tbuckley/cabot-search huggingface dataset:
Nitrofurantoin 100 mg versus 50 mg prophylaxis for urinary tract infections, a cohort study
Authors: Thijs ten Doesschate, Kelly Hendriks, Cornelis Henri van Werkhoven, Evelien C. van der Hout, Tamara N. Platteel, Irene A.M. Groenewegen, Anouk E. Muller, Andy I.M. Hoepelman, Marc J.M. Bonten, Suzanne E. Geerlings
Journal: Clinical Microbiology and Infection (2021)

Guidelines do not distinguish between 50 mg or 100 mg nitrofurantoin as daily prophylaxis for recurrent urinary tract infection (UTI), although 50 mg might have a better safety profile. Our objective was to compare the effectiveness and safety of both regimens.Data were retrospectively collected from 84 Dutch GP practices between 2013 and 2020. Nitrofurantoin prescriptions of 100 mg and 50 mg every 24 hours in women were included. Cox proportional hazard regression analysis was used to calculate hazard ratios on first episode of UTI, pyelonephritis and (adverse) events. Patients were followed for the duration of consecutive repeated prescriptions, assuming non-informative right censoring, up to 1 year.Nitrofurantoin prophylaxis was prescribed in 1893 patients. Median lengths of follow up were 90 days (interquartile range (IQR) 37-179 days) for 100 mg (n = 551) and 90 days (IQR 30-146 days) for 50 mg (n = 1342) with few differences in baseline characteristics between populations. Under 100 mg and 50 mg, 82/551 (14.9%) and 199/1342 (14.8%) developed UTI and 46/551 (8.3%) and 81/1342 (6.0%) developed pyelonephritis, respectively. Adjusted HRs of 100 mg versus 50 mg were 1.01 (95% CI 0.78-1.30) on first UTI, 1.37 (95% CI 0.95-1.98) on first pyelonephritis episode, 1.82 (95% CI 1.20-2.74) on first consultation for cough, 2.68 for dyspnoea (95% CI 1.11-6.45) and 2.43 for nausea (95% CI 1.03-5.74).Daily prophylaxis for recurrent UTI with 100 mg instead of 50 mg nitrofurantoin was associated with an equivalent hazard on UTI or pyelonephritis, and a higher hazard on cough, dyspnoea and nausea. We recommend 50 mg nitrofurantoin as daily prophylaxis.
LGG-01. <i>NF1</i> MUTATION DRIVES NEURONAL ACTIVITY-DEPENDENT OPTIC GLIOMA INITIATION
Authors: Yuan Pan, Jared Hysinger, Nicki Schindler, Olivia Cobb, Xiaofan Guo, Belgin Yalçın, Corina Anastasaki, Sara Mulinyawe, Anitha Ponnuswami, Suzanne Scheaffer, Yu Ma, Kun-Che Chang, Xin Xia, Joseph Toonen, James Lennon, Erin Gibson, Linda Liau, Jeffrey Goldberg, Michelle Monje, David Gutmann
Journal: Neuro-Oncology (2021)

Abstract Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic gliomas) during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1 optic glioma to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing optic nerve activity via light deprivation prevents tumor formation and maintenance. By manipulating environmental light to modulate optic pathway (retinal) neuron activity, we show that Nf1 optic glioma initiation depends on neuronal activity during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacologic inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce optic glioma incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.
A phase 3, double-blind, randomized study of pamiparib versus placebo as maintenance therapy in patients with inoperable, locally advanced, or metastatic gastric cancer that responded to platinum-based first-line chemotherapy.
Authors: Fortunato Ciardiello, Yung-Jue Bang, Johanna C. Bendell, Andres Cervantes, Rainer Karl Brachmann, Yuting Zhang, Mitch Raponi, Heinrich Farin, Lin Shen
Journal: Journal of Clinical Oncology (2018)

TPS3114 Background: Gastric cancer is the fifth most common cancer, and is the third leading cause of cancer deaths worldwide. A subset of gastric cancers exhibit platinum sensitivity and genomic instability that is characteristic of homologous recombination deficiency (HRD). Poly(ADP-ribose) polymerase proteins 1 and 2 (PARP1/2) are involved in DNA damage repair, and their inhibition is cytotoxic for cells with HRD. Pamiparib (previously known as BGB-290) is a selective PARP1/2 inhibitor that crosses the blood-brain barrier, has shown potent DNA–PARP trapping, and has demonstrated robust antitumor activity in preclinical models. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed promising antitumor activity. These studies also established 60 mg orally twice daily as the recommended pivotal dose. Methods: This double-blind, placebo-controlled, randomized, multicenter phase 3 study (NCT03427814) conducted in Asia, Australia, Europe, and North America is designed to compare the efficacy, safety, and tolerability of pamiparib with placebo as maintenance therapy in ~540 patients with advanced gastric cancer who have responded to first-line, platinum-based chemotherapy. Patients who are ≤8 weeks after their last platinum dose of first-line chemotherapy will be randomized 1:1 to receive either pamiparib 60 mg twice daily or placebo. Patient randomization will be stratified by genomic loss of heterozygosity status (ie, high versus low), region, and ECOG status. Radiologic assessments will be centrally evaluated per RECIST every 8 weeks after first dose. The primary endpoint is progression-free survival; key secondary endpoints include safety/tolerability, overall survival, objective response rates, and duration of response. Clinical trial information: NCT03427814.
Characterization of smoldering multiple myeloma: A population-based cohort study.
Authors: Raleigh Ayoolu Fatoki, Adnan Ahmed Khan, Diane M. Carpenter, David M. Baer
Journal: Journal of Clinical Oncology (2021)

e20028 Background: There is increasing interest in characterizing Smoldering Multiple Myeloma (SMM) due to the availability of novel therapies shown to delay symptomatic progression to Multiple Myeloma (MM) with considerably less toxicity. The lack of population-based disease registries has made epidemiologic data on SMM difficult to acquire. Existing cohort studies of SMM patients have largely been conducted in specialized referral centers. This surveillance study characterizes the epidemiology of SMM in a real-world, clinical population using data from a large, integrated healthcare delivery system. Methods: We performed a retrospective study of all new SMM cases identified in Kaiser Permanente Northern California (KPNC) during 2010-2017, based on either (or (2) a new MM diagnosis in the KPNC Cancer Registry without initiation of plasma cell-directed therapy within 1 year of diagnosis. Those without KPNC membership for at least 1 year after diagnosis were excluded. Age at diagnosis, sex, race/ethnicity, and Charlson Comorbidity Index (CCI) at diagnosis were examined. The incidence of SMM was calculated using KPNC membership denominators, and a 2-sided Cochran-Armitage test was used to test for trend. Among the SMM cohort, characteristics were examined using the chi-squared test, including data before/after the Nov 2014 International Myeloma Working Group (IMWG) diagnostic criteria update. Results: A total of 251 new SMM cases were identified from 2010-2017. The average annual incidence of SMM was 1.2 per 100,000, increasing from 1.0 per 100,000 in 2010 to 1.5 per 100,000 in 2017 (p&lt;0.05 for trend). The demographic characteristics of the SMM cohort were notable for mean age 70.0 ± 11.7 years, 63.8% male, and 61.0% non-Hispanic White, 17.1% Black, 10.0% Hispanic, and 11.6% Asian. Overall, 73.7% had at least 1 comorbidity, based on CCI. When comparing 116 SMM cases diagnosed after the IMWG update to 135 cases diagnosed before the IMWG update, those diagnosed after the revised IMWG guidelines were significantly more likely to have at least 1 existing comorbidity (80.2% vs 68.2%, p=0.03). Conclusion We identified a contemporary cohort of patients with SMM from a large, integrated healthcare system. During our 8-year study period, the annual incidence of SMM increased slightly, including after 2014 when the IMWG criteria for SMM were refined. We observed that patients diagnosed after the 2014 IMWG update were more likely to have at least 1 comorbidity. Whether these trends relate to background population characteristics or are specific to recognized SMM cases bears further study. Follow-up analyses will examine the rate of progression from SMM to MM and the presence or absence of severe, irreversible, end-organ damage at the time of progression.
Can high Ki67 predict distant recurrence in early-stage breast cancer with low Oncotype Dx score?
Authors: Parvaneh Fallah, Nasser Khleel Mulla, Raquel Aloyz, Olga Aleynikova, Anca Florea, Manuela Pelmus, Lawrence C. Panasci
Journal: Journal of Clinical Oncology (2021)

e12561 Background: Ki-67 is a marker of proliferating cells. The recurrence score based on the 21-gene breast cancer assay also called Oncotype Dx provides prognostic and predictive information for recurrence in early stage breast cancer patients. We previously showed that there is a moderate correlation between Ki67 and oncotype Dx recurrence score. In this retrospective study, we aimed to examine whether high Ki67 could predict the distant recurrence in early stage breast cancer with low oncotype Dx scores ( &lt; 25). Methods: This retrospective study included 278 consecutive cases of hormone receptor-positive, HER2 negative (T1-2 N0 M0) breast cancer who were diagnosed between 2008 and 2015 with low oncotype Dx ( &lt; 25). Patients’ clinical outcome in terms of distant recurrence after breast surgery was determined up to December 2020 (median follow-up of 7 years). Patients were divided in to low risk (Ki67 &lt; 15%) and high risk (Ki67 &gt; = 15%) groups. Results: Of 278 cases with average and median age of 59 and 60 respectively, 148 (53%) were in Ki67 low risk and 130 (47%) were in Ki67 high risk group. Average and median oncotype Dx were 13.86 and 15 respectively in Ki67 low risk versus 15.23 and 16 respectively in Ki67 high risk group. 13 patients (4%) experienced distant metastasis in lung, liver, bone and skin. Of these 13 cases with average and median oncotype Dx 15.84 and 19 respectively, 12 (92%) were in the Ki67 high risk group and only 1 (8%) belonged to the low risk category. High Ki67 patients were overrepresented in group with recurrent distant metastasis compare to group without recurrent disease (Pearson Chi-Square = 51.18 with 1 degree of freedom and P = &lt; 0.001). Conclusions: Ki67 high patients in the low risk oncotype Dx group are relapsing at a significantly higher rate suggesting that Ki67 combined with low oncotype Dx further refines the risk of distant relapse.
Phase 1 Combination Study of the CHK1 Inhibitor Prexasertib and the PARP Inhibitor Olaparib in High-grade Serous Ovarian Cancer and Other Solid Tumors
Authors: Khanh T. Do, Bose Kochupurakkal, Sarah Kelland, Adrienne de Jonge, Jennifer Hedglin, Allison Powers, Nicholas Quinn, Courtney Gannon, Loan Vuong, Kalindi Parmar, Jean-Bernard Lazaro, Alan D. D'Andrea, Geoffrey I. Shapiro
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Checkpoint kinase 1 (CHK1) plays a central role in the response to replication stress through modulation of cell-cycle checkpoints and homologous recombination (HR) repair. In BRCA-deficient cancers with de novo or acquired PARP inhibitor resistance, the addition of the CHK1 inhibitor prexasertib to the PARP inhibitor olaparib compromises replication fork stability, as well as HR proficiency, allowing for sensitization to PARP inhibition. Patients and Methods: This study followed a 3+3 design with a 7-day lead-in of olaparib alone, followed by 28-day cycles with prexasertib administered on days 1 and 15 in combination with an attenuated dose of olaparib on days 1–5 and 15–19. Pharmacokinetic blood samples were collected after olaparib alone and following combination therapy. Patients enrolled to the expansion phase of the study underwent paired tumor biopsies for pharmacodynamic (PD) assessments. Results: Twenty-nine patients were treated. DLTs included grade 3 neutropenia and grade 3 febrile neutropenia. The MTD/recommended phase 2 dose (RP2D) was prexasertib at 70 mg/m2 i.v. with olaparib at 100 mg by mouth twice daily. Most common treatment-related adverse events included leukopenia (83%), neutropenia (86%), thrombocytopenia (66%), and anemia (72%). Four of 18 patients with BRCA1-mutant, PARP inhibitor–resistant, high-grade serous ovarian cancer (HGSOC) achieved partial responses. Paired tumor biopsies demonstrated reduction in RAD51 foci and increased expression of γ-H2AX, pKAP1, and pRPA after combination exposure. Conclusions: Prexasertib combined with olaparib has preliminary clinical activity in BRCA-mutant patients with HGSOC who have previously progressed on a PARP inhibitor. PD analyses show that prexasertib compromises HR with evidence of induction of DNA damage and replication stress.
Early detection of pancreatic cancers by novel nanobiosensor-based protease biomarkers using hierarchical decision structure.
Authors: Anup Kasi, Weijing Sun, Sumia Ehsan, Jose Covarrubias, Kayla Eschliman, Raul Neri, Deepesh Agarwal, Obdulia Covarrubias Zambrano, Stefan H Bossmann, Bala Natarajan
Journal: Journal of Clinical Oncology (2021)

e16273 Background: There is a critical need to develop fast, reliable, and cost-effective methods for the detection of pancreatic cancer (PC) at the earliest stage to maximize the impact of treatment. To-date, early detection of PC is close to impossible due to the location of the pancreas and the absence of characteristic symptoms in early cancer stages. Methods: Our team of clinicians and scientists has established a fast and reliable nanobiosensor technology that comprises iron/iron oxide nanoparticles attached to a protease or arginase activatable FRET pair (tetrakis (4- carboxyphenyl) porphyrin (TCPP) /cyanine 5.5). Arginase and seven proteases (MMP1, 3, and 9, cathepsin B, and E, urokinase plasminogen activator, and neutrophil elastase) were identified using the Gene Expression Omnibus (GEO) web tool based on their different expression pattern in pancreatic cancer patients, pancreatitis and healthy control subjects. Protease/arginase activities were measured in serum after 1h of incubation. Based on this data, a novel engineering approach to improved early stage detection of pancreatic cancer is reported here. This study was funded by American Cancer Society Institutional Research Grant (IRG‐16‐194‐07), awarded to the University of Kansas Medical Center. Results: In our study, 159 patients were enrolled at KU Cancer Center from 2000-2019, 47 with metastatic PC, 36 with localized PC, 26 pancreatitis and 50 healthy controls using KUCC Biospecimen Repository. The problem of early stage detection of pancreatic cancer can be modeled as a multi-class classification problem. Conventional classification approaches provide at most 77% accuracy for the dataset under consideration. A new hierarchical decision structure with specific feature engineering at each step is introduced here to improve the performance of the classifier. The fundamental premise of this information fusion-based framework involves tailoring the statistically most significant features with appropriate weights to execute an efficient binary classification task at each hierarchical step. An overall accuracy of 95% was achieved for the detection of patients with early pancreatic cancer (see table). Conclusions: Because of the dire survival statistics of pancreatic cancer, detection at the earliest possible time by means of a liquid biopsy will offer the greatest benefit. Novel nanobiosensor based protease biomarkers achieved high accuracy in early detection of pancreatic cancers by applying hierarchical decision structure. Our results need validation in a larger cohort. Predicted true class considering the following combination of classification methods: Step1 – kNN * , step2 – kNN * , step3 – RFC * (Accuracy = 94.97%).[Table: see text]
Pan-cancer evaluation of homologous repair deficiency somatic mutations and response to first-line anti-neoplastic therapy.
Authors: Jessica A Lavery, Samantha Brown, Gregory J. Riely, Philippe L. Bedard, Ben Ho Park, Jeremy Lyle Warner, Kenneth L. Kehl, Eva M Lepisto, Hira Rizvi, Michele LeNoue-Newton, Caroline G. McCarthy, Celeste Yu, Ritika Kundra, Brooke Mastrogiacomo, Nikolaus Schultz, Julia Elizabeth Rudolph, Shawn Sweeney, Deborah Schrag, Katherine Panageas
Journal: Journal of Clinical Oncology (2021)

10535 Background: Homologous recombination is a major mechanism of defective DNA repair, but it remains uncertain whether homologous repair deficient (HRD) tumors have favorable prognosis or are more/less likely to respond to treatment than tumors lacking such mutations. Objective: To determine whether lung (NSCLC) and colorectal (CRC) HRD+ tumors have better survival or response to chemotherapy than HRD- tumors. Methods: Patients with de novo stage IV NSCLC or CRC who had next generation sequencing (NGS) between 2015-2018 from one of four cancer centers were identified. Records were curated using the PRISSMM framework to ascertain treatment, overall survival (OS) and progression free survival based on imaging (PFS-I) and oncologists’ notes (PFS-M). Each NSCLC or CRC tumor was categorized as HRD+ if NGS revealed an oncogenic/likely oncogenic mutation in: ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, PALB2, RAD50, RAD51, RAD51C, RTEL1, or MRE11A based on the OncoKB database. The tumor was categorized as HRD- if no oncogenic mutation in any of these genes was evident and HRD indeterminate (HRD?) if no mutation was identified but the panel did not include all genes. OS, PFS-I and PFS-M from start of first line therapy were reported by HRD status. The percentage with a good response to first line therapy (≥2x the median) and exceptional response (≥3x the median) was estimated for each endpoint. Results: For NSCLC 4% were HRD+, 59% HRD- and 37% HRD?. For CRC there were 5% HRD+, 60% HRD- and 35% HRD?. There were no significant differences for any survival endpoint between patients who were HRD+ vs HRD- in univariable analyses. The proportion of good and exceptional responders to first line systemic chemotherapy also did not vary by HRD status, though patients with HRD+ CRC were potentially more likely to be exceptional responders. Similarly, no differences between HRD+ and HRD- tumors were apparent for the subgroup receiving platinum containing therapy. Conclusions: NSCLC and CRC patients with somatic mutations in HRD oncogenic genes did not differ from patients lacking such a mutation with respect to OS or PFS. CRC patients with HRD+ tumors may be more likely to be exceptional responders, but sample sizes are limited. By May, the analysis will include breast and pancreatic cancer cases.[Table: see text]
EMBR-33. YAP1 FUNCTION IN SHH MEDULLOBLASTOMA PROGRESSION AND IMMUNE EVASION
Authors: Nourhan Abdelfattah, Sivaraman Natarajan, David Baskin, Kyuson Yun
Journal: Neuro-Oncology (2021)

Abstract Our incomplete understanding of the key players in Medulloblastoma (MB) development and progression, and their roles in modulating highly Immune desert-like microenvironment in MBs present major hurdles in successfully applying existing therapies and developing new therapies for MBs. Here, we demonstrate that Yap1 acts as a critical modulator of SHH MB (fSmoM2; GFAPcre (SG) and Ptch;p53 SHH-MB mouse models) progression and immune evasion. Yap1 genetic deletion in SG mice significantly extends survival and normalizes brain development by increasing neuronal differentiation. Both bulk and single-cell RNA sequencing analyses show that Yap1 deleted tumors contain cells with more differentiated molecular signatures similar to late CGNPs and differentiating neurons, and less stem-like cells, compared to SG tumors. Additionally, integrated analyses of ChiPseq, RNAseq, and scRNAq data suggest that Yap1 directly binds to the Super enhancer region containing Sox2 and promotes Sox2 expression in SHH MB cells. We postulate that Yap1 expression is maintained or re-activated in SHH MB cells to generate long-term self-renewing tumor cells. Consistently, Yap1-deleted SHH MB or Verteporfin (a small molecule inhibitor of Yap1) -treated Ptch;p53 MB cells lose self-renewal ability in vitro. Furthermore, we hypothesize that a molecular mechanism underlying this stemness promoting function is mediated through Sox2 expression. Intriguingly, Yap1 deletion in SG MBs is accompanied by a significant change in the immune microenvironment, when compared to age-matched SG MBs. There is a significant increase in the number of bone marrow-derived immune cells (including cytotoxic T-cells, neutrophils, and macrophages). RNAseq analysis of rescued tumors shows marked enrichment of interferon-gamma response genes and pro-inflammatory cytokines. This study highlights Yap1 as a crucial mediator of MB progression and a molecular regulator of inflammatory immune cell infiltration into SHH MBs. Consequently, our work paves the way for improving immunotherapy treatments in brain malignancies.