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Background/Objectives: Endocrine therapies that comprise anti-estrogens and aromatase inhibitors (AIs) are the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer-the most prevalent subtype. However, the emergence of resistance restricts their success by causing tumor relapse and re-growth, which demands a switch towards other therapeutic approaches in order to minimize or overcome resistance. Indeed, this clinical limitation highlights the search for new molecules to improve cancer treatment. Recently, strategies that address multiple targets have been emerging, and multi-target drugs have the potential to become the future anti-cancer molecules. Our group has been searching for new multi-target compounds, and as part of this, our study aims to understand the anti-cancer and multi-target potential of three new steroidal aromatase inhibitors (AIs): 7α-methylandrost-4-en-17-one ( 6 ), 7α-methylandrost-4-ene-3,17-dione ( 10a ) and androsta-4,9(11)-diene-3,17-dione ( 13 ). Methods: Their in vitro actions and molecular mechanisms were elucidated in a sensitive ER+ aromatase-overexpressing breast cancer cell line, MCF-7aro cells, as well as in an AI-resistant ER+ breast cancer cell line, LTEDaro cells. Results: All the new AIs (10 µM) prevented the proliferation of MCF-7aro cells by arresting cell cycle progression. Interestingly, all AIs (10 µM) act as androgen receptor (AR) agonists and modulate ER levels, synthesis and signaling to induce the apoptosis of ER+ breast cancer cells. Additionally, these new AIs (10 µM) also re-sensitize resistant cells by promoting apoptosis, offering a therapeutic benefit. Conclusions: Overall, new steroidal polypharmacological compounds have been discovered that, by acting as AIs, ER modulators and AR agonists, impair ER+ breast cancer cell growth. Overall, this study is a breakthrough on drug discovery as it presents new molecules with appealing anti-cancer properties and multi-target action for the treatment of ER+ breast cancer.

Introduction: The presence of blood in the urine should be promptly investigated to rule out urological malignancies, bladder cancer being the most frequent. Given its frequency among general population and the lack of unlimited health resources in an era of cost-effectiveness, it is important to prioritize patients with higher risk of malignancy., Objectives: To identify predictive factors of bladder cancer among patients presenting with hematuria., Patients and Methods: We retrospectively reviewed 296 cases referred to our department for hematuria. We evaluated different demographic, clinical and ultrasound features to uncover possible associations with diagnosis of bladder cancer in those patients, to estimate the individual risk of being diagnosed with bladder cancer during the investigation of hematuria., Results: A total of 296 patients were studied for hematuria between January 1, 2017 and December 31, 2019, 23.6% of those having ultimately bladder cancer confirmed after transurethral resection. Older age, male gender (OR 2.727, p = 0.069), a history of smoking (OR 3.84, p < 0.05), recurrent hematuria (OR 3.396, p < 0.05) and positive ultrasound exam for bladder cancer (OR 30.423, p < 0.05) were identified as predictors of bladder cancer in patients with hematuria., Conclusions: This study suggests that it is possible to reliably estimate the risk of bladder cancer in patients with hematuria, using clinical and imaging data to help defining who should be investigated first and in whom the investigation could be postponed.

Around 70-85% of all breast cancer (BC) cases are estrogen receptor-positive (ER + ). The third generation of aromatase inhibitors (AIs) is the first-line treatment option for these tumors. Despite their therapeutic success, they induce several side effects and resistance, which limits their efficacy. Thus, it is crucial to search for novel, safe and more effective anti-cancer molecules. Currently, multi-target drugs are emerging, as they present higher efficacy and lower toxicity in comparison to standard options. Considering this, this work aimed to investigate the anti-cancer properties and the multi-target potential of the compound 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione ( Oxy ), also designated by Oxymestane-D1, a derivative of Exemestane, which we previously synthesized and demonstrated to be a potent AI. For this purpose, it was studied for its effects on the ER + BC cell line that overexpresses aromatase, MCF-7aro cells, as well as on the AIs-resistant BC cell line, LTEDaro cells. Oxy reduces cell viability, impairs DNA synthesis and induces apoptosis in MCF-7aro cells. Moreover, its growth-inhibitory properties are inhibited in the presence of ERα, ERβ and AR antagonists, suggesting a mechanism of action dependent on these receptors. In fact, Oxy decreased ERα expression and activation and induced AR overexpression with a pro-death effect. Complementary transactivation assays demonstrated that Oxy presents ER antagonist and AR agonist activities. In addition, Oxy also decreased the viability and caused apoptosis of LTEDaro cells. Therefore, this work highlights the discovery of a new and promising multi-target drug that, besides acting as an AI, appears to also act as an ERα antagonist and AR agonist. Thus, the multi-target action of Oxy may be a therapeutic advantage over the three AIs applied in clinic. Furthermore, this new multi-target compound has the ability to sensitize the AI-resistant BC cells, which represents another advantage over the endocrine therapy used in the clinic, since resistance is a major drawback in the clinic.

Introduction: Prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and is the sixth leading cause of cancerrelated deaths amongst men worldwide. Abiraterone and enzalutamide were the first two novel hormonal agents approved for the treatment of metastatic prostate cancer but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs., Objective: To evaluate the clinical outcomes of real-world patients submitted to treatment with novel hormonal agents, enzalutamide and abiraterone, for castration resistant metastatic prostate cancer in an academic center., Patients and Methods: We retrospectively reviewed patients treated for castration-resistant prostate cancer with either abiraterone or enzulatamide between January 1, 2016 and December 31, 2019. The primary endpoints were biochemical response, biochemical progression, radiological progression, clinical deterioration (attributed to disease progression) and death., Results: Enzalutamide had a higher biochemical response rate than abiraterone in patients with mCRPC (77.1% vs 58.1%, p = 0.016). Achieving a biochemical response was associated with a lower risk of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038)., Conclusions: Enzalutamide conferred higher biochemical response rate than abiraterone in patients with mCRPC. Despite the trend to better performance of other endpoints in the enzalutamide group, it did not achieve statistical significance. Well-designed prospective studies are needed to elucidate the comparative efficacies of these agents.

A new promising steroid derivative of Exemestane (Exe), the drug used for the treatment of estrogen-dependent breast cancer, was synthesized and evaluated against a set of human cancer cell lines. The new compound (Oxymestane-D1, Oxy) was tested comparatively with Exe against colon (C2BBe1, WiDr), liver (HepG2, HuH-7), lung (A549, H1299) and prostate (LNCaP, PC3) human cancer cell lines. Likewise, its effect on human colon normal cells (CCD-841 CoN) and human normal fibroblast cells (HFF-1) was studied. The cytostatic activity of Oxy was also compared with that of the reference cytostatic drugs used in chemotherapy protocols, namely carboplatin, cisplatin, doxorubicin, epirubicin, etoposide, flutamide, 5-fluorouracil, irinotecan, oxaliplatin and sorafenib. In all cell lines tested, Oxy proved to be more powerful cytostatic than Exe. Additionally, the IC 50 at 72 h showed a three-fold activity greater than 5-fluorouracil in the WiDr cell line, twice as high as cisplatin for cell line A549 and five times higher than cisplatin for cell line H1299. Also, Oxy surprisingly revealed to induce DNA damage and inhibit the DNA damage response (DDR) proteins ATM, ATR, CHK1 and CHK2. The results obtained allow concluding that Oxy can be a promising anticancer agent to be used in chemotherapy protocols. Furthermore, its ability to inhibit crucial components of DDR can also be useful for the monotherapy or for combination with chemo and/or radiotherapy of cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Recommended imaging modalities for prostate cancer staging have disappointing sensitivities, whereas [68Ga]-PSMA PET/CT (PET-PSMA) shows promising sensitivities and specificities in the initial management of prostate cancer. Recent studies have revealed that a significant change of management when PET-PSMA was used, with favorable negative predictive values., Methods: In this retrospective study, we analyzed every PET-PSMA performed in our center for initial staging of intermediate and high-risk prostate cancer. Patients were divided into two groups based on whether imaging modalities other than PET-PSMA were performed. In patients submitted to radical prostatectomy, PET-PSMA findings were compared to histological analysis of the specimen., Results: PET-PSMA results of 57 patients were gathered, with 77.2% (n=44) having performed CT scan or bone scan (BS) prior to PET-PSMA. Prostate cancer management strategy was changed in 61.4% (n=27), when PET-PSMA was performed following CT and BS. BS and CT results were consistent with PET-PSMA in 43.2% and 44.8%, respectively. In 30 cases, a curative strategy was used based on PET-PSMA findings. PET-PSMA revealed a negative predictive value of 95.2% in 23 patients submitted to radical prostatectomy with bilateral pelvic lymphadenectomy. Prostate SUV values on preoperative PET-PSMA correlated with initial PSA, ISUP grade, PC risk staging and presence of extraprostatic lesions., Conclusions: PET-PSMA is a key element for prostate cancer staging and management, with high diagnostic accuracy. More prospective studies need to be implemented to determine its role as a first-line staging tool., Competing Interests: The authors certify that there are no conflicts of interest with any financial organization regarding the material discussed in the manuscript., (© 2021 P Lima et al.)

Background: Benign prostatic hyperplasia (BPH) is common in older adults. Although BPH may be asymptomatic in patients with chronic kidney disease (CKD) with low diuresis, the condition may become troublesome when diuresis resumes after transplantation. This study evaluated the effect that developing acute urinary retention (AUR) in first 4 months after kidney transplantation (KT) can have on graft function at 6 months. The study identified predictive factors and analyzed treatment of AUR in these patients., Methods: This study retrospectively included 303 men who received KT. Independent samples Student t test was used to compare glomerular filtration rates (GFRs) at 6 months. Logistic regression was applied to identify predictors of AUR., Results: The study found that 14 patients developed AUR within the first 4 months after KT. This group had lower GFR at 6 months post-KT. Nine patients required transurethral resection of the prostate, and 2 of these patients developed acute graft pyelonephritis following resection. Residual diuresis and recipient age were predictive factors. Recipient age >55 years was a risk factor. Medical therapy of BPH before transplantation was a protective factor., Conclusions: Developing AUR in the first 4 months after KT was associated with lower graft GFR at 6 months, and transurethral resection of the prostate was required in 64% of these patients, with good results. Medical therapy for BPH before the transplant was associated with a lower risk of AUR. Older patients and patients with pretransplant low urine output had a higher risk of AUR. These patients should be closely monitored in the posttransplant period for the presence of obstructive uropathy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Antitumor therapies based on Cold Atmospheric Plasma (CAP) are an emerging medical field. In this work, we evaluated CAP effects on bladder cancer. Two bladder cancer cell lines were used, HT-1376 (stage III) and TCCSUP (stage IV). Cell proliferation assays were performed evaluating metabolic activity (MTT assay) and protein content (SRB assay). Cell viability, cell cycle, and mitochondrial membrane potential (Δψ m ) were assessed using flow cytometry. Reactive oxygen and nitrogen species (RONS) and reduced glutathione (GSH) were evaluated by fluorescence. The assays were carried out with different CAP exposure times. For both cell lines, we obtained a significant reduction in metabolic activity and protein content. There was a decrease in cell viability, as well as a cell cycle arrest in S phase. The Δψ m was significantly reduced. There was an increase in superoxide and nitric oxide and a decrease in peroxide contents, while GSH content did not change. These results were dependent on the exposure time, with small differences for both cell lines, but overall, they were more pronounced in the TCCSUP cell line. CAP showed to have a promising antitumor effect on bladder cancer, with higher sensitivity for the high-grade cell line.

Background: Metastatic castration-resistant prostate cancer (mCRPC) is associated with a very unfavorable prognosis. At this advanced stage of the disease, there are several therapeutic strategies approved in recent times, being one of them Radium-223 dichloride (Radium-223). However, its mechanisms of action and the process that conducts to cell death are not fully understood. Given this, our main goal is to characterize the radiobiological effects induced by Radium-223 and to evaluate its kinetics on metastatic Prostate Cancer (mPCa) cells., Materials and Methods: In vitro studies were conducted using two mPCa cell lines, the LNCaP and PC3, the first being derived from lymph node metastasis and the second from bone metastasis. Kinetic studies were conducted to access the capacity of these cell lines to uptake, retain and internalize the Radium-223. For the assessment of radiobiological effects, cells were first exposed to different doses of Radium-223 and the clonogenic assay was done to evaluate cell survival and to determine lethal doses (LD50). Then, the effects were also evaluated in terms of proliferation, oxidative stress, morphological changes and cell damage., Results: Radium-223 is uptaken by mPCa cells and reaches the nucleus, where it is retained over time. Irradiation decreases cell survival and proliferation, with LNCaP cells (LD50 = 1.73mGy) being more radiosensitive than PC3 cells (LD50 = 4.20mGy). Irradiated cells showed morphological changes usually associated with apoptosis and a dose-dependent increase in DNA damage. Moreover, activation of cell cycle checkpoints occurs through ATM/CHK2 pathway, which is involved in cell cycle arrest and cell death., Conclusions: The cytotoxic and anti-proliferative effects on both cell lines showed that Radium-223 can decrease the aggressiveness of tumor cells by decreasing the cell survival and proliferation and, also, by increasing the DNA damage. The similar results observed in both cell lines indicated that Radium-223 may have the potential to be used as a therapeutic option also for mCRPC patients with lymph node metastasis. The activation of DNA Damage Response pathways allows the possibility to understand the importance of these checkpoints as targets for new combined therapies.

Pluronics are a class of amphiphilic tri-block copolymers with wide pharmaceutical applicability. In the past decades, the ability to form biocompatible nanosized micelles was exploited to formulate stable drug nanovehicles with potential use in antitumor therapy. Due to the great potential for tuning physical and structural properties of Pluronic unimers, a panoply of drug or polynucleotide-loaded micelles was prepared and tested for their antitumoral activity. The attractive inherent antitumor properties of Pluronic polymers in combination with cell targeting and stimuli-responsive ligands greatly improved antitumoral therapeutic effects of tested drugs. In spite of that, the extraordinary complexity of biological challenges in the delivery of micellar drug payload makes their therapeutic potential still not exploited to the fullest. In this review paper we attempt to present the latest developments in the field of Pluronic based nanovehicles and their application in anticancer therapy with an overview of the chemistry involved in the preparation of these nanovehicles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: The impact of positive surgical margins (PSMs) after partial nephrectomy (PN) is controversial., Objective: To evaluate the risk factors for a PSM and its impact on overall survival., Design Setting and Participants: This is a retrospective study of 388 patients were submitted to PN between November 2005 and December 2016 in a single centre. Two groups were created: PSM and negative surgical margin (NSM) after PN. A p value of <0.05 was considered significant., Outcome Measurements and Statistical Analysis: Relationships with outcome were assessed using univariable and multivariable tests and log-rank analysis., Results and Limitations: The PSM rate was 3.8% ( N  = 16). The mean age at the time of surgery (PSM group: 64.1 ± 11.3 vs NSM group: 61.8 ± 12.8 yr, p  =  0.5) and the mean radiological tumour size (4.0 ± 1.5 vs 3.4 ± 1.8 cm, p  =  0.2) were similar. Lesion location ( p  =  0.3), surgical approach ( p  =  0.4), warm ischaemia time ( p  =  0.9), and surgery time ( p  =  0.06) had no association with PSM. However, higher surgeon experience was associated with a lower PSM incidence (2.6% if ≥30 PNs vs 9.6% if <30 PNs; p  =  0.02). Higher operative blood loss ( p  =  0.02), higher-risk tumours ( p  =  0.03), and larger pathological size ( p  =  0.05) were associated with an increase in PSM. In the PSM group, recurrence rate (18.7% vs 4.2%, p  =  0.007) and secondary total nephrectomy rate (25% vs 4.4%, p  <  0.001) were higher. However, overall survival was similar. Multivariate analysis revealed that high-risk tumour ( p  =  0.05) and low experience ( p  =  0.03) could predict a PSM. Limitations include retrospective design and reduced follow-up time., Conclusions: PSMs were mainly associated with high-risk pathological tumour ( p  =  0.05) and low-volume surgeon experience. Recurrence rate and need for total nephrectomy were higher in that group, but no impact on survival was noticed., Patient Summary: The impact of positive surgical margins (PSMs) after partial nephrectomy is a matter of debate. In this study, we found that PSMs were mainly associated with aggressive disease and low surgeon experience., (© 2020 The Author(s).)

Introduction: Prostate cancer is the most commonly diagnosed cancer in men. Radical prostatectomy is a potentially curative alternative for localized disease, although a significant percentage of these patients will suffer a biochemical recurrence with associated mortality. A wide spectrum of anticancer properties of statins has been demonstrated and the role of these drugs in prevention and treatment of other types of cancer is being increasingly studied., Objective: The aim of this study was to investigate whether the use of statins is associated with reduced risk of biochemical recurrence among patients submitted to radical prostatectomy., Patients and Methods: We retrospectively reviewed 875 patients submitted to radical prostatectomy between January 2009 and December 2018. Approximately 45.7% of the patients were on medication with statins at the time of surgery. We evaluated a possible association between statin use and biochemical recurrence and which patients would benefit the most with statin treatment., Results: Overall, statins were associated with an approximately 40% reduction in risk of biochemical recurrence at a median follow-up time of 51.2 months (HR 0.599, p <0.05). Patients with pT2c staging (HR 0.486, p =0.017) and ISUP ≥3 (HR 0.61, p =0.011) seem to have benefited more from statin use., Conclusion: In this cohort, use of statins proved beneficial in reducing the risk of biochemical recurrence among patients submitted to radical prostatectomy. Prospective studies are required to confirm this result and to evaluate its safety profile in those patients., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Jarimba et al.)

Purpose of Review: Kidney transplantation is the best treatment for end-stage renal disease. However, due to organ shortage, suboptimal grafts are increasingly being used., Recent Findings: We carried out a review on the methods and techniques of organ optimization in the cadaveric setting. Donor care is the first link in a chain of care. Right after brain death, there is a set of changes, of which hormonal and hemodynamic changes are the most relevant. Several studies have been conducted to determine which drugs to administer, although in most cases, the results are not definitive. The main goal seems rather achieve a set of biochemical and hemodynamic objectives. The ischemia-reperfusion injury is a critical factor for kidney damage in transplantation. One of the ways found to deal with this type of injury is preconditioning. Local and remote ischemic preconditioning has been studied for various organs, but studies on the kidney are scarce. A new promising area is pharmacological preconditioning, which is taking its first steps. Main surgical techniques were established in the late twentieth century. Some minor new features have been introduced to deal with anatomical variations or the emergence of donation after circulatory death. Finally, after harvesting, it is necessary to ensure the best conditions for the kidneys until the time of transplantation. Much has evolved since static cold preservation, but the best preservation conditions are yet to be determined. Conservation in the cold has come to be questioned, and great results have appeared at temperatures closer to physiological.

Introduction/objective: Transplantation is the treatment of choice in end-stage renal disease. However, there are complications that require transplantectomy. The objective of this study was to evaluate predictive factors for transplantectomy in the first 3 months after renal transplantation., Material and Methods: This retrospective study included 770 kidney transplants performed between June 2011 and June 2017. Logistic regression was applied to study the relationship between independent variables and the occurrence of transplantectomy., Results: Analyzing variables of the recipients, it was verified that age over 65 years; body mass index; dialysis time; history of previous transplant and comorbidities such as obesity, overweight, hypertension, diabetes mellitus, dyslipidemia, peripheral arterial disease; or history of a thrombotic episode were not predictive factors. It was found that the use of expanded criteria donors, their age, or cause of death were not predictive factors. The use of a right renal graft or grafts with multiple arteries; the duration of surgery; the performance of surgery at dawn; the need for transfusion; the cold ischemia time; and hemodynamic parameters at reperfusion (central venous pressure, systolic or diastolic blood pressure) were not predictive factors. The recipient age at transplantation (p = .014; B=-0.059; Exp(B)=0.943 [0.899-0.988]) and reoperation in the first 10 days after transplantation (p < .001; B= -2.574; Exp(B)=0.076 [0.028-0.210]) were predictive factors., Conclusion: Reoperation in the first 10 days after transplantation decreased the risk of transplantectomy in the first 3 months. The lower the age of the recipient, the greater the risk of transplantectomy., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Kidney transplantation (KT) is a surgery performed worldwide and has some complications. The objective of this study is to evaluate our surgical complications, comparing the outcomes with those KTs without surgical complications., Patients and Methods: An observational cross-sectional study of all surgical complications among 3102 kidney transplants performed between June 1980 and April 2018., Results: Of 3102 kidney transplantations, 490 (15.8%) had the following complications: surgical complications (n = 527); urinary (n = 184; 5.9%); vascular (n = 140; 4.5%); wound-related (n = 78; 2.5%); lymphocele (n = 56; 1.8%); and others (n = 69; 2.2%). The most common complications were ureteral obstruction (n = 85; 2.7%) and urinary fistula (n = 72; 2.3%). The immunosuppression regimen did not influence the surgical complications rate. Surgical complications mainly occurred in male (71.4% vs 66.7%) and heavier (67.6 ± 13.9 vs 65.9 ± 13.5 kg) recipients (P < .05). The hospitalization time was also different (26.3 ± 30.6 vs 15.0 ± 38.8 days, P < .05). Serum creatinine values were different until the second year. After that, the renal function was approximately the same. Nearly 26.1% of complicated kidney transplants had delayed graft function (vs 14.8%, P < .001). Only 23.9% of complicated kidney transplants needed transplant nephrectomy (vs 6.2%, P < .001). The survival of kidneys with surgical complications was lower (64.2 ± 4.5 vs 94.09 ± 2.6 months, P < .001)., Discussion/conclusion: Kidney transplant surgical complications occur over time, especially urinary and vascular complications, remaining a problem that leads to prolonged hospitalization and decreased graft survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Standard multi-port laparoscopic adrenalectomy (LA) is considered the gold standard for benign adrenal tumors. Single-site LA has been proposed as a feasible and safe alternative because of lower invasiveness, improved cosmetics, less pain and shorter hospital stay. The objective was to evaluate and compare results of single-site transumbilical laparoendoscopic adrenalectomy with standard LA for adrenal tumors., Materials and Methods: One hundred consecutive adrenalectomies from 93 patients, performed between March 2009 and June 2017, were laparoscopically excised: 59 by standard multi-port LA (group 1) and 41 by transumbilical laparoendoscopic single-site adrenalectomy (group 2). Data gathered included demographics, comorbidities, preoperative imaging, tumor characteristics, perioperative data, surgical complications, pathology and follow-up. IBM SPSS Statistics 23 software was used and p value < 0.05 was considered significant., Results: Patients of group 2 were younger (48.7 ± 13.9 versus 59.7 ± 15.1 years; p < 0.001) and had fewer comorbidities (p < 0.05). Mean tumor diameter in group 2 was lower than those of group 1 (27.52 ± 14.3 versus 47.9 ± 30.6 mm; p < 0.001). Tumor laterality did not influence the choice of technique nor the surgical morbidity. All procedures were successfully completed, although one standard LA needed conversion to open surgery. Mean operative time, hemorrhagic losses, postoperative opioid analgesic requirement and hospital stay were not statistically different between groups. Most patients in group 2 (31 patients, 85.4%) did not require drainage, compared to 14 (25.4%) patients of group 1 (p < 0.001). Patients who underwent single-site LA resumed normal diet earlier (1.0 ± 0.2 versus 1.6 ± 0.7 days; p < 0.001). There were no reoperations and no perioperative mortality. Overall mean follow-up time was 94.9 ± 3.1 months, not statiscally different between groups (p = 0.7)., Conclusions: Our results revealed that transumbilical approach for laparoendoscopic single-site adrenalectomy for adrenal tumors is a feasible and safe alternative to standard laparoscopic adrenalectomy.

Introduction: Hospitals are dealing with patients who may have clinical discharge but cannot return to their home due to non-medical issues., Material and Methods: Cross-sectional analysis of all the cases referred to the Integrated Care Network during the year 2016. Evaluation of waiting times, typology, reason for referral and clinical parameters. IBM SPSS 24.0 software was used for all statisticalanalyses., Results: In the evaluated period, 2294 patients were discharged from our department. Of these, 55 were referred to Integrated Care Network. The mean length of hospitalization of the patients referred to the network was 20.6 ± 11.4 days, and the mean overall length of hospital stay in the period analyzed was 4.8 ± 0.9 days. The mean time between hospitalization and referral for continuing care was 10.7 ± 7.2 days. The time between referral and discharge of the hospital was 10.0 ± 8.7 days. Thirty-nine (70.9%) patients were hospitalized for oncological diseases. The most common referral was to Palliative Care units (n = 16; 29.1%). Patients referred to Palliative Care units showed the largest waiting times between the referral for the network and the hospital discharge, 12.2 ± 10.51 days. We observed 289 hospitalization days with patients who had no need of specialized urological care., Discussion: In order to reduce time between referral to the network and hospital discharge, there is a need for enhanced cooperation and coordination among doctors, nurses and social workers., Conclusion: Early identification by physicians and nurses of patients who will require care after discharge will provide a better response from social workers and increased hospital performance.

Osteosarcoma (OS), the main primary malignancy of bone, is the second leading cause of cancer in children and young adults. Despite the advances in modern treatments, the 5-year survival rate is retained in 60-70%, since the conventional treatment options available are associated with relapse, chemoresistance, and development of metastases, which frequently lead to patients death. In this regard, there is an increasing need to search and develop novel and alternative therapeutic approaches. Concerning this, gene therapy appears as an innovative and promising treatment option. This therapeutic option aims to deliver genetic material, through nanosystems, to repress or replace the expression of mutated genes involved in important regulatory pathways. To attain this goal, gene therapy is decidedly dependent on the efficiency of utilized vectors, constituting such a very important parameter to take in consideration. In this work, the main goal was centered on the development and full characterization of an efficient micellar nanosystem, based on the chemical conjugation between the amphiphilic copolymer Pluronic® L64 and the cationic polymer polyethyleneimine (PEI), to deliver the therapeutic miRNA-145 into OS cells leading to inhibition of cell proliferation and migration, and ultimately inducing cell death, crafting a novel anticancer therapeutic approach to OS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The leading cause of cancer death in women around the world is breast cancer. The aromatase inhibitors (AIs) are considered - as first-line treatment for estrogen receptor-positive (ER + ) breast tumors, in postmenopausal women. Exemestane (Exe) is a powerful steroidal AI, however, despite its therapeutic success, Exe-acquired resistance may occur leading to tumor relapse. Our group previously demonstrated that autophagy acts as a pro-survival process in Exe-induced cell death of ER + sensitive breast cancer cells. In this work, the role of autophagy and its relationship with the PI3K/AKT/mTOR pathway in Exe-acquired resistance was explored. In that way, the mechanism behind the effects of the combination of Exe with pan-PI3K, or autophagic inhibitors, was studied in a long-term estrogen deprived ER + breast cancer cell line (LTEDaro cells). Our results indicate that Exe induces autophagy as a cytoprotective mechanism linked to acquired resistance. Moreover, it was demonstrated that by inhibiting autophagy and/or PI3K pathway it is possible to revert Exe-resistance through apoptosis promotion, disruption of cell cycle, and inhibition of cell survival pathways. This work provides new insights into the mechanisms involved in Exe-acquired resistance, pointing autophagy as an attractive therapeutic target to surpass it. Thus, it highlights new targets that together with aromatase inhibition may improve ER + breast cancer therapy, overcoming AIs-acquired resistance., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The last edition of the AJCC staging system eliminated the pT2 subclassification of prostate cancer (PCa). Our objective was to evaluate the association of pT2 subclassification with the oncological results of patients with PCa who underwent radical prostatectomy (RP)., Material and Methods: We evaluated 367 patients who underwent RP between 2009 and 2016, with pT2 disease in the final pathological evaluation. We assessed differences in rates of biochemical recurrence (BCR), metastasis and mortality between T2 substages (pT2a/b vs pT2c)., Results: Fifty-three (14.4%) patients presented pT2a/b disease and 314 (85.6%) pT2c disease. The mean follow-up time was 4.9 ± 2.6 years. Grade group scores (p = 0.1) and prostate specific antigen (PSA) (p = 0.2) did not differed between pT2 substages. The rate of BCR in pT2a/b and pT2c patients was 11.3% and 18.2%, respectively (p = 0.2). Five (9.4%) patients with pT2a/b and 45 (14.3%) with pT2c substage underwent salvage radiotherapy (p = 0.3). The rate of positive surgical margins did not differ between groups (p = 0.2). Seven (2.2%) patients with pT2c had lymph nodes or distant metastases. The overall survival was 92.5% and 93.6% in pT2a/b and pT2c, respectively (p = 0.2)., Conclusion: Our results are in accordance with the changes introduced in the 8th edition of the AJCC staging system in which the pT2 subclassification was eliminated.

Objective: Our aim was to evaluate the effects of glucose levels and diabetes mellitus in prostate cancer (PCa) biology., Materials and Methods: Two PCa cell lines (LNCap and PC3) were cultured in RPMI medium with different glucose concentrations [5mM (LG) and 25mM (HG)]. Expressions of androgen receptor, Her2/neu and glucose transporters (GLUT1, 3, 5 and 12) were evaluated by flow cytometry. Proliferation rate was assessed by colorimetric assay MTT and cellular characterization was performed by haematoxylin and eosin staining. Additionally, we performed a cross sectional analysis of 704 patients undergoing radical prostatectomy who were divided into two groups (diabetic and non-diabetic). An analysis of clinical and histological data seeking to identify the differences on tumor aggressiveness between the two groups was performed., Results: In LNCaP cell line, when the glucose concentration in the medium increased, there was an increased in AR expression. Regarding expression of Her2/neu receptor, medium's glucose concentration significantly changed the expression of this receptor in both PC3 and LNCaP cell lines. Growth rate was higher on the HG medium for both cell lines. The clinical study of patients undergoing radical prostatectomy revealed no relationship between the presence of diabetes and the development of more aggressive tumours. Diabetic patients had significantly higher prostatic volumes, however, no significant difference was found between the relapse risk classification or the ISUP classification between the two groups., Conclusions: Our results showed that medium glucose concentration could influence prostate cancer cells growing but not the aggressiveness.

With the advance of the use of ionizing radiation in therapy, targeted alpha therapy (TAT) has assumed an important role around the world. This kind of therapy can potentially reduce side effects caused by radiation in normal tissues and increased destructive radiobiological effects in tumor cells. However, in many countries, the use of this therapy is still in a pioneering phase. Radium-223 ( 223 Ra), an alpha-emitting radionuclide, has been the first of its kind to be approved for the treatment of bone metastasis in metastatic castration-resistant prostate cancer. Nevertheless, the interaction mechanism and the direct effects of this radiopharmaceutical in tumor cells are not fully understood neither characterized at a molecular level. In fact, the ways how TAT is linked to radiobiological effects in cancer is not yet revised. Therefore, this review introduces some physical properties of TAT that leads to biological effects and links this information to the hallmarks of cancer. The authors also collected the studies developed with 223 Ra to correlate with the three categories reviewed - properties of TAT, 5 R's of radiobiology and hallmarks of cancer- and with the promising future to this radiopharmaceutical., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Immunosuppressed organ transplant patients have an elevated risk of malignancies. The aim of this study was to determine the incidence of urologic malignancies in renal transplant recipients, as well as to evaluate their monitoring, treatment, and outcomes., Methods: We conducted a retrospective single-center study of 2897 renal transplants between January 1987 and December 2016. Recipients presenting with de novo urologic malignancies were evaluated. We retrospectively assessed the stage of the disease, treatment performed, and subsequent oncologic outcome. Patients with a history of preexisting cancers were excluded., Results: Sixty-one de novo urologic malignancies were recorded in 58 patients. The overall incidence of urologic malignancies was 2.2%. We identified 29 cases of prostate cancer, 23 of renal cell carcinoma, 6 of transitional cell carcinoma of the bladder, and 1 case of penile carcinoma. No cases of testicular tumors were found. The mean age at tumor diagnosis was 58.7 ± 10.1 years. The median time between renal transplantation and tumor development was 84 months (range, 2-310 months). Fifty-six (96.6%) patients received deceased donor kidneys. The overall survival rate at 5 years after diagnosis of urologic tumor was 82.8%. Tumor-related death was reported in 13.8% of patients. Nineteen (32.8%) patients had graft loss. Of these, 8 patients had no functional graft when the diagnosis of urologic tumor was made. The therapeutic options did not differ from those used in nontransplanted patients., Conclusions: Due to the increased incidence of tumors and possibly worse prognosis, renal transplant recipients should be screened more regularly., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: In Europe, pediatric transplantation accounts for only about 4% of all kidney transplantations performed. The aim of our work is to evaluate the evolution of pediatric renal transplantation in our department over time, but also to compare this special population with the adult one., Methods: We evaluated all pediatric renal transplantations performed in our department between January 1981 and December 2016. We performed the analysis of clinical, analytical, and surgical factors to look for predictive factors of graft loss or decrease of survival. In addition, we performed a comparative study of pediatric and adult populations and an evaluation of the evolution of pediatric renal transplantation in our department over time., Results: We evaluated 101 renal transplantations performed in patients younger than 18 years. Pediatric transplantations corresponded to 3.4% of all renal transplantations performed in our department. The rate of living donors was 12%. Donors of grafts for the pediatric population were significantly younger than in the adult population. The increase in donor age was associated with lower renal graft survival rates. Acute rejections were more frequent in the pediatric population. Eleven pediatric recipients (10.9%) died in the follow-up period. Renal graft survival in the pediatric population was 94.8%, 77.4%, and 66.5% at 1, 5, and 10 years, respectively. There was no significant difference in graft survival in the pediatric and adult population. The pediatric overall survival rate at 1, 5 and 10 years was 97.9%, 96.8%, and 91.9%, respectively., Conclusion: Pediatric renal transplantation presents results identical to those identified in adults., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Renal transplantation is the best treatment for end-stage renal disease, including when using expanded criteria donors (ECD) kidneys. However, these suboptimal kidneys should be evaluated rigorously to meet their usefulness. Opinions differ about the best way to evaluate them., Materials and Methods: We retrospectively reviewed kidneys from ECD harvested by a single academic institution between January 2008 and September 2013. Needle biopsies were performed at the time of the harvest when considered relevant by the transplant team. Two pathologists where responsible for their analysis; the Remuzzi classification has been used in all cases., Results: We evaluated 560 ECD kidneys. Biopsies were made in 197 (35.2%) organs, 20 of which were considered not usable and 36 good only for double transplantation. Sixty-three kidneys (11.3%) were discarded by the transplant team based on the biopsy result and clinical criteria. Donors who underwent a biopsy were older (P < .001) and had a worse glomerular filtration rate (GFR; P = .001). Comparing donors approved and rejected by the biopsy, the rejected donors were heavier (P = .003) and had a lower GFR (P = .002). Cold ischemia time was longer for the biopsy group (P < .001). Regarding graft function, the biopsy overall score correlated with the transplant outcome in the short and long term. Separately, glomeruli and interstitium scores were correlated with recipient's GFR in the earlier periods (3 months; P = .025 and .037), and the arteries and tubules correlated with GFR in the longer term (at 3 years P = .004 and .010)., Conclusion: The decision on the usability of ECD grafts is complex. At our center, we chose a mixed approach based on donor risk. Low-risk ECD do not require biopsy. In more complex situations, especially older donors or those with a lower GFR, prompted a pretransplant biopsy. The biopsy results proved to be useful as they relate to subsequent transplant outcomes, thereby allowing us to exclude grafts whose function would most probably be less than optimal., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Exemestane is a third-generation steroidal aromatase inhibitor that has been used in clinic for hormone-dependent breast cancer treatment in post-menopausal women. It is known that exemestane undergoes a complex metabolization, giving rise to some already identified metabolites, the 17β-hydroxy-6-methylenandrosta-1,4-dien-3-one (17-βHE) and the 6-(hydroxymethyl)androsta-1,4,6-triene-3,17-dione (6-HME). In this study, four metabolites of exemestane have been analyzed, three of them were synthesized (6β-spirooxiranandrosta-1,4-diene-3,17-dione (2), 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione (3) and 17-βHE (4)) while one was acquired, the 6-HME (6). The stereochemistry of the epoxide group of 2 and 3 has been unequivocally elucidated for the first time on the basis of NOESY experiments. New structure-activity relationships (SAR) have been established through the observation that the substitution of the double bonds by epoxide groups led to less potent derivatives in microsomes. However, the reduction of the C-17 carbonyl group to a hydroxyl group originating 17-βHE (4) resulted in a significant increase in activity in MCF-7aro cells when compared to exemestane (IC50 0.25 μM vs 0.90 μM, respectively). All the studied metabolites reduced MCF-7aro cells viability in a dose and time-dependent manner, and metabolite 3 was the most potent one. Altogether our results showed that not only exemestane but also its main metabolites are potent aromatase inhibitors and reduce breast cancer cells viability. This suggests that exemestane efficacy may also be due to the active metabolites that result from its metabolic transformation. Our results emphasize the importance of performing further studies to expand our understanding of exemestane actions in breast cancer cells., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

The androgens testosterone (T) and dihydrotestosterone (DHT), besides playing an important role in prostate development and growth, are also responsible for the development and progression of benign prostate hyperplasia (BPH) and prostate cancer. Therefore, the actions of these hormones can be antagonized by preventing the irreversible conversion of T into DHT by inhibiting 5α-reductase (5α-R). This has been a useful therapeutic approach for the referred diseases and can be achieved by using 5α-reductase inhibitors (RIs). Steroidal RIs, finasteride and dutasteride, are used in clinic for BPH treatment and were also proposed for chemoprevention of prostate cancer. Nevertheless, due to the increase in bone and muscle loss, impotency and occurrence of high-grade prostate tumours, it is important to seek for other potent and specific molecules with lower side effects. In the present work, we designed and synthesized steroids with the 3-keto-Δ(4) moiety in the A-ring, as in the 5α-R substrate T, and with carboxamide, carboxyester or carboxylic acid functions at the C-17β position. The inhibitory 5α-R activity, in human prostate microsomes, as well as the anti-proliferative effects of the most potent compounds, in a human androgen-responsive prostate cancer cell line (LNCaP cells), were investigated. Our results showed that steroids 3, 4 and 5 are good RIs, which suggest that C-17β lipophylic amides favour 5α-R inhibition. Moreover, these steroids induce a decrease in cell viability of stimulated LNCaP cells, in a 5α-R dependent-manner, similarly to finasteride., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Different hormonal therapies are used for estrogen receptor positive (ER(+)) breast cancers, being the third-generation of aromatase inhibitors (AIs), an effective alternative to the classical tamoxifen. AIs inhibit the enzyme aromatase, which is responsible for catalyzing the conversion of androgens to estrogens. In this study, it was evaluated the effects of several steroidal AIs, namely 3β-hydroxyandrost-4-en-17-one (1), androst-4-en-17-one (12), 4α,5α-epoxyandrostan-17-one (13a) and 5α-androst-2-en-17-one (16), on cell proliferation, cell cycle progression and cell death in an ER(+) aromatase-overexpressing human breast cancer cell line (MCF-7aro). All AIs induced a decrease in cell proliferation and these anti-proliferative effects were due to a disruption in cell cycle progression and cell death, by apoptosis. AIs 1 and 16 caused cell cycle arrest in G0/G1, while AIs 12 and 13a induced an arrest in G2/M. Moreover, it was observed that these AIs induced apoptosis by different pathways, since AIs 1, 12 and 13a activated the apoptotic mitochondrial pathway, while AI 16 induced apoptosis through activation of caspase-8. These results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer cells and will also highlight the importance of AIs as inducers of apoptosis in hormone-dependent breast cancers.

The androgens testosterone (T) and dihydrotestosterone (DHT) play a key role in the function and integrity of prostate tissue, but are also implicated in prostate cancer and benign prostatic hyperplasia (BPH). The reduction of androgen levels can be achieved by the inhibition of 3-oxo-5α-steroid-4-dehydrogenase (5α-reductase), which is responsible for the irreversible conversion of T into its more active metabolite DHT. In fact, the use of 5α-reductase inhibitors (RIs), like finasteride, can be a valuable strategy for the treatment of BPH and in chemoprevention of prostate tumors. In this work a new method based on a dispersive liquid-liquid microextraction (DLLME) procedure, followed by gas chromatography-mass spectrometry (GC-MS), to evaluate the 5α-reductase activity, by measuring the conversion percentage of T into DHT was optimized and validated. Enzymatic assays were carried out in human prostate microsomes, using T as substrate. T and DHT were extracted by the developed DLLME technique and quantified, after silylation, by GC-MS. Variables affecting the extraction efficiency and derivatization of T and DHT were evaluated. The optimized method showed good linearity (with correlation coefficients over 0.9994 for T and 0.9995 for DHT), good recoveries (higher than 80%), and good intra- and inter-day precision (below 13%, 3 levels, n=6). The detection limits for T and DHT were 0.5 nM and the limits of quantification were 5 nM. The new GC-MS method is a good alternative to the already described methods, to evaluate 5α-reductase activity, since it avoids the use of radioactive compounds and corresponds to a fast and sensitive methodology with a good extraction efficiency, accuracy and high recovery. As this method allows the evaluation of 5α-reductase activity, also permits the study of inhibitory efficacy of new molecules as potential RIs., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In the title compound, C(17)H(27)NO(4), which is an hydro-sinapic acid derivative with increased lipophilicity conferred by an additional alkyl chain, the central and the hexyl linear chains contain slightly shorter bond lengths [C-N = 1.316 (2) Å; average linear chain C-C = 1.487 (6) Å] than reported average values [Csp(2)-N = 1.334, C-C for CH(2)-CH(2) = 1.524 and 1.513 Å for CH(2)-CH(3)]. The 4-hy-droxy-3,5-dimeth-oxy-phenyl plane [r.m.s. deviation 0.055 (12) Å] makes an angle of 59.89 (5)° with the central plane of the mol-ecule (composed of the N atom, the carbonyl group and the two methyl-ene C atoms linking the carbonyl group and the ring, [r.m.s. deviation 0.0026 (10) Å], which, in turn, makes an angle of 64.24 (13)° with the essentially planar hexyl chain [r.m.s. deviation 0.035 (18) Å]. The N-H group of the amide group is involved in a bifurcated hydrogen bond towards the hy-droxy and one of the meth-oxy O atoms of the 4-hy-droxy-3,5-dimeth-oxy-phenyl substituent of a neighbouring mol-ecule, forming a two-dimensional network in the (100) plane. In addition, the same hy-droxy group acts as a donor towards the carbonyl O atom of another neighbouring mol-ecule, forming chains running along the b axis.

In the title compound, C(20)H(26)O(2), which is the 6-methyl-ene derivative of androstenedione and a synthetic percursor of exemestane, the steroid A ring approximates to a sofa (or envelope) conformation, with the methyl-ene group adjacent to the link to the B ring lying out of the plane of the other atoms. The B and C rings have slightly flattened chair conformations and the D ring is an envelope, with the CH group forming the flap. In the crystal, mol-ecules are linked by two distinct C-H⋯O hydrogen bonds, involving acidic H atoms close to C=C and C=O double bonds.

In the crystal structure of the title compound, C(21)H(32)O(2), ring A is highly distorted, with a conformation inter-mediate between 10β-sofa and 1α,10β-half chair; rings B and C have slightly flattened chair conformations. Ring D assumes an unusual 13β-envelope conformation, probably induced by the acet-oxy substituent. Cohesion of the crystal structure is due only to weak van der Waals inter-actions.

The title compound, C(21)H(32)O(3), results from modifications of the A and D rings of the aromatase substrate androstenedione. Ring A adopts a conformation between 10β-sofa and 1α,10β half-chair. Rings B and C are in slightly flattened chair conformations. Ring D approaches a 13β-envelope conformation, probably due to the acet-oxy substituent, and shows a very short Csp(3)-Csp(3) bond next to the epoxide ring, which is characteristic of 3-4 epoxides. .

The title compound, C(19)H(29)NO, is a C17-oxime derivative of a potent aromatase inhibitor, which surprisingly has been found to have no inhibitory power. It crystallizes with two independent molecules in the asymmetric unit. C=N-O-H...N hydrogen bonds link pairs of molecules to form dimers almost parallel to the bc plane. Cohesion of the structure is also due to another three C-H...O hydrogen bonds directed along the a axis. This hydrogen-bonding scheme can be correlated to the almost complete loss of inhibitory power of the title compound.

The title compound, C(21)H(28)O(4), has a 4-acetoxy substituent positioned on the steroid alpha face. The six-membered ring A assumes a conformation intermediate between 1alpha,2beta-half chair and 1alpha-sofa. A long Csp(3)-Csp(3) bond is observed in ring B and reproduced in quantum-mechanical ab initio calculations of the isolated molecule using a molecular-orbital Hartree-Fock method. Cohesion of the crystal can be attributed to van der Waals interactions and weak C-H...O hydrogen bonds.

The title compounds, both C23H34O5, are the 5alpha and 5beta configurations of two diacetate epimers. The 5beta-diacetate crystallizes in an hexagonal structure, unusual for steroid molecules. The unit cell has an accessible solvent volume of 358 A(3), responsible for clathrate behaviour. The 5beta-epimer also features some shorter than average bond lengths in the 3alpha,4beta-acetoxy groups. The conformations of the molecules of both epimers are compared with those obtained through ab initio quantum chemistry calculations. Cohesion of the crystals can be attributed to van der Waals and weak molecular C-H...O interactions.