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Non-small cell lung cancer (NSCLC) is the most frequent cause of death from cancer worldwide. Despite the availability of active chemotherapy regimens and EGFR tyrosine kinase inhibitors, all advanced patients develop recurrent disease after first-line therapy. Although Hsp27 is a stress-induced chaperone that promotes acquired resistance in several cancers, its relationship to treatment resistance in NSCLC has not been defined. Understanding adaptive responses of acquired resistance will help guide new strategies to control NSCLC. Hsp27 levels were evaluated in an HCC827 erlotinib-resistant-derived cell line (HCC-827Resistant), and sensitivity to erlotinib was examined in Hsp27-overexpressing A549 cells. The role of Hsp27 in both erlotinib and cytotoxic treatment resistance was evaluated in HCC-827 and A549 NSCLC cells using the Hsp27 antisense drug OGX-427. The effect of OGX-427 in combination with erlotinib was also assessed in mice bearing A549 xenografts. Hsp27 is induced by erlotinib and protects NSCLC cells from treatment-induced apoptosis, whereas OGX-427 sensitizes NSCLC cells to erlotinib. Interestingly, increased resistance to erlotinib was observed when Hsp27 was increased either in HCC827 erlotinib-resistant or overexpressing A549 cells. Combining OGX-427 with erlotinib significantly enhanced antitumor effects in vitro and delayed A549 xenograft growth in vivo. OGX-427 also significantly enhanced the activity of cytotoxic drugs used for NSCLC. These data indicate that treatment-induced Hsp27 contributes to the development of resistance, and provides preclinical proof-of-principle that inhibition of stress adaptive pathways mediated by Hsp27 enhances the activity of erlotinib and chemotherapeutics.
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http://dx.doi.org/10.1158/1535-7163.MCT-14-0866DOI Listing
May 2015
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