bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant itraconazole (I) in patients (pts) with resectable basal cell carcinoma (BCC): A phase II multistage study.
Authors: Pereira Rodrigo Perez , Azevedo Sergio Jobim , Cé Coelho Juliano , Rebelatto Taiane Francieli , Viapiana Gabriela Lusa , Zaffaroni Facundo , Schreiner Leonardo Augusto , Gössling Gustavo Cartaxo de Lima , Rivero Luis , Bakos Renato Marchiori 
Published: May 2020

e22081 Background: Targeting the hedgehog (HH) protein family pathway has consistently shown activity in locally advanced and metastatic BCC. Itraconazole is an affordable agent with known toxicity profile that demonstrates in vitro HH signaling inhibition, suggesting a possible role in BCC treatment. Initial results of a phase 2 study designed to investigate efficacy of Itraconazole as neoadjuvant treatment in patients with resectable BCC are reported. Methods: Eligible pts had biopsy-proven resectable BCC, ECOG PS 0-3, adequate organ function and measurable disease. Dosing of I consisted of 200mg twice daily for 60 days followed by surgery. Simon two-stage design was used to test a null rate of 5% vs. 20% (power = 0.80; α = 0.05, unilateral). If ≥1 of 13 pts in stage 1 have objective response (OR) according to RECIST 1.1 criteria, 14 more pts will be enrolled. If ≥4 of 27 pts have OR, the treatment is worthy of further study. Secondary endpoints include safety and change in Ki-67 and Gli1. Results: Thirteen pts with 14 measurable lesions enrolled from Jan/2018 to Feb/2019; 1 pt was not evaluable, but was included in safety analysis. Demographics and outcomes are summarized in Table. After 60 days of treatment, all patients had R0 resection as primary planned and 1 (8.3%) PR was observed. There were no progressions during the study. OR rate was 8.3%. No grade 3 AE or SAE were reported. 6 pts had grade 1 or 2 AEs at least possibly related to I including depression, headache, GPT elevation, diarrhea, abdominal pain and bilirubin elevation. Conclusions: Itraconazole showed initial anti-tumor activity in pts with resectable BCC, no safety concerns were observed. Study will proceed to Simon’s second stage. Clinical Trial Information: NCT03972748 , 47011715.0.0000.5327 . [Table: see text]
Chronic neurogenic pain activates growth factors in the blood of patients with cutaneous melanoma.
Authors: Bandovkina Valeria A. , Frantsiyants Elena M. , Rozenko Ludmila Ya. , Pozdnyakova Viktoria V. , Cheryarina Natalia D. , Przhedetskiy Yuriy V. , Khokhlova Olga V. , Przhedetskaya Viktoria Yu. , Zakharova Natalia A. , Kit Oleg I. 
Published: May 2020

e22082 Background: Clusters of tumor cells in blood vessels secrete VEGF family factors necessary for the formation of premetastatic niches. TGF-β activates the epidermal-mesenchymal transition (EMT). The purpose of the study was to analyze levels of angiogenesis and EMT factors in the blood of patients with cutaneous melanoma (M) and chronic neurogenic pain (CNP). Methods: Blood levels of VEGF-A, VEGF-C, VEGFR-1, VEGFR-3, TGF-β1 and TGF-βR2 were measured by ELISA in patients with Т3-4NxM0 melanoma: 21 women with CNP (pelvic pain - 7, osteochondrosis – 14), mean age 67.2±2.7 years; 17 men with CNP (osteochondrosis), mean age 65.6±3.1 years. The control group included patients with melanoma similar in age, gender and disease stages without CNP. Results: VEGF-A in women and men with M+CNP was higher than in controls by 2.7 and 24.9 times respectively; VEGFR-1 was decreased in women by 1.8 times and increased in men by 1.8 times. VEGF-С was unchanged in women and 1.5 times higher in men, and VEGFR-3 was increased by 2.2 times in women and unchanged in men. TGF-β1 was elevated in women and men with M+CNP by 1.4 and 1.8 times, compared to controls, TGF-βR2 – by 1.9 and 2 times respectively. Conclusions: In the blood of women with M+CNP, CNP activates the blood vascular endothelial growth factor VEGF-A and the factor of epidermal-mesenchymal transition TGF-β, while in the blood of men with M+CNP it activates the blood vascular endothelial growth factor VEGF-A, the lymphatic vascular endothelial growth factor VEGF-C and the factor of epidermal-mesenchymal transition TGF-β. VEGF mediates vascular permeability and is associated with the mobilization of endothelial progenitor cells from the bone marrow into premetastatic niches. Activation of TGF-β signaling promotes the induction of the epidermal-mesenchymal transition and supports the properties of cancer stem cells.
Identification of stage IIA melanoma patients at high risk for disease relapse using a clinicopathologic and gene expression model.
Authors: Wever Renske , Tjien-Fooh Félicia , Bellomo Domenico , Quattrocchi Enrica , Sominidi Damodaran Sindhuja , Van Vliet Martin , Dwarkasing Jvalini , Meves Alexander , Eggermont Alexander M. 
Published: May 2020

e22088 Background: In recent years, adjuvant therapy trials in stage III melanoma have been successful and trials have started with the inclusion of stage IIB/C patients. However, stage IIA melanoma patients are currently not eligible for adjuvant therapy, even though a large part of all melanoma related deaths occur in this patient group. Therefore, a strong clinical need has emerged for diagnostic tools that can identify high-risk patients who currently have no access to adjuvant therapy. Here, we sought to assess the ability of a recently introduced clinicopathologic gene expression model (CP-GEP) (Bellomo et al., JCO Precis Oncol. 2020: in press) to select stage IIA patients at high risk for disease relapse, upon design of a stage-specific operating point. Methods: We assessed the prognostic performance of the CP-GEP model in all 141 stage IIA patients from a Mayo Clinic cohort of 837 consecutive melanoma patients who had a sentinel lymph node biopsy (SLNb) performed within 90 days of their diagnosis. The CP-GEP model combines Breslow thickness and patient age, with the expression of 8 genes in the primary tumor. Moreover, it stratifies patients according to their risk of relapse: CP-GEP High Risk or CP-GEP Low Risk, based on an operating point that was specifically developed for stage IIA. This stage-specific operating point was selected to fulfill the following criteria: hazard ratio RFS > 2 with a p-value < 0.05, and risk groups of similar size. The main clinical endpoint was five-year relapse free survival (RFS). Results: The CP-GEP High Risk group corresponds to 45% (63/141) of all stage IIA patients and captures 62% (18/29) of the total relapses in this substage. Moreover, CP-GEP High Risk patients relapse more frequently than CP-GEP Low Risk patients (RFS of 56% versus 78%; HR, 2.23; P < 0.05). The prognosis for stage IIA CP-GEP High Risk patients in our cohort is worse than for stage IIC/IIIA patients with reported RFS ranging from 63% to 77%. Conclusions: The CP-GEP model can be optimized by designing a stage-specific operating point, to identify a subset of stage IIA patients with an increased risk for disease relapse, not very different from IIC/IIIA patients. Therefore, stage IIA CP-GEP High Risk patients may be considered for inclusion in adjuvant trials. Independent validation studies are ongoing for the newly developed operating point. [Table: see text]
Implications of a prognostic 40-gene expression profile (40-GEP) test for high-risk cutaneous squamous cell carcinoma (cSCC) on staging-based risk assessment and adjuvant therapy trial design.
Authors: Schmults Chrysalyne , Covington Kyle R. , Kurley Sarah J. , Cook Robert W. 
Published: May 2020

e22091 Background: Deaths due to cSCC are expected to exceed melanoma-specific deaths. With the demonstration of effective therapies for advanced cSCC, and as treatment of patients in the adjuvant setting is considered, accurate prognosis is critical. For improved identification of ‘high-risk’ patients, with biologically aggressive disease capable of metastasis, a prognostic 40-gene expression profile (40-GEP) test was validated using an independent cohort of patients with high-risk cSCC and known clinical outcomes. The test identified three groups with increasing metastasis risk profiles: Class 1 (low risk), Class 2A (high risk), and Class 2B (highest risk) having metastasis rates of 8.9%, 20.4%, and 60%, respectively. Multivariable analysis demonstrated prognostic efficacy of the 40-GEP test alone and in combination with clinicopathological staging systems. This study evaluated risk stratification with concurrent consideration of the 40-GEP result and the Brigham and Women’s Hospital (BWH) stage. The primary objective was evaluation of the potential impact of the 40-GEP on adjuvant clinical trial design. Methods: To determine if a 40-GEP Class 2B result could optimize clinical trial accrual, metastasis rates of BWH high-risk T stage patients (T2b-T3) alone and in combination with 40-GEP results from the validation cohort were used for two-arm trial sample size calculations. Results: Metastasis rates for cases with T2b-T3 tumors increased from 35.1% to 71.4% when selecting for T2b-T3 cases with a 40-GEP Class 2B result. To provide 80% power to detect hazard ratio of 0.6 with 3 years of follow-up (alpha = 0.05), in line with improvement rates by addition of radiation to surgery, 434 T2b-T3 patients are required for randomization. However, sample size could be reduced by 51% to 214 patients by focusing enrollment on T2b-T3 patients with a 40-GEP Class 2B result. Conclusions: These results support the incorporation of the 40-GEP test into selection processes for patients with T2b-T3 tumors who are at the highest risk for metastasis and appropriate for adjuvant clinical trials.
ZEB1 expression in tumor tissues in patients with localized and advanced Ewing's sarcoma.
Authors: Yurchenko Darya Yu. , Ulianova Elena P. , Kit Oleg I. , Novikova Inna A. , Burtsev Dmitriy V. , Sagakyants Aleksandr B. , Kuznetsov Sergei A. , Lapteva Tatiana O. , Shulgina Oksana G. , Popovyan Olga P. 
Published: May 2020

e22511 Background: Ewing's sarcoma is the second most common malignant tumor of bones and soft tissues in children and adolescents; it is characterized by an aggressive clinical course and extremely high metastatic potential. The process of its onset is well studied, but the processes of metastasis are of great interest both from a scientific point of view and in clinical practice. Epithelial-mesenchymal transition plays an essential role in tumor progression, and the ZEB1 protein is one of its key regulators. Our purpose was to evaluate the expression of ZEB1 as a prognostic factor in patients with localized and advanced Ewing's Sarcoma (ES) in children and adolescents. Methods: The study included 50 samples of primary ES of various locations. The patients (0-18 years) were divided into groups 1 (localized ES, n = 27) and 2 (advanced ES, n = 23). Rabbit polyclonal antibodies to ZEB1 (Biorbyt Ltd.) at a dilution of 1:200 and the Reveal Polyvalent HRP-DAB Detection System were used for IHC. The percentage and intensity of staining were evaluated: 0, 1+ weak, 2+ moderate, 3+ strong. ZEB1 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells with intensities of 2+ and 3+. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: The average ZEB1 expression was in group 1 - 30.0±3.5%, in group 2 - 41.7±11.1%. The maximal accumulation of ZEB1 in the nuclei of tumor cells was observed in patients with advanced ES - 1.4 times (p = 0.248) higher than in patients with localized ES. However, the difference was not statistically significant (the Mann-Whitney U-test, p > 0.05). Conclusions: An IHC analysis revealed a tendency toward increased expression of ZEB1 in patients with advanced ES. However, a more extensive study is needed to evaluate the possible prognostic value of this marker.
The role of long non-coding RNA ANRIL in chemosensitivity in osteosarcoma and clinical outcomes.
Authors: Ferdjallah Asmaa , Lee Adam M , Moore Elise , Nath Aritro , Huang R. Stephanie 
Published: May 2020

e22515 Background: Osteosarcoma is a skeletal malignancy affecting children, adolescents, and young adults. Surgical resection and chemotherapy are the mainstay of therapy with a three-drug regimen - cisplatin, doxorubicin, and methotrexate. However, prognosis remains poor mainly due to chemo-resistance and/or metastases. Emerging evidence has shown that long non-coding RNAs (lncRNAs) are implicated in drug sensitivity and cancer metastasis. Our lab has recently identified strong significant association between cellular sensitivity to cisplatin and doxorubicin and expression of a lncRNA ANRIL in a collection of osteosarcoma cell lines. Methods: SiRNA knockdown experiments were carried out in an osteosarcoma cell line, SAOS2. Cells were exposed to multiple concentrations of cisplatin or doxorubicin. Cellular sensitivity to these two drugs was quantified after siRNA experiment with siRNA targeting ANRIL and scramble control at 24, 48 and 72h. Clinical outcome analysis was performed using data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Results: We successfully knocked down ANRIL expression in SAOS2 cells with 88.5% efficiency. A significant decreased rate of proliferation was detected for cisplatin (7 uM, 72h) in knockdown cells (16.5% +/- 4.1) compared to scramble control (26.4% +/- 0.8). The cisplatin IC50 was decreased in the siRNA knockdown condition as compared to scramble control at 72h (p = 0.02). For doxorubicin, the IC50 was also significantly decreased in the siRNA knockdown condition as compared to scramble control (p = 0.002 and 0.007 at 24h and 72h, respectively). Survival outcomes, metastases at diagnosis, and percent necrosis (an indicator of treatment response) were evaluated in TARGET osteosarcoma patients (n = 121 and n = 43 for OS, percent necrosis, respectively) with varying degrees of ANRIL expression. Above the median ANRIL expression was associated with a greater number of death (p = 0.004) and higher chances of metastases at diagnosis (p = 0.013). Conclusions: Reducing ANRIL expression led to increased cellular sensitivity to cisplatin and doxorubicin, two key treatment agents for osteosarcoma. Higher ANRIL expression was significantly associated with higher rates of osteosarcoma death and metastases at diagnosis in a clinical cohort of patients. These findings may suggest ANRIL serves as a novel biomarker of cisplatin and doxorubicin sensitivity in osteosarcoma.
HemeOncoPoeisis: A fellow’s perspective on training.
Authors: Farooqui Marwah Wafa , Simeone Stephen , Desai Yatri , Srinivasan Krishnan , Ghouse Masood 
Published: May 2020

e23000 Background: The incidence of cancer is projected to increase 67% by 2030. Current projections suggest a 40% increase in demand for hematologists/oncologists (HO) yet only a 25% increase in trainees. This discrepancy between supply and demand represents an emerging challenge to public health. There are 3 types of training programs across the US: 1. Academic (69%), 2. Hybrid, which have both community and academic exposure (~15%), and 3. Community ( < 15%). The purpose of this study is to get feedback from fellows. Methods: Contact information was collected for 126 HO programs across the US and a short questionnaire was sent. Results: There were 36 respondents, 72% from academic programs, 20% from hybrid, and 8% were community based. 25%, 42%, and 33% were 1st, 2nd, and 3rd year fellows respectively. Only a quarter of the respondents had worked or pursued another fellowship prior to starting training and the majority were directly out of residency. Only 19% of the respondents indicated interest in practicing in the community setting, 30% wanted to practice in an academic-community hybrid, and 39% wanted to practice in an academic setting. Of note about 31% of academic fellows reported not attending any national meetings (ASH/ASCO/other) in the last 2 years, 71% of hybrid trainees reported attending more than two conferences, and 75% of the community trainees attended 1 or more national meetings. Most common concerns from trainees from all programs was workload, research support, and didactics. Most of the trainees (70%) felt prepared clinically, but only 40% felt prepared academically. See Table for additional results. Conclusions: Trainees in hybrid programs appear to be most satisfied with their training. Also, trainees in academic programs indicated they wanted more exposure to community settings for future jobs. A large HO workforce will be needed in the community setting yet there is a vacuum when it comes to community based HO training. Perhaps future directions in trainee education can be towards encouraging relationships between the academic and community centers to help trainees get a broad exposure in order to be prepared for the future demands the current projections predict. [Table: see text]
Bioinformatic analysis of selinexor-induced gene expression in patient-derived-chordomas to reveal mechanisms of action leading to tumor growth inhibition.
Authors: Walker Christopher James , Chang Hua , Henegar Leah , Kashyap Trinayan , Unger Thaddeus J , Shacham Sharon , Cogswell Patricia , Fechner Stacy , Wick Michael , Levy Joan , Landesman Yosef 
Published: May 2020

e23502 Background: Selinexor is a selective inhibitor of nuclear export that inhibits XPO1 from shuttling its cargo from the nucleus to the cytoplasm. This leads to accumulation of tumor suppressor proteins in the nucleus, activation of cell cycle checkpoints, cell cycle arrest and apoptosis in cancer cells. Chordomas are rare cancers emanating from the skull base and spine that originate from remnants of the notochord. Patients with chordomas have poor prognosis with limited treatment options. To investigate the in vivo efficacy and assess molecular effects of selinexor treatment in chordoma, two patient-derived xenograft (PDX) mouse models were tested. Methods: Murine chordoma PDX models of recurrent clival chordoma (SF8894) and metastatic sacral chordoma (CF466) were treated with selinexor (5mg/kg PO, 4x weekly). Tumor volume was monitored for 6 weeks of treatment, then excised tumors were used for immunohistochemistry (IHC) analysis and RNA sequencing. Results: Selinexor treatment significantly reduced the tumor volume of mice bearing CF466-derived tumors (5 mice/group; 57.6% reduction in volume compared to control; P = 0.031), and SF8894-derived tumors (4 mice/group; 76.2% reduction; P < 0.001). Differential gene expression between selinexor and vehicle treated samples showed significant differences in 428 genes and 156 genes in the CF466 and SF8894 tumors, respectively (adjusted P-value [Padj] < 0.01). In both models, XPO1 protein levels were markedly decreased and expression of the tumor suppressors TP53 (CF466: Padj = 1.4x10−17; SF8894: Padj = 0.002) and ARRDC3 (CF466: Padj = 2.2x10−72; SF8894: Padj = 2.9x10−12) were increased. In the CF466 chordoma model, selinexor reduced SOX9 (Padj = 1.6x10−18), SMAD4 (Padj = 0.019), and SHH (Padj = 0.028), which were confirmed to be reduced at the protein level by IHC. The SF8894 model showed reduction in EZH2 expression (Padj = 0.0012). Pathway analysis of both models showed activated TP53 signaling (CF466: z-score = 0.82; SF8894: z-score = 2.16) and apoptosis (CF466: P = 5.2x10−8; SF8894: P = 1.2x10−8). G2/M checkpoint regulators were upregulated in the CF466 model (z-score = 2.83). Conclusions: Selinexor treatment led to reduction in tumor growth in two PDX models of chordoma. Both models showed upregulation of TP53 signaling and apoptosis upon treatment, with downregulation of distinct oncogenic pathways. Further investigation of selinexor as a treatment option for chordoma is warranted.
Update of NGS analysis of Italian survey of second tumors in patients with diagnosis of GIST (gastrointestinal stromal tumor).
Authors: Gasperoni Silvia , Castiglione Francesca , Vannucchi Margherita , Papi Laura , Fumagalli Elena , Manglaviti Sara , Vincenzi Bruno , Mazzocca Alessandro , Nannini Margherita , Vancheri Giovanni , Adragna Tommaso , Ottaviano Margaret , Palmieri Giovannella , Meoni Giulia , Ribecco Angela Stefania , Grignani Giovanni , Tolomeo Francesco , Tofani Lorenzo , Paderi Agnese , Mini Enrico 
Published: May 2020

e23518 Background: In patients with GIST, literature reports a risk of second primary tumors between 4.5% and 33% with different distribution in the worldwide. The network of 7 italian EURACAN centers has collected clinical and molecular features of GIST patients with second primary tumors. Methods: We reviewed the clinical characteristics of 201 patients with GIST and second primary tumors in order to evaluate association between risk of dead and each possible factor, using Kaplan meier curve, log-rank test and Cox model for Hazard Ratio and it’s interval Confidence 95% estimation. Furthermore, NGS analysis ( 56 gene onco panel) in 72 patients with GIST was performed. Results: On the basis of the significant correlation previously observed between the Miettinen risk criteria of GIST (low/very low) and the incidence of second primary tumors (gastrointestinal tumors),P < 0.001 (Abstr 11032 ASCO 2019), we observed in these patients a median age of diagnosis of GIST of 68, with prevalent gastric site localization ( KIT exon 11 mutation), NF1 and Lynch (kit/pdgfra WT) syndromes in the low risk subgroup. The more frequent site of second epithelial tumor in gastrointestinal tract was the colon followed by gastric, pancreatic and biliary tract. In patients with GIST with low-very low risk according Miettinen classification, after a median follow-up period of 25 years, we have observed that the gastroenteric site of second tumors occurrence is significantly related to the survival (p < .0003). In the NGS analysis of the GIST we observed the pathogenetic somatic mutations in the following genes: BRCA 2 (p.Thr2125fs), but germline test negative, TP53 (p.Arg192*,p.Gly244Ser,p.His168Leu), RET (p.Lys120Asn, p.His168Leu, p.Thr930Met ), NRAS (p.Gly134Asp), CTNNB1 (p.Ser45Phe), MSH6 (P.Ala164Val), SMARCB1 (p.Arg192), VHL (p.Gly93Val), PTEN(p.Val158Ile, p.Asn323fs), STK1I (p.Arg40Cys), SMO (p.Glu194Lys), EGFR (p.Gly721Asp), ATM (p.Asp2708Asn), ERBB4 (p.Asn181Ile). Conclusions: In our analysis patients with GIST (low-very low classes according to Miettinen) have significant risk to death because of second primary tumors in gastrointestinal tract. Specific attention to gastrointestinal screening during the follow-up of GIST (low and very low risk) is required.