We read with interest the results of GuttmanYasky et al's paper utilizing dupilumab in the treatment of longstanding alopecia areata.1 We propose that dupilumab is working by correcting the imbalance of Tregs that is induced by overexpression of IL4, a cytokine that is characteristic of atopic states. This is further supported by the fact that the greatest responses were seen in those with high levels of IgE, noting that IL4 is responsible for inducing immunoglobulin class switching to IgE production. IL4 is a pleiotropic cytokine that affects multiple Tcell subsets including regulatory T cells (Treg).2 Its major effect on Tregs is downregulation by virtue of inducing polar differentiation and abrogating the ability to recover a suppressive phenotype once differentiated.3 This restriction is due to the expression of canonical Th2 Tcell transcription factor, GATA3. In fact, this restriction is also observed in response to Tbet expression, the canonical Th1 transcription factor, induced by Th1 cytokines like IFNy. Furthermore, this restriction is independent of the presence of Tcell polarizing cytokines themselves, as it persists when canonical transcription factor expression is present despite the absence of polarizing cytokines.2 Prevailing evidence suggests that alopecia areata is a Tcellmediated autoimmune process. Previously thought to be primarily mediated by IFN producing Th1 cytotoxic T cells reacting against an as of yet undiscovered autoantigen in the hair follicle, new information has surfaced to suggest that Th2 to inflammation may contribute to the pathogenesis as well.4 Interestingly, it is known that atopic dermatitis and asthma are allergic inflammatory conditions frequently associated with alopecia areata and are characterized by a Th2 phenotype with higher expression of IL4.4 Furthermore, these conditions are characterized by a deficiency in Tregs.5 In aggregate, these findings suggest that when the immune system is stimulated in the context of polarizing cytokines, naïve T cells are committed to Th polar forms and are subsequently incapable of developing a regulatory phenotype. Finally, there is evidence that Treg cells can directly influence hair follicle cycling and hair growth in models of alopecia areata.6 Ali et al. showed the absence of Tregs around hair bulbs results in decreased transition from telogen to anagen, decreased hair regrowth, and decreased differentiation of hair follicle stem cells.6 Of note, alopecia areata is characterized by an increase in the proportion of hair follicles in the telogen phase. The authors further demonstrated that decreased hair growth in Tregdeficient environments is associated with decreased Notch signaling within hair follicle stem cells. Tregs in proximity to hair bulbs express a Notch ligand, Jag1 that stimulates Notch signaling, directly leading to anagen hair growth. This would suggest any process that impairs FOXP3 expression, and thus Treg function would also impair Treg cells’ influence on the return of the follicle to anagen phase, growth of the hair, and the mobilization of hair follicle stem cells. We conclude that alopecia areata is primarily a Th1 disorder, and dupilumab results in hair growth by improving Treg function that is impaired in typical Th2 inflammation. As IgE is a good biomarker of allergic inflammation, the report by Guttman showing greater hair growth in patients with higher IgE supports our conclusion.

To the Editor: We read with interest the case report describing the development of hidradenitis suppurativa (HS) lesions after radiation treatment in a patient with uterine adenocarcinoma.1Haber R. Gottlieb J. Zagdanski A. Battistella M. Bachelez H. Radiation-induced hidradenitis suppurativa: a case report.JAAD Case Rep. 2017; 3: 182-184Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar The authors provided several thoughts on the possible mechanism behind radiation-induced HS. The purpose of this letter is to provide additional insight about the likely immunologic mechanisms behind radiation-induced HS. The reported case is an example of an abscopal-like effect2Postow M.A. Callahan M.K. Barker C.A. et al.Immunologic correlates of the abscopal effect in a patient with melanoma.N Engl J Med. 2012; 366: 925-931Crossref PubMed Scopus (1536) Google Scholar sharing adenocarcinoma antigens to antigens of apocrine glands of the groin. Abscopal effect is an immune-mediated phenomenon that has been heavily discussed in metastatic melanoma, whereby there is regression of nonirradiated metastatic lesions after irradiation of a distant melanoma tumor location.3Espenel S. Vallard A. Rancoule C. et al.Melanoma: last call for radiotherapy.Crit Rev Oncol. 2017; 110: 13-19Crossref PubMed Scopus (32) Google Scholar, 4Dany M. Sphingosine metabolism as a therapeutic target in cutaneous melanoma.Translational Res. 2017; 185: 1-12Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Abscopal effects were also recently reported in advanced melanoma patients after immunotherapy, highlighting the therapeutic implications of this phenomenon.5Sharabi A.B. Lim M. DeWeese T.L. Drake C.G. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy.Lancet Oncol. 2015; 16: e498-509Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar As the authors point out, apoptosis can be induced by irradiation.1Haber R. Gottlieb J. Zagdanski A. Battistella M. Bachelez H. Radiation-induced hidradenitis suppurativa: a case report.JAAD Case Rep. 2017; 3: 182-184Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar It is likely that apoptotic uterine adenocarcinoma cells result in T-cell cross priming after radiation6Morisada M. Moore E.C. Hodge R. et al.Dose-dependent enhancement of T-lymphocyte priming and CTL lysis following ionizing radiation in an engineered model of oral cancer.Oral Oncol. 2017; 71: 87-94Crossref PubMed Scopus (19) Google Scholar and activate Th17 subset. A recent article points out that Th17 is an important subset in the immunopathogenesis of HS,7Matusiak Ł. Szczęch J. Bieniek A. Nowicka-Suszko D. Szepietowski J.C. Increased interleukin (IL)-17 serum levels in patients with hidradenitis suppurativa: implications for treatment with anti-IL-17 agents.J Am Acad Dermatol. 2017; 76: 670-675Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 8Dany M. Elston D. Gene expression of sphingolipid metabolism pathways is altered in hidradenitis suppurativa.J Am Acad Dermatol. 2017; 77: 268-273.e6Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar like it is in psoriasis.9Di Cesare A. Di Meglio P. Nestle F.O. The IL-23/Th17 axis in the immunopathogenesis of psoriasis.J Invest Dermatol. 2009; 129: 1339-1350Abstract Full Text Full Text PDF PubMed Scopus (830) Google Scholar This case and the article by Matusiak et al7Matusiak Ł. Szczęch J. Bieniek A. Nowicka-Suszko D. Szepietowski J.C. Increased interleukin (IL)-17 serum levels in patients with hidradenitis suppurativa: implications for treatment with anti-IL-17 agents.J Am Acad Dermatol. 2017; 76: 670-675Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar make a strong case that HS, like psoriasis, is an autoimmune disease with Th17 and the attendant polymorphonuclear leukocytes involved. Oppman et al10Oppmann B. Lesley R. Blom B. et al.Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.Immunity. 2000; 13: 715-725Abstract Full Text Full Text PDF PubMed Scopus (2280) Google Scholar identified the p19 third subunit of interleukin (IL)-12, and designated it as IL-23. This finding predicted the potential for treating psoriasis with anti–IL-12 ustekinumab and anti–IL-23 (guselkumab). This case of radiation-induced HS is likely to predict a positive outcome with clinical trials for HS with ustekinumab (IL-12 antagonist),11Leonardi C.L. Kimball A.B. Papp K.A. et al.Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).Lancet. 2008; 371: 1665-1674Abstract Full Text Full Text PDF PubMed Scopus (1397) Google Scholar secukinumab (IL-17 antagonist),12McInnes I.B. Mease P.J. Kirkham B. et al.Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2015; 386: 1137-1146Abstract Full Text Full Text PDF PubMed Scopus (627) Google Scholar and guselkumab (IL-23 antagonist).13Sofen H. Smith S. Matheson R.T. et al.Guselkumab (an IL-23–specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis.J Allergy Clin Immunol. 2014; 133: 1032-1040Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar Radiation-induced hidradenitis suppurativa: A case reportJAAD Case ReportsVol. 3Issue 3PreviewHidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by abscesses, fistulas, and scarring affecting the groin, anogenital area, and axillae. HS has an estimated prevalence of 1%, and moderate-to-severe forms have a high disease burden.1 The disease is a combination of homeostasis abnormalities of the pilosebaceous unit and dysregulation of the skin immune responses. Pathogenesis involves the interaction between a person's genetic background (potentially heterozygous mutations of genes belonging to the gamma secretase complex) and environmental triggers, among which are the skin microbiome, cigarette smoking, and obesity. Full-Text PDF Open Access

To the Editor: In an investigation of a pneumonic plague outbreak in Madagascar, Ramasindrazana et al. reported isolation of Yersinia pestis from 2 patients and seroconversion in 2 additional patients; these data indicated 4 (28.7%) of 14 diagnosed cases among described cases (1). The risk for overestimation of pneumonic plague contagion was illustrated by an outbreak in the Democratic Republic of the Congo that included cases of leptospirosis (2). In fact, thorough investigations in Uganda indicated that 2 index patients transmitted Y. pestis to only 1 caregiver each and none to 23 additional untreated close contacts (3). Another investigation in China showed that 3 index patients exposed 214 contacts during 3–13 days; all contacts were quarantined, and no secondary cases were reported (4). Transmission of Y. pestis by respiratory droplets requires face-to-face exposure with a coughing patient, as can occur during funerals by close contact with coughing persons who may have been exposed to the pathogen while visiting or attending the patient before he or she died. Therefore, the threat for plague epidemics fueled by pneumonic plague can be reduced by measures such as isolating patients and wearing a mask when exposure is likely (5). We propose the hypothesis that only the transmission of Y. pestis by ectoparasites, such as lice and fleas, by close contact with infected humans can sustain outbreaks and epidemics. In plague-endemic regions, to support the appropriate management of patients and provide a rapid and accurate microbiological diagnosis, we recommend point of care laboratories, some of which are now operating in a few remote regions of Africa. In addition to direct diagnosis of disease in humans, direct detection of Y. pestis at the point-of-care in potential sources and vectors would facilitate understanding of how plague epidemics sustain.

We read with interest the article by Myles et al. [1] on CD8 T cells producing a dialyzable Ag-specific activator of dendritic cells. Because we run the New York Hansen’s Disease Program at Bellevue Hospital Center, we were especially interested in the historical connection with the Lawrence TF, a DLE obtained from Ag-reactive patients, which has been shown to reproduce CMI responses in Ag-naive patients when infused [2]. Much of the research that exists in the literature on TF was performed decades ago, during a time when many current, potential candidates for its identity, such as noncoding RNAs, had not yet been discovered. Thus, the molecular structure of TF remains elusive. Myles et al. [1] have identified dialyzable peptide sequences, s100a9 and the TCR-b chain from CD8 T cells, which serve as potential candidates for the identity of TF. However, we did not see commentary on noncoding RNAs in that article, and we now know that they are dialyzable and could also be the potential identity of TF. It is important to identify the molecular structure of TF because of its therapeutic potential in many diseases, including HIV infection and leprosy. In HIV-infected patients, a robust CMI response is important for suppressing viral replication. However, most antiviral CD8 T cells are either excluded from B cell follicles or do not effectively control viral replication in follicular helper CD4 T cells, which serve as viral sanctuaries [3]. However, unselected CD8 T cells that have been genetically engineered to express CXCR5—the receptor that facilitates cellular entry into B cell follicles—have been able to be redirected into these follicles, potentially augmenting CMI responses and aiding in eliminating the virus [3]. If TF infusion can also augment CMI in HIV-infected patients, then it could also be a potential treatment to help eliminate viral sanctuaries. Leprosy protects against HIV disease progression in coinfected patients [4]. Known as the LHP, the exact mechanism remains unclear, but it is plausible that this immune response is transferrable from patient to patient via TF. Although HIV-infected patients with comorbid tuberculosis exhibit an impaired granulomatous response, HIVinfected patients with comorbid leprosy preserve CMI responses to Mycobacterium leprae in biopsies of skin lesions despite evidence that CMI is diminished systemically [4]. However, it remains unclear whether M. leprae augments CMI in patients coinfected with HIV because many patients with HIV may be subclinically infected with M. leprae and not present with symptoms that resemble immune reconstitution inflammatory syndrome, which is how leprosy usually presents in patients with HIV. SIV is often used in primate research to better understand HIV behavior in humans. In a study examining the interactions between M. leprae and SIV in rhesus monkeys, M. leprae was shown to decrease the pathogenicity of SIV when inoculated 2 wk after SIV inoculation when compared with monkeys inoculated with SIV and M. leprae on the same day and monkeys inoculated with SIV alone; this correlated with a less severe loss of CD4 T cells [5]. The genes that mediate the LHP remain unelucidated, but new methods of editing cellular genomes, such as CRISPRs, have repurposed programmable, DNA-cutting machinery from a bacterial immune system to discover antiviral targets in HIV [6]. If this method is used in a T cell line susceptible to SIV, genes that confer resistance to SIV may also be discovered, perhaps including those that have a role in facilitating the protective effect of leprosy in SIV-infected monkeys [7]. Then, a CD8 T cell line producing TF can be used in conjunction with RNA sequencing, tandem mass spectrometry, and other modern biochemistry techniques to compare TF to the SIV gene products isolated from CRISPR, potentially including noncoding RNAs, to help us gain a better understanding of the molecular identity of TF.

Autochthonous leprosy has been reported in New York City, where there are no wild armadillos. Recent autochthonous cases also have been reported in Georgia and Florida and blamed on armadillos, including cases with no known armadillo exposure. International migration needs to be considered as a cause of autochthonous leprosy.

To the Editor: Domozych et al1Domozych R. Kim E. Hart S. Greenwald J. Increasing incidence of leprosy and transmission from armadillos in Central Florida: a case series.JAAD Case Rep. 2016; 2: 189-192Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar reported 4 cases of leprosy in a single medical dermatology practice in central Florida in a report entitled Increasing incidence of leprosy and transmission from armadillos in Central Florida: A case series. This title is misleading and would lead the reader to assume that their data have identified armadillos as the source of transmission of leprosy in this cluster of central Florida autochthonous cases when, in fact, they had no molecular data linking their cases to armadillos. In a place where just less than a third of the population was born in state, Florida continues to be dominated by people from elsewhere in the country and in the world. The foreign-born population in Orlando is at 14.2% (408,137 immigrants) of a total population of 2,875,341 in 2013 (http://immigrationforum.org). In a recent report, Ramos et al2Ramos J.M. Romero D. Belinchón I. Epidemiology of leprosy in Spain: the role of the international migration.PLoS Negl Trop Dis. 2016; 10: e0004321Google Scholar emphasized the role of international migration on leprosy in Spain, a country of low prevalence similar to the that of United States, by analyzing Spanish immigration statistics and World Health Organization leprosy statistics on the countries of origin. They concluded that the registered incidence of leprosy was lower than expected every year, often more than 50% and as high as 90% per year.2Ramos J.M. Romero D. Belinchón I. Epidemiology of leprosy in Spain: the role of the international migration.PLoS Negl Trop Dis. 2016; 10: e0004321Google Scholar We reported autochthonous leprosy cases in New York City,3Levis W.R. Vides E.A. Cabrera A. Leprosy in the eastern United States.JAMA. 2000; 283: 1004-1005Crossref PubMed Google Scholar including proof with molecular techniques.4Keo T. Martiniuk F. Latkowski J. Cabrera A. Rom W. Levis W.R. Molecular origin of endemic leprosy in New York City.Clin Infect Dis. 2008; 46: 899-901Crossref PubMed Scopus (5) Google Scholar In our original epidemiologic evaluation of leprosy in New York City, we found an average lag from onset of symptoms to diagnosis of leprosy of 4.8 years with some cases going undiagnosed for more than 30 years,5Levis W.R. Schuman J.S. Friedman S.M. Newfield S.A. An epidemiologic evaluation of leprosy in New York City.JAMA. 1982; 247: 3221-3226Crossref PubMed Scopus (15) Google Scholar findings that tend to confirm the lower incidence than expected in the Ramos study. Although the transmission of leprosy is still poorly understood, it stands to reason that the international migration of patients with leprosy is playing a role in what has been identified as a secondary attack of leprosy in New York City, and New York City is well above the armadillo belt. For this reason, additional autochthonous cases of leprosy being reported from the Eastern United States should not be assumed to be from armadillos, especially if there is no history of armadillo exposure. Increasing incidence of leprosy and transmission from armadillos in Central Florida: A case seriesJAAD Case ReportsVol. 2Issue 3PreviewLeprosy, or Hansen's disease, is caused by the acid-fast bacillus Mycobacterium leprae. Leprosy is transmitted by human-to-human contact, although zoonotic transmission has been described, and contact with the nine-banded armadillo (Dasypus novemcinctus) is a risk factor for development of leprosy.1-4 Cases 1 and 2 in this case series show zoonotic transmission from armadillos. An additional source of M leprae infection may be soil or land contaminated by leprosy-infected armadillos.3,5,6 Cases 3 and 4 support this potential mode of transmission. Full-Text PDF Open AccessArmadillos: An emerging zoonosis in FloridaJAAD Case ReportsVol. 3Issue 4PreviewTo the Editor: We read with considerable puzzlement Dr Levis' critique of our case report conclusion that armadillos infected with Mycobacterium leprae were the likely source of our patients' Hansen's disease. We believe that both the clinical and genotypic evidence that the armadillo is an important vector for Hansen's disease in Florida is quite overwhelming. Full-Text PDF Open Access

Lawrence transfer factor (TF) is defined as dialyzable leukocyte extract (DLE) that can transfer antigen-specific cell-mediated immunity from a person testing positive for the antigen in a delayed type hypersensitivity skin test manner to a person negative for the same antigen. A recent article by Myles et al1 has identified a DLE isolated from an established CD8+ T cell line capable of transferring antigen-specific immunity. The DLE contains a portion of the beta chain of the T cell receptor and additional nucleotide and protein factors that are being subjected to further modern biochemical analysis. After months of study that included interviews of TF physician-scientists, we conclude that an antigen-specific TF exists for most, if not all, antigens. By working from a CD8+ T cell line with modern biochemical technology, it should be possible to identify and patent products capable of treating infectious diseases, antigen-responsive cancers, and autoimmune disorders.

Reply to Singh et al.—Singh et al. reported that clofazimine blockade of Kv1.3 K+ channels enhances BCG vaccine efficacy by expanding central memory T lymphocytes [1]. This discovery, along with the recent discovery of clofazimine increasing the anti-inflammatory interleukin-1 receptor antagonist (IL1RA) [2], help explain the long-known, empirically proven efficacy of clofazimine for leprosy, both as an antimycobacterial antibiotic and as an anti-inflammatory treatment for leprosy reactions, including late neuropathies. The use of clofazimine for leprosy was empirically developed over years treating various types of leprosy. The current U.S. guidelines according to National Hansen’s Disease Program (www.hrsa. gov/hansensdisease) recommend 1 year for paucibacillary (tuberculoid and borderline tuberculoid) clinically and 2 years for multibacillary diseases (mid– borderline, borderline lepromatous, and lepromatous) by the Ridley–Jopling classification [3]. Many patients develop reactions, both type I and type II, beyond the recommended 2 years, including serious late neuropathies. These cases respond nicely to clofazimine monotherapy and only rarely require corticosteroids. The Singh et al. discovery may also explain how clofazimine shortens the duration of experimental chemotherapy in tuberculosis [4]. Human immunodeficiency virus (HIV) protein trans-activator of transcription (Tat) [5] increases the Kv1.3K+ channel, suggesting that clofazimine could play a role in improving HIV outcomes and may be involved in what Ustanowski et al. have called the HIV paradox, as leprosy patients appear to handle HIV infection better than tuberculosis patients [6]. Trinchieri has suggested that the study of intracellular infections such as tuberculosis and leprosy can also help us understand modern cancer immunotherapy [7, 8]. In this regard, clofazimine is effective in both murine B16 melanoma and pancreatic cancer [9]. IL1 and IL1RA [10] play a role in cancer progression and amelioration. Thus, further study of clofazimine mechanisms have the potential for improving our understanding of mycobacterial and HIV pathogenesis, as well as cancer immunotherapy.

Leprosy is a disease caused by Mycobacterium leprae that presents on a spectrum of both clinical manifestations and T cell response. On one end of this spectrum, tuberculoid leprosy is a well-controlled disease, characterized by a cell-mediated immunity and immunosurveillance. On the opposite end of the spectrum, lepromatous leprosy is characterized by M. leprae proliferation and T cell anergy. Similar to progressive tumor cells, M. leprae escapes immunosurveillance in more severe forms of leprosy. The mechanisms by which M. leprae is able to evade the host immune response involve many, including the alterations of lipid droplets, microRNA, and Schwann cells, and involve the regulation of immune regulators, such as the negative checkpoint regulators CTLA-4, programmed death 1, and V-domain Ig suppressor of T cell activation—important targets in today’s cancer immunotherapies. The means by which tumor cells become able to escape immunosurveillance through negative checkpoint regulators are evidenced by the successes of treatments, such as nivolumab and ipilimumab. Many parallels can be drawn between the immune responses seen in leprosy and cancer. Therefore, the understanding of how M. leprae encourages immune escape during proliferative disease states has potential to add to our understanding of cancer immunotherapy.

Five of 10 paucibacillary leprosy patients were Quantiferon Gold (Q-G) positive with negative chest X-rays. Forty multibacillary leprosy patients were negative. Reports have shown 100% cross-reactivity of ESAT6 and CFP10 between Mycobacterium leprae and Mycobacterium tuberculosis. The Q-G test cannot detect latent tuberculosis in patients with leprosy.

Diphencyprone (DPCP) is a potent topical sensitizing agent that has been used since the late 1970s by physicians for the treatment of alopecia areata (AA), viral warts (human papillomavirus) and cutaneous metastases of melanoma. Although to date the compound is not approved as a drug by the FDA or EMA, physicians have continued to use DPCP because of its proven effects in these dermatological conditions. The use of the drug has been highly variable because of differences in compounding, and as a result, the literature reports vary widely in the concentrations used for sensitization and challenge treatment with DPCP. The efficacy of DPCP has generally been ascribed to immunological reactions by the host. Inducing inflammation with a contact sensitizer is counterintuitive to treating AA, an autoimmune disorder. We have hypothesized that the body's attempt to downregulate the inflammation caused by the contact sensitizer may also ameliorate AA. Studies using microarray and miRNA profiling may provide information about how DPCP induces inflammation in human skin at different times. Gene targets and microRNAs identified through these data may be modulated by an RNA interference approach to enhance DPCP efficacy and response rates. In addition, this approach may result in the discovery and development of drugs that are more potent and selective for the treatment of AA.

We recently reported a tuberculosis-negative patient with leprosy, who displayed a giant purified protein derivative (PPD) reaction and had a positive QuantiFERON-TB Gold (QTF; Cellestis, Valencia, CA) test result. 1 Murthy V. Horowitz H.W. Pham V.P. Levis W.R. Giant PPD reaction with positive QuantiFERON-TB Gold in a patient with lepromatous leprosy. J Drugs Dermatol. 2012; 11: 1151-1152 PubMed Google Scholar Concurrently, work was published showing Mycobacterium tuberculosis antigens, early secretory antigenic target (ESAT)-6 kd and culture filtrate protein (CFP)-10 kd, are cross-reactive with M leprae and can lead to false-positive QTF results. 2 Hatermi G. Melikoglu M. Ozbakir F. Tascilar K. Yazici H. QuantiFERON-TB Gold in tube assay for the screening of tuberculosis before and during treatment with tumor necrosis factor alpha antagonists. Arthritis Res Ther. 2012; 14: R147 Crossref PubMed Scopus (25) Google Scholar This supports the notion that QTF assays cannot reliably measure, in patients with leprosy, latent infection with M tuberculosis. However, the test can possibly establish a measurement of anergy in Hansen disease. The challenge of diagnosing latent M tuberculosis infection in the lepromatous patient and the utility of the QTF test are discussed.

Prior studies have identified local heat therapy as a treatment for recalcitrant warts. We have employed a thermal pad that raises local temperature to 42-43ºC for at least 2 hours in a proof of concept study of three patients with recalcitrant warts. The recalcitrant warts cleared in all three patients beginning in the fourth and fifth weeks after daily treatment with the pads. There were no adverse events. We conclude that the timing of clearance following use of these thermal pads is likely via direct viral killing and immunologic mechanisms. Further controlled trials are underway.

Primary malignant melanoma arising from the eustachian tube is extremely rare. We report the case of a 63-year-old white man who presented with a 1-month history of left-sided hearing loss and aural fullness. Flexible fiberoptic laryngoscopy detected a blue-purple mass that appeared to arise from the left lateral nasopharynx. Computed tomography demonstrated an enhancing mass arising from an orifice of the left eustachian tube. The tumor was debulked endoscopically and was confirmed to have originated in the left eustachian tube. Histologically, the tumor was made up of heavily pigmented pleomorphic spindle cells with frequent mitoses. The tumor cells were immunohistochemically positive for S-100 protein, HMB-45, Melan-A, and PNL-2. The final diagnosis was a mucosal malignant melanoma. We also performed a nested polymerase chain reaction assay for several genes of interest, including CTLA-4, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, PLZF, Foxp3, RORγt, CD27, and CD70. These genes have been studied mainly in cutaneous melanomas, especially for the development of immunotherapy, but only very limited studies have been done on mucosal melanomas. Our investigation found upregulation of CTLA-4, IL-17A, IL-17C, and IL-17E. Based on our finding of CTLA-4 upregulation, it may be suggested that our patient might have had low antitumor immunity and that he might have benefited from CTLA-4 blockade. On the other hand, upregulation of IL-17A and IL-17E might reflect increased antitumor immunity, which could suggest that patients with a mucosal melanoma might benefit from immunomodulators associated with the effect of T17. These genes also have great potential to help melanoma patients obtain tailored treatment, and they can be used as biomarkers for predicting prognosis.