Publications by authors named "Nicole R LeBoeuf"

63 Publications

A Crisis-Responsive Framework for Medical Device Development Applied to the COVID-19 Pandemic.

Front Digit Health 2021 Mar 22;3. Epub 2021 Mar 22.

Greater Boston Pandemic Fabrication Team (PanFab) c/o Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, MA, United States.

The disruption of conventional manufacturing, supply, and distribution channels during the COVID-19 pandemic caused widespread shortages in personal protective equipment (PPE) and other medical supplies. These shortages catalyzed local efforts to use nontraditional, rapid manufacturing to meet urgent healthcare needs. Here we present a crisis-responsive design framework designed to assist with product development under pandemic conditions. The framework emphasizes stakeholder engagement, comprehensive but efficient needs assessment, rapid manufacturing, and modified product testing to enable accelerated development of healthcare products. We contrast this framework with traditional medical device manufacturing that proceeds at a more deliberate pace, discuss strengths and weakness of pandemic-responsive fabrication, and consider relevant regulatory policies. We highlight the use of the crisis-responsive framework in a case study of face shield design and production for a large US academic hospital. Finally, we make recommendations aimed at improving future resilience to pandemics and healthcare emergencies. These include continued development of open source designs suitable for rapid manufacturing, education of maker communities and hospital administrators about rapidly-manufactured medical devices, and changes in regulatory policy that help strike a balance between quality and innovation.
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http://dx.doi.org/10.3389/fdgth.2021.617106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064560PMC
March 2021

De novo Powered Air-Purifying Respirator Design and Fabrication for Pandemic Response.

medRxiv 2021 Mar 29. Epub 2021 Mar 29.

The rapid spread of COVID-19 and disruption of normal supply chains resulted in severe shortages of personal protective equipment (PPE), particularly devices with few suppliers such as powered air-purifying respirators (PAPRs). A scarcity of information describing design and performance criteria represents a substantial barrier to new approaches to address these shortages. We sought to apply open-source product development to PAPRs to enable alternative sources of supply and further innovation. We describe the design, prototyping, validation, and user testing of locally manufactured, modular, PAPR components, including filter cartridges and blower units, developed by the Greater Boston Pandemic Fabrication Team (PanFab). Two designs, one with a fully custom-made filter and blower unit housing, and the other with commercially available variants (the "Custom" and "Commercial" designs respectively) were developed. Engineering performance of the prototypes was measured and safety validated using NIOSH-equivalent tests on apparatus available under pandemic conditions, at university laboratories. Feedback on designs was obtained from four individuals, including two clinicians working in an ambulatory clinical setting and two research technical staff for whom PAPR use is a standard part of occupational PPE. Respondents rated the PanFab Custom PAPR a 4 to 5 on a 5 Likert-scale 1) as compared to current PPE options, 2) for the sense of security with use in a clinical setting, and 3) for comfort. The three other versions of the designs (with a commercial blower unit, filter, or both) performed favorably, with survey responses consisting of scores ranging from 3-5. Engineering testing and clinical feedback demonstrate that the PanFab designs represents favorable alternative PAPRs in terms of user comfort, mobility, and sense of security. A nonrestrictive license promotes innovation in respiratory protection for current and future medical emergencies.
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http://dx.doi.org/10.1101/2021.03.25.21252076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020994PMC
March 2021

Conversion of Existing UVB Phototherapy Units to UVC Germicidal Chambers for N95 Decontamination: Lessons Learned.

Photobiomodul Photomed Laser Surg 2021 Feb 21;39(2):83-85. Epub 2021 Jan 21.

Greater Boston Pandemic Fabrication Team (PanFab) c/o Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1089/photob.2020.4968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106246PMC
February 2021

Analysis of SteraMist ionized hydrogen peroxide technology in the sterilization of N95 respirators and other PPE.

Sci Rep 2021 01 21;11(1):2051. Epub 2021 Jan 21.

Greater Boston Pandemic Fabrication Team (PanFab) c/o Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, MA, USA.

The COVID-19 pandemic has led to widespread shortages of personal protective equipment (PPE) for healthcare workers, including of N95 masks (filtering facepiece respirators; FFRs). These masks are intended for single use but their sterilization and subsequent reuse has the potential to substantially mitigate shortages. Here we investigate PPE sterilization using ionized hydrogen peroxide (iHP), generated by SteraMist equipment (TOMI; Frederick, MD), in a sealed environment chamber. The efficacy of sterilization by iHP was assessed using bacterial spores in biological indicator assemblies. After one or more iHP treatments, five models of N95 masks from three manufacturers were assessed for retention of function based on their ability to form an airtight seal (measured using a quantitative fit test) and filter aerosolized particles. Filtration testing was performed at a university lab and at a National Institute for Occupational Safety and Health (NIOSH) pre-certification laboratory. The data demonstrate that N95 masks sterilized using SteraMist iHP technology retain filtration efficiency up to ten cycles, the maximum number tested to date. A typical iHP environment chamber with a volume of ~ 80 m can treat ~ 7000 masks and other items (e.g. other PPE, iPADs), making this an effective approach for a busy medical center.
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http://dx.doi.org/10.1038/s41598-021-81365-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819989PMC
January 2021

De novo cutaneous connective tissue disease temporally associated with immune checkpoint inhibitor therapy: A retrospective analysis.

J Am Acad Dermatol 2021 Mar 24;84(3):864-869. Epub 2020 Oct 24.

Harvard Medical School, Boston, MA; Department of Dermatology, Brigham and Women's Hospital, Boston, MA; Center for Cutaneous Oncology, Department of Dermatology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.10.054DOI Listing
March 2021

Predictors of immunotherapy benefit in Merkel cell carcinoma.

Oncotarget 2020 Nov 24;11(47):4401-4410. Epub 2020 Nov 24.

GJS Associated with Laboratory of Cellular Oncology, CCR/NCI, Bethesda, MD, USA.

Merkel cell carcinoma is a rare cancer for which immune checkpoint blockade is standard-of-care for recurrent/metastatic disease. However, not all patients benefit from immunotherapy. A greater understanding of molecular mechanisms and predictive biomarkers are unmet needs. We retrospectively analyzed electronic health records and next-generation sequencing data of 45 patients treated at our institution from 2013 to 2020 to understand clinical and genomic correlates of benefit from immunotherapy. Our cohort predominantly included individuals with stage III disease at primary disease diagnosis and individuals with stage IV disease at recurrent/metastatic disease diagnosis. Most received immunotherapy as first-line treatment. 43% experienced objective response (median duration of response 24.2 months, 95% confidence interval 8.8-not reached). Median overall survival was 15.5 months (95% confidence interval 9.0-28.7) (median follow-up 25.2 months). Less advanced stage at primary disease diagnosis and shorter disease-free interval between completion of initial treatment and recurrence were each associated with greater odds of response (odds ratio of 0.06, = 0.04 for stage; odds ratio 0.75, = 0.05 for disease-free interval). Single-nucleotide variants in and were associated with response ( = 0.05, without Bonferroni correction), while none of Merkel cell polyomavirus status, total mutational burden, ultraviolet mutational signatures, and copy-number alterations predicted outcomes. Patients with shorter disease-free interval may be particularly suitable immunotherapy candidates. Our molecular findings point to and as potential predictive markers and/or therapeutic targets (e.g., with Trk inhibitors), although this association needs to be confirmed in a larger sample.
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http://dx.doi.org/10.18632/oncotarget.27823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720777PMC
November 2020

Considerations for the Selection and Use of Disinfectants Against SARS-CoV-2 in a Health Care Setting.

Open Forum Infect Dis 2020 Sep 31;7(9):ofaa396. Epub 2020 Aug 31.

Greater Boston Pandemic Fabrication Team (PanFab) c/o Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, Massachusetts, USA.

Proper disinfection using adequate disinfecting agents will be necessary for infection control strategies against coronavirus disease 2019 (COVID-19). However, limited guidance exists on effective surface disinfectants or best practices for their use against severe acute respiratory coronavirus 2. We outlined a process of fully characterizing over 350 products on the Environmental Protection Agency List N, including pH, method of delivery, indication for equipment sterilization, and purchase availability. We then developed a streamlined set of guidelines to help rapidly evaluate and select suitable disinfectants from List N, including practicality, efficacy, safety, and cost/availability. This resource guides the evaluation of ideal disinfectants amidst practical considerations posed by the COVID-19 pandemic.
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http://dx.doi.org/10.1093/ofid/ofaa396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499694PMC
September 2020

Real-world outcomes treating patients with advanced cutaneous squamous cell carcinoma with immune checkpoint inhibitors (CPI).

Br J Cancer 2020 11 1;123(10):1535-1542. Epub 2020 Sep 1.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Background: Immunotherapy has revolutionised the treatment of advanced cutaneous squamous cell carcinoma (cSCC). It is important to understand both safety and efficacy in a real-world and trial-ineligible cSCC population. We aimed to evaluate safety, efficacy and molecular insights among a broader cSCC population, including immunosuppressed patients, treated with immune checkpoint inhibitors (CPI).

Methods: We present a cohort of advanced cSCC patients (n = 61) treated from 2015 to 2020 evaluating the best overall response (BOR) (RECISTv1.1) to CPI therapy, immune-related adverse events (irAEs) and tumour mutational burden (TMB) to correlate with outcomes. A validated geriatric scoring index (CIRS-G) was utilised to assess comorbidities among patients ≥75. These data were compared with published clinical trial results among the broader cSCC population.

Results: BOR to CPI was lower among the entire cohort when compared with trial data (31.5 vs. 48%, P < 0.01), with higher rates of progression (59 vs. 16.5%, P < 0.01), regardless of immunosuppression history or age. Grade 3+ irAEs were more common among responders (P = 0.02), while pre-treatment lymphocyte count and TMB predicted response (P = 0.02).

Conclusions: We demonstrate comparatively lower response rates to CPI among real-world cSCC patients not explained by older age or immunosuppression history alone. Immune-related toxicity, absolute lymphocyte count and TMB predicted CPI response.
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http://dx.doi.org/10.1038/s41416-020-01044-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653959PMC
November 2020

Cutaneous Langerhans Cell Histiocytosis Responsive to Topical Nitrogen Mustard.

J Drugs Dermatol 2020 Aug;19(8):803-805

Langerhans cell histiocytosis (LCH) limited to the skin is rare in adult patients. Given the challenges of prospective clinical trials for this rare disease, there is paucity in data to guide the management of cutaneous LCH. Topical nitrogen mustard is a possible treatment for cutaneous LCH with positive responses in five known adult cases in the literature. In this report, we present two adult patients with recalcitrant cutaneous LCH and no evidence of systemic involvement who had rapid and complete response on topical nitrogen mustard therapy. We provide support for topical nitrogen mustard as a treatment option for primary cutaneous LCH which may spare patients from requiring systemic immunosuppressive treatments. J Drugs Dermatol. 2020;19(8):803-805. doi:10.36849/JDD.2020.4943.
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http://dx.doi.org/10.36849/JDD.2020.4943DOI Listing
August 2020

Regulatory and Safety Considerations in Deploying a Locally Fabricated, Reusable Face Shield in a Hospital Responding to the COVID-19 Pandemic.

Med (N Y) 2020 Dec 19;1(1):139-151.e4. Epub 2020 Jun 19.

Greater Boston Pandemic Fabrication Team (PanFab) c/o Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, MA, USA.

Background: Due to supply chain disruption, the COVID-19 pandemic has caused severe shortages in personal protective equipment for health care professionals. Local fabrication based on 3D printing is one way to address this challenge, particularly in the case of products such as protective face shields. No clear path exists, however, for introducing a locally fabricated product into a clinical setting.

Methods: We describe a research protocol under Institutional Review Board supervision that allowed clinicians to participate in an iterative design process followed by real-world testing in an emergency department. All designs, materials used, testing protocols, and survey results are reported in full to facilitate similar efforts in other clinical settings.

Findings: Clinical testing allowed the incident command team at a major academic medical center to introduce the locally fabricated face shield into general use in a rapid but well-controlled manner. Unlike standard hospital face shields, the locally fabricated design was intended to be reusable. We discuss the design and testing process and provide an overview of regulatory considerations associated with fabrication and testing of personal protective equipment, such as face shields.

Conclusions: Our work serves as a case study for robust, local responses to pandemic-related disruption of medical supply chains with implications for health care professionals, hospital administrators, regulatory agencies, and concerned citizens in the COVID-19 and future health care emergencies.

Funding: : This work was supported by the Harvard MIT Center for Regulatory Sciences, NIH/NCI grants U54-CA225088 and T32-GM007753, and the Harvard Ludwig Center. M.-J.A. is a Friends of McGovern Graduate Fellow.
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http://dx.doi.org/10.1016/j.medj.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304404PMC
December 2020

Novel platform leveraging electronic medical record (EMR) to triage patients admitted with high-grade immune-related adverse events (irAEs) to the immune-toxicity (ITOX) service.

J Immunother Cancer 2020 08;8(2)

Harvard Medical School, Boston, Massachusetts, USA

Background: The incidence of high-grade immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) is increasing due to the rapid expansion of indications for their use. There is an urgent need for a feasible approach of identifying patients with high-grade irAEs to ensure early detection and proper management of this unique set of toxicities.

Methods: We established one of the first inpatient services that are specifically devoted to mitigating irAEs. The service uses a multidisciplinary approach with consulting service from experts in managing irAEs. We are leveraging the electronic medical record (EMR) to triage patients who are admitted to the hospital and have received or are currently receiving ICIs. A list of patients with ICI exposure is generated daily by EMR and then curated manually to identify patients with potential irAEs.

Results: A total of 129 patients with high-grade irAEs were admitted between June 2018 and June 2019. The most common irAEs were colitis (32%), pneumonitis (30%), and hepatitis (14%). Eighty five per cent of the patients had grade 3 irAEs and 15% had grade 4-5. About half of the patients had received ICI monotherapy; 30% had received combination of ICIs and non-ICIs; and 19% had received a combination of ICIs. Only 9% of patients had steroid-refractory irAEs requiring other immunosuppressive agents. The average length of stay for irAE-related admission was 11 days with a readmission rate due to recurrent irAEs of 26% within a year.

Conclusion: We demonstrated the feasibility of using the EMR to accurately triage patients with suspected irAEs to a dedicated immune-toxicity service. Our model is adaptable in major academic centers and could have a major impact on quality of care and future clinical research addressing irAEs.
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http://dx.doi.org/10.1136/jitc-2020-000992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437713PMC
August 2020

An Update on the Role of Talimogene Laherparepvec (T-VEC) in the Treatment of Melanoma: Best Practices and Future Directions.

Am J Clin Dermatol 2020 Dec;21(6):821-832

Division of Surgical Oncology, Massachusetts General Hospital, 55 Fruit Street, Warren 408C, Boston, MA, 02114, USA.

Talimogene laherparepvec (T-VEC) is the first agent approved for cancer in the emerging class of oncolytic viral therapies. While T-VEC was approved for the treatment of advanced melanoma in 2015, clinical utilization has been hampered by rapid changes in the therapeutic landscape of melanoma related to advances in both immune checkpoint blockade and targeted therapy, cumbersome logistics involved in T-VEC administration, biosafety concerns, and a perception that T-VEC has limited impact on uninjected, visceral disease. However, with further survival follow-up from the phase III OPTiM (Oncovex Pivotal Trial in Melanoma), along with new real-world data and consensus guidelines on safe administration of oncolytic viruses, a roadmap for when and how to use T-VEC has been emerging. In addition, preliminary data have demonstrated improved therapeutic responses to T-VEC in combination with immune checkpoint blockade in patients with melanoma without additive toxicity. This review provides an update on recent data with T-VEC alone and in combination with other agents. The emerging data provide guidance for how to better utilize T-VEC for patients with melanoma and identifies critical areas for clinical investigation to expand the role of T-VEC in combination strategies for the treatment of melanoma and perhaps other cancers.
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http://dx.doi.org/10.1007/s40257-020-00554-8DOI Listing
December 2020

3D Printed frames to enable reuse and improve the fit of N95 and KN95 respirators.

medRxiv 2020 Jul 26. Epub 2020 Jul 26.

Greater Boston Pandemic Fabrication Team (PanFab) c/o Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, MA, USA.

Background: In response to supply shortages during the COVID-19 pandemic, N95 filtering facepiece respirators (FFRs or "masks"), which are typically single-use devices in healthcare settings, are routinely being used for prolonged periods and in some cases decontaminated under "reuse" and "extended use" policies. However, the reusability of N95 masks is often limited by degradation or breakage of elastic head bands and issues with mask fit after repeated use. The purpose of this study was to develop a frame for N95 masks, using readily available materials and 3D printing, which could replace defective or broken bands and improve fit.

Results: An iterative design process yielded a mask frame consisting of two 3D-printed side pieces, malleable wire links that users press against their face, and cut lengths of elastic material that go around the head to hold the frame and mask in place. Volunteers (n= 41; average BMI= 25.5), of whom 31 were women, underwent qualitative fit with and without mask frames and one or more of four different brands of FFRs conforming to US N95 or Chinese KN95 standards. Masks passed qualitative fit testing in the absence of a frame at rates varying from 48 - 92% (depending on mask model and tester). For individuals for whom a mask passed testing, 75-100% (average = 86%) also passed testing with a frame holding the mask in place. Among users for whom a mask failed in initial fit testing, 41% passed using a frame. Success varied with mask model and across individuals.

Conclusions: The use of mask frames can prolong the lifespan of N95 and KN95 masks by serving as a substitute for broken or defective bands without adversely affecting fit. Frames also have the potential to improve fit for some individuals who cannot fit existing masks. Frames therefore represent a simple and inexpensive way of extending the life and utility of PPE in short supply. For clinicians and institutions interested in mask frames, designs and specifications are provided without restriction for use or modification. To ensure adequate performance in clinical settings, qualitative fit testing with user-specific masks and frames is required.
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http://dx.doi.org/10.1101/2020.07.20.20151019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386530PMC
July 2020

Assessing the quality of nontraditional N95 filtering face-piece respirators available during the COVID-19 pandemic.

medRxiv 2020 Jul 27. Epub 2020 Jul 27.

Background: During the current COVID-19 pandemic, supply chains for Personal Protective Equipment (PPE) have been severely disrupted and many products, particularly surgical N95 filtering facepiece respirators (FFRs; "masks") are in short supply. As a consequence, an Emergency Use Authorization (EUA) from the FDA has allowed importation of N95-type masks manufactured to international standards; these include KN95 masks from China and FFP2 masks from the European Union.

Methods: We conducted a survey of mask in the inventory of major academic medical centers in Boston, MA to determine provenance and manufacturer. We then assembled a simple apparatus for performing a necessary (but not sufficient) test of filtration performance and tested masks from the inventory; an accompanying website shows how to build and use the testing apparatus.

Results: Our survey showed that, seven months after the start of the COVID-19 pandemic, over 100 different makes and models of N95-type masks are in the inventory of local hospitals as opposed to 2-5 models under normal circumstances. A substantial number of unfamiliar masks are from unknown manufacturers. Many did not perform to accepted standards and are likely to be counterfeit. Due to the absence of publicly available information on mask suppliers in the FDA EUA and confusing or inconsistent labeling of KN95 masks, it is difficult to distinguish legitimate and counterfeit products.

Conclusions: Many of the FFR masks available for procurement during the COVID-19 pandemic do not provide levels of fit and filtration similar to those of N95 masks and are not acceptable for use in healthcare settings. Based on these results, and in consultation with occupational health officers, we make six recommendations for end users to assist in acquiring legitimate products. In particular, institutions should always assess masks from non-traditional supply chains by checking their markings and manufacturer information against data provided by NIOSH and the latest FDA EUA Appendix A. In the absence of verifiable information on the legitimacy of mask source, institutions should consider measuring mask fit and filtration directly. We also make suggestions for U.S and Chinese regulatory agencies with regard to labeling and public disclosure aimed at increase pandemic resilience.
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http://dx.doi.org/10.1101/2020.07.25.20161968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386520PMC
July 2020

Geographic Disparities in Access to Scalp Cooling for the Prevention of Chemotherapy-Induced Alopecia in the United States.

J Am Acad Dermatol 2020 Jun 28. Epub 2020 Jun 28.

Department of Dermatology, Brigham and Women's Hospital, Boston, MA; Center for Cutaneous Oncology, Department of Dermatology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA. Electronic address:

Introduction: Chemotherapy-induced alopecia is psychologically challenging for patients undergoing cancer treatment, and scalp cooling has been shown to prevent or decrease the hair loss.

Methods: Cancer treatment centers offering scalp cooling were identified using data from The Rapunzel Project. Medicare claims data were queried to evaluate the number of chemotherapy infusions occurring in each zip code in the US. Geographic distribution of chemotherapy infusions and scalp cooling centers was determined using ArcGIS software. The average distance from the geographic center of all 5-digit zip codes in which chemotherapy infusions occur to the nearest scalp cooling center was calculated in miles.

Results: There are 366 chemotherapy infusion centers in the United States that offer scalp cooling. 43.9% of Medicare-billed chemotherapy infusions in the United States occur in zip codes less than 12.5 miles from a scalp cooling center, 24.8% occur between 12.5 and 49.9 miles away, and 31.3% occur greater than 50 miles away.

Limitations: Our results are only generalizable to patients seen at Medicare-accepting institutions in the US.

Conclusions: Geographic disparities affect which patients can access scalp cooling therapy, and implementation in suburban and rural areas would increase access for patients who wish to preserve their hair while undergoing chemotherapy.
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http://dx.doi.org/10.1016/j.jaad.2020.06.073DOI Listing
June 2020

Evaluation of a Comprehensive Skin Toxicity Program for Patients Treated With Epidermal Growth Factor Receptor Inhibitors at a Cancer Treatment Center.

JAMA Dermatol 2020 10;156(10):1079-1085

Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Up to 90% of patients treated with an epidermal growth factor receptor inhibitor (EGFRi) experience cutaneous toxic effects that are negatively associated with quality of life and lead to treatment interruptions. The Skin Toxicity Evaluation Protocol With Panitumumab trial found reduced incidence of skin toxicity and quality of life impairment with preemptive use of doxycycline hyclate, topical corticosteroids, moisturizers, and sunscreen, demonstrating the benefit of prophylactic treatment for skin toxicity.

Objective: To evaluate the association of a comprehensive skin toxicity program with adherence to prophylaxis guidelines for the prevention of EGFRi-associated cutaneous toxic effects.

Design, Setting, And Participants: A retrospective cohort study was conducted of all adult patients receiving at least 1 dose of cetuximab at the Dana-Farber Cancer Institute in the calendar year 2012 (2 years after publication of the Skin Toxicity Evaluation Protocol With Panitumumab) or the calendar year 2017 (2 years after full implementation of the Skin Toxicities from Anticancer Therapies program).

Main Outcomes And Measures: Primary outcomes were rate of preemptive rash treatment and selection of preemptive agents. Secondary outcomes were incidence of rash, rates of rescue treatments, rates of cetuximab dose changes or interruptions, and overall survival at 2 years.

Results: There were 118 patients (85 men; median age, 62.4 years [range, 23.5-91.7 years]) treated with cetuximab in 2012 and 90 patients (70 men; median age, 62.5 years [range, 30.7-90.5 years]) treated with cetuximab in 2017; 11 patients (9%) in 2012 and 31 patients (34%) in 2017 were treated at Dana-Farber Cancer Institute affiliate sites. At cetuximab treatment initiation, 29 patients (25%) in 2012 and 42 patients (47%) in 2017 were prophylactically treated for skin toxicity (P < .001). From 2012 to 2017, preemptive tetracycline use (13 of 29 [45%] to 30 of 42 [71%]; P = .02) and topical corticosteroid use (2 of 29 [7%] to 24 of 42 [57%]; P < .001) increased and topical antibiotic use (23 of 29 [79%] to 18 of 42 [43%]; P = .002) decreased. There was no significant difference in incidence of rash by prophylaxis status. Patients prescribed prophylactic treatment were 94% less likely to require a first rescue treatment for rash (adjusted odds ratio, 0.06; 95% CI, 0.02-0.16; P < .001), 74% less likely to require a second rescue treatment for rash (adjusted odds ratio, 0.26; 95% CI, 0.08-0.83; P = .02), and 79% less likely to experience a cetuximab dose change or interruption (adjusted odds ratio, 0.21; 95% CI, 0.06-0.81; P = .02) than patients not prescribed prophylactic treatment, adjusting for treatment site and year.

Conclusions And Relevance: Dermatologists can add value to oncology care by raising awareness of appropriate treatment options and increasing adherence to evidence-based prophylaxis protocols for EGFRi-associated rash, which is associated with decreased interventions and toxicity-associated chemotherapy interruptions.
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http://dx.doi.org/10.1001/jamadermatol.2020.1795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330823PMC
October 2020

A pilot study of the impact of facial skin protectants on qualitative fit testing of N95 masks.

J Am Acad Dermatol 2021 Feb 24;84(2):554-556. Epub 2020 Jun 24.

Harvard Medical School, Boston, Massachusetts; Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.06.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313513PMC
February 2021

Association of Programmed Death 1 Protein Ligand (PD-L1) Expression With Prognosis in Merkel Cell Carcinoma.

Front Med (Lausanne) 2020 5;7:198. Epub 2020 Jun 5.

Head and Neck Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.

Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer. Prior to the advent of immunotherapy, treatment options were limited. In our study, we evaluate the impact of tumor cell PD-L1 expression and tumor immune microenvironment on survival in MCC patients who were not treated with immune checkpoint inhibitors. Clinical data and tissue samples were collected from 78 patients with confirmed MCC treated at Dana-Farber Cancer Institute. Specimens were analyzed for the distribution of PD-L1 by immunohistochemistry staining (IHC) and standardized analysis. Results were correlated with survival data. In this study, membrane and cytoplasmic MCC tumor cell staining for PD-L1 was detected in 22.4% (15 of 67) of cases and PD-L1 staining of intratumoral microvessels and PD-L1 positive immune cells at the infiltrative margins of the tumor in 92.5% (62 of 67) of cases. In patients untreated with immune checkpoint inhibitors, median overall survival was not different for patients based on PD-L1 expression (PD-L1+ 64 months vs. PD-L1- not reached; HR = 1.26, 95% CI: 0.46-3.45; = 0.60). PD-L1 expression is frequently detected in MCC tumor cells and tumor microenvironment. PD-L1 expression did not affect prognosis in this cohort that had not received PD-1/L1 blockade.
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http://dx.doi.org/10.3389/fmed.2020.00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291775PMC
June 2020

Rapid prototyping and clinical testing of a reusable face shield for health care workers responding to the COVID-19 pandemic.

medRxiv 2020 Apr 15. Epub 2020 Apr 15.

Greater Boston Pandemic Fabrication Team (PanFab) c/o Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, MA, USA.

Due to supply chain disruption, the COVID-19 pandemic has caused severe shortages in personal protective equipment (PPE) for health care professionals. Local fabrication based on 3D printing is one way to address this challenge, particularly in the case of simple products such as protective face shields. As a consequence, many public domain designs for face shields have become available. No clear path exists, however, for introducing a locally fabricated and unapproved product into a clinical setting. In a US health care setting, face shields are regulated by the Food and Drug Administration (FDA); similar policies exist in other countries. We describe a research protocol under which rapid iteration on an existing design, coupled with clinical feedback and real-world testing in an emergency department, allowed a face shield to be adopted by the incident command team at a major academic medical center. We describe our design and testing process and provide an overview of regulatory considerations associated with fabrication and testing of face shields and related products. All designs, materials used, testing protocols, and survey results are reported in full to facilitate the execution of similar face shield efforts in other clinical settings. Our work serves as a case study for development of a robust local response to pandemics and other health care emergencies, with implications for healthcare professionals, hospital administrators, regulatory agencies and concerned citizens.
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http://dx.doi.org/10.1101/2020.04.11.20061960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276039PMC
April 2020

Analysis of SteraMist ionized hydrogen peroxide technology in the sterilization of N95 respirators and other PPE: a quality improvement study.

medRxiv 2020 Apr 23. Epub 2020 Apr 23.

Greater Boston Pandemic Fabrication Team (PanFab) c/o Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, MA, USA.

Objective: The COVID-19 pandemic has led to widespread shortages of personal protective equipment (PPE) for healthcare workers, including filtering facepiece respirators (FFRs) such as N95 masks. These masks are normally intended for single use, but their sterilization and subsequent reuse could substantially mitigate a world-wide shortage.

Design: Quality assurance.

Setting: A sealed environment chamber installed in the animal facility of an academic medical center.

Interventions: One to five sterilization cycles using ionized hydrogen peroxide (iHP), generated by SteraMist equipment (TOMI; Frederick, MD).

Main Outcome Measures: Personal protective equipment, including five N95 mask models from three manufacturers, were evaluated for efficacy of sterilization following iHP treatment (measured with bacterial spores in standard biological indicator assemblies). Additionally, N95 masks were assessed for their ability to efficiently filter particles down to 0.3um and for their ability to form an airtight seal using a quantitative fit test. Filtration efficiency was measured using ambient particulate matter at a university lab and an aerosolized NaCl challenge at a National Institute for Occupational Safety and Health (NIOSH) pre-certification laboratory.

Results: The data demonstrate that N95 masks sterilized using SteraMist iHP technology retain function up to five cycles, the maximum number tested to date. Some but not all PPE could also be sterilized using an iHP environmental chamber, but pre-treatment with a handheld iHP generator was required for semi-enclosed surfaces such as respirator hoses.

Conclusions: A typical iHP environment chamber with a volume of ~80 m3 can treat ~7000 masks per day, as well as other items of PPE, making this an effective approach for a busy medical center.
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http://dx.doi.org/10.1101/2020.04.19.20069997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273248PMC
April 2020

What's the Price? Toxicities of Targeted Therapies in Breast Cancer Care.

Am Soc Clin Oncol Educ Book 2020 May;40:55-70

Division of Hematology and Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.

Agents with mechanisms novel to breast cancer care have been approved to treat breast cancer. These agents include drugs that target cyclin-dependent kinases, phosphoinositide 3-kinase gene mutations, PARP, checkpoint regulation, and novel antibody-drug conjugates. However, these novel approaches bring a risk of toxicities quite different from those of conventional cytotoxic chemotherapy. Here, we review these agents and discuss related adverse events, with particular attention to endocrine, pulmonary, and dermatologic toxicities. Endocrine toxicities associated with novel cancer therapies for breast cancer are distinct and often present with symptoms related to the specific hormonal deficiencies and rarely hormonal excess. Given the complex and sometimes irreversible nature of these toxicities, once recognized, transdisciplinary management with an endocrinologist experienced with managing drug-related toxicities is encouraged. Drug-related pneumonitis is a serious concern with new targeted therapies. Presentation may not be easily distinguished, and a multidisciplinary team approach can optimize patient care. Heightened awareness is crucial for early detection and treatment. Management should follow recommendations provided by the National Cancer Institute Common Terminology Criteria for Adverse Events and agent-specific guidelines. Cutaneous toxicities from anticancer therapies represent a common and often poorly characterized challenge for patients with breast cancer. Although our understanding of dermatologic effects from novel therapies continues to improve, the breadth of toxicities spans all dermatologic conditions. Targeted therapies offer effective and often novel therapeutic strategies for patients with breast cancer but also bring new adverse event profiles. In this era, it will be important both to closely follow monitoring recommendations and to remain vigilant for emerging toxicities.
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http://dx.doi.org/10.1200/EDBK_279465DOI Listing
May 2020

Dermatologic Adverse Events of Systemic Anticancer Therapies: Cytotoxic Chemotherapy, Targeted Therapy, and Immunotherapy.

Am Soc Clin Oncol Educ Book 2020 May;40:485-500

Division of Dermatology, Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, NY.

Over the past 2 decades, rapid advancement in systemic anticancer therapeutics has led to astounding improvement in survival rates of patients with cancer. However, this celebrated progress has brought with it an evolving spectrum of drug toxicities that limit their prodigious capabilities. Cutaneous adverse events are of the most frequent of these toxicities, with substantial impact on quality of life and commonly resulting in dose reduction or change in therapy. Thus, familiarity with the array of dermatologic manifestations caused by these drugs is prudent for patient treatment. As such, the advent of dedicated oncodermatologists, and their introduction into multidisciplinary cancer care, has been crucial in optimizing treatment through therapeutic achievement and overall well-being. This review will address the epidemiology, clinical presentations, and management strategies of the major dermatologic adverse events of systemic anticancer agents, including cytotoxic chemotherapy, targeted therapy, and immunotherapy.
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http://dx.doi.org/10.1200/EDBK_289911DOI Listing
May 2020

Reply to: "Comment on Bullous pemphigoid after anti-PD-1 therapy: a retrospective case-control study evaluating impact on tumor response and survival outcomes".

J Am Acad Dermatol 2020 May 14. Epub 2020 May 14.

Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Cutaneous Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.05.023DOI Listing
May 2020

Evidence for separate transformation to acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm from a shared ancestral hematopoietic clone.

Leuk Lymphoma 2020 09 4;61(9):2258-2261. Epub 2020 May 4.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1080/10428194.2020.1755856DOI Listing
September 2020

Blastic Plasmacytoid Dendritic Cell Neoplasm: The Dermatologist's Perspective.

Hematol Oncol Clin North Am 2020 06 20;34(3):501-509. Epub 2020 Mar 20.

Department of Dermatology, The Center For Cutaneous Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 375 Longwood Avenue, Boston, MA 02115, USA. Electronic address:

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive malignancy derived from the plasmacytoid dendritic cell that commonly involves the skin. Cutaneous involvement is often the initial presentation, with deep purple or red-brown macules, plaques, or tumors. As such, dermatologists may be the first to see these patients and, in addition to oncologists, should be familiar with its presentation to facilitate early diagnosis, helping to distinguish it from acute myelogenous leukemia cutis.
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http://dx.doi.org/10.1016/j.hoc.2020.01.001DOI Listing
June 2020

Surface applicator high-dose-rate fractionated brachytherapy for superficial cancers of the penis: A single-center case series and national database comparison.

J Am Acad Dermatol 2021 Jan 19;84(1):168-172. Epub 2020 Apr 19.

Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts; Division of Brachytherapy, Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.04.041DOI Listing
January 2021

Comprehensive metagenomic analysis of blastic plasmacytoid dendritic cell neoplasm.

Blood Adv 2020 03;4(6):1006-1011

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematologic malignancy believed to originate from plasmacytoid dendritic cells (pDCs), the immune cells responsible for producing type 1 interferons during infection. Nearly all patients with BPDCN have prominent skin involvement, with cutaneous infiltration occupying the dermis and subcutis. One half of patients present with BPDCN cells only in the skin, with no evidence of disease elsewhere. Because normal pDCs are rare or absent in cutaneous sites, and they only traffic to the skin after activation by pathogen or inflammation, our aim was to determine if a microorganism is associated with BPDCN. We performed RNA sequencing in BPDCN skin and bone marrow, with cutaneous T-cell lymphoma (CTCL) and normal skin as controls. GATK-PathSeq was used to identify known microbial sequences. Bacterial reads in BPDCN skin were components of normal flora and did not distinguish BPDCN from controls. We then developed a new computational tool, virID (Viral Identification and Discovery; https://github.com/jnoms/virID), for identification of microbial-associated reads remaining unassigned after GATK-PathSeq. We found no evidence for a known or novel virus in BPDCN skin or bone marrow, despite confirming that virID could identify Merkel cell polyomavirus in Merkel cell carcinoma, human papillomavirus in head and neck squamous cell carcinoma, and Kaposi's sarcoma herpesvirus in Kaposi's sarcoma in a blinded fashion. Thus, at the level of sensitivity used here, we found no clear pathogen linked to BPDCN.
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http://dx.doi.org/10.1182/bloodadvances.2019001260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094006PMC
March 2020

Genomic and Immunologic Characterization of INI1-Deficient Pediatric Cancers.

Clin Cancer Res 2020 06 2;26(12):2882-2890. Epub 2020 Mar 2.

Department of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts.

Purpose: Several aggressive pediatric cancers harbor alterations in , including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors.

Experimental Design: We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or genomic alterations on prior somatic sequencing.

Results: two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors.

Conclusions: A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3089DOI Listing
June 2020