Publications by authors named "Daniel Lin"

345 Publications

Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment during Chemoradiotherapy Is Prognostic in HPV16 Cancers.

Cancer Immunol Res 2022 Jan 19. Epub 2022 Jan 19.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Human papillomavirus (HPV) infection causes 600,000 new cancers worldwide each year. HPV-related cancers express the oncogenic proteins E6 and E7, which could serve as tumor-specific antigens. It is not known whether immunity to E6 and E7 evolves during chemoradiotherapy or affects survival. Using T cells from 2 HPV16 patients, we conducted functional T-cell assays to identify candidate HPV-specific T cells and common T-cell receptor motifs, which we then analyzed across 86 patients with HPV-related cancers. The HPV-specific clones and E7-related T-cell receptor motifs expanded in the tumor microenvironment over the course of treatment, whereas non-HPV-specific T cells did not. In HPV16 patients, improved recurrence-free survival was associated with HPV-responsive T-cell expansion during chemoradiotherapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-21-0119DOI Listing
January 2022

Considerations on Integrating Prostate-Specific Membrane Antigen Positron Emission Tomography Imaging Into Clinical Prostate Cancer Trials by National Clinical Trials Network Cooperative Groups.

J Clin Oncol 2022 Jan 11:JCO2102440. Epub 2022 Jan 11.

Cancer Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: As prostate-specific membrane antigen (PSMA) positron emission tomography (PET) becomes increasingly available in the United States, the greater sensitivity of the technology in comparison to conventional imaging poses challenges for clinical trials. The NCI Clinical Imaging Steering Committee (CISC) PSMA PET Working Group was convened to coordinate the identification of these challenges in various clinical scenarios and to develop consensus recommendations on how best to integrate PSMA PET into ongoing and upcoming National Clinical Trials Network (NCTN) trials.

Methods: NCI CISC and NCI Genitourinary Steering Committee members and leadership nominated clinicians, biostatisticians, patient advocates, and other imaging experts for inclusion in the PSMA PET Working Group. From April to July 2021, the working group met independently and in conjunction with the CISC to frame challenges, including stage migration, response assessment, trial logistics, and statistical challenges, and to discuss proposed solutions. An anonymous, open-ended survey was distributed to members to collect feedback on challenges faced. Representatives from each NCTN group were invited to present an overview of affected trials. From these discussions, the consensus document was developed and circulated for the inclusion of multiple rounds of feedback from both the Working Group and CISC.

Results: The current consensus document outlines the key challenges for clinical prostate cancer trials resulting from the increasing availability of PSMA PET. We discuss implications for patient selection and definition of end points and provide guidance and potential solutions for different clinical scenarios, particularly with regard to best practices in defining eligibility criteria and outcome measures.

Recommendations: This article provides guidance regarding clinical trial design and conduct, and the interpretation of trial results.
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http://dx.doi.org/10.1200/JCO.21.02440DOI Listing
January 2022

Paracrine Wnt signaling is necessary for prostate epithelial proliferation.

Prostate 2022 Jan 11. Epub 2022 Jan 11.

Department of Urology, University of Washington, Seattle, Washington, USA.

Introduction: The Wnt proteins play key roles in the development, homeostasis, and disease progression of many organs including the prostate. However, the spatiotemporal expression patterns of Wnt proteins in prostate cell lineages at different developmental stages and in prostate cancer remain inadequately characterized.

Methods: We isolated the epithelial and stromal cells in the developing and mature mouse prostate by flow cytometry and determined the expression levels of Wnt ligands. We used Visium spatial gene expression analysis to determine the spatial distribution of Wnt ligands in the mouse prostatic glands. Using laser-capture microscopy in combination with gene expression analysis, we also determined the expression patterns of Wnt signaling components in stromal and cancer cells in advanced human prostate cancer specimens. To investigate how the stroma-derived Wnt ligands affect prostate development and homeostasis, we used a Col1a2-CreER mouse model to disrupt the Wnt transporter Wntless specifically in prostate stromal cells.

Results: We showed that the prostate stromal cells are a major source of several Wnt ligands. Visium spatial gene expression analysis revealed a distinct spatial distribution of Wnt ligands in the prostatic glands. We also showed that Wnt signaling components are highly expressed in the stromal compartment of primary and advanced human prostate cancer. Blocking stromal Wnt secretion attenuated prostate epithelial proliferation and regeneration but did not affect cell survival and lineage maintenance.

Discussion: Our study demonstrates a critical role of stroma-derived Wnt ligands in prostate development and homeostasis.
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http://dx.doi.org/10.1002/pros.24298DOI Listing
January 2022

Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

HGG Adv 2022 Jan 19;3(1). Epub 2021 Nov 19.

Odette Cancer Centre, Sunnybrook Health and Sciences Centre, University of Toronto, Toronto, ON, Canada.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (, p = 6.9×10 and , p = 2.0×10). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS- treatment for the initial management of patients with low-risk PC.
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http://dx.doi.org/10.1016/j.xhgg.2021.100070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8725988PMC
January 2022

Stereotactic Versus Conventional Radiation Therapy for Patients With Pancreatic Cancer in the Modern Era.

Adv Radiat Oncol 2021 Nov-Dec;6(6):100763. Epub 2021 Jul 29.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Patients with pancreatic cancer often receive radiation therapy before undergoing surgical resection. We compared the clinical outcomes differences between stereotactic body radiation therapy (SBRT) and 3-dimensional (3D)/intensity-modulated radiation therapy (IMRT).

Methods And Materials: We retrospectively collected data from the University of Texas MD Anderson Cancer Center. Patients with borderline resectable/potentially resectable or locally advanced pancreatic cancer receiving neoadjuvant SBRT (median, 36.0 Gy/5fx), 3D conformal radiation (median, 50.4 Gy/28 fx) or IMRT (median, 50.4 Gy/28 fx) were included. Overall survival (OS) and progression-free survival were analyzed using Cox regression.

Results: In total, 104 patients were included in our study. Fifty-seven patients (54.8%) were treated with SBRT, and 47 patients (45.2%) were treated with 3D/IMRT. Patients in the SBRT group were slightly older (median age: 70.3 vs 62.7 in the 3D/IMRT group). Both groups had similar proportions of patients with locally advanced pancreatic cancer (SBRT: 30, 52.6%; 3D/IMRT: 24, 51.1%). All patients were treated with chemotherapy. Patients in the SBRT group underwent more surgical resection compared with the 3D/IMRT group (38.6% vs 23.4%, respectively). At a median follow-up of 22 months, a total of 60 patients (57.7%) died: 25 (25/57, 43.9%) in the SBRT group, and 35 (35/47, 74.5%) in the 3D/IMRT group. Median OS was slightly higher in the SBRT group (29.6 months vs 24.1 months in the 3D/IMRT group). On multivariable Cox regression, the choice of radiation therapy technique was not associated with differences in OS (adjusted hazard ratios [aHR] = 0.5; 95% confidence interval [CI], 0.2%-1.3%,  = .18). Moreover, patients that underwent surgical resection had better OS (aHR = 0.3, 95% CI, 0.1%-0.8%,  = .01). Furthermore, progression-free survival was also similar between patients treated with SBRT and those treated with 3D/IMRT (aHR = 0.9, 95% CI, 0.5%-1.8%,  = .81).

Conclusions: SBRT was associated with similar clinical outcomes compared with conventional radiation techniques, despite being delivered over a shorter period of time which would spare patients prolonged treatment burden. Future prospective data are still needed to better assess the role of SBRT in patients with pancreatic cancer.
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http://dx.doi.org/10.1016/j.adro.2021.100763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655391PMC
July 2021

Evaluating the Outcomes of Active Surveillance in Grade Group 2 Prostate Cancer: Prospective Results from the Canary PASS Cohort.

J Urol 2021 Dec 2:101097JU0000000000002354. Epub 2021 Dec 2.

Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Purpose: Active surveillance (AS) for grade group (GG) 2 patients is not yet well defined. We sought to compare clinical outcomes of men with GG1 and GG2 prostate cancer undergoing AS in a large prospective North American cohort.

Materials And Methods: Participants were prospectively enrolled in an AS study with protocol-directed followup at 10 centers in the U.S. and Canada. We evaluated time from diagnosis to biopsy grade reclassification and time to treatment. In men treated after initial surveillance, adverse pathology and recurrence were also analyzed.

Results: At diagnosis, 154 (9%) had GG2 and 1,574 (91%) had GG1. Five-year reclassification rates were similar between GG2 and GG1 (30% vs 37%, p=0.11). However, more patients with GG2 were treated at 5 years (58% vs 34%, p <0.001) and GG at diagnosis was associated with time to treatment (HR=1.41; p=0.01). Treatment rates were similar in patients who reclassified during AS, but in patients who did not reclassify, those diagnosed with GG2 underwent definitive treatment more often than GG1 (5-year treatment rates 52% and 12%, p <0.0001). In participants who underwent radical prostatectomy after initial surveillance, the adjusted risk of adverse pathology was similar (HR=1.26; p=0.4). Biochemical recurrence within 3 years of treatment for GG2 and GG1 patients was 6% for both groups.

Conclusions: In patients on AS, the rate of definitive treatment is higher after an initial diagnosis of GG2 than GG1. Adverse pathology after radical prostatectomy and short-term biochemical recurrence after definitive treatment were similar between GG2 and GG1.
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http://dx.doi.org/10.1097/JU.0000000000002354DOI Listing
December 2021

Active Surveillance: Very Much "Preferred" for Low-Risk Prostate Cancer.

J Urol 2022 02 15;207(2):262-264. Epub 2021 Nov 15.

Section of Urology, Department of Surgery, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1097/JU.0000000000002341DOI Listing
February 2022

HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells.

Redox Biol 2021 11 25;47:102149. Epub 2021 Sep 25.

Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, 74074, USA. Electronic address:

Epithelial-to-mesenchymal transition (EMT) is an essential mechanism for development and wound healing, but in cancer it also mediates the progression and spread of aggressive tumors while increasing therapeutic resistance. Adoption of a mesenchymal state is also associated with increased iron uptake, but the relationship between EMT and the key regulators of cellular iron metabolism remains undefined. In this regard, the human adrenal cortical carcinoma SW13 cell line represents an invaluable research model as HDAC inhibitor treatment can convert them from an epithelial-like (SW13-) cell type to a mesenchymal-like (SW13+) subtype. In this study we establish SW13 cells as a model for exploring the link between iron and EMT. Increased iron accumulation following HDAC inhibitor mediated EMT is associated with decreased expression of the iron export protein ferroportin, enhanced ROS production, and reduced expression of antioxidant response genes. As availability of redox active iron and loss of lipid peroxide repair capacity are hallmarks of ferroptosis, a form of iron-mediated cell death, we next examined whether HDAC inhibitor treatment could augment ferroptosis sensitivity. Indeed, HDAC inhibitor treatment synergistically increased cell death following induction of ferroptosis. The exact mechanisms by which HDAC inhibition facilitates cell death following ferroptosis induction requires further study. As several HDAC inhibitors are already in use clinically for the treatment of certain cancer types, the findings from these studies have immediate implications for improving iron-targeted chemotherapeutic strategies.
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http://dx.doi.org/10.1016/j.redox.2021.102149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487084PMC
November 2021

Treatment in the absence of disease reclassification among men on active surveillance for prostate cancer.

Cancer 2022 Jan 13;128(2):269-274. Epub 2021 Sep 13.

Department of Urology, University of Washington, Seattle, Washington.

Background: Maintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort.

Methods: This study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66).

Conclusions: A substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions.

Lay Summary: This analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.
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http://dx.doi.org/10.1002/cncr.33911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8738121PMC
January 2022

Factors Associated with Time to Conversion from Active Surveillance to Treatment for Prostate Cancer in a Multi-Institutional Cohort.

J Urol 2021 11 10;206(5):1147-1156. Epub 2021 Sep 10.

Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer.

Materials And Methods: A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses.

Results: Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69), and younger age (age continuous per 5-year increase aHR 0.96, 95% CI 0.93-0.99). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry.

Conclusions: A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.
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http://dx.doi.org/10.1097/JU.0000000000001937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8734323PMC
November 2021

Preface to "Current and Future Topics on Prostate Cancer".

Transl Androl Urol 2021 Jul;10(7):3089-3090

University of Washington, Seattle, WA, USA. (Email:

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http://dx.doi.org/10.21037/tau-2021-04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350240PMC
July 2021

Elucidation of Tumor-Stromal Heterogeneity and the Ligand-Receptor Interactome by Single-Cell Transcriptomics in Real-world Pancreatic Cancer Biopsies.

Clin Cancer Res 2021 11 23;27(21):5912-5921. Epub 2021 Aug 23.

Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. With molecular subtypes of PDAC gaining relevance in the context of therapeutic stratification, the ability to characterize heterogeneity of cancer-specific gene expression patterns is of great interest. In addition, understanding patterns of immune evasion within PDAC is of importance as novel immunotherapeutic strategies are developed.

Experimental Design: Single-cell RNA sequencing (scRNA-seq) is readily applicable to limited biopsies from human primary and metastatic PDAC and identifies most cancers as being an admixture of previously described epithelial transcriptomic subtypes.

Results: Integrative analyses of our data provide an in-depth characterization of the heterogeneity within the tumor microenvironment, including cancer-associated fibroblast subclasses, and predicts for a multitude of ligand-receptor interactions, revealing potential targets for immunotherapy approaches.

Conclusions: Our analysis demonstrates that the use of biopsies from patients with PDAC paired with scRNA-seq may facilitate therapeutic prediction from limited biopsy samples.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563410PMC
November 2021

A 25-year perspective on evaluation and understanding of biomarkers in urologic cancers.

Urol Oncol 2021 09 24;39(9):602-617. Epub 2021 Jul 24.

Department of Urology, University of Washington, Seattle, WA.

The past 25 years have witnessed an explosion of investigative attempts to identify clinically useful biomarkers which can have meaningful impacts for patients with urologic cancers. However, in spite of the enormous amount of research aiming to identify markers with the hope of impacting patient care, only a handful have proven to have true clinical utility. Improvements in targeted imaging, pan-omics evaluation, and genetic sequencing at the tissue and single-cell levels have yielded many potential targets for continued biomarker investigation. This article, as one in this series for the 25th Anniversary Issue of Urologic Oncology: Seminars and Original Investigations, serves to give a perspective on our progress and failures over the past quarter-century in our highest volume urologic cancers: prostate, bladder, and kidney cancers.
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http://dx.doi.org/10.1016/j.urolonc.2021.06.010DOI Listing
September 2021

RNA Splicing Factors SRRM3 and SRRM4 Distinguish Molecular Phenotypes of Castration-Resistant Neuroendocrine Prostate Cancer.

Cancer Res 2021 09 26;81(18):4736-4750. Epub 2021 Jul 26.

Department of Urology, University of Washington, Seattle, Washington.

Neuroendocrine (NE) differentiation in metastatic castration-resistant prostate cancer (mCRPC) is an increasingly common clinical feature arising from cellular plasticity. We recently characterized two mCRPC phenotypes with NE features: androgen receptor (AR)-positive NE-positive amphicrine prostate cancer (AMPC) and AR-negative small cell or neuroendocrine prostate cancer (SCNPC). Here, we interrogated the regulation of RE1-silencing transcription factor (REST), a transcriptional repressor of neuronal genes, and elucidated molecular programs driving AMPC and SCNPC biology. Analysis of prostate cancer cell lines, mCRPC specimens, and LuCaP patient-derived xenograft models detected alternative splicing of REST to REST4 and attenuated REST repressor activity in AMPC and SCNPC. The REST locus was also hypermethylated and REST expression was reduced in SCNPC. While serine/arginine repetitive matrix protein 4 (SRRM4) was previously implicated in alternative splicing of REST in mCRPC, we detected SRRM3 expression in REST4-positive, SRRM4-negative AMPC, and SCNPC. In CRPC cell lines, SRRM3 induced alternative splicing of REST to REST4 and exacerbated the expression of REST-repressed genes. Furthermore, SRRM3 and SRRM4 expression defined molecular subsets of AMPC and SCNPC across species and tumor types. Two AMPC phenotypes and three SCNPC phenotypes were characterized, denoted either by REST attenuation and ASCL1 activity or by progressive activation of neuronal transcription factor programs, respectively. These results nominate SRRM3 as the principal REST splicing factor expressed in early NE differentiation and provide a framework to molecularly classify diverse NE phenotypes in mCRPC. SIGNIFICANCE: This study identifies SRRM3 as a key inducer of cellular plasticity in prostate cancer with neuroendocrine features and delineates distinct neuroendocrine phenotypes to inform therapeutic development and precision medicine applications.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448969PMC
September 2021

25-year perspective on prostate cancer: Conquering frontiers and understanding tumor biology.

Urol Oncol 2021 09 12;39(9):521-527. Epub 2021 Jul 12.

Department of Urology, University of California Davis Comprehensive Cancer Center. Davis, CA.

Major changes in the field of prostate cancer over the last 25 years include the implementation of prostate specific antigen screening and the recognition that BRCA confers hereditary risk of prostate cancer. Quality of life and survivorship have driven risk stratification for localized prostate cancer, facilitated by molecular signatures and leading to increased acceptance of active surveillance as a mainstream treatment option. Advances in technology have improved efficacy and reduced toxicity in both radical prostatectomy and radiation therapy for localized prostate cancer. Improved understanding of the androgen receptor has yielded substantially more effective therapies. Future growth areas include personalized treatment based on genomic and genetic information, theranostics radiopharmaceuticals, and more aggressive treatment of metastatic disease to include focal therapy. Multidisciplinary management between specialized urologists, radiation oncologists, and medical oncologists remains central to maximizing patient outcomes.
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http://dx.doi.org/10.1016/j.urolonc.2021.04.016DOI Listing
September 2021

The immunotherapeutic role of indoleamine 2,3-dioxygenase in head and neck squamous cell carcinoma: A systematic review.

Clin Otolaryngol 2021 09 30;46(5):919-934. Epub 2021 May 30.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Background: Novel cancer immunotherapy seeks to harness the body's own immune system and tip the balance in favour of antitumour activity. The intracellular enzyme indoleamine 2,3-dioxygenase (IDO) is a critical regulator of the tumour microenvironment (TME) via tryptophan metabolism. The potential immunotherapeutic role of IDO in head and neck squamous cell carcinoma (HNSCC) requires further exploration. We aim to assess the evidence on IDO in HNSCC.

Methods: A systematic review of literature and clinical trials databases.

Results: We included 40 studies: seven involved cell lines: eight assessed tumour immunohistochemistry: ten measured IDO gene transcription: 15 reported on clinical trials. Increased cell line IDO expression was postulated to adversely affect tumour metabolism and apoptosis. Immunohistochemical IDO expression correlated with worse survival. Gene transcription studies associated IDO with positive PD-L1 and human papillomavirus (HPV) status. Phase I/II clinical trials showed (a) overall response (34%-55%) and disease control rates (62%-70%) for IDO1 inhibitor in combination with a PD-1 inhibitor, (b) similar safety profiles when both are used in combination therapy compared to each as monotherapies and (c) IDO gene expression as a predictive biomarker for response to PD-L1 therapy.

Conclusions: IDO expression is increased in the TME of HNSCC, which correlates with poor prognosis. However, the exact mechanism of IDO-driven immune modulation in the TME is an enigma. Future translational studies should map IDO activity during HNSCC treatment and elucidate its precise role in the TME, such research will underpin the development of clinical trials establishing the efficacy of IDO inhibitors in HNSCC.
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http://dx.doi.org/10.1111/coa.13794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600953PMC
September 2021

Development of an Objective Scoring System for Endoscopic Assessment of Radiation-Induced Upper Gastrointestinal Toxicity.

Cancers (Basel) 2021 Apr 29;13(9). Epub 2021 Apr 29.

Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

We developed and implemented an objective toxicity scoring system to be used during endoscopic evaluation of the upper gastrointestinal (GI) tract in order to directly assess changes in toxicity during the radiation treatment of pancreatic cancer. We assessed and validated the upper GI toxicity of 19 locally advanced pancreatic cancer trial patients undergoing stereotactic body radiation therapy (SBRT). Wilcoxon-signed rank tests were used to compare pre- and post-SBRT scores. Comparison of the toxicity scores measured before and after SBRT revealed a mild increase in toxicity in the stomach and duodenum ( < 0.005), with no cases of severe toxicity observed. Kappa and AC1 statistics analysis were used to evaluate interobserver agreement. Our toxicity scoring system was reliable in determining GI toxicity with a good overall interobserver agreement for pre-treatment scores (stomach, κ = 0.71, < 0.005; duodenum, κ = 0.88, < 0.005) and post-treatment scores (stomach, κ = 0.71, < 0.005; duodenum, κ = 0.76, < 0.005). The AC1 statistics yielded similar results. With future usage, we hope this scoring system will be a useful tool for objectively and reliably assessing changes in GI toxicity during the treatment of pancreatic cancer and for GI toxicity assessments and comparisons during radiation therapy research trials.
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http://dx.doi.org/10.3390/cancers13092136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124711PMC
April 2021

Impact of Fiducial Marker Placement Before Stereotactic Body Radiation Therapy on Clinical Outcomes in Patients With Pancreatic Cancer.

Adv Radiat Oncol 2021 Mar-Apr;6(2):100621. Epub 2020 Nov 23.

University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Localized pancreatic cancer is commonly treated with stereotactic body radiation therapy (SBRT), which often requires the placement of fiducial markers. We compared the clinical outcomes of patients with and without fiducial markers.

Methods And Materials: We retrospectively collected data on patients with pancreatic cancer treated with neoadjuvant SBRT at a single institution. Patients were divided into 2 groups based on the placement of a fiducial marker. Local recurrence was the primary outcome. Time to event endpoints were analyzed using COX regression.

Results: We included 96 patients with unresectable pancreatic cancer: 46 patients (47.9%) did not have a fiducial marker, and 50 patients (52.1%) had a fiducial placed. Patients in the fiducial group were older and had more locally advanced pancreatic cancer compared with those who did not have a fiducial placed. Most patients in both groups (92.7%) received chemotherapy before SBRT treatment. SBRT was delivered to a median of 36 Gy over 5 fractions in the no-fiducial group, and 38 Gy over 5 fractions in the fiducial group. At a median follow-up of 20 months, local recurrence was similar irrespective of fiducial placement (adjusted hazard ratio [aHR] 0.6, 95% CI 0.3-1.3, = .59). Furthermore, no difference in overall survival was noted between the 2 groups (aHR 0.8, 95% CI 0.3-1.9, = .65). In patients who eventually underwent surgery post-SBRT, no difference in surgical margins ( = .40) or lymphovascular invasion ( = .76) was noted between the 2 groups. No patient developed acute pancreatitis after fiducial placement.

Conclusions: Our data suggest that the use of fiducial markers does not negatively affect clinical outcomes in patients with localized pancreatic cancer. Prospective confirmation of our results is still needed.
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http://dx.doi.org/10.1016/j.adro.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071717PMC
November 2020

Targeting backdoor androgen synthesis through AKR1C3 inhibition: A presurgical hormonal ablative neoadjuvant trial in high-risk localized prostate cancer.

Prostate 2021 05 23;81(7):418-426. Epub 2021 Mar 23.

Division of Oncology, Department of Medicine, University of Washington, Seattle, Washington, USA.

Background: Localized prostate cancers (PCs) may resist neoadjuvant androgen receptor (AR)-targeted therapies as a result of persistent intraprostatic androgens arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of neoadjuvant indomethacin (Indo), which inhibits the steroidogenic enzyme AKR1C3, in addition to combinatorial anti-androgen blockade, in men with high-risk PC undergoing radical prostatectomy (RP).

Methods: This was an open label, single-site, Phase II neoadjuvant trial in men with high to very-high-risk PC, as defined by NCCN criteria. Patients received 12 weeks of apalutamide (Apa), abiraterone acetate plus prednisone (AAP), degarelix, and Indo followed by RP. Primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included minimal residual disease (MRD) rate, defined as residual cancer burden (RCB) ≤ 0.25cm (tumor volume multiplied by tumor cellularity) and elucidation of molecular features of resistance.

Results: Twenty patients were evaluable for the primary endpoint. Baseline median prostate-specific antigen (PSA) was 10.1 ng/ml, 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had pCR and 6 (30%) had MRD. Therapy was well tolerated. Over a median follow-up of 23.8 months, 1 of 7 (14%) men with pathologic response and 6 of 13 (46%) men without pathologic response had a PSA relapse. There was no association between prostate hormone levels or HSD3B1 genotype with pathologic response.

Conclusions: In men with high-risk PC, pCR rates remained low even with combinatorial AR-directed therapy, although rates of MRD were higher. Ongoing follow-up is needed to validate clinical outcomes of men who achieve MRD.
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http://dx.doi.org/10.1002/pros.24118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044035PMC
May 2021

Psychometric Properties of the MDADI-A Preliminary Study of Whether Less is Truly More?

Dysphagia 2021 Mar 11. Epub 2021 Mar 11.

School of Health Sciences, University of Liverpool, Liverpool, UK.

The MD Anderson Dysphagia Inventory (MDADI) is a 20-item dysphagia-specific QOL questionnaire with four subscales: global, emotional, functional, and physical. It is widely used in clinical practice and in research; however, its psychometric properties have been under-researched. We aim to evaluate the organisation of the MDADI subscales and identify any redundant items. The MDADI is a routinely collected outcome measure at two centres in northeast England. Questionnaires completed at three months following treatment were extracted from these existing databases. Factor analysis was carried out with the aim of reducing redundancy among the set of questionnaire items. Cases with missing values were excluded. A total of 196 complete patient questionnaires were used in factor analysis. A one-factor model accounted for around 50% of the total variance in item responses. The top five endorsed items (abbreviated by the questionnaire item keywords: Excluded, Irritate, Esteem, Social, and Why) in this one factor appeared in three (emotional, functional, and physical) of the four supposed MDADI subscales, i.e. global, emotional, functional, and physical. Our results suggest an overlap of three MDADI subscales across the top five endorsed items. The content of the top five questions all appear related to the psychosocial aspects of swallowing. This implies some redundancy of the items in the original subscales of the questionnaire. Using the most endorsed items, it appears feasible to abbreviate the 20-item MDADI questionnaire to a 5-item "MiniDADI" questionnaire, which is likely to have greater utility in routine clinical practice outside of research settings.
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http://dx.doi.org/10.1007/s00455-021-10281-9DOI Listing
March 2021

Use of Molecular Assays and Circulating Tumor DNA in Early-Stage Colorectal Cancer: A Roundtable Discussion of the Gastrointestinal Cancer Therapy Expert Group.

Oncologist 2021 08 28;26(8):651-659. Epub 2021 Mar 28.

Huntsman Cancer Center at University of Utah, Salt Lake City, Utah, USA.

The use of genomic testing is rapidly emerging as an important clinical tool both for cancer diagnosis and for guiding treatment decisions in a wide range of malignancies, including gastrointestinal (GI) cancers such as colorectal cancer (CRC). Advances in technologies such as polymerase chain reaction and next-generation sequencing methods have made it possible to noninvasively screen for CRC through, for example, the use of blood- or stool-based testing, with high specificity. Tests are also available that can provide prognostic information beyond traditional clinicopathologic factors such as tumor size, grade, and nodal status, which can enable clinicians to more accurately risk stratify patients for recurrence. Lastly, in the setting of resected CRC, tests are now available that can detect circulating tumor DNA as a means for noninvasive minimal/molecular residual disease monitoring, thereby potentially guiding the use of adjuvant chemotherapy and/or escalating or de-escalating therapy. The Gastrointestinal Cancer Therapy Expert Group (GICTEG) recently convened a virtual meeting to discuss current issues related to genomic testing in GI cancer, with the goal of providing guidance on the use of these tests for the practicing community oncologist, for whom GI cancer may be only one of many tumor types encountered. This article provides a summary of the discussion and highlights the key opinions of the GICTEG on this topic. IMPLICATIONS FOR PRACTICE: The Gastrointestinal Cancer Therapy Expert Group seeks to provide practical guidance and opinion on the treatment of gastrointestinal malignancies, including colorectal cancer (CRC), for the practicing community oncologist in situations for which guidelines from established bodies, such as the National Comprehensive Cancer Network and the American Society of Clinical Oncology, may be less clear. In the present report, clinical guidance on the use of molecular assays for a range of clinical indications in CRC is presented, including the use of circulating tumor DNA to detect minimal/molecular residual disease in patients with successfully resected early-stage CRC.
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http://dx.doi.org/10.1002/onco.13738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342566PMC
August 2021

Patterns and timing of perioperative blood transfusion and association with outcomes after radical cystectomy.

Urol Oncol 2021 08 5;39(8):496.e1-496.e8. Epub 2021 Feb 5.

Department of Urology, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. Electronic address:

Background: Perioperative blood transfusion (PBT) has been associated with worse outcomes across tumor types, including bladder cancer. We report our institutional experience with PBT utilization in the setting of radical cystectomy (RC) for patients with bladder cancer, exploring whether timing of PBT receipt influences perioperative and oncologic outcomes.

Methods: Consecutive patients with bladder cancer treated with RC were identified. PBT was defined as red blood cell transfusion during RC or the postoperative admission. Clinicopathologic and peri and/or postoperative parameters were extracted and compared between patients who did and did not receive PBT using Mann Whitney U Test, chi-square, and log-rank test. Overall (OS) and recurrence-free survival (RFS) were estimated with the Kaplan Meier method. Univariate/multivariate logistic and Cox proportional hazards regression were used to identify variables associated with postoperative and oncologic outcomes, respectively.

Results: The cohort consisted of 747 patients (77% men; median age 67 years). Median follow-up was 61.5 months (95% CI 55.8-67.2) At least one postoperative complication (90-day morbidity) occurred in 394 (53%) patients. Median OS and RFS were 91.8 months (95% CI: 76.0-107.6) and 66.0 months (95% CI: 48.3-83.7), respectively. On multivariate analysis, intraoperative, but not postoperative, BT was independently associated with shorter OS (HR: 1.74, 95% CI: 1.32-2.29) and RFS (HR: 1.55, 95%CI: 1.20-2.01), after adjusting for relevant clinicopathologic variables. PBT (intra- or post- operative) was significantly associated with prolonged postoperative hospitalization ≥10 days.

Conclusions: Intraoperative BT was associated with inferior OS and RFS, and PBT overall was associated with prolonged hospitalization following RC. Further studies are needed to validate this finding and explore potential causes for this observation.
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http://dx.doi.org/10.1016/j.urolonc.2021.01.009DOI Listing
August 2021

Cabozantinib can block growth of neuroendocrine prostate cancer patient-derived xenografts by disrupting tumor vasculature.

PLoS One 2021 20;16(1):e0245602. Epub 2021 Jan 20.

Department of Urology, University of Washington School of Medicine, Seattle, Washington, United States of America.

With the advent of potent second-line anti-androgen therapy, we and others have observed an increased incidence of androgen receptor (AR)-null small cell or neuroendocrine prostate cancer (SCNPC) in metastatic castration-resistant prostate cancer (mCRPC). Our study was designed to determine the effect of cabozantinib, a multi-targeted tyrosine kinase inhibitor that inhibits VEGFR2, MET and RET on SCNPC. Transcriptome analysis of the University of Washington rapid autopsy and SU2C mCRPC datasets revealed upregulated MET and RET expression in SCNPCs relative to adenocarcinomas. Additionally, increased MET expression correlated with attenuated AR expression and activity. In vitro treatment of SCNPC patient-derived xenograft (PDX) cells with the MET inhibitor AMG-337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability of LuCaP 93, but not LuCaP 173.1. Notably, MET+/RET+ LuCaP 93 and MET-/RET- LuCaP 173.1 tumor volumes were significantly decreased with cabozantinib treatment in vivo, and this activity was independent of MET or RET expression in LuCaP 173.1. Tissue analysis indicated that cabozantinib did not inhibit tumor cell proliferation (Ki67), but significantly decreased microvessel density (CD31) and increased hypoxic stress and glycolysis (HK2) in LuCaP 93 and LuCaP 173.1 tumors. RNA-Seq and gene set enrichment analysis revealed that hypoxia and glycolysis pathways were increased in cabozantinib-treated tumors relative to control tumors. Our data suggest that the most likely mechanism of cabozantinib-mediated tumor growth suppression in SCNPC PDX models is through disruption of the tumor vasculature. Thus, cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245602PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817027PMC
June 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Social and Clinical Correlates of Neoadjuvant Chemotherapy in Medicare Beneficiaries With Muscle Invasive Bladder Cancer From 2004-2015.

Urology 2021 03 26;149:154-160. Epub 2020 Dec 26.

Department of Urology, University of Washington Medical Center, WA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, WA; Department of Urology, Seattle Veterans Affair, WA.

Objective: To assess social and clinical correlates of neoadjuvant chemotherapy (NAC) utilization among Medicare beneficiaries.

Materials And Methods: A cohort of SEER-Medicare (2004-2015) patients with muscle-invasive bladder cancer treated by radical cystectomy were stratified into 3-groups: standard of care NAC (cisplatin-based combination), non-standard of care NAC, and upfront cystectomy. Multivariable logistic regression analysis was used to assess social, demographic and clinical correlates of each treatment category. Survival analyses were performed to compare propensity matched treatment groups.

Results: In total, 6214 patients were identified with a median follow-up of 21 [IQR 7-54] months. NAC utilization increased from 10.7% to 39.1%, between 2004 and 2015, largely due to increased use of standard of care regimens. The most commonly used nonstandard regimen was gemcitabine/carboplatin (50.2%). Older age, Hispanic and Black race, lower socioeconomic status, and contraindications to cisplatin were associated with increased odds of receiving nonstandard of care NAC compared to standard of care. Standard of care NAC was associated with improved overall survival HR 0.85 (95% CI 0.76, 0.94) and HR 0.75 (95% CI 0.63, 0.89) compared to both upfront cystectomy and nonstandard of care NAC, respectively.

Conclusion: NAC utilization has increased to nearly 40%; however, the use of non-standard of care NAC regimen have persisted (~8%). Cisplatin-ineligibility, older age, race/ethnicity, and lower socioeconomic status were correlated with nonstandard of care NAC, which provided no clinical benefit at the risk of potential harm. In accordance with current clinical guidelines, cisplatin-ineligible patients should be considered for timely upfront cystectomy or novel clinical trials.
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http://dx.doi.org/10.1016/j.urology.2020.12.020DOI Listing
March 2021

Prognostic Genomic Biomarkers in Patients With Localized Prostate Cancer: Is Rising Utilization Justified by Evidence?

JAMA Oncol 2021 Jan;7(1):59-60

Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.

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http://dx.doi.org/10.1001/jamaoncol.2020.6045DOI Listing
January 2021
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