tbuckley/cabot-search huggingface dataset:
Expansion cohort validation of a clinical predictive model for head and neck cancer survival in patients treated with immune checkpoint inhibitors.
Authors: Georgios I. Laliotis, Majd Issa, Brett Klamer, Vidhya Karivedu, Priyanka Bhateja, Khaled Dibs, Nikol Mladkova, Xueliang Jeff Pan, Matthew O. Old, Mauricio Gamez, John C. Grecula, Sachin R Jhawar, Darrion L Mitchell, Sujith Baliga, Ricardo Carrau, James William Rocco, Dukagjin Blakaj, Marcelo Raul Bonomi
Journal: Journal of Clinical Oncology (2021)

6030 Background: Immune checkpoint inhibitors (ICI) therapy is approved for patients (pts) with recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). The majority of pts will die within two years of diagnosis. We have shown that pretreatment clinical characteristics may predict overall survival (OS). Here, we expand our analysis to a total of 201 pts. Methods: Between January 15, 2016 and April 9, 2020, 201 pts with R/M HNSCC were treated with ICI as first, second line and beyond. Data on p16 status, hemoglobin (Hb), albumin, lactate dehydrogenase (LDH), neutrophil, platelet and lymphocyte count was recorded initially. OS was defined from the start of ICI to death. Progression Free Survival (PFS) was defined from the start of ICI to disease progression (PD) or death. A nomogram was created using the rms package to generate individualized survival prediction. Results: 201 pts were analyzed, sex: 154 male (77%), 47 female (23%), median age 61 (IQR: 55-68). ICI drug: pembrolizumab 100 (50%), nivolumab 91 (45%), ipilimumab+nivolumab 10 (5%). Line of therapy: First: 98 (49%), second and beyond: 103 (51%). Tumor site: oropharynx 84 (42%), oral cavity 45 (22%), others 72 (36%). p16 status: negative 132 (66%), positive 69 (34%). Laboratory values: Median neutrophil count: 4.58 (IQR: 3.43-6.47), Median lymphocyte count: 0.69 (IQR: 0.47-1.08), Median Platelet count: 229 (IQR: 187-300), hemoglobin (Hb) normal/low 101/100 (50%/50%), albumin: normal/low 156/45 (78%/22%), LDH: normal/high 124/77 (62%/38%). Overall response rate: 36 (18%). Median OS: 12 months (CI: 9.4-14.8), median PFS: 4 months (CI: 3.5-5.7). The variables associated with OS were neutrophil count (high) [HR 1.28 (1.08 – 1.51), p=0.004], lymphocyte count (high) [HR 0.75 (0.60 – 0.95), p=0.015], albumin (low) [HR 2.06 (1.37 – 3.10), p&lt;0.001], hemoglobin (low) [HR 1.64 (1.14 – 2.35), p=0.007], LDH (high) [HR 1.78 (1.23 – 2.56), p=0.002] and p16 status (positive) [HR 0.58 (0.39-0.87), p=0.009]. Using the prognostic index of the chosen model, we stratified patients into three risk groups at the 33 rd and 66 th percentile. Median OS in the good risk group was 24 months (CI: 18.5-NR), average risk group 13.8 months (CI: 11-20), poor risk group 2.3 months (CI: 1.7-4.4). The discrimination of the model after internal validation was c-index of 0.72. Conclusions: A small percentage of R/M HNSCC pts treated with ICI have good long-term survival outcomes. In a larger cohort, we internally validated the utilization of a simple, inexpensive and widely accessible nomogram based on clinical and laboratory variables which can predict OS in this patient population.
Comparative analyses of survival differences in patients with urothelial versus non-urothelial upper tract carcinomas: Results from the National Cancer Database (NCDB).
Authors: Jeanny B. Aragon-Ching, Hongkun Wang
Journal: Journal of Clinical Oncology (2021)

e16582 Background: The true incidence of upper tract cancers in the United States is not well defined, with cancers combined with kidney cancer and ureteral cancers grouped with rare urinary organ cancer. It is estimated to occur at 5% of urothelial carcinomas with a rough estimate of 3750 cases annually. Little data exists for non-urothelial variants of upper tract cancers. Methods: The primary objective of this retrospective review is to evaluate trends and differences between urothelial (UC) versus non-urothelial (nUC) histologies (squamous, sarcomatoid, small cell or neuroendocrine, adenocarcinoma) for upper tract cancers and compare the demographics, disease characteristics, treatment, incidence of stage and survival according to NCDB. Results: Data from diagnosis in year 2004 – 2017 were extracted from the NCDB. A total of 29743 urothelial and 561 non-urothelial cases for upper tract cancers were identified. More men were diagnosed with urothelial carcinoma, UC (62%) and non-urothelial carcinoma, nUC (58%) for non-urothelial carcinoma. The median age was similar for both groups, 73 years (UC) and 72 years (nUC). Majority were Caucasian at 92% (UC) and 91% (nUC) with incidence of 4% in the UC and 6% in the nUC cohorts for African-American patients. Primary surgery with nephroureterectomy occurred more frequently in the UC cohort (85%) compared to the nUC (58%). More patients were diagnosed with stage IV cancer based on the AJCC Clinicopathologic stage grouping in the nUC group (29%) compared to UC at 8.1%, but overall survival was not different for stage IV cancers with median OS of 8.57 mos (CI, 8.05-9.10) for UC vs 7 mos (CI, 5.62 – 9.26) nUC; logrank p = 0.283 although survival was significantly different for earlier stages of Stage 0 &amp; 1 at 80.53 mos UC (CI, 78.13, 83.25) vs 28.98 mos nUC (CI, 20.3, 46.78), p &lt; 0.001; and for stage II &amp; III at median OS of 35.65 mos UC (CI, 33.38, 38.05) vs 15.75 mos nUC (CI, (11.17, 26.87) that is also significantly different though with lesser significance with longer follow-up. Conclusions: Upper tract urothelial cancers compared to non-urothelial cancers have similar poor outcomes upon diagnosis of metastatic disease though outcomes are with urothelial upper tract is better with earlier stage upon diagnosis compared to non-urothelial cancers, highlighting the importance of early diagnosis with perhaps curative intent treatment.
PD-L1-R: A MR based surrogate for PD-L1 expression in Glioblastoma multiforme.
Authors: Francesco Sforazzini, Patrick Salome, Andreas Kudak, Matthias Ulrich, Laila König, Rolf Warta, Nina Bougatf, Juergen Debus, Christel Herold-Mende, Maximilian Knoll, Amir Abdollahi
Journal: Journal of Clinical Oncology (2021)

2041 Background: Efficacy of PD-L1 immune checkpoint inhibitor therapy in Glioblastoma multiforme (GBM) is limited and the prognostic value of PD-L1 in GBM is an active field of research. We therefore sought to identify a MR based surrogate for PD-L1 expression in GBM. Methods: T1 post contrast images (T1ce) acquired immediately before surgery of 121 subjects with primary GBM (RTK I, II and mesenchymal subtype, as determined from Illumina Human Methylation array data) were analyzed. Following standard pre-processing (bias filed correction, brain extraction), 1150 radiomics features were calculated from gross tumor volumes (GTV). The cohort was then divided into training/validation (70%/30%). Cross-validation and model-selection were applied to identify features associated with PD-L1-M expression (estimated from methylation data and highly correlated with PD-L1 RNA-sequencing based measure, as recently reported). Features were used to identify two groups of tumors differing in PD-L1-M expression (PD-L1-R high and low), for which a logistic regression model was trained. Overall survival was assessed between PD-L1-R high/low. Results: PD-L1-R high and low groups showed significant differences in PD-L1-M values (training: p=0.002, validation: p=0.04, full cohort: p&lt;0.001). The same model was used to split tumors into 2 groups, using features from non-T1ce sequences. All of the tested MR modalities showed at least a trend in PD-L1-M values in the two groups (T2w: p=0.037, T1w: p=0.089, FLAIR: p=0.091). Further investigations on the whole cohort (121 subjects) showed that PD-L1-R low group was enriched for RTK II sub-type (48%), while PD-L1-R high for mesenchymal sub-type (48%). Refer to Table 1 for more information. In addition, evaluation of survival data showed a difference in overall survival (likelihood ratio test p value 0.048, OR 0.52, 95% CI [0.27; 0.98]), with the PD-L1-R high group having a better prognosis. Conclusions: We presented a radiomics model PD-L1-R which allowed to identify GBM with low and high PD-L1-M expression from T1 post contrast agent images. Future work should validate these findings in independent cohorts.[Table: see text]
EPCT-08. TRIAL WORKING GROUPS FOR PAEDIATRIC BRAIN TUMOURS
Authors: Ruman Rahman, David Walker, Emma Campbell, Kristian Aquilina
Journal: Neuro-Oncology (2021)

Abstract Introduction Brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children. These include ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial, intra-CSF and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate any of these. The science and technology underlying these developments is not traditionally embedded within the standard paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures and, in some cases, the testing and licensing of implantable devices, add difficulty at the regulatory level. Methods The authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this workshop and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) in 2018 and 2020, the CBTDDC and the recently developed ITCC (Innovative Therapies for Children with Cancer) brain tumour group started working together to set up a new initiative. This aims to develop CNS-delivery-focused trial working groups for paediatric brain tumours. Results We have assembled a prestigious steering group, comprising international researchers and clinicians with expertise in diverse aspects of translational and clinical research in CNS drug delivery. At our first group meeting in March, participants will discuss the most effective ways of translating the emerging drug delivery modalities into clinical trials. Prioritised actions will be taken forward and the group will reconvene to discuss developments and next steps at a workshop in the Autumn. Conclusion We present this abstract to the SNO Paediatric conference to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.
DNA and RNA sequencing analysis revealed alterations of <i>ANK3</i>, <i>PKHD1</i> and olfactory transduction as potential biomarker of three-year survival in gastric cancer.
Authors: Jian Wang, Si Li, Wenjing Xi, Dongsheng Chen, Mingzhe Xiao
Journal: Journal of Clinical Oncology (2021)

4034 Background: Gastric cancer is the third leading cause of cancer related death worldwide. Although targeted and immune therapy have brought new benefit for patients, it still faces challenges of limited effective group and survival. Here we investigate the association of overall survival with DNA and RNA alterations to explore potential biomarkers of prognosis in gastric cancer. Methods: Whole-exome sequencing, RNA sequencing and clinical data of 442 patients with stomach cancer were downloaded from TCGA. Clinical factors and mutational landscape (insertion/ deletion/ single nucleotide variant) were compared between group of OS3+ (overall survival &gt; 3 years) and OS3- (OS &lt; 3 years). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed based on differentially expressed RNAs between the two groups. Results: 415 of 442 patients with stage information were included. The corresponding rates of OS3+ for patients in stage of I/II/III/IV was 15.5% (9/58), 10.8% (9/58), 10.9% (9/58), 13.6% (9/58), respectively. When comparing the 49 patients with OS3+ to others with OS3-, no difference of stage or sex distribution was discovered, except that OS3+ group had lower median age at diagnosis than OS3- group (63 vs. 71 years, P = 0.029). Tumor mutation burden was comparable between groups. Mutational landscape showed that the two groups shared 70% of top 20 mutations. Among the 20 hot genes, mutations of ANK3(P = 0.006), PKHD1(P = 0.008) were more frequent in OS3+ group, Studies in breast and prostate cancer inferred that, ANK3 was involved in activity of androgen receptor signaling and cyclins, increased expression of ANK3 in cancer was probably associated with better survival. PKHD1 was involved in calcium ion binding and actin binding and was identified as a protective factor for colorectal cancer. OS3- group tend to have higher mutation frequency of HMCN1(P = 0.062). Previous reports showed that mutation of HMCN1 was enriched in peritoneal metastasis of gastric cancer, it might contribute to progression in gastric cancer. Enrichment analysis revealed difference between the two groups in olfactory transduction ( P &lt; 0.01, KEGG analysis), neuroactive ligand-receptor interaction ( P &lt; 0.05, KEGG analysis) and detection of chemical stimulus in sensory perception of smell ( P &lt; 0.01, GO analysis). Numbers of discussions have inferred that genes involved in olfactory transduction may also participate in tumor cell proliferation, migration, and invasion. Conclusions: Patients with OS3+ was enriched with mutations of ANK3 and PKHD1 and present significant functional difference in olfactory transduction. These are potential biomarkers of better survival in gastric cancer. Further studies are needed to figure out their roles in tumor activity and provide insight for novel antitumor treatment development.
The mutational landscape of older patients with IDH wild-type glioblastoma (GBM).
Authors: Margaret O Johnson, Joanne Xiu, Michael J. Glantz, Jia Zeng, Clark C Chen, Erin M. Dunbar, Ekokobe Fonkem, Santosh Kesari, Andrew J. Brenner, Herbert B. Newton, Justin Low, Ashley Love Sumrall, Wolfgang Michael Korn, David M. Ashley
Journal: Journal of Clinical Oncology (2021)

e14033 Background: Advanced age is associated with poorer outcomes in GBM and current NCCN guidelines distinguish older GBM patients (≥70 years, oGBM) from their younger counterparts ( &lt; 70 years, yGBM). We aim to characterize age-related comprehensive mutational profiles with the long-term goal of improving treatment strategies, outcomes, and rational clinical trial design. Specifically, we focused on IDH-wildtype (WT) oGBM, investigated if oGBM are more likely to acquire temozolomide-induced hypermutations, and finally, compared the frequency of high-tumor mutational burden (TMB) between oGBM vs. yGBM. Methods: Comprehensive molecular profiles of 1,657 adult IDH-WT GBM tumors tested at Caris Life Sciences (Phoenix, AZ) were queried. Tests included NGS of DNA (NextSeq, 592 Genes and NovaSEQ, WES) and RNA (NovaSeq) sequencing. SBS11 gene signature (i.e temozolomide-induced hypermutational profile) was queried using SigProfiler (Alexandrov 2020, Nature). Significance was determined by X 2 and Fisher-Exact and p adjusted for multiple comparisons ( q) was &lt; 0.05. Results: We identified 1,657 patients (range 21-89 years old, median 61 years) with IDH-wildtype GBM, 22% (360) of whom were ≥ 70 years. There was a slight male predominance (60%) for all ages. The most prevalent alterations in oGBM were TERT promoter mutation (105/131,80%), MGMT promoter methylation (pMe) (175/346, 51%), and PTEN mutation (129/349, 37%). EGFR amplification was seen in 35% (125/356) and EGFRvIII in 23% (81/360); Overall, fusions were seen in 12% (44 of 360) oGBM; events &gt; 1% included MET (3.6%), FGFR3 (3.1%), EGFR (2.6%) and ROS1 (1.4%). 17% (56/349) of oGBM had positive PD-L1 by IHC. High TMB ( &gt; 10mt/Mb) tumors were rare (3.1%) and MSI-high tumors even rarer (0.8%) in oGBM. When compared to yGBM, MGMT pMe was more prevalent (51% vs 38%, risk ratio (RR) 1.35 [1.19-1.52], q &lt; 0.05) and NF1 mutations were less frequent in oGBM (21% v 34%, RR 0.62 [0.50-0.77], q &lt; 0.05). No significant differences were seen in other key markers examined. The prevalence of SBS11 gene signature across all ages (data available for 1,141 patients) was 1.2% and was comparable across the age spectrum; no significant difference seen in the MGMT pMe group when oGBM was compared to yGBM (3.9% vs. 1.8 %, p= 0.3). Conclusions: This study represents the largest comprehensive molecular characterization of older IDH-WT GBM patients. We show that molecular profiles of IDH-WT GBM are remarkably similar across the age spectrum, including immunotherapy-associated markers, gene fusion landscape, EGFR amplification, and TMB. The significantly higher prevalence of MGMT pMe and lower NF-1 mutation rate in the older population bear significant prognostic and therapeutic implications.
Association of genes copy number in extracellular DNA in patients with prostate cancer and sensitivity to radiotherapy.
Authors: Denis S. Kutilin, Mikhail S. Zinkovich, Marina A. Gusareva, Aleksandr V. Faenson, Elena A. Karnauhova, Anna A. Solntseva, Natalya B. Fatkina, Julia N. Krokhmal, Ekaterina O. Vasilieva, Alexey N. Shevchenko, Elena V. Filatova, Irina A. Khomutenko, Lyudmila Ya. Rozenko, Irina A. Udalenkova, M. A. Gappoeva, Aliya K. Donskaya
Journal: Journal of Clinical Oncology (2021)

e15014 Background: Radiotherapy (RT) is one of the main treatments for prostate cancer (PC). The effectiveness of such therapy depends on the initial radioresistance of tumor cells, which is ensured by their certain molecular features, which include the genes copy number variation (CNV). Model experiments on cell cultures (obtained from surgical material) have shown that CNVs have high potential as predictors of RT sensitivity. However, this potential is limited by the high level of invasiveness in obtaining biomaterials. A possible solution to this problem lies in the transition to CNV study in the extracellular DNA (cfDNA) of blood plasma. The aim of the study was to screen predictors of radioresistant PC based on the genes CNV in cfDNA. Methods: The study included 400 patients with diagnosed PC (T2a-3bN0M0, st. II-III), 40 of them after RT had a state of biochemical relapse (RT was performed on a Novalis TX linear accelerator (Varian, USA) (TFDisoeff = 75 Gr), mean time to biochemical relapse 7.5 months). Blood samples were separated into plasma and cell fraction by centrifugation. Isolation of cfDNA from blood plasma was performed using a set of reagents “DNA-Plasma-M” (Russia). Determination of the relative CNV of 13 genes (CDK1, CCND3, CDKN1B, TP53, PTEN, BCL2, XRCC4, BAX, RBBP8, H2AX, BRCA2, RAD50, EP300) was performed using the Real-Time qPCR method. Differences were assessed using the Mann-Whitney test; the Benjamin-Hochberg correction was used to correct multiple comparisons. Results: In the group with biochemical relapse (n = 40), the CNV of genes CDK1, CDKN1B, RBBP8, XRCC4, BRCA2 and RAD50 was statistically significantly (p &lt; 0.05) higher by 2.0 times, 2.3 times, 2.1 times, 1.4 times, 2.4 times and 2.8 times, respectively, relative to the CNV of these genes in the cfDNA of the group without relapse (n = 360). Conclusions: Thus, it was found that the CNV of 6 genes (CDK1, CDKN1B, RBBP8, XRCC4, BRCA2 and RAD50) may be a potential molecular marker of radiosensitivity of prostate tumors. Based on the obtained data, a low invasive method for determining the prostate tumors sensitivity to RT has been developed.
Differential effects of the 2015 American Cancer Society guidelines on screening mammography exams based on socioeconomic status.
Authors: Kathleen M. Capaccione, Sophia Huang, Elizabeth West, Aileen Deng, Mary M. Salvatore, Elise Desperito
Journal: Journal of Clinical Oncology (2021)

10539 Background: Guidelines for screening mammography have changed several times since initiation of regular screening mammography in the 1970’s. Most recently, in 2015, the American Cancer Society (ACS) revised their screening guidelines, recommending that a patient discuss screening mammography with her primary care doctor (PCP) between the ages of 40-44 and should begin yearly screening at age 45; after age 54, ACS recommended screening every other year. Prior to this, from 2003-2015, ACS had recommended screening mammography every year beginning at the age of 40. We hypothesized that these guidelines were adopted to varying degrees in different patient populations and may have disproportionately reduced screening mammography utilization in socioeconomically disadvantaged populations. Methods: Here, we analyzed monthly screening mammography rates over time in two large New York City hospitals, one in a socioeconomically advantaged area and the other in a socioeconomically disadvantaged area. Using our radiology records query system, we searched for monthly screening mammography numbers for women by decade from 2012 to 2018. We performed statistical analysis to evaluate changes in number of exams over time. Student’s t-tests were used to evaluate for significant differences. Results: In both groups of 40-49 year old patients, monthly mammograms increased from 2012-2016. In the socioeconomically advantaged group, this increase continued until 2018 resulting in an overall 400% increase in screening mammograms over time. The change in ACS screening guidelines had no effect on the rate of screening mammography in this group. Conversely, after the revision of the ACS guidelines in 2015, there was a marked decline in screening mammography in the 40-49 year old group in the socioeconomically disadvantaged population. By 2018, there was a statistically significant difference in women screened in all age groups (40-49, p&lt;.0001; 50-59, p&lt;.0001; 60-69, p&lt;.01; 70-79, p&lt;.0001; 80+, p&lt;.0001) between these two patient populations. Conclusions: These data suggest that implementation of the 2015 ACS screening guidelines had a disproportionate effect on patients from socioeconomically disadvantaged areas and that these effects have led to significant disparities in screening mammography trends over time. We postulate that lower levels of health literacy may have contributed to misunderstanding of the screening guidelines. More research is needed to elucidate the underlying etiology of these disparities and ensure that women from all socioeconomic backgrounds receive appropriate screening mammography. Over time, this may result in disproportionate breast cancer morbidity and mortality in populations not receiving appropriate screening.
Variable Expression Levels of the Hematopoietic Stem Cell Surface Antigen ESAM Depict Heterogeneity and Fluctuations in Leukemic Stem Cells
Authors: Yasuhiro Shingai, Takafumi Yokota, Tomoaki Ueda, Yukiko Doi, Tomohiko Ishibashi, Akira Tanimura, Michiko Ichii, Sachiko Ezoe, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
Journal: Blood (2017)
Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma
Authors: Oskar Marin-Bejar, Aljosja Rogiers, Michael Dewaele, Julia Femel, Panagiotis Karras, Joanna Pozniak, Greet Bervoets, Nina Van Raemdonck, Dennis Pedri, Toon Swings, Jonas Demeulemeester, Sara Vander Borght, Stefan Lehnert, Francesca Bosisio, Joost J. van den Oord, Isabelle Vanden Bempt, Diether Lambrechts, Thierry Voet, Oliver Bechter, Helen Rizos, Mitchell P. Levesque, Eleonora Leucci, Amanda W. Lund, Florian Rambow, Jean-Christophe Marine
Journal: Cancer Cell (2021)