tbuckley/cabot-search huggingface dataset:
Comparison of diagnostic characteristics between sentinel lymph node biopsy (SLNB) and radio-guide elective neck dissection (RGEND) in patients with T1-2N0 oral tongue cancer.
Authors: Maxim Kotov, Zamira Radzhabova, Sergey Novikov
Journal: Journal of Clinical Oncology (2021)

e18037 Background: Elective neck dissection remains the standard treatment for cN0 oral cancer due to the high incidence of occult lymph node (LN) metastases. Sentinel lymph node biopsy (SNB) might be a less morbid alternative to neck dissection. Diagnostic value of SLNB depends on the number of sampled LNs. We aimed to compare the diagnostic features of SNB and RGEND in patients with T1-2N0 oral tongue cancer. Methods: A prospective study was conducted in patients with cT1-2N0M0 oral tongue squamous cell carcinoma treated between January 2016 and December 2020. The procedure included SLNB ollowed by immediate extent ipsilateral neck dissection. SLNB included accumulated radiotracer LNs, which located close to the primary tumor. RGEND included LNs accumulated radiotracer with all LNs located at the same level. Pathology assessment was performed and diagnostic characteristics were compared between SLNB and RGEND. Results: A total of 38 patients were enrolled. The mean age was 55.7±13,1. Twenty-four patients had unilateral lymph flow and 14 had bilateral. Sentinel LNs were located at levels IIa-III. Occult metastases were found in 15,8% (n = 6) of patients. The median number of LNs in the sample was 3 (IQR: 1-5). The sensitivities of SLNB and RGEND were 50% (95%CI: 15.7 - 84.3) and 100% (95%CI: 54.7-100), respectively, p-value = 0.001. Specificity was similar among groups: 100% (95%CI: 88-100) and 100% (95%CI: 89.1-100. SLNB had accuracy of 89.5% (95%CI: 77.2 - 97), and RGEND 100% (95% CI: 90.7-100), p-value = 0.001. Positive predictive value (PPV) was similar among groups. Negative predictive value (NPV) was 88.2% (95% CI: 78.9 - 93.7) in SLNB and 100% (95%CI: 91-100) in RGEND groups. p-value = 0.001. Conclusions: SLNB and RGEND have high rates of specificity, accuracy, PPV, and NPV, regardless of sampling size. RGEND has the highest sensitivity in patients with cT1-2N0 oral tongue cancer.
Human <i>STAT3</i> variants underlie autosomal dominant hyper-IgE syndrome by negative dominance
Authors: Takaki Asano, Joëlle Khourieh, Peng Zhang, Franck Rapaport, András N. Spaan, Juan Li, Wei-Te Lei, Simon J. Pelham, David Hum, Maya Chrabieh, Ji Eun Han, Antoine Guérin, Joseph Mackie, Sudhir Gupta, Biman Saikia, Jamila E.I. Baghdadi, Ilham Fadil, Aziz Bousfiha, Tanwir Habib, Nico Marr, Luckshman Ganeshanandan, Jane Peake, Luke Droney, Andrew Williams, Fatih Celmeli, Nevin Hatipoglu, Tayfun Ozcelik, Capucine Picard, Laurent Abel, Stuart G. Tangye, Stéphanie Boisson-Dupuis, Qian Zhang, Anne Puel, Vivien Béziat, Jean-Laurent Casanova, Bertrand Boisson
Journal: The Journal of Experimental Medicine (2021)

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.
LGG-02. PEDIATRIC LOW-GRADE GLIOMA RISK STRATIFICATION IN THE MOLECULAR ERA
Authors: Jessica Hata, Mustafa Barbour, Michael Angelo Huang
Journal: Neuro-Oncology (2021)

Abstract Background Pediatric low-grade gliomas (LGG), in particular those not amenable to surgical resection, are a therapeutic challenge owing to their heterogeneity in clinical behavior. Identification of the RAS/MAPK pathway as a universal feature of these tumors has led to an improved understanding and the development of targeted therapeutics. We examined the impact of known biological and novel molecular risk factors on patient outcomes at our institution. Methods We retrospectively reviewed risk factors and clinical outcomes in 38 LGG cases diagnosed by histopathology at Norton Children’s Hospital in Louisville, KY, USA from March 2015 to Jan 2019. Progression free survival (PFS) rates were generated using the Kaplan-Meier method. Log-rank tests and hazard ratios were used to identify prognostic factors by univariable analysis. Results Among previously described biological risk factors, subtotal resection/biopsy only (HR 3.67, p=0.0257), non-WHO Grade I histology (HR 3.34, p=0.0101), and infant age (&amp;lt; 3 years) (HR 4.19, p=0.0031) were associated with shorter PFS. Brainstem location had no significant impact on PFS. (HR 0.86, p=0.8071). H3K27M mutant status was predictably associated with worse PFS (HR 5.86, p=0.0012). BRAF v600e mutant status, however, was not associated with inferior outcomes. On the contrary, in our study population, BRAF v600e mutant status had a suggested protective effect (HR 0.14, p=0.0247). Patients with 2 or more oncogenic driver mutations demonstrated worsened PFS (HR 4.78, p=0.0059). We utilized the following scoring system for risk stratification: 1 point was allocated for each of the above biological and molecular risk factors except for H3K27M, which was allocated 3 points. A score of &amp;lt; 3 was designated low risk. Non-low risk classification was associated with significantly inferior PFS (median PFS 13 vs. 62 mos, HR 4.26, p=0.0012). Conclusion We herein demonstrate the utility of a combined biological and molecular risk classification for pediatric LGG.
Identification of genetic markers associated with ibrutinib-related cardiovascular toxicity.
Authors: Issam Hamadeh, Ryan Jacobs, Bei Hu, Tamara Kay Moyo, Amy Soni, Steven I. Park, Jai Narendra Patel, Nury Steuerwald, Nilanjan Ghosh
Journal: Journal of Clinical Oncology (2021)

7526 Background: Cardiovascular side effects (CVSEs: atrial fibrillation, hypertension, etc.) are common in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib and often lead to dose reductions or discontinuation. However, the etiology of ibrutinib related CVSEs has not been elucidated. This study sought to interrogate the association between ibrutinib related CVSEs and polymorphisms in genes of the Bruton Tyrosine Kinase (BTK) signaling pathway (identified through Ingenuity Pathway Analysis) Methods: Newly diagnosed and relapsed patients with CLL who underwent treatment with ibrutinib between December 2019 and November 2020 at Levine Cancer Institute were identified. Buccal swabs were collected through an IRB approved specimen collection protocol. Data extraction included: demographics, CLL stage, cytogenetics, previous treatments, ibrutinib start dates and dose, drug related SEs, and other medications. DNA isolated from buccal swabs was genotyped for 40 single nucleotide polymorphisms (SNPs) in GATA4, SGK1, KCNQ1, KCNA4, NPPA and SCN5A genes using a custom NGS panel. Logistic regression analysis evaluated the association between SNPs and CVSEs. Results: In 50 evaluable patients, the median age was 71 years (range:48-90) and 50% received frontline ibrutinib monotherapy. CVSEs occurred in 20% of patients (n=10). In univariate analysis, 4 SNPs in 3 genes were significantly associated with CVSEs (Table). Because the genes were in the same pathway, a genetic risk score was developed which indicated that patients with at least 2 SNPs had a 12-fold increase in risk of CVSEs (Table). Conclusions: Our findings provide insights into the genetic determinants of ibrutinib related CVSEs. If replicated in a larger study, this will facilitate utility of pharmacogenetic testing (for GATA4, KCNQ1 and KCNA5 polymorphisms ) as a clinical tool to individualize ibrutinib treatment.[Table: see text]
Combination therapy with anti-PD-1 or PD-1 antibody alone in pediatric patients with relapsed or refractory cancer.
Authors: Yi Que, Juan Wang, Jia Zhu, Na Li, Junting Huang, Suying Lu, Feifei Sun, Lian Zhang, Zijun Zhen, Li Zhang, Ruiqing Cai, Haixia Guo, Xiaofei Sun, Yizhuo Zhang
Journal: Journal of Clinical Oncology (2021)

e22004 Background: There is limited experience of PD-1 combined with other therapies in children. We aimed to explore the antitumor activity and safety of PD-1 antibody monotherapy or combination with other regimens in relapsed or refractory pediatric cancer. Methods: This was an observational retrospective study performed at two academic medical centers (Sun Yat-sen University Cancer Center and Nanfang Hospital, Southern Medical University) The primary objective of this study was to describe the overall response rate (ORR) and disease control rate (DCR). Secondary objectives included characterizing toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 as well as describing progression free survival (PFS) and overall survival (OS). Results: Of the 22 pediatric cancer patients who received PD-1 inhibitors, the median follow-up for all patients after the commencement of PD-1 therapy with or without other regimens was 12.3 months (0-43 months). The objective response rate (ORR) and disease control rate (DCR) of the 6 patients with HL were 83.3% (3CR and 2PR) and 100%, respectively. No objective response was observed in patients with melanoma or Burkitt lymphoma evaluated in this study. For patients treated with PD-1 inhibitor combination therapy, PD-1 antibody combined with decitabine showed potential efficacy in advanced pediatric cancer patients. One of the Three of patients who received PD-1 combined with decitabine achieved CR and another two other patients achieved PR. At the data cutoff, 10 of the 13 (76.9%) patients achieved disease control as the best objective response. The median PFS and OS were 90 days (95%CI: 10.733-169.267) and 158 days (95%CI: 131.514-184.486) respectively. There were no severe treatment-related adverse events (TRAEs) directly attributed to PD-1 monotherapy. The severe TRAEs are due to chemotherapy in the combination regimen. Conclusions: PD-1 monotherapy demonstrated antitumor activity in a population of pediatric patients with HL. The regimen of PD-1 inhibitor combined with decitabine showed potential in treating with pediatric cancer patients.
Comments and Concerns on the LASER Trial
Authors: Arianna Birindelli, Salomone Di Saverio, Lucio Taglietti
Journal: JAMA Surgery (2021)

To the Editor We read with great interest the article by Santos et al1 on the opportunity of treating recurrent, complicated, or symptomatic diverticulitis by conservative management or elective sigmoidectomy and related quality of life (QoL).
EPEN-12. MULTIPLE RECURRENCES OF ANAPLASTIC EPENDYMOMA WITH EXTRA AXIAL AND EXTRA NEURAL METASTASIS IN A PEDIATRIC PATIENT
Authors: Clay Hoerig, Aaron Goldberg, Jordan Xu, Jody Pathare, Venita Williams, William Loudon, Ashley Plant-Fox, Michael Muhonen, Chenue Abongwa
Journal: Neuro-Oncology (2021)

Abstract Background Ependymomas are the third most common CNS tumor in the pediatric population, accounting for 10% of all CNS tumors. Co-occurring extraneural and extracranial metastasis of ependymomas are extremely rare, with only 1 reported adult case in current literature. Case Description We describe the case of a patient with multiple reoccurrences of anaplastic ependymoma. Initial imaging showed a 5 x 8 x 8 cm complex cystic mass with nodular enhancing components within the left occipital lobe. The 4th ventricle was intact and imaging was negative for metastasis. Pathology following resection demonstrated perivascular pseudorosettes, areas of calcification, and increased mitotic activity. Biopsy revealed GFAP, EMA, neurofilament, INI-1, and was negative for CAM5.2, confirming anaplastic ependymoma. Methylation studies for PFA or PFB subgroup differentiation were not available. The patient had recurrences at 4-, 5-, and 6-years after his initial diagnosis. Seven years from his initial diagnosis, the patient underwent resection of four nodular lesions from the occipital lobe and surrounding soft tissue. Pathology of these lesions and the lymph nodes/soft tissue confirmed anaplastic ependymoma. A PET scan showed increase uptake in the supraclavicular lymph nodes and had multiple bilateral pulmonary nodules. Scans at 3 months post-surgery were negative for leptomeningeal metastases but showed further lymph node involvement with progression of pulmonary disease. Conclusion Co-occurring extraneural and extracranial metastasis of ependymoma is a rare occurrence across all populations. To our knowledge, this would be the first published pediatric case of anaplastic ependymoma with lymph node, soft tissue, and pulmonary involvement. Treatment of ependymoma itypically local and the utility of chemotherapy remains unclear. Treatment options for extraneural mets is very limited, illustrating the need for new therapies and further studies directed at understanding the biology of these tumors and the factors that could influence their ability to metastasize to extraneural and extracranial sites.
Analysis of the relationship between different prognosis factors in patients with advanced colon cancer and progression-free survival.
Authors: Eduardo Richardet, Ignacio Magi, Luciana Paola Acosta, Maria gimena Ferreira, Matias Molina, Martin Eduardo Richardet
Journal: Journal of Clinical Oncology (2021)

e15518 Background: Colon tumors are a heterogeneous group of disease. As a result of the accumulation of different genetic and epigenetic alterations, the mutation of the RAS, BRAF oncogene and microsatellite instability stands out. A new line of research are immunological and inflammatory factors, the infiltrating lymphocytes of the tumor stroma (TILs) and the neutrophil to lymphocyte radio (NLR) have been studied by our work team. We understood could that these factors were associated with the survival rate in our patients. The main objective of this reseach is to determine the relationship between NLR and progression-free survival (PFS) in patients with advanced colon cancer. Secondary objective is to determine the relationship between the location of the primary tumor, RAS status, TILs, and PFS. in the same group of patients. Methods: A total of 93 medical records of patients with advanced colon cancer was analyzed. Those pts who had recieved first-line chemotherapy treatment with a FOLFOX scheme plus a monoclonal antibody were included. All patients had to have a minimum follow-up of 12 months. Regarding NLR, the patients were classified into two groups: high ( = &gt; 4) and low ( &lt; 4). Four TILs cut-off points were determined: &gt; 40% intense; between 11-40% moderate, 1-10% mild, and 0% absent, which were group into two categories: intense and moderate; slight and absent. Localization was divided into left and right, and KRAS status was divided into mutated and wild-type (WT). PFS was calculated using the Kaplan-Meier test. Results: The median PFS of the general population was 8.74 (7.39-11.07) months. The median PFS was 9.86 (7.82-13.41) vs 5.09 (4.43-10.84) months for low and high NLR respectively, with statistical significance (p: 0.01). When the percentage of patients without progression after one year of treatment was analyzed, the difference was 45% vs 14% in favor of NLR &lt; 4 on ≥4, this difference was also statistically significant (p: 0.02). PFS in relation to TILs after one year of follow up was 33% (8.61 months) for moderate-intense infiltrate vs 30% of mild-absent (7.10 months). PFS was 9.79 months for KRAS WT pts vs 7.82 months for mutated KRAS. In terms of location, PFS was 9.79 months for the left colon vs 8.28 months for the right colon. These factors did not have a statistically significant difference. Conclusions: The results of the study show how NLR &lt; 4 is a prognostic factor with a positive impact on PFS. It should be noted that the median survival rates were numerically higher in moderate-intense vs mild-absent TILs, also in KRAS WT vs mutated and in left vs right location. It should also be noted that the possibly there was not a statistically significant difference between them due to the limited number of patients per what we will continue working on in the recruitment and analysis of these patients.
LGG-15. COMPREHENSIVE ANALYSIS OF MYB/MYB1-ALTERED GLIOMAS: A MULTI-INSTITUTIONAL EXPERIENCE OF 33 GLIOMAS
Authors: Daniel Moreira, Susan Spiller, Thomas Bouldin, Alan Davidson, Nasjla Saba-Silva, Daniel Sullivan, Ryuma Tanaka, Aaron Wagner, Matthew Wood, Amar Gajjar, Jason Chiang
Journal: Neuro-Oncology (2021)

Abstract Background Pediatric diffuse gliomas harbor recurrent genetic alterations, including those in MYB and MYBL1. Regardless of histopathologic classification, low-grade diffuse gliomas with MYB/MYBL1 alterations represent a single disease entity. Additional insight is needed to define optimal therapeutic strategies for these tumors. Methods We retrospectively reviewed gliomas with MYB or MYB1L alterations treated or referred for pathologic review at St. Jude Children’s Research Hospital (St. Jude). Tumor specimens were centrally reviewed. Molecular characterization and clinical data were collated from St. Jude and referring institutions. Results Thirty-three patients were identified. Two tumors had MYBL1 alterations, while 31 had MYB alterations. MYB-QKI fusion was the most common alteration. Eighteen (55%) were male. The median age at diagnosis was 5 years (range, 0–40 years). Most tumors were in the cerebral cortex (22/33), and the most common presentation was seizures (16/33). Three patients (9%) presented with hydrocephalus and required cerebrospinal fluid diversion. Two patients (6%) presented with metastatic disease. Gross-total resection was achieved in 15 patients (45%). Of the 7 patients receiving cytotoxic chemotherapy, no substantial response was observed. Of the 6 patients who received RT, one had disease progression. The median follow-up was 5.9 years. The 5-year event-free survival was 88.1%, while the 5-year overall survival was 96.3%. Two patients died, one of unclear cause and one of treatment-related acute myelogenous leukemia. Using log-rank tests, no difference in outcomes was observed based on molecular characteristics, degree of resection, metastatic status, or treatment modality. Conclusions Although tumors with MYB and MYBL1 alterations present with varying molecular and clinical features, they represent a group of tumors with favorable outcomes. Further characterization is required to identify the subgroup of tumors with a higher propensity for progression.
EPCT-07. ID1 IS A KEY TRANSCRIPTIONAL REGULATOR OF DIPG INVASION AND IS TARGETABLE WITH CANNABIDIOL
Authors: Viveka Nand Yadav, Micah K Harris, Chase Thomas, Stefanie Stallard, Rinette Woo, Robert Siddaway, Tingting Qin, Jessica R Cummings, Brendan Mullan, Ruby Siada, Ramya Ravindran, Michael Niculcea, Xuhong Cao, Maria G Castro, Pedro R Lowenstein, Rajen Mody, Arul Chinnaiyan, Cynthia Hawkins, Pierre Desprez, Sean McAllister, Sriram Venneti, Carl Koschmann
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with no effective therapies beyond radiation. The highly invasive nature of DIPG is key to its aggressive phenotype, but the factors and mechanisms contributing to this aggressive invasion are unknown. Inhibitor of DNA binding (ID) proteins, key regulators of lineage commitment during embryogenesis, are implicated in tumorigenesis in multiple human solid tumors. Prior work showed that recurrent H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes. However, the impact and targetability of ID1 have not been explored in human DIPG. Exome and transcriptome sequencing analyses of multi-focal DIPG tumors and normal brain tissue from autopsy (n=52) revealed that ID1 expression is significantly elevated in DIPG samples. Higher ID1 expression correlates with reduced survival in DIPG patients and increased regional invasion in multi-focal autopsy samples. Analyses of developing mouse brain RNA/ChIP-Seq data revealed high ID1 expression and H3K27ac promoter binding in prenatal hindbrain compared to all other prenatal and postnatal brain regions. ChIP-qPCR for H3K27ac and H3K27me3 revealed that ID1 gene regulatory regions are epigenetically poised for upregulation in DIPG tissues compared to normal brain, regardless of H3/ACVR1 mutational status. These data support that the developing pons is regionally poised for ID1 activation. Genetic (shRNA) ID1 knockdown of primary human H3.3K27M-DIPG cells (DIPG007) resulted in significantly reduced invasion/migration and significantly improved survival of K27M-DIPG mice. Knockdown of ID1 in DIPG cells also resulted in down-regulation of the WNK1-NKCC1 pathway, which regulates tumor cell electrolyte homeostasis and migration. Finally, treatment of DIPG007 cells with cannabidiol (CBD) reduced ID1 levels, viability of DIPG cells and significantly improved survival of K27M-DIPG mice. In summary, our findings indicate that multifactorial (genetic and regional) epigenetic upregulation of ID1 drives DIPG invasiveness; and that targeting ID1 with CBD could potentially be an effective therapy for DIPG.
Highly Sensitive Viral RNA-Seq Is a Powerful Tool to Analyze the Viral Transcripts in HTLV-1-Infected Individuals
Authors: Yuki Inada, Hiroo Katsuya, Paola Miyazato, Benjy Jek Yang Tan, Saori Iwase, Misaki Kakoki, Misaki Matsuo, Saiful Islam, Masahito Tokunaga, Hiroyuki Hata, Yoshihisa Yamano, Atae Utsunomiya, Yorifumi Satou
Journal: Blood (2017)
Exportin-1 Connects Dynamic Transcription and Translation of Genotoxic Stress Genes in Diffuse Large B-Cell Lymphoma Patients
Authors: Rossella Marullo, Maria Revuelta, Nahuel Zamponi, Biljana Culjkovic, Shao Ning Yang, Haelee Ahn, Giorgio Inghirami, Katherine L. B. Borden, Leandro Cerchietti
Journal: Blood (2017)