e22007 Background: BICR methodology can evaluate investigator bias in open label studies. Here (BICR W2218), we address potential investigator bias in the open-label evaluation of EFS in a subset of NMTRC003B patients selected for comparison to patients from ANBL0032 (COG trial; NCT00026312) using imaging and clinical assessments. BICR results were then compared to the propensity-score (PS)-matched external control (NO DFMO) patients from ANBL0032. Methods: NMTRC003B DFMO-treated patients (≤2 years, 750 ±250 mg/m 2 BID) on (n = 87) or per (n = 5) ANBL0032 and in remission post-dinutuximab completion were selected for inclusion in the BICR. Imaging evaluations (incl. anatomical [CT/MRI] and nuclear [MIBG and/or PET]) were determined at end of immunotherapy (baseline; to confirm remission); at 3, 6, 9, 12, 18, and 24 months; and, per Standard of Care after 24 months. While only required for the 2-year on-therapy period, imaging data were collected during follow up and also evaluated by BICR. All available imaging data (per patient at each visit; baseline via long-term follow up) from NMTRC003B patients were evaluated by two independent radiologists (IR) with adjudication by a third independent radiologist. BICR data from DFMO patients (N = 92) were used to evaluate BICR-EFS vs. EFS in DFMO-treated patients (N = 92) meeting selection criteria (demographic and risk characteristics) for PS-matched comparison (1:3 ratio for DFMO:NO-DFMO) to ANBL0032 (N = 270). ANBL0032 had enrolled N = 1328 HNRB patients assigned to dinutuximab and follow up (≤10 years) 1 and required similar imaging evaluations that were unavailable for the BICR. Concordance was evaluated with Cohen’s Kappa coefficient analysis, and EFS using Kaplan-Meier and Cox regression analyses. Results: All 92 patients had adequate imaging at baseline and were included in the BICR. N = 21/92 (22.8%) cases were adjudicated with a final outcome of unequivocal EFS event in N = 15. Despite discordance in n = 2 patients, concordance was very high during the on-treatment (2 years) and full follow-up (≤7) periods with near perfect agreement. In line with previously reported data 1 , DFMO treatment was associated with significant improvement in relapse events in BICR-DFMO cases vs. PS-matched, external NO DFMO patients over the full BICR period [hazard ratio, HR 0.54 (95% CI: 0.31, 0.95), p = 0.0337] with 2- and 4-year BICR-EFS for DFMO vs. NO DFMO of 88% vs. 80%, and 84% vs. 73%, respectively. Conclusions: This BICR indicates minimal, if any, bias in imaging evaluations in the original NMTRC003B study, providing confidence in the finding that DFMO treatment in HNRB patients in remission post upfront dinutuximab approximately halves the risk of relapse compared to matched control patients.

BACKGROUND:For locally advanced esophageal squamous cell carcinoma (ESCC), chemoradiation (ChemoRT) followed by surgery offers the best chance of cure, with a 35-50% pathologic complete response (pCR) rate. Given the morbidity of esophagectomy and the possibility of pCR with ChemoRT, a 'watch and wait' strategy has been proposed, particularly for squamous cell carcinoma. The ability to accurately predict which patients will have pCR from ChemoRT is critical in treatment decision making. This study assessed positron emission tomography (PET) in predicting pCR after neoadjuvant ChemoRT for ESCC.METHODS:ESCC patients treated with ChemoRT followed by surgery were identified. Maximum standard uptake value (SUV), metabolic tumor volume, total lesion glycolysis, and first-order textual features of standard deviation, kurtosis and skewness were measured from PET. Univariable and multivariable generalized linear method analyses were performed. A metabolic complete response (mCR) was defined as a post-therapy PET scan with maximum SUV < 4.0.RESULTS:Twenty-seven patients underwent ChemoRT followed by surgery, with overall pCR seen in 11 (41%) patients and radiographic mCR seen in 12 (44%) patients. Final pathology for these 12 patients revealed pCR (ypT0N0M0) in 5 (42%) patients and persistent disease in 7 (58%) patients. Univariate analysis did not reveal PET parameters predictive of pCR.CONCLUSION:Treatment of ESCC with ChemoRT often results in a robust clinical response. Among patients with an mCR after ChemoRT, disease persistence was found in 58%. The inability of PET to predict pCR is important in the context of a 'watch and wait' strategy for ESCC treated with ChemoRT.

PurposePrimary pancreatic carcinoma and pancreatic metastases are rare in the pediatric population. Pancreatoblastoma is the most common pancreatic malignant tumor in young children and solid-pseudopapillary tumor in teenagers. Pancreatic adenocarcinoma is extremely rare under the age of 40 and is usually associated with underlying genetic abnormalities. Secondary malignancies of the pancreas occur more frequently than primary pancreatic malignancies in children and are most commonly seen with non-Hodgkin lymphomas (NHL) and mesenchymal sarcomas. The purpose of this study was to characterize the metabolism of primary and secondary tumors of the pancreas in pediatric patients. Materials and methodsA retrospective analysis of all primary and secondary pancreatic malignancies imaged with 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) computed tomography (CT) was conducted. ResultsThree patients with primary pancreatic cancers were identified, one each with pancreatoblastoma, solid-pseudopapillary tumor, and adenocarcinoma. Each tumor showed elevated uptake of FDG. Metastatic disease in the pancreas was identified in 12 patientsfive NHL (including three Burkitt lymphomas), six sarcomas (three osteosarcomas, two rhabdomyosarcomas, and one Ewing sarcoma family tumor), and one malignant rhabdoid tumor. Elevated but variable uptake of FDG was found in each of the tumors of patients with metastatic disease within the pancreas. ConclusionBoth primary malignancies and metastatic disease within the pancreas, though very rare in children, adolescents, and young adults, are metabolically active and can be functionally characterized using FDG-PET CT.

1707 Objectives 1. To determine the metabolic activity of non-Wilms renal tumors in children. 2. Assess potential utility of FDG PET/CT in managing patients with these very rare tumors. Methods 15 pts with non-Wilms renal tumors underwent FDG PET/CT (total 54) scans. 13 ♂, 2 ♀; age at diagnosis (dx) 4 months to 17 years. Diagnoses ( # pts, # scans): Rhabdoid sarcoma (5, 27), renal cell carcinoma (3, 6), undifferentiated sarcoma (3, 3), clear cell sarcoma (2, 4), transitional cell carcinoma (1, 7), and renal medullary carcinoma (1, 7). Results Rhabdoid sarcoma: 1 scan at dx and 26 during followup. Each pt had at least 1 abnormal study indicating tumor. 4 of the 5 pts died of disease. 1 pt whose studies became negative during treatment has been free of disease for 3 years. Renal cell carcinoma: 1 study done at dx showed no uptake within the renal tumor. In a 2nd pt, 2 scans showed recurrent disease. In a 3rd pt, 3 scans showed uptake within pulmonary nodules. Disease has been stable for 8 years. Undifferentiated sarcoma: All scans performed to assess for recurrent disease. 1 showed uptake in pulmonary nodules. 1 pt studied postoperatively and a 2nd pt 4 years after treatment had no areas of abnormal uptake. Clear cell sarcoma: One pt studied post nephrectomy had a negative study. During followup he developed brain metastases which showed only slight uptake compared to white matter. These were excised and he remains free of disease 5 years later. Another pt had 2 studies done after treatment, both negative. Renal medullary carcinoma: A pt was studied before resection and multiple times during therapy. Scans were positive in the tumor bed and in the lungs. Transitional cell carcinoma: 1 pt was studied x 7 for recurrent disease, all scans abnormal indicating tumor. Conclusions Most non-Wilms renal tumors in childhood are metabolically active. FDG PET CT is useful in the management of these patients, particularly in determining the response to therapy. As in adults, renal cell carcinomas may not be metabolically active.

531 Objectives To identify & characterize findings on FDG PET CT of pancreatic involvement in pediatric patients (pts) with malignancies. Methods Pts with pancreatic tumors who underwent FDG PET/CT examinations were identified by an institutional database search. Whole body FDG PET/CT scans were acquired ~1 hr after injection of 0.15mCi/kg 18F-FDG (min 2, max 12). SUVmax was determined by ROIs placed on the tumors. Contrast enhanced CT scans were reviewed for comparison. Results 15 pts had pancreatic involvement (primary n=3, metastatic n=12). Primary tumors were pancreatoblastoma, adenocarcinoma, & solid-pseudopapillary tumor. In the 1st pt, FDG PET CT was useful in demonstrating liver metastases at diagnosis and pulmonary metastases following extensive organ transplantation. In the 2nd pt, FDG PET CT was useful in demonstrating liver metastases & directing biopsy. In the 3rd pt, FDG PET CT confirmed absence of disease following resection. 12 pts (6 ♂, 6 ♀, age 1-22 years) had secondary pancreatic involvement: osteosarcomas (n=3), Burkitt lymphomas(n=3), other NHL (n=2), rhabdomyosarcomas (n=2), malignant rhabdoid tumor (n=1) & Ewing sarcoma (n=1). 7 of the 12 presented with pancreatic metastases, & 5 developed pancreatic involvement from disease progression. Metastases to the pancreas were hypermetabolic assisting use of FDG PET/CT for response evaluation. All pancreatic involvement was confirmed on anatomic imaging. SUVmax ranged from 4.1 to 21.1. Conclusions Pancreatic involvement in malignant diseases in children is uncommon. Unlike adults, tumors in the pancreas usually represent metastases. FDG PET CT is useful for the evaluation of pediatric patients with malignancies involving the pancreas, assisting in selection of sites for biopsy, determination of response to therapy, & search for metastatic disease. Research Support Methodist University of Tennessee Department of Radiology and ALSAC (American Lebanese Syrian Associated Charities)

We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35- to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications.

Several new androgen receptor antagonists were synthesized and found to have varying activities across typically anti-androgen resistant mutants (Thr877 → Ala and Trp741 → Leu) and markedly improved potency over previously reported pan-antagonists. X-ray crystallography of a new anti-androgen in an androgen receptor mutant (Thr877 → Ala) shows that the receptor can accommodate the added bulk presented by phenyl to naphthyl substitution, casting doubt on previous reports of predicted binding orientation and the causes of antagonism in bulky-B-ring antagonists.

Background Cachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation. Methods A 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men (>60 years of age) and postmenopausal women. The primary endpoint was total lean body mass assessed by dual energy X-ray absorptiometry, and secondary endpoints included physical function, body weight, insulin resistance, and safety. Results GTx-024 treatment resulted in dose-dependent increases in total lean body mass that were statistically significant ( P < 0.001, 3 mg vs. placebo) and clinically meaningful. There were also significant improvements in physical function ( P = 0.013, 3 mg vs. placebo) and insulin resistance ( P = 0.013, 3 mg vs. placebo). The incidence of adverse events was similar between treatment groups. Conclusion GTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated. GTx-024 may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.

Purpose of reviewCachexia affects millions of cancer patients around the world. Though its causes are poorly understood, its devastating impact on the patient and their loved ones underscore the urgency of this unmet medical need. Recent research efforts suggest multiple body systems are dysregulated in cachexia, not only increasing the challenge in effectively treating the disease but also expanding the opportunities for intervention.Recent findingsAgents as diverse as anti-inflammatory monoclonal antibodies and novel anabolic small molecules are under clinical evaluation for their ability to prevent and treat wasting. The therapies evaluated to date range in their ability to improve appetite, mitigate weight loss and reverse undesirable changes in body composition and physical function.SummaryAn increased understanding of cancer cachexia, both mechanistically and its impact on cancer patients' struggle with their disease, has resulted in diverse therapeutic concepts. Recent clinical efforts demonstrate progress with novel therapies but fall short of effectively treating most cachectic patients and highlight a clear need for further research. Given the inherent heterogeneity of cancer patients and the significant impact of muscle wasting on morbidity and mortality, continued research efforts are critical in developing effective therapies to prevent and treat cancer cachexia.

Despite the success of medical strategies to reduce androgen levels in the treatment of prostate cancer, this disease invariably relapses to a castrate-resistant state that is generally fatal. Although it had been thought that androgen-insensitive cancers no longer relied on the androgen receptor (AR) for growth and survival, it is now clear that this is not the case. Because relapses are known to occur by many mechanisms that keep the AR functionally active, strategies to block AR accumulation in the nucleus may be therapeutically useful. Here, we report the discovery of a selective nuclear androgen receptor exporter (SNARE) that functions to exclude AR from the nucleus. SNARE-1 binds wild-type and mutant ARs and efficiently inhibits their transactivation activity and ability to induce PSA gene expression. SNARE-1 inhibits the androgen-sensitive growth of LNCaP cells and tumor xenografts. Quantitative subcellular localization studies suggest that SNARE-1 inhibits nuclear translocation of AR, but also facilitates export of nuclear AR that has been translocated by an agonist. Mechanistic studies indicate that SNARE-1 rapidly phosphorylates p38 mitogen-activated protein kinase (MAPK) and Ser(650) of the AR. Additionally, SNARE-1 was found to promote ubiquitination of AR in LNCaP cells. Lastly, SNARE-1 functions as a tissue-selective AR inhibitor, as it fails to phosphorylate p38 MAPK in U2OS bone cells that are stably transfected with AR. In summary, SNARE-1 inhibits AR function by a mechanism that is distinct from clinically available antiandrogens, such that it might inform novel methods to block AR function in androgen-independent prostate cancer.

Interest in the development and therapeutic potential of nonsteroidal tissue-selective androgen receptor modulators (SARMs) has increased dramatically within the past decade. Rapidly expanding knowledge of nuclear hormone receptor structure and function and successful proof-of-principle clinical trials with SARMs have revived an almost dormant search for improved androgens. This Award Address attempts to chronicle the landmark discoveries (with emphasis on our work), organize the SARM landscape into clinically relevant bins, and provide insight into the clinical prospects for SARMs. 1.1. Origins of Androgen Use. An early (1889) and unusual experiment in androgen therapy was performed by Charles Edouard Brown-Sequard, age 72. He administered a testicular extract to himself and reported that he felt “increased vigor and capacity for work”. Despite retrospective suggestions that any effect was purely placebo, this report resulted in widespread use of testicular extracts throughout Europe and North America for several decades. Attempts to isolate the active components of testicular extract failed until 1935 when testosterone (17 hydroxy-4-andosten-3-one) was isolated from bull testes. Shortly thereafter, its synthesis was reported. In the same year, extracts of urine from males were shown to cause nitrogen retention, an indicator of anabolic metabolism. Testosterone was the first anabolic androgen to be used clinically, but its use is limited by its androgenicity and pharmacokinetic (PK) issues. 1 In the latter half of the 20th century, the chemical scaffold of testosterone was modified extensively, producing many

Androgen deprivation therapy (ADT) results in a rapid decline in gonadal steroids leads to a rapid loss of bone mineral density (BMD). Men on ADT are at increased risk for fractures, and the consequence of fractures in these men is a 39 month reduction in median life expectancy. We conducted a double blind, placebo controlled trial to determine if toremifene 80 mg daily would prevent fractures in men on ADT. We report the fracture incidence in the placebo group, which represents an estimate of the fracture risk for men with prostate cancer on ADT.

Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.

Selective androgen receptor modulators (SARMs) are essentially prostate sparing androgens, which provide therapeutic potential in osteoporosis, male hormone replacement, and muscle wasting. Herein we report crystal structures of the androgen receptor (AR) ligand-binding domain (LBD) complexed to a series of potent synthetic nonsteroidal SARMs with a substituted pendant arene referred to as the B-ring. We found that hydrophilic B-ring para-substituted analogs exhibit an additional region of hydrogen bonding not seen with steroidal compounds and that multiple halogen substitutions affect the B-ring conformation and aromatic interactions with Trp741. This information elucidates interactions important for high AR binding affinity and provides new insight for structure-based drug design.

La presente invention concerne des composes de liaison aux recepteurs hormonaux nucleaires, des compositions contenant ces composes, ainsi que des methodes d'utilisation de ceux-ci dans le traitement, chez un sujet, d'une multitude de maladies ou etats comprenant notamment le cancer de la prostate et/ou des maladies ou troubles des os et des muscles.