Focal high-intensity focused ultrasound (HIFU) for clinically localized prostate cancer: disease control or definitive treatment?

==inizio objective==

To report our intermediate results on the use of focal ablation for the treatment of clinically localized prostate cancer.
Thanks to the improvement of the diagnostic tools (MRI and prostatic biopsy) which has occurred in the last 10 years, the possibility of carrying out ablative treatments with high intensity focused ultrasound (HIFU) has been the natural step in the concept of precision therapy.
The HIFU technique allows to treat prostate cancer lesions effectively and with a low profile of side effects.

==fine objective==

==inizio methodsresults==

Consecutive patients with PCa treated with primary focal HIFU at our centre since 2015 were assessed. Patients were submitted to either focal ablation or zonal-ablation using HIFU (Focal One®). The primary objective of the study was to assess medium-term oncological outcomes, defined as overall survival, freedom from biopsy failure, freedom from radical treatment after focal HIFU. The secondary objective was to evaluate the changes in functional outcome referred by patients treated with focal HIFU, through validated questionnaires (IPSS, IIEF-5).

==fine methodsresults==

==inizio results==

A total of 92 focal HIFU treatment between February 2015 and May 2019 were assessed. 79 (85.9%) patients underwent to a primary treatment, 9 (9.8%) patients a second controlateral treatment (for a new lesion discovered during follow-up), 4 (4.3%) patients a re-HIFU (for disease persistence). The median age was 66 years and median prostate-specific antigen level was 6.8 ng/mL.
A total of 41% (38) had high volume Gleason 6 disease, 46% had Gleason 3+4 disease, and 13% had Gleason ≥ 4+3 disease.
The median (interquartile range) follow-up was 25 (14-40) months. The overall survival rates were 100% up to 48 months. Freedom from biopsy failure, defined as absence of prostate cancer in the treated area, was 95%. Of those that underwent a second HIFU treatment (4 re-HIFU for persistence and 9 new-HIFU for a metachronous lesion) all of them are free from disease.
Freedom from radical treatment was 96,7%, 93,4% and 91,3% at 12, 24 and 48 months.
No significant changes were recorded in the IPSS and IIEF-5 questionnaires. Postoperative complications included 1% urethral stricture, 3.2% post-HIFU THULEP, and new onset ED of 5.4%.

==fine results==

==inizio discussions==

==fine discussions==

==inizio conclusion==

New therapeutic methods have emerged in recent years as “focal” treatment alternatives greatly reducing the side effects associated with radical treatment. HIFU appears to have short or medium term cancer control, with a low complication rate comparable to that of standard treatment. Longer-term follow-up studies are needed to assess overall and specific cancer survival. If our promising results will be confirmed in future prospective studies, focal therapy could begin to challenge the current standard of care.

==fine conclusion==

==inizio reference==

J Endourol. 2017 Apr;31(S1):S30-S37. High-Intensity Focused Ultrasound for the Treatment of Prostate Cancer: A Review. Chaussy CG, Thüroff S.
J Urol. 2018 Sep;200(3):512-519. Prostate Ablation Using High Intensity Focused Ultrasound: A Literature Review of the Potential Role for Patient Preference Information. Babalola O, Lee TJ, Viviano CJ.
Curr Opin Urol. 2017 Mar;27(2):138-148. High-intensity focused ultrasound for focal therapy: reality or pitfall?
Schulman AA, Tay KJ, Robertson CN, Polascik TJ.

==fine reference==

THE ROLE OF MULTIPARAMETRIC RISONANCE AND FUSION BIOPSY IN PROSTATE CANCER DETECTION: THE “NEW ERA” OF MINIMALLY INVASIVE APPROACH WITH HIGH DIAGNOSTIC ACCURACY COMPARED WITH DEFINITIVE HISTOPATHOLOGICAL SPECIMEN AFTER LAPAROSCOPIC/ROBOTIC RADICAL PROSTATECTOMY

==inizio objective==

The diagnosis of PCa is determined by histopathology of the biopsy taken in case of clinical suspicion, high PSA level and abnormal digital rectal examination (DRE). The current standard technique for PCa detection is transrectal and trans perineal ultrasound-guided biopsy (TRUS-GB/ TRUS-TP) and many strategies for prostate biopsy have been described, but the gold standard remains to be the 10-12 core format under transrectal ultrasound (TRUS) guidance. Developments of multiparametric MRI (mpMRI) techniques have increased the sensitivity of imaging for PCa8. Clinical guidelines advise performing an mpMRI when initial TRUS biopsy results are negative but the suspicion of PCa persists9. Usage of a 3 Tesla (3-T) magnet has further enhanced resolution and quality of imaging compared with 1.5-T 10. The Prostate Imaging-Reporting and Data System (PI-RADS) classification was introduced in 2012 by the ESUR, and has recently been updated to version 2.0.The aim of the study is to evaluate the diagnostic accuracy of mpMRI side of lesion and MRI/US fusion biopsy compared to final hystopatologic after the radical prostatectomy.
The main endpoint is to evaluate the correlation between mpMRI suspicious area, fusion/standard biopsy and histopathological definite specimens after radical prostatectomy.

==fine objective==

==inizio methodsresults==

We collected data about 65 patients with suspicious PCa undergoing targeted Biopsy prostatic transrectal Fusion from March 2018 to September 2019 at the Hospital Pederzoli, Peschiera del Garda (Vr) Italy. We analyzed the following information:
– Anagraphical: age, informed consent
– PSA before the mpMRI
– Urological examination: DRE
– Prostate volume at MRI (ml)
– Number of previous biopsies
– mpMRI: PIRADS score, lesion(s) position(s)
– Histological examination of the prostate biopsies: number of cores, Gleason score or ASAP, total involvement by cancer and the side of positive core (right or left sides).
– Definitive histopathological examination on the surgical specimen: T stage and localization. The correspondence between Gleason score at the fusion and/or random biopsy and at the definitive examination was assessed.
We created an excel database (named DB FUSION PEDERZOLI) and used the same sheet for collecting the data of patients who underwent radical prostatectomy after positive biopsy.
All statistical analysed were conducted using SPSS software (version 25, SPSS Inc.,Chicago, IL). Chi-square tests were used to calculate the relations between respectively: laterality of target lesion at MRI and at biopsy; laterality of target lesion at MRI and at definitive histologic report; laterality at biopsy and definitive histologic report; laterality of biopsy and definitive histologic report; PIRADS score and definitive histologic report; Gleason score at biopsy and definitive histologic report; PIRADS score and Gleason score at biopsy. Relation between variables was considered significant for p<0.05. All results were also reported as bar charts. All data were analyzed with chi square test and were statistical significant with p<0.05.

1. Multiparametric magnetic resonance (mpMRI) and type of machine.
We used a Ultrasound Hitachi Arietta V70 and Stereotactic Navigated Biopsy Biopsee for fusion of MRI. All patients underwent MP-MRI on a 1.5-T and 3.0-T MRI. Prior to biopsy, an MP-MRI was interpreted by the radiologists; the images were segmented, and lesion locations were recorded. Patients with lesions identified on MP-MRI underwent a targeted biopsy performed by one operator.
All biopsies were carried out at the Urology Clinic –Pederzoli Hospital following a standardized protocol. T2-weighted axial, sagittal and coronal sequences of the mpMRI were uploaded into a MRI/US fusion device (Hitachi Arietta v70 with integrated real-time ultrasonography) and the suspicious lesions were marked in the 3 planes using the RVS software. The targeted biopsy was performed with the previously identified MP-MRI lesions overlap using the T2-weighted sequence on the real-time TRUS images. Each lesion was sampled both in axial and sagittal planes by an Bi-Convex TRUS probe (Fig.8-9-10).
The standard biopsy was typically 16 cores collected in an extended-sextant template of biopsies from the lateral and medial aspects of the base, mid, and apical prostate on the left and right side14.

==fine methodsresults==

==inizio results==

A total of 60 patients underwent mpMRI fusion biopsy and radical prostatectomy during the study period. 65% patients with suspicious area on the right side on mpMRI had a concordance with the positive core biopsy. In the 70% of cases with suspicious area on the left side, had a concordance with the positive core biopsy: in patients with bilateral lesions on mpMRI there were a concordance of 100% with the positive core biopsy (p <0.000). However, mpMRI missing respectively 35% and 30% cases of bilateral cancer, confirmed at biopsy cores but described as unilateral on mpMRI. The laterality to the definitive histology was confirmed in 50% of the patients who showed a right laterality to prostatic biopsy and in 35.7% of the patients who showed a left laterality to the prostatic biopsy. Furthermore, the concordance is 100% in patients who showed the presence of suspected bilaterally lesions (p 7. PIRADS score 5 was associated with a total GS of 7 in 53.3%, while in 26.7% of cases was 8 and only in 10% of cases was >7. Moreover in another 10% of cases was negative or associated with ASAP (p=0.015).

==fine results==

==inizio discussions==

MpMRI is increasingly used as a tool to improve the diagnostic pathway for prostate cancer. Recently more studies have provide evidence to support a large use of mpMRI, the detection and characterization of PCa is more accurate when the lesion was previously identified using mpMRI specially in biopsy-naïve patients, thus reducing the number of unnecessary biopsies. PRECISION trial randomized biopsy-naïve patients with clinical suspicion of PCa to undergo mpMRI followed or not by target biopsy or upfront standard biopsy. In this study, despite an improved detection rate with mpMRI and fusion biopsy, there is a small number of patients in whom negative target biopsy was revealed to be a false negative on saturation biopsy or showed upgrade at saturation biopsy when compared to target biopsy19. PROMIS study proposed the use of mpMRI as a ‘triage’ test, therefore avoiding prostate biopsy in 27% of the patients and the diagnosis of non-CSPCa clinically-significant PCa in 5%. However, any mpMRI suspicious lesion needs to be confirmed by biopsy prior to any further therapeutic decision20. Another study by Siddiqui et al. showed that target biopsy is able to detect PCa with a higher GS compared to standard biopsy or to upgrade the GS of a cancer already detected at standard biopsy15. This study have a led a fraction of patients with CSPCa is still missed by target biopsy, in fact Muthigi et al 16 hypothesized four different mechanisms explaining why a CSPCa could be missed or downgraded at target biopsy; Failing to identify the lesion at a first exam with detection in a second exam, failing to identify a suspicious area at mpMRI, failing to biopsy accurately the lesion detected at mpMRI for technical problem during registration, heterogeneity of the intralesional Gleason score. This can be true especially for large tumors where an larger intralesional heterogeneity can be expected; target sampling and random sampling could therefore give a different representation of the various grading areas present in the same tumor 17. From the result of the study, we learned that the Fusion biopsy is a complex procedure influenced by various factors, experience of the operator, contouring of prostate in first step of procedure, by the eye-hand coordination of the operator during navigation, the adjustment of the image coupling in case of patient’s movement or deformation of the prostate during the procedure. We show target and standard saturation biopsy are complementary in the diagnosis of PCa in setting of biopsy-naïve patient. In this moment the guidelines do not support the execution of exclusively target biopsies because the risk of missing a CSPCa and our experience support this idea. In case of patients with previous negative biopsy the fusion technique improve the diagnostic accuracy of standard biopsy, with similar result of patients under Active surveillance. Several different studies have evaluated the ability of mpMRI to detect CSPCa comparing the imaging results with the definitive histopathology at RP. A work by Turkbey et al 18 aimed to evaluate the detection rate of cancer for 3T mpMRI, with sensitivity and specificity evaluate the influence of tumor volume and GS on the sensitivity of mpMRI. The results showed that mpMRI was more sensitive in cancers > 5 mm and GS > 7, thus confirming the adequacy of the imaging study for CSPCa detection. Moreover, the correlation analysis between mpMRI, fusion biopsy and GS at RP histopathology represents a further tool for evaluating the diagnostic accuracy of mpMRI. A study by Siddiqui et al 14 showed that target biopsy significantly improved the prediction of Gleason grade and risk group at definitive RP pathology. Of 170 included patients, 17 were positive at standard.
LIMITATIONS
The main limitation of the present study is the reduced number of patients in each subgroup. Therefore, the observations drawn from the analysis do not have statistical significance and should be regarded as trends rather than as conclusions. Another possible limitation could be seen in the fact that not all the mpMRI were carried out in our hospital: 145/267 patients of the general database and 60 in the RP subgroup. To overcome this limitation, all the external scan were assessed for quality (and, if minimal standard not met, excluded from the analysis) and the reviewed by dedicated uro-radiologists. Another problem in studies dealing with fusion biopsy is how to define CSPCa: in the absence of an universally-supported definition, the comparison between different studies is very difficult. Finally, another technical limitation is the difference between the maps used by the radiologist and the pathologist for reporting. The 39 regions sector map provided PIRADSv2 and used by the radiologist did not show concordance with the macro-sections used by the pathologists and there is a risk for mismatch when comparing the position of lesions in mpMRI and pathology. In the future this will need to be improved through the use of a shared map allowing radiologist and pathologist to speak the same language.

==fine discussions==

==inizio conclusion==

Regarding the ability of mpMRI-targeted sampling to identify cancer compared to random biopsy according to the current literature show improve on detection rate of PCa. Our analysis showed that the most frequent PCa patients have bilateral tumors, despite resonance and biopsy report homolateral lesions. Data suggest the existence of a positive correlation among PIRADS score at mpMRI and Gleason score at definitive histological examination. The multidisciplinary approach with radiologist and urologist is important to obtain an analysis very close to reality.

==fine conclusion==

==inizio reference==

1. Ferlay, J. et al. Reprint of: Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur. J. Cancer (2015). doi:10.1016/j.ejca.2015.05.004
2. Siegel RL, Miller KD, J. a. Cancer Statistics,2015. CA Cancer J Clin (2015).
3. T., R. et al. PSA screening of black veterans before, during, and after implementation of the 2012 us preventative services task force recommendations. J. Urol. (2018).
4. Brierley, J. D., Gospodarowicz, M. K. & Wittekind, C. TNM classification of malignant tumours – 8th edition. Union for International Cancer Control (2017). doi:10.1002/ejoc.201200111
5. Epstein, J. I. et al. The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. in American Journal of Surgical Pathology (2005). doi:10.1097/01.pas.0000173646.99337.b1

==fine reference==

THE COST OF ROBOT-ASSISTED LAPAROSCOPIC PROSTATECTOMY. ECONOMIC EVALUATIONS AT A REFERRAL CENTRE

==inizio objective==

Since the introduction of robotic surgery for radical prostatectomy, the cost-benefit of this technology has been under scrutiny (1, 2). While robotic surgery has shown to offer multiple advantages, including reduced blood loss, reduced length of stay, and expedient recovery, the associated costs tend to be significantly higher, secondary to the fixed cost of the robot as well as the variable costs associated with instrumentation. This study analyzes the cost of robotic prostatectomy in a referral center and compares it to the DRG reimbursement amount.

==fine objective==

==inizio methodsresults==

Our experienced surgical team performed robotic assisted laparoscopic prostatectomy (RALP) at the Multidisciplinary Centre for Robotic Surgery of Pisa Hospital. A retrospective analysis of patients who underwent RALP for prostate cancer was performed: preoperative, operative and post-operative costs were evaluated.

==fine methodsresults==

==inizio results==

According to our analysis, preoperative assessment cost € 111.0. The total amount of the operative phase was € 5693,0, including € 801,0 for surgical team, € 1110,4 for surgical room and € 3781,8 for medical devices and drugs. Post-operative period was estimated to cost € 739.0. Hence, a total amount of € 7852,0 per patient submitted to RALP was estimated.

==fine results==

==inizio discussions==

While potential benefits of robotic technology include decreased morbidity and improved recovery, some have suggested a prohibitively high cost. According to a recent revision of the Regional Government of Tuscany, the DRG reimbursement amount has been raised from € 4234.0 to € 9677.0 leading to a positive financial balance for the hospital of € 1824.9. Before this modification took place, considering the DRG reimbursement of € 4234.0, the financial loss per patient was € 3618,0.

==fine discussions==

==inizio conclusion==

Robotic technology in prostate cancer surgery has shown to offer several advantages in comparison to open procedure; however the higher cost of robotic surgery has been matter of debate in the recent years. The recent modification of the DRG reimbursement allows the hospital to offer patients an excellent treatment avoiding the loss of a significative amount of money

==fine conclusion==

==inizio reference==

1. Ramsay C, Pickard R, Soomro N et al. Systematic review and economic modelling of the relative clinical benefit and cost‐effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer. Health Technol Assess 2012; 16: 1– 313

2. Hughes D, Camp C, O’Hara J, Adshead J. Health resource use after robot‐assisted surgery vs open and conventional laparoscopic techniques in oncology: analysis of English secondary care data for radical prostatectomy and partial nephrectomy. BJU Int 2016; 117: 940– 7

==fine reference==

Primary transrectal random prostate biopsy: is still actual?

==inizio objective==

Random prostate biopsy is still the gold standard procedure to detect prostate cancer. Multiparametric MRI has been introduced to guide target prostate biopsy to improve detection of clinically significant prostate cancer. Today is debated whether primary biopsy should be performed with random or target approach. We evaluated outcomes of patients undergone first transrectal random prostate biopsy. We also evaluated predictive factors of prostate cancer diagnosis.

==fine objective==

==inizio methodsresults==

Patients with suspicious of prostate cancer based on PSA, DRE, ultrasound findings underwent a TRUS guided transrectal biopsy. Procedure were performed under local anaesthesia or intravenous sedation as indicated. Clinical and pathological data were prospectively collected from May 2010 to September 2019 in our database. We calcolated cacer detection rate and we identified predicitve factors of cancer. Statistical analysis was performed using Chi square test, Mann Whitney, logistic regression test, as appropriate (SPSS 19).

==fine methodsresults==

==inizio results==

Data on 1974 patients were available. Patients characteristics are reported in table 1. Indications for biopsy are reported in table 2. Prostate cancer has been diagnosed in 46.4% of the patients (table 3). Positive patients presented ≥3 positive cores or Gleason ≥3+4 in 78,5% and 86,7%, respectively. At multivariate analysis, age, PSA, DRE, prostate volume, number of cores, and year of biopsy are predictive of cancer diagnosis (tab 4).

==fine results==

==inizio discussions==

Random prostate biopsy is still the gold standard procedure to detect prostate cancer. Multiparametric MRI has been introduced to guide target prostate biopsy to improve detection of clinically significant prostate cancer. Today is debated whether primary biopsy should be performed with random or target approach

==fine discussions==

==inizio conclusion==

Random transrectal prostate biopsy identified cancer in 46% of all patients. In the last three years, cancer detection rate is more than half of the patients. More than three quarters of patients presented a clinically significant cancer. Age, PSA, positive DRE, prostate volume and number of cores are correlated with presence of cancer

==fine conclusion==

==inizio reference==

==fine reference==

Pelvic floor Muscle Training after Radical Prostatectomy: is there any differences when we compare retropubic radical prostatectomy with laparoscopic radical prostatectomy?

==inizio objective==

To evaluate the effectiveness of pelvic floor muscle training (PFMT) for treating urinary incontinence (UI) after radical prostatectomy (RP), both retropubic radical prostatectomy (RRP) and videolaparoscopic radical prostatectomy (VLRP).

==fine objective==

==inizio methodsresults==

Between February 2016 and May 2019, a total of 60 patients with different grades of UI have been retrospectively examined to understand if there were any differences in the effectiveness of PFMT between patients underwent RRP (30 patients) versus VLRP (30 patients) at Urological Clinic of “Madonna delle Grazie” hospital, in Matera, Italy. Median age was 66,8±6,1 years and median BMI was 27,1±3,2. Inclusion criteria were: diagnosis of localized prostate cancer (stage between T0 and T3c and Gleason 6-9), nerve sparing technique when indicated, absence of UI before surgery, BMI 5pads/die) was observed in 6,7% of RRP patients (ICIQ-SF medium score 18) vs 16,7% of VLRP patients (ICIQ-SF medium score 17,8). After three months: 83,3% of RRP patients achieved continence or had a low grade UI (0-2 pads/die, ICIQ-SF medium score 6,22) vs 86,7% of VLRP patients (ICIQ-SF medium score 6,15); medium grade of UI (3-4 pads/die) was obeserved in 16,7% of RRP patients (ICIQ-SF medium score 15,2) vs 13,3% of VLRP patients (ICIQ-SF medium score 15,25); no patients had high grade UI. After six months: 93,3% of both RRP and VLRP patients achieved continence or had low grade UI (ICIQ-SF medium score 4 vs 4,27); 3,3% (1 patient) of both group had medium grade UI (ICIQ-SF medium score 14 in both RRP and VLRP patients); high grade UI was observed in 3,3% (1 patient) of both RRP and VLRP group (ICIQ-SF medium score 21 vs 18).

==fine results==

==inizio discussions==

Open retropubic radical prostatectomy has been the “gold standard” treatment for locally confined prostate cancer (PCa) but in recent years minimal invasive techniques as laparoscopy and robot-assisted prostatectomy have become widely available. The trifecta of the surgical treatment of PCa is cancer control, the preservation of continence, and erectile potency (1). Incontinence after RP (P-RP-I) varies widely (2% to <60%) according to the definition and quantification of incontinence, timing of evaluation, and who evaluates (physician or patient) (2). Conservative treatments, including pelvic floor muscle training (PFMT), anal electrical stimulation (AES), lifestyle adjustment, or combination are usually recommended at first for P-RP-I (3). In our study we compare the benefits of PFMT on P-RP-I after retropubic radical prostatectomy and after laparoscopic radical prostatectomy. We found an earlier (after 1 month) recovery of continence in patients underwent retropubic radical prostatectomy vs laparoscopic approach but, after 6 months the results were the same. Just one patient in RRP group and one patient in VLRP group manifested a high grade UI at six months, but they both had adjuvant radiotherapy.

==fine discussions==

==inizio conclusion==

As is known, PFMT is an effective treatment for urinary incontinence in men after radical prostatectomy (4). There were no differences between RRP group patients and VLRP group patients in terms of long-term results.

==fine conclusion==

==inizio reference==

(1). Van Poppel H et al. Asian J Urol 2019 Apr;6(2):125-128. (2). O’Callaghan ME et al. Prostate Cancer Prostatic Dis. 2017 Dec;20(4):378-388. (3). EAU Guidelines 2019. (4). MacDonald R et al. BJU Int. 2007 Jul;100(1):76-81.

==fine reference==

Laparoscopic treatment of a big urinoma after RARP

==inizio abstract==

Nowadays robotic prostatectomy (RARP) is performed increasingly with improved precision and fewer post -operative complications. Despite the miniinvasivilly technique, linfocele and urinoma remain the most complex and severe complications and the most challenging problem is to resolve and treat it. 
In this video we present a case of a 59-year-old man who underwent a RARP and after 15 Post – op days complained a left ureteral fistula and a big abscessualized urinoma (14 x 10 cm) between bladder and rectum and an homolateral perirenal extravasation of contrast.
We performed a laparoscopic complete drainage of the urinoma and irrigation of the cavity. Samples were obtained for bacterial culture and drug testing.
In literature urinoma and ureteral fistula rates are not widely reported, and it is usually reported with urinary leakage, at rates of 2.4%. The most cause is represented by anastomotic leakage and only in rare case it is necessary to perform a surgery revision.
In order to avoid this complication, and eventually treat it faster, maybe an accurate post- operative imaging is necessary to check the pelvis status following RARP.
In our case, the percutaneous aspiration of the urinoma was not a safe procedure for the presence of ileal adherence and laparoscopic drainage remained a safe and minimally invasive approach.

==fine abstract==

ADAR1 is highly expressed in primary prostate cancer and correlated with CD8+ T-lymphocytes density

==inizio objective==

It is now recognized that the evolution of cancer cells is dependent by genetic or epigenetic alterations. However, this concept has recently been challenged by another mode of nucleotide alteration, RNA editing, which is frequently upregulated in cancer(1) RNA editing is a biochemical process in which either Adenosine or Cytosine is deaminated by a group of RNA editing enzymes including ADAR (Adenosine deaminase; RNA specific) The result of RNA editing is usually adenosine to inosine (A-to-I) or cytidine to uridine (C-to-U) transition, which can affect protein coding, RNA stability, splicing and microRNA-target interactions(2). The aim of this study was to preliminarily investigate the expression of ADAR1 in a series of prostate cancer specimens and benign prostatic hyperplasia (BPH) following transurethral resection of the prostate (TURP).

==fine objective==

==inizio methodsresults==

Sixty prostate specimens were investigated. Fifty specimens were diagnosed as prostate carcinoma and 15 as benign prostate hyperplasia. The samples were fixed in 10% formaldehyde and paraffin-embedded. Two-micrometer thick sections were cut and processed for immunohistochemistry with primary antibodies raised against ADAR1 (SantaCruz Biotechnology, Dallas, TX, USA) or CD8+ T-lymphocytes (Dako, Milan, Italy). 3,3’-Diaminobenzidine tetrahydrochloride was used as a chromogen to yield brown reaction products. To quantify the surface covered by infiltrating CTLs each histological section was digitized using an automated image analysis system with incorporated ad hoc constructed image analysis software. The system automatically selected the surface covered by the CTL on the basis of red, green and blue (RGB) color segmentation.

==fine methodsresults==

==inizio results==

ADAR1 up-regulation was heterogeneously detected in a high percentage of prostate cancer tissues, but to a much lesser extent in adjacent non-malignant tissues or tissue affected by BPH (p <0.001). Prostate cancers with high ADAR1 expression exhibited high tumor-infiltrating CD8 + T lymphocyte. ADAR expression is associated with several diseases including cancer, neurological disorders, metabolic diseases, viral infections, and autoimmune disorders

==fine results==

==inizio discussions==

This study first shows that ADAR1 is highly expressed in a high percentage of prostate cancer tissues, but to a much lesser extent in adjacent non-malignant tissues or tissue affected by benign prostatic hyperplasia. Additionally, prostate cancers with high ADAR1 expression exhibited high tumor-infiltrating CD8 + T lymphocyte

==fine discussions==

==inizio conclusion==

Our findings indicated that ADAR1 might play an important role in the occurrence, progression, and prognosis of prostate cancer, and open new ways for the development of new and more effective immunological therapeutic strategies.

==fine conclusion==

==inizio reference==

1) A-to-I RNA editing in leukemia stem cells – set ADAR1 on the radar. Jiang Q, Diep R, Jamieson C.
Oncotarget. 2019 Oct 22;10(58):6047-6048. doi: 10.18632/oncotarget.27261. eCollection 2019 Oct 22

2) IL6R-STAT3-ADAR1 (P150) interplay promotes oncogenicity in 1q21(amp) multiple myeloma.
Teoh PJ, Chung TH, Chng PYZ, Toh SHM, Chng WJ.
Haematologica. 2019 Aug 14. pii: haematol.2019.221176. doi: 10.3324/haematol.2019.221176.

==fine reference==

Video content analysis of 20 robot-assisted laparoscopic prostatectomies for evaluating potential mechanisms of iatrogenic nerve lesions and preventive practical suggestions

==inizio objective==

Robot-assisted laparoscopic prostatectomy (RALP)[1]is the most frequent strategy used for the surgical remedy of patients with localized prostate cancer. Although there is awareness about potential patient positioning nerve injuries, iatrogenic nerve lesions are less described in the literature [2]. Here, we report 3 cases of patients who presented with neuropathic painful complications due to RALP-associated nerve lesions.

==fine objective==

==inizio methodsresults==

A 62-year-old patient (case 1), a 72-year-old male (case 2), and a 57-year-old patient (case 3) presented at the clinic with symptoms of neuropathic pain after RALP surgery.
Patients were diagnosed with a potential injury of different branches of the pudendal nerve (cases 1 and 2), and left obturator nerve (case 3).
Patients underwent multimodal pharmacologic treatment through pregabalin, weak opioids, strong opioid, paracetamol, and adjuvants. In cases 2 and 3, a multidisciplinary approach was needed. As the patients responded to conservative treatment, invasive approaches were not necessary.

==fine methodsresults==

==inizio results==

After treatment, the patients of case 1 showed pain relief after 4 days, paresthesia resolved in 15 days, whereas the anal crushing sensation lasted for approximately 1 month. In case 2, after 4 weeks of treatment, the patient experienced a considerable decrement in pain intensity with complete response after 4 months. In case 3, pain relief was achieved after 2 days, motor symptoms recovery after 2 weeks, and neuropathic features resolved completely after 5 weeks although the obturator sign resolved within 2 months.

==fine results==

==inizio discussions==

During RALP surgery, a wide range of surgical injury to the pelvic nerves may occur. The pathophysiology of these damages recognizes different mechanisms such as compression (e.g., due to hematoma or pelvic lymphoceles), transection, incision, traction, thermal injuries, entrapment with clips.
The evaluation of possible risk factors is of fundamental importance both for the prevention of complications and for their rapid identification and treatment [3-6]. In case 1, the damage to the inferior rectal nerve occurred for thermal injury or traction on straight during the preparation procedure of the backplane, or during Rocco stitch. The complication was probably also related to the extent of prostatic pathology, as reported by the definitive histologic examination. The extent of the pathology, therefore, was certainly a major risk factor. Concerning the mechanism of neuropathy responsible for the clinical picture described in the second case, it can be explained as a possible injury occurred during the running stitch and the additional suture of Santorini plexus. The bilateral nerve damage may explain the severity of the neuropathic painful condition, whereas the presence of a particularly represented plexus and a connective tissue at the pubic symphysis represented a considerable risk factor. Case 3 regards a lesion of the left obturator nerve. This nerve originates from the ventral rami of the 2nd, 3rd, and 4th lumbar nerve roots. It follows the iliopectineal line into the lesser pelvis, runs along the lateral pelvic wall and then enters into the obturator foramen via the obturator canal. Within the canal, the nerve divides into an anterior branch, posterior branch, and a branch to the external obturator muscle then. Then, it exits through the obturator tunnel and enters the thigh. The sensory distribution of the nerve encompasses the anteromedial hip joint, the medial knee joint, and the skin on the inner thigh just above the medial knee from the anterior branch. The obturator nerve injury is described as a rare complication of robotic-assisted PLND. Because the obturator nerve can be adherent to lymph nodes or enclosed by them, a careful nerve mobilization should be performed, and fixed lymph nodes should not be mobilized roughly. Specifically, the proximal part of the obturator nerve runs closely the external iliac vein and the internal iliac artery. This is the location of the internal iliac lymph nodes. In our case, we suppose that the nerve damage was caused during the extensive PLND through a thermal injury of the nerve at the entrance of the obturator fossa . Alternatively, a compressive effect on the nerve was produced by a PLND-induced lymphocele. The combination of both mechanisms seems to be another plausible explanation. According to this latter hypothesis, the early multimodal pain strategy and antiedematous therapy may explain the rapid resolution of the clinical picture [7-8].
Several suggestions focused on improving surgical technique and aimed at avoiding neurologic complications can be proposed. Firstly, the thermal energy should be minimized by using bipolar output energy <35 and <50 W in monopolar. Furthermore, hemostasis through microsutures (e.g., 4-0 brainded absorbable suture CV-25 TAPER 1/2 circle 17 mm Polysorb; Covidien) can represent a less invasive approach. Other suggestions concern the use of titanium clip during dissection, Rocco stitch (e.g., 3-0 V-Loc barbed absorbable suture GU-46 TAPER 5/8 circle 27 mm; Covidien) performed not through full-thickness modality. Finally, because the different branches of the pudendal nerve run laterally and dorsal to the rectum it should be recommended to minimize traction maneuvers during the procedure of prostate detachment.

==fine discussions==

==inizio conclusion==

The RALP-associated neurologic injuries may occur even when performed by highly experienced surgeons. A better understanding of the potential iatrogenic nerve lesions can surely allow an improvement in the surgical technique. A multidisciplinary approach and early multimodal pain strategy are mandatory for managing these complications.

==fine conclusion==

==inizio reference==

1. Du Y, Long Q, Guan B, et al. Robot-assisted radical prostatectomy is more beneficial for prostate cancer patients: a system review and meta-analysis. Med Sci Monit 2018;24:272–87
2. Ahmed F, Rhee J, Sutherland D, et al. Surgical complications after robot-assisted laparoscopic radical prostatectomy: the initial 1000 cases stratified by the Clavien classification system. J Endourol 2012;26:135–9.
3. Novara G, Ficarra V, D’Elia C, et al. Prospective evaluation with standardised criteria for postoperative complications after robotic-assisted laparoscopic radical prostatectomy. Eur Urol 2010;57:363–70
4. Ou YC, Yang CR, Wang J, et al. The learning curve for reducing complications of robotic-assisted laparoscopic radical prostatectomy by a single surgeon. BJU Int 2011;108:420–5.
5. Ou YC, Yang CK, Chang KS, et al. Prevention and management of complications during robotic-assisted laparoscopic radical prostatectomy following comprehensive planning: a large series involving a single surgeon. Anticancer Res 2016;36:1991–8.
6. Murphy DG, Bjartell A, Ficarra V, et al. Downsides of robot-assisted laparoscopic radical prostatectomy: limitations and complications. Eur Urol 2010;57:735–46.
7. Maerz DA, Beck LN, Sim AJ, et al. Complications of robotic-assisted laparoscopic surgery distant from the surgical site. Br J Anaesth 2017;118:492–503.

==fine reference==

Physical Activity decreases the risk of cancer progression in patients on active surveillance: a multicenter retrospective study

==inizio objective==

Active surveillance (AS) is a viable and recommended option for men diagnosed with low-risk (LR) prostate cancer (PCa). However, a non-negligible share of them will receive radical treatments within 10 years due tof disease progression. Exercise has been shown to delay PCa upgrading/upstaging in animal models but its role in humans remains unclear. In the present study, we assessed the effect of physical activity on disease progression in a cohort of patients on AS.

==fine objective==

==inizio methodsresults==

Two participating institutions shared data from their prospectively maintained AS databases in the context of the PRIAS (Prostate Cancer Research International Active Surveillance) protocol.
Baseline demographic, anthropometric, clinical and pathologic data were collected. All patients had no more than 2 Gleason score 6 positive cores at biopsy, baseline PSA <10 ng/mL and PSA density <0.2. A validated PASE (Physical Activity Scale for the Elderly) score was provided to patients for a self-assessment ofg physical activity. Sedentary lifestyle was accordingly stratified into three classes: mild (PASE ≥ 120), moderate (45120), severe (PASE ≤45).
Disease progression (DP) was defined as PCa upgrading and/or upstaging. Chi square and Mann-Withney tests compared categorical and continuous variables, respectively. Uni-/multivariable Cox regression analyses assessed predictors of DP. Kaplan-Meier method was performed to estimate the predictive role of the three Sedentary lifestyle classes on the same outcome.

==fine methodsresults==

==inizio results==

Overall, 85 patients were included in the analysis with a median age of 66 (IQR 59-70) years and a BMI of 25.3 (23.5-27). Overall, 14 (16%) were active smokers, 7 (8%) were obese and one presented with metabolic syndrome. Median PASE score was 86 (61.5-115.8). DP occurred in 29% (n=25) of patients. Patients who experienced DP were comparable to those who did not for all baseline variables but PASE score (69.3 vs 87.8; p=0.05). Univariable Cox regression analysis identified physical activity as the only significant predictor of DP (HR 0.98, 95%CI 0.97-0.99, p=0.014). At Kaplan Meier analysis PASE stratification effectively depicted the risk of upgrading/upstaging during AS (log rank p=0.028).

==fine results==

==inizio discussions==

==fine discussions==

==inizio conclusion==

Physical activity, assessed by means of the validated PASE questionnaire, represents a significant driver of PCa upgrading/upstaging during AS. Results from the upcoming randomized controlled trials are awaited to confirm our data.

==fine conclusion==

==inizio reference==

==fine reference==

Androgen receptor copy number and circulating tumor cells as liquid biopsy profiling in castration resistant prostate cancer patients treated with cabazitaxel

==inizio objective==

Cabazitaxel demonstrated overall survival (OS) benefit for the treatment of metastatic castration resistant prostate cancer (mCRPC) patients progressing after docetaxel [1]. Predictive biomarkers able to identify responsive patients are urgently needed to improve outcome of mCRPC patients. Liquid biopsy, including circulating plasma DNA and circulating tumor cells (CTCs), has the potential to guide treatment decision. Plasma androgen receptor (AR) copy number (CN) status has been identified as one of potential biomarker of response in patients with mCRPC receiving docetaxel [2] or the AR-targeted therapies (abiraterone or enzalutamide) [3]. CTCs profiling could also help to establish novel biomarkers. In this study (NCT03381326), we aimed to evaluate the prognostic role of plasma AR CN and CTCs biomarkers expression in mCRPC patients treated with cabazitaxel.

==fine objective==

==inizio methodsresults==

We included patients receiving cabazitaxel from January 2015 to December 2018. Progressive disease was defined according to Prostate Cancer Working Group 2 (PCWG2) criteria. Plasma DNA was isolated using QIAamp Circulating Nucleic Acid Kit and digital PCR was performed to assess AR CN status. CTCs enrichment was evaluated with AdnaTest EMT-2/StemCell kit. Expression analyses using real time PCR were performed for 17 genes and CTCs positivity was defined as the expression of at least one of the following seven relevant markers: AR-V7, AKT, AR, EPCAM, PSMA, PI3KCA, PSCA. This study is partially funded by Sanofi Genzyme.

==fine methodsresults==

==inizio results==

We enrolled 80 patients, all receiving prior docetaxel and 85% prior abiraterone and/or enzalutamide. Median age was 72 years (range 49-82). Median OS and progression-free survival (PFS) were 16.4 months (95% CI 11.1-27.0) and 6.7 months (95% CI 5.2-8.3), respectively. Baseline plasma AR CN gain was detected in 36 (45%) patients. AR CN normal and AR CN gain patients had a OS of 27 and 11.1 months, respectively (p=0.013). AR CN normal and AR CN gain patients had a PFS of 8.5 and 5.9 months, respectively (p=0.032). Fifty-eight (72.5%) patients showed CTCs positivity at baseline, whose 15 (26%) expressed >3 markers in CTCs. Significantly worse OS was observed in patients with >3 markers expressed in CTCs compared to those with ≤3 markers and CTCs negative patients [4.7 months vs 15.2 vs 31.7 months respectively, hazard ratio 6.05 (95% CI 2.07-17.73), p=0.004]. No significant difference was observed for PFS and PSA response. Twenty-eight patients showed AR CN gain and CTCs positivity, whose 9 expressed ≥3 markers, whereas 30 patients showed AR CN normal and CTCs positivity, whose 6 expressed ≥3 markers. No significant correlation between AR CN and CTCs positivity was found (p=0.3130). Expression analyses on CTCs biomarkers are ongoing.

==fine results==

==inizio discussions==

In this study we have investigated the role of AR CN and CTCs positivity in stratifying mCRPC patients treated with cabazitaxel. We found significantly worse OS and PFS in patients with AR CN gain compared to AR CN normal. These results are in line with those found in a recent multicenter study [4]. Moreover, we observed a significantly shorter OS in patients expressing >3 markers compared to the others, showing the importance to characterize CTCs expression markers. Although no significant correlation was found between AR CN and CTCs positivity, ongoing expression analyses could reveal potential responsive or more aggressive tumors, leading to a better personalized treatment selection.

==fine discussions==

==inizio conclusion==

Liquid biopsy profiling, beyond any single biomarker, may improve prognostication of mCRPC patients treated with cabazitaxel. Further prospective larger studies are needed to validate the results.

==fine conclusion==

==inizio reference==

[1] De Bono J. S. et al., Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial, Lancet, 2010.
[2] Conteduca V. et al., Plasma Androgen Receptor and Docetaxel for Metastatic Castration-resistant Prostate Cancer., Eur Urol. 2019.
[3] Conteduca V et al., Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study. Ann Oncol., 2017.
[4] Conteduca V et al., Plasma AR status and cabazitaxel in heavily treated metastatic castration-resistant prostate cancer, Eur. J. Cancer, 2019.

==fine reference==