tbuckley/cabot-search huggingface dataset:
First-in-human, phase I study of PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in biochemical relapse (BCR) and metastatic castration-resistant prostate cancer (mCRPC).
Authors: Karen A. Autio, Celestia S. Higano, Luke T. Nordquist, Leonard Joseph Appleman, Tian Zhang, Xinhua Zhu, Hani M. Babiker, Nicholas J. Vogelzang, Sandip Prasad, Michael Thomas Schweizer, Stephane Billotte, Joseph Binder, Nora Cavazos, Ruifeng Li, Kam Chan, Helen Cho, Michael Dermyer, Robert Hollingsworth, Kenneth Alan Kern, Daniel P. Petrylak
Journal: Journal of Clinical Oncology (2021)

2612 Background: Therapeutic vaccines targeting PC-associated antigens represent attractive approaches in combination with immune checkpoint inhibitors (ICI). Safety/antitumor activity of PF-06753512 (PrCa VBIR) was evaluated in a phase I, dose-escalation and expansion study in patients (pts) with BCR prior to ADT and in pts with mCRPC either prior to or after failure of novel hormone therapy. PrCa VBIR consists of: 1) priming immunization with a replication-deficient adenoviral vector (AdC68) expressing PSA, prostate-specific membrane antigen and prostate stem cell antigen; 2) boosts with plasmid DNA (pDNA) encoding the same antigens by IM electroporation; 3) ICI given subcutaneously, including anti CTLA-4 antibody tremelimumab (TRM) and anti PD-1 antibody sasanlimab (SSL). Methods: AdC68 ± ICI(s) were given on months (mos) 1 and 5 and pDNA ± ICI(s) on mos 2–4 and 6–8. After 8 mos, maintenance pDNA + ICI(s) were given every 1 or 2 mos. In Part A (6 escalation cohorts), pts with mCRPC received AdC68 (4 or 6x10e11 viral particles) + pDNA 5 mg ± ICIs (TRM alone 80 mg; TRM 40 or 80 mg + SSL 130 or 300 mg). In Part B (3 expansion cohorts), pts with mCRPC received AdC68 6x10e11 + pDNA 5 mg + TRM 80 mg + SSL 300 mg; pts with BCR received similar vector and pDNA + TRM 80 mg ± SSL 130 mg. Primary objectives: Assess overall safety (CTCAE v4.03), determine expansion dose. Secondary objectives: Anti-tumor activity (RECIST v1.1, Prostate Cancer Working Group 3, PSA 50 response) and immune response. (Note: Database remains open, some queries pending). Results: As of Sept 15, 2020, 91 pts were treated in dose-escalation (n=38) and expansion (n=53; BCR=35, mCRPC=18). Immune responses (ELISpot) were positive in some pts. Grade (G) 3 or 4 treatment-related adverse events (TRAEs) developed in 38.5% (35/91) of pts. G5 TRAEs occurred in 2 pts (n=1 G4 myasthenia gravis + G5 pulmonary embolism; n=1 G5 myocarditis). irAEs were more frequent in BCR compared to mCRPC. See the table for efficacy data. Conclusions: Vaccination with PrCa VBIR had a manageable safety profile. TRAEs increased when 2 ICIs were given. Some pts with BCR experienced durable PSA-50 responses without ADT; patients with mCRPC had few objective tumor responses, but had prolonged median rPFS. PrCa VBIR appears to stimulate antigen-specific immunity and results in noticeable antitumor activity, particularly in androgen sensitive disease. Clinical trial information: NCT02616185. [Table: see text]
a Decrease in Vitamin D Levels Is Associated with Methotrexate-Induced Oral Mucositis in Children with Acute Lymphoblastic Leukemia
Authors: Natanja Oosterom, Niek Dirks, Sandra Heil, Robert de Jonge, Wim Tissing, Rob Pieters, Marry M van den Heuvel-Eibrink, Annemieke Heijboer, Saskia Pluijm
Journal: Blood (2017)
HPV associated cancers in the United States over the last 15 years: Has screening or vaccination made any difference?
Authors: Cheng-I Liao, Michelle Ann P. Caesar, Chloe Chan, Michael Richardson, Daniel Stuart Kapp, Alex Andrea Francoeur, John Chan
Journal: Journal of Clinical Oncology (2021)

107 Background: Human papillomavirus is a causative agent of many human cancers. This study aims to determine the incidence and trends of HPV-related cancers in the United States. Methods: HPV-associated cancers as classified by the CDC were included: oropharyngeal squamous cell carcinoma (SCC), anal &amp; rectal SCC, vulvar SCC, vaginal SCC, cervical carcinoma, and penile SCC. Data were obtained from the United States Cancer Statistics program from 2001-2017. SEER*Stat 8.3.8 and Joinpoint regression program 4.8.0.1 were used to calculate incidence trends of HPV-associated cancers per 100,000. Results: The overall incidence of HPV related cancers for women was 13.68/100,000, more than half of which (52%) were cervical cancer, at 7.12/100,000 in the year 2017. Over the last 16 years, the incidence of cervical cancer has decreased at an annual percent change (APC) of 1.03% (p &lt; 0.001). In contrast, oropharyngeal (APC = 0.77%, p &lt; 0.001), anal &amp; rectal (APC = 2.75%, p &lt; 0.001), and vulvar SCC all increased significantly (APC = 1.27%, p &lt; 0.001). For older women, the incidence of anal &amp; rectal cancer approached that of cervical cancer. In those over 80, the incidence of cervical cancer was 6.95 (-2.90% APC, p &lt; 0.001), compared to 6.36 for anal &amp; rectal cancer (1.23% APC, p &lt; 0.001). Using a projection model, incidence of anal &amp; rectal cancer is expected to surpass that of cervical cancer by year 2025 for every age group over 55. For men, the incidence of all HPV-related cancers was 11.0/100,000 in the year 2017, 81% were associated with oropharyngeal cancer. Over the last 16 years, there was an overall annual increase in HPV related cancers at 2.36% per year (p &lt; 0.001) with the highest increase in oropharyngeal (APC = 2.71%, p &lt; 0.001) and anal &amp; rectal SCC (APC = 1.71%, p &lt; 0.001). Those at greatest risk of oropharyngeal cancer were older men aged 65-69 years with an incidence of 36.5/100,000 and annual percent increase of 4.24% (p &lt; 0.001). The intersectionality of age and race showed that White men age 65-69 years had the highest incidence of oropharyngeal at 41.6/100,000. Conclusions: Overall, there was a decrease in cervical cancer incidence likely due to screening or vaccination. However, over 80% of men with HPV related cancers had oropharyngeal cancer, a nearly fivefold higher incidence compared to women. In contrast, there was a significant increase in non-screenable HPV-related cancers and anal &amp; rectal SCC incidence is projected to surpass that of cervical cancer within 5 years for certain at-risk groups. Further resources and research should be conducted to address the lack of screening or vaccination in these preventable cancers.
Impact of socioeconomic disparities on diagnosis and overall survival in small cell lung cancer: A National Cancer Database analysis.
Authors: Logan Roof, Wei Wei, Katherine Tullio, Nathan A. Pennell, James Stevenson
Journal: Journal of Clinical Oncology (2021)

8515 Background: Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer diagnoses in the United States. The demographics of this disease have evolved over time; in the 1970s 28% of patients with SCLC were female, while in the early 2000s, 50% were female. Remarkable differences in incidence, mortality rates, and trends by race and geographic location have also been noted. There has been a paucity of data regarding changes in epidemiology and patient demographics in SCLC since the early 2000s. Given recent treatment advances, the impact these factors have on patient outcomes for SCLC requires further evaluation. Methods: We identified all patients with SCLC in the NCDB from 2004 to 2016. Differences in demographic, disease, and treatment characteristics were assessed by year of diagnosis using Chi-square test. The effect of age, race, insurance status, income, distance to treatment center, and education level on overall survival (OS) was assessed by log-rank test. Results: There were 137,253 cases of SCLC diagnosed in the NCDB between 2004-2010 and 124,796 cases between 2011-2016. Patients diagnosed after 2010 were significantly older, had more comorbidities, had more stage IV disease, were more frequently treated at academic centers, more commonly had government primary payer insurance, and lived significantly further away from their treatment center. There were significant differences in gender, race/ethnicity groups, education level, and residence area, with more females, more African Americans, more patients without a high school diploma, and more rural patients diagnosed after 2010. OS in general improved between the two time periods, with median OS of 8.41 months (95% CI: 8.34-8.48%) and 5-year OS rate of 6.8% (95% CI: 6.6-6.9%) in patients diagnosed between 2004-2010 and median OS of 8.61 months (95% CI: 8.54-8.67%) and 5-year OS rate of 8.7% (95% CI: 8.5-8.9%) in patients diagnosed after 2010, despite an increase in stage IV disease in the latter group. Some of the differences in demographics were associated with changes in OS. Older patients, male patients, Caucasian patients, patients with stage IV disease, patients with government primary payer insurance, and rural patients all had significantly worse OS. Patients without comorbidities and patients treated at an academic center had significantly better OS. OS was found to significantly increase as both income and education level increase. Conclusions: SCLC continues to be a frequent cancer diagnosis. Despite improvement in overall survival during the time frame studied, there were significant disparities noted in key demographics that negatively affect access to healthcare resources, including rural communities, distance to an academic center, income, insurer, and education level. Collective efforts to impact these disparities will likely lead to improved outcomes for patients with SCLC.
Seroprevalence of Measles-, Mumps-, and Rubella-specific antibodies in the German adult population – cross-sectional analysis of the German Health Interview and Examination Survey for Adults (DEGS1)
Authors: Nicole Friedrich, Christina Poethko-Müller, Ronny Kuhnert, Dorothea Matysiak-Klose, Judith Koch, Ole Wichmann, Sabine Santibanez, Annette Mankertz
Journal: The Lancet Regional Health - Europe (2021)

The WHO European Region targets the elimination of measles, rubella, and the congenital rubella syndrome and welcomes mumps elimination via the joint MMR vaccine. In a push towards this elimination goal, Germany introduced a recommendation on MMR vaccination for adults in 2010 to prevent increasing numbers of measles cases among adults and to strengthen herd immunity.
Association of Child Maltreatment With Risk of Death During Childhood in South Australia
Authors: Leonie Segal, James Doidge, Jason M. Armfield, Emmanuel S. Gnanamanickam, David B. Preen, Derek S. Brown, Ha Nguyen
Journal: JAMA Network Open (2021)

Child maltreatment is a prominent public health concern affecting 20% to 50% of children worldwide. Consequences for mental and physical health have been reported, but population-level estimates of risk of death during childhood that are adjusted for confounders have not been published to date.
Novel Therapeutic Targets for DNMT3A Mutant Myeloid Neoplasms
Authors: Vera Adema, Suresh K. Balasubramanian, Cassandra M. Hirsch, Bartlomiej P. Przychodzen, James G Phillips, Daniel Lindner, Tomas Radivoyevitch, Sudipto Mukherjee, Aziz Nazha, Hetty E. Carraway, Francesc Sole, Mikkael A. Sekeres, Valeria Visconte, Jaroslaw P. Maciejewski
Journal: Blood (2017)
Mechanisms of Therapeutic Antitumor Monoclonal Antibodies
Authors: Li-Chung Tsao, Jeremy Force, Zachary C. Hartman
Journal: Cancer Research (2021)

Abstract Monoclonal antibodies (mAb) are a major component of cancer therapy. In this review, we summarize the different therapeutic mAbs that have been successfully developed against various tumor-expressed antigens and examine our current understanding of their different mechanisms of antitumor action. These mechanisms of action (MOA) largely center on the stimulation of different innate immune effector processes, which appear to be principally responsible for the efficacy of most unconjugated mAb therapies against cancer. This is evident in studies of mAbs targeting antigens for hematologic cancers, with emerging data also demonstrating the critical nature of innate immune-mediated mechanisms in the efficacy of anti-HER2 mAbs against solid HER2+ cancers. Although HER2-targeted mAbs were originally described as inhibitors of HER2-mediated signaling, multiple studies have since demonstrated these mAbs function largely through their engagement with Fc receptors to activate innate immune effector functions as well as complement activity. Next-generation mAbs are capitalizing on these MOAs through improvements to enhance Fc-activity, although regulation of these mechanisms may vary in different tumor microenvironments. In addition, novel antibody-drug conjugates have emerged as an important means to activate different MOAs. Although many unknowns remain, an improved understanding of these immunologic MOAs will be essential for the future of mAb therapy and cancer immunotherapy.
Phase 2 analysis on Covid-19-adopted etoposide (E) and cisplatin (P) regimens for patients (pts) with an advanced germ cell tumor (GCT): The CovGCT study.
Authors: Nabeel Naban, Gesa Tiemeier, Arwa Kocache, Rory Taylor, Georgina Keogh, Lindsay Hennah, Naveed Sarwar, Michael Seckl, Michael Gonzalez
Journal: Journal of Clinical Oncology (2021)

e17013 Background: The Covid19 pandemic has imposed risks to healthcare delivery for all cancer pts including young adults diagnosed with a GCT. Here, we examine Emergency EP (EmEP, Cohort A) and a novel 1-day Escalated-dose EP (EscEP, Cohort B) administered every 2 weeks as upfront or first-relapse therapy to minimise hospital days. Methods: Single-centre analysis in GCT pts receiving emergency and routine chemotherapy following our first National lockdown on 23 rd March 2020. In Cohort A, eligible pts receive EmEP E100mg/m 2 , P20mg/m 2 prior to EscEP within the acute setting as previously defined. In Cohort B, EscEP E500mg/m 2 , P60mg/m 2 is compared to standard care chemotherapy BEP or POMB-ACE. Data collection includes demographics, treatment details, clinical outcome and Covid19 complications. Results: To date, we have accrued 19 pts with a median age 32 (range 18 to 65). In Cohort A, 7 pts with symptomatic high-volume disease received a median 1 cycle EmEP, 6/7 for a new GCT diagnosis and 1/7 for a first relapse, including 2 males with IGCCCG intermediate-prognosis disease, 5 females with FIGO Stage III (n = 2) and IV (n = 3) disease. One pt required higher-level support for organ dysfunction at presentation. In Cohort B, 19 pts including 7 pts from Cohort A received a median 4 cycles EscEP: 8 males (2 seminomas, 6 non-seminomas; IGCCCG good-prognosis in 4, intermediate-prognosis in 2, poor-prognosis in 2), 11 females (1 dysgerminoma, 10 non-dysgerminomas; FIGO Stage Ic in 6, III in 2, IV in 3). A majority (14/19, 74%) received EscEP for a new cancer diagnosis, 5/19 (26%) for a first relapse. Total median hospital stay: EscEP 5 days, BEP 21 days, POMB-ACE 28 days. Grade 3/4 neutropenic events: EscEP 28%, BEP 50%, POMB-ACE 43%. From April 2020, 16/16 pts were SARS-CoV-2 screened prior to each cycle: 3/19 (16%) testing positive, one prior to intubation and ventilation, 2 with asymptomatic infection. For Cohort B, at median follow-up 121 days (range 9-323 days), we have observed a complete response in 10 pts (53%), partial response in 3 pts (16%) and disease progression in 1 pt (5%). Five pts are still on treatment (26%). All pts remain alive. Conclusions: EmEP and EscEP represent safe options during the pandemic that minimise myelosuppression and total length in hospital days whilst bypassing the potential pulmonary toxicity from Bleomycin. Further follow-up will inform on long-term efficacy including a multicentre evaluation.
BIOL-09. HNRNPA1 SPLICED VARIANT: KEY RESISTANT GENE SIGNATURE IN GLIOMAS
Authors: Ajay Yadav
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is inevitably a recurrent cancer. Despite of recent advancement, temozolomide remain the prescribed lifeline drug, after the surgery. Inadvertently, MGMT (O6-methylguanine-DNA-methyltransferase) expression mechanistically linked with Temozolomide (alkylating drug) glioma resistant development. To understand the resistant against Temozolomide sought to deciphered, by making invitro drug resistant glioma cell lines. RNA seq analysis over a illumina platform; drug resistant glioma cell lines showed various critical key factor such as splice factor hnRNPA1 and deubiquitinating enzymes were showed to highly upregulated in resistant cell lines. Commonly, from our previous study, the stability of hnRNPA1 in presence of USP5 were showed to promote cell survival, whereas knocking down of USP5 significantly lower down the telomerase activity and NAD/NADH ratio enlarge. Furthermore, expression of MGMT was showed significantly downregulated in hnRNPA1 knock down T98G glioma cells, as well as in U87 Temozolomide resistant cells. Extrinsic apoptosis pathway was showed more prevalent in hnRNPA1 knock down glioma cells in presence of Trail ligand. Interestingly, we found one more spliced variants of hnRNPA1 exclusively expressing in drug resistant cells is new finding. Selectively knocking down of hnRNPA1 splice variant promotes apoptosis. RNA seq analysis followed the comparison between two hnRNPA1 spliced variant knock down, drug resistant glioma cell lines showed differentially expressed transcript support our finding to be distinctly regulated by hnRNPA1 spliced variants. Spliced variant of hnRNPA1 showed a potential therapeutic candidate signature.
Abstract 1359: The Heme Oxygenase Inducer Hemin Protects Against Cardiac Dysfunction And Ventricular Fibrillation In Ischemic/reperfused Rat Hearts: Role Of Connexin 43
Authors: Paivi Lakkisto, Csaba Csonka, Gabriella Fodor, Peter Bencsik, Liisa-Maria Voipio-Pulkki, Peter Ferdinandy, Kari Pulkki
Journal: Circulation (2007)

Cardiac expression of the cytoprotective gene heme oxygenase-1 (HO-1) is modulated by ischemia and reperfusion (I/R). Therefore, we hypothesized that pretreatment with hemin, an inductor of HO-1, w...
RARE-22. THERAPEUTIC TARGETING OF PURINE METABOLISM IN DIPG
Authors: Ian Mersich, Biplab Dasgupta
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma is a universally lethal disease primarily impacting pediatric patients. There are currently no targeted therapies increasing overall for patients with these tumors; therefore, our lab set out to elucidate metabolic dependencies in DIPG patient-derived cell lines with the ultimate goal of identifying novel therapeutic targets. Through untargeted metabolomics and gene expression analyses, we have identified the purine metabolism gene ATIC to be important for DIPG tumor cell survival and proliferation. Anti-folate drugs such as methotrexate target de novo purine biosynthesis and are used to treat other pediatric cancers; however, we have identified a small molecule inhibitor of ATIC that may offer clinical benefits over other inhibitors of this pathway. In vitro cell viability experiments have demonstrated DIPG cell lines are much more sensitive to the ATIC inhibitor relative to normal neural stem cells and glial cell lines. Furthermore, we have started in vivo studies on pre-clinical mouse models of DIPG with promising results. Treatment with the ATIC inhibitor has significantly increased overall survival relative to control and vehicle treated mice. The dosage we started at was well tolerated in these mice so we are following up on this in vivo work through dose-escalation studies as well as combination treatment strategies. Mechanistically, the ATIC inhibitor works differently than anti-folate compounds such as methotrexate; therefore we are also elucidating why cancer cells are much more sensitive to this compound.
Integrated DNA and RNA sequencing to reveal early drivers of metastasis in gastric cancer.
Authors: Jieyun Zhang, Fatao Liu, Ya'nan Yang, Xiaoling Weng, Yue Yang, Zhe Gong, Shenglin Huang, Lu Gan, Xiaowei Zhang, Yiwei Gong, Yun Liu, Weijian Guo
Journal: Journal of Clinical Oncology (2021)

e16096 Background: Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy to identify early drivers in primary gastric tumors. In this study, we conducted an integrative genomic analysis on GC patients and identified early drivers that lead to metastases. Methods: Tumors and matched normal tissues from 400 Chinese GC patients were characterized by whole-exome sequencing (WES), transcriptome sequencing and targeted exome sequencing (TES), especially the comparative analysis results between higher metastatic potential (HMP) group with T1 stage and lymph-node metastases, and lower metastatic potential (LMP) group without lymph-nodes or distant metastases. Functional experiments on candidate driver mutations were applied in GC cell lines to explore their roles in metastasis and immune escape. Results: HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, lower tumor purity, more stromal and immune cell infiltration than LMP group. We identified 262 differentially expressed mRNA, lncRNA and miRNA between HMP and LMP group (with more than twice proportion of 2-fold increased or decreased tumor than normal tissue in HMP than LMP group, and with significantly 2-fold higher or lower in HMP tumors than LMP tumors). 168 candidate prometastatic mutations were found by WES and 8 were selected for following TES to detect their association with distant metastasis. We found that four candidate mutations were related to distant metastasis and mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. It’s worth noting that though with low mutational rate, MADCAM1 mutations were only observed in patients with metastasis within three years after surgery or at diagnosis. We demonstrated that MADCAM1-mutated proteins act as GOF mutants and could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing complicated immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages (TAMs). Conclusions: Our results showed that the GCs with different metastatic potential are distinguishable at the genetic level. A number of potential metastatic driver mutations was revealed in this study including known cancer-associated genes TP53. We also discovered some novel driver mutations, such as MADCAM1. The results indicate driver mutations in early-onset metastatic GC could promote metastasis not only by directly empower cancer cells to disseminate but also by establishing an immunosuppressive microenvironment. This study increased the understanding of molecular landscape of GC patients and provided possibility for future target therapy.