Brain-derived neurotrophic factor (BDNF) regulates a variety of physiological processes, and several studies have explored the role of BDNF in addiction-related brain regions like the nucleus accumbens core (NAcore). We sought to understand the rapid effects of endogenous BDNF on cocaine seeking. Rats were trained to self-administer cocaine and extinguished. We then microinjected two inhibitors of BDNF stimulation of tropomyosin receptor kinase B (TrkB), the non-competitive receptor antagonist ANA-12 and TrkB/Fc, a fusion protein that binds BDNF and prevents TrkB stimulation. Blocking TrkB or inactivating BDNF in NAcore potentiated active lever pressing, showing that endogenous BDNF tone was present and supplying inhibitory tone on cue-induced reinstatement. To determine if exogenous BDNF also negatively regulated reinstatement, BDNF was microinjected into NAcore 15 minutes before cue-induced reinstatement. BDNF decreased cocaine seeking through TrkB receptor binding, but had no effect on inactive lever pressing, spontaneous or cocaine-induced locomotion, or on reinstated sucrose seeking. BDNF-infusion potentiated within trial extinction when microinjected in the NAcore during cue- and context + cue induced reinstatement, and the inhibition of lever pressing lasted at least 3 days post injection. Although decreased reinstatement endured for 3 days when BDNF was administered prior to a reinstatement session, when microinjected before an extinction session or in the home cage, BDNF did not alter subsequent cued-reinstatement. Together, these data show that endogenous BDNF acts on TrKB to provide inhibitory tone on reinstated cocaine seeking, and this effect was recapitulated by exogenous BDNF.
e16047 Background: Management of stage I SGCC depends on pathological findings after orchiectomy. Four risk-adapted strategies were sequentially applied in a single institution during a 24-year (yr) period according to national guidelines. Here, we compare treatment burden and outcomes of each of them. Methods: From 1/1994 to 1/2018, 208 patients with stage I SGCC were prospectively included in 4 cohorts. Those without risk criteria underwent close surveillance. Patients received active treatment as follow: Group 1: 1994-1999, only patients with T > pT1 received 2 cycles of carboplatin (CBDCA AUC7 x2); Group 2: 1999-2003, patients received CBDCA AUC7 x2 if either tumor size > 4cm or rete testis invasion; Group 3 : 2004-2009, CBDCA AUC7 x2 if both tumor size > 4cm and rete testis invasion were present; Group 4 : ≥2010, CBDCA AUC7 x1 if either tumor size > 4cm or rete testis invasion. Kaplan Meier and log-rank tests were used to evaluate disease-free survival (DFS), Kruskal-Wallis test to compare amount of chemotherapy received per patient. Results: At a median follow-up of 108 months [range 3-423], 19 (9.1%) relapses had occurred. Global 3 and 5-yr DFS were 92.3% and 90%. All relapsing patients were rendered disease-free with 4 cycles of cisplatin (CDDP) - etoposide. Table 1 summarizes results by cohort: Conclusions: A risk-adapted program provided an overall specific survival of 100%. A clinically significant difference in RR was observed when 1 or 2 courses of CBDCA were given. In our series and considering treatment burden, vascular invasion was a better criteria for patient selection to adjuvant chemotherapy, showing a similar DFS but a lower no of total platinum cycles per patient.[Table: see text]
1582 Background: Despite the use of clinical eligibility criteria and mutation predictive models, a great proportion of families are negative for germline mutations in BRCA1/2 genes. Traditionally, risk assessment of inconclusive results included the recommendation of high-risk surveillance protocol, the update of incident cancer cases in the family and the consideration of additional testing to rule out the possibility of phenocopy. More recently, next generation sequencing multigene panels have become a standard practice in cancer genetics clinics worldwide. We addressed the value of multigene panel retesting of BRCA1/2 negative HBOC families in our institution. Methods: After genetic counseling session and informed consent, a total of 137 individuals (119 probands and 18 extra cancer-affected relatives) from distinct BRCA1/2 negative families were retested using a panel containing 11 breast and ovarian cancer susceptibility genes ( BRCA1/2, PALB2, ATM, CHEK2, PTEN, TP53, STK11, BRIP1, RAD51C, RAD51D). Results: According to the BOADICEA model, the remaining probability of mutation in BRCA1/2 or PALB2 genes in our cohort was 5.5% (0.1-61). The reasons for considering retesting were the addition of any incident cancer diagnosis in 33 cases (24%), a prior study with a low sensitivity screening technique (dHPLC) in 6 families (5%) and the expansion of the study to other putative breast and ovarian susceptibility genes in 98 families (71%). Overall, 3 pathogenic (2 BRCA2, 1 CHEK2) and 8 likely pathogenic variants (1 BRCA2, 4 CHEK2 and 3 ATM) were found. The prevalence was 8%. The detection rate among 19 families with a > 10% remaining probability of mutation in BRCA1/2 and PALB2 genes was 26%. The 3 clinically significant variants in BRCA2 were detected in 2 families and 1 updated cancer family history (BOADICEA remaining probability of 59, 61 and 12%, respectively). Cascade testing was subsequently done in 15 relatives resulting 8 in mutation carriers and 9 true negatives. Conclusions: Our results support the value of updating cancer incident cases and considering expanded panels in selected families.
e17544 Background: Patients with HPV-positive oropharyngeal cancer (OPC) have better prognosis and a lower risk of appearance of second primary neoplasm (SPN) than HPV-negative OPC patients. The aim of our study was to analyze the risk of developing SPN in a large group of patients with OPC according to HPV status in the primary tumor and its relationship with toxic habits. Methods: This study includes patients from a prospective data-base: 484 OPC patients were treated from 1991 to 2017 for which the HPV DNA positivity was evaluated by PCR in available tumor specimens. HPV DNA positive samples were further tested for HPV E6*I mRNA detection and/or p16INK4a immunohistochemistry. The mean follow-up of patients included in the study was 4.9 years (SD 5.1 years). We estimated the incidence of SPN in all cancer sites and in cancer sites related to tobacco and alcohol consumption according to the HPV status in the primary tumor. Results: Ninety-nine (20.5%) out of 484 OPCs included in the study were HPV-related. During the follow-up period, 127 patients with HPV-negative tumors (33.0%) and 19 patients with HPV-positive tumors (19.2%) had a SPN. Considering only the tobacco/alcohol-related SPNs, 106 of the patients with HPV-negative tumors (27.5%), and 12 patients with HPV-positive tumors (12.1%) had a tobacco/alcohol-related SPN (P < 0.0001). Five-year and 10-year SPN-free survival for HPV-negative versus HPV-positive OPC patients was 61.0% versus 81.5%, and 37.6% versus 73.8%, respectively (P < 0.001). When restricting the analyses to tobacco/alcohol-related SPNs, the corresponding survival rates were 66.6% versus 86.8% and 45.9% versus 83.5% for 5-year and 10-year survival rates, respectively (P < 0.0001). The frequency of tobacco/alcohol-related SPNs occurrence throughout the follow-up period for patients with HPV-negative OPC was 27.5%, for patients with HPV-positive tumors with a previous history of severe tobacco and/or alcohol use was 21.4%, and for patients with HPV-positive tumors without a history of severe tobacco and/or alcohol consumption it was 8.5% (P < 0.0001). Conclusions: HPV status and previous toxic habits might allow classifying patients regarding the risk of tobacco/alcohol-related SPNs. HPV-related OPC patients without previous history of severe tobacco and/or alcohol use have a significant low risk of SPN development, particularly in those locations related to tobacco use or alcohol consumption
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