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  • 1
    Online Resource
    Online Resource
    Suitability factors of core needle biopsies for pharmacodynamic (PD) studies.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 2540-2540
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 2540-2540
    Abstract: 2540 Background: There are different requirements of biopsies for diagnosis vs. pharmacologic evaluation of drug mechanism biomarkers. Evaluation of core needle biopsy pairs collected pre-dose and at a defined timepoint post-dose provides insight into the pharmacodynamics of agents in early development. Adequate biopsies are key for quantifying response of the tumor cell population to molecular drug action. Tumor heterogeneity and variable tumor content make many biopsy pairs unsuitable for biomarker evaluation with any assay platform (microscopy, immunoassay, etc.). We analyzed biopsies obtained from the Developmental Therapeutics Clinic (DTC) for suitability for PD assays. Methods: Specimens obtained from 2010-2016 across 4 trials were analyzed. For microscopy measurements, biopsy pairs collected using image guidance are snap-frozen, thawed under fixative, and embedded in paraffin with control tissues. The likelihood of finding optimal regions for analysis is maximized by preparing a series of sections with H & E stained flanking slides, and annotation by an anatomic pathologist. Results: Of 112 biopsies evaluated, 26% were found to contain 〈 5% tumor, making them inadequate for quantitative microscopy due to a mixture of factors, with the primary factor being predominantly non-neoplastic tissue, followed by extensive mucin content, necrosis, fibrosis, inadequate size and tissue artifact post-collection. Another 20% contained ≤25% tumor, and in this group, tumor segmentation methodology during image analysis increased the rate of evaluable biopsies. 56% of tissues had 〉 25% tumor and were suitable for analysis. Conclusions: Improved communication between oncologists, radiologists and pathologists is key to a better understanding of factors that affect suitability of biopsies for robust PD biomarker analyses. NCI’s DTC has implemented protocol modifications including increased tissue collection and frequent case reviews by the Phase 1 team, interventional radiologists and PD team aimed at understanding features during image guidance that relate to suitability. Implementation of a scoring system has allowed the assessment of suitability of biopsies for analysis. Funded by NCI Contract No HHSN261200800001E.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.2540
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Phase I and Preliminary Phase II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 16 ( 2017-08-15), p. 4633-4641
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 16 ( 2017-08-15), p. 4633-4641
    Abstract: Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium. Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum. Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months). Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-3171
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
    Online Resource
    Online Resource
    Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics : A Randomized Clinical Trial
    American Medical Association (AMA) ; 2013
    In:  JAMA Vol. 310, No. 8 ( 2013-08-28), p. 804-
    Details
    In: JAMA, American Medical Association (AMA), Vol. 310, No. 8 ( 2013-08-28), p. 804-
    Type of Medium: Online Resource
    ISSN: 0098-7484
    URL: Article
    DOI: 10.1001/jama.2013.109309
    RVK:
    XA 10000
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2013
    detail.hit.zdb_id: 2958-0
    detail.hit.zdb_id: 2018410-4
    SSG: 5,21
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  • 4
    Online Resource
    Online Resource
    Are all biopsies created equal? comparison of extended sextant prostate biopsies performed with and without MRI-TRUS fusion biopsy system.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 6_suppl ( 2018-02-20), p. 117-117
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 6_suppl ( 2018-02-20), p. 117-117
    Abstract: 117 Background: Extended sextant systematic prostate biopsies have the inherent risk of under-sampling prostate cancer. Fusion guided multiparametric magnetic resonance imaging (mpMRI) biopsies have been employed to better represent the disease and guide treatment. We sought to determine if due to heightened suspicion of cancer and/or visualization of mpMRI there were any discrepancies between systematic biopsies done with a Fusion System as compared to those done without (TRUS alone). Methods: From a prospectively collected database, we performed a review collecting age, race, clinical stage, PSA, and time until repeat systematic biopsy as part of fusion guided biopsy (IB). We also collected pathology results reported as Gleason Score (GS), for both the patients’ OB and our IB. Patients were stratified into groups based on time between OB and IB/fusion biopsy ( 〈 6 months, 〈 1 year and 〈 2 years). Results: 69 patients with a previous OB underwent combined fusion and IB within our designated time intervals. Cancer detection rates between the OB and IB results were similar at 6 months, 1 year and 2 years (80 vs 90%, 87.5 vs 87.5% and 65 vs 69%). Detection rates of GS ≥ 3+4 were higher with IB within 12 months compared with IB from 12-24 months (72.7 vs 40.9%, p = 0.03 OR 3.85 (1.09-13.66). Of the patients who were upgraded (n = 24), 54.2% (n = 13) went from benign pathology to a diagnosis of prostate adenocarcinoma. Of all OB GS 3+3 (n = 31), 29% were restaged to higher risk disease on IB. Rates of IB upgrading were similar within 6 months, 1 year and 2 year, 40%, 33.33% and 31.91%). Patients who were upgraded on IB compared to those who were not upgraded were of similar age (67.0 ± 6.53 vs 66.50 ± 6.47), race (17.4% African-American vs 13%), PSA (7.60 ± 5.61 vs 7.50 ± 4.39) and prostate volume on MRI (51.30 ± 26.87 vs 59.26 ± 38.52). Conclusions: A systematic biopsy at our referral center during a mpMRI fusion biopsy was over 3.5 times more likely to detect GS ≥ 3+4 when done within 1 year of the outside biopsy. There continued to be a risk, 34.7% overall, of disease upgrading in all time periods. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.6_suppl.117
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    Ability of multiparametric magnetic resonance imaging (MRI) to predict prostate tumor heterogeneity on targeted biopsy.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 6_suppl ( 2018-02-20), p. 113-113
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 6_suppl ( 2018-02-20), p. 113-113
    Abstract: 113 Background: Prostate cancer (PCa) can show heterogeneous histology within lesions. MRI-targeted biopsy (Tbx) of the prostate improves PCa detection, but sampling within lesions has yet to be standardized. Furthermore, Tbx results are often heterogeneous as evidenced by differing histologic grades of Tbx cores within the same lesion. This introduces potential variability in biopsy results, on which clinical decisions are made. Here we aim to characterize lesion heterogeneity and identify predictive multiparametric MRI (mpMRI) features. Methods: A cohort of men who underwent mpMRI and Tbx between 2014-2017 were selected for analysis from a prospectively maintained database. To characterize lesion heterogeneity, only men with ≥2 positive Tbx cores were included. Histologic grades were scored according to International Society of Urological Pathology (ISUP) grades. Lesion heterogeneity, reported as a heterogeneity index (HI), was calculated as the difference of the average ISUP grades of Tbx cores per lesion from the maximum sampled ISUP grade of that lesion. Statistical analyses identified associations between imaging features and lesion heterogeneity. Results: 157 lesions in 114 patients met inclusion criteria. Maximum ISUP grade ranged from 1 to 5, with a median ISUP grade of 2. Higher ISUP grades were associated with greater lesion heterogeneity, HI for ISUP grade ≥3 = 0.58±0.11 vs 〈 3 = 0.29±0.08, p = 0.0001. In addition, increasing lesion size on mpMRI was associated with greater lesion heterogeneity, HI for ≥2cm = 0.52±0.14 vs 〈 2cm = 0.32±0.08, p = 0.0096. Finally, higher mpMRI suspicion scores were associated with increased heterogeneity vs lower suspicion scores, p = 0.048. Conclusions: mpMRI aids in characterizing PCa lesion heterogeneity to predict variability of histologic grades on Tbx. This information can assist Tbx planning to potentially reduce risks of upgrading on final pathology. Future research will examine how lesion heterogeneity can impact risk stratification and clinical decision-making for patients and practitioners. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH and NIH Medical Research Scholars Program.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.6_suppl.113
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 6
    Online Resource
    Online Resource
    Is BMI a risk factor for active surveillance progression in patients with prostate cancer diagnosed by MRI-Trus fusion biopsy?
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 6_suppl ( 2018-02-20), p. 124-124
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 6_suppl ( 2018-02-20), p. 124-124
    Abstract: 124 Background: MRI−TRUS fusion biopsy (FBx) use in the diagnosis of prostate cancer (PCa) results in a more accurate assessment of disease burden and has increasingly been incorporated into urologic practice. In addition, with more men choosing active surveillance (AS) and the reports of increased PCa aggressiveness with obesity, we wanted to study the impact of obesity on the risk of PCa progression in men on AS diagnosed and followed by MRI and MRI−TRUS FBx. Methods: A retrospective review was performed on a prospectively maintained database of all men who underwent MRI−TRUS FBx at our institution from January 2007 to May 2015. Patient demographics, clinical data, imaging, pathology, treatment and outcomes were recorded. Patients who enrolled on AS were stratified by BMI into normal weight (BMI 18.5−24.9), overweight (BMI 25.0−29.9), and obese (BMI ≥ 30.0). Statistical analysis was performed using SPSS software. Results: 204 men were enrolled in AS. Within the AS cohort, 51 (25%) had a normal weight, 101 (49.5%) were overweight, and 52 (25.5%) were obese. Age, BMI, PSA and mean estimated progression free survival time are described for each of these groups in Table 1. The overall rate of progression was 32.8%. Of the patients who progressed, 18 (26.9%) were normal weight, 32 (15.7%) were overweight and 17 (25.4%) were obese. On multivariate analysis, BMI was not a risk factor for AS progression, HR = 1.00 (p = 0.99, 95% CI = 0.95−1.06). Conclusions: There is evidence of increased risk of aggressive PCa specific death in obese patients. However, we demonstrate that in patients diagnosed by FBx, obesity does not confer an additional risk of progression on AS. This may be due to the improved characterization of cancer volume and grade by MRI−TRUS fusion biopsy. Further study is required to determine risk factors for AS progression in patients undergoing FBx. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH, Medical Research Scholars Program.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.6_suppl.124
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 7
    Online Resource
    Online Resource
    Phase 1 trial to model primary, secondary, and tertiary dengue using a monovalent vaccine
    Springer Science and Business Media LLC ; 2023
    In:  BMC Infectious Diseases Vol. 23, No. 1 ( 2023-05-23)
    Details
    In: BMC Infectious Diseases, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2023-05-23)
    Abstract: The four co-circulating and immunologically interactive dengue virus serotypes (DENV1-4) pose a unique challenge to vaccine design because sub-protective immunity can increase the risk of severe dengue disease. Existing dengue vaccines have lower efficacy in DENV seronegative individuals but higher efficacy in DENV exposed individuals. There is an urgent need to identify immunological measures that are strongly associated with protection against viral replication and disease following sequential exposure to distinct serotypes. Methods/Design This is a phase 1 trial wherein healthy adults with neutralizing antibodies to zero (seronegative), one non-DENV3 (heterotypic), or more than one (polytypic) DENV serotype will be vaccinated with the live attenuated DENV3 monovalent vaccine rDEN3Δ30/31-7164. We will examine how pre-vaccine host immunity influences the safety and immunogenicity of DENV3 vaccination in a non-endemic population. We hypothesize that the vaccine will be safe and well tolerated, and all groups will have a significant increase in the DENV1-4 neutralizing antibody geometric mean titer between days 0 and 28. Compared to the seronegative group, the polytypic group will have lower mean peak vaccine viremia, due to protection conferred by prior DENV exposure, while the heterotypic group will have higher mean peak viremia, due to mild enhancement. Secondary and exploratory endpoints include characterizing serological, innate, and adaptive cell responses; evaluating proviral or antiviral contributions of DENV-infected cells; and immunologically profiling the transcriptome, surface proteins, and B and T cell receptor sequences and affinities of single cells in both peripheral blood and draining lymph nodes sampled via serial image-guided fine needle aspiration. Discussion This trial will compare the immune responses after primary, secondary, and tertiary DENV exposure in naturally infected humans living in non-endemic areas. By evaluating dengue vaccines in a new population and modeling the induction of cross-serotypic immunity, this work may inform vaccine evaluation and broaden potential target populations. Trial Registration NCT05691530 registered on January 20, 2023.
    Type of Medium: Online Resource
    ISSN: 1471-2334
    URL: Article
    DOI: 10.1186/s12879-023-08299-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2041550-3
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  • 8
    Online Resource
    Online Resource
    Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer (BTC).
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 4_suppl ( 2018-02-01), p. 365-365
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 4_suppl ( 2018-02-01), p. 365-365
    Abstract: 365 Background: Treatment option for patients with advanced BTC is limited and prognosis is poor with a median survival of less than 1 year in the locally advanced or metastatic setting. It has been shown deregulation of the immune system plays an important role in the pathogenesis of BTC. This study aimed to investigate whether tremelimumab (Treme), anti-CTLA4, could be combined safely and feasibly with microwave ablation therapy to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Methods: Patients with refractory BTC were enrolled in a study of monthly Treme (10mg/kg, IV, 6 doses), followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal microwave ablation. Staging image was performed every 8 weeks. Adverse events (AEs) were collected and managed. Tumor samples and peripheral blood samples were collected to perform immune monitoring. Results: Twenty patients with refractory BTC were enrolled. Male: female ratio was 10:10 with median age 56.5 years (range 37-67). Six patients had extrahepatic cholangiocarcinoma (ECC), two patients had gallbladder cancer, whereas the remaining 12 patients had intrahepatic cholangiocarcinoma (ICC). No dose-limiting toxicities were encountered. The common AEs included lymphocytopenia, colitis, adrenal insufficiency, anemia, and elevated transaminases. The most common clinical toxicity was diarrhea. Sixteen patients were evaluable for response analysis, one (6%) patient achieved a confirmed partial response (lasting for 8 months), 6 (37.5%) achieved stable disease with the longest lasting for 9.2 months. Among all 20 patients, median progression free survival, time to progression, and overall survival were 3.4 months (95% CI 2.5-5.2 months), 3.3 months (95% CI: 2.5-4.6 months) and 6.0 months (95% CI 3.8-8.8 months) respectively in this small pilot cohort. T cell receptor (TCR) b screening showed Treme expanded TCR repertoire though non-significantly. RNA seq is ongoing and will be presented. Conclusions: Treme in combination with tumor ablation is a potential new treatment for patients with advanced BTC. TCR repertoire expansion induced by Treme may contribute to treatment benefit. Clinical trial information: NCT01853618.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.4_suppl.365
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 9
    Online Resource
    Online Resource
    Twice-weekly pegylated interferon-α-2a and ribavirin results in superior viral kinetics in HIV/hepatitis C virus co-infected patients compared to standard therapy
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  AIDS Vol. 25, No. 9 ( 2011-06-1), p. 1179-1187
    Details
    In: AIDS, Ovid Technologies (Wolters Kluwer Health), Vol. 25, No. 9 ( 2011-06-1), p. 1179-1187
    Type of Medium: Online Resource
    ISSN: 0269-9370
    URL: Article
    DOI: 10.1097/QAD.0b013e3283471d53
    RVK:
    XA 16838
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 2012212-3
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  • 10
    Online Resource
    Online Resource
    Remarkable vessel enlargement within lung consolidation in COVID-19 compared to AH1N1 pneumonia: A retrospective study in Italy
    Elsevier BV ; 2021
    In:  Heliyon Vol. 7, No. 5 ( 2021-05), p. e07112-
    Details
    In: Heliyon, Elsevier BV, Vol. 7, No. 5 ( 2021-05), p. e07112-
    Type of Medium: Online Resource
    ISSN: 2405-8440
    URL: Article
    DOI: 10.1016/j.heliyon.2021.e07112
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2835763-2
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