Citations

Abstract Background: Pathological complete response (pCR) is accepted by FDA as a surrogate endpoint for accelerated approval of targeted agents in combination with chemotherapy based on better long-term outcomes compared to residual disease (Cortazar 2014). Methods: The multi-center, adaptively-randomized I-SPY2 platform trial uses pCR as the primary endpoint to identify investigational agents that will improve outcomes in women with stage 2/3 breast cancer with high risk of early recurrence, across all signatures, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status. For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (> 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8). Local pathologists were centrally trained using the Residual Cancer Burden (RCB) assessment to ensure uniform evaluation and response classification; RCB 0 = pCR. Results: We evaluated the relationship between pCR and event free (EFS) and distant disease free survival (DDFS) in the first 522 pts (median follow-up:2.5 years). 180 pts achieved pCR (36%) while 338 did not (RCB=1-3). There were 82 EFS and 65 DRFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p<0.001 for both). Pts achieving pCR had a 3% recurrence risk (RR) at 3 years; those with non-pCR had 24% RR over this time period. For distant recurrence, the 3-year RR with pCR was 2%, compared to 20% in pts with non-pCR. As expected, pCR rates varied by breast cancer subtype (HR+/HER2: 18% (35/196), HR+/HER2+: 40% (33/82), HR-/HER2+:68% (34/50), HR-/HER2-:41% (76/188)). The relationship between pCR and EFS was significant and clinically impactful within each subtype. 3-year survival (pCR group)Hazard Ratio OverallOverallHR+/HER2-HER2+TNBCEFS97%0.08 (0.03-0.23)0.14 (0.02-1.04)0 (NA)0.11 (0.03-0.37)DDFS98%0.08 (0.03-0.26)0.17 (0.01-1.23)0 (NA)0.09 (0.02-0.40) Conclusions: The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR vs not in Cortazar (hazard ratio 0.49), demonstrating important differences between a metaanalysis compared to a platform trial with uniform high-risk eligibility, standardized pathology assessment, and multiple targeted therapies. Our data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population. Based on these findings, the I-SPY2 TRIAL will test whether therapy can be deescalated or escalated for individual patients with the goal of achieving pCR for all. Citation Format: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-08.

While superficial (cutaneous/subcutaneous) solitary fibrous tumor (SFT) have been described, definitive diagnosis is difficult due to overlapping features with other tumors. We describe the largest series to date of superficial SFT. For inclusion, SFT had to arise in dermis or subcutis. Twenty-six cases were identified. Patients ranged from 16 to 80 years (mean, 47 y) with a marked female predominance (19 F; 7 M). Tumors involved the head (11), thigh (7), back (3), shoulder (2), upper arm (1), ankle (1), and great toe (1). Mean size was 2.9 cm (range, 1.0 to 7.0 cm). The majority (n=19) had typical histologic features (cellular SFT) with irregular fascicles of spindled cells, staghorn-like blood vessels, and variable amounts of collagen. Necrosis was evident in 3 cases (all <25%). Mitotic activity ranged from 0 to 10 mitotic figures/10 high-power fields (mean, 2 mitotic figures/10 high-power fields). Seventeen of the 18 were positive for STAT6, whereas 21/22 expressed CD34. All were low risk (23/23) by proposed criteria (Demicco and colleagues), including 2 cases with malignant histology. Three could not be risk stratified due to lack of information on tumor size. Follow-up, available on 7 cases, showed no recurrence/metastasis (mean follow-up, 100 mo; range, 2 to 241 mo). Cutaneous SFT are more common in women and most often involve the head. They are usually low risk by proposed criteria and appear to behave in an indolent manner, though larger studies are needed to confirm this. Recognition that SFT may present as a superficial mass will avoid misclassification as other CD34-positive neoplasms that frequently arise in the skin and subcutaneous tissue.

PurposeThe aim of this work was to develop an efficient daily quality assurance (QA) program with strict tolerance levels for pencil beam scanning (PBS) proton radiotherapy featuring simultaneous dosimetric testing on a single, nonuniform field.MethodsA nonuniform field measuring beam output, proton range, and spot position was designed for delivery onto a Sun Nuclear Daily‐QA 3 device. A custom acrylic block permitted simultaneous measurement of low‐ and high‐energy proton ranges in addition to beam output. Sensitivities to output, range, and spot position were evaluated to quantitate the device's response. Reproducibility tests were used to identify and control sources of measurement error as well as to assess the QA procedure's robustness. This procedure was implemented in each of our four treatment rooms independently; 4–6 months of daily QA measurements were collected.ResultsThe 1% output, 0.5 mm range, and 1.5 mm spot position tolerances derived from preliminary tests were tighter overall than tolerances found in the literature and equivalent to the limits used for proton system commissioning. The simplicity and automation of the procedure reduced the time required for daily QA to 10 min per treatment room, and competition for beam between multiple treatment rooms was minimized.ConclusionsAn efficient daily PBS QA procedure can be performed using a single, nonuniform field on a nondedicated QA device. A thorough quantitation of the device's response and careful control of measurement uncertainties allowed daily tolerances to match commissioning standards.

ABSTRACT Bacteria that produce heat‐stable enterotoxins (STs), a leading cause of secretory diarrhea, are a major cause of morbidity and mortality worldwide. ST stimulates guanylyl cyclase C (GCC) and accumulation of intracellular cyclic GMP ([cGMP] i ), which opens the cystic fibrosis transmembrane conductance regulator (CFTR)‐related chloride channel, triggering intestinal secretion. Although the signaling cascade mediating ST‐induced diarrhea is well characterized, antisecretory therapy targeting this pathway has not been developed. 2‐ChloroATP (2ClATP) and its cell‐permeant precursor, 2‐chloroadenosine (2ClAdo), disrupt ST‐dependent signaling in intestinal cells. However, whether the ability to disrupt guanylyl cyclase signaling translates into effective antisecretory therapy remains untested. In this study, the efficacy of 2ClAdo to prevent ST‐induced water secretion by human intestinal cells was examined. In Caco‐2 human intestinal cells, ST increased [cGMP] i , induced a chloride current, and stimulated net basolateral‐to‐apical water secretion. This effect on chloride current and water secretion was mimicked by the cell‐permeant analog of cGMP, 8‐bromo‐cGMP. Treatment of Caco‐2 cells with 2ClAdo prevented ST‐induced increases in [cGMP] i , chloride current and water secretion. Inhibition of the downstream consequences of ST‐GCC interaction reflects proximal disruption of cGMP production because 8‐bromo‐cGMP stimulated chloride current and water secretion in 2ClAdo‐treated cells. Thus, this study demonstrates that disruption of guanylyl cyclase signaling is an effective strategy for antisecretory therapy and provides the basis for developing mechanism‐based treatments for enterotoxigenic diarrhea.—Zhang, W., Mannan, I., Schulz, S., Parkinson, S. J., Alekseev, A. E., Gomez, L. A., Terzic, A., Waldman, S. A. Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea. FASEB J. 13, 913–922 (1999)

Background Accurate determination of right ventricular ejection fraction (RVEF) is challenging because of the unique geometry of the right ventricle. Tricuspidannular plane systolic excursion (TAPSE) and fractional area change (FAC) are commonly used echocardiographic quantitative estimates of RV function. Cardiac MRI (CMRI) has emerged as the gold standard for assessment of RVEF. We sought to summarise the available data on correlation of TAPSE and FAC with CMRI-derived RVEF and to compare their accuracy. Methods We searched PubMed, EMBASE, Web of Science, CINAHL, ClinicalTrials.gov and the Cochrane Library databases for studies that assessed the correlation of TAPSE or FAC with CMRI-derived RVEF. Data from each study selected were pooled and analysed to compare the correlation coefficient of TAPSE and FAC with CMRI-derived RVEF. Subgroup analysis was performed on patients with pulmonary hypertension. Results Analysis of data from 17 studies with a total of 1280 patients revealed that FAC had a higher correlation with CMRI-derived RVEF compared with TAPSE (0.56vs0.40, P=0.018). In patients with pulmonary hypertension, there was no statistical difference in the mean correlation coefficient of FAC and TAPSE to CMR (0.57vs0.46, P=0.16). Conclusions FAC provides a more accurate estimate of RV systolic function (RVSF) compared with TAPSE. Adoption of FAC as a routine tool for the assessment of RVSF should be considered, especially since it is also an independent predictor of morbidity and mortality. Further studies will be needed to compare other methods of echocardiographic measurement of RV function.