bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and predicators of insomnia among cancer survivors.
Authors: Peppercorn Jeffrey M. , Jimenez Rachel , Rabin Julia , Quain Katharine , Chinn Garrett , McDonough Allison , O'Donnell Elizabeth , Park Elyse R. , Perez Giselle Katiria
Published: September 2018

e21603

Background: Insomnia is prevalent among cancer survivors. However, screening and treatment is inconsistent across U.S. cancer centers. We sought to identify factors associated with moderate to severe insomnia (MSI) to inform the development of a screening and treatment program for survivors. Methods: As part of a comprehensive supportive care needs assessment, we evaluated the prevalence and correlates of insomnia among patients receiving follow-up cancer care. Patients reported on a 5 point Likert scale (0 = never to 5 = always) how often they have “problems falling or staying asleep”. MSI was defined as those who endorsed “4 = very often” or “5 = always,” and remaining responses were characterized as “No Insomnia” (NI). Descriptive statistics summarized patterns of insomnia and sleep hygiene. Chi-square and Fisher’s exact tests compared differences in sleep hygiene, fatigue, anxiety, depression, and other clinical and demographic characteristics between patients with and without insomnia. Results: Among 312 respondents, 83 (27%) endorsed MSI. Women were more likely to endorse MSI compared to men (32% vs. 19%, p = 0.02). Age was not associated with MSI. MSI was most common among patients with hematologic malignancy (36%), breast cancer (32%), gynecologic cancer (31%), and melanoma (29%). Regarding sleep hygiene: Most reported frequent exposure to bright light before sleep (89% MSI vs. 85% NI). Patients with MSI, compared to NI, were more likely to report watching the clock (86% vs. 75%, p = 0.04) and an irregular sleep schedule (47% vs. 32%, p = 0.02). Patients with MSI were also less likely to meet exercise guidelines (31% vs. 45% NI, p = 0.03) and more likely to report fatigue (29% vs. 14%, p = 0.004). Further, those with MSI were more likely to report anxiety (40% vs. 8%), fear of recurrence (74% vs. 46%), and financial concerns (35% vs. 15%) (all p < 0.001). 67% of patients with MSI were interested in supportive care to address insomnia. Conclusions: A simple one-item screener identified survivors susceptible to moderate to severe insomnia. Interventions beyond attention to sleep hygiene are needed to improve insomnia and its impact on fatigue and emotional distress. The relationships between insomnia, fitness, anxiety and distress merit further evaluation.
Long-term patient reported outcomes following radiation therapy for oropharyngeal cancer: A symptom assessment study in patients >65 years old.
Authors: Eraj Salman Ali , Jomaa Mona K , Rock Crosby Douglas , Mohamed Abdallah , Garden Adam S. , Sturgis Erich M. , Hutcheson Kate A. , Lu Charles , Frank Steven J. , Morrison William H. , Rosenthal David Ira , Fuller Clifton David , Gunn Gary Brandon ,   MD Anderson Head and Neck Cancer Symptom Working Group
Published: September 2018

e21611

Background: Given the potential for older patients (pts) to experience exaggerated toxicity and symptoms, this study was performed to characterize pt reported outcomes (PROs) in older pts following definitive radiation therapy (RT) for oropharyngeal cancer (OPC). Methods: Disease-free head and neck cancer survivors ( > 6 mos. since tx) were eligible for participation in a questionnaire-based study. Participants completed the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN). Those who had been treated for OPC with definitive RT (w/ or w/o systemic therapy) and were > 65 y/o at time of RT were included. Individual and overall symptom severity and clinical variables were analyzed. Results: Of the 79 participants analyzed, 82% were male, 95% white, 41% T3/4 disease, 39% RT alone, 27% induction chemotherapy, 52% concurrent, and 18% both, and 96% IMRT. Median age at the time of RT was 71 yrs. (range: 65-85); median time from end of RT to MDASI-HN completion was 46 mos. (2/3 > 24 mos.). The top 5 MDASI-HN items rated most severe in terms of mean (±SD) ratings (0-10 scale) were dry mouth (3.48±2.95), taste (2.81±3.29), swallowing (2.59±2.96), mucus in mouth/throat (2.04±2.68), and choking (1.30±2.38) reported at moderate to severe levels (≥5) by 35, 29, 29, 18, and 13%, respectively. Thirty-nine % reported none (0) or no more than mild (1-4) symptoms across all 22 MDASI-HN symptoms items, and 38% had at least one item rated as severe (≥7). Hierarchal cluster analysis resulted in 3 patient groups: 1) ~75% with generally no to moderate symptom burden, 2) ~25% with moderate to severe ratings for a subset of classically RT-related symptoms (e.g. dry mouth, mucus, swallow, taste), and 3) only 2 pts with severe ratings of nearly all items. Subgroup comparisons will be presented. Conclusions: The overall long-term symptom burden seen in this older OPC cohort was largely favorable, yet a higher symptom group (~25%) with a distinct pattern of mostly local symptoms was identified. We have implemented the routine use of symptom assessment tools as part of OPC survivorship programs and plan to explore age-dose-modeling of symptoms identified and associated normal structures.
Evaluation of nutritional parameters in prechemotherapy of oncology patients in a service of the Unified Health System.
Authors: Graziani Silvia Regina , Vital Carolina Graziani , Fernandes Hezio Jadir , Naime Fauzia de Fátima , Fonseca Ricardo Oliveira Da , Dias Carla Andressa Rodrigues , Almeida Ligia Rabello De , Neto Raphael Francisco Azuaga , Yamada Karina Emi , De Abreu Maria Stella Sa Granja , Pontes Tatiana Caldeira , D'Alvia Thiago , Ferreira Rafael Sanches , Eyzaguirre Velasquez Arianne Renata , Orias Valéria Urresti , Vanderlinde Fabiano Garcia , de Almeida Leandro Maritan , Diniz Paula Calixto Batistela , Van Eyll Brigitte M. , Costa Cassia
Published: September 2018

e21628

Background: Pre-chemotherapy nutritional evaluation is fundamental strategy as predictive factor for the possibility of response to oncological treatment and treatment-related toxicity. As in the Unified Health System patients usually arrive for evaluation with advanced disease, we believe that medical evaluation of the nutritional parameters is important in the therapeutic decision. Methods: From October 2015 through July 2016, we evaluated 210 patients referred for cancer treatment at the Arnaldo Vieira de Carvalho Cancer Institute in São Paulo (Brazil), which is an Institution that exclusively serves the Unified Health System. We evaluated the clinical parameters of weight and height, for estimation of BMI; evaluation the muscle of the fold of the thumb; and laboratory parameters as hemoglobin, lymphocytes, albumin, PCR (C-reactive protein) levels. We included 54 patients with gastrointestinal tract carcinoma; 32 colorectal carcinoma, 14 gastric carcinoma, 8 esophageal carcinoma, 12 lung carcinoma, 16 head and neck carcinomas, 38 breast carcinoma, 6 cervical carcinoma, 4 uterine carcinoma, 6 ovarian carcinoma, 4 malignant melanoma carcinoma, 2 soft tissue sarcomas, 10 prostate carcinoma, and 4 bladder carcinoma. Results: We found significant changes in the clinical nutritional parameters in patients with gastric, esophageal, lung and head and neck carcinomas, whose hemoglobin levels were among the mean normal values of 8.9 g/dL (6.5-10.3 g/dL), the lymphocytes levels were 850/mm3 (450-1200/mm3), the albumin levels were 3.2 g/dL (2.3-3.8 g/dL), the PCR levels were 126 mg/L (80-620 mg/L) and the Adductor muscle of the thumb were < 1 mm. Although all the evaluated patients presented advanced stages in diagnosis, the tumors of breast, prostate, uterine body, malignant melanoma and bladder did not present any significant alterations in the nutritional state. Conclusions: Our strategy shows that nutrition evaluation is an easy-to-use instrument, and opens the possibility of using in the therapeutic decision in patients with severe mal nutrition and compromising the general condition, since palliative chemotherapy has no impact on the overall survival of this population.
Online yoga as a non-pharmacologic symptom management approach in myeloproliferative neoplasms.
Authors: Huberty Jennifer , Eckert Ryan , Gowin Krisstina L. , Ginos Brenda F. , Kosiorek Heidi E. , Dueck Amylou C. , Larkey Linda , Mesa Ruben A.
Published: September 2018

e21704

Background: Patients with myeloproliferative neoplasms (MPN) have difficult symptom burden (i.e. fatigue, pruritus, night sweats) not resolved by current medical therapies including jak inhibitor therapy. We hypothesize that on-line (at home) yoga might alleviate MPN symptoms and complement medical therapy. Methods: MPN patients, recruited by social media, were asked to complete 60 min/week of online yoga (designed for MPN patients) for 12 weeks and completed online self-report surveys (weeks 0,7,12 and 16) on participation (Qualtrics), disease features, and symptom burden (MPN Symptom Assessment Form; NIH PROMIS measures of pain, anxiety, depression, sleep, and sexual function). Results: Two hundred and forty-four MPN patients completed the eligibility survey, 134 were eligible, 55 completed the informed consent, and 38 MPN patients completed the 12-week intervention. The majority of participants were diagnosed with either PV (n = 16) or ET (n = 16), with MF being less common (n = 6). Approximately 37% (n = 14) of study participants averaged ≥60 min/week of yoga (i.e., demand). Yoga participation averaged 50.8±36.2 min/week. Overall, 68% of participants were satisfied with online yoga and 75% felt that is was helpful for coping with MPN-related symptoms (i.e., acceptability, practicality). Additionally, 75% of participants felt safe from injury while participating in online yoga. Only one adverse event was reported (irritated enlarged spleen). From week 0 to week 12 (n = 38), there were significant improvements in total symptom burden (effect size [ES] in standard deviation units = -0.36, p = 0.004), anxiety (ES = -0.67, p = 0.002), depression (ES = -0.41, p = 0.049), sleep (ES = -0.58, p < 0.001), and fatigue (ES = -0.33, p = 0.04). These improvements remained significant at follow-up week 16 (n = 28) for all outcome measures with a trend for maintained fatigue improvement (ES = -0.34, p = 0.06) (see Table 1). There were no significant differences in outcomes between those that averaged < 60 min/week of yoga compared to those that averaged ≥60 min/week of yoga. Conclusions: A 12-week online yoga intervention is feasible (i.e., accepted, practical) for MPN patients and merits a randomized trial as complementary therapy.
Acupuncture for breast cancer related lymphedema: A randomized controlled trial.
Authors: Bao Ting , Van Zee Kimberly J. , Cassileth Barrie R. , Coleton Marci , Li Qing Susan , Mehrara Babak , Vertosick Emily , Vickers Andrew J. , Mao Jun J.
Published: September 2018

e21706

Background: Up to 20% of breast cancer survivors develop breast cancer related lymphedema (BCRL), and current therapies are limited. In a previous single armed study, acupuncture appeared to reduce BCRL. In this study, we compared our specific protocol of acupuncture (AC) to usual care wait list control (WL). Methods: Women with moderate persistent BCRL were randomized to AC or WL. The AC protocol included twice-weekly manual acupuncture over 6 weeks. The primary endpoint was change in circumference difference between affected/unaffected arms. Responders were defined as having > 30% improvement in arm circumference difference between arms. We also evaluated the change in difference between affected/unaffected arm bioimpedance. We used analysis of covariance for circumference and bioimpedance measurements and Fisher’s exact test for proportion of responders. Results: Among 82 patients, 73 (89%) were evaluable for the primary endpoint (36 in AC and 37 in WL). The median age in AC was 65 (IQR 54, 71) and 58 (IQR 49, 70) in WL. Most patients in both arms had undergone mastectomy (74%) and axillary lymph node dissection (96%), and had a history of prior lymphedema treatment (96%). Median duration of lymphedema was 2.2 years in AC (IQR 1.3, 3.0) and 2.5 years in WL (IQR 1.4, 3.4). We found no evidence of a difference in either arm circumference difference improvement (β -0.38cm, 95% CI -0.89, 0.12, p = 0.14) or bioimpedance difference improvement (β -1.06, 95% CI -7.85, 5.72, p = 0.8) between AC and WL at Week 6. There was also no difference in proportion of responders: 17% AC vs. 11% WL (6% difference, 95% CI -10%, 22%, p = 0.5). No severe adverse events (AE) were reported. Grade 1 treatment-related AEs such as bruising (58%), hematoma (2%), and pain (2%) were reported in patients receiving AC. Among the 837 acupuncture treatments provided, one possibly related grade 2 skin infection was reported. Conclusions: Although it appears to be safe and well tolerated, our acupuncture protocol did not offer additional clinically meaningful reductions in BCRL compared with usual care among patients who had received lymphedema treatment. This regimen should not be recommended for breast cancer survivors with persistent BCRL. Clinical trial information: NCT01706081.
Sarcoma tumor size (T) staging: Are radiology or pathology measurements more appropriate?
Authors: Pang Angela , Carbini Mariana , Demicco Elizabeth , Maki Robert G.
Published: September 2018

e22522

Background: In the AJCC version 7 TNMG staging of soft tissue sarcomas (STS), the longest dimension (1D) of the primary tumor at pathology analysis is the gold standard for tumor size (T) staging. However, measurements may differ between scans and actual tissue measurement, due to tissue elasticity, deformation, and/or formalin fixation. Thus, tumor size may change compared to preoperative imaging. Should STS T stage be defined by imaging or by direct tumor measurement? We examined the variability of the measurements between radiology and pathology data, examining 1D, cross sectional area (2D), and tumor volume (3D) to assign a T stage. Methods: We reviewed all patients (pts) with extremity STS who had surgery at Mt Sinai Hospital New York (2010-2015). MRI or CT and resected gross tumor measurements were available for 79 pts. After eliminating 10 samples with grossly irregular shapes and 11 samples with incomplete data, 58 tumors had complete 3D measurements. We calculated Pearson correlation coefficients for paired variables (radiology vs pathology size in 1D, 2D and 3D). Results: Imaging measures correlated well with direct tumor measurements. Pearson correlation coefficients for 1D, 2D and 3D measurements were 0.93, 0.72 and 0.78, respectively (all p < 0.01). The SEM (radiology/pathology size) = 0.13, i.e. 13% for 1D measurements. Thus, T stage could be incorrectly assigned in up to 13% of samples near 5 cm in size; this proportion decreases the further the tumor is from the 5 cm cutoff. Conclusions: As shown previously in the rationale for RECIST, 1D measures provide the smallest variance between radiology and pathology. The situation is made more complex in AJCC version 8, with four T categories. It remains unclear how to stage the 10-15% of primary STS with irregular shapes. These data support the use of nomograms for risk assessment rather than using bins created by the AJCC tumor staging system. 3D tumor volumes, if used at all, may play a greater role when assessing therapy responses or contending with tumors of irregular shape, rather than for routine STS staging.
miR-106b-5p, miR-17-5p to predict recurrence and progression in breast DCIS model based on TGFβ paradox.
Authors: Lee Jieun , Yim Kwangil , Kim Dong-Min , Song Young-Seok , Lee Ahwon
Published: September 2018

e23019

Background: Ductal carcinoma in situ (DCIS) is a well-known precursor of invasive ductal carcinoma (IDC). Part of patients show disease recurrence as DCIS or IDC after local treatment, but there are no established markers for prediction of recurrence. Methods: Authors analyzed 30 patients diagnosed as pure DCIS, recurrent DCIS, and IDC progressed in DCIS background. miRNA was extracted from archival tissue, and hierarchical clustering of miRNA microarray was performed. We selected highly expressed miR-17-5p and miR-106b-5p as marker for recurrence of DCIS. Two miRNAs were transfected to MCF-12 and MCF-7 cell line. Cell proliferation assay and Western blot analysis was performed for analyzing the interaction between cell proliferation and TGFβ downstream pathway. Results: miR-106b-5p single and combined miR-106b-5p and miR-17-5p transfected MCF-12 cell line showed increased proliferation index compared to un-transfected cell line. In MCF-7, miR-106b and miR-17-5p transfected cell line showed inferior proliferation index compared to un-transfected cell line. Western blot analysis showed minimal increased expression of SMAD4, phosphorylated SMAD2 (pSMAD2) in miR-106b-5p and miR-17-5p transfected MCF-12 cell line. However, decreased expression of TGFBR2 and no interval change of SMAD4 and pSMAD2 was detected in miR-106b-5p and miR-17-5p transfected MCF-7 cell line. Conclusions: miR-106-5p, miR-17-5p showed increased expression in recurrent DCIS or IDC based on miRNA hierarchical microarray. miRNA transfected MCF-12 cell line showed increased proliferation index and activated TGFβ downstream pathway. miRNA transfection might have made normal cell line to pre-cancerous cell line and TGFβ pathway might have influenced to promote tumor proliferation, based on TGFβ paradox hypothesis.
ctDNA detection of EGFR mutations in NSCLC patients using TargetSelector.
Authors: Beerkens Frans , Kim Chul , Hasan Syed P. , Subramaniam Deepa Suresh , Liu Stephen V. , Arnold Lyle , Vibat Cecile Rose T. , Singh Veena M. , Giaccone Giuseppe
Published: September 2018

e23037

Background: EGFR mutations are the most frequent targetable genomic alterations in non-small cell lung cancer (NSCLC) patients (pts). While tissue biopsy remains the standard for assessing of EGFR mutation status, it is invasive and not always feasible. Liquid biopsy is a minimally invasive alternative. Biocept’s proprietary TargetSelector system evaluates circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in blood. We aimed to clinically validate the accuracy of EGFR-specific TargetSelector in NSCLC pts. Methods: At three time points (T0: baseline before TKI, T1: during EGFR-TKI therapy, T2: after progression), blood samples were collected in Biocept OncoCEE BCT validated to preserve DNA up to 8 days. These samples were interrogated for three EGFR mutations: exon 19 deletions (Del 19), L858R, and T790M. The objectives are to assess detection sensitivity of liquid biopsy using EGFR mutation status vs the tissue as gold standard and to evaluate whether the detection sensitivity changes with EGFR-TKI therapy. Results: A total of 53 study pts were enrolled (male, 21; female, 32). The mean age was 70.6 (range: 46 – 90). Most pts had stage IV disease (43, 81.1%) and lung adenocarcinoma (48, 90.6%). 26 (49.1%) pts had EGFR mutations in tumor tissue: Del 19, 13; L858R, 8; T790M, 6; other, 8. Detection sensitivity for sensitizing EGFR mutations (Del 19 and L858R) at T0, T1, and T2 was 60.0% (6/10), 33.3% (5/15), and 33.3% (1/3), respectively. There was no statistical difference in CTC counts between activating EGFR mutation-positive and -negative pts (mean CTC count: 10.5 vs 20.1; p = 0.11 by two-sided t-test). Detection sensitivity for T790M was 33.3% (2/6) and 5 of 6 pts were receiving T790M directed therapy (3, rociletinib; 2, osimertinib) at the time of blood draw. Two pts – one patient before initiation of EGFR-TKI and the other during treatment with erlotinib – were found to have T790M mutations only in blood and not in tissue. Conclusions: Activating EGFR mutation detection may decrease during the course of TKI therapy, possibly due to treatment response. Further research with an expanded sample size and serial collections are needed to evaluate this finding, and to investigate possible implications of the presence of T790M only in blood.
PDL1 test to assess the dynamic range of mRNA expression from platelet enriched plasma in patients with NSCLC.
Authors: Mellert Hestia S. , Jackson Leisa , Pestano Gary Anthony
Published: September 2018

e23063

Background: Therapeutic options for patients with non-small cell lung cancer (NSCLC) continue to expand with the advent of immunotherapies. Lack of tissue and drawbacks with IHC have increased the need for blood-based diagnostics that measure continuous variables. Thus these tests are of increasing relevance for clinical testing. Methods: We focused on mechanisms of blood-based testing for the sensitive measurement of circulating RNA using ddPCR. Specifically, we optimized methods for the detection of PD-L1 and cytokeratin 19 (CK19) transcripts recovered from plasma. Specimens included tumor derived cell-lines, activated and resting immune cells, normal donor plasma and NSCLC (stages 1-4) donor plasma. Results: Assessing PD-L1 in circulation is complicated by its expression in both immune and cancer cells. Analytic performance was initially evaluated with cancer cell lines and activated lymphocytes and monocytes expressing variable levels of cytokeratins and PD-L1. A preliminary threshold was defined based on CK19 expression levels in normal donor plasma (n = 35). Of the 79 NSCLC donors tested 49% expressed CK19 above the threshold, indicating they contained sufficient circulating RNA derived from tumor. These donor samples tested either positive for EGFR del19 E746-A750 or L858R (n = 13), negative for EGFR (n = 10) or positive for KRAS G12C/V (n = 16). We found no differentiation in PD-L1 levels on the basis of EGFR sensitizing and EGFR wild-type status. We observed only three donors that expressed PD-L1 at high levels, and this was regardless of EGFR mutation status. In contrast, 30% of KRAS mutation-positive donor samples were above the pre-defined PDL1 threshold (n = 6 of 16 samples tested). These data are consistent with tissue-based studies that report trends of higher PD-L1 expression in KRAS positive NSCLC patients. Conclusions: We have developed sensitive and specific methods to measure the dynamic range of PD-L1 in circulation and have shown utility of these methods by evaluating key immune and cancer-specific RNAs.
Anticancer applications of allosteric inhibitors of proteasome.
Authors: Osmulski Pawel A. , Cropper Jodie , Giletto Matt , Jones Corey , Killer Caleb , Jiang Shoulei , Tepe Jetze , Chatterjee Bandana , Huang Tim , Gaczynska Maria E
Published: September 2018

e23066

Background: Proteasome as a hub protease of the ubiquitin proteasome pathway is an established anticancer drug target. Several drugs that inhibit proteasome are currently used to successfully treat aggressive blood cancers. These drugs are based on their competition with protein substrates of proteasome. However, efficacy of these drugs toward solid cancers is inadequate. Besides, the side effects and developing drug resistance are increasingly hampering the therapy. Therefore, there is an unmet challenge to develop new types of proteasome targeting compounds that are efficient against solid cancers and utilize other mechanisms to stop proteasome. Here we present a compound with a novel molecular mechanism, potentially bypassing limitations of the available drugs. Methods: We rationally designed and synthesized a series of small molecule “B” compounds, derivatives of a binding domain of seco-rapamycin that noncompetitively interfere with peptidase activities of proteasome. We tested effects of the compounds in vitro on purified proteasome, in cellulo with selected cancer cell lines and in a xenograft mouse model of prostate cancer. Results: We found that compound B1 binds to the catalytic core of proteasome far from the catalytic sites, destabilizes assembly of the 26S proteasome responsible for digest of polyUb substrates and allosterically inhibits its proteolytic activities. Molecularly, B1 impedes the gating mechanism responsible for substrate uptake as found with AFM. Tryptophan fluorescence indicates that B1 changes proteasome fold and the binding mode of competitive inhibitors. B1 substantially decreases viability of selected cancer cell lines and shifts their mechanical phenotype toward noncancerous status. B1 synergizes with bortezomib decreasing the IC50 5-10 fold. In a xenograft hormone resistant prostate cancer model, B1 treatment leads to shrinkage of the tumor size, decreases enumeration of aggressive, EpCAM+ CTCs and shifts the macrophage profile toward predator M1 type. Conclusions: B1 compounds constitute a new class of noncompetitive allosteric inhibitors of proteasome that could be useful to develop to treat aggressive prostate cancers alone or in synergy with competitive inhibitors.
Effect of bavituximab in combination with nivolumab on tumor immune response in a 3D ex vivo system of lung cancer patients.
Authors: Mediavilla-Varela Melanie , Page Melba Marie , Kreahling Jenny , Freimark Bruce D , Shan Joseph , Kallinteris Nikoletta Lea , Antonia Scott Joseph , Altiok Soner
Published: September 2018

e23091

Background: Bavituximab is a chimeric monoclonal antibody that targets the membrane phospholipid phosphatidylserine (PS) exposed on endothelial cells and cancer cells in solid tumors. Our previous studies showed that bavituximab enhances the activation of CD8+ TILs that correlates with increased cytokine production by lymphoid and myeloid cells in lung cancer with low PD-L1 expression suggesting that the interruption of the PD-1/PD-L1 axis by nivolumab may enhance the bavituximab effect in tumors. Methods: Fresh tumor tissues obtained from consented patients with NSCLC at the time of surgical resection were utilized in a 3D ex vivo tumor miscrosphere assay, where 3D tumor microspheres were treated with bavituximab or nivolumab alone or in combination at 10 mg/ml for 36 hours. At the end of the treatment, a multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines, including human IFNg, in culture media as a surrogate of TIL activation. In addition, a gene expression analysis using a NanoString platform containing probes to quantitate 770 immune function genes. Results: Preliminary results indicate the combination treatment with bavituximab and nivolumab led to increased expression of genes involved in M1 polarization of tumor associated macrophages in a subpopulation of lung tumors that closely correlated with release of cytokines such as MIP1b (CCL4) which is a chemoattractant for natural killer cells, monocytes and a variety of other cells involved in tumor immune response. Conclusions: This lung patient derived ex-vivo approach indicates that bavituximab in combination with nivolumab may enhance immune response. This response likely involves M1 polarization of tumor associated macrophages and suggests potential clinical implications in the treatment of lung cancer.
Metabolic intratumor heterogeneity of breast cancer.
Authors: Giskeødegård Guro Fanneløb , Badia Marina Perea , Bofin Anna , Madssen Torfinn Støve , Lundgren Steinar , Fjøsne Hans , Bathen Tone Frost
Published: September 2018

e23095

Background: Breast tumors are highly heterogeneous due to subpopulations of cancer cells that differ in genetic and phenotypic characteristics. Tumor heterogeneity has been associated with treatment resistance and relapse. Therefore, it can be questioned how representative one biopsy is for the whole tumor. Tumor phenotypic heterogeneity cannot be solely attributed to genetic differences, as epigenetics and interaction with the tumor microenvironment also contribute. In this study we have examined intra-tumor heterogeneity by measuring metabolite expression in breast cancer tissue compared with fibroadenomas. Methods: Fresh frozen tissue slices from surgically removed breast tumors were used. Five cores from different areas of the slices were drilled out from 10 tumors; 6 invasive ductal carcinomas grade 2-3, and 4 fibroadenomas. Histological examination of HES-stained sections from each core was done, and metabolic profiling was performed by magnetic resonance spectroscopy (MRS). The relative concentrations of 23 metabolites were quantified. Metabolic heterogeneity was assessed by coefficient of variation (CoV) and PLSDA classification was used for prediction of tumor origin. Results: Cancer tissue showed significantly higher heterogeneity than fibroadenomas for 16/23 metabolites (mean CoV range: 0.15-0.94 for cancer samples, 0.09-0.37 for fibroadenomas, p < 0.05). However, 23/50 samples did not contain tumor tissue on histological examination. After exclusion of tumor-free samples, the heterogeneity of 3 metabolites (glycine, glycerophosphocholine (GPC) and phosphocholine (PCho) remained significantly different between cancer and fibroadenomas (mean CoV range: 0.12-0.65 for cancer, 0.07-0.42 for fibroadenomas, p < 0.05). GPC and PCho are involved in building of cell membranes and may reflect cell-turnover. Multivariate classification could correctly predict which patient a sample belonged to with 78% accuracy. Conclusions: Metabolic heterogeneity could partly be explained by differences in tumor cell and stromal content, and the origin of an unknown sample could be successfully predicted, showing that metabolic intratumor heterogeneity is smaller than the heterogeneity between patients.
Verification of targeted gene expression profiling panel for identifying biomarker signatures for immunotherapy research.
Authors: Pankov Aleksandr , Ku Yuan-Chieh , Tom Warren , Zheng Jianping , Sun Yongming , Looney Timothy , Looney Timothy , Au-Young Janice , Mongan Ann , Hyland Fiona
Published: September 2018

e23208

Background: Immunotherapy has led to an unprecedented and long-lasting response in susceptible populations. Despite the therapeutic potential of the treatment, identifying biomarkers and stratifying populations that are likely to respond has been a challenge. While gene expression profiling has previously been successfully used to stratify individuals, there exist limitations with the prevalent technologies. In particular, full transcriptome gene expression estimates use limited biological material to measure the concentrations of thousands of uninformative genes and often lacks the depth required to accurately measure expression of lowly-expressed genes. These low-expressing genes may be critical to the identification of a signature associated with susceptible population. Methods: To efficiently measure the expression of the genes potentially informative of an immunotherapy response, we developed a high-throughput targeted gene expression solution measured with our RNA Ion Oncomine™ Immune Response Research Assay panel* containing 395 genes. This panel provides information about the expression of genes involved in tumor checkpoint inhibition, as well as markers of T cell signaling pathway, interferon signaling, tumor infiltrating lymphocytes (TIL). Results: We used publicly-available TCGA data to characterize the complexities of estimating unbiased gene expression from a targeted panel and developed a solution using a new normalization procedure that allows for accurate comparisons of samples within cancer types. Furthermore, we verified that lowering the RNA input amount or changing the assay operator does not contribute to a large variation in the gene expression estimates; each only accounts for less than 10% of variance of the average gene when the assay is compared across biological samples. Conclusions: Creating a panel that achieved high reproducibility and accurate expression estimates of key immune response genes allowed us to accurately separate high and low TIL samples within squamous and adenocarcinoma samples, emphasizing the utility of the panel to biomarker immunotherapy research. *For Research Use Only. Not for use in diagnostic procedures.
PARP inhibitor combination therapy in desmoplastic small round cell tumors.
Authors: Mellado-Lagarde Marcia , Federico Sara Michele , Tinkle Christopher , Shelat Anang , Stewart Elizabeth
Published: September 2018

e23212

Background: Desmoplastic small round cell tumor (DSRCT) is a rare but pernicious mesenchymal neoplasm that expresses the EWS-WT1 gene fusion transcript. It has similar histopathology to Ewing sarcoma (EWS). In previous work, we showed that addition of Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi) to the existing standard of care (SOC) therapy of irinotecan (IRN) and temozolomide (TMZ) was remarkably successful at treating mouse models of EWS, resulting in > 80% complete response compared to 100% mortality with SOC alone. EWS has high levels of the protein Schlafen-11 (SLFN11), a putative biomarker for defective DNA damage repair. The goal of this study is to determine whether DSCRT also expresses SLFN11, and whether high levels of the protein sensitize the tumor to PARPi as single-agent or in combination with other drugs and ionizing radiation. Methods: SLFN11 mRNA and protein levels were assessed by immunohistochemistry, quantitative PCR, Western blot, and immunofluorescence microscopy. Viability of the DSRCT cell line, JN-DSCRT-1, was measured using CellTiterGlo and the colony forming assay. Ionizing radiation (IR) was delivered using an orthovoltage irradiator calibrated to deliver graded doses of 0-16 Gy. Results: We found that SLFN11 was detected at high levels in several DSRCT patient tumor samples, and we confirmed that SLFN11 transcript and protein levels in JN-DSCRT-1were comparable to EWS cell lines. JN-DSCRT-1 demonstrated sensitivity to PARPi as single-agent or in combination with either the topoisomerase I inhibitor irinotecan or ionizing radiation comparable to EWS cell lines. To supplement our in vitro studies and to utilize more accurate models of the clinical disease, we developed orthotopic patient derived xenograft models (O-PDX) from three patients with DSCRT. Preliminary findings suggest that these O-PDX models maintain SLFN11 expression and recapitulate important aspects of DSRCT biology, including widespread dissemination of tumor in the abdominal cavity and characteristic cellular phenotype. Preclinical in vivo efficacy studies with PARPi combinations are in progress. Conclusions: Our work suggests that DSCRT expresses the SLFN11 biomarker and is sensitive to PARPi combination therapy.
Phase 1 multicenter trial of CUDC-907 in children and young adults with relapsed or refractory solid tumors, CNS tumors, and lymphoma.
Authors: Shulman David Stephen , Gustafson Clay , Vo Kieuhoa Tran , Fox Elizabeth , Muscal Jodi Ann , Supko Jeffrey G. , Place Andrew E. , Chi Susan N. , Shusterman Suzanne , Hanna Gina , O'Brien Jane , Ezrre Suzanne , Carlowicz Cecilia , London Wendy B. , DuBois Steven G.
Published: September 2018

TPS10576

Background: CUDC-907 is an oral first-in-class small molecule inhibitor of histone deacetylases (HDACs) and phosphatidylinositol-3-kinases (PI3Ks), two enzyme classes commonly implicated in pediatric malignancies. Preclinical data demonstrate that inhibition of these enzymes decreases tumor growth across a range of histologies. Data from preclinical and clinical studies suggest that down-regulation of Myc or Mycn signaling may be important in the antineoplastic effects of CUDC-907. Myc or Mycn signaling appears to drive a number of pediatric cancers, heralds a poor prognosis in many of these diseases and has proven difficult to target. CUDC-907 has completed adult phase I testing in patients with hematologic malignancies. The drug was tolerable using a 5 days on/2 days off (5/2) dosing strategy, with a recommended phase II dose of 60 mg. Diarrhea, fatigue, nausea and thrombocytopenia were the most commonly reported side effects. Partial and complete responses were observed in patients with Myc-altered diffuse large B cell lymphoma. Methods: This study is a phase I, open-label, multicenter trial of CUDC-907 in patients 1-21 years of age with relapsed/refractory solid tumors, brain tumors and lymphomas (NCT02909777). The primary objectives are to determine the recommended phase II dose, describe toxicities, and describe pharmacokinetic parameters of CUDC-907 in this population. Other objectives include evaluation of disease response and exploration of the pharmacodynamic effects of CUDC-907. Patients receive CUDC-907 orally on a 5/2 schedule in 28-day cycles, with a pediatric mini-tab formulation available for younger children. Part A consists of a standard 3+3 design evaluating up to three dose levels. Following dose escalation, Part B consists of two expansion cohorts for patients with Mycn/Myc-driven neuroblastoma or mature B-cell lymphoma. Up to 44 patients may be enrolled across Parts A and B. Detailed pharmacokinetic testing is required in the first two cycles. Optional pharmacodynamic testing will quantify histone acetylation, Myc protein, and phospho-S6 in serial blood samples. Enrollment began in October 2016 and is ongoing. Clinical trial information: NCT02909777.
A bi-shRNAfurin and GMCSF engineered autologous tumor cell immunotherapy vs. gemcitabine + docetaxel for Ewing sarcoma and with cryoablation in Ewing family tumors.
Authors: Anderson Peter Meade , Ghisoli Maurizio , Barve Minal A. , Gill Jonathan Benjamin , Wexler Leonard H. , DeAngulo Guillermo , Neville Kathleen , Manning Luisa , Wallraven Gladice , Senzer Neil N. , Birkhofer Martin , Nemunaitis John J.
Published: September 2018

TPS11079

Background: Vigil, an immuno-stimulatory autologous cellular therapy, uses patient tumor cells transfected with a plasmid encoding genes for GM-CSF and furin (to down regulate TGFβ 1&2). A Phase I study in relapsed Ewing’s sarcoma. (N = 16) had one 9 month partial response and a two-year survival rate of 44% [1]. Rapid, durable systemic immune activation was seen in the majority of patients using an IFNƔ ELISPOT assay [2]. We seek to extend these early findings in a randomized Phase 2 study (NCT02511132). Methods: Following surgery (for Vigil manufacture), patients are randomized 1:1 to Vigil (1 x 107cells/ml by monthly intradermal injection), or to chemotherapy with gemcitabine 675mg/m2 IV D1 and D8 and docetaxel 75 mg/m2 IV D8 every 21 days. Key eligibility criteria include: Age > 2, histologically documented metastatic Ewing's, refractory or intolerant to ≥2 prior lines of chemotherapy, and availability of at least 4 doses of manufactured Vigil. Patients with bone only disease are ineligible. The primary objective is to compare the overall survival of patients treated with Vigil vs. chemotherapy. The sample size of 62 patients assumes a one-year survival rate of 25% in the chemotherapy group vs. 60% in the Vigil group, corresponding to a hazard ratio of 0.383 favoring Vigil. Results: As of January 2017, thirteen patients have been randomized at 10 centers in the U.S. The design allows for reduction in disease burden prior to surgery using modalities like SBRT and interventional radiology. Toxicity of Vigil has been low compared to chemotherapy. Time to disease progression is being assessed in patients who crossover to Vigil after progressing on chemotherapy. Systemic control of metastatic lesions using cryoablation is also being assessed in other patients (e.g. DSRCT liver metastases) using a separate IND. Conclusions: Although associated with systemic immune activation, additional means to reduce disease burden such as SBRT and cryoablation can possibly improve patient health and augment Vigil efficacy. References: 1.Ghisoli M, Barve M, et al. Mol Ther. 2016 Apr 25 2. Oh J, Barve M, et al. Gynecologic Oncology 2016; 143: 504–510. Clinical trial information: NCT02511132.
A randomized, double-blind, placebo-controlled, phase III study of crenolanib in advanced or metastatic GIST patients bearing a D842V mutation in PDGFRA: The CrenoGIST study.
Authors: Blay Jean-Yves , Heinrich Michael C. , Hohenberger Peter , Casali Paolo Giovanni , Rutkowski Piotr , Serrano-Garcia Cesar , Jones Robin Lewis , Hall Kirsten Sundby , Eckardt John Randall , von Mehren Margaret
Published: September 2018

TPS11080

Background: Activating mutations in the kinase domain of PDGFRA account for 10-15% of GIST. The most common PDGFRA mutation reported is D842V, which is known to confer resistance to imatinib and sunitinib. Currently, there is no approved treatment for GIST patients carrying such mutation. Cassier PA et al. showed that patients with D842V mutated GIST had a short median progression free survival (PFS) of 2.8 months with first line imatinib and 2.1 months with second line (2012 Clin Cancer Res). Crenolanib is a highly selective PDGFRA and FLT3 inhibitor with nanomolar activity against PDGFRα D842V mutation. In a previous dose-finding study, crenolanib showed a 31% clinical benefit rate with 2 pts achieving PR and 3 pts maintaining SD (total evaluable: 16 pts) in heavily pretreated GIST patients harboring the PDGFRA D842V mutation. In this study, 35% patients stayed on study for at least 7 months despite 80% patients having progressed after prior imatinib (15 pts), sunitinib (7 pts), dasatinib (5 pts), sorafenib (4 pts), nilotinib (2 pts), and regorafenib (2 pts). Therefore, a phase III trial has been initiated to further confirm the clinical activity of crenolanib in patients with PDGFRA D842Vmutation. Methods: This randomized phase III study will enroll adult subjects with histologically or cytologically confirmed advanced or metastatic GIST with a PDGFRA D842V mutation. Prior treatment with TKI is allowed. Approximately 120 subjects will be randomized in a 2:1 ratio to receive either crenolanib 100 mg or matching placebo orally 3 times daily in combination with best supportive care. Randomization will be stratified by prior tyrosine kinase inhibitor exposure and ECOG performance status. The primary objective is PFS; key secondary objectives include OS. A formal interim analysis is planned after approximately 50 subjects have met the primary outcome. This study is already opened in the US, France, Norway, and Poland, and will soon be opened in Germany, Italy, Spain, UK and Asia. NCT02847429; EudraCT: 2015-000287-34 Clinical trial information: NCT02847429.
Tappas: An adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (AAS).
Authors: Jones Robin Lewis , Attia Steven , Mehta Cyrus R. , Liu Lingyun , Sankhala Kamalesh Kumar , Robinson Steven Ian , Ravi Vinod , Penel Nicolas , Stacchiotti Silvia , Tap William D. , Alvarez Delia , Yocum Richard , Theuer Charles P. , Maki Robert G.
Published: September 2018

TPS11081

Background: AAS is an aggressive soft tissue sarcoma (STS) of endothelial cell origin with an expected median overall survival of 8-12 months. Pazopanib (P) is approved for treatment of advanced STS following progression on chemotherapy. In a retrospective study of 40 AAS patients treated with single agent P the median PFS was 3.1 months and median OS 9.9 months with no complete responses. Endoglin is an essential angiogenic receptor expressed on AAS that is upregulated following VEGF inhibition, and TRC105, an endoglin antibody, given with P produced durable complete responses in AAS patients with median PFS of 5.6 months in refractory patients including those receiving prior P. The TAPPAS trial is the first randomized Phase 3 trial performed in AAS, and was initiated following protocol assistance from the EMA and Special Protocol Assessment from the FDA. Methods: TAPPAS is a randomized multicenter study of TRC105/P vs P alone in the United States and Europe that is actively enrolling cutaneous and non-cutaneous AAS patients and incorporates an adaptive enrichment design. Key inclusion criteria: 0, 1 or 2 prior lines of therapy, ECOG ≤ 1. Primary endpoint is PFS and secondary endpoints include ORR and OS. The initial sample size of 124 patients, followed until 95 PFS events, provides more than 80% power to detect a hazard ratio of 0.55. At the time of interim analysis, projected to occur upon the occurrence of 40 events in approximately 70 patients, the result will be classified as belonging to either the favorable, promising, enrichment or unfavorable zones, based on conditional power. The sample size and PFS events will be unchanged in the favorable and unfavorable zones, and will be increased to a total of 200 patients followed for 170 PFS events in the promising zone. The trial will enroll 100 additional patients, with cutaneous disease only, in the enrichment zone and will follow them until 110 events are observed in the total cutaneous population. An independent DMC will follow the trial for safety and futility. The adaptive design requires the enrollment of fewer patients, preserves type-1 error, and protects power to detect a clinically meaningful survival benefit. (NCT 02979899). Clinical trial information: NCT02979899.
A phase II randomized study to compare abemaciclib plus trastuzumab with or without fulvestrant to standard of care chemotherapy plus trastuzumab in hormone receptor positive, HER2-positive advanced breast cancer (monarcHER).
Authors: Tolaney Sara M. , Bourayou Nawel , Goel Shom , Hossain Anwar , Andre Fabrice
Published: September 2018

TPS1109

Background: Inhibition of CDK4 in preclinical models, demonstrated efficacy in HER2+ breast cancer and enhanced activity of HER2-targeted therapy suggesting a crosstalk between HER2 signaling and the cyclin D/CDK4 signaling pathway in which CDK4 & CDK6 inhibitors may re-sensitize resistant tumors to HER2 blockade.Abemaciclib is a selective inhibitor of CDK4 & CDK6 inhibitor that demonstrates single-agent anti-tumor activity on a continuous dosing schedule in women with hormone receptor positive (HR+) advanced breast cancer. Triple regimens with abemaciclib have been tolerable. Methods: monarcHER is an ongoing Phase 2, open-label, study in postmenopausal women with HR+, HER2+ locally advanced or metastatic breast cancer. Eligible patients (pts) are those previously treated with ≥2 HER2-directed therapies in advanced disease setting; T-DM1 and a taxane in any disease setting; no prior treatment with fulvestrant or any CDK4 & CDK6 inhibitor or with ECOG PS ≤1; LVEF ≥50%; no visceral crisis and no CNS metastases that are untreated, symptomatic or requiring steroids. Pts are randomized 1:1:1 to Arm A (abemaciclib [150mg PO Q12H] plus trastuzumab [IV infusion Q3 weeks] plus fulvestrant [IM injection on D1, 15, 29 then Q4 weeks]), Arm B (abemaciclib plus trastuzumab), or Arm C (trastuzumab plus SOC single-agent chemotherapy of physician’s choice); stratified based on number of prior systemic regimens (excluding single agent endocrine therapy) and disease status (measurable vs nonmeasurable). The primary objective evaluates investigator-assessed progression-free survival (PFS). Secondary objectives include overall survival, objective response rate, duration of response, disease control rate, clinical benefit rate, safety and tolerability, efficacy, health outcomes and pharmacokinetics. Analysis is planned at 165 PFS events, providing ≥80% power to detect superiority of Arm A and Arm B over Arm C, assuming a hazard ratio of 0.67 at a one-sided alpha of 0.10. First pt visit occurred in May 2016; with a target enrollment of 225 pts. Contact information: 1-877-CTLILLY (1-877-285-4559) Clinical trial information: NCT02675231.