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While overall survival has improved significantly for children with cancer over the past 75 years, cancer remains the leading cause of death from disease among children and adolescents. Further, despite the many advances in medical and nursing care, children with cancer still experience significant physical and emotional suffering over the course of their illness, especially at the end of life (EOL). Children endure significant rates of high-intensity medical interventions (e.g., intubation, intensive care unit admission) at the EOL despite many parents, adolescents, and young adult patients identifying home as their preferred location of death. Hospice care has the potential to ease suffering at the EOL and facilitate home deaths, and yet, most children still die in acute care settings without hospice care. Numerous barriers prevent timely enrollment in hospice among children with cancer who are in the EOL period. This report describes the development and testing of a palliative care/EOL communication intervention designed to overcome some of these barriers and subsequently improve EOL outcomes (i.e., earlier hospice enrollment, less use of high-intensity medical interventions, reduced pain and suffering) among children with cancer and their parents (i.e., less emotional distress and uncertainty, improved hope and healthcare satisfaction).

Purpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133

Background: Chronic edema (CO) is a complex condition, arising from different factors, including immobility and obesity. Edema and obesity can have a significant impact on quality of life of patien...

BackgroundA first-in-human, randomized pilot phase II clinical trial combining vaccines targeting overexpressed, non-mutated tumor blood vessel antigens (TBVA) and tyrosine kinase inhibitor dasatinib was conducted in human leukocyte antigen (HLA)-A2+ patients with advanced melanoma.MethodsPatient monocyte-derived type-1-polarized dendritic cells were loaded with HLA-A2-presented peptides derived from TBVA (DLK1, EphA2, HBB, NRP1, RGS5, TEM1) and injected intradermally as a vaccine into the upper extremities every other week. Patients were randomized into one of two treatment arms receiving oral dasatinib (70 mg two times per day) beginning in week 5 (Arm A) or in week 1 (Arm B). Trial endpoints included T cell response to vaccine peptides (interferon-γ enzyme-linked immunosorbent spot), objective clinical response (Response Evaluation Criteria in Solid Tumors V.1.1) and exploratory tumor, blood and serum profiling of immune-associated genes/proteins.ResultsSixteen patients with advanced-stage cutaneous (n=10), mucosal (n=1) or uveal (n=5) melanoma were accrued, 15 of whom had previously progressed on programmed cell death protein 1 (PD-1) blockade. Of 13 evaluable patients, 6 patients developed specific peripheral blood T cell responses against ≥3 vaccine-associated peptides, with further evidence of epitope spreading. All six patients with specific CD8+ T cell response to vaccine-targeted antigens exhibited evidence of T cell receptor (TCR) convergence in association with preferred clinical outcomes (four partial response and two stabilization of disease (SD)). Seven patients failed to respond to vaccination (one SD and six progressive disease). Patients in Arm B (immediate dasatinib) outperformed those in Arm A (delayed dasatinib) for immune response rate (IRR; 66.7% vs 28.6%), objective response rate (ORR) (66.7% vs 0%), overall survival (median 15.45 vs 3.47 months; p=0.0086) and progression-free survival (median 7.87 vs 1.97 months; p=0.063). IRR (80% vs 25%) and ORR (60% vs 12.5%) was greater for females versus male patients. Tumors in patients exhibiting response to treatment displayed (1) evidence of innate and adaptive immune-mediated inflammation and TCR convergence at baseline, (2) on-treatment transcriptional changes associated with reduced hypoxia/acidosis/glycolysis, and (3) increased inflammatory immune cell infiltration and tertiary lymphoid structure neogenesis.ConclusionsCombined vaccination against TBVA plus dasatinib was safe and resulted in coordinating immunologic and/or objective clinical responses in 6/13 (46%) evaluable patients with melanoma, particularly those initiating treatment with both agents.Trial registration numberNCT01876212.

CONTEXT: Cancer and symptom experiences of adolescents and young adults (AYAs) with cancer can be highly variable, creating challenges for clinicians and researchers who seek to optimize AYAs’ health outcomes. Understanding the heuristics AYAs use to designate priority symptoms can provide insight into the meaning they assign to their symptoms and self-management behaviors. OBJECTIVES: This study described the frequency and characteristics of priority symptoms. It qualitatively explored reasons for a symptom’s designation as a priority symptom, perceived causes of priority symptoms, and strategies AYAs use to manage priority symptoms. METHODS: Participants in this single group, longitudinal study reported symptoms using a heuristics-based symptom reporting tool, the Computerized Symptom Capture Tool, at two scheduled visits for chemotherapy. AYAs designated priority symptoms and responded to two short answer questions: What makes this a priority symptom? and What do you do to make it better? RESULTS: Eighty-six AYAs, 15-29 years of age (median 19 years), identified 189 priority symptoms. Priority symptoms were of greater severity (t=3.43; p< .01) and distress (t=4.02; p< .01) compared with non-priority symptoms. Lack of energy, nausea, difficulty sleeping, and pain comprised 39% of priority symptoms. Reasons for priority designation included the impact of the symptom and the attributes of the symptom. Categories of self-management strategies included “Physical Care Strategies,” “Things I take (or not),” and “Psychosocial Care Strategies.” CONCLUSION: Supporting AYAs to identify their priority symptoms may facilitate a more personalized approach to care. Seeking the patient’s perspective regarding priority symptoms could enhance patient-clinician collaboration in symptom management.

Background Immunotherapy has changed the treatment landscape for melanoma, although many patients (pts) do not respond to treatment. While there are likely multiple mechanisms of resistance at play, one key mechanism is the generation of an immunosuppressive and metabolically harsh tumor microenvironment (TME).1 This is likely the result of an altered angiogenic pattern along with dysregulated metabolism of the tumor itself, which leads to hypoxia.2 CD8+ tumor infiltrating lymphocytes (TIL) isolated from tumors with high oxidative metabolism have an exhausted phenotype and decreased functionality (decreased IFN-У and TNF-α production).3 Thus, TIL may be blunted due to failure to meet their metabolic needs. Vascular endothelial growth factor (VEGF) is a critical mediator of angiogenesis and is overexpressed in many solid tumors, including melanoma. Axitinib has high inhibitory activity for VEGF receptors1, 2, and 3. In a preclinical B16 melanoma model, we found that anti-PD1 plus axitinib provided an improved and durable response compared to monotherapy with either agent. We hypothesize that by modulating angiogenesis, axitinib will reduce intra-tumoral hypoxia and resultant T cell dysfunction, which will re-sensitize melanoma to anti-PD1 therapy. Methods This is an investigator-initiated, phase II trial of nivolumab plus axitinib for pts with unresectable stage III or IV melanoma who have progressed on prior anti-PD1 therapy with or without concomitant anti-CTLA4. Prior treatment with BRAF/MEK inhibitors is permitted. Pts with brain metastases are permitted if they are asymptomatic and have stable disease 2 weeks after CNS-directed treatment. Pts will receive nivolumab 480 mg IV every 4 weeks and axitinib PO 5 mg twice daily for up to two years or until progression or unacceptable toxicity. Timing of biopsies is reported in figure 1, with an optional biopsy at progression. Pts will receive an oral dose of pimonidazole 0.5 mg/m2 before each biopsy to permit in vivo evaluation of intra-tumoral hypoxia. Primary endpoint: overall response rate (ORR). Secondary endpoints: safety, progression-free survival, overall survival, and correlative analyses (evaluation of hypoxia in the TME, TIL function, immune phenotype, and tumor cell metabolism). Statistical analysis includes Simon’s minimax two-stage design. The null hypothesis is that the true ORR is 10%, tested against a one-sided alternative of 25% or higher. N=31 patients with a type I error rate of 0.08 and power 0.81 when the true response rate is 0.25. Results N/A Conclusions N/A Trial Registration NCT04493203 Ethics Approval The study was approved by the University of Pittsburgh Institutional Review Board, approval number HCC 20-101. References Romero IL, Mukherjee A, Kenny HA, Litchfield LM, Lengyel E. Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. Clin Cancer Res 2015;21(4):680–6. doi: 10.1158/1078-0432.CCR-14-2198. PubMed PMID: 25691772. Justus CR, Sanderlin EJ, Yang LV. Molecular connections between cancer cell metabolism and the tumor microenvironment. Int J Mol Sci 2015;16(5):11055–86. doi: 10.3390/ijms160511055. PubMed PMID: 25988385. Najjar YG, Menk AV, Sander C, Rao U, Karunamurthy A, Bhatia R, et al. Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma. JCI insight. 2019;4(5). Epub 2019/02/06. doi: 10.1172/jci.insight.124989. PubMed PMID: 30721155; PubMed Central PMCID: PMCPMC6483505.

Background Neoadjuvant PD-1 blockade produces major pathological responses (MPR) in ~30% of patients (pts) with high-risk resectable melanoma (MEL) with durable relapse-free benefit, and increased circulating activated CD8+ T cells.1 2 CMP-001 is a type A CpG packaged within a virus-like particle that activates tumor-associated plasmacytoid dendritic cells (pDC) via TLR9 inducing type I interferons and anti-tumor CD8+ T cells. CMP-001/pembrolizumab produces durable anti-tumor responses in PD-1 refractory melanoma.3 We previously reported preliminary evidence of efficacy of neoadjuvant IT CMP/Nivo in high-risk resectable MEL; and herein present final results on 30 evaluable patients. Methods 30 pts with stage III B/C/D MEL were enrolled. Pre-operatively, CMP-001 was dosed at 5 mg subcutaneous (SC, 1st), then 10 mg IT (2nd-7th) weekly; Nivo was dosed 240 mg q2 weeks for 3 doses – both agents given for 7 weeks. Post-operatively, Nivo was dosed 480 mg q4 weeks with CMP-001 5 mg q4 weeks SC for 48 weeks. Primary endpoints included major pathologic response rate (MPR), and incidence of dose-limiting toxicities (DLT). Secondary endpoints were radiographic response, relapse-free survival (RFS) and overall survival (OS). Pathological response was scored blinded by pathologists based on residual volume of tumor (RVT) using prior specified cutoffs:4 60% (complete response, pCR); 0% Results 30 pts with regionally advanced MEL were enrolled, of stages IIIB (57%), IIIC (37%), IIID (7%). 29/30 (97%) of pts completed 7 weeks of neoadjuvant Nivo/CMP; while 1 pt had a delay in surgery related to a pre-operative infection unrelated to therapy. No DLTs were reported; grade 3/4 irAE were reported in 3 pts (11%) leading to CMP-001 discontinuation in 2 pts (7%). Radiographic responses were seen in 13 pts (43%), while 9 pts (30%) had stable disease and 8 pts (27%) had progressive disease. Pathological responses (RVT Conclusions Neoadjuvant CMP/Nivo has acceptable toxicity and promising efficacy. MPR is 60% in 30 pts. 1-year RFS was 82% (all pts) and 89% (among those with pCR/pMR); median RFS is 9 months (among pNR/pPR) and not reached (among pCR/pMR). Response is associated with evidence of immune activation intra-tumorally and peripherally. IT CMP001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in pts with regionally advanced MEL. Further study of this combination in high-risk resectable MEL is planned. Acknowledgements We thank Dr. Jagjit Singh and the pathology grossing room staff for their assistance and Checkmate Pharmaceuticals for funding and CMP-001. Trial Registration Clinical trial information: NCT03618641 Ethics Approval The study was approved by University of Pittsburgh’s Institutional Review Board, approval number MOD19040237-002. Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. References Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med 2018. Nov;24(11):1649–1654. Huang AC, Orlowski RJ, Xu X, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med 2019. Mar;25(3):454–461. doi: 10.1038/s41591-019-0357-y. Milhem M, Gonzales R, Medina T, et al. Abstract CT144: Intratumoral toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab can reverse resistance to PD-1 inhibition in a phase Ib trial in subjects with advanced melanoma. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14–18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract CT144. Tetzlaff MT, Messina JL, Stein JE, et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann Oncol 2018. Aug 1;29(8):1861–1868. Cottrell TR, Thompson ED, Forde PM, et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann Oncol 2018 Aug 1;29(8):1853–1860. doi: 10.1093/annonc/mdy218. Stein JE, Soni A, Danilova L, et al. Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response. Ann Oncol 2019 Apr 1;30(4):589–596. doi: 10.1093/annonc/mdz019.

Background: Monoclonal antibodies (mAb) targeting the programmed cell death protein 1 (PD-1) receptor provide durable long-term benefit in a subset of patients (pts) with advanced melanoma with response rates of 35-42% and 4-year progression-free survival (PFS) rate of 27%. Separately, the composition of the gut microbiota has been shown to correlate with anti-PD-1 efficacy in human cancer pts with melanoma, renal cell cancer and non-small cell lung cancer (NSCLC) although the precise organisms differ considerably across various studies. In preclinical models, responder-derived fecal microbiome and microbiome consortia produce anti-tumor responses. The effect of microbiome modulation in pts with anti-PD-1 refractory melanoma has not been evaluated. Methods: To evaluate whether primary resistance to anti-PD-1 immunotherapy could be overcome by intestinal microbiome modulation, we designed and conducted a phase II study (NCT03341143). We enrolled pts with primary refractory metastatic melanoma with best response of short-term stable disease (≤6 months) or progressive disease (PD) to prior anti-PD-1 based immunotherapy. Pts received single-administration of responder-derived fecal microbiota transplantation (R-FMT) together with pembrolizumab. Candidate donors were pts with advanced melanoma treated with anti-PD-1 immunotherapy with durable partial or complete response (PR, CR). Pembrolizumab was continued till intolerable toxicity or disease progression. Safety and clinical activity (based on RECIST v1.1) were main objectives; while progression-free survival (PFS) was a key secondary endpoint. Results: As of December 1, 2020, 16 pts with primary refractory melanoma were enrolled, of whom 15 were evaluable. LDH was elevated in 14/15 pts; and the median number of prior therapies was 2. Recipient pts were seromatched to receive a single R-FMT from one of eight candidate donors (5 CR; 3 PR; median PFS 58 months, range 43-70). R-FMT was administered via colonoscopy after bowel preparation with no use of antibiotics. Pembrolizumab was administered IV per label. R-FMT/pembrolizumab was well-tolerated, with no unusual toxicity signals. R-FMT induced rapid and durable microbiota perturbation in most pts; while 6 of 15 evaluable pts had evidence of clinical benefit. Response to R-FMT/pembrolizumab was associated with an increased abundance of taxa previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of IL-8 expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Conclusions: In pts with anti-PD-1 primary refractory melanoma, R-FMT/pembrolizumab changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 immunotherapy. Response was associated with CD8 T cell induction and reduction of IL-8 expressing myeloid cells. Citation Format: Diwakar Davar, Amiran Dzutsev, John A. McCulloch, Richard R. Rodrigues, Joe-Marc Chauvin, Robert M. Morrison, Richelle N. Deblasio, Carmine Menna, Quanquan Ding, Ornella Pagliano, Bochra Zidi, Shuowen Zhang, Jonathan H. Badger, Marie Vetizou, Alicia M. Cole, Miriam R. Fernandes, Stephanie Prescott, Raquel G. Costa, Ascharya K. Balaji, Andrey Morgun, Ivan Vujkovic-Cvijin, Hong Wang, Amir A. Borhani, Marc B. Schwartz, Howard M. Dubner, Scarlett J. Ernst, Amy Rose, Yana G. Najjar, Yasmine Belkaid, John M. Kirkwood, Giorgio Trinchieri, Hassane M. Zarour. Efficacy of Responder-derived Fecal Microbiota Transplant (R-FMT) and Pembrolizumab in Anti-PD-1 Refractory Patients with Advanced Melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB062.

There is a paucity of data to support evidence-based practices in the provision of patient/family education in the context of a new childhood cancer diagnosis. Since the majority of children with cancer are treated on pediatric oncology clinical trials, lack of effective patient/family education has the potential to negatively affect both patient and clinical trial outcomes. The Children’s Oncology Group Nursing Discipline convened an interprofessional expert panel from within and beyond pediatric oncology to review available and emerging evidence and develop expert consensus recommendations regarding harmonization of patient/family education practices for newly diagnosed pediatric oncology patients across institutions. Five broad principles, with associated recommendations, were identified by the panel, including recognition that (1) in pediatric oncology, patient/family education is family-centered; (2) a diagnosis of childhood cancer is overwhelming and the family needs time to process the diagnosis and develop a plan for managing ongoing life demands before they can successfully learn to care for the child; (3) patient/family education should be an interprofessional endeavor with 3 key areas of focus: (a) diagnosis/treatment, (b) psychosocial coping, and (c) care of the child; (4) patient/family education should occur across the continuum of care; and (5) a supportive environment is necessary to optimize learning. Dissemination and implementation of these recommendations will set the stage for future studies that aim to develop evidence to inform best practices, and ultimately to establish the standard of care for effective patient/family education in pediatric oncology.

Objective: The aim of this study is to report the benefits and burdens of palliative research participation on children, siblings, parents, clinicians, and researchers. Background: Pediatric palliative care requires research to mature the science and improve interventions. A tension exists between the desire to enhance palliative and end-of-life care for children and their families and the need to protect these potentially vulnerable populations from untoward burdens. Methods: Systematic review followed PRISMA guidelines with prepared protocol registered as PROSPERO #CRD42018087304. MEDLINE, CINAHL, PsycINFO, EMBASE, Scopus, and The Cochrane Library were searched (2000-2017). English-language studies depicting the benefits or burdens of palliative care or end-of-life research participation on either pediatric patients and/or their family members, clinicians, or study teams were eligible for inclusion. Study quality was appraised using the Mixed Methods Appraisal Tool (MMAT). Results: Twenty-four studies met final inclusion criteria. The benefit or burden of palliative care research participation was reported for the child in 6 papers; siblings in 2; parents in 19; clinicians in 3; and researchers in 5 papers. Benefits were more heavily emphasized by patients and family members, whereas burdens were more prominently emphasized by researchers and clinicians. No paper utilized a validated benefit/burden scale. Discussion: The lack of published exploration into the benefits and burdens of those asked to take part in pediatric palliative care research and those conducting the research is striking. There is a need for implementation of a validated benefit/burden instrument or interview measure as part of pediatric palliative and end-of-life research design and reporting.

This work aims to assess the efficacy of current x-ray quality assurance (QA) testing regimes on tube and generator systems for general radiographic usage in the UK. 1393 sets of QA results data from nine UK medical physics departments were collected and analysed. Test failure rates ranged from 0% to 39% and were used to assess the likelihood of the test finding a fault. The magnitude of the recorded faults were used to assess the severity of the failure with due consideration to its impact on image quality and patient dose. The severity and likelihood of the faults were used along with a risk matrix to assess the efficacy of each test. Eleven tests were graded 'orange' (indicating an effective test that should be continued), four tests were graded 'yellow' (indicating a less effective test that may be continued with a lower frequency considered) and four tests were graded green (indicating a low efficacy test that could be removed from test regimes).

Purpose Objective responses are reported in 34% to 37% of patients with programmed death-1 (PD-1)–naïve advanced melanoma treated with PD-1 inhibitors. Pre-existing CD8+ T-cell infiltrate and interferon (IFN) gene signature correlate with response to PD-1 blockade. Here, we report a phase Ib/II study of pembrolizumab/pegylated (PEG)-IFN combination in PD-1–naïve advanced melanoma. Patients and Methods PEG-IFN (1, 2, and 3 μg/kg per week) was dose escalated using a modified toxicity probability interval design in three cohorts of four patients each, whereas pembrolizumab was dosed at 2 mg/kg every 3 weeks in the phase Ib portion. Thirty-one patients were enrolled in the phase II portion. Primary objectives were safety and incidence of dose-limiting toxicities. Secondary objectives included objective response rate, progression-free survival (PFS), and overall survival. Results Forty-three patients with stage IV melanoma were enrolled in the phase Ib and II portions of the study and included in the analysis. At the data cutoff date (December 31, 2017), median follow-up duration was 25 months (range, 1 to 38 months). All 43 patients experienced at least one adverse event; grade 3/4 treatment-related adverse events occurred in 21 of 43 patients (48.8%). Objective responses were seen at all three dose levels among 43 evaluable patients. The objective response rate was 60.5%, with 46.5% of patients exhibiting ongoing response. Median PFS was 11.0 months in all patients and unreached in responders, whereas median overall survival remained unreached in all patients. The 2-year PFS rate was 46%. Conclusion Pembrolizumab/PEG-IFN demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in PD-1–naïve metastatic melanoma. These results support the rationale to further investigate this pembrolizumab/PEG-IFN combination in this disease.

Purpose: In order to develop an evidence-based, sport-specific minimum impairment criteria (MIC) for the sport of vision-impaired (VI) shooting, this study aimed to determine the relative influence of losses in visual acuity (VA) and contrast sensitivity (CS) on shooting performance. Presently, VA but not CS is used to determine eligibility to compete in VI shooting.\ud \ud Methods: Elite able-sighted athletes (n = 27) shot under standard conditions with their habitual vision, and with their vision impaired by the use of simulation spectacles (filters which reduce both VA and CS) and refractive blur (lenses which reduce VA with less effect on CS). Habitual shooting scores were used to establish a cut-off in order to determine when shooting performance was ‘below expected’ in the presence of vision impairment. Logistic regression and decision tree analyses were then used to assess the relationship between visual function and shooting performance.\ud \ud Results: Mild reductions in VA and/or CS did not alter shooting performance, with greater reductions required for shooting performance to fall below habitual levels (below 87% of normalized performance). Stepwise logistic regression selected CS as the most significant predictor of shooting performance, with VA subsequently improving the validity of the model. In an unconstrained decision tree analysis, CS was selected as the sole criterion (80%) for predicting ‘below expected’ shooting score.\ud \ud Conclusion: Shooting performance is better predicted by losses in CS than by VA. Given that it is not presently tested during classification, the results suggest that CS is an important measure to include in testing for the classification of vision impairment for athletes competing in VI shooting.

Objectives To examine nurses' experiences of prognosis-related communication (PRC) with parents of children with cancer. Sample & setting Cross-sectional, correlational study in the pediatric oncology setting involving 316 members of the Association of Pediatric Hematology/Oncology Nurses. Methods & variables Online survey regarding individual nurse factors, PRC, interprofessional collaboration, moral distress, and perceived quality of care. Results Nurses strongly agreed that prognostic disclosure is critical for decision making, but they are challenged in determining their role. Nurses with more years of experience and training in PRC, those working in an outpatient setting, and those with higher levels of nurse-physician collaboration reported more positive experiences with PRC. Positive experiences with PRC and collaboration were significantly associated with higher nurse-perceived quality of care and reduced nurse moral distress. Implications for nursing Nurses should work to be active participants in the process of PRC by collaborating with physician colleagues. When nurses sense that prognostic discussions have been absent or unclear, they should feel confident in approaching physician colleagues to ensure parent understanding and satisfaction with communication.

Research on the effects of adolescent employment on primarily middle-class youth suggests that intense employment, working more than 15 or 20 hours during the school year, is associated with increased participation in risky behavior. Despite these findings, scholars who focus on the development of youth living in low-income urban areas often hypothesize that adolescent employment will have beneficial effects on this population. There is some evidence that adolescent employment is associated with increased educational achievement and adult employment for low-income urban youth. The impact of adolescent employment on future engagement in risky behavior across levels of neighborhood deprivation and employment intensity was investigated on a sample of 1,057 adolescents from the Project on Human Development in Chicago Neighborhoods, a longitudinal study of neighborhood effects on development. After controlling for individual characteristics, intense employment during adolescence did predict increased use of cigarettes and alcohol and having a greater number of sexual partners 2 years after employment was measured. There were no significant interactions between neighborhood SES and adolescent employment status on involvement in risky behavior. These findings suggest that intense adolescent employment is associated with detrimental developmental outcomes for youth regardless neighborhood context.

This work aims to assess the efficacy of x-ray quality assurance tests undertaken on fluoroscopy units in the UK. Information was gathered on the results of dosimetry and safety tests recommended by the reports of the Institute of Physics and Engineering in Medicine, and those additionally undertaken by medical physics departments. The assessment of efficacy considers the frequency with which a test result breaches the remedial level or other relevant threshold where applicable. The third quartile of those results exceeding the remedial level or threshold is used to estimate the severity of such a breach in terms of potential impact on patient dose and image quality. A risk assessment approach is then used to recommend to what degree, if any, the test should be included in an on-going test regimen. Data was analysed from 468 testing sessions to 336 unique fluoroscopy units throughout the UK. Across all tests, the rate with which the remedial level was exceeded varied from 0%-29.5%, with severity ranging from little or none to major degradation to image quality or significant increase on population dose. Where possible, the data has also been used to produce representative ranges for the results of dosimetric tests. These could be useful as an up to date comparator for those sites considering the purchase of or commissioning new equipment. Overall the results indicate a wide range for the efficacy of those tests undertaken at present; this can be used to review local test protocols and to inform future changes to national guidance in the UK. The results also highlight some tests where measurement technique varies significantly throughout the UK, making any valid comparison difficult. This may indicate a need for further guidance on how best to undertake these tests.

9586 Background: A trial of neoadjuvant pembrolizumab (P) in combination with high dose interferon-α (HDI) in high-risk patients (pts) with locoregionally advanced melanoma (mel) has completed enrollment. Methods: Primary endpoint: safety of combination P-HDI. Pts were treated with P x 2 doses followed by definitive surgery, then x1 year. HDI was given concurrently, and both agents were per standard regimen. Tumor and blood samples were obtained at baseline and at surgery (wk 6-8), blood at 6 wks, 3,6,12 months (mos). Results: 30 pts were treated (22 male, 8 female, age 26-83). 16 had cutaneous primary, 3 mucosal, 11 unknown. At enrollment, 16 had recurrent disease, 6 received prior adjuvant therapy with ipilimumab (4) or HDI (2). 16 had AJCC 7 stage IIIB, 9 IIIC, 5 IV. 332 P cycles have been delivered (median 13), 496 doses of HDI induction (median 17), 1329 doses of HDI maintenance (median 44). HDI was dose reduced in 20 pts, discontinued in 27, P discontinued in 8. Radiologic preoperative RR was 77% (95% CI, 59-88) (6 CR, 17 PR). 20% (6) had SD and 1 had PD. All pts underwent definitive surgery. The pathologic complete response (pCR) of 26 pts was 32% (95% CI, 18-51). 6 pts recurred and 3 died. No pt with pCR has recurred. Median f/u time is 17.4 mos, median PFS/OS not reached. Most common grade (Gr) 3 toxicities: hypophosphatemia (10; 33%), fatigue (10; 33%), ↑CPK (6; 20%), ↑lipase (4; 13%). 3 Gr 4 events (↑CPK, hyperglycemia, lymphocyte count decreased). 1 suspected grade 5 event occurred 6 months after completion of therapy. PD-L1 expression at baseline did not correlate with clinical outcomes. In 8 pts with pre and post treatment tumor samples, IHC expression of PD-1, PD-L1, CD11b, CD8, Foxp3 and CD25 increased post-treatment (p < 0.05). Conclusions: Neoadjuvant P-HDI has promising clinical activity, although treatment is limited by HDI toxicity. Treatment increases the immune cell infiltrate, and outcomes do not correlate with baseline expression of PD-L1. Longer follow up and further mechanistic studies are underway. Clinical trial information: NCT02339324.

9572 Background: Retrospective studies suggest that various med could dichotomous effects in regards to immunotherapy. These include adverse (antibiotics) and positive (aspirin, beta-blockers) influences. To evaluate potential additive or detrimental effects of various med in patients (pts) receiving PD-1 immunotherapy, we performed a retrospective evaluation of med intake in 172 pts with stage IV cutaneous MEL focusing on aspirin (asp), antacid (ant), antibiotic (abx), bisphosphonate (bisp), metformin (met) and statin (stat) intake. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Med intake was documented based on chart review in all pts. Intake was confirmed by analyzing at least one other note from a non-oncological provider. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how categorical variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mths). Results: 172 pts with advanced MEL were evaluated. Asp, ant, abx, bisp, met and stat use was documented in 62, 82, 29, 4, 15 and 57 pts respectively. ORR was not significantly related to intake of asp, ant, bisp, met and stat use; although ORR was lower in pts who received abx (p=0.0328). There was no significant difference in PFS and OS in pts who received asp, ant, bisp, met and stat. In patients who received abx compared to those who did not, median PFS (16.6 mths vs. 19.8 mths) and median OS (23.8 mths vs. 35.4) were both lower. Abx use did not interact with other meds. Conclusions: In this retrospective series of advanced MEL pts treated with PD-1 blockade, abx use was adversely associated with response to PD-1 blockade. Abx use was also associated with poorer PFS and OS. Conversely, neither a positive nor negative association with ORR, PFS and/or OS was seen with asp, ant, bisp, met and stat use. These results validate prior studies suggesting that abx use is associated with worse outcomes in pts receiving PD-1 blockade possibly by mediating intestinal dysbiosis.

9571 Background: Inflammation is an adverse prognostic factor in cancer. Neutrophil-to-lymphocyte ratio (NLR) is an easily derived biomarker of systemic inflammation. Several studies have demonstrated that elevated NLR is linked with adverse prognosis in patients (pts) receiving immunotherapy including PD-1 inhibitors. To evaluate the prognostic utility of NLR, we performed a retrospective evaluation of NLR and other covariates in stage IV cutaneous MEL. Methods: Stage IV cutaneous MEL pts who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Baseline NLR was defined based on values at the first treatment date. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mos). Results: 172 pts with advanced MEL were evaluated. Elevated NLR was associated with poorer PFS and OS and ORR at all cutoffs (NLR≥2 to NLR≥5) with NLR≥5 having the greatest discriminative value. ORR steadily declined with increasing NLR: NLR≥1 (ORR 64%), NLR≥2 (ORR 61%), NLR≥3 (ORR 52%), NLR≥4 (ORR 43%), NLR≥5 (ORR 43%). Elevated NLR ( < 5 vs. ≥5) was associated with poorer PFS (median 21.5 mths vs. 5.2 mos; p = 0.00041) and OS (median 35.4 os vs. 10.6 mos; p < 0.0001). In a multivariate model, elevated NLR ( < 5 vs. ≥5) was independently associated with poorer OS/PFS separate from ulceration, performance status and elevated LDH. There was no evidence of an age-related increase or decrease in NLR. Conclusions: Baseline NLR was independently associated with response, PFS and OS in the largest retrospective series of advanced MEL pts treated with PD-1 blockade. NLR independent of other factors predicted poorer PFS and OS at NLR cutoffs (NLR≥3 to NLR≥5), although NLR≥5 segregated pts best. NLR is an inexpensive and easily obtained real-world biomarker that has a high value in predicting outcomes to PD-1 blockade.

9579 Background: Obesity promotes PD-1–mediated T cell dysfunction but also improves tumor response to PD-1 blockade. Obesity has been linked with positive outcomes in pts treated with PD-1 blockade. To evaluate the prognostic utility of BMI, we performed a retrospective evaluation of BMI and other covariates in 172 pts with stage IV cutaneous MEL. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. BMI was defined based on values at the first treatment date and dichotomized into two groups: ≥30 vs. < 30. Fisher exact test was used to evaluate the correlation between BMI group and ORR. Kaplan Meier method and Cox proportional hazard models were performed to analyzed the time-to-event outcomes (OS and PFS). Results: 172 pts with advanced MEL were evaluated. Greater BMI was associated with greater ORR, PFS and OS across various BMI cutoffs (BMI≥28, BMI≥30 and BMI≥35) although this effect was most obvious at BMI≥30. Pts with BMI≥30 achieved higher ORR than those with BMI < 30 (74% vs. 58%, p-value = 0.04). Concordantly, pts with BMI≥30 had improved PFS and OS: median PFS (BMI≥30 21.1 mos vs. BMI < 30 10.7 mos) and median OS (BMI≥30 35.4 mos vs. BMI < 30 22.8 mos). Higher BMI was independently associated with improved OS (p = 0.018) and PFS (p = 0.047) adjusting for age, Breslow thickness and sex. No significant interaction was observed between the effects of BMI and that of age, sex, or Breslow thickness. Conclusions: Increased BMI was associated with greater ORR in addition to previously reported associations with PFS/OS in a large retrospective series of advanced MEL pts treated with PD-1 blockade. This data was independent of other prognostic factors and underscore the “inflammaging” effects of obesity and age in relation to anti PD-1 therapy in advanced cancer.

e21507Background: Prior reports have described an association with hepatic metastases and total TB with reduced response rates to anti-PD-1 treatment in subjects with advanced MEL. We explored base...

9586Background: Optimal surveillance for MEL recurrence is elusive. While consensus guidelines agree on surveillance imaging for high-risk MEL, there is no consensus regarding optimal modality for ...

Ethnographic methods were used to gather illness narratives on 11 men and 38 women diagnosed with interstitial cystitis (IC). Content analysis using the Spradley ethnographic method reveals that patients directly link IC pain to diminished sexual functioning. We conclude: (1) Patients with IC are deeply concerned about diminished sexual function. Physicians and rehabilitation specialists should actively investigate and treat this problem. (2) Management of IC pain is inadequate and leads to disability and changes in sexual practices. (3) Linking treatments for sexual dysfunction with appropriate pain management strategies could substantially improve the quality of life for patients with IC. Structural factors in medical delivery along with health insurance policies reduce patient access to a comprehensive and interdisciplinary set of needed health interventions that could make a difference in the treatment of persistent pelvic pain and sexual dysfunction. Recognition of these structural issues is the key to improved health service delivery.

Wilms tumor (WT) is the most common kidney tumor of children. Over the last three decades, clinical trials employing multi-modality therapies have resulted in overall survival of greater than 90% for patients with low-risk disease. In spite of these advances, treatment of patients with advanced, anaplastic, and relapsed Wilms tumors remains challenging, with substantial rates of treatment failure and death. To improve risk stratification and identify novel therapeutic targets, we used high-accuracy mass spectrometry urine proteomics to identify urine tumors markers associated with relapsed WT and non-WT renal tumors. We measured urine proteomes at diagnosis of 54 patients with renal WT, clear cell sarcoma, rhabdoid tumor, and age-matched controls, leading to the quantitation of 6,519 urine proteins. In particular, we identified specific urine WT markers, including those that were enriched in patients with relapsed WT, such as mitochondrial regulators prohibitin and DAD1, β-catenin antagonist DACT2, and DNA repair factor SUN1. Using a specific enzyme-linked immunosorbent assay (ELISA) developed to measure urine prohibitin in an independent cohort of 139 WT and control samples, we found that urine prohibitin concentrations over 1000 ng/mL were significantly associated with the risk of disease relapse, with an odds ratio of relapse of 153 and receiver operating characteristic area under the curve of 0.77 (95% confidence interval of 0.64-0.99). Immunohistochemical tumor analysis revealed that prohibitin was highly expressed in primary Wilms tumor specimens. Importantly, using loss- and gain-of-function genetic experiments, we found that prohibitin was required for the growth and survival of Wilms tumor cells, and its overexpression conferred concomitant resistance to vincristine, doxorubicin and actinomycin D. Consistent with prohibitin’s functions in mitochondria, we are using BH3 profiling to elucidate specific intrinsic apoptotic dependencies in distinct subsets of refractory Wilms tumors, as a prelude to rational combination blockade of chemotherapy resistance, such as blockade of BCL2 dependence using venetoclax. In all, the use of urine prohibitin measurements may improve initial therapy stratification, and enable monitoring of response to therapy and early detection of relapse. In addition, therapeutic targeting of chemotherapy resistance induced by prohibitin overexpression may offer improved therapies for patients with relapsed or refractory Wilms tumors. Citation Format: Michael Vincent Ortiz, Melissa Burns, Amy Eisenberg, Saima Ahmed, Lyvia Gaewsky, Gary Bradwin, Paolo Cifani, Anton Henssen, Ian Macarthur, Michael LaQuaglia, Anthony Letai, Arlene Naranjo, Samantha Gadd, Yueh-Yun Chi, Jeffrey Dome, Elizabeth Perlman, Elizabeth Mullen, Hanno Steen, Alex Kentsis. Prohibitin is a prognostic marker of treatment failure and therapeutic target to block chemotherapy resistance in Wilms tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 708. doi:10.1158/1538-7445.AM2017-708

PURPOSE/OBJECTIVES: To establish the reliability and validity of a previously developed survey measuring nurses' experiences with prognosis-related communication. DESIGN: Psychometric testing of survey. SETTING: Mailed survey of Oncology Nursing Society (ONS) members. SAMPLE: 392 ONS members. METHODS: Reliability was analyzed using Cronbach's alpha. Total scale and subscale characteristics were evaluated through inter-item correlation matrices, average inter-item correlations, corrected item-to-total correlations, and Cronbach's alpha coefficients if the items were removed. Construct validity was assessed using exploratory factor analysis and contrasted group comparisons. MAIN RESEARCH VARIABLES: Measures of attitudes toward prognosis-related communication, demographic variables. FINDINGS: A three-factor structure emerged with acceptable reliability and validity. Contrasted group comparisons revealed differences in prognosis-related communication by nurses' years of experience with patients with cancer, level of education, and extent of education about prognosis-related communication. CONCLUSIONS: The final three-factor instrument, Prognosis-Related Communication in Oncology Nursing, was found to have acceptable reliability and validity. IMPLICATIONS FOR NURSING: The final instrument can serve as a tool to measure nurses' experiences with prognosis-related communication. Such measurements may guide interventions that aim to improve the process of prognostic disclosure and elucidate the role of the nurse in the process.

e21042Background: Uveal and mucosal melanomas are rare subtypes with a mean age-adjusted incidence of 5.6 and 2.3 cases per million person-years. Metastatic uveal and mucosal patients (pts) tend to...

9539Background: Overall responses (OR) are reported in 34% of patients (pts) with advanced MEL treated with Pembro. Landmark survival is 66%/49% at 1-/2- years respectively. Pre-existing CD8+ T-cell infiltrates and IFN gene signature at tumor sites correlate with response to PD-1 blockade. To evaluate synergy between PD-1 blockade and Peg-IFN, we implemented a phase Ib study of Pembro/Peg-IFN combination with dose-seeking and dose-expansion phases in stage IV MEL. Methods: Pts with IV MEL were enrolled. Peg-IFN was dose-escalated using modified toxicity probability interval (mTPI) design in 3 cohorts (4 pts each) at 1,2 and 3 mcg/kg SC while Pembrolizumab was dosed at 2mg/kg q3weeks in all pts. Primary endpoints were safety and incidence of dose-limiting toxicities (DLTs). Secondary endpoints were OR rate (ORR), progression free and overall survival. Response was assessed every 12 weeks (RECIST 1.1). Sequential blood draws and tumor biopsies were collected. Here, we report on response observed in 24 pts t...

9585Background: Neoadjuvant ipilimumab (ipi) at 3 or 10 mg/kg in combination with high dose IFNα2b (HDI) for locally/regionally advanced or recurrent melanoma may improve the clinical outcomes of t...

The metatarsophalangeal joints (MTPJ) are the only joints that bear weight directly through synovium. The purpose of this study was to determine whether there is an association between synovial stresses during running and increases in volume of joint fluid.This was a prospective case controlled study (nine healthy athlete volunteers acting as own controls). High-resolution coronal 3D T2W magnetic resonance imaging of the MTPJs were obtained following 24 h rest and after a 30-min run. The volume of joint fluid in each MTPJ (n = 90) was measured by two independent observers using an automated propagating segmentation tool.The median volume of synovial fluid in the MTPJs at rest was 0.018 ml (inter-quartile range (IQ) range 0.005-0.04) and after running 0.019 ml (IQ range 0.005-0.04, p = 0.34, 99% confidence interval (CI), 0.330.35). The volume of fluid in the MTPJs of the great toes was substantially larger than other toes (0.152 ml at rest, 0.154 ml after exercise, p = 0.903). Median volumes decrease from second to fifth MTPJs (0.032-0.007 ml at rest and 0.035-0.004 ml after exercise). Subset analysis for each toe revealed no significant difference in volumes before and after running (p = 0.39 to p = 0.9). The inter-rater reliability for observer measurements was good with an intra-class correlation of 0.70 (95% CI, 0.60 to 0.78).It appears to be normal to find synovial fluid, particularly in the MTPJs of the great toes, of athletes at rest and after running. There does not appear to be an association between moderate distance running and an increase in the volume of synovial fluid.

9043 Background: For clinical stage I and II node negative melanoma the histologic status of the sentinel lymph node (SLN) is the most significant predictor of survival. Molecular characterization of node positive and node negative SLNs through gene expression profiling may improve the understanding of the molecular mechanisms of metastasis and identify specific gene signatures for SLN+/SLN- that correlate with clinical outcome. Methods: We characterized 15 SLN+ and 15 SLN- melanoma patients (T3a/b, T4a/b) who underwent SLN dissection for routine staging using transcriptome profiling analysis on 5μ sections of fresh LN samples. The primary endpoint was mRNA expression profiling using the U133A 2.0 Affymetrix gene chips. Significance Analysis of Microarrays v.4 was used to perform non-parametric analysis and statistical comparison for each transcript corrected for false discovery rate (q value) to control for type 1 errors arising from multiple tests. Pathway analysis was performed using Ingenuity Pathway Analysis software. Results: Tumor size ranged from 1-2mm in size. Twenty-one genes were expressed at significantly (q value 1.4 fold; q < 0.12) identified the top disease categories as “Cancer” (26 genes, p = 5.7x10-9) and “Dermatological” (14 genes, p = 3.9x10-6). The top functional categories included “Cell Cycle” (21 genes p= 2.3x10-12) and “Cell Growth and Proliferation” (26 genes p=9x10-9). The relevant canonical pathways were “Eumelanin Biosynthesis” (p=3x10-5) and “Cell Cycle: G2/M DNA Damage Checkpoint Regulation” (p=1.2x10-4). Conclusions: We identified a 21 gene signature that is consistent with metastatic melanoma and its microenvironment and is differentially expressed in SLNs that are tumor involved. These gene families provide a signature of nodal involvement that may assist in diagnosis, and may be further explored towards prediction of outcome and development of therapy. A validation study is ongoing with clinical outcome association analyses as follow up is mature.

Background Bladder distention is commonly used in diagnosis and treatment of interstitial cystitis (IC). Traditionally performed in the operating room under general or spinal anesthesia (GA), it is expensive and associated with short term morbidity. Office bladder distention using electromotive drug administration (EMDA) has been suggested as an alternative that is well tolerated by patients. We report the first comparative findings of patients undergoing both office distention with EMDA and distention in the operating room (OR) with GA. Methods This retrospective chart review identified 11 patients participating in two protocols of EMDA bladder distention who also underwent bladder distention under GA either prior to or after the EMDA procedure. Results The median absolute difference in bladder capacity between GA and EMDA was only 25 cc; the median percent difference was 5%. Cystoscopic findings, while not prospectively compiled, appear to have been similar. Conclusion This study represents the first comparison between distention with EMDA versus GA and confirms the technical feasibility of performing bladder distention in an office setting. The distention capacity achieved in the office was nearly identical to that in the OR and the cystoscopic findings very similar. Further investigation into the comparative morbidity, cost, and other outcome measures is warranted to define the ultimate role of EMDA bladder distention in the clinical evaluation and care of patients with IC.