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Introduction: Benign tracheobronchial stenosis is a abnormal tracheal lumen narrowing that may incur progressive dyspnea and life-threatening hypoxemia. There is no consensus on which patients should be treated with endoscopic or surgical method. This study investigates the outcomes of bronchoscopic dilatation in the treatment of benign tracheal stenosis using a device equipped with a blade to cut the stenotic lesions with dense fibrosis., Materials and Methods: The procedure was carried out in an operating room under general anesthesia. All patients were intubated with a Rigid Bronchoscope (RB) placed just above the stenosis. Through Rigid Bronchoscopy combined modalities were used as needed: radial incisions of the mucosal stenosis with blade at the levels of 4, 8 and 12 o'clock, with back and forth movements, then the stenotic area was dilated more easily with a rigid bronchoscope. Dilatation was performed by passing the RB of increasing diameter through stenotic areas and then Balloon dilatation of increasing diameter. There were no complications during the procedure., Result: We conducted an observational, retrospective, single-centre study in the Thoracic Surgery Unit of the University of 'Luigi Vanvitelli' of Naples from November 2011 to September 2021. We included all consecutive patients with benign tracheal stenosis inoperable. During the study period, 113 patients were referred to our department with benign tracheal stenosis inoperable. 61 patients were treated with the blade. During the follow-up, a recurrence of the stenosis was observed in 8 patients in the first month and in 4 patients in the third month. Instead in the patients treated with the use of laser (52 patients), during the follow-up a recurrence was observed in 16 patients in the first month and in 6 patients in the third month; no patient relapsed after 6 months and after 1 year. Long term successful bronchoscopic management with blade was attained by 99% in simple and 93% in mixed stenosis and in complex type stenosis., Conclusion: Our study underlines the importance of the use of the blade in bronchoscopic treatment as a valid conservative approach in the management of patients with inoperable benign tracheal stenosis as an alternative to the use of the laser, reducing the abnormal inflammatory reaction in order to limit recurrences., (© 2024. The Author(s).)

In hepatocytes, the Wilson disease protein ATP7B resides on the trans-Golgi network (TGN) and traffics to peripheral lysosomes to export excess intracellular copper through lysosomal exocytosis. We found that in basal copper or even upon copper chelation, a significant amount of ATP7B persists in the endolysosomal compartment of hepatocytes but not in non-hepatic cells. These ATP7B-harbouring lysosomes lie in close proximity of ~10 nm to the TGN. ATP7B constitutively distributes itself between the sub-domain of the TGN with a lower pH and the TGN-proximal lysosomal compartments. The presence of ATP7B on TGN-lysosome colocalising sites upon Golgi disruption suggested a possible exchange of ATP7B directly between the TGN and its proximal lysosomes. Manipulating lysosomal positioning significantly alters the localisation of ATP7B in the cell. Contrary to previous understanding, we found that upon copper chelation in a copper-replete hepatocyte, ATP7B is not retrieved back to TGN from peripheral lysosomes; rather, ATP7B recycles to these TGN-proximal lysosomes to initiate the next cycle of copper transport. We report a hitherto unknown copper-independent lysosomal localisation of ATP7B and the importance of TGN-proximal lysosomes but not TGN as the terminal acceptor organelle of ATP7B in its retrograde pathway., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Video-assisted thoracoscopic surgery (VATS) resection of deep-seated lung nodules smaller than 1 cm is extremely challenging. Several methods have been proposed to overcome this limitation but with not neglectable complications. Intraoperative lung ultrasound (ILU) is the latest minimally invasive proposed technique. The aim of the current study was to analyze the accuracy and efficacy of ILU associated with VATS to visualize solitary and deep-seated pulmonary nodules smaller than 1 cm., Methods: Patients with subcentimetric solitary and deep-seated pulmonary nodules were included in this retrospective study from November 2020 to December 2022. Patients who received VATS aided with ILU were considered as group A and patients who received conventional VATS as group B (control group). The rate of nodule identification and the time for localization with VATS alone and with VATS aided with ILU in each group were analyzed., Results: A total of 43 patients received VATS aided with ILU (group A) and 31 patients received conventional VATS (group B). Mean operative time was lower in group A (p < 0.05). In group A all the nodules were correctly identified, while in group B in one case the localization failed. The time to identify the lesion was lower in group A (7.1 ± 2.2 vs. 13.8 ± 4.6; p < 0.05). During hospitalization three patients (6.5%; p < 0.05) in group B presented air leaks that were conservatively managed., Conclusion: Intracavitary VATS-US is a reliable, feasible, real-time and effective method of localization of parenchymal lung nodules during selected wedge resection procedures., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Antibiotic stewardship interventions are urgently needed to reduce antibiotic overuse in hospitalized COVID-19 patients, particularly in small community hospitals (SCHs), who often lack access to infectious diseases (ID) and stewardship resources. We implemented multidisciplinary tele-COVID rounds plus tele-antibiotic stewardship surveillance in 17 SCHs to standardize COVID management and evaluate concurrent antibiotics for discontinuation. Antibiotic use was compared in the 4 months preintervention versus 10 months postintervention. Interrupted time-series analysis demonstrated an immediate decrease in antibiotic use by 339 days of therapy/1000 COVID-19 patient days (p < .001), and an estimated 5258 antibiotic days avoided during the postintervention period. Thirty-day mortality was not significantly different, and a significant reduction in transfers was observed following the intervention (23.3% vs. 7.8%, p < .001). A novel tele-ID and tele-stewardship intervention significantly decreased antibiotic use and transfers among COVID-19 patients at 17 SCHs, demonstrating that telehealth is a feasible way to provide ID expertise in community and rural settings., (© 2023 Society of Hospital Medicine.)

Background: Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm, generally arising in the visceral pleura. It rarely originates from other sites such as trachea, orbital cavities, nasal cavities, peritoneum, paranasal sinuses, meninges, salivary glands, thyroid gland, diaphragm, liver, pancreas, lung kidney, adrenal gland, mediastinum, spermatid cord, pericardium, urinary bladder, prostate, uterine cervix, testis, spinal cord, periosteum, skin, soft tissue and bone., Case Description: We present a surgical case of a rare primary tracheal tumor. High resolution computed tomography (HRCT) scan of the chest showed a 5 mm hypodense lesion, located on the right lateral wall of the proximal third of trachea; however the tracheal lumen was normal. We performed a rigid bronchoscopy in order to remove the endotracheal tumor with palliative purposes only. For this reason, we did not perform a prior histologic examination. The lesion was easily removed with common biopsy forceps and with standard aspirator. The debulking of the tumor was achieved with the use of laser Nd-YAP, electrocautery was used also for hemostasis to prevent bleeding during the operation. Without complications during the endoscopic treatment, the procedure was well tolerated by the patient. The pathological diagnosis was SFT., Conclusions: SFT located in the trachea can be endoscopically resceted. Endoscolical treatment is indicated for patients with poor clinical conditions (heart disease, respiratory failure) that are not elegible for surgical resection., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-1622/coif). The authors have no conflicts of interest to declare., (2023 Translational Cancer Research. All rights reserved.)

Glioblastoma multiforme is one of the most frequent and aggressive primary tumors in the central nervous system, representing >60% of all brain tumors in adults. Despite treatment, prognosis remains poor with most if not all patients experiencing disease recurrence and a 2-year survival rate of 27%. At present, no confirmed standard treatment exists for recurrent glioblastoma. Regorafenib is one of the few options available, based on results from the REGOMA trial. In the present study, a real-life retrospective investigation on the role of regorafenib in patients with recurrent glioblastoma (>60 years old) from two main Oncological Units in South Italy (Azienda Ospedaliera Universitaria Luigi Vanvitelli, Naples, Italy and Ospedale Civile San Giovanni di Dio, Frattamaggiore, Naples, Italy), was performed. The primary endpoint was overall survival (OS), whereas progression-free survival (PFS), objective response rate and disease control were secondary endpoints. Survival was then analyzed according to age, isocitrate dehydrogenase (IDH) and methylated methylguanine-DNA-methyltransferase (MGMT) status. A total of 56 patients met the eligibility criteria. The intention to treat population median PFS (mPFS) was 4.1 months and median OS (mOS) was 6.8 months. Age did not appear to have a significant influence on mPFS. mOS in MGMT-methylated patients was improved compared with that of the unmethylated group (7.7 months vs. 5.6 months). Both mOS and mPFS were longer in IDH-mutant patients. The present study was one of the first real life analyses of regorafenib in recurrent glioblastoma. The results were in line with the REGOMA trial. Age did not appear to be a prognostic factor, thus suggesting that treatment choice should not be different in elderly. MGMT methylation appeared to influence OS. To the best of our knowledge, this was the first report of regorafenib activity in older patients and, while the results were statistically significant, these should be confirmed in further studies., Competing Interests: MF: Advisory boards for MSD and Merck Serono. All other authors declare that they have no competing interests., (Copyright: © Fasano et al.)

Introduction: Central airway tumors involving the trachea and main-stem bronchi are a common cause of airway obstruction and a significant cause of mortality among the patients of thoracic diseases with respiratory failure. Debulking in rigid bronchoscopy is quick, safe, and effective. It can be complex and hard in patients with severe bronchial or tracheal obstruction and/or with intraluminal bleeding tumors because of inadequate distal airway control. We have used laser tube as a new technique of ventilation for severe central airway obstruction., Materials and Methods: Forty-six patients with severe airway obstruction undergoing rigid bronchoscopy from September 2020 to June 2022 at the Thoracic Surgery Department of the University L. Vanvitelli of Naples underwent placement of laser tube., Results: In all patients who underwent rigid bronchoscopy with the use of the laser tube, a reduction of obstruction of more than 50% was obtained and in all patients no hypoxia (saturation < 88%), nor hypercapnia, nor significant bleeding were reported., Discussion: The results of this study suggest that rigid bronchoscopic debulking with the use of laser tube is a safe and effective technique in the management of central airway obstruction., Conclusions: The use of the laser tube allows the monitoring of gas exchange, which controls hypoxemia. Thanks to the double cuff put distally to the tracheal obstruction or in the contralateral bronchus to the obstructed one, the laser tube prevents the flooding of blood from debulking below the stenosis. Rigid bronchoscopy with laser tube will expand its use in the future., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: The study aimed to evaluate quality of nephrolithometric nomograms to predict stone-free rates (SFRs) and complication rates (CRs) in case of minimally invasive percutaneous nephrolithotomy (PNL). In the last decade, nomograms have been introduced to estimate the SFRs and CRs of PNL. However, no data are available regarding their reliability in case of utilization of miniaturized devices. Herein we present a prospective multicentric study to evaluate reliability of Guy's stone score (GSS), the stone size, tract length, obstruction, number of involved calyces, and essence of stone (S.T.O.N.E.) nephrolithometry score and Clinical Research Office of the Endourological Society (CROES) score in patients treated with minimally invasive PNL., Methods: We evaluated SFRs and CRs of 222 adult patients treated with miniaturized PNL. Patients were considered stone-free if no residual fragments of any size at post-operative unenhanced computed tomography scan. Patients demographics, SFRs, and CRs were reported and analyzed. Performances of nomograms were evaluated with the area under the curve (AUC)., Results: We included 222 patients, the AUCs of GSS, CROES score, and S.T.O.N.E. nephrolithometry score were 0.69 (95% confidence interval [CI] 0.61-0.78), 0.64 (95% CI 0.56-0.73), and 0.62 (95% CI 0.52-0.71), respectively. Regarding SFRs, at multivariate binomial logistic regression, only the GSS had significance with an odds ratio of 0.53 (95% CI 0.31-0.95, p =0.04). We did not find significant correlation with complications, with only a trend for GSS., Conclusion: This is the first study evaluating nomograms in miniaturized PNL. They still show good reliability; however, our data showed lower performances compared to standard PNL. We emphasize the need of further studies to confirm this trend. A dedicated nomogram for minimally invasive PNL may be necessary., Competing Interests: The authors declare no conflict of interest., (© 2022 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

Introduction: The aim of the study was to provide data related to endoscopic combined intra-renal surgery learning curve using minimally invasive techniques with vacuum-assisted devices. Minimal data exist on the learning curve for these techniques., Methods: We conducted a prospective study monitoring the training of a mentored surgeon learning ECIRS with vacuum assistance. We use varied parameters for improvements. After collection of peri-operative data, tendency lines and CUSUM analysis were used to investigate the learning curves., Results: 111 patients have been included. Guy's Stone Score 3 and 4 stones 51.3% of all cases. The mostly used percutaneous sheath was 16 Fr (87.3%). SFR was 78.4%. 52.3% patients were tubeless, and 38.7% achieved trifecta. High-degree complication rate was 3.6%. Operative time improved after 72 cases. We observed a decrease of complications throughout the case series, with improvement after 17 cases. In terms of trifecta, proficiency was reached after 53 cases. Proficiency seems achievable in a limited number of procedures, but results did not plateau. Higher number of cases might be necessary for excellence., Discussion: A surgeon learning ECIRS with vacuum assistance can obtain proficiency in 17-50 cases. The number of procedures required for excellence remains unclear. Exclusion of more complex cases might positively affect the training, reducing unnecessary complications., (© 2023 S. Karger AG, Basel.)

Background: Malignant pleural mesothelioma (MPM) is an invasive, aggressive pleural tumor with a predominantly local spread. The objective of this study was to assess thoracic ultrasound (TUS) as an imaging modality with high sensitivity for the identification of malignant pleural involvement and in order to guide pleural biopsies., Methods: In this retrospective single-center study between January 2018 and June 2022, 51 consecutive patients with impassable circumferential pleural thickening underwent TUS at the Thoracic Surgery Unit of the Vanvitelli University of Naples. Pleural biopsies were performed, and then large and multiple samples were sent to the pathological anatomy for histological examination., Results: In all patients who underwent ultrasound examination, we chose the optimal point of entry to perform pleural biopsies and selected the areas of greater thickening without pleural effusion. No patient had any complications. No drainage tubes were placed after the pleural biopsies and no pneumothorax was present during the following days of hospitalization. The patients were discharged on the second postoperative day., Conclusion: With TUS the precise pleural thickening localization, local infiltration, mass extent, its nature (solid, cystic or complex) and ultrasound features can be easily defined. Furthermore, ultrasound is more economical than computed tomography and avoids the risks associated with radiation. Thoracic ultrasound is an important component of the diagnostic procedure in detecting a safe entry site for biopsies of MPMs., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: Staging of the mediastinum lymph nodes involvement in patients with non-small cell lung cancer (NSCLC) is an important prognostic factor determining the most appropriate multimodality treatment plan. The objective of this study is to assess ultrasound characteristics of mediastinal lymph nodes metastasis and effectiveness of intraoperative ultrasound-guided mediastinal nodal dissection in patients with resected NSCLC., Materials and Methods: All patients undergoing video-assisted thoracoscopic surgery lobectomy and pulmonary lymphadenectomy from November 2020 to March 2022 at the thoracic surgery department of the Vanvitelli University of Naples underwent intraoperative ultrasound-guided mediastinal lymph nodal dissection., Results: This study evaluates whether individual B-mode features and a compounding thereof can be used to accurately and reproducibly predict lymph node malignancy., Discussion: Intraoperative ultrasound, during systematic mediastinal lymph node dissection, is helpful in preventing lesion to mediastinal structures. Pathological nodal sonographic characteristics are round shape, short-axis diameter, echogenicity, margin, the absence or presence of coagulation necrosis sign, and the absence or presence of central hilar structure, increased color Doppler flow, the absence or presence of calcification, and nodal conglomeration. Operating time was not substantially prolonged. The procedure is simple, safe and highly accurate., Conclusions: Ultrasonic techniques allow surgeons to detect the relationship between lymph nodes and surrounding large blood vessels during biopsy, improving the safety and simplicity of the operation, increasing the number of harvested lymph nodes, and reducing the risk of intraoperative injury; it is a fast, easily reproducible, and inexpensive method., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Traditionally, lymph node metastases (LNM) evaluation is essential to the staging of colon cancer patients according to the TNM (tumor-node-metastasis) system. However, in recent years evidence has accumulated regarding the role of emerging pathological features, which could significantly impact the prognosis of colorectal cancer patients. Lymph Node Ratio (LNR) and Log Odds of Positive Lymph Nodes (LODDS) have been shown to predict patients' prognosis more accurately than traditional nodal staging and it has been suggested that their implementation in existing classification could help stratify further patients with overlapping TNM stage. Tumor deposits (TD) are currently factored within the N1c category of the TNM classification in the absence of lymph node metastases. However, studies have shown that presence of TDs can affect patients' survival regardless of LNM. Moreover, evidence suggest that presence of TDs should not be evaluated as dichotomic but rather as a quantitative variable. Extranodal extension (ENE) has been shown to correlate with presence of other adverse prognostic features and to impact survival of colorectal cancer patients. In this review we will describe current staging systems and prognostic/predictive factors in colorectal cancer and elaborate on available evidence supporting the implementation of LNR/LODDS, TDs and ENE evaluation in existing classification to improve prognosis estimation and patient selection for adjuvant treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arrichiello, Pirozzi, Facchini, Facchini, Paragliola, Nacca, Nicastro, Canciello, Orlando, Caterino, Ciardiello, Della Corte, Fasano, Napolitano, Troiani, Ciardiello, Martini and Martinelli.)

Glioblastoma multiforme (GBM) is one of the most frequent and aggressive primary tumors in the central nervous system, representing more than 60% of all brain tumors in adults. Primary GBM remains incurable with a poor prognosis both for limited therapeutic alternatives and for a high risk of progression or recurrence. In fact, at recurrence, the few treatment options available, and often characterized by limited effectiveness, have always been an Achilles' heel. The recent approval of second line of regorafenib, a multikinase inhibitor, has given hope after several years of darkness for new therapies in the treatment of GBM. Indeed, in the REGOMA trial, a phase 2 study, regorafenib was the first drug to show a statistically significant improvement in median overall survival compared with lomustine group, usually used in the second-line treatment after temozolomide failure. We report a case of a 43-year-old patient affected by GBM in treatment with regorafenib in third line of therapy with good disease control and long PFS., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Background: In literature, the reports of outcomes after percutaneous nephrolithotomies are rather heterogeneous. This may influence studies comparison, it may also render difficult to evaluate surgical adequacy, perioperative morbidity, and patient's Quality of Life between studies. For this reason, we propose to introduce PNL-Trifecta as composite measure to standardize data reporting outcomes after percutaneous nephrolithotomies., Methods: We performed a prospective multicentric study on consecutive patients undergone PNL to treat renal stones between 2018 and 2020. Successful PNL-trifecta was considered achieved when procedures obtained the three following results: no residual fragments >2 mm at unenhanced CT scan at 3 months postop, no complications (defined as Clavien-Dindo Score 0) and operation carried out without placing a nephrostomy tube (tubeless or totally tubeless). We compared results of standard versus mini-PNL and between stones of different complexity (evaluated with Guy's Stone Score and S.T.O.N.E. Nephrolithometry Score). Univariate analysis was utilized to identify other factors influencing achievement of PNL-Trifecta., Results: Two hundred forty-five patients fulfilled inclusion/exclusion criteria and have been enrolled in the study (median age: 56, IQR 48-57). The overall PNL-Trifecta achievement rate was 22.85% (28.66% in the mini-PNL group and 13.68% in the standard-PNL group, P=0.010). The stone free rate, CD 0 rate and tubeless/totally tubeless rate in the mini-PNL group were 60.66%, 89.33% and 51.33% respectively. In the standard-PNL group they were 44.21%, 40.00% and 15.78% respectively. At the univariate analysis, differences between Guy's Stone Score groups in achieving PNL-Trifecta were significant (P=0.001). Also, the level of upper puncture (P=0.010) and utilization of device with active suction (P=0.002) showed statistically significant differences. Furthermore, the length of stay in the patient's group achieving Trifecta was 2.28 versus a mean length of stay of 4.64 days in the group of patients not achieving Trifecta (P=0.046)., Conclusions: We present Trifecta for PNLs as a potential tool to evaluate quality of percutaneous nephrolithotomies and to provide an instrument for an adequate standard data reporting. It can represent a valid way to assess and monitor surgeon's learning curves. It will require further external validation and studies to evaluate its correlation with mid- and long-term results and patient's health related Quality of Life outcomes.

Differentiated thyroid cancer (DTC) includes papillary and follicular carcinomas and is the most common type of thyroid cancer. The incidence of this cancer has increased in the last few years, and even if its prognosis is generally good for a subset of patients that does not respond to radioactive iodine (RAI) therapy, the prognosis is much worse: the median overall survival (OS) from discovery of metastasis is 3-5 years and the 10-year survival rate is only 10%. Several mutations, including RAS or RET, as well as BRAF signaling, are associated with thyroid cancer. Liquid biopsy may be useful in selected patient to identify genomic alterations and thus allowing for a precision medicine approach with target therapy. Sorafenib, an oral multi-kinase inhibitor, can be used in the treatment of DTC. Case presentation: A 77 years old. man with diagnosis of metastatic DTC and evidence of presence of mutation of BRAF K601E on liquid biopsy was treated with sorafenib, showing a good response to the treatment and an improvement in the quality of life (QoL). Currently, this patient is still on treatment with sorafenib, gaining control of a multi-metastatic disease, generally characterized by a very poor prognosis. In conclusion, sorafenib has an active role in the treatment of DTC. It also has been considered the standard of care for patients with advanced unresectable hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). In our case we observe the efficacy of using sorafenib in Papillary thyroid carcinoma (PTC) such as confirming both stable disease (SD) in the CT scan as clinical benefit with an increase in QoL. Therefore, use of sorafenib remains an important treatment option, even in case of BRAF mutation, despite a rapidly evolving treatment landscape. It also seems important to perform liquid biopsies, especially in patients in whom it is not possible to repeat a new tissue biopsy. Ongoing clinical trials continue to evaluate sorafenib in different settings, and in combination with other therapies in DTC and HCC.

Introduction: Video-assisted thoracic surgery (VATS) for ipsilateral reoperations is controversial, because after the first surgical intervention, pleural adhesions occur frequently in the thoracic cavity and/or chest wall. This study assessed the usefulness of preoperative ultrasonography to reduce the incidence of lung injury at the time of the initial port insertion during secondary ipsilateral VATS., Materials and Methods: This was a retrospective, single-center study. Nine patients who underwent thoracic surgery at Vanvitelli Hospitalfrom September 2019 to February 2022, were scheduled for a second VATS surgeryon ipsilateral lung, because of inconclusive intraoperative histologic examination. All nine patients underwent preoperative ultrasonography to assess the possible presence of pleural adhesions. We evaluated the lung sliding, since the presence of pleural adhesions does not permit to appreciate it., Statistical Analysis: Hard severe adhesions were observed in all nine patients without sliding lung sign (specificity 100%). In this series, the sensitivity, PPV, and NPV of the sliding lung sign were 93%, 100% and 94% respectively., Results: The presence of the lung respiratory changes can be evaluated as the "sliding lung sign" by chest ultrasonography; we believe that the sliding lung sign might also predict intrathoracic adhesion., Conclusions: Preoperative detection of pleural adhesions using transthoracic ultrasonography was useful for ipsilateral secondary pulmonary resection patients undergoing VATS. Using preoperative ultrasonography can improve the safety and feasibility of placing the initial port in VATS., (© 2022. The Author(s).)

Background: Craniopharyngioma is a rare intracranial tumor, with a high morbidity rate due to its common refractiveness to conventional treatments. BRAF V600E mutation has recently been identified as the principal oncogenic molecular driver of papillary craniopharyngiomas (PCP), one of the two main variants of craniopharyngioma., Case Presentation: A 49-year-old man with recurrent craniopharyngioma, harboring BRAF V600E mutation, has been treated with targeted therapy based on a combination of a BRAF-inhibitor, dabrafenib (150 mg, orally two times daily), and a MEK-inhibitor, trametinib (2 mg, orally two times daily). Before starting treatment, the patient was symptomatic: he lamented confusion, dysphasia, and intense fatigue, that did not allow him to work normally. After just one cycle of treatment, the patient showed an important clinical improvement, reporting a progressive regression of the basal symptoms, hinting at a rapid and dramatic response, which was confirmed at the first radiological assessment. Thus, treatment was continued and at the time of writing, the treatment is still ongoing (total duration of treatment: 14 months) and it is well tolerated, with very good quality of life: the patient has no limitations in daily activities and he has even been able to restart to work., Conclusion: The use of targeted therapies-as a clinical practice or in clinical trials-represents an important therapeutic alternative and a great evolution for patients' prognosis vs. the standard of care, historically represented by unselected chemotherapies. The discovery of the BRAF V600E mutation in patients with PCP is very rare, resulting in a lack of data on the efficacy of the combination of dabrafenib and trametinib., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fasano, Della Corte, Caterino, Pirozzi, Rauso, Troiani, Martini, Napolitano, Morgillo and Ciardiello.)

Head and neck squamous cell carcinomas (HNSCC) constitute the sixth most common malignancy worldwide, with approximately 25-40% of the diagnosed patients older than 70 years. HNSCC patients are often frail and frequently have multiple comorbidities due to their unhealthy lifestyle, and evidence suggests that older patients may receive less aggressive and suboptimal treatment than younger patients with the same disease status. The aim of this review is to depict and summarize the evidence regarding the different strategies that can be used in the clinical management of elderly HNSCC patients. Key references were derived from a PubMed query. Hand searching and clinicaltrials.gov were also used. This paper contains a narrative report and a critical discussion of clinical approaches in the context of elderly HNSCC.

Adenosine diphosphate (ADP)-ribosylation is a posttranslational modification involved in key regulatory events catalyzed by ADP-ribosyltransferases (ARTs). Substrate identification and localization of the mono-ADP-ribosyltransferase PARP12 at the trans -Golgi network (TGN) hinted at the involvement of ARTs in intracellular traffic. We find that Golgin-97, a TGN protein required for the formation and transport of a specific class of basolateral cargoes (e.g., E-cadherin and vesicular stomatitis virus G protein [VSVG]), is a PARP12 substrate. PARP12 targets an acidic cluster in the Golgin-97 coiled-coil domain essential for function. Its mutation or PARP12 depletion, delays E-cadherin and VSVG export and leads to a defect in carrier fission, hence in transport, with consequent accumulation of cargoes in a trans -Golgi/Rab11-positive intermediate compartment. In contrast, PARP12 does not control the Golgin-245-dependent traffic of cargoes such as tumor necrosis factor alpha (TNFα). Thus, the transport of different basolateral proteins to the plasma membrane is differentially regulated by Golgin-97 mono-ADP-ribosylation by PARP12. This identifies a selective regulatory mechanism acting on the transport of Golgin-97- vs. Golgin-245-dependent cargoes. Of note, PARP12 enzymatic activity, and consequently Golgin-97 mono-ADP-ribosylation, depends on the activation of protein kinase D (PKD) at the TGN during traffic. PARP12 is directly phosphorylated by PKD, and this is essential to stimulate PARP12 catalytic activity. PARP12 is therefore a component of the PKD-driven regulatory cascade that selectively controls a major branch of the basolateral transport pathway. We propose that through this mechanism, PARP12 contributes to the maintenance of E-cadherin-mediated cell polarity and cell-cell junctions., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

The Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis-trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here, we show that the Golgi matrix protein GRASP55 directs the compartmentalized localization of key enzymes involved in glycosphingolipid (GSL) biosynthesis. GRASP55 binds to these enzymes and prevents their entry into COPI-based retrograde transport vesicles, thus concentrating them in the trans-Golgi. In genome-edited cells lacking GRASP55, or in cells expressing mutant enzymes without GRASP55 binding sites, these enzymes relocate to the cis-Golgi, which affects glycosphingolipid biosynthesis by changing flux across metabolic branch points. These findings reveal a mechanism by which a matrix protein regulates polarized localization of glycosylation enzymes in the Golgi and controls competition in glycan biosynthesis., (© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background: The aim of this study is to evaluate the incidence and risk factors of incidental prostate cancer (IPCA) in a contemporary cohort of lower urinary tract symptoms (LUTS) patients who underwent trans-urethral resection of the prostate (TURP)., Methods: A series of 458 consecutive patients who underwent TURP were evaluated between January 2016 to June 2018. Evaluated factors included age (years), Body Mass Index (BMI; kg/square meters), treatment with inhibitors of 5-alpha reductase, previous prostate biopsies, basal prostate specific antigen (PSA) levels (ng/mL), serum leukocyte count (×10 9 /L), weight of resected prostate tissue (grams), grade and stage of IPCA. The multivariate logistic regression model evaluated associations of significant clinical factors with the risk of IPCA., Results: Overall, IPCA was detected in 30 of 454 patients (6.6%). A mean of 21.8 g of tissue was resected. The mean number of positive chips was 5.6 (mean percentage 3.9%) with tumor grade group 1 in 22 cases (73.4%) and tumor stage cT1a in 23 patients (76.7%). On multivariate analysis, independent factors that were positively associated with the risk of IPCA were BMI (odds ratio, OR=1.121; P=0.017) and leukocyte count (OR=1.144; P=0.027)., Conclusions: In a contemporary cohort of patients undergoing TURP for the treatment of LUTS, the risk of IPCA was not negligible with a rate of being 6.6%. BMI and serum leukocyte count were found to be independent factors that were positively associated with the risk of IPCA.

Objective: To evaluate the factors associated with the risk of hospital readmission after robot assisted radical prostatectomy (RARP) with or without extended pelvic lymph node dissection (ePLND) for prostate cancer (PCA) over a long term., Materials and Methods: The risk of readmission was evaluated by clinical, pathological, and perioperative factors. Skilled and experienced surgeons performed the procedures. Patients were followed for complications and hospital readmission for a period of six months. The logistic regression model and Cox's proportional hazards assessed the association of factors with the risk of readmission., Results: From January 2013 to December 2018, 890 patients underwent RARP; ePLND was performed in 495 of these patients. Hospital readmission was detected in 25 cases (2.8%); moreover, it was more frequent when RARP was performed with ePLND (4.4% of cases) than without (0.8% of patients). On the final multivariate model, ePLND was the only independent factor that was positively associated with the risk of hospital readmission (hazard ratio, HR = 5935; 95%CI 1777-19,831; p = 0.004)., Conclusions: Over the long term after RARP for PCA, the risk of hospital readmission is associated with ePLND. In patients who underwent RARP and ePLND, 4.4% of them had a readmission, compared to RARP alone, in which only 0.8% of cases had a readmission. When ePLND is planned for staging pelvic lymph nodes, patients should be informed of the increased risk of hospital readmission.

The objective of this study is to evaluate if surgeon volume and stratifying positive surgical margins (PSM) into focal and non-focal may differentially impact the risk of biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP). Between January 2013 and December 2017, 732 consecutive patients were evaluated. The population included negative cases (control group) and PSM subjects (study group). PSMs were stratified as focal (≤ 1 mm) or non-focal (> 1 mm). A logistic regression model assessed the independent association of factors with the risk of PSM. The risk of BCR of PSM and other factors was assessed by Cox's multivariate proportional hazards. Overall, 192 (26.3%) patients had PSM focal in 133 patients; non-focal in 59 cases. Focal PSM was associated with the percentage of biopsy positive cores (BPC; OR 1.011; p = 0.015), extra-capsular extension (pT3a stage; OR 2.064; p = 0.016), seminal vesicle invasion (pT3b; OR 2.150; p = 0.010), body mass index (odds ratio, OR 0.914; p = 0.006), and high surgeon volume (OR 0.574; p = 0.006). BPC (OR 1.013; p = 0.044), pT3a (OR 4.832; p < 0.0001) and pT3b stage (OR 5.153; p = 0.001) were independent predictors of the risk of non-focal PSM. Surgeon volume was not a predictor of non-focal PSM (p = 0.224). Independent factors associated with the risk of BCR were baseline PSA (hazard ratio, HR 1.064; p = 0.004), BPC (HR 1.015; p = 0.027), ISUP biopsy grade group (BGG) 2/3 (HR 2.966; p 0.003) and BGG 4/5 (HR 3.122; p = 0.022) pathologic grade group 4/5 (HR 3.257; p = 0.001), pT3b (HR 2.900; p = 0.003), and non-focal PSM (HR 2.287; p = 0.012). Surgeon volume was not a predictor of BCR (p = 0.253). High surgeon volume is an independent factor that lowers the risk of focal PSM. Surgeon volume does not affect non-focal PSM and BCR. Negative as well as focal PSM are not associated with BCR.

Objective: To assess the association between prostate volume index (PVI), and prostatic chronic inflammation (PCI) as predictors of prostate cancer (PCA). PVI is the ratio between the central transition zone volume (CTZV) and the peripheral zone volume (PZV)., Materials and Methods: Parameters evaluated included age, prostate specific antigen (PSA), total prostate volume (TPV), PSA density (PSAD), digital rectal exam (DRE), PVI, PCI and number of positive cores (NPC). All patients underwent baseline 14-core, trans-perineal random biopsies. Associations of parameters with the NPC were investigated by univariate and multivariate linear regression analysis., Results: Between September 2010 to September 2017, 945 patients were evaluated. PCA was detected in 477 cases (50.7%), PCI in 205 cases (21.7%). PCA patients, compared to negative cases, were older (68.3 vs. 64.4 years) with smaller TPV (36 vs. 48.3mL) and CTZV (19.2 vs. 25.4), higher PSAD (0.24 vs. 0.15ng/mL/mL), further PVI values were lower (0.9 vs. 1.18) and biopsy cores less frequently involved by PCI (9.4% vs. 34.2%). High PVI and the presence of PCI were independent negative predictors of NPC in model I considering PSA and TVP (PVI, regression coefficient, RC -0,6; p=0.002) and PCI (RC -1,4; p<0.0001); and in model II considering PSAD (PVI:RC -0,7; p<0,0001; and PCI: RC -1,5; p<0.0001)., Conclusions: High PVI and the presence of PCI lowered the mean rate of NPC and is associated with less aggressive tumor biology expressed by low tumor burden. PVI can give prognostic information before planning baseline random biopsies. Confirmatory studies are required., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Objective: To evaluate the association between basal total testosterone (TT) levels with the European Association of Urology (EAU) risk classes at the time of diagnosis of prostate cancer (PCA)., Methods: A retrospective review of prospectively collected data was carried out between November 2014 and March 2018. Preoperative basal TT levels and PSA were measured in 601 consecutive Caucasian patients who were not under androgen deprivation and undergoing surgery at a tertiary referral center. Patients were classified into low (reference group), intermediate- and high-risk/locally advanced classes. The multinomial logistic regression model evaluated associations of TT and other clinical factors with EAU risk classes., Results: One hundred twenty four patients (24%) were low risk, 316 (52.6%) were intermediate, 199 (16.5%) were high risk and 42 (7%) were locally advanced. Median circulating basal TT levels increased along EAU classes. TT, PSA, percentage of biopsy-positive cores and tumor clinical stage were independently associated with the high-risk class (odds ratio, OR = 1.002; p = 0.030) but were not associated with intermediate-risk or locally advanced PCA when compared to the low-risk class. TT above the median value was an independent predictor of high-risk class PCA., Conclusions: Basal TT levels are positively associated with low, intermediate and high EAU risk classes. The association is significant for the high-risk class when compared to the low-risk group, but was lost in locally advanced risk class. In PCA patients, high TT serum levels are associated with high-risk disease. Endogenous TT should be considered as a biological marker for assessing EAU PCA risk classes.

Aims: The study aimed to evaluate associations of preoperative total testosterone (TT) with the risk of aggressive prostate cancer (PCA)., Materials & Methods: From 2014 to 2018, basal TT levels were measured in 726 consecutive PCA patients. Patients were classified according to the International Society of Urologic Pathology (ISUP) system. Aggressive PCA was defined by the detection of ISUP > 2 in the surgical specimen. The logistic regression model evaluated the association of TT and other clinical factors with aggressive PCA., Results: On univariate analysis, there was a significant association of basal TT with the risk of aggressive PCA as well as age, prostate-specific antigen (PSA), percentage of biopsy positive cores (BPC), tumor clinical stage (cT), and biopsy ISUP grade groups. On multivariate analysis, two models were considered. The first (model I) excluded biopsy ISUP grading groups and the second (model II) included biopsy ISUP grade groups. Multivariate model I, revealed TT as well as all other variables, was an independent predictor of the risk of aggressive disease [odds ratio (OR) = 1.585; 95% confidence interval (CI): 1.113-2.256; p  = 0.011]. Elevated basal PSA greater than 20 µg/dl was associated with the risk of aggressive PCA. Multivariate model II revealed that basal TT levels maintain a positive association between aggressive PCA, whereas age, BPC, and clinical stage cT3 lost significance. In the final adjusted model, the level of risk of TT did not change from univariate analysis (OR = 1.525; 95% CI: 1.035-2.245; p  = 0.011)., Conclusion: Elevated preoperative TT levels are associated with the risk of aggressive PCA in the surgical specimen. TT may identify patients who are at risk of aggressive PCA in the low and intermediate European Association of Urology (EAU) risk classes., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Objective: To evaluate predictors of prostatic chronic inflammation (PCI) and prostate cancer (PCa) in patients undergoing transperineal baseline random prostatic needle biopsies (BNB)., Patient and Methods: According to BNB outcomes, patients were divided into four groups: cases without PCI or PCa (Control group), cases with PCI only (PCI group), cases with PCa and PCI (PCa+PCI group) and cases with PCa only (PCa group). A multinomial logistic regression model was used to evaluate the association of clinical factors with BNB outcomes. Additionally, clinical factors associated with the risk of PCa in the overall population were investigated using a multivariable logistic regression model (univariate and multivariate analysis)., Results: Overall, 945 patients were evaluated and grouped as follows: Control group, 308 patients (32.6%); PCI group, 160 (16.9%); PCa+PCI group, 45 (4.8%); and PCa group, 432 (45.7%). Amongst these, PCa was independently predicted by age (odds ratio [OR] 1.081), prostate specific-antigen level (PSA; OR 1.159), transition zone volume (TZV; OR 0.916), and abnormal digital rectal examination (DRE; OR 1.962). PCa and PCI (4.8%) were independently predicted by age (OR 1.081), PSA level (OR 1.122) and TZV (OR 0.954). In the group without PCa, the PSA level was the only factor associated with the risk of PCI when compared to the control group (OR 1.051, P = 0.042). Among patients with PCa, independent factors associated with the risk of only PCa compared to cases with PCA+PCI were TZV (OR 0.972) and number of positive cores (OR 1.149). In the overall population, PCI was the strongest predictor of a decreased risk of PCa (multivariate model, OR 0.212; P < 0.001)., Conclusions: At BNB, PCI was associated with both a decreased risk of PCa and less aggressive tumour biology amongst patients with PCa. The presence of PCI on biopsy cores should be reported because of its implications in clinical practice., Abbreviations: BGG: biopsy Gleason Group; BPC: biopsy positive (cancer) cores; BMI: body mass index; FGF-2: fibroblast growth factor 2; IL: interleukin; ISUP: International Society of Urologic Pathology; NIH: National Institutes of Health; OR: odds ratio; PCa: prostate cancer; PCI: prostatic chronic inflammation; TGF: transforming growth factor; TPV: total prostate volume; TZV: transition zone volume., Competing Interests: The authors have no conflicts of interest., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Our aim is to evaluate the association between body mass index (BMI) and preoperative total testosterone (TT) levels with the risk of single and multiple metastatic lymph node invasion (LNI) in prostate cancer patients undergoing radical prostatectomy and extended pelvic lymph node dissection. Preoperative BMI, basal levels of TT, and prostate-specific antigen (PSA) were evaluated in 361 consecutive patients undergoing radical prostatectomy with extended pelvic lymph node dissection between 2014 and 2017. Patients were grouped into either nonmetastatic, one, or more than one metastatic lymph node invasion groups. The association among clinical factors and LNI was evaluated. LNI was detected in 52 (14.4%) patients: 28 (7.8%) cases had one metastatic node and 24 (6.6%) had more than one metastatic node. In the overall study population, BMI correlated inversely with TT (r = -0.256; P < 0.0001). In patients without metastases, BMI inversely correlated with TT (r = -0.282; P < 0.0001). In patients with metastasis, this correlation was lost. In the overall study population, BMI (odds ratio [OR] = 1.268; P = 0.005) was the only independent clinical factor associated with the risk of multiple metastatic LNI compared to cases with one metastatic node. In the nonmetastatic group, TT was lower in patients with BMI >28 kg m -2 (P < 0.0001). In patients with any LNI, this association was lost (P = 0.232). The median number of positive nodes was higher in patients with BMI >28 kg m -2 (P = 0.048). In our study, overweight and obese patients had a higher risk of harboring multiple prostate cancer lymph node metastases and lower TT levels when compared to patients with normal BMI., Competing Interests: None

Purpose: To assess associations of prostate volume index (PVI), defined as the ratio of the volume of the central transition zone to the volume of the peripheral zone of the prostate and prostatic chronic inflammation (PCI) as predictors of tumor load by number of positive cores (PC) in patients undergoing baseline random biopsies., Methods: Parameters evaluated included age, PSA, total prostate volume, PSA density, digital rectal exam, PVI, and PCI. All patients underwent standard transperineal random biopsies. Tumor load was evaluated as absent (no PC), limited (1-3 PC), and extensive (more than 3 PC). The association of factors with the risk of tumor load was evaluated by the multinomial logistic regression model., Results: The study evaluated 945 patients. Cancer PC were detected in 477 (507%) cases of whom 207 (43.4%) had limited tumor load and 270 (56.6%) had extensive tumor load. Among other factors, comparing patients with limited tumor load with negative cases, PVI [odds ratio, OR = 0.521, 95% confidence interval (CI) 0.330-0.824; p < 0.005] and PCI (OR = 0.289, 95% CI 0.180-0.466; p < 0.0001) were inversely associated with the PCA risk. Comparing patients with extensive tumor load with negative patients, PVI (OR = 0.579, 95% CI 0.356-0.944; p = 0.028), and PCI (OR = 0.150, 95% CI 0.085-0.265; p < 0.0001), predicted PCA risk. Comparing extensive tumor load with limited tumor load patients, PVI and PCI did not show any association with the tumor load., Conclusions: Increased PVI and the presence of PCI decreased the risk of increased tumor load and associated with less aggressive prostate cancer biology in patients at baseline random biopsies.

To evaluate if diffusion tensor imaging (DTI) is able to detect morphological changes of peri-prostatic neurovascular fibers (PNF) before and after robot-assisted radical prostatectomy (RARP) and if these changes are related to urinary incontinence (UI) and erectile dysfunction (ED). From October 2014 and August 2017, 26 patients with biopsy-proven prostate cancer underwent prostatic multiparametric magnetic resonance imaging (mp-MRI) including DTI sequencing before, and 6 months after, RARP. Images were analyzed by placing six regions of interest (ROI), respectively, at base, mid gland, and apex, one for each side, to obtain tractographic reconstruction of the PNF. Patients were asked to complete International Consultation Incontinence Questionnaire-Short Form (ICIQ-SF) and International Index of Erectile Function (IIEF-5) questionnaires before RARP and 6 months post-operatively. Fractional anisotropy (FA), number (N), and length (L) of PNF before and after RARP were compared by means of Student's t test; Spearman's test was used to evaluate correlation between DTI parameters and questionnaires' scores. We observed a significant difference in N values before and after RARP (p < 0.001) and a negative correlation between IIEF-5 score and post-operative FA values at both the right (rho = - 0.42; p = 0.0456) and left (rho = - 0.66; p = 0.0006) base of the prostate. DTI with tractography of PNF is able to detect quantitative changes in N, L, and FA values in PNF after RARP. In particular, we observed an inverse correlation between FA of PNF and ED at 6 months after RARP. Further investigations are needed to confirm this trend.

The aim of the study was to evaluate clinical, pathological and peri-operative factors associated with the risk of positive surgical margins (PSM) after robot-assisted radical prostatectomy (RARP) in a high-volume center. The study is a retrospective analysis of prospectively collected data. We excluded cases who were under androgen deprivation or had prior treatments. The population included negative cases (control group) and PSM subjects (study groups). The logistic regression model assessed the independent association of factors with the risk of PSM. From January 2013 to December 2017, 732 patients underwent RARP. Extended pelvic lymph node dissection was performed in 342 cases (46.7%). Overall, 192 cases (26.3%) had PSM. Independent factors associated with the risk of focal PSM were body mass index (odds ratio, OR = 0.936; p = 0.021), percentage of biopsy-positive cores (BPC; OR = 1.012; p = 0.004), pathological extracapsular extension (OR = 2.702; p < 0.0001), seminal vesicle invasion (OR = 2.889; p < 0.0001) and high-volume surgeon (OR = 0.607; p = 0.006). In high-volume centers, features related to host, tumor biology and surgeon are independent factors associated with the risk of PSM after RARP, which are decreased by the high-volume surgeon. The inverse association between BMI and PSM risk needs further clinical research. These issues should be discussed when counseling patients.

Background: The aim of this study is to evaluate factors (clinical, pathological and perioperative) associated with the risk of hospital readmission after radical prostatectomy (RP) over the long term in a single tertiary referral center where both open RP (ORP) and robot assisted RP (RARP) are performed., Methods: From January 2013 to December 2018 patients older than 18 years, who provided signed consent and underwent open or robot assisted radical prostatectomy were enrolled and retrospectively evaluated. Patients who underwent any previous prostate cancer (PCA) treatments were excluded. Specifically, skilled and experienced surgeons performed the two surgical approaches. Patients were followed for complications and hospital readmission (RAD) for a period of six months. The association of factors with the risk of readmission was assessed by Cox's multivariate proportional hazards., Results: A total of 1062 patients underwent RP. RARP was performed in 891 cases and ORP in 171 subjects. Extended pelvic lymph node dissection (ePLND) was performed in 651 patients. Hospital readmission occurred in 53 cases (5%). Based on the final multivariate model, independent factors associated with the risk of hospital readmission were seminal vesicle invasion (HR=2.093; 95% CI: 1.177-3.722), ORP (HR=4.393; 95% CI: 2.516-7.672) and ePLND (HR=4.418; 95% CI: 1.544-12.639)., Conclusions: ORP, ePLND and seminal vesicle invasion are independent predictors of the risk of hospital readmission over the long term at a large single tertiary referral center. When surgery is chosen as a primary treatment of PCA, patients should be informed of the risk of hospital readmission and related risk factors. Assessing seminal vesicle invasion by preoperative clinical staging identifies locally advanced disease, which is associated with an increased risk of hospital readmission.

Background: The aim of this study is to evaluate clinical factors associated with the risk of tumor upgrading patterns in low risk prostate cancer (PCA) patients undergoing radical prostatectomy., Methods: In a period running from January 2013 to December 2016, 245 low risk patients underwent RP. Patients were classified into three groups, which included case with pathology grade group one (no upgrading pattern), two-three (intermediate upgrading pattern), and four-five (high upgrading pattern). The association of factors with the upgrading risk was evaluated by the multinomial logistic regression model. It was used a receiver operating characteristic (ROC) curve and area under the curve (AUC) analysis to assess the efficacy of predictors., Results: Overall, tumor upgrading was detected in 158 patients (67.3%). Tumor upgrading patterns were absent in 80 patients (32.7%), intermediate in 152 cases (62%) and high in 13 subjects (5.3%). Median prostate specific (PSA) levels and proportion of biopsy positive core (BPC) were higher in patients with intermediate (PSA=6 ng/mL; BPC=0.28) and high (PSA=8.9 ng/mL; BPC=0.33) than those without (PSA=5.7 ng/mL; BPC=0.17) and the difference was significant (PSA: P=0.002; BPC: P=0.001). When compared to not upgraded cases, higher BPC proportions were independent predictors of intermediate upgrading patterns (odds ratio, OR=36.711; P<0.0001; AUC=0.613) while higher PSA values were independent predictors of high upgrading patterns (OR=2.033, P<0.0001; AUC=0.779)., Conclusions: PSA and BPC were both independent predictors of tumor upgrading in low risk PCA. BPC associated with the risk of intermediate tumor upgrading patterns, but showed a low discrimination power. PSA associated with high upgrading patterns and showed a fair discrimination power in the model. Tumor upgrading risk patterns should be evaluated in low risk PCA patients before treatment.

Innate immune memory is characterized by a modulation in the magnitude with which innate immune cells such as monocytes and macrophages respond to potential dangers, subsequent to previous exposure to the same or unrelated agents. In this study, we have examined the capacity of gold nanoparticles (AuNP), which are already in use for therapeutic and diagnostic purposes, to modulate the innate memory induced by bacterial agents. The induction of innate memory was achieved in vitro by exposing human primary monocytes to bacterial agents (lipopolysaccharide -LPS-, or live Bacille Calmette-Guérin -BCG) in the absence or presence of AuNP. After the primary activation, cells were allowed to return to a resting condition, and eventually re-challenged with LPS. The induction of memory was assessed by comparing the response to the LPS challenge of unprimed cells with that of cells primed with bacterial agents and AuNP. The response to LPS was measured as the production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). While ineffective in directly inducing innate memory per se, and unable to influence LPS-induced tolerance memory, AuNP significantly affected the memory response of BCG-primed cells, by inhibiting the secondary response in terms of both inflammatory and anti-inflammatory factor production. The reprogramming of BCG-induced memory towards a tolerance type of reactivity may open promising perspectives for the use of AuNP in immunomodulatory approaches to autoimmune and chronic inflammatory diseases., Competing Interests: The authors declare no conflict of interest.

Current knowledge on the role of exosomal microRNA (miRNA) in canine leishmaniasis (CL), with particular regards to the interaction between miR-122 and lipid alterations, is limited. The aim of this study was to isolate/characterize exosomes in canine serum and evaluate the expression of miR-122 in ten healthy and ten leishmaniotic dogs. Serum exosomes were isolated using a polymer-based kit, ExoQuick ® and characterized by flow cytometry and transmission electron microscopy, whereas miR-122-5p expression was evaluated by quantitative reverse-transcriptase polymerase chain reaction. A significant decreased expression of exosomal miR-122-5p, decreased serum levels of high-density lipoproteins, and increased serum levels of low-density lipoproteins were seen in leishmaniotic dogs when compared with healthy dogs. These results suggest that hepatic dysfunctions induced by the parasite interfere with lipoprotein status. The decreased expression of exosomal miR122 represents an additional effect of Leishmania infection in dogs as in people.

Purpose: The coronavirus disease 2019 (COVID-19) pandemic has put a substantial burden on the Italian healthcare system, resulting in the restructuring of hospitals to care for COVID-19 patients. However, this has likely impacted access to care for patients experiencing other conditions. We aimed to quantify the impact of COVID-19 on access to care for patients with urgent/emergent urological conditions throughout Italy., Materials and Methods: A questionnaire was sent to 33 urological units in the AGILE consortium, asking clinicians to report on the number of urgent/emergent urological patients seen and/or undergoing surgery over a 3-week period during the peak of the COVID-19 outbreak and a reference week prior to the outbreak. ANOVA and linear regression models were used to quantify these changes., Results: Data from 27 urological centres in Italy showed a decrease from 956 patients/week seen just prior to the outbreak to 291 patients/week seen by the end of the study period. There was a difference in the number of patients with urgent/emergent urological disease seen within/during the different weeks (all p values < 0.05). A significant decrease in the number of patients presenting with haematuria, urinary retention, urinary tract infection, scrotal pain, renal colic, or trauma and urgent/emergent cases that required surgery was reported (all p values < 0.05)., Conclusion: In Italy, during the COVID-19 outbreak there has been a decrease in patients seeking help for urgent/emergent urological conditions. Restructuring of hospitals and clinics is mandatory to cope with the COVID-19 pandemic; however, the healthcare system should continue to provide adequate levels of care also to patients with other conditions., (© 2020 S. Karger AG, Basel.)

Objective: To test the hypothesis that basal total testosterone (TT) serum levels are associated with the D'Amico risk classification at diagnosis of prostate cancer (PCA)., Materials and Methods: From November 2014 to March 2018, preoperative basal levels of TT and prostate-specific antigen (PSA) were measured in 601 consecutive PCA patients who were not under androgen deprivation therapy or undergoing prior prostate surgery. Patients were classified into low (reference group), intermediate, and high risk classes according to biopsy findings. The association of TT and other clinical factors with risk classes was evaluated using a multivariate multinomial logistic regression model., Results: According to the D'Amico classification, 124 patients (24%) were low risk, 316 (52.6%) were intermediate risk, and 141 (23.4%) were high risk. Median basal TT circulating levels were significantly increased along clinical risk classes. TT along with PSA, percentage of biopsy positive cores, and tumor clinical stage were independently associated with a high risk (OR = 1.002; p = 0.022) but not with an intermediate risk of PCA when compared to the low risk class. In the intermediate-risk group, endogenous TT together with PSA were independently associated with tumor grade groups 2 (OR = 1.003; p = 0.022) and 3 (OR = 1.003; p = 0.043) compared to grade group 1 cancers., Conclusions: Basal TT levels are positively associated with the D'Amico risk classification, but the association is significant for the high-risk group compared to the low-risk group., (© 2020 S. Karger AG, Basel.)

Objective: To evaluate the predictors of the risk of long-term hospital readmission after radical prostatectomy (RP) in a single tertiary referral center where both open RP (ORP) and robot assisted RP (RARP) are performed., Materials and Methods: The risk of readmission was evaluated by clinical, pathological, and perioperative factors. Skilled and experienced surgeons performed the 2 surgical approaches. Patients were followed for complications and hospital readmission for a period of 6 months. The association of factors with the risk of readmission was assessed by Cox's multivariate proportional hazards., Results: From December 2013 to 2017, 885 patients underwent RP. RARP was performed in 733 cases and ORP in 152 subjects. Extended pelvic lymph node dissection (ePLND) was performed in 479 patients. Hospital readmission was detected in 46 cases (5.2%). Using a multivariate model, independent factors associated with the risk of hospital readmission were seminal vesicle invasion (hazard ratio [HR] 2.065; 95% CI 1.116-3.283; p = 0.021), ORP (HR 3.506; 95% CI 1.919-6.405; p < 0.0001), and ePLND (HR 5.172; 95% CI 1.778-15.053; p < 0.0001)., Conclusions: In a large single tertiary referral center, independent predictors of the risk of long-term hospital readmission after RP included ORP, ePLND, and seminal vesicle invasion. When surgery is chosen as a primary treatment of PCA, patients should be informed of the risk of long-term hospital readmission and its related risk factors., (© 2020 S. Karger AG, Basel.)

Objectives: The aim of this study is to evaluate the association between total testosterone density (TTD), defined as the ratio of serum TT to prostate volume (PV), and high tumor load (HTL) in low-risk prostate cancer (PCA) patients who underwent radical prostatectomy., Materials and Methods: Tumor load was defined as the percentage of prostate volume invaded by cancer (PPI-PCA) in the surgical specimen. Pathologic features including tumor upgrading, upstaging or positive surgical margins in the specimen defined unfavorable disease (UD). PSA, TT, PSA density (PSAD), TTD, percentage of biopsy positive cores (BPC), PV and body mass index (BMI). The association of factors with the risk UD and HTL was evaluated by statistical methods., Results: The cohort included 144 consecutive low-risk PCA patients. Overall, 104 patients (72.2%) had at least one feature indicating UD. TTD was associated with BMI, TT, PSA, PV and PPI-PCA ≥ 20% defined as HTL. A higher PPI-PCA was associated with an increased risk of UD with a fair discriminant power (area under the curve, AUC = 0.775; p < 0.0001). Patients with PPI-PCA > 20% were considered the study group versus patients with a PPI-PCA < 20% (control group). BPC, PSAD and TTD were independently associated with the risk of HTL (PPI-PCA ≥ 20%) with receiver-operating characteristics (ROC) curves indicating the same discriminant power for BPC (AUC = 0.628; p = 0.013), PSAD (AUC = 0.611; p = 0.032) and TTD (AUC = 0.610; p = 0.032)., Conclusions: Among low-risk PCA patients, TTD is associated with the risk of HTL, which is an independent predictor of UD and should be evaluated in the management of these patients.

Background: The aim of this study was to investigate the risk factors contributing to multiple lymph node invasion (LNI) in patients with prostate cancer (PCa) undergoing extended pelvic lymph node dissection (ePLND) during robot assisted radical prostatectomy (RARP)., Methods: A total of 211 patients who underwent RARP and ePNLD from June 2013 to March 2017 were classified according to lymph node status in the surgical specimen (absent, single or multiple). Risk factors of LNI were evaluated by the multinomial logistic regression model. A receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to assess the efficacy of factors and model evaluation., Results: On multivariate analysis, the risk of multiple LNI, was independently increased by Body Mass Index (BMI) (odds ratio [OR] 1.194; P=0.026) and prostate-specific antigen (PSA) (OR=1.089; P=0.014) when compared to patients without LNI. ROC curves indicated that both BMI (AUC=0.702) and PSA (AUC=0.732) had fair discrimination power. For each unit of increase in PSA, the odds of multiple lymph node invasion increased by 8.9% and for each unit increase of BMI, the odds of multiple LNI increased by 19.4%., Conclusions: The risk of multiple LNI was independently predicted by PSA and BMI with fair discrimination power.

Background: The aim of this study was to determine whether any clinical factors are independent predictors of positive surgical margins (PSM), and to assess the association of PSM and biochemical recurrence (BR) after robot-assisted radical prostatectomy (RARP)., Methods: The population included cases with negative surgical margins (control group) and patients with PSM (study group). Tumor grade was evaluated according to the International Society of Urologic Pathology (ISUP) system. A logistic regression model assessed the independent association of factors with the risk of PSM. The risk of BR was assessed by Cox's multivariate proportional hazards., Results: A total of 732 consecutive patients were evaluated. Extend pelvic lymph node dissection (ePLND) was performed in 342 cases (46.7%). Overall, 192 cases (26.3%) had PSM. The risk of PSM was positively associated with the percentage of biopsy positive cores (BPC; odds ratio, OR = 1.012; p  = 0.004), extracapsular extension (pT3a; OR=2.702; p  < 0.0001), invasion of seminal vesicle (pT3b; OR = 2.889; p  < 0.0001), but inversely with body mass index (OR = 0.936; p  = 0.021), and high surgeon volume (OR = 0.607; p  = 0.006). Independent clinical factors associated with the risk of BR were baseline prostate-specific antigen (PSA; hazard ratio, HR = 1.064; p  = 0.004), BPC (HR = 1.015; p  = 0.027), ISUP biopsy grade group (BGG) 2/3 (HR = 2.966; p  = 0.003), and BGG 4/5 (HR = 3.122; p  = 0.022). Pathologic factors associated with the risk of BR were ISUP group 4/5 (HR = 3.257; p  = 0.001), pT3b (HR = 2.900; p  = 0.003), and PSM (HR = 2.096; p  = 0.045)., Conclusions: In our cohort, features related to host, tumor, and surgeon volume are associated with the risk of PSM, which is also an independent parameter predicting BR after RARP. The surgical volume of the operating surgeon is an independent factor that decreases the risk of PSM, and, as such, the risk of BR., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2019.)

Background: To assess the association of prostate volume index (PVI), defined as the ratio of the central transition zone volume (CTZV) to the peripheral zone volume (PZV), and prostatic chronic inflammation (PCI) as predictors of prostate cancer (PCA) load in patients presenting with normal digital rectal exam (DRE) and prostate-specific antigen (PSA) ⩽ 10 ng/ml at baseline random biopsies., Methods: Parameters evaluated included age, PSA, total prostate volume (TPV), PSA density (PSAD), PVI and PCI. All patients underwent 14 core transperineal randomized biopsies. We considered small and high PCA load patients with no more than three (limited tumor load) and greater than three (extensive tumor load) positive biopsy cores, respectively. The association of factors with the risk of PCA was evaluated by logistic regression analysis, utilizing different multivariate models., Results: 564 Caucasian patients were included. PCA and PCI were detected in 242 (42.9%) and 129 (22.9%) cases, respectively. On multivariate analysis, PVI and PCI were independent predictors of the risk of detecting limited or extensive tumor load. The risk of detecting extensive tumor load at baseline biopsies was increased by PSAD above the median and third quartile as well as PVI ⩽ 1 [odds ratio (OR)=1.971] but decreased by PCI (OR=0.185; 95% CI: 0.088-0.388)., Conclusions: Higher PVI and the presence of PCI predicted decreased PCA risk in patients presenting with normal DRE, and a PSA ⩽ 10 ng/ml at baseline random biopsy. In this subset of patients, a PVI ⩽ or >1 is able to differentiate patients with PCA or PCI., Competing Interests: Conflict of interest statement: The authors declare that they have no conflict of interest.

Introduction: Prostate cancer (PCa) patients who are classified into the intermediate risk category represent a heterogeneous population needing further preoperative risk assessment., Objectives: To evaluate clinical total testosterone (TT) associations with lymph node invasion (LNI) in intermediate risk PCa., Material and Methods: Between November 2014 and July 2016, intermediate risk PCa was assessed in 154 patients who underwent extended pelvic lymph node dissection if the risk of LNI was higher than 5%. Clinical factors associated with the risk LNI were investigated by the multinomial logistic regression model., Results: The risk of LNI was assessed higher than 5% in 40.9% of cases of whom 15.5% had LNI. In the multivariate model, the risk of LNI was independently increased by prostate specific antigen (OR = 1.185; p = 0.021) and TT (OR = 1.004; p = 0.036). As a result, TT was an independent factor that associated with LNI because it increased the risk of LNI by 4% for each increment unit of TT., Conclusion: Preoperative TT independently increased the risk of LNI in the intermediate risk class of PCa patients elected to radical prostatectomy and extended pelvic lymph node dissection. TT might be a useful preoperative factor for stratifying intermediate risk patients because of the positive association of TT with high grade tumors., (Copyright © 2019 by S. Karger AG, Basel.)

Objectives : To evaluate clinicopathological and perioperative factors associated with the risk of focal and non-focal positive surgical margins (PSMs) after robot-assisted radical prostatectomy (RARP). Patients and methods : The study was retrospective and excluded patients who were under androgen-deprivation therapy or had prior treatments. The population included: negative SM cases (control group), focal and non-focal PSM cases (study groups). PSMs were classified as focal when the linear extent of cancer invasion was ≤1 mm and non-focal when >1 mm. The independent association of factors with the risk of focal and non-focal PSMs was assessed by multinomial logistic regression. Results : In all, 732 patients underwent RARP, from January 2013 to December 2017. An extended pelvic lymph node dissection was performed in 342 cases (46.7%). In all, 192 cases (26.3%) had PSMs, which were focal in 133 (18.2%) and non-focal in 59 (8.1%). Independent factors associated with the risk of focal PSMs were body mass index (odds ratio [OR] 0.914; P = 0.006), percentage of biopsy positive cores (BPC; OR 1.011; P = 0.015), pathological extracapsular extension (pathological tumour stage [pT]3a; OR 2.064; P = 0.016), and seminal vesicle invasion (pT3b; OR 2.150; P = 0.010). High surgeon volume was a protective factor in having focal PSM (OR 0.574; P = 0.006). Independent predictors of non-focal PSMs were BPC (OR 1,013; P = 0,044), pT3a (OR 4,832; P < 0.001), and pT3b (OR 5,153; P = 0.001). Conclusions : In high-volume centres features related to host, tumour and surgeon volume are factors that predict the risk of focal and non-focal PSMs after RARP. Abbreviations: AJCC: American joint committee on cancer; AS: active surveillance; ASA: American society of anesthesiologists; BCR: biochemical recurrence; BMI: body mass index; BPC: percentage of biopsy positive cores; ePLND: extended lymph node dissection; H&E: haematoxylin and eosin; IQR, interquartile range; ISUP: international society of urologic pathology; LNI: lymph node invasion; LOS: length of hospital stay; mpMRI: multiparametric MRI; (c)(p)N: (clinical) (pathological) nodal stage; OR: odds ratio; OT: operating time; PSA-DT: PSA-doubling time; (P)SM: (positive) surgical margin; (NS)(RA)RP: (nerve-sparing) (robot-assisted) radical prostatectomy; RT: radiation therapy; (c)(p)T: (clinical) (pathological) tumour stage.

Signal-sequence-lacking interleukin (IL)-1β, is cleaved by caspase-1 to mature mIL-1β, which is secreted, without entering the endoplasmic reticulum. We report that macrophages of GRASP55 -/- mice are defective in mIL-1β secretion and retain it as intracellular aggregates. Intriguingly, GRASP55 -/- macrophages are defective in the IRE1α branch of the unfolded protein response. This finding fits well with our data that inhibition of IRE1α also impairs mIL-1β secretion and causes its accumulation in intracellular aggregates. PERK inhibition, on the other hand, controls caspase-1-mediated conversion of proIL-1β to mIL-1β. These findings reveal translation-independent functions of PERK and IRE1α: PERK controls the production of mIL-1β, which is then followed by GRASP55 and IRE1α activity to keep mIL-1β in a secretion-competent form., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to assess the anatomical prevalence and secondary involvement of Cloquet's nodes in patients undergoing robotic radical prostatectomy (RRP) and extended pelvic lymph node dissection (ePLND) for prostate cancer (PCa)., Methods: RRP and ePLND were performed by two expert surgeons (WA and VDM). Data were prospectively collected and retrospectively analyzed. Dissected pelvic lymph nodes were sampled according to an anatomical template as follows: external iliac, obturator, Marcille's, and Cloquet's. Node packages were sent to the dedicated pathologist separately. Baseline characteristics, perioperative and pathological outcomes were analyzed., Results: Between January 2014 and December 2017 a total of 258 patients were evaluated. In aggregate 247 out of 258 patients (95.7%) presented at least a lymph node in the in the Cloquet's fossa tissue and 105 (40.6%) had more than one node. Patients with multiple nodes in Cloquet fossa presented higher median lymph node amount (27 vs. 33; P<0.0001). 13.5% of patients had lymph node invasion Pathological evaluation of the Cloquet's nodes showed metastatic PCa in 3 out of 35 (8.6%) pN+ patients. No differences were found when patients with metastatic Cloquet's nodes were compared with the pN+ population in terms of demographics, PSA, D'Amico classification, biopsy and pathological Gleason Grouping, clinical and pathological stage and complications., Conclusions: To the best of our knowledge this is the first study that analyses specifically the quantitative prevalence of Cloquet's nodes and the incidence of malignancy involvement in patients undergoing RRP and ePLND for PCa. The occurrence of multiple lymph nodes in the Cloquet fossa is a rare event. Our series showed that Cloquet involvement seems to be associated with multiple nodes cohabitation and contemporarily multiple lymph node metastases in other template locations. Related morbidity rate is sporadic and cannot justify the Cloquet preservation. Wider series are required to comprehend predictor factors of Cloquet nodes involvement. Until then the Cloquet lymphadenectomy would be recommended and should not be an option.

Objective: To determinate benefits of the combination of local anesthetic wounds infiltration and ultrasound transversus abdominal plane (US-TAP) block with ropivacaine on postoperative pain, early recovery, and hospital stay in patients undergoing robot-assisted radical prostatectomy (RARP)., Methods: The study is double-blinded randomized controlled trial. Our hypothesis was that the combination of wound infiltration and US-TAP block with ropivacaine would decrease immediate postoperative pain and opioids use. Primary outcomes included postoperative pain and opioids demand during the hospital stay. Secondary outcomes were nausea/vomiting rate, stool passing time, use of prokinetics, length of hospital stay (LOS), and 30-days readmission to the hospital for pain or other US-TAP block-related complications., Results: A total of 100 patients who underwent RARP were eligible for the analysis; 57 received the US-TAP block with 20 mL of 0.35% ropivacaine (US-TAP block group) and 43 did not receive US-TAP block (no-US-TAP group). All the patients received the local wound anesthetic infiltration with 20 mL of 0.35% ropivacaine. US-TAP block group showed a decreased mean Numerical Rating Scale (NRS) within 12 hours after surgery (1.6 vs 2.6; p = 0.02) and mean NRS (1.8 vs 2.7; p = 0.04) with lesser number of patients who used opioid (3.5% vs 18.6%; p = 0.01) during the first 24 hours. Moreover, we found a shorter mean LOS (4.27 vs 4.72, days; p = 0.04) with a lower requirement of prokinetics administration during the hospital stay (21% vs 72%; p < 0.001). No US-TAP block-related complications were reported., Conclusion: Combination of anesthetic wound infiltration and US-TAP block with ropivacaine as part of a multimodal analgesic regimen can be safely offered to patients undergoing RARP and extended pelvic lymph node dissection. It improves the immediate postoperative pain control, reducing opioids administration and is associated to a decreased use of prokinetics and shorter hospital stay.

Maintaining the optimal performance of cell processes and organelles is the task of auto-regulatory systems. Here we describe an auto-regulatory device that helps to maintain homeostasis of the endoplasmic reticulum (ER) by adjusting the secretory flux to the cargo load. The cargo-recruiting subunit of the coatomer protein II (COPII) coat, Sec24, doubles as a sensor of folded cargo and, upon cargo binding, acts as a guanine nucleotide exchange factor to activate the signaling protein Gα12 at the ER exit sites (ERESs). This step, in turn, activates a complex signaling network that activates and coordinates the ER export machinery and attenuates proteins synthesis, thus preventing large fluctuations of folded and potentially active cargo that could be harmful to the cell or the organism. We call this mechanism AREX (autoregulation of ER export) and expect that its identification will aid our understanding of human physiology and diseases that develop from secretory dysfunction., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Robot assisted radical prostatectomy (RARP) with extensive pelvic lymph node dissection (ePLND) is an effective procedure for treating and staging prostate cancer; however, high grade complications represent a critical issue. To investigate clinical factors associated with the risk of Clavien-Dindo grade 3 complications in patients undergoing RARP with ePLND. The study included 211 consecutive patients who were operated in a period running from June 2013 to March 2017. Factors associated with grade 3 complications were evaluated by the logistic regression model. Receiver operating characteristic curves and area under the curve (AUC) were used to assess the risk model. Of the 211 patients included in the study, 55 (26.1%) had complications, which were classified Clavien grade one in 36 cases (17.1%), two in 7 (3.3%), 3a in 9 (4.3%) and 3b in 3 (1.4%). Higher median measurements of body mass index (BMI) were detected in grade 3 subjects (27.6 kg/m 2 ) when compared to grade 0-2 cases (25 kg/m 2 ) and the difference was significant (P = 0.015). BMI increased the risk of high grade complications (odds ratio, OR 1.184; P = 0.047) with a fair discrimination power (AUC 0.709). It generated a risk curve by the model, which stratified patients in low (BMI < 26 kg/m 2 ; probability risk less than 5%), intermediate (26 ≤ BMI (kg/m 2 ) ≤ 30; risk between 5 and 10%), and high (BMI > 30 kg/m 2 ; risk between 10 and 20%) risk classes for grade 3 complications. BMI is an independent predictor of grade 3 complications, which are increased by 18.4% for each unit rise. Patients may be stratified preoperatively by BMI into grade 3 risk categories, which include low (normal weight), intermediate (overweight), and high (obese) risk cases.

Introduction: To test the hypothesis that basal total testosterone (TT) levels are associated with International Society of Urologic Pathology (ISUP) tumor grade groups at the time of diagnosis of prostate cancer (PCA)., Methods: From November 2014 to March 2018, preoperative TT and PSA were measured in 601 consecutive patients who were not under androgen deprivation and undergoing surgery for PCA. Patients were classified into low (ISUP 1; reference group), intermediate (ISUP 2/3), and high (ISUP 4/5) tumor grade groups. The association of TT and other clinical factors with tumor groups was evaluated by multinomial multivariate regression analysis., Results: 218 patients (36.3%) were biopsy low grade (ISUP 1), 297 (49.4%) intermediate grade (ISUP 2/3), and 86 (14.3) high grade (ISUP 4/5). Median basal circulating TT levels progressively increased as tumor grade groups increased. On multivariate models, TT, among other clinical factors, was positively associated with the risk of intermediate (OR 1.001; p = 0.023) and high tumor grades (OR 1.002, p = 0.022) compared to low-grade cancers., Conclusions: Increased endogenous circulating basal TT levels were positively associated with ISUP tumor grade groups at the time of diagnosis indicating a close association with tumor biology. Basal TT levels may reflect the heterogeneity of the cancer population., (© 2019 S. Karger AG, Basel.)