==inizio objective==

In the era of minimally invasive surgery, partial adrenalectomy has been certainly underused. We aimed to report
on postoperative and early functional outcomes of a two-center robotic partial adrenalectomy (RPA) series.

==fine objective==

==inizio methodsresults==

From June 2014 to June 2017 RPA was performed on 10 consecutive patients affected by aldosterone-secreting adenomas. Preoperative,
postoperative and early functional outcomes data were prospectively collected and reported.

==fine methodsresults==

==inizio results==

All cases were completed robotically. Median nodule size was 18,1 mm (range 10-30) (Table 1). Intraoperative blood loss was negligible,
postoperative course was uneventful in 9 cases; a single (10%) postoperative Clavien grade 2 complication occurred (fever requiring antibiotics); mean hospital
stay was 3,6 days (range 2-13). Patients became normotensive immediately after surgery (mean preoperative blood pressure: 152/93 mmHg; mean postoperative
blood pressure: 120/71 mmHg, respectively). None of the patients required further hypotensive treatment (Table 2).
Aldosterone and plasmatic renin activity (PRA) levels decreased and returned within the normal range after surgery (mean post-operative aldosterone: 152 pg/ml [
normal range: 17.6-232] and mean post-operative PRA:2.4 ng/ml h [range: 0.2–2.8], respectively). At one-yr follow-up, all patients were normotensive and
hypotensive treatment free.

==fine results==

==inizio discussions==

In the era of minimally invasive surgery, partial adrenalectomy has been certainly underused, and adrenal masses are treated through robotic total adrenalectomy [1]. We reported safety and feasibility of robotic partial adrenalectomy for patients with aldosterone-secreting adenomas.

==fine discussions==

==inizio conclusion==

RPA is a safe, feasible and minimally invasive surgical approach. The excellent perioperative and early functional outcomes suggest
an increasing adoption of this technique in the near future.

==fine conclusion==

==inizio reference==

1. Robotic assisted adrenalectomy: Surgical techniques, feasibility, indications, oncological outcome and safety.
Yiannakopoulou E.
Int J Surg. 2016 Apr;28:169-72. doi: 10.1016/j.ijsu.2016.02.089. Epub 2016 Feb 27. Review

==fine reference==

==inizio objective==

RCC is a potentially lethal cancer with aggressive behaviour, and has a propensity for distant metastatic spread.
Up to one-third of patients with newly diagnosed RCC have metastatic diseases [1].
Furthermore,more than 30% of patients with localized disease will develop metastases after nephrectomy, and have a poor 5-year survival rate below 10% [2].
The earlier detection of metastases can offer more opportunities to act early and elicit a better therapeutic effect, especially when the metastatic lesion is confined and isolated. Conventional imaging procedures for staging and restaging of RCC patients commonly consist of computed tomography, MRI, and bone scintigraphy.
Positron emission tomography (PET)/CT is a powerful noninvasive tool used for characterizing solid tumors. Currently, clinical PET imaging for metastatic RCC is primarily obtained through metabolic imaging with Fluorodeoxyglucose (FDG)-PET/CT used for staging and assessing treatment response [3].
For the clear cell subtype (ccRCC), there is growing interest in non-FDG molecular imaging agents that may have greater sensitivity and specificity and may potentially add phenotypic information for patient/tumor-specific treatment strategies.
Prostate specific membrane antigen (PSMA) is a 750 amino acid, type II transmembrane glycoprotein that has been shown to be over-expressed in both prostate cancer cells and the vasculature of solid tumours [4].
PSMA is highly expressed in the proximal tubules of normal kidney tissues, and specifically in the neovasculature of ccRCC (75%), chromophobe (31%), oncocytoma (53%) and transitional cell carcinoma (21%) [5].
Due to the enzymatic activity of PSMA it was possible to develop specific inhibitors from which “small molecule” radiopharmaceuticals were derived. Recently methods have been developed to label PSMA ligands with 68Ga enabling PET/CT imaging to detect prostate cancer by targeting the extracellular domain of PSMA.
The most widely used PSMA-ligand for PET-imaging in Europe is a 68Ga-labelled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC ([68Ga]-PSMA-HBED-CC).
In this study, we evaluate the diagnostic potential of [68Ga]-PSMA-HBED-CC PET/CT (PSMA-PET/CT) in restaging patients with ccRCC.

==fine objective==

==inizio methodsresults==

Ten patients with ccRCC were submitted to PSMA-PET/CT exam In order to verify the real staging of the disease or for inconclusive results of conventional imaging.
Synthesis of [68Ga]-PSMA-HBED-CC was performed using a fully automated module (Scintomics GRP®, Fuerstenfeldbruck, Germany) and 68Ga was obtained from a IGG100 68Ge/68Ga generator (Eckert & Ziegler, E&Z, Berlin, Germany). Our method to assess the radiochemical and chemical purity of [68Ga]-PSMA-HBED-CC was previously validated [6-7]. The mean yield of labelling reaction was 65.53% and the radiochemical purity 99.90% .
Whole body PET/CT was acquired, from vertex to medium thigh of the femur. 60 min after i.v. injection of [68Ga]PSMA-HBED-CC (150 MBq) on a hybrid scanner Discovery IQ (GE Healthcare). In all patients, a non-diagnostic CT was acquired for attenuation correction.
Tracer uptake was evaluated using spherical volumes of interest (VOIs) semi-automatically drawn on orthogonal planes. For each study maximum standardized uptake value (SUVmax) was recorded for each lesion.

==fine methodsresults==

==inizio results==

PSMA-PET/CT detected multiple areas of avid tracer uptake in 7 pts with mean SUVmax 46,4 (range 21-114). PSMA-PET/CT revealed greater disease extension in comparison with CT in the same anatomic context (i.e. bone, lymphnodes). Moreover, PSMA-PET/CT detected occult metastatic lesions in 4 pts not revealed by conventional imaging in thyroid, bone, cerebellum, adrenal gland, lung.
In 1 patient PSMA-PET/CT demonstrated an unknown single brain metastic lesion that was submitted to IGRT with complete remission.

==fine results==

==inizio discussions==

ccRCC is the most common (70–90%) and more aggressive RCC than other common histological types such as papillary and chromophobe. Increased angiogenesis by ccRCC can be utilised to potentially improve staging using PSMA-targeted imaging technologies as PET/CT. We show that PSMA-PET/CT may identify small metastatic lesions not obvious on routine imaging.
In general, clear-cell RCC metastases are depicted with high visual contrast in various anatomic sites including the lung, pleura, bone and lymph nodes.
There is growing interest in molecular imaging agents that may have greater sensitivity and specificity and may potentially add phenotypic information for the tailoring of individualized targeted-therapies.  In this context, PSMA-PET/CT has emerged as a promising, more accurate method.  The multidisciplinary context of the PCa Unit allows appropriate utilization of complex diagnostic tools as PSMA-PET/CT directly connecting disease assessment and treatment planning decisions.

==fine discussions==

==inizio conclusion==

In our patients, PET/CT with [68Ga]-PSMA-HBED-CC demonstrated high in vivo PSMA expression in ccRCC metastatic lesions improving diagnostic sensitivity by detection of occult lesions at the conventional imaging (thyroid, adrenal gland) and real assessment of disease burden.
Moreover, PSMA-targeted imaging may potentially be used to predict and/or assess response to systemic therapy.

==fine conclusion==

==inizio reference==

1) Surveillance, Epidemiology, and End Results Program. SEER stat fact sheets: kidney and renal pelvis cancer. Bethesda, MD: National Cancer Institute (http://seer.cancer.gov/statfacts/html/kidrp.html).
2) Dabestani S, Thorstenson A, Lindblad P, Harmenberg U, Ljungberg B, Lundstam S. Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study. World J Urol 2016;34:1081-6.
3) Yiyan Liu. The Place of FDG PET/CT in Renal Cell Carcinoma: Value and Limitations. Front Oncol. 2016; 6: 201.
4) Chang, S.S., Reuter, V.E., Heston, W.D. et al. Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res. 1999; 59:3192
5) Baccala A, Sercia L, Li J, Heston W, Zhou M. Expression of prostate-specific membrane antigen in tumor-associated neovasculature of renal neoplasms. Urology. 2007 Aug;70(2):385-90.
6) Eder, M.; Neels, O.; Müller, M. Novel preclinical and radiopharmaceutical aspects of [68Ga]Ga-PSMA-HBED-CC: A New PET tracer for imaging of prostate cancer Pharmaceuticals 2014, 7, 779– 796 DOI: 10.3390/ph7070779
7) Silvia Migliari, Antonino Sammartano, Maura Scarlattei, Giulio Serreli, Caterina Ghetti, Carla Cidda, Giorgio Baldari, Ornella Ortenzia, and Livia Ruffini. Development and Validation of a High-Pressure Liquid Chromatography Method for the Determination of Chemical Purity and Radiochemical Purity of a [68Ga]-Labeled Glu-Urea-Lys(Ahx)- HBED-CC (Positron Emission Tomography) Tracer. ACS Omega 2017, 2, 7120-7126

==fine reference==

==inizio objective==

To compare renal functional outcomes after either off-clamp (Off-C) or on-clamp (On-C) PN in patients with cT1- 2/N0 M0 renal tumors and baseline estimated eGFR >60 ml/min.

==fine objective==

==inizio methodsresults==

A prospective ‘renal cancer” database of two high volume centers was queried for cT1-2/N0/M0 tumors and baseline eGFR>60 mL/min. Overall 1073 patients met the inclusion criteria, 588 On-C PN and 485 Off-C PN. A 1:3 propensity score-matched (PSM) analysis was employed to minimize the potential selection bias.
Joinpoint regression analysis was used to plot the 2 to 8 yrs probabilities of experiencing eGFR decreases of 0%,< 25% and between 25 and 50% in both PSM cohorts and, therefore,to compare the trends for each of these 3 subgroups. Kaplan-Meier method was used to compare the risk of developing a CKD stage>=3b during follow-up in the PSM cohorts. Univariable and multivariable analyses were performed to identify independent predictors of developing a CKD stage>=3b.

==fine methodsresults==

==inizio results==

In the whole cohort On-C patients were significantly younger (p=0.001), less frequently smokers (p=0.01), with a lower incidence of diabetes (p=0.001) and hypertension (p=0.001), lower ASA scores (p<0.001), higher baseline eGFR values (p=0.003), smaller tumor sizes (p<0.001), longer warm ischemia time (17 minutes vs 0, p<0.001) and higher incidence of positive surgical margins (p=0.021). After applying the PSM analysis, the two cohorts of 157 On-C and 471 Off-C PN cases did not differ for all clinical and pathologic covariates (all p>0.08), except for mean warm ischemia time (p<0.001). At Joinpoint regression analysis Off-C group displayed significantly higher probabilities of maintaining unmodified eGFR after surgery (p=0.02), and significantly lower probabilities of experiencing eGFR decrease >25% in the first 8-yr follow-up (p=0.02).
The probability of developing a CKD stage>=3b was significantly higher (log rank p=0.006) in the On-C cohort (2, 5 and 8yr risk 0.9%, 5.1% and 12.8% versus 0.6%, 1.2% and 1.2% in the Off-C cohort, respectively.
At multivariable Cox regression analysis, eGFR at discharge (HR 0.94; 95% CIs 0.91-0.98, p=0.002) and Off-clamp approach (HR 7.33; 95% CIs 1.8-29.4, p=0.005) were independent predictors of improved renal functional outcomes.

==fine results==

==inizio discussions==

==fine discussions==

==inizio conclusion==

Off-C PN is associated with a significantly higher probability of maintaining 100% eGFR after surgery compared with On-C PN in patients with cT1-2/N0/MO renal tumors and good baseline renal function candidate to elective PN. Patients treated with On-C PN had a 7.3 fold increased risk of developing a severe CKD during follow-up.

==fine conclusion==

==inizio reference==

1. Patard JJ, Bensalah KC, Pantuck AJ, et al. Radical nephrectomy is not superior to nephron sparing surgery in PT1B-PT2N0M0 renal tumours: A matched comparison analysis in 546 cases. Eur. Urol. Suppl. 2008; 7:194.

2. Simone G, Gill I, Mottrie A, et al. Indications, Techniques, Outcomes, and Limitations for Minimally Ischemic and Off-clamp Partial Nephrectomy: A Systematic Review of the Literature. Eur. Urol. 2015; 68: 632–640.

3. Simone G, Papalia R, Guaglianone S, Gallucci M. ‘‘Zero ischaemia’’ sutureless laparoscopic partial nephrectomy for renal tumours with a low nephrometry score. BJU Int. 2011; 110: 124–130.

4. Simone G, Papalia R, Guaglianone S, Carpanese L, Gallucci M. Zero ischemia laparoscopic partial nephrectomy after superselective transarterial tumor embolization for tumors with moderate nephrometry score: long-term results of a single-center experience. J. Endourol. 2011; 25: 1443–1446.

5. Capitanio U, Larcher A, Terrone C, et al. End-Stage Renal Disease After Renal Surgery in Patients with Normal Preoperative Kidney Function: Balancing Surgical Strategy and Individual Disorders at Baseline. Eur. Urol. 2016; 70: 558-561.

==fine reference==

==inizio objective==

Small renal masses detection is increasing with the use of cross-sectional imaging and the desirable treatment, when technically feasible, is nephron sparing surgery (NSS).
A pseudocapsule (PC) surrounds most masses and a method to identify its integrity would aid to keep a safe surgical margin improving excisional precision.
To evaluate MRI likelihood scale of detection of renal tumor PC infiltration.

==fine objective==

==inizio methodsresults==

From January 2016 to September 2017, 58 consecutive patients with renal masses were enrolled in the study. Exclusion criteria included gross hematuria. All patients underwent MRI prior to tumor surgery. Data were collected in a prospective maintained dataset. The patients underwent MRI exams using high resolution protocol including morphological sequenceses (T2 & T1 imaging), Diffusion MRI (DWI) and Dynamic Contrast Enhanced MRI (DCE).
Two experienced Radiologists evaluated the MRI based on a predefined algorithm in advice with Urologists , and applied a score to tumor PC (MRIpC): MRIpC1) intact and continues ; MRIpC2) infiltrated and uninterrupted; MRIpC3) infiltrated and interrupted; NoMRIpC) absent PC.
Figure 1.
Similarly, two experienced pathologists reported PC integrity according to the Renal Tumor Capsule Invasion Scoring System (i-Cap).
The MRIpC score was compared to histology.

==fine methodsresults==

==inizio results==

There is no standardization in terms of semetiocs MRI. On MRI, a PC was described in 45 cases and confirmed at pathology. It was absent in 3 cases (all ccRCC). In 1 patient, a very thin PC was identified at pathology and not reported on MRI (pT3a G3 renal cell carcinoma). On MRI, the PC was intact in 28 cases, infiltrated in 9, disrupted in 14 and absent in 7 cases.
On pathology, a correlation between MRI and i-Cap was found in 53 lesions (91.4%).
The PC disruption was observed at the same level reported on MRI images.
Sensitivity and specificity were 97.92% and 60%, respectively. PPV and NPV were 92.16% and 85.71 %.
Absence and interruption of the PC and tumor volume correlated with high grade disease (G3-G4).

==fine results==

==inizio discussions==

Standard NSS requires a minimal layer of normal-appearing parenchyma.

Nevertheless tumor enucleation showed excellent results in the treatment of pT1 renal tumors.

A detailed preoperative identification of PC integrity can drive indications to NSS versus enucleation.

Our findings show how preoperative MRI can identify PC status.

Measuring the length of the integral PC and knowing where to expect an interruption/invasion, we can have an imaging-guided landmark to figure out where a minimal margin could be oncologically safer.

==fine discussions==

==inizio conclusion==

Our findings show how preoperative MRI can identify PC status helping optimizing surgical procedures selection.

==fine conclusion==

==inizio reference==

==fine reference==

==inizio objective==

Bone metastases develop in about 30% of ccRCC patients and an involvement of TGFβ1 in promoting the development of these metastases has been described (1). In breast cancer the extracellular matrix modifying enzyme Lysyl oxidase (Lox) has a key role in formation of pre-metastatic bone lesions through osteoclast activation and osteoblast inhibition (2). Our recent data evidenced that Lox is overexpressed in ccRCC (3) and TGFβ1 production is modulated by Arg tyrosine kinase in human renal tubular cells under high glucose conditions (4). Arg is also involved in modulation of invasion and metastasis in breast and prostate cancer through the induction of invadopodia, the cytoskeletal protrusions used by carcinoma cells to invade matrix during metastatic process (5). All these data suggest that Arg, TGFβ1 and Lox might be molecularly and functionally related to promote tumor invasion and metastasis. The aim of our study was to analyse the molecular and functional interactions among Arg, TGFβ1 and Lox in ccRCC and to evaluate their impact on osteoclast- and osteoblast- dependent formation of pre-metastatic bone lesions. Our study took advantage of an in vitro model of ccRCC primary cell cultures and cell lines.

==fine objective==

==inizio methodsresults==

Primary cell cultures, obtained from specimens of ccRCC and matched normal renal cortex, were characterized by FACS analysis. 786-O and Caki-1 ccRCC, Raw264 macrophage and MC3T3-E1 osteoblast cell lines were also used. ccRCC cell lines were treated with 5-10 ng/ml TGFβ1 or with Arg siRNA with or without the TGFβ-receptor inhibitor SB431542. The osteoclastic differentiation/activation of Raw264 cells and the proliferation of MC3T3-E1 osteoblasts was evaluated after treatment with conditioned media of Arg-silenced ccRCC cells by TRAP staining and MTT assay, respectively. Arg, TGFβ1-precursor, phospho-Smad2 and Smad2/3 protein expression was evaluated by Western blot, Lox and TGFβ1 in culture media by ELISA.

==fine methodsresults==

==inizio results==

TGFβ1 and Lox were significantly more abundant in media of high-grade ccRCC primary cultures than in those of low-grade ccRCC and normal cortex. Arg protein was upregulated in low-grade with respect to high-grade ccRCC primary cultures. Even in ccRCC cell lines the expression of Arg and TGFβ1 were inversely correlated. Treatment of ccRCC cell lines with TGFβ1 induced an activation of Smad pathway and an increase of Lox secretion. Moreover, Arg silencing in ccRCC cells increased TGFβ1 secretion and activated Smad pathway. We are now evaluating Lox secretion after treatment of Arg-silenced ccRCC cells with SB431542 as well as Raw264 cell activation and MC3T3-E1 cell proliferation after treatment with Arg-silenced ccRCC cell conditioned media.

==fine results==

==inizio discussions==

Our data highlighted that Arg expression is inversely correlated with TGFβ1 and Lox production in high-grade ccRCC cultures and cell lines accordingly with an expected more invasive and metastatic behaviour. Moreover, the effects of TGFβ1 treatment and Arg silencing in ccRCC cell lines suggest an involvement of Arg in regulation of TGFβ1 secretion that, through Smad pathway activation, induced Lox secretion. The eventual osteoclast activation and osteoblast inhibition induced by Arg-silenced ccRCC cell conditioned media, if confirmed by our ongoing analyses, might suggest that the complex interactions among Arg, TGFβ1 and Lox are important also for bone pre-metastatic niche formation.

==fine discussions==

==inizio conclusion==

The evidence of complex functional interactions among Arg, TGFβ1 and Lox may help to shed light on the molecular mechanisms responsible for ccRCC progression and bone pre-metastatic niche formation.

==fine conclusion==

==inizio reference==

1. Kominsky et al. J Bone Miner Res, 2007
2. Coxe et al. Nature, 2015
3. Di Stefano et al. Am J Pathol, 2016
4. Torsello et al. J Cell Sci, 2016
5. Beaty et al. Mol Biol Cell, 2013

==fine reference==