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  Table of Contents 
EDITORIAL
Year : 2022  |  Volume : 38  |  Issue : 1  |  Page : 3-6
 

Round up


Department of Urology, AIIMS, Bhubaneshwar, Odisha, India

Date of Web Publication1-Jan-2022

Correspondence Address:
Swarnendu Mandal
Department of Urology, AIIMS, Bhubaneshwar, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/iju.iju_460_21

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How to cite this article:
Mandal S. Round up. Indian J Urol 2022;38:3-6

How to cite this URL:
Mandal S. Round up. Indian J Urol [serial online] 2022 [cited 2022 Jan 29];38:3-6. Available from: https://www.indianjurol.com/text.asp?2022/38/1/3/334610



   The Emerging Role of Dual Tracer Fludeoxyglucose-Prostate-Specific Membrane Antigen Positron Emission Tomography–Computed Tomography in Carcinoma Prostate Top


The prostate-specific membrane antigen (proPSMA) study inferred that the accuracy of 68Ga- PSMA positron emission tomography–computed tomography (PET/CT) was 27% higher than that of combined CT and bone scintigraphy.[1] However, some prostate cancer (PCa) tumors have low PSMA activity, evading PSMA-PET detection, and fludeoxyglucose (FDG) PET could pick these tumors.

Chen et al. retrospectively studied 72 patients with biochemical recurrence and negative 68Ga-PSMA PET/CT.[2] The concomitant 18F-FDG PET/CT done was found to be positive in 16.7% (12/72) patients. Multivariate analysis showed that prostate-specific antigen (PSA) ≥2.3 ng/mL and Gleason score ≥8 correlated with 18F-FDG-positive findings (P < 0.001 and P = 0.015, respectively). The probabilities of 18F-FDG-positive findings in the low-potential (PSA <2.3 ng/ml and Gleason score <8), moderate potential (PSA ≥2.3 ng/ml or Gleason score ≥8, but not both), and high potential (PSA ≥2.3 ng/ml and Gleason score ≥8)) groups were 0%, 11.5%, and 90% (9/10), respectively (P < 0.001). Thus, dual-tracer PET/CT can help characterize high-risk disease during primary staging and restaging. In advanced PCa disease, FDG-positive disease and concurrently negative PSMA PET have a poor prognosis. Further studies are required for validation and selective incorporation into therapeutic clinical trials.


   Prognostic Value of Preoperative Neutrophil to Lymphocytes Ratio in Histological Variant of Nonmuscle-Invasive Bladder Cancer Top


At diagnosis, while non-muscle invasive bladder cancer (NMIBC) accounts for 70%–75% of bladder cancer, variant histology (VH) is seen in 15%–25%.VH is more aggressive and linked to a worse prognosis. There is a need to identify criteria that can be used to stratify VH to aid in making suitable decisions. Preoperative neutrophil to lymphocyte ratio (PNLR) has been seen to predict prognosis in NMIBC, but its role in VH-NMIBC is unknown. The purpose of this study was to see if the PNLR has any predictive significance in patients with VH-NMIBC.[3]

A total of 243 patients planned for TURBT were analyzed at a single center from January 2009 to May 2019 in a retrospective study. The best cut-off value for PNLR measured by receiver operating characteristic curve and Youden index was taken as 2.2 (usually 2–3 in NMIBC) and determined two weeks before surgery. The Kaplan–Meier method and Cox proportional hazard regression models were used to assess the relation between PNLR and disease prognosis.

Patients with high PNLR had a worse prognosis, including recurrence-free survival, progression-free survival (PFS), cancer-specific survival, and overall survival than patients with low PNLR (P < 0.001). Therefore, relation of PNLR to prognosis could help in therapeutic decision and identifying patients for more aggressive treatment, such as early radical cystectomy. The study is a retrospective analysis with data derived from a hospital information system. Prospective clinical studies with robust data are required to offer a greater level of proof.


   Prolieve Transurethral Thermodilatation – An Option for Treating Symptomatic Benign Prostatic Hyperplasia Top


Prolieve (TUTD) is the only available third-generation transurethral microwave therapy system that incorporates the delivery of temperature-regulated microwave energy, balloon dilation/compression of the prostatic urethra, and urethral cooling, enabling effective prostate tissue ablation at lower power under local anesthesia. Olweny et al. assessed the 5-year outcomes of Prolieve in an open-label, prospective multicenter trial to treat symptomatic benign prostatic hyperplasia (BPH) for the prostate size of 20–80 g without a median lobe.[4]

This study included 220 patients with a mean age of 65 ± 8.8 years, prostate size 41.4 ± 14.5 gm, AUASS 20.1 ± 5.9, QOL 22.0 ± 4.5, and Qmax 8.6 ± 2.6 mL/s. The mean treatment duration was 47 (±3.4) minutes, with a peak rectal temperature of 40.9 ± 1.2°C. Overall, 34 patients (15.5%) required catheterization after treatment for a median duration of 4 days. AUASS, QOL, Qmax, and BPH impact index scores significantly improved from baseline within 3 months, with continued improvements to 5 years. The cumulative 5-year surgical retreatment rate was 14.2% (95% confidence interval 9.5–20.8). Transient urinary urgency and dysuria were the most common adverse effects. Authors conclude that Prolieve is a safe and effective therapeutic option for BPH, with long-term improvements in voiding symptoms, urinary flow rates, low catheterization rate, and rare sexual side effects.

The main limitations were a significant attrition rate of >50% (131 patients) and the non-generalizability of the results to all prostate sizes. However, the study provides acceptable and effective results for the limited patients.


   Belzutifan: A Novel Oral Drug for Renal Cancer in von Hippel Lindau Disease Top


von Hippel–Lindau (VHL) disease is an autosomal dominant disorder associated with a tumor suppressor gene mutation on Chromosome three, leading to constitutive activation of hypoxia-inducible factor (HIF-2)-alpha, and in turn, upregulation of growth factors. The most common tumors associated are renal cell carcinoma, pancreatic lesions, cerebellar hemangioblastoma, and retinal hemangiomas. These neoplasms are currently managed with resection or ablation to reduce metastasis and disease burden. These patients have a lifelong risk of tumors, and most undergo several surgical procedures with considerable comorbidity. An effective nonsurgical alternative may reduce the surgical burden on these patients.

Belzutifan is an oral HIF-2-alpha inhibitor studied at a dose of 120 mg daily in a phase-2, open-label, single-group, multicentric trial, enrolling 61 patients.[5] Patients were 18 years and older with germline VHL mutation and at least one measurable RCC 1–3 cm with no metastatic disease with ECOG of 0 or 1. The primary end-point was objective response measured according to RECIST v1.1, with 49% showing partial response and 49% having stable disease. At 24 months, PFS was seen in 96%. At the patient level, the median growth rate of the tumor decreased from 3.6 mm/year to 3.7 mm/year. Objective response was observed in 77% of pancreatic lesions and 30% of CNS hemangioblastomas. The most common adverse events were anemia, fatigue, headache, and dizziness.

The study's limitations were the absence of a control group and a small sample size. Reduction in tumor size results in fewer indications for surgery, and cost-benefit analysis with a randomized controlled trial (RCT) is required.


   Disparate Genomic Profiles of Prostate Cancer Tissue and Liquid Biopsies Top


PCa is a heterogeneous disease with emerging novel targeted therapies and evolving mechanisms of therapy resistance, requiring personalized treatment based on tumor genomic profiling. Metastatic tissue biopsies though desirable, may not always be achievable in clinical practice, and genomic profiling of circulating tumor DNA (ctDNA) from liquid biopsies may be a noninvasive alternative. Necchi et al. reported heterogeneity in the genomic alterations (GAs) detected in the primary tumors, metastatic sites, and ctDNA.[6]

Biopsies of primary tumors/metastatic sites (n = 1200) and ctDNA liquid biopsies (n = 2400) were analyzed, revealing a high rate of GAs in TP53, PTEN, RB1, BRCA2, and AR (androgen receptor) genes, and variability in the frequencies of these alterations between the sample types. GAs in AR were 2% in primary tumors, 33% in metastatic sites ranging from 24% in lungs to 50% in liver metastases, and 31% in the ctDNA. Brain metastases had the highest concentration of GAs, especially for PTEN.

Biomarkers associated with response to immune checkpoint inhibitors were CDK12 GAs (16% in lung metastases) and microsatellite instability-high status (29% in brain metastases). Biomarkers of defects in homologous recombination repair (BRACA2, ATM) were associated with the efficacy of poly ADP-ribose polymerase inhibitors. The frequency of BRCA2 GAs ranged from none in the brain to 15% in liver metastases. Tumor suppressor gene RB1 alterations were highest in liver metastases (30%).

Overall concordance was observed in the GA frequencies between the tissue biopsies of metastatic sites and the ctDNA liquid biopsies. The authors concluded that the observed heterogeneity in the genomic profiles of primary tumors and metastases might be linked to tumor progression or evolution and natural selection under exposure to systemic therapies. Moreover, ctDNA liquid biopsies can serve as a non-invasive real-time representative of the PCa genomic profile, replacing metastatic tissue biopsies and increasing the odds of detecting a targetable GA.


   Intraprostatic Depot Antiandrogens for Patients on Active Surveillance Top


Among men with low-to-intermediate-risk PCa on active surveillance (AS), around 40% undergo definitive treatment within ten years, primarily because of disease upgrading. There is a growing interest in a non-morbid treatment option for this subset of patients to delay disease progression. LiprocaTM Depot (LD) is an intraprostatic depot injection of the antiandrogen 2-hydroxyflutamide (2-HOF), with a gradual release over 6 months. A multicenter phase 2b single-blind RCT evaluated the safety and efficacy of LD in men with low to intermediate-risk PCa (Gleason score of 3 + 3 or 3 + 4 and PSA ≤20 ng/ml) assigned to AS.[7]

Research part-1 (n = 20) assessed the safety and tolerability of high-dose LD, with a dosage of either 35% or 45% of prostate volume (5–24 ml, 1150–5520 mg 2-HOF), distributed equally between both prostate lobes. Research part-2 (n = 41) assessed the efficacy of a fixed-dose of 16 or 20 ml (3680 or 4600 mg 2-HOF) injected close to the prostatic lesions. PSA response was defined as a PSA reduction of more than 15%.

All doses were well tolerated with no hormonal adverse events, transient urinary retention in 20%, and prostatitis in 10%. At 5 months, the PSA response rate was more significant with 16 ml dosage (57% vs. 40%), with a mean PSA decrease of 14% and 95% of patients having some PSA reduction. Overall, 78% of patients showed a decrease in prostate volume. Prostate mpMRI and biopsies confirmed stable or decreased lesion size. The authors concluded that LD is safe, well-tolerated, and may halt disease progression while avoiding systemic hormonal adverse effects.


   TR-4 Nuclear Receptor and Docetaxel Resistance in Prostate Cancer Top


Docetaxel is a well-established treatment modality for mCRPC. Treatment response is variable, with non-responders amounting to up to 50%. The reason is unknown, and it is impossible to predict treatment response with the available tools. TR4 is a nuclear receptor that is probably responsible for PCa progression. However, the mechanism and the involved signaling pathways are not well known.

Linyi et al. investigated the expression of TR4 in PCa cell culture, benign prostatic tissue culture, and clinical tissue sample after docetaxel chemotherapy.[8] TR4 expression was upregulated in mCRPC who had received docetaxel chemotherapy with a higher-level conferring chemoresistance. Cancer cell lines were inserted with a luciferase at the target gene of the TR4 receptor, which acted as an indicator of cell replication. This system was used to test the effect of Bexarotene, an inhibitor of TR4. Bexarotene suppressed TR4 transactivation and this increased docetaxel chemosensitivity. A gene correlation analysis revealed that TR4 might alter the docetaxel chemosensitivity by modulating the TR4/lincRNA-p21/HIF-1a/VEGF-A signaling. The results open up an opportunity to synergistically use Bexarotene to improve response to docetaxel chemotherapy. Bexarotene is a retinoid and is FDA approved for cutaneous T-cell lymphoma. It is also used off-label for lung cancer and breast cancer.


   Altering The Tumor Micro-Environment to Enhance Prostate Cancer Treatment Top


Recently, there have been great strides in the treatment of PCa. The most recent additions to the armamentarium are immuno-oncology agents. However, many patients progress, and the probable reason is the hijacking of the tumor microenvironment by the PCa cells. Regulatory cells are a population of T-cells that suppress the immune system and are thought to be the reason for the failure of immunotherapy.

Firdaus et al. studied the in vivo and in vitro effects of a combination of S-nitrosoglutathione (GSNO) and colony-stimulating factor-1 inhibitor (CSF1Ri).[9] The GSNO-CSF1Ri combination decreased the population of the T-regulatory cell (T-regs) and myeloid-derived suppressor cells and inhibited the transformation of monocytes into anti-inflammatory macrophages. The decrease in the tumor burden was more significant with the combination compared to either of the drugs alone. The combination also suppresses several important growth-promoting cytokines such as interleukin-12, oncostatin, BLC, FGF4, GCP2, IGFBP3, IP-10, and TGFB3.

A combination of GSNO and CSF1Ri prevents the polarization of macrophages into T-regs, which may improve the response to immune checkpoint therapy.

 
   References Top

1.
Hofman MS, Lawrentschuk N, Francis RJ, Tang C, Vela I, Thomas P, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): A prospective, randomised, multicentre study. Lancet 2020;395:1208-16.  Back to cited text no. 1
    
2.
Chen R, Wang Y, Shi Y, Zhu Y, Xu L, Huang G, et al. Diagnostic value of 18F-FDG PET/CT in patients with biochemical recurrent prostate cancer and negative 68Ga-PSMA PET/CT. Eur J Nucl Med Mol Imaging 2021;48:2970-7.  Back to cited text no. 2
    
3.
Li DX, Wang XM, Tang Y, Yang YB, Feng DC, Li A, et al. Prognostic value of preoperative neutrophil-to-lymphocyte ratio in histological variants of non-muscle-invasive bladder cancer. Investig Clin Urol 2021;62:641-9.  Back to cited text no. 3
    
4.
Olweny EO, Jow SL, Jow WW. Prolieve transurethral thermodilatation for treatment of symptomatic benign prostatic hyperplasia: 5-year results from a prospective multicenter trial. J Endourol 2021. [doi: 10.1089/end.2021.0240] Last Accessed December 16, 2021  Back to cited text no. 4
    
5.
Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med 2021;385:2036-46.  Back to cited text no. 5
    
6.
Necchi A, Cucchiara V, Grivas P, Bratslavsky G, Jacob J, Spiess PE, et al. Contrasting genomic profiles from metastatic sites, primary tumors, and liquid biopsies of advanced prostate cancer. Cancer 2021;127:4557-64.  Back to cited text no. 6
    
7.
Klotz L, Grudén S, Axén N, Gauffin C, Wassberg C, Bjartell A, et al. Liproca depot: A new antiandrogen treatment for active surveillance patients. Eur Urol Focus 2021; S2405-8.  Back to cited text no. 7
    
8.
Hu L, Sun Y, Luo J, He X, Ye M, Li G, et al. PD05-02 targeting TR4 nuclear receptor with antagonist bexarotene increases docetaxel sensitivity to better suppress the metastatic castration-resistant prostate cancer progression. J Urol. 2021;206 Suppl 3:e55-6.  Back to cited text no. 8
    
9.
Firdaus F, Kuchakulla M, Soni Y, Qureshi R, Van BD, Shah K, et al. Pd05-04 increased nitric oxide suppresses macrophage polarization to augment the effect of csfr1 inhibition therapy against castration resistant prostate cancer. J Urol 2021;206 Suppl: e56-7.  Back to cited text no. 9
    




 

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