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.
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.
e17589 Background: The term ovarian carcinoma (OC) refers to a heterogeneous collection of five distinct diseases known as histotypes. While histotype-specific treatment is still a clinical challenge, well-characterized models are required for testing new therapies. OncoTherad is a nanoimmunotherapy developed by University of Campinas/Brazil, which exhibits antitumor properties. Erythropoietin (EPO) has cytoprotective effects including in the ovaries. We assessed whether a chemically-induced animal OC model was representative of human disease by evaluating which histotype it best represents. We evaluated both mutational and immunohistochemical (IHC) biomarkers routinely used for human OC and used the observed features to provide context in the evaluation of OncoTherad and EPO effects. Methods: Thirty-five Fischer rats were distributed into 5 groups: Control (Sham surgery); Cancer (7,12-dimethylbenzoanthracene – DMBA injection in the ovarian bursa, 1.25 mg/kg); OncoTherad (20mg/kg IP); EPO (8.4 µg/kg IP); and OncoTherad+EPO (same doses). Ovary specimens were formalin-fixed into paraffin-embedded donor blocks. After DNA extraction and tissue microarray construction, we assessed typical gene mutations directly by Sanger sequencing (Pik3ca, Ctnnb1, and Kras) or indirectly using IHC surrogates (Arid1a and p53). Finally, we examined biomarkers typical of different OC histotypes (Wt1, Pr, Hnf1β) as well as lymphocyte density (CD3) by IHC. Results: The results were consistent across the cancer-induced animals. The majority of abnormal epithelial cells were Wt1+, Pr-, and Hnf1b-. Therefore, our rat model of DMBA-induced ovarian cancer was most likely serous type ovarian carcinoma, in agreement with the histopathological analysis. The ovarian lesions were molecularly similar to low-grade serous ovarian carcinoma as abnormal pattern of p53 staining was rarely observed. Loss of immunoreactivity for Arid1a protein was seen in some abnormal epithelium. However, the interpretability of mutation surrogates in rat tissues may not always be consistent with IHC analysis systems applied for human tissues. Furthermore, DNA sequencing did not reveal driver mutations in any of the sampled specimens. The treatments, especially OncoTherad+EPO, increased the number of CD3 positive immune cells. After EPO treatment, the tumor and abnormal areas showed a higher number of CD3+ lymphocytes than the normal regions; following a previous work, this could be due to substantial presence of Foxp3 positive cells. Conclusions: The features analyzed favored a low-grade serous carcinoma model in which treatments with OncoTherad and EPO showed immunomodulatory properties related to the reduction of ovarian lesions seen in previous work. The overall data highlight the importance of further characterizations of animal models to provide a complete and specific panel for testing new drugs.
e17560 Background: Ovarian cancer (OC) ranks fifth among cancer deaths in women and remains the deadliest of all gynecological cancers. OncoTherad is a nanostructured complex developed by University of Campinas/Brazil, which exhibits immunomodulatory and antitumor properties. Erythropoietin (EPO) can exert non-hematopoietic functions and the association of immunotherapy and EPO is a reality in anemic patients due to cancer or chemotherapy who may use immunotherapies. We evaluated the effects of OncoTherad and EPO, alone or in combination, on PD-1/PDL-1 and CTLA-4 checkpoints, pro-angiogenic (VEGF) and anti-angiogenic (Endostatin) markers, and microvessel density (CD31-labeled capillaries) in chemically induced ovarian cancer in rats. Methods: Thirty-five Fischer rats were distributed into groups: Control (Sham surgery); Cancer (7,12-dimethylbenzoanthracene – DMBA injection in the ovarian bursa, 1.25 mg/kg); OncoTherad (20mg/kg); EPO (8.4 µg/kg); and OncoTherad+EPO (same doses of the isolated treatments). Intraperitoneal doses were administered twice a week for 4 weeks. Immunohistochemistry was analyzed as total immunoreactivity and intensity of immunoreaction. Results: The Cancer group showed an increase (p < 0.05) in microvascular density and histopathological lesions, predominantly high-grade dysplasias with non-metastatic phenotype, which was related to the little involvement of PD-1/PD-L1 and CTLA-4 checkpoints in this carcinogenesis stage. The treatments altered the frequency of ovarian lesions, especially OncoTherad promoted a significant reduction of cystic lesions, while in the EPO group there was marked hyperplasia of the interstitial tissue and the associated treatment led to intermediate results. OncoTherad immunotherapy was effective in reducing angiogenesis, promoting a decrease (p < 0.05) in VEGF immunostaining and microvessel count, and an increase (p < 0.05) in endostatin immunoreactivity. EPO treatment decreased (p < 0.05) endostatin levels in comparison with OncoTherad group and led to a weaker (p < 0.05) immunoreaction intensity of PD-1/PD-L1 and CTLA-4 compared to the Cancer group. These effects might be related to the modification of the tumor microenvironment modulated by EPO with a decrease in the population of immune cells with immunosuppressive phenotype as well as histopathological alterations including reduction of folliculogenesis and luteogenesis. Conclusions: OncoTherad was able to prevent histopathological lesions and reduce the angiogenesis involved in the ovarian carcinogenesis. EPO treatment decreased endostatin, which possibly had effects on angiogenic activity. However, EPO also modulated the OC microenvironment by reducing PD-1/PD-L1 and CTLA-4. The association of OncoTherad+EPO might have triggered a compensatory effect between the isolated treatments.
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