Publications by authors named "Ana Aparicio"

106 Publications

A 2-Step Strategy Combining FIB-4 With Transient Elastography and Ultrasound Predicted Liver Cancer After HCV Cure.

Am J Gastroenterol 2021 Sep 9. Epub 2021 Sep 9.

Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Spain.

Introduction: Despite the direct-acting antiviral therapy has dramatically decreased the likelihood of having liver-related complications and extrahepatic outcomes, the risk of developing hepatocellular carcinoma (HCC) is not totally eliminated after sustained virological response (SVR). We aimed to develop an easy-to-apply strategy to be adopted in clinical practice for accurately classifying the HCC risk in hepatitis C virus patients after SVR.

Methods: Prospective and multicenter study enrolling hepatitis C virus patients with advanced fibrosis (transient elastography [TE] > 10 kPa) or cirrhosis by ultrasound showing SVR. They were followed up until HCC, liver transplantation, death, or until October 2020, which occurred first, with a minimum follow-up period of 6 months after SVR (follow-up: 49 [interquartile range 28-59] months).

Results: Patients with cirrhosis by ultrasound represented 58% (611/1,054) of the overall cohort. During the study, HCC occurrence was 5.3% (56/1,054). Multivariate analyses revealed that Fibrosis-4 (FIB-4) > 3.25 (hazard ratio [HR] 2.26 [1.08-4.73]; P = 0.030), TE (HR 1.02 [1.00-1.04]; P = 0.045) and cirrhosis by ultrasound (HR 3.15 [1.36-7.27]; P = 0.007) predicted HCC occurrence. Baseline HCC screening criteria (TE > 10 kPa or cirrhosis) identified patients at higher risk of HCC occurrence in presence of FIB-4 > 3.25 (8.8%; 44/498) vs FIB-4 < 3.25 (2.4%; 12/506), while those with only FIB > 3.25 had no HCC (0%; 0/50) (logRank 22.129; P = 0.0001). A combination of baseline FIB-4 > 3.25 and HCC screening criteria had an annual incidence >1.5 cases per 100 person-years, while the rest of the groups remained <1 case. Patients who maintained post-treatment FIB-4 > 3.25 and HCC screening criteria remained at the highest risk of HCC occurrence (13.7% [21/153] vs 4.9% [9/184]; logRank 7.396, P = 0.007).

Discussion: We demonstrated that a two-step strategy combining FIB-4, TE, and ultrasound could help stratify HCC incidence risk after SVR.
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http://dx.doi.org/10.14309/ajg.0000000000001503DOI Listing
September 2021

Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment.

J Immunother Cancer 2021 10;9(10)

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: Immune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) promotes intratumoral T cell infiltration but induces upregulation of PD-1 and programmed death ligand-1 (PD-L1) within the prostate TME. Combined anti-CTLA-4 plus anti-PD-1 can partly overcome this adaptive resistance and was recently shown to augment responses in patients with mCRPC with measurable disease. Although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are frequently excluded from trials because they lack measurable disease, which limits assessment of disease progression and tissue sampling. We therefore designed this study to investigate combined ICT in mCRPC to bone.

Hypothesis: Combined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone.

Patients And Methods: In this single-arm pilot study, men with chemotherapy-naïve mCRPC to bone received tremelimumab (75 mg intravenous) plus durvalumab (1500 mg intravenous) every 4 weeks (up to four doses), followed by durvalumab (1500 mg intravenous) maintenance every 4 weeks (up to nine doses). The primary endpoint was incidence of adverse events. Secondary endpoints included serum prostate-specific antigen (PSA), progression-free survival (PFS), radiographic PFS (rPFS), and maximal PSA decline.

Results: Twenty-six patients were treated between August 8, 2017 and March 28, 2019. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 patients (42%), with no grade 4 or 5 events. TRAEs leading to discontinuation occurred in three patients (12%). PSA decline ≥50% occurred in three patients (12%). Six patients (24%) achieved stable disease for >6 months. At a median follow-up of 43.6 months, median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased expression of inhibitory immune checkpoints.

Conclusions: Tremelimumab plus durvalumab was safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone, with potential activity in a small number of patients as measured by rPFS. Combination of CTLA-4 and PD-L1 blockade with therapies targeting the myeloid compartment or other inhibitory immune receptors may be necessary to overcome mechanisms of resistance within prostate bone microenvironment.

Trial Registration Number: NCT03204812.
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http://dx.doi.org/10.1136/jitc-2021-002919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524287PMC
October 2021

Abiraterone acetate plus prednisone in non-metastatic biochemically recurrent castration-naïve prostate cancer.

Eur J Cancer 2021 11 15;157:259-267. Epub 2021 Sep 15.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: Intermittent androgen deprivation therapy (ADT) in biochemically recurrent castration-naïve prostate cancer is non-inferior to continuous therapy. We hypothesised that finite-duration abiraterone acetate plus prednisone (Abi +P) added to ADT will further reduce the duration of treatment exposure by prolonging time to prostate-specific antigen (PSA) recurrence without impacting eugonad state recovery.

Methods: This phase II, randomised, open-label trial enrolled patients with rising PSA ≥ 0.2 ng/ml after radical prostatectomy and/or a PSA ≥ 1 following radiotherapy. Patients were randomised 1:1 to receive Abi (1 g PO daily) + P (5 mg PO daily) + ADT or ADT alone for 8 months. The primary end-point was PSA-free survival difference at 1 year following completion of therapy.

Results: Between February 2013 and July 2016, 200 patients were enrolled. Of 100 patients randomised to each arm, 99 in the Abi +P arm and 98 in the ADT arm were evaluable. Median follow-up was 64.4 months. Median PSA-free survival was 27.0 months for the Abi +P-treated group versus 19.9 months for the ADT-treated group (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87). The PSA-free survival at 1 year post-treatment completion was 98% for the Abi +P group and 88% for the ADT group. Median time to eugonad state was 13.1 months for the abiraterone-treated group and 12.8 months for the ADT-treated group. Median eugonad PSA-free survival was 12.5 months for the abiraterone-treated group versus 9.0 for the ADT-treated group (HR 0.72, 95% CI 0.53-0.98). There were no significant between-group differences in androgen deprivation-related adverse events.

Conclusions: In men with biochemically recurrent prostate cancer following definitive treatment of the primary, finite duration treatment with ADT and Abi +P results in a significantly longer PSA relapse-free interval than treatment with ADT alone.
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http://dx.doi.org/10.1016/j.ejca.2021.06.017DOI Listing
November 2021

Platelet-Coated Circulating Tumor Cells Are a Predictive Biomarker in Patients with Metastatic Castrate-Resistant Prostate Cancer.

Mol Cancer Res 2021 Aug 30. Epub 2021 Aug 30.

Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, California.

Metastatic castration-resistant prostate cancer (mCRPC) includes a subset of patients with particularly unfavorable prognosis characterized by combined defects in at least two of three tumor suppressor genes: , , and as aggressive variant prostate cancer molecular signature (AVPC-MS). We aimed to identify circulating tumor cells (CTC) signatures that could inform treatment decisions of patients with mCRPC with cabazitaxel-carboplatin combination therapy versus cabazitaxel alone. Liquid biopsy samples were collected prospectively from 79 patients for retrospective analysis. CTCs were detected, classified, enumerated through a computational pipeline followed by manual curation, and subjected to single-cell genome-wide copy-number profiling for AVPC-MS detection. On the basis of immunofluorescence intensities, detected rare cells were classified into 8 rare-cell groups. Further morphologic characterization categorized CTC subtypes from 4 cytokeratin-positive rare-cell groups, utilizing presence of mesenchymal features and platelet attachment. Of 79 cases, 77 (97.5%) had CTCs, 24 (30.4%) were positive for platelet-coated CTCs (pc.CTCs) and 25 (38.5%) of 65 sequenced patients exhibited AVPC-MS in CTCs. Survival analysis indicated that the presence of pc.CTCs identified the subset of patients who were AVPC-MS-positive with the worst prognosis and minimal benefit from combination therapy. In AVPC-MS-negative patients, its presence showed significant survival improvement from combination therapy. Our findings suggest the presence of pc.CTCs as a predictive biomarker to further stratify AVPC subsets with the worst prognosis and the most significant benefit of additional platinum therapy. IMPLICATIONS: HDSCA3.0 can be performed with rare cell detection, categorization, and genomic characterization for pc.CTC identification and AVPC-MS detection as a potential predictive biomarker of mCRPC.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0383DOI Listing
August 2021

Evaluation of Technology-Enabled Monitoring of Patient-Reported Outcomes to Detect and Treat Toxic Effects Linked to Immune Checkpoint Inhibitors.

JAMA Netw Open 2021 Aug 2;4(8):e2122998. Epub 2021 Aug 2.

Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Immune checkpoint inhibitors can produce distinct toxic effects that require prompt recognition and timely management.

Objective: To develop a technology-enabled, dynamically adaptive protocol that can provide the accurate information needed to inform specific remedies for immune toxic effects in patients treated with immune checkpoint inhibitors.

Design, Setting, And Participants: An open-label cohort study was conducted at a single tertiary referral center from September 6, 2019, to September 3, 2020. The median follow-up duration was 63 (interquartile range, 35.5-122) days. Fifty patients with genitourinary cancers treated with immune checkpoint inhibitors were enrolled.

Interventions: A fit-for-purpose electronic platform was developed to enable active patient and care team participation. A smartphone application downloaded onto patients' personal mobile devices prompted them to report their symptoms at least 3 times per week. The set of symptoms and associated queries were paired with alert thresholds for symptoms requiring clinical action.

Main Outcomes And Measures: The primary end point of this interim analysis was feasibility, as measured by patient and care team adherence, and lack of increase in care team staffing. Operating characteristics were estimated for each symptom alert and used to dynamically adapt the alert thresholds to ensure sensitivity while reducing unnecessary alerts.

Results: Of the 50 patients enrolled, 47 had at least 1 follow-up visit and were included in the analysis. Median age was 65 years (range, 37-86), 39 patients (83%) were men, and 39 patients (83%) had metastatic cancer, with the most common being urothelial cell carcinoma and renal cell carcinoma (22 [47%] patients each). After initial onboarding, no further care team training or additional care team staffing was required. Patients had a median study adherence rate of 74% (interquartile range, 60%-86%) and 73% of automated alerts were reviewed within 3 days by the clinic team. Symptoms with the highest positive predictive value for adverse events requiring acute intervention included dizziness (21%), nausea/vomiting (26%), and shortness of breath (14%). The symptoms most likely to result in unnecessary alerts were arthralgia and myalgia, fatigue, and cough.

Conclusions And Relevance: The findings of this cohort study suggest an acceptable and fiscally sound method can be developed to create a dynamic learning system to detect and manage immune-related toxic effects.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.22998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406081PMC
August 2021

Durable responses in patients with genitourinary cancers following immune checkpoint therapy rechallenge after moderate-to-severe immune-related adverse events.

J Immunother Cancer 2021 07;9(7)

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: Immune checkpoint therapy (ICT) prolongs survival in subsets of patients with cancer but can also trigger immune-related adverse events (irAEs) requiring treatment discontinuation. Recent studies have investigated safety of ICT rechallenge after irAEs, and evidence suggests that rechallenge may be associated with improved antitumor responses. However, data are limited on response duration after ICT rechallenge, particularly after severe irAEs.

Objective: To evaluate safety and efficacy of ICT rechallenge after moderate-to-severe irAEs in patients with renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer.

Methods: In this retrospective cohort study, medical records from September 25, 2013, to June 1, 2020, for patients with genitourinary (GU) cancers at MD Anderson Cancer Center who were rechallenged with the same or different ICT following irAEs were reviewed. Demographics, ICT exposure, irAEs (grade and treatment), ICT discontinuation or rechallenge, rates of subsequent irAEs (new or recurrent) and antitumor activity (objective response rates and response duration) were reviewed.

Results: Sixty-one patients with RCC, UC, and prostate cancer were rechallenged with ICT after experiencing 105 total irAEs. Objective response rates after rechallenge, that is, upgrade in response, were 14% in RCC (4/28), 21% in UC (3/14), and 0% in prostate cancer. All seven patients who achieved upgrade in response had initial grade 2 or 3 irAEs. Responses were durable among these seven patients, with median radiographic progression-free survival not reached (range: 3.7-66.4 months) as of the March 8, 2021, data cut-off (median follow-up 40.9 months (95% CI 35.3 to 46.5)). All achieved complete response except one patient who was lost to follow-up. The rate of subsequent grade 3 or 4 irAEs after rechallenge was 30%, with no fatal irAEs. The rate of recrudescence of the same irAE was 26% (16/61). 54% of patients received corticosteroids (33/61), and 21% received targeted immunosuppression (13/61) for the initial irAEs.

Conclusions And Relevance: ICT rechallenge after moderate-to-severe irAEs was associated with deep and durable responses in a subset of patients with RCC and UC, with acceptable safety and no fatal events. Strategies to enable ICT resumption after moderate-to-severe irAEs, such targeted immunosuppression, warrant further study.
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http://dx.doi.org/10.1136/jitc-2021-002850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323401PMC
July 2021

A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kβ Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer.

Clin Cancer Res 2021 Jul 19. Epub 2021 Jul 19.

The Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom.

Purpose: In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory PTEN activates PI3K/AKT signaling and contributes to resistance to androgen deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance.

Patients And Methods: In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100-mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended phase II dose, and assess the 12-week non-progressive disease (PD) rate.

Results: Overall, 37 patients were enrolled; 36 received ≥1 dose of GSK2636771 (200 mg: = 22; 300 mg: = 12; 400 mg: = 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: = 1; 300 mg: = 2, 400 mg: = 2). No new or unexpected adverse events or evidence of drug-drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% confidence interval: 28.2-71.8, = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of ≥50%.

Conclusions: Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1115DOI Listing
July 2021

Beyond the Androgen Receptor: The Sequence, the Mutants, and New Avengers in the Treatment of Castrate-Resistant Metastatic Prostate Cancer.

Am Soc Clin Oncol Educ Book 2021 Jun;41:e190-e202

US Oncology Research, Virginia Oncology Associates, Norfolk, VA.

Targeting the androgen receptor by depriving testosterone with gonadotropin-releasing hormone agonists or antagonists, or surgical castration, has been the backbone of metastatic prostate cancer treatment. Although most prostate cancers initially respond to androgen deprivation, metastatic castration-resistant prostate cancer evolves into a heterogeneous disease with diverse drivers of progression and mechanisms of therapeutic resistance. Development of castrate resistance phenotype is associated with lethality despite the recent noteworthy strides gained via increase in therapeutic options. Identification of novel therapeutics to further improve survival and achieve durable responses in metastatic castration-resistant prostate cancer is a clinical necessity. In this review, we outline the existing avengers for treatment of metastatic castration-resistant prostate cancer by clinical presentation, placing into context the clinical state of the patient, such as burden of disease and symptoms. Doing so might aid in the ability to optimize the sequence of agents and allow for maximal exposure to life-prolonging therapeutics. Realizing the limitations of the androgen signaling inhibition, we explore the androgen-indifferent prostate cancer: the mutants. Classically, these subtypes have been associated with variant histology, but androgen-indifferent prostate cancer features are now frequently observed in association with heterogeneous morphologies, including double-negative prostate cancers, lacking both androgen receptor and neuroendocrine features, or clinicopathologic criteria, such as the aggressive variant prostate cancer criteria. The framework of new avengers against metastatic castration-resistant prostate cancer based on mechanism, including DNA repair, immune checkpoint inhibition, PTEN/PI3K/AKT pathway, prostate-specific membrane antigen targets, bispecific T-cell engagers, and radionuclide therapies, is summarized in this review.
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http://dx.doi.org/10.1200/EDBK_321209DOI Listing
June 2021

Optimizing the diagnosis and management of ductal prostate cancer.

Nat Rev Urol 2021 Jun 6;18(6):337-358. Epub 2021 Apr 6.

Department of Urology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

Ductal adenocarcinoma (DAC) is the most common variant histological subtype of prostate carcinoma and has an aggressive clinical course. DAC is usually characterized and treated as high-risk prostatic acinar adenocarcinoma (PAC). However, DAC has a different biology to that of acinar disease, which often poses a challenge for both diagnosis and management. DAC can be difficult to identify using conventional diagnostic modalities such as serum PSA levels and multiparametric MRI, and the optimal management for localized DAC is unknown owing to the rarity of the disease. Following definitive therapy for localized disease with radical prostatectomy or radiotherapy, the majority of DACs recur with visceral metastases at low PSA levels. Various systemic therapies that have been shown to be effective in high-risk PAC have limited use in treating DAC. Although current understanding of the biology of DAC is limited, genomic analyses have provided insights into the pathology behind its aggressive behaviour and potential future therapeutic targets.
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http://dx.doi.org/10.1038/s41585-021-00447-3DOI Listing
June 2021

Impact of Definitive Local Therapy in Men with Primary Small Cell Prostate Carcinoma.

Eur Urol 2021 09 3;80(3):389-390. Epub 2021 Apr 3.

Division of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2021.03.022DOI Listing
September 2021

Large Extracellular Vesicle Characterization and Association with Circulating Tumor Cells in Metastatic Castrate Resistant Prostate Cancer.

Cancers (Basel) 2021 Mar 2;13(5). Epub 2021 Mar 2.

USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA.

Liquid biopsies hold potential as minimally invasive sources of tumor biomarkers for diagnosis, prognosis, therapy prediction or disease monitoring. We present an approach for parallel single-object identification of circulating tumor cells (CTCs) and tumor-derived large extracellular vesicles (LEVs) based on automated high-resolution immunofluorescence followed by downstream multiplexed protein profiling. Identification of LEVs >6 µm in size and CTC enumeration was highly correlated, with LEVs being 1.9 times as frequent as CTCs, and additional LEVs were identified in 73% of CTC-negative liquid biopsy samples from metastatic castrate resistant prostate cancer. Imaging mass cytometry (IMC) revealed that 49% of cytokeratin (CK)-positive LEVs and CTCs were EpCAM-negative, while frequently carrying prostate cancer tumor markers including AR, PSA, and PSMA. HSPD1 was shown to be a specific biomarker for tumor derived circulating cells and LEVs. CTCs and LEVs could be discriminated based on size, morphology, DNA load and protein score but not by protein signatures. Protein profiles were overall heterogeneous, and clusters could be identified across object classes. Parallel analysis of CTCs and LEVs confers increased sensitivity for liquid biopsies and expanded specificity with downstream characterization. Combined, it raises the possibility of a more comprehensive assessment of the disease state for precise diagnosis and monitoring.
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http://dx.doi.org/10.3390/cancers13051056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958848PMC
March 2021

Clinical considerations for the management of androgen indifferent prostate cancer.

Prostate Cancer Prostatic Dis 2021 09 10;24(3):623-637. Epub 2021 Feb 10.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Many systemic therapies for advanced prostate cancer work by disrupting androgen receptor signaling. Androgen indifferent prostate cancer (AIPC) variants, including aggressive variant prostate cancer (AVPC), neuroendocrine prostate cancer (NEPC), and double-negative prostate cancer (DNPC), are increasingly common and often overlapping resistance phenotypes following treatment with androgen receptor signaling inhibitors in men with metastatic castration-resistant prostate cancer and are associated with poor outcomes. Understanding the underlying biology and identifying effective therapies for AIPC is paramount for improving survival for men with prostate cancer.

Methods: In this review, we summarize the current knowledge on AIPC variants, including our current understanding of the clinical, morphologic, and molecular features as well as current therapeutic approaches. We also explore emerging therapies and biomarkers aimed at improving outcomes for men with AIPC.

Results And Conclusions: Establishing consensus definitions, developing novel biomarkers for early and accurate detection, further characterization of molecular drivers of each phenotype, and developing effective therapies will be critical to improving outcomes for men with AIPC. Significant progress has been made toward defining the clinical and molecular characteristics of AVPC, NEPC, and DNPC. Novel diagnostic approaches, including cell-free DNA, circulating tumor cells, and molecular imaging are promising tools for detecting AIPC in clinical practice. Building on previous treatment advances, several clinical trials are underway evaluating novel therapeutic approaches in patients with AIPC informed by an understanding of variant-specific biology. In this review, we discuss how these recent and ongoing studies will help to improve diagnosis, prognosis, and therapy for men with AIPC.
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http://dx.doi.org/10.1038/s41391-021-00332-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353003PMC
September 2021

Phase II study of the histone deacetylase inhibitor vorinostat (Suberoylanilide Hydroxamic Acid; SAHA) in recurrent or metastatic transitional cell carcinoma of the urothelium - an NCI-CTEP sponsored: California Cancer Consortium trial, NCI 6879.

Invest New Drugs 2021 06 6;39(3):812-820. Epub 2021 Jan 6.

City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

Background: Until the advent of T cell check point inhibitors standard second-line therapy for patients with metastatic urothelial cancer (mUC) was undefined. Histone deacetylase inhibitors (HDACi) have anti-cancer activity in a variety of tumor models including modulation of apoptosis in bladder cancer cell lines. We evaluated the efficacy and toxicity of the HDACi vorinostat in patients with mUC failing first-line platinum-based therapy either in the adjuvant/neoadjuvant setting or for recurrent/advanced disease.

Methods: Vorinostat was given orally 200 mg twice daily continuously until progression or unacceptable toxicity. The primary end point was RECIST response rate (RR); a RR > 20% was deemed interesting in a 2-stage design requiring one response in the first 12 patients to proceed to 2nd stage for a total of 37 subjects. CT or MRI scan imaging occurred every 6 weeks.

Results: Fourteen patients were accrued characterized by: median age 66 years (43-84); Caucasian (79%); males (86%); and Karnofsky performance status ≥90 (50%). Accrual was terminated in the first stage as no responses were observed. Best response was stable disease (3 patients). Progression was observed in 8 patients. Two patients came off therapy prior to re-imaging and a 3rd patient died while on treatment and was not assessed for response. Median number of cycles was 2 (range 1-11). Median disease-free survival and overall survival times were 1.1 (0.8, 2.1) & 3.2 (2.1, 14.5) months, respectively. Toxicities were predominantly cytopenias and thrombocytopenic bleeding. Two pts. had grade 5 toxicity unlikely related to treatment. Two pts. had grade 4 and 6 had grade 3 toxicities observed. Two patients with stable disease remained on therapy for 6+ cycles.

Conclusions: Vorinostat on this dose-schedule had limited efficacy and significant toxicity resulting in a unfavorable risk:benefit ratio in patients with mUC. NCT00363883.
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http://dx.doi.org/10.1007/s10637-020-01038-6DOI Listing
June 2021

Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies.

Eur Urol 2021 02 3;79(2):298-306. Epub 2020 Dec 3.

The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: Ductal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC).

Objective: To assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC.

Design, Setting, And Participants: A single-center retrospective review of all patients with cT1-4/N0-1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients.

Outcome Measurements And Statistical Analysis: Metastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models.

Results And Limitations: A total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation.

Conclusions: Men undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed.

Patient Summary: This study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.
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http://dx.doi.org/10.1016/j.eururo.2020.11.015DOI Listing
February 2021

A Phase 2 Trial of Abiraterone Followed by Randomization to Addition of Dasatinib or Sunitinib in Men With Metastatic Castration-Resistant Prostate Cancer.

Clin Genitourin Cancer 2021 02 30;19(1):22-31.e5. Epub 2020 May 30.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC.

Patients And Methods: In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety.

Results: From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years.

Conclusion: There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.
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http://dx.doi.org/10.1016/j.clgc.2020.05.013DOI Listing
February 2021

The MD Anderson Prostate Cancer Patient-derived Xenograft Series (MDA PCa PDX) Captures the Molecular Landscape of Prostate Cancer and Facilitates Marker-driven Therapy Development.

Clin Cancer Res 2020 09 23;26(18):4933-4946. Epub 2020 Jun 23.

Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Advances in prostate cancer lag behind other tumor types partly due to the paucity of models reflecting key milestones in prostate cancer progression. Therefore, we develop clinically relevant prostate cancer models.

Experimental Design: Since 1996, we have generated clinically annotated patient-derived xenografts (PDXs; the MDA PCa PDX series) linked to specific phenotypes reflecting all aspects of clinical prostate cancer.

Results: We studied two cell line-derived xenografts and the first 80 PDXs derived from 47 human prostate cancer donors. Of these, 47 PDXs derived from 22 donors are working models and can be expanded either as cell lines (MDA PCa 2a and 2b) or PDXs. The histopathologic, genomic, and molecular characteristics (androgen receptor, ERG, and loss) maintain fidelity with the human tumor and correlate with published findings. PDX growth response to mouse castration and targeted therapy illustrate their clinical utility. Comparative genomic hybridization and sequencing show significant differences in oncogenic pathways in pairs of PDXs derived from different areas of the same tumor. We also identified a recurrent focal deletion in an area that includes the speckle-type POZ protein-like () gene in PDXs derived from seven human donors of 28 studied (25%). is a paralog, and mutations define a molecular subclass of prostate cancer. deletions are found in 7% of The Cancer Genome Atlas prostate cancers, which suggests that our cohort is a reliable platform for targeted drug development.

Conclusions: The MDA PCa PDX series is a dynamic resource that captures the molecular landscape of prostate cancers progressing under novel treatments and enables optimization of prostate cancer-specific, marker-driven therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501166PMC
September 2020

Predictive factors of functional outcome in patients with bipolar I disorder: a five-year follow-up.

J Affect Disord 2020 07 30;272:249-258. Epub 2020 Apr 30.

Department of Psychiatry, Hospital Virgen de La Luz, CIBERSAM, Cuenca, Spain; Neurobiological Research Group. Institute of Technology, Universidad de Castilla-La Mancha, Cuenca, Spain.

Background: Functional impairment is commonly encountered among patients with bipolar disorder (BD) during periods of remission. The distribution of the impairment of the functional outcome is heterogeneous. The objective of this current investigation was to identify neurocognitive and clinical predictors of psychosocial functioning in a sample of patients with BD.

Methods: Seventy-six patients (59.2% females) and 40 healthy controls (50% females), aged 18 to 55 years, were assessed using a comprehensive neurocognitive battery (six neurocognitive domains), and the Functioning Assessment Short Test (FAST), at baseline and after a 5-year follow-up. Stepwise regression models were used to identify predictor variables related to psychosocial functioning.

Results: The number of hospitalizations during the follow-up, the change occurred in the neurocognitive composite index (NCI change), and NCI at baseline explained 30.8% of the variance of functioning. The number of hospitalizations during the follow-up was the variable that explained a greater percentage of the variance (16.9%). Verbal memory at baseline and the change in sustained attention during the follow-up explained 10% and 5.9% of the variance of the psychosocial functioning, respectively.

Limitations: The interval of 5 years between the two assessments could be too short to detect a possible progression in functional outcome for the overall sample.

Conclusions: The clinical course during the follow-up is the factor that has a greater impact on psychosocial functioning in patients with BD. Thus, the interventions aimed to promote prevention of relapses should be considered as essential for avoiding functional impairment in these patients.
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http://dx.doi.org/10.1016/j.jad.2020.03.140DOI Listing
July 2020

Patterns of metastases of prostatic ductal adenocarcinoma.

Cancer 2020 08 26;126(16):3667-3673. Epub 2020 May 26.

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: The current study was conducted to investigate the patterns of metastases in men with metastatic prostatic ductal adenocarcinoma (DAC) and recurrence patterns after therapy.

Methods: All patients with a new diagnosis of DAC with de novo metastases and those with localized disease who developed metastases after treatment and were treated at the study institution from January 2005 to November 2018 were included. All patient and tumor characteristics and outcome data were collected.

Results: A total of 164 patients (37.7%) had metastatic DAC, including 112 with de novo metastases and 52 who developed metastases after treatment. Men with de novo metastases were found to have a significantly higher median prostate-specific antigen level and International Society of Urological Pathology grade but a lower cT3 and/or T4 classification compared with those with metastases that developed after treatment (all P < .05). Approximately 87% of men with de novo metastases progressed despite multiple systemic therapies, 37.6% required intervention for the palliation of symptoms, and 10.1% responded to systemic therapy and underwent treatment of the primary tumor. Men with de novo metastatic DAC and those who developed metastases after treatment had multiple metastatic sites (including bone and viscera), with higher rates of lung metastases noted in the posttreatment group (23.2% vs 44.2%; P = .01). A total of 45 patients who were treated with curative intent developed metastases at a median of 22 months (range, 0.9-74.8 months) after treatment, at low prostate-specific antigen levels (median, 4.4 ng/mL [interquartile range, 1.7-11.1 ng/mL]).

Conclusions: The current study described the metastatic patterns of DAC in both patients with de novo metastatic disease and those who later progress to metastases. Men receiving treatment for DAC with curative intent require stringent long-term follow-up with imaging modalities, including chest imaging given the predilection toward lung metastases noted among these patients.
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http://dx.doi.org/10.1002/cncr.32957DOI Listing
August 2020

Increased Frequency of Mesorectal and Perirectal LN Involvement in T4 Prostate Cancers.

Int J Radiat Oncol Biol Phys 2020 08 27;107(5):982-985. Epub 2020 Apr 27.

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

Purpose: Patients with prostate cancer presenting with advanced T stage, mainly T4, might have a unique pattern of nodal failure and disease involvement that is not typically covered when local therapy is offered. We attempted to identify common sites of nodal disease presentation and failure for patients presenting with cT4 prostate cancer.

Methods And Materials: All patients with treatment-naïve cT4 prostate cancer were retrospectively identified. All patients were required to have a confirmed diagnosis reviewed by our genitourinary pathologist and completed baseline staging. Lymph node (LN) involvement and location at diagnosis were reviewed by a genitourinary radiologist. All patients' follow-up scans were also reviewed; based on LN size, imaging characteristics, and progression/regression characteristics on systemic therapy, the locations of sites of LN failure were recorded. For patients who underwent surgery, any pathologically involved LNs and their anatomic locations were recorded. A total of 103 patients met these criteria, with a median follow-up of 8 years (range, 0.5-14 years).

Results: Rectal involvement by the primary disease was associated with a higher risk of perirectal and mesorectal LN involvement (45%) relative to no rectal involvement (26%) (P < .05). These echelons are typically not covered with conventional pelvic external beam radiation therapy and are not routinely part of pelvic LN dissection in patients treated surgically. Conversely, bladder or pelvic side wall invasion did not correlate with increased frequency of involvement of perirectal/mesorectal LNs (P > .05).

Conclusions: When offering local therapy, target modification to include the perirectal and mesorectal LNs should be considered for patients presenting with T4 prostate cancer with rectal involvement.
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http://dx.doi.org/10.1016/j.ijrobp.2020.04.025DOI Listing
August 2020

Single-Cell Circulating Tumor Cell Analysis Reveals Genomic Instability as a Distinctive Feature of Aggressive Prostate Cancer.

Clin Cancer Res 2020 08 27;26(15):4143-4153. Epub 2020 Apr 27.

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Aggressive variant prostate cancer (AVPC) represents a clinical subset distinguished by therapy resistance and poor prognosis, linked to combined losses of the tumor suppressor genes (TSG) , and . Circulating tumor cells (CTC) provide a minimally invasive opportunity for identification and molecular characterization of AVPC. We aimed to evaluate the incidence and clinical significance of compound (2+)TSG losses and genomic instability in prostate cancer CTC, and to expand the set genomic biomarkers relevant to AVPC.

Experimental Design: Genomic analysis of chromosomal copy-number alterations (CNA) at single-cell resolution was performed in CTC from patients with and without AVPC before initiating chemotherapy with cabazitaxel or cabazitaxel and carboplatin. We evaluated associations between single-CTC genomics and clinical features, progression-free survival, and overall survival.

Results: A total of 257 individual CTC were sequenced from 47 patients (1-22 CTC/patient). Twenty patients (42.6%) had concurrent 2+TSG losses in at least one CTC in association with poor survival and increased genomic instability, inferred by high large-scale transitions scores. Higher LST in CTC were independent of CTC enumerated, clinically more indicative of aggressive behavior than co-occurring TSG losses, and molecularly associated with gains in chromosomal regions including , and ; increased androgen receptor expression; and loss. In 57 patients with matched cell-free tumor DNA data, CTC were more frequently detectable and evaluable for CNA analysis (in 73.7% vs. 42.1%, respectively).

Conclusions: Our findings suggest that genomic instability in CTC is a hallmark of advanced prostate cancer aggressiveness, and support single-CTC sequencing as a compelling tool to noninvasively characterize cancer heterogeneity.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043601PMC
August 2020

Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer.

Sci Transl Med 2020 04;12(537)

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Tumors with high mutational burden (TMB) tend to be responsive to immune checkpoint blockade (ICB) because there are neoantigens available for targeting by reinvigorated T cells, whereas those with low TMB demonstrate limited clinical responses. To determine whether antigen-specific T cell responses can be elicited after treatment with ICB in cancers that have a low TMB, we conducted a clinical trial with ipilimumab in 30 patients with metastatic castration-resistant prostate cancer. We identified two distinct cohorts by survival and progression times: "favorable" ( = 9) and "unfavorable" ( = 10). Patients in the favorable cohort had high intratumoral CD8 T cell density and IFN-γ response gene signature and/or antigen-specific T cell responses. Two patients with a relatively low TMB had T cell responses against unique neoantigens. Moreover, six of nine patients in the favorable group are still alive at the time of analysis, with survival ranging from 33 to 54 months after treatment. All 10 patients in the unfavorable cohort have succumbed to their disease and had survival ranging from 0.6 to 10.3 months. Collectively, our data indicate that immunological correlates associated with effector T cell responses are observed in patients with metastatic prostate cancer who benefit from ICB.
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http://dx.doi.org/10.1126/scitranslmed.aaz3577DOI Listing
April 2020

Association of Sociodemographic and Health-Related Factors With Receipt of Nondefinitive Therapy Among Younger Men With High-Risk Prostate Cancer.

JAMA Netw Open 2020 03 2;3(3):e201255. Epub 2020 Mar 2.

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

Importance: Multiple randomized clinical trials have shown that definitive therapy improves overall survival among patients with high-risk prostate cancer. However, many patients do not receive definitive therapy because of sociodemographic and health-related factors.

Objective: To identify factors associated with receipt of nondefinitive therapy (NDT) among patients aged 70 years and younger with high-risk prostate cancer.

Design, Setting, And Participants: This cohort study identified 72 036 patients aged 70 years and younger with high-risk prostate cancer and Charlson Comorbidity Index scores of 2 or less who were entered in the National Cancer Database between January 2004 and December 2014. Data analysis was conducted from November 2018 to December 2019.

Exposure: Receipt of NDT as an initial treatment approach.

Main Outcomes And Measures: Survival rates were compared based on receipt of definitive therapy or NDT, and sociodemographic and health-related factors were associated with the type of therapy received. Residual life expectancy was estimated from the National Center for Health Statistics to calculate person-years of life lost.

Results: A total of 72 036 men with a median (range) age of 63 (30-70) years, Charlson Comorbidity Index scores of 2 or less, and high-risk prostate cancer without regional lymph node or distant metastatic disease were analyzed. Among eligible patients, 5252 (7.3%) received NDT as an initial therapeutic strategy. On univariate and multivariate analyses, NDT was associated with worse overall survival (univariate analysis hazard ratio, 2.54; 95% CI, 2.40-2.69; P < .001; multivariate analysis hazard ratio, 2.40; 95% CI, 2.26-2.56; P < .001). Compared with patients with private insurance or managed care, those with no insurance, Medicaid, or Medicare were more likely to receive systemic therapy only (no insurance: odds ratio [OR], 3.34; 95% CI, 2.81-3.98; P < .001; Medicaid: OR, 2.92; 95% CI, 2.48-3.43; P < .001; Medicare: OR, 1.36; 95% CI, 1.20-1.53; P < .001) or no treatment (no insurance: OR, 2.63; 95% CI, 2.24-3.08; P < .001; Medicaid: OR, 1.71; 95% CI, 1.45-2.01; P < .001; Medicare: OR, 1.14; 95% CI, 1.04-1.24; P = .004). Compared with white patients, black patients were more likely to receive systemic therapy only (OR, 1.93; 95% CI, 1.74-2.14; P < .001) or no treatment (OR, 1.46; 95% CI, 1.32-1.61; P < .001), and Hispanic patients were more likely to receive systemic therapy only (OR, 1.36; 95% CI, 1.13-1.64; P = .001) or no treatment (OR, 1.36; 95% CI, 1.14-1.60; P < .001). Between 2004 and 2014, patients without insurance or enrolled in Medicaid had 1.83-fold greater person-years of life lost compared with patients with private insurance (area under the curve, 77 600 vs 42 300 person-years of life lost).

Conclusions And Relevance: In this study, receipt of NDT was associated with insurance status and race/ethnicity. While treatment decisions should be individualized for every patient, younger men with high-risk prostate cancer and minimal comorbidities should be encouraged to receive definitive local therapy regardless of other factors. These data suggest that significant barriers to life-extending treatment options for patients with prostate cancer remain.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.1255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082722PMC
March 2020

Interaction between Solvatochromic Dyes and Water Sampled from a Natural Source Treated with High Dilutions of Phosphorus.

Homeopathy 2020 08 12;109(3):126-132. Epub 2020 Feb 12.

Graduation Program on Environmental and Experimental Pathology, Universidade Paulista, São Paulo, Brazil.

Background: Highly diluted and succussed solutions interact with solvatochromic dyes, indicating that changes in solvent and solute polarity could be related to their mechanism of action. It is not known, however, how the activity associated with succussed high dilutions is transferred to untreated water and what the limits of this process are.

Aims: The aims of the present study were to ascertain whether a succussed high dilution of phosphorus (1.5 × 1 M; Phos 30cH) seeded into a natural water source that fed a fjord and two connected lakes could propagate itself through the lake system (total volume 2200 m) and, moreover, whether the process could be tracked using solvatochromic dyes.

Methods: Samples of water were collected before and after seeding, at different times and places throughout the lake system. Controls comprised water taken from an untreated and adjacent, but independent, lake (1385 m).

Results: Water samples taken up to 72 hours after the source treatment produced significant increases ( ≤ 0.03) in the absorbance of the solvatochromic dye methylene violet (MV), while samples from the control lake produced no changes.

Conclusions: The study indicates that activity associated with Phos 30c can propagate itself through large volumes of water, causing changes throughout a whole connected lake system, and that these changes can be tracked using the solvatochromic dye MV. This in turn means the use of homeopathic medicines in large volumes of drinking water, in farming and ecological contexts, now has the potential to be assessed with physico-chemical monitoring.
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http://dx.doi.org/10.1055/s-0039-3400255DOI Listing
August 2020

A candidate androgen signalling signature predictive of response to abiraterone acetate in men with metastatic castration-resistant prostate cancer.

Eur J Cancer 2020 03 24;127:67-75. Epub 2020 Jan 24.

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Centre, Houston, TX, USA. Electronic address:

Background: The unmet need for predictive biomarkers emerged from the unpredictable pattern of response to androgen signalling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the testing of a previously identified candidate androgen signalling signature associated with response to androgen signalling inhibition.

Patients And Methods: We report on the outcome of the first module of a phase II trial on abiraterone acetate (AA) followed by combination with dasatinib or sunitinib. Bone marrow biopsies (BMBs) with matched bone marrow aspirate and blood samples were collected at baseline and upon progression. End-points included assessment of a prespecified molecular signature consisting of nuclear androgen receptor (AR) overexpression, cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17) expression, and AR-C-/N terminal expression ratio of ≥0.8 by immunohistochemistry (IHC) in patients with benefit versus primary resistance to AA (i.e. progression within 4 months). Tumour markers also included v-ets avian erythroblastosis virus E26 oncogene homologue (ERG), androgen receptor splice variant (ARV7) by IHC and steroids by liquid chromatography-tandem mass spectrometry.

Results: Of 170 patients accrued from 03/2011 to 02/2015, 44 (26%) were primary resistant to AA. Forty-eight patients had tumour infiltrated BMB at baseline. Pretreatment androgen signalling signature was linked to benefit from AA (p < 0.001). Presence of ERG was associated with benefit (p = 0.05), whereas nuclear ARV7 presence and 20 or more bone lesions at baseline with primary resistance (p = 0.04 and p = 0.0006, respectively).

Conclusion: Testing of a prespecified androgen signalling signature was highly supportive of its predictive value in maximal androgen deprivation strategies in mCRPC. Further validation is under way.

Trial Registration: ClinicalTrials.gov NCT01254864.
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http://dx.doi.org/10.1016/j.ejca.2019.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350510PMC
March 2020

A Phase II Study of Cabozantinib and Androgen Ablation in Patients with Hormone-Naïve Metastatic Prostate Cancer.

Clin Cancer Res 2020 03 15;26(5):990-999. Epub 2020 Jan 15.

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

Purpose: Cabozantinib, an oral inhibitor of c-MET/VEGFR2 signaling, improved progression-free survival (mPFS) but not overall survival (OS) in metastatic castrate-resistant prostate cancer. We evaluated cabozantinib plus androgen deprivation therapy (ADT) in hormone-naïve metastatic prostate cancer (HNMPCa).

Patients And Methods: Patients received ADT plus cabozantinib starting at 60 mg daily. The primary endpoint was castrate-resistant PFS by radiographic criteria, clinical progression, or receipt of additional therapy. Secondary endpoints included OS, safety, radiographic responses, and biomarker modulation.

Results: Sixty-two patients received treatment. With a median follow-up of 31.2 months, the mPFS was 16.1 months (95% CI, 14.6-22.7 months), and mOS was not reached. Reductions in PSA ≥ 90%, bone-specific alkaline phosphatase ≥ 50%, and urine N-telopeptides ≥ 50% occurred in 83%, 87%, and 86% of evaluable patients, respectively. Responses in bone scan and measurable disease were observed in 81% of and 90% of evaluable patients, respectively. Most common grade 3 adverse events were hypertension (19%), diarrhea (6%), and thromboembolic events (6%), and dose reductions occurred in 85% of patients. Analysis of baseline cytokine and angiogenic factors (CAFs) revealed that higher plasma concentrations of Lumican, CXCL5, CD25, and CD30 were associated with shorter PFS as was high tumor expression of pFGFR1.

Conclusions: Cabozantinib plus ADT has promising clinical activity in HNMPCa. CAF profiles and tissue markers suggest candidate prognostic and predictive markers of cabozantinib benefit and provide insights for rational therapy combinations.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2389DOI Listing
March 2020

Epigenetics and prostate cancer: defining the timing of DNA methyltransferase deregulation during prostate cancer progression.

Pathology 2020 Feb 18;52(2):218-227. Epub 2019 Dec 18.

Department of Pathology, Medical School, University of Patras, Greece.

DNA methyltransferases (DNMTs) regulate gene expression by methylating cytosine residues within CpG dinucleotides. Aberrant methylation patterns have been shown in a variety of human tumours including prostate cancer. However, the expression of DNMTs in clinical samples across the spectrum of prostate cancer progression has not been studied before. Tissue microarrays were constructed from the prostatectomy specimens of 309 patients across the spectrum of prostate cancer progression: hormone-naïve low-grade prostate cancer (n=49), hormone-naïve high-grade prostate cancer (n=151), hormonally treated high-grade prostate cancer (n=65), and castrate-resistant prostate cancer (CRPC) including neuroendocrine carcinoma (n=44). Adjacent non-neoplastic parenchyma was also available in 100 patients. In 71 patients with high-grade carcinoma and lymph node metastasis, tissue from the metastasis was also available for analysis. Immunohistochemical staining was performed with antibodies against DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L. Our results showed that DNMT1 and DNMT3L were upregulated early in prostate cancer progression, whereas DNMT2 was upregulated as a response to androgen ablation. DNMT1, DNMT3A, and DNMT3B were higher in the late stages of prostate cancer progression, i.e., the emergence of castrate resistance and androgen-independent growth. Lastly, DNMT1, DNMT2, and DNMT3L were upregulated in lymph node metastases compared to primary carcinomas. Our results highlight a cascade of epigenetic events in prostate cancer progression.
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http://dx.doi.org/10.1016/j.pathol.2019.10.006DOI Listing
February 2020

Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy.

Cell 2019 Nov;179(5):1177-1190.e13

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center UTHealth, Houston, TX 77030, USA. Electronic address:

Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients' bone marrow samples revealed increased T17 instead of T1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral T1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to T17 rather than T1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-β, which restrains T1 lineage development. Blocking TGF-β along with ICT increases T1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.
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http://dx.doi.org/10.1016/j.cell.2019.10.029DOI Listing
November 2019

Characterization of Antimonium crudum Activity Using Solvatochromic Dyes.

Homeopathy 2020 05 11;109(2):79-86. Epub 2019 Oct 11.

DiagnOx Laboratory, Cherwell Innovation Centre, Upper Heyford, Oxon, United Kingdom.

Background: The mechanism by which highly diluted and agitated solutions have their effect is still unknown, but the development in recent years of new methods identifying changes in water and solute dipole moments is providing insights into potential modes of action.

Objective: The objective of the current study was to compare the biological effects of (AC) previously obtained by our group and already described in the literature with now measurable physico-chemical effects on solvatochromic dyes.

Methods: Different dilutions of AC and succussed water have been characterized with respect to their effect on the visible spectra of the solvatochromic dyes methylene violet (MV), a pyridinium phenolate (ET33), and a dimethylamino naphthalenone (BDN) compared with in-vitro action against -infected macrophages.

Results: Dye responses varied according to the dye used and the level of AC dilution and results were found to corroborate previously published in-vivo and in-vitro effects of AC. In addition, a very significant enhancement in the absorbance increase of MV was seen using the supernatant from AC 200cH-treated cells (15%;  < 0.0001) over that seen with AC 200cH itself (4%;  = 0.034), suggesting the amplification of ultra-high dilution effects by biological systems. Furthermore, supernatants from AC-treated cells increased the range of dilutions of AC that were capable of producing effects on the spectra of MV. The effect of AC dilutions on dye ET33 was eliminated by a weak electric current passed through potency solutions.

Conclusion: The data confirm a correspondence between the biological effects of dilutions of AC in-vitro and physico-chemical effects on solvatochromic dyes as measured by changes in their visible spectra. Results also indicate high dilutions of AC are sensitive to exposure to electric currents and biological systems.
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http://dx.doi.org/10.1055/s-0039-1697000DOI Listing
May 2020

Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1-2 trial.

Lancet Oncol 2019 10 9;20(10):1432-1443. Epub 2019 Sep 9.

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: Taxane-platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer.

Methods: We did a phase 1-2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20-25 mg/m and intravenous carboplatin area under the curve (AUC) 3-4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov, number NCT01505868.

Findings: Between Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5-37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5-5·7) to 7·3 months (95% CI 5·5-8·2; hazard ratio 0·69, 95% CI 0·50-0·95, p=0·018). In the phase 2 study, the most common grade 3-5 adverse events were fatigue (7 [9%] of 79 in the cabazitaxel group vs 16 [20%] of 81 in the combination group), anaemia (3 [4%] vs 19 [23%]), neutropenia (3 [4%] vs 13 [16%]), and thrombocytopenia (1 [1%] vs 11 [14%]). There were no treatment-related deaths.

Interpretation: Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane-platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned.

Funding: Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund.
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http://dx.doi.org/10.1016/S1470-2045(19)30408-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858999PMC
October 2019

Radiotherapy for metastatic prostate cancer.

Lancet 2019 09;394(10201):829-830

Genitourinary Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.

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http://dx.doi.org/10.1016/S0140-6736(19)31783-0DOI Listing
September 2019
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