Publications by authors named "David C Smith"

162 Publications

The Effects of Hydrogen Annealing on Carbon Nanotube Field-Effect Transistors.

Nanomaterials (Basel) 2021 Sep 23;11(10). Epub 2021 Sep 23.

School of Electronics and Computer Science, University of Southampton, Southampton SO17 1BJ, UK.

We have systematically investigated the effects of hydrogen annealing on Ni- and Al-contacted carbon nanotube field-effect transistors (CNTFETs), whose work functions have not been affected by hydrogen annealing. Measured results show that the electronic properties of single-walled carbon nanotubes are modified by hydrogen adsorption. The Ni-contacted CNTFETs, which initially showed metallic behavior, changed their p-FET behavior with a high on-current over 10 µA after hydrogen annealing. The on-current of the as-made p-FETs is much improved after hydrogen annealing. The Al-contacted CNTFETs, which initially showed metallic behavior, showed unipolar p-FET behavior after hydrogen annealing. We analyzed the energy band diagrams of the CNTFETs to explain experimental results, finding that the electron affinity and the bandgap of single-walled carbon nanotubes changed after hydrogen annealing. These results are consistent with previously reported ab initio calculations.
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http://dx.doi.org/10.3390/nano11102481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540963PMC
September 2021

Ecological causes of fluctuating natural selection on habitat choice in an amphibian.

Evolution 2021 Jul 19;75(7):1862-1877. Epub 2021 Jun 19.

Biology Department, Williams College, Williamstown, Massachusetts, 01267.

We estimated natural selection targeting three traits related to habitat choice in a frog (Pseudacris maculata) breeding in pools on the rocky shores of Isle Royale, Michigan, over 16 years. Our aim was to identify the form and ecological causes of annual variation in directional and correlational selection as expressed in the survival and growth of tadpoles. We found directional selection favoring early breeding, but pool choice was under weak stabilizing selection. However, the form of stabilizing selection and the position of the optimum trait value shifted among years with the severity of disturbance and the intensity of biotic interactions. In years when wave wash and pool desiccation were severe, selection shifted to favor tadpoles in habitats where these risks were less pronounced. If predatory dragonfly larvae were abundant, selection favored tadpoles in small pools where dragonflies did not occur. When intraspecific competition was strong, selection favored early broods within a broader range of pool types. The agents of selection in this study-biotic interactions and disturbance-are common to many ecological systems and frequently exhibit temporal variation; this suggests that fluctuating selection may be widespread in natural populations.
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http://dx.doi.org/10.1111/evo.14282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362115PMC
July 2021

Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours.

Br J Cancer 2021 Jul 3;125(1):28-37. Epub 2021 May 3.

Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours.

Methods: Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, plus additional dosing schedules.

Results: The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8).

Conclusions: Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity.

Clinical Trial Registration: NCT01351103.
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http://dx.doi.org/10.1038/s41416-021-01389-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257624PMC
July 2021

The contribution of water radiolysis to marine sedimentary life.

Nat Commun 2021 02 26;12(1):1297. Epub 2021 Feb 26.

Graduate School of Oceanography, University of Rhode Island, Narragansett, RI, USA.

Water radiolysis continuously produces H and oxidized chemicals in wet sediment and rock. Radiolytic H has been identified as the primary electron donor (food) for microorganisms in continental aquifers kilometers below Earth's surface. Radiolytic products may also be significant for sustaining life in subseafloor sediment and subsurface environments of other planets. However, the extent to which most subsurface ecosystems rely on radiolytic products has been poorly constrained, due to incomplete understanding of radiolytic chemical yields in natural environments. Here we show that all common marine sediment types catalyse radiolytic H production, amplifying yields by up to 27X relative to pure water. In electron equivalents, the global rate of radiolytic H production in marine sediment appears to be 1-2% of the global organic flux to the seafloor. However, most organic matter is consumed at or near the seafloor, whereas radiolytic H is produced at all sediment depths. Comparison of radiolytic H consumption rates to organic oxidation rates suggests that water radiolysis is the principal source of biologically accessible energy for microbial communities in marine sediment older than a few million years. Where water permeates similarly catalytic material on other worlds, life may also be sustained by water radiolysis.
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http://dx.doi.org/10.1038/s41467-021-21218-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910440PMC
February 2021

Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors.

JAMA Oncol 2021 Apr;7(4):525-533

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor.

Importance: Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain.

Objective: To determine which patients derived the greatest degree of clinical benefit from NGS profiling.

Design, Setting, And Participants: Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020.

Main Outcomes And Measures: Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer.

Results: During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses.

Conclusions And Relevance: The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.
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http://dx.doi.org/10.1001/jamaoncol.2020.7987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907987PMC
April 2021

TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer.

J Clin Oncol 2021 04 22;39(12):1371-1382. Epub 2021 Feb 22.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

Purpose: Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC).

Methods: The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL).

Results: The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; = .80). OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT.

Conclusion: This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.
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http://dx.doi.org/10.1200/JCO.20.02759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274807PMC
April 2021

Propensity-Matched Cost of Infection Overdiagnosis.

Open Forum Infect Dis 2021 Feb 21;8(2):ofaa630. Epub 2020 Dec 21.

Division of Infectious Diseases & International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Background: is the leading health care-associated pathogen, but clinicians lack a test that can reliably differentiate colonization from infection. Health care costs attributed to are substantial, but the economic burden associated with false positives is poorly understood.

Methods: A propensity score matching model for cost per hospitalization was developed to estimate the costs of both true infection and false positives. Predictors of positivity used to estimate the propensity score were age, Charlson comorbidity index, white cell count, and creatinine. We used polymerase chain reaction (PCR) cycle threshold to identify and compare 3 groups: (1) true infection, (2) colonization, and (3) negative.

Results: A positive test was associated with $3018 higher unadjusted hospital cost. Among the 3 comparisons made with propensity-matched negative controls (all positives [+$179; = .934], true positives [-$1892; = .100], and colonized positives), only colonization was associated with significantly increased (+$3418; = .012) cost. Differences in lengths of stay (all positives 0 days, = .126; true 0 days, = .919; colonized 1 day, = .019) appeared to underly cost differences.

Conclusions: In the first cost analysis to utilize PCR cycle threshold to differentiate colonization, we found high propensity-matched hospital costs associated with colonized but not true positives. This unexpected finding may be due to misdiagnosis of non- diarrhea or unadjusted factors associated with colonization.
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http://dx.doi.org/10.1093/ofid/ofaa630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863872PMC
February 2021

From People to : Natural SARS-CoV-2 Infection in Tigers and Lions at the Bronx Zoo.

mBio 2020 10 13;11(5). Epub 2020 Oct 13.

Department of Population Medicine and Diagnostic Sciences, Animal Health Diagnostic Center, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

Despite numerous barriers to transmission, zoonoses are the major cause of emerging infectious diseases in humans. Among these, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and ebolaviruses have killed thousands; the human immunodeficiency virus (HIV) has killed millions. Zoonoses and human-to-animal cross-species transmission are driven by human actions and have important management, conservation, and public health implications. The current SARS-CoV-2 pandemic, which presumably originated from an animal reservoir, has killed more than half a million people around the world and cases continue to rise. In March 2020, New York City was a global epicenter for SARS-CoV-2 infections. During this time, four tigers and three lions at the Bronx Zoo, NY, developed mild, abnormal respiratory signs. We detected SARS-CoV-2 RNA in respiratory secretions and/or feces from all seven animals, live virus in three, and colocalized viral RNA with cellular damage in one. We produced nine whole SARS-CoV-2 genomes from the animals and keepers and identified different SARS-CoV-2 genotypes in the tigers and lions. Epidemiologic and genomic data indicated human-to-tiger transmission. These were the first confirmed cases of natural SARS-CoV-2 animal infections in the United States and the first in nondomestic species in the world. We highlight disease transmission at a nontraditional interface and provide information that contributes to understanding SARS-CoV-2 transmission across species. The human-animal-environment interface of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important aspect of the coronavirus disease 2019 (COVID-19) pandemic that requires robust One Health-based investigations. Despite this, few reports describe natural infections in animals or directly link them to human infections using genomic data. In the present study, we describe the first cases of natural SARS-CoV-2 infection in tigers and lions in the United States and provide epidemiological and genetic evidence for human-to-animal transmission of the virus. Our data show that tigers and lions were infected with different genotypes of SARS-CoV-2, indicating two independent transmission events to the animals. Importantly, infected animals shed infectious virus in respiratory secretions and feces. A better understanding of the susceptibility of animal species to SARS-CoV-2 may help to elucidate transmission mechanisms and identify potential reservoirs and sources of infection that are important in both animal and human health.
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http://dx.doi.org/10.1128/mBio.02220-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554670PMC
October 2020

Atribacteria Reproducing over Millions of Years in the Atlantic Abyssal Subseafloor.

mBio 2020 10 6;11(5). Epub 2020 Oct 6.

Department of Earth and Environmental Sciences, Paleontology and Geobiology, Ludwig-Maximilians-Universität München, Munich, Germany

How microbial metabolism is translated into cellular reproduction under energy-limited settings below the seafloor over long timescales is poorly understood. Here, we show that microbial abundance increases an order of magnitude over a 5 million-year-long sequence in anoxic subseafloor clay of the abyssal North Atlantic Ocean. This increase in biomass correlated with an increased number of transcribed protein-encoding genes that included those involved in cytokinesis, demonstrating that active microbial reproduction outpaces cell death in these ancient sediments. Metagenomes, metatranscriptomes, and 16S rRNA gene sequencing all show that the actively reproducing community was dominated by the candidate phylum " Atribacteria," which exhibited patterns of gene expression consistent with fermentative, and potentially acetogenic, metabolism. " Atribacteria" dominated throughout the 8 million-year-old cored sequence, despite the detection limit for gene expression being reached in 5 million-year-old sediments. The subseafloor reproducing " Atribacteria" also expressed genes encoding a bacterial microcompartment that has potential to assist in secondary fermentation by recycling aldehydes and, thereby, harness additional power to reduce ferredoxin and NAD Expression of genes encoding the Rnf complex for generation of chemiosmotic ATP synthesis were also detected from the subseafloor " Atribacteria," as well as the Wood-Ljungdahl pathway that could potentially have an anabolic or catabolic function. The correlation of this metabolism with cytokinesis gene expression and a net increase in biomass over the million-year-old sampled interval indicates that the " Atribacteria" can perform the necessary catabolic and anabolic functions necessary for cellular reproduction, even under energy limitation in millions-of-years-old anoxic sediments. The deep subseafloor sedimentary biosphere is one of the largest ecosystems on Earth, where microbes subsist under energy-limited conditions over long timescales. It remains poorly understood how mechanisms of microbial metabolism promote increased fitness in these settings. We discovered that the candidate bacterial phylum " Atribacteria" dominated a deep-sea subseafloor ecosystem, where it exhibited increased transcription of genes associated with acetogenic fermentation and reproduction in million-year-old sediment. We attribute its improved fitness after burial in the seabed to its capabilities to derive energy from increasingly oxidized metabolites via a bacterial microcompartment and utilize a potentially reversible Wood-Ljungdahl pathway to help meet anabolic and catabolic requirements for growth. Our findings show that " Atribacteria" can perform all the necessary catabolic and anabolic functions necessary for cellular reproduction, even under energy limitation in anoxic sediments that are millions of years old.
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http://dx.doi.org/10.1128/mBio.01937-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542362PMC
October 2020

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer.

Br J Cancer 2020 11 11;123(11):1590-1598. Epub 2020 Sep 11.

Sarah Cannon Research Institute/Tennessee Oncology, Drug Development Unit, 250 25th Ave., North Nashville, TN, 37203, USA.

Background: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours.

Methods: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients).

Results: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers.

Conclusions: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.

Clinical Trial Registration: ClinicalTrials.gov, NCT01058707.
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http://dx.doi.org/10.1038/s41416-020-01041-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686313PMC
November 2020

Efficacy and Effect of Cabozantinib on Bone Metastases in Treatment-naive Castration-resistant Prostate Cancer.

Clin Genitourin Cancer 2020 08 7;18(4):332-339.e2. Epub 2020 Mar 7.

University of Michigan Rogel Cancer Center, Ann Arbor, MI; Department of Urology, University of Michigan, Ann Arbor, MI.

Background: Cabozantinib is active in advanced prostate cancer with improvement on bone scans in men on phase II trials. This trial evaluated the efficacy and changes in bone lesions in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabozantinib.

Patients And Methods: Eligible patients with mCRPC involving bone underwent biopsy of a bone lesion followed by cabozantinib starting at 60 mg daily and continuing until progression or intolerable toxicity. The primary study endpoint was progression-free survival at 12 weeks. The bone lesion was rebiopsied at 6 weeks. Expression of CMET, phospho-CMET, and VEGFR2 was assayed by immunohistochemistry. Serum was obtained at baseline, and at 3, 6, and 12 weeks and assayed for bone remodeling markers.

Results: A total of 25 patients were enrolled: 22 were evaluable, and 3 were excluded before receiving cabozantinib. At 12 weeks, 17 (77%) of 22 patients had stable disease or better. The median time on treatment was 24 weeks (range, 3-112 weeks). The overall median progression-free survival was 43.7 weeks (95% confidence interval, 23.7-97.0 weeks). Eight (36%) of 22 patients had markedly reduced uptake on bone scan. Patients with significant response on bone scan had higher bone morphogenic protein-2 levels at baseline, stable N-telopeptides levels, increased vascular endothelial growth factor receptor 2 expression, and a trend towards increased phospho-CMET while on cabozantinib compared with patients with stable disease.

Conclusions: Cabozantinib is active in men with mCRPC, inducing significant changes on bone scan in one-third of patients with changes in markers of bone formation and the tumor microenvironment.
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http://dx.doi.org/10.1016/j.clgc.2019.10.019DOI Listing
August 2020

A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma.

Invest New Drugs 2020 10 27;38(5):1421-1429. Epub 2020 Jan 27.

Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with very limited treatment options. Nevanimibe HCl (formerly ATR-101), a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, has been shown in nonclinical studies to decrease adrenal steroidogenesis at lower doses and to cause apoptosis of adrenocortical cells at higher doses. Methods This phase 1, multicenter, open-label study assessed the safety and pharmacokinetics (PK) of nevanimibe in adults with metastatic ACC (NCT01898715). A "3 + 3" dose-escalation design was used. Adverse events (AEs), PK, and tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were evaluated every 2 months. Results 63 patients with metastatic ACC, all of whom had previously failed systemic chemotherapy and only 2 of whom were mitotane-naïve, were dosed with oral nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. Subjects who did not experience tumor progression or a dose-limiting toxicity (DLT) could continue to receive additional cycles. No patients experienced a complete or partial response; however, 13 of the 48 (27%) patients who underwent imaging at 2 months had stable disease (SD), and 4 of these had SD > 4 months. In addition, drug-related adrenal insufficiency, considered a pharmacologic effect of nevanimibe, was observed in two patients. The most common treatment-emergent AEs were gastrointestinal disorders (76%), including diarrhea (44%) and vomiting (35%). A maximum tolerated dose (MTD) could not be defined, as very few dose-limiting toxicities (DLTs) occurred. Because the large number of tablets required at the highest dose (i.e., ~24 tablets/day) resulted in low-grade gastrointestinal adverse effects, a maximum feasible dose of 128.2 mg/kg/day was established as a dose that could be taken on a long-term basis. Conclusions This study demonstrated the safety of nevanimibe at doses of up to ~6000 mg BID. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC.
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http://dx.doi.org/10.1007/s10637-020-00899-1DOI Listing
October 2020

First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy.

Cancer Manag Res 2019 13;11:10463-10476. Epub 2019 Dec 13.

Sarah Cannon Research Institute, Drug Development Unit, Tennessee Oncology, Nashville, TN, USA.

Purpose: This first-in-human Phase I study investigated the safety, pharmacokinetics (PK), pharmacodynamic profile, and preliminary efficacy of CC-115, a dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase.

Patients And Methods: Patients with advanced solid or hematologic malignancies were enrolled in dose-finding and cohort expansion phases. In dose-finding, once-daily or twice-daily (BID) ascending oral doses of CC-115 (range: 0.5-40 mg/day) in 28-day continuous cycles identified the maximum-tolerated dose for cohort expansion in 5 specified tumor types. Twelve additional patients with mixed solid tumors participated in a bioavailability substudy.

Results: Forty-four patients were enrolled in the dose-finding cohort. Dose-limiting toxicity included thrombocytopenia, stomatitis, hyperglycemia, asthenia/fatigue, and increased transaminases. CC-115 10 mg BID was selected for cohort expansion (n=74) in which fatigue, nausea, and decreased appetite were the most frequent toxicities. Dose-proportional PK was found. CC-115 distributed to glioblastoma tissue (mean tumor/plasma concentration ratio: 0.713). Total exposure of CC-115 was similar under fasting and fed conditions. A patient with endometrial carcinoma remained in complete remission >4 years. Partial response (PR; n=2) and stable disease (SD; n=4) were reported in the bioavailability substudy; SD was reached in 53%, 22%, 21%, and 64% of patients with head and neck squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme, and castration-resistant prostate cancer, respectively. Chronic lymphocytic leukemia/small lymphocytic lymphoma showed 38% PR and 25% SD.

Conclusion: CC-115 was well-tolerated, with toxicities consistent with mTOR inhibitors. Together with biomarker inhibition and preliminary efficacy, oral CC-115 10 mg BID is a promising novel anticancer treatment.

Clinical Trial Registration: NCT01353625.
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http://dx.doi.org/10.2147/CMAR.S208720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916675PMC
December 2019

Testicular Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2019 12;17(12):1529-1554

28National Comprehensive Cancer Network.

Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.
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http://dx.doi.org/10.6004/jnccn.2019.0058DOI Listing
December 2019

PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open-label single-arm phase 2 study.

Prostate 2020 01 19;80(1):99-108. Epub 2019 Nov 19.

Progenics Pharmaceuticals, Inc, New York, New York.

Background: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy.

Methods: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed.

Results: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis.

Conclusions: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.
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http://dx.doi.org/10.1002/pros.23922DOI Listing
January 2020

Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies.

Clin Cancer Res 2020 03 16;26(6):1247-1257. Epub 2019 Sep 16.

University of Alabama, Birmingham, Alabama.

Purpose: Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137).

Patients And Methods: Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability.

Results: Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses.

Conclusions: INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528620PMC
March 2020

Five-Year Survival and Correlates Among Patients With Advanced Melanoma, Renal Cell Carcinoma, or Non-Small Cell Lung Cancer Treated With Nivolumab.

JAMA Oncol 2019 Oct;5(10):1411-1420

Department of Internal Medicine (Section of Medical Oncology), Yale Cancer Center, New Haven, Connecticut.

Importance: Nivolumab, a monoclonal antibody that inhibits programmed cell death 1, is approved by the US Food and Drug Administration for treating advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and other malignancies. Data on long-term survival among patients receiving nivolumab are limited.

Objectives: To analyze long-term overall survival (OS) among patients receiving nivolumab and identify clinical and laboratory measures associated with tumor regression and OS.

Design, Setting, And Participants: This was a secondary analysis of the phase 1 CA209-003 trial (with expansion cohorts), which was conducted at 13 US medical centers and included 270 patients with advanced melanoma, RCC, or NSCLC who received nivolumab and were enrolled between October 30, 2008, and December 28, 2011. The analyses were either specified in the original protocol or included in subsequent protocol amendments that were implemented between 2008 and 2012. Statistical analysis was performed from October 30, 2008, to November 11, 2016.

Intervention: In the CA209-003 trial, patients received nivolumab (0.1-10.0 mg/kg) every 2 weeks in 8-week cycles for up to 96 weeks, unless they developed progressive disease, achieved a complete response, experienced unacceptable toxic effects, or withdrew consent.

Main Outcomes And Measures: Safety and activity of nivolumab; OS was a post hoc end point with a minimum follow-up of 58.3 months.

Results: Of 270 patients included in this analysis, 107 (39.6%) had melanoma (72 [67.3%] male; median age, 61 [range, 29-85] years), 34 (12.6%) had RCC (26 [76.5%] male; median age, 58 [range, 35-74] years), and 129 (47.8%) had NSCLC (79 [61.2%] male; median age, 65 [range, 38-85] years). Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC. In a multivariable analysis, the presence of liver (odds ratio [OR], 0.31; 95% CI, 0.12-0.83; P = .02) or bone metastases (OR, 0.31; 95% CI, 0.10-0.93; P = .04) was independently associated with reduced likelihood of survival at 5 years, whereas an Eastern Cooperative Oncology Group performance status of 0 (OR, 2.74; 95% CI, 1.43-5.27; P = .003) was independently associated with an increased likelihood of 5-year survival. Overall survival was significantly longer among patients with treatment-related AEs of any grade (median, 19.8 months; 95% CI, 13.8-26.9 months) or grade 3 or more (median, 20.3 months; 95% CI, 12.5-44.9 months) compared with those without treatment-related AEs (median, 5.8 months; 95% CI, 4.6-7.8 months) (P < .001 for both comparisons based on hazard ratios).

Conclusions And Relevance: Nivolumab treatment was associated with long-term survival in a subset of heavily pretreated patients with advanced melanoma, RCC, or NSCLC. Characterizing factors associated with long-term survival may inform treatment approaches and strategies for future clinical trial development.

Trial Registration: ClinicalTrials.gov identifier: NCT00730639.
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http://dx.doi.org/10.1001/jamaoncol.2019.2187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659167PMC
October 2019

Archaea dominate oxic subseafloor communities over multimillion-year time scales.

Sci Adv 2019 06 19;5(6):eaaw4108. Epub 2019 Jun 19.

Department of Earth and Environmental Sciences, Paleontology & Geobiology, Ludwig-Maximilians-Universität München, 80333 Munich, Germany.

Ammonia-oxidizing archaea (AOA) dominate microbial communities throughout oxic subseafloor sediment deposited over millions of years in the North Atlantic Ocean. Rates of nitrification correlated with the abundance of these dominant AOA populations, whose metabolism is characterized by ammonia oxidation, mixotrophic utilization of organic nitrogen, deamination, and the energetically efficient chemolithoautotrophic hydroxypropionate/hydroxybutyrate carbon fixation cycle. These AOA thus have the potential to couple mixotrophic and chemolithoautotrophic metabolism via mixotrophic deamination of organic nitrogen, followed by oxidation of the regenerated ammonia for additional energy to fuel carbon fixation. This metabolic feature likely reduces energy loss and improves AOA fitness under energy-starved, oxic conditions, thereby allowing them to outcompete other taxa for millions of years.
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http://dx.doi.org/10.1126/sciadv.aaw4108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584578PMC
June 2019

Cardiovascular and Metabolic Toxicity of Abiraterone in Castration-resistant Prostate Cancer: Post-marketing Experience.

Clin Genitourin Cancer 2019 06 12;17(3):e592-e601. Epub 2019 Mar 12.

Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI; VA Ann Arbor Healthcare System, Ann Arbor, MI.

Introduction: Abiraterone improves survival in metastatic castration-resistant prostate cancer (mCRPC) but may result in the development or worsening of comorbid conditions. We assessed the course of these conditions in patients receiving abiraterone in clinical practice and compared outcomes with those in clinical trials.

Materials And Methods: Medical records of patients with mCRPC who started abiraterone at an academic institution between 2012 and 2015 were reviewed for emergency department (ED) visits, hospitalizations, and the development and/or worsening of key comorbid conditions while on abiraterone. Patient characteristics and adverse events were compared with those from clinical trials.

Results: In a cohort of 174 patients, 28% experienced either the development or worsening of a comorbid disease; 8% required an ED visit or hospitalization owing to known adverse effects of abiraterone. Increasing age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.17), higher prostate-specific antigen at initiation of treatment (OR, 1.68; 95% CI, 1.18-2.47), preexisting uncontrolled hypertension (OR, 7.61; 95% CI, 1.22-38.70), congestive heart failure (OR, 7.61; 95% CI, 1.22-38.70), and cardiac arrhythmias (OR, 4.73; 95% CI, 1.39-15.12) were associated with increased odds of an ED visit or hospitalization owing to known adverse effects of abiraterone. The rate of discontinuation (6%) was similar to 1 phase III trial that demonstrated the drug's efficacy in chemotherapy-naive patients.

Conclusion: Few patients discontinued abiraterone owing to toxicity; however, the fact that over one-quarter of patients experienced the development or worsening of cardiovascular and metabolic diseases warrants development of team-based approaches to the management of these comorbid conditions.
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http://dx.doi.org/10.1016/j.clgc.2019.03.001DOI Listing
June 2019

Detection of CTC Clusters and a Dedifferentiated RNA-Expression Survival Signature in Prostate Cancer.

Adv Sci (Weinh) 2019 Jan 15;6(2):1801254. Epub 2018 Nov 15.

Department of Chemical Engineering University of Michigan 2300 Hayward Street Ann Arbor MI 48109 USA.

Rates of progression and treatment response in advanced prostate cancer are highly variable, necessitating non-invasive methods to assess the molecular characteristics of these tumors in real time. The unique potential of circulating tumor cells (CTCs) to serve as a clinically useful liquid biomarker is due to their ability to inform via both enumeration and RNA expression. A microfluidic graphene oxide-based device (GO Chip) is used to isolate CTCs and CTC clusters from the whole blood of 41 men with metastatic castration-resistant prostate cancer. Additionally, the expression of 96 genes of interest is determined by RT-qPCR. Multivariate analyses are conducted to determine the genes most closely associated with overall survival, PSA progression, and radioclinical progression. A preliminary signature, comprising high expression of stemness genes and low expression of epithelial and mesenchymal genes, potentially implicates an undifferentiated CTC phenotype as a marker of poor prognosis in this setting.
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http://dx.doi.org/10.1002/advs.201801254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343066PMC
January 2019

A phase 1 trial of SGN-CD70A in patients with CD70-positive, metastatic renal cell carcinoma.

Cancer 2019 04 9;125(7):1124-1132. Epub 2019 Jan 9.

University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.

Background: Cluster of differentiation 70 (CD70) is frequently expressed in renal cell carcinoma (RCC) and has immunomodulatory properties. An antibody-drug conjugate targeting CD70, SGN-CD70A, was developed to treat patients with CD70-positive RCC.

Methods: The objective of this phase 1, open-label, dose-escalation, multicenter study was to evaluate the safety and tolerability of SGN-CD70A and establish its maximum tolerated dose in patients with CD70-positive, metastatic RCC (mRCC). All subtypes of RCC were permitted, and no limit was set on the number of prior therapies. Safety assessments consisted of monitoring and recording all adverse events (AEs) and dose-limiting toxicities (DLTs). Treatment response was assessed by radiographic tumor evaluation according to the Response Evaluation Criteria for Solid Tumors, version 1.1. A model-based, modified continual-reassessment method was used to estimate the probabilities of DLT and response.

Results: The maximum tolerated dose was determined to be 30 μg/kg, with thrombocytopenia as the DLT. The most common AEs were fatigue (67%), anemia (61%), and thrombocytopenia (56%). Of 18 enrolled patients, 1 achieved a partial response and 13 achieved stable disease, for a clinical benefit rate of 78%. Limitations of the study included the heavily pretreated nature of patients, receipt of a median of 4 prior lines of therapy (range, 1-8 prior lines of therapy), and diminishing response potential.

Conclusions: The modest antitumor activity of SGN-CD70A does not support its development in mRCC. However, given the high disease control rate in a heavily pretreated population and the modest toxicity profile, CD70 remains of interest because of its immunomodulatory properties.
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http://dx.doi.org/10.1002/cncr.31912DOI Listing
April 2019

A phase 1 dose escalation and expansion study of Tarextumab (OMP-59R5) in patients with solid tumors.

Invest New Drugs 2019 08 28;37(4):722-730. Epub 2018 Dec 28.

START, San Antonio, TX, USA.

Purpose This Phase I trial evaluated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of tarextumab (OMP-5948), a novel cross-reactive antibody which binds and selectively inhibits signaling via both Notch2 and Notch3, in adult patients with advanced malignancies. Methods Standard 3 + 3 design with tarextumab 0.5, 1, 2.5, or 5 mg/kg weekly, or 5, 7.5, or 10 mg/kg every other week, or 7.5 mg every 3 weeks. Dose-limiting toxicities (DLT) were assessed during the first 28 days. Results Forty-two patients received tarextumab (21 weekly, 15 every other week, 6 every three weeks). 2/6 subjects at the 5 mg/kg weekly dose, 2/3 at 10 mg/kg every other week, and 0/6 at 7.5 mg/kg every three weeks had a DLT. The maximum tolerated dose (MTD) was 2.5 mg/kg weekly, and 7.5 mg/kg on the every other and every three week schedules. Gastrointestinal (GI) toxicity was the most common adverse event with diarrhea (81%), fatigue (48%), nausea (45%), anorexia (38%), and vomiting (38%) and abdominal pain and constipation (24% each). Biomarker analysis showed regulation of stem cell and Notch gene signaling. Conclusion Tarextumab was generally well-tolerated at doses <2.5 mg weekly and 7.5 mg/kg every other and every third week. Diarrhea was dose-limiting above these levels, but relatively easily managed at lower doses. Inhibition of Notch pathway signaling was demonstrated at these doses. ClinicalTrials.gov Identifier: NCT01277146.
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http://dx.doi.org/10.1007/s10637-018-0714-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647865PMC
August 2019

Impact of summer season on pre-hospital time delays in women and men undergoing primary percutaneous coronary intervention.

Sci Total Environ 2019 Mar 26;656:322-330. Epub 2018 Nov 26.

Montreal Heart Institute, Montreal, Canada; Department of Medicine, Université de Montréal, Montreal, Canada.

Background: Pre-hospital delays have been associated with poor outcomes in patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). It is currently unknown how environmental variables affect treatment delays in these patients.

Methods And Results: The association between environmental variables, time to treatment including transportation times and adverse in-hospital events was assessed in 1828 consecutive patients with STEMI undergoing primary PCI between 2010 and 2014 in the Montreal metropolitan area. Median[Q1;Q3] total ischemia time was significantly longer during summer season (April-September) as compared to winter season (October-March, 201[140;305] min vs 187[126;266] min, p = 0.022). This difference between seasons was due to a significant increase in median decision time to seek treatment for symptoms during summer (90[46;185] min vs 78[40;156], p = 0.004). The former peaked during July and August and was most pronounced in men. Hence, outside temperature and summer season were identified as strong predictors of prolonged decision time in patients with STEMI (p < 0.001 and p = 0.002, respectively). Transportation times slightly increased during winter season and snow fall, this difference, however, was not significant (p = 0.46). A significant increase in in-hospital adverse outcomes following primary PCI was observed during summer season as compared to winter season (7.2% vs 4.8%, p = 0.032). Accordingly, multivariate logistic regression models adjusted for baseline variables identified summer season as a strong predictor of periprocedural adverse events (OR 1.83, 95% CI 1.2-3.11, p = 0.037).

Conclusion: Contrary to our initial hypothesis, pre-hospital delays in patients with STEMI are considerably longer and associated with adverse in-hospital outcomes during summer season. Considering the consequences of global warming, it is imperative that educational efforts targeting patients' perception are implemented to counter treatment delays.
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http://dx.doi.org/10.1016/j.scitotenv.2018.11.363DOI Listing
March 2019

Towards a 3D GeSbTe phase change memory with integrated selector by non-aqueous electrodeposition.

Faraday Discuss 2019 02;213(0):339-355

School of Electronics and Computer Science, University of Southampton, Southampton, SO17 1BJ, UK.

We have recently reported a new method for the electrodeposition of thin film and nanostructured phase change memory (PCM) devices from a single, highly tuneable, non-aqueous electrolyte. The quality of the material was confirmed by phase cycling via electrical pulsed switching of both 100 nm nano-cells and thin film devices. This method potentially allows deposition into extremely small confined cells down to less than 5 nm, 3D lay-outs that require non-line-of-sight techniques, and seamless integration of selector devices. As electrodeposition requires a conducting substrate, the key condition for electronic applications based on this method is the use of patterned metal lines as the working electrode during the electrodeposition process. In this paper, we show the design and fabrication of a 2D passive memory matrix in which the word lines act as the working electrode and nucleation site for the growth of confined cells of Ge-Sb-Te. We will discuss the precursor requirement for deposition from non-aqueous, weakly coordinating solvents, show the transmission electron microscopy analysis of the electrodeposition growth process and elemental distribution in the deposits, and show the fabrication and characterisation of the Ge-Sb-Te memory matrix.
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http://dx.doi.org/10.1039/c8fd00126jDOI Listing
February 2019

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037).

J Clin Oncol 2018 Nov 28;36(32):3223-3230. Epub 2018 Sep 28.

Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.

Purpose: Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported.

Patients And Methods: Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks.

Results: Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in ≥ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non-small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies.

Conclusion: Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.
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http://dx.doi.org/10.1200/JCO.2018.78.9602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225502PMC
November 2018

A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors.

Invest New Drugs 2019 06 19;37(3):461-472. Epub 2018 Sep 19.

University of Michigan, Ann Arbor, MI, USA.

Purpose Navicixizumab (OMP-305B83) is a bispecific antibody that inhibits delta-like ligand 4 and vascular endothelial growth factor. This Phase 1a trial assessed escalating doses of navicixizumab in refractory solid tumors patients. Design A 3 + 3 dose escalation design was used followed by the treatment of additional patients in an expansion cohort. Study objectives were determination of the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, immunogenicity and efficacy. Results Sixty-six patients were treated once every 3 weeks in 8 dose-escalation cohorts (0.5, 1, 2.5, 3.5, 5, 7.5, 10, and 12.5 mg/kg) and an expansion cohort (7.5 mg/kg). The median age was 60 years and 68% of the patients were female. The most commonly enrolled tumor types were ovarian (12), colorectal (11) and breast, pancreatic, uterine and endometrial (4 each) cancers. As only 1 dose limiting toxicity occurred, the maximum tolerated dose was not reached, but 7.5 mg/kg was chosen as the dose for the expansion cohort. The treatment related adverse events (≥15% of patients) were hypertension (57.6%), headache (28.8%), fatigue (25.8%), and pulmonary hypertension (18.2%). Pulmonary hypertension was mostly asymptomatic at doses ≤5 mg/kg (6 Gr1, 1 Gr2), but was more severe at higher doses (4 Gr2, 1 Gr3). Navicixizumab's half-life was 11.4 days and there was a moderate (29%) incidence of anti-drug antibody formation. Four patients (3 ovarian cancer, 1 uterine carcinosarcoma) had a partial response and 17 patients had stable disease. Nineteen patients had a reduction in the size of their target lesions including 7/11 patients with ovarian cancer. Four patients remained on study for >300 days and 2 of these patients were on study for >500 days. Conclusions Navicixizumab can be safely administered with manageable toxicities and these data showed preliminary signs of antitumor activity in multiple tumor types, but was most promising in ovarian cancer. As a result these data justify its continued development in combination Phase 1b clinical trials.
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http://dx.doi.org/10.1007/s10637-018-0665-yDOI Listing
June 2019

Thermal Atomic Layer Etching of Silica and Alumina Thin Films Using Trimethylaluminum with Hydrogen Fluoride or Fluoroform.

ACS Appl Mater Interfaces 2018 Sep 4;10(37):31784-31794. Epub 2018 Sep 4.

Department of Materials Science and Engineering , University of Texas at Dallas , Richardson , Texas 75080 , United States.

Thermal atomic layer etching (ALE) is an emerging technique that involves the sequential removal of monolayers of a film by alternating self-limiting reactions, some of which generate volatile products. Although traditional ALE processes rely on the use of plasma, several thermal ALE processes have recently been developed using hydrogen fluoride (HF) with precursors such as trimethylaluminum (TMA) or tin acetylacetonate. While HF is currently the most effective reagent for ALE, its potential hazards and corrosive nature have motivated searches for alternative chemicals. Herein, we investigate the feasibility of using fluoroform (CHF) with TMA for the thermal ALE of SiO and AlO surfaces and compare it to the established TMA/HF process. A fundamental mechanistic understanding is derived by combining in situ Fourier transform infrared spectroscopy, ex situ X-ray photoemission spectroscopy, ex situ low-energy ion scattering, and ex situ spectroscopic ellipsometry. Specifically, we determine the role of TMA, the dependence of the etch rate on precursor gas pressure, and the formation of a residual fluoride layer. Although CHF reacts with TMA-treated oxide surfaces, etching is hindered by the concurrent deposition of a fluorine-containing layer, which makes it unfavorable for etching. Moreover, since fluorine contamination can be deleterious to device performance and its presence in thin films is an inherent problem for established ALE processes using HF, we present a novel method to remove the residual fluorine accumulated during the ALE process by exposure to water vapor. XPS analysis herein reveals that an AlO film etched using TMA/HF at 325 °C contains 25.4 at. % fluorine in the surface region. In situ exposure of this film to water vapor at 325 °C results in ∼90% removal of the fluorine. This simple approach for fluorine removal can easily be applied to ALE-treated films to mitigate contamination and retain surface stoichiometry.
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http://dx.doi.org/10.1021/acsami.8b10899DOI Listing
September 2018

A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma.

Invest New Drugs 2019 04 22;37(2):297-306. Epub 2018 Aug 22.

University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Dr. SPC 591, Ann Arbor, MI, 48109, USA.

Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure.
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http://dx.doi.org/10.1007/s10637-018-0655-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440937PMC
April 2019

Multimodal imaging provides insight into targeted therapy response in metastatic prostate cancer to the bone.

Am J Nucl Med Mol Imaging 2018 5;8(3):189-199. Epub 2018 Jun 5.

Department of Radiology, University of Michigan Ann Arbor, Michigan, United States of America.

Metastatic prostate cancer to bone remains incurable, driving efforts to develop individualized, targeted therapies to improve clinical outcomes while limiting adverse side-effects. Due to the complexity in cellular signaling pathways and the interaction between cancer and its microenvironment, multiparametric imaging approaches for treatment response may improve understanding of the biological effects of therapy. An orthotopic model of castration resistant prostate cancer (CRPC) bone metastasis was treated with the tyrosine kinase inhibitor Cabozantinib (CABO). Response was assessed using CT to monitor bone volumes, Tc-MDP SPECT for bone metabolism, and anatomical and diffusion MRI for tumor volume and cell death. A concurrent clinical trial of CABO for CRPC patients also evaluated multimodality imaging in correlation with standard response criteria. Response in the preclinical study found significant slowing in tumor growth rate (P<0.01), rise in tumor apparent diffusion coefficient (ADC, P<0.001), and drop in Tc-MDP adsorption (P<0.05). Loss of bone volume did not slow with treatment, attributed to the highly aggressive and osteolytic nature of the PC3 cell line. Clinical trial analysis found only a single subject who progressed after 12 weeks of therapy. Imaging at 6 weeks corroborated the 12-week radiological assessment with positive response visible as increased ADC and decreased vascular metrics. Conversely, the subject who progressed at 12 weeks had no change in ADC, and substantial drops in vascular metrics. These results showcase a multifaceted translational imaging approach for detecting targeted treatment response with effective blockade of tumor vascularization, tumor cell kill, and reduced proliferation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056245PMC
June 2018
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