Anabolic androgenic steroids (AAS) are recommended for therapeutic clinic, but their use has increased in recent decades for aesthetic reasons. No study has evaluated the impact of AAS in the fallopian tube, after treatment and recovery periods. Herein, the aim of study was to investigate the effects of Nandrolone Decanoate (ND), administered in different doses (1.87; 3.75; 7.5 and 15 mg/kg) on the ampulla of the fallopian tube in rats, following post-treatment (PT; 15 consecutive days) and post-recovery (PR; 30 consecutive days) periods. The control group received mineral oil. Estrous cycle was monitored daily during both periods and in sequence the rats (n = 8/group/period) were killed. All ND-treated animals showed estral acyclicity during the PT and PR periods, but the histomorphometric changes in the fallopian tube varied according to the ND dose level. The expression of AR, ERα and ERβ varied in the nucleus and cytoplasm of epithelial cells. No AR expression was observed in the stroma. The muscle cells exhibited variation in immunostaining. In conclusion, ND promoted histomorphometric and immunohistochemical changes in the ampullary portion of the fallopian tube after treatment and recovery periods in a dose-independent manner.

Objective: Frequently, reproductive toxic substances such as androgenic anabolic steroids, alcohol and nicotine are used in association by adolescents and adults, in an indiscriminate manner. This study investigated the testicular and epididymal tissue of adult rats submitted to a recovery period after treatment with anabolic steroid, alcohol and /or nicotine. Materials and Methods: The animals (n=42) were divided into three control groups simulating the drugs administration routes (CI: distilled water, oral; CII: saline solution, subcutaneous; CIII: water and saline solution) and groups treated with a testosterone esters mixture (T: 7.5 mg/kg body weight-b.w., subcutaneous), alcohol (AL: 3.5 g/kg b.w. of ethanol 25%, oral), nicotine (N: 2.0 mg/kg b.w., subcutaneous), and co-administration of these three substances (T/AL/N). After 15 consecutive days of treatment (once a day), the animals were kept for 30 days in recovery. At the end of this period, the testes and epididymides were collected, weighed and processed for histological and morphometric analysis by light microscope. Results: All groups treated with toxic substances presented histopathological changes in testes and epididymis after the recovery period. There was a significant decrease (p<0.05) in testicular weight and in the morphometric parameters of the testis and epididymis in T and T/AL/N groups. Conclusion: The testis and epididymis of rats treated with anabolic steroid, alcohol and/or nicotine exhibited histopathological changes after a recovery period and the damages were more evident in the groups receiving the anabolic steroid alone or co-administered with other drugs.

e17048 Background: Standard treatment for high-grade non-muscle-invasive bladder cancer (HGNMIBC) is transurethral resection of the bladder tumor followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. Up to 40% of patients with HGNMIBC will fail intravesical BCG therapy. A promising therapeutic perspective is represented by OncoTherad immunotherapy. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein developed by University of Campinas/Brazil that exhibits antitumor properties. The aims of this study were to evaluate the efficacy and safety of OncoTherad immunotherapy for BCG-refractory or relapsed HGNMIBC. Methods: We conducted a prospective, single-center (Municipal Hospital of Paulinia, São Paulo, Brazil), single-arm phase I/ II study of OncoTherad immunotherapy in 29 (18 male, 11 female) patients with BCG-unresponsive HGNMIBC (≥ 1 previous course of BCG intravesical therapy). The schedule was initiated with weekly intravesical (120 mg/mL) and intramuscular (25 mg/mL) OncoTherad treatment for 6 weeks, followed by one every other week application for 3 months and, one monthly application until the end of the treatment (24 months). Follow-up was performed with systematic mapping biopsies of the bladder, cystoscopy and ultrasound. The primary endpoint was pathological complete response (pCR) and recurrence-free survival (RFS). The recurrence was defined as histology proven tumor recurrence (any grade) and monitored at 3-month intervals. Secondary endpoints were time to disease recurrence and safety response. Results: The median age of the 29 patients was 64 years (range 34-94). At baseline pTis, pTaG2-3, pT1G2-3 occurred in 10%, 59% and 31% of patients respectively. OncoTherad treatment showed pCR rates (95% CI) of 100% at 3, 6 and 9 months, 89,6% (26/29) at 12 months and, 89,6% (26/29) at 24 months. A 24-months RFS rate in all patients was 79,3%. Also, the median time to disease recurrence for patients was 459 days (15,3 months; 95% CI) at 24-months follow-up. 95% of adverse events were Grade 1 or 2. The most commonly reported treatment-related adverse events were dysuria (51,7%), cystitis (34,5%), pruritus (44,8%), rash (27,6%), arthralgia (27,6%) and fatigue (27,6%). Conclusions: In conclusion, OncoTherad seems a safe and effective treatment option for BCG-unresponsive HGNMIBC patients and may provide benefit for preventing tumor recurrence. Clinical trial information: RBR-6swqd2.

No abstract

461 Background: Effective intravesical therapies remain lacking for non-muscle invasive bladder cancer (NMIBC) when Bacillus Calmette-Guerin fails. OncoTherad is a nanostructured inorganic phosphate complex associated with glycosidic protein, developed by the University of Campinas/Brazil, which triggers immunomodulatory and antitumor activities. Previous studies have shown that Platelet Rich Plasma (PRP) acts on immune activation and exerts antitumor effects. This study characterized the effects of the OncoTherad associated with PRP in the treatment of NMIBC chemically induced in mice and the modulation promoted in the Toll-like receptors (TLRs) signaling pathway. Methods: Forty-two C57BL/6J mice were divided into groups: Control; Cancer (N-ethyl-N-nitrosourea carcinogen, 50 mg/ml); PRP (0.1 ml); OncoTherad (20 mg/ml); OncoTherad+PRP 10 mg/ml and OncoTherad+PRP 20 mg/ml. The intravesical doses (0.1 ml) were instilled once a week for 6 weeks after induction. Results: The NMIBC induction decreases (p<0.05) body weight, although after treatments the body weight was recovered similarly to the healthy mice. The treatments did not significantly alter the biochemical patterns of the urine and food and water consumption. There was no acute toxicity or kidney damage, and the presence of hydroureter was variable. The urinary bladders of mice treated with Oncotherad associated or not with PRP showed hyperemia associated with the inflammatory condition. The thickening of the urinary bladder wall in the Cancer group was more evident than in the treated groups, in which there were bladders without thickening or macroscopic lesions. Flat carcinoma in situ (pTis) was present in 100% of the mice in the Cancer group and the intensity of immunoreactivities for TLR2, IL-6, TLR4, and IRF-3 was significantly weaker in comparison with the Control, indicating suppression of the immune system in the tumor microenvironment. When treated intravesically with PRP only, mice showed 28.6% of tumor progression inhibition rate; with OncoTherad 85.7% and with OncoTherad+PRP 10 mg/ml or 20 mg/ml 71.4%. Intravesical treatments led to distinct activation of TLRs 2 and 4-mediated innate immune system in the interleukins (MyD88-dependent) and interferons (TRIF-dependent) signaling pathways. The combined treatment of OncoTherad+PRP increased (p<0.05) the percentage of positive TLR4 urothelial cells and the intensity of immunoreaction for TLR4 compared to the isolated treatments and the immunoreactivities of NF-kB, IL-6, TLR4, IRF-3, and IFN-γ in comparison to the Cancer. Conclusions: Intravesical treatment with OncoTherad plus PRP promoted significant inhibition of tumor progression, possibly due to immunomodulatory activity involving the TLR pathway. This association can constitute a therapeutic strategy for refractory NMIBC patients.

No abstract

e16551 Background: This study detailed and characterized the mechanisms of action of OncoTherad nano-immunotherapy based on modulation of Toll-like Receptor 4 (TLR4) signaling pathway, CX3C chemokine receptor 1 (CX3CR1, a marker of T-cell differentiation) and immune checkpoints in patients with Bacillus Calmette-Guérin (BCG)-unresponsive high-grade non-muscle invasive bladder cancer. Methods: A single-center open-label (Paulinia Municipal Hospital, Brazil) and single-arm phase 1/2 study (Clinical Trial: RBR-6swqd2) was applied in 44 patients (30 male and 14 female) with BCG-unresponsive NMIBC (≥ 1 prior course of BCG therapy) submitted to OncoTherad immunotherapy for 24 months. Patient follow-ups were performed with systematic mapping biopsies of the bladder every 3 months for the first year and every 6 months thereafter for up to 2 years. Bladder biopsies of each patient (n = 44) were divided into 2 groups: Group 1 (initial biopsy, before OncoTherad treatment); and Group 2 (bladder biopsy after OncoTherad treatment). Subsequently, the samples were submitted to immunohistochemistry analysis: TLR4-mediated IFN-γ production signaling pathway (TRIF, TBK1, IRF-3), CX3CR1+CD8+ T-cells, immune checkpoints (PD-1/PD-L1 CTLA-4) and Regulatory T cells (FOXP3). Results: After 24-months follow-up, pathological complete response rate was 72.7% (95% CI) and recurrence-free survival of 21.4 months. Bladder samples from patients submitted to OncoTherad treatment (Group 2) showed intensified TLR4, TRIF, TBK1, IRF-3 and IFN-γ immunoreactivities when compared (p < 0.01) to initial biopsies (Group 1). Furthermore, as result of interferon signaling pathway (TRIF-dependent pathway) induction by OncoTherad, intensified CX3CR1 immunoreactivities (p < 0.01) were found in the Group 2. In contrast, PD-1/PD-L1 immunoreactivities were decreased (p < 0.01) in the Group 2 when compared to Group 1. No statistical differences were found between the two groups for FOXP3 and CTLA4. Conclusions: OncoTherad nano-immunotherapy led to activation of TLR4-mediated innate immune system, resulting in increased interferon signaling pathway, which was fundamental in the activation of antitumor CD8+ T-cells and decrease of PD-1/PD-L1 expression in the bladder microenvironment. These important findings are relevant concerning the treatment of patients with NMIBC presenting high-risk of progression that are BCG-unresponsive.

Resumo: Este artigo é resultado de estágio de pesquisa no exterior realizado na Universidade de Essex - Inglaterra, nos meses de outubro e novembro do ano de 2019. Objetiva apresentar algumas aproximações sobre o debate do Serviço Social inglês, especialmente no que diz respeito às tendências do Serviço Social Radical e Neoliberal, bem como apontar alguns dados levantados em visitas institucionais e em entrevistas realizadas com assistentes sociais desse país.