bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome of patients with refractory malignant peripheral nerve sheath tumors (MPNST) enrolled on phase 2 trials.
Authors: Akshintala Srivandana , Mallory Nicole C. , Lu Yao , Ballman Karla V. , Kim AeRang 
Published: March 2020

e22534 Background: Multiple phase 2 trials using objective radiographic response rates (ORR) as end point have shown negative results in MPNST. Alternative endpoints such as progression free survival (PFS) may be more appropriate for identifying active agents. PFS from prior trials can provide a historical baseline for future single arm phase 2 trials in this rare disease. Methods: Outcomes of patients with recurrent or unresectable MPNST enrolled on one of five negative phase 2 trials (SARC001, 002, 009, 016, and 023) conducted by the Sarcoma Alliance for Research through Collaboration (SARC) from Nov 2001 – Mar 2016 were retrospectively analyzed to calculate PFS. PFS from SARC006, the phase 2 trial of upfront chemotherapy in newly diagnosed patients with unresectable or metastatic MPNST, was analyzed separately. The impact of neurofibromatosis type 1 (NF1) status, tumor location, metastatic involvement, and prior therapy on PFS was evaluated. Results: Sixty-four patients (29 male, median age 39 years (range 15-81)) with MPNST were enrolled on one of five trials of primarily single agent or combined targeted therapy that were determined to be inactive. Primary endpoint was ORR per RECIST, WHO, or Choi criteria. Patients had received a median of 1 (range 0-5) prior systemic therapies and majority had received prior surgery (77%) and radiation (61%), and had metastatic disease (73%) at enrollment. Median PFS was 1.77 months (95% CI 1.61-3.45), and PFS at 4 months was 16%. Greater number of prior systemic therapies was associated with worse PFS (univariate hazard ratio 1.31, 95% CI 1.03-1.68, p = 0.03). There was no significant difference in PFS based on treatment trial, response criteria, NF1 status, presence of metastatic disease, disease site at enrollment, and prior surgery or radiation. PFS at 4 months was 94% in 40 patients enrolled on SARC006 trial, none of whom had received prior systemic or radiation therapy. Conclusions: PFS in patients with recurrent/refractory MPNST enrolled on phase 2 trials is poor and the number of prior regimens may impact PFS. Our data provides a historical baseline PFS that can be used as a comparator in future single arm phase 2 trials in refractory and upfront MPNST patients.
Prognostic implications of tumor associated macrophages (TAMs) in soft tissue sarcoma.
Authors: Raj Shailaja KS , Kooshki Mitra , Winters Melissa , Russell Greg B. , Miller Lance D , Laurini Javier A , Pierre Triozzi , Savage Paul David 
Published: March 2020

e22548 Background: Clinical responses in patients with soft tissue sarcoma administered immune checkpoint inhibitors have been infrequent. Little is known regarding the immune microenvironment in soft tissue sarcoma that leads to a lack of effective responses with immune therapies. Whilst several studies have shown T cell infiltration in sarcomas, these tumors do not respond to immunotherapies. Macrophages are important regulators of immune responses in the tumor microenvironment. Studies in mouse models indicate that macrophages regulate immune checkpoint inhibitor response. With the overall goal of developing more effective combination immunotherapies for sarcoma, we examined tumor associated macrophages in patients with soft tissue sarcoma administered neoadjuvant chemotherapy. Interactions between macrophage infiltration, tumor immunogenicity and overall survival were also assessed using publicly available RNAseq and exome mutation data. Methods: Immunohistochemistry was performed on formalin fixed soft tissue sarcoma tissue. Tissues from 20 patients with soft tissue sarcoma pre and post neo-adjuvant chemotherapy were included. TAMs were detected by CD68; M2 subtype were detected by CD163. CD4, CD8, and CD25 T cells were also examined. The density of CD68+ TAMs, CD163+ TAMs and the ratio of CD163+ TAMs / CD68+ TAMs were calculated and their correlation with survival was also made. Publicly available RNAseq and exome mutation data were assembled from The Cancer Genome Atlas (TCGA) sarcoma cohort (n = 259). For each tumor, a relative measure of abundance of tumor-infiltrating macrophages was estimated using gene expression. Tumor mutational burden (TMB), expressed as the rate of non- synonymous mutations per megabase of sequenced DNA, was used as a measure of tumor immunogenicity. Interactions between macrophage infiltration, tumor immunogenicity and overall survival were assessed by Cox regression and Kaplan-Meier analysis. Categorical relationships involving clinical, immunologic, and genomic features of the tumor immune subclasses were compared. Results: Specific alteration in the density of CD68+ TAMs, CD163+ TAMs, and the CD163 / CD68 ratio were observed in patients with soft tissue sarcoma responding to neoadjuvant chemotherapy. Categorical relationships involving macrophage infiltration, TMB, and survival were also observed. Conclusions: These study support the targeting of tumor associated macrophages in patients with soft tissue sarcoma and suggest that changes in TAMs may be achievable using neoadjuvant chemotherapy.
Alveolar soft PART sarcomas (ASPS): A tertiary care center experience from India.
Authors: Simha Vijai , Mullapally Sujith Kumar , Dandekar Sonal , Turkar Siddharth , Rekhi Bharat , Bajpai Jyoti 
Published: March 2020

e22553 Background: Alveolar soft part sarcomas (ASPS) are rare, vascular, soft tissue sarcomas and response to conventional chemotherapy is disappointing. There is sparse data from India and other lower and middle-income countries (LMICs) and merits exploration. Methods: This is a retrospective analysis of patients of ASPS treated at Tata Memorial Center, patterns of care and outcomes were analyzed. Results: Fifty four patients of ASPS were treated between January 2002 to July 2018. The median age was 30 years and most common primary site 45 (80%) was extremities. Distant metastasis were seen in 36 (67%) patients; 20 upfront and 16 on recurrence. In the period from 2002-2014, 18/34 (54%) patients were declared “best supportive care” for want of effective systemic therapies. Only 16 (47%) patients with metastatic disease received systemic chemotherapy. 8 (11%) patients received conventional chemotherapy. Most commonly used regimen was combination of Ifosfamide and Adriamycin, however, 5/8 ( 62.5%) had progressive disease on chemotherapy and 37.5% had grade ≥3 toxicity mainly in form of neutropenias . Since the year 2015, the pattern of care evolved and 6 patients with metastatic disease were treated with antiangiogenic therapies (Sunitinib and Pazopanib). Responses were seen in 4/6 (66.6%) including 2 partial and 2 complete responses. The median progression free survival of these patients was 23 months (95% CI 14.3- 27.3 months) and was significantly better than that of conventional therapies - 7 months (95% CI 5.1-9.8 months) p = 0.03. Conclusions: ASPS is a systemic disease with high metastatic potential and poor chemosensitivity. Our institute practice has evolved from a policy of therapeutic nihilism to that of effective and feasible treatment in form of antiangiogenic therapy with meaningful responses.
Exploring ceramide metabolism as a potential target in dedifferentiated liposarcoma.
Authors: Demoret Bryce , Patt Andrew , Stets Colin W , Hoang Mindy , Hays John L. , Mathe Ewy , Chen James Lin 
Published: March 2020

e22558 Background: Dedifferentiated liposarcomas (DDLPS) are highly aggressive mesenchymal tumors characterized by MDM2 amplification. Elevated MDM2 amplification levels are associated with tumor growth, chemoresistance, and changes in cellular metabolism. Previous work from our laboratory has demonstrated that lipid metabolism, particularly increased glycosylated ceramides (Gly-Cer), is profoundly altered as a function of MDM2 amplification. Importantly, ceramides have been identified to play a key role in proliferation arrest and apoptosis or autophagy by stabilizing p53 through the binding and disrupting the MDM2-p53 interaction. Gly-Cer clears out ceramides, thereby preventing the ceramides from performing their anti-proliferative activity. We hypothesized that restoring Gly-Cer levels would induce anti-proliferative effects in DDLPS. Methods: 6 DDLPS cell lines (MDM2-high: Lipo224, Lipo141, Lipo224B, Lipo246; MDM2-low: Lipo815, Lipo863) were selected for in vitro assessment. MDM2 levels were ascertained via Western blot and RNA-sequencing. Metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling were conducted on all cell lines. Inhibitory concentration 50% (IC50) of the C6-ceramide (C6C) and nanoliposomal C6-Ceramides (C6CNL) were tested in vitro by XTT . Adjusted t-tests were used to determine metabolite relevance. Results: Metabolomic/lipidomic analyses identified a correlation between MDM2 amplification status and elevated levels of glycosylated ceramides (nom: Pval < 0.001), including GlcCer_NS(d18:1/24:1), GlcCer_NS(d19:1/24:1), GlcCer_NS(d18:1/25:0), glycosyl-N-palmitoyl-sphingosine, and glycosyl-N-stearoyl-sphingosine. Further, the ratio of glycosylated to un-glycosylated ceramides in DDLPS cell was also associated with MDM2 status for Cer(d19:1/24:1) (Pval < 0.01) and borderline associated for Cer(d18:1/16:0) and Cer(d18:1/25:0) (Pval < 0.2). In vitro treatment of DDLPS cell lines with C6C resulted in a reduction of cellular viability most prominent in MDM2-high cell lines (IC50: 17 vs. 55 µM). When treated with C6CNL, all DDLPS cell lines exhibited equal sensitivity (IC50: ~9 µM). Western blots demonstrate C6CNL treatment resulted in a reduction in MDM2 expression and restoration of p53 function. Conclusions: Exogenous ceramide treatment reduces MDM2 expression, restores TP53 status, and manifests anti-proliferative activity in DDLPS. C6CNL exhibited lower effective concentrations relative to free C6 ceramide. Prospective in vivo studies are underway to confirm these findings.
The impact of blinding on patient-reported outcomes (PROs) in randomized controlled trials of immune checkpoint inhibitors versus traditional chemotherapies.
Authors: Dickerson James , Hall Evan Thomas , Singhal Surbhi , Gabster Brooke Peterson , Schapira Lidia 
Published: March 2020

e23160 Background: Immune checkpoint inhibitors (ICIs) have been met with a wave of excitement due to their novel mechanism. We hypothesized that this may impact how patients (via PROs) report treatment tolerability in comparison to traditional therapies. We sought to examine if there was a notable difference in PROs in blinded vs unblinded trials of ICIs. Methods: We systematically searched PubMed, CINAHL, Embase, Web of Science, and Scopus in August 2018 for publications with quantitative PRO data comparing ICIs to cytotoxic chemotherapy. Case series, narrative reviews, and publications lacking original data were excluded. Eligible publications were reviewed to assess if patients were blinded to the agent received, and a comparison for common PRO metrics was performed. Results: Of the 1,450 unique references identified, eight met inclusion criteria: 1 double blinded placebo-controlled trial and 7 trials where patients were aware of the assigned arm. The blinded trial had quantitative PRO data in the form of the European Organisation for Research and Treatment of Cancer (EORTC) global health status (GHS) score and patient reported symptom burden at week 12. Most (6 of 7; 86%) unblinded trials reported the GHS at either week 12 or 15, and patient symptom burden at these time points as well (5 of 7; 71%). For the EORTC GHS, the blinded trial showed no inter-arm difference at week 12. 4 of 6 (67%) open label trials noted statistically significant differences in GHS favoring the ICI arm. For symptom burden at week 12 or 15, there was no difference found in the blinded study. In unblinded trials, there were domains where patients receiving ICIs reported a statistically significant lower symptom burden than those receiving chemotherapy: fatigue (4 of 5 trials favoring ICIs; 80%), dyspnea (2 of 5; 40%), insomnia (1 of 4; 25%), appetite loss (1 of 4; 25%), and diarrhea (1 of 5; 20%). There were no differences in pain (n = 5), nausea/vomit (n = 5), and constipation (n = 5). Conclusions: We found a trend towards more favorable reporting on common symptoms in unblinded studies of patients receiving ICIs. Our analysis is limited by the lack of available comparisons in the published literature.
One-minute time interval estimation as a novel potent indicator of need for help in cancer patients prior to starting chemotherapy.
Authors: Stoyanov Dragomir , Donev Ivan , Conev Nikolay Vladimirov , Panayotova Teodorika , Ivanova Martina 
Published: March 2020

e23161 Background: Perception of time strongly correlates with people’s current emotional state. Our study explored the potential relationship between the time estimation and the need of help in cancer patients prior to starting chemotherapy. Methods: Time estimation was assessed in 375 chemonaïve patients with solid tumors by evaluating each subject’s prospective estimation of how fast one minute passed compared to the actual time. The median value (40 sec) of time estimation was used to stratify the patients into two categories of fast and slow time estimation. The National Comprehensive Cancer Network Distress Thermometer and Problem List were used at the beginning of treatment to evaluate levels of distress and patients’ concerns. Additional question was asked “Do you need help?”. Results: Patients who reported the need of help were 134 (35.7%). The need of help correlated with fast time estimation, high level of distress and younger age (< 65y). Patients who reported a need of help estimated time significantly faster than those who did not report it (37.2±15.5 vs 42.7±17.2; p = 0.004). ROC analysis revealed that at the optimal cutoff value of time estimation, patients who reported a need of help and those who did not can be discriminated with an AUC = 0.59 (95% CI: 0.53-0.65, p = 0.003) and with a sensitivity of 61.9% and a specificity of 50.6%. Moreover, in a multivariate logistic regression model, fast time estimation was an independent predictor of reporting the need of help (OR 1.59; 95% CI 1.02-2.45; p = 0.04). Conclusions: Time estimation is a novel potent indicator for the need of help in cancer patients. This test is an easily performed, time-saving and nonintrusive ultrashort screening tool for the need of help that is even suitable for patients who are not willing to reveal their need of help via direct questionnaires.
The development of an instrument to identify cancer caregivers at risk for metabolic syndrome.
Authors: Jones Reyna , Moore Debra , Geller David A. , Miceli Jessica , Hecht Carol Lynn , Spring Michael , Pathak Ritambhara , Chen Qi , Steel Jennifer Lynne 
Published: March 2020

e23174 Background: Cancer caregivers are at increased risk for cardiovascular disease. The aims of the present study were to develop an instrument to identify cancer caregivers at risk for the development of cardiovascular disease. Methods: Cancer caregivers were enrolled in a prospective study examining predictors of metabolic syndrome. Predictors included perceived stress, caregiver stress, depression, hostility, physical activity, diet, alcohol and tobacco use, social support and relationship with the patient. Regression analyses and factor analyses was performed to reduce the number of items to develop an instrument that would identify cancer caregivers at risk for cardiovascular disease. Internal consistency and Area Under the Receiver Operator Curve was also performed to test the new instrument. Results: A total of 111 caregivers were included in the analyses. The mean age of caregivers was 59.6 ( SD= 12.7) and the majority of caregivers were female (74.8%), Caucasian (94.6%), and were the spouse of the cancer patient (65.8%).Using regression analyses, the items from the caregiver stress, hostility, and social support questionnaires were most likely to predict metabolic syndrome. Preliminary findings suggest that a 35-item instrument was predictive of metabolic syndrome [B = 0.067, HR = 1.07, p = 0.001]. The reliability of the instrument was good with a Cronbach Alpha = 0.83. The Area Under the Receiver Operator Curve was also fair (AUROC = 0.703; 95% CI = 0.597-0.808, p = 0.001). Based on the AUROC, the best cut point to detect metabolic syndrome would be a score of 24 (Sensitivity = 0.75 and Specificity = 0.55). Conclusions: Preliminary findings suggest that this 35-item questionnaire may be useful in identifying cancer caregivers at risk for metabolic syndrome, an intermediate endpoint for cardiovascular disease. The questionnaire may be used to screen cancer caregivers for interventions to reduce metabolic syndrome.
MDM2 inhibitor AMG-232 and radiation therapy in treating patients with soft tissue sarcoma with wild-type TP53: A phase IB study (NRG-DT001).
Authors: WELLIVER Meng XU , Van Tine Brian Andrew , Houghton Peter , Rudek Michelle A. , Pollock Raphael E. , Kane John Michael , Schwartz Gary K. , Zhang Peixin , Kirsch David G. , Wakely Paul , Jiang Steve B. , Jiwani Shahanawaz , Rogers Alan D. , Wang Dian 
Published: March 2020

TPS11076 Background: Over-expression of mdm2 is a major block to p53 activation in soft tissue sarcoma (STS). AMG-232 specifically inhibits human MDM2-p53 interactions in vitro and in vivo, thereby activating p53. Resistance mechanisms to MDM2 inhibition by AMG-232 is through accumulation of MDM2 and MDMX. However, DNA damaging agents, such as radiotherapy (RT), promote MDMX degradation and lead to sustained p53 activation, which is critically important for radiation-induced tumor cell killing in STS. Indeed, preclinical studies reveal that AMG-232 synergizes with RT in vitro and in vivo when treating STS with wild type (WT) P53 gene . Since a majority of STS harbor WT TP53 gene and RT is part of the standard of care in treating STS; it is the next rational step to test the safety and efficacy of combination of AMG-232 and RT followed by surgery. In this clinical trial, we hypothesize that preoperative AMG-232 plus RT is safe and well tolerated in 2 separate cohorts: (A) extremity and body wall; (B) abdomen/pelvis/retroperitoneum. Methods: A key feature of this trial is to incorporate TP53 NGS sequencing result as one of the eligibility criteria. Adult patients with pathologically proven grade 2-3 STS with size ≥ 5 cm are eligible to enroll if there is a planned definitive surgical resection of the primary tumor. There must be sufficient tissue to submit to central laboratory for NGS sequencing of the TP53 gene, which is an integral biomarker. Only those with tumors harboring WT p53 gene will be allowed to continue protocol treatment. The primary objective is to evaluate the safety and tolerability of AMG-232 in combination with standard-dose RT in STS in two separate cohort; as well as to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of AMG-232 in combination with RT. We define DLT as grade 4-5 toxicities attributable to AMG-232 for up to 4 weeks after the completion of combination treatment (prior to surgery) as well as any AMG-232 related grade 3 toxicity that should lead to > 2 weeks treatment delay or ≥ two dose reductions. There are 3 dose levels for AMG-232: dose level 1 is 120 mg daily for 3 days per week; dose level 2 is 120 mg daily 4 days per week and dose level 5 is 120 mg daily 5 days a week. If patients did not tolerate dose level 1, AMG-232 will be de-escalated to a lower level, which is 120 mg daily 2 days a week. The trial was open since 11/2017; 3 patients have been enrolled to cohort A and 2 patients in cohort B at dose level 1. The first patient has a tumor with WT p53 gene and has completed protocol treatment safely. Clinical trial information: NCT03217266.
CBT-1 in combination with doxorubicin in patients with metastatic, unresectable sarcomas who previously progressed on doxorubicin.
Authors: Cote Gregory Michael , Chawla Sant P. , Burgess Melissa Amber , Thornton Katherine Anne , Oldham Robert K. , Okuno Scott H. , Ballman Karla V. , Matlow Susan , Barnett Daryl , Attia Steven 
Published: March 2020

TPS11077 Background: The response rates of advanced soft tissue sarcomas (STS) to single-agent, first-line anthracycline are typically less than 25%. P-glycoprotein 1 (P-gp), a cell membrane drug efflux pump, is believed to be a resistance mechanism in STS. CBT-1 is a small molecule, orally administered, P-gp antagonist currently under clinical development. This is a multi-institutional open label phase I study of CBT-1 in combination with doxorubicin in patients with anthracycline-refractory sarcoma. The study is designed to determine a maximum tolerable dose (MTD), recommended phase II dose (RP2D), and the safety/tolerability of the combination of CBT-1 and doxorubicin. The study will evaluate anti-cancer activity as a secondary objective as measured by Disease Control Rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]) at 12 weeks. Objective Response Rate (ORR; CR+PR) and Progression Free Survival (PFS) will be monitored. Correlative studies include assessment of pharmacokinetic and pharmacodynamicendpoints. Methods: Patients 18 years or older with locally advanced metastatic, unresectable STS, prior progression on ≤ 150 mg/m2 of doxorubicin (or another anthracycline equivalent), ECOG PS ≤ 1 and normal organ function, are eligible for this study. Dosing includes fixed doxorubicin (37.5 mg/m2 IV day 5 and day 6) and escalation of oral CBT-1 on days 1-7 of a 21 day cycle. This study follows a standard 3+3 phase I design where dose escalation will occur if < 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted at Week 6 and Week 12. For patients with response or stable disease, treatment is allowed to continue for 4-5 cycles to a maximum of 450 mg/m2 lifetime doxorubicin exposure. Once RP2D is defined, an additional 10 patients will be enrolled into the dose expansion phase. To date, Cohorts 1 (50 mg CBT-1) and 2 (100 mg CBT-1) have been completed with one DLT of grade 4 neutropenia lasting longer than 7 days in Cohort 1. Enrollment to Cohort 3 began December 2018. (References: Oldham, R. K., Reid, W. K., Preisler, H. D., and Barnett, D. (1998) Cancer Biother. Radiopharm. 13, 71-80; Kelly, R. J., Robey, R. W., Chen, C. C., Draper, D., Luchenko, V., Barnett, D., Oldham, R. K., Caluag, Z., Frye, R. A., Steinberg, S. M., Fojo, T., Bates, S. E. (2012) The Oncologist 17 (4) 512-e523; Robey, R. W., Shukla, S., Finely, E. M., Oldham, R. K., Barnett, D., Ambudkar, S. V., Fojo, T., Bates, S. E., (2008) Biochemical Pharmacology 75, 6, 1302-1312). Clinical trial information: NCT03002805.