bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world tumor response (rwTR) to ramucirumab plus docetaxel (R+D) post platinum-based (Pt) and immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (aNSCLC) patients (pts).
Authors: Clarke Jeffrey Melson , Mathur Raina , Molife Cliff , Batus Marta , Stefaniak Victoria Jennifer , Winfree Katherine B. , Baxi Shrujal , Cui Zhanglin Lin , Lenis David , Bonomi Philip D.
Published: March 2020

e20725

Background: In REVEL, adding ramucirumab to docetaxel improved response rates among Pt-treated aNSCLC pts. This observational study evaluated rwTR in aNSCLC pts treated with R+D after Pt & ICI or other (non-ICI) therapies. Methods: Adult aNSCLC pts receiving 2L/3L R+D between 3/1/15 & 6/30/18, after 1L/2L Pt therapy, with ≥ 1 documented rwTR assessment, & ≥ 3 months of potential follow-up were selected from the Flatiron Health EHR-derived de-identified database (n = 172). Based on prior ICI exposure, pts were assigned to either the R+D post-ICI or the R+D post non-ICI [other] unmatched cohort. Study endpoints during R+D therapy included real-world (rw) objective response rate [rwORR], rw disease control rate [rwDCR], rw time to first response [rwTTFR], rw duration of response [rwDOR] & rw best response [rwBR]. Results: Overall, median age was 66.0 years and most pts were male (54.7%), white (70.3%), treated in the community (99.4%), had nonsquamous histology (79.7%), were stage IV at diagnosis (70.9%), had a low (≤ 1) Charlson comorbidity index (90.7%) & ECOG ≤ 1 (57.6%). Among tested pts, most were negative for EGFR (93.0%), ALK (94.9%) ROS1 (96.6%), or PD-L1 (75.0%). Baseline characteristics were similar between cohorts. Table shows significant differences in rwBR & rwDCR when stratified by cohort. Conclusions: Pts receiving R+D in the post-ICI setting had improved rwDCR compared to the R+D post-Other group, driven by a greater proportion of rwPR & a higher rate of rwSD as rwBR. The proportion of rwPD as rwBR was lower in R+D post-ICI pts. rwTR rates were generally similar to tumor response outcomes reported in REVEL. Understanding impact on OS is warranted given the increasing use of ICIs in earlier lines of therapy. [Table: see text]
Effects of COJEC induction on neuroblastoma patient-derived xenografts (PDX).
Authors: Manas Nunez Adriana , Aaltonen Kristina , Hansson Karin , Radke Katarzyna , Esfandyari Javanshir , Gisselsson David , Bexell Daniel
Published: March 2020

e21503

Background: Neuroblastoma (NB) is a solid pediatric tumor that causes 15% of childhood cancer deaths. High-risk patients have 50 to 70% mortality after 5 years. Currently, the standard way to treat high risk patients is COJEC induction followed by surgery, chemotherapy with stem cell transplants, irradiation and immunotherapy. This intense treatment has significantly increased overall survival, but mortality is still high, survivors are prone to relapse and treatment resistance is a major clinical problem. COJEC induction consists in the cycled administration of the chemotherapeutics Cisplatin, Vincristine, Etoposide, Cyclophosphamide and Carboplatin. These drugs have been long used in the clinic, but a comprehensive preclinical study combining all of them had not been done. The aim of this project was to establish a PDX model for chemotherapy induction in high-risk NB and investigate tumor characteristics and response upon treatment. Methods: NB cells from previously developed high-risk PDX models were injected subcutaneously in nude mice. When tumors reached an appropriate size, they were treated with either a COJEC-like protocol or single agent induction with high dose cisplatin. After treatment, tumors were analyzed by immunohistochemistry, chromosomal copy number analysis and RNA sequencing. Results: Most mice responded well to COJEC induction and 8/10 tumors were reduced. Within the reduced tumors, 4 were subjected to total resection and relapsed after several weeks, mimicking the clinical situation. Cisplatin treatment alone led to no significant tumor reduction and 6/10 tumors were highly resistant. Thus, as for humans, multidrug induction is more successful in reducing tumor size but presents an uneven response with high relapse rate. The responsive tumors show a higher degree of cellular differentiation when compared to resistant tumors. Cisplatin treated tumors have accumulation of chromosomal aberrations when compared to controls, and subclonal dynamics are enhanced in resistant tumors. Conclusions: We established a PDX model for chemotherapy induction in high-risk NB. The results mimic clinical findings seen in high-risk NB patients. The model is useful to understand the mechanisms of treatment resistance and for the testing of novel therapies against high-risk NB.
MRI based radiomic signature to predict treatment response to intraventricular natural killer (NK) cell infusion therapy for recurrent/refractory pediatric brain tumors.
Authors: Khatua Soumen , Idris Tagwa , Kotrotsou Aikaterini , Gupta Sumit , Zaky Wafik Tharwat , Gopalakrishnan Vidya , Lee Dean Anthony , Colen Rivka R.
Published: March 2020

e21511

Background: NK cell therapy is a novel immunotherapeutic strategy used in cancer therapy. We conducted first-in-human, loco-regional infusion of autologous ex-vivo expanded NK cell directly into the brain in children with recurrent medulloblastoma (MB) and ependymoma (EP). Radiomics is considered an emerging method to predict treatment response as well as evaluate prognosis and tumor milieu. This is the first study evaluating the ability of radiomics to predict response to intraventricular infusions of NK cell in children with recurrent/refractory posterior fossa malignant brain tumors. Methods: We evaluated 7 patients (5 males: 2 females; mean age 11.8 years) with refractory/recurrent MB or EP (MBs = 3, EPs = 4), who were enrolled on a Phase-1 trial (NCT02271711) and received 3 cycles of intraventricular NK cell infusions. Patients were categorized based on their clinical response into responders (N = 2) and non-responders (N = 5). After semiautomatic segmentation of the tumor, 3,660 radiomic features were extracted from the baseline (before treatment) MRI scan. The least absolute shrinkage and selection operator regression was used for feature selection, and the radiomics signature was built using the unsupervised anomaly detection algorithm. The performance of the radiomics model was assessed using leave-one-out cross-validation. Results: The radiomic signature/model was comprised of 6 radiomic features and demonstrated high discriminatory performance in predicting response to NK cell therapy with an area under the curve, sensitivity, and specificity of 100% ( P = 0.09486). In addition, patients clustered into responders and non-responders using unsupervised hierarchical clustering. Conclusions: To our knowledge, this is the first study to identify the ability of radiomics to predict those who will likely benefit from NK cell therapy. Though this small study did not attain statistical significance, the robust discriminatory results warrant larger prospective studies, evaluating radiomics as a potential tool to identify responders to NK cell therapy at diagnosis.
Factors impacting time to diagnosis in pediatric, adolescent and young adult (AYA) patients with solid tumors.
Authors: Alvarez Elysia Marie , Winestone Lena , McPheeters Jeffrey , Puccetti Diane , Wilkes Jennifer Jill , Henk Henry J. , Bhatia Smita , Ginsberg Jill P. , Keegan Theresa , Pollock Brad H.
Published: March 2020

e21515

Background: While cancer is the leading cause of non-accidental death in children and AYAs, factors associated with delays in diagnosis in young patients with cancer are poorly understood; we sought to fill this knowledge gap. Methods: Using the OptumLabs Data Warehouse’s claims data for commercially insured enrollees in a large US health plan—we identified pediatric [0-14 years (y)] and AYA (15–39 y) patients diagnosed with soft tissue sarcomas (STS), bone tumors (BT) and germ cell tumors (GCT) during 2001–17 and continuously enrolled 6 months prior to diagnosis. Time to diagnosis was calculated as days between first medical encounter associated with a possible cancer symptom and diagnosis date. Median times from first symptom to diagnosis were compared using Wilcoxon Rank Sum test. Multivariable logistic regression identified sociodemographic and clinical factors associated with longer time ( > 3 months) from symptom to diagnosis. Results: Of the 11,395 patients, 86% presented to medical care with symptoms prior to diagnosis [STS: 2,228 (89%); BT: 1,565 (87%); GCT: 5,904 (84%)]. The most common symptoms were pain and swelling. STS had the longest median days to diagnosis (92), followed by BT (91) and GCT (49). There was a significant difference (p < 0.001) in median days to diagnosis by age for BT (0–14y: 69; 15–21y: 77; 22–39y: 105) and GCT (0–14y: 96; 15–21y: 34; 22–39y: 49), but not for STS. Patients in households with ≥ a college degree (OR 1.96, 95% CI 1.06–3.64, vs < high school) and seeing a specialist (excluding oncologists) (OR 2.54, CI 2.03–3.19, vs primary care) at first symptom presentation was associated with a longer delay, while older age (22–39y: OR 0.77, CI 0.63–0.94, vs 0-14y) and male sex (OR 0.58, CI 0.51–0.66) were associated with a shorter delay in diagnosis. Conclusions: This study demonstrates that, in a commercially insured population, time to diagnosis varies by cancer type and is impacted by clinical and sociodemographic factors. Shorter time to diagnosis may represent delays in presenting to medical care or more acute presentations of symptoms, therefore patient-reported symptoms and barriers to care data should be collected to better define strategies to reduce delays in diagnosis.
Modeling and identifying therapeutic targets in Hepatoblastoma.
Authors: Smith Jordan L. , Mou Haiwei , Zhang Xiao-Ou , Ozata Deniz , Xue Wen
Published: March 2020

e21518

Background: Hepatoblastoma, an aggressive pediatric liver tumor, most often affects young children under five years of age. Surgical resection and chemotherapy have saved many children’s lives; yet, the overall five-year survival rate is 70%, and worse for children who present with unresectable tumors. Addressing the clinical need for HB-targeted therapies requires a better understanding of how HB tumors maintain their tumorigenic potential. Recent studies suggest that YAP1, the transcriptional co-regulator, and the Wnt/β-catenin pathway cooperate for HB tumor initiation. Further YAP1 is hyperactivated in nearly 80% of children’s HB tumors; however, will YAP1 inhibition result in therapeutic benefit for pediatric patients? Methods: To assess the role of YAP1 signaling in HB tumor maintenance, we generated a conditional mouse model of HB driven by doxycycline-inducible YAP1S127A and constitutively active β-Catenin. Delivery of doxycycline induces YAP1S127A expression and mice develop HB tumors within six weeks. After tumor formation, doxycycline is withdrawn, turning off YAP1 expression, and tumor progression is monitored using in vivo bioluminescent imaging. Results: Here we show in our conditional mouse model of HB that YAP1 is essential for tumor maintenance. In vivo YAP1 withdrawal leads to > 90% tumor regression within 10 weeks. Transcriptional analyses reveal that YAP1 withdraw in regressing tumors potently induces hepatocyte differentiation and metabolism genes, including HNF4a and FoxA2 target genes. Conclusions: Establishment of a luminescent conditional model of HB provides a new platform to critically address and explore therapeutic vulnerabilities in HB. Specifically, our data suggest HB tumor maintenance requires YAP1. Finally, in vivo tumor regression following YAP1 withdraw serves as preclinical evidence for the therapeutic potential of YAP1 inhibitory therapies in children with HB.
Assessment of knowledge, attitude and practice and associated factors towards palliative care among health care providers to the pediatric oncology patients in southern Philippines.
Authors: Pasaol Jayson Cagadas
Published: March 2020

e21536

Background: Palliative care (PC) aims to prevent, relieve and manage the symptoms of cancer and the adverse effects of cancer treatment; however, lack of education is among the biggest challenges facing PC in Philippines. Education and Awareness are dismal, especially in Southern Philippines. This study aimed to assess the level of knowledge, attitude, and practice of Health Care Provider towards pediatric PC. And to discover associated factors that limits the pediatric oncology patients to receive PC and identify the barriers in providing PC by the cancer centers to the pediatric oncology patients. Methods: A cross-sectional study design, conducted at tertiary care hospital that offers PC to pediatric oncology patients at Southern Philippines. Structured questionnaire was circulated to identify the barriers of PC, and assess the Knowledge, Attitude and Practices (KAP) of health care provider using a systematic random sampling method. The data was entered, cleaned and analyzed using excel and SPSS version 19.0 software. The chisquare test was employed to assess the association between variables. A p-value of less than 0.05 was considered as statistically significant. Results: From the total of 508 health care providers selected, a response rate of 500 (98.4%) were registered. Among the respondents 287(57.4%) had good knowledge and 259 (58.1%) had favorable attitude towards pediatric PC. In contrast, the level of practice showed that the majority 384 (76.8%) of health care providers had poor practice towards PC. Results showed that 94% to 99% of health care providers believed that the inadequate research evidence base to guide and measure the quality of life and lack of staff training in pediatric PC were the major barriers in providing PC by the cancer centers to the pediatric oncology patients. And 100% health care providers affirmed that the ignorance and lack of awareness about the existing program and resources of PC were the major factors that limits the pediatric oncology patients to receive pediatric PC in Southern Philippines. Conclusions: The health care providers had poor training and knowledge aspect of practice, but their attitude towards PC was favorable. Recommendations are the needs to be incorporated in the Department of Health through Continuing Professional Development to promote regular training for PC. Also, Educational awareness to assist healthcare professionals and pediatric oncology patients involved in PC needs to be regulated and provide.
Comprehensive genomic profiling of patients with favorable prognosis in osteosarcoma.
Authors: Liu Weifeng , Huang Zhen , Ding Yi , Yang Yongkun , Jin Tao , Deng Zhiping , Xu Hairong , Wang Xuan , Zhang Yanrui , Wang Huina , Lou Feng , Cao Shanbo , Niu Xiaohui
Published: March 2020

e22501

Background: Osteosarcoma (OS) is characterized by complex genetic features and mysterious biological behavior. Genomic technologies are starting to give more insights. However, recent investigations have focused on patients with the advanced or metastatic disease. This study intended to evaluate the genetic landscape and identify new prognostic biomarkers in OS pts with good prognosis. Methods: This study conducted in-depth genomic profiling in a cohort of 21 patients (MSTS stage II) with long-term follow-up. Whole exome sequencing of primary tumors with matched normal tissues were performed. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (Indels), copy number variations (CNV) and chromosomal rearrangements and their prevalence was compared to the pts with metastatic disease reported before (Wang et al, 2018). Tumor mutation burden (TMB) and microsatellite instability (MSI) was analyzed, with additional analysis for mutational signatures. The endpoint was disease free survival (DFS). Results: 21 participants were enrolled between July. 23th, 2008 and Aug. 19th, 2013. 21 pts (M/F 13/8), median age 17y (5-33). Median DFS was 88.4 (95% CI 61.27–111.77) months. The top ranked altered genes were MUC4 (67%), FRG1 (62%), TXNDC2 (62%), ZNF717 (62%), ANKRD20A4 (57%), IGSF3 (52%), MUC16 (52%), NBPF10 (52%), MUC12 (48%) and ARID1A (43%). TMB was evaluated as lower level with a median value of 1.11 muts/MB (range from 0.78 to 3.58), relative to the other solid tumors. None pathogenic and likely pathogenic germline mutations were detected. Mutation signature 5 and 6 were most prevalent. CNV were frequently happened in stage II OS with an incidence of 80.9% (17/21). Among these, The co-occurrence of copy number gain (CNG) and copy number loss (CNL) significantly correlated with DFS (p = 0.0164), comparing with pts of either CNG or CNL . While CNV of driver genes in stage II OS were different from those of stage III published before (Wang et al, 2018), TP53 (0% vs 30% ), RB1 (4.5% vs 60%), CDKN2A (0% vs 30% ), MYC (0% vs 60%) and MDM2 (0% vs 60%). Conclusions: Stage II OS with favorable prognosis has unique genetic characterizes relative to metastatic OS. This study indicates that MUC family could be one of prognostic indicators. Genes with CNV, and the state which CNV occurs could provide clinical significance for the discovery of prognostic markers, which need to be validated by prospective prognostic data.
Evaluation of the TPO-receptor agonist Eltrombopag in the Pediatric Preclinical Testing Consortium osteosarcoma in vivo models.
Authors: Roth Michael , Nevil Grace , Gill Jonathan Benjamin , Zhang Wendong , Teicher Beverly A. , Erickson Stephen W , Gatto Gregory , Smith Malcolm A. , Kolb E. Anders , Gorlick Richard Greg
Published: March 2020

e22502

Background: Eltrombopag (EP) is a small molecule, thrombopoietin receptor (TPO-R) agonist indicated for the treatment of patients with chronic immune thrombocytopenia and severe aplastic anemia. EP is a polyvalent cation chelator and inhibits leukemia cell proliferation via depletion of intracellular iron. Recent studies show EP inhibits the proliferation of osteosarcoma cells lines via depletion of polyvalent cations. The in vivo effects of EP were studied in osteosarcoma patient derived xenograft models by the Pediatric Preclinical Testing Consortium (PPTC). Methods: The in vivo anticancer effects of EP were assessed in a panel of six osteosarcoma PPTC PDX models with limited MPL mRNA expression (OS2, OS9, OS31, OS33, OS36, OS60). EP was administered at an oral dose of 5 mg/kg/day given for 5 days each week with planned treatment period of 4 weeks. High dose EP (50mg/kg/day) was also tested in 2 PDX models (OS2, OS9) on the same schedule. A control cohort that received vehicle was included for each PDX model. Tumor volumes were measured and responses defined utilizing the PPTC statistical analyses. Results: EP at 5 mg/kg failed to inhibit tumor growth or induce significant differences in event-free survival (EFS) in any of the 6 osteosarcoma PDX models. At the higher dose of 50 mg/kg a significant prolongation in time to event in the EP-treated group was observed, but the effect was small with the ratio of the median time to event for treated versus control animals (EFS T/C) being only 1.2 in the 2 OS PDX models tested. No objective responses were observed with EP at either dose, with all models demonstrating progressive disease. Conclusions: EP did not exhibit significant antitumor activity against the PPTC osteosarcoma PDX panel. However, EP also did not enhance tumor growth. EP’s lack of anti-tumor activity against the OS PDX models suggests leukemia and osteosarcoma cells likely have different dependencies on intracellular polyvalent cations. Given EPs effect on stimulating platelet production, and the demonstration that EP does not stimulate in vivo growth of osteosarcoma, EP may be considered in patients with osteosarcoma as a supportive care agent in supporting platelet recovery.
Combination treatment for giant cell tumors of the bone.
Authors: Barashev Artem A. , Kit Oleg I. , Vashchenko Larisa N. , Nepomnyashchaya Evgeniya M. , Karnaukhov Nikolay S. , Ulianova Elena P. , Sidorenko I. P. , Ausheva Tatiana V. , Dashkova Irina , Andreyko Elena A. , Mozulyaka V. V.
Published: March 2020

e22504

Background: Positive effect of the monoclonal antibody denosumab in cancer treatment has been reported in recent years. Since surgical treatment is considered the main method of treatment for giant-cell tumors of the bone (GCTB), the purpose of our study was to improve treatment outcomes using denosumab. Methods: The study included 10 patients with verified GCTB (5 men, 5 women, mean age 36±3.14 years). Tumors were located in the upper third of the tibia (3 patients), the lower third of the tibia (3), iliac bone (1), heel bone - 1, the lower third of the femur - 1, the lower third of the humerus - 1.Patients received 2 cycles of neoadjuvant denosumab treatment (120 mg subcutaneously once every 4 weeks) with further tumor resection. The bone defect was reconstructed with bone grafting in marginal resections and endoprosthetics in segmental resections. The effect of neoadjuvant therapy was assessed morphologically by optical light microscopy; histological and histochemical methods were used. Results: Neoadjuvant treatment reduced pain syndrome and restored the support ability. X-ray and spiral X-ray CT showed sclerotic sites in the lytic foci. Consolidation of pathological fractures in the tumor area was registered, as well as fibrosis of the tumor focus. The tissue on the sections of removed material appeared dryish and whitish, it replaced the medullary canal. Microscopic examination of tumors revealed areas of extensive sclerosis foci, and a slight lymphohistiocytic infiltration in some cases. Osteoclasts and osteoblasts were absent in the histological preparations. Conclusions: Neoadjuvant denosumab in GCTB with the following surgery has a pronounced positive effect. This was confirmed by the morphological picture of the operative material demonstrating the development of extensive foci of loose and dense fibrous connective tissue with a small amount of lymphohistiocytic elements.
Metabolic profile and neoadjuvant chemotherapy sensitivity in high-grade bone sarcoma.
Authors: Boudou-Rouquette Pascaline , Gataa Ithar , Jouinot Anne , De Percin Sixtine , Bellesoeur Audrey , Alexandre Jerome , Dumaine Valérie , Babinet Antoine , Biau David , Audard Virginie , Larousserie Frederique , Anract Philippe , Tlemsani Camille , Goldwasser Francois
Published: March 2020

e22506

Background: Neoadjuvant chemotherapy with intercalated surgery is the standard of care for resectable high-grade bone sarcoma (BS) but identification of biomarkers for chemosensitivity prediction is still needed. Methods: We recruited 121 pts with new primary localized or metastatic BS, measured fasting blood glucose and insulin, body mass index (BMI). The HOMA-IR (Homeostasis Model Assessment) score ((Glucose (mmol/l) x Insulin) / 22.5), which has been proven to reliably detect insulin resistance was calculated, and patients with HOMA-IR > 2.6 were considered as insulin resistant (IR). We collected characteristics usually associated with insulin resistance (IR): age, obesity, diabetes, dyslipidemia and hypertension. Results: Out of 121 pts, 48 (40%) were IR: HOMA-IR > 2.6. Thirty IR patients (62%) had no cardiovascular risk factor. In univariate analysis, IR was associated with obesity (BMI > 30 kg/m2)(23% vs 3%, p = 0.0013), but not with age (median 38.4 vs 43.3 years, p = 0.15). IR was more prevalent in Ewing sarcoma (12/21; 57%) and chondrosarcoma (7/13; 54%) followed by osteosarcoma (25/61; 41%) and other rare bone sarcomas (4/26; 15.3%)(p = 0.037). After preoperative chemotherapy and surgery of Ewing tumor and osteosarcoma, pathologic tumor necrosis was higher in IR pts (85.8 vs 69.3%, p = 0.012). Using multivariate linear regression models, IR was independently associated with pathologic tumor necrosis (p = 0.042) but not with obesity (p = 0.55). Conclusions: Our results suggest that tumor-induced metabolic profile may help to discriminate best candidates for preoperative chemotherapy in high-grade bone sarcomas. Further studies are needed to confirm and explain these results.
Antitumor activity of pazopanib (P) and trametinib (T) in preclinical models of osteosarcoma (OS).
Authors: Chiabotto Giulia , Centomo Maria Laura , Merlini Alessandra , D'Ambrosio Lorenzo , Sangiolo Dario , Miglio Umberto , Todorovic Maja , Napione Lucia , Berrino Enrico , Capozzi Federica , Venesio Tiziana , Maldi Elena , Sapino Anna , Aglietta Massimo , Grignani Giovanni , Pignochino Ymera
Published: March 2020

e22509

Background: Receptor tyrosine kinases (RTKs) and their signal transducers are suitable targets for the treatment of advanced OS. We evaluated the antitumor activity of the RTK inhibitor P and the MEK inhibitor T and deeply investigated molecular mechanisms behind their activity and potential escape. Methods: Flow cytometry and western blot analyses were carried out in 7 OS cell lines to study the expression of RTK P targets and the activation of their pathways, respectively. Cell viability and colony growth were evaluated after 72h and 7-day treatment respectively, with scalar doses of both single agents and their constant combination. Cell cycle distribution and apoptosis were evaluated by flow cytometry after 72h. In vivo antitumor activity was studied in NOD/SCID mice bearing MNNG-HOS xenografts after 3 weeks of treatment. Cell migration was studied by scratch assays. The involvement of MAPK-PI3K pathway key transducers was explored by Vantage 3D RNA Panel and Nanostring technology, validated by western blot and confirmed by silencing experiments. Results: P targets are expressed on OS cell lines and their pathways are activated. P+T have synergistic antitumor activity (combination index < 1) in OS cell lines by inducing apoptosis (6/7) and inhibiting both ERK1/2(7/7) and AKT (7/7). Furthermore, in vivo antitumor activity was shown in OS bearing mice (tumor volume: P+T/untreated = 0.036, p = 0.002). P+T significantly down-modulated RTK EphaA2 (mean log2 fold change RNA P+T/untreated = -2.02±0.50) and induced Janus kinase MEK6 (mean log2 fold change RNA P+T/untreated = 2.9±0.51). EphA2 silencing reduced cellular proliferation and migration of OS cells. Impeding MEK6-up-regulation in P+T treated cells significantly increased the antitumor effect (51.5±14.3%) of the studied drugs. Conclusions: P+T exert antitumor activity in OS preclinical models through ERK and AKT inhibition and EphA2 downmodulation. MEK6-upregulation after P+T is likely implied in escape mechanism.
Relationship among ETV1 genetic polymorphisms, PFS, and microRNA in gastrointestinal stromal tumors.
Authors: Qiu Haibo , Zhuang Wei , Zhou Xiaojun , Wang Xueding , Zhou Zhiwei , Huang Min
Published: March 2020

e22513

Background: In order to evaluate the pharmacokinetic and pharmacogenomic determinants for prognosis of gastrointestinal stromal tumor (GIST). It is necessary to explore a biological predictors to predict and optimal therapeutic strategy. But there were few studied conducted to explore the germline mutation and its mechanisms. Methods: A total of 75 GIST patients treated with Imatinib were enrolled. 35 SNPs (single nucleotide polymorphisms) in KIT/ PDGFRA/ PDGFRB/ ETV1/ FLT1/ MAPK1 et. al were detected using Agena Massarray matrix-assisted laser desorption / ionization-time of flight (MALDI-TOF) platform. COX regression analyses were performed to evaluate the key factors of PFS. The luciferase reporter system of rs3735343 wild type and mutation were established. The GIST-T1 cell line was used to evaluate the biology effect of rs3735343. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: Several factors influence the PFS, including KIT somatic mutation, tumor size and germline mutation ABCC4 rs4148551, ETV1 rs3735343, FLT1 rs3751397, KIT rs3822214. And COX regression showed that rs3735343 and tumor size are associated with PFS (P = 0.009 and 0.032, Risk Ratio = 8.995 and 4.173). And we found that rs3735343 mutation type can regulate ETV1 3’UTR and protein expression level through miR-4311 in vitro. Conclusions: The primary determinants of PFS in this somatic and germline mutation model suggested new biomarkers and different mechanisms involved in prognosis. This is the first report showed that ETV1 genetic polymorphisms may influence the prognosis through miRNA-4311. Targeting ETV1, miRNA-4311 or their relative pathway might be a new therapy strategy.
Comparative DNA cytometry of primary and recurrent soft tissue sarcomas.
Authors: Dashkova Irina , Vashchenko Larisa N. , Kit Oleg Ivanovich , Novikova Inna A. , Komarova Ekaterina , Ausheva Tatiana V. , Andreyko Elena A. , Komarova Elizaveta , Kechedzhieva Emma
Published: March 2020

e22516

Background: Soft tissue sarcomas (STS) are aggressive tumors with a high degree of recurrence. Radical resection within healthy tissues allows to reduce the recurrence percentage to 25-30% without subsequent therapy. The literary analysis has shown that the study of various biological properties of primary and recurrentsoft tissue tumorsis being conducted. However, currently there is a lack of information to understand the reasons for STS recurrence. The goal of investigation was to reveal the distinctive features of the DNA content and cell distribution in the phases of the cell cycle of recurrent STS. Methods: DNA cytometry in the tumor tissue of 30 primary soft tissue sarcomas and 30 STS recurrences was carried out using the method of flow cytofluorometry. The tumor ploidy and cell distribution in the cell cycle phases were analyzed. Results: A number of differences in the DNA cytometric parameters of primary and recurrent STS have been revealed, they include: an increase in the proportion of aneuploid tumors in case of recurrence, the number of tumors with DNA index within the mitotic cycle, an increase in the proportion of cells in G2+M- phase of diploid and aneuploid tumors and a decrease in S- phase of aneuploid ones. It has been shown that with a G2 differentiation degree, the proportion of cells in G2+M, S- and proliferation index of recurrent STS is significantly lower than the primary parameters. An increase in the proportion of cells in G2+M- phase and a decrease in the rate of proliferation of recurrent STS, depending on the stage, are shown only in case of stage III. Conclusions: The revealed features of DNA content and cell cycle of tumor cells of soft tissue sarcomas will allow to approach to understanding of biological bases of recurrence of this malignant disease.
Survival outcomes following cytoreductive nephrectomy (CN) in patients with metastatic renal cell sarcomas (MRCS).
Authors: Malla Midhun , Johnston Sarah E , Zhao Yan D , Pareek Vipul
Published: March 2020

e22519

Background: RCS are rare soft tissue sarcomas and account for 0.8-2.7% of malignant kidney tumors. Level 1 evidence guiding optimal patient management is lacking due to the rarity of this disease. Utilizing the NCDB, we analyzed prognostic factors, the current treatment patterns and outcomes in patients with RCS in the United States. Methods: The NCDB was queried from 2004- 2015 for patients diagnosed with MRCS. Baseline patient characteristics were summarized using descriptive statistics. Impact of baseline demographic, Clinicopathologic variables and treatment on overall survival (OS) was evaluated using univariate (UV) and multivariable (MV) cox proportional hazards analysis. Results: 454 patients diagnosed with MRCS between 2004- 2015 were included in this analysis. Median age at diagnosis was 63. Males (62%) had higher incidence of RCS compared with females. 86% (n = 389) were Caucasian, while only 9.5% (n = 43) were African American. Right and left kidneys were equally affected. Spindle cell sarcoma was the most common histology (n = 276). 37.5% (n = 170) underwent CN. 49% of patients received chemotherapy (n = 216) and 24% received radiation therapy (n = 109). Overall, 48% (n = 82) of patients who underwent nephrectomy had chemotherapy. Median OS was 4.5 months (3.8-5.2 mos.). On UV analysis age ≥ 55 years (HR: 1.92, p < 0.001), no systemic treatment (HR: 1.91, P < 0.01), and no CN (HR: 2.1, p < .001) had worse OS. On MV analysis, patients who did not undergo CN had significantly worsened OS compared to CN (7.56 vs 3.35 mos., HR-1.91, CI: 1.52- 2.41 p < 0.001). Patients who received chemotherapy after CN had a better OS (13.3 vs 3.7 mos., p < 0.001). Conclusions: MRCS is an aggressive malignancy with a median OS of less than 5 months. Age at diagnosis, CN and systemic therapy had a statistically significant impact on OS. Given the rarity of the tumor and inadequacy of guidelines, these results can be considered in making management decisions. We understand the limitations of a registry-based study and hence, prospective multi-national clinical trials are essential to further guide us on management of this rare tumor. [Table: see text]
Cardio-toxicity among patients with sarcoma: A Cardio-Oncology Registry.
Authors: Shamai Sivan , Merimsky Ofer , laufer-Perl Michal
Published: March 2020

e22530

Background: Chemotherapy induced cardio-toxicity has been recognized as a serious side effect since the first introduction to anthracycline (ANT). Cardio-toxicity among patients with breast cancer is well studied but the impact on patients with sarcoma is limited, even though they are exposed to higher ANT doses. The commonly used term for cardio-toxicity is cancer therapeutic related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction (EF) reduction of > 10%, to a value below 53%. Our objective was to estimate the prevalence of CTRCD among patients with sarcoma, to evaluate echocardiography parameters associated with its development and whether CTRCD is associated with mortality. Methods: Data were collected as part of the International Cardio-Oncology Registry (ICOR), enrolling all patients who were evaluated in the cardio-oncology clinic at our institution. All sarcoma patients were enrolled and divided into two groups - CTRCD group vs. "Preserved EF" group. Results: Among 43 consecutive patients, 6 (14%) developed CTRCD. Elevated left ventricular end systolic diameter (p = 0.007) and a trend of reduced Global Longitudinal Strain (p = 0.092) were observed among the CTRCD group. During follow-up, 2 (33%) patients died in the CTRCD group vs. 3 (8.1%) patients in the "Preserved EF" group. In a multivariate analysis, adjusted to age and EF, CTRCD remained a significant predictor for mortality (p = 0.039). Conclusions: CTRCD is an important concern among patients with sarcoma, regardless of baseline risk factors, and is associated with mortality. Echocardiography parameters may provide an early diagnosis of cardio-toxicity.
Chinese largest cohort data from NCT03120846: Efficacy and safety of VEGFR2 inhibitor apatinib for metastatic soft tissue sarcomas.
Authors: Yang Jilong , Liao Zhichao , Liu Xinyue
Published: March 2020

e22532

Background: There is no standard treatment for stage IV soft tissue tumor (STS) after the failure of Adriamycin-based chemotherapy. This opening, single-arm, multi-center phase II study (NCT03120846) assessed the efficacy and safety of Apatinib (YN968D1), a new tyrosine kinase inhibitor that targets VEGFR-2, for patients with stage IV soft tissue tumor after the failure of chemotherapy. Methods: Between September 2015 and February 2018, we recruited 42 patients with stage IV STS who had failed chemotherapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were progression-free survival rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Secondary endpoint was overall survival (OS). Treatment-related adverse effects (AEs) were evaluated. Results: Patients (19 men, 23 women; 14-83 years, average age: 47.67years) received 500 mg apatinib on Days 1–28 of 4-week cycles (median 5.7 cycles; range: 0–23 cycles). Median follow-up was 9 months (range: 1–28 months). We assessed 42 patients for AEs and 38 for efficacy. At 12 weeks, PFR was 70% and the ORR was 26.32% (10/38) and DCR was 86.84% (33/38). For the overall responses, the ORR was 23.68% (9/38) and DCR was 57.89% (22/38). The median PFS was 7.87 months and median OS was 17.55 months. The top AEs included hypertension ( n= 18, 42.86%), hand-foot-skin reaction ( n= 15, 35.71%), Apositia (13, 30.95%), and proteinuria ( n= 11, 26.19%). No patients had grade-4 AEs. 11 (26.19%) had grade-3 AEs. 2 patients (4.76%) quit because the AE. Notably, the 26 patients (61.90%) who suffered hypertension, hand-foot-skin reaction or proteinuria had significantly longer OS than those without these AEs (20.94 vs. 8.93 months; Log Rank (Mantel-Cox) = 12.94, P= 0.0003). Conclusions: Apatinib is effective and well tolerated in patients with advanced soft tissue sarcomas. The adverse events hypertension, hand-foot-skin reaction, or proteinuria may indicate a favorable prognosis, representing a novel finding in STS patients. Clinical trial information: NCT03120846.
10-year follow-up results of perioperative chemotherapy with doxorubicin (DXR) and ifosfamide (IFM) for high-grade soft tissue sarcomas (STS) in the extremities: Japan Clinical Oncology Group study JCOG0304.
Authors: Tanaka Kazuhiro , Mizusawa Junki , Naka Norifumi , Kawai Akira , Katagiri Hirohisa , Hiruma Toru , Matsumoto Yoshihiro , Tsuchiya Hiroyuki , Nakayama Robert , Hatano Hiroshi , Emori Makoto , Hosaka Masami , Yoshida Yukihiro , Okamoto Takeshi , Abe Satoshi , Asanuma Kunihiro , Yokoyama Ryohei , Fukuda Haruhiko , Ozaki Toshifumi , Iwamoto Yukihide
Published: March 2020

e22533

Background: STS are rare malignant tumors and relatively resistant against chemotherapy. We have previously reported 3-year follow-up on the efficacy results of perioperative chemotherapy with DXR and IFM for STS in the extremities (JCOG0304) in ASCO 2011 (abstract ID:#10078). In the present report, we analyzed 10-year follow-up results of JCOG0304. Methods: Patients with operable, FNCLCC grade 2/3 STS (T2bN0M0, AJCC 6th edition) in the extremities were treated with 3 courses of preoperative and 2 courses of postoperative chemotherapy consisted of DXR 60 mg/m2plus IFM 10 g/m2in 3-week interval. Primary endpoint was progression-free survival (PFS). Prognostic factors were evaluated by log-rank test. Results: A total of 72 patients were enrolled between March 2004 and September 2008, and 70 patients were eligible. Median follow-up period was 10.0 years for all eligible cases. The local recurrence and distant metastasis were observed in 5 and 19 patients, respectively. Ten-year progression-free survival (PFS) was 65.7% (95% CI, 53.4%-75.5%) with no PFS event within last 5-year of follow-up. Ten-year overall survival (OS) was 78.1% (95% CI, 66.3%-86.2%). Subgroup analysis demonstrated no significant difference in PFS and OS regarding age, sex, histological grade, and histology. Secondary malignancy occurred in 6 patients. Conclusions: Only a few long-term results of clinical trials of perioperative chemotherapy for STS have been reported. Our results demonstrated that the 10-year outcome of JCOG0304 for the patients with operable, high-grade STS in the extremities was stable and remained favorable. Clinical trial information: C000000096.
Clinicopathological prognostic and predictive factors of malignant peripheral nerve sheath tumors (MPNST) survival and treatment efficacy.
Authors: Sobczuk Pawel , Teterycz Pawel , Zdzienicki Marcin , Napierala Marcin , Morysinski Tadeusz , Switaj Tomasz , Rutkowski Piotr , Czarnecka Anna Malgorzata
Published: March 2020

e22537

Background: MPNST accounts for about 5% of soft tissue sarcomas. It is known to have high metastatic potential and poor prognosis, but reported long-term outcomes vary widely across published series. Our study aimed to determine factors affecting clinical outcome in a large cohort of patients (pts) with MPNSTs treated at reference sarcoma center. Methods: 289 consecutive pts (144 woman and 145 man) referred, diagnosed and treated between 03/1998 and 04/2018 were analyzed. Kaplan-Meier estimator and the log-rank test were used in survival analysis and multivariate Cox proportional hazards model was used to confirm the correlation. Results: Mean age at diagnosis was 50y (15-86). 39 (13.5%) pts were NF1 positive, 12 were primary diagnosed with metastatic disease. After median follow-up of 66.5 months (m) (95% confidence interval, CI 58.1 – 85.2) 151 pts continue treatment or follow-up. Median OS was 55.7m (39.3 - 148.9) in the whole group while 5y survival rate was 48.8% (CI: 42.8-55.7%). 37/167 pts with radical resection in reference center developed local recurrence, and 75/92 pts operated first in regional hospitals. Median DFS was 29.7m (CI: 16.1-58.3) in case of treatment in reference center and 4.1m (CI: 2.4-9.2) in case of regional hospital (p < 0.001).72 pts developed metastatic disease and were treated with chemotherapy. Median PFS on 1st line was 5.6m (CI: 3.3 - 8.1), There were no statistically significant differences in survival rates nor in response rates between doxorubicin- and ifosfamid-based regiments. Tumor size at diagnosis (HR:2.33, CI: 1.50-3.62), high grade (HR:3.31, CI:2.14-5.12) and R0 resection (HR:0.47, CI:0.30-0.72) were the strongest independent predictors of DFS and OS. (neo)adjuvant radiotherapy did not influenced LRFS in case of R0 resection but improved LRFS when complete resection was not feasible (HR: 0.22 CI: 0.08-0.58 p = 0.002). Conclusions: MPSNT is a highly aggressive tumor with poor prognosis. High quality surgery remains the mainstay of management for these patients, but multimodal treatment should be considered in majority of cases in MDT units. There is unmet need for new therapies in advanced/metastatic cases.
Profiling of targetable aberrations in advanced sarcoma.
Authors: Hamid Muhammad Saad , Al Masalmeh Nada , Poorman Kelsey Anne , Weise Amy M.
Published: March 2020

e22559

Background: Soft tissue and bone sarcoma (STS/BS) are heterogeneous and difficult to treat malignancies. Recent advances in molecular testing improved our understanding of the disease biology. Methods: Retrospective data on non-GIST sarcoma cases were analyzed using next genomic sequencing (NGS) (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry (IHC), fusion transcript detection and copy number alterations (CNA) by Caris Life Sciences between July 2010 and November 2018 at Karmanos Cancer Institute. Targetable aberrations (TA) were identified by searching available literature on therapeutics tested in clinical trials. Results: Demographic data on 64 patients were analyzed; median age 56 (21-87y) and a 1:1 gender ratio. Most frequent histologies include Leimyosarcoma (LMS) 15.3% (n = 10) and Undifferentiated Pleomorphic Sarcoma (UPS) 12.5% (n = 8). Genetic aberrations occurred in 78% of cases, with a cumulative 302 aberrations and a mean 4.7 TA (1-11)/case. Frequent aberrations by methodologies include a) IHC: TOP2A 64.3% (n = 36), MGMT 53.9% (n = 28), TUBB3 49% (n = 24); b) NGS: TP53 37.8% (n = 17); c) CNA: CDK4 and MDM2 at 9.3% (n = 4) respectively; d) fusion transcript: NOTCH2 fusion (n = 1), p < 0.05. All cases were MSI stable. TA constituted 37.1% (n = 112) of the identified aberrations in the cohort and existed in 89.1% (n = 57) cases with a mean of 3.08 TA/case, p < 0.05. Frequent TA other than TOP2A, TP53, MGMT by histologies included a) LMS: RRM1 28.6% (n = 4), PI3KCA and ER/PR at 14.3% (n = 1) each respectively; b) UPS: TUBB3 50% (n = 4), PD-1 25% (n = 2); c) Sarcoma NOS: CDK4 28.6% (n = 2), TS 28.6% (n = 2), C-MET and EGFR at 14.3% (n = 1) each respectively; d) Well Differentiated/Dedifferentiated Liposarcoma: CDK4, MDM2 and PD-1 at 20% (n = 1) each respectively. Conclusions: Incorporating genomic profiling has helped personalize treatment to include clinical trial enrollment. Further drug development and prospective studies are required in this population.
Fast time estimation to predict levels of anxiety in cancer patients.
Authors: Tonev Ivan , Conev Nikolay Vladimirov , Valev Spartak Stoyanov , Panayotova Teodorika , Karanikolova Teodora , Donev Ivan
Published: March 2020

e23162

Background: Our study explored the potential relationship between the time estimation and the level of anxiety in cancer patients prior to starting chemotherapy. Methods: Time estimation was assessed in 90 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 (37 sec) of time estimation was used to stratify the patients into two categories of fast and slow time estimation. We used generalized anxiety disorder (GAD-7) as a screening tool for detecting levels of anxiety. Scores ≥10 we considered as clinically significant. Results: Patients with clinically significant levels of anxiety were 23 (25.5%). The pattern of the time estimation distributions significantly changed according to the reported levels of GAD-7 scales. Scores ≥10 correlated with fast time estimation and gender. Patients who scores ≥10 estimated time significantly faster than the rest (27.3±9.2 vs 43.4±17.3; p < 0.001). ROC analysis revealed that at the optimal cutoff value of time estimation, clinically significant levels of anxiety can be discriminated with an AUC = 0.78 (95% CI: 0.68-0.87, p < 0.001) and with a sensitivity of 78.3% and a specificity of 65.2%. Moreover, in a multivariate logistic regression model, fast time estimation was an independent predictor of clinically significant levels of anxiety (OR 7.07; 95% CI 2.2-22.8; p = 0.001). Conclusions: Time estimation is a novel potent indicator for moderate and severe levels of anxiety in cancer patients. This test is an easily performed, time-saving and nonintrusive ultrashort screening tool for clinically significant levels of anxiety.
Risk factors of psychological distress and quality of life in lung cancer patients.
Authors: Zhang Fan , Wang Junyan , Hong Lei , Xu Yu , Jiang Da , Wei Suju
Published: March 2020

e23187

Background: Most patients with lung cancer have psychological problems, which has a significant impact on patients' rehabilitation, treatment and quality of life. Through the distress and quality of life assessment, to understand the risk factors of distress, in order to improve the quality of life of lung cancer patients. Methods: The investigation was consisted of 209 lung cancer patients who were treated in Fourth Hospital of Hebei Medical University from February 2014 to December 2015.Patients were assessed through the use of distress thermometer, problem list, quality of life questionnaire. Lung cancer patients were divided into a significant distress group and a non-significant distress group. Chi-square test was used to analyze the relationship between demographic characteristics, disease information and significant distress. Logistic regression analysis was used to analyze risk factors for distress. The Spearman rank correlation was used to analyze the correlation between the significant distress group and each area of the quality of life questionnaire. The test level was significantly different at P< 0.05. Results: The distress of majority lung cancer patients was 0-4 points, 68 cases were significant distress, significant distress rate was 32.5%. Logistic regression showed PS scores, family residence, informed condition were risk factors of significant distress( P< 0.001 < P= 0.035, P= 0.031). Economic problems were the most common cause of psychological distress in lung cancer patients. Other risk factors included the lack of time and energy to take care for the elderly/children, fear, sadness, dizziness and pain. The significant distress of lung cancer patients was negatively correlated with health status, physical function, emotional function, cognitive function, social function, and was positively correlated with symptoms as fatigue, nausea and vomiting, pain, shortness of breath, insomnia, loss of appetite and constipation. Conclusions: The incidence of significant distress in patients with lung cancer is 32.5%. PS score, fully informed, and family residence are the risks of significant distress in patients. The distress of lung cancer patients is significantly related to the quality of life.