tbuckley/cabot-search huggingface dataset:
Abstract 11855: Cognitive Function in the Elderly With Heart Failure: A Significant Mediator for the Relationship Between Physical Activity and In-Hospital Delirium
Authors: Michiaki Nagai, Keigo Dote, Masaya Kato, Noboru Oda, Eiji Kunita, Eisuke Kagawa, Aya Yamane, Tasuku Higashihara, Yusuke Kobayashi, Makoto Takeuchi
Journal: Circulation (2018)

Introduction: Delirium is a serious syndrome in critically ill patients. Cognitive decline and heart failure (HF) frequently coexist in the elderly. Six-minute walking test (6MWT), an easy and reli...
EMBR-19. SHH-DRIVEN MEDULLOBLASTOMA WITH CONCURRENT UNILATERAL RENAL AGENESIS
Authors: Ashley Aaroe, Sanila Sarkar, Farha Sherani, Mary McAleer, Greg Fuller, Wafik Zaky
Journal: Neuro-Oncology (2021)

Abstract Case Presentation A 3-year-old female with insignificant past medical history presented with 6 weeks of headaches, emesis, and lethargy. MR imaging identified a heterogeneously enhancing right cerebellar hemispheric mass and obstructive hydrocephalus. Gross total resection was performed without complications; pathology revealed classical WHO grade 4 medulloblastoma (MB). MR imaging of the spine and cerebrospinal fluid testing were negative for disseminated disease. Treatment for standard risk medulloblastoma was initiated, comprising proton craniospinal irradiation with posterior fossa boost and concurrent vincristine, followed by adjuvant chemotherapy with vincristine, lomustine, cisplatin, and cyclophosphamide as standard of care. Next generation sequencing of the tumor tissue performed using a high-multiplex PCR-based NGS panel was negative for alteration of the SMO, PTCH1 and CTBNN1 genes. Further molecular characterization via methylation profiling demonstrated the sonic hedgehog (SHH) molecular subtype. Prior to initiation of chemotherapy, renal ultrasound was performed and identified congenitally absent right kidney; audiology evaluation was unremarkable. Discussion In patients with Gorlin syndrome, cases of unilateral renal agenesis in association with germline SHH-pathway mutations have been reported [1]. SHH signaling is implicated in multiple steps in the development of the urinary system [2]. Outside Gorlin syndrome, however, to the best of our knowledge unilateral renal agenesis coinciding with SHH-driven MB has not been reported. Our patient notably lacks any clinical stigmata of Gorlin syndrome (skeletal abnormalities, skin pits, macrocephaly) and does not exhibit the characteristic germline genetic abnormalities that define GS (PTCH1 mutation or 9q22.3 microdeletion). There are important treatment implications for patients with the constellation of abnormalities we describe here, particularly regarding the requisite frequent monitoring of renal function during multi-agent chemotherapy courses. Our patient tolerated chemoradiation well, and is currently on maintenance chemotherapy with favorable course to date.
Point of care genetic testing in a breast cancer survivorship clinic.
Authors: Lori Ranallo, Lauren Elizabeth Nye, Mary Williams, Carol J. Fabian F.A.S.C.O, Anne O'Dea, Jennifer R. Klemp
Journal: Journal of Clinical Oncology (2021)

10580 Background:: Breast cancer survivorship care (BCSC) includes the ongoing assessment of personal and family cancer history and offering genetic education, counseling and testing to survivors who meet NCCN, ASBrS and Medicare guidelines for germline genetic testing. It is reported that approximately 8% of patients with breast cancer (BC) will have a clinically actionable germline mutation. However, lower than expected rates of testing are seen in both the acute and extended phases of BCSC. We sought to identify the number of patients seen in a long-term survivorship clinic who had previously undergone or currently qualified for germline testing, and the prevalence of germline variants in BC survivors. Methods: In a Nurse Practitioner (NP) led clinic, 2,184 non-selected BC survivors were screened to determine if: germline testing was previously completed or if update germline testing or initial germline testing is needed (with a 3-generation review of family history). BC survivors eligible for initial or update germline testing (411 patients) were provided with genetic education, counseling, and offered multigene panel testing. Seven (7) BC survivors declined testing. Results: From May 2019 – January 2021, 2,184 BC survivors were seen in the clinic. The average age of survivors = 60.2 yrs; average time since diagnosis = 10.7 yrs; and average age at diagnosis = 50.1 yrs, gPV were identified in 10.4%. Out of pocket cost on average was $50.00 for 2.0% of those tested. Conclusions: Within a comprehensive Breast Cancer program where genetic testing is common practice, there is an ongoing need to screen breast cancer (BC) survivors for genetic testing eligibility. A significant number of BC survivors will test positive for a pathogenic mutation (10.4%) a decade after an initial diagnosis. Genetic testing is a necessary step to stratify a BC survivors’ risk of developing secondary cancers, appropriate screening and prevention strategies, cascade testing, and for some, treatment planning. This individualized approach to BCSC is often described, but difficult to put into action. Time/access and drop rates with a referral model are barriers. Incorporating a point of care genetic testing model requires additional support (genetic extender), professional development, education, and a commitment to provide patient centric care.[Table: see text]
Impact of updated 2013 human epidermal growth factor receptor-2 testing guidelines on HER2 positive invasive breast cancer diagnosis: A three year retrospective study.
Authors: Hemendra Mhadgut, Purva Sharma, Fady Tawadros, Bill Brooks, Anna Yakubenko, Devapiran Jaishankar
Journal: Journal of Clinical Oncology (2021)

e12554 Background: Breast cancer is a frequently diagnosed malignancy in the United States accounting for approximately 266,000 cases and 40,000 deaths annually. Human epidermal growth factor receptor 2 (HER2) is a surface protein shown to affect cell proliferation, migration and survival - the hallmarks of neoplastic cells. HER2 is overexpressed in 20-35% of breast cancer cases and has a strong prognostic and therapeutic significance. This discovery led to development of therapeutic agents targeting HER 2 receptor. In 2013, College of American Pathologists (CAP) updated their recommendations for HER2 testing by incorporating an algorithm with immunohistochemistry (IHC) and In situ hybridization (ISH). The primary objective of our study was to assess for variance in HER2 interpretation by applying the updated 2013 criteria to all diagnosed cases in our hospital for the immediate previous three years. Methods: We retrospectively reviewed charts of patients diagnosed with invasive breast carcinoma from January 1, 2010 to December 31, 2012 at our hospital. The new American college of pathology criteria assessing FISH HER2 copy number and HER2/CEP ratio for each patient was compared to the old criteria to assess for variance in HER2 interpretation. Categorical variables are presented as percentages and kappa statistic was used to assess for variance. Results: We reviewed 526 charts with an invasive breast cancer diagnosis over a 3-year period. 10.83% of patients were HER2 amplified, 86.12% were non-amplified and 3.04% were equivocal. Applying the updated 2013 CAP criteria, we found that 11.21% were amplified, 74.33% were non amplified, and 14.44% remained equivocal. Kappa statistic indicated substantial agreement (0.804) between the old and new criteria. A review of our cohort revealed an overall lower level of HER2 positive cases at 10.83% (old criteria) and 11.21% (updated criteria) when compared to historical studies. The increase in equivocal cases from 3.04% to 14.44% with the new criteria suggests under diagnosis of HER2 positive cases. Due to the lack of IHC performed (as per old standards), further classification of equivocal cases (based on new criteria) was not possible. While we saw some movement in our data from non-amplified to equivocal, our analysis indicated substantial statistical agreement between the old and the new diagnostic criteria Conclusions: Our study did not show a variance in HER2 interpretation between the 2007 and 2013 CAP criteria which is reassuring. An increase of 11.4% cases in the equivocal category was noted and may reveal a significant difference if further delineation is feasible. This variance could be important given the prognostic and therapeutic implications in HER2 positive breast cancer.[Table: see text]
Exploring molecular profiles of uterine carcinosarcoma with alterations in the chromatin remodeling pathway.
Authors: Annelise M. Wilhite, Sharon Wu, Joanne Xiu, Rodney Paul Rocconi, Britt Kristina Erickson, Tenley Klc, Jamie Lee Lesnock, Jubilee Brown, Thomas J. Herzog, Robert W. Holloway, Wolfgang Michael Korn, Matthew A. Powell, Nathaniel L. Jones
Journal: Journal of Clinical Oncology (2021)

5587 Background: In a preliminary data analysis to identify prognostic molecular biomarkers in uterine carcinosarcoma (UCS), we found that alterations in KMT2C, a gene involved in the chromatin remodeling pathway, correlated with improved survival. We sought to explore relevant biomarkers of KMT2C-mutated (KMT2C-mut) tumors compared to wildtype (KMT2C-wt) tumors. Methods: Tumor samples were analyzed using next generation sequencing (NGS) of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off &gt;1%). Microsatelite instability (MSI) was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high &gt; 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be &lt;0.05. Results: Molecular analysis was performed on 1,144 UCS tumors. 7.7% were found to be KMT2C-mut. Patients with pathogenic alterations in KMT2C had longer median OS than patients without (OS not yet reached vs 19.0 months HR(95% CI): 0.37(0.19-0.72) p&lt; 0.01). The most common mutations in KMT2C-mut tumors are shown in Table and resulted in more frequent dysregulation in the following pathways compared to KMT2C-wt tumors: chromatin remodeling (100% vs 28%; q&lt;0.01), WNT (39% vs 12%; q=0.01), base/nucleotide excision repair (29% vs 5%; q&lt;0.01), homologous recombination (26% vs 6%; q=0.02), DNA damage sensors (23% vs 4%; q=0.02) and Fanconi anemia (13% vs 1%; q=0.04). KMT2C-mut tumors were more frequently MSI-H (32% vs 6%; q&lt;0.01) and TMB-H (42% vs 5%; q&lt;0.01). Among MSS tumors, KMT2C-mut tumors had increased mutations in JAK1 and POLE (q&lt;0.01) and higher frequency of TMB-H (24% vs 1%; q&lt;0.01) than KMT2C-wt tumors. Additionally, MSS patients with KMT2C-mut had longer OS than patients with KMT2C-wt tumors (OS not yet reached vs 18.9 months; HR(95% CI): 0.33(0.15-0.75) p&lt; 0.01). Conclusions: Mutations in KMT2C correlate with improved OS in UCS. KMT2C-mut tumors have distinct molecular profiles from wild type tumors. They exhibit greater immunogenicity, including more frequent MSI-H and TMB-H. This suggests a potential role for Immune-oncology (IO) therapy. Further study of the impact of IO therapies in the cohort is warranted as this may contribute to the improved survival of these patients.[Table: see text]
Ensuring the most effective strategy for cancer treatment of patients with brain tumors.
Authors: Elena A. Sheiko, Elena M. Frantsiyants, Eduard E. Rostorguev, Irina V. Kaplieva, Valeria A. Bandovkina, Irina V. Neskubina, Ekaterina I. Surikova, Natalya S. Kuznetsova, Oleg I. Kit, Sergey E. Kavitskiy, Olga V. Pandova, Vladislav E. Khatyushin
Journal: Journal of Clinical Oncology (2021)

e14000 Background: The purpose of the study was to analyze changes in the total activity of trypsin-like proteinases (TLPs) in the blood plasma in patients with brain tumors for the preoperative differential diagnosis of benign, primary and secondary malignant brain tumors. Methods: TLPs were measured in 164 patients with brain tumors. The blood had been collected from the patients in a standard plastic tube with 3.8% sodium citrate (9:1) 3 days prior to the surgery. Citrate blood was centrifuged; citrated plasma was obtained and used to determine the total TLP activity by the unified kinetic method. Results were compared with the data in donors. Results: TLP activity in 37 (22.6%) of 164 patients was within the normal range (258–402 IU/mL, on the average 333.0±27.1 IU/mL). Benign brain tumors (meningioma) were diagnosed in all 37 patients after the tumor removal and histological analysis. In 74 (45.1%) of 164 patients, TLP activity was within 1158–1626 IU/mL (on the average 1331.0±102.4 IU/mL, p &lt; 0.05), i.e. 3.8-5.3 times higher than the norm in donors (malignancy coefficient on average 4.4±0.3 times). Primary malignant brain tumors (glioblastoma) were diagnosed in all 74 patients after the tumor removal and histological analysis. In 53 (32.3%) of 164 patients, TLP activity was within 1794–2868 IU/mL (on the average 2227.0±174.1 IU/mL, p &lt; 0.05), i.e. 5.9-9.4 times higher than the norm in donors (malignancy coefficient on average 7.3±0.5 times). Secondary malignant brain tumors (metastases) were diagnosed in all 53 patients after the tumor removal and histological analysis. Conclusions: The specificity of the proposed method for the differential diagnosis of brain tumors was very high: for benign tumors - 97.2%, for primary malignant tumors - 98.6% and for secondary malignant tumors - 98.1%. So, TLP activity indices in the blood plasma are an informative auxiliary laboratory test that will help in clarifying and/or confirming the differential diagnosis of brain tumors.
Immune-related acute myocarditis in patients treated with immune checkpoints inhibitors: Systematic review with individual patient-level data meta-analysis.
Authors: Alexey Rumyantsev, Edgar Israelyan, Alexandra Tyulyandina, Elena Glazkova, Yury Sergeev, Sergey Tjulandin
Journal: Journal of Clinical Oncology (2021)

e24096 Background: Immune checkpoint inhibitors can sometimes lead to fatal outcomes or significant morbidity due to immune-related adverse events (IRAE). Cardiac IRAE, especially myocarditis, are among the most fatal IRAE. There are scarce of the trials addressing the optimal therapeutic approaches for patients with IR-myocarditis. Initial therapy with high-dose steroids (1000 mg of prednisolone for 3-5 days) may be beneficial for many patients with this IRAE and this approach is endorsed by NCCN guidelines. We conducted a systematic review with individual patient-level data meta-analysis of published clinical cases to assess impact of various initial therapeutic modalities and adherence to NCCN guidelines on outcomes of immune-related myocarditis, associated with checkpoint inhibitors. Methods: We searched PubMed database for all full-text articles and abstracts on the treatment of patients with cardiac-related IRAE treated with various PD-1/PD-L1 or CTLA-4 inhibitors for years between 2012 and 2020 in English. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) tool was used to ensure transparent reporting. Main study inclusion criteria were: 1) morphologically confirmed immune-related myocarditis or highly clinically suspected autoimmune myocarditis (based on Bonaca et al, 2019 criteria); 2) clear association of IRAE and administration of check-point inhibitors; 3) availability of individual patient and treatment data. Pooled analysis of outcomes and multiple logistic regression analysis were conducted. The primary outcome of this study was rate of major cardiac adverse events (MACE) due to immune-related autoimmune myocarditis according to adherence to NCCN guidelines. MACE was defined as death or persisting significant disabilities due to myocarditis (ie, chronic heart failure, rhythm abnormalities or deterioration leading to impossibility of further anticancer treatment). Results: We identified 277 articles and screened them for title and abstract. After the review process we selected 81 studies for further analysis which described treatment course for 111 patients. Overall, 26 and 85 patients were treated with high-dose and non-high dose steroids. Among patients treated high-dose steroids therapy and non-high dose steroids 10 (38.5%) and 57 (67.1%) of patients respectively experienced MACE (HR 0.185; 95% CI 0.07-0.47; p = 0.0091). Initial treatment failure was associated with high rate of morbidity; however, 9 patients were rescued with various immunosuppressive drugs (eg, tacrolimus, alemtuzumab, tocilizumab). Conclusions: Our results support use of high-dose pulse therapy as a preferred therapeutic approach for all patients with suspected or proven immune-related myocarditis.
Is radiation necrosis in radiated melanoma brain metastasis increasing because immunotherapy is contributing to this or are patients just living longer?
Authors: Elizabeth Iannotti Buchbinder, Diana D. Shi, Kathleen L. Pfaff, Michael P. Manos, Olivia Ouyang, David Liu, Scott J. Rodig, Ayal Aizer
Journal: Journal of Clinical Oncology (2021)

e21518 Background: The use of immune checkpoint inhibitors, particularly combination ipilimumab and nivolumab, has drastically changed the management of patients with melanoma brain metastasis. Select patients also benefit from brain-directed stereotactic radiation. Radiation necrosis is a risk associated with stereotactic radiation that oncologists have been observing more frequently in the era of immunotherapy. Methods: Patients were identified who had a history of metastatic melanoma treated with stereotactic brain radiation who subsequently developed radiation necrosis. Brain tissue from those patients with a subsequent resection of their radiation necrosis was obtained and examined for immune infiltrate and other factors. The tissue obtained was evaluated by blinded pathologists who graded % viable tissue, % necrosis, % tumor and % fibrosis. In addition, they graded inflammation on a scale of 1-3. Results: Seven patients were identified who had surgery for radiation necrosis following radiation to melanoma brain metastasis. Tissue was available for five patients. Two patients had received no prior immunotherapy, one patient had received ipilimumab and two patients received combination ipilimumab and nivolumab. The samples obtained consisted of almost entirely viable brain tissue or necrosis. There was minimal inflammation seen in all patients’ samples including those who had not received immunotherapy and those who had. Conclusions: Radiation necrosis in patients on immunotherapy who receive brain-directed stereotactic radiation is a rising problem. On pathologic evaluation increased immune infiltrate is not observed in patients on immunotherapy with radiation necrosis compared to those who never received immunotherapy. This suggests that the increased rates of radiation necrosis may be more likely associated with longer survival as opposed to a direct causative effect from the immunotherapy although with our limited sample size this will need further exploration.[Table: see text]
OMIC-03. TRANSLATIONAL CONTROL IN MYC AND MYCN MEDULLOBLASTOMA
Authors: Christin Schmidt, Albertas Navickas, Frederique Zindy, Dana Farmer, Davide Ruggero, Hani Goodarzi, Martine F Roussel, Bjoern Schwer, William Weiss
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma has been extensively characterized at the genomic and transcriptional levels, but little is known about how alterations in translational control underlie tumor development. Myc and Mycn are often deregulated in medulloblastoma and play important roles in tumor initiation, maintenance and progression. Although both proteins have similar structures and are functionally redundant in hindbrain development, their amplification in cerebellar granule neural precursor cells leads to different medulloblastoma subtypes. In this project we are employing ribosome profiling on mouse medulloblastoma tumors generated from granule neural precursor cells with enforced expression of Myc or Mycn. Ribosome-protected mRNA sequencing allows us to quantitatively assess the specific transcripts regulated at the level of translation, identify translation regulatory sequences within the mammalian transcriptome, and understand genotype-to-phenotype processes. We discovered that Myc- and Mycn-driven tumors exhibit many more changes at the translational rather than at the transcriptional level. In particular, we found that Mycn-driven medulloblastoma upregulates the translation of Myc target genes, while mRNA levels of those genes show no difference between Myc- and Mycn-driven tumors. Furthermore, we find that the most significant translationally upregulated Myc target genes in the Mycn tumors are transcripts that encode ribosome biogenesis factors. We will further study the role of Myc and Mycn on translational regulation of the medulloblastoma transcriptome using our xenograft model of human iPSC-derived neuroepithelial stem cells overexpressing Myc or Mycn. Our goal is to understand the regulatory function of the translational landscape in Myc- and Mycn-driven medulloblastoma and to decipher the oncogenic signaling cascades leading to different medulloblastoma subtypes.