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Article ; Online: The Lung Microbiome in Carcinogenesis and Immunotherapy Treatment.

Kennedy, Kathleen / Khaddour, Karam / Ramnath, Nithya / Weinberg, Frank

2023 Volume 29, Issue 2, Page(s) 61–69

Abstract: Abstract: Lung cancer is the leading cause of cancer-related deaths. Over the past 10 years, significant advances in treatment modalities, including immune checkpoint inhibitor (ICI) blockade, have led to improved outcomes. Elucidating predicative ... ...

Abstract	Abstract: Lung cancer is the leading cause of cancer-related deaths. Over the past 10 years, significant advances in treatment modalities, including immune checkpoint inhibitor (ICI) blockade, have led to improved outcomes. Elucidating predicative biomarkers in responders and nonresponders to ICI will lead to development of therapeutic targets that could enhance ICI efficacy. Recently, the gut microbiome was identified as a predictive biomarker for ICI in patients with multiple cancer types. However, it is unclear how other host microbiomes influence tumorigenesis and response to ICI. Other groups have explored the lung microbiome as it relates to carcinogenesis and immunotherapy efficacy. In this review, we explore the role of the lung microbiome in health and disease. We also review the current state of lung microbiome research as it relates to tumorigenesis and treatments and provide potential insights into how the lung microbiome could improve outcomes in patients with cancer.
MeSH term(s)	Humans ; Immunotherapy/adverse effects ; Microbiota ; Lung Neoplasms/drug therapy ; Carcinogenesis ; Biomarkers ; Cell Transformation, Neoplastic ; Lung
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-03-21
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	2018400-1
ISSN	1540-336X ; 1528-9117 ; 1081-4442
ISSN (online)	1540-336X
ISSN	1528-9117 ; 1081-4442
DOI	10.1097/PPO.0000000000000644
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Article: Case Report: Stereotactic body radiation treatment for immunotherapy escaped oligometastatic progression in cutaneous melanoma and merkel cell carcinoma.

Khaddour, Karam / Zhou, Alice / Butt, Omar / Huang, Jiayi / Ansstas, George

Frontiers in oncology

2023 Volume 13, Page(s) 1276729

Abstract: Oligometastatic progression represents a unique manifestation of tumor immune-escape that can lead to disease progression during treatment with immune checkpoint inhibitor (ICI). The diagnosis and further optimal management of oligometastatic progression ...

Abstract	Oligometastatic progression represents a unique manifestation of tumor immune-escape that can lead to disease progression during treatment with immune checkpoint inhibitor (ICI). The diagnosis and further optimal management of oligometastatic progression through ICI remains unclear. Diagnostic challenges include practical limitations due to the anatomical sites of oligometastatic progression, such as the para-aortic region, where traditional tissue biopsy carries high risk, and circulating-tumor DNA (ctDNA) could aid in diagnosis and disease monitoring as a supplement to surveillance imaging. In this report, we describe two cases of one patient with metastatic melanoma and the other with metastatic Merkel cell carcinoma (MCC) who were treated with ICI and later developed localized resistance due to oligometastatic progression. We further highlight our experience using stereotactic body radiation therapy (SBRT) as a salvage approach to treat the oligometastatic progression. In addition, we describe the temporal and dynamic relationship of circulating-tumor DNA (ctDNA) prior to, during and after SBRT, which highly suggested the diagnosis without obtaining a histological specimen. Our cases highlight a potential role for SBRT in the management of oligometastatic progression. However, large prospective trials are essential to confirm the utility of this approach.
Language	English
Publishing date	2023-09-20
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1276729
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Article: BRAF-MEK inhibitors as steroid-sparing bridge prior to checkpoint blockade therapy in symptomatic intracranial melanoma.

Khaddour, Karam / Johanns, Tanner M / Ansstas, George

Melanoma management

2021 Volume 8, Issue 2, Page(s) MMT55

Abstract: The introduction of immune checkpoint blockade (ICB) and BRAF-MEK inhibitors has substantially improved outcomes in patients with metastatic melanoma. However, several challenging factors may hinder the efficacy of ICB in patients with symptomatic ... ...

Abstract	The introduction of immune checkpoint blockade (ICB) and BRAF-MEK inhibitors has substantially improved outcomes in patients with metastatic melanoma. However, several challenging factors may hinder the efficacy of ICB in patients with symptomatic intracranial metastatic melanoma who are immunosuppressed due to the use of steroids prior to the administration of ICB. This has resulted in the exclusion of patients treated with high dose steroid at baseline from the majority of ICB clinical trials. In addition, despite the high efficacy of BRAF-MEK inhibitors in
Language	English
Publishing date	2021-02-15
Publishing country	England
Document type	Case Reports
ISSN	2045-0885
ISSN	2045-0885
DOI	10.2217/mmt-2020-0022
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Article ; Online: Determining PARP Inhibition as a Treatment Strategy in Melanoma Based on Homologous Recombination Deficiency-Related Loss of Heterozygosity.

Zhou, Alice / Butt, Omar / Ansstas, Michael / Mauer, Elizabeth / Khaddour, Karam / Ansstas, George

Journal of the National Comprehensive Cancer Network : JNCCN

2023 Volume 21, Issue 7, Page(s) 688–693.e3

Abstract: There is a lack of effective treatments for immunotherapy-refectory melanoma. Although PARP inhibitors (PARPi) are an effective treatment strategy in cancers with homologous recombination deficiency (HRD), determining HRD status is challenging in ... ...

Abstract	There is a lack of effective treatments for immunotherapy-refectory melanoma. Although PARP inhibitors (PARPi) are an effective treatment strategy in cancers with homologous recombination deficiency (HRD), determining HRD status is challenging in melanoma. Here, we chart the longitudinal relationship between PARPi response and HRD scores derived from genome-wide loss of heterozygosity (LOH) in 4 patients with metastatic melanoma. When next examining 933 melanoma cases, using an updated threshold, we observed HRD-related LOH (HRD-LOH) in nearly one-third of all cases compared with <10% using traditional gene panels. Taken together, HRD-LOH in refractory melanoma is both a common occurrence and a potential biomarker for response to PARPi.
MeSH term(s)	Humans ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Melanoma/drug therapy ; Melanoma/genetics ; Immunotherapy ; Loss of Heterozygosity ; Homologous Recombination
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2023-07-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2250759-0
ISSN	1540-1413 ; 1540-1405
ISSN (online)	1540-1413
ISSN	1540-1405
DOI	10.6004/jnccn.2022.7102
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Article ; Online: Patterns of initial distant metastases in 151 patients undergoing surveillance for treated Merkel cell carcinoma.

Kim, Emily Y / Liu, Mofei / Giobbie-Hurder, Anita / Bahar, Furkan / Khaddour, Karam / Silk, Ann W / Thakuria, Manisha

Journal of the European Academy of Dermatology and Venereology : JEADV

2024

Abstract: Background: Merkel cell carcinoma (MCC) is associated with high rates of recurrence and distant metastatic progression. Current guidelines for surveillance imaging are not evidence based. Better characterization of the pattern of distant metastatic ... ...

Abstract	Background: Merkel cell carcinoma (MCC) is associated with high rates of recurrence and distant metastatic progression. Current guidelines for surveillance imaging are not evidence based. Better characterization of the pattern of distant metastatic spread will better inform surveillance and facilitate earlier detection of metastases. Objectives: This retrospective study aimed to assess potential relationships between primary tumour site and site of initial distant metastasis, time to distant metastasis, overall survival (OS) and MCC-specific death (MSD). Methods: Patients with local or regional (Stage I-III) disease who were treated with curative intent and progressed to Stage IV were included in this study (n = 151). Fisher's exact test was used to assess differences in patterns of initial distant metastases based on primary tumour site. Time to initial distant metastasis was calculated from date of MCC diagnosis. OS and MSD were calculated from date of initial distant metastasis to date of death from any or MCC-related causes, respectively. Results: Of 151 patients included in analysis, 89 (58.9%) had a single initial distant metastatic site, and 62 (41.1%) had multiple sites. Patients with upper limb primary tumours were significantly less likely to develop distant lymph node or liver metastases (p = 0.02 and 0.04, respectively). Median time to distant metastasis was 11 months (IQR 6.7-17.9 months). Median OS was 15.3 months, and was shorter for patients with liver (7.0 months, p = 0.0004) or bone metastases (8.9 months, p < 0.0001). Using skin/soft tissue metastasis as a reference group, patients with multiple metastatic sites had significantly higher hazards of MSD (HR = 3.46 univariate, 3.77 multivariate analysis). Time to distant metastasis, OS and MSD did not differ by viral status. Conclusion: Sites of initial distant metastasis are related to primary tumour sites and survival outcomes. Because patients often have multiple initial metastases, full-body cross-sectional rather than region-specific imaging may facilitate earlier detection of metastatic disease.
Language	English
Publishing date	2024-03-03
Publishing country	England
Document type	Journal Article
ZDB-ID	1128828-0
ISSN	1468-3083 ; 0926-9959
ISSN (online)	1468-3083
ISSN	0926-9959
DOI	10.1111/jdv.19907
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Zs.A 3492: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 413: Show issues

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Article ; Online: Clinical outcomes and longitudinal circulating tumor DNA changes after treatment with nivolumab and olaparib in immunotherapy relapsed melanoma with detected homologous recombination deficiency.

Khaddour, Karam / Ansstas, Michael / Ansstas, George

Cold Spring Harbor molecular case studies

2021 Volume 7, Issue 5

Abstract: The treatment of immunotherapy relapsed cutaneous melanoma constitutes a challenge in both research and clinical practice fields given the lack of effective therapeutic options. Homologous recombination deficiency (HRD) has been identified in several ... ...

Abstract	The treatment of immunotherapy relapsed cutaneous melanoma constitutes a challenge in both research and clinical practice fields given the lack of effective therapeutic options. Homologous recombination deficiency (HRD) has been identified in several solid cancers including cutaneous melanoma. However, the utility of medications targeting HRD cancer cells is an uncharted territory in melanoma. Moreover, preclinical evidence suggests a synergistic role of combining immune checkpoint blockade (ICB) with drugs targeting HRD cancer cells such as PARP inhibitors. Here, we present a case study of a patient with immunotherapy relapsed melanoma who was found to have detected HRD and was treated with nivolumab (ICB) and olaparib (PARP inhibitors).
MeSH term(s)	Circulating Tumor DNA ; Homologous Recombination ; Humans ; Immunotherapy ; Melanoma/drug therapy ; Melanoma/genetics ; Nivolumab/therapeutic use ; Phthalazines ; Piperazines ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics
Chemical Substances	Circulating Tumor DNA ; Phthalazines ; Piperazines ; Nivolumab (31YO63LBSN) ; olaparib (WOH1JD9AR8)
Language	English
Publishing date	2021-10-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2835759-0
ISSN	2373-2873 ; 2373-2873
ISSN (online)	2373-2873
ISSN	2373-2873
DOI	10.1101/mcs.a006129
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Article ; Online: Addendum: Successful administration of sequential TVEC and pembrolizumab followed by Temozolomide in immunotherapy refractory intracranial metastatic melanoma with acquired B2M mutation.

Khaddour, Karam / Dowling, Joshua / Huang, Jiayi / Council, Martha / Chen, David / Cornelius, Lynn / Johanns, Tanner / Dahiya, Sonika / Ansstas, George

Oncotarget

2023 Volume 14, Page(s) 126

Language	English
Publishing date	2023-02-11
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.28365
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Article: Case report: Real-world experience using a personalized cancer-specific circulating tumor DNA assay in different metastatic melanoma scenarios.

Khaddour, Karam / Zhou, Alice / Butt, Omar H / Budde, Griffin / Malashevich, Allyson Koyen / Ansstas, George

Frontiers in oncology

2022 Volume 12, Page(s) 978996

Abstract: Circulating-tumor DNA (ctDNA) has emerged as an important biomarker for monitoring disease status in cancer patients. Different ctDNA testing platforms have shown promising results in the early detection of disease, monitoring response to treatment, and ... ...

Abstract	Circulating-tumor DNA (ctDNA) has emerged as an important biomarker for monitoring disease status in cancer patients. Different ctDNA testing platforms have shown promising results in the early detection of disease, monitoring response to treatment, and prognostication in metastatic melanoma. However, several challenges exist, including the reduced shedding of ctDNA into the bloodstream in the metastatic setting, differences in sensitivity among various ctDNA assays, and the inherent inability to distinguish tumor-specific mutations from other mutations that are not related to the cancer of interest. Using a ctDNA assay that is designed to detect multiple single-nucleotide variants (SNVs) that are specific to the tumor itself may allow for more accurate monitoring of disease status in metastatic melanoma. In this case series, we describe a real-world experience using a personalized, tumor-informed ctDNA assay to monitor the clinical trajectories of four patients with metastatic melanoma. Our report highlights potential benefits and limitations using ctDNA in this setting to inform clinical decision-making. This report provides a proof of concept of the technique using an mPCR-NGS-based ctDNA assay (Signatera
Language	English
Publishing date	2022-11-17
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.978996
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Article: The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions.

Khaddour, Karam / Johanns, Tanner M / Ansstas, George

Pharmaceuticals (Basel, Switzerland)

2020 Volume 13, Issue 11

Abstract: Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. ... ...

Abstract	Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments.
Language	English
Publishing date	2020-11-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph13110389
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Article ; Online: Novel immunotherapeutic options for BCG-unresponsive high-risk non-muscle-invasive bladder cancer.

Hannouneh, Zein Alabdin / Hijazi, Amjad / Alsaleem, Alaa Aldeen / Hami, Siwan / Kheyrbek, Nina / Tanous, Fadi / Khaddour, Karam / Abbas, Abdulfattah / Alshehabi, Zuheir

Cancer medicine

2023 Volume 12, Issue 24, Page(s) 21944–21968

Abstract: Background: High-risk non-muscle-invasive bladder cancer (HR-NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette-Guérin (BCG) intravesical therapy and the substantial rate of progression into muscle-invasive ... ...

Abstract	Background: High-risk non-muscle-invasive bladder cancer (HR-NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette-Guérin (BCG) intravesical therapy and the substantial rate of progression into muscle-invasive bladder cancer (MIBC). Patients who are BCG-unresponsive have worse prognosis and thus require further management including radical cystectomy (RC), which significantly impacts quality of life. Moreover, the ongoing worldwide shortage of BCG warrants the need for policies that prioritize drug use and utilize alternative treatment strategies. Hence, there is a significant unmet need for bladder preserving therapy in this subset of patients. Methods: To address this issue, we searched the relevant literature in PUBMED for articles published from 2019 through May of 2023 using appropriate keywords. All clinical trials of patients with HR-NMIBC treated with immune-related agents were retrieved from clinicaltrials.gov. Findings and future perspectives: Exploratory treatments for BCG-Unresponsive HR-NMIBC included immune checkpoint inhibitors (ICI), oncolytic viral therapy, cytokine agonists, and other immunomodulators targeting TLR, EpCaM, FGFR, MetAP2, and IDO1. Some combination therapies have been found to work synergistically and are preferred therapeutically over monotherapy. Three drugs-pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec-vncg-have been FDA approved for the treatment of BCG-unresponsive NMIBC in patients who are ineligible for or decline RC. However, all explored treatment options tend to postpone RC rather than provide long-term disease control. Additional combination strategies need to be studied to enhance the effects of immunotherapy. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR-NMIBC is essential for the discovery of new targets and the development of effective treatments.
MeSH term(s)	Humans ; BCG Vaccine/therapeutic use ; Non-Muscle Invasive Bladder Neoplasms ; Quality of Life ; Urinary Bladder Neoplasms/drug therapy ; Immunotherapy ; Neoplasm Invasiveness ; Neoplasm Recurrence, Local
Chemical Substances	BCG Vaccine
Language	English
Publishing date	2023-12-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2659751-2
ISSN	2045-7634 ; 2045-7634
ISSN (online)	2045-7634
ISSN	2045-7634
DOI	10.1002/cam4.6768
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