tbuckley/cabot-search huggingface dataset:
Real-world utilization and safety of ipilimumab plus nivolumab (I+N) in metastatic renal cell carcinoma (mRCC) patients: Results from the Canadian Kidney Cancer Information System (CKCis).
Authors: Myuran Thana, Naveen S. Basappa, Sunita Ghosh, Christian K. Kollmannsberger, Daniel Yick Chin Heng, Jeffrey Graham, Denis Soulieres, Aaron Richard Hansen, Aly-Khan A. Lalani, Vincent Castonguay, M. Neil Reaume, Georg A. Bjarnason, Rodney H. Breau, Frederic Pouliot, Anil Kapoor, Lori Wood
Journal: Journal of Clinical Oncology (2020)

633 Background: I+N is now standard of care for first line treatment of intermediate/poor risk mRCC patients (pts). Real world data is vital to understand drug usage, toxicity and outcomes in non-trial pts. This project describes the amount and tolerability of treatment delivered including discontinuation rates, reasons for discontinuation and outcomes from the CKCis database. Methods: Pts in CKCis, a prospective Canadian database from 15 academic centers, who received first line I+N were included. The number of doses of I+N, number of pts who received single-agent nivolumab (N) and duration of single agent N were determined. Reasons for treatment discontinuation, including the rate, type, and grade of toxicities were identified. Efficacy outcomes included time to failure (TTF – time to progression, death, or second line therapy), overall response rate (ORR) and overall survival (OS). Results: The cohort consists of 182 pts. Median age was 63 yrs, 71% had clear cell histology, 11% were on a clinical trial, the IMDC risk distribution was 5% good, 63% intermediate, 32% poor. Median follow up was 8.8 m. All 4 I+N doses were received by 30% of pts of which 78% went on to receive single-agent N. Less than 4 doses of I+N were received by 70% of pts of which 28% went on to receive single-agent N. The median time on single agent N was 5.7 m. In the entire cohort, 21% of patients discontinued therapy due to toxicity. The most common toxicity events were colitis (56% of all events), pneumonitis (19%), and hepatitis (8%). There were no toxicity-related deaths. Median OS has not been reached (22 events to date). Median TTF was 12.4 m. ORR was 32% (5% complete responses). 26% of pts received second line treatment, the most common being sunitinib in 79%. Conclusions: In this real world cohort, the majority of mRCC pts did not receive all 4 doses of I+N, contrasting with clinical trial reporting, yet many of these pts went on to receive single agent N. Discontinuation rates due to toxicity were similar to those reported in CheckMate 214. Further follow up is ongoing and efficacy outcomes analyzed on the basis of treatment quantity/duration will be presented.
Early Introduction of Peanut, Egg, and Milk Among Black and White Food-Allergic Children in the FORWARD Study
Authors: Jialing Jiang, Christopher Warren, Jamie Fierstein, Olivia Negris, Avneet Chadha, Alexandria Bozen, Lucy Bilaver, Jacqueline Pongracic, Ruchi Gupta, Perry Catlin, Annika Chura, Amal Assa'ad, Aame Andy-Nweye, Susan Fox, Mahboobeh Mahdavinia, Mary Tobin, Iman Abdikarim, Adam Robinson, Amaziah Coleman, Hemant Sharma
Journal: Journal of Allergy and Clinical Immunology (2020)
Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia
Authors: Dai Chihara, Evgeny Arons, Maryalice Stetler-Stevenson, Constance M. Yuan, Hao-Wei Wang, Hong Zhou, Mark Raffeld, Liqiang Xi, Seth M. Steinberg, Julie Feurtado, Lacey James, Wyndham Wilson, Raul C. Braylan, Katherine R. Calvo, Irina Maric, Alina Dulau-Florea, Robert J. Kreitman
Journal: Journal of Clinical Oncology (2020)

PURPOSE Single-agent purine analog, usually cladribine, has been the standard first-line therapy of hairy cell leukemia (HCL) for 30 years. High complete remission (CR) rates often include minimal residual disease (MRD), leading to relapse and repeated treatments. Rituximab can clear MRD, but long-term results are unknown and optimal timing of rituximab undefined. PATIENTS AND METHODS Patients were randomly assigned to first-line cladribine 0.15 mg/kg intravenously days 1-5 with 8 weekly doses of rituximab 375 mg/m 2 begun either day 1 (concurrent, CDAR) or ≥ 6 months later (delayed) after detection of MRD in blood. MRD tests included blood and bone marrow (BM) flow cytometry, and BM immunohistochemistry. RESULTS Sixty-eight patients with purine analog-naïve classic HCL were randomly assigned 1:1 to concurrent versus delayed arms. At 6 months after CDAR versus cladribine monotherapy, CR rates were 100% versus 88% ( P = .11), MRD-free CR rates 97% versus 24% ( P &lt; .0001, primary end point), and blood MRD-free rates 100% versus 50% ( P &lt; .0001), respectively. At 96 months median follow-up, 94% versus 12% remained MRD free. Compared with CDAR, delayed rituximab after cladribine achieved lower rate (67% of 21 evaluable patients; P = .0034) and durability ( P = .0081, hazard radio favoring CDAR, 0.094) of MRD-free CR. Nevertheless, 12 patients in the delayed arm remained MRD free when restaged 6-104 (median, 78) months after last delayed rituximab treatment. Compared with cladribine monotherapy, CDAR led to brief grade 3/4 thrombocytopenia (59% v 9%; P &lt; .0001) and platelet transfusions without bleeding (35% v 0%; P = .0002), but higher neutrophil ( P = .017) and platelet ( P = .0015) counts at 4 weeks. CONCLUSION Achieving MRD-free CR of HCL after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if MRD-free survival leads to less need for additional therapy or cure of HCL.
Stepwise targeting and responsive lipid-coated nanoparticles for enhanced tumor cell sensitivity and hepatocellular carcinoma therapy
Authors: Ying Li, Yunqiu Miao, Mingshu Chen, Xi Chen, Feifei Li, Xinxin Zhang, Yong Gan
Journal: Theranostics (2020)

Rationale: Antitumor drug delivery faces multiple barriers that require consecutively achieving tumor targeting, selective cellular uptake and sufficient intracellular drug dosage. Methods: Herein, we designed smart nanoparticles (GPDC-MSNs) that can accumulate stepwise in tumor tissues, selectively enter cancer cells by responding to the acidic tumor extracellular environment, and achieve considerable drug release in the intracellular microenvironment. The GPDC-MSNs comprise the synthesized material galactosyl-conjugated PEO-PPO-PEO (Gal-P123) for hepatocellular carcinoma (HCC) targeting, the tumor extracellular pH-responsive lipid (2E)-4-(dioleostearin)-amino-4-carbonyl-2-butenonic (DC) for selective cellular internalization, and antitumor drug irinotecan (CPT-11)-loaded mesoporous silica nanoparticles (MSNs) for on-demand intracellular drug release. Results: GPDC-MSNs are negatively charged at pH 7.4 and promote active HCC targeting mediated by the asialoglycoprotein receptor. Upon reaching the weakly acidic tumor microenvironment, the nanoparticles undergo charge conversion to neutral, enhancing cellular internalization. Moreover, the encapsulated CPT-11 can be retained within GPDC-MSNs in the blood circulation but undergo intracellular burst release, which facilitates the apoptosis of tumor cells. GPDC-MSNs significantly increased HCC selectivity in vivo and exhibited up to 25 times higher accumulation in tumor tissue than in normal hepatic tissue, thus achieving superior antitumor efficacy and low systemic toxicity. Conclusion: This stepwise-responsive nanoparticle should serve as a valuable platform and promising strategy for HCC treatment.
Mother-to-child transmission of oncogenic polyomaviruses BKPyV, JCPyV and SV40
Authors: Elisa Mazzoni, Elena Pellegrinelli, Chiara Mazziotta, Carmen Lanzillotti, John Charles Rotondo, Ilaria Bononi, Maria Rosa Iaquinta, Marco Manfrini, Fortunato Vesce, Mauro Tognon, Fernanda Martini
Journal: Journal of Infection (2020)
Rates and determinants of prostatectomy in prostate cancer (PCa) patients with node-positive disease.
Authors: Lova Sun, Neha Vapiwala, Daniel Lee, Samuel U Takvorian, Naomi B. Haas, David J. Vaughn, Vivek Narayan
Journal: Journal of Clinical Oncology (2020)

362 Background: Consensus guidelines recommend that PCa patients with “regional risk” clinical node positive (cN1) disease undergo EBRT and ADT. However, many of these patients still undergo radical prostatectomy (RP), and the role of clinical node status in predicting benefit from RP is debated. Using National Cancer Database (NCDB), we sought to characterize the rates and determinants of initial RP for cN1 patients, and to assess the prognostic significance of clinical nodal stage for patients undergoing RP with pathologic node involvement (pN1). Methods: Among incident cases of nonmetastatic PCa within NCDB (2004-2012), we identified two cohorts: (1) patients with cN1 disease, and (2) patients with pN1 post-RP. For the cN1 cohort, factors associated with initial RP were evaluated using univariate logistic regression, and post-surgical pathologic staging and adjuvant therapies were described. For the pN1 cohort, multivariate Cox regression was used to compare overall survival (OS) by preoperative clinical stage (cN1 vs cN0). Results: Of 7787 patients with cN1 disease, 2166 underwent initial RP, with consistent annual rates (24-31%) over the study period. Factors independently associated with higher likelihood of RP included age ≤ 65 (HR 1.8), white race (HR 1.4), private insurance (HR 1.8), T stage ≥ T2C (HR 1.3), PSA ≤ 10 (HR 1.6), and Gleason score &lt;8 (HR 1.4). Of cN1 patients who underwent RP, 84% were pN1 and 26% were pN0. 26% of these cN1/pN1 patients later received RT, 49% received ADT, and 20% received both. Separately, among 7396 PCa patients with pN1 disease after RP, 17% were initial cN1 and 83% were cN0. After adjustment for practice setting, patient, and disease variables, initial cN1 clinical stage was associated with significantly worse OS (HR = 1.2, p=0.04). Conclusions: The initial treatment of regional risk cN1 disease is highly variable, with approximately 1 in 4 patients undergoing initial prostatectomy, the vast majority of whom are confirmed pN1. Among all patients with pN1 disease, clinical nodal staging retains prognostic significance for OS. These findings underscore the utility of initial clinical staging when considering initial and adjuvant treatments for regional risk patients.
PSA progression compared to radiographic or clinical progression in metastatic castration-resistant prostate cancer patients treated with enzalutamide.
Authors: Shruti U. Gandhy, Fatima Karzai, Jennifer L. Marte, Marijo Bilusic, Sheri McMahon, Julius Strauss, Anna Couvillon, Monique Williams, Amy Hankin, Seth M. Steinberg, William Douglas Figg, Philip M. Arlen, William L. Dahut, James L. Gulley, Ravi Amrit Madan
Journal: Journal of Clinical Oncology (2020)

105 Background: Enzalutamideis ahighly effective treatment in patients with metastatic castration resistant prostate cancer (mCRPC). Although Prostate Cancer Working Group Guidelines (PCWG) recommend continuing treatment until radiographic progression of disease (rPD) or clinical progression (cPD), many patients discontinue therapy for rising PSA alone. Methods: We conducted an open label, randomized phase 2 clinical trial in mCRPC patients (on testosterone suppression therapy) previously untreated with docetaxel, abiraterone, or enzalutamide, comparing enzalutamide alone or in combination with PROSTVAC, a therapeutic cancer vaccine designed to induce an anti-tumor immune response. The study discontinued accrual after a planned interim analysis indicated no difference in progression between the two arms. Patients were followed beyond PSA progression (first of three confirmed PSA rises, evaluated monthly) until rPD per PCWG (scans done every 3 months per protocol). Results: A total of 57 patients were enrolled with a median follow up time of 55.4 months. Of those, 47 (82%) patients were Caucasian and seven (12%) patients were African American. The median age of patients on enrollment was 67.2 years. 49/57 (86%) patients had PSA progression and the median time to first PSA rise for all 57 patients combined was 6.4 months (95% CI: 3.7-11.0 months) after starting enzalutamide. 38/57 (67%) patients experienced progressive disease (majority with rPD and 1/38 (3%) with cPD), with the median time to progression for all 57 patients of 23.3 months (95% CI: 16.1-27.8 months). Conclusions: Consistent with PCWG recommendations, these data suggest that a rising PSA may not be a warning of near-term clinically significant disease progression in mCRPC patients given the nearly 17-month difference between the first rise in PSA and ultimate rPD or cPD seen in this analysis. These data highlight the need to continue to educate patients and providers on PCWG criteria for progression, which were also used in original trials that led to the FDA approval of enzalutamide, so as not to substantially limit the potential efficacy of mCRPC therapies such as enzalutamide. Clinical trial information: NCT01867333.
Abstract 213: Secondary CPR Training via Mobile Application Compared to Video Self Instruction Kit
Authors: Andrew Murray, Shaun McGovern, Marion Leary, Benjamin Abella, Audrey L Blewer
Journal: Circulation (2018)

Introduction: Hands-only CPR training via a video self-instruction (VSI) kit (DVD &amp; manikin) or a mobile application (app, video-only) allows trainees to share the training materials with others (“secondary training”). This secondary training can amplify the number of individuals trained in CPR, thus increasing the chances of bystander intervention in an out-of-hospital cardiac arrest. Health apps are an emerging tool through which public health information and education can be disseminated. No study has examined whether laypersons trained in CPR via an app share the training as frequently as those trained via VSI. Hypothesis: We hypothesized that laypersons trained via mobile app will share the training material more than those trained with VSI. Methods: This work represents a sub-investigation of an in-hospital CPR training study for families of cardiac patients. Subjects were trained with either a VSI kit or a mobile app and completed an interview 6-month post-training that measured whether training materials were shared and with how many others they were shared. Multivariate logistic regression was performed controlling for age, race and level of education to determine the likelihood that an individual shared the training. Results: Of 697 participants who completed the interview between 6/2016-5/2018, 281 stated they shared the training with at least 1 person (VSI n=213/356, App n=68/341). Subjects who received VSI training were more likely to share than those trained with the app (OR: 7.16, 95% CI: 4.91-10.43, p&lt;0.01). Subjects trained with VSI had an average multiplier rate of 2.27 ±4.13 versus 0.56 ±1.66 (p&lt;0.01) for those trained with the app. Subject-level analysis revealed that increased age is associated with decreased likelihood that an individual shared the training in both training arms (App OR: 0.98, 95% CI: 0.96-0.99, VSI OR: 0.98, 95% CI: 0.97-0.99). Conclusion: Subjects in the app arm were less likely to share CPR training. While it has been widely assumed that app-based solutions may afford unique dissemination opportunities, these results suggest the most effective solution to increasing hands-only CPR training may lie in kit-based options currently available. Further work is needed to determine why app-based training is shared less.
Intense 68Ga-Pentixafor Activity in Aldosterone-Producing Adrenal Adenomas
Authors: Jie Ding, Anli Tong, Yushi Zhang, Jin Wen, Li Huo
Journal: Clinical Nuclear Medicine (2020)

Abstract 68 Ga-pentixafor, a ligand of CXCR4 (CXC chemokine receptor type 4), has been reported as a potential PET tracer to evaluate a variety of pathological entities. We report intense 68 Ga-pentixafor activity on PET/CT in 2 patients in the histopathologically confirmed adrenal adenomas, which were the cause of their Conn syndrome.
CDK12 upregulation and adverse correlation with tumor-associated immune cell infiltrates in prostate cancer.
Authors: Marie C. Hupe, Anne Offermann, Cleopatra Schreiber, Axel Stuart Merseburger, Sven Perner
Journal: Journal of Clinical Oncology (2020)

181 Background: Biallelic loss of CDK12 has recently been identified as a novel subtype of prostate cancer (PCa). CDK12 altered PCa associates with elevated neoantigen burden and thus may be suitable for checkpoint inhibition. Up to now, data about CDK12 refer to its genetic alterations in PCa while its characterization on protein level and its association with tumor infiltrating T-cells are lacking. Methods: Immunohistochemistry (IHC) for CDK12 was performed on a PCa cohort including 74 benigns, 391 primary tumors from 222 patients, 63 locally advanced tumors, 92 lymph node (LN) metastases, and 56 distant metastases. CDK12 was categorized into negative, weak, moderate and high expression. Density of tumor associated T-cells per tumor area was assessed by IHC for CD3 and graduated into negative (&lt;1%), slight (1-5%), weak (5-10%), moderate (10-50%) and high (&gt;50%). Results: CDK12 significantly increases during PCa progression showing highest levels in LN and distant metastases while benign samples harbor no or weak CDK12 expression (ANOVA p&lt;0.001). Kaplan-Meier curve reveals 5-year-biochemical recurrence free survival rates of 89.5%, 69.1%, 59.1% and 20.0% for primary tumors expressing no, weak, moderate and high CDK12 (log-rank p=0.05). High CDK12 expression significantly associates with attenuated tumor associated T-cells (p=0.009) revealing CD3 negativity in 64.7% of CDK12 high expressing tumors. Intratumoral CDK12 and density of CD3 positive T-cells correlates adversely in particular in locally advanced tumors (p=0.007). Overall, tumor associated T-cells are significantly reduced in distant metastases compared to local PCa (p&lt;0.001). Conclusions: Our study highlights the prognostic potential of CDK12 for PCa and its overexpression in advanced tumors. Of note, CDK12 overexpressing tumors can be designated as immunologic “cold” tumors which is in line with their more aggressive phenotype. Concordantly, distant metastases show attenuated tumor associated T-cells supporting the poor response to immunotherapy.
The choice of targets and ligands for site-specific delivery of nanomedicine to atherosclerosis
Authors: Adil Zia, Yuao Wu, Tuan Nguyen, Xiaowei Wang, Karlheinz Peter, Hang T Ta
Journal: Cardiovascular Research (2020)

Abstract As nanotechnologies advance into clinical medicine, novel methods for applying nanomedicine to cardiovascular diseases are emerging. Extensive research has been undertaken to unlock the complex pathogenesis of atherosclerosis. However, this complexity presents challenges to develop effective imaging and therapeutic modalities for early diagnosis and acute intervention. The choice of ligand-receptor system vastly influences the effectiveness of nanomedicine. This review collates current ligand-receptor systems used in targeting functionalized nanoparticles for diagnosis and treatment of atherosclerosis. Our focus is on the binding affinity and selectivity of ligand-receptor systems, as well as the relative abundance of targets throughout the development and progression of atherosclerosis. Antibody-based targeting systems are currently the most commonly researched due to their high binding affinities when compared with other ligands, such as antibody fragments, peptides, and other small molecules. However, antibodies tend to be immunogenic due to their size. Engineering antibody fragments can address this issue but will compromise their binding affinity. Peptides are promising ligands due to their synthetic flexibility and low production costs. Alongside the aforementioned binding affinity of ligands, the choice of target and its abundance throughout distinct stages of atherosclerosis and thrombosis is relevant to the intended purpose of the nanomedicine. Further studies to investigate the components of atherosclerotic plaques are required as their cellular and molecular profile shifts over time.
Host-associated microbiomes are predicted by immune system complexity and climate
Authors: Douglas C. Woodhams, Molly C. Bletz, C. Guilherme Becker, Hayden A. Bender, Daniel Buitrago-Rosas, Hannah Diebboll, Roger Huynh, Patrick J. Kearns, Jordan Kueneman, Emmi Kurosawa, Brandon C. LaBumbard, Casandra Lyons, Kerry McNally, Klaus Schliep, Nachiket Shankar, Amanda G. Tokash-Peters, Miguel Vences, Ross Whetstone
Journal: Genome biology (2020)

Abstract Background Host-associated microbiomes, the microorganisms occurring inside and on host surfaces, influence evolutionary, immunological, and ecological processes. Interactions between host and microbiome affect metabolism and contribute to host adaptation to changing environments. Meta-analyses of host-associated bacterial communities have the potential to elucidate global-scale patterns of microbial community structure and function. It is possible that host surface-associated (external) microbiomes respond more strongly to variations in environmental factors, whereas internal microbiomes are more tightly linked to host factors. Results Here, we use the dataset from the Earth Microbiome Project and accumulate data from 50 additional studies totaling 654 host species and over 15,000 samples to examine global-scale patterns of bacterial diversity and function. We analyze microbiomes from non-captive hosts sampled from natural habitats and find patterns with bioclimate and geophysical factors, as well as land use, host phylogeny, and trophic level/diet. Specifically, external microbiomes are best explained by variations in mean daily temperature range and precipitation seasonality. In contrast, internal microbiomes are best explained by host factors such as phylogeny/immune complexity and trophic level/diet, plus climate. Conclusions Internal microbiomes are predominantly associated with top-down effects, while climatic factors are stronger determinants of microbiomes on host external surfaces. Host immunity may act on microbiome diversity through top-down regulation analogous to predators in non-microbial ecosystems. Noting gaps in geographic and host sampling, this combined dataset represents a global baseline available for interrogation by future microbial ecology studies.
Nasal administration of nanoencapsulated geraniol/ursodeoxycholic acid conjugate: Towards a new approach for the management of Parkinson's disease
Authors: Edilson Ribeiro de Oliveira Junior, Eleonora Truzzi, Luca Ferraro, Marco Fogagnolo, Barbara Pavan, Sarah Beggiato, Cecilia Rustichelli, Eleonora Maretti, Eliana Martins Lima, Eliana Leo, Alessandro Dalpiaz
Journal: Journal of Controlled Release (2020)