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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 4_suppl ( 2018-02-01), p. 386-386
    Abstract: 386 Background: The efficacy of immune checkpoint inhibition (CPI) has not been established in ABC. GM-CSF modulates immune effector cells and has demonstrated safety and improved survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial aims to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Design: Simon’s 2-stage. Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior CPI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 Safety Cohort) or in cycles 1 and 2 (Stage 2). Endpoints: 1 ◦ : Progression-free survival at 6 months (PFS6) with H 0 25% vs. H 1 50%. Key 2 ◦ : Safety, overall response rate (ORR) and duration (DOR), OS, PD-L1 expression. Exploratory: PBMC and tumor immune cell profiles, tumor genotype, microsatellite (in)stability (MSI or MSS). Results: Accrual has completed with 27 patients (pts) enrolled 5/2016-6/2017: F/M 13/14; median age 61 (range 37-77); intrahepatic 19 (70%), extrahepatic 7 (26%), mixed 1 (4%) cholangiocarcinoma; stage IVA/B 85%, II/III 15%; median prior therapies 2 (range 1-6). Adverse events (AE): Related grade(Gr) ≥3 AE occurred in 4/27 (15%) pts including immune-related (ir)AE of Gr4 diabetes mellitus and Gr3 thrombocytopenia in 1 pt each. Gr≤2 irAE in ≥5% were: arthralgia (33%), dry eye/mouth (15%), hyperthyroid/thyroiditis (15%), hypothyroid (15%), neuropathy (11%), rash (11%), and adrenal insufficiency (7%). Steroids were required in 3/27 (11%) pts. Disposition: 19 pts removed for PD, 1 for Gr2 irAE; 7 pts remain active on treatment. Median time on treatment: 6 cycles (range 2-22+). Best response by RECIST 1.1: Partial response (PR) in 5/24 (21%) evaluable pts (1 MSI, 4 MSS); minor regression and ≥50% CA 19-9 decline in 2 additional MSS pts for 11+ and 16+ months. PBMC analyses show changes in expression of activating and inhibitory markers including PD-1 on various immune cell populations. Conclusions: PEM plus induction GM-CSF is safe and tolerable in ABC. Durable radiographic and tumor marker responses including MSS pts warrant further study. PFS6, OS, and correlative analyses are ongoing. Clinical trial information: NCT02703714.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 4087-4087
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 3
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 11033-11033
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 11033-11033
    Abstract: 11033 Background: Immune-related adverse events (irAE) requiring hospitalization involve complex, multidisciplinary management. Expertise in oncology and/or the affected organ(s) may be required in the form of inpatient consults. Trainees (fellows and residents) often provide such consults. irAE consults may be rich learning opportunities, but it is unclear whether the cognitive load, or mental effort, required for these complex cases may overwhelm trainees and impair learning. To investigate the cognitive load of irAE consults, we surveyed trainees who had recently completed an irAE consult and compared the results to a control dataset. Methods: Between October 2021 and January 2023, we identified patients hospitalized due to irAEs at the University of California, San Francisco by reviewing patient lists (oncology consults and hospital medicine admissions) daily. We emailed the published Consult Cognitive Load (CCL) survey to any residents or fellows who had signed initial consult notes in the charts of identified patients. The CCL uses 4-point scales to measure three types of cognitive load related to one consult: intrinsic load (IL) related to the consult task itself, extraneous load (EL) related to distractions during the consult, and germane load (GL), the mental effort left over for learning after IL and EL are accounted for. IL, EL, and GL scores range from 4 to 16. Using two-tailed t tests, we compared mean IL, EL, GL, and total cognitive load (the sum of IL, EL, and GL) between the irAE group and a control group of fellows and residents who performed a variety of consults at five University of California hospitals during a 2018-2019 study (n = 142). Detecting a difference of 0.5 with a variance of 0.5 (calculated for the control group), 80% power, and 95% confidence required an irAE group sample size of 18. Results: Of 36 trainees contacted for the irAE group, 18 completed the CCL (50% response rate, 61% fellows, 39% residents). The irAE group and the control group (80% fellows, 17% residents, 3% not reported) spanned multiple specialties. Total cognitive load (p = 0.49) and IL (p = 0.95) did not differ. EL was significantly lower (8.4 vs 10.3, p = 0.002) and GL higher (11.9 vs 10.8, p = 0.04) in the irAE group. Conclusions: Trainees experienced similar cognitive load when performing irAE consults as compared to other consults, but the sources of cognitive load differed. Trainees performing irAE consults expended less mental effort on distractions (EL) and more on learning (GL) as compared to other consults. The consult task itself (IL) imposed a similar amount of cognitive load whether or not it was an irAE consult. Complex irAE cases did not overwhelm trainees or preclude learning; rather, trainees performing irAE consults exhibited a sharpened focus on the task at hand and extracted more learning than trainees performing other consults. Educators should foster trainee exposure to inpatient irAE consults to promote worthwhile learning.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 2668-2668
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 2668-2668
    Abstract: 2668 Background: Immune checkpoint inhibitors (CPI) are known to rarely cause new onset diabetes (CPI DM). While rare, this adverse event is quite challenging for patients and clinicians to manage. Therefore, it is important to identify risk factors and clinical characteristics. This is the first comprehensive, multi-institutional study of CPI-DM across multiple agents and cancer types. Methods: The NCI Cancer Therapy Program (CTEP) database of adverse events (AEs) was queried for AEs related to diabetes (Grade 3 or 4 hyperglycemia, Acidosis including Diabetic Ketoacidosis (DKA), glucose intolerance and diabetes mellitus) among 6,925 patients who had been treated with a PD-(L)1 inhibitor alone or in combination from 6/2015 to 12/2019. Each AE report was reviewed and classified as due to CPI DM, new onset type 2 diabetes mellitus (T2DM), T2DM exacerbation without medication non-compliance, existing DM with medication non-compliance, or association with steroids (SDM). CPI DM was diagnosed based on: evidence of insulin deficiency either through presentation in DKA or low c-peptide with need for long term basal bolus insulin to maintain euglycemia and/or positive islet autoantibodies. Results: In total, there were 82 cases with at least one of these AEs; 41 had CPI-DM, 22 had SDM, 1 had new T2DM, 4 had T2DM exacerbation, 3 had medication noncompliance and 11 had acidosis not attributable to diabetes or had insufficient data. After excluding non-hyperglycemic acidosis, 57.8% had CPI-DM. Furthermore, if not on steroids and in good compliance with diabetes medications, 89.1% had CPI-DM. The incidence of CPI-DM was 0.59%; it was most common on combination PD-1/CTLA-4 inhibitor therapy (0.85%, 15/1767), followed by PD-(L)1 inhibitor monotherapy (0.54%, 18/3354), followed by CPIs combined with additional agents including chemotherapy and targeted agents (0.44%, 8/1804)(p = 0.25). Hospitalization was required for 87.5% of CPI-DM cases with 74.3% of those requiring an inpatient endocrine consult. All but one CPI-DM case had an endocrine consult at as either an inpatient or outpatient. Conclusions: While rare, this cohort shows the large health care burden of CPI-DM and that any hyperglycemia, and especially marked hyperglycemia, should be treated as CPI-DM until proven otherwise. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 5
    In: eLife, eLife Sciences Publications, Ltd, Vol. 11 ( 2022-10-27)
    Abstract: Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2022
    detail.hit.zdb_id: 2687154-3
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  • 6
    Online Resource
    Online Resource
    Spandidos Publications ; 2017
    In:  Molecular and Clinical Oncology Vol. 6, No. 4 ( 2017-04), p. 589-592
    In: Molecular and Clinical Oncology, Spandidos Publications, Vol. 6, No. 4 ( 2017-04), p. 589-592
    Type of Medium: Online Resource
    ISSN: 2049-9450 , 2049-9469
    Language: English
    Publisher: Spandidos Publications
    Publication Date: 2017
    detail.hit.zdb_id: 2796865-0
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  • 7
    Online Resource
    Online Resource
    Elsevier BV ; 2019
    In:  The Lancet Diabetes & Endocrinology Vol. 7, No. 6 ( 2019-06), p. 421-423
    In: The Lancet Diabetes & Endocrinology, Elsevier BV, Vol. 7, No. 6 ( 2019-06), p. 421-423
    Type of Medium: Online Resource
    ISSN: 2213-8587
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
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  • 8
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 18 ( 2021-09-15), p. 5131-5140
    Abstract: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE). Experimental Design: In patients with non–small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI. Results: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52–0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29–1.37; AUROC = 0.6] . The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08–1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit. Conclusions: Thyroid irAEs were associated with response to anti–PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 9
    In: JCI Insight, American Society for Clinical Investigation, Vol. 7, No. 17 ( 2022-9-8)
    Type of Medium: Online Resource
    ISSN: 2379-3708
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2022
    detail.hit.zdb_id: 2874757-4
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  • 10
    Online Resource
    Online Resource
    The Endocrine Society ; 2020
    In:  Journal of the Endocrine Society Vol. 4, No. Supplement_1 ( 2020-05-08)
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 4, No. Supplement_1 ( 2020-05-08)
    Abstract: Background: Autoimmune diabetes mellitus (CPI-DM) caused by immune checkpoint inhibitors (CPIs) is rare- occurring in approximately one percent of patients exposed to this form of cancer immunotherapy. Typically, this immune related adverse event occurs after treatment with PD-1/PD-L1 inhibitors. It is characterized by abrupt insulinopenia leading to acute hyperglycemia. Beta cell autoantibodies are positive in approximately half the cases. DKA is common at the time of diagnosis. Recovery of beta cell function has been reported in only two case reports. In one case, spontaneous resolution occurred following cessation of CPI therapy and in the other the patient was treated with infliximab for concurrent inflammatory arthritis prior to resolution of CPI-DM. Clinical Case: A 50-year-old woman was started on adjuvant pembrolizumab for stage IIIC melanoma following surgery. She had no prior history of diabetes mellitus, thyroid disease, or other autoimmune disease. Pre-infusion random blood glucoses (RBG) were 84 - 105 mg/dL. After 36 weeks, she developed hypothyroidism (TSH 17.5 (0.5-4.1 mIU/L), FT4 6 (10-18 ug/dL)) and started levothyroxine. Pembrolizumab was continued. For nine weeks following her diagnosis with CPI- hypothyroidism, her pre-infusion RBG ranged from 102-133. At 45 weeks (15 cycles) after initiating pembrolizumab, her RBG was 260. She was not on glucocorticoids and had no other signs of inflammation or stress. Pembrolizumab was continued. Just prior to her 17th cycle, 48 weeks after initiating adjuvant pembrolizumab, her RBG was 482 with a normal anion gap and HCO3, and her A1c was 8.9%. Her last dose of pembrolizumab was held. She started metformin and liraglutide. In just three weeks, a random c-peptide was inadequate at 1.7 (0.8-3.5 ng/mL) with a recent RBG of 220 and A1c of 10.3%, showing the acuity and extremity of her hyperglycemia. Over the course of the year, she has achieved excellent glucose control (A1c 6.3-7.1) on this regimen with preservation of insulin production (c-peptides 1.4-1.8 with matched RBG 92-129). She never required insulin. Her beta cell autoantibodies are negative. Clinical Lessons: This is a case of CPI-DM in which the patient did not have complete loss of beta-cell function. The acuity of her hyperglycemia is not consistent with new onset type 2 diabetes. At diagnosis, her c-peptide was inadequate suggesting insufficient insulin production rather than insulin resistance. Therefore, her hyperglycemia is more consistent with CPI-DM than type 2 diabetes. Atypically, she did not progress to fulminant beta cell failure, which could have been due to cessation of pembrolizumab (which is not unique to this case), initiation of liraglutide and metformin, or other unknown immunologic responses that inhibited full beta cell loss. This case raises the possibility of preventing fully insulin dependent CPI-DM if hyperglycemia is caught and treated early.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2020
    detail.hit.zdb_id: 2881023-5
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