Introduction: Renal cell carcinoma (RCC) with sarcomatoid component carries a poor prognosis. Immune checkpoint inhibitors (CPIs) have been approved for the treatment of metastatic RCC, but their efficacy in patients with sarcomatoid component is not known. Materials and Methods: We conducted a retrospective chart review of 30 consecutive patients at our center who were treated for metastatic RCC with sarcomatoid component. Results: Ten patients were treated with CPI group while 20 patients were in No-CPI group. There were no significant differences in age, sex, race, and stage at diagnosis between the two groups. After a median follow-up of 35 months, 3 of 10 patients in CPI arm and 5 of 20 patients in No-CPI group were alive. The median overall survival was 33.8 m in immunotherapy group compared to 8.8 m in nonimmunotherapy group (p = .001). Discussion: In our experience, CPI therapy resulted in better outcomes compared to traditional therapy with molecular-targeted agents or chemotherapy in these patients.

The incidence of cardiovascular disease is increasing in young adults. We are reporting a case of acute stroke in a young patient with severe ischaemic cardiomyopathy in the absence of traditional risk factors. After ruling out atherosclerotic disease, his presentation was attributed to synthetic cannabinoid use. We then discussed the typical barriers in early diagnosis and limitations of laboratory testing in this condition. Due to the increase in abuse of these synthetic drugs among young adults, there is a need for high clinical suspicion which can help with early recognition and improve morbidity and mortality associated with these chemicals.

Background Post‐procedural aortic insufficiency (AI) continues to be prevalent following transcatheter aortic valve replacement (TAVR). While several studies have assessed the outcomes of moderate‐severe AI following TAVR, the incidence, predictors, and outcomes of mild AI remain unclear. Methods A systematic literature review was performed to identify studies reporting on mild AI following TAVR. The primary outcome was pooled incidence of post‐TAVR mild AI. Secondary outcomes included pooled incidence of mild AI at 30 days and long term. The pooled incidence of midterm mortality in patients with post‐TAVR mild AI was also evaluated. The random effect generalized linear mixed‐effects model with logit‐transformed proportions and Hartung–Knapp adjustment was used to calculate pooled incidence rates. Meta‐regression was performed to identify predictors of mild AI. Results The pooled analysis included 19,241 patients undergoing TAVR across 50 studies. The mean age of patients ranged from 73 to 85 years, and female patients ranged from 20.0% to 83.3%. The overall pooled incidence of post‐TAVR mild AI was 56.1% (95% confidence interval [CI] 0.31–0.64). The pooled incidence of mild AI at 30 days was 33.7% (95% CI 0.12–0.37). At mean follow‐up of 1.15 years, the pooled incidence of mild AI was 37.0% (95% CI 0.16–0.45). The overall pooled incidence of Midterm mortality (mean follow‐up 1.22 years) in patients with mild AI was 14.8% (95% CI 0.10–0.25). At meta‐regression, none of the explored variables correlated with a difference in mild AI incidence. Conclusions In published studies to date, 50% of patients undergoing TAVR develop mild AI postoperatively. In 37% of patients, this persists in long term. Though the incidence of AI is likely improving with newer generation TAVR valves, the prevalence and outcomes of mild AI should be closely monitored as TAVR volume and indications expand to younger patients with long life expectancy. The long‐term outcomes of mild AI remain unclear. Further dedicated studies on post‐TAVR mild AI are needed.

Background: The spectrum of FL varies from an indolent disease course spanning decades to early transformation and death. Longitudinal studies have identified a subset of high risk patients (pts) who progress within 24 months of frontline therapy. It is still unclear how best to treat these patients and as yet, there is no standard 2nd line therapy for FL. Given the multitude of treatments available and the heterogenous disease course, it is challenging to compare outcomes of 2nd line therapy. It is unclear if the efficacy of second-line therapy in FL is influenced by the type of therapy, disease biology (early vs. late progression) or both. We conducted a single institute, retrospective study to determine the clinical benefit of 2nd line therapy in FL and to evaluate if any particular type of therapy was associated with improved outcomes in FL patients with early progression (EP). Methods: All patients with relapsed/refractory FL treated at our Institute between 1990 and 2014 were included. Patients were included if they received anti-CD20 monoclonal antibody (mAb)-based therapy in the first-line setting and completed both, first-line and second-line therapy at our Institution. Demographic, clinical, pathological and outcomes data was collected by retrospective chart review. Clinical endpoints included overall response rate (ORR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). Treatments were divided in two groups for comparison: immunotherapy alone (anti-CD20 mAb) (IT) or chemo-immunotherapy (CIT). Differences in clinical outcomes were analyzed between FL patients with early progression after 1st line therapy (EP, i.e. progression ≤ 2yrs) vs. FL with late relapse (LP, i.e. progression > 2yrs). Comparisons were made using the Mann-Whitney U and Person chi-square tests as appropriate. Survival outcomes were assessed using standard Kaplan-Meier methods. All analyses were conducted in SAS v9.4 (Cary, NC) at a significance level of 0.05. Results: A total of 537 newly diagnosed FL pts were identified of which 291 pts received 1st line therapy at our Institute. IT or CIT was given to 19.6% and 80.4% pts respectively. IT treated pts were older (median age: 61y vs 57y, p=0.033) and had lower FLIPI scores (1.5 vs 2.1, p<0.001) than CIT treated pts. Disease progression requiring 2nd line therapy was observed in 108 of 291 pts (36.4%) , 64 (59.3%) of which had EP vs 44 (40.7%) had LP. Baseline characteristics including age, gender and FLIPI scores were similar between EP and LP groups. ORR to 2nd line therapy was similar between EP and LP pts (64.3 vs. 78%, P=0.53). After a median follow up of 89.5 months (mo), the PFS, TTNT and OS of pts requiring 2nd line therapy was 14.3 mo, 17.5 mo and 92.9 mo respectively. Pts with EP had a significantly lower PFS (6.6 vs 32.8 mo, p <0.001) and TTNT (11.7 vs 36.2 mo, p <0.001) compared to LP pts with no difference in OS (77 vs 132 mo, p=0.36) [Figure 1]. Among pts with EP receiving 2nd line therapy, there were no differences between IT and CIT in terms of PFS (9.3 vs 6.4 mo, P=0.50) or TTNT (15 vs 11.6 mo, P=0.59). The OS was better in IT vs CIT (NR vs 47.6 mo, p=0.036) but has to be interpreted in the context of most pts (except one) in each group going on to receive subsequent therapies [Figure 2]. Of interest, the ORR of 2nd line therapy among pts with LP was excellent regardless of the use of IT or CIT (90.4 vs 100%, P=0.07). Moreover, in pts with LP, there were no difference in PFS (29.4 vs 32.8 mo, p=0.83), TTNT (102 vs 36.2 mo, p=0.96) and OS (132 vs 93 mo, p=0.34) based on the choice of 2nd line therapy (IT or CIT) [Figure 3]. Conclusion: FL pts with LR have excellent outcomes to 2nd line therapy and treatment selection could be determined by the agent(s) toxicity profile. In contrast, EP predicts poor clinical outcomes with short duration of response to standard IT or CIT. Therapeutic approaches incorporating clinically available targeted agents (i.e. immunomodulatory agents of B-cell receptor signaling inhibitors) or novel agents in the context of clinical trials, may provide a more effective disease control in this subgroup. Disclosures No relevant conflicts of interest to declare.

Background: X-linked inhibitor of apoptosis protein (XIAP) has been implicated in development of resistance to chemotherapy via its direct inhibition of caspases 3,7 and 9. It is overexpressed in several lymphoma cell lines including rituximab-resistant cell lines (RRCL), Raji4RH and RL4RH, produced by our group. We have previously demonstrated that XIAP is critical for chemotherapy-resistance and survival in RRCL by knocking down XIAP using siRNA interference which demonstrated that XIAP is critical for chemotherapy-sensitivity and survival in RRCL. MDM2 inhibition activates p53 transcription and inhibits translation of XIAP, thus promoting apoptosis of cancer cells. Here, we targeted XIAP at a translational level by inhibiting it with MX69, a dual inhibitor of MDM2 and XIAP. Materials and Methods: Cell lines representing Burkitt’s lymphoma (BL), activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL, germinal center B-cell like DLBCL (GCB-DLBCL), mantle cell lymphoma (MCL) and B-cell lymphoblastic leukemia were exposed to MX69 as a single agent (0-80 uM) over 24, 48 and 72 hrs and IC50 concentrations were calculated. Subsequently, Raji, Raji4RH, RL, RL4RH, HBL-2, TMD-8, Daudi and Reh cell lines were exposed to MX69 (0-80 uM), in combination with doxorubicin (0-1 uM), cytarabine (0-50 uM), vincristine (0-10 nM), etoposide (0-50 uM), carboplatin (0-10 uM), ixazomib (0-1.5 uM), ibrutinib (0-10 uM) and venetoclax (0-10 uM) for 48 hours. Cell viability was determined by Cell Titer-Glo. Coefficient of synergy was calculated using CalcuSyn. Induction of apoptosis was evaluated by flow cytometry (Annexin V/PI stain). MDM2, p53, XIAP and PARP protein expression was determined by Western blotting. Results: MX69 induced cell death in a dose- and time-dependent manner in all cell lines. Annexin/PI staining showed caspase-dependent apoptosis with MX69 in all cell lines. Western blotting confirmed significant inhibition of MDM2, XIAP and changes in p53 and PARP following exposure to MX69. MX69 demonstrated significant synergistic activity when combined with doxorubicin, ixazomib, ibrutinib or venetoclax; synergy was strongest for the MX69- venetoclax combination. Conclusion: Our data suggests that in vitro exposure to MX69 resulted in anti-tumor activity in a wide variety of B-cell lymphoma cells lines (including BL, DLBCL, MCL). Perhaps related to its anti-tumor effects, MX69 inhibited XIAP levels. These findings are similar to prior siRNA XIAP knockdown experiments. Strong synergistic activity was observed when XIAP was combined with various chemotherapy agents and small molecules inhibitors (such as venetoclax, ixazomib or ibrutinib). Ex vivo experiments using primary tumor cells isolated from lymphoma patients and lymphoma mouse models have been planned. Targeting MDM2 and XIAP can be an attractive therapeutic strategy in patients with rituximab-sensitive or -resistant B-cell lymphoma. Citation Format: Sumera Khan, Cory Mavis, Ahmad Hanif, Juan Gu, Pallawi Torka, Francisco Hernandez-Ilizaliturri. MX69 induces apoptosis by inhibiting XIAP in both rituximab sensitive and resistant lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 723.