ImportanceWhile several medications are known to induce dermatomyositis (DM), most existing studies are case reports or small case series from a single institution. There is also limited information on DM induced by immune checkpoint inhibitors, which are increasingly used in oncologic therapy.ObjectiveTo characterize causes and clinical presentation of drug-induced DM based on the current literature.Evidence ReviewA systematic review was performed in PubMed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines, from inception to August 22, 2022. Articles meeting preestablished inclusion criteria (written in English and classified as original articles, case reports, literature reviews, and observation letters) were selected and data abstracted. Articles that met the scope of the review were also added from reference lists. When possible, study results were quantitatively combined.FindingsIn 134 studies (114 from the literature search and 20 additional studies pulled from reference lists) describing 165 cases, 88 patients (53.3%) were female, and the median (IQR) age was 61 (49-69) years. Among the cases of drug-induced DM, the most common associated medications were hydroxyurea (50 [30.3%]), immune checkpoint inhibitors (27 [16.4%]), statins (22 [13.3%]), penicillamine (10 [6.1%]), and tumor necrosis factor inhibitors (10 [6.1%]). Histopathologic testing, when undertaken, helped establish the diagnosis. There was a median (IQR) of 60 (21-288) days between drug initiation and drug-induced DM onset. History of cancer was reported in 85 cases (51.6%).Conclusions and RelevanceIn this systematic review, drug-induced DM was associated with multiple types of medications, including chemotherapies and immunotherapies. It is essential that dermatologists promptly recognize and diagnose drug-induced DM so that they can guide management to minimize interruption of therapy when possible.

MEK inhibitors cause a wide spectrum of mucocutaneous toxicities which can delay or interrupt life-saving therapy. To summarize the morphology, incidence, and clinical presentation of mucocutaneous toxicities from MEK inhibitors via a scoping review of the literature. We conducted a scoping review of the published literature, including clinical trials, retrospective and prospective studies, reviews, and case reports and series. All included literature was analyzed by a panel of pediatric and adult oncodermatologists. Of 1626 initial citations, 227 articles met final inclusion criteria. Our review identified follicular reactions, ocular toxicities, xerosis, eczematous dermatitis, edema, and paronychia as the most common mucocutaneous side effects from MEK inhibitor therapy. Grade 1 and 2 reactions were the most prevalent and were typically managed while continuing treatment; however, grade 3 toxicities requiring dose reductions or treatment interruptions were also reported. Mucocutaneous toxicities to MEK inhibitor therapy are common and most often mild in severity. Early recognition and treatment can mitigate disruptions in oncologic therapy.

Chronic skin ulcers in patients with suspected pyoderma gangrenosum can, on closer inspection and further workup, have a different cause. Recognition of key features on clinical examination such as the presence of atrophie blanche is key to avoid misdiagnosis of pyoderma gangrenosum and its subsequent treatment with high-dose corticosteroids and other immunosuppressive medications.

A 60-year-old woman was referred to Allergy and Immunology for a persistent rash of 9 months. The rash started as mild itching and swelling of the upper lip and eyelid (Figure 1) with "small bumps" on the forehead and chest. The rash would last for several weeks to months, and the eyelid lesion would never fully resolve. The rash would also become exacerbated as weekly "flares" with co-occurring nausea and general malaise. She denied nonsteroidal anti-inflammatory drug or over-the-counter supplement use, had no family history of angioedema, and reported being up-to-date with age-appropriate cancer screenings. Urticaria and angioedema were considered; however, she trialed multiple high-dose H1 and H2 antagonists without relief. Allergic contact dermatitis was also considered for which patch testing was positive for ethylenediamine dihydrochloride on initial read that reportedly self-resolved the following day. She reported partial improvement with systemic corticosteroid tapers, but her rash worsened after their completion. Additional therapies included topical corticosteroids, topical ruxolitinib, montelukast, and 3 months of omalizumab without relief. She then started dupilumab for 4 months, which led to extension of the rash to the bilateral axillae (Figure 2) and scalp. Figure 2Erythematous scaly thin plaques in the bilateral axillary vault. View Large Image Figure Viewer Download Hi-res image

Livedoid vasculopathy is a painful thrombo-occlusive vascular disorder characterized by spontaneous thrombosis in medium-size arterioles, which causes localized hypoxia and skin ulceration. As livedoid vasculopathy is rare, case reports are the primary means of expanding collective knowledge about its presentation and response to various therapies.

Scalp melanomas are associated with poor disease-related and survival outcomes compared with melanomas affecting other anatomical sites, partially due to high rates of in-transit metastases (ITM), defined as localized >2 cm from the primary tumor but not beyond draining lymph nodes.1,2 The standard treatment for ITMs is surgical excision3; however, surgery is often impractical for multiple or diffuse ITMs. Currently, the only Food and Drug Administration-approved therapy, specifically directed at ITMs is talimogene laherparepvec, an injectable modified oncolytic herpes simplex virus, which has shown modest response rates in phase III studies in patients with locally advanced melanoma.

Von Zumbusch generalized pustular psoriasis (GPP) is a rare and severe type of psoriasis that presents as superficial pustules which coalesce into lakes of pus with erythema and scaling, with associated fever and life-threatening complications including sepsis. Here we describe a patient with a history of von Zumbusch GPP who presented with erythroderma, neutrophilic leukocytosis, and hyperbilirubinemia in the setting of missed medication dose and hip surgery. While her laboratory abnormalities were initially attributed to a flare of her underlying skin disease, when treatment of her psoriasis flare failed to correct the laboratory abnormalities, review of her biopsy showed evidence of a concomitant adverse drug effect and the patient ultimately expired due to sepsis.

Although rare, small lymphocytic lymphoma can present as chronic lip swelling and papules, thus mimicking the features of orofacial granulomatosis, a chronic inflammatory disorder characterized by subepithelial noncaseating granulomas, or papular mucinosis, characterized by localized dermal mucin deposition of mucin. When assessing lip swelling, one must carefully consider the clinical clues and have a low threshold to perform a diagnostic tissue biopsy, preventing delays in treatment or progression of the lymphoma.

IMPORTANCE There exists a paucity of literature that summarizes the effective management of cutaneous immune-related adverse events (cirAEs) in patients with cancer who are receiving immune checkpoint inhibitors (ICIs). Most published articles are small case series from a single institution. To our knowledge, the spectrum of possible treatments has not been systematically reviewed to highlight the breadth of options when caring for patients with cirAEs. OBJECTIVE To further characterize the development of subtypes of cirAEs in patients with cancer treated with ICIs and provide recommendations on optimal treatment regimens based on the current literature. EVIDENCE REVIEW A search was performed in PubMed, Embase European, Web of Science, and Google Scholar on June 26, 2020, according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines, limited to the years 2010 to 2020. Articles that met predetermined inclusion criteria (published between January 1, 2010, and June 1, 2020; written in the English language; and original articles, brief reports, case reports, and research letters that reported primarily on cirAE management) were selected, and data were abstracted. Articles that met the scope of the review were also added from reference lists. When possible, the results of studies that addressed a similar question were combined quantitatively. FINDINGS In total, 138 studies (87 from the aforementioned literature search and 51 additional studies pulled from the reference lists of included articles) were included that reported on 879 cirAEs. The subtypes of cirAEs included maculopapular, pruritus, lichenoid, immunobullous, psoriasiform, granulomatous, erythema multiforme or Stevens Johnson Syndrome, drug rash with eosinophilia and systemic symptoms, connective tissue disease, hair, oral, and miscellaneous. Treatments for cirAEs included a combination of topical corticosteroids, systemic corticosteroids, steroid-sparing agents, and discontinuation or cessation of immunotherapy. CONCLUSIONS AND RELEVANCE This systematic review found that treatment with ICIs was associated with many types of skin toxic effects, each with unique treatment options beyond current published guidelines. Further research into key differences between subtypes is critical to improve the care provided to patients with cancer.

While novel immunotherapies, particularly immune checkpoint inhibitors, have improved outcomes in patients with melanoma, many patients have primary or secondary resistance to these treatments or develop substantial immune-related toxicities. Moreover, surgery is often impractical to control locally advanced disease. A variety of local therapeutic methods have previously been tried including intra-arterial regional perfusion therapy, intralesional interleukin 2, Bacille Calmette-Guerin vaccination, diphencyprone, CO2 laser, electrochemotherapy, and radiation therapy, all with varying degrees of success.

Background: Misdiagnosis of skin and soft tissue infections (SSTIs) due to clinical mimics can result in delay of care, unnecessary antibiotic exposure, and inappropriate hospitalization. Comprehensive screening of inflammatory genes in SSTIs could identify biomarkers to distinguish SSTIs from mimics. Methods: We performed a search of the MGH James Homer Wright Pathology Laboratories database from 2008-2018 for diagnoses of necrotizing fasciitis, cellulitis, and stasis dermatitis, yielding 103 cases. Diagnoses were verified by chart review and categorized by discharge diagnosis. Three samples from each category, along with three controls from location-matched skin were selected for further study. mRNA isolated from paraffin-embedded skin biopsies was analyzed by Nanostring, with 594 inflammatory genes profiled. Results: We identified differentially expressed genes between necrotizing fasciitis, cellulitis, and infectious cases (necrotizing fasciitis and cellulitis) compared to non-infectious stasis dermatitis. Differentially upregulated genes in SSTIs included those with known roles in inflammation (CXCR2, IL6, IFI16, TNFRSF1B) and transcriptional regulation (BCL3, MBP). We also identified differential upregulation of genes not previously associated with SSTIs including S100A8, S100A9, MCL1, CD14, and LTF. Conclusions: We characterized transcriptomic signatures of severe and moderate SSTIs compared to stasis dermatitis and normal skin from the lower extremities. Though limited by small sample size, these data support the utility of a prospective study analyzing outcomes of patients diagnosed with SSTIs based on gene expression signatures. Identifying SSTI-specific gene expression signatures could help differentiate true skin infections from non-infectious inflammatory skin conditions, facilitating more accurate diagnoses and improving patient care.

American Journal of HematologyVolume 96, Issue 4 p. E95-E98 CORRESPONDENCEFree Access Targeting constitutively active STAT3 in chronic lymphocytic leukemia: A clinical trial of the STAT3 inhibitor pyrimethamine with pharmacodynamic analyses Jennifer R. Brown, Jennifer R. Brown Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorSarah R. Walker, Sarah R. Walker Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorLisa N. Heppler, Lisa N. Heppler Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorSvitlana Tyekucheva, Svitlana Tyekucheva Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorErik A. Nelson, Erik A. Nelson Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorJosephine Klitgaard, Josephine Klitgaard Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorMaria Nicolais, Maria Nicolais Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorYasmin Kroll, Yasmin Kroll Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorMichael Xiang, Michael Xiang Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorJennifer E. Yeh, Jennifer E. Yeh Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorMousumi Chaudhury, Mousumi Chaudhury Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorZachary T. Giaccone, Zachary T. Giaccone Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorStacey M. Fernandes, Stacey M. Fernandes Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorEric D. Jacobsen, Eric D. Jacobsen Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorDavid C. Fisher, David C. Fisher Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorArnold S. Freedman, Arnold S. Freedman orcid.org/0000-0002-8227-8916 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorMatthew S. Davids, Matthew S. Davids Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorJeffrey G. Supko, Jeffrey G. Supko Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorCatherine Wu, Catherine Wu Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorDavid A. Frank, Corresponding Author David A. Frank david_frank@dfci.harvard.edu orcid.org/0000-0002-7698-8364 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA Correspondence David A. Frank, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 522B, Boston, MA 02215. Email: david_frank@dfci.harvard.eduSearch for more papers by this author Jennifer R. Brown, Jennifer R. Brown Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorSarah R. Walker, Sarah R. Walker Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorLisa N. Heppler, Lisa N. Heppler Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorSvitlana Tyekucheva, Svitlana Tyekucheva Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorErik A. Nelson, Erik A. Nelson Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorJosephine Klitgaard, Josephine Klitgaard Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorMaria Nicolais, Maria Nicolais Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorYasmin Kroll, Yasmin Kroll Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorMichael Xiang, Michael Xiang Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorJennifer E. Yeh, Jennifer E. Yeh Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorMousumi Chaudhury, Mousumi Chaudhury Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorZachary T. Giaccone, Zachary T. Giaccone Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorStacey M. Fernandes, Stacey M. Fernandes Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorEric D. Jacobsen, Eric D. Jacobsen Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorDavid C. Fisher, David C. Fisher Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorArnold S. Freedman, Arnold S. Freedman orcid.org/0000-0002-8227-8916 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorMatthew S. Davids, Matthew S. Davids Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorJeffrey G. Supko, Jeffrey G. Supko Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorCatherine Wu, Catherine Wu Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorDavid A. Frank, Corresponding Author David A. Frank david_frank@dfci.harvard.edu orcid.org/0000-0002-7698-8364 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA Correspondence David A. Frank, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 522B, Boston, MA 02215. Email: david_frank@dfci.harvard.eduSearch for more papers by this author First published: 29 December 2020 https://doi.org/10.1002/ajh.26084Citations: 10 Funding information Lymphoma Research Foundation, Grant/Award Number: None; National Institutes of Health, Grant/Award Number: R01-CA160979 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat To the Editor: Despite the recent development of targeted therapies, chronic lymphocytic leukemia (CLL) remains incurable. Survival of CLL cells depends on constitutively activated signaling pathways that converge on a small number of transcription factors which mediate the altered gene expression that underlies the pathobiology of CLL. One such oncogenic transcription factor, which is downstream of both B cell receptor signaling and cytokines that drive B cell proliferation and survival, is STAT3. STAT3 regulates the expression of genes controlling central cellular events, including proliferation, survival, and pluripotency. In essentially all patients with CLL, STAT3 is phosphorylated on serine-727,1 which drives changes in gene expression underlying the pathogenesis of this disease.2 Through a chemical biology approach, we identified the anti-microbial agent pyrimethamine as an inhibitor of STAT3 transcriptional function.3, 4 To test the hypothesis that an inhibitor of the transcriptional function of STAT3 would have therapeutic benefit in CLL, we first evaluated the effects of pyrimethamine on CLL cells in vitro (methods found in supplementary material). Pyrimethamine caused a dramatic decrease in viable CLL cells, and did so through the induction of apoptosis (Figure S1). Peripheral blood mononuclear cells (PBMC) from healthy donors showed little effect from pyrimethamine, consistent with the known excellent safety profile of this drug. To identify genes regulated by STAT3 in CLL cells, which could serve as biomarkers for STAT3 inhibition, we first started with a set of 361 genes known to be upregulated in CLL cells compared to normal B lymphocytes5 (Figure S2A). We then filtered these genes based on regulation by STAT3 in independent data sets, or STAT3 binding in proximity to the gene by chromatin immunoprecipitation (ChIP). From this analysis, we identified five genes (AIM2, ATXN1, ENPP2, GAB1, and ID3) that showed increased expression in CLL cells compared to healthy B lymphocytes, and which had the criteria of direct STAT3 target genes. When primary CLL cells were treated ex vivo with pyrimethamine, decreased expression of all five STAT3 signature genes was consistently observed (Figure S2B). As expected, lymphocytes purified from the blood of healthy donors showed minimal expression of these genes and no significant change with pyrimethamine treatment. Given that pyrimethamine decreased the expression of STAT3 target genes and the survival of CLL cells in vitro, along with its known excellent safety profile, we designed a clinical trial to assess the efficacy of pyrimethamine as a single agent in patients with relapsed refractory CLL. This trial was initiated prior to the introduction of BTK, PI3K, or BCL-2 inhibitors into clinical use for this disease. Sixteen heavily pretreated patients, with a median of six prior therapies, enrolled on the phase one portion of this study. Patient characteristics are provided in Table S1. Three patients each were enrolled on cohorts one (12.5 mg daily) and two (25 mg daily) with no dose-limiting toxicities (DLTs) and no significant drug-related toxicities (Table S2). Cohort three (50 mg daily) enrolled 10 patients, also with no DLTs observed. The maximum tolerated dose was not reached at doses up to 50 mg daily. Plasma levels of pyrimethamine increased progressively in samples obtained during the first 2 weeks of treatment, with apparent steady state conditions achieved after dosing for 2 weeks. The steady state plasma concentration of pyrimethamine increased linearly with escalation of the daily dose from 12.5 to 50 mg (Figure S3 and Table S3). The geometric mean steady state concentration of pyrimethamine in plasma was 6.17 μM for the five patients with evaluable samples who received the 50 mg daily dose, somewhat less than the target concentration of 10 μM projected for maximal STAT3 inhibition.3, 4 The steady state concentration of pyrimethamine in PBMCs, was also linearly related to the dose (Figure S3B) and correlated with the corresponding concentration of the drug in plasma. No objective responses by IW-CLL 2008 criteria were observed. However, 50% of patients achieved stable disease, with one patient dosed at 50 mg/d on therapy for 12 months, and two at 25 mg/d on therapy for 4 and 6 months. The remaining patients had progressive disease, with all but one patient discontinuing for progressive disease. The median overall survival was 22.2 months (Figures S4 and S5), consistent with the heavily pretreated status and limited therapeutic options for these patients. To determine whether pyrimethamine was inhibiting STAT3 transcriptional function in the CLL cells in vivo, mRNA was harvested from CLL cells from each patient prior to initiating pyrimethamine and while on therapy. Decreased expression of the STAT3 signature could be detected at a minimum of two different time points in eight of the 16 patients within the first 2 months of treatment (Figure 1A). However, at the time of clinical progression, increasing expression of the STAT3 signature generally occurred (Figure 1B). The expression of the five signature genes was generally highly concordant and was well reflected with an arithmetic mean. FIGURE 1Open in figure viewerPowerPoint Changes in the STAT3 gene expression signature in patients on therapy. Samples for pharmacodynamic analysis of changes in expression of STAT3 target genes were obtained prior to treatment (Pre-Med), and then 2 hours post drug on day 1 of cycle one (PD3), 1 day among days 2 through 5 of therapy (optional; PD4), day 8 (PD5), 15 (PD6), and 22 (PD7) of cycle one, day 1 (PD8) and 15 (PD9) of cycle two, and day 1 of subsequent cycles (PD10-18). (A), Expression of the five-gene signature for each patient normalized to pre-treatment levels. (B), Expression of the STAT3 signature showed increasing expression at the time of progression in most patients These analyses also revealed correlations between pharmacokinetic and pharmacodynamic data that suggest mechanistic underpinnings for clinical effects. For example, in patient six (Figure S6A), expression of the five STAT3 signature genes remained suppressed at the times of most of the pharmacodynamic blood sampling. However, at the last four samplings, the trough level of pyrimethamine decreased significantly in the setting of intermittent drug holds, and this coincided with increased expression of all five of the signature genes and clinical progression. In patient eight, by contrast, pyrimethamine levels were relatively high, and expression of the signature genes remained suppressed (Figure S6B). These findings suggest that quantitation of this five-gene signature may be an effective way to measure on-target effects of STAT3 inhibition for pyrimethamine (and likely other STAT3 inhibitors) and that loss of suppression of these genes may presage clinical progression. To determine whether the response of a patient's CLL cells to pyrimethamine ex vivo would be a predictive marker for a patient's clinical response, we treated pre-treatment patients' cells in culture with vehicle or 10 μM pyrimethamine. Samples were available from four patients for analysis (Figure S7). All showed varying levels of loss of viability in the presence of pyrimethamine compared to vehicle treatment. Of the two patients from the highest dose cohort who were analyzed in this way (patients nine and 12), both showed relatively little loss of viability ex vivo (Figure S7), and both showed relatively little effect on the STAT3 gene expression signature in vivo (Figure S6). For six patients, we were able to analyze change in expression of the five STAT3 signature genes following 24 hours of treatment with pyrimethamine (10 μM) ex vivo (Figure S8). Variable degrees of inhibition of the STAT3 signature genes were observed, though four of the six patients had a majority of the signature genes decrease by at least 25%. Of the three patients who had both gene expression analysis and ex vivo cell survival analysis (patients four, five, and nine), only one showed a decrease of viable cell number greater than 50% (patient four), and this was the only one of these patients in whose cells gene expression was suppressed by greater than 25% in a majority of the STAT3 signature genes. This patient also showed notable suppression of STAT3 target genes in vivo (Figure S6A). These findings are suggestive of a correlation between inhibition of STAT3 transcriptional activity and inhibition of CLL cell survival. Two of the six patients for whom ex vivo gene expression analysis was performed (patients seven and nine) had been in the highest dose cohort. Patient seven showed suppression of a majority of STAT3 signature genes when treated ex vivo and also showed suppression of the gene signature at multiple time points in vivo (Figure S6). By contrast, patient nine showed little repression of the STAT3 signature with either ex vivo or in vivo treatment with pyrimethamine. These data raise the possibility that testing for the response to pyrimethamine ex vivo, either based on cell survival or suppression of expression of STAT3 target genes, may be a predictive marker for the response to this STAT3 inhibitor. We anticipate that single agent activity of pyrimethamine would require dose escalation above 50 mg daily, which should be feasible and safe based on our data. By decreasing expression of pro-survival genes, pyrimethamine can also sensitize cells to undergoing apoptosis. Thus, combinations of pyrimethamine with signaling inhibitors active in CLL, such as BTK or PI3K inhibitors, might result in enhanced activity. In addition, by decreasing expression of anti-apoptotic genes such as MCL1 and BCL-xl, pyrimethamine may also synergize with a BCL2 inhibitor active in CLL, such as venetoclax. Finally, STAT3 activation leads to modulation of expression of immune-regulatory genes resulting in tumor cells that are more resistant to immune-based killing as well as the establishment of an immunosuppressive microenvironment, and this can be reversed with pyrimethamine.6 Therefore, combinations of pyrimethamine with immune activating treatments, such as immune checkpoint inhibitors, may be particularly active in CLL, a disease that has not generally been sensitive to single agent immunotherapies. ACKNOWLEDGEMENTS This clinical trial was supported by a grant from the Lymphoma Research Foundation (D.A.F.), and the related studies were supported by NIH grant R01-CA160979, the Gabrielle's Angel Foundation (New York, NY), The Joan Harris Cancer Foundation (Boston, MA), and the Brent Leahey Fund (Dana-Farber Cancer Institute) (D.A.F.). This research was also supported by a generous gift from Stephen P. Koster, Esq. DISCLOSURES None. Open Research DATA AVAILABILITY STATEMENT The data that support the findings of this study are available in the supplementary material of this article. Supporting Information Filename Description ajh26084-sup-0001-Supinfo.docxWord 2007 document , 1.1 MB Appendix S1. Supplementary Materials: Methods Table S1. Patient Characteristics Table S2. Adverse Events Occurring in at Least Two Patients, by Dose Level Table S3. Mean steady state concentration of pyrimethamine in plasma and PBMCs. Figure S1. Pyrimethamine selectively decreases survival and induces apoptosis in CLL cells in vitro. Figure S2. Identification of a STAT3 gene expression signature in CLL. Figure S3. Pyrimethamine pharmacokinetics. Figure S4. Progression-Free Survival For All Patients. Figure S5. Overall Survival For All Patients. Figure S6. Changes in the STAT3 gene expression signature in patients on therapy. Figure S7. Sensitivity of pre-treatment patient samples treated with pyrimethamine ex vivo. Figure S8. Changes in expression of STAT3 target genes in pre-treatment patient samples treated with pyrimethamine ex vivo Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Frank DA, Mahajan S, Ritz J. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J Clin Invest. 1997; 100(12): 3140- 3148. 2Hazan-Halevy I, Harris D, Liu Z, et al. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood. 2010; 115(14): 2852- 2863. 3Takakura A, Nelson EA, Haque N, et al. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum Mol Genet. 2011; 20(21): 4143- 4154. 4Nelson EA, Sharma SV, Settleman J, Frank DA. A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation. Oncotargets. 2011; 2: 518- 524. 5Wang L, Shalek AK, Lawrence M, et al. Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL. Blood. 2014; 124(7): 1089- 1098. 6Khan MW, Saadalla A, Ewida AH, et al. The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer. Cancer Immunol Immunother. 2018; 67(1): 13- 23. Citing Literature Volume96, Issue4April 2021Pages E95-E98 FiguresReferencesRelatedInformation

Porokeratoses are precancerous keratinocyte proliferations with distinct hyperkeratotic rims called cornoid lamellae. The most common porokeratosis is disseminated superficial actinic porokeratosis, characterized by multiple thin papules on the lower extremities. The second most common porokeratosis is porokeratosis of Mibelli (PM), which typically begins as one to a few small brown papules on the extremities that enlarge into plaques.

Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers.

Folliculitis decalvans is a rare scarring alopecia that presents with indurated, tender pustules and papules on the vertex and occipital scalp. Although systemic antibiotics with activity against Staphylococcus species provide some symptomatic improvement, folliculitis decalvans remains a significant management challenge and often exhibits a relapsing-and-remitting course. In this report, we posit the potential utility of medical grade honey as a safe and cost-effective adjuvant therapy in the treatment of folliculitis decalvans. We describe a patient with painful, boggy scalp pustules who achieved clearance of his scalp lesions with the addition of Manuka honey. To our knowledge, this report is the first to demonstrate the clinical use of honey in the management of folliculitis decalvans and may lend support to the role of Staphylococcus in the pathogenesis of this disease.

A 69-year-old Vietnamese female presented with fever and new-onset tender subcutaneous nodules on her trunk and lower extremities initially thought to be clinically consistent with erythema nodosum. A biopsy showed an atypical, predominantly lobular lymphocytic panniculitis with admixed neutrophils, karyorrhectic debris, and histiocytes with subcutaneous fat necrosis. Immunohistochemistry was consistent with gamma-delta T-cell lymphoma. The patient was initiated on a chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) with partial remission, and is currently undergoing evaluation for bone marrow transplant. This case highlights the ability of cutaneous gamma-delta T-cell lymphoma to mimic more common cutaneous conditions such as erythema nodosum, and stresses the importance of a broad differential for new presentation of tender subcutaneous nodules with concomitant systemic symptoms.

Despite advances in targeted therapy, chronic lymphocytic leukemia (CLL) remains a highly prevalent and essentially incurable malignancy. One molecular hallmark of CLL is the constitutive serine phosphorylation and transcriptional activation of the oncogenic transcription factor STAT3. Targeting STAT3 may have a high therapeutic index since normal cells can tolerate a loss of STAT3 function. To identify STAT3 inhibitors that could be rapidly introduced into proof-of-concept clinical trials, we screened a chemical library of drugs known to be safe in humans for specific inhibitors of STAT3-dependent transcription. Using this strategy, we identified the anti-parasitic agent pyrimethamine as a drug that could inhibit STAT3 at levels safely achieved for months at a time in humans. Pyrimethamine inhibited STAT3-dependent gene expression in CLL cells ex vivo, and decreased survival of CLL cells, but not peripheral blood mononuclear cells from healthy donors. To determine whether STAT3 inhibition would confer clinical benefit in patients with CLL, we conducted a phase I clinical trial of continuous daily pyrimethamine, in the era before targeted therapy, in relapsed CLL patients whose disease progressed despite standard therapies. We used a typical 3+3 dose escalation design with three cohorts, 12.5, 25 and 50 mg per day (mg/d). Samples for PK/PD analysis were drawn weekly in the first month and every other week in the second. Sixteen heavily pretreated patients enrolled on the phase 1 portion of this study. The median age was 63 (36-85) and the median time from diagnosis to study therapy was 74 months (range, 6-176 months). Six patients had 17p deletion and 4 had 11q deletion, while 12 of 13 evaluable patients had unmutated IGHV. The patients had a median of 6 prior therapies, including 8 patients who had received prior high dose methylprednisolone, five who had received prior alemtuzumab, and one each with prior allogeneic and autologous stem cell transplantation. Three patients each enrolled on cohorts 1 and 2, and ten patients enrolled on cohort 3. There were no dose limiting toxicities and no significant drug-related toxicities. No objective responses by IW-CLL 2008 criteria were observed. Half of patients achieved stable disease, with one patient dosed at 50 mg/d on therapy for 12 months, and two at 25 mg/d on therapy for 4 and 6 months. The remaining patients had progressive disease, and all but one patient discontinued therapy for progressive disease. The median time on therapy was 1.1 months (0.23-9.99), with median progression free survival of 1.5 months (0.92-5.52) and median overall survival of 22 months (11.75-NA).

The transcription factor STAT3 is activated inappropriately in 70% of breast cancers, most commonly in triple negative breast cancer (TNBC). Although the transcriptional function of STAT3 is essential for tumorigenesis, the key target genes regulated by STAT3 in driving tumor pathogenesis have remained unclear. To identify critical STAT3 target genes, we treated TNBC cell lines with two different compounds that block STAT3 transcriptional function, pyrimethamine and PMPTP. We then performed gene expression analysis to identify genes whose expression is strongly down-regulated by both STAT3 inhibitors. Foremost among the down-regulated genes was TNFRSF1A, which encodes a transmembrane receptor for TNFα. We showed that STAT3 binds directly to a regulatory region within the TNFRSF1A gene, and that TNFRSF1A levels are dependent on STAT3 function in both constitutive and cytokine-induced models of STAT3 activation. Furthermore, TNFRSF1A is a major mediator of both basal and TNFα-induced NF-κB activity in breast cancer cells. We extended these findings to primary human breast cancers, in which we found that high TNFRSF1A transcript levels correlated with STAT3 activation. In addition, and consistent with a causal role, increased TNFRSF1A expression was associated with an NF-κB gene expression in signature in breast cancers. Thus, TNFRSF1A is a STAT3 target gene that regulates the NF-κB pathway. These findings reveal a novel functional crosstalk between STAT3 and NF-κB signaling in breast cancer. Furthermore, elevated TNFRSF1A levels may predict a subset of breast tumors that are sensitive to STAT3 transcriptional inhibitors, and may be a biomarker for response to inhibition of this pathway.

Pyoderma gangrenosum (PG) is a rare infiltrative neutrophilic dermatosis that characteristically presents with painful ulcers with violaceous, undermined borders on the lower extremities and less commonly presents with tender nodules or pustules.1 Along with erythema nodosum, PG is one of the most frequent extraintestinal manifestations of inflammatory bowel disease (IBD). Although it is a common extraintestinal manifestation of IBD, PG does not always resolve when a patient's IBD is in remission, suggesting that PG may not be related to the activity of IBD.