Citations

AbstractAn 8‐year‐old girl born to a family with more than three generations of dominant dystrophic epidermolysis bullosa (DDEB) presented with life‐threatening confluent skin erosions, mitten hand deformity, and failure to thrive. Reassessment of her family history and genetic testing showed compound heterozygous COL7A mutations, one inherited from her DDEB‐affected mother and one from her unaffected, healthy father. This family illustrates the risk of unexpected, severe, autosomal recessive epidermolysis bullosa (EB) in a family with milder, multigenerational autosomal dominant EB. Clinicians should recognize the clinical spectrum of dystrophic EB and recommend genetic consultation when the phenotype conflicts with family history.

Abstract Purpose: Investigate the utility of patient-specific spatial predictions of tumor cell density from a bio-mathematical model. Introduction: Glioblastomas (GBMs) are the most malignant of all primary brain tumors. While it is known there is always a non-detectable portion of the tumor, current techniques of monitoring GBM progression, imaging and initial histological assessment, are not able to reliably estimate the tumor invasion past the enhancing region on T2-Weighted (T2W) imaging. Over the last two decades, a large effort has been made to create a simple patient-specific mathematical model of gliomas. The resulting model, referred to as the Proliferation-Invasion (PI) model, is based on two key parameters, the net growth rate, ρ, and the dispersal coefficient, D. In this model, the ratio of D/ρ is related to degree of invasion and the product D*ρ, is related to the speed of growth. The intuitive understanding provided by this model has been able to provide patient-specific understanding of disease kinetics enabling prediction of outcomes following surgical resection, radiation and the development of a prognostic response metric. Previous literature utilizing this model has been based on the assumption that what is seen on the pretreatment T1-Weighted contrast-enhanced (T1Gd) and T2W, images correspond to an 80% and 16% tumor cell density threshold respectively. This assumption allows for an estimate of D/ρ from a single time point of imaging. While these values were based on extensive experience, for ethical and technical reasons, they have never been rigorously investigated histologically. Recent technological advances have made it possible for surgeons to use an MRI to guide the acquisition of tissue making it possible to know with a good degree of accuracy where on the MR image the histological specimen comes from. Methods: Model Calibration : To estimate D/ρ for each patient, we assume abnormalities on the T1Gd and T2W images correspond to an 80% and 16% tumor cell density threshold respectively. We then utilize a Bayesian calibration approach based on adaptive grid refinement while holding the velocity constant to find the most likely value of D/ρ to match the observed radial measurements. Three-Dimensional Density Maps : Given a gray/white segmentation and an estimate for D/ρ, we can build a tumor cell density prediction in the patient's anatomy using the Eikonal equations and the modified Fast Marching Method (FMM) algorithm presented by Konukoglu et al. Patient Cohort : Eighteen patients were recruited with clinically suspected GBM undergoing preoperative stereotactic MRI for surgical resection with IRB approval Barrow Neurological Institute and Mayo Clinic in Arizona. Surgical Biopsy : Pre-operative conventional MRI, including T1Gd and T2W, was utilized to guide stereotactic biopsies. An average of 5–6 tissue specimens were acquired from each tumor by using stereotactic surgical localization, following the smallest possible diameter craniotomies to minimize brain shift. Histological Analysis : 4 μm tissue sections were stained with hematoxylin and eosin (H&E) for neuropathology review. H&E slides were reviewed by a neuropathologist. The percent tumor nuclei in the field was estimated. Results and Conclusion: Our analysis showed that the intuitive ordering of diffuse to nodular tumor profiles from the PI model is consistent with the histologic data. Further, utilizing the histologic data, limitations to a universal threshold cutoff of the T2/FLAIR region are specified and a better threshold cutoff value is suggested. We hope that this paper will lead to more studies of this kind resulting in more accurate ways to predict the spatial distribution of GBM tumor cells from medical imaging. Such advances could revolutionize surgical procedures and radiation therapy and may enable additional insights into tumor kinetic differences meaningful for treatment. Citation Format: Andrea Hawkins-Daarud, Lauren DeGirolamo, Joshua Jacobs, Kamala Clark-Swanson, Jennifer M. Eschbacher, Kris A. Smith, Peter Nakaji, Leslie C. Baxter, John P. Karis, Teresa Wu, J. Ross Mitchell, Jing Li, Leland Hu, Kristin R. Swanson. Histologic evidence for a bio-mathematical model of glioblastoma invasion. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A08.

Abstract Background LIV-1, a transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells. It is associated with lymph node involvement and metastatic progression. SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which binds to tubulin and induces G2/M arrest and apoptosis. Methods This is an ongoing, phase 1 dose-escalation study evaluating safety, tolerability, pharmacokinetics, and antitumor activity of SGN-LIV1A (q3 wks IV) in women with LIV-1-positive, unresectable, locally advanced or metastatic breast cancer (LA/MBC) (NCT01969643). Patients (pts) with measurable disease and ≥2 prior cytotoxic regimens for LA/MBC were eligible. Pts with ≥Grade 2 neuropathy were excluded. Response was assessed per RECIST v1.1; pts with stable disease (SD) or better could continue treatment until disease progression or intolerable toxicity. At completion of dose escalation in hormone receptor-positive/HER2-negative (HR+/HER2–) and triple-negative (TN) pts, expansion cohorts were opened to further evaluate safety and antitumor activity of monotherapy in TN pts and combination therapy with trastuzumab (Tz) in HER2-positive (HER2+) pts. Pre- and post-treatment tumor biopsies were done to evaluate LIV-1 expression and other correlative endpoints. Results To date, 39 pts (18 HR+/HER2–, 21 TN) have received a median of 3 cycles (range, 1–10) of SGN-LIV1A monotherapy at doses of 0.5–2.8 mg/kg. Median age was 57 yrs (range, 33–79). At baseline, pts had a median of 4 prior cytotoxic regimens for LA/MBC (range, 2–8); 36 had visceral disease and 25 had bone involvement. No dose-limiting toxicities (DLT) occurred in 19 DLT-evaluable pts; maximum tolerated dose was not exceeded at 2.8 mg/kg. Treatment-emergent adverse events (AEs) reported in ≥30% of pts were: fatigue (64%), nausea (54%), alopecia (46%), decreased appetite (41%), constipation (39%), neutropenia (33%), and vomiting (31%). Peripheral neuropathy was reported in 9 pts (23%). Most AEs were Grade 1/2, except neutropenia (all ≥Grade 3). Four pts discontinued treatment due to AEs (acute respiratory distress syndrome, nausea, pneumonia, tachycardia). In dose escalation, modest activity was observed in 17 efficacy evaluable (EE) HR+/HER2- pts, with a disease control rate (DCR) of 59% (10 SD), including 1 pt with SD≥24 wks. Among the 17 EE TN pts (dose escalation plus cohort expansion), the overall response rate (ORR) was 41% (7 PR), DCR was 82% (7 PR, 7 SD) and clinical benefit rate (CBR=OR+SD≥24 wks) was 53% (9 pts). For TN pts, median PFS was 17.1 wks (95% CI: 6.0, 18.4); 6 pts remain on treatment. Of 281 MBC tumor samples evaluated for LIV-1, 93% were positive; 81% had moderate-to-high expression (H-score ≥100). Conclusions LIV-1 is expressed in almost all MBC tumors. SGN-LIV1A monotherapy has been generally well tolerated and shown encouraging antitumor activity in heavily pretreated TN MBC, with a PR rate of 41% and a CBR at ≥24 wks of 53%. Response duration data continue to evolve. Enrollment continues in the TN monotherapy expansion cohort and the HER2+ combination cohort with Tz. Citation Format: Forero-Torres A, Modi S, Specht J, Miller K, Weise A, Burris III H, Liu M, Krop I, Pusztai L, Kostic A, Li M, Mita M. Phase 1 study of the antibody-drug conjugate (ADC) SGN-LIV1A in patients with heavily pretreated metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-04.

Key Points Depletion of CD123-redirected CAR T cells with monoclonal antibodies preserves leukemia remission in human AML xenograft models. AML CAR T-cell depletion enhances feasibility of subsequent allogeneic stem cell transplantation.

The purpose of this study was to introduce a planning strategy for dynamic conformal arc therapy (DCAT), named negative margin technique (NMT), and evaluate its dosimetric gain in lung stereotactic body radiation therapy (SBRT). In DCAT, the field aperture is continuously conformed to the planning target volume (PTV) with an aperture margin (AM) to compensate for the penumbra effect with gantry rotation. It is a common belief the AM should be positive (or at least ‘zero'). However, the radial penumbra width becomes significantly wider because of continuously overlapped beams in arc delivery. Therefore, we hypothesize if the ‘negative margin’ is applied in the radial direction, it would improve the PTV dose conformation while reducing normal tissue dose. For verification, trial plans were made using the NMT and compared with ‘zero margin (ZM)’ plans for five lung SBRT cases representing different situations depending on the location of the PTV and organs at risk. All plans met 95% PTV coverage with the prescription dose and spared the spinal cord below the tolerance. Two conventional conformation indices (the ratio of prescription isodose volume to the PTV (CI100) and the ratio of 50% prescription isodose volume to the PTV (CI50)) and a modified conformation index were investigated. The maximum dose at 2 cm from the PTV and the percent of lung volume receiving 20 Gy were also evaluated. Another planning simulation was performed with a total of ten randomly selected lung SBRT cases to mimic actual practice. In this simulation, optimization with ZM was first performed and further optimization using the NMT was processed for cases that could not meet a goal of with the ZM optimization. In all cases, both the and values were significantly reduced (overall, and for and , respectively). The modified conformation index values also showed similar improvement (overall, increase). Reduction of was also observed in all cases . values decreased in all cases but one (, excluding the increased case). In the random group simulation, it was possible to achieve the goal with just one NMT trial for five out of six cases that did not meet the goal in the ZM optimization. Interestingly, however, one case needed as many as six iterations to get the goal. The NMT turned out to be an effective planning strategy that could bring significant improvement of dose conformation. The NMT can be easily implemented in most clinics with no prerequisite.PACS number: 87.55.D‐

Sarcopenia is associated with increased wait‐list mortality, but a standard definition is lacking. In this retrospective study, we sought to determine the optimal definition of sarcopenia in end‐stage liver disease (ESLD) patients awaiting liver transplantation (LT). Included were 396 patients newly listed for LT in 2012 at 5 North American transplant centers. All computed tomography scans were read by 2 individuals with interobserver correlation of 98%. Using image analysis software, the total cross‐sectional area (cm 2 ) of abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI), which normalizes muscle area to patient height, was then calculated. The primary outcome was wait‐list mortality, defined as death on the waiting list or removal from the waiting list for reasons of clinical deterioration. Sex‐specific potential cutoff values to define sarcopenia were determined with a grid search guided by log‐rank test statistics. Optimal search methods identified potential cutoffs to detect survival differences between groups. The overall median SMI was 47.6 cm 2 /m 2 : 50.0 in men and 42.0 in women. At a median of 8.8 months follow‐up, mortality was 25% in men and 36% in women. Patients who died had lower SMI than those who survived (45.6 versus 48.5 cm 2 /m 2 ; P < 0.001), and SMI was associated with wait‐list mortality (hazard ratio, 0.95; P < 0.001). Optimal search method yielded SMI cutoffs of 50 cm 2 /m 2 for men and 39 cm 2 /m 2 for women; these cutoff values best combined statistical significance with a sufficient number of events to detect survival differences between groups. In conclusion, we recommend that an SMI < 50 cm 2 /m 2 for men and < 39 cm 2 /m 2 for women be used to define sarcopenia in patients with ESLD awaiting LT. Liver Transplantation 23 625–633 2017 AASLD .

498 Background: Surgery for RCC patients with IVC thrombus above the hepatic veins is complex and associated with an increased risk of perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with adverse surgical outcomes. The objective of this study is to determine the preoperative predictors of major complications and 90 day mortality after surgery in RCC patients with IVC thrombus above the hepatic veins. Methods: Records were reviewed of all RCC patients with IVC tumor thrombus above hepatic veins who had surgery from 1/2000 to 12/2012 at Mayo Clinic, MD Anderson, UT Southwestern and the University of Wisconsin. Major complications were recorded were defined as 3A or greater according to the Clavien- Dindo system within 90 days of surgery. Univariate and multivariate (MV) analyses were used to evaluate associations of preoperative clinical, pathological or laboratory variables with risk of major complications or 90-day mortality. Results: A total of 162 patients were identified for study (thrombus level 3,4 in 69 and 93 patients, respectively, according to Neves classification). Cardiopulmonary bypass was used in 60/162 (37.5%), while 40 (24.7%) patients underwent pre-operative angioembolization. Major complications were reported in 55 (34.0%) patients, with the most common being respiratory (12.4%), hematologic (9.2%) and cardiac (8.6%). On MV analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with an increased risk of major complications. Mortality was reported in 17 (10.5%) patients within 90 days after surgery. On MV analysis, ECOG performance status and low serum albumin were independently associated with increased risk of 90 day mortality. Conclusions: Contemporary perioperative mortality and major complication rates for RCC patients with upper level thrombus are 10 and 34%, respectively. ECOG PS >1 and low serum albumin are associated with an increased risk of perioperative mortality, and should be considered when selecting patients for neoadjuvant systemic therapy trials.

97 Background: Optimal management of chronic medications is uncertain in life-limiting illness. To inform shared decision making, we assessed patient perceptions in a trial on the safety of discontinuing statins in life-limiting illness. Methods: Eligible adults (life expectancy 1–12 months, on statin for ≥ 3 months for primary/secondary prevention, recent functional decline, no active cardiovascular disease) were randomized to discontinue or continue statins and were followed monthly for up to 1 year. Cognitively intact participants were asked 9 questions regarding discontinuing statins prior to randomization. We used Pearson chi-square to compare responses between study groups and between those with and without cancer. Of 381 participants, 297 (78%) were cognitively intact (138 discontinued, 159 continued statins). Mean age was 72 years (SD 11) and mean number of medications used was 11.5 (SD 5.0); 58% (N = 173) had cancer. Results: There were no statistically significant differences between the study groups in responses to the medication perception questions. Aggregate findings are presented (Table). Patients with cancer were less likely to think that they may be able to stop other medications (28% vs. 42%, p=0.007) and that statin discontinuation means that the doctor is giving up on them (1% vs. 7%, p=0.013). Conclusions: Few participants expressed concerns about discontinuing statins; many perceived potential benefits. Cancer patients may perceive less impact from stopping statins. Clinicians should inquire about patient concerns when engaging in shared decision making about discontinuing chronic medications in the setting of advanced cancer. Clinical trial information: NCT01415934. [Table: see text]