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Article ; Online: Emergence and onward transmission of a SARS-CoV-2 E484K variant among household contacts of a bamlanivimab-treated patient.

Sabin, Arick P / Richmond, Craig S / Kenny, Paraic A

Diagnostic microbiology and infectious disease

2022 Volume 103, Issue 1, Page(s) 115656

Abstract: The implementation of monoclonal antibody therapeutics during the COVID-19 pandemic altered the selective pressures encountered by SARS-CoV-2, raising the possibility of selection for resistant variants. Within-host viral evolution was reported in ... ...

Abstract	The implementation of monoclonal antibody therapeutics during the COVID-19 pandemic altered the selective pressures encountered by SARS-CoV-2, raising the possibility of selection for resistant variants. Within-host viral evolution was reported in treated immunocompromised individuals but whether this signifies a real risk of onward transmission is unclear. We used a regional SARS-CoV-2 sequencing program to monitor lineages with clinically relevant variants in identified patients, which facilitated analysis of parameters potentially relevant to new variant emergence. Here we describe a newly acquired spike E484K mutation detected within the B.1.311 lineage. Multiple individuals in 2 households of the same extended family were infected. The timing and patterns of spread were consistent with de novo emergence of this E484K variant in the bamlanivimab-treated index patient. Our study suggests that the selective pressures introduced by the widespread administration of these antibodies may warrant increased genomic surveillance to identify and mitigate spread of therapy-induced variants.
MeSH term(s)	Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; COVID-19 ; Humans ; Mutation ; Pandemics ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; bamlanivimab (45I6OFJ8QH)
Language	English
Publishing date	2022-02-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	604920-5
ISSN	1879-0070 ; 0732-8893
ISSN (online)	1879-0070
ISSN	0732-8893
DOI	10.1016/j.diagmicrobio.2022.115656
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Article ; Online: Exceptional Response to Crizotinib With Subsequent Response to Cabozantinib in Metastatic, ROS1-GOPC Fusion-Mutated Breast Cancer.

O'Neil, Sean R / Weber, Garrett A / Deming, Dustin A / Burkard, Mark E / Kenny, Paraic A / Richmond, Craig S / Parsons, Benjamin M

JCO precision oncology

2023 Volume 7, Page(s) e2300174

MeSH term(s)	Humans ; Crizotinib ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins ; Anilides ; Neoplasms ; Golgi Matrix Proteins ; Adaptor Proteins, Signal Transducing
Chemical Substances	cabozantinib (1C39JW444G) ; Crizotinib (53AH36668S) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Proto-Oncogene Proteins ; Anilides ; ROS1 protein, human (EC 2.7.10.1) ; GOPC protein, human ; Golgi Matrix Proteins ; Adaptor Proteins, Signal Transducing
Language	English
Publishing date	2023-07-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2473-4284
ISSN (online)	2473-4284
DOI	10.1200/PO.23.00174
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Article ; Online: Acquisition and onward transmission of a SARS-CoV-2 E484K variant among household contacts of a bamlanivimab-treated patient

Sabin, Arick P / Richmond, Craig S / Kenny, Paraic A

medRxiv

Abstract: The implementation of monoclonal antibody therapeutics during the COVID19 pandemic has altered the selective pressures encountered by SARS-CoV-2, raising the possibility of selection for variants resistant to one or more monoclonal antibodies and ... ...

Abstract	The implementation of monoclonal antibody therapeutics during the COVID19 pandemic has altered the selective pressures encountered by SARS-CoV-2, raising the possibility of selection for variants resistant to one or more monoclonal antibodies and subsequent transmission into the wider population. Early studies indicated that monoclonal antibody treatment in immunocompromised individuals could result in within-host viral evolution preferentially affecting epitopes recognized by these antibodies, although whether this signifies a real risk of transmissible antibody resistant virus is unclear. In this study we have taken advantage of a regional SARS-CoV-2 genomic surveillance program encompassing regions in Wisconsin, Minnesota and Iowa to monitor the introduction or de novo emergence of SARS-Cov-2 lineages with clinically relevant variants. Here we describe a newly acquired E484K mutation in the SARS-CoV-2 spike protein detected within the B.1.311 lineage. Multiple individuals in two related households were infected. The timing and patterns of subsequent spread were consistent with de novo emergence of this E484K variant in the initially affected individual who had been treated with bamlanivimab monotherapy. The subsequent transmission to close contacts occurred several days after the resolution of symptoms and the end of this patient9s quarantine period. Our study suggest that the selective pressures introduced by the now widespread administration of these antibodies may warrant increased genomic surveillance to identify and mitigate spread of therapy-induced variants.
Keywords	covid19
Language	English
Publishing date	2021-10-05
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2021.10.02.21264415
Database	COVID19

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Article ; Online: Optimized infection control practices augment the robust protective effect of vaccination for ESRD patients during a hemodialysis facility SARS-CoV-2 outbreak.

Meller, Megan E / Pfaff, Bridget L / Borgert, Andrew J / Richmond, Craig S / Athas, Deena M / Kenny, Paraic A / Sabin, Arick P

American journal of infection control

2022 Volume 50, Issue 10, Page(s) 1118–1124

Abstract: Background: While dialysis patients are at greater risk of serious SARS-CoV-2 complications, stringent infection prevention measures can help mitigate infection and transmission risks within dialysis facilities. We describe an outbreak of 14 cases ... ...

Abstract	Background: While dialysis patients are at greater risk of serious SARS-CoV-2 complications, stringent infection prevention measures can help mitigate infection and transmission risks within dialysis facilities. We describe an outbreak of 14 cases diagnosed in a hospital-based outpatient ESRD facility over 13 days in the second quarter of 2021, and our coordinated use of epidemiology, viral genome sequencing, and infection control practices to quickly end the transmission cycle. Methods: Symptomatic patients and staff members were diagnosed by RT-PCR. Facility-wide screening utilized SARS-CoV-2 antigen tests. SARS-CoV-2 genome sequences were obtained from residual diagnostic specimens. Results: Of the 106 patients receiving dialysis in the facility, 10 were diagnosed with SARS-CoV-2 infection, as was 1 patient support person. Of 3 positive staff members, 2 were unvaccinated and had provided care for 6 and 4 of the affected patients, respectively. Sequencing demonstrated that all cases in the cluster shared an identical B.1.1.7./Alpha substrain. Attack rates were greatest among unvaccinated patients and staff. Vaccine effectiveness was 88% among patients. Conclusions: Prompt recognition of an infection cluster and rapid intervention efforts successfully ended the outbreak. Alongside consistent adherence to core infection prevention measures, vaccination was highly effective in reducing disease incidence and morbidity in this vulnerable population.
MeSH term(s)	COVID-19/epidemiology ; COVID-19/prevention & control ; Disease Outbreaks/prevention & control ; Humans ; Infection Control ; Kidney Failure, Chronic/complications ; Kidney Failure, Chronic/therapy ; Renal Dialysis/adverse effects ; SARS-CoV-2 ; Vaccination
Language	English
Publishing date	2022-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	392362-9
ISSN	1527-3296 ; 0196-6553
ISSN (online)	1527-3296
ISSN	0196-6553
DOI	10.1016/j.ajic.2022.06.025
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Article ; Online: Optimized infection control practices augment the robust protective effect of vaccination for ESRD patients during a hemodialysis facility SARS-CoV-2 outbreak

Meller, Megan E / Pfaff, Bridget L / Borgert, Andrew J / Richmond, Craig S / Athas, Deena M / Kenny, Paraic A / Sabin, Arick P

medRxiv

Abstract: Background: While dialysis patients are at greater risk of serious SARS-CoV-2 complications, stringent infection prevention measures can help mitigate the risk of infection and transmission within dialysis facilities. We describe an outbreak of 14 cases ... ...

Abstract	Background: While dialysis patients are at greater risk of serious SARS-CoV-2 complications, stringent infection prevention measures can help mitigate the risk of infection and transmission within dialysis facilities. We describe an outbreak of 14 cases diagnosed in a 13-day period between May and June of 2021 in a hospital-based ESRD facility, and our coordinated use of epidemiology, viral genome sequencing, and infection control practices to quickly end the cycle of transmission. Methods: Symptomatic patients and staff members were diagnosed via RT-PCR tests. Facility-wide screening was conducted using rapid SARS-CoV-2 antigen tests. SARS-CoV-2 genome sequences were obtained from residual diagnostic PCR specimens. Results: Of the 106 patients who received dialysis in the facility, 10 were diagnosed with SARS-CoV-2 infection, as was one patient support person. Of three positive staff members, two were unvaccinated and had provided care for six and four of the affected patients, respectively. Sequencing demonstrated that all the cases in the cluster shared an identical B.1.1.7./Alpha substrain. Attack rates were greatest among unvaccinated patients and staff. Vaccine effectiveness was 88% among patients. Conclusions: Prompt recognition of an infection cluster and rapid intervention efforts successfully ended the outbreak. Alongside consistent adherence to core infection prevention measures, vaccination was highly effective in reducing disease incidence and morbidity in this vulnerable population.
Keywords	covid19
Language	English
Publishing date	2022-03-25
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2022.03.18.22272356
Database	COVID19

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Article ; Online: Acquisition of Cabozantinib-Sensitive MET D1228N Mutation During Progression on Crizotinib in MET-Amplified Triple-Negative Breast Cancer.

Parsons, Benjamin M / Meier, David R / Richmond, Craig S / Gurda, Grzegorz T / Lofgren, Kristopher A / Burkard, Mark E / Deming, Dustin A / Kenny, Paraic A

Clinical breast cancer

2020 Volume 20, Issue 4, Page(s) e433–e438

Abstract: Background: Targeting of somatic MET mutations using crizotinib has led to strong clinical responses, most frequently in patients with lung cancer, raising the possibility of adopting similar treatment strategies in patients with MET alterations in ... ...

Abstract	Background: Targeting of somatic MET mutations using crizotinib has led to strong clinical responses, most frequently in patients with lung cancer, raising the possibility of adopting similar treatment strategies in patients with MET alterations in other cancer types. Patient and methods: We describe a patient with advanced triple-negative breast cancer with a 30-fold amplification of MET. Next-generation sequencing of pre- and postprogression biopsies was performed to identify the resistance mechanism emerging after an initial exceptional response to crizotinib. The response of the resistance mutant to type I and II MET inhibitors was assessed in cultured cells. Results: After progressing on crizotinib, a MET-D1228N mutation was detected, which is located in the crizotinib-binding region of the MET kinase domain. Experimental studies demonstrated that this mutation confers complete resistance to crizotinib yet retains cabozantinib sensitivity. Treatment of the patient with cabozantinib led to a subjective improvement in clinical symptoms, but the patient progressed after 7 weeks. Conclusion: Although MET mutations are rare in breast cancer, these patients may experience substantial clinical benefit from crizotinib treatment. Nevertheless, drug resistance owing to on-target MET mutations will likely be frequently encountered and comprehensive mechanistic studies to assess sensitivity of these mutants to a series of potential second-line therapies may help guide subsequent treatment for these patients.
MeSH term(s)	Adult ; Amino Acid Substitution/drug effects ; Anilides/pharmacology ; Anilides/therapeutic use ; Biopsy ; Breast/pathology ; Crizotinib/pharmacology ; Crizotinib/therapeutic use ; DNA Mutational Analysis ; Disease Progression ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Female ; Gene Amplification ; Humans ; Male ; Positron Emission Tomography Computed Tomography ; Primary Cell Culture ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Proto-Oncogene Proteins c-met/genetics ; Pyridines/pharmacology ; Pyridines/therapeutic use ; Treatment Outcome ; Triple Negative Breast Neoplasms/diagnosis ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/pathology ; Tumor Cells, Cultured
Chemical Substances	Anilides ; Protein Kinase Inhibitors ; Pyridines ; cabozantinib (1C39JW444G) ; Crizotinib (53AH36668S) ; MET protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
Language	English
Publishing date	2020-02-19
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2106734-X
ISSN	1938-0666 ; 1526-8209
ISSN (online)	1938-0666
ISSN	1526-8209
DOI	10.1016/j.clbc.2020.02.003
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Zs.A 5800: 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)
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Article ; Online: SARS-CoV-2 sequencing reveals rapid transmission from college student clusters resulting in morbidity and deaths in vulnerable populations

Richmond, Craig S / Sabin, Arick P / Jobe, Dean A / Lovrich, Steven D / Kenny, Paraic A

medRxiv

Abstract: College reopening decisions during the SARS-CoV-2 pandemic represent a trade-off between competing risks to students, faculty and staff, and college finances. Additionally, risks taken in reopening colleges can impose significant burdens on individuals ... ...

Abstract	College reopening decisions during the SARS-CoV-2 pandemic represent a trade-off between competing risks to students, faculty and staff, and college finances. Additionally, risks taken in reopening colleges can impose significant burdens on individuals living in surrounding communities. Many colleges that reopened for in-person instruction have reported frequent SARS-CoV-2 outbreaks. La Crosse County, Wisconsin experienced a substantial SARS-CoV-2 outbreak (2,002 cases in September 2020) that coincided with the return to in-person instruction at three local academic institutions. Genomic sequencing of SARS-CoV-2 cases in La Crosse during that period found rapid expansion of two viral substrains. Although the majority of cases were among college-age individuals, from a total of 111 genomes sequenced we identified rapid transmission of the virus into more vulnerable populations. Eight sampled genomes represented two independent transmission events into two skilled nursing facilities, resulting in two fatalities. Our study highlights the very significant risks imposed by college administrator reopening decisions, not just on college-associated populations, but on vulnerable individuals in surrounding communities.
Keywords	covid19
Language	English
Publishing date	2020-10-14
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2020.10.12.20210294
Database	COVID19

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Article ; Online: SARS-CoV-2 sequencing reveals rapid transmission from college student clusters resulting in morbidity and deaths in vulnerable populations

Richmond, Craig S / Sabin, Arick P / Jobe, Dean A / Lovrich, Steven D / Kenny, Paraic A

Abstract	College reopening decisions during the SARS-CoV-2 pandemic represent a trade-off between competing risks to students, faculty and staff, and college finances. Additionally, risks taken in reopening colleges can impose significant burdens on individuals living in surrounding communities. Many colleges that reopened for in-person instruction have reported frequent SARS-CoV-2 outbreaks. La Crosse County, Wisconsin experienced a substantial SARS-CoV-2 outbreak (2,002 cases in September 2020) that coincided with the return to in-person instruction at three local academic institutions. Genomic sequencing of SARS-CoV-2 cases in La Crosse during that period found rapid expansion of two viral substrains. Although the majority of cases were among college-age individuals, from a total of 111 genomes sequenced we identified rapid transmission of the virus into more vulnerable populations. Eight sampled genomes represented two independent transmission events into two skilled nursing facilities, resulting in two fatalities. Our study highlights the very significant risks imposed by college administrator reopening decisions, not just on college-associated populations, but on vulnerable individuals in surrounding communities.
Keywords	covid19
Publisher	MedRxiv; WHO
Document type	Article ; Online
Note	WHO #Covidence: #20210294
DOI	10.1101/2020.10.12.20210294
Database	COVID19

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Article ; Online: Outbreak or pseudo-outbreak? Integrating SARS-CoV-2 sequencing to validate infection control practices in a dialysis facility.

Pfaff, Bridget L / Richmond, Craig S / Sabin, Arick P / Athas, Deena M / Adams, Jessica C / Meller, Megan E / Usha, Kumari / Schmitz, Sarah A / Simmons, Brian J / Borgert, Andrew J / Kenny, Paraic A

American journal of infection control

2021 Volume 49, Issue 10, Page(s) 1232–1236

Abstract: Background: The COVID-19 pandemic poses a particularly high risk for End Stage Renal Disease (ESRD) patients so rapid identification of case clusters in ESRD facilities is essential. Nevertheless, with high community prevalence, a series of ESRD ... ...

Abstract	Background: The COVID-19 pandemic poses a particularly high risk for End Stage Renal Disease (ESRD) patients so rapid identification of case clusters in ESRD facilities is essential. Nevertheless, with high community prevalence, a series of ESRD patients may test positive contemporaneously for reasons unrelated to their shared ESRD facility. Here we describe a series of 5 cases detected within 11 days in November 2020 in a hospital-based 32-station ESRD facility in Southwest Wisconsin, the subsequent facility-wide testing, and the use of genetic sequence analysis to evaluate links between cases. Methods: Four patient cases and one staff case were identified in symptomatic individuals by RT-PCR. Facility-wide screening was conducted using rapid SARS-CoV-2 antigen tests. SARS-CoV-2 genome sequences were obtained from residual diagnostic specimens. Results: Facility-wide screening of 47 staff and 107 patients identified no additional cases. Residual specimens from 4 of 5 cases were available for genetic sequencing. Clear genetic differences proved that these contemporaneous cases were not linked. Conclusions: With high community prevalence, epidemiological data alone is insufficient to deem a case cluster an outbreak. Cluster evaluation with genomic data, when available with a short turn-around time, can play an important role in infection prevention and control response programs.
MeSH term(s)	COVID-19 ; Disease Outbreaks ; Humans ; Infection Control ; Pandemics ; Renal Dialysis ; SARS-CoV-2 ; Sequence Analysis
Language	English
Publishing date	2021-08-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	392362-9
ISSN	1527-3296 ; 0196-6553
ISSN (online)	1527-3296
ISSN	0196-6553
DOI	10.1016/j.ajic.2021.08.001
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Article ; Online: Sequential treatment failures in response to BRAF/MEK and immune checkpoint inhibitors mediated by MAP2K2 and B2M mutations in melanoma.

Richmond, Craig S / Vallatharasu, Yazhini / Deviley, Jake A / Vos, Cullen R / Parsons, Benjamin M / Kenny, Paraic A

Experimental and molecular pathology

2019 Volume 110, Page(s) 104260

Abstract: Although the treatment of metastatic melanoma has been significantly improved by both anti-BRAF/MEK and checkpoint immunotherapies, resistance to these treatment modalities remains a substantial clinical problem. Multiple clinical studies are addressing ... ...

Abstract	Although the treatment of metastatic melanoma has been significantly improved by both anti-BRAF/MEK and checkpoint immunotherapies, resistance to these treatment modalities remains a substantial clinical problem. Multiple clinical studies are addressing the optimal sequencing of these agents in larger patient cohorts, but successful long-term individualized treatment will likely require the elucidation of resistance mechanisms from post-progression samples. Here, we describe a patient with BRAF-V600E-positive metastatic melanoma who was sequentially treated with BRAF/MEK inhibitors (dabrafenib/trametinib) and checkpoint inhibitor immunotherapy (nivolumab, followed by pembrolizumab). After the emergence of resistance, whole exome sequencing was performed, implicating MAP2K2 and B2M mutations in loss of response to anti-BRAF/MEK and anti-PD1 therapies, respectively.
MeSH term(s)	Antibodies, Monoclonal, Humanized/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Humans ; Imidazoles/administration & dosage ; MAP Kinase Kinase 2/antagonists & inhibitors ; MAP Kinase Kinase 2/genetics ; MAP Kinase Kinase Kinases/antagonists & inhibitors ; MAP Kinase Kinase Kinases/metabolism ; Male ; Melanoma/drug therapy ; Melanoma/genetics ; Middle Aged ; Mutation ; Nivolumab/administration & dosage ; Oximes/administration & dosage ; Protein Kinase Inhibitors/administration & dosage ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Pyridones/administration & dosage ; Pyrimidinones/administration & dosage ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Treatment Failure ; beta 2-Microglobulin/antagonists & inhibitors ; beta 2-Microglobulin/genetics
Chemical Substances	Antibodies, Monoclonal, Humanized ; B2M protein, human ; Imidazoles ; Oximes ; Protein Kinase Inhibitors ; Pyridones ; Pyrimidinones ; beta 2-Microglobulin ; Nivolumab (31YO63LBSN) ; trametinib (33E86K87QN) ; pembrolizumab (DPT0O3T46P) ; MAP2K2 protein, human (EC 2.7.1.-) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP Kinase Kinase 2 (EC 2.7.12.2) ; dabrafenib (QGP4HA4G1B)
Language	English
Publishing date	2019-05-11
Publishing country	Netherlands
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207655-x
ISSN	1096-0945 ; 0014-4800
ISSN (online)	1096-0945
ISSN	0014-4800
DOI	10.1016/j.yexmp.2019.104260
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