Browsing by Subject "Antineoplastic Agents, Immunological"

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    ItemOpen Access
    Effect at One Year of Adjuvant Trastuzumab for HER2+ Breast Cancer Combined with Radiation or an Anthracycline on Left Ventricular Ejection Fraction.
    (The American journal of cardiology, 2020-06) Andersen, Mousumi M; Ayala-Peacock, Diandra; Bowers, Jessie; Kooken, Banks W; D'Agostino, Ralph B; Jordan, Jennifer H; Vasu, Sujethra; Thomas, Alexandra; Klepin, Heidi D; Brown, Doris R; Hundley, W Gregory
    To determine the impact of radiation therapy (XRT) in addition to trastuzumab (TZB) adjuvant chemotherapy for HER2+ breast cancer on left ventricular systolic function, we assessed demographics, oncologic treatment history including XRT exposure, and serial measurements of left ventricular ejection fraction (LVEF) in 135 consecutively identified women receiving TZB for treatment of adjuvant breast cancer. Longitudinal mixed effects models were fit to identify baseline to treatment changes in LVEF among those receiving TZB with or without concomitant anthracycline or XRT. Women averaged 53 ± 3 years in age, 77% were white, 62% patients had 1 or more cardiovascular risk factors at baseline, and mean duration of TZB was 11 ± 5 months. Seventy-seven women were treated with XRT and received between 4000 and 5500 cGy of radiation. The LVEF declined by an average of 3.4% after 1 year for those in the study. Relative to baseline upon completion of adjuvant TZB, LVEF remained reduced for those receiving anthracycline with or without XRT (p=0.002 for both), or XRT alone (p=0.002), but not in those without these therapies. Amongst patients treated only with XRT and TZB, LVEF declined 3.1% on average in those with left-sided disease and 6.9% on average in those with right-sided disease (p= 0.06, p= 0.008 respectively). Among women receiving TZB for adjuvant treatment of HER-2 positive breast cancer, the administration of XRT, anthracycline, or the combination of the 2 is associated with a persistent post-treatment as opposed to a temporary treatment related decline in LVEF.
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    First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800.
    (Journal of neuro-oncology, 2018-08) Miller, Sarah E; Tummers, Willemieke S; Teraphongphom, Nutte; van den Berg, Nynke S; Hasan, Alifia; Ertsey, Robert D; Nagpal, Seema; Recht, Lawrence D; Plowey, Edward D; Vogel, Hannes; Harsh, Griffith R; Grant, Gerald A; Li, Gordon H; Rosenthal, Eben L

    Introduction

    Maximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection.

    Methods

    Fluorescently labeled cetuximab-IRDye800 was systemically administered to three patients 2 days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue.

    Results

    The mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0 ± 0.5) compared to non-CE tumors (1.2 ± 0.3; p = 0.02). The TBR was higher at a 100 mg dose than at 50 mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70 mg with 50 mg of dye and 10 mg with 100 mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50 mg dose, 98.2% for 100 mg dose) and specific (66.3% for 50 mg dose, 69.8% for 100 mg dose) for viable tumor tissue in CE tumors while normal peri-tumoral tissue showed minimal fluorescence.

    Conclusion

    This first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas.
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    Identification of a Germline Pyrin Variant in a Metastatic Melanoma Patient With Multiple Spontaneous Regressions and Immune-related Adverse Events.
    (Journal of immunotherapy (Hagerstown, Md. : 1997), 2022-07) Oswalt, Cameron J; Al-Rohil, Rami N; Theivanthiran, Bala; Haykal, Tarek; Salama, April KS; DeVito, Nicholas C; Holtzhausen, Alisha; Ko, Dennis C; Hanks, Brent A
    The mechanisms underlying tumor immunosurveillance and their association with the immune-related adverse events (irAEs) associated with checkpoint inhibitor immunotherapies remain poorly understood. We describe a metastatic melanoma patient exhibiting multiple episodes of spontaneous disease regression followed by the development of several irAEs during the course of anti-programmed cell death protein 1 antibody immunotherapy. Whole-exome next-generation sequencing studies revealed this patient to harbor a pyrin inflammasome variant previously described to be associated with an atypical presentation of familial Mediterranean fever. This work highlights a potential role for inflammasomes in the regulation of tumor immunosurveillance and the pathogenesis of irAEs.
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    Preclinical and Coclinical Studies in Prostate Cancer.
    (Cold Spring Harbor perspectives in medicine, 2018-04-02) Chen, Ming; Pandolfi, Pier Paolo
    Men who develop metastatic castration-resistant prostate cancer (mCRPC) will invariably succumb to their disease. Thus there remains a pressing need for preclinical testing of new drugs and drug combinations for late-stage prostate cancer (PCa). Insights from the mCRPC genomic landscape have revealed that, in addition to sustained androgen receptor (AR) signaling, there are other actionable molecular alterations and distinct molecular subclasses of PCa; however, the rate at which this knowledge translates into patient care via current preclinical testing is painfully slow and inefficient. Here, we will highlight the issues involved and discuss a new translational platform, "the co-clinical trial project," to expedite current preclinical studies and optimize clinical trial and experimental drug testing. With this platform, in vivo preclinical and early clinical studies are closely aligned, enabling in vivo testing of drugs using genetically engineered mouse models (GEMMs) in defined genetic contexts to personalize individual therapies. We will discuss the principles and essential components of this novel paradigm, representative success stories and future therapeutic options for mCRPC that should be explored.