Marker selection strategies for circulating tumor DNA guided by phylogenetic inference.

Motivation: Blood-based profiling of tumor DNA ("liquid biopsy") has offered great prospects for non-invasive early cancer diagnosis, treatment monitoring, and clinical guidance, but require further advances in computational methods to become a robust quantitative assay of tumor clonal evolution. We propose new methods to better characterize tumor clonal dynamics from circulating tumor DNA (ctDNA), through application to two specific questions: 1) How to apply longitudinal ctDNA data to refine phylogeny models of clonal evolution, and 2) how to quantify changes in clonal frequencies that may be indicative of treatment response or tumor progression. We pose these questions through a probabilistic framework for optimally identifying maximum likelihood markers and applying them to characterizing clonal evolution. Results: We first estimate a distribution over plausible clonal lineage models, using bootstrap samples over pre-treatment tissue-based sequence data. We then refine these lineage models and the clonal frequencies they imply over successive longitudinal samples. We use the resulting framework for modeling and refining tree distributions to pose a set of optimization problems to select ctDNA markers to maximize measures of utility capturing ability to solve the two questions of reducing uncertain in phylogeny models or quantifying clonal frequencies given the models. We tested our methods on synthetic data and showed them to be effective at refining distributions of tree models and clonal frequencies so as to minimize measures of tree distance relative to the ground truth. Application of the tree refinement methods to real tumor data further demonstrated their effectiveness in refining a clonal lineage model and assessing its clonal frequencies. The work shows the power of computational methods to improve marker selection, clonal lineage reconstruction, and clonal dynamics profiling for more precise and quantitative assays of tumor progression. Availability: https://github.com/CMUSchwartzLab/Mase-phi.git. Contact: russells@andrew.cmu.edu.

Optimizing Design of Genomics Studies for Clonal Evolution Analysis.

Genomic biotechnologies have seen rapid development over the past two decades, allowing for both the inference and modification of genetic and epigenetic information at the single cell level. While these tools present enormous potential for basic research, diagnostics, and treatment, they also raise difficult issues of how to design research studies to deploy these tools most effectively. In designing a study at the population or individual level, a researcher might combine several different sequencing modalities and sampling protocols, each with different utility, costs, and other tradeoffs. The central problem this paper attempts to address is then how one might create an optimal study design for a genomic analysis, with particular focus on studies involving somatic variation, typically for applications in cancer genomics. We pose the study design problem as a stochastic constrained nonlinear optimization problem and introduce a simulation-centered optimization procedure that iteratively optimizes the objective function using surrogate modeling combined with pattern and gradient search. Finally, we demonstrate the use of our procedure on diverse test cases to derive resource and study design allocations optimized for various objectives for the study of somatic cell populations.

Modeling the Effect of Spatial Structure on Solid Tumor Evolution and Circulating Tumor DNA Composition.

Circulating tumor DNA (ctDNA) monitoring, while sufficiently advanced to reflect tumor evolution in real time and inform cancer diagnosis, treatment, and prognosis, mainly relies on DNA that originates from cell death via apoptosis or necrosis. In solid tumors, chemotherapy and immune infiltration can induce spatially variable rates of cell death, with the potential to bias and distort the clonal composition of ctDNA. Using a stochastic evolutionary model of boundary-driven growth, we study how elevated cell death on the edge of a tumor can simultaneously impact driver mutation accumulation and the representation of tumor clones and mutation detectability in ctDNA. We describe conditions in which invasive clones are over-represented in ctDNA, clonal diversity can appear elevated in the blood, and spatial bias in shedding can inflate subclonal variant allele frequencies (VAFs). Additionally, we find that tumors that are mostly quiescent can display similar biases but are far less detectable, and the extent of perceptible spatial bias strongly depends on sequence detection limits. Overall, we show that spatially structured shedding might cause liquid biopsies to provide highly biased profiles of tumor state. While this may enable more sensitive detection of expanding clones, it could also increase the risk of targeting a subclonal variant for treatment. Our results indicate that the effects and clinical consequences of spatially variable cell death on ctDNA composition present an important area for future work.

Sc-TUSV-ext: Single-cell clonal lineage inference from single nucleotide variants (SNV), copy number alterations (CNA) and structural variants (SV).

Clonal lineage inference ("tumor phylogenetics") has become a crucial tool for making sense of somatic evolution processes that underlie cancer development and are increasingly recognized as part of normal tissue growth and aging. The inference of clonal lineage trees from single cell sequence data offers particular promise for revealing processes of somatic evolution in unprecedented detail. However, most such tools are based on fairly restrictive models of the types of mutation events observed in somatic evolution and of the processes by which they develop. The present work seeks to enhance the power and versatility of tools for single-cell lineage reconstruction by making more comprehensive use of the range of molecular variant types by which tumors evolve. We introduce Sc-TUSV-ext, an integer linear programming (ILP) based tumor phylogeny reconstruction method that, for the first time, integrates single nucleotide variants (SNV), copy number alterations (CNA) and structural variations (SV) into clonal lineage reconstruction from single-cell DNA sequencing data. We show on synthetic data that accounting for these variant types collectively leads to improved accuracy in clonal lineage reconstruction relative to prior methods that consider only subsets of the variant types. We further demonstrate the effectiveness on real data in resolving clonal evolution in the presence of multiple variant types, providing a path towards more comprehensive insight into how various forms of somatic mutability collectively shape tissue development.

Modeling the effect of spatial structure on solid tumor evolution and ctDNA composition.

Circulating tumor DNA (ctDNA) monitoring, while sufficiently advanced to reflect tumor evolution in real time and inform on cancer diagnosis, treatment, and prognosis, mainly relies on DNA that originates from cell death via apoptosis or necrosis. In solid tumors, chemotherapy and immune infiltration can induce spatially variable rates of cell death, with the potential to bias and distort the clonal composition of ctDNA. Using a stochastic evolutionary model of boundary-driven growth, we study how elevated cell death on the edge of a tumor can simultaneously impact driver mutation accumulation and the representation of tumor clones and mutation detectability in ctDNA. We describe conditions in which invasive clones end up over-represented in ctDNA, clonal diversity can appear elevated in the blood, and spatial bias in shedding can inflate subclonal variant allele frequencies (VAFs). Additionally, we find that tumors that are mostly quiescent can display similar biases, but are far less detectable, and the extent of perceptible spatial bias strongly depends on sequence detection limits. Overall, we show that spatially structured shedding might cause liquid biopsies to provide highly biased profiles of tumor state. While this may enable more sensitive detection of expanding clones, it could also increase the risk of targeting a subclonal variant for treatment. Our results indicate that the effects and clinical consequences of spatially variable cell death on ctDNA composition present an important area for future work.

A Clonal Evolution Simulator for Planning Somatic Evolution Studies.

Somatic evolution plays a key role in development, cell differentiation, and normal aging, but also in diseases such as cancer. Understanding mechanisms of somatic mutability and how they can vary between cell lineages will likely play a crucial role in biological discovery and medical applications. This need has led to a proliferation of new technologies for profiling single-cell variation, each with distinctive capabilities and limitations that can be leveraged alone or in combination with other technologies. The enormous space of options for assaying somatic variation, however, presents unsolved informatics problems with regard to selecting optimal combinations of technologies for designing appropriate studies for any particular scientific questions. Versatile simulation tools are needed to explore and optimize potential study designs if researchers are to deploy multiomic technologies most effectively. In this study, we present a simulator allowing for the generation of synthetic data from a wide range of clonal lineages, variant classes, and sequencing technology choices, intended to provide a platform for effective study design in somatic lineage analysis. Users can input various properties of the somatic evolutionary system, mutation classes, and biotechnology options, and then generate samples of synthetic sequence reads and their corresponding ground truth parameters for a given study design. We demonstrate the utility of the simulator for testing and optimizing study designs for various experimental queries.

Patient-Reported Outcome Measures of Psychosocial Quality of Life in Oropharyngeal Cancer Patients: A Scoping Review.

Background: Oropharyngeal squamous cell carcinoma (OPSCC) patients are burdened by the effect of the disease process and treatment toxicities on organs important in everyday activities, such as breathing, speaking, eating, and drinking. There is a rise in OPSCC due to human papilloma virus (HPV)-associated OPSCC, affecting younger and healthier patients and with a better overall prognosis. Emphasis must be shared between oncologic outcomes and the effects on quality of life. While there have been efforts to study global and physical quality of life, the impact on psychosocial quality of life has not yet been specifically reviewed. Methods: A scoping review methodology was employed to explore the emotional, social, and mental quality of life in OPSCC patients and determine the impact of HPV status or treatment modalities. Results: Eighty-seven full-text articles were evaluated for eligibility. Fifteen articles met final inclusion criteria. The majority of the studies were conducted in the United States (n = 10) and study methodology was divided between cross-sectional (n = 6), prospective (n = 5), and retrospective studies (n = 4). Four psychosocial quality of life themes were explored: the impact on mental health and emotional wellbeing, social wellbeing and function, stress, and relationship and sexual behavior. Eighteen different patient-reported outcome measures were used, including both general head and neck oncology questionnaires and symptom-specific surveys. Conclusion: There is a paucity of research regarding the effect of OPSCC on patients' psychosocial quality of life. Learning more about this component of quality of life can guide outreach programs and multidisciplinary involvement in improving patient care.

Interpretable deep learning for chromatin-informed inference of transcriptional programs driven by somatic alterations across cancers.

Cancer is a disease of gene dysregulation, where cells acquire somatic and epigenetic alterations that drive aberrant cellular signaling. These alterations adversely impact transcriptional programs and cause profound changes in gene expression. Interpreting somatic alterations within context-specific transcriptional programs will facilitate personalized therapeutic decisions but is a monumental task. Toward this goal, we develop a partially interpretable neural network model called Chromatin-informed Inference of Transcriptional Regulators Using Self-attention mechanism (CITRUS). CITRUS models the impact of somatic alterations on transcription factors and downstream transcriptional programs. Our approach employs a self-attention mechanism to model the contextual impact of somatic alterations. Furthermore, CITRUS uses a layer of hidden nodes to explicitly represent the state of transcription factors (TFs) to learn the relationships between TFs and their target genes based on TF binding motifs in the open chromatin regions of tumor samples. We apply CITRUS to genomic, transcriptomic, and epigenomic data from 17 cancer types profiled by The Cancer Genome Atlas. CITRUS predicts patient-specific TF activities and reveals transcriptional program variations between and within tumor types. We show that CITRUS yields biological insights into delineating TFs associated with somatic alterations in individual tumors. Thus, CITRUS is a promising tool for precision oncology.

Reconstructing tumor clonal lineage trees incorporating single-nucleotide variants, copy number alterations and structural variations.

MOTIVATION: Cancer develops through a process of clonal evolution in which an initially healthy cell gives rise to progeny gradually differentiating through the accumulation of genetic and epigenetic mutations. These mutations can take various forms, including single-nucleotide variants (SNVs), copy number alterations (CNAs) or structural variations (SVs), with each variant type providing complementary insights into tumor evolution as well as offering distinct challenges to phylogenetic inference. RESULTS: In this work, we develop a tumor phylogeny method, TUSV-ext, which incorporates SNVs, CNAs and SVs into a single inference framework. We demonstrate on simulated data that the method produces accurate tree inferences in the presence of all three variant types. We further demonstrate the method through application to real prostate tumor data, showing how our approach to coordinated phylogeny inference and clonal construction with all three variant types can reveal a more complicated clonal structure than is suggested by prior work, consistent with extensive polyclonal seeding or migration. AVAILABILITY AND IMPLEMENTATION: https://github.com/CMUSchwartzLab/TUSV-ext. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Semi-deconvolution of bulk and single-cell RNA-seq data with application to metastatic progression in breast cancer.

MOTIVATION: Identifying cell types and their abundances and how these evolve during tumor progression is critical to understanding the mechanisms of metastasis and identifying predictors of metastatic potential that can guide the development of new diagnostics or therapeutics. Single-cell RNA sequencing (scRNA-seq) has been especially promising in resolving heterogeneity of expression programs at the single-cell level, but is not always feasible, e.g. for large cohort studies or longitudinal analysis of archived samples. In such cases, clonal subpopulations may still be inferred via genomic deconvolution, but deconvolution methods have limited ability to resolve fine clonal structure and may require reference cell type profiles that are missing or imprecise. Prior methods can eliminate the need for reference profiles but show unstable performance when few bulk samples are available. RESULTS: In this work, we develop a new method using reference scRNA-seq to interpret sample collections for which only bulk RNA-seq is available for some samples, e.g. clonally resolving archived primary tissues using scRNA-seq from metastases. By integrating such information in a Quadratic Programming framework, our method can recover more accurate cell types and corresponding cell type abundances in bulk samples. Application to a breast tumor bone metastases dataset confirms the power of scRNA-seq data to improve cell type inference and quantification in same-patient bulk samples. AVAILABILITY AND IMPLEMENTATION: Source code is available on Github at https://github.com/CMUSchwartzLab/RADs.

De novo Prediction of Cell-Drug Sensitivities Using Deep Learning-based Graph Regularized Matrix Factorization.

Application of artificial intelligence (AI) in precision oncology typically involves predicting whether the cancer cells of a patient (previously unseen by AI models) will respond to any of a set of existing anticancer drugs, based on responses of previous training cell samples to those drugs. To expand the repertoire of anticancer drugs, AI has also been used to repurpose drugs that have not been tested in an anticancer setting, i.e., predicting the anticancer effects of a new drug on previously unseen cancer cells de novo. Here, we report a computational model that addresses both of the above tasks in a unified AI framework. Our model, referred to as deep learning-based graph regularized matrix factorization (DeepGRMF), integrates neural networks, graph models, and matrix-factorization techniques to utilize diverse information from drug chemical structures, their impact on cellular signaling systems, and cancer cell cellular states to predict cell response to drugs. DeepGRMF learns embeddings of drugs so that drugs sharing similar structures and mechanisms of action (MOAs) are closely related in the embedding space. Similarly, DeepGRMF also learns representation embeddings of cells such that cells sharing similar cellular states and drug responses are closely related. Evaluation of DeepGRMF and competing models on Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) datasets show its superiority in prediction performance. Finally, we show that the model is capable of predicting effectiveness of a chemotherapy regimen on patient outcomes for the lung cancer patients in The Cancer Genome Atlas (TCGA) dataset*.

Joint Clustering of Single-Cell Sequencing and Fluorescence In Situ Hybridization Data for Reconstructing Clonal Heterogeneity in Cancers.

Aneuploidy and whole genome duplication (WGD) events are common features of cancers associated with poor outcomes, but the ways they influence trajectories of clonal evolution are poorly understood. Phylogenetic methods for reconstructing clonal evolution from genomic data have proven a powerful tool for understanding how clonal evolution occurs in the process of cancer progression, but extant methods so far have limited the ability to resolve tumor evolution via ploidy changes. This limitation exists in part because single-cell DNA-sequencing (scSeq), which has been crucial to developing detailed profiles of clonal evolution, has difficulty in resolving ploidy changes and WGD. Multiplex interphase fluorescence in situ hybridization (miFISH) provides a more unambiguous signal of single-cell ploidy changes but it is limited to profiling small numbers of single markers. Here, we develop a joint clustering method to combine these two data sources with the goal of better resolving ploidy changes in tumor evolution. We develop a probabilistic framework to maximize the probability of latent variables given the pre-clustered datasets, which we optimize via Markov chain Monte Carlo sampling combined with linear regression. We validate the method by using simulated data derived from a glioblastoma (GBM) case profiled by both scSeq and miFISH. We further apply the method to two GBM cases with scSeq and miFISH data by reconstructing a phylogenetic tree from the joint clustering results, demonstrating their synergistic value in understanding how focal copy number changes and WGD events can collectively contribute to tumor progression.

Tumor heterogeneity assessed by sequencing and fluorescence in situ hybridization (FISH) data.

MOTIVATION: Computational reconstruction of clonal evolution in cancers has become a crucial tool for understanding how tumors initiate and progress and how this process varies across patients. The field still struggles, however, with special challenges of applying phylogenetic methods to cancers, such as the prevalence and importance of copy number alteration (CNA) and structural variation events in tumor evolution, which are difficult to profile accurately by prevailing sequencing methods in such a way that subsequent reconstruction by phylogenetic inference algorithms is accurate. RESULTS: In this work, we develop computational methods to combine sequencing with multiplex interphase fluorescence in situ hybridization to exploit the complementary advantages of each technology in inferring accurate models of clonal CNA evolution accounting for both focal changes and aneuploidy at whole-genome scales. By integrating such information in an integer linear programming framework, we demonstrate on simulated data that incorporation of FISH data substantially improves accurate inference of focal CNA and ploidy changes in clonal evolution from deconvolving bulk sequence data. Analysis of real glioblastoma data for which FISH, bulk sequence and single cell sequence are all available confirms the power of FISH to enhance accurate reconstruction of clonal copy number evolution in conjunction with bulk and optionally single-cell sequence data. AVAILABILITY AND IMPLEMENTATION: Source code is available on Github at https://github.com/CMUSchwartzLab/FISH_deconvolution. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Accuracy of Clarius, Handheld Wireless Point-of-Care Ultrasound, in Evaluating Prostate Morphology and Volume Compared to Radical Prostatectomy Specimen Weight: Is There a Difference between Transabdominal vs Transrectal Approach?

Background: Prostate size estimation is a valuable clinical measure widely utilized in urology. This study evaluated the accuracy of preoperative transabdominal ultrasound (TAUS) compared to radical prostatectomy specimens and transrectal ultrasound (TRUS) in estimating prostate volume and identifying presence of median lobe, across different size groups, using the standard ellipsoid formula. The effect of median lobe on accuracy was also assessed. Materials and Methods: Ninety-eight men undergoing robot-assisted radical prostatectomy were enrolled in this study. Preoperative evaluation of prostate volume was done using measurements obtained from TAUS using the Clarius C3 handheld wireless point-of-care ultrasound (POCUS) and from TRUS Clarius EC7. Participants were grouped based on prostate size (<30, 30-60, and >60 g). Mean absolute percentage of error was used to evaluate accuracy. Mean percentage of error determined if there was an overestimation or underestimation. Correlation between each TAUS size group, true prostate weight and TRUS was assessed. Results: Irrespective of body mass index, TAUS accurately identified median lobe in all men. No statistically significant difference was found between specimen weight and TAUS prostate size for the >60 g group. Among this same group, a strong correlation was noted between specimen weight and TAUS prostate size (r = 0.911, p < 0.001). There was also a strong correlation between TAUS and TRUS measurements for this group (r = 0.950, p < 0.001). Presence of median lobe did not have an impact on measurement accuracy. Conclusions: Bedside handheld wireless POCUS provides rapid, inexpensive, noninvasive, and clinically accurate TAUS prostate assessments for larger prostates. Such features as identifying median lobes and measuring prostate volumes are valuable tools, whereas patient counseling on lower urinary tract symptoms, elevated prostate-specific antigen, and benign prostate hyperplasia are surgical options.

3D Collagen Vascular Tumor-on-a-Chip Mimetics for Dynamic Combinatorial Drug Screening.

Disease models, including in vitro cell culture and animal models, have contributed significantly to developing diagnostics and treatments over the past several decades. The successes of traditional drug screening methods were generally hampered by not adequately mimicking critical in vivo features, such as a 3D microenvironment and dynamic drug diffusion through the extracellular matrix (ECM). To address these issues, we developed a 3D dynamic drug delivery system for cancer drug screening that mimicks drug dissemination through the tumor vasculature and the ECM by creating collagen-embedded microfluidic channels. Using this novel 3D ECM microsystem, we compared viability of tumor pieces with traditionally used 2D methods in response to three different drug combinations. Drug diffusion profiles were evaluated by simulation methods and tested in the 3D ECM microsystem and a 2D 96-well setup. Compared with the 2D control, the 3D ECM microsystem produced reliable data on viability, drug ratios, and combination indeces. This novel approach enables higher throughput and sets the stage for future applications utilizing drug sensitivity predicting algorithms based on dynamic diffusion profiles requiring only minimal patient tissue. Our findings moved drug sensitivity screening closer to clinical implications with a focus on testing combinatorial drug effects, an option often limited by the amount of available patient tissues.

Assessing the contribution of tumor mutational phenotypes to cancer progression risk.

Cancer occurs via an accumulation of somatic genomic alterations in a process of clonal evolution. There has been intensive study of potential causal mutations driving cancer development and progression. However, much recent evidence suggests that tumor evolution is normally driven by a variety of mechanisms of somatic hypermutability, which act in different combinations or degrees in different cancers. These variations in mutability phenotypes are predictive of progression outcomes independent of the specific mutations they have produced to date. Here we explore the question of how and to what degree these differences in mutational phenotypes act in a cancer to predict its future progression. We develop a computational paradigm using evolutionary tree inference (tumor phylogeny) algorithms to derive features quantifying single-tumor mutational phenotypes, followed by a machine learning framework to identify key features predictive of progression. Analyses of breast invasive carcinoma and lung carcinoma demonstrate that a large fraction of the risk of future clinical outcomes of cancer progression-overall survival and disease-free survival-can be explained solely from mutational phenotype features derived from the phylogenetic analysis. We further show that mutational phenotypes have additional predictive power even after accounting for traditional clinical and driver gene-centric genomic predictors of progression. These results confirm the importance of mutational phenotypes in contributing to cancer progression risk and suggest strategies for enhancing the predictive power of conventional clinical data or driver-centric biomarkers.

Reasons to go for Rezum steam therapy: an effective and durable outpatient minimally invasive procedure.

PURPOSE: In this review, we will discuss the state of the literature regarding Rezum and opportunities for its application in the treatment of BPH. METHODS: A comprehensive review of original research on convective water vapor thermal therapy (Rezum) was conducted. Articles related to transurethral resection of the prostate, holmium laser enucleation of the prostate, Aquablation, and greenlight photoselective vaporization of the prostate were reviewed for discussion. RESULTS: Rezum distinguishes itself from other treatment options by its durable improvement in objective clinical outcomes such as IPSS and BPH Impact Index, while being cost-effective and versatile in its ability to treat a variety of prostate gland morphologies. This treatment option shows good lower urinary tract symptom relief, especially in small-to-moderate prostate sizes (30-80 cc). The use of convective heat transfer is unique and allows for localized treatment, avoiding damage to surrounding structures, thus providing an excellent safety profile and sexual function preservation. CONCLUSION: The current evidence on Rezum warrants its consideration as a therapeutic alternative to transurethral surgery in selected patients.

Reasons to overthrow TURP: bring on Aquablation.

PURPOSE: In this review, we will discuss the state of the literature regarding Aquablation, its limitations, and opportunities for its application in the treatment of benign prostatic enlargement (BPE). METHODS: A comprehensive review of original research on Aquablation was conducted. Articles related to transurethral resection of the prostate, holmium laser enucleation of the prostate, greenlight photoselective vaporization of the prostate, and simple prostatectomy were reviewed for discussion. RESULTS: For small-medium prostates (30-80 mL), Aquablation's main advantages include better ejaculatory function and similar functional outcomes compared to TURP. For large prostates (80-150 mL), Aquablation demonstrates shorter operative time and superior ejaculatory function when compared to simple prostatectomy, HoLEP, and Greenlight PVP. In addition, Aquablation displays shorter hospital stays than simple prostatectomy. The integration of software programming and semi-automatic technology increases the reproducibility of the procedure and helps standardize overall outcomes, while also accelerating the learning curve. Its ability to preserve antegrade ejaculation makes Aquablation a very compelling option for sexually active patients. However cost and postoperative bleeding risks remain a concern. CONCLUSION: The current evidence suggests that Aquablation is a safe and effective alternative for BPE for small to large prostates. Further prospective clinical trials, with comparisons to other BPE modalities, and data from longer follow-up periods are still required.

Detectable Prostate-specific antigen value between 0.01 and 0.1 ng/ml following robotic-assisted radical prostatectomy (RARP): does it correlate with future biochemical recurrence?

PURPOSE: The aim of the study is to evaluate the impact of having a nadir and persistently detectable ultrasensitive prostate-specific antigen (uPSA) between 0.01 and 0.1 ng/ml post-robot-assisted radical prostatectomy (RARP), on future biochemical recurrence (BCR). METHODS: We conducted a retrospective analysis of a prospectively maintained cohort of 1359 men who underwent RARP, between 2006 and 2019. Patients were followed with uPSA at 1, 3, 6, 9, 12, 18, 24, 30, 36 months and annually thereafter. We included patients with PSA nadir values between 0.01 and 0.1 ng/ml within 6 months of surgery and with at least 2 follow-up measurements within the same range. We divided patients based on their BCR status and analyzed uPSA changes. Multivariable Cox-regression models (CRMs) were used to analyze variables predicting BCR-free survival (BCR-FS). RESULTS: We identified 167 (12.3%) patients for analyses, with a mean follow-up time of 60.2 ± 31.4 months. In our cohort, 5-year BCR-FS rate was 86%. Overall, 32 (19.1%) patients had BCR, with a mean time to BCR of 43.7 ± 24.3 months. BCR-free patients had stable mean uPSA values ≤ 0.033 ng/ml, while patients who developed BCR showed a slowly rising trend over time, with a significant difference between groups starting at 9 months (p < 0.02). In multivariable CRMs, a rising uPSA starting at 9 months was an independent predictor of BCR (HR: 2.7; 95% CI 1.6-3.82; p = 0.013). CONCLUSION: In the present cohort, our results demonstrated that a considerable number of men have detectable uPSA values ranging between 0.01 and 0.1 ng/ml post-RARP. They can still be followed regularly to avoid patients' anxiety and salvage radiotherapy. Close follow-up is still required.

Reasons to believe in vaporization: a review of the benefits of photo-selective and transurethral vaporization.

PURPOSE: In the current review, we will discuss the state of the literature of vaporization of the prostate for the treatment of benign prostatic enlargement (BPE). We discuss two methods of vaporization of the prostate: Transurethral Vaporization of the Prostate (TUVP) and Greenlight Photo-selective Vaporization of the Prostate (PVP). METHODS: A comprehensive review of the literature was performed on TUVP and PVP. The literature on transurethral resection of the prostate (TURP) was also extensively reviewed as a comparative surgical method. RESULTS: The evidence shows that TUVP appears to be the safer choice, as compared to TURP due to less intra- and peri-operative complications. PVP was associated with less bleeding complications than TURP with outpatient discharge. Importantly, PVP was not associated with serious bleeding events requiring blood transfusions or medical treatment in patients under anticoagulation or antiplatelet therapies. PVP was also shown to be a cost-effective option compared to TURP. CONCLUSION: Prostate vaporization for the treatment of BPE appears to be an efficient and safer alternative to TURP. Vaporization techniques, particularly Greenlight PVP, should be offered to most men, especially those under anticoagulation therapy, as well as patients at risk of bleeding complications.