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Background Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase (BTK) that is FDA-approved for several lymphoproliferative disorders and chronic GVHD. Objective To characterize cutaneous eruptions arising from ibrutinib and highlight overlap with epidermal growth factor receptor inhibitor (EGFRi)-induced dermatologic adverse events (dAEs). Methods Single-center retrospective cohort of patients referred to the Skin Toxicities Program for management of cutaneous eruptions while taking ibrutinib. Results Among 19 patients, cutaneous eruptions manifested as facial-predominant papulopustular eruptions, petechiae or ecchymoses, photosensitivity, panniculitis, xerosis, and clinical staphylococcal overgrowth. The majority of patients were able to continue ibrutinib therapy with focused management of their cutaneous toxicities. Limitations This study represents cases at a single tertiary care center and is limited to patients referred for toxicity. Conclusions With the exception of petechiae, the cutaneous toxicities of ibrutinib overlap with those associated with selective EGFR inhibitors. We observed that these reactions can be successfully managed using approaches for EGFR inhibitor-induced cutaneous adverse events.

BackgroundCutaneous immune-related adverse events (cirAEs) occur in up to 40% of immune checkpoint inhibitor (ICI) recipients. However, the association of cirAEs with survival remains unclear.ObjectiveTo investigate the association of cirAEs with survival among ICI recipients.MethodsICI recipients were identified from the Mass General Brigham healthcare system (MGB) and Dana-Farber Cancer Institute (DFCI). Patient charts were reviewed for cirAE development within 2 years after ICI initiation. Multivariate time-varying Cox proportional hazards models, adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, ICI type, cancer type, and year of ICI initiation were utilized to investigate the impact of cirAE development on overall survival.ResultsOf the 3,731 ICI recipients, 18.1% developed a cirAE. 6-month landmark analysis and time-varying Cox proportional hazards models demonstrated that patients who developed cirAEs were associated with decreased mortality (HR=0.87,p=0.027), particularly in melanoma patients (HR=0.67,p=0.003). Among individual morphologies, lichenoid eruption (HR=0.51,pLimitationsRetrospective design; single geography.ConclusionCirAE development is associated with improved survival among ICI recipients, especially melanoma patients.Capsule SummaryPatients on immune checkpoint inhibitors (ICIs) who developed cutaneous immune-related adverse events (cirAEs) had favorable outcomes. This was especially notable for melanoma patients who had cirAEs, both those with vitiligo and other morphologies.Development of cirAEs in ICI-treated patients can be used to prognosticate survival and guide treatment decisions.

TABLE OF CONTENTS GENERAL INFORMATION TITLE AUTHORS AND BEST CONTACT LICENSES USEFUL LINKS DATE OF DATA COLLECTION FILE ORGANIZATION FUNDING ---- Release Notes:This is a pre-publication placeholder for primary data release for the publication listed below. In common with GEO, PRIDE, and other data repositories, this will be populated with final data following peer review. ---- GENERAL INFORMATION Publication Title:Immune Profiling of Dermatologic Adverse Events from Checkpoint Blockade using Tissue Cyclic Immunofluorescence Authors:Zoltan Maliga, Daniel Y. Kim, Ai-Tram N. Bui, Jia-Ren Lin, Anna K. Dewan, George G. Murphy, Ajit J. Nirmal, Christine G. Lian, Peter K. Sorger, Nicole R. LeBoeuf Contact Information Nicole LeBoeuf, MD, MPH Vice Chair of Dermatology,Dana-FarberCancer Institute,; Chief, Division of Oncodermatology, Brigham and Women's Hospital; Clinical Director, Center for Cutaneous Oncology, Dana-Farber/Brigham Cancer Center, HarvardMedical School nleboeuf@partners.org Publications that cite or use the data:** Maliga, M, Kim, DY, Tram, B, Lin, JR, Dewan, AK, Jadeja, S, Murphy, G, Nirmal, AJ, Lian, C, Sorger, PK, LeBoeuf, NR. Immune Profiling of Dermatologic Adverse Events from Checkpoint Blockade using Tissue Cyclic Immunofluorescence.https://doi.org/10.1101/2023.04.03.535435 Licenses/restrictions placed on the data:CC BYhttps://creativecommons.org/licenses/by/4.0/ ---- FILE ORGANIZATION FILE TYPES/SUMMARY:Each folder corresponds to a patient sample (N). The following files are available for each patient and are located on [Synapse/AWS/Etc]. File Type Description Location N.ome.tif Stitched multiplex CyCIF image pyramid in ome.tif format AWS N_IHC.ome.tiff Immunohistochemistry stained image of serial FFPE tissue section in .ome.tiff format AWS N_HE.ome.tiff Hematoxylin and eosin stained image of FFPE tissue section in .ome.tiff format AWS markers.csv List of all markers in ome.tif image Synapse N_Quantification.csv Single-cell feature table, including intensity data for all channels Synapse segmentation/ Folder of segmentation maps for tissue image in .tif format AWS Synapse Library:Edit this to link directly to your public Synapse Library Free account registration is required to download files from Synapse. Images and metadata are available in the bucket at the following AWS location:[ADD BUCKET DETAILS] To browse and download the data use either a graphical file transfer application that supports S3 such asCyberDuck, or theAWS CLI tools. A graphical tool may be more convenient but the CLI tools will likely offer higher download speeds. FILE LIST N.ome.tif LSP Slide ID File Name File Size LSP10925 LSP10925_CyCIF_Image.ome.tif 9.3 GB LSP10929 LSP10929_CyCIF_Image.ome.tif 6.0 GB LSP10931 LSP10931_CyCIF_Image.ome.tif 8.7 GB LSP10933 LSP10933_CyCIF_Image.ome.tif 6.7 GB LSP10951 LSP10951_CyCIF_Image.ome.tif 11 GB LSP10980 LSP10980_CyCIF_Image.ome.tif 9.3 GB 51 GB markers.csv File name File Size Synapse ID markers.csv 0.7 KB N_Quantification.csv LSP Slide ID File Name File Size Synapse ID LSP10925 LSP10925_CyCIF_Quantification.csv 20 MB LSP10929 LSP10929_CyCIF_Quantification.csv 12 MB LSP10931 LSP10931_CyCIF_Quantification.csv 5.9 MB LSP10933 LSP10933_CyCIF_Quantification.csv 7.5 MB LSP10951 LSP10951_CyCIF_Quantification.csv 8.3 MB LSP10980 LSP10980_CyCIF_Quantification.csv 12 MB segmentation/ LSP Slide ID File Name File Size LSP10925 LSP10925_cellRingMask.tif 20 MB LSP10929 LSP10929_cellRingMask.tif 12 MB LSP10931 LSP10931_cellRingMask.tif 5.9 MB LSP10933 LSP10933_cellRingMask.tif 7.5 MB LSP10951 LSP10951_cellRingMask.tif 8.3 MB LSP10980 LSP10980_cellRingMask.tif 12 MB 66 MB N_IHC.ome.tiff LSP Slide ID Description File name File Size LSP16237 CD103 Image LSP16237_IHC_CD103.ome.tiff 2.8 GB LSP16240 PD1 Image LSP16240_IHC_PD1.ome.tiff 3.1 GB LSP16241 MART1 Image LSP16241_IHC_MART1.ome.tiff 2.9 GB LSP16242 FOXP3 Image LSP16242_IHC_FOXP3.ome.tiff 3.5 GB LSP16243 CD3 Image LSP16243_IHC_CD3.ome.tiff 2.9 GB LSP16244 CD4 Image LSP16244_IHC_CD4.ome.tiff 3.2 GB LSP16245 CD8 Image LSP16245_IHC_CD8.ome.tiff 3.2 GB LSP16246 CD20 Image LSP16246_IHC_CD20.ome.tiff 3.2 GB LSP16247 CD19 Image LSP16247_IHC_CD19.ome.tiff 3.7 GB LSP16248 CD163 Image LSP16248_IHC_CD163.ome.tiff 4.0 GB LSP16249 PDL1 Image LSP16249_IHC_PDL1.ome.tiff 3.7 GB LSP16250 CD69 Image LSP16250_IHC_CD69.ome.tiff 3.2 GB 39 GB N_HE.ome.tiff LSP Slide ID Description File name File Size LSP16237 H&E Image LSP16234_HE.ome.tiff 14 GB 14 GB ---- FUNDING R50-CA252138, U2C-CA233262 and Ludwig Cancer Research

Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-TCLPD) was reclassified in 2016 as a rare benign entity with an excellent prognosis, yet its clinical features and best treatments remain poorly defined. We collected clinical data, treatments, and treatment-responses from our institution's patients with PCSM-TCLPD through September 2018 and an identical PubMed review through June 2021. Among 36 cases (median-age 54 years; 58.3% head/neck), diagnostic biopsy resulted in sustained complete remission (CR) in 13/33 punch/shave biopsies and 3/3 excisional biopsies. The remaining 20 patients further required topical corticosteroids (

Radiation-induced morphea (RIM) is a rare but distinctive inflammatory complication of therapeutic radiation.1 It most commonly presents as painful sclerosis of the epidermis and dermis limited to the irradiated field. Morphea has also been reported as an immune-related adverse event (irAE) induced by anti-programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs).2,3 We report a patient who first received local radiation therapy to the thorax for lung adenocarcinoma that was complicated by RIM. The patient’s morphea then progressed widely beyond the irradiated field in the setting of pembrolizumab therapy. Histopathology and imaging confirmed morphea extending beyond the irradiated field and with deeper muscular and fascial involvement. Pain and edema progressed through multiple lines of toxicity-directed therapy, but ultimately responded significantly to dupilumab. Response was confirmed clinically and radiographically, and the patient was able to resume ICI therapy. This case report highlights the ability of ICIs to induce progression of pre-existing RIM and supports the consideration of dupilumab in refractory cases.

PDOTS Movie 2

In vitro kinase inhibitory activity of Compound 1

Pathological analysis of human BPDCN growing as a patient-derived xenograft (PDX) in mice. Splenic tissue is shown stained with H&E (at 40x and 100x magnification), and human BCL-2, CD45, CD4, CD56, and CD123 (all at 40x) from animals bearing a representative BPDCN PDX.

Supplementary Figure Legends

Device loading, media addition, media extraction

Supplementary Figure Legends and Figures

Response of BPDCN and AML cells to navitoclax and A-1331852. (A) MTT assay results for the indicated cell lines after 72 hours of exposure to the indicated doses of navitoclax (combined BCL-2/BCL-XL inhibitor). (B) MTT assay results for the indicated cell lines after 72 hours of exposure to the indicated doses of A-1331852 (BCL-XL only inhibitor). In both panels, data points represent mean of 3 replicates +/- SEM, line represents non-linear regression (curve fit).

PDOTS Movie

Time and dose-dependent response of primary BPDCN to venetoclax in vitro. (A) Cell death measurement by flow cytometry at 4 and 8 hours after addition of venetoclax at the indicated doses in a primary BPDCN, represented as change in Annexin V positivity relative to vehicle. (B) Dose response of primary BPDCNs and AMLs to venetoclax in vitro measured as in (A).

Venetoclax induces dose-dependent apoptotic cell death in BPDCN and AML cell lines. (A) Representative Annexin V-FITC vs propidium iodide (PI) flow cytometry staining to measure apoptosis induction in CAL1 cells after 24 hours of exposure to vehicle, or 10 nM or 100 nM venetoclax are shown. (B) Quantitation of cell death by Annexin V and PI flow cytometry after 24 hours of exposure to the indicated concentrations of venetoclax. Graphs represent mean +/- SEM of 3 independent experiments, *P

BPDCN expresses BCL-2 protein. Photomicrographs of H&E stains and BCL-2, CD123, and TCL-1 immunohistochemistry for BPDCN and AML biopsies from bone marrow and skin are shown. Each of the biopsies (each row) is from a different patient. The BPDCN from Figure 1A is re-presented here for comparison to other BPDCNs and AMLs.

Additional pharmacodynamic data showing in vivo PDX response to venetoclax. PD assessment of percent human CD45+CD123+ cells in the peripheral blood (PB), spleen, and bone marrow (BM) of six animals bearing PDX1 after 21 days of treatment with vehicle (n=3) or venetoclax (n=3).

Genetic analysis of the primary BPDCNs and AMLs, and PDXs.

Purpose:Mycosis fungoides is the most common subtype of cutaneous T-cell lymphoma. Skin-directed treatments often improve but do not cure mycosis fungoides skin lesions. The purpose of this study was to (i) assess whether remission was associated with malignant T-cell clone depletion at treated sites using either low-dose radiotherapy (LDRT, 8 Gy) or topical steroids and (ii) assess whether a clone-ablative therapy, like LDRT, is associated with overall survival in patients with high-risk early-stage CTCL.Experimental Design:Pre- and posttreatment biopsies from 20 lesional skin samples of 18 patients with mycosis fungoides who received either 8 Gy LDRT (n = 16) or topical steroids (n = 4) underwent high-throughput T-cell receptor sequencing of the TCRB gene to quantify the malignant T-cell clone. For the retrospective chart review, overall survival of 47 high-risk early-stage patients was compared between patients who did or did not receive radiation.Results:LDRT eradicated the clone in 5 of 16 lesions and reduced it >90% in 11 of 16; there were no recurrences in these lesions. Patients treated with topical steroids appeared to clinically improve, but the malignant clone persisted. We found that the number of residual malignant T cells predicted lesion recurrence. A retrospective review showed that early-stage high-risk patients who received radiation as part of their treatment regimen had prolonged overall survival compared with patients who did not.Conclusions:These findings demonstrate that LDRT can eradicate malignant T cells in mycosis fungoides, provides robust disease control, and is associated with improved survival in high-risk early-stage patients.

Table S1 shows PD-L1, CD8 and CD163 staining in INI1-negative tumors

Supplemental Tables S1-S7

Figure S1 shows Tier 1-3 genomic events in INI1-negative tumors

The novel messenger RNA (mRNA)–based COVID-19 vaccines protect individuals from SARS-CoV-2 infection and severe forms of the disease.1 Clinical trials data and observational evidence have reported diverse cutaneous responses to these vaccines, including local injection site erythema, urticaria, and morbilliform eruptions.2 Delayed localized hypersensitive reactions have also been reported; however, these do not preclude subsequent vaccination, emphasizing that serious cutaneous reactions to the vaccines are rare.3 We report 2 cases of de novo disseminated varicella-zoster virus (VZV) infection, without expansion from a preceding dermatomal presentation, after receiving an mRNA-based COVID-19 vaccine in patients who were not actively on immunosuppression.

Background Chemotherapy-induced alopecia is psychologically challenging for patients undergoing cancer treatment, and scalp cooling has been shown to prevent or decrease the hair loss. Objective To evaluate whether access to scalp cooling varies by geographic area in the United States. 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 United States. 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. Overall, 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 more than 50 miles away. Limitations Our results are only generalizable to patients seen at Medicare-accepting institutions in the United States. 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.

Primary cutaneous CD4