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  • 1
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    A phase I study of nivolumab (NIVO) in combination with TheraSphere (Yttrium-90) in patients with advanced hepatocellular cancer.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e16183-e16183
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e16183-e16183
    Abstract: e16183 Background: Significant advances have been made in the management of hepatocellular carcinoma (HCC) with the introduction of locoregional therapies including Theraspere, a treatment utilizing glass microspheres coated in radioactive yttrium-90 (Y-90). Hepatocyte exposure to Y-90 results in immunogenic cell death and tumor-specific immunity, suggesting this treatment may synergize with checkpoint inhibitor therapies to improve response rates and disease control. This abstract presents the results of combination therapy with Y-90 and NIVO in patients with advanced HCC. Methods: This study is a prospective, open-label, phase I clinical trial of NIVO plus Y-90. Eligible patients were diagnosed with advanced HCC (CP A6-B7) and were not transplant or resection candidates. Patients were treated with Y-90 following institutional procedures. The NIVO dose was escalated in a standard 3+3 format. Patients at DL1 began therapy 4 weeks after Y90 administration and received 80 mg of NIVO every two weeks. Patients at DL2 began therapy 2 weeks after Y90 administration and received 240 mg of NIVO every two weeks. The primary objective was to determine a maximum tolerated dose (MTD) of NIVO in combination with Y-90 therapy. Secondary objectives included objective response rate (RECIST v1.1), toxicity evaluation, disease control rate and progression free survival. Results: Fifteen patients were registered to DL1, 8 received Y90 and 6 were eligible and received NIVO. Twelve patients were registered to DL2, 9 were eligible for Y90, 7 were eligible for NIVO and 6 completed therapy. Patients that did not complete therapy either withdrew consent, had a decline in performance status or a worsening in hepatic function. Fifty-nine percent of patients were male (N = 10), 82% were Caucasian (N = 14), 12% were Hispanic or Latino (N = 2) and 6% were African American (N = 1). Of the patients who received both Y90 and NIVO, 82% patients were CP B7. The MTD of NIVO is 240mg given 2 weeks after Y90. The disease control rate was 82% (N = 9/11 with stable disease). Forty-six percent of patients (N = 6) had a decrease in circulating levels of AFP, the most significant change was a decrease from 11,080 ng/mL to 260 ng/mL following cycle 2 of NIVO and normalization by cycle 4 of NIVO. The most common toxicities in both treatment groups were Grade 1-2 elevations in ALT/AST, frequency of these side effects was not higher than expected given this patient population. Conclusions: Therapy with Y-90 and NIVO in advanced HCC was tolerable and a maximum tolerated dose of NIVO was established. Combination therapy resulted in a clinical benefit rate of 82%, with 9 patients achieving stable disease. In a notably sick patient population with advanced CP scores this combination offered good disease control without increasing the adverse event rate. Study was stopped early due to lack of funding. Clinical trial information: NCT02837029.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.e16183
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Pembrolizumab in combination with the oncolytic virus pelareorep in patients progressing on systemic chemotherapy for advanced pancreatic adenocarcinoma: A phase II study.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. e16789-e16789
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e16789-e16789
    Abstract: e16789 Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Analysis of tumor tissue from patients treated with pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination pembrolizumab in patients with PDAC would lead to improved response, effective T-cell recognition of tumor antigens and expand peripheral T-cell repertoire. Methods: This investigator-initiated phase II study enrolled PDAC patients who progressed after first-line treatment. Patients received pelareorep at a dose of 4.5x10 10 TCID 50 IV on Days 1, 2, 3 & 8of Cycle (C) 1, and Days 1 & 8 with C2 onwards. Pembrolizumab was administered on Day 1 of each 21-day cycle at 200 mg IV. Primary objective was overall response rate (ORR) by RECIST v 1.1 criteria. Secondary objectives included evaluation for reovirus replication and immune analysis in peripheral blood and tumor biopsies. The study was designed using Simon’s two-stage design with 90% power and one-sided alpha = 0.025 to compare 10% vs. 35% ORR. A total of ≥2/11 responses were needed to proceed to stage 2. Results: Thirteen patients were enrolled. Disease control was achieved in 30% of the 12 efficacy-evaluable patients. One patient achieved partial response. Three additional patients achieved stable disease. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed a high degree of peripheral repertoire turnover and creation of new T-cell clones during treatment. Immune correlation with efficacy analysis is ongoing. Conclusions: Pelareorep with pembrolizumab showed manageable safety profiles and modest efficacy in an unselected PDAC population. The study will not proceed to stage II, however further evaluation of anti-tumor activity of pelareorep and anti-PD-1 therapy is now planned in biomarker defined patients. Clinical trial information: NCT03723915 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.e16789
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Synthesis and fabrication of BST/SPVdF-co-HFP composites for proton exchange membrane fuel cell applications
    Springer Science and Business Media LLC ; 2022
    In:  Journal of Polymer Research Vol. 29, No. 12 ( 2022-12)
    Details
    In: Journal of Polymer Research, Springer Science and Business Media LLC, Vol. 29, No. 12 ( 2022-12)
    Type of Medium: Online Resource
    ISSN: 1022-9760 , 1572-8935
    URL: Article
    DOI: 10.1007/s10965-022-03358-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2065616-6
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  • 4
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    Genomic Landscape of Advanced Solid Tumors in Circulating Tumor DNA and Correlation With Tissue Sequencing: A Single Institution's Experience
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  JCO Precision Oncology , No. 6 ( 2022-06)
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 6 ( 2022-06)
    Abstract: Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker for baseline characterization and longitudinal monitoring of a tumor throughout disease management. The aim of this study was to evaluate the utility of ctDNA across a wide spectrum of tumor types. METHODS We retrospectively identified 1,763 patients with advanced cancers who had next-generation sequencing of ctDNA or tumor tissue completed by a designated commercial assay at Northwestern University. RESULTS ctDNA identified at least one gene alteration in 90% of patients. The number of detected alterations (NDA) and mutant allele frequency (MAF) of the most frequently mutated genes varied significantly across tumor types, with the highest MAF observed in gastric, colorectal, and breast cancers and the highest NDA observed in colorectal, lung squamous, and ovarian/endometrial cancers. TP53 was the most mutated gene in all tumor types. PIK3CA, ERBB2, BRCA1, and FGFR1 alterations were associated with breast cancer, and ESR1 mutations were exclusively detected in this tumor type. Colorectal cancer was characterized by alterations in KRAS and APC mutations, whereas KRAS, EGFR, PIK3CA, and BRAF mutations were common in lung adenocarcinoma. Concordance between blood and tissue sequencing was notably observed for truncal gene alterations (eg, APC and KRAS), whereas low concordance was often observed in genes associated with treatment resistance mechanisms (eg, RB1 and NF1). Tumor mutational burden (TMB) varied significantly across tumor types, and patients with high MAF or NDA had a significantly higher TMB score with one of the investigated platforms. CONCLUSION The study provided new insights into the ctDNA mutational landscape across solid tumors, suggesting new hypotheses-generating data and caveats for future histotype-agnostic workflows integrated with tissue-based biomarkers such as TMB.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.21.00289
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 5
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    A phase Ib/II study of sotorasib combined with chemotherapy for second-line treatment of KRAS p. G12C–mutated advanced pancreatic cancer.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS4194-TPS4194
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS4194-TPS4194
    Abstract: TPS4194 Background: Kirsten rat sarcoma viral oncogene homolog( KRAS) p.G12C mutation is an oncogenic driver mutation in several solid tumors. Sotorasib is a specific, irreversible, small molecule inhibitor of KRAS G12C that has demonstrated durable clinical benefit in NSCLC, with mild and manageable toxicities. Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related death in the world, although recent advances in chemotherapeutic regimens for metastatic PDAC provide better clinical outcomes. KRAS p.G12C mutations are found in 1-2% of PDAC. Modest single agent activity of Sotorasib was observed in chemo-refractory PDAC patients (pts). Combination of Sotorasib with approved PDAC chemotherapy regimens is expected to enhance antitumor efficacy. This study is designed to evaluate safety, tolerability and efficacy of Sotorasib in combination with second line chemotherapy in pts with KRASp.G12C mutated advanced PDAC who have progressed on first-line chemotherapy. Methods: This investigator initiated study run through Hoosier Cancer Research Network, is a phase Ib/II study evaluating Sotorasib in combination with either Liposomal Irinotecan/5-Fluorouracil/Leucovorin or Gemcitabine/nab-paclitaxel. Physician choice of chemotherapy based on first line chemotherapy regimen used. Histologically confirmed PDAC pts who have KRAS p.G12C mutation identified through tumor or blood based testing, progressed on first-line chemotherapy, adequate organ function and performance status are eligible. A safety lead-in will be conducted to evaluate the safety of Sotorasib at a dose of 960 mg in combination with each of the two chemotherapy regimens. A “3+3” dose de-escalation design will be used for each combination separately. All patients treated at the RP2D in the initial safety cohort will be evaluable for response and included in the first stage of Simon’s two stage design. The phase II trial conducted at the RP2D follows Simon’s two-stage “minimax” design. The trial is designed to test whether addition of Sotorasib to chemotherapy will improve the objective response rate (ORR), from 16% to 31%. In Stage 1, 22 evaluable patients will be enrolled, and the trial will be stopped if 3 or fewer of the 22 evaluable patients respond. If ≥ 4 responses are observed, an additional 28 patients will be enrolled in Stage 2, for a total of 50 evaluable patients. Up to 59 subjects will be enrolled across 15 academic cancer institutions in order to obtain the required number of 50 evaluable subjects, assuming 15% attrition rate. Primary endpoint is to determine the objective response rate (ORR) by RECIST 1.1. The secondary endpoint to evaluate safety, and further evaluate efficacy in terms of disease control rate, duration of response, progression-free survival and overall survival. Correlative endpoints will determine biomarkers based on analysis of blood and/or tumor on study. Clinical trial information: IND 159412.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.TPS4194
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 6
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    A single-arm, phase II study of autophagy modulation using hydroxychloroquine in addition to encorafenib and cetuximab or panitumumab in metastatic BRAF-mutated colorectal cancer refractory to standard therapy.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 4_suppl ( 2023-02-01), p. TPS262-TPS262
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 4_suppl ( 2023-02-01), p. TPS262-TPS262
    Abstract: TPS262 Background: BRAF mutations drive 5-10% of colon cancers. BRAF + EGFR inhibition with encorafenib + cetuximab is standard second-line therapy, per the BEACON trial, but responses are short-lived. Autophagy induction is implicated as a mechanism for this acquired resistance to therapy. Preclinical models have shown that BRAF inhibition leads to increased ATF4 phosphorylation and an overreliance on oxidative phosphorylation, both markers of autophagy induction. Use of hydroxychloroquine (HCQ), an antimalarial agent with anti-autophagy activity, reduces such markers and improves the cellular metabolic profile. This was confirmed clinically in the BAMM trial, a phase I/II study in which patients with advanced BRAF-mutated melanoma received dabrafenib, trametinib and HCQ (Mehnert JM et al, Clin Cancer Res 2022). This study asks a similar question in advanced, BRAF-mutated colon cancer, of whether autophagy inhibition overcomes acquired resistance to BRAF inhibition. Methods: This is a Phase II, single-arm, open-label study to be conducted at Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL. The study was approved by the Northwestern University Institutional Review Board on 9/22/22 (IRB #: STU00217727); clinicaltrials.gov listing is pending. Key eligibility criteria: BRAF-mutated, stage IV colon cancer, with at least one line of therapy; ECOG PS 0/1, preserved organ function, and measurable disease at baseline. Key exclusion criteria: prior treatment with BRAF/MEK inhibitors; history of acute/chronic pancreatitis, psoriasis, or porphyria. Patients will receive standard of care encorafenib 300 mg daily and cetuximab IV weekly (panitumumab IV q 2 weeks can be used per investigator discretion). After a 14-day lead-in, HCQ 400 mg BID will be added. Each cycle is 28 days. CT scans will be done every 2 cycles, and blood will be taken every 2 weeks during the first 2 cycles for metabolomics analysis. The trial utilizes a Simon 2-stage admissible design. 14 patients will be enrolled in stage 1; if 4 or more responses are observed, the trial will continue to Stage 2 in which an additional 24 patients will be enrolled for a total sample size of 38 patients. The primary endpoint is objective response rate (ORR). Secondary endpoints are safety/efficacy, progression-free survival, overall survival and duration of response/stable disease. The exploratory endpoint is changes in markers of autophagy over time. The null hypothesis is an ORR of 20% (per the BEACON trial), and the alternative hypothesis is an ORR of 40%. This is the first trial exploring autophagy modulation in advanced, BRAF-mutated colon cancer. This study aims to show that autophagy inhibition with HCQ circumvents acquired resistance to BRAF + EGFR inhibition in advanced colon cancer.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.4_suppl.TPS262
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Treatment with pembrolizumab in combination with the oncolytic virus pelareorep promotes anti-tumor immunity in patients with advanced pancreatic adenocarcinoma.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 4144-4144
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 4144-4144
    Abstract: 4144 Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). In prior studies, tumor tissue analysis from patients treated with pelareorep shows pelareorep replication, increased T cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab in patients with PDAC would lead to improved responses and anti-tumor immunological changes within peripheral blood and tumor biopsies in responding patients. Methods: PDAC patients who progressed after first-line treatment received pelareorep at a dose of 4.5x10 10 TCID 50 IV on Days 1, 2, 3 & 8 of Cycle (C) 1, and Days 1 & 8 with C2 onwards. Pembrolizumab was administered on Day 1 of each 21-day cycle at 200 mg IV. The primary objective was overall response rate by RECIST v 1.1 criteria. Secondary objectives included evaluating immunological changes within tumor tissue and peripheral blood, performed by multi-plex immunohistochemistry and spectral flow cytometry (Cytek), respectively. Results: Thirteen patients were enrolled. Disease control was achieved in 33% of the 12 efficacy-evaluable patients. One patient achieved a partial response (PR). Three additional patients achieved stable disease (SD). On-treatment tumor biopsies, collected during C1, showed pelareorep replication, increased infiltration of CD8+ T cells and PD-L1+ cells, and decreased expression of VDAC1, a mitochondrial gatekeeper for tumor promotion, relative to archival tissue. Reduced infiltration of Foxp3+ regulatory T cells (Treg) was observed in patients showing tumor response. Peripheral blood was collected at day 1 of each cycle and on C1 day 8. Relative to pretreatment samples, the number of CD8+ effector memory T cells and B cells tend to increase while the number of Treg cells declined in C2 onwards in patients with tumor response. Furthermore, these patients had increased expression of the mitochondrial protein TOMM20 in CD8+ T cells and decreased expression of PD-1 and the H3K27me3 epigenetic mark in Treg. Treatment was well tolerated with most treatment-related adverse events, including flu-like symptoms, being grade 1 or 2. Conclusions: The combination of pelareorep and pembrolizumab showed a manageable safety profile and modest efficacy in an unselected PDAC population. Additional correlation analyses between treatment efficacy and immunological changes will be presented. The anti-tumor activity of pelareorep and checkpoint blockade therapy is being evaluated further in additional ongoing studies. Clinical trial information: NCT03723915.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.4144
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 8
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    Guillain–Barré Syndrome with Preserved Reflexes in a Child after COVID-19 Infection
    Springer Science and Business Media LLC ; 2021
    In:  Indian Journal of Pediatrics Vol. 88, No. 8 ( 2021-08), p. 831-832
    Details
    In: Indian Journal of Pediatrics, Springer Science and Business Media LLC, Vol. 88, No. 8 ( 2021-08), p. 831-832
    Type of Medium: Online Resource
    ISSN: 0019-5456 , 0973-7693
    URL: Article
    DOI: 10.1007/s12098-021-03792-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2065273-2
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  • 9
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    Yttrium-90 Radioembolization of Unresectable Intrahepatic Cholangiocarcinoma: Long-Term Follow-up for a 136-Patient Cohort
    Springer Science and Business Media LLC ; 2022
    In:  CardioVascular and Interventional Radiology Vol. 45, No. 8 ( 2022-08), p. 1117-1128
    Details
    In: CardioVascular and Interventional Radiology, Springer Science and Business Media LLC, Vol. 45, No. 8 ( 2022-08), p. 1117-1128
    Type of Medium: Online Resource
    ISSN: 0174-1551 , 1432-086X
    URL: Article
    DOI: 10.1007/s00270-022-03183-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1458490-6
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  • 10
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    Global burden of chronic respiratory diseases and risk factors, 1990–2019: an update from the Global Burden of Disease Study 2019
    Elsevier BV ; 2023
    In:  eClinicalMedicine Vol. 59 ( 2023-05), p. 101936-
    Details
    In: eClinicalMedicine, Elsevier BV, Vol. 59 ( 2023-05), p. 101936-
    Type of Medium: Online Resource
    ISSN: 2589-5370
    URL: Article
    DOI: 10.1016/j.eclinm.2023.101936
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2946413-4
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