Citations

HIV-1 infections usually start at a mucosal surface after sexual contact. Creating a barrier of protection at these mucosal sites may be a good strategy for to protect against HIV-1 infections. While HIV-1 enters at mucosa, most vaccines are not delivered here. Most are instead injected into the muscle, a site well distant and functionally different than mucosal tissues. This study tested if delivering HIV vaccines at mucosa or in the muscle makes a difference in the quality, quantity, and location of immune responses against the virus. These data suggest that there are indeed advantages to educating the immune system at mucosal sites with an HIV-1 vaccine.

Rationale: We recently reported the association of S75Y, a point mutation in the Rag GTPase protein C ( RRAGC ) gene, with pediatric DCM. Because RRAGC directly binds and regulates mTOR and the S75Y mutation results in abnormally activated mTOR, these in vitro data prompts that the mTOR pathway could be harnessed for therapeutic benefits. Methods: We aimed to integrate in vitro neonatal rat ventricle cardiomyocytes (NRVCM) and in vivo zebrafish system to elucidate underling mechanism of RRAGC -S75Y-based cardiomyopathy, and to seek targeted therapeutic strategies. Results: Overexpression of RRAGC with S75Y mutation, but not RRAGC WT, significantly increased cell size of NRVCM, suggesting the establishment of a cellular model of RRAGC - S75Y-based cardiomyopathy. At the molecular level, overexpression of RRAGC S75Y mutant increased activity of mammalian target of rapamycin (mTOR) and decreased activity of transcription factor EB (tfeb), a direct downstream target of mTOR. Intriguingly, treatment with rapamycin, a mTOR inhibitor, did not affect cellular hypertrophy, whereas adenovirus-mediated overexpression of TFEB was able to rescue cellular hypertrophy induced by RRAGC S75Y mutation. Consistently, treatment with trehalose, an mTOR-independent tfeb activator, rescued cellular hypertrophy induced by RRAGC -S75Y. To confirm the in vitro results, we generated a knock-in (KI) zebrafish line harboring the S75Y corresponding point mutation in rragc via the TALEN (Transcription Activator-Like Effector Nucleases) technology. The cardiac function of rragc KI fish was determined by high frequency echocardiography, and the KI fish showed a significant decrease in fractional shortening compared with control littermates. Conclusion: Both cellular and in vivo models of RRAGC -S75Y-based cardiomyopathy have been generated. Studies in the cellular model suggested that tfeb, but not mTOR, is a therapeutic target for this particular type of cardiomyopathy. We will report our progress in validating this conclusion in our in vivo model, and will discuss potential mechanisms.

451 Background: Gemcitabine plus platinum (GP) is the standard of care first-line treatment for advanced biliary tract cancers (BTC). There is no established second-line therapy, and retrospective reviews report progression-free survival (PFS) for second-line treatment to be < 3 months. 5-Fluorouracil plus irinotecan (FOLFIRI) is a commonly used regimen in patients (pts) with BTC who have progressed on GP, though there is a paucity of data regarding its efficacy in this population. Methods: We retrospectively evaluated pts with advanced BTC who were treated with FOLFIRI at MD Anderson, University of Michigan and Mayo Clinic in Jacksonville. Data were obtained on pt demographics, type of BTC, PFS, and overall survival (OS). Results: Ninety-eight pts were included of which 74 (76%) had metastatic disease at the time of treatment with FOLFIRI. The median age was 59 (range, 22 to 86) years. The number of pts with extrahepatic cholangiocarcinoma (CCA)/gall bladder (GB)/intrahepatic CCA were 10, 17, and 71. FOLFIRI was used as 1st, 2nd, 3rd or 4th – Nth lines in 8, 50, 36, and 4 pts, respectively. Of the 65 pts whose best responses were documented, 23 (35%) had stable disease and 7 (11%) had a partial response per RECIST v1.1. Median duration on FOLFIRI was 2.2 months. The median PFS and OS were 2.4 (95% CI 1.7 to 3.1) and 6.6 (95% CI 4.7 to 8.4) months, respectively. Median PFS for pts treated with FOLFIRI in 1st, 2nd, 3rd or 4th – Nth lines were 3.1, 2.5, 2.3 and 1.5 months, respectively. Eighteen pts received concurrent bevacizumab (13) or EGFR-targeted therapy (5) with FOLFIRI, and both of groups exhibited a median PFS of 2.7 months. Eastern Cooperative Oncology Group performance status (PS) of 0-1 was associated with improved OS (P = 0.006) compared to PS of 2-3. Conclusions: In this multi-institution retrospective review of 98 pts with BTC treated with FOLFIRI, efficacy of this regimen appears to be modest. While PFS and OS outcomes were similar to what has been previously reported, the 46% disease control rate in this group of predominantly pretreated pts is encouraging. Given the lack of other standard therapies, FOLFIRI may still have a role in this pt population, but these results emphasize the need for more effective treatment options for pts with advanced, pretreated BTC.

AbstractBackgroundAn association is suggested between gastroesophageal reflux disease (GERD) or laryngopharyngeal reflux (LPR) and malignancy of the larynx in elderly patients in the United States. Early detection with flexible fiberoptic laryngoscopy (FFL) or CT remains poorly defined.MethodsThe Surveillance, Epidemiology, and End Results (SEER)‐Medicare linked database was queried from 2003 to 2011.A case‐cohort design evaluated patients aged 66 and older with a diagnosis of GERD and/or LPR for the occurrence of FFL or CT within 6 months of the exposure diagnosis.ResultsOf a total 156 426 Medicare beneficiaries, the relative risk of early cancer diagnosis with FFL was 14.61(95% confidence interval [CI], 13.59‐15.70), corresponding to a number needed to detect (NND) a case of cancer of 13(95% CI, 13‐14). The relative risk of an early cancer diagnosis with CT was 31.83 (95% CI, 29.57‐34.26), with a NND of 5 (95% CI, 5‐5).ConclusionsEarly FFL and CT are associated with a higher likelihood of laryngeal cancer diagnosis in elderly individuals with a diagnosis of reflux. Screening trials are necessary to establish this relationship.

Background The prognostic significance of obstructive sleep apnea ( OSA ) in patients with acute coronary syndrome ( ACS ) in the contemporary era is unclear. We performed a large, prospective cohort study and did a landmark analysis to delineate the association of OSA with subsequent cardiovascular events after ACS onset. Methods and Results Between June 2015 and May 2017, consecutive eligible patients admitted for ACS underwent cardiorespiratory polygraphy during hospitalization. OSA was defined as an apnea‐hypopnea index ≥15 events·h −1 . The primary end point was major adverse cardiovascular and cerebrovascular event ( MACCE ), including cardiovascular death, myocardial infarction, stroke, ischemia‐driven revascularization, or hospitalization for unstable angina or heart failure. OSA was present in 403 of 804 (50.1%) patients. During median follow‐up of 1 year, cumulative incidence of MACCE was significantly higher in the OSA group than in the non‐ OSA group (log‐rank, P =0.041). Multivariate analysis showed that OSA was nominally associated with incidence of MACCE (adjusted hazard ratio, 1.55; 95% CI, 0.94–2.57; P =0.085). In the landmark analysis, patients with OSA had 3.9 times the risk of incurring a MACCE after 1 year (adjusted hazard ratio, 3.87; 95% CI, 1.20–12.46; P =0.023), but no increased risk was found within 1‐year follow‐up (adjusted hazard ratio, 1.18; 95% CI, 0.67–2.09; P =0.575). No significant differences were found in the incidence of cardiovascular death, myocardial infarction, and ischemia‐driven revascularization, except for a higher rate of hospitalization for unstable angina in the OSA group than in the non‐ OSA group (adjusted hazard ratio, 2.10; 95% CI, 1.09–4.05; P =0.027). Conclusions There was no independent correlation between OSA and 1‐year MACCE after ACS . The increased risk associated with OSA was only observed after 1‐year follow‐up. Efficacy of OSA treatment as secondary prevention after ACS requires further investigation.

350 Background: BTCs are often diagnosed at an advanced stage and have a poor prognosis. The standard therapy for aBTCs is the combination of GC. However, the median overall survival (mOS) is dismal at 11.7 months (mos) with a median progression free survival (mPFS) of 8 mos. Methods: A single arm, phase II study was conducted at MD Anderson and Mayo Clinic Arizona. Patients (pts) with aBTC were treated at initial dose level of G/C/N (in mg/m2) at 1000/25/125 (n = 30) which was reduced to lower doses due to grade 3/4 hematological (heme) toxicity (tox) - G/C/N: 800/25/100 (n = 30). Cycles were q21 days with restaging q3 cycles until progression. PFS was the primary endpoint (endpt). Using a Bayesian hypothesis test-based design, we assumed mPFS of 8 mos under the null hypothesis (H0), 10 mos under the alternative (H1). Secondary endpts included mOS, RECIST v1.1 response rate (RR), safety and CA19-9 response. Results: 60 pts were enrolled with 51 being response-evaluable having received more than 1 cycle of therapy (age: median 60 yrs [range 31-77], ECOG PS 0/1 (22/38), M/F (33/27), intrahepatic cholangiocarcinoma/extrahepatic/gallbladder (38/9/13). Median follow-up was 14 mos and median number of treatment (trmt) cycles = 5.24. Pts at initial dose level had significant grade 3/4 heme tox: neutropenia, febrile neutropenia, anemia, and thrombocytopenia leading to trmt discontinuation in 6/30 pts. After dose reduction to G/C/N (in mg/m2) at 800/25/100, trmt was better tolerated with only 3 pts experiencing grade 4 heme tox. Non-heme tox were grade 3 in 19 pts: nausea/vomiting, diarrhea, thromboembolic event/CVA, hypokalemia, constipation, cystitis, LFT elevations. The mPFS = 11.4 mos (95% CI: 6.1, 16.1) and mOS = 19.2 (95%CI: 13.6, NA), 1-year survival rate 67.6%. 51 pts evaluable for response: disease control rate (PR+CR+SD)-84.3% and RR-39%. 12 unresectable cases were operated post trmt with 1 pathologic CR. Conclusions: The combination of GCN was well tolerated at adjusted doses and demonstrates encouraging efficacy having met its mPFS endpt and an impressive mOS higher than historical control. These results merit evaluating GC +/-N in a randomized controlled study. Clinical trial information: NCT02392637.