Eiken, Patrick W.

249 Background: Evaluating tumor specific pathologic and genetic profiles in mCRPC stage is difficult due to the limited availability of mCRPC tissue. We describe findings from a prospective cohort study performed to obtain concomitant histopathology and genetic information in mCRPC. Methods: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial (3 months apart) metastatic (met) site needle core biopsies (NCB1/2). Bone lesions were biopsied using 11-13G core needles and 18G core biopsy devices were used for non-osseous masses. Up to 4 cores were obtained at each biopsy with the 1st core (S1) sent for DNA sequencing, the 2nd (S2) for RNA sequencing, and the 3rd/4th (X3, X4) submitted for xenograft implantation. From each, 1-2 mm segments were separated and formalin-fixed for histopathologic examination (HPE). Results: A total of 54 patients, enrolled between June 2013 and July 2014, underwent 94 NCB (54 NCB1, 40 NCB2), rendering a total of 259 samples (94 S1; 75 S2; 59 X3 and 31 X4) of which 85 (32%) were positive (pos) for tumor by HPE. Positivity for tumor in S1, S2, X3, and X4 cores was 42%, 33%, 22%, and 19%, respectively. At least one core pos for met tumor was observed in 62% NCB1 and 52% NCB2 (overall 52/94; 56%). Met sites biopsied include bone (71), lymph nodes (18), liver (3), penile (1) and pelvic (1) soft tissues. HPE revealed met adenocarcinoma in 44/52, and poorly differentiated carcinoma in 8/52. Gleason grade applied to the met ranged from 3+4 to 5+5. 45/85 pos samples (53%) had > 50% tumor cellularity. Pos NCB in bone lesions was observed in 23/71 (32%), compared to 17/23 (73%) of non-bone sites (p=.0004). 85 S1 samples yielded DNA material, of which 66 (77%) had ≥10% tumoral DNA. 24 cases with negative HPE had ≥10% tumoral DNA; 7 cases with pos HPE had <10 tumoral DNA. In all, 76/94 (81%) NCB yielded tumor material either by HPE or DNA analysis. Conclusions: NCB of mCRPC is feasible and provides adequate tissue for pursuing HPE and sequencing studies. HPE of extracted material correlates with DNA sequencing data and provides complementary information on tumor features. Bone lesions yield significantly less tumoral material than non-osseous sites.

190 Background: It is not known if biopsy of CRPC stage metastases alters CTC results. We evaluated pre & post biopsy CTC counts in a prospective cohort undergoing pre-chemotherapy abiraterone acetate/prednisone (AA/P). Methods: CTC enumeration was performed on 7.5mL blood using the FDA cleared immunomagnetic/immunofluorescence assay (CellSearch). Time of blood draw for CTC counts pre/post biopsy was recorded for each biopsy. Biopsies were performed using 11/13 gauge core biopsy device for bone lesions and 18 gauge core needle biopsy device for soft tissue/nodal metastases. All patients (pts) underwent two serial biopsies 3 months apart. Change in CTC counts pre/post biopsy for visits 1 and 2 were evaluated using Wilcoxon signed rank test (significance at p<0.05). Differences in CTC count change (visit1) pre/post biopsy based on metastatic site (skeletal vs. non-skeletal) was compared using Wilcoxon rank-sum test. Results: Median age of the cohort was 74 years (IQR: 68-78); median PSA at V1 was 16.4 ng/ml (IQR: 6.4-87.6); at V2 was 11.5 ng/ml (IQR: 1.8-23.7). Of 59 pts undergoing biopsies 42 were in bone and 17 in nodal/soft tissue masses. At V1, pre/post biopsy CTC counts were measured on 50 and 49 pts, respectively; at V2, pre/post CTC counts were measured on 43 and 36 pts. High volume metastatic disease at V1 was observed in 67.8 % of all pts. Table lists CTC counts and time of collection pre/post biopsy for both visits. Mean change in pre/post biopsy CTC counts for skeletal sites was 0.7 (range: -12 to 64) compared to 12.1 (range: -21 to 13) for non-skeletal sites (p=0.23). Conclusions: An increase in mean CTC counts after biopsy of CRPC metastases was observed. No significant differences in change of CTC counts based on site biopsied (skeletal versus non-skeletal) was noted. Correlation with clinical outcomes is on-going. Clinical trial information: NCT# 01953640. [Table: see text]

174 Background: AA/P is an FDA approved treatment for mCRPC. Since markers of early resistance to AA/P are unknown, we report initial findings of androgen receptor (AR) based associations with short term (12 week) progression on AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemotherapy AA/P underwent metastatic site biopsies at baseline (pre AA/P) and after 12 weeks. Baseline somatic whole exome DNA, tumor gene expression for AR full length (ARFL), AR splice variant 7 (ARV7) and ARV7/ARFL ratios were compared in progessors versus non-progressors. Progression at or within 12 weeks of AA/P therapy was defined as death or disease progression by PCWG2 “composite progression (CP)” and/or “radiographic progression” endpoints. Wilcoxon rank-sum tests were used to test for differences in the two groups for comparing ARFL, ARV7 expressions and ARV7/ARFL ratios and chi square tests were used for differences in copy number variation. Results: Between 1/2013 and 6/2014, 59 pts were enrolled of which 44 have disease assessment data at the12-week time point. CP was observed in 17/44 patients. DNA seq and clinical data was available for 42/44 pts. Using radiographic progression at 12 weeks, AR Amplification/Gain was observed in 20/26 non-progressors (13 with Amplification) and in 9/16 progressors (P-value = 0.19; OR 2.5). ARFL and ARV7 gene expressions in both groups is provided in table. Conclusions: A trend towards higher ARV7/ARFL gene expression ratio in metastases was observed with early progression on AA/P. AR gain/amplification is observed less often in pts with early progression. Validation of these findings is on-going in this prospective trial. Clinical trial information: NCT# 01953640. [Table: see text]

237 Background: AA/P is an approved treatment for mCRPC but there are no known predictive markers of response or resistance. We conducted a prospective trial to evaluate if Androgen Receptor (AR) & AR-variant (ARV) expression in tissue metastases can predict resistance to AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemo AA/P underwent metastatic site biopsies prior to (pre-AA/P) and after 12 weeks of treatment. Composite progression at 12 weeks, (primary endpoint) was evaluated with PSA, RECIST, bone scan and symptoms (per PCWG2). mRNA expressions of pre-AA/P ARFL, ARV3, ARV7, ARV9, ARV23, ARV45, four cell cycle division genes, Chromogranin-A (CHGA) together with PSA/testosterone levels, Gleason Score (GS) at initial diagnosis; high versus low volume disease; time from starting hormone therapy to mCRPC stage and serum CHGA levels were evaluated using a logistic regression model for predicting resistance at 12 weeks of therapy. A final multivariate model fitted only those factors thought to be clinically relevant or with an entry threshold of p ≤ 0.3 in univariate analysis. Results: Between 6/2013 & 3/2015, 82 pts were enrolled of which 52 had complete mRNA expression & disease assessment data at the12-week time point for analysis. Median age of the cohort was 72.5 yrs (IQR: 68.5-78); median pre-AA/P PSA was 18 ng/ml (IQR: 8.1- 46.6); GS distribution at initial diagnosis for GS 2-6; 7; 8-10 was 11; 14; 27 respectively. Progression was observed in 21/52 pts after 12 weeks. At the univariate level elevated pre-AA/P expression of ARV3 (p = 0.08), ARV7 (p = 0.26), ARV9 (p = 0.04), and cell division cycle gene CDC45 (p = 0.19) along with GS at diagnosis (p = 0.29) met the threshold for inclusion into multivariate analysis. Elevated expression of pre-therapy ARV9 in metastases alone was associated with progression at 12 weeks (OR: 3.9; CI 1.07 – 14.16; C-Index: 0.63). The 12-week biopsy of pts with progression had increased ARV9 mRNA expression compared to pts responding at 12 weeks (p = 0.14). Conclusions: Increased ARV9 mRNA expression in metastases is associated with early resistance to AA/P. This observation will need further validation in comparable datasets. Clinical trial information: NCT #0195364.

SummaryObjectiveThe role of percutaneous adrenal biopsy in a high‐risk population for adrenal malignancy has not been fully investigated. Our aim was to describe the clinical presentation leading to the adrenal biopsy and evaluate the diagnostic performance, complications and non diagnostic rate of adrenal biopsy.DesignSingle‐centre, retrospective cohort study.Patients and MeasurementsMedical records of patients who underwent adrenal biopsy between 1994 and 2014 were reviewed. Adrenal biopsy outcome was compared to a predefined reference standard.ResultsBiopsy was performed in 418 patients [62% men, median age 69 years (range, 15–91)] on 419 adrenal lesions, median size 3·1 cm (range, 0·6–24). The main indication for adrenal mass biopsy was (349/419, 83%) suspected adrenal metastasis from a known or suspected extra‐adrenal primary source. Only 116 of 419, 28% of cases had prebiopsy biochemical testing for pheochromocytoma. Biopsy‐related complications occurred in 4% of the patients. Histology revealed a metastasis in 231 of 419 (55%), benign adrenal tissue in 137 of 419 (33%), adrenocortical carcinoma in eight of 419 (2%), other lesions in 23 of 419 (5%) including seven cases of pheochromocytoma and six cases of infectious process. Biopsy was nondiagnostic in 20 of 419 (5%). All adrenal masses with unenhanced radiodensity ≤10 HU (42/137, 31%) proved to be benign adrenal adenomas. Adrenal biopsy diagnosed malignancy with a sensitivity of 88·5%, specificity of 91·5%, positive predictive value of 93·4% and negative predictive value of 85·5%.ConclusionWhen used in the appropriate clinical setting, adrenal biopsy is a powerful tool in the diagnostic algorithm of the evaluation of adrenal masses with features suspicious for malignancy. Efforts to increase awareness to perform biochemical testing for pheochromocytoma prior to adrenal biopsy are needed.

Abstract Background Frailty in non‐transplant populations increases morbidity and mortality. Muscle wasting is an important frailty characteristic. Low body mass index is used to measure wasting, but can over‐ or underestimate muscle mass. Computed tomography ( CT ) software can directly measure muscle mass. It is unknown if muscle wasting is important in lung transplantation. Aim and Methods The aim of this single‐center, retrospective cohort study was to determine whether pre‐transplant low muscle mass (as measured by CT using Slice‐O‐matic software at L2–L3 interspace) was associated with post‐transplantation mortality, hospital and intensive care unit length of stay ( LOS ), duration of mechanical ventilation, or primary graft dysfunction. Lung transplant recipients from 2000 to 2012 with a CT scan less than six months prior to transplant were included. Univariate, multivariate, and Kaplan–Meier analyses were conducted. Results Thirty‐six patients were included. Those with low muscle index (lower 25th percentile) had a worse survival (hazard ratio = 3.83; 95% confidence interval 1.42–10.3; p = 0.007) and longer hospital LOS by an estimated 7.2 d (p = 0.01) when adjusted for age and sex as compared to those with higher muscle index. Conclusion Low muscle index at lung transplantation is associated with worse survival and increased hospital LOS .

AbstractBackgroundProper management of small bowel obstruction (SBO) requires a methodology to prevent nontherapeutic laparotomy while minimizing the chance of overlooking strangulation obstruction causing intestinal ischemia. Our aim was to identify preoperative risk factors associated with strangulating SBO and to develop a model to predict the need for operative intervention in the presence of an SBO. Our hypothesis was that free intraperitoneal fluid on computed tomography (CT) is associated with the presence of bowel ischemia and need for exploration.MethodsWe reviewed 100 consecutive patients with SBO, all of whom had undergone CT that was reviewed by a radiologist blinded to outcome. The need for operative management was confirmed retrospectively by four surgeons based on operative findings and the patient’s clinical course.ResultsPatients were divided into two groups: group 1, who required operative management on retrospective review, and group 2 who did not. Four patients who were treated nonoperatively had ischemia or died of malignant SBO and were then included in group 1; two patients who had a nontherapeutic exploration were included in group 2. On univariate analysis, the need for exploration (n = 48) was associated (p < 0.05) with a history of malignancy (29% vs. 12%), vomiting (85% vs. 63%), and CT findings of either free intraperitoneal fluid (67% vs. 31%), mesenteric edema (67% vs. 37%), mesenteric vascular engorgement (85% vs. 67%), small bowel wall thickening (44% vs. 25%) or absence of the “small bowel feces sign” (so‐called fecalization) (10% vs. 29%). Ischemia (n = 11) was associated (p < 0.05 each) with peritonitis (36% vs. 1%), free intraperitoneal fluid (82% vs. 44%), serum lactate concentration (2.7 ± 1.6 vs. 1.3 ± 0.6 mmol/l), mesenteric edema (91% vs. 46%), closed loop obstruction (27% vs. 2%), pneumatosis intestinalis (18% vs. 0%), and portal venous gas (18% vs. 0%). On multivariate analysis, free intraperitoneal fluid [odds ratio (OR) 3.80, 95% confidence interval (CI) 1.5–9.9], mesenteric edema (OR 3.59, 95% CI 1.3–9.6), lack of the “small bowel feces sign” (OR 0.19, 95% CI 0.05–0.68), and a history of vomiting (OR 4.67, 95% CI 1.5–14.4) were independent predictors of the need for operative exploration (p < 0.05 each). The combination of vomiting, no “small bowel feces sign,” free intraperitoneal fluid, and mesenteric edema had a sensitivity of 96%, and a positive predictive value of 90% (OR 16.4, 95% CI 3.6–75.4) for requiring exploration.ConclusionClinical, laboratory, and radiographic factors should all be considered when making a decision about treatment of SBO. The four clinical features—intraperitoneal free fluid, mesenteric edema, lack of the “small bowel feces sign,” history of vomiting—are predictive of requiring operative intervention during the patient’s hospital stay and should be factored strongly into the decision‐making algorithm for operative versus nonoperative treatment.