bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shedding Light on T2 Bright Masses on Breast MRI: Benign and Malignant Causes
Authors: Gibson Averi L , Watkins Jade E , Agrawal Anushree , Tyminski Monique M , DeBenedectis Carolynn M 
Published: June 2022

AbstractWhile T2 hyperintense masses on breast MRI are often benign, there are several malignant etiologies that can also be T2 hyperintense. Delineation between benign and malignant entities is important for the accurate interpretation of breast MRI. Common benign T2 hyperintense masses include cysts, fibroadenomas, and lymph nodes. Malignant processes that are T2 hyperintense include metastatic lymph nodes, mucinous breast carcinomas, papillary breast carcinomas, and breast cancers with central necrosis. Evaluation of the morphology and enhancement pattern of a T2 hyperintense mass can help to differentiate a benign process from a malignant one. This educational review will present both benign and malignant causes of T2 hyperintense masses on breast MRI and review common imaging findings and pertinent imaging characteristics that can be used to help accurately identify benign entities while also recognizing suspicious lesions that require additional evaluation.
Efficient least-squares reverse time migration using local cross-correlation imaging condition
Authors: Kim Sumin , Kim Young Seo , Chung Wookeen 
Published: June 2022

Abstract
The data-domain least-squares reverse time migration (LSRTM), a promising imaging method for obtaining a high-resolution reflectivity image, can be implemented by matching the de-migrated data to the observed one. However, LSRTM requires expensive computational costs in its implementation due to tremendous memory usage (direct storage on disk/memory) for saving source wavefields and repeatable forward/backward wavefield simulations with iterations compared to conventional RTM. Although the source wavefield reconstruction technique can be used to reduce the memory usage, additional computational cost is inevitable because it is implemented during backward wavefield simulation. To alleviate the computational burden, we have developed an efficient LSRTM scheme with local cross-correlation imaging condition (LSRTM-LC), which can use pre-saved source wavefields according to the window size. Because the window size is much shorter than the total recording time for wavefield extrapolation, storing source wavefields into computer memory can be feasible. In addition, the procedure for storing source wavefields is implemented only at the first iteration because the background velocity is fixed during iterations of LSRTM. To validate the feasibility of the LSRTM-LC scheme, we have carried out several numerical tests with synthetic datasets. Numerical tests demonstrated that LSRTM-LC can provide us with equivalent de-migrated data from saved source wavefields and the gradient vector obtained from LSRTM-LC compared to those obtained from the conventional LSRTM. As a result, LSRTM-LC can generate the same quality of reflectivity models as conventional LSRTM, however, it requires less computational costs compared to conventional LSRTM.
Expression profiles of the genes associated with zinc homeostasis in normal and cancerous breast and prostate cells
Authors: Barman Shital K , Zaman Mohammad S , Veljanoski Filip , Malladi Chandra S , Mahns David A , Wu Ming J 
Published: June 2022

Abstract
Zn2+ dyshomeostasis is an intriguing phenomenon in breast and prostate cancers, with breast cancer cells exhibiting higher intracellular Zn2+ level compared to their corresponding normal epithelial cells, in contrast to the low Zn2+ level in prostate cancer cells. In order to gain molecular insights into the zinc homeostasis of breast and prostate cancer cells, this study profiled the expression of 28 genes, including 14 zinc importer genes (SLC39A1–14) that encode Zrt/Irt-like proteins 1–14 to transport Zn2+ into the cytoplasm, 10 zinc exporter genes (SLC30A1–10) which encode Zn2+ transporters 1–10 to transport Zn2+ out of the cytoplasm, and 4 metallothionein genes (MT1B, MT1F, MT1X, MT2A) in breast (MCF10A, MCF-7, MDA-MB-231) and prostate (RWPE-1, PC3, DU145) cell lines in response to extracellular zinc exposures at a mild cytotoxic dosage and a benign dosage. The RNA samples were prepared at 0 min (T0), 30 min (T30), and 120 min (T120) in a time course with or without zinc exposure, which were used for profiling the baseline and dynamic gene expression. The up-regulation of MT genes was observed across the breast and prostate cancer cell lines. The expression landscape of SLC39A and SLC30A was revealed by the quantitative reverse transcription polymerase chain reaction data of this study, which sheds light on the divergence of intracellular Zn2+ levels for breast and prostate cancer cells. Taken together, the findings are valuable in unraveling the molecular intricacy of zinc homeostasis in breast and prostate cancer cells.
The Xer activation factor of TLCΦ expands the possibilities for Xer recombination
Authors: Miele Solange , Provan James Iain , Vergne Justine , Possoz Christophe , Ochsenbein Françoise , Barre François-Xavier 
Published: June 2022

Abstract
The chromosome dimer resolution machinery of bacteria is generally composed of two tyrosine recombinases, XerC and XerD. They resolve chromosome dimers by adding a crossover between sister copies of a specific site, dif. The reaction depends on a cell division protein, FtsK, which activates XerD by protein-protein interactions. The toxin-linked cryptic satellite phage (TLCΦ) of Vibrio cholerae, which participates in the emergence of cholera epidemic strains, carries a dif-like attachment site (attP). TLCΦ exploits the Xer machinery to integrate into the dif site of its host chromosomes. The TLCΦ integration reaction escapes the control of FtsK because TLCΦ encodes for its own XerD-activation factor, XafT. Additionally, TLCΦ attP is a poor substrate for XerD binding, in apparent contradiction with the high integration efficiency of the phage. Here, we present a sequencing-based methodology to analyse the integration and excision efficiency of thousands of synthetic mini-TLCΦ plasmids with differing attP sites in vivo. This methodology is applicable to the fine-grained analyses of DNA transactions on a wider scale. In addition, we compared the efficiency with which XafT and the XerD-activation domain of FtsK drive recombination reactions in vitro. Our results suggest that XafT not only activates XerD-catalysis but also helps form and/or stabilize synaptic complexes between imperfect Xer recombination sites.
ATRT-22. Outcomes for children with recurrent atypical teratoid rhabdoid tumor: A single institution study with updated molecular and germline analysis
Authors: Carey Steven S , Huang Jie , Myers Jason R , Mostafavi Roya , Orr Brent , Michalik Layna H , Klimo Paul , Boop Frederick , Nichols Kim E , Merchant Thomas , Ellison David W , Robinson Giles W , Onar-Thomas Arzu , Gajjar Amar , Upadhyaya Santhosh 
Published: June 2022

Abstract
BACKGROUND: Children with recurrent atypical teratoid rhabdoid tumor (recATRT) who fail frontline therapies have dismal outcomes. The association of ATRT molecular groups (SHH, TYR and MYC) and presence of underlying cancer predisposition with survival post-recurrence (postRD) is unknown. METHODS: We previously reported outcomes from a single-institution retrospective study of children &lt;21 years with recATRT treated at St. Jude Children’s Research Hospital from 2000 to 2020. Herein we report updated progression-free survival (PFS2: time from initial recurrence to subsequent first progression) and overall survival (OSpostRD: time from initial recurrence to death/last follow-up) outcomes by molecular groups determined by tumor DNA methylation and by germline SMARCB1/SMARCA4 alterations (GLA). RESULTS: Median age and time from initial diagnosis to recurrence for 64 eligible patients were 2.1 years (range: 0.5-17.9 years) and 5.4 months (range: 0.5–125.6 months), respectively. The 2- and 5-year PFS2 and OSpostRD were 3.1% (±1.8%)/1.6% (±1.1%) and 20.3% (±4.8%)/7.9% (±3.8%), respectively. PFS2 did not differ by molecular groups (p=0.210) for 42 participants with available data (MYC=11, SHH=21, TYR=10). Children with TYR group had a better 2-year OSpostRD [60.0% ±14.3% (TYR) vs. 18.2% ±9.5% (MYC) or 4.8% ±3.3% (SHH)] (p=0.018). In univariate analyses, OSpostRD was also better with older age at diagnosis (≥ 1 year vs &lt;1 year; p=0.03), female gender (p=0.008), and metastatic site of recurrence compared to local or combined sites of disease (p&lt;0.001). OSpostRD did not differ for those with positive GLA (n=12) compared to those without (n=21) (p=0.231). Only 6 children (9.4%) (TYR=4, SHH=1, NA=1) were alive at median follow-up of 7.7 years from recurrence. CONCLUSION: Children with recATRT have extremely poor outcomes. Older age at diagnosis, female gender, TYR group, and metastatic site of initial recurrence were associated with longer survival in our study. These results reinforce the dire need for better therapeutic options.
ATRT-26. The PI3k inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors
Authors: Findlay Tyler , Malebranche Kristen , Raabe Eric , Eberhart Charles , Rubens Jeffrey 
Published: June 2022

Abstract
We previously identified high activation of mTORC1 and mTORC2 in AT/RT by immunohistochemistry of 18 primary tumors expanding over each molecular subgroup of AT/RT. Paxalisib is a highly brain-penetrant PI3k inhibitor acting upstream of mTORC1/2 to fully inhibit the activation of both complexes. Ongoing pediatric clinical trials have reported Paxalisib as safe and well-tolerated. We find that Paxalisib leads to minimal toxicities in mice bearing AT/RT orthotopic xenografts, slows tumor growth (as determined by bioluminescent imaging), and significantly extends survival (CHLA-06: 40 to 54 days, p=0.0011; BT12: 21 to 35 days, p=0.02). However, due to limited durability of single agent therapy, we conducted pilot studies to identify rational combination therapies to further enhance these survival benefits. RG2833 is a novel, highly brain penetrant, histone deacetylase 1/3 (HDAC1/3) inhibitor. HDAC inhibitors have previously been identified as synergistic partners with PI3k/mTOR inhibitors through complementary activation of FOXO signaling pathways. We hypothesized that RG2833 would synergize with Paxalisib, minimize toxicities compared with pan-HDAC inhibitors, and maximize therapeutic benefits due to superior CNS penetration. We demonstrate that Paxalisib and RG2833 combine synergistically to decrease AT/RT cell growth (SynergyFinder ZIP score 11.1; CellTiter-Blue Cell Viability Assay, p&lt;0.0001), and increase apoptosis (Western blot cPARP, MUSE Annexin V Assay, ANOVA p&lt;0.001) compared to each agent alone and DMSO control. Our pilot combination study in orthotopic xenograft models of AT/RT demonstrate that combination therapy is well tolerated and slows tumor growth more significantly than each agent alone and vehicle control (IVIS bioluminescent imaging). This novel combination therapy could readily translate into a new clinical trial aimed at improving survival in this deadly pediatric brain tumor.
RARE-05. Legal degree of disability in childhood-craniopharyngioma survivors during long-term follow-up – results of the HIT-ENDO study
Authors: Boekhoff Svenja , Beckhaus Julia , Eveslage Maria , Friedrich Carsten , Müller Hermann L 
Published: June 2022

Abstract
BACKGROUND: Cranioparyngiomas are rare low-grade embryonic malformational tumors of the sellar/parasellar region. The prognosis after diagnosis during childhood and adolescence is influenced by endocrine and hypothalamic long-term sequelae. A legal status of the degree of disability (GdB), according to the German Social Code Book V that is worthy of support, provides financial means for psychosocial rehabilitation and participation of craniopharyngioma survivors. The aim of this study was to determine the association of clinical/psychosocial characteristics and quality of life (QoL) indicators with the resulting GdB. PATIENTS AND METHODS: HIT-Endo is a German registry study on craniopharyngioma patients aged ≤ 18 years at diagnosis and included before the year 2000. In a sample of 108 patients, the degree of disability and the association with endocrine, ophthalmological, neuropsychological and psychosocial parameters was analyzed after a mean follow-up period of 16 years (95% CI: 9.8-36.4). RESULTS: 44 patients (41%) did not receive a GdB, three patients (3%) received a GdB of 30-40, 43 patients (40%) a GdB of 50-90 and 18 patients (17%) the maximum GdB of 100. Higher GdB were associated with lower education, higher body mass index standard deviation and a higher degree of visual impairment and hypothalamic involvement of the craniopharyngeoma. Patients with a GdB of 100 reported loss in physical and cognitive function, as well as fatigue, dyspnea, and pain conditions, and limitations in social and occupational contexts. They further had a lower functional capacity (German daily life ability scale (FMH)) compared to those with a smaller GdB. CONCLUSION: The GdB is associated with psychosocial and physical impairments and reflects the long-term consequences of craniopharyngioma during childhood and adolescence. A low functional capacity (assessed by FMH) may indicate the eligibility for a high GdB in later life of craniopharyngioma survivors.
DIPG-12. Induced mitotic abnormalities associated with BMI-1 modulation sensitize diffuse intrinsic pontine glioma cells to ionizing radiation
Authors: Kumar Shiva Senthil , Mishra Deepak , Mchugh Todd , Drissi Rachid 
Published: June 2022

Abstract
Diffuse intrinsic pontine glioma (DIPG) remains an incurable childhood brain cancer with a median overall survival of less than 12 months, affecting 200-300 children annually in the United States. Hence, there is an unmet need for the development of novel and effective targeted therapies. BMI-1 is a subunit of the multimeric protein complex Polycomb repressor complex 1 (PRC1) implicated in self-renewal of normal and cancer cells, and in DNA damage signaling. We have previously identified BMI-1 as a potential therapeutic target in DIPG and have shown that BMI-1 is highly expressed in DIPG tumors regardless of H3K27 mutational status. Treatment of DIPG cells with PTC596, a small molecule initially identified as a BMI-1 modulator, and ionizing radiation (IR) impairs the kinetics of DNA damage response. in vivo, treatment with PTC596 alone delayed tumor growth kinetics and induced in-tumor apoptosis. However, we observed tumor regrowth once PTC596 treatment is completed or discontinued. In the present study, we evaluated the use of PTC596 in combination with IR. Our in vivo results indicate that PTC596 sensitizes DIPG cells to IR inducing a prolonged cell growth arrest 14 days post-treatment compared to IR or PTC596 alone. The effectiveness of this combination is currently evaluated in murine orthotopic DIPG models and the results will be presented. PTC596 is being tested in newly diagnosed children with DIPG and high-grade gliomas (NCT03605550). Data collected from this study will support the development of a novel therapy including PTC596 in combination with radiotherapy to treat children with DIPG.
DIPG-13. Immune profiling by RNA-seq deconvolution and single-cell sequencing reveal myeloid cell enrichment in DIPG tumor microenvironment
Authors: Zhu Xiaoting , Mishra Deepak , Kumar Shiva Senthil , Mchugh Todd , Lazow Margot , Fouladi Maryam , Drissi Rachid 
Published: June 2022

Abstract
Diffuse intrinsic pontine glioma (DIPG) remains an incurable disease with median overall survival &lt;12 months despite decades of clinical trials investigating multimodal therapies. Immunotherapy represents a promising treatment paradigm which has been successfully used in other cancers. An adequate understanding of the tumor microenvironment and immunologic profile is essential to identify potential immunotherapeutic targets to inform immunotherapy design. Previous studies have shown that most DIPG tumors harbor low mutational burden compared to adult cancers and are characterized by a non-inflammatory microenvironment, limiting the development of immunotherapies in this disease. Our team’s prior work similarly demonstrated that most DIPG tumors have an immunologically “cold” microenvironment, but a subset of tumors harbors a more inflammatory gene expression profile and/or higher mutational burden, with trends toward improved survival and favorable radiographic response to radiation. Here, we applied a deconvolution analysis using CIBERSORTx on bulk RNA-seq data from 28 DIPG patients’ tumors paired with matched normal tissue specimens, to profile the immune microenvironment of DIPG and evaluate immune-related gene expression to determine percentages of different types of immune cells. Our results indicate that DIPGs have very limited lymphocyte infiltration. However, the infiltration of macrophages “M2-like” type cells and CD4 memory resting T cells were significantly higher in tumors compared to normal tissue samples. Similar results were found using single-cell RNA sequencing performed on biopsy and autopsy tissue, with less than 5% of total cells identified as immune cells. MHC I components were widely expressed in DIPGs with no significant difference between tumor and normal tissue. Expression of CD11B and CD68 were higher in tumor compared to normal tissue, suggesting enrichment of myeloid cells. Overall, deconvolution analysis of bulk RNA-seq can be used to profile DIPG tumors’ immune microenvironment to aid in the thoughtful design of effective immunotherapeutic strategies for this disease.
DIPG-60. Avapritinib for targeting PDGFRA in H3K27M – mutated diffuse midline glioma
Authors: Mayr Lisa , Madlener Sibylle , Weiler-Wichtl Liesa , Rosenmayr Verena , Furtner-Srajer Julia , Guntner Armin , Stepien Natalia , Baumgartner Alicia-Christina , Dorfer Christian , Haberler Christine , Müllauer Leonhard , Palova Hana , Pokorna Petra , Sterba Jaroslav , Dieckmann Karin , Azizi Amedeo , Peyrl Andreas , Kim Sean , Hsieh Antony , Dimitrijevic Sasa , Gojo Johannes 
Published: June 2022

Abstract
H3K27M-mutated diffuse midline glioma (H3K27M DMG) are an almost universally fatal disease with a median survival of less than 6 months post progression and no effective therapy. PDGFRA-signaling has shown to promote and sustain a subset of oligodendrocyte precursor-like tumor cells that are responsible for tumor propagating potential and high proliferation rates. However, first attempts to target PDGFRA in adult glioblastoma with dasatinib/imatinib or pediatric refractory brain tumors with sunitinib were not successful. We report on the first experience in two patients receiving avapritinib, a highly potent, selective, brain penetrant PDGFRA/KIT inhibitor under a compassionate use program. Our first patient with spinal H3K27M DMG developed supratentorial metastases ten months after initial diagnosis. Molecular profiling revealed de novo PDGFRA and KIT amplifications and treatment with dasatinib was initiated. Due to disease progression and novel metastases, therapy was switched to avapritinib showing near complete resolution of the previously unirradiated frontal lesion with additional disease stabilization of other metastatic sites. Following re-resection and irradiation of progressing cerebellar lesions, the patient remains clinically stable on avapritinib therapy over 12 months. The second patient with diffuse intrinsic pontine glioma showed disease progression nine months after diagnosis and was treated with focal re-irradiation (30Gy). As the tumor harbored a PDGFRA R841del alteration, avapritinib was initiated seven weeks after radiation upon further tumor progression resulting in partial response. Pharmacokinetic sampling of cerebrospinal fluid (CSF) detected an increasing CSF/plasma ratio over time and up to 4 µM avapritinib in tumor tissue. Avapritinib CSF levels in both patients were distinctly higher than dasatinib levels. Avapritinib was generally well tolerated besides lower limb edema, elevated LDH and liver enzymes. Hence, effective CNS penetration of avapritinib at pharmacologically relevant brain tumor concentrations resulted in clinical response in two patients with rapidly progressive H3K27M DMG.
EPID-09. Characterizing the epidemiology of radiation-induced gliomas following cranial radiotherapy for pediatric cancers: a population-based study
Authors: Leary Jacob , Anderson-Mellies Amy , Green Adam 
Published: June 2022

Abstract
BACKGROUND: Cranial radiotherapy (RT) is used to treat pediatric central nervous system (CNS) cancers and leukemias. RT carries a risk of secondary CNS malignancies, including radiation-induced gliomas, the epidemiology of which is poorly understood. METHODS: This retrospective study using SEER registry data (1975-2016) included two cohorts. Cohort 1 included patients diagnosed with Grade III/IV or ungraded glioma as a second malignancy &gt;/=2 years after receiving beam radiation and/or chemotherapy for a first malignancy diagnosed at ages 0-19 years, either a primary CNS tumor treated with RT (1a, n=77) or leukemia with unknown RT treatment (1b, n=20). Cohort 2 included patients with possible missed RIG who received RT for a primary CNS tumor diagnosed at 0-19 and then died of presumed progressive disease more than 5 years after diagnosis, since previous studies have documented many missed RIGs in this group (n=296). Controls (n=10,687) included all other patients ages 0-19 who received RT for a first CNS tumor or leukemia who did not fit inclusion criteria above. RESULTS: For Cohort 1 (likely/definite RIGs), 0.97% of patients receiving cranial RT went on to develop RIG. 3.39% of patients receiving cranial RT for primary CNS tumors fell in Cohort 2 (possible RIGs). Median latency to RIG diagnosis was 11.1 years; latency was significantly shorter for Cohort 1b (median 10.0, range 5.0-16.1) vs. 1a (12.0, 3.6-34.4, p=0.018). Median OS for Cohort 1 was 9.0 months. Receiving surgery, radiation, or chemotherapy were all associated with a non-statistically significant improvement in OS (p 0.1-0.2). CONCLUSION: Within the limitations of a population-based study, 1-4% of patients undergoing cranial RT for pediatric cancers later develop RIG, which is incurable and can occur anywhere from 3-35 years later. Effective treatment of RIG remains unclear and is thus deserving of increased attention in preclinical and clinical studies.