bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective observational trial of low-dose skin electron therapy in mycosis fungoides using rotational technique.
Authors: Newman Neil , Kirschner Austin Noah , Patel Chirayu
Published: May 2020

e22077

Background: Low dose total skin electron therapy (TSET) utilizing 12 Gy in 12 fractions has been shown to provide a durable treatment response for dermal lesions caused by mycosis fungoides secondary to cutaneous T cell lymphoma (CTCL). We sought to prospectively assess the durability of response and quality of life (QOL) for patients receiving low dose TSET using the rotational technique technique. Methods: We prospectively enrolled patients with CTCL on an IRB approved study from 2016 to 2019 who had pathologically confirmed CTCL from stage IB-III. Patients completed a baseline validated Skindex-29 survey encompassing 29 questions assessing QOL. Physicians graded the appearance of the skin using the modified severity-weighted assessment tool (mSWAT) at baseline. Patients received 12 Gy in 12 Fractions on consecutive dates and patients were treated with a dual field rotational technique. The mSWAT was reassessed on ensuing follow-up visits along with the Skindex. The primary outcome was overall response rate with the secondary outcomes being time to treatment response, duration of clinical benefit (time to requiring an additional intervention), as well as improvements in Skindex questionnaire items. Results: We enrolled 20 patients and recorded an overall response rate (ORR) of 90% with four complete responses. The time to treatment response was 9.7 weeks. While the baseline mSWAT was 55.6 it declined to a median mSWAT of 2.2 at last follow-up (p < 0.001) with there being a median decline of nearly 97% in the scores. The median duration of clinical benefit was 15.7 months. There was a precipitous decline in the Skindex total score and every subdomain when comparing each follow-up visit (p = 0.004) with post-hoc analysis demonstrating the decline between the baseline visit and first follow-up as the primary driver of the decline (p < 0.0001). Conclusions: This prospective study demonstrates the subjective and objective clinical benefits of utilizing low dose TSE with a dual beam rotational technique. This control rates and QOL will continue to be observed for ongoing feasibility as a treatment modality.
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.
Diagnostic algorithm for gastrointestinal stromal tumor (GIST) using patient registry data impacts pathology guidelines.
Authors: Rothschild Sara , Call Jerry , Corless Christopher L. , Gill Anthony , Miettinen Markku , Rubin Brian
Published: May 2020

e23519

Background: The Life Raft Group (LRG) identified that succinate dehydrogenase (SDH) deficient GISTs are under-recognized. In the LRG Registry only 30% of KIT/PDGFRA wildtype patients had received the advanced mutational testing (or SDHB staining) required to identify this unique subtype of GIST with a different natural history and response to treatment, and very strong familial associations. We proposed that two changes would significantly increase the diagnosis of SDH-deficient GIST patients: 1. SDHB staining for all GIST patients with a stomach primary tumor at initial biopsy, 2. Initial pathology report should contain strong recommendations for specific mutational testing. Methods: The LRG collaborated with key medical opinion leaders on a diagnostic algorithm that illustrated the need for wider use of targeted diagnostic procedures and submitted the algorithm to the College of American Pathologists (CAP) GIST editorial board. Results: Because SDH-deficient GISTs require germline genetic analysis and, if mutation related, subsequent surveillance for paragangliomas/pheochromocytomas, and cascade genetic testing for family members, it is necessary to screen all gastric GISTs for loss of SDH by immunohistochemistry. This is best accomplished by immunohistochemical staining for SDHB, which is lost in all genetic subtypes of SDH-deficient GISTs. If SDHB is absent, additional staining for SDHA may be performed, as this protein is selectively lost in SDHA-mutant GISTs and this may help focus genetic analysis. All patients with SDH-deficient GIST should be referred to a genetic counselor. The CAP incorporated both SDHB and SDHA testing paradigms into the updated GIST protocols which were published in August 2019. Conclusions: We believe this will result in significantly better diagnosis and treatment for SDH-deficient GIST patients. We encourage other groups that advise on guidelines to develop similar recommendations. This is a great example of a patient advocacy group utilizing real world evidence derived from a patient registry to influence protocols for treatments that affect GIST patients on a large scale.
A comprehensive characterization of anatomical and molecular risk factors in gastric gastrointestinal stromal tumor.
Authors: Boye Kjetil , Wiedswang Anne Marit , Meza-Zepeda Leonardo A. , Hompland Ivar , Lobmaier Ingvild , Berner Jeanne-Marie , Stoldt Stephan , Hølmebakk Toto
Published: May 2020

e23522

Background: Gastric gastrointestinal stromal tumors (GISTs) demonstrate a remarkable diversity in clinical behavior. Established risk criteria identify patients prone to recurrence with high sensitivity, but factors that could add specificity are needed. The aim of this study was to give a comprehensive picture of localized, gastric GIST and to investigate prognostic factors in a large population-based series. Methods: Patients with primary gastric GISTs completely resected between 2000 and 2018 were identified in the sarcoma database at Oslo University Hospital. Gastric subsite was divided into the upper, middle and lower thirds. Macroscopic growth pattern was coded as luminal, exophytic or transmural based on imaging and surgical reports. Mutation analysis was performed by Sanger sequencing of selected exons in KIT and PDGFRA and by targeted next-generation sequencing. Results: The cohort comprised 295 patients, representing 98% of patients in the region reported to the Cancer Registry of Norway. Of 292 tumors suitable for anatomical classification, 122 were located in the upper third of the stomach (41.8%), 120 in the middle (41.1%), and 50 in the lower third (17.1%). The number of luminal, exophytic and transmural tumors were 100 (34.1%), 94 (32.1%) and 99 (33.8%), and 2 tumors were not possible to classify. KIT mutations were detected in 183 of 256 tumors (71.5%), PDGFRA mutations in 62 (24.2%), whereas only 11 patients (4.3%) had KIT and PDGFRA wild-type tumors. Transmural tumors were larger, more often located in the upper third, had higher mitotic activity, and more frequently had KIT del557/558 mutations. KIT mutated tumors had a predilection for the upper two thirds and PDGFRA mutated tumors for the lower two thirds. Recurrences were rare among patients with luminal or exophytic tumors, with a 5-year RFS of 96% versus 71% with transmural tumors (HR 8.45; 95% CI 3.69-19.36; P< 0.001). RFS was inferior with transmural tumor growth also among high-risk patients, 46% versus 83% at 5 years ( P= 0.001). Excluding patients with tumor rupture, there was only one recurrence among 24 high-risk patients with luminal or exophytic primaries, of whom 11 did not receive adjuvant therapy. Conclusions: This study provides a comprehensive, population-based description of the anatomical and molecular landscape of gastric GIST, with findings of potential clinical relevance. Transmural tumor growth was a predictor of poor outcome and could supplement established risk factors in selecting patients for adjuvant imatinib treatment.
The real world outcomes of 3-year adjuvant therapy with imatinib in patients with high-risk molecular profiled gastrointestinal stromal tumors (GIST).
Authors: Rutkowski Piotr , Zietek Marcin , Cybulska-Stopa Bozena , Streb Joanna , Gluszek Stanislaw , Jankowski Michał , Lopacka-Szatan Karolina , Las-Jankowska Manuela , Hudziec Piotr , Klimczak Anna , Olesinski Tomasz , Switaj Tomasz , Kosela-Paterczyk Hanna , Bylina Elzbieta , Osuch Czeslaw
Published: May 2020

e23524

Background: The real-world data on outcomes of adjuvant therapy in high-risk gastrointestinal stromal tumors (GIST) are very limited. Methods: We have analyzed the data of 107 consecutive patients (52 male, 56 female) with GIST after resection treated with adjuvant imatinib (for planned 3 years with initial dose 400 mg daily, started not later than 4 months after operation) in 6 oncological centers in 2013-2018. All patients were required to have high risk of recurrence (at least 50% according to NCCN/AFIP criteria), known mutational status to exclude PDGFRA D842V mutants and KIT/PDGFRA-wild type cases from therapy. Median follow-up time was 24 months. Results: The most common primary localization of GIST was small bowel (63 patients; 59%), followed by the stomach (40 patients; 37%). The majority of GIST cases harbored exon 11 KIT mutations (88 cases, 82%), 11 cases had exon 9 KIT mutations (10%), 8 had other KIT/PDGFRA mutations potentially sensitive to imatinib. Thirty three patients (31%) finished 3-year adjuvant imatinib therapy as planned, 59 (55%) still continue therapy, 4 (4%) patients had finished adjuvant therapy prematurely due to toxicity, 6 (6%) due to disease progression on treatment and 5 (4%) due to other reasons. The disease relapse was detected in 16 patients, of them in 4 cases in exon 9 KIT mutants (36%), and 10 cases in patients with exon 11 KIT mutations (11%) [p < 0.05]. Estimated 4-year relapse-free survival (RFS) rate is 78%. Conclusions: The early results of adjuvant therapy with imatinib in routine practice outside clinical trials in high-risk mutation-drive GIST patients only confirm high efficacy of this therapy with better tolerability than in clinical trials. Moreover, overrepresentation of exon 9 KIT mutants in a group of patients with disease relapse may indicate that standard 400 mg dose in adjuvant treatment is not sufficient for prevention of disease relapse.
The prognostic value of CINSARC in a randomised trial comparing histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001).
Authors: Pasquali Sandro , Braglia Luca , Chibon Frederic , Coindre Jean Michel , Italiano Antoine , Romagosa Cleofe , Bague Silvia , Dei Tos Angelo Paolo , Palmerini Emanuela , Quagliuolo Vittorio , Martin Broto Javier , Lopez-Pousa Antonio , Grignani Giovanni , Brunello Antonella , Blay Jean-Yves , Diaz Beveridge Robert , Stacchiotti Silvia , Merlo Domenico F , Casali Paolo Giovanni , Gronchi Alessandro
Published: May 2020

e23531

Background: The Complexity INdex in SARComas (CINSARC) is a gene expression signature related to mitosis and chromosome integrity that stratifies risk for recurrence of soft tissue sarcoma (STS) patients. The aim of this study was to validate the prognostic value of CINSARC in patients enrolled in a randomised trial that compared histotype-tailored neoadjuvant chemotherapy with standard chemotherapy in patients with high-risk STS (ISG-STS 1001). Methods: CINSARC is 67-gene-expression-based signature that has been previously tested in retrospective series. The ISG-STS 1001 was a phase 3 RCT comparing histotype-tailored and anthracycline-based chemotherapy in localised, high-risk STS of the extremities or trunk wall, with one of five histological STS subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Outcome variables were disease-free survival (DFS), overall survival (OS) and tumour response according to RECIST v1.1. Results: CINSARC was assessed in pre-treatment biopsies of 87 in 435 patients participating in the study. Thirty and 57 patients segregated in the lower (C1) and higher (C2) CINSARC risk group, respectively. Incidence of local recurrences (LR) and distant metastasis (DM) did not differ between C1 and C2 CINSARC groups [2 (6.6%) and 11 (19.3%) patients had a LR, respectively, and 10 (33.3%) and 14 (24.5%) patients had DM, respectively, P = 0.800]. Consistently, we did not observe statistically significant differences for DFS and OS between patients in the CINSARC C1 and C2 groups (log-rank test, P = 0.522 and P = 0.480, respectively). RECIST tumour response was analysed in a subset of patients (N = 39), showing that a RECIST SD was more likely in C1 (N = 12/14, 85.6%) compared to C2 (N = 18/25, 72%) group, while both RECIST PD and PR were more commonly detected in C2 [3/25 (12%) and 4/25 (16%), respectively] compared to C1 [0/14 (0%) and 1/14 (7.1%), respectively] group. Conclusions: In high-risk STS patients treated with preoperative chemotherapy within a RCT, CINSARC did not correlate with different DFS and OS. While this may well be due to a failure of this gene signature in this patient population, an alternative hypothesis is that preoperative chemotherapy may improve the prognosis of higher-risk patients. Clinical trial information: NCT01710176 .
Potential use of homologous recombination deficiency score as an indicator of therapy selection in leiomyosarcoma patients.
Authors: Zhou Yuhong , Guo Xi , Guo He , Zhuang Rongyuan , Liu Wenshuai , Zhang Yong , Tong Hanxing , Wang Zhiming , Wang Yan , Lv Chentao , Lu Weiqi , Dai Chun , Liu Jun
Published: May 2020

e23539

Background: Leiomyosarcoma (LMS) is one of the most frequent sarcoma subtypes. While surgical resection is the standard treatment of LMS, chemotherapy and radiation have shown additional survival benefit. However, the treatment response is variable and selection of appropriate agents is difficult due to the great heterogeneity of LMS. Matching DNA damaging reagents or PARP inhibitors, to tumors with a general homologous recombination deficit (HRD), can help to deploy these reagents more precisely. We explored the correlation of HRD score with the activation of PARP signaling pathway and retrospectively tested the effect of platinum-based therapy on an LMS patient with high HRD score. Methods: Nineteen LMS samples were subjected to whole exome sequencing and their HRD scores were calculated using a published algorithm. Nine of the LMS samples were also subjected to RNA-seq analysis and undergone GSEA to profile PARP pathway expression. CIBERSORT was employed to profile infiltrating immune cells. Results: The 19 LMS samples are defined as HRD-high (11 samples) or HRD-low (8 samples) if their HRD score is above or equal to, or below the medium respectively. For the 9 samples undergone RNA-seq, 97 genes have differential expression between the two groups (p-value < 0.05, fold change≥ 2). GSEA revealed 23 enriched pathways. Interestingly, PPAR signaling pathway is the most highly enriched one (EnrichmentScore = 0.506, P.adj = 0.005). No other pathogenic germline or somatic mutation in HRD related genes, for example BRCA1/2, is enriched. Additionally, high HRD score is significantly correlated with infiltrating Tregs, monocyte, and M0 macrophages as found in CIBERSORT analysis. To retrospectively test whether HRD score can be used to predict the response to inhibitors of DNA repair pathway, we identified one patient who had received platinum-based combination therapy after failure of first-line chemotherapy. The patient is a 40-year-old female with stage IV LMS and has a high HRD score. She achieved PR with 6-month PFS and remains progression free up to the abstract date, supporting a good correlation between high HRD score and advanced chemotherapy in LMS patients. Conclusions: High HRD score is correlated with activated PPAR pathway and infiltrating Tregs, monocytes and M0 macrophages, and can potentially be used to identify LMS patients with good response to platinum-based chemotherapy even though they have no obvious germline and somatic mutation in genes involved in DNA repair.
Uterine sarcomas, insight into its risk factors: A systematic review.
Authors: Hana Caroline , D'Amato Gina Z.
Published: May 2020

e23540

Background: Uterine sarcomas are rare and aggressive malignant tumors that arise from the smooth muscle or connective tissue cells of the uterus. They account for approximately 1% of the female tract malignancies and 3% of all malignant tumors of the uterus. The risk factors that would predispose to uterine sarcomas have always been unknown, with no clear correlation with specific etiologies. This review is to investigate the risk factors that have been looked at by prior studies to have a better understanding of the population at higher risk for uterine sarcomas. Methods: A total of 88 studies were obtained via Pubmed search. The search terms included: Uterus, sarcoma, and risk factors. We also included reviews with the following mesh terms: Uterus, Sarcoma, Etiology and factors. We reviewed studies in English (n = 75) and French (n = 4) languages, human studies and comprising adults. We included only studies with electronic copies. Retrospective, case-control studies and systematic reviews were included. Results: Of the 88 studies, 18 mentioned risk factors and demographic characteristics of the population with uterine sarcomas. Some studies have shown an association with the tumor size – especially more than or equal to 8cm-, uterine weight, patient’s age being > 45-50 years old, age at menarche, obesity, tamoxifen use, previous pelvic irradiation, as well as genetic associations. Mixed evidence has been found regarding the role of the ethnicity, age at menopause, age at first live birth and exogenous estrogen use. Breast cancer has been linked to more aggressive histologic cell types. Conclusions: Given its relatively rare incidence, uterine sarcoma has been mysterious in regards to its risk factors. The results of this review highlight the need for further studies to investigate the risk factors and exposures that may lead to development of uterine sarcomas, as well as linking them to the different histologic types.
The Epstein-Barr virus and osteosarcoma in Iranian children.
Authors: Rahbar Mahtab , Mardanpour Keykhosro
Published: May 2020

e23543

Background: This study was conducted to describe the possible association between EBV infection and OS in Iranian children. Methods: This study carried out at Kermanshah university hospital on 48 OS tissue and ten non-cancerous bone tissue as a control group by three laboratory methods. The real-time polymerase chain reaction (RT-PCR) and Chromogenic in-situ hybridization (CISH) done to detect the Epstein Barr Encoded RNA (EBER1) expression as long as immunohistochemistry staining (IHC) to detect EBV latent membrane protein-1 (LMP-1) in tumor cells and controls. Overall-survival (O-S), prognosis free survival (PFS) and disease-free survival (DFS) provided based on the Kaplan-Meier method. Results: Specimen considered positive when EBER using PCR and CISH associated with LMP-1 using IHC stain were expressed separately in the same sample. Six out of eighty-four (12.5%) of OS cases were simultaneously EBV positive in all three methods within the tumor cells as compared to the control group. (P < 0.22) Association between EBV positivity and histologic characteristics of OS cases such as nodal involvement (P < 0.04), metastasis (P < 0.04), Ki67 reactivity (as proliferation index) (P < 0.03), and tumor stage (P < 0.05) were significant. EBV Positive patients show worse clinical symptoms in older age as well as the worse prognosis compared with negative patients. EBV positive patients presented shorter DFS, PFS, and OS. Conclusions: Our research could not find a statistical association between EBV infection and OS in Iranian children significantly. Meanwhile, we found, EBV infection could interfere in the invasive behavior of tumors. [Table: see text]
Factors of angiogenesis (VEGF and CD34) in primary and recurrent soft tissue sarcomas.
Authors: Nepomnyashchaya Evgeniya M. , Ulianova Elena P. , Sagakyants Aleksandr B. , Novikova Inna A. , Vashchenko Larisa N. , Ausheva Tatiana V. , Shulgina Oksana G. , Dashkova Irina R. , Vladimirova Liubov Yu , Kit Oleg I.
Published: May 2020

e23545

Background: The tumor ability to induce and maintain angiogenesis is one of the main stages of its development. Studies of molecular mechanisms of angiogenesis showed that the dynamic balance that ensures the formation and development of new vessels inside the tumor depends on pro- and anti-angiogenic factors. VEGF and the CD34 endothelial cell marker are considered among the main activators of angiogenesis. Our purpose was to study characteristics of angiogenesis in primary and recurrent soft tissue sarcomas. Methods: The study included 30 patients with primary sarcomas (group 1) and 26 patients with recurrent sarcomas (group 2). Sections of tissues embedded in paraffin blocks were studied by immunohistochemistry using the Thermo Scientific 480S automated stainer. The Reveal Polyvalent HRP-DAB Detection System was used for the visualization. The density of blood vessels stained with antibodies against VEGF and CD34 was determined. The statistical analysis of results was performed in the STATISTICA 10.0 program (StatSoftInc., USA). Results: The numbers of blood vessels ranged: CD34 in group 1 – 7-16 blood vessels in one field of view; in group 2 – 2-18 vessels. VEGF in group 1 – 2-20 vessels, with up to 40 vessels in 3 cases (11.5%) only; in group 2 – 5-11 vessels, with up to 20 vessels in 2 cases (7.7%). The average numbers of microcirculatory vessels stained with antibodies against VEGF and CD34 were: CD34 –12.2±1.04 and 8.4±1.4 (p = 0.0247) in groups 1 and 2, respectively; VEGF – 12.8±4.06 and 8.4±11.6 (p = 0.3074) in groups 1 and 2, respectively. Conclusions: The IHC analysis showed the minimal numbers of microcirculatory vessels in one field of view in patients with recurrent soft tissue sarcomas. The value was 1.5 times lower for both CD34 and VEGF, compared to patients with primary tumors. However, only CD34 value was statistically significant (the Mann–Whitney U-test). Probably, a certain decrease in angiogenesis factors in recurrent tumors can be explained by adjuvant chemotherapy suppressing tumor growth.
Analysis of trends in race and gender disparities in incidence-based mortality in patients diagnosed with soft tissue sarcomas from 2000 to 2016.
Authors: Pappoppula Lakshmi Priyanka , Ajebo Germame Hailegiorgis , Yeh Justin , Hector Picon , Krutchik Allan N. , Guddati Achuta Kumar
Published: May 2020

e23549

Background: The clinical course of soft tissue sarcomas is often dependent on the grade of the tumor. The incidence of soft tissue sarcomas have been known to be higher in males compared to females and more in African Americans compared to Caucasians (1995 to 2008 SEER data). The variability of incidence-based mortality in low grade and high grade soft tissue sarcomas with respect to gender and race over the past decade has not been well studied. This study analyzes the rates of incidence-based mortality from the years 2000 to 2016 amongst for both the grades, genders and racial groups. Methods: The Surveillance, Epidemiology, and End Results (SEER) Database was queried to conduct a nation-wide analysis for the years 2000 to 2016. Incidence-based mortality for all stages of low grade and high grade soft tissue sarcomas was queried and the results were grouped by race (Caucasian/White vs African American/Black) and gender. All stages and ages were included in the analysis and trend from 2000 to 2016 was analyzed. Results: Incidence-based mortality rates (per 10000) for low grade and high grade soft tissue sarcomas for both races and genders are shown in the table below. The incidence-based mortality rates for Caucasians are similar to African American in both grades and genders. Rates were not analyzed for American Indian and Asian/Pacific Islanders due to small sample size. Mortality rates of high grade soft tissue sarcomas were significantly higher compared to low grade tumors. A higher rate of mortality is noted in Caucasian males compared to African Americans males despite past observations of higher incidence in African Americans. There was no significant change in the rate when trended over the past decade (2007 to 2016). Conclusions: This study highlights the higher rate of incidence-based mortality in Caucasian males compared to African American males in the past 15 years despite a lower incidence reported in the 1995 to 2008 period. With no significant change in mortality rates/year noted during this time period, this study implies that soft tissue sarcomas in Caucasian males have worse outcomes. Further research is needed to understand the mechanism underlying this disparity. [Table: see text]