Citations

PURPOSEThe phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.PATIENTS AND METHODSI-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.RESULTSMK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).CONCLUSIONThe Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

AbstractA recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.

342 Background: Palliation of dysphagia (Dys) in patients with inoperable esophageal cancer (EC) can be challenging. The major goal of palliation therapy is to improve patient’s quality of life (QoL) and Dys and allow adequate caloric intake. The most commonly used palliative modalities for Dys are radiation therapy (RT) and esophageal stenting. However, RT is limited by total dose and adverse events (AE) in patients receiving systemic therapy (ST), and stenting suffers from a high rate of AE including reflux and chest pain. A relatively new modality of liquid nitrogen endoscopic spray cryotherapy (cryo) has been reported in retrospective studies to improve Dys in patients receiving systemic therapy. We prospectively evaluated Dys and QoL of patients with inoperable EC undergoing cryo in addition to ST for palliation. Methods: A prospective multicenter study of 24 adult inoperable EC patients undergoing cryo and ST for palliation at 4 specialized cancer centers from Sep 2017 to Aug 2019. QoL was assessed using a modified EORTC QLQ-OES18 questionnaire (score 18 to 72, with higher scores indicating worse QoL). Dys was measured using a 4-point Likert scale: 0, no Dys; 1, Dys to solids; 2, Dys to semi-solids; 3, Dys to liquids; 4, Dys to saliva. Paired t-test was used to evaluate change in QoL and Dys between pre- and post-cryo. Results: There were 19 males and 5 females (17 stage IV, 5 stage III, and 2 stage II at diagnosis). Among 24 patients, a total of 71 cryo were performed, with a mean of 2.9 treatments per patient. After a median follow-up of 2 months, the mean EORTC score improved significantly from 35.4 at baseline to 25.5 at last follow-up ( p < 0.001). Similarly, the Dys score improved significantly from 2.0 at baseline to 0.87 at last follow-up ( p < 0.001). Grade 3 or higher AE were seen in only one patient (4%) who had GI bleeding 2 weeks after cryo and was diagnosed with bleeding from severe reflux esophagitis related to gastric outlet obstruction. Conclusions: The analysis of this multicenter prospective study shows that cryo in addition to ST for palliation of EC is well tolerated with significant improvement in Dys and QoL.

225 Background: ICIs induce durable responses in dMMR CRC patients. However, clinical and molecular biomarkers of response to ICIs have not been well-established. In this study, we investigated impact of specific MMR gene loss, BRAF V600E mutation and clinical characteristics of pts on clinical outcomes of ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or MSI-H by PCR and received ICIs between 01/01/2012 and 05/01/2019 at Winship Cancer Institute of Emory University, Mayo Clinic, Vanderbilt or Stanford University. Due to the functional dependency, the groups were categorized as protein loss of MLH1+PMS2 vs MSH2+MSH6. Log-rank test, Cox hazard model and Fisher’s exact test were used for survival outcomes, the best response and the distribution of variables among the subgroups. Results: A total of 66 pts with dMMR CRC were identified and BRAF status was available for 41 pts. ORRs in MLH1+PMS2 and MSH2+MSH6 groups were 72.9% and 56.5% respectively (P = 0.189). At 2 years, PFS rates were 55.6% and 78.2% for MLH1+PMS2 and MSH2+MSH6 groups respectively (P < 0.001). Pts with BRAF V600E mutations had significantly worse outcomes as compared to pts with wild-type BRAF (2-year PFS rate of 35.0% and 73.3% respectively; P < 0.001). Notably pts < 65 had better 2-year disease control rates when compared to > 65 (71.1% and 41.5% respectively; P < 0.001). We also observed worse 2-year PFS rates in pts with liver metastases (P = 0.014). CRC side and tumor volume did not impact 2-year PFS rates in our cohort. Conclusions: Our data suggest that pts with loss of function in MSH2+MSH6 may have better 2 year-PFS rates compared pts with MLH1+PMS2 even though ORR favored MLH1+PMS2 group suggesting that ORR may not reflect the durability of ICI response in dMMR CRC patients. Consistently, pts with BRAF V600E mutation which is associated with MLH1 promoter methylation had significantly worse 2-year PFS rates. Overall, our findings suggest that BRAFV600E mutation, the affected MMR proteins, pt age, and site of metastasis may impact durability of ICI response in dMMR CRC patients.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

AbstractAdipose‐derived mesenchymal stem cell (ADSC)‐based regenerative therapies have shown potential for use in many chronic diseases. Aging diminishes stem cell regenerative potential, yet it is unknown whether stem cells from aged donors cause adverse effects in recipients. ADSCs can be obtained using minimally invasive approaches and possess low immunogenicity. Nevertheless, we found that transplanting ADSCs from old donors, but not those from young donors, induces physical dysfunction in older recipient mice. Using single‐cell transcriptomic analysis, we identified a naturally occurring senescent cell‐like population in ADSCs primarily from old donors that resembles in vitro‐generated senescent cells with regard to a number of key pathways. Our study reveals a previously unrecognized health concern due to ADSCs from old donors and lays the foundation for a new avenue of research to devise interventions to reduce harmful effects of ADSCs from old donors.

AbstractBackgroundSystemic sirolimus (rapamycin) has recently been found effective in treating complex vascular anomalies by reducing the size and associated complications. Many vascular anomalies have a cutaneous component, and thus, we sought to determine whether topical administration of sirolimus may be an effective therapy, as data on the use of topical sirolimus are limited.ObjectiveWe reviewed the efficacy and tolerability of topical formulations of sirolimus in the treatment of various simple and combined vascular malformations and tumors.MethodsEighteen patients with any vascular anomaly treated exclusively with topical sirolimus were retrospectively reviewed.ResultsEleven patients had combined venous lymphatic malformations, three had tufted angiomas, two had a lymphatic malformation, one had a venous malformation, and one had a verrucous venous malformation. All (100%) patients reported some degree of improvement and 50% of patients reported marked improvement in one or more symptoms, most commonly blebs and lymphatic drainage, and bleeding.LimitationsThe retrospective nature, small number of patients, and differences in topical preparations limit the broad application of the results.ConclusionTopical sirolimus appears to be a safe and useful non‐invasive therapy that is well‐tolerated in the treatment of the cutaneous portion of a variety of vascular anomalies.

Abstract Background Noninvasive parameters of LV filling pressure (E/e’) and pulmonary pressures (RVSP) by Doppler echocardiography correlate with functional capacity and outcome in sinus rhythm (SR). Their role in AF is less clear. Elevated left ventricular filling pressures (E/e’) and pulmonary artery systolic pressures (PASP) by Doppler stress echocardiography correlate with impaired functional capacity in patients in sinus rhythm (SR). However, there is limited data in atrial fibrillation (AF). Purpose The aim of this study was to delineate the characteristics of patients with AF referred for exercise stress echocardiography and determine the prevalence and significance of E/e’ and PASP elevations in AF. Methods Subjects were patients referred for exercise treadmill stress echocardiography (n= 14,937) and underwent regional wall motion assessment, Doppler assessment of mitral inflow (E) and early tissue relaxation (e’) velocities and PASP at rest and immediately following maximum symptom limited exercise. Exclusion criteria included significant valvular heart disease (moderate or greater stenosis and/or regurgitation of any cardiac valve or previous valve repair or replacement) (1%), congenital heart disease (&lt;1%) or refusal to participate in research (&lt;1%). Results Patients with AF (n = 310, 2%) were older (71 ± 10 vs 59 ± 13 years, p &lt; 0.001). While resting blood pressure was similar, resting heart rates were higher in AF (80 ± 17 bpm vs 73 ± 13 bpm, p &lt; 0.0001). AF patients achieved lower workloads (6.4 ± 2.4 METS vs 9 ± 2.4 METS, p &lt; 0.001) with lower peak double products (22336 ± 6677 vs 25148 ± 5438, p &lt; 0.001). Rates of resting (27% vs 10%, p &lt; 0.0001) and exercise-induced (37% vs 20%, p &lt; 0.0001) regional wall motion abnormalities were higher in AF. Mean E/e’ was higher in AF at rest (12 ± 5 vs 9 ± 3, p &lt; 0.001) and with exercise (12 ± 5 vs 10 ± 4, p &lt; 0.001), with a higher percentage of patients in AF having E/e’ ≥15 at rest (20% vs 6% in SR, p= &lt;0.001) and with exercise in (23% vs 8%, p &lt; 0.001). PASP was higher in AF at rest (33 ± 8 mm Hg vs 28 ± 6 mm Hg, p &lt; 0.001) and with exercise (48 ± 12 vs 42 ± 11, p &lt; 0.001) compared to SR. E/e’ correlated with exercise capacity in AF and in SR, with an E/e’ cutoff of 11.7 that was best predictive of impaired functional capacity (&lt; 5 METS in women and &lt; 7 METS in men). Conclusions Abnormalities of E/e’ and PASP are more prevalent in patients with AF and correlate with impaired functional capacity. In patients with AF, a medial E/e’ ratio of ≥ 12 immediately following exercise is best associated with impaired functional capacity.