Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma-A Proof of Principle Study.

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1-13C]pyruvate (HP-13C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP-13C-MRI and conventional proton (1H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant (kPL) between 13C-pyruvate and 13C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing kPL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset (p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP-13C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP-13C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.

A call for HoLEP: AEEP for mega-prostates (≥ 200 cc).

PURPOSE: To evaluate the efficiency and efficacy of HoLEP, and methods of tissue retrieval, in patients with prostate volume (PV) ≥ 200 cc (Group 1) and to compare these to patients with PV 80-199 cc (Group 2). METHODS: A database of all cases performed under the care of two surgeons at a tertiary HoLEP centre was reviewed. RESULTS: 157 patients with PV ≥ 200 cc were compared to 157 of the most recent consecutive cases with PV 80-199 cc. Median (IQR) enucleation efficiency was greater in Group 1 [2.8 g/min (2.2-3.5)] than Group 2 [2.1 g/min (1.6-2.5), p < 0.001]. Morcellation efficiency did not differ significantly. Cystotomy was required for tissue retrieval in Group 1 only (5.7%). Decrease in serum haemoglobin (Hb) was greater in Group 1 (19 g/l (30-8) vs 12 (18-3.5), p < 0.001) with a transfusion rate of 4.5% vs 1.3%, respectively (p = 0.104). Length of stay was longer in Group 1 than Group 2 (1 day (1-2) vs 1 (1-1), p < 0.001). There were no significant differences between groups in: time to and success of first trial without catheter, pre- and post-operative IPSS, Qmax and PVR, and 3 month catheter-free and urinary incontinence rates. CONCLUSION: HoLEP outcomes are largely PV-independent even when PV is ≥ 200 cc, although length of stay and reduction in Hb are greater in this group. Alternatives to pure morcellation, such as cystotomy and resection of nodules, are more likely to be necessary with PV ≥ 200 cc.

Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors.

BACKGROUND: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. METHODS: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. RESULTS: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. CONCLUSIONS: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.

The VENUSS prognostic model to predict disease recurrence following surgery for non-metastatic papillary renal cell carcinoma: development and evaluation using the ASSURE prospective clinical trial cohort.

BACKGROUND: The current World Health Organization classification recognises 12 major subtypes of renal cell carcinoma (RCC). Although these subtypes differ on molecular and clinical levels, they are generally managed as the same disease, simply because they occur in the same organ. Specifically, there is a paucity of tools to risk-stratify patients with papillary RCC (PRCC). The purpose of this study was to develop and evaluate a tool to risk-stratify patients with clinically non-metastatic PRCC following curative surgery. METHODS: We studied clinicopathological variables and outcomes of 556 patients, who underwent full resection of sporadic, unilateral, non-metastatic (T1-4, N0-1, M0) PRCC at five institutions. Based on multivariable Fine-Gray competing risks regression models, we developed a prognostic scoring system to predict disease recurrence. This was further evaluated in the 150 PRCC patients recruited to the ASSURE trial. We compared the discrimination, calibration and decision-curve clinical net benefit against the Tumour, Node, Metastasis (TNM) stage group, University of California Integrated Staging System (UISS) and the 2018 Leibovich prognostic groups. RESULTS: We developed the VENUSS score from significant variables on multivariable analysis, which were the presence of VEnous tumour thrombus, NUclear grade, Size, T and N Stage. We created three risk groups based on the VENUSS score, with a 5-year cumulative incidence of recurrence equalling 2.9% in low-risk, 15.4% in intermediate-risk and 54.5% in high-risk patients. 91.7% of low-risk patients had oligometastatic recurrent disease, compared to 16.7% of intermediate-risk and 40.0% of high-risk patients. Discrimination, calibration and clinical net benefit from VENUSS appeared to be superior to UISS, TNM and Leibovich prognostic groups. CONCLUSIONS: We developed and tested a prognostic model for patients with clinically non-metastatic PRCC, which is based on routine pathological variables. This model may be superior to standard models and could be used for tailoring postoperative surveillance and defining inclusion for prospective adjuvant clinical trials.

Holmium Laser Enucleation of the Prostate: Simulation-Based Training Curriculum and Validation.

OBJECTIVE: To evaluate the face, content, and construct validity of a novel virtual reality simulator for holmium laser enucleation of the prostate (HoLEP) and to assess its feasibility and acceptability as a training model. METHODS: This prospective observational study recruited 53 participants, comprising of 3 groups: HoLEP experts (n = 11), intermediates (n = 24), and novices (n = 18). All participants received an educational package and a 15-minute familiarization exercise with the simulator. All participants then carried out a full enucleation on an identical 60 cm(3) virtual prostate. Performance was assessed using in-built simulator metrics, and a questionnaire was distributed assessing face and content validity, as well as feasibility, and acceptability. Novice, intermediate, and expert groups were compared using the Mann-Whitney U test. RESULTS: Construct validity data revealed significant differences in enucleation efficiency (grams enucleated per hour) when comparing experts to intermediates (P = .003), experts to novices (P <.001), and intermediates to novices (P = .001). Face validity was rated by experts as acceptable, with a mean score of 5.6 out of 10 when asked to rate the overall realism. Content validity questions showed that 85% of participants agreed that simulator-based assessment is essential for patient safety and 87% agreed that there was a role for a validated virtual reality simulator for use in HoLEP training. CONCLUSION: This study established face, content, and construct validity for this novel virtual reality HoLEP simulator. The majority of participants also thought that it is a feasible and acceptable model for HoLEP training.

Holmium laser enucleation of the prostate: a paradigm shift in benign prostatic hyperplasia surgery.

Holmium laser enucleation (HoLEP) was developed in the 1990s as a more efficient and cost effective method of benign prostatic hyperplasia surgery than laser vaporization and resection techniques. As a true anatomical enucleation it mimics open prostatectomy and is as durable. There is a significant body of level 1 evidence in support of HoLEP, including 2 meta-analyses and 14 randomized trials which compare HoLEP with a number of other procedures. This review describes the development of and summarizes the evidence for HoLEP.

Current techniques for laser prostatectomy -PVP and HoLEP / Técnicas actuales para la prostatectomía láser-PVP y HoLEP

Objectives: The objective of this review is to provide an evidence-based update on laser surgery for BPH with a focus on comparing Greenlight Photoselective Vaporisation of the Prostate (PVPj to Holmium Laser Enucleation of the Prostate (HoLEP). Methods: We reviewed all HoLEP and PVP papers identified by a Pubmed search using the keywords: laser, prostate, BPH, holmium, HoLEP, PVP and greenlight. The published randomised trials investigating HoLEP and PVP are summarised. As there are no head to head randomised trials comparing HoLEP to PVP, we compare data from individual HoLEP and PVP papers. Data on multiple aspects of laser surgery for BPH are summarised and contrasted for the 2 procedures including: Perioperative management, subjective and objective measures of success, complications, sexual function, prostate volume reduction, durability, and surgery for men with large prostates and those in urinary retention. Results/Conclusions: PVP and HoLEP are very different laser techniques. An important difference between the Green-light laser and holmium and thulium is that its only urological application is prostate ablation. HoLEP is the most advanced laser technique currently available. In contrast to PVP, it has been rigorously evaluated in 8 randomised trials. It is a size independent procedure suitable for any prostate, and highly effective at treating urinary retention. HoLEP has been reported to be durable to periods up to 6 years. More tissue is removed with HoLEP than PVP, and this raises concerns regarding the long term durability of PVP for which there is no comparable data. The increase in HoLEP expertise world-wide and the development of lasers that are faster at ablating tissue and have other urological uses (eg thulium) may threaten the longevity of Greenlight PVP (AU)

Objetivo: El objetivo de ésta revisión es ofrecer una puesta al día basada en la evidencia sobre cirugía láser para el tratamiento de la HBP, enfocada a la comparación entre vaporización fotoselectiva con láser verde (PVP) y la enucleación prostática con láser de Holmio(HoLEP). Métodos: Revisamos todos los artículos sobre HoLEP y PVP identificados en una búsqueda bibliográfica en PubMed utilizando los términos: láser, próstata, HBP, Holmio, HoLEP, PVP, y luz verde. Como no existen ensayos clínicos aleatorizados comparando directamente HoLEP y PVP comparamos los datos de artículos individuales de cada técnica. Se resumen y contrastan los datos de múltiples aspectos de la cirugía láser de la HBP mediante ambos procedimientos incluyendo: manejo perioperatorio, medidas objetivas y subjetivas de éxito, complicaciones, función sexual, reducción del volumen prostático, durabilidad y cirugía en varones con próstatas grandes y pacientes con retención urinaria. Resultados/Conclusiones: La PVP y la HoLEP son técnicas láser muy diferentes. Una diferencia importante entre el láser de luz verde y los de Holmio o Tulio es que su única aplicación es la ablación prostática. La técnica de enucleación con láser de Holmio es la técnica láser más avanzada disponible actualmente. En contraste con la fotovaporización ha sido rigurosamente evaluada en ocho ensayos clínicos. Es un procedimiento independiente del tamaño prostático, válido para cualquier próstata, altamente eficaz en el tratamiento de la retención urinaria. Se ha comunicado que la enucleación prostática con láser de Holmio es duradera hasta seis años. Se quita más tejido con la HOLEP y con la PVP y esto suscita una preocupación en cuanto a la duración a largo plazo del resultado de la PVP, de la que no existen datos comparables. El aumento de la experiencia con HoLEP en todo el mundo y el desarrollo de láseres más rápidos en la ablación de tejidos y con otros usos urológicos (Ej tulio) puede amenazar la supervivencia de la PVP con láser de luz verde (AU)

Current techniques for laser prostatectomy--PVP and HoLEP.

OBJECTIVES: The objective of this review is to provide an evidence-based update on laser surgery for BPH with a focus on comparing Greenlight Photoselective Vaporisation of the Prostate (PVP) to Holmium Laser Enucleation of the Prostate (HoLEP). METHODS: We reviewed all HoLEP and PVP papers identified by a Pubmed search using the keywords: laser, prostate, BPH, holmium, HoLE, PVP and greenlight. The published randomised trials investigating HoLEP and PVP are summarised. As there are no head to head randomised trials comparing HoLEP to PVP, we compare data from individual HoLEP and PVP papers. Data on multiple aspects of laser surgery for BPH are summarised and contrasted for the 2 procedures including: Perioperative management, subjective and objective measures of success, complications, sexual function, prostate volume reduction, durability, and surgery for men with large prostates and those in urinary retention. RESULTS/CONCLUSIONS: PVP and HoLEP are very different laser techniques. An important difference between the Greenlight laser and holmium and thulium is that its only urological application is prostate ablation. HoLEP is the most advanced laser technique currently available. In contrast to PVP, it has been rigorously evaluated in 8 randomised trials. It is a size independent procedure suitable for any prostate, and highly effective at treating urinary retention. HoLEP has been reported to be durable to periods up to 6 years. More tissue is removed with HoLEP than PVP and this raises concerns regarding the long term durability of PVP for which there is no comparable data. The increase in HoLEP expertise worldwide and the development of lasers that are faster at ablating tissue and have other urological uses (eg thulium) may threaten the longevity of Greenlight PVP.

Holmium laser enucleation of the prostate: results at 6 years.

OBJECTIVES: The issue of durability is an important concern when evaluating new surgical modalities. To date, only 24-mo data have been published on holmium enucleation of the prostate (HoLEP) despite its widespread use worldwide although 4-yr data exist for the earlier technique of holmium resection. This study addresses the issue of durability of HoLEP. METHODS: All patients who had undergone HoLEP and been evaluated in three prospective trials conducted at this institution between 1997 and 2002 were evaluated. Patients available at follow-up had data assessed on the International Prostate Symptom Score (IPSS), maximal flow rate (Qmax), quality of life (QOL), International Continence Society Male Short Form (ICS-SF), International Index of Erectile Function (IIEF), Benign Prostatic Hyperplasia Impact Index (BPHII), and continence questionnaire. RESULTS: The mean follow-up was 6.1 yr (range: 4.1-8.1 yr). The mean age of the patients at follow-up was 75.7 yr (range: 58-88 yr). Of 71 HoLEP patients originally studied on the protocol, 38 (54%) were available for analysis, 14 were deceased, and 19 were lost to follow-up. The mean IPSS for this group was 8.5 (range: 0-24) and Q(max) 19 ml/s (range: 6-28 ml/s). The QOL score was 1.8 (range: 0-5) and the BPHII 2.0 (range: 0-11). One patient (1.4%) had undergone reoperation, an additional HoLEP. Overall, 92% were either satisfied or extremely satisfied with their outcome. CONCLUSIONS: HoLEP is durable and most patients remain satisfied or extremely satisfied with the long-term outcome.

Holmium laser bladder neck incision versus holmium enucleation of the prostate as outpatient procedures for prostates less than 40 grams: a randomized trial.

PURPOSE: Bladder neck incision (BNI) is a common, minimally invasive treatment option for bladder outflow obstruction in men with a small prostate. We compared BNI using the holmium:YAG laser to holmium enucleation of the prostate (HoLEP) in a prospective, randomized, urodynamically based trial. MATERIALS AND METHODS: A total of 40 patients with urodynamic obstruction (Schafer grade 2 or greater) and a prostate of 40 gm or greater on transrectal ultrasound (TRUS) were randomized equally to holmium laser BNI (HoBNI) or HoLEP as an outpatient procedure. The outcomes assessed were operative time, catheter time and hospital time. American Urological Association and quality of life scores, and maximal urinary flow rates were measured at baseline, and 1, 3, 6 and 12 months postoperatively, while pressure flow studies and TRUS volume measurement were performed at baseline and 6 months. RESULTS: The 2 groups were well matched for all variables at baseline. HoBNI was significantly more rapid to perform than HoLEP (p <0.001). Two patients (10%) in the HoBNI group required recatheterization compared with none in the HoLEP group. There was no significant difference in catheter time (22.9 vs 23.2 hours) or hospital time (12.3 vs 13.7 hours) between the groups. Five patients remained obstructed urodynamically at 6 months. All were in the HoBNI group and 4 of the 5 men had a prostate that was greater than 30 gm. Four of these patients required HoLEP for persistent lower urinary tract symptoms. In the remaining unoperated patients there were no significant differences in American Urological Association and quality of life scores or in the maximal urinary flow rate at each assessment. At 6 months detrusor pressure at maximal urinary flow was significantly lower (p <0.05) and TRUS volume was significantly smaller (p <0.001) in the HoLEP group There was significantly more early stress incontinence postoperatively in the HoLEP group but no bladder neck contractures were detected. CONCLUSIONS: Relief of obstruction was better after HoLEP and fewer patients required recatheterization or reoperation, although more reported early postoperative stress incontinence. Catheter time, hospital time and perioperative morbidity were similar. HoBNI and HoLEP are safe and feasible as outpatient procedures in patients with a small prostate but HoBNI is more rapid to perform.

Laser therapy for benign prostatic hyperplasia: a review of recent developments.

PURPOSE OF REVIEW: Over the past 10-15 years a variety of endoscopic laser techniques have evolved for the treatment of benign prostatic hyperplasia. The laser is merely an energy source with the ability to coagulate, incise, vaporize, resect and dissect (enucleate), all fundamentally different procedures. Generalization regarding "laser prostatectomy" is therefore inappropriate. The potential for shorter hospital stays and decreased morbidity while maintaining the efficacy and durability of transurethral resection of the prostate has been the driving force behind the laser techniques that acutely remove tissue, whereas the ideal minimally invasive non-tissue removing laser technique is a well-tolerated office procedure, performed under local anaesthesia. We define the various laser techniques currently available for the treatment of benign prostatic hyperplasia, and review developments reported during the period July 2001 to July 2002. RECENT FINDINGS: Although there are few long-term data available on laser techniques, more medium-term data is emerging. Issues such as cost-effectiveness and applicability to certain sub-groups of patients are being investigated as each laser technique aims to find its own niche in the ever-expanding treatment armamentarium for benign prostatic hyperplasia. SUMMARY: Satisfactory moderate term results are now available for several minimally invasive laser techniques including interstitial laser coagulation and visual laser ablation of the prostate. There are promising early results for holmium laser enucleation of the prostate and potassium titanyl-phosphate, which have the potential to rival transurethral resection if proved durable in the long-term. Holmium laser enucleation is currently a serious contender for the "gold standard" for large prostates.